US20100305100A1 - Methods for treating hepatitis c - Google Patents

Methods for treating hepatitis c Download PDF

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Publication number
US20100305100A1
US20100305100A1 US12/828,597 US82859710A US2010305100A1 US 20100305100 A1 US20100305100 A1 US 20100305100A1 US 82859710 A US82859710 A US 82859710A US 2010305100 A1 US2010305100 A1 US 2010305100A1
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Prior art keywords
optionally substituted
alkyl
group
aryl
substituted
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US12/828,597
Inventor
Gary Mitchell Karp
Peter Seongwoo Hwang
James J. Takasugi
Hongyu Ren
Richard Gerald Wilde
Anthony Turpoff
Alexander Arefolov
Guangming Chen
Jeffrey Allen Campbell
Chunshi Li
Steven Paget
Nanjing Zhang
Xiaoyan Zhang
Jin Zhu
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PTC Therapeutics Inc
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PTC Therapeutics Inc
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Priority claimed from US11/180,961 external-priority patent/US8013006B2/en
Priority claimed from US11/331,180 external-priority patent/US7868037B2/en
Application filed by PTC Therapeutics Inc filed Critical PTC Therapeutics Inc
Priority to US12/828,597 priority Critical patent/US20100305100A1/en
Assigned to PTC THERAPEUTICS, INC. reassignment PTC THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ZHANG, NANJING, LI, CHUNSHI, PAGET, STEVEN, ZHANG, XIAOYAN, ZHU, JIN, CAMPBELL, JEFFREY A., AREFOLOV, ALEXANDER, HWANG, PETER SEONGWOO, REN, HONGYU, WILDE, RICHARD GERALD, CHEN, GUANGMING, KARP, GARY MITCHELL, TAKASUGI, JAMES J., TURPOFF, ANTHONY A.
Publication of US20100305100A1 publication Critical patent/US20100305100A1/en
Abandoned legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions for treating infection by a virus, or for affecting viral IRES activity.
  • HCV hepatitis C virus
  • hepatitis C virus the causative agent of hepatitis C. Seventy to eighty percent of HCV infections lead to chronic liver infection, which in turn may result in severe liver disease, including liver fibrosis, cirrhosis, and hepatocellular carcinoma (115).
  • HCV constitutes the Hepacivirus genus of the family Flaviviridae (106), and contains a positive-stranded 9.6 kb RNA genome.
  • the features of the HCV genome include a 5′-untranslated region (UTR) that encodes an internal ribosome entry site (IRES) that directs the translation of a single long open reading frame (ORF) encoding a polyprotein of 3,010 amino acids.
  • the HCV ORF is followed by a 3′-UTR of variable length, depending on the HCV variant, that encodes the sequences required for the initiation of antigenomic strand synthesis (79).
  • HCV IRES-mediated translation (1) integrity of the global structure of HCV IRES, (2) the 3′-terminal region of the HCV genome; and (3) trans-acting cellular factors that interact with the HCV IRES element and assist in translation initiation (35).
  • a bicistronic expression system can be used to define and evaluate the function of IRES elements.
  • This test system harbors two different reporter genes in which the 5′-proximal reporter gene is expressed by a cap dependent translation mechanism while the second reporter is expressed only if an upstream sequence inserted in the intergenic space contains an IRES sequence element.
  • a putative IRES in the HCV 5′ UTR was unambiguously demonstrated to function as an IRES involved in translational control of viral proteins (133).
  • IRES element 23, 41, 42, 108, 129, 132, 133, 134.
  • HCV IRES guides cellular translation initiation factors to an internal site of the viral RNA (56, 58, 120), thus functionally demonstrating the HCV IRES activity.
  • HCV 5′-UTR contains an IRES element that plays an active and crucial role in the mechanism of internal initiation for HCV protein translation.
  • the IRES is one of the most conserved regions of the HCV genome, reflecting its essential nature for viral replication and protein synthesis (13, 118, 122). Although both 5′ and 3′ sequences of the IRES appear to play a role in the control of initiation of translation (42, 109, 110, 113, 136), the minimal sequence requirement for HCV IRES function has been mapped to a region between nucleotides 44-354 (40).
  • HCV IRES and its 5′ sequence is folded into a distinct structure that consists of four major domains and a pseudoknot (11, 42, 122).
  • Domain I contains a small stem-loop structure that does not appear to be a functional part of the IRES element while domains II, III, and IV contain the HCV IRES activity (43, 111).
  • the relationships between secondary and tertiary structures of the HCV IRES and their function have recently been established (5, 55, 56, 99, 124).
  • the IRES functionally replaces the 5′ cap structure, allowing the 40S ribosomal subunit and eIF3 to bind directly to the RNA.
  • Subdomain IIId of the HCV IRES harbors the binding site for the 40S ribosomal subunit and the only initiation factors required for translation initiation are eIF2, eIF3, and eIF4E (15, 58, 94, 100, 120, 124).
  • HCV IRES-mediated translation initiation Other cellular factors involved in HCV IRES-mediated translation initiation include proteasome ⁇ -subunit PSMA7 (62), ribosomal protein S5 (26), ribosomal protein S9 (24, 25, 100), and hnRNPL (33).
  • proteasome ⁇ -subunit PSMA7 62
  • ribosomal protein S5 26
  • ribosomal protein S9 24, 25, 100
  • hnRNPL hnRNPL
  • the present invention includes a compound of Formula (I)
  • Y is:
  • R is a hydrogen, a halo or an alkoxy
  • R 1 is:
  • R 2 is:
  • R 3 is:
  • the present invention includes compounds of Formula I, with the proviso that at least one of Y, Z, R 1 and R 2 is selected from the following:
  • Y is:
  • R 2 is:
  • a compound of Formula I is included, with the proviso that at least one of X, Y, Z, R 1 , and R 2 is selected from the following:
  • X is:
  • Y is:
  • R 1 is:
  • the present invention includes compounds of Formula I, with the proviso that with the proviso that at least one of Y, Z, and R 2 is selected from the following:
  • Y is:
  • R 2 is:
  • alkyl generally refers to saturated hydrocarbyl radicals of straight or branched configuration, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, octyl, n-octyl, and the like.
  • alkyl substituents may be C 1 to C 12 , or C 1 to C 8 or C 1 to C 6 alkyl groups.
  • aryl refers to a carbocyclic aromatic ring structure. Included in the scope of aryl groups are aromatic rings having from five to twenty carbon atoms.
  • Aryl ring structures include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds. Examples of aryl groups that include phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, phenanthrenyl (i.e., phenanthrene), and napthyl (i.e., napthalene) ring structures. In certain embodiments, the aryl group may be optionally substituted.
  • heteroaryl refers to cyclic aromatic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon. Heteroatoms are typically O, S or N atoms. Included within the scope of heteroaryl, and independently selectable, are O, N, and S heteroaryl ring structures.
  • the ring structure may include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds.
  • the heteroaryl groups may be selected from heteroaryl groups that contain two or more heteroatoms, three or more heteroatoms, or four or more heteroatoms.
  • Heteroaryl ring structures may be selected from those that contain five or more atoms, six or more atoms, or eight or more atoms.
  • heteroaryl ring structures include: acridine, benzimidazole, benzoxazole, benzodioxole, benzofuran, 1,3-diazine, 1,2-diazine, 1,2-diazole, 1,4-diazanaphthalene, furan, furazan, imidazole, indole, isoxazole, isoquinoline, isothiazole, oxazole, purine, pyridazine, pyrazole, pyridine, pyrazine, pyrimidine, pyrrole, quinoline, quinoxaline, thiazole, thiophene, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, tetrazole and quinazoline.
  • heterocycle refers to cyclic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon. Heteroatoms are typically O, S or N atoms. Included within the scope of heterocycle, and independently selectable, are O, N, and S heterocycle ring structures.
  • the ring structure may include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds.
  • heterocyclo groups include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl or tetrahydrothiopyranyl and the like.
  • the heterocycle may optionally be substituted.
  • alkoxy generally refers to a group with the structure —O—R, where R is an alkyl group as defined above.
  • halo substituents may be independently selected from the halogens such as fluorine, chlorine, bromine, iodine, and astatine.
  • a haloalkyl is an alkyl group, as defined above, substituted with one or more halogens.
  • a haloalkoxy is an alkoxy group, as defined above, substituted with one or more halogens.
  • each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently substituted.
  • a more generic substituent is set forth for any position in the molecules of the present invention, it is understood that the generic substituent may be replaced with more specific substituents, and the resulting molecules are within the scope of the molecules of the present invention.
  • substituted or “optionally substituted” it is meant that the particular substituent may be substituted with a chemical group known to one of skill in the art to be appropriate for the referred-to substituent, unless a chemical group is specifically mentioned.
  • X is:
  • Y is:
  • R is a hydrogen, a halo or an alkoxy
  • R 1 is:
  • R 2 is:
  • R 3 is:
  • the present invention includes compounds of Formula (I-Xa)
  • X is:
  • Y is:
  • R is a hydrogen, a halo or an alkoxy
  • R 1 is:
  • R 2 is:
  • R 3 is:
  • Y is:
  • R 2 is:
  • R is selected from the R substituents of compounds 1330-2128 and 2600-3348.
  • R is selected from the following non-limiting substituents:
  • R is hydrogen
  • R 1 is selected from the following non-limiting substituents:
  • R 2 is selected from the following non-limiting substituents:
  • R 3 is selected from the R 3 substituents of compounds 1330-2128, and 2600-3348.
  • R 3 is selected from the following non-limiting substituents:
  • the present invention includes a compound of Formula (I-XI)
  • X is:
  • Y is:
  • R 1 is:
  • R 2 is:
  • compounds of the present invention include compounds of Formula (I-XIa)
  • X is:
  • Y is:
  • R 1 is:
  • R 2 is:
  • X is:
  • Y is:
  • R 1 is:
  • R 2 is:
  • Formula I-XIb a compound is provided wherein all substituents except X are as stated for Formula I-XI, and X is an electron withdrawing group.
  • Formula I-XIc a compound is provided wherein all substituents except X are as stated for Formula I-XIa, and X is an electron withdrawing group.
  • an electron withdrawing group includes any electronegative element, which may be attached to or adjacent to an aromatic ring.
  • an electron withdrawing group can include a cyano group, an alkynyl group, a nitro group, an oxime, a halo, a halosubstituted alkyl, a carbonyl group, a sulfonyl group, and a heterocycle.
  • X is a cyano group.
  • Formulas I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe X is a halo.
  • X is a fluorine, chlorine, bromine or iodine.
  • X is a fluorine, bromine or iodine.
  • I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe X is a fluorine, bromine or iodine.
  • X is a fluorine or chlorine.
  • X is a fluorine. In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, X is a chlorine. In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, X is bromine.
  • X is iodine.
  • X is an alkyl substituted with one or more halos.
  • X is a trifluoromethyl group.
  • X is selected from the X substituents of compounds 1330-2128, and 2600-3348.
  • X is selected from the group consisting of:
  • X is selected from the group consisting of
  • R 1 is selected from the R 1 substituents of compounds 1330-2128, and 2600-3348.
  • R 1 is selected from the group consisting of
  • the present invention includes compounds of Formula (I-XII)
  • X is:
  • Y is:
  • R 2 is:
  • the present invention includes compound of Formula (I-XIIa)
  • X is:
  • Y is:
  • R 2 is:
  • Y is:
  • R 2 is:
  • the present invention includes compounds of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Y is a C 6 to C 8 aryl, optionally substituted with one or more of the following:
  • the present invention includes compounds wherein Y is a C 6 to C 8 aryl, optionally substituted with:
  • the present invention includes compounds wherein Y is a —NR t COOR u group, where R u is:
  • R t is:
  • the present invention includes compounds of the following:
  • X is:
  • Y is:
  • R 1 is:
  • R 2 is:
  • X is:
  • Y is:
  • R 1 is:
  • R 2 is:
  • X is:
  • R 1 is:
  • R 2 is:
  • X is:
  • Y is:
  • R 1 is:
  • R 2 is:
  • X is:
  • Y is:
  • R 2 is:
  • Z is C 1 to C 6 alkyl;
  • R is hydrogen;
  • R 1 is hydrogen;
  • R 2 is alkoxy substituted with sulfonyl-C 1 to C 6 alkyl; and
  • R 3 is hydrogen.
  • Y is C 6 to C 8 aryl substituted with one or more substituents independently selected from NR t COOR u , wherein R t is hydrogen, and wherein R u is C 1 to C 12 alkyl optionally substituted with one or more halos.
  • X is cyano;
  • Y is C 6 to C 8 aryl substituted with one or more substituents independently selected from:
  • Z is C 1 to C 6 alkyl; R is hydrogen; R 1 is hydrogen; R 2 is 5 or 6 membered heterocyclo; and R 3 is hydrogen.
  • Y is C 6 to C 8 aryl substituted with NR v SO 2 R w , wherein R w is hydrogen, and wherein R w is C 1 to C 6 alkyl.
  • 30 The compound of embodiment 28 wherein Y is C 6 to C 8 aryl substituted with
  • Z is C 1 to C 6 alkyl; R is hydrogen; R 1 is hydrogen; R 2 is (O)-5 or 6 membered heterocyclo; and R 3 is hydrogen.
  • Y is C 6 to C 8 aryl substituted with NR t COOR u , wherein R t is hydrogen, and wherein R u is C 1 to C 12 alkyl optionally substituted with one or more substituents independently selected from C 6 to C 8 aryl optionally substituted with one or more halos and/or haloalkyls.
  • X is cyano
  • Y is C 6 to C 8 aryl substituted with one or more substituents independently selected from NR t COOR u , wherein R t is hydrogen, and wherein R 1 is C 1 to C 12 alkyl substituted with one or more halos
  • Z is C 1 to C 6 alkyl
  • R is hydrogen
  • R 2 is:
  • R 2 is:
  • X is cyano
  • Y is C 6 to C 8 aryl substituted with one or more substituents independently selected from:
  • R 2 is:
  • X is cyano
  • Y is C 6 to C 8 aryl substituted with one or more substituents independently selected from:
  • R 1 is:
  • X is hydrogen
  • Y is C 6 to C 8 aryl substituted with one or more substituents independently selected from:
  • X is:
  • Y is:
  • R 1 is:
  • R 2 is:
  • R 3 is hydrogen; or nitro; with the proviso that at least one of X, Y, Z, R 1 , R 2 and R 3 is selected from the following:
  • X is:
  • Y is:
  • R 1 is:
  • R 2 is:
  • R 3 is nitro. 90. The compound of embodiment 89, wherein:
  • X is:
  • Y is:
  • R 1 is:
  • R 2 is:
  • Y is:
  • Z is C 1 to C 6 alkyl; R is hydrogen; R 1 is hydrogen; R 2 is —(O)-5 or 6 membered heteroaryl substituted with cyano; and R 3 is hydrogen.
  • 97 The compound of embodiment 96, wherein the C 6 to C 8 aryl is phenyl.
  • X is hydrogen
  • Y is phenyl is para substituted with —NR t COOR u , wherein R t is hydrogen, and wherein R u is C 1 to C 12 alkyl
  • Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl
  • R 2 is —(O)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.
  • Y is:
  • a composition comprising the compound of embodiment 1 and one or more pharmaceutically acceptable excipient(s). 106. A composition comprising the compound of embodiment 39 and one or more pharmaceutically acceptable excipient(s). 107. A composition comprising the compound of embodiment 77 and one or more pharmaceutically acceptable excipient(s). 108. A composition comprising the compound of embodiment 83 and one or more pharmaceutically acceptable excipient(s). 109. A composition comprising the compound of embodiment 89 and one or more pharmaceutically acceptable excipient(s). 110.
  • a method for treating Hepatitis C viral infection in a subject in need thereof comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 1 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 1.
  • a method for treating Hepatitis C viral infection in a subject in need thereof comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 39 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 39. 112.
  • a method for treating Hepatitis C viral infection in a subject in need thereof comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 77 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 77.
  • a method for treating Hepatitis C viral infection in a subject in need thereof comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 83 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 83.
  • a method for treating Hepatitis C viral infection in a subject in need thereof comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 89 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 89.
  • a method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 1 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 1.
  • 117. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 77 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 77.
  • 119. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 89 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 89.
  • the present invention includes compounds of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Y is a —NR t COOR u group and R u is a C 1 to C 6 alkyl.
  • compounds are provided wherein Y is a —NR t COOR u group and R u is a C 1 to C 6 alkyl in the para position.
  • the present invention includes compounds of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Y is a —NR t COOR u group and R u is a branched C 1 to C 6 alkyl.
  • Y is a —NR t COOR u group and R 1 is a branched C 1 to C 6 alkyl in the para position.
  • the present invention includes compounds of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Y is a —NR t COOR u group and R u is an isopropyl.
  • the present invention includes compounds of I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Y is a —NR t COOR u group and R u is a methyl cyclopropyl.
  • the present invention includes compounds of I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Y is a —NR t COOR u group and R 1 is an ethyl cyclopropyl.
  • the present invention includes compounds of I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Y is a —NR v SO 2 R w group, R v is a hydrogen, and where R w is a C 1 to C 6 alkyl.
  • the present invention includes compounds wherein Y is a —NR v SO 2 R w group and R w is a propyl group.
  • compounds are provided wherein Y is a C 6 to C 8 aryl that is substituted. In an embodiment of the present invention, compounds are provided wherein Y is a phenyl that is substituted. In an embodiment of the present invention, compounds are provided wherein Y is a C 6 to C 8 aryl that has one, two, three, or four substituents. In another embodiment of the compounds of the present invention, Y is a C 6 to C 8 aryl that has one, two, or three substituents. In another embodiment, Y is a C 6 to C 8 aryl that has one or two substituents. In a further embodiment, Y is a C 6 to C 8 aryl that has three substituents. In a further embodiment, Y is a C 6 to C 8 aryl that has two substituents. In a further embodiment, Y is a C 6 to C 8 aryl that has one substituent.
  • Y is a C 6 to C 8 aryl with at least one substituent in the ortho, meta, or para position.
  • Y is a C 6 to C 8 aryl with at least one substituent in the meta or para position.
  • Y is a C 6 to C 8 aryl with a substituent in the para position.
  • Y is a C 6 to C 8 aryl, optionally substituted with one of the following in the para position:
  • Y is selected from the Y substituents of compounds 1330-2128, and 2600-3348.
  • the present invention includes compounds of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Z is a 5 or 6 membered heterocycle.
  • Z is a 5 membered heterocycle.
  • the present invention includes compounds of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Z is a C 1 to C 6 alkyl optionally substituted with a 5 or 6 membered heterocycle.
  • the present invention includes compounds wherein Z is a C 1 to C 6 alkyl. In another embodiment, the present invention includes compounds wherein Z is a C 1 alkyl. In another embodiment, the present invention includes compounds wherein Z is a C 2 alkyl. In another embodiment, the present invention includes compounds wherein Z is a C 3 alkyl. In another embodiment, the present invention includes compounds wherein Z is a C 4 alkyl. In another embodiment, the present invention includes compounds wherein Z is a C 5 alkyl. In another embodiment, the present invention includes compounds wherein Z is a C 6 alkyl.
  • the present invention includes compounds wherein Z is a straight chain C 1 to C 6 alkyl. In another embodiment, the present invention includes compounds wherein Z is a cyclic C 1 to C 6 alkyl. In another embodiment, the present invention includes compounds wherein Z is a C 1 to C 6 alkyl that is a combination of straight and cyclic. In yet another embodiment, the present invention includes compounds wherein Z is selected from the group consisting of cyclobutyl, cyclopropyl, cyclopropyl methyl, ethyl, cyclopentyl, and isopropyl. In a further embodiment, the present invention includes compounds wherein Z is cyclobutyl, cyclopropyl or ethyl.
  • the present invention includes compounds wherein Z is cyclobutyl, cyclopropyl, or cyclopropyl methyl. In an embodiment, the present invention includes compounds wherein Z is cyclobutyl or cyclopropyl. In an embodiment of the present invention, a compound is provided wherein Z is cyclobutyl.
  • Z is selected from the Z substituents of compounds 1330-2128, and 2600-3348.
  • Z is selected from the group consisting of
  • the Z substituent is a hydrogen. In other embodiments, Z is a C 1 to C 6 alkyl optionally substituted with a five membered heterocycle. In other embodiments, Z is a C 1 to C 6 alkyl optionally substituted with a six membered heterocycle.
  • compounds are provided wherein R 2 is an alkoxy group. In an embodiment, the present invention provides compounds wherein R 2 is a methoxy or an ethoxy group. In an embodiment of the compounds of the present invention, R 2 is a methoxy group. In an embodiment of the compounds of the present invention, R 2 is an ethoxy group. In an embodiment, the present invention provides compounds wherein R 2 is an alkoxy group optionally substituted with one or more groups independently selected from the following:
  • the present invention provides compounds wherein R 2 is an alkoxy group substituted with an imidazole, a triazole, a thiazole. In another embodiment, R 2 is an alkoxy group substituted with a hydroxy group and an imidazole, a triazole, or a thiazole.
  • the present invention provides compounds wherein R 2 is an —OR kk group, where R kk is a 5 to 6 membered heterocycle, optionally substituted with a C 1 to C 6 alkyl, optionally substituted with a C 6 to C 8 aryl group.
  • R 2 is a C 1 to C 6 alkyl group, optionally substituted with one or more 5 or 6 membered heterocycle groups.
  • R 2 is a —C(O)-5 or 6 membered heterocycle optionally substituted with one or more C 6 to C 8 aryl groups.
  • R 2 is selected from the R 2 substituents of compounds 1330-2128, and 2600-3348.
  • R 2 is selected from the group consisting of the following substituents:
  • R 2 is selected from the group consisting of the following substituents:
  • Z is a C 1 to C 6 alkyl group
  • Y is a—NR t COOR u group, where R u is—a C 1 to C 12 alkyl and R t is—a hydrogen
  • R 2 is:
  • Z is a C 1 to C 6 alkyl group
  • Y is a —NR t COOR u group, where R u is—a C 1 to C 12 alkyl and R t is—a hydrogen
  • R 2 is:
  • Z is a C 1 to C 6 alkyl group
  • Y is a —NR t COOR u group, where R u is—a C 1 to C 12 alkyl and R t is—a hydrogen
  • R 2 is:
  • Z is a C 1 to C 6 alkyl group
  • Y is a —NR t COOR u group, where R u is—a C 1 to C 12 alkyl and R t is—a hydrogen
  • R 2 is:
  • Z is a C 1 to C 6 alkyl group
  • Y is a —NR t COOR u group, where R u is—a C 1 to C 12 alkyl and R t is—a hydrogen
  • R 2 is:
  • Exemplary compounds include the following:
  • Exemplary compounds include the following:
  • Indole compounds of the present invention can be obtained via standard, well-known synthetic methodology. Many of the indole starting materials can be prepared the routes described below or by those skilled in the art.
  • An ⁇ -nitroketone derivative A2 can be derived from treatment of the anion of nitromethane, obtained from the treatment of nitromethane with a base, such as, e.g., sodium or potassium t-butoxide or sodium hydride, with an activated carboxylic acid derivative, e.g., the acyl imidazolide A1.
  • a base such as, e.g., sodium or potassium t-butoxide or sodium hydride
  • an activated carboxylic acid derivative e.g., the acyl imidazolide A1.
  • Reaction of the ⁇ -nitroketone A2 with amine derivative A3 can afford the nitro enamine A4 by mixing the components A3 and A4 and heating in a suitable solvent such as an alcohol or an aprotic solvent.
  • Treatment of the nitro enamine A4 with quinone A5 in a polar protic solvent such as acetic acid at or near ambient temperature gives the compound of formula II.
  • B1 Treatment of B1 with a reactive alkyl or aryl group containing a leaving group L in a suitable solvent, with or without heat in the presence of a base, such an inorganic base, e.g., sodium or potassium carbonate or an organic base, e.g., triethylamine, can afford the compound of structure III.
  • a base such an inorganic base, e.g., sodium or potassium carbonate or an organic base, e.g., triethylamine
  • leaving groups include but are not limited to halogens (e.g., chlorine, bromine or iodine) or alkyl or arylsulfonates.
  • Compounds of structure IV can be obtained by nitrating an indole of structure C1, to give the 3-nitroindole C2.
  • the nitration can be carried out by treatment of C1 with a nitrating agent, such as nitric acid or sodium nitrite in a solvent such as acetic acid, acetic anhydride, sulfuric acid or in a mixed solvent system containing an organic solvent such as dichloromethane.
  • the reaction can be carried out a temperature of ⁇ 30° C. to +50° C.
  • Treatment of C2 with a reactive functional group R 9 containing a suitable leaving group L (C3) can give compounds of structure IV.
  • Reactive functional groups can consist of but are not limited to alkyl and aralkyl.
  • L can represent a halide, particularly chloro, bromo or iodo or an alkylsulfonate.
  • the reaction between C2 and C3 can be carried out in a suitable solvent in the presence of an inorganic base such as potassium carbonate or sodium hydride or an organic base such as a trialkylamine.
  • the group R 9 can represent an aryl or heteroaryl group and L can represent a halide, particularly chloro, bromo or iodo.
  • the reaction can be carried out in a polar or nonpolar solvent at a temperature from ambient to 200° C.
  • a copper catalyst e.g., CuI
  • a base such as Cs 2 CO 3 or K 3 PO 4
  • an amine ligand such as 1,2-bis(methylamino)ethane or 1,2-cyclohexanediamine
  • Indole-3-carboxylic esters E1 can be converted to indole-3-carboxylic acids E2 by treatment of compounds of structure E1 with, for example, either acid or base in aqueous or mixed aqueous-organic solvents at ambient or elevated temperature or by treatment with nucleophilic agents, for example, boron tribromide or trimethylsilyl iodide, in a suitable solvent.
  • nucleophilic agents for example, boron tribromide or trimethylsilyl iodide
  • Compounds of type E2 can then be activated and treated with amines of type E3 to give compounds E4.
  • Activation of the carboxylic acid can be carried out, for example, by any of the standard methods.
  • the acid E2 can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of the amine E3, or alternatively the acid can be activated as the acid chloride by treatment of the acid with, e.g., thionyl chloride or oxalyl chloride or as the acyl imidazolide, obtained by treatment of the acid with carbonyl diimidazole, followed by treatment of the amine E3.
  • Compounds E4 can be converted to compounds of structure VI by treatment of E4 with a reactive functional group R 9 containing a suitable leaving group L (E5) as described previously.
  • compounds of type E1 can be converted to compounds of structure E6 by treatment with E5.
  • Indole-3-carboxylic esters E6 can then be converted to indole-3-carboxylic acids E7 by the methods described above. Conversion of E7 to compounds of structure VI can be carried out by the activation and reaction with an amine E3 as described above.
  • Indoles F1 can be formylated with reagents such as phosphorous oxychloride in the presence of DMF to give the indole-3-carboxaldehydes F2.
  • Conversion to compounds of structure VII can be accomplished by treatment of F2 with compounds F3 as described previously.
  • compounds of type F1 can first be converted to F4 and then be formylated to compounds of structure VII.
  • Indole-3-carboxaldehydes of structure G1 can be converted to the indole-3-carboxylic acid derivatives by oxidation with reagents such as potassium permanganate under aqueous conditions.
  • Indole-3-carboxaldehydes of structure H1 can be converted to the indole-3-carbonitrile derivatives H2 by a variety of methods.
  • Treatment of H1 with a nitroalkane, e.g., nitropropane, in the presence of an amine source, e g, ammonium hydrogen phosphate gives the indole-3-carbonitrile H2 derivative.
  • An alternative pathway to compound H2 is via the intermediate H3.
  • Conversion of H1 to the oxime derivative H3 can be followed by dehydration, e.g., treatment of the oxime with acetic anhydride and a base, or reaction of the oxime with thionyl chloride to give H2.
  • the compound H2 can then be reacted with a reactive functional group R 9 containing a suitable leaving group L (H4) as described previously to afford compounds of structure IX.
  • H1 can be reacted with a reactive functional group R 9 containing a suitable leaving group L (H4) to give the intermediate H5, which can be reacted with a nitroalkane as above to give the indole-3-carbonitrile IX compound.
  • Compound IX can also be obtained by conversion to the oxime H6 followed by a dehydration reaction as described above.
  • Indoles I1 can be cyanated with an appropriate cyanating agent, e.g., chlorosulfonyl isocyanate (I2) or a dialkyl phosphoryl isocyanate in a suitable solvent or solvent mixture, e.g. DMF, CH 3 CN or dioxane, to afford compounds of structure I3.
  • an appropriate cyanating agent e.g., chlorosulfonyl isocyanate (I2) or a dialkyl phosphoryl isocyanate in a suitable solvent or solvent mixture, e.g. DMF, CH 3 CN or dioxane
  • a suitable solvent or solvent mixture e.g. DMF, CH 3 CN or dioxane
  • compound I1 can be reacted with a reactive functional group R 9 containing a suitable leaving group L to give compounds of structure I5 that can then be cyanated as above to give compounds of formula X.
  • Amino crotonates J1 can be reacted with amines J2 to give J3.
  • Aldehydes of structure K1 can be reacted with an alkyl azidoacetate K2 by heating the components together in a suitable organic solvent, e.g., a protic or non-protic solvent, in the presence of an organic or inorganic base, to give the ⁇ -azidoacrylate K3.
  • a suitable organic solvent e.g., a protic or non-protic solvent
  • Heating K3 in the presence of a suitable non-reactive organic solvent e.g., toluene or xylenes
  • Reduction of the ester functionality with a suitable reducing reagent, for example, lithium aluminum hydride, in a suitable solvent, e.g., ether or THF can give the intermediate K5.
  • intermediate K4 An alternative use of intermediate K4 is exemplified below.
  • Hydrolysis of the 2-alkoxycarbonyl group of the indole K4 either under acidic or basic conditions followed by decarboxylation can give the intermediate K9.
  • Decarboxylation can be carried out thermally, i.e., heating in an appropriate solvent, e.g., toluene, xylenes, or quinoline.
  • a source of copper can be added, for example, copper bronze, to facilitate decarboxylation.
  • Reaction of K9 with a reactive functional group R 9 containing a suitable leaving group L (K6) as described above can afford the compounds K10.
  • Compounds of formula L1 can be halogenated on the 2-methyl group to give 2-bromomethyl or chloromethyl indoles L2.
  • the halogenation reaction can be conducted with reagents, e.g., N-bromo- or chlorosuccinimide.
  • the reaction can be conducted in a suitable solvent, such as chloroform, carbon tetrachloride, or THF and carried out in a range between ambient temperature and 80° C.
  • a radical initiator may be added, e.g., benzoyl peroxide or AIBN.
  • the compound L2 can then be reacted with a nucleophile R 5 —W (L3) to give compounds of structure XIV.
  • the reaction can be conducted in a suitable solvent, e.g., THF, CH 2 Cl 2 or DMF, within a temperature range of 0° C. to 120° C.
  • a base e.g., an inorganic base, such as potassium carbonate or an organic base, such as a trialkylamine can be used to remove the acid formed in the reaction.
  • the group W can refer to an N, O or S atom.
  • Anilines of structure M1 can be diazotized and the resulting diazonium salt can be reduced to give the phenyl hydrazine compound M2.
  • Reaction between the hydrazine M2 and a ketone M3 under acidic conditions can give the indole compound M4.
  • the conditions for the cyclization reaction can be carried out under typical conditions utilized by one skilled in the art, for example, acidic conditions, utilizing acids such as a Bronstead acid, e.g., acetic acid, hydrochloric acid or polyphosphoric acid or a Lewis acid, e.g., zinc chloride.
  • reaction can be carried out in the presence of a co-solvent, e.g., CH 2 Cl 2 or THF typically within a temperature range of 0° C. to 120° C.
  • a co-solvent e.g., CH 2 Cl 2 or THF typically within a temperature range of 0° C. to 120° C.
  • Reaction of M4 with a reactive functional group R 9 containing a suitable leaving group L (M5) as described previously, can afford compounds M6.
  • Cyanation of the indole M6 with a cyanating agent such as chlorosulfonyl isocyanate can give the compound of structure XV.
  • the indoles M4 can be cyanated to give compounds of structure M7.
  • Reaction of M7 with a reactive functional group R 9 containing a suitable leaving group L (M5) as described above can give compounds of structure XV.
  • Compounds of formula N1 can be reacted with a dialkylformamide dialkyl acetal, N2, e.g., dimethylformamide dimethyl acetal, optionally in the presence of a suitable solvent, e.g., DMF or dioxane, at a temperature range from ambient to 150° C. to give the compound of structure N3.
  • a suitable solvent e.g., DMF or dioxane
  • Reduction of the nitro group of compounds of type N3 under standard conditions can give the indole compounds of structure N4.
  • the reduction can be carried out via hydrogenation, using a sub-stoichiometric amount of a hydrogenation catalyst, e.g., platinum or palladium, in the presence of a hydrogen source in a protic or aprotic solvent.
  • the reduction can be carried out in a temperature range of ambient to 80° C.
  • the reduction can be carried out via chemical reduction, e.g., in the presence of stoichiometric amounts of Fe or Sn compounds in a suitable solvent at a temperature range of ambient to 100° C.
  • the compound N4 can then be reacted with a reactive functional group R 9 containing a suitable leaving group L (N5) as described previously to afford compounds of structure N6.
  • Cyanation of N6 with a cyanating agent such as chlorosulfonyl isocyanate in a suitable solvent can give the compounds of structure XVI.
  • compounds of structure N4 can be cyanated to give compounds of structure N7.
  • Reaction with N7 with a reactive functional group R 9 containing a suitable leaving group L (N5) as described above can give compounds of structure XVI.
  • Compounds of structure O1 can be converted to 2-iodo- or bromoindoles O2.
  • a strong base such as n-butyllithium or s-butyllithium or lithium diisopropylamide or lithium or potassium hexamethyldisilazide is employed, with formation of the 2-indolyl anion generated in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them.
  • a suitable unreactive solvent e.g., ether or THF, or solvent mixtures containing them.
  • the reaction is typically carried out in the range of ⁇ 78° C. to ambient temperature.
  • the 2-indolyl anion can then be quenched with an electrophilic source of halogen, including but not limited to iodine, bromine or N-bromosuccinimide to give compounds of structure O2.
  • an electrophilic source of halogen including but not limited to iodine, bromine or N-bromosuccinimide
  • Reaction of 2-iodo- or bromoindoles O2 with a boronic acid commonly referred to as a Suzuki reaction
  • trialkyl stannane commonly referred to as a Stille reaction
  • the coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as tetrakis(triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand.
  • a catalyst such as tetrakis(triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand.
  • the reactions are carried out in a suitable solvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at a temperature range of ambient to 150° C.
  • a base is usually added for the Suzuki reaction.
  • the base can be in aqueous solution, e.g., aqueous sodium carbonate or sodium bicarbonate, or the base can be employed under anhydrous conditions, e.g., cesium or potassium fluoride.
  • a copper co-catalyst e.g., copper iodide, can be added.
  • indoles O1 can be converted to the indole-2-boronic acid or indole-2-trialkylstannane derivatives O3 by reacting the 2-indolyl anion described above with a trialkylborate or chlorotrialkyl stannane derivative, respectively.
  • Compounds of type O3 can be reacted with aryl and heteroaryl bromides and iodides under similar conditions to those described above to form compounds of structure XVII.
  • Compounds of structure P1 can be converted to compounds P3 by treatment of P1 with an aryl or heteroaryl halide (P2) in the presence of organometallic catalysis.
  • P2 aryl or heteroaryl halide
  • Such catalyst combinations can include palladium catalysts, e.g., palladium acetate and a source of copper, e.g., copper iodide.
  • the reaction can be carried out in the presence of a base, e.g., cesium carbonate.
  • the reaction can be carried out within a temperature range of ambient temperature to 150° C.
  • Compounds of structure XIX can be prepared by protecting an indole compound of structure Q1 as e.g., the N-Boc derivative Q2.
  • other protecting groups that can be utilized but not limited to include, e.g., benzyl, alkyl or aryl sulfonyl, or trialkyl silyl.
  • Q2 with a strong base, e.g., lithium diisopropyl amide in an aprotic solvent, e.g., THF followed by quenching with a trialkylborate derivative can give the indolyl-2-boronic acid Q3.
  • Reaction with an aryl or heteroaryl halide Q4 in the presence of palladium catalysis e.g., tetrakis(triphenylphosphine) palladium (0), bis(triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand, can give the compound Q5.
  • Removal of the protecting group can give Q6.
  • Reaction with Q6 with a reactive functional group R 9 containing a suitable leaving group L as described above can give compounds of structure Q7. Cyanation of compound Q7 can give the compounds of structure XIX.
  • Compounds of structure R1 can be prepared by protecting an indole compound of structure R1 as e.g., the N-Boc derivative R2 as above.
  • Compounds of structure R2 can be converted to 2-iodo- or bromoindoles R3.
  • a strong base such as n-butyllithium or s-butyllithium or lithium diisopropylamide or lithium or potassium hexamethyldisilazide is employed, with formation of the 2-indolyl anion generated in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them.
  • the reaction is typically carried out in the range of ⁇ 78° C. to ambient temperature.
  • the 2-indolyl anion can then be quenched with an electrophilic source of halogen, including but not limited to iodine, bromine or N-bromosuccinimide to give compounds of structure R3.
  • an electrophilic source of halogen including but not limited to iodine, bromine or N-bromosuccinimide
  • compounds of R4 can be reacted with aryl or heteroaryl boronic acids or esters (R5) (commonly referred to as a Suzuki reaction) to give compounds of structure R6.
  • the coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as tetrakis(triphenylphosphine) palladium (0), bis(triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand.
  • a catalyst such as tetrakis(triphenylphosphine) palladium (0), bis(triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand.
  • Reaction with R6 with a reactive functional group R 9 containing a suitable leaving group L as described above can give compounds of structure XX.
  • 2-iodo- or bromoindoles of structure S1 can be reacted with alkenes in the presence of a palladium catalyst (commonly referred to as the Heck reaction) to give compounds of type XXI.
  • a palladium catalyst commonly referred to as the Heck reaction
  • the coupling reactions can be carried out by methods known to those skilled in the art. The choice of catalyst and solvents are similar to those described previously.
  • 2-Iodo- or 2-bromoindoles of structure T1 can be reacted with acetylenes in the presence of a palladium catalyst (commonly referred to as the Sonagashira reaction) to give compounds of type XXII.
  • the coupling reactions can be carried out by methods known to those skilled in the art.
  • a typical set of reaction conditions includes reacting the indoles of structure T1 with an acetylene compound T2 in the presence of a source of palladium, a copper co-catalyst and an amine source. The reaction is carried out in a suitably unreactive solvent and conducted within a temperature range from ambient to 150° C.
  • Compounds of structure XXIII can be obtained from the reduction of compounds XXI and XXII.
  • Conditions for the reduction can include, but are not limited to catalytic reduction, e.g., hydrogenation over a source of platinum or palladium in a suitable solvent, e.g., CH 2 Cl 2 , ether, THF, methanol or solvent combinations.
  • Indoles of structure V1 can be reacted with a suitable base, such as lithium diisopropylamide or potassium hexamethyldisilazide to generate the 2-indolyl anion in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them.
  • a suitable unreactive solvent e.g., ether or THF, or solvent mixtures containing them.
  • the reaction is typically carried out in the range of ⁇ 78° C. to ambient temperature.
  • the 2-indolyl anion can then be quenched with a source of zinc halide, e.g., zinc halide metal or solutions containing them to give organozinc compounds of structure V2.
  • Reaction of V2 with an arylhalide (V3) in the presence of a palladium catalyst gives compounds of structure XXIV.
  • a palladium catalyst commonly referred to as the Negishi reaction
  • 2-iodo or bromoindoles of structure V4 prepared from compounds V1 as described previously, can be reacted with organozinc compounds of structure V5 in the presence of a suitable palladium catalyst to give compounds of structure XXIV.
  • the organozinc compound V5 can be derived from, e.g., an alkyl or alkenyl halide after treatment with activated zinc or an aryl or heteroaryl lithium or magnesium compound after treatment with zinc halide.
  • V2 or V4 can be carried out in the presence of a palladium source, e.g., as tetrakis(triphenylphosphine) palladium (0) or bis(triphenylphosphine) palladium (II) dichloride in a suitable solvent and at a temperature range from ambient to 150° C.
  • a palladium source e.g., as tetrakis(triphenylphosphine) palladium (0) or bis(triphenylphosphine) palladium (II) dichloride in a suitable solvent and at a temperature range from ambient to 150° C.
  • 2-Iodo- or bromoindoles of structure W1 can be reacted with acetylenes of structure W2 in the presence of a palladium catalyst (commonly referred to as the Sonagashira reaction) to give compounds of type XXV.
  • the coupling reactions can be carried out by methods known to those skilled in the art.
  • a typical set of reaction conditions includes reacting the indoles of structure W1 with an acetylene compound W2 in the presence of a source of palladium, an optional copper co-catalyst and an amine source.
  • the reaction is carried out in a suitably unreactive solvent and conducted within a temperature range from ambient to 150° C.
  • Reaction with XXV with a reactive functional group R 9 containing a suitable leaving group L as described above can give compounds of structure XXVI.
  • 2-iodo- or bromoindoles of structure W1 can also be reacted with alkenes in the presence of a palladium catalyst (commonly referred to as the Heck reaction) to give compounds of type XXVII.
  • a palladium catalyst commonly referred to as the Heck reaction
  • the coupling reactions can be carried out by methods known to those skilled in the art. The choice of catalyst and solvents are similar to those described previously.
  • Reaction with XXVII with a reactive functional group R 9 containing a suitable leaving group L as described above can give compounds of structure XXVIII.
  • the reaction can be promoted with a Lewis acid.
  • the choice of Lewis acid can be chosen from, but is not limited to aluminum chloride, ferric chloride, stannic chloride or diethyl aluminum.
  • the reaction is typically carried out in a suitable non-reactive solvent including CH 2 Cl 2 , carbon disulfide or dichloroethane and is typically conducted within a temperature range of ⁇ 20° C. to 80° C.
  • 3-Cyanoindoles of structure Y1 can be converted to tetrazoles of structure Y2 by treatment with, e.g., sodium azide. Heating a mixture of Y2 and the reagent Y3 can give the 3-(1,2,4-oxadiazolyl)indole compound XXX.
  • the reagent Y3 can be, e.g., an acyl halide or an acid derivative activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide.
  • the reaction can be carried out in a variety of solvents, including e.g., toluene, dioxane, pyridine and dichloroethane and can be carried out by heating Y2 and Y3 at a temperature range of 30° to 130° C.
  • solvents including e.g., toluene, dioxane, pyridine and dichloroethane and can be carried out by heating Y2 and Y3 at a temperature range of 30° to 130° C.
  • 3-Cyanoindoles of structure Z1 can be treated with hydroxylamine to give hydroxyamidine compounds of formula Z2.
  • Reaction of hydroxyamidines of structure Z2 with compounds of structure Z3 can give O-acylhydroxyamidines Z4.
  • Compounds Z3 can represent, for example, acyl halides or carboxylic acids activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide.
  • Heating compounds of structure Z4 in a non-reactive organic solvent, e.g., toluene, dichloroethane or dioxane in a temperature range of 30° C. to 150° C. can give compounds of structure XXXI.
  • Ketoindoles of type AA1 can be converted to oximes of structure AA2 by heating the ketoindoles with hydroxylamine (free base or acid salt) in a suitable solvent.
  • Bis-deprotonation of compounds of type AA2 with a strong organic base e.g., n-butyllithium or sec-butyllithium or tert-butyllithium
  • DMF dimethyl methyllithium
  • 3-Ketoindoles of structure AB 1 can be homologated to vinylogous amides of structure AB3 by reaction with dialkyl amide dialkyl acetals AB2.
  • the dialkyl amides can include e.g., lower alkyl amides such as formamide, acetamide and propionamide. Examples would include dimethlformamide dimethyl acetal and dimethyl acetamide dimethyl acetal.
  • the reaction can be conducted by reacting AB 1 and AB2 with or without additional solvent at a temperature from ambient to 150° C. Treatment of AB3 with hydroxylamine (free base or acid salt) in a suitable solvent can give compounds of structure XXXIII. The reaction is typically conducted within a temperature range from ambient to 120° C.
  • Vinylogous amides of structure AC1 (as prepared above) can be treated with hydrazines AC2 in a suitable organic solvent (DMF, alcohol or acetic acid) at temperatures ranging from ambient temperature to 150° C. to give compounds of structure XXXIV.
  • a suitable organic solvent DMF, alcohol or acetic acid
  • Indole-3-carboxaldehydes of structure AD1 (as prepared in Scheme F) can be reacted with p-(toluenesulfonyl)methyl isocyanate (TOSMIC) in the presence of a base to give compounds of structure XXXV.
  • Bases can include potassium carbonate or 1,8-diazabicyclo[5.4.0]undec-7-ene and the reaction can be carried out in a suitable organic solvent from ambient temperature to 150° C.
  • 3-Indolecarboxylic acids of structure AE1 can be converted to amides of structure AE2.
  • Compounds of structure AE2 can be activated by any of the standard methods.
  • the acid AE1 can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of ammonia.
  • the acid can be activated as the acid chloride or as the acyl imidazolide as described previously, followed by treatment of ammonia.
  • the indole-3-carboxamides of structure AE2 can be reacted with substituted aldehydes or ketones (AE3) containing a suitable leaving group L, in a suitable solvent at temperatures above ambient and up to 200° C.
  • the reaction can be performed with or without added base to afford oxazoles of structure XXXVI.
  • the indole-3-carboxamides of structure AE2 can also be converted to thioamides of structure AE4 by treating the primary amides with Lawesson's reagent or phosphorous pentasulfide at or above ambient temperature in a suitable organic solvent.
  • the resulting thioamides AE4 can be reacted with substituted aldehydes or ketones containing a suitable leaving group L (AE3), in a suitable solvent at temperatures above ambient and up to 150° C.
  • the reaction can be performed with or without added base to afford thiazoles of structure XXXVII.
  • 3-Ketoindoles of structure AF1 can be halogenated (e.g., brominated) to give compounds of structure AF3.
  • Suitable brominating agents can include but are not limited to phenyltrimethylammonium tribromide (AF2), N-bromosuccinimide or bromine and can be carried out in a variety of organic solvents.
  • Indoles of structure AG1 can be brominated or iodinated to give compounds of structure AG2.
  • Brominating agents may include but are not limited to bromine or N-bromosuccinimide and iodinating reagents may include iodine monochloride or bis-trifluoroacetoxy iodobenzene.
  • Reaction of 3-iodo- or bromoindoles AG2 with a boronic acid AG3 (commonly referred to as a Suzuki reaction) can give the compounds of structure XL.
  • the coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as tetrakis(triphenylphosphine) palladium (0), bis(triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand.
  • a catalyst such as tetrakis(triphenylphosphine) palladium (0), bis(triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand.
  • the reactions are carried out in a suitable solvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at a temperature range of ambient to 150° C. and typically in the presence of a base e.g., aqueous sodium carbonate or sodium bicarbonate, or the base can be employed under anhydrous conditions,
  • indole AG2 can be converted to the indole-3-boronic acid derivative AG5 by reacting the 3-haloindole AG2 with a strong organic base (alkyllithium or Grignard reagent) and reacting the resultant anion with a trialkylborate reagent AG4.
  • a strong organic base alkyllithium or Grignard reagent
  • Compounds of type AG5 can be reacted with aryl and heteroaryl bromides and iodides under similar conditions to those described above to form compounds of structure XL.
  • 3-iodo- or bromoindoles of structure AH1 can be reacted with alkenes AH2 in the presence of a palladium catalyst (commonly referred to as the Heck reaction) to give compounds of type XLI.
  • a palladium catalyst commonly referred to as the Heck reaction
  • the coupling reactions can be carried out by methods known to those skilled in the art.
  • the choice of catalyst and solvents are similar to those described in Scheme AG.
  • 3-Iodo- or bromoindoles of structure All can be reacted with acetylenes AI2 in the presence of a palladium catalyst (commonly referred to as the Sonagashira reaction) to give compounds of type XLII.
  • the coupling reactions can be carried out by methods known to those skilled in the art.
  • a typical set of reaction conditions includes reacting the indole of structure All with an acetylene compound AI2 in the presence of a source of palladium, a copper co-catalyst and an amine source and carrying out the reaction at a temperature range of ambient to 150° C.
  • Nitroanilines of structure AJ1 can be converted to indoles of structure XLIII by condensation and cyclization with nitriles of structure AJ2.
  • the reaction can be carried out in a suitable organic solvent, e.g., DMF or dioxane.
  • a suitable organic solvent e.g., DMF or dioxane.
  • Treatment of compounds of structure XLIII with a base followed by reaction with a reactive functional group R 9 containing a suitable leaving group L can give the compounds of formula XLIV.
  • 2-aminoindoles of structure XLV can be alkylated with a reactive functional group R 15 containing a suitable leaving group L in the presence of a base, e.g., sodium hydride or potassium carbonate in a suitable organic solvent to give compounds of structure XLVI.
  • a base e.g., sodium hydride or potassium carbonate in a suitable organic solvent
  • a second alkylation utilizing a reactive functional group R′ 15 containing a suitable leaving group L similarly can give compounds of structure XLVII.
  • Acylation of compounds of structure XLV with acyl chlorides of structure AK1 can give compounds of structure XLVIII.
  • the reaction is typically carried out in the presence of an organic base, e.g., a trialkylamine or an inorganic base, e.g., potassium carbonate in a suitable organic solvent.
  • Indole-3-carboxylic acids of structure AL1 can be activated to give compounds of structure AL2.
  • Compounds of structure AL2 can represent, for example, acyl halides or carboxylic acids activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide.
  • Reaction of compounds of structure AL2 with hydroxyamidines of structure AL3 can give O-acylhydroxyamidines AL4.
  • Hydroxyamidines may be obtained commercially or by treatment of nitrile compounds with hydroxylamine.
  • Heating compounds of structure AL4 in a non-reactive organic solvent, e.g., toluene, dichloroethane or dioxane in a temperature range of 30° C. to 150° C. can give compounds of structure XLIX.
  • 3-Cyanoindoles of structure AM1 can be converted to tetrazoles of structure AM2 by treatment with, e.g., sodium azide. Heating a mixture of AM2 and the reagent AM3 can give the 3-(1,2,4-oxadiazolyl)indole compound L.
  • the reagent AM3 can be, e.g., an acyl halide or an acid derivative activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide.
  • the reaction can be carried out in a variety of solvents, including e.g., toluene, dioxane, pyridine and dichloroethane and can be carried out by heating AM2 and AM3 at a temperature range of 30° to 130° C.
  • solvents including e.g., toluene, dioxane, pyridine and dichloroethane and can be carried out by heating AM2 and AM3 at a temperature range of 30° to 130° C.
  • 3-Cyanoindoles of structure AN1 can be treated with hydroxylamine to give hydroxyamidine compounds of formula AN2.
  • Reaction of hydroxyamidines of structure AN2 with compounds of structure AN3 can give O-acylhydroxyamidines AN4.
  • Compounds AN3 can represent, for example, acyl halides or carboxylic acids activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide.
  • Heating compounds of structure AN4 in a non-reactive organic solvent, e.g., toluene, dichloroethane or dioxane in a temperature range of 30° C. to 150° C. can give compounds of structure LI.
  • Ketoindoles of type AO1 can be converted to oximes of structure AO2 by heating the ketoindoles with hydroxylamine (free base or acid salt) in a suitable solvent.
  • Bis-deprotonation of compounds of type AO2 with a strong organic base e.g., n-butyllithium or sec-butyllithium or tert-butyllithium
  • DMF dimethyl methyllithium
  • 3-Ketoindoles of structure AP1 can be homologated to vinylogous amides of structure AP3 by reaction with dialkyl amide dialkyl acetals AP2.
  • the dialkyl amides can include e.g., lower alkyl amides such as formamide, acetamide and propionamide. Examples would include dimethlformamide dimethyl acetal and dimethyl acetamide dimethyl acetal.
  • the reaction can be conducted by reacting AP1 and AP2 with or without additional solvent at a temperature from ambient to 150° C. Treatment of AP3 with hydroxylamine (free base or acid salt) in a suitable solvent can give compounds of structure LIII. The reaction is typically conducted within a temperature range from ambient to 120° C.
  • Vinylogous amides of structure AQ1 (as prepared above) can be treated with hydrazines AQ2 in a suitable organic solvent (DMF, alcohol or acetic acid) at temperatures ranging from ambient temperature to 150° C. to give compounds of structure LIV.
  • a suitable organic solvent DMF, alcohol or acetic acid
  • Indole-3-carboxaldehydes of structure AR1 (as prepared in Scheme F) can be reacted with p-(toluenesulfonyl)methyl isocyanate (TOSMIC, AR2) in the presence of a base to give compounds of structure LV.
  • Bases can include potassium carbonate or 1,8-diazabicyclo[5.4.0]undec-7-ene and the reaction can be carried out in a suitable organic solvent from ambient temperature to 150° C.
  • 3-Indolecarboxylic acids of structure AS1 can be converted to amides of structure AS2.
  • Compounds of structure AS1 can be activated by any of the standard methods.
  • the acid AS1 can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of ammonia.
  • the acid can be activated as the acid chloride or as the acyl imidazolide as described previously, followed by treatment of ammonia.
  • the indole-3-carboxamides of structure AS2 can be reacted with substituted aldehydes or ketones (AS3) containing a suitable leaving group L, in a suitable solvent at temperatures above ambient and up to 200° C.
  • the reaction can be performed with or without added base to afford oxazoles of structure LVI.
  • the indole-3-carboxamides of structure AS2 can also be converted to thioamides of structure AS4 by treating the primary amides with Lawesson's reagent or phosphorous pentasulfide at or above ambient temperature in a suitable organic solvent.
  • the resulting thioamides AS4 can be reacted with substituted aldehydes or ketones containing a suitable leaving group L (AS3), in a suitable solvent at temperatures above ambient and up to 150° C.
  • the reaction can be performed with or without added base to afford thiazoles of structure LVII.
  • 3-Ketoindoles of structure AT1 can be halogenated (e.g., brominated) to give compounds of structure AT3.
  • Suitable brominating agents can include but are not limited to phenyltrimethylammonium tribromide (AT2), N-bromosuccinimide or bromine and can be carried out in a variety of organic solvents.
  • Indole-3-carboxylic acids of structure AU1 can be activated to give compounds of structure AU2.
  • Compounds of structure AU2 can represent, for example, acyl halides or carboxylic acids activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide. Reaction of compounds of structure AU2 with hydroxyamidines of structure AU3 can give O-acylhydroxyamidines AU4.
  • Hydroxyamidines may be obtained commercially or by treatment of nitrile compounds with hydroxylamine Heating compounds of structure AU4 in a non-reactive organic solvent, e.g., toluene, dichloroethane or dioxane in a temperature range of 30° C. to 150° C. can give compounds of structure LX.
  • a non-reactive organic solvent e.g., toluene, dichloroethane or dioxane in a temperature range of 30° C. to 150° C.
  • the reactions are carried out in a suitable solvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at a temperature range of ambient to 150° C. and typically in the presence of a base e.g., aqueous sodium carbonate or sodium bicarbonate, or the base can be employed under anhydrous conditions, e.g., cesium or potassium fluoride.
  • a suitable solvent e.g., DMF, toluene, dimethoxy ethane or dioxane
  • a base e.g., aqueous sodium carbonate or sodium bicarbonate
  • anhydrous conditions e.g., cesium or potassium fluoride.
  • Compounds of formula AW1 can be reacted with a protecting group, e.g., di-tert-butyl dicarbonate, to form the boc-protected indole, in the presence of a suitable base and solvent at ambient temperature to give compounds of structure AW2.
  • a protecting group e.g., di-tert-butyl dicarbonate
  • a suitable base and solvent at ambient temperature
  • Treatment of compounds of structure AW2 with base in a polar aprotic solvent at temperatures from ⁇ 78° C. to ambient temperature, followed by addition of a trialkyl borate would yield compounds of type AW3 upon hydrolytic workup.
  • Reaction of reactive aryl halides or triflates (of the type AW4) with compounds of formula AW3 at or around ambient temperature, in a suitable solvent system containing base and catalytic amounts of palladium catalyst, can give compounds of formula AW5.
  • Removal of the protecting group in compounds of structure AW5, e.g., acid treatment to remove the Boc group would yield compounds of structure AW6.
  • Compounds of type AW6 can be alkylated at the indole nitrogen to give compounds of structure LXII.
  • the alkylation can be carried out in the presence of a suitable alkylating agent and base in a polar solvent at temperatures ranging from ambient temperature to 150° C. to yield compounds of formula LXII.
  • Compounds of formula AX1 can be fluorinated at the 3-position with an electrophilic fluorinating agent, e.g., N-fluorocollidine tetrafluoroborate, in a suitable non-polar solvent at temperatures ranging from ⁇ 78° C. to 100° C. to yield compounds of structure LXIII.
  • an electrophilic fluorinating agent e.g., N-fluorocollidine tetrafluoroborate
  • Compounds of formula AY1 can be chlorinated at the 3-position with an electrophilic chlorinating agent, e.g., N-chlorosuccinimide or chlorine, in a suitable solvent at temperatures ranging from ⁇ 78° C. to 100° C. to yield products of structure LXIV.
  • an electrophilic chlorinating agent e.g., N-chlorosuccinimide or chlorine
  • Compounds of formula AZ1 can be brominated at the 3-position with an electrophilic brominating agent, e.g., N-bromosuccinimide or bromine) in a suitable solvent at temperatures ranging from ⁇ 78° C. to 100° C. to yield products of structure LXV.
  • an electrophilic brominating agent e.g., N-bromosuccinimide or bromine
  • Compounds of formula BA1 can be iodinated at the 3-position with an electrophilic iodinating agent, e.g., N-iodosuccinimide, (bis-trifluoroacetoxy)iodobenzene, or ICl, in a suitable solvent at temperatures ranging from ⁇ 78° C. to 100° C. to yield products of structure LXVI.
  • an electrophilic iodinating agent e.g., N-iodosuccinimide, (bis-trifluoroacetoxy)iodobenzene, or ICl
  • 3-Iodo- or bromoindoles of structure BB1 can be reacted with acetylenes BB2 in the presence of a palladium catalyst (commonly referred to as the Sonagashira reaction) to give compounds of type LXVII.
  • the coupling reactions can be carried out by methods known to those skilled in the art.
  • a typical set of reaction conditions includes reacting the indole of structure BB1 with an acetylene compound BB2 in the presence of a source of palladium, a copper co-catalyst and an amine and carrying out the reaction at a temperature range of ambient to 150° C.
  • Carboxaldehydes of formula BD1 can be treated with a fluorinating reagent, e.g., (diethylammonium sulfur trifluoride) in a suitable solvent at temperatures ranging from 0° C. to 80° C. to yield compounds of formula LXIX.
  • a fluorinating reagent e.g., (diethylammonium sulfur trifluoride) in a suitable solvent at temperatures ranging from 0° C. to 80° C. to yield compounds of formula LXIX.
  • Carboxaldehydes of formula BE1 can react with hydroxylamines of structure BE2 in the presence of a suitable polar solvent system and base at temperatures ranging from ambient to 100° C. to yield compounds of formula LXX.
  • Carboxaldehydes of formula BF1 can react with hydrazines of structure BF2, in the presence of a suitable solvent and base at temperatures ranging from ambient to 100° C. to yield compounds of formula LXXI.
  • Indolecarboxaldehydes of formula BG1 can be oxidized to carboxylic acids of formula LXXII, using reagents known to those skilled in the art, e.g., KMnO 4 or chromic acid.
  • the oxidation can usually be carried out in aqueous or mixed-aqueous/organic solvent systems and carried out at ambient or elevated temperature.
  • Carboxylic acids of formula BH1 can be converted to amides by treatment of the carboxylic acid with a suitable activating reagent (thionyl chloride, oxalyl chloride or carbonyldiimidazole) and then treated with amines of formula BH2 to give compounds of formula LXXIII.
  • a suitable activating reagent thionyl chloride, oxalyl chloride or carbonyldiimidazole
  • Carboxylic acids of formula BI1 can be converted to hydrazides and N-alkoxyamides by treatment of the carboxylic acid with a suitable activating reagent (thionyl chloride, oxalyl chloride or carbonyldiimidazole) and then treating the activated carboxylic acids with hydrazines and alkoxylamines of formula BI2 to give compounds of formula LXXIV.
  • a suitable activating reagent thionyl chloride, oxalyl chloride or carbonyldiimidazole
  • Carboxaldehydes of formula BJ1 can be treated with the appropriate alkyllithium or Grignard reagent of formula BJ2 at temperatures between ⁇ 78° C. to ambient temperature in a suitable aprotic solvent to produce secondary alcohols of formula LXXV.
  • An alternative reduction of the carboxaldehydes with an appropriate hydride reducing agent at ⁇ 78° C. to ambient temperatures can produce primary alcohols of formula LXXV.
  • Compounds of structure BK1 can be sulfonated at the 3-position with sulfur trioxide or some similar sulfuric acid equivalent to produce compounds of formula BK2.
  • Compounds of formula BK2 can be treated with reagents such as, but not limited to, POCl 3 at temperatures from 50° C. to 100° C. to convert them into sulfonyl chlorides of formula BK3.
  • reagents such as, but not limited to, POCl 3 at temperatures from 50° C. to 100° C. to convert them into sulfonyl chlorides of formula BK3.
  • treatment of compounds of structure BK1 with reagents such as chlorosulfonic acid can directly afford compounds of structure BK3.
  • Compounds BK3 can react with amines of formula BK4 at ambient temperature in the presence of a suitable base and solvent to produce sulfonamides of formula LXXVI.
  • Iodides or bromides of structure BL1 can be transformed into 3-thioalkyl indoles using an appropriate copper catalyst, e.g., CuI, and a suitable thiol or disulfide.
  • the reaction can generally be carried out at temperatures between ambient and 150° C. to yield compounds of structure BL2.
  • Compounds of structure BL2 can be oxidized to sulfones of formula LXXVII, using oxidizing agents such as, but not limited to, m-CPBA in chloroform at ambient or elevated temperatures.
  • Iodides or bromides of structure BM1 can be transformed into 3-thioalkyl indoles using an appropriate copper catalyst, e.g., CuI, and a suitable thiol or disulfide.
  • the reaction can generally be carried out at temperatures between ambient and 150° C. to yield compounds of structure BM2.
  • Compounds of structure BM2 can be selectively oxidized to sulfoxides of formula LXXVIII, using oxidizing agents such as, but not limited to, sodium periodate in methanol at ambient temperature.
  • Compounds of structure BN1 can be converted to ketones of formula LXXIX via a Friedel-Crafts reaction using an acid chloride of formula BN2.
  • the reaction can typically be carried out in a non-polar solvent such as dichloromethane or CS 2 in the presence of a suitable Lewis acid, e.g., AlCl 3 or FeCl 3 and carried out in a temperature range of 0° C. to 100° C.
  • Compounds of structure BO1 can be selectively nitrated at the 3-position using stoichiometric amounts of nitric acid under mild reaction conditions to produce compounds of formula LXXX. These conditions may include, but are not limited to, the use of nitric acid in acetic anhydride at a temperature range of ⁇ 40° C. to room temperature.
  • 3-Nitroindoles of structure BP1 can be reduced to 3-aminoindoles of structure BP2 using any number of standard conditions familiar to chemist skilled in the art, such as hydrogenation or iron reduction.
  • Compounds of formula BP2 can be further elaborated by mono- or di-alkylation of the amino group, using the appropriate alkylating agent, solvent, and base at temperatures ranging from ambient to 150° C. to yield compounds of formula LXXXI.
  • 3-haloindoles of structure BP3 can undergo Buchwald coupling with mono- or di-alkylamines of formula BP4 in the presence of copper or palladium catalysts, using conditions familiar to chemists skilled in the art, to produce compounds of formula LXXXI.
  • 3-Aminoindoles of structure BQ1 can be reacted with acyl halides or anhydrides of formula BQ2 in the presence of a suitable base and solvent at ambient temperature to yield amides of structure LXXXII.
  • 3-Aminoindoles of structure BR1 can react with chloroformates or carbonates or dicarbonates of formula BR2 in the presence of a suitable base and solvent at ambient or elevated temperature to yield carbamates of structure LXXXIII.
  • Alternative conditions involve the synthesis of a reactive carbamoyl intermediate of compounds BR1, e.g., by treatment of the amine BR1 with p-nitrophenyl chloroformate or phosgene, followed by reaction of the activated carbamoyl intermediate with alcohols of formula BR3 at temperatures ranging from ambient to 100° C. in a suitable solvent to form carbamates of formula LXXXIII.
  • 3-Aminoindoles of structure BS1 can react with isocyanates of formula BS2 in the presence of a suitable base and solvent at ambient or elevated temperature to yield ureas of structure LXXXIV.
  • Alternative conditions involve the synthesis of a reactive carbamoyl intermediate of compounds BS1, e.g., by treatment of the amine BS1 with p-nitrophenyl chloroformate or phosgene, followed by reaction of the activated carbamoyl intermediate with amines of formula BS3 at ambient temperature to form ureas of structure LXXXIV.
  • 3-Aminoindoles of structure BT1 can be reacted with sulfonyl chlorides of formula BT2 in the presence of a suitable base and solvent and reacted at temperatures in the range of ⁇ 20° C. to 50° C. to yield sulfonamides of structure LXXXV.
  • 3-Iodo- or bromoindoles of structure BU1 can be reacted with alkenes BU2 in the presence of a palladium catalyst (commonly referred to as the Heck reaction) to give compounds of structure LXXXVI.
  • a palladium catalyst commonly referred to as the Heck reaction
  • the coupling reactions can be carried out by methods known to those skilled in the art. The choice of catalyst and solvents are similar to those described in Scheme AG.
  • Hydrazines of structure BV1 can react with 3,3,3-trifluoropropanal to form hydrazone intermediates. Heating the hydrazone intermediates in a suitable solvent and at temperatures from ambient to 150° C. can form indoles of formula BV2.
  • a Lewis acid catalyst is used, e.g., AlCl 3 , TiCl 4 or ZnCl 4 .
  • Compounds of formula BV2 can be reacted with a protecting group, e.g., di-tert-butyl dicarbonate, to prepare the Boc derivative BV3.
  • Proteolytic cleavage of the Boc group of compounds of type BV6 can give compounds of structure BV7.
  • the indole BV7 can be alkylated in the presence of a suitable alkylating agent and base in a suitable solvent at temperatures ranging from 0° C. to 150° C. to yield indoles of formula LXXXVII.
  • Compounds of structure BW1 are commercially available, or can be prepared by well-known methodology, e.g., from the hydrolysis of substituted phenylacetonitriles. BW1 can then be activated, e.g., using peptide coupling reagents, or converted to an acid halide, and then reacted with amines (BW2) to provide substituted acetamides BW3.
  • BW2 peptide coupling reagents
  • BW2 amines
  • Compounds of type BW3 can undergo cyclization in the presence of a base, such as potassium carbonate or sodium hydride, and a catalyst, such as Cut or CuBr to form compounds of structure BW4.
  • Reduction of compounds BW4 with a reducing agent, such as DIBALH or lithium aluminum hydride can furnish indoles of type BW5.
  • Compounds of type BW5 can then be cyanated with a reagent such as chlorosulfonyl isocyanate (BW6) to afford compounds of type BW7.
  • a base e.g., lithium diisopropyl amide in a solvent such as THF or DME and a trialkyl borate
  • a 2-indolylboronic acid intermediate Reaction of the 2-indolylboronic acid intermediate with a group L-R 12 in the presence of a palladium catalyst can afford compounds of structure LXXXVIII.
  • Indoles BX1 can be cyanated with an appropriate cyanating agent, e.g., chlorosulfonyl isocyanate (BX2) or a dialkyl phosphoryl isocyanate in a suitable solvent or solvent mixture, e.g. DMF, CH 3 CN or dioxane, and carrying out the reaction at or above ambient temperature to afford compounds of structure BX3.
  • an appropriate cyanating agent e.g., chlorosulfonyl isocyanate (BX2) or a dialkyl phosphoryl isocyanate in a suitable solvent or solvent mixture, e.g. DMF, CH 3 CN or dioxane
  • BX3 Treatment of BX3 with a reactive functional group Z containing a suitable leaving group L (BX4) can give compounds of structure BX5.
  • L can represent a halide, particularly chloro, bromo or iodo or an alkylsulfonate.
  • the reaction between BX3 and BX4 can
  • Compounds of structure BX5 can be converted to indolyl-2-boronic acids BX6.
  • a strong base such as lithium diisopropylamide or lithium or potassium hexamethyldisilazide is employed in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them.
  • a suitable unreactive solvent e.g., ether or THF, or solvent mixtures containing them.
  • the reaction is typically carried out in the range of ⁇ 78° C. to ambient temperature. Quenching with a trialkylborate derivative can give the indolyl-2-boronic acid BX6.
  • Reaction of the indolyl-2-boronic acid BX6 with an aryl or heteroaryl halide BX7 can give the compounds of structure BX8.
  • the coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as 1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex.
  • the reactions are carried out in a suitable solvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at a temperature range of ambient to 150° C. in the presence of a base.
  • the base can be in aqueous solution, e.g., aqueous sodium carbonate or sodium bicarbonate, or the base can be employed under anhydrous conditions, e.g., cesium or potassium fluoride.
  • Compounds BX8 can be de-methylated to give compounds of structure BX9.
  • Suitable de-methylating reagents can include, but are not limited to boron tribromide, boron trichloride or iodotrimethylsilane in a variety of organic solvents, such as methylene chloride.
  • Indoles of structure BX9 can be alkylated with an electrophile, L(CH 2 ) n OP (BX10), to give compounds of structure BX11.
  • L can represent a halide, particularly chloro, bromo or iodo or an alkylsulfonate.
  • N can be equal 2, 3 or 4.
  • P can represent any acid-labile protecting group, such as tert-butyldimethylsilyl, triethylsilyl or tetrahydropyranyl.
  • the reaction can be conducted in a suitable solvent, e.g., THF, CH 2 Cl 2 or DMF, within a temperature range of 20° C. to 100° C.
  • a base e.g., an inorganic base, such as potassium or cesium carbonate or an organic base, such as a trialkylamine can be used to remove the acid formed in the reaction.
  • Compounds BX11 can be deprotected to give compounds of structure BX12.
  • Suitable deprotecting reagents can include, but are not limited to any mild organic acid, such as para-toluenesulfonic acid or pyridinium para-toluenesulfonate or an inorganic acid, such as acetic or hydrochloric acid in a variety of organic solvents, such as methylene chloride, THF or methanol.
  • any mild organic acid such as para-toluenesulfonic acid or pyridinium para-toluenesulfonate
  • an inorganic acid such as acetic or hydrochloric acid in a variety of organic solvents, such as methylene chloride, THF or methanol.
  • Oxidation of compounds BX12 to carboxylic acids with structure BX13 can be accomplished with various oxidating reagents such as potassium permanganate or pyridinium dichromate. Compounds of type BX13 can then be activated and treated with amines of type BX14 to form compounds of structure LXXXIX. Activation of the carboxylic acid can be carried out by any of the standard methods.
  • the acid BX13 can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of the amine BX14, or alternatively the acid can be activated as the acid chloride by treatment of the acid with, e.g., thionyl chloride or oxalyl chloride or as the acyl imidazolide, obtained by treatment of the acid with carbonyl diimidazole, followed by treatment of the amine BX14.
  • coupling reagents such as EDCI or DCC with or without HOBt
  • the acid can be activated as the acid chloride by treatment of the acid with, e.g., thionyl chloride or oxalyl chloride or as the acyl imidazolide, obtained by treatment of the acid with carbonyl diimidazole, followed by treatment of the amine BX14.
  • a compound of formula BY1 is treated with a reagent of structure BY2, wherein L and L′ represent leaving groups (halogen, arylsulfonate, etc.) and can be the same or different. If different, the more reactive of the two will be displaced by the phenol oxygen atom to give compound BY3.
  • Conditions for this reaction include solvents such as, but not limited to, acetonitrile, acetone, 2-butanone or dimethylformamide; bases such as sodium carbonate, potassium carbonate, cesium carbonate, tertiary amine bases or sodium hydride; and reaction temperatures from ambient to the reflux temperature of the chosen solvent.
  • the remaining leaving group in this molecule may be displaced by a reagent of formula R 18 SH (BY4),
  • R 18 may be alkyl, aryl or heteroaryl to give compounds of structure XC.
  • the conditions for this reaction may be similar but not necessarily the same as used for the transformation of BY1 to BY3.
  • Oxides of the resulting sulfide group in compound XC may be prepared, utilizing oxidizing reagents, such as m-chloroperbenzoic acid, potassium permanganate, potassium peroxymonosulfate or dimethyldioxirane, in stoichiometries chosen to optimize the particular oxidation state, using solvents such as dichloromethane, ethanol, methanol or acetone, and at temperatures ranging from ⁇ 30° C. to 120° C. to afford compounds of structure XCI.
  • oxidizing reagents such as m-chloroperbenzoic acid, potassium permanganate, potassium peroxymonosulfate or dimethyldioxirane
  • a compound of formula BZ1 is treated with a reagent of structure BZ2, wherein L and L′ represent leaving groups (halogen, arylsulfonate, etc.) and can be the same or different.
  • the resulting compounds of formula BZ3 may be alkylated by an amine of formula R 18 R 19 NH to prepare compounds of formula XCII.
  • Conditions for this alkylation reaction may include solvents such as ethanol, tetrahydrofuran or dimethylformamide.
  • a basic reagent such as pyridine, diisopropylethylamine or potassium carbonate, may be utilized.
  • a phenol compound, CAL can be reacted with an alkylating agent CA3, which can be derived from a compound of structure CA2.
  • an alkylating agent CA3 which can be derived from a compound of structure CA2.
  • a reagent of the formula CA2 may be purchased from commercial sources or be prepared by means familiar to those skilled in the art of organic synthesis and is then converted to compounds of structure CA3, wherein L represents a leaving group.
  • Compound CA3 is then used in an alkylation reaction with the phenol compound CAL employing the usual alkylation reaction conditions discussed above, to give the compound of formula XCIII.
  • Compounds of structure CB1 can be prepared starting from bromo-substituted indoles using the methodology discussed elsewhere in this invention (introduction of the Z group, installation of the cyano group at C-3 of the indole ring, and cross-coupling of the indole with an aryl reagent to give the corresponding 2-aryl group).
  • the bromide may be introduced at a later stage by bromination of the indole ring, employing brominating reagents such as bromine, N-bromosuccinimide or HOBr.
  • the bromide compound can be then subjected to a metal-halogen exchange reaction to generate an organometallic compound CB2, which is not isolated but taken on directly to the next reaction, wherein M is a metal atom such as magnesium or lithium.
  • Organomagnesium reagents may be prepared from aryl bromides by treating with magnesium metal in refluxing ether-like solvents, or treatment with other organomagnesium reagents such as isopropyl magnesium chloride.
  • Organolithium reagents may be prepared from aryl bromides by treating with lithium metal in refluxing solvents, or by treatment with other organolithium reagents such as sec- or tert-butyllithium.
  • the metallated indole may then be treated in situ with a thionating reagent to afford compounds such as XCIV or CB3.
  • a thionating reagent such as XCIV or CB3.
  • R 18 —(CH 2 ) p — is relatively simple, it may prove convenient to employ a reagent of the structure R 18 —(CH 2 ) p —S—S—(CH 2 ) p —R 18 , which will give sulfide compound XCIV directly. Otherwise, it may be more efficient to react compound CB2 with a reagent such as atomic sulfur (S 8 ), which will afford a thiol compound CB3.
  • the thiol group may be alkylated with a reagent of structure CB4, where L represents a suitable leaving group. Typical alkylation conditions known to those skilled in the art can be employed.
  • Oxides of the resulting sulfide group in compound XCV can be prepared using oxidizing reagents, such as m-chloroperbenzoic acid, potassium permanganate, potassium peroxymonosulfate or dimethyldioxirane in stoichiometries chosen to optimize the particular oxidation state desired, in solvents such as dichloromethane, ethanol, methanol or acetone, and at temperatures ranging from ⁇ 30° C. to 120° C.
  • oxidizing reagents such as m-chloroperbenzoic acid, potassium permanganate, potassium peroxymonosulfate or dimethyldioxirane in stoichiometries chosen to optimize the particular oxidation state desired, in solvents such as dichloromethane, ethanol, methanol or acetone, and at temperatures ranging from ⁇ 30° C. to 120° C.
  • a compound of formula CC1 may be nitrated at the indole C-5 position with reagents such as concentrated nitric acid optionally with solvents such as acetic acid or sulfuric acid.
  • reagents such as concentrated nitric acid optionally with solvents such as acetic acid or sulfuric acid.
  • the resulting nitro group in compound CC2 may be reduced to the amino compounds of structure CC3 with the use of reducing reagents such as hydrogen (with a catalyst such as palladium on carbon), tin dichloride (in the presence of HCl), sodium thiosulfate (in the presence of ammonia) or iron powder.
  • Suitable protecting groups include e.g., tert-butyldimethylsilyl, benzyl, or tetrahydropyranyl, and their synthesis and subsequent removal are well known to those skilled in the art.
  • Functionalization of the indole nitrogen to give compound CD2, followed by cyanation of CD2 to give CD3, and aryl cross-coupling of CD3 to give CD4 have been discussed elsewhere in this invention.
  • the protecting groups on the phenol oxygen atoms may then be removed, and the oxygens used in various cyclocondensation reactions.
  • reaction with a reagent of structure CD6 in the presence of a suitable base can afford the dioxanyl-fused ring system of compound XCIX.
  • treatment of CD5 with phosgene or a phosgene equivalent (CD7) can give compounds of structure XCVIII.
  • Condensation of CD5 with ketones of formula CD8 or ketal derivatives of the ketone CD8 can afford the cyclic ketal compounds of structure C.
  • CE1 Treatment of CE1 with a reactive heteroaryl group containing a leaving group L in a suitable solvent, with or without heat in the presence of a base, such an inorganic base, e.g., sodium or potassium carbonate or an organic base, e.g., a trialkylamine, can afford the compound of structure CI.
  • a base such an inorganic base, e.g., sodium or potassium carbonate or an organic base, e.g., a trialkylamine
  • the leaving group L can be a halide, particularly choro, bromo or iodo.
  • R 18 can be an alkyl, aryl or heteroaryl group.
  • L and L′ independently represent a leaving group, including but are not limited to halogens (e.g., chlorine, bromine or iodine) or alkyl or arylsulfonates, and p is an integer between 1 and 6.
  • the reactive heterocycle or heteroaryl compound CF4 can be reacted with the compound CF3 in a suitable solvent, with or without heat in the presence of a base, such an inorganic base, e.g., sodium or potassium carbonate or an organic base, e.g., triethylamine, diisopropylamine, to afford the compound of structure CII.
  • a base such an inorganic base, e.g., sodium or potassium carbonate or an organic base, e.g., triethylamine, diisopropylamine
  • the compound CF1 can be treated with a reactive compound CF5 containing a suitable leaving group L as described above to afford the compound of structure CII.
  • Indoles CG1 can be cyanated with an appropriate cyanating agent, e.g., chlorosulfonyl isocyanate (CG2) or a dialkyl phosphoryl isocyanate in a suitable solvent or solvent mixture, e.g. DMF, CH 3 CN or dioxane, carrying out the reaction at a temperature between ⁇ 20° C. and 80° C. to afford compounds of structure CG3.
  • the compounds CG3 can then be reacted with a reactive functional group Z containing a suitable leaving group L (CG4) as described previously to afford the compound CG6.
  • compound CG1 can be reacted with a reactive functional group Z containing a suitable leaving group L to give compounds of structure CG5, which can then be cyanated as above to give compounds of formula CG6.
  • an appropriate cyanating agent e.g., chlorosulfonyl isocyanate (CG2) or a dialkyl phosphoryl isocyanate in a suitable solvent or solvent mixture,
  • Compounds of structure CG6 can be converted to indolyl-2-boronic acid CG7.
  • a strong base such as lithium diisopropylamide or lithium or potassium hexamethyldisilazide is employed in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them.
  • a suitable unreactive solvent e.g., ether or THF, or solvent mixtures containing them.
  • the reaction is typically carried out in the range of ⁇ 78° C. to ambient temperature. Quenching with a trialkylborate derivative can give the indolyl-2-boronic acid CG7.
  • Reaction of indolyl-2-boronic acid CG7 with aryl or heteroaryl halide CG8 (commonly referred to as a Suzuki reaction) can give the compounds of structure CG9.
  • the coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as 1,1′-bis(diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex.
  • a catalyst such as 1,1′-bis(diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex.
  • the reactions are carried out in a suitable solvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at a temperature range of ambient to 150° C. in the presence of a base.
  • the base can be in aqueous solution, e.g., aqueous sodium carbonate or sodium bicarbonate, or the base can be employed under anhydrous conditions, e.g., cesium or potassium fluoride.
  • Indole-carboxylic esters CG9 can be converted to indole-carboxylic acids CG10 by treatment of compounds of structure CG9 with, for example, either acid or base in aqueous or mixed aqueous-organic solvents at ambient or elevated temperature or by treatment with nucleophilic agents, for example, boron tribromide or trimethylsilyl iodide, in a suitable solvent.
  • nucleophilic agents for example, boron tribromide or trimethylsilyl iodide
  • Compounds of type CG10 can then be activated and treated with amines of type CG11 to form compounds of structure CIII. Activation of the carboxylic acid can be carried out by any of the standard methods.
  • the acid CG10 can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of the amine CG11, or alternatively the acid can be activated as the acid chloride by treatment of the acid with, e.g., thionyl chloride or oxalyl chloride or as the acyl imidazolide, obtained by treatment of the acid with carbonyl diimidazole, followed by treatment with amines CG11.
  • coupling reagents such as EDCI or DCC with or without HOBt
  • the acid can be activated as the acid chloride by treatment of the acid with, e.g., thionyl chloride or oxalyl chloride or as the acyl imidazolide, obtained by treatment of the acid with carbonyl diimidazole, followed by treatment with amines CG11.
  • Compounds of formula CH1 can be reduced at the 6-ester group to give 6-hydroxymethyl indoles CH2.
  • the reduction reaction can be carried out using a hydride regent such as lithium borohydride, in an ethereal solvent such as THF, ethyl ether or DME at temperatures ranging from ambient to reflux to give the alcohol CH2.
  • the benzylic alcohol group in CH2 can be converted to a leaving group L (halogen, aryl sulfonate or alkyl sulfonate) by treatment with reagents such as thionyl chloride, phosphorous trichloride, thionyl bromide, methane sulfonyl chloride or toluenesulfonyl chloride in a solvent such as but not limited to dichloromethane, 1,2-dichloroethane or chloroform.
  • the leaving group L in compounds of formula CH3 can be displaced by a reagent of formula R 18 H to afford compounds of formula CIV, wherein R 18 maybe a heterocycle or a heteroaryl compound.
  • Conditions for this reaction include solvents such as but not limited to acetonitrile, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide; bases such as potassium carbonate, cesium carbonate or sodium hydride; and reaction temperatures ranting from ambient to reflux.
  • Compounds of formula CI1 in which V represents bromide or iodide can undergo reaction with alkyl vinyl ethers such as ethyl vinyl ether in the presence of palladium catalysts such as but not limited to palladium acetate, palladium (tetrakis)triphenylphosphine, in solvents such as but not limited to dimethyl formamide or dimethoxyethane to give the addition products of formula CI2.
  • Vinyl ethers of formula CI2 can be hydrolyzed to aldehydes of formula CI3 using aqueous acids, such as but not limited to, hydrochloric acid, sulfuric acid or acetic acid.
  • Compounds of formula CI3 can be reduced to the alcohol using hydrides such as lithium borohydride or sodium borohydride, in solvents such as methanol or tetrahydrofuran to give primary alcohols CI4.
  • the alcohol group in CI4 can be converted to a leaving group L (halogen or aryl sulfonate or alkyl sulfonate) by treatment with reagents such as thionyl chloride, phosphorous trichloride, thionyl bromide, methane sulfonyl chloride or toluenesulfonyl chloride in a solvent such as but not limited to dichloromethane, 1,2-dichloroethane or chloroform.
  • the leaving group L in compounds of formula CI5 can be displaced by a reagent of formula R 18 H to afford compounds of formula CV, wherein R 18 maybe a heterocycle or a heteroaryl group.
  • Conditions for this reaction include using solvents such as but not limited to acetonitrile, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide; bases such as potassium carbonate, cesium carbonate or sodium hydride; and reaction temperatures ranging from ambient to reflux.
  • solvents such as but not limited to acetonitrile, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide
  • bases such as potassium carbonate, cesium carbonate or sodium hydride
  • reaction temperatures ranging from ambient to reflux.
  • Compounds of formula CJ1 in which V represents iodine or bromine can undergo reaction with acrylic esters in the presence of palladium catalysts such as palladium acetate, palladium (tetrakis)triphenylphosphine or palladium (bis)-triphenylphosphinedichloride, and ligands such as triphenylphosphine or tri-ortho-tolylphosphine, in solvents such as but not limited to, dimethyl formamide, dimethoxyethane or toluene to give compounds of structure CJ2.
  • palladium catalysts such as palladium acetate, palladium (tetrakis)triphenylphosphine or palladium (bis)-triphenylphosphinedichloride
  • ligands such as triphenylphosphine or tri-ortho-tolylphosphine
  • Hydrogenation of compounds of type CJ2 can give products of type CJ3 by addition of hydrogen in the presence of a catalyst such a palladium or platinum in a solvent such as, but not limited to, methanol, ethanol or acetic acid at pressures ranging from 1-5 atmospheres.
  • a catalyst such as palladium or platinum
  • a solvent such as, but not limited to, methanol, ethanol or acetic acid
  • Reduction of the ester group in compounds CJ3 can be accomplished using hydride reagents such as lithium borohydride to give the alcohols CJ4.
  • Conversion of the alcohol in CJ4 to a leaving group L can be accomplished by treatment with reagents such as thionyl chloride, phosphorous trichloride, thionyl bromide, methane sulfonyl chloride or toluenesulfonyl chloride in a solvent such as but not limited to dichloromethane, 1,2-dichloroethane or chloroform.
  • reagents such as thionyl chloride, phosphorous trichloride, thionyl bromide, methane sulfonyl chloride or toluenesulfonyl chloride in a solvent such as but not limited to dichloromethane, 1,2-dichloroethane or chloroform.
  • the leaving group L in compounds of formula CJ5 can be displaced by a reagent of formula R 18 1-1 to afford compounds of formula CVI, wherein R 18 maybe a heterocycle or a heteroaryl group.
  • Conditions for this reaction include solvents such, as but not limited to, acetonitrile, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide; bases such as potassium carbonate, cesium carbonate or sodium hydride; and reaction temperatures ranging from ambient to reflux.
  • solvents such as but not limited to, acetonitrile, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide
  • bases such as potassium carbonate, cesium carbonate or sodium hydride
  • reaction temperatures ranging from ambient to reflux.
  • Phosphonium salt CK2 can be converted to olefin compounds of type CK3 by treatment with a base such as butyllithium, sodium hydride, sodium amide or potassium t-butoxide in a solvent such as tetrahydrofuran, ethyl ether or DME followed by addition of an aldehyde R 18 CHO (in which R 18 is an aryl, heterocycle or heteroaryl) at temperatures ranging from ambient to reflux.
  • Hydrogenation of compounds of type CK3 can be accomplished in the presence of a catalyst such a palladium or platinum in a solvent such as but not limited to methanol, ethanol or acetic acid at pressures ranging from ambient to 100° C. under a hydrogen atmosphere to give compounds of formula CVII.
  • CM1 Compounds of formula CM1 (in which L represents iodide, bromide or chloride or methanesulfonate) can undergo reaction with metal sulfinates (in which R 18 is an alkyl, aryl or heteroaryl) in solvents such as but not limited to acetone, dimethylformamide or toluene at temperatures from ambient to reflux to give the addition product CIX.
  • metal sulfinates in which R 18 is an alkyl, aryl or heteroaryl
  • solvents such as but not limited to acetone, dimethylformamide or toluene at temperatures from ambient to reflux
  • Compounds of formula CS1 can be treated with a triflate source, such as triflic anhydride, and a base, such as pyridine, in solvents such as but not limited to tetrahydrofuran, dichloromethane or toluene at temperatures from ambient to reflux to provide intermediate CS2.
  • a triflate source such as triflic anhydride
  • a base such as pyridine
  • solvents such as but not limited to tetrahydrofuran, dichloromethane or toluene at temperatures from ambient to reflux to provide intermediate CS2.
  • CS2 can either be directly reacted with palladium (0) and a R 12 substituted trialkyl tin compound in the presence of cesium fluoride and copper (I) iodide in solvents such as but not limited to tetrahydrofuran, dimethylformamide or toluene at temperatures from ambient to reflux to provide product CXV or reacted in a two step sequence of coupling with a pinacol borane source such as bis-pinacol diborane in the presence of palladium (II) and a base, such as potassium acetate, in solvents such as but not limited to tetrahydrofuran, dioxane or toluene at temperatures from ambient to reflux and then a second palladium coupling with palladium (0), cesium fluoride and an appropriate R 12 L compound in solvents such as but not limited to tetrahydrofuran, dimethoxy ethane or toluene at temperatures from ambient to reflux to provide CXV.
  • Another aspect of the invention relates to a method for treating Hepatitis C viral (HCV) infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, or a pharmaceutical composition comprising an effective amount of one of more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, as described above.
  • HCV Hepatitis C viral
  • treating refers to: (i) preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; (ii) inhibiting a disease, disorder or condition, i.e., arresting its development; and/or (iii) relieving a disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
  • the term “subject” refers to an animal or any living organism having sensation and the power of voluntary movement, and which requires for its existence oxygen and organic food.
  • Nonlimiting examples include members of the human, equine, porcine, bovine, murine, canine and feline species.
  • the subject is a mammal or a warm-blooded vertebrate animal. In other embodiments, the subject is a human.
  • the term “patient” may be used interchangeably with “human”.
  • the compounds of the present invention inhibit IRES-mediated initiation, elongation and termination, i.e., translation by interfering with function of the IRES directly and/or with the interaction of the IRES and a cellular and/or viral factor.
  • another aspect of the invention relates to a method for treating an infection by a wild type virus or a virus that is resistant to a currently available antiviral agent, in a subject in need thereof, wherein the wild type or resistant virus comprises an internal ribosome entry site (IRES), comprising administering to the subject an effective amount of one or more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, or a pharmaceutical composition comprising an effective amount of one of more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, as described above.
  • IRS internal ribosome entry site
  • Nonlimiting examples of such virus include viruses of the picornavirus genus, such as poliovirus, hepatitis A virus, coxsackievirus and rhinovirus; viruses of the coronaviridae genus, such as SARS; viruses of the arbovirus genus; viruses of the flavivirus genus, such as yellow fever, dengue, and West Nile virus; herpesviruses, such as herpes simplex virus and Kaposi's sarcoma-associated herpesvirus, and other viruses with a similar mode of replication; and HIV, human leukemia viruses (HTLV) and other viruses with a similar mode of translation.
  • viruses of the picornavirus genus such as poliovirus, hepatitis A virus, coxsackievirus and rhinovirus
  • viruses of the coronaviridae genus such as SARS
  • viruses of the arbovirus genus viruses of the flavivirus genus, such as yellow fever, dengue, and West Nile virus
  • Yet another aspect of the invention relates to a method for inhibiting HCV IRES-mediated initiation and/or translation in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, or a pharmaceutical composition comprising an effective amount of one of more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, as described above.
  • the term “effective amount” refers to the amount required to produce a desired effect.
  • the effective amount may be the amount required to treat a Hepatitis C viral (HCV) infection, the amount required to treat an infection by a virus which comprises an internal ribosome entry site (IRES), the amount required to inhibit HCV IRES-mediated initiation and/or translation, or the amount required to inhibit viral replication or infectivity, in a subject or, more specifically, in a human.
  • the desired effect can be determined by analyzing (1) the presence of HCVRNA; (2) the presence of anti-HCV antibodies; (3) the level of serum alanine amino transferase (ALT) and aspartate aminotransferase (AST) (ALT and AST are elevated in patients chronically infected with HCV); (4) hepatocellular damage resulting from HCV infection, including steatosis, fibrosis and cirrhosis; (5) hepatocellular carcinoma as a result of chronic HCV infection; and (5) extrahepatic sequelae (non-limiting examples include pruritis, encephalopathies, mental disorders such as anxiety or depression) of infection with HCV or other viruses which contain an IRES element.
  • the effective amount for a subject will depend upon various factors, including the subject's body weight, size and health. Effective amounts for a given patient can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • the concentration-biological effect relationships observed with regard to the compound(s) of the present invention indicate an initial target plasma concentration ranging from approximately 0.1 ⁇ g/ml to approximately 100 ⁇ g/mL, from approximately 1 ⁇ g/mL to approximately 50 ⁇ g/mL, from approximately 5 ⁇ g/mL to approximately 50 ⁇ g/mL, or from approximately 10 ⁇ g/mL to approximately 25 ⁇ g/mL.
  • the compounds of the invention may be administered at doses that vary from 0.1 ⁇ g to 100,000 mg, depending upon the route of administration.
  • Guidance as to particular dosages and methods of delivery is provided in the literature and is generally available to practitioners in the art.
  • the dose will be in the range of about 1 mg/day to about 10 g/day, or about 0.1 g to about 3 g/day, or about 0.3 g to about 3 g/day, or about 0.5 g to about 2 g/day, in single, divided, or continuous doses for a patient weighing between about 40 to about 100 kg (which dose may be adjusted for patients above or below this weight range, particularly children under 40 kg).
  • the exact dosage will be determined by the practitioner, in light of factors related to the subject. Dosage and administration may be adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.
  • the compounds and compositions of the present invention may be administered to the subject via any drug delivery route known in the art.
  • Nonlimiting examples include oral, ocular, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intraveneous (bolus and infusion), intracerebral, transdermal, and pulmonary routes of administration.
  • the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammalian tissue or a mammal for a period of time sufficient to yield a metabolic product thereof.
  • Such products typically are identified by preparing a radio-labeled (e.g.
  • C 14 or H 3 compound of the invention, administering it in a detectable dose (e.g., greater than about 0.5 mg/kg) to a mammal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating its conversion products from urine, blood or other biological samples.
  • a detectable dose e.g., greater than about 0.5 mg/kg
  • a mammal such as rat, mouse, guinea pig, monkey, or to man
  • sufficient time for metabolism to occur typically about 30 seconds to 30 hours
  • the metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis. In general, analysis of metabolites may be done in the same way as conventional drug metabolism studies well-known to those skilled in the art.
  • the conversion products so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they
  • Yet another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising: (i) an effective amount of one or more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, or a pharmaceutical composition comprising an effective amount of one of more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, as described above.
  • a pharmaceutical composition of the present invention may be formulated to achieve a physiologically compatible pH, ranging from a pH of about 3 to a pH of about 11. In some embodiments, the pharmaceutical composition is formulated to achieve a pH of about 3 to a pH of about 7. In other embodiments, the pharmaceutical composition is formulated to achieve a pH of about 5 to a pH of about 8.
  • the pharmaceutical composition may comprise a combination of compounds of the present invention, or may include a second active ingredient useful in the treatment of viral infections, such as anti-viral agents that include, but are not limited to: pegylated interferon, including by way of non-limiting example pegylated ⁇ -interferon; un-pegylated interferon, including by way of non-limiting example, un-pegylated ⁇ -interferon; ribavirin or prodrugs or derivatives thereof; a glucosidase inhibitor; protease inhibitors; polyermase inhibitors; p7 inhibitors; entry inhibitors, including fusion inhibitors such as FuzeonTM (Trimeris); helicase inhibitors; a Toll-like receptor agonist, a caspase inhibitor, anti-fibrotics; drugs that target IMPDH (inosine monophosphate dehydrogenase inhibitors), such as MerimepadibTM (Vertex Pharmaceuticals Inc.); synthetic thymosin alpha 1 (ZADAX
  • pharmaceutically acceptable excipient refers to an excipient for administration of a pharmaceutical agent, such as the compounds of the present invention.
  • the term refers to any pharmaceutical excipient that may be administered without undue toxicity.
  • Pharmaceutically acceptable excipients may be determined in part by the particular composition being administered, as well as by the particular mode of administration and/or dosage form.
  • Nonlimiting examples of pharmaceutically acceptable excipients include carriers, solvents, stabilizers, adjuvants, diluents, etc. Accordingly, there exist a wide variety of suitable formulations of pharmaceutical compositions of the present invention (see, e.g., Remington's Pharmaceutical Sciences).
  • Suitable excipients may be carrier molecules that include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles.
  • Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA; carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid; liquids such as oils, water, saline, glycerol and ethanol; wetting or emulsifying agents; pH buffering substances; and the like. Liposomes are also included within the definition of pharmaceutically acceptable excipients.
  • compositions of the invention may be formulated in any form suitable for the intended method of administration.
  • suitable formulations for oral administration include solids, liquid solutions, emulsions and suspensions, while suitable inhalable formulations for pulmonary administration include liquids and powders.
  • Alternative formulations include syrups, creams, ointments, tablets, and lyophilized solids which can be reconstituted with a physiologically compatible solvent prior to administration.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • compositions suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as croscarmellose sodium, cross-linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • inert diluents such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate
  • disintegrating agents such as
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with non-aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example celluloses, lactose, calcium phosphate or kaolin
  • non-aqueous or oil medium such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.
  • compositions of the invention may be formulated as suspensions comprising one or more compound(s) of the present invention in admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension.
  • pharmaceutical compositions of the invention may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of one or more excipient(s).
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth; naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents.
  • compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous emulsion or oleaginous suspension.
  • emulsion or suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,2-propane-diol.
  • the sterile injectable preparation may also be prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • the compounds of the invention may be substantially insoluble in water and sparingly soluble in most pharmaceutically acceptable protic solvents and vegetable oils, but generally soluble in medium-chain fatty acids (e.g., caprylic and capric acids) or triglycerides and in propylene glycol esters of medium-chain fatty acids.
  • medium-chain fatty acids e.g., caprylic and capric acids
  • propylene glycol esters of medium-chain fatty acids e.g., caprylic and capric acids
  • contemplated in the invention are compounds which have been modified by substitutions or additions of chemical or biochemical moieties which make them more suitable for delivery (e.g., increase solubility, bioactivity, palatability, decrease adverse reactions, etc.), for example by esterification, glycosylation, PEGylation, etc.
  • the compound of the invention is formulated for oral administration in a lipid-based composition suitable for low solubility compounds.
  • Lipid-based formulations can generally enhance the oral bioavailability of such compounds.
  • pharmaceutical compositions of the invention may comprise a effective amount of one or more compound(s) of the invention, together with at least one pharmaceutically acceptable excipient selected from medium chain fatty acids or propylene glycol esters thereof (e.g., propylene glycol esters of edible fatty acids such as caprylic and capric fatty acids) and pharmaceutically acceptable surfactants, such as polyoxyl 40 hydrogenated castor oil.
  • the pharmaceutical composition may further comprise one or more aqueous solubility enhancer(s), such as a cyclodextrin.
  • a cyclodextrin include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ⁇ -, ⁇ -, and ⁇ -cyclodextrin, and hydroxypropyl- ⁇ -cyclodextrin (HPBC).
  • any compound of the present invention with one or more other active ingredients useful in the treatment of HCV infection, including compounds, in a unitary dosage form, or in separate dosage forms intended for simultaneous or sequential administration to a patient in need of treatment.
  • the combination may be administered in two or more administrations.
  • active ingredients may be administered in combination with the compounds of the present invention that may act to augment or synergistically enhance the viral inhibiting activity of the compounds of the invention.
  • active ingredients include anti-HCV agents.
  • Anti-HCV agents include agents that target the virus as well as agents that have an immunomodulatory effect.
  • anti-HCV agents include, but are not limited to, interferon, including, for example without limitation, IFN- ⁇ , ribavirin or prodrugs or derivatives thereof; a glucosidase inhibitor, protease inhibitors, polymerase inhibitors, helicase inhibitors, a Toll-like receptor agonist, a caspase inhibitor and a glycosidase inhibitor.
  • the compounds of the invention may also be administered in combination with other compounds that affect IRES activity.
  • the combination of active ingredients may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art.
  • the methods of the invention may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e., serially
  • simultaneous therapy effective dosages of two or more active ingredients are administered together.
  • Various sequences of intermittent combination therapy may also be used.
  • Step A A solution of 6-methoxyindole (10.0 g, 68.0 mmol) in DMF (120 mL) is cooled to 0° C. and treated with chlorosulfonyl isocyanate (7.72 mL, 88.4 mmol). After the addition, the reaction mixture is stirred at this temperature for 1 h. The dark solution is poured into ice water (600 mL) and the light brown solid is collected by filtration, washed with additional H 2 O and dried to afford 9.9 g (85%) of 6-methoxy-1H-indole-3-carbonitrile as a light brown solid.
  • Step B To a solution of 6-methoxy-1H-indole-3-carbonitrile (9.9 g, 57.6 mmol) in DMF (150 mL) is added NaH (60% dispersion in mineral oil, 3.45 g, 86.3 mmol). The reaction mixture is stirred for 15 min and then ethyl iodide (5.53 mL, 69.1 mmol) is added and the mixture is stirred at room temperature overnight. The reaction mixture is then diluted with H 2 O and extracted with EtOAc (2 ⁇ ). The organic phases are washed with H 2 O (3 ⁇ ) and saturated NaCl and then dried and concentrated to a semi-solid.
  • the crude product is purified via column chromatography on silica gel (200 g) using CH 2 Cl 2 /hexanes (50-100%) as eluent to yield 6-methoxy-1-ethyl-1H-indole-3-carbonitrile as a tan solid.
  • Step A To a solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (2.85 g, 14.2 mmol), prepared by example 1A, step B, in CH 2 Cl 2 (40 mL) is added a 1M solution of BBr 3 in CH 2 Cl 2 (28.5 mL, 28.5 mmol) at 0° C. The mixture is allowed to warm to room temperature and kept for 2.5 h. The dark reaction mixture is then poured onto ice and sufficient 1M NaOH is added until the pH is 8-9. The product is extracted with CH 2 Cl 2 (3 ⁇ ) and the combined organic phases are washed with saturated NaHCO 3 , H 2 O and saturated NaCl.
  • Step B To a solution 6-hydroxy-1-ethyl-1H-indole-3-carbonitrile (80 mg, 0.43 mmol) in 5 mL of methyl ethyl ketone is added anhydrous K 2 CO 3 (71 mg, 0.52 mmol) and iodomethane (0.05 mL, 0.60 mmol). After stirring overnight at reflux, the reaction mixture is cooled, diluted with H 2 O and extracted with EtOAc (3 ⁇ ). The combined organic phases are dried and concentrated. Flash chromatography (CH 2 Cl 2 ) gives 94 mg (100%) of 6-ethoxy-1-ethyl-1H-indole-3-carbonitrile as a white wax.
  • step A To a solution of 1-ethyl-6-hydroxy-1H-indole-3-carbonitrile (60 mg, 0.32 mmol) prepared as described in example 1A, step A, in DMF (5 mL) is added K 2 CO 3 (55 mg, 0.40 mmol) and 2-chloropyridazine (45 mg, 0.40 mmol). The mixture is heated at 110° C. for 18 h. After cooling to room temperature, the reaction mixture is diluted with H 2 O and extracted with EtOAc (3 ⁇ ). The combined organic phases are washed with H 2 O and saturated NaCl, dried and concentrated.
  • Step A A solution of methyl 3-cyano-1-ethyl-1H-indole-6-carboxylate (1.60 g, 7.02 mmol), prepared by the method described in example 1A from methyl 1H-indole-6-carboxylate, in THF (35 mL) is treated with 1N NaOH (7.7 mL, 7.7 mmol) and heated at reflux for 2.5 h. After cooling to room temperature, most of the THF is removed and the solution is diluted with H 2 O and extracted with ether (2 ⁇ ). The ether extracts are discarded. The aqueous phase is then acidified with 6N HCl to pH 2 and then extracted with EtOAc (3 ⁇ ). The EtOAc layers are combined, washed with saturated NaCl and then dried and concentrated to afford 1.43 g (95%) of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid as a white solid.
  • Step B A suspension of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid (0.42 g, 1.96 mmol) in CH 2 Cl 2 (15 mL) is cooled to 0° C. The suspension is treated with DMF (2 drops) and then oxalyl chloride (0.34 mL, 3.92 mmol) is added via syringe during 2 minutes after which the ice bath is removed and the reaction mixture is allowed to warm to ambient temperature during 1.5 h during which time the reaction became a yellow solution. The solution is then concentrated in vacuo to afford 0.46 g (quantitative yield) of 3-cyano-1-ethyl-1H-indole-6-carbonyl chloride as a yellow solid.
  • Step C A suspension of 3-cyano-1-ethyl-1H-indole-6-carbonyl chloride (70 mg, 0.30 mmol) in THF (5 mL) is cooled to 0° C. and treated with aniline (0.08 mL, 0.90 mmol). After the addition the reaction is warmed to ambient temperature and after stirring for an additional 16 hours, the reaction mixture is diluted with H 2 O and extracted with EtOAc (2 ⁇ ). The combined organic phases are washed with saturated NaCl and then dried and concentrated to afford the product.
  • Step A A 2M solution of lithium diisopropyl amide in THF/hexanes (Acros) (3.9 mL, 7.8 mmol) is diluted with THF (5 mL) in a flame-dried flask. After cooling the reaction to ⁇ 30° C., a solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.30 g, 6.5 mmol) in THF (10 mL) is added dropwise during 10 min, maintaining the temperature at ⁇ 30° C. After stirring for an additional 30 min at this temperature, a solution of iodine (2.31 g, 9.1 mmol) in THF (5 mL) is added during 10 min.
  • Step B A mixture of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile (1.25 g, 3.83 mmol), 4-(4,4,5,5-tetramethyl)-1,3-2-dioxaboralanyl-2-yl-aniline (0.96 g, 4.90 mmol), CsF (1.46 g, 9.58 mmol) and Pd(PPh 3 ) 2 Cl 2 (110 mg, 0.15 mmol) in DME (20 mL) is added to a flask and alternatively evacuated and flushed with N 2 . The reaction is then heated at reflux for 24 h and then cooled to room temperature.
  • reaction mixture is diluted with H 2 O and extracted with EtOAc (2 ⁇ ). The combined organic phases are washed with H 2 O and saturated NaCl and then dried over MgSO 4 and concentrated.
  • the crude reaction mix is purified by flash chromatography on silica gel using EtOAc/CH 2 Cl 2 (5/95) as eluent to afford 765 mg (69%) of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile as a yellow solid.
  • a concentrated THF solution of 6-methoxy-1-propyl-1H-indole-3-carbonitrile (2.77 g, 12.9 mmol; prepared analogously to compound 5 of Example 1A) is added slowly, and the resulting solution is maintained at ⁇ 78° C. for 30 min.
  • the flask is then transferred to a water-ice bath and allowed to come to 0° C. for about 15 minutes.
  • the solution is once again cooled to ⁇ 78° C., and ZnCl 2 (0.5 M solution in THF, 27.0 mL, 13.5 mmol) is slowly added.
  • a precipitate is observed at this point, which may be the bis(indole)zinc compound, but the solution becomes homogeneous when the entire volume of zinc chloride solution is added.
  • Step A A solution of THF (60 mL) and diisopropylamine (5.5 mL, 39 mmol) is cooled to ⁇ 78° C. n-Butyllithium (14.5 mL, 2.5M in hexanes, 36.2 mmol) is added dropwise over 5 minutes. The LDA mixture is stirred at ⁇ 78° C. for 10 minutes, and then at 0° C. for 20 minutes. The solution is re-cooled to ⁇ 78° C. 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (5.0 g, 25 mmol), prepared as in example 1A, is taken up in THF (30 mL) and added dropwise to the LDA mixture over 15 minutes.
  • Step B 1-Ethyl-6-methoxy-2-tributylstannanyl-1H-indole-3-carbonitrile (1.0 g, 2.05 mmol), prepared in step A, is combined with 3-iodophenol (474 mg, 2.15 mmol), Pd(PPh 3 ) 2 Cl 2 (67 mg, 0.102 mmol), CuI (75 mg, 0.39 mmol) and THF (4.0 mL). This mixture is heated at 65° C. overnight. The reaction mixture is diluted in EtOAc, and is filtered through celite. The filtrate is concentrated and the residue is purified by silica gel chromatography (4:1, CH 2 Cl 2 /EtOAc) to yield crude product. Ether trituration yields 1-ethyl-2-(3-hydroxy-phenyl)-6-methoxy-1H-indole-3-carbonitrile (430 mg, 72%) as a yellow-white solid.
  • Step A A solution of 6-difluoromethoxy-1-ethyl-1H-indole (402.8 mg, 2.04 mmol), ethanesulfonic acid (4-iodo-phenyl)-amide (712.1 mg, 2.29 mmol), cesium carbonate (733.2 mg, 3.82 mmol), triphenylphosphine (33.1 mg, 0.13 mmol) and palladium acetate (5.7 mg, 0.025 mmol) in DMA (5 ml) is heated to 135° C. for 48 h. The reaction mixture is diluted with water and extracted with EtOAc (2 ⁇ 10 mL). The combined organic phases are washed with brine, dried over MgSO 4 , and then concentrated.
  • Step B Following the procedure 1A, step A, ethanesulfonic acid [4-(6-difluoromethoxy-1-ethyl-1H-iodo-2-yl)-phenyl]-amide is converted to ethanesulfonic acid [4-(3-cyano-6-difluoromethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-amide, compound 519.
  • Step A A solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.00 g, 5.00 mmol) in MeOH (10 mL) is treated with a 50% aqueous solution of hydroxylamine (0.38 mL, 6.25 mmol) and heated at reflux for 18 h. After cooling to room temperature, the heterogeneous mixture is filtered to afford 525 mg of desired product as a tan solid. The filtrate is concentrated to an oil, which is then dissolved in CH 2 Cl 2 and chromatographed over silica gel using EtOAc/CH 2 Cl 2 (15-50%) to afford an additional 295 mg of product as a tan solid. Total yield of 1-ethyl-N-hydroxy-6-methoxy-1H-indole-3-carboxamidine is 820 mg (70%).
  • Step B The N-hydroxycarboxamidine above (50 mg, 0.21 mmol), polystyrene-diisopropylethylamine 165 mg, 3.90 mmol/g loading) and propionyl chloride (0.03 mL, 0.32 mmol) in CH 2 Cl 2 (10 mL) are placed in a tube and rotated for 22 h at room temperature. After this time, trisamine resin (77 mg, 2.71 mmol/g loading) is then added and the tube rotated for an additional 30 min at room temperature. Solids are filtered and then the filtrate is concentrated and diluted with toluene (5 mL) and heated at 110° C. overnight.
  • Step A A mixture of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.00 g, 5.00 mmol) in toluene (30 mL) is treated with triethylamine hydrochloride (1.03 g, 7.50 mmol) and sodium azide (0.49 g, 7.50 mmol) and is heated at reflux for 16 h. After cooling to room temperature, the reaction mixture is diluted with saturated NaHCO 3 and extracted with EtOAc. The organic layer is then washed with additional NaHCO 3 (2 ⁇ ). The combined aqueous phases are acidified to pH 2 with 6N HCl.
  • Step B A suspension of the tetrazole above (50 mg, 0.21 mmol) and propionyl chloride (0.03 mL, 0.31 mmol) in dichloroethane (5 mL) is heated at reflux for 21 h. After cooling the reaction mixture to room temperature, polystyrene trisamine resin (70 mg, 3.4 meq/g) is added and the reaction is rotated for 4 h at room temperature.
  • Freon-22 (HCF 2 Cl) gas is bubbled into a solution of ethyl 5-hydroxy-1-(4-methoxyphenyl)-2-methyl-1H-indole-3-carboxylate (250 mg, 0.77 mmol) in CH 2 Cl 2 (5 mL) at 0° C. containing a small amount of tetrabutylammonium bromide as a phase transfer catalyst.
  • a 50% solution of NaOH is added dropwise at 0° C. After the addition, the mixture is stirred at 0° C. for 2 h. After the addition of H 2 O, the organic phase is separated and washed with brine and dried over Na 2 SO 4 .
  • the solvent is then concentrated and the residue is purified by column chromatography over silica gel using EtOAc/petroleum ether (1/2) as eluent to yield the desired product in 40% yield.
  • Step A A mixture of 1-(1-ethyl-6-methoxy-1-H-indole-3-yl)ethanone (200 mg, 0.92 mmol), prepared from 1-ethyl-6-methoxy-1H-indole by the procedure described in example 1L, hydroxylamine hydrochloride (128 mg, 1.84 mmol), NaOAc (151 mg, 1.84 mmol) and EtOH (7 mL) is heated at 85° C. for 4 h. The reaction mixture is then partitioned between H 2 O and EtOAc. The organic phase is dried and concentrated in vacuo.
  • Step B 1-(1-Ethyl-6-methoxy-1-H-indole-3-yl)ethanone oxime (100 mg, 0.43 mmol) is dissolved in THF (900 ⁇ L) at 0° C. n-BuLi (450 ⁇ L, 2.5 M in hexanes, 1.12 mol) is added dropwise, resulting in instant precipitation of solids. DMF (70 ⁇ L, 0.9 mol) in 260 ⁇ L of is then added dropwise. This is stirred at 0° C. for 1 h, then at room temperature for 1 h.
  • reaction mixture is pipetted into a mixture containing 1 mL of H 2 O, 1 mL of THF, and 100 ⁇ L of concentrated H 2 SO 4 .
  • This mixture is heated at 75° C. for 1 h and then is partitioned between H 2 O and EtOAc.
  • the organic phase is dried and concentrated. Purification by column chromatography (CH 2 Cl 2 ) yields 1-ethyl-3-isoxazol-3-yl-6-methoxy-1-H-indole product as a white solid (13 mg, 12%).
  • 1-(1-Ethyl-6-methoxy-1H-indol-3-yl)ethanone (100 mg, 0.46 mmol), prepared from 1-ethyl-6-methoxy-1H-indole by the procedure described in example 1L, is heated with 1.5 mL of dimethylformamide dimethylacetal and 100 ⁇ L of pyrrolidine at 110° C. overnight. The dimethylformamide dimethylacetal is then concentrated in vacuo. The residue is redissolved in 1.25 mL of EtOH and 250 ⁇ L of H 2 O, and is treated with hydroxylamine hydrochloride (66 mg, 0.95 mmol) and heated at 80° C. for 2 h.
  • 1-(1-Ethyl-6-methoxy-1H-indol-3-yl)-ethanone (100 mg, 0.46 mmol), prepared from 1-ethyl-6-methoxy-1H-indole by the procedure described in example 1L, is heated with 1.5 mL of dimethylformamide dimethyl acetal and 100 ⁇ L pyrrolidine at 110° C. overnight. The DMF dimethyl acetal is removed in vacuo. The residue is redissolved in 3 mL of acetic acid, hydrazine hydrate (70 ⁇ L, 1.38 mmol) is added, and the mixture is heated to 100° C. for 2 h.
  • Step A 1-Ethyl-1H-indole-6-carboxylic acid methyl ester (900 mg, 4.45 mmol) is dissolved in DMF (3.3 mL). This is added dropwise to an ice-cold solution of POCl 3 (430 ⁇ L, 4.5 mmol) in DMF (1.5 mL). The reaction mixture is stirred at room temperature for 90 minutes. The reaction mixture is then treated with 6N NaOH (3.5 ml). The mixture is then partitioned between H 2 O and ethyl acetate.
  • Step B 1-Ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (100 mg, 0.42 mmol), TOSMIC (100 mg, 0.52 mmol), K 2 CO 3 (178 mg, 1.29 mmol), and MeOH (800 ⁇ L) are heated at 80° C. overnight. The reaction mixture is then partitioned between H 2 O and ether. After drying and concentrating the organic phase, the product is purified by silica gel chromatography (EtOAc/CH 2 Cl 2 , 10/90) to give methyl 1-ethyl-3-oxazol-5-yl-1H-indole-6-carboxylate (26 mg, 23%) as an off-white solid.
  • Step A 1-Ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (800 mg, 3.5 mmol), prepared as shown in example 1P, step A, is dissolved in acetone (98 mL). A solution of KMnO 4 (655 mg, 4.15 mmol) in H 2 O (31 mL) is added. The reaction mixture is stirred at room temperature for 90 minutes. Another addition of KMnO 4 (108 mg) in H 2 O (6 mL), followed by stirring for another 45 minutes is required to drive the reaction to completion. The reaction mixture is then quenched with 10% H 2 O 2 (1.5 mL). The mixture is filtered through celite. The filtrate is stripped down under vacuum to roughly 1/3 of the volume.
  • Step B 1-Ethyl-1H-indole-3,6-dicarboxylic acid 6-methyl ester (600 mg, 2.43 mmol) is suspended in a solution of CH 2 Cl 2 (27 ml) and DMF (20 ⁇ L). Oxalyl chloride (470 ⁇ L, 5.38 mmol) is added, and the reaction mixture is stirred for 1 hour at room temperature. This mixture is then slowly poured into a rapidly stirring solution of concentrated NH 4 OH (10 mL). This is then partitioned in H 2 O and EtOAc. The residue from the ethyl acetate layer is triturated with acetone to yield 6-methoxycarbonyl-1-ethyl-1H-indole-3-carboxamide (511 mg, 85%) as a white solid.
  • Step C A mixture of 150 mg (0.61 mmol) of 6-methoxycarbonyl-1-ethyl-1H-indole-3-carboxamide in diglyme (3.6 mL), and bromoacetaldehyde dimethyl acetal (430 ⁇ L, 3.7 mmol) is heated at 125° C. for 2 h. The reaction mixture is cooled and partitioned in H 2 O and EtOAc. The organic phase is dried and concentrated and the product is purified by silica gel chromatography (EtOAc/CH 2 Cl 2 5-10%).
  • Step A 1-Ethyl-6-methoxy-1H-indole (900 mg, 5.14 mmol) is dissolved in DMF (1.5 mL). This is added dropwise to an ice-cold solution of POCl 3 (500 ⁇ L, 5.2 mmol) in DMF (1.75 ml). After stirring at room temperature for 90 minutes, the reaction mixture is re-cooled in an ice bath and is slowly quenched with 6N NaOH (4 mL). The reaction mixture is partitioned between EtOAc and H 2 O.
  • Step B 1-Ethyl-6-methoxy-1H-indole-3-carbaldehyde (600 mg, 2.95 mmol) is dissolved in acetone (85 mL). A solution of KMnO 4 (450 mg, 2.85 mmol) in H 2 O (28 mL) is added. This is stirred at room temperature for 5 hours. Another solution of KMnO 4 (450 mg, 2.85 mmol) in H 2 O (25 mL) is then added. After stirring for another hour at room temperature, the reaction is complete. The reaction mixture is quenched with 10% H 2 O 2 (1.5 mL), and is then filtered through celite. The filtrate is stripped down under vacuum to roughly 1/3 of the volume.
  • Step C 1-Ethyl-6-methoxy-1H-indole-3-carboxylic acid (250 mg, 1.14 mmol) is suspended in a solution of CH 2 Cl 2 (12.5 mL) and DMF (10 ⁇ L). Oxalyl chloride (230 ⁇ L, 2.64 mmol) is added, and the reaction mixture is stirred for 1 hour at room temperature. This mixture is then slowly poured into a rapidly stirring solution of concentrated NH 4 OH (5 mL). This is then partitioned in H 2 O and EtOAc. The residue from the ethyl acetate layer is triturated with acetone to yield 1-ethyl-6-methoxy-1H-indole-3-carboxamide (134 mg, 54%) as a white solid.
  • Step D 1-Ethyl-6-methoxy-1H-indole-3-carboxamide (120 mg, 0.55 mmol), Lawesson's reagent (240 mg, 0.6 mmol), and toluene (2 mL) are heated at 90° C. for 90 min. The reaction mixture is concentrated and purified by silica gel chromatography (EtOAc/CH 2 Cl 2 , 1/9) to yield 1-ethyl-6-methoxy-1H-indole-3-thiocarboxamide as a yellow solid (92 mg, 71%).
  • Step E 1-Ethyl-6-methoxy-1H-indole-3-thiocarboxamide (83 mg, 0.36 mmol), glyme (3.6 mL) and bromoacetaldehyde dimethyl acetal (220 ⁇ L, 1.86 mmol) are heated at 80° C. for 16 h. More bromoacetaldehyde dimethyl acetal (250 ⁇ L is added. This is heated at 80° C. for 2 h. Addition of 250 ⁇ L more bromoacetaldehyde dimethyl acetal is followed by heating for another 2 hours.
  • reaction mixture is cooled to room temperature, absorbed onto silica and purified by silica gel chromatography (hexanes/EtOAc, 7/3) to afford 1-ethyl-6-methoxy-3-thiazol-2-yl-1H-indole as a brown oil (44 mg, 47%).
  • Step A To a suspension of LiAlH 4 (7.6 g, 0.2 mol) in dioxane (100 mL) is added dropwise a solution of methyl 6-methoxy-1H-indole-2-carboxylate (8.2 g, 0.04 mol) in dioxane (50 mL) at 0° C. After the addition, the mixture is stirred at room temperature for 1 h and then heated at reflux for 5 h. After cooling to 0° C., the reaction is quenched by water (dropwise) and then 15% aqueous NaOH. After stirring at room temperature for 1 h, the mixture is filtered through Celite. The solid is washed with a large amount of EtOAc.

Abstract

The present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions for treating infection by a virus, or for affecting viral IRES activity.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application is a divisional application of U.S. application Ser. No. 11/653,448, filed Jan. 16, 2007, which claims the benefit of priority under 35 U.S.C. 119(e) of U.S. Provisional Application No. 60/758,527, filed Jan. 13, 2006 and U.S. Provisional Application No. 60/921,482, filed Jan. 13, 2007 (converted on May 4, 2007 from U.S. application Ser. No. 11/653,436); and is a continuation-in-part of U.S. application Ser. No. 11/331,180, filed Jan. 13, 2006, which is a continuation-in-part of U.S. application Ser. No. 11/180,961, filed Jul. 14, 2005, (having corresponding International Application No. PCT/US2005/024881, filed Jul. 14, 2005) which claims the benefit of each of U.S. Provisional Application No. 60/587,487, filed Jul. 14, 2004, U.S. Provisional Application No. 60/634,979, filed Dec. 13, 2004, U.S. Provisional Application No. 60/645,586, filed Jan. 24, 2005, U.S. Provisional Application No. 60/665,349, filed Mar. 28, 2005, and U.S. Provisional Application No. 60/675,440, filed Apr. 28, 2005; the entire contents of which applications are incorporated herein by reference.
    • GOVERNMENT SUPPORT
  • The present invention was made with U.S. Government support under DHHS Grant No. 5R44AI054029-03. The U.S. Government has certain rights in the invention.
    • FIELD OF THE INVENTION
  • The present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions for treating infection by a virus, or for affecting viral IRES activity.
    • BACKGROUND OF THE INVENTION
  • An estimated 170 million people worldwide are reported to be infected with hepatitis C virus (HCV), the causative agent of hepatitis C. Seventy to eighty percent of HCV infections lead to chronic liver infection, which in turn may result in severe liver disease, including liver fibrosis, cirrhosis, and hepatocellular carcinoma (115).
  • HCV constitutes the Hepacivirus genus of the family Flaviviridae (106), and contains a positive-stranded 9.6 kb RNA genome. The features of the HCV genome include a 5′-untranslated region (UTR) that encodes an internal ribosome entry site (IRES) that directs the translation of a single long open reading frame (ORF) encoding a polyprotein of 3,010 amino acids. The HCV ORF is followed by a 3′-UTR of variable length, depending on the HCV variant, that encodes the sequences required for the initiation of antigenomic strand synthesis (79).
  • The HCV IRES and 3′-UTR both encode regions of RNA structures that are required for genome translation and replication. The HCV polyprotein is posttranslationally processed into at least 10 mature viral proteins, including the structural proteins core (putative nucleocapsid), E1 and E2 and the nonstructural (NS) proteins NS2 to NS5B.
  • Three distinct elements have been shown to be involved in HCV IRES-mediated translation: (1) integrity of the global structure of HCV IRES, (2) the 3′-terminal region of the HCV genome; and (3) trans-acting cellular factors that interact with the HCV IRES element and assist in translation initiation (35).
  • The initiation of protein synthesis in eukaryotic cells predominantly follows the 5′ cap-dependent, first AUG rule (61). However, an increasing number of viral (6, 12, 28, 31a, 50, 95, 97, 98, 105, 128) and cellular mRNAs (18, 39, 45, 78, 91, 130) have been shown to use an IRES element to direct translation initiation. In 1992, an IRES element was reported in the 5′ UTR of the HCV RNA genome (129), indicating that synthesis of the viral protein is initiated in a cap-independent fashion.
  • A bicistronic expression system can be used to define and evaluate the function of IRES elements. This test system harbors two different reporter genes in which the 5′-proximal reporter gene is expressed by a cap dependent translation mechanism while the second reporter is expressed only if an upstream sequence inserted in the intergenic space contains an IRES sequence element. Using this system, a putative IRES in the HCV 5′ UTR was unambiguously demonstrated to function as an IRES involved in translational control of viral proteins (133). In vitro translation, RNA transfection, and mutagenesis studies provided further evidence that the HCV 5′ UTR contains an IRES element (23, 41, 42, 108, 129, 132, 133, 134). Both in vitro and cell-based studies demonstrated that the HCV IRES guides cellular translation initiation factors to an internal site of the viral RNA (56, 58, 120), thus functionally demonstrating the HCV IRES activity. Taken together, these results demonstrate that the HCV 5′-UTR contains an IRES element that plays an active and crucial role in the mechanism of internal initiation for HCV protein translation.
  • The IRES is one of the most conserved regions of the HCV genome, reflecting its essential nature for viral replication and protein synthesis (13, 118, 122). Although both 5′ and 3′ sequences of the IRES appear to play a role in the control of initiation of translation (42, 109, 110, 113, 136), the minimal sequence requirement for HCV IRES function has been mapped to a region between nucleotides 44-354 (40).
  • Biochemical probing and computer modeling indicate that the HCV IRES and its 5′ sequence is folded into a distinct structure that consists of four major domains and a pseudoknot (11, 42, 122). Domain I contains a small stem-loop structure that does not appear to be a functional part of the IRES element while domains II, III, and IV contain the HCV IRES activity (43, 111). The relationships between secondary and tertiary structures of the HCV IRES and their function have recently been established (5, 55, 56, 99, 124). Both domains II and III consist of multiple stems, loops, and bulges and are important for IRES activity (23, 40, 51, 52, 54, 56, 64, 74, 75, 93, 107, 108, 110, 124, 127, 131, 139, 141, 142). Domain II can induce conformational changes on the ribosome that have been implicated in the decoding process (124). Domain III has the highest degree of structural conservation among the different HCV strains. It comprises the core of the flavivirus IRES and has 6 subdomains (40). Various studies have shown that subdomain IIId forms complex secondary/tertiary structures and is critical for initiation activity (55, 56, 57, 124, 129). Domain IV has one stem-loop that spans the initiation codon and is specific for the HCV IRES (41, 122), but the precise role of domain IV in IRES activity remains controversial (41, 112).
  • The role of the HCV IRES is to position the translational machinery near an internal initiator codon in the viral mRNA. The translation initiation mechanism of the HCV and other viral IRES differs significantly from that of 5′-cap-dependent translation initiation (7, 21, 31, 35, 61, 71, 72, 81, 88, 96, 114, 123). Most cellular capped mRNAs utilize a number of initiation factors (eIFs) that are required for the translation initiation process. The initial steps of the process require proteins that interact with the 5′ cap structure and recruit the 40S ribosomal subunit to the cap-proximal region of mRNA. This complex then scans 3′ of the cap, until reaching an AUG codon at which translation will initiate (21, 114). However, in the case of HCV, the IRES functionally replaces the 5′ cap structure, allowing the 40S ribosomal subunit and eIF3 to bind directly to the RNA. Subdomain IIId of the HCV IRES harbors the binding site for the 40S ribosomal subunit and the only initiation factors required for translation initiation are eIF2, eIF3, and eIF4E (15, 58, 94, 100, 120, 124).
  • The polypyrimidine track-binding protein (PTB) and La autoantigen are noncanonical translation initiation factors that bind to and enhance HCV IRES activity (1, 2, 3, 4, 5, 30, 48, 49, 53). PTB, a 57-kDa protein involved in RNA splicing, is also necessary for efficient IRES-mediated translation initiation of picornavirus mRNA, and some cellular mRNAs (10, 11, 36, 53, 59, 89, 92). The La autoantigen, a 52 kDa double-stranded RNA unwinding protein, also increases the activity of poliovirus and cellular IRES (38, 85, 86). Other cellular factors involved in HCV IRES-mediated translation initiation include proteasome α-subunit PSMA7 (62), ribosomal protein S5 (26), ribosomal protein S9 (24, 25, 100), and hnRNPL (33). However, the role of these RNA-binding proteins in HCV IRES-mediated initiation of translation is unclear. Recently, it was reported that the activity of interferon (IFN) α against HCV replication might target HCV IRES-mediated translation initiation by causing a reduction of La protein levels (117) Some HCV proteins, such as NS5A, core and NS4A/4B, also reported to be involved in the HCV IRES function (143-146). Thus, an inhibitor that blocks interaction between the IRES and the noncanonical factors might efficiently inhibit HCV replication and lack cytotoxicity.
  • Currently, only IFN α and the nucleoside analogue ribavirin, in combination, are marketed for the treatment of HCV infection. However, these two agents are immunomodulators and have limited efficacy, relatively high toxicity, and high cost (80, 83, 84, 138). Although the treatment outcome is variable among the six major HCV genotypes, only about one-half of all treated patients respond to therapy, suggesting that the virus encodes protein products that may directly or indirectly attenuate the antiviral action of IFN. IFNs are naturally produced in response to virus infection, and cellular exposure to IFN leads to the induced expression of a variety of IFN-stimulated genes (ISGs), many of which have an antiviral function. ISG action can limit virus replication at multiple points within the replicative cycle.
  • There remains a need for a more effective means of treating patients afflicted with HCV. Specifically, a need exists for novel antiviral drugs that have no cross-resistance with existing treatment modalities, and which demonstrate synergy with other anti-HCV agents.
  • All documents referred to herein are incorporated by reference into the present application as though fully set forth herein.
    • SUMMARY OF THE INVENTION
  • The present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions for treating infection by a virus, or for affecting viral IRES activity.
    • DETAILED DESCRIPTION OF THE INVENTION A. Compounds of the Invention
  • In another embodiment, the present invention includes a compound of Formula (I)
  • Figure US20100305100A1-20101202-C00001
  • wherein:
    • X is:
      • hydrogen;
      • a cyano group;
      • a nitro group;
      • a formyl group;
      • a —COOH group;
      • a CORx group, wherein Rx is a C1 to C6 alkyl;
  • Figure US20100305100A1-20101202-C00002
      • a halo;
      • an alkyl optionally substituted with one or more halo;
      • an alkyne optionally substituted with a C1 to C6 alkyl optionally substituted with one or more independently selected halo or cyano groups;
      • an oxime;
      • SO2Rx;
      • SO2NH2;
      • SO2NH(Rx);
      • SO2N(Rx)2;
      • an amino optionally substituted with one or more C1 to C6 alkyl groups or C1 to C6 alkylcarbonyl groups;
      • an amide group optionally substituted with one or more independently selected C1 to C6 alkyl group;
      • a 5 or 6 membered heterocycle;
      • a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyl groups optionally substituted with one or more halos;
      • a C6 to C8 aryl group optionally substituted with one or more of the following:
        • C1 to C6 alkyl optionally substituted with one or more halos,
        • halo, or
        • cyano;
    Y is:
      • a hydrogen;
      • a haloalkyl;
      • a halo;
      • a benzofuran;
      • a benzothiophene;
      • a dibenzofuran;
      • a dibenzothiophene;
      • a benzothiazole optionally substituted with an amino group optionally substituted with one or more C1 to C6 alkyls;
      • a naphthalene;
      • an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl or an —SO2Rx group;
  • Figure US20100305100A1-20101202-C00003
      •  where Rb is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;
  • Figure US20100305100A1-20101202-C00004
      •  where Rc is a hydrogen, a —CONHRx, where Rx is a C1 to C6 alkyl, or an —SO2Rx, where Rx is a C1 to C6 alkyl; or
  • Figure US20100305100A1-20101202-C00005
      •  where Rd is a C1 to C6 alkyl or a C6 to C8 aryl;
      • a —NHCORe group, where Re is:
        • a C1 to C6 alkyl;
        • a C6 to C8 aryl optionally substituted with:
          • a C1 to C6 alkyl,
          • an alkoxy,
          • a cyano group,
          • a nitro group, or
          • a halo;
      • a —NHCOORx group, where Rx is a C1 to C6 alkyl;
      • a —NRgRh group, where Rg is a C1 to C6 alkyl or a hydrogen and Rh is a hydrogen, C1 to C6 alkyl, or C6 to C8 aryl, the C1 to C6 alkyl or C6 to C8 aryl optionally substituted with an alkoxy;
      • a C1 to C6 alkyl;
      • a 5 or 6 membered heteroaryl, optionally substituted with one or more of the following:
        • a C1 to C6 alkyl, optionally substituted with one or more halos or a C6 to C8 aryl,
        • a C6 to C8 aryl, optionally substituted with —COORx, where Rx is a C1 to C6 alkyl,
        • an amino group, or
        • a substituent from Group A;
      • a 5 or 6 membered heterocycle optionally substituted with:
        • a —COORx group, where Rx is as defined above, or
        • a —NHCOORx group, where Rx is as defined above;
      • a C6 to C8 aryl, optionally substituted with one or more of the following:
        • an alkoxy, optionally substituted with:
          • an alkoxy,
          • a hydroxy,
          • one or more halos,
          • a 5 or 6 membered heterocycle, optionally substituted with:
            • a C1 to C6 alkyl, or
            • a hydroxy,
          • a C6 to C8 aryl, optionally substituted with one or more substituents independently selected from Group A,
          • a 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from Group A,
          • an amino optionally substituted with one or more C1 to C6 alkyls,
          • a —NRiSO2Rx group, where Rx is a C1 to C6 alkyl and Ri is:
            • a hydrogen,
            • a C1 to C6 alkyl,
            • a —CORx group, where Rx is as defined above,
            • a haloalkyl, or
            • a haloalkoxy,
          • a —NRjCORk group, where Rk is:
            • a C1 to C6 alkyl,
            • a hydrogen, or
            • an amino optionally substituted with one or more C1 to C6 alkyls, and Rj is:
            • a hydrogen,
            • a C1 to C6 alkyl,
            • a —CORx group, where Rx is a C1 to C6 alkyl,
            • a haloalkyl, or
            • a haloalkoxy,
          • a —N═N+═N− group, or
          • a —CORl, where Rl is a 5 or 6 membered heterocycle optionally substituted with a hydroxy,
        • an amino,
        • a C1 to C6 alkyl group, optionally substituted with:
          • a —NHSO2Rx group, where Rx is as defined above, or
          • a —NRxSO2Rx group, where Rx is as defined above,
        • a haloalkoxy,
        • a halo,
        • a hydroxy,
        • OC(O)NHRx,
        • OC(O)N(Rx)2,
        • OC(O)NH(ORx),
        • OC(O)NRx(ORx),
        • OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group,
        • a —COORx group, where Rx is a C1 to C6 alkyl,
        • a —CORm group, where Rm is:
          • an amino optionally substituted with one or more C1 to C6 alkyls, where the C1 to C6 alkyls are optionally substituted with:
            • a hydroxy
            • a 5 or 6 membered heterocycle,
            • an amino optionally substituted with one or more C1 to C6 alkyls,
            • an alkoxy,
          • a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino,
          • a —NHRn group, where Rn is:
            • a —CH2CONH2, or
            • a C6 to C8 aryl optionally substituted with:
            •  an alkyl,
            •  one or more halos,
            • a nitro group, or
            •  one or more alkoxys,
        • a —NRoCORp group, where Rp is:
          • a C1 to C6 alkyl optionally substituted with:
          • a halo,
          • an alkoxy, or
          • a C6 to C8 aryl,
        • a 5 or 6 membered heterocycle, optionally substituted with one or more C1 to C6 alkyl or C6 to C8 aryl groups,
        • a C6 to C8 aryl, optionally substituted with a halo,
        • a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls,
        • a hydrogen,
  • Figure US20100305100A1-20101202-C00006
        • and where Ro is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is a C1 to C6 alkyl,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —NRqCONRqRr group, where Rq is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a haloalkoxy, or
          • a —CORx group, where Rx is as defined above,
        • and where Rr is:
          • a C6 to C8 aryl optionally substituted with:
  • Figure US20100305100A1-20101202-C00007
            • halo,
            • a C1 to C6 alkyl optionally and independently substituted with one or more C6 to C8 aryl, halo and/or C1 to C6 alkoxy groups,
            • a C1 to C6 alkoxy,
            • a C1 to C6 haloalkoxy,
            • a —ORs group, where Rs is a C6 to C8 aryl, or
            • a —COORx group, where Rx is as defined above,
          • a C1 to C6 alkyl optionally substituted with one or more of the following:
            • a halo,
            • a hydroxyl,
            • an alkoxy,
            • an alkylene,
            • a 5 or 6 membered heterocycle optionally substituted with one or more halo, C1 to C6 alkyl, C1 to C6 haloalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy,
            • a 5 or 6 membered heteroaryl optionally substituted with one or more halo, C1 to C6 alkyl, C1 to C6 haloalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy,
            • a C6 to C8 aryl optionally substituted with one or more halo, C1 to C6 alkyl, C1 to C6 haloalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, or
            • a —COORx group, where Rx is as defined above,
          • a C2 to C6 alkylene group,
          • a C1 to C6 alkoxy group,
          • a 5 or 6 membered heterocycle group optionally substituted with one or more halo, C1 to C6 alkyl, C1 to C6 haloalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy,
          • a —COORx group, where Rx is as defined above,
        • a —NRtCOORu group, where Ru, is:
          • a C1 to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
            • a C6 to C8 aryl optionally substituted with one or more halo, C1 to C6 alkyl, C1 to C6 haloalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy,
            • an alkylene,
            • an alkoxy,
            • an alkyne,
            • an alkoxy group optionally substituted with one or more alkoxy groups,
            • an amino optionally substituted with one or more C1 to C6 alkyl,
            • halo, or
            • a 5 or 6 membered heterocycle,
            • a 5 or 6 membered heteroaryl,
          • a C2 to C6 alkylene,
          • a C6 to C8 aryl, optionally substituted with:
            • an alkoxy,
            • a halo, or
            • a C1 to C6 alkyl, or
          • a 5 or 6 membered heterocycle,
        • and Rt is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is as defined above,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —NRvSO2Rw, group, where Rv is:
          • a hydrogen,
          • a —CORx, where Rx is as defined above, or
          • a C1 to C6 alkyl, optionally substituted with:
            • a halo,
            • a —CORx group, where Rx is as defined above,
            • a —OCORx group, where Rx is as defined above,
            • a hydroxyl, or
            • an alkoxy,
        • and where Rw is:
          • a C1 to C6 alkyl optionally substituted with:
            • a halo,
            • a haloalkyl,
            • a C6 to C8 aryl, or
            • a 5 or 6 membered heterocycle,
          • a C2 to C6 alkylene,
          • an alkyl- or dialkyl-amino optionally substituted with a halo,
          • a 5 or 6 membered heterocycle, or
          • a 5 or 6 membered heteroaryl optionally substituted with one or more of the following:
            • halo,
            • a C1 to C6 alkyl,
            • —C1 to C6 haloalkyl,
            • —C1 to C6 alkoxy,
            • C1 to C6 haloalkoxy,
            • a 5 or 6 membered heterocycle, or
  • Figure US20100305100A1-20101202-C00008
        •  where Ry is a hydrogen, C1 to C6 alkyl optionally substituted with a C1 to C6 alkoxy, C1 to C6 haloalkyl, C6 to C8 aryl, 5 or 6 membered heteroaryl, or 5 or 6 membered heterocycle, where the C6 to C8 aryl, 5 or 6 membered heteroaryl, and 5 or 6 membered heterocycle are each optionally and independently substituted with one or more halo, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl, C1 to C6 haloalkoxy,
  • Figure US20100305100A1-20101202-C00009
        •  where Ry is as described above,
  • Figure US20100305100A1-20101202-C00010
        •  where Ry is as described above and Rz is hydrogen or a C1 to C6 alkyl optionally substituted with a C6 to C8 aryl,
  • Figure US20100305100A1-20101202-C00011
        • where Ry is as described above,
        • a —SRx group, where Rx is as defined above,
        • a —SO2Raa group, where Raa is:
          • a C1 to C6 alkyl,
          • an amino group,
          • an alkyl- or dialkyl-amino group optionally substituted with a hydroxy, a 5 or 6 membered heterocycle, a 5 or 6 membered heteroaryl, or a —COORx group, where Rx is as defined above,
          • a 5 or 6 membered heteroaryl,
          • a 5 or 6 heterocycle optionally substituted with hydroxy, a C1 to C6 alkoxy, or a a C1 to C6 alkyl, where the alkyl is optionally substituted with one or more hydroxy,
        • a C6 to C8 aryl, or
        • a —NHRbb group, where Rbb is:
  • Figure US20100305100A1-20101202-C00012
          • a —C(═S)NH2 group, or
          • a —PO(ORx)2, where Rx is as defined above;
  • Figure US20100305100A1-20101202-C00013
      •  where Rcc is:
        • a naphthalene,
        • a 5 or 6 membered heteroaryl,
  • Figure US20100305100A1-20101202-C00014
        • a C6 to C8 aryl, optionally substituted with one or more of the following:
          • an alkoxy,
          • an hydroxy,
          • a halo,
          • a C1 to C6 alkyl, optionally substituted with a cyano group,
          • an amino optionally substituted with one or more C1 to C6 alkyls,
          • a —NHPORxRx, where Rx is as defined above,
          • a —NReeCONRffRff group, where Ree is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halo, and Rif is:
            • a hydrogen,
            • a haloalkyl,
            • a haloalkoxy,
            • a C1 to C6 alkyl, or
            • a —CORx, where Rx is as defined above,
          • a —NRggCORhh group, where Rhh is:
            • a hydrogen,
            • a C1 to C6 alkyl optionally substituted with:
            •  an alkoxy,
            •  a halo, or
            •  an amino optionally substituted with one or more C1 to C6 alkyls,
            • an amino optionally substituted with one or more C1 to C6 alkyls, where the alkyls are optionally substituted with a halo,
            • a 5 or 6 membered heterocycle,
            • a 5 or 6 membered heteroaryl,
          • and Rgg is:
            • a hydrogen,
            • a C1 to C6 alkyl,
            • a haloalkyl,
            • a haloalkoxy, or
            • a —CORx group, where Rx is as defined above,
          • a haloalkyl,
          • 5 or 6 membered heterocycle groups,
          • an amino optionally substituted with one or more C1 to C6 alkyls,
          • a —NRiiSO2Rx group, where Rx is as defined above, and Rii is:
            • a hydrogen,
            • a C1 to C6 alkyl,
            • a haloalkyl,
            • a haloalkoxy,
            • a —CORx group, where Rx is as defined above;
    Z is:
      • a hydrogen;
      • a C1 to C6 alkyl optionally substituted with:
        • an alkoxy,
        • one or more halos,
        • a 5 or 6 membered heterocycle, or
        • a C6 to C8 aryl;
      • a 5 or 6 membered heterocycle;
      • a C2 to C6 alkylene;
      • a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyls;
      • a —COORx group, where Rx is as defined above; or
  • Figure US20100305100A1-20101202-C00015
  • R is a hydrogen, a halo or an alkoxy;
    • R1 is:
      • a hydrogen;
      • a hydroxy;
      • a halo;
      • a haloalkyl;
      • a nitro group;
      • a 5 or 6 membered heteroaryl;
      • a 5 or 6 membered heterocycle;
      • an alkoxy optionally substituted with:
        • one or more halos,
        • a C6 to C8 aryl optionally substituted with one or more halo, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl, C1 to C6 haloalkoxy, C1 to C6 hydroxy, and/or SO2Rx groups,
        • a 5 or 6 membered heterocycle optionally substituted with one or more halo, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl, C1 to C6 haloalkoxy, C1 to C6 hydroxy, and/or SO2Rx groups,
        • a 5 or 6 membered heteroaryl optionally substituted with one or more halo, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl, C1 to C6 haloalkoxy, C1 to C6 hydroxy, and/or SO2Rx groups,
        • an amino optionally substituted with a heterocycle;
      • a C6 to C8 aryl optionally substituted with an alkoxy;
      • a —CORx group, where Rx is as defined above;
      • a C1 to C6 alkyl optionally substituted with one or more dialkyl-amino, a C6 to C8 aryl, a 5 or 6 membered heteroaryl, and/or a 5 or 6 membered heterocycle, where each of the C6 to C8 aryl, 5 or 6 membered heteroaryl, and 5 or 6 membered heterocycle is optionally substituted with one or more halo, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl, C1 to C6 haloalkoxy, C1 to C6 hydroxy, and/or SO2Rx groups; or
        R1 joins together with R2 to form:
  • Figure US20100305100A1-20101202-C00016
    • R2 is:
      • a nitro group;
      • a hydrogen;
      • a halo;
      • a hydroxy group;
      • a C1 to C6 alkyl group, optionally substituted with one or more of the following:
        • halos,
        • 5 or 6 membered heterocycle group, optionally substituted with one or more halo, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl, C1 to C6 haloalkoxy, C1 to C6 hydroxy, and/or SO2Rx groups,
        • 5 or 6 membered heteroaryl group, is optionally substituted with one or more halo, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl, C1 to C6 haloalkoxy, C1 to C6 hydroxy, and/or SO2Rx groups,
        • C6 to C8 aryl group, is optionally substituted with one or more halo, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl, C1 to C6 haloalkoxy, C1 to C6 hydroxy, and/or SO2Rx groups,
        • amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups,
      • an amino group optionally substituted with one or more C1 to C6 alkyl groups;
      • an alkoxy group optionally substituted with one or more groups independently selected from the following:
        • halos,
        • hydroxy group,
        • an alkoxy group optionally substituted with an alkoxy group,
        • an —OCORx group, where Rx is as defined above,
        • an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
          • a 5 or 6 membered heterocycle, or
          • an amino optionally substituted with one or more alkyl groups;
        • a dialkyl-amino optionally substituted with an alkoxy,
        • a 4 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C1 to C6 alkyl group, the C1 to C6 alkyl group optionally substituted with one or more independently selected C1 to C6 alkoxy group,
        • a 5 or 6 membered heteroaryl group optionally substituted with one or more independently selected halo, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl, C1 to C6 haloalkoxy, C1 to C6 hydroxy, and/or SO2Rx groups, or
        • a C6 to C8 aryl group optionally substituted with one or more independently selected halo, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl, C1 to C6 haloalkoxy, C1 to C6 hydroxy, and/or SO2Rx groups;
      • a —C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
      • a —COOH group;
      • a —COORx group, where Rx is as defined above;
      • a haloalkyl;
      • a —C(O)NH2 optionally substituted with one or more of the following:
        • —C1 to C6 alkyl groups optionally substituted with one or more independently selected halo, C1 to C6 alkoxy, C1 to C6 hydroxy, a 5 or 6 membered heterocycle and/or a 5 or 6 membered heteroaryl,
        • hydroxy groups, or
        • C6 to C8 aryl groups;
      • a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
        • C1 to C6 alkyl,
        • SO2Rx,
        • C(O)—C6 to C8 aryl,
        • C(O)ORx; or
        • hydroxy,
      • a 5 or 6 membered heteroaryl optionally substituted with one or more independently selected halo, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl, C1 to C6 haloalkoxy, C1 to C6 hydroxy, and/or SO2Rx groups;
      • a —OCORx group, where Rx is as defined above;
      • a —NHCORjj group, where Rjj is:
        • an alkyl,
        • a C6 to C8 aryl,
        • an alkoxy, or
        • an amino optionally substituted with one or more C1 to C6 alkyls;
      • an —ORkk group, where Rkk is
        • a C6 to C8 aryl optionally substituted with one or more independently selected halo, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl, C1 to C6 haloalkoxy, C1 to C6 hydroxy, and/or SO2Rx groups,
        • a 5 to 6 membered heteroaryl, optionally substituted with a halo, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl, C1 to C6 haloalkoxy, C1 to C6 hydroxy, and/or SO2Rx groups,
        • a 5 to 6 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or
        • an Si(Rx)3;
      • a —NHSO2Rx group, where Rx is as defined above; or
        R2 joins together with R1 to form:
  • Figure US20100305100A1-20101202-C00017
    • R3 is:
      • a hydrogen; or
      • CH2OCORx, and Rx is as defined above;
    Group A is
      • a halo,
      • C1 to C6 alkyl,
      • C1 to C6 alkoxy,
      • C1 to C6 haloalkyl,
      • C1 to C6 haloalkoxy,
      • a —NRoCORp group, where Rp is:
        • a C1 to C6 alkyl optionally substituted with:
          • a halo,
          • an alkoxy, or
          • a C6 to C8 aryl,
        • a 5 or 6 membered heterocycle, optionally substituted with one or more C1 to C6 alkyl or C6 to C8 aryl groups,
        • a C6 to C8 aryl, optionally substituted with a halo,
        • a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls,
        • a hydrogen,
  • Figure US20100305100A1-20101202-C00018
        • and where Ro is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is a C1 to C6 alkyl,
          • a haloalkyl, or
          • a haloalkoxy,
      • a —NRqCONRqRr group, where Rq is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a haloalkyl,
        • a haloalkoxy, or
        • a —CORx group, where Rx is as defined above,
        • and where Rr is:
          • a C6 to C8 aryl optionally substituted with:
  • Figure US20100305100A1-20101202-C00019
            • halo,
            • a C1 to C6 alkyl optionally and independently substituted with one or more C6 to C8 aryl, halo and/or C1 to C6 alkoxy groups,
            • a C1 to C6 alkoxy,
            • a C1 to C6 haloalkoxy,
            • a —ORs group, where Rs is a C6 to C8 aryl, or
            • a —COORx group, where Rx is as defined above,
          • a C1 to C6 alkyl optionally substituted with one or more of the following:
            • a halo,
            • a hydroxyl,
            • an alkoxy,
            • an alkylene,
            • a 5 or 6 membered heterocycle optionally substituted with one or more halo, C1 to C6 alkyl, C1 to C6 haloalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy,
            • a 5 or 6 membered heteroaryl optionally substituted with one or more halo, C1 to C6 alkyl, C1 to C6 haloalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy,
            • a C6 to C8 aryl optionally substituted with one or more halo, C1 to C6 alkyl, C1 to C6 haloalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, or
            • a —COORx group, where Rx is as defined above,
          • a C2 to C6 alkylene group,
          • a C1 to C6 alkoxy group,
          • a 5 or 6 membered heterocycle group optionally substituted with one or more halo, C1 to C6 alkyl, C1 to C6 haloalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy,
          • a —COORx group, where Rx is as defined above,
      • a —NRtCOORu group, where Ru is:
        • a C1 to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
          • a C6 to C8 aryl optionally substituted with one or more halo, C1 to C6 alkyl, C1 to C6 haloalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy,
          • an alkylene,
          • an alkoxy,
          • an alkyne,
          • an alkoxy group optionally substituted with one or more alkoxy groups,
          • an amino optionally substituted with one or more C1 to C6 alkyl,
          • halo, or
          • a 5 or 6 membered heterocycle,
          • a 5 or 6 membered heteroaryl,
        • a C2 to C6 alkylene,
        • a C6 to C8 aryl, optionally substituted with:
          • an alkoxy,
          • a halo, or
          • a C1 to C6 alkyl, or
        • a 5 or 6 membered heterocycle,
        • and Rt is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is as defined above,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —NRvSO2Rw, group, where Rv is:
          • a hydrogen,
          • a —CORx, where Rx is as defined above, or
          • a C1 to C6 alkyl, optionally substituted with:
            • a halo,
            • a —CORx group, where Rx is as defined above,
            • a —OCORx group, where Rx is as defined above,
            • a hydroxyl, or
            • an alkoxy,
        • and where R1 is:
          • a C1 to C6 alkyl optionally substituted with:
            • a halo,
            • a haloalkyl,
            • a C6 to C8 aryl, or
            • a 5 or 6 membered heterocycle,
          • a C2 to C6 alkylene,
          • an alkyl- or dialkyl-amino optionally substituted with a halo,
          • a 5 or 6 membered heterocycle, or
          • a 5 or 6 membered heteroaryl optionally substituted with one or more of the following:
            • halo,
            • a C1 to C6 alkyl,
            • C1 to C6 haloalkyl,
            • C1 to C6 alkoxy,
            • C1 to C6 haloalkoxy,
            • a 5 or 6 membered heterocycle, or
  • Figure US20100305100A1-20101202-C00020
      • a —SO2Raa group, where Raa is:
        • a C1 to C6 alkyl,
        • an amino group,
        • an alkyl- or dialkyl-amino group optionally substituted with a hydroxy, a 5 or 6 membered heterocycle, a 5 or 6 membered heteroaryl, or a —COORx group, where Rx is as defined above,
        • a 5 or 6 membered heteroaryl,
        • a 5 or 6 heterocycle optionally substituted with hydroxy, a C1 to C6 alkoxy, or a a C1 to C6 alkyl, where the alkyl is optionally substituted with one or more hydroxy,
      • a —NHRbb group, where Rbb is:
        • a —C(═S)NH2 group, or
        • a —PO(ORx)2, where Rx is as defined above;
      • a —CORm group, where Rm is:
        • an amino optionally substituted with one or more C1 to C6 alkyls, where the C1 to C6 alkyls are optionally substituted with:
          • a hydroxy,
          • a 5 or 6 membered heterocycle,
          • an amino optionally substituted with one or more C1 to C6 alkyls,
          • an alkoxy,
        • a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino,
        • a —NHRn group, where Rn is:
          • a —CH2CONH2, or
          • a C6 to C8 aryl optionally substituted with:
            • an alkyl,
            • one or more halos,
            • a nitro group, or
            • one or more alkoxys;
              and
              L is a direct bond, C1 to C12 alkylene, C2 to C12 alkenylene or C2 to C12 alkynylene, wherein one or more —CH2— group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with —O—, —S—, —SO2— and/or —NRmm—, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s), halos, and/or hydroxy(s), where Rmm is hydrogen or C1 to C6 alkyl;
              or a pharmaceutical salt thereof.
  • In a further embodiment, the present invention includes compounds of Formula I, with the proviso that at least one of Y, Z, R1 and R2 is selected from the following:
    • Y is:
      • a benzothiazole substituted with an amino group optionally substituted with one or more C1 to C6 alkyls;
      • an indole substituted on the nitrogen with an —SO2Rx group;
      • a C6 to C8 aryl substituted with one or more of the following:
        • an amino optionally substituted with one or more of the following:
          • SO2Rx, or
          • C1 to C6 alkyl substituted with one or more 5 or 6 membered heteroaryl group,
        • OC(O)NHRx,
        • OC(O)N(Rx)2,
        • OC(O)NH(ORx),
        • OC(O)NRx(ORx),
        • OC(O)N(ORx)2,
        • OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group,
        • a —NRoCORp group, where Rp is:
          • an amino group optionally substituted with one or more C1 to C6 alkyl groups where the C1 to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups, or
          • a 5 or 6 membered heterocycle, substituted with one or more C1 to C6 alkyl or C6 to C8 aryl groups,
        • a —NRqCONRqRr group, where Rr is:
          • a C1 to C6 alkyl substituted with one or more of the following:
            • a hydroxyl,
            • an alkoxy,
            • a 5 or 6 membered heterocycle,
            • a 5 or 6 membered heteroaryl, or
            • a C6 to C8 aryl substituted with a halo,
          • a C2 to C6 alkylene group,
          • a C1 to C6 alkoxy group, or
          • a 5 or 6 membered heterocycle group,
        • a —NRtCOORu group, where Ru is:
          • a C1 to C12 alkyl, substituted with one or more of the following:
            • an alkoxy group substituted with one or more alkoxy groups,
            • an amino optionally substituted with one or more C1 to C6 alkyl, or
            • a 5 or 6 membered heteroaryl,
          • a C2 to C6 alkylene, or
  • Figure US20100305100A1-20101202-C00021
    • Z is:
      • a C1 to C6 alkyl substituted with a 5 or 6 membered heterocycle, or
      • a 5 or 6 membered heterocycle; or
        R1 is an alkoxy substituted with an amino, where the amino is optionally substituted with a heterocycle;
    R2 is:
      • a C1 to C6 alkyl group, substituted with one or more of the following:
        • 5 or 6 membered heterocycle groups, or
        • amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups,
      • an alkoxy group substituted with one or more groups independently selected from the following:
        • a hydroxy group,
        • an alkoxy group optionally substituted with an alkoxy group,
        • an amino group substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
          • a 5 or 6 membered heterocycle, or
          • an amino optionally substituted with one or more alkyl groups;
        • a 7 membered heterocycle group;
        • a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected C1 to C6 alkyl groups substituted with C1 to C6 alkoxy, or
        • a 5 or 6 membered heteroaryl group substituted with one or more C1 to C6 alkyl groups;
      • a —C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
      • a —COOH group;
      • an amide group substituted with one or more C1 to C6 alkyl groups;
      • a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
        • C1 to C6 alkyl,
        • SO2Rx,
        • C(O)—C6 to C8 aryl, or
        • C(O)ORx groups;
      • an —ORkk group, where Rkk is:
        • a 5 to 6 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or
        • an —Si(Rx)3;
          or a pharmaceutically acceptable salt thereof.
  • In another embodiment, a compound of Formula I is included, with the proviso that at least one of X, Y, Z, R1, and R2 is selected from the following:
    • X is:
      • a —COOH group;
  • Figure US20100305100A1-20101202-C00022
      • a halo;
      • an alkyl optionally substituted with one or more halo;
      • an alkyne optionally substituted with a C1 to C6 alkyl optionally substituted with one or more halo or cyano groups;
      • an oxime;
      • SO2Rx;
      • SO2NH2;
      • SO2NH(Rx);
      • SO2N(Rx)2;
      • an amino optionally substituted with one or more C1 to C6 alkyl groups or C(O)—C1 to C6 alkyl groups;
      • an amide group optionally substituted with one or more independently selected C1 to C6 alkyl group;
      • a 5 or 6 membered heterocycle;
      • a 5 or 6 membered heteroaryl substituted with one or more C1 to C6 alkyl groups substituted with one or more halos; or
      • a C6 to C8 aryl group substituted with one or more of the following:
        • C1 to C6 alkyl optionally substituted with one or more halos,
        • halo, or
        • cyano;
    Y is:
      • a benzothiazole substituted with an amino group optionally substituted with one or more C1 to C6 alkyls;
      • an indole substituted on the nitrogen with an SO2Rx group;
      • a C6 to C8 aryl substituted with one or more of the following:
        • an amino optionally substituted with one or more of the following:
          • SO2Rx, or
          • C1 to C6 alkyl substituted with one or more 5 or 6 membered heteroaryl group,
        • OC(O)NHRx,
        • OC(O)N(Rx)2,
        • OC(O)NH(ORx),
        • OC(O)NRx(ORx),
        • OC(O)N(ORx)2,
        • OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group,
        • a —NRoCORp group, where Rp is:
          • an amino group optionally substituted with one or more C1 to C6 alkyl groups where the C1 to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups, or
          • a 5 or 6 membered heterocycle, substituted with one or more C1 to C6 alkyl or C6 to C8 aryl groups,
        • a —NRqCONRqRr group, where Rr is:
          • a C1 to C6 alkyl substituted with one or more of the following:
            • a hydroxyl,
            • an alkoxy,
            • a 5 or 6 membered heterocycle,
            • a 5 or 6 membered heteroaryl, or
            • a C6 to C8 aryl substituted with a halo,
          • a C2 to C6 alkylene group,
          • a C1 to C6 alkoxy group,
          • a 5 or 6 membered heterocycle group,
        • a —NRtCOORu group, where Ru is:
          • a C1 to C12 alkyl, substituted with one or more groups independently selected from the following:
            • an alkoxy group substituted with one or more alkoxy groups,
            • an amino optionally substituted with one or more C1 to C6 alkyl, or
            • a 5 or 6 membered heteroaryl,
          • a C2 to C6 alkylene, or
  • Figure US20100305100A1-20101202-C00023
    • Z is:
      • a C1 to C6 alkyl substituted with a 5 or 6 membered heterocycle, or
      • a 5 or 6 membered heterocycle;
    R1 is:
      • a C1 to C6 alkyl substituted with:
      • an amide optionally substituted with a C1 to C6 alkyl, or
      • a 5 or 6 membered heteroaryl;
      • a C1 to C6 alkoxy substituted with:
        • an amino optionally substituted with a heterocycle,
        • an amide optionally substituted with a C1 to C6 alkyl,
        • a 5 or 6 membered heterocycle substituted with a C1 to C6 alkyl, or
        • a 5 or 6 membered heteroaryl;
      • an (O)-5 or 6 membered heterocycle;
      • an (O)-5 or 6 membered heteroaryl;
      • an —SO2Rx group optionally substituted with the following:
        • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl,
        • a 5 or 6 membered heteroaryl; or
      • alkylthio optionally substituted with the following:
        • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl,
        • a 5 or 6 membered heteroaryl; or
        • R2 is:
      • a C1 to C6 alkyl group, substituted with one or more of the following:
        • 5 or 6 membered heterocycle groups,
        • 5 or 6 membered heteroaryl groups,
        • C6 to C8 aryl groups,
        • an amide optionally substituted with a C1 to C6 alkyl, or
        • amino groups optionally substituted with one or more heterocycle, alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups;
      • an alkylthio group optionally substituted with a 5 or 6 membered heteroaryl group optionally substituted with an alkyl group;
      • an alkylthio group optionally substituted with a 5 or 6 membered heterocycle group;
      • an alkylthio group optionally substituted with a C6 to C8 aryl group;
      • an alkylthio group optionally substituted with a C1 to C6 alkyl group;
      • an SO2Rx group optionally substituted with a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyl groups;
      • an SO2Rx group optionally substituted with a 5 or 6 membered heterocycle group;
      • an SO2Rx group optionally substituted with a C6 to C8 aryl group;
      • an SO2Rx group optionally substituted with a C1 to C6 alkyl group;
      • an S(O)Rx group optionally substituted with a 5 or 6 membered heteroaryl group;
      • an S(O)Rx group optionally substituted with a 5 or 6 membered heterocycle group;
      • an S(O)Rx group optionally substituted with a C6 to C8 aryl group;
      • an S(O)Rx group optionally substituted with a C1 to C6 alkyl group;
      • an alkoxy group substituted with an alkoxy group,
        • an amino group substituted with one or more 5 or 6 membered heteroaryl, 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
          • a 5 or 6 membered heterocycle, or
          • an amino optionally substituted with one or more alkyl groups;
        • an amide optionally substituted with a C1 to C6 alkyl,
        • S-5 or 6 membered heterocycle,
        • S-5 or 6 membered heteroaryl optionally substituted with a C1 to C6 alkyl,
        • S—C1 to C6 alkyl,
        • S—C6 to C8 aryl,
        • sulfinyl-5 or 6 membered heterocycle,
        • sulfinyl-5 or 6 membered heteroaryl,
        • sulfinyl-C1 to C6 alkyl,
        • sulfinyl-C6 to C8 aryl,
        • sulfonyl-5 or 6 membered heterocycle,
        • sulfonyl-5 or 6 membered heteroaryl optionally substituted with a C1 to C6 alkyl,
        • sulfonyl-C1 to C6 alkyl,
        • sulfonyl-C6 to C8 aryl,
        • a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected C1 to C6 alkyl groups substituted with C1 to C6 alkoxy, or
        • a 5 or 6 membered heteroaryl group substituted with one or more C1 to C6 alkyl groups
        • a C6 to C8 aryl group;
      • a —C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
      • a —C(O)—C6 to C8 aryl;
      • a —COOH group;
      • an amide group substituted with one or more C1 to C6 alkyl groups optionally substituted with one or more C1 to C6 alkoxy;
      • a 5 or 6 membered heterocycle, substituted with one or more of the following:
        • hydroxy,
        • C1 to C6 alkyl,
        • SO2Rx groups,
        • C(O)—C6 to C8 aryl, or
        • C(O)ORx groups;
      • an —ORkk group, where Rkk is:
        • a C6 to C8 aryl,
        • a 5 to 6 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or
        • an —Si(Rx)3;
      • an (O)-5 or 6 membered heterocycle; or
      • an (O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected C1 to C6 alkyl groups;
        or a pharmaceutically acceptable salt thereof.
  • In another embodiment the present invention includes compounds of Formula I, with the proviso that with the proviso that at least one of Y, Z, and R2 is selected from the following:
    • Y is:
      • a benzothiazole substituted with an amino group optionally substituted with one or more C1 to C6 alkyls;
      • an indole substituted on the nitrogen with an —SO2Rx group;
      • a C6 to C8 aryl substituted with one or more of the following:
        • an amino optionally substituted with one or more of the following:
          • SO2Rx, or
          • C1 to C6 alkyl substituted with one or more 5 or 6 membered heteroaryl group,
        • OC(O)NHRx,
        • OC(O)N(Rx)2,
        • OC(O)NH(ORx),
        • OC(O)NRx(ORx),
        • OC(O)N(ORx)2,
        • OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group,
        • a —NRoCORp group, where Rp is:
          • an amino group optionally substituted with one or more C1 to C6 alkyl groups where the C1 to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups,
          • a 5 or 6 membered heterocycle, substituted with one or more C1 to C6 alkyl or C6 to C8 aryl groups,
        • a —NRqCONRqRr group, where Rr is:
          • a C1 to C6 alkyl substituted with one or more of the following:
            • a hydroxyl,
            • an alkoxy,
            • a 5 or 6 membered heterocycle,
            • a 5 or 6 membered heteroaryl, or
            • a C6 to C8 aryl substituted with a halo,
          • a C2 to C6 alkylene group,
          • a C1 to C6 alkoxy group,
          • a 5 or 6 membered heterocycle group,
        • a —NRtCOORu group, where Ru is:
          • a C1 to C12 alkyl, substituted with one or more groups independently selected from the following:
            • an alkoxy group substituted with one or more alkoxy groups,
            • an amino optionally substituted with one or more C1 to C6 alkyl, or
            • a 5 or 6 membered heteroaryl,
          • a C2 to C6 alkylene,
  • Figure US20100305100A1-20101202-C00024
    • Z is:
      • a C1 to C6 alkyl substituted with a 5 or 6 membered heterocycle, or
      • a 5 or 6 membered heterocycle;
    R2 is:
      • a C1 to C6 alkyl group, substituted with one or more of the following:
        • 5 or 6 membered heterocycle groups,
        • amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups,
      • an alkoxy group substituted with one or more groups independently selected from the following:
        • hydroxy group,
        • an alkoxy group optionally substituted with an alkoxy group,
        • an amino group substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
          • a 5 or 6 membered heterocycle, or
          • an amino optionally substituted with one or more alkyl groups;
        • a 7 membered heterocycle group;
        • a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected C1 to C6 alkyl groups substituted with C1 to C6 alkoxy, or
        • a 5 or 6 membered heteroaryl group substituted with one or more C1 to C6 alkyl groups;
      • a —C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
      • a —COOH group;
      • an amide group substituted with one or more C1 to C6 alkyl groups;
      • a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
        • C1 to C6 alkyl,
        • SO2Rx group,
        • C(O)—C6 to C8 aryl, or
        • C(O)ORx groups;
      • an —ORkk group, where Rkk is:
        • a 5 to 6 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or
        • an —Si(Rx)3;
          or a pharmaceutically acceptable salt thereof.
  • As used herein, the term “alkyl” generally refers to saturated hydrocarbyl radicals of straight or branched configuration, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, octyl, n-octyl, and the like. In some embodiments, alkyl substituents may be C1 to C12, or C1 to C8 or C1 to C6 alkyl groups.
  • As used herein, “alkylene” generally refers to straight, branched or cyclic alkene radicals having one or more carbon-carbon double bonds, such as C2 to C6 alkylene groups including 3-propenyl.
  • As used herein, “aryl” refers to a carbocyclic aromatic ring structure. Included in the scope of aryl groups are aromatic rings having from five to twenty carbon atoms. Aryl ring structures include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds. Examples of aryl groups that include phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, phenanthrenyl (i.e., phenanthrene), and napthyl (i.e., napthalene) ring structures. In certain embodiments, the aryl group may be optionally substituted.
  • As used herein, “heteroaryl” refers to cyclic aromatic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon. Heteroatoms are typically O, S or N atoms. Included within the scope of heteroaryl, and independently selectable, are O, N, and S heteroaryl ring structures. The ring structure may include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds. In some embodiments, the heteroaryl groups may be selected from heteroaryl groups that contain two or more heteroatoms, three or more heteroatoms, or four or more heteroatoms. Heteroaryl ring structures may be selected from those that contain five or more atoms, six or more atoms, or eight or more atoms. Examples of heteroaryl ring structures include: acridine, benzimidazole, benzoxazole, benzodioxole, benzofuran, 1,3-diazine, 1,2-diazine, 1,2-diazole, 1,4-diazanaphthalene, furan, furazan, imidazole, indole, isoxazole, isoquinoline, isothiazole, oxazole, purine, pyridazine, pyrazole, pyridine, pyrazine, pyrimidine, pyrrole, quinoline, quinoxaline, thiazole, thiophene, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, tetrazole and quinazoline.
  • As used herein, “heterocycle” refers to cyclic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon. Heteroatoms are typically O, S or N atoms. Included within the scope of heterocycle, and independently selectable, are O, N, and S heterocycle ring structures. The ring structure may include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds. Example of heterocyclo groups include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl or tetrahydrothiopyranyl and the like. In certain embodiments, the heterocycle may optionally be substituted.
  • As used herein, “alkoxy” generally refers to a group with the structure —O—R, where R is an alkyl group as defined above.
  • For the purposes of this invention, halo substituents may be independently selected from the halogens such as fluorine, chlorine, bromine, iodine, and astatine. A haloalkyl is an alkyl group, as defined above, substituted with one or more halogens. A haloalkoxy is an alkoxy group, as defined above, substituted with one or more halogens.
  • For the purposes of this invention, where one or more functionalities encompassing X, Y, Z, R, R1, R2, and R3, are incorporated into a compound of the present invention, each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently substituted. Further, where a more generic substituent is set forth for any position in the molecules of the present invention, it is understood that the generic substituent may be replaced with more specific substituents, and the resulting molecules are within the scope of the molecules of the present invention.
  • By “substituted” or “optionally substituted” it is meant that the particular substituent may be substituted with a chemical group known to one of skill in the art to be appropriate for the referred-to substituent, unless a chemical group is specifically mentioned.
  • In another embodiment, the present invention includes compounds of Formula (I-X)
  • Figure US20100305100A1-20101202-C00025
  • wherein:
    • X is:
      • a cyano group;
    Y is:
      • a hydrogen;
      • a haloalkyl;
      • a halo;
      • an amino optionally substituted with one or more C1 to C6 alkyls;
      • a benzofuran;
      • a benzothiophene;
      • a dibenzofuran;
      • a dibenzothiophene;
      • a benzothiazole optionally substituted with an amino group optionally substituted with one or more C1 to C6 alkyls;
      • a naphthalene;
      • an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl or an —SO2Rx group;
  • Figure US20100305100A1-20101202-C00026
      •  where Rb is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;
  • Figure US20100305100A1-20101202-C00027
      •  where Rc is a hydrogen, a —CONHRx, where Rx is a C1 to C6 alkyl, or an —SO2Rx, where Rx is a C1 to C6 alkyl; or
  • Figure US20100305100A1-20101202-C00028
      •  where Rd is a C1 to C6 alkyl or a C6 to C8 aryl;
      • a —NHCORe group, where Re is:
        • a C1 to C6 alkyl;
        • a C6 to C8 aryl optionally substituted with:
          • a C1 to C6 alkyl,
          • an alkoxy,
          • a cyano group,
          • a nitro group, or
          • a halo;
      • a —NHCOORx group, where Rx is a C1 to C6 alkyl;
      • a —CH2O—Rf group, where Rf is a C6 to C8 aryl;
      • a —NRgRh group, where Rg is a C1 to C6 alkyl or a hydrogen and Rh is a C6 to C8 aryl optionally substituted with an alkoxy;
      • a C1 to C6 alkyl;
      • a 5 or 6 membered heteroaryl, optionally substituted with:
        • a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
        • a C6 to C8 aryl, optionally substituted with —COORx, where Rx is a C1 to C6 alkyl, or
        • an amino group;
      • a 5 or 6 membered heterocycle optionally substituted with:
        • a —COORx group, where Rx is as defined above, or
        • a —NHCOORx group, where Rx is as defined above;
      • a C6 to C8 aryl, optionally substituted with one or more of the following:
        • an alkoxy, optionally substituted with:
          • an alkoxy,
          • a hydroxy,
          • one or more halos,
          • a 5 or 6 membered heterocycle, optionally substituted with:
            • a C1 to C6 alkyl, or
            • a hydroxy,
          • an amino optionally substituted with one or more C1 to C6 alkyls,
          • a —NRiSO2Rx group, where Rx is a C1 to C6 alkyl and Ri is:
            • a hydrogen,
            • a C1 to C6 alkyl,
            • a —CORx group, where Rx is as defined above,
            • a haloalkyl, or
            • a haloalkoxy,
          • a —NRjCORk group, where Rk is:
            • a C1 to C6 alkyl,
            • a hydrogen, or
            • an amino optionally substituted with one or more C1 to C6 alkyls, and Rj is:
            • a hydrogen,
            • a C1 to C6 alkyl,
            • a —CORx group, where Rx is a C1 to C6 alkyl,
            • a haloalkyl, or
            • a haloalkoxy,
          • a —N═N+═N− group, or
          • a —CORl, where Rl is a 5 or 6 membered heterocycle optionally substituted with a hydroxy,
        • an amino optionally substituted with one or more of the following:
          • SO2(Rx), or
          • C1 to C6 alkyl, the C1 to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group,
        • a nitro group,
        • a C1 to C6 alkyl group, optionally substituted with:
          • a —NHSO2Rx group, where Rx is as defined above, or
          • a —NRxSO2Rx group, where Rx is as defined above,
        • a haloalkoxy,
        • a halo,
        • a hydroxy,
        • OC(O)NHRx,
        • OC(O)N(Rx)2,
        • OC(O)NH(ORx),
        • OC(O)NRx(ORx),
        • OC(O)N(ORx)2,
        • OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group,
        • a —COORx group, where Rx is a C1 to C6 alkyl,
        • a —CORm group, where Rm is:
          • an amino optionally substituted with one or more C1 to C6 alkyls, where the C1 to C6 alkyls are optionally substituted with:
            • a hydroxy,
            • a 5 or 6 membered heterocycle,
            • an amino optionally substituted with one or more C1 to C6 alkyls, or
            • an alkoxy,
          • a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino, or
          • a —NHRn group, where Rn is:
            • a —CH2CONH2, or
            • a C6 to C8 aryl optionally substituted with:
            •  an alkyl,
            •  one or more halos,
            •  a nitro group, or
            •  one or more alkoxys,
        • a —NRoCORp group, where Rp is:
          • a C1 to C6 alkyl optionally substituted with:
            • a halo,
            • an alkoxy, or
            • a C6 to C8 aryl,
          • an amino group optionally substituted with one or more C1 to C6 alkyl groups where the C1 to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups,
          • a 5 or 6 membered heterocycle, optionally substituted with one or more C1 to C6 alkyl or C6 to C8 aryl groups,
          • a C6 to C8 aryl, optionally substituted with a halo,
          • a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls,
          • a hydrogen,
  • Figure US20100305100A1-20101202-C00029
        • and where Ro is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is a C1 to C6 alkyl,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —NRqCONRqRr group, where Rq is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a haloalkoxy, or
          • a —CORx group, where Rx is as defined above,
        • and where Rr is:
          • a C6 to C8 aryl optionally substituted with:
  • Figure US20100305100A1-20101202-C00030
            • a C1 to C6 alkyl,
            • a haloalkyl,
            • a —ORs group, where Rs is a C6 to C8 aryl, or
            • a —COORx group, where Rx is as defined above,
          • a C1 to C6 alkyl optionally substituted with one or more of the following:
            • a halo,
            • a hydroxyl,
            • an alkoxy,
            • an alkylene,
            • a 5 or 6 membered heterocycle,
            • a 5 or 6 membered heteroaryl,
            • a C6 to C8 aryl optionally substituted with a halo, or
            • a —COORx group, where Rx is as defined above,
          • a C2 to C6 alkylene group,
          • a C1 to C6 alkoxy group,
          • a 5 or 6 membered heterocycle group, or
          • a —COORx group, where Rx is as defined above,
        • a —NRtCOORu group, where Ru is:
          • a C1 to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
            • a C6 to C8 aryl optionally substituted with halo, C1 to C6 alkyl, or alkoxy,
            • an alkylene,
            • an alkoxy,
            • an alkyne,
            • an alkoxy group optionally substituted with one or more alkoxy groups,
            • an amino optionally substituted with one or more C1 to C6 alkyl,
            • halo,
            • a 5 or 6 membered heterocycle, or
            • a 5 or 6 membered heteroaryl,
          • a C2 to C6 alkylene,
          • a C6 to C8 aryl, optionally substituted with:
            • an alkoxy,
            • a halo, or
            • a C1 to C6 alkyl, or
          • a 5 or 6 membered heterocycle,
        • and Rt is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is as defined above,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —NRvSO2Rw group, where Rv is:
          • a hydrogen,
          • a —CORx, where Rx is as defined above, or
          • a C1 to C6 alkyl, optionally substituted with:
            • a halo,
            • a —CORx group, where Rx is as defined above,
            • a —OCORx group, where Rx is as defined above,
            • a hydroxyl, or
            • an alkoxy,
        • and where Rw is:
          • a C1 to C6 alkyl optionally substituted with:
            • a halo,
            • a haloalkyl,
            • a C6 to C8 aryl, or
            • a 5 or 6 membered heterocycle,
          • a C2 to C6 alkylene,
          • an alkyl- or dialkyl-amino optionally substituted with a halo,
          • a 5 or 6 membered heterocycle, or
          • a 5 or 6 membered heteroaryl optionally substituted with:
            • a C1 to C6 alkyl,
            • a 5 or 6 membered heterocycle, or
  • Figure US20100305100A1-20101202-C00031
        •  optionally substituted with a C1 to C6 alkyl, where Ry is a C1 to C6 alkyl or hydrogen,
  • Figure US20100305100A1-20101202-C00032
        •  where Rz is hydrogen or a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
        • a —SRx group, where Rx is as defined above,
        • a —SO2Raa group, where Raa is:
          • a C1 to C6 alkyl,
          • an amino group,
          • an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a —COORx group, where Rx is as defined above, or
          • a 5 or 6 membered heteroaryl,
        • a C6 to C8 aryl, or
        • a —NHRbb group, where Rbb is:
          • a —C(═S)NH2 group, or
          • a —PO(ORx)2, where Rx is as defined above; or
  • Figure US20100305100A1-20101202-C00033
      •  where Rcc is:
        • a naphthalene,
        • a 5 or 6 membered heteroaryl,
  • Figure US20100305100A1-20101202-C00034
        • a C6 to C8 aryl, optionally substituted with one or more of the following:
          • an alkoxy,
          • a hydroxy,
          • a halo,
          • a C1 to C6 alkyl, optionally substituted with a cyano group,
          • an amino optionally substituted with one or more C1 to C6 alkyls,
          • a —NHPORxRx, where Rx is as defined above,
          • a —NReeCONRffRff group, where Ree is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halo, and Rff is:
            • a hydrogen,
            • a haloalkyl,
            • a haloalkoxy,
            • a C1 to C6 alkyl, or
            • a —CORx, where Rx is as defined above,
          • a —NRggCORhh group, where Rhh is:
            • a hydrogen,
            • a C1 to C6 alkyl optionally substituted with:
            •  an alkoxy,
            •  a halo, or
            •  an amino optionally substituted with one or more C1 to C6 alkyls,
            • an amino optionally substituted with one or more C1 to C6 alkyls, where the alkyls are optionally substituted with a halo,
            • a 5 or 6 membered heterocycle, or
            • a 5 or 6 membered heteroaryl,
          • and Rgg is:
            • a hydrogen,
            • a C1 to C6 alkyl,
            • a haloalkyl,
            • a haloalkoxy, or
            • a —CORx group, where Rx is as defined above,
          • a haloalkyl,
          • 5 or 6 membered heterocycle groups,
          • an amino optionally substituted with one or more C1 to C6 alkyls, or
          • a —NRiiSO2Rx group, where Rx is as defined above, and Rii is:
            • a hydrogen,
            • a C1 to C6 alkyl,
            • a haloalkyl,
            • a haloalkoxy, or
            • a —CORx group, where Rx is as defined above;
    Z is:
      • a hydrogen;
      • a C1 to C6 alkyl optionally substituted with:
        • an alkoxy,
        • one or more halos,
        • a 5 or 6 membered heterocycle, or
        • a C6 to C8 aryl;
      • a 5 or 6 membered heterocycle;
      • a C2 to C6 alkylene;
      • a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyls;
      • a —COORx group, where Rx is as defined above; or
  • Figure US20100305100A1-20101202-C00035
  • R is a hydrogen, a halo or an alkoxy;
    • R1 is:
      • a hydrogen;
      • a hydroxy;
      • a halo;
      • a haloalkyl;
      • a nitro group;
      • a 5 or 6 membered heteroaryl;
      • a 5 or 6 membered heterocycle;
      • an alkoxy optionally substituted with:
        • one or more halos,
        • a C6 to C8 aryl,
        • a 5 or 6 membered heterocycle, or
        • an amino optionally substituted with a heterocycle;
      • a C6 to C8 aryl optionally substituted with an alkoxy;
      • a —CORx group, where Rx is as defined above; or
      • a C1 to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
        R1 joins together with R2 to form:
  • Figure US20100305100A1-20101202-C00036
    • R2 is:
      • a nitro group;
      • a hydrogen;
      • a halo;
      • a hydroxy group;
      • a C1 to C6 alkyl group, optionally substituted with one or more of the following:
        • halos,
        • 5 or 6 membered heterocycle groups, or
        • amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups,
      • an amino group;
      • an alkoxy group optionally substituted with one or more groups independently selected from the following:
        • halos,
        • a hydroxy group,
        • an alkoxy group optionally substituted with an alkoxy group,
        • an —OCORx group, where Rx is as defined above, or
        • an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
          • a 5 or 6 membered heterocycle, or
          • an amino optionally substituted with one or more alkyl groups;
        • a dialkyl-amino optionally substituted with an alkoxy,
        • a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C1 to C6 alkyl group, the C1 to C6 alkyl group optionally substituted with one or more independently selected C1 to C6 alkoxy group,
        • a 5 or 6 membered heteroaryl group optionally substituted with one or more C1 to C6 alkyl groups, or
        • a C6 to C8 aryl group;
      • a —C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
      • a —COOH group;
      • a —COORx group, where Rx is as defined above;
      • a haloalkyl;
      • an amide group optionally substituted with one or more of the following:
        • C1 to C6 alkyl groups,
        • hydroxy groups, or
        • C6 to C8 aryl groups;
      • a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
        • C1 to C6 alkyl,
        • C(O)—C6 to C8 aryl, or
        • C(O)ORx groups;
      • a 5 or 6 membered heteroaryl;
      • a —OCORx group, where Rx is as defined above;
      • a —NHCORjj group, where Rjj is:
        • an alkoxy, or
        • an amino optionally substituted with one or more C1 to C6 alkyls;
      • an —ORkk group, where Rkk is:
        • a 5 to 6 membered heteroaryl,
        • a 5 to 6 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or
        • an Si(Rx)3; or
      • a —NHSO2Rx group, where Rx is as defined above; or
        R2 joins together with R1 to form:
  • Figure US20100305100A1-20101202-C00037
    • R3 is:
      • a hydrogen; or
      • CH2OCORx, and Rx is as defined above;
        or a pharmaceutically acceptable salt thereof.
  • In another embodiment, the present invention includes compounds of Formula (I-Xa)
  • Figure US20100305100A1-20101202-C00038
  • wherein
    • X is:
      • a cyano group;
    Y is:
      • a hydrogen;
      • a haloalkyl;
      • a halo;
      • an amino optionally substituted with one or more C1 to C6 alkyls;
      • a benzofuran;
      • a benzothiophene;
      • a dibenzofuran;
      • a dibenzothiophene;
      • a benzothiazole optionally substituted with an amino group optionally substituted with one or more C1 to C6 alkyls;
      • a naphthalene;
      • an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl or an —SO2Rx;
  • Figure US20100305100A1-20101202-C00039
      •  where Rb is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;
  • Figure US20100305100A1-20101202-C00040
      •  where Rc is a hydrogen, a —CONHRx, where Rx is a C1 to C6 alkyl, or an —SO2Rx, where Rx is a C1 to C6 alkyl; or
  • Figure US20100305100A1-20101202-C00041
      •  where Rd is a C1 to C6 alkyl or a C6 to C8 aryl;
      • a —NHCORe, group, where Re is:
        • a C1 to C6 alkyl;
        • a C6 to C8 aryl optionally substituted with:
          • a C1 to C6 alkyl,
          • an alkoxy,
          • a cyano group,
          • a nitro group, or
          • a halo;
      • a —NHCOORx group, where Rx is a C1 to C6 alkyl;
      • a —CH2O—Rf group, where Rf is a C6 to C8 aryl;
      • a —NRgRh group, where Rg is a C1 to C6 alkyl or a hydrogen and Rh is a C6 to C8 aryl optionally substituted with an alkoxy;
      • a C1 to C6 alkyl;
      • a 5 or 6 membered heteroaryl, optionally substituted with:
        • a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
        • a C6 to C8 aryl, optionally substituted with —COORx, where Rx is a C1 to C6 alkyl, or
        • an amino group;
      • a 5 or 6 membered heterocycle optionally substituted with:
        • a —COORx group, where Rx is as defined above, or
        • a —NHCOORx group, where Rx is as defined above;
      • a C6 to C8 aryl, optionally substituted with one or more of the following:
        • an alkoxy, optionally substituted with:
          • an alkoxy,
          • a hydroxy,
          • one or more halos,
          • a 5 or 6 membered heterocycle, optionally substituted with:
            • a C1 to C6 alkyl, or
            • a hydroxy,
          • an amino optionally substituted with one or more C1 to C6 alkyls,
          • a —NRiSO2Rx group, where Rx is a C1 to C6 alkyl and Ri is:
            • a hydrogen,
            • a C1 to C6 alkyl,
            • a —CORx group, where Rx is as defined above,
            • a haloalkyl, or
            • a haloalkoxy,
          • a —NRjCORk group, where Rk is:
            • a C1 to C6 alkyl,
            • a hydrogen, or
            • an amino optionally substituted with one or more C1 to C6 alkyls, and Rj is:
            • a hydrogen,
            • a C1 to C6 alkyl,
            • a —CORx group, where Rx is a C1 to C6 alkyl,
            • a haloalkyl, or
            • a haloalkoxy,
          • a —N═N+═N− group, or
          • a —CORl, where Rl is a 5 or 6 membered heterocycle optionally substituted with a hydroxy,
        • an amino optionally substituted with one or more of the following:
          • SO2(Rx), or
          • C1 to C6 alkyl, the C1 to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group,
        • a nitro group,
        • a C1 to C6 alkyl group, optionally substituted with:
          • a —NHSO2Rx group, where Rx is as defined above, or
          • a —NRxSO2Rx group, where Rx is as defined above,
        • a haloalkoxy,
        • a halo,
        • a hydroxy,
        • OC(O)NHRx,
        • OC(O)N(Rx)2,
        • OC(O)NH(ORx),
        • OC(O)NRx(ORx),
        • OC(O)N(ORx)2,
        • OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group,
        • a —COORx group, where Rx is a C1 to C6 alkyl,
        • a —CORm group, where Rm is:
          • an amino optionally substituted with one or more C1 to C6 alkyls, where the C1 to C6 alkyls are optionally substituted with:
            • a hydroxy
            • a 5 or 6 membered heterocycle,
            • an amino optionally substituted with one or more C1 to C6 alkyls, or
            • an alkoxy,
          • a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino,
          • a —NHRn group, where Rn is:
            • a —CH2CONH2, or
            • a C6 to C8 aryl optionally substituted with:
            •  an alkyl,
            •  one or more halos,
            •  a nitro group, or
            •  one or more alkoxys,
        • a —NRoCORp group, where Rp is:
          • a C1 to C6 alkyl optionally substituted with:
            • a halo,
            • an alkoxy, or
            • a C6 to C8 aryl,
          • an amino group optionally substituted with one or more C1 to C6 alkyl groups where the C1 to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups,
          • a 5 or 6 membered heterocycle, optionally substituted with one or more C1 to C6 alkyl or C6 to C8 aryl groups,
          • a C6 to C8 aryl, optionally substituted with a halo,
          • a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls,
          • a hydrogen,
  • Figure US20100305100A1-20101202-C00042
          •  and where Ro is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is a C1 to C6 alkyl,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —NRqCONRqRr group, where Rq is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a haloalkoxy, or
          • a —CORx group, where Rx is as defined above, and where Rr is:
          • a C6 to C8 aryl optionally substituted with:
  • Figure US20100305100A1-20101202-C00043
            • a C1 to C6 alkyl,
            • a haloalkyl,
            • a —ORs group, where Rs is a C6 to C8 aryl, or
            • a —COORx group, where Rx is as defined above,
          • a C1 to C6 alkyl optionally substituted with one or more of the following:
            • a halo,
            • a hydroxyl,
            • an alkoxy,
            • an alkylene,
            • a 5 or 6 membered heterocycle,
            • a 5 or 6 membered heteroaryl,
            • a C6 to C8 aryl optionally substituted with a halo, or
            • a —COORx group, where Rx is as defined above,
          • a C2 to C6 alkylene group,
          • a C1 to C6 alkoxy group,
          • a 5 or 6 membered heterocycle group, or
          • a —COORx group, where Rx is as defined above,
        • a —NRtCOORu group, where Ru is:
          • a C1 to C12 alkyl, optionally substituted with one or more of the following:
            • a C6 to C8 aryl optionally substituted with halo, C1 to C6 alkyl, or alkoxy,
            • an alkylene,
            • an alkoxy,
            • an alkyne,
            • an alkoxy group optionally substituted with one or more alkoxy groups,
            • an amino optionally substituted with one or more C1 to C6 alkyl,
            • halo,
            • a 5 or 6 membered heterocycle, or
            • a 5 or 6 membered heteroaryl,
          • a C2 to C6 alkylene,
          • a C6 to C8 aryl, optionally substituted with:
            • an alkoxy,
            • a halo, or
            • a C1 to C6 alkyl, or
          • a 5 or 6 membered heterocycle,
        • and Rt is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is as defined above,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —NRvSO2Rw group, where Rv is:
          • a hydrogen,
          • a —CORx, where Rx is as defined above, or
          • a C1 to C6 alkyl, optionally substituted with:
            • a halo,
            • a —CORx group, where Rx is as defined above,
            • a —OCORx group, where Rx is as defined above,
            • a hydroxyl, or
            • an alkoxy,
        • and where Rw is:
          • a C1 to C6 alkyl optionally substituted with:
            • a halo,
            • a haloalkyl,
            • a C6 to C8 aryl, or
            • a 5 or 6 membered heterocycle,
          • a C2 to C6 alkylene,
          • an alkyl- or dialkyl-amino optionally substituted with a halo,
          • a 5 or 6 membered heterocycle, or
          • a 5 or 6 membered heteroaryl optionally substituted with:
            • a C1 to C6 alkyl,
            • a 5 or 6 membered heterocycle, or
  • Figure US20100305100A1-20101202-C00044
        •  optionally substituted with a C1 to C6 alkyl, where Ry is a C1 to C6 alkyl or hydrogen,
  • Figure US20100305100A1-20101202-C00045
        • where Rz is hydrogen or a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
        • a —SRx group, where Rx is as defined above,
        • an —SO2Raa group, where Raa is:
          • a C1 to C6 alkyl,
          • an amino group,
          • an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a —COORx group, where Rx is as defined above, or
          • a 5 or 6 membered heteroaryl,
        • a C6 to C8 aryl, or
        • a —NHRbb group, where Rbb is:
  • Figure US20100305100A1-20101202-C00046
          • a —C(═S)NH2 group, or
          • a —PO(ORx)2, where Rx is as defined above; or
  • Figure US20100305100A1-20101202-C00047
      •  where Rcc is:
        • a naphthalene,
        • a 5 or 6 membered heteroaryl,
  • Figure US20100305100A1-20101202-C00048
        •  or
        • a C6 to C8 aryl, optionally substituted with one or more of the following:
          • an alkoxy,
          • a hydroxy,
          • a halo,
          • a C1 to C6 alkyl, optionally substituted with a cyano group,
          • an amino optionally substituted with one or more C1 to C6 alkyls,
          • a —NHPORxRx, where Rx is as defined above,
          • a —NReeCONRffRff group, where Ree is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halo, and Rff is:
            • a hydrogen,
            • a haloalkyl,
            • a haloalkoxy,
            • a C1 to C6 alkyl, or
            • a —CORx, where Rx is as defined above,
          • a —NRggCORhh group, where Rhh is:
            • a hydrogen,
            • a C1 to C6 alkyl optionally substituted with:
            •  an alkoxy,
            •  a halo, or
            •  an amino optionally substituted with one or more C1 to C6 alkyls,
            • an amino optionally substituted with one or more C1 to C6 alkyls, where the alkyls are optionally substituted with a halo,
            • a 5 or 6 membered heterocycle, or
            • a 5 or 6 membered heteroaryl,
          • and Rgg is:
            • a hydrogen,
            • a C1 to C6 alkyl,
            • a haloalkyl,
            • a haloalkoxy, or
            • a —CORx group, where Rx is as defined above,
          • a haloalkyl,
          • 5 or 6 membered heterocycle groups,
          • an amino optionally substituted with one or more C1 to C6 alkyls, or
          • a —NRii SO2Rx group, where Rx is as defined above, and Rii is:
            • a hydrogen,
            • a C1 to C6 alkyl,
            • a haloalkyl,
            • a haloalkoxy, or
            • a —CORx group, where Rx is as defined above;
    Z is:
      • a hydrogen;
      • a C1 to C6 alkyl optionally substituted with:
        • an alkoxy,
        • one or more halos,
        • a 5 or 6 membered heterocycle, or
        • a C6 to C8 aryl;
      • a 5 or 6 membered heterocycle;
      • a C2 to C6 alkylene;
      • a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyls;
      • a —COORx group, where Rx is as defined above; or
  • Figure US20100305100A1-20101202-C00049
  • R is a hydrogen, a halo or an alkoxy;
    • R1 is:
      • a hydrogen;
      • a hydroxy;
      • a halo;
      • a haloalkyl;
      • a nitro group;
      • a 5 or 6 membered heteroaryl;
      • a 5 or 6 membered heterocycle;
      • an alkoxy optionally substituted with:
        • one or more halos,
        • a C6 to C8 aryl,
        • a 5 or 6 membered heterocycle, or
        • an amino optionally substituted with a 5 or 6 membered heterocycle;
      • a C6 to C8 aryl optionally substituted with an alkoxy;
      • a —CORx group, where Rx is as defined above; or
      • a C1 to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
        R1 joins together with R2 to form:
  • Figure US20100305100A1-20101202-C00050
    • R2 is:
      • a nitro group;
      • a hydrogen;
      • a halo;
      • a hydroxy group;
      • a C1 to C6 alkyl group, optionally substituted with one or more of the following:
        • halos,
        • 5 or 6 membered heterocycle groups, or
        • amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups,
      • an amino group;
      • an alkoxy group optionally substituted with one or more of the following:
        • halos,
        • a hydroxy group,
        • an alkoxy group optionally substituted with an alkoxy group,
        • an —OCORx group, where Rx is as defined above,
        • an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
          • a 5 or 6 membered heterocycle, or
          • an amino optionally substituted with one or more alkyl groups;
        • a dialkyl-amino optionally substituted with an alkoxy,
        • a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C1 to C6 alkyl group, the C1 to C6 alkyl group optionally substituted with one or more independently selected C1 to C6 alkoxy group,
        • a 5 or 6 membered heteroaryl group optionally substituted with one or more C1 to C6 alkyl groups, or
        • a C6 to C8 aryl group;
      • a —C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
      • a —COOH group;
      • a —COORx group, where Rx is as defined above;
      • a haloalkyl;
      • an amide group optionally substituted with one or more of the following:
        • C1 to C6 alkyl groups,
        • hydroxy groups, or
        • C6 to C8 aryl groups;
      • a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
        • C1 to C6 alkyl,
        • SO2Rx groups,
        • C(O)—C6 to C8 aryl, or
        • C(O)ORx groups;
      • a 5 or 6 membered heteroaryl;
      • a —OCORx group, where Rx is as defined above;
      • a —NHCORjj group, where Rjj is:
        • an alkoxy, or
        • an amino optionally substituted with one or more C1 to C6 alkyls;
      • an —ORkk group, where Rkk is:
        • a 5 to 6 membered heteroaryl,
        • a 5 to 6 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or
        • an —Si(Rx)3;
      • a —NHSO2Rx group, where Rx is as defined above; or
        R2 joins together with R1 to form:
  • Figure US20100305100A1-20101202-C00051
    • R3 is:
      • a hydrogen; or
      • CH2OCORx, and Rx is as defined above;
        with the proviso that at least one of Y, Z, R1 and R2 is selected from the following:
    Y is:
      • a benzothiazole substituted with an amino group optionally substituted with one or more C1 to C6 alkyls;
      • an indole substituted on the nitrogen with an —SO2Rx group;
      • a C6 to C8 aryl substituted with one or more of the following:
        • an amino optionally substituted with one or more of the following:
          • SO2Rx, or
          • C1 to C6 alkyl substituted with one or more 5 or 6 membered heteroaryl group,
        • OC(O)NHRx,
        • OC(O)N(Rx)2,
        • OC(O)NH(ORx),
        • OC(O)NRx(ORx),
        • OC(O)N(ORx)2,
        • OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group,
        • a —NRoCORp group, where Rp is:
          • an amino group optionally substituted with one or more C1 to C6 alkyl groups where the C1 to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups, or
          • a 5 or 6 membered heterocycle, substituted with one or more C1 to C6 alkyl or C6 to C8 aryl groups,
        • a —NRqCONRqRr group, where Rr is:
          • a C1 to C6 alkyl substituted with one or more of the following:
            • a hydroxyl,
            • an alkoxy,
            • a 5 or 6 membered heterocycle,
            • a 5 or 6 membered heteroaryl, or
            • a C6 to C8 aryl substituted with a halo,
          • a C2 to C6 alkylene group,
          • a C1 to C6 alkoxy group, or
          • a 5 or 6 membered heterocycle group,
        • a —NRtCOORu group, where Ru is:
          • a C1 to C12 alkyl, substituted with one or more of the following:
            • an alkoxy group substituted with one or more alkoxy groups,
            • an amino optionally substituted with one or more C1 to C6 alkyl, or
            • a 5 or 6 membered heteroaryl,
          • a C2 to C6 alkylene, or
  • Figure US20100305100A1-20101202-C00052
    • Z is:
      • a C1 to C6 alkyl substituted with a 5 or 6 membered heterocycle, or
      • a 5 or 6 membered heterocycle; or
        R1 is an alkoxy substituted with an amino, where the amino is optionally substituted with a heterocycle;
    R2 is:
      • a C1 to C6 alkyl group, substituted with one or more of the following:
        • 5 or 6 membered heterocycle groups, or
        • amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups,
      • an alkoxy group substituted with one or more groups independently selected from the following:
        • a hydroxy group,
        • an alkoxy group optionally substituted with an alkoxy group,
        • an amino group substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
          • a 5 or 6 membered heterocycle, or
          • an amino optionally substituted with one or more alkyl groups;
        • a 7 membered heterocycle group;
        • a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected C1 to C6 alkyl groups substituted with C1 to C6 alkoxy, or
        • a 5 or 6 membered heteroaryl group substituted with one or more C1 to C6 alkyl groups;
      • a —C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
      • a —COOH group;
      • an amide group substituted with one or more C1 to C6 alkyl groups;
      • a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
        • C1 to C6 alkyl,
        • SO2Rx,
        • C(O)—C6 to C8 aryl, or
        • C(O)ORx groups;
      • an —ORkk group, where Rkk is:
        • a 5 to 6 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or
        • an —Si(Rx)3;
          or a pharmaceutically acceptable salt thereof.
  • In some embodiments, R is selected from the R substituents of compounds 1330-2128 and 2600-3348.
  • In some embodiments of the invention, compounds are provided wherein R is selected from the following non-limiting substituents:
  • Figure US20100305100A1-20101202-C00053
  • In other embodiments of the invention, R is hydrogen.
  • In some embodiments of the invention, R1 is selected from the following non-limiting substituents:
  • Figure US20100305100A1-20101202-C00054
  • In some embodiments of the invention, R2 is selected from the following non-limiting substituents:
  • Figure US20100305100A1-20101202-C00055
    Figure US20100305100A1-20101202-C00056
    Figure US20100305100A1-20101202-C00057
    Figure US20100305100A1-20101202-C00058
  • In some embodiments, R3 is selected from the R3 substituents of compounds 1330-2128, and 2600-3348.
  • In some embodiments of the invention, compounds are provided wherein R3 is selected from the following non-limiting substituents:
  • Figure US20100305100A1-20101202-C00059
  • In other embodiments of the invention, compounds are provided wherein R3 is hydrogen.
  • In another embodiment, the present invention includes a compound of Formula (I-XI)
  • Figure US20100305100A1-20101202-C00060
  • wherein:
    • X is:
      • hydrogen;
      • a cyano group;
      • a nitro group;
      • a formyl group;
      • a —COOH group;
      • a CORx group, wherein Rx is a C1 to C6 alkyl;
  • Figure US20100305100A1-20101202-C00061
      • a halo;
      • an alkyl optionally substituted with one or more halo;
      • an alkyne optionally substituted with a C1 to C6 alkyl optionally substituted with one or more independently selected halo or cyano groups;
      • an oxime;
      • SO2Rx;
      • SO2NH2;
      • SO2NH(Rx);
      • SO2N(Rx)2;
      • an amino optionally substituted with one or more C1 to C6 alkyl groups or C(O)—C1 to C6 alkyl groups;
      • an amide group optionally substituted with one or more independently selected C1 to C6 alkyl group;
      • a 5 or 6 membered heterocycle;
      • a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyl groups optionally substituted with one or more halos; or
      • a C6 to C8 aryl group optionally substituted with one or more of the following:
        • C1 to C6 alkyl optionally substituted with one or more halos,
        • halo, or
        • cyano;
    Y is:
      • a benzothiazole optionally substituted with an amino group optionally substituted with one or more C1 to C6 alkyls;
      • an indole, optionally substituted on the nitrogen with an —SO2Rx group; or
      • a C6 to C8 aryl, optionally substituted with one or more of the following:
        • halo;
        • a C1 to C6 alkyl;
        • an alkoxy,
        • an amino optionally substituted with one or more of the following:
          • SO2Rx,
          • C1 to C6 alkyl, the C1 to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, or
          • PO2Rx,
        • OC(O)NHRx,
        • OC(O)N(Rx)2,
        • OC(O)NH(ORx),
        • OC(O)NRx(ORx),
        • OC(O)N(ORx)2,
        • OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group,
        • a —NRoCORp group, where Rp is:
          • a C1 to C6 alkyl,
          • an amino group optionally substituted with one or more C1 to C6 alkyl groups where the C1 to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups, or
          • a 5 or 6 membered heterocycle, optionally substituted with one or more C1 to C6 alkyl or C6 to C8 aryl groups,
        • and where Ro is:
          • a hydrogen, or
          • a C1 to C6 alkyl,
        • a —NRqCONRqRr group, where Rq is a hydrogen,
        • and where Rr is:
          • a C1 to C6 alkyl optionally substituted with one or more of the following:
            • halo,
            • hydroxyl,
            • an alkoxy,
            • a 5 or 6 membered heterocycle,
            • a 5 or 6 membered heteroaryl, or
            • a C6 to C8 aryl optionally substituted with a halo,
          • a C2 to C6 alkylene group optionally substituted with one or more halo,
          • a C1 to C6 alkoxy group, or
          • a 5 or 6 membered heterocycle group,
        • a —NRtCOORu group, where Ru is:
          • a C1 to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
            • a C6 to C8 aryl optionally substituted with halo,
            • an alkoxy group optionally substituted with one or more alkoxy groups,
            • an amino optionally substituted with one or more C1 to C6 alkyl,
            • halo, or
            • a 5 or 6 membered heteroaryl,
          • a C2 to C6 alkylene, or
          • a C6 to C8 aryl, optionally substituted with halo,
        • and Rt is:
          • a hydrogen;
        • a —NHRbb group, where Rbb is:
          • a —C(═S)NH2 group, or
          • a —PO(ORx)2, where Rx is as defined above;
        • a —NRvSO2Rw group, where Rv is a hydrogen, and where Rw is a C1 to C6 alkyl,
  • Figure US20100305100A1-20101202-C00062
    • Z is:
      • a C1 to C6 alkyl optionally substituted with a 5 or 6 membered heterocycle, or
      • a 5 or 6 membered heterocycle;
        R is a hydrogen;
    R1 is:
      • a hydrogen;
      • a C1 to C6 alkyl optionally substituted with:
        • an amino optionally substituted with a heterocycle,
        • an amide optionally substituted with a C1 to C6 alkyl,
        • a 5 or 6 membered heterocycle optionally substituted with a C1 to C6 alkyl,
        • a 5 or 6 membered heteroaryl, or
        • a C6 to C8 aryl;
      • a C1 to C6 alkoxy optionally substituted with:
        • an amino optionally substituted with a heterocycle,
        • an amide optionally substituted with a C1 to C6 alkyl,
        • a 5 or 6 membered heterocycle optionally substituted with a C1 to C6 alkyl,
        • a 5 or 6 membered heteroaryl, or
        • a C6 to C8 aryl;
      • an (O)-5 or 6 membered heterocycle;
      • an (O)-5 or 6 membered heteroaryl;
      • an —SO2Rx group optionally substituted with the following:
        • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl,
        • a 5 or 6 membered heteroaryl; or
      • alkylthio optionally substituted with the following:
        • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl,
        • a 5 or 6 membered heteroaryl;
    R2 is:
      • a C1 to C6 alkyl group, optionally substituted with one or more of the following:
        • 5 or 6 membered heterocycle groups,
        • 5 or 6 membered heteroaryl groups,
        • C6 to C8 aryl groups,
        • an amide optionally substituted with a C1 to C6 alkyl, or
        • amino groups optionally substituted with one or more heterocycle, alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups;
      • an alkylthio group optionally substituted with a 5 or 6 membered heteroaryl group optionally substituted with an alkyl group;
      • an alkylthio group optionally substituted with a 5 or 6 membered heterocycle group;
      • an alkylthio group optionally substituted with a C6 to C8 aryl group;
      • an alkylthio group optionally substituted with a C1 to C6 alkyl group;
      • an SO2Rx group optionally substituted with a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyl groups;
      • an SO2Rx group optionally substituted with a 5 or 6 membered heterocycle group;
      • an SO2Rx group optionally substituted with a C6 to C8 aryl group;
      • an SO2Rx group optionally substituted with a C1 to C6 alkyl group;
      • an S(O)Rx group optionally substituted with a 5 or 6 membered heteroaryl group;
      • an S(O)Rx group optionally substituted with a 5 or 6 membered heterocycle group;
      • an S(O)Rx group optionally substituted with a C6 to C8 aryl group;
      • an S(O)Rx group optionally substituted with a C1 to C6 alkyl group;
      • an alkoxy group optionally substituted with one or more groups independently selected from the following:
        • halo,
        • hydroxy group,
        • an alkoxy group optionally substituted with an alkoxy group,
        • an amino group optionally substituted with one or more 5 or 6 membered heteroaryl groups, 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
          • 5 or 6 membered heterocycle, or
          • amino optionally substituted with one or more alkyl groups,
        • an amide optionally substituted with a C1 to C6 alkyl,
        • S-5 or 6 membered heterocycle,
        • S-5 or 6 membered heteroaryl optionally substituted with a C1 to C6 alkyl,
        • S—C1 to C6 alkyl,
        • S—C6 to C8 aryl,
        • sulfinyl-5 or 6 membered heterocycle,
        • sulfinyl-5 or 6 membered heteroaryl,
        • sulfinyl-C1 to C6 alkyl,
        • sulfinyl-C6 to C8 aryl,
        • sulfonyl-5 or 6 membered heterocycle,
        • sulfonyl-5 or 6 membered heteroaryl optionally substituted with a C1 to C6 alkyl,
        • sulfonyl-C1 to C6 alkyl,
        • sulfonyl-C6 to C8 aryl,
        • a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C1 to C6 alkyl group, the C1 to C6 alkyl group optionally substituted with one or more independently selected C1 to C6 alkoxy group,
        • a 5 or 6 membered heteroaryl group optionally substituted with one or more C1 to C6 alkyl groups,
        • a C6 to C8 aryl group;
      • a C6 to C8 aryl group;
      • an (O)-5 or 6 membered heterocycle;
      • an (O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected C1 to C6 alkyl groups;
      • a —C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
      • a —C(O)-5 or 6 membered heteroaryl;
      • a —C(O)—C6 to C8 aryl;
      • a —COOH group;
      • an amide group optionally substituted with one or more C1 to C6 alkyl groups optionally substituted with one or more C1 to C6 alkoxy;
      • a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
        • hydroxy,
        • C1 to C6 alkyl,
        • SO2Rx,
        • C(O)—C6 to C8 aryl, or
        • C(O)ORx groups;
      • an —ORkk group, where Rkk is:
        • a C6 to C8 aryl,
        • a 5 to 6 membered heteroaryl,
        • a 5 to 6 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or
        • an —Si(Rx)3; and
          R3 is a hydrogen;
          or a pharmaceutically acceptable salt thereof.
  • In a further embodiment of the present invention, compounds of the present invention include compounds of Formula (I-XIa)
  • Figure US20100305100A1-20101202-C00063
  • wherein:
    • X is:
      • hydrogen;
      • a cyano group;
      • a nitro group;
      • a formyl group;
      • a —COOH group;
      • a CORx group, wherein Rx is a C1 to C6 alkyl;
  • Figure US20100305100A1-20101202-C00064
      • a halo;
      • an alkyl optionally substituted with one or more halo;
      • an alkyne optionally substituted with a C1 to C6 alkyl optionally substituted with one or more halo or cyano groups;
      • an oxime;
      • SO2Rx;
      • SO2NH2;
      • SO2NH(Rx);
      • SO2N(Rx)2;
      • an amino optionally substituted with one or more C1 to C6 alkyl groups or C(O)—C1 to C6 alkyl groups;
      • an amide group optionally substituted with one or more independently selected C1 to C6 alkyl group;
      • a 5 or 6 membered heterocycle;
      • a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyl groups optionally substituted with one or more halos; or
      • a C6 to C8 aryl group optionally substituted with one or more of the following:
        • C1 to C6 alkyl optionally substituted with one or more halos,
        • halo, or
        • cyano;
    Y is:
      • a benzothiazole optionally substituted with an amino group optionally substituted with one or more C1 to C6 alkyls;
      • an indole, optionally substituted on the nitrogen with a —SO2Rx group;
      • a C6 to C8 aryl, optionally substituted with one or more of the following:
        • halo;
        • a C1 to C6 alkyl;
        • an alkoxy,
        • an amino optionally substituted with one or more
          • SO2Rx groups,
          • C1 to C6 alkyl, the C1 to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, or
          • PO2Rx groups,
        • OC(O)NHRx,
        • OC(O)N(Rx)2,
        • OC(O)NH(ORx),
        • OC(O)NRx(ORx),
        • OC(O)N(ORx)2,
        • OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group,
        • a —NRoCORp group, where Rp is:
          • a C1 to C6 alkyl,
          • an amino group optionally substituted with one or more C1 to C6 alkyl groups where the C1 to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups,
          • a 5 or 6 membered heterocycle, optionally substituted with one or more C1 to C6 alkyl or C6 to C8 aryl groups,
        • and where Ro is:
          • a hydrogen,
          • a C1 to C6 alkyl,
        • a —NRqCONRqRr group, where Rq is a hydrogen,
        • and where Rr is:
          • a C1 to C6 alkyl optionally substituted with one or more of the following:
            • halo,
            • hydroxyl,
            • an alkoxy,
            • a 5 or 6 membered heterocycle,
            • a 5 or 6 membered heteroaryl, or
            • a C6 to C8 aryl optionally substituted with a halo,
          • a C2 to C6 alkylene group optionally substituted with one or more halo,
          • a C1 to C6 alkoxy group, or
          • a 5 or 6 membered heterocycle group,
        • a —NRtCOORu group, where Ru is:
          • a C1 to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
            • a C6 to C8 aryl optionally substituted with halo,
            • an alkoxy group optionally substituted with one or more alkoxy groups,
            • an amino optionally substituted with one or more C1 to C6 alkyl,
            • halo, or
            • a 5 or 6 membered heteroaryl,
          • a C2 to C6 alkylene,
          • a C6 to C8 aryl, optionally substituted with halo,
        • and Rt is a hydrogen;
        • a —NHRbb group, where Rbb is:
          • a —C(═S)NH2 group, or
          • a —PO(ORx)2, where Rx is as defined above;
        • a —NRvSO2Rw group, where Rv is a hydrogen, and where Rw is a C1 to C6 alkyl,
  • Figure US20100305100A1-20101202-C00065
    • Z is:
      • a C1 to C6 alkyl optionally substituted with a 5 or 6 membered heterocycle, or
      • a 5 or 6 membered heterocycle;
        R is a hydrogen;
    R1 is:
      • a hydrogen;
      • a C1 to C6 alkyl optionally substituted with:
        • an amino optionally substituted with a heterocycle,
        • an amide optionally substituted with a C1 to C6 alkyl,
        • a 5 or 6 membered heterocycle optionally substituted with a C1 to C6 alkyl,
        • a 5 or 6 membered heteroaryl, or
        • a C6 to C8 aryl;
      • a C1 to C6 alkoxy optionally substituted with:
        • an amino optionally substituted with a heterocycle,
        • an amide optionally substituted with a C1 to C6 alkyl,
        • a 5 or 6 membered heterocycle optionally substituted with a C1 to C6 alkyl,
        • a 5 or 6 membered heteroaryl, or
        • a C6 to C8 aryl;
      • an (O)-5 or 6 membered heterocycle;
      • an (O)-5 or 6 membered heteroaryl;
      • an —SO2Rx group optionally substituted with the following:
        • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl,
        • a 5 or 6 membered heteroaryl; or
      • alkylthio optionally substituted with the following:
        • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl,
        • a 5 or 6 membered heteroaryl;
    R2 is:
      • a C1 to C6 alkyl group, optionally substituted with one or more of the following:
        • 5 or 6 membered heterocycle groups,
        • 5 or 6 membered heteroaryl groups,
        • C6 to C8 aryl groups,
        • an amide optionally substituted with a C1 to C6 alkyl, or
        • amino groups optionally substituted with one or more heterocycle, alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups;
      • an alkylthio group optionally substituted with a 5 or 6 membered heteroaryl group optionally substituted with an alkyl group;
      • an alkylthio group optionally substituted with a 5 or 6 membered heterocycle group;
      • an alkylthio group optionally substituted with a C6 to C8 aryl group;
      • an alkylthio group optionally substituted with a C1 to C6 alkyl group;
      • an SO2Rx group optionally substituted with a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyl groups;
      • an SO2Rx group optionally substituted with a 5 or 6 membered heterocycle group;
      • an SO2Rx group optionally substituted with a C6 to C8 aryl group;
      • an SO2Rx group optionally substituted with a C1 to C6 alkyl group;
      • an S(O)Rx group optionally substituted with a 5 or 6 membered heteroaryl group;
      • an S(O)Rx group optionally substituted with a 5 or 6 membered heterocycle group;
      • an S(O)Rx group optionally substituted with a C6 to C8 aryl group;
      • an S(O)Rx group optionally substituted with a C1 to C6 alkyl group;
      • an alkoxy group optionally substituted with one or more groups independently selected from the following:
        • halo,
        • hydroxy group,
        • an alkoxy group optionally substituted with an alkoxy group,
        • an amino group optionally substituted with one or more 5 or 6 membered heteroaryl groups, 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
          • a 5 or 6 membered heterocycle, or
          • an amino optionally substituted with one or more alkyl groups,
        • an amide optionally substituted with a C1 to C6 alkyl,
        • S-5 or 6 membered heterocycle,
        • S-5 or 6 membered heteroaryl optionally substituted with a C1 to C6 alkyl,
        • S—C1 to C6 alkyl,
        • S—C6 to C8 aryl,
        • sulfinyl-5 or 6 membered heterocycle,
        • sulfinyl-5 or 6 membered heteroaryl,
        • sulfinyl-C1 to C6 alkyl,
        • sulfinyl-C6 to C8 aryl,
        • sulfonyl-5 or 6 membered heterocycle,
        • sulfonyl-5 or 6 membered heteroaryl optionally substituted with a C1 to C6 alkyl,
        • sulfonyl-C1 to C6 alkyl,
        • sulfonyl-C6 to C8 aryl,
        • a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C1 to C6 alkyl group, the C1 to C6 alkyl group optionally substituted with one or more independently selected C1 to C6 alkoxy group,
        • a 5 or 6 membered heteroaryl group optionally substituted with one or more C1 to C6 alkyl groups,
        • a C6 to C8 aryl group;
      • a C6 to C8 aryl group;
      • an (O)-5 or 6 membered heterocycle;
      • an (O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected C1 to C6 alkyl groups;
      • a —C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
      • a —C(O)-5 or 6 membered heteroaryl;
      • a —C(O)—C6 to C8 aryl;
      • a —COOH group;
      • an amide group optionally substituted with one or more of the following:
        • C1 to C6 alkyl groups optionally substituted with one or more C1 to C6 alkoxy,
      • a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
        • hydroxy,
        • C1 to C6 alkyl,
        • SO2Rx,
        • C(O)—C6 to C8 aryl, or
        • C(O)ORx groups;
      • an —ORkk group, where Rkk is:
        • a C6 to C8 aryl,
        • a 5 to 6 membered heteroaryl,
        • a 5 to 6 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or
        • an —Si(Rx)3; and
          R3 is a hydrogen;
          with the proviso that at least one of X, Y, Z, R1, and R2 is selected from the following:
    X is:
      • a —COOH group;
  • Figure US20100305100A1-20101202-C00066
      • a halo;
      • an alkyl optionally substituted with one or more halo;
      • an alkyne optionally substituted with a C1 to C6 alkyl optionally substituted with one or more halo or cyano groups;
      • an oxime;
      • SO2Rx;
      • SO2NH2;
      • SO2NH(Rx);
      • SO2N(Rx)2;
      • an amino optionally substituted with one or more C1 to C6 alkyl groups or C(O)—C1 to C6 alkyl groups;
      • an amide group optionally substituted with one or more independently selected C1 to C6 alkyl group;
      • a 5 or 6 membered heterocycle;
      • a 5 or 6 membered heteroaryl substituted with one or more C1 to C6 alkyl groups substituted with one or more halos; or
      • a C6 to C8 aryl group substituted with one or more of the following:
        • C1 to C6 alkyl optionally substituted with one or more halos,
        • halo, or
        • cyano;
    Y is:
      • a benzothiazole substituted with an amino group optionally substituted with one or more C1 to C6 alkyls;
      • an indole substituted on the nitrogen with an SO2Rx group;
      • a C6 to C8 aryl substituted with one or more of the following:
        • an amino optionally substituted with one or more of the following:
          • SO2Rx, or
          • C1 to C6 alkyl substituted with one or more 5 or 6 membered heteroaryl group,
        • OC(O)NHRx,
        • OC(O)N(Rx)2,
        • OC(O)NH(ORx),
        • OC(O)NRx(ORx),
        • OC(O)N(ORx)2,
        • OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group,
        • a —NRoCORp group, where Rp is:
          • an amino group optionally substituted with one or more C1 to C6 alkyl groups where the C1 to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups, or
          • a 5 or 6 membered heterocycle, substituted with one or more C1 to C6 alkyl or C6 to C8 aryl groups,
        • a —NRqCONRqRr group, where Rr is:
          • a C1 to C6 alkyl substituted with one or more of the following:
            • a hydroxyl,
            • an alkoxy,
            • a 5 or 6 membered heterocycle,
            • a 5 or 6 membered heteroaryl, or
            • a C6 to C8 aryl substituted with a halo,
          • a C2 to C6 alkylene group,
          • a C1 to C6 alkoxy group,
          • a 5 or 6 membered heterocycle group,
        • a —NRtCOORu group, where Ru is:
          • a C1 to C12 alkyl, substituted with one or more groups independently selected from the following:
            • an alkoxy group substituted with one or more alkoxy groups,
            • an amino optionally substituted with one or more C1 to C6 alkyl, or
            • a 5 or 6 membered heteroaryl,
          • a C2 to C6 alkylene, or
  • Figure US20100305100A1-20101202-C00067
    • Z is:
      • a C1 to C6 alkyl substituted with a 5 or 6 membered heterocycle, or
      • a 5 or 6 membered heterocycle;
    R1 is:
      • a C1 to C6 alkyl substituted with:
      • an amide optionally substituted with a C1 to C6 alkyl, or
      • a 5 or 6 membered heteroaryl;
      • a C1 to C6 alkoxy substituted with:
        • an amino optionally substituted with a heterocycle,
        • an amide optionally substituted with a C1 to C6 alkyl,
        • a 5 or 6 membered heterocycle substituted with a C1 to C6 alkyl, or
        • a 5 or 6 membered heteroaryl;
      • an (O)-5 or 6 membered heterocycle;
      • an (O)-5 or 6 membered heteroaryl;
      • an —SO2Rx group optionally substituted with the following:
        • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl,
        • a 5 or 6 membered heteroaryl; or
      • alkylthio optionally substituted with the following:
        • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl,
        • a 5 or 6 membered heteroaryl; or
    R2 is:
      • a C1 to C6 alkyl group, substituted with one or more of the following:
        • 5 or 6 membered heterocycle groups,
        • 5 or 6 membered heteroaryl groups,
        • C6 to C8 aryl groups,
        • an amide optionally substituted with a C1 to C6 alkyl, or
        • amino groups optionally substituted with one or more heterocycle, alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups;
      • an alkylthio group optionally substituted with a 5 or 6 membered heteroaryl group optionally substituted with an alkyl group;
      • an alkylthio group optionally substituted with a 5 or 6 membered heterocycle group;
      • an alkylthio group optionally substituted with a C6 to C8 aryl group;
      • an alkylthio group optionally substituted with a C1 to C6 alkyl group;
      • an SO2Rx group optionally substituted with a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyl groups;
      • an SO2Rx group optionally substituted with a 5 or 6 membered heterocycle group;
      • an SO2Rx group optionally substituted with a C6 to C8 aryl group;
      • an SO2Rx group optionally substituted with a C1 to C6 alkyl group;
      • an S(O)Rx group optionally substituted with a 5 or 6 membered heteroaryl group;
      • an S(O)Rx group optionally substituted with a 5 or 6 membered heterocycle group;
      • an S(O)Rx group optionally substituted with a C6 to C8 aryl group;
      • an S(O)Rx group optionally substituted with a C1 to C6 alkyl group;
      • an alkoxy group substituted with an alkoxy group,
        • an amino group substituted with one or more 5 or 6 membered heteroaryl, 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
          • a 5 or 6 membered heterocycle, or
          • an amino optionally substituted with one or more alkyl groups;
        • an amide optionally substituted with a C1 to C6 alkyl,
        • S-5 or 6 membered heterocycle,
        • S-5 or 6 membered heteroaryl optionally substituted with a C1 to C6 alkyl,
        • S—C1 to C6 alkyl,
        • S—C6 to C8 aryl,
        • sulfinyl-5 or 6 membered heterocycle,
        • sulfinyl-5 or 6 membered heteroaryl,
        • sulfinyl-C1 to C6 alkyl,
        • sulfinyl-C6 to C8 aryl,
        • sulfonyl-5 or 6 membered heterocycle,
        • sulfonyl-5 or 6 membered heteroaryl optionally substituted with a C1 to C6 alkyl,
        • sulfonyl-C1 to C6 alkyl,
        • sulfonyl-C6 to C8 aryl,
        • a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected C1 to C6 alkyl groups substituted with C1 to C6 alkoxy, or
        • a 5 or 6 membered heteroaryl group substituted with one or more C1 to C6 alkyl groups
        • a C6 to C8 aryl group;
      • a —C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
      • a —C(O)—C6 to C8 aryl;
      • a —COOH group;
      • an amide group substituted with one or more C1 to C6 alkyl groups optionally substituted with one or more C1 to C6 alkoxy;
      • a 5 or 6 membered heterocycle, substituted with one or more of the following:
        • hydroxy,
        • C1 to C6 alkyl,
        • SO2Rx groups,
        • C(O)—C6 to C8 aryl, or
        • C(O)ORx groups;
      • an —ORkk group, where Rkk is:
        • a C6 to C8 aryl,
        • a 5 to 6 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or
        • an —Si(Rx)3;
      • an (O)-5 or 6 membered heterocycle; or
      • an (O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected C1 to C6 alkyl groups;
        or a pharmaceutically acceptable salt thereof.
  • In another embodiment, Formula I-XIb, a compound is provided wherein all substituents except X are as stated for Formula I-XI, and X is an electron withdrawing group. In a further embodiment, Formula I-XIc, a compound is provided wherein all substituents except X are as stated for Formula I-XIa, and X is an electron withdrawing group. As an example, an electron withdrawing group includes any electronegative element, which may be attached to or adjacent to an aromatic ring. By way of non-limiting example, an electron withdrawing group can include a cyano group, an alkynyl group, a nitro group, an oxime, a halo, a halosubstituted alkyl, a carbonyl group, a sulfonyl group, and a heterocycle. In an embodiment of the present invention, X is a cyano group. In another embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, X is a halo. In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, X is a fluorine, chlorine, bromine or iodine. In an embodiment of I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, X is a fluorine, bromine or iodine. In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, X is a fluorine or chlorine. In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, X is a fluorine. In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, X is a chlorine. In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, X is bromine. In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, X is iodine. In a further embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, X is an alkyl substituted with one or more halos. In another embodiment, X is a trifluoromethyl group.
  • In some embodiments, X is selected from the X substituents of compounds 1330-2128, and 2600-3348.
  • In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, X is selected from the group consisting of:
  • Figure US20100305100A1-20101202-C00068
    Figure US20100305100A1-20101202-C00069
  • In other non-limiting examples of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, or IIe, X is selected from the group consisting of
  • Figure US20100305100A1-20101202-C00070
  • In some embodiments, R1 is selected from the R1 substituents of compounds 1330-2128, and 2600-3348.
  • In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, R1 is selected from the group consisting of
  • Figure US20100305100A1-20101202-C00071
  • In another embodiment, the present invention includes compounds of Formula (I-XII)
  • Figure US20100305100A1-20101202-C00072
  • wherein:
    • X is:
      • a cyano group;
    Y is:
      • a benzothiazole optionally substituted with an amino group optionally substituted with one or more C1 to C6 alkyls;
      • an indole, optionally substituted on the nitrogen with an SO2Rx group;
      • a C6 to C8 aryl, optionally substituted with one or more of the following:
        • an alkoxy,
        • an amino optionally substituted with one or more of the following:
          • SO2Rx group, or
          • C1 to C6 alkyl, the C1 to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group,
        • OC(O)NHRx,
        • OC(O)N(Rx)2,
        • OC(O)NH(ORx),
        • OC(O)NRx(ORx),
        • OC(O)N(ORx)2,
        • OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group,
        • a —NRoCORp group, where Rp is:
          • a C1 to C6 alkyl,
          • an amino group optionally substituted with one or more C1 to C6 alkyl groups where the C1 to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups,
          • a 5 or 6 membered heterocycle, optionally substituted with one or more C1 to C6 alkyl or C6 to C8 aryl groups,
        • and where Ro is:
          • a hydrogen,
          • a C1 to C6 alkyl,
        • a —NRqCONRqRr group, where Rq is a hydrogen,
        • and where Rr is:
          • a C1 to C6 alkyl optionally substituted with one or more of the following:
            • a hydroxyl,
            • an alkoxy,
            • a 5 or 6 membered heterocycle,
            • a 5 or 6 membered heteroaryl, or
            • a C6 to C8 aryl optionally substituted with a halo,
          • a C2 to C6 alkylene group,
          • a C1 to C6 alkoxy group,
          • a 5 or 6 membered heterocycle group,
        • a —NRtCOORu group, where Ru is:
          • a C1 to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
            • a C6 to C8 aryl optionally substituted with halo,
            • an alkoxy group optionally substituted with one or more alkoxy groups,
            • an amino optionally substituted with one or more C1 to C6 alkyl,
            • halo, or
            • a 5 or 6 membered heteroaryl,
          • a C2 to C6 alkylene,
          • a C6 to C8 aryl, optionally substituted with halo,
        • and Rt is:
          • a hydrogen;
        • a —NHRbb group, where Rbb is:
          • a —C(═S)NH2 group, or
          • a —PO(ORx)2, where Rx is as defined above;
        • a —NRvSO2Rw group, where Rv is a hydrogen, and where Rw is a C1 to C6 alkyl,
  • Figure US20100305100A1-20101202-C00073
    • Z is:
      • a C1 to C6 alkyl optionally substituted with a 5 or 6 membered heterocycle, or
      • a 5 or 6 membered heterocycle;
        R is a hydrogen;
        R1 is a hydrogen;
    R2 is:
      • a C1 to C6 alkyl group, optionally substituted with one or more of the following:
        • 5 or 6 membered heterocycle groups,
        • amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups,
      • an alkoxy group optionally substituted with one or more groups independently selected from the following:
        • halo,
        • hydroxy group,
        • an alkoxy group optionally substituted with an alkoxy group,
        • an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
          • a 5 or 6 membered heterocycle, or
          • an amino optionally substituted with one or more alkyl groups;
        • a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C1 to C6 alkyl group, the C1 to C6 alkyl group optionally substituted with one or more independently selected C1 to C6 alkoxy group,
        • a 5 or 6 membered heteroaryl group optionally substituted with one or more C1 to C6 alkyl groups,
      • a —C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
      • a —COOH group;
      • an amide group optionally substituted with one or more —C1 to C6 alkyl groups;
      • a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
        • C1 to C6 alkyl,
        • SO2Rx,
        • C(O)—C6 to C8 aryl, or
        • C(O)ORx groups;
      • an —ORkk group, where Rkk is:
        • a 5 to 6 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or
        • an —Si(Rx)3;
          R3 is a hydrogen;
          or a pharmaceutically acceptable salt thereof.
  • In another embodiment, the present invention includes compound of Formula (I-XIIa)
  • Figure US20100305100A1-20101202-C00074
  • wherein:
    • X is:
      • a cyano group;
    Y is:
      • a benzothiazole optionally substituted with an amino group optionally substituted with one or more C1 to C6 alkyls;
      • an indole, optionally substituted on the nitrogen with an SO2Rx group;
      • a C6 to C8 aryl, optionally substituted with one or more of the following:
        • an alkoxy,
        • an amino optionally substituted with one or more of the following:
          • SO2Rx, or
          • C1 to C6 alkyl, the C1 to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group,
        • OC(O)NHRx,
        • OC(O)N(Rx)2,
        • OC(O)NH(ORx),
        • OC(O)NRx(ORx),
        • OC(O)N(ORx)2,
        • OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group,
        • a —NRoCORp group, where Rp is:
          • a C1 to C6 alkyl,
          • an amino group optionally substituted with one or more C1 to C6 alkyl groups where the C1 to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups,
          • a 5 or 6 membered heterocycle, optionally substituted with one or more C1 to C6 alkyl or C6 to C8 aryl groups,
        • and where Ro is:
          • a hydrogen,
          • a C1 to C6 alkyl,
        • a —NRqCONRqRr group, where Rq is a hydrogen,
        • and where Rr is:
          • a C1 to C6 alkyl optionally substituted with one or more of the following:
            • a hydroxyl,
            • an alkoxy,
            • a 5 or 6 membered heterocycle,
            • a 5 or 6 membered heteroaryl, or
            • a C6 to C8 aryl optionally substituted with a halo,
          • a C2 to C6 alkylene group,
          • a C1 to C6 alkoxy group,
          • a 5 or 6 membered heterocycle group,
        • a —NRtCOORu group, where Ru is:
          • a C1 to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
            • a C6 to C8 aryl optionally substituted with halo,
            • an alkoxy group optionally substituted with one or more alkoxy groups,
            • an amino optionally substituted with one or more C1 to C6 alkyl,
            • halo, or
            • a 5 or 6 membered heteroaryl,
          • a C2 to C6 alkylene,
          • a C6 to C8 aryl, optionally substituted with halo,
        • and Rt is:
          • a hydrogen;
        • a —NHRbb group, where Rbb is:
          • a —C(═S)NH2 group, or
          • a —PO(ORx)2, where Rx is as defined above;
        • a —NRvSO2Rw group, where Rv is a hydrogen, and where R1 is a C1 to C6 alkyl,
  • Figure US20100305100A1-20101202-C00075
    • Z is:
      • a C1 to C6 alkyl optionally substituted with: a 5 or 6 membered heterocycle, or
      • a 5 or 6 membered heterocycle;
        R is a hydrogen;
        R1 is a hydrogen;
    R2 is:
      • a C1 to C6 alkyl group, optionally substituted with one or more of the following:
        • 5 or 6 membered heterocycle groups,
        • amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups,
      • an alkoxy group optionally substituted with one or more groups independently selected from the following:
        • halo,
        • hydroxy group,
        • an alkoxy group optionally substituted with an alkoxy group,
        • an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
          • a 5 or 6 membered heterocycle, or
          • an amino optionally substituted with one or more alkyl groups;
        • a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C1 to C6 alkyl group, the C1 to C6 alkyl group optionally substituted with one or more independently selected C1 to C6 alkoxy group,
        • a 5 or 6 membered heteroaryl group optionally substituted with one or more C1 to C6 alkyl groups,
      • a —C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
      • a —COOH group;
      • an amide group optionally substituted with one or more C1 to C6 alkyl groups;
      • a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
        • C1 to C6 alkyl,
        • SO2Rx,
        • C(O)—C6 to C8 aryl, or
        • C(O)ORx groups;
      • an —ORkk group, where Rkk is:
        • a 5 to 6 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or
        • an —Si(Rx)3;
          R3 is a hydrogen;
          with the proviso that at least one of Y, Z, and R2 is selected from the following:
    Y is:
      • a benzothiazole substituted with an amino group optionally substituted with one or more C1 to C6 alkyls;
      • an indole substituted on the nitrogen with an —SO2Rx group;
      • a C6 to C8 aryl substituted with one or more of the following:
        • an amino optionally substituted with one or more of the following:
          • SO2Rx, or
          • C1 to C6 alkyl substituted with one or more 5 or 6 membered heteroaryl group,
        • OC(O)NHRx,
        • OC(O)N(Rx)2,
        • OC(O)NH(ORx),
        • OC(O)NRx(ORx),
        • OC(O)N(ORx)2,
        • OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group,
        • a —NRoCORp group, where Rp is:
          • an amino group optionally substituted with one or more C1 to C6 alkyl groups where the C1 to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups,
          • a 5 or 6 membered heterocycle, substituted with one or more C1 to C6 alkyl or C6 to C8 aryl groups,
        • a —NRqCONRqRr group, where Rr is:
          • a C1 to C6 alkyl substituted with one or more of the following:
            • a hydroxyl,
            • an alkoxy,
            • a 5 or 6 membered heterocycle,
            • a 5 or 6 membered heteroaryl, or
            • a C6 to C8 aryl substituted with a halo,
          • a C2 to C6 alkylene group,
          • a C1 to C6 alkoxy group,
          • a 5 or 6 membered heterocycle group,
        • a —NRtCOORu group, where Ru is:
          • a C1 to C12 alkyl, substituted with one or more groups independently selected from the following:
            • an alkoxy group substituted with one or more alkoxy groups,
            • an amino optionally substituted with one or more C1 to C6 alkyl, or
            • a 5 or 6 membered heteroaryl,
          • a C2 to C6 alkylene,
  • Figure US20100305100A1-20101202-C00076
    • Z is:
      • a C1 to C6 alkyl substituted with a 5 or 6 membered heterocycle, or
      • a 5 or 6 membered heterocycle;
    R2 is:
      • a C1 to C6 alkyl group, substituted with one or more of the following:
        • 5 or 6 membered heterocycle groups,
        • amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups,
      • an alkoxy group substituted with one or more groups independently selected from the following:
        • hydroxy group,
        • an alkoxy group optionally substituted with an alkoxy group,
        • an amino group substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
          • a 5 or 6 membered heterocycle, or
          • an amino optionally substituted with one or more alkyl groups;
        • a 7 membered heterocycle group;
        • a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected C1 to C6 alkyl groups substituted with C1 to C6 alkoxy, or
        • a 5 or 6 membered heteroaryl group substituted with one or more C1 to C6 alkyl groups;
      • a —C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
      • a —COOH group;
      • an amide group substituted with one or more C1 to C6 alkyl groups;
      • a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
        • C1 to C6 alkyl,
        • SO2Rx group,
        • C(O)—C6 to C8 aryl, or
        • C(O)ORx groups;
      • an —ORkk group, where Rkk is:
        • a 5 to 6 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or
        • an —Si(Rx)3;
          or a pharmaceutically acceptable salt thereof.
  • In another embodiment, the present invention includes compounds of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Y is a C6 to C8 aryl, optionally substituted with one or more of the following:
      • a —NRqCONRqRr group, where Rq is a hydrogen,
      • and where Rr is:
        • a C1 to C6 alkyl optionally substituted with one or more of the following:
          • a hydroxyl,
          • an alkoxy,
          • a 5 or 6 membered heterocycle,
          • a 5 or 6 membered heteroaryl, or
          • a C6 to C8 aryl optionally substituted with a halo,
        • a C2 to C6 alkylene group,
        • a C1 to C6 alkoxy group,
        • a 5 or 6 membered heterocycle group,
      • a —NRtCOORu group, where Ru is:
        • a C1 to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
          • a C6 to C8 aryl optionally substituted with halo,
          • an alkoxy group optionally substituted with one or more alkoxy groups,
          • an amino optionally substituted with one or more C1 to C6 alkyl,
          • halo, or
          • a 5 or 6 membered heteroaryl,
        • a C2 to C6 alkylene,
        • a C6 to C8 aryl, optionally substituted with halo,
      • and Rt is:
        • a hydrogen;
      • a —NHRbb group, where Rbb is:
        • a —C(═S)NH2 group, or
        • a —PO(ORx)2, where Rx is as defined above;
          or
      • a —NRvSO2Rw group, where Rv is a hydrogen, and where R1 is a C1 to C6 alkyl.
  • In another embodiment, the present invention includes compounds wherein Y is a C6 to C8 aryl, optionally substituted with:
      • a —NRqCONRqRr group, where Rq is a hydrogen,
      • and where Rr is:
        • a C1 to C6 alkyl optionally substituted with one or more of the following:
          • a hydroxyl,
          • an alkoxy,
          • a 5 or 6 membered heterocycle,
          • a 5 or 6 membered heteroaryl, or
          • a C6 to C8 aryl optionally substituted with a halo,
        • a C2 to C6 alkylene group,
        • a C1 to C6 alkoxy group, or
        • a 5 or 6 membered heterocycle group.
  • In a further embodiment, the present invention includes compounds wherein Y is a —NRtCOORu group, where Ru is:
      • a C1 to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
        • a C6 to C8 aryl optionally substituted with halo,
        • an alkoxy group optionally substituted with one or more alkoxy groups,
        • an amino optionally substituted with one or more C1 to C6 alkyl,
        • halo, or
        • a 5 or 6 membered heteroaryl,
      • a C2 to C6 alkylene,
      • a C6 to C8 aryl, optionally substituted with halo,
  • and Rt is:
      • a hydrogen.
  • In yet another embodiment, the present invention includes compounds of the following:
  • 1. A compound of formula IIa
  • Figure US20100305100A1-20101202-C00077
  • or a pharmaceutically acceptable salt thereof, wherein:
    • X is:
      • cyano;
      • nitro;
      • formyl;
      • COOH;
      • CORx, wherein Rx is C1 to C6 alkyl;
      • CH═N—(C1 to C6 alkoxy);
      • CH═N-(amino optionally substituted with one or more C1 to C6 alkyls);
      • halo;
      • alkyl optionally substituted with one or more halos;
      • alkynyl optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos;
      • oximyl;
      • SO2Rx;
      • SO2NH2;
      • SO2NH(Rx);
      • SO2N(Rx)2;
      • amino optionally substituted with one or more C1 to C6 alkyls and/or —C(O)—C1 to C6 alkyls;
      • amido optionally substituted with one or more independently selected C1 to C6 alkyls;
      • 5 or 6 membered heterocyclo;
      • 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more halos; or
      • C6 to C8 aryl optionally substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more halos;
        • halo; and
        • cyano;
    Y is:
      • benzothiazolyl optionally substituted with amino, which amino is optionally substituted with one or more C1 to C6 alkyls;
      • indolyl optionally substituted on the nitrogen with —SO2Rx;
      • C6 to C8 aryl optionally substituted with one or more substituents independently selected from:
        • halos;
        • C1 to C6 alkyl;
        • alkoxy optionally substituted with one or more substituents independently selected from:
          • one or more halos; and
          • 5 or 6 membered heterocyclo;
        • hydroxy;
        • amino optionally substituted with one or more substituents independently selected from:
          • SO2Rx;
          • C1 to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryls; and
          • PO2Rx;
        • OC(O)NHRx;
        • OC(O)N(Rx)2;
        • OC(O)NH(ORx);
        • OC(O)NRx(ORx);
        • OC(O)N(ORx)2;
        • OC(O)Rab, wherein Rab is 5 or 6 membered heterocyclo;
        • NRoCORp, wherein Rp is:
          • C1 to C6 alkyl;
          • amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally and independently substituted with one or more C6 to C8 aryls and/or alkoxys; or
          • 5 or 6 membered heterocyclo optionally substituted with one or more C1 to C6 alkyls and/or C6 to C8 aryls;
        • and wherein Ro is:
          • hydrogen; or
          • C1 to C6 alkyl;
        • NRqCONRqRr, wherein Rq is hydrogen;
        • and wherein Rr is:
          • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
            • halo;
            • hydroxy;
            • alkoxy;
            • 5 or 6 membered heterocyclo;
            • 5 or 6 membered heteroaryl; and
            • C6 to C8 aryl optionally substituted with one or more halos;
            • C2 to C6 alkenyl optionally substituted with one or more halos;
            • C1 to C6 alkoxy; or
            • 5 or 6 membered heterocyclo;
          • SO2Raa, wherein Raa is:
            • 5 or 6 heterocyclo optionally substituted with hydroxy;
            • C1 to C6 alkoxy; or
            • C1 to C6 alkyl;
          • CORm, wherein Rm is:
            • amino optionally substituted with one or more C1 to C6 alkyls, wherein the C1 to C6 alkyls are optionally substituted with a 5 or 6 membered heterocyclo; or
            • 3 to 7 membered heterocyclo optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with dialkyl-amino;
          • NRtCOORu wherein Rt is hydrogen, and wherein Ru is:
            • C1 to C12 alkyl optionally substituted with one or more substituents independently selected from:
            •  C6 to C8 aryl optionally substituted with one or more halos and/or haloalkyls;
            •  alkoxy optionally substituted with one or more alkoxys;
            •  amino optionally substituted with one or more C1 to C6 alkyls;
            •  halo;
            •  5 or 6 membered heteroaryl; and
            •  5 or 6 membered heterocyclo;
          • C2 to C6 alkenyl; or
          • C6 to C8 aryl optionally substituted with halo;
        • NHRbb, wherein Rbb is:
          • C(═S)NH2; or
          • PO(OR)2;
        • NRvSO2Rw wherein Rv is hydrogen, and wherein Rw is:
          • C1 to C6 alkyl; or
          • alkyl- or dialkyl-amino optionally substituted with halo;
  • Figure US20100305100A1-20101202-C00078
    • Z is:
      • C1 to C6 alkyl optionally substituted with 5 or 6 membered heterocyclo; or
      • 5 or 6 membered heterocyclo;
        R is hydrogen;
    R1 is:
      • hydrogen;
      • 5 or 6 membered heterocyclo;
      • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
        • amino optionally substituted with heterocyclo;
        • amido optionally substituted with C1 to C6 alkyl;
        • 5 or 6 membered heterocyclo optionally substituted with C1 to C6 alkyl;
        • 5 or 6 membered heteroaryl; and
        • C6 to C8 aryl;
      • C1 to C6 alkoxy optionally substituted with one or more substituents independently selected from:
        • amino optionally substituted with heterocyclo;
        • amido optionally substituted with C1 to C6 alkyl;
        • 5 or 6 membered heterocyclo optionally substituted with C1 to C6 alkyl;
        • 5 or 6 membered heteroaryl; and
        • C6 to C8 aryl;
      • (O)-5 or 6 membered heterocyclo;
      • (O)-5 or 6 membered heteroaryl;
      • SO2Rx optionally substituted with one or more substituents independently selected from:
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and
        • 5 or 6 membered heteroaryl; or
      • alkylthio optionally substituted with one or more substituents independently selected from:
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and
        • 5 or 6 membered heteroaryl;
    R2 is:
      • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
        • 5 or 6 membered heterocyclo;
        • 5 or 6 membered heteroaryl;
        • C6 to C8 aryl;
        • amido optionally substituted with C1 to C6 alkyl; and
        • amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys;
      • alkylthio optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with alkyl;
      • alkylthio optionally substituted with 5 or 6 membered heterocyclo;
      • alkylthio optionally substituted with C6 to C8 aryl;
      • alkylthio optionally substituted with C1 to C6 alkyl;
      • SO2Rx optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more C1 to C6 alkyls;
      • SO2Rx optionally substituted with 5 or 6 membered heterocyclo;
      • SO2Rx optionally substituted with C6 to C8 aryl;
      • SO2Rx optionally substituted with C1 to C6 alkyl;
      • S(O)Rx optionally substituted with 5 or 6 membered heteroaryl;
      • S(O)Rx optionally substituted with 5 or 6 membered heterocyclo;
      • S(O)Rx optionally substituted with C6 to C8 aryl;
      • S(O)Rx optionally substituted with C1 to C6 alkyl;
      • alkoxy optionally substituted with one or more substituents independently selected from:
        • halo;
        • hydroxy;
        • alkoxy optionally substituted with alkoxy;
        • amino optionally substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
          • 5 or 6 membered heterocyclo; and
          • amino optionally substituted with one or more alkyls;
        • amido optionally substituted with C1 to C6 alkyl;
        • S-5 or 6 membered heterocyclo;
        • S-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
        • S—C1 to C6 alkyl;
        • S—C6 to C8 aryl;
        • sulfinyl-5 or 6 membered heterocyclo;
        • sulfinyl-5 or 6 membered heteroaryl;
        • sulfinyl-C1 to C6 alkyl;
        • sulfinyl-C6 to C8 aryl;
        • sulfonyl-5 or 6 membered heterocyclo;
        • sulfonyl-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
        • sulfonyl-C1 to C6 alkyl;
        • sulfonyl-C6 to C8 aryl;
        • 5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
        • 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls; and
        • C6 to C8 aryl;
      • C6 to C8 aryl;
      • (O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected C1 to C6 alkyls;
      • C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C6 to C8 aryls;
      • C(O)—C6 to C8 aryl;
      • COOH;
      • C(O)NH2 optionally substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
      • amido optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more C1 to C6 alkoxys;
      • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl; and
      • 5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
        • hydroxy;
        • C1 to C6 alkyl;
        • SO2Rx;
        • C(O)—C6 to C8 aryl; and
        • C(O)ORx; or
      • ORkk, wherein R is:
        • C6 to C8 aryl;
        • 5 or 6 membered heterocyclo optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with C6 to C8 aryl;
        • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl;
        • SO2Rx; or
        • Si(Rx)3; and
          R3 is hydrogen;
          with the proviso that at least one of X, Y, Z, R1, and R2 is selected from the following:
    X is:
      • COOH;
      • CH═N—(C1 to C6 alkoxy);
      • CH═N-(amino optionally substituted with one or more C1 to C6 alkyls);
      • halo;
      • alkyl optionally substituted with one or more halos;
      • alkynyl optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos;
      • oximyl;
      • SO2Rx;
      • SO2NH2;
      • SO2NH(Rx);
      • SO2N(Rx)2;
      • amino optionally substituted with one or more C1 to C6 alkyls and/or —C(O)—C1 to C6 alkyls;
      • amido optionally substituted with one or more independently selected C1 to C6 alkyls;
      • 5 or 6 membered heterocyclo;
      • 5 or 6 membered heteroaryl substituted with one or more C1 to C6 alkyls, which alkyls are substituted with one or more halos; or
      • C6 to C8 aryl substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more halos;
        • halo; and
        • cyano;
    Y is:
      • benzothiazolyl substituted with amino, which amino is optionally substituted with one or more C1 to C6 alkyls;
      • indolyl substituted on the nitrogen with SO2Rx; or
      • C6 to C8 aryl substituted with one or more substituents independently selected from:
        • amino optionally substituted with one or more substituents independently selected from:
          • SO2Rx, and
          • C1 to C6 alkyl substituted with one or more 5 or 6 membered heteroaryls;
        • OC(O)NHRx;
        • OC(O)N(Rx)2;
        • OC(O)NH(ORx);
        • OC(O)NRx(ORx);
        • OC(O)N(ORx)2;
        • OC(O)Rab, wherein Rab is 5 or 6 membered heterocyclo;
        • NRoCORp, wherein Rp is:
          • amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally and independently substituted with one or more C6 to C8 aryls and/or alkoxys, or
          • 5 or 6 membered heterocyclo substituted with one or more C1 to C6 alkyls and/or C6 to C8 aryls,
        • NRqCONRqRr, wherein Rr is:
          • C1 to C6 alkyl substituted with one or more substituents independently selected from:
            • hydroxy;
            • alkoxy;
            • 5 or 6 membered heterocyclo;
            • 5 or 6 membered heteroaryl; and
            • C6 to C8 aryl substituted with one or more halos;
          • C2 to C6 alkenyl;
          • C1 to C6 alkoxy; or
          • 5 or 6 membered heterocyclo;
        • NRtCOORu wherein Ru is:
          • C1 to C12 alkyl substituted with one or more substituents independently selected from:
            • alkoxy substituted with one or more alkoxys;
            • amino optionally substituted with one or more C1 to C6 alkyls; and
            • 5 or 6 membered heteroaryl; or
          • C2 to C6 alkenyl; and
  • Figure US20100305100A1-20101202-C00079
    • Z is:
      • C1 to C6 alkyl substituted with 5 or 6 membered heterocyclo; or
      • 5 or 6 membered heterocyclo;
    R1 is:
      • C1 to C6 alkyl substituted with:
        • amido optionally substituted with C1 to C6 alkyl; and/or
        • 5 or 6 membered heteroaryl;
      • C1 to C6 alkoxy substituted with:
        • amino optionally substituted with heterocyclo;
        • amido optionally substituted with C1 to C6 alkyl;
        • 5 or 6 membered heterocyclo substituted with C1 to C6 alkyl; and/or
        • 5 or 6 membered heteroaryl;
      • (O)-5 or 6 membered heterocyclo;
      • (O)-5 or 6 membered heteroaryl;
      • SO2Rx optionally substituted with:
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and/or
        • 5 or 6 membered heteroaryl; or
      • alkylthio optionally substituted with:
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and/or
        • 5 or 6 membered heteroaryl;
    R2 is:
      • C1 to C6 alkyl substituted with one or more substituents independently selected from:
        • 5 or 6 membered heterocyclo;
        • 5 or 6 membered heteroaryl;
        • C6 to C8 aryl;
        • amido optionally substituted with C1 to C6 alkyl; and
        • amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys;
      • alkylthio optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with alkyl;
      • alkylthio optionally substituted with 5 or 6 membered heterocyclo;
      • alkylthio optionally substituted with C6 to C8 aryl;
      • alkylthio optionally substituted with C1 to C6 alkyl;
      • SO2Rx optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more C1 to C6 alkyls;
      • SO2Rx optionally substituted with 5 or 6 membered heterocyclo;
      • SO2Rx optionally substituted with C6 to C8 aryl;
      • SO2Rx optionally substituted with C1 to C6 alkyl;
      • S(O)Rx optionally substituted with 5 or 6 membered heteroaryl;
      • S(O)Rx optionally substituted with 5 or 6 membered heterocyclo;
      • S(O)Rx optionally substituted with C6 to C8 aryl;
      • S(O)Rx optionally substituted with C1 to C6 alkyl;
      • alkoxy substituted with:
        • alkoxy;
        • amino substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
          • 5 or 6 membered heterocyclos; and
          • amino optionally substituted with one or more alkyls;
        • amido optionally substituted with C1 to C6 alkyl;
        • S-5 or 6 membered heterocyclo;
        • S-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
        • S—C1 to C6 alkyl;
        • S—C6 to C8 aryl;
        • sulfinyl-5 or 6 membered heterocyclo;
        • sulfinyl-5 or 6 membered heteroaryl;
        • sulfinyl-C1 to C6 alkyl;
        • sulfinyl-C6 to C8 aryl;
        • sulfonyl-5 or 6 membered heterocyclo;
        • sulfonyl-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
        • sulfonyl-C1 to C6 alkyl;
        • sulfonyl-C6 to C8 aryl;
        • 5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and C1 to C6 alkyl, which alkyl is substituted with one or more C1 to C6 alkoxys;
        • 5 or 6 membered heteroaryl substituted with one or more C1 to C6 alkyls; or
        • C6 to C8 aryl;
      • C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C6 to C8 aryls;
      • C(O)—C6 to C8 aryl;
      • COOH;
      • amido substituted with one or more C1 to C6 alkyls optionally substituted with one or more C1 to C6 alkoxys;
      • 5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
        • hydroxy;
        • C1 to C6 alkyl;
        • SO2Rx;
        • C(O)—C6 to C8 aryl; and
        • C(O)ORx;
      • ORkk, wherein Rkk is:
        • C6 to C8 aryl;
        • 5 or 6 membered heterocyclo optionally substituted with C1 to C6 alkyl and/or C6 to C8 aryl; or
        • Si(Rx)3;
      • (O)-5 or 6 membered heterocyclo optionally substituted with one or more independently selected C1 to C6 alkyls; or
      • (O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected C1 to C6 alkyls.
        2. The compound of embodiment 1, wherein:
    X is:
      • COOH;
      • CH═N—(C1 to C6 alkoxy);
      • CH═N-(amino optionally substituted with one or more C1 to C6 alkyls);
      • halo;
      • alkyl optionally substituted with one or more halos;
      • alkynyl optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos;
      • oximyl;
      • SO2Rx;
      • SO2NH2;
      • SO2NH(Rx);
      • SO2N(Rx)2;
      • amino optionally substituted with one or more C1 to C6 alkyls and/or —C(O)—C1 to C6 alkyls;
      • amido optionally substituted with one or more independently selected C1 to C6 alkyls;
      • 5 or 6 membered heterocyclo;
      • 5 or 6 membered heteroaryl substituted with one or more C1 to C6 alkyls, which alkyls are substituted with one or more halos; or
      • C6 to C8 aryl substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more halos;
        • halo; and
        • cyano.
          3. The compound of embodiment 2, wherein X is cyano, halo, or alkyl substituted with one or more halos.
          4. The compound of embodiment 3, wherein X is cyano.
          5. The compound of embodiment 3, wherein X is fluoro, bromo, chloro, or iodo.
          6. The compound of embodiment 3, wherein X is trifluoromethyl.
          7. The compound of embodiment 1, wherein:
          Y is C6 to C8 aryl substituted with one or more of the following:
      • amino optionally substituted with one or more substituents independently selected from:
        • SO2Rx; and
        • C1 to C6 alkyl substituted with one or more 5 or 6 membered heteroaryls;
      • OC(O)NHRx;
      • OC(O)N(Rx)2;
      • OC(O)NH(ORx);
      • OC(O)NRx(ORx);
      • OC(O)N(ORx)2;
        • OC(O)Rab, wherein Rab is 5 or 6 membered heterocyclo;
      • NRoCORp, wherein Rp is:
        • amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally and independently substituted with one or more C6 to C8 aryls and/or alkoxys; or
        • 5 or 6 membered heterocyclo substituted with one or more C1 to C6 alkyls and/or C6 to C8 aryls;
      • NRqCONRqRr, wherein Rr is:
        • C1 to C6 alkyl substituted with one or more substituents independently selected from:
          • hydroxy;
          • alkoxy;
          • 5 or 6 membered heterocyclo;
          • 5 or 6 membered heteroaryl; and
          • C6 to C8 aryl substituted with halo;
        • C2 to C6 alkenyl;
        • C1 to C6 alkoxy; or
        • 5 or 6 membered heterocyclo;
      • NRtCOORu, wherein Ru is:
        • C1 to C12 alkyl substituted with one or more substituents independently selected from the following:
          • alkoxy substituted with one or more alkoxys;
          • amino optionally substituted with one or more C1 to C6 alkyls; and
          • 5 or 6 membered heteroaryl;
        • C2 to C6 alkenyl, or
  • Figure US20100305100A1-20101202-C00080
  • 8. The compound of embodiment 7, wherein C6 to C8 aryl is phenyl.
    9. The compound of embodiment 8, wherein phenyl has at least one substituent at the para position.
    10. The compound of embodiment 1, wherein Z is:
      • C1 to C6 alkyl substituted with 5 or 6 membered heterocyclo; or
      • 5 or 6 membered heterocyclo.
        11. The compound of embodiment 1, wherein Z is C1 to C6 alkyl.
        12. The compound of embodiment 11, wherein Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl.
        13. The compound of embodiment 1, wherein:
    R1 is:
      • C1 to C6 alkyl substituted with:
        • amido optionally substituted with C1 to C6 alkyl; and/or
        • 5 or 6 membered heteroaryl;
      • C1 to C6 alkoxy substituted with:
        • amino optionally substituted with heterocyclo;
        • amido optionally substituted with C1 to C6 alkyl;
        • 5 or 6 membered heterocyclo substituted with C1 to C6 alkyl; and/or
        • 5 or 6 membered heteroaryl; —(O)-5 or 6 membered heterocyclo;
      • (O)-5 or 6 membered heteroaryl;
      • SO2Rx optionally substituted with:
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and/or
        • 5 or 6 membered heteroaryl; or
      • alkylthio optionally substituted with:
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and/or
        • 5 or 6 membered heteroaryl.
          14. The compound of embodiment 1, wherein:
    R2 is:
      • C1 to C6 alkyl substituted with one or more substituents independently selected from:
        • 5 or 6 membered heterocyclo;
        • 5 or 6 membered heteroaryl;
        • C6 to C8 aryl;
        • amido optionally substituted with C1 to C6 alkyl; and
        • amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys;
      • alkylthio optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with alkyl;
      • alkylthio optionally substituted with 5 or 6 membered heterocyclo;
      • alkylthio optionally substituted with C6 to C8 aryl;
      • alkylthio optionally substituted with C1 to C6 alkyl;
      • SO2Rx optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more C1 to C6 alkyls;
      • SO2Rx optionally substituted with 5 or 6 membered heterocyclo;
      • SO2Rx optionally substituted with C6 to C8 aryl;
      • SO2Rx optionally substituted with C1 to C6 alkyl;
      • S(O)Rx optionally substituted with 5 or 6 membered heteroaryl;
      • S(O)Rx optionally substituted with 5 or 6 membered heterocyclo;
      • S(O)Rx optionally substituted with C6 to C8 aryl;
      • S(O)Rx optionally substituted with C1 to C6 alkyl;
      • alkoxy substituted with:
        • alkoxy;
        • amino substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
          • 5 or 6 membered heterocyclos; and
          • amino optionally substituted with one or more alkyls;
        • amido optionally substituted with C1 to C6 alkyl;
        • S-5 or 6 membered heterocyclo;
        • S-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
        • S—C1 to C6 alkyl;
        • S—C6 to C8 aryl;
        • sulfinyl-5 or 6 membered heterocyclo;
        • sulfinyl-5 or 6 membered heteroaryl;
        • sulfinyl-C1 to C6 alkyl;
        • sulfinyl-C6 to C8 aryl;
        • sulfonyl-5 or 6 membered heterocyclo;
        • sulfonyl-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
        • sulfonyl-C1 to C6 alkyl;
        • sulfonyl-C6 to C8 aryl;
        • 5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and C1 to C6 alkyl, which alkyl is substituted with C1 to C6 alkoxy;
        • 5 or 6 membered heteroaryl substituted with one or more C1 to C6 alkyls; or
        • C6 to C8 aryl;
      • C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C6 to C8 aryls;
      • C(O)—C6 to C8 aryl;
      • COOH;
      • amido substituted with one or more C1 to C6 alkyls optionally substituted with one or more C1 to C6 alkoxys;
      • 5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
        • hydroxy;
        • C1 to C6 alkyl;
        • SO2Rx;
        • C(O)—C6 to C8 aryl; and
        • C(O)ORx;
      • ORkk, wherein Rkk is:
        • C6 to C8 aryl;
        • 5 or 6 membered heterocyclo optionally substituted with C1 to C6 alkyl and/or C6 to C8 aryl; or
        • Si(Rx)3;
      • (O)-5 or 6 membered heterocyclo; or
      • (O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected C1 to C6 alkyls.
        15. The compound of embodiment 1, wherein:
    X is:
      • cyano;
      • halo; or
      • alkynyl optionally substituted with C1 to C6 alkyl;
    Y is:
      • C6 to C8 aryl substituted with one or more substituents independently selected from:
        • halo;
        • hydroxy;
        • alkoxy optionally substituted with:
          • one or more halos; or
          • 5 or 6 membered heterocyclo;
        • C1 to C6 alkyl;
        • amino optionally substituted with one or more substituents independently selected from:
          • SO2Rx; and
          • C1 to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryls;
        • OC(O)NHRx;
        • NRoCORp, wherein Rp is:
          • C1 to C6 alkyl; or
          • amino optionally substituted with one or more C1 to C6 alkyls;
        • and wherein Ro is hydrogen;
        • NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is:
          • C1 to C6 alkyl optionally substituted with one or more halos; or
          • C6 to C8 aryl optionally substituted with halo;
        • SO2Raa, wherein Raa is:
          • 5 or 6 heterocyclo optionally substituted with hydroxy;
          • C1 to C6 alkoxy; or
          • C1 to C6 alkyl;
        • CORm, wherein Rm is:
          • amino optionally substituted with one or more C1 to C6 alkyls, wherein the C1 to C6 alkyls are optionally substituted with a 5 or 6 membered heterocyclo; or
          • 3 to 7 membered heterocyclo optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with dialkyl-amino;
        • NRtCOORu, wherein Rt is hydrogen, and wherein Ru is:
          • C1 to C12 alkyl optionally substituted with one or more substituents independently selected from:
            • C6 to C8 aryl optionally substituted with one or more halos and/or haloalkyls;
            • halo; and
            • 5 or 6 membered heteroaryl;
          • C6 to C8 aryl optionally substituted with halo; or
          • 5 or 6 membered heterocyclo;
        • NHRbb, wherein Rbb is:
          • C(═S)NH2; or
          • PO(ORx)2;
        • NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is:
          • C1 to C6 alkyl; or
          • alkyl- or dialkyl-amino optionally substituted with halo; or
  • Figure US20100305100A1-20101202-C00081
    • Z is:
      • C1 to C6 alkyl; or
      • 5 or 6 membered heterocyclo;
        R is hydrogen;
    R1 is:
      • hydrogen;
      • C1 to C6 alkoxy substituted with one or more substituents independently selected from:
        • 5 or 6 membered heterocyclo; and
        • 5 or 6 membered heteroaryl;
      • (O)-5 or 6 membered heterocyclo;
      • (O)-5 or 6 membered heteroaryl; or
      • 5 or 6 membered heterocyclo;
    R2 is:
      • alkoxy substituted with one or more substituents independently selected from:
        • halo;
        • hydroxy;
        • alkoxy optionally substituted with alkoxy;
        • amino optionally substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
          • 5 or 6 membered heterocyclo; and
          • amino optionally substituted with one or more alkyl;
        • amido optionally substituted with C1 to C6 alkyl;
        • S-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
        • S—C1 to C6 alkyl;
        • sulfinyl-C1 to C6 alkyl;
        • sulfonyl-C1 to C6 alkyl;
        • 5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy and C1 to C6 alkyl, which alkyl is optionally substituted with one or more independently selected C1 to C6 alkoxys; and
        • 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls;
      • SO2Rx optionally substituted with C1 to C6 alkyl;
      • S(O)Rx optionally substituted with C1 to C6 alkyl;
      • (O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected C1 to C6 alkyls;
      • C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C6 to C8 aryls;
      • C(O)—C6 to C8 aryl;
      • COOH;
      • C(O)NH2 optionally substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
      • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl; and,
      • 5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
        • one or more halos;
        • C1 to C6 alkyl; and
        • SO2Rx;
      • amido optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more C1 to C6 alkoxys; or
      • ORkk, wherein Rkk is:
        • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl; or
        • 5 or 6 membered heterocyclo optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with C6 to C8 aryl; and
          R3 is hydrogen.
          16. The compound of embodiment 15, wherein:
    X is:
      • cyano; or
      • halo;
    Y is:
      • phenyl substituted with one or more substituents independently selected from:
        • halo; and
        • NRtCOORu, wherein Rt is hydrogen, and wherein Ru is:
          • C1 to C12 alkyl optionally substituted with one or more substituents independently selected from:
            • C6 to C8 aryl optionally substituted with one or more halos;
            • halo; and
            • 5 or 6 membered heteroaryl;
          • C6 to C8 aryl optionally substituted with halo; or
          • 5 or 6 membered heterocyclo;
            Z is C1 to C6 alkyl;
            R is hydrogen;
            R1 is hydrogen;
    R2 is:
      • alkoxy substituted with one or more substituents independently selected from:
        • halo; and
        • alkoxy optionally substituted with alkoxy;
      • (O)-5 or 6 membered heterocyclo;
      • amido optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more C1 to C6 alkoxys;
      • 5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
        • one or more halos;
        • C1 to C6 alkyl; and
        • SO2Rx; and
          R3 is hydrogen.
          17. The compound of embodiment 15, wherein:
          X is cyano;
          Y is C6 to C8 aryl substituted with one or more substituents independently selected from NRtCOORu, wherein is hydrogen, and wherein Ru is C1 to C12 alkyl optionally substituted with one or more C6 to C8 aryls;
          Z is 5 or 6 membered heterocyclo;
          R is hydrogen;
          R1 is hydrogen;
          R2 is alkoxy; and
          R3 is hydrogen.
          18. The compound of embodiment 15, wherein:
          X is cyano;
          Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
      • amino optionally substituted with C1 to C6 alkyl;
      • NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is C1 to C6 alkyl;
      • CORm wherein Rm is:
        • amino optionally substituted with one or more C1 to C6 alkyls, wherein the C1 to C6 alkyls are optionally substituted with a 5 or 6 membered heterocyclo; or
        • 3 to 7 membered heterocyclo; and
      • NRtCOORu, wherein Rt is hydrogen, and wherein Ru is:
        • C1 to C12 alkyl optionally substituted with one or more substituents independently selected from:
          • C6 to C8 aryl optionally substituted with one or more haloalkyls; and
          • halo; or
        • 5 or 6 membered heterocyclo;
          Z is C1 to C6 alkyl;
          R is hydrogen;
          R1 is hydrogen;
          R2 is alkoxy substituted with alkoxy; and
          R3 is hydrogen.
          19. The compound of embodiment 15, wherein:
          X is cyano;
          Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
      • NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl optionally substituted with one or more halos; and
      • NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is C1 to C6 alkyl;
        Z is C1 to C6 alkyl;
        R is hydrogen;
        R1 is hydrogen;
        R2 is amido optionally substituted with one or more C1 to C6 alkyls, which alkyls are substituted with one or more C1 to C6 alkoxys; and
        R3 is hydrogen.
        20. The compound of embodiment 15, wherein:
        X is cyano;
        Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
      • amino optionally substituted with one or more C1 to C6 alkyls;
      • NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl optionally substituted with one or more halos;
      • NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is C1 to C6 alkyl; and
  • Figure US20100305100A1-20101202-C00082
  • Z is C1 to C6 alkyl;
    R is hydrogen;
    R1 is hydrogen;
    R2 is alkoxy substituted with sulfonyl-C1 to C6 alkyl; and
    R3 is hydrogen.
    21. The compound of embodiment 15, wherein Y is C6 to C8 aryl substituted with one or more substituents independently selected from NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl optionally substituted with one or more halos.
    22. The compound of embodiment 15, wherein:
    X is cyano;
    Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
      • C1 to C6 alkyl;
      • amino optionally substituted with one or more C1 to C6 alkyls;
      • NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is C1 to C6 alkyl;
      • NRtCOORu, wherein Rt is hydrogen, and wherein Ru, is C1 to C12 alkyl;
      • NRvSO2Rw, wherein Rv is hydrogen and wherein Rw is:
        • C1 to C6 alkyl; or
        • alkyl- or dialkyl-amino;
          Z is C1 to C6 alkyl;
          R is hydrogen;
          R1 is hydrogen;
          R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl; and
          R3 is hydrogen.
          23. The compound of embodiment 22, wherein:
          X is cyano;
          Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
      • NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl; and
      • NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is:
        • C1 to C6 alkyl; or
        • alkyl- or dialkyl-amino;
          Z is C1 to C6 alkyl;
          R is hydrogen;
          R1 is hydrogen;
          R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl; and
          R3 is hydrogen.
          24. The compound of embodiment 22, wherein R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with one or more C1 to C6 haloalkyls.
          25. The compound of embodiment 22, wherein R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with one or more C1 to C6 alkyls.
          26. The compound of embodiment 1, wherein:
          X is cyano;
          Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
      • NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl; and
      • NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is C1 to C6 alkyl;
        Z is C1 to C6 alkyl;
        R is hydrogen;
        R1 is hydrogen;
        R2 is C(O)-5 or 6 membered heterocyclo; and
        R3 is hydrogen.
        27. The compound of embodiment 1, wherein:
        X is halo;
        Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
      • amino;
      • NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is C1 to C6 alkyl; and
      • NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl;
        Z is C1 to C6 alkyl;
        R is hydrogen;
        R1 is hydrogen;
        R2 is alkoxy; and
        R3 is hydrogen.
        28 The compound of embodiment 15 wherein:
        X is cyano;
        Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
      • halo;
      • NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is C1 to C6 alkyl;
      • NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl optionally substituted with one or more substituents independently selected from:
        • C6 to C8 aryl optionally substituted with one or more halos; and
        • halo;
      • NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is:
        • C1 to C6 alkyl; or
        • alkyl- or dialkyl-amino optionally substituted with halo; and
  • Figure US20100305100A1-20101202-C00083
  • Z is C1 to C6 alkyl;
    R is hydrogen;
    R1 is hydrogen;
    R2 is 5 or 6 membered heterocyclo; and
    R3 is hydrogen.
    29. The compound of embodiment 28, wherein Y is C6 to C8 aryl substituted with NRvSO2Rw, wherein Rw is hydrogen, and wherein Rw is C1 to C6 alkyl.
    30. The compound of embodiment 28 wherein Y is C6 to C8 aryl substituted with
  • Figure US20100305100A1-20101202-C00084
  • 31. The compound of embodiment 15, wherein:
    X is cyano;
    Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
      • halo;
      • amino optionally substituted with one or more C1 to C6 alkyls;
      • OC(O)NHRx;
      • NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is C1 to C6 alkyl;
      • NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl optionally substituted with one or more substituents independently selected from:
        • C6 to C8 aryl optionally substituted with one or more halos and/or haloalkyls; and
        • halo;
      • NHRbb, wherein Rbb is —C(═S)NH2;
        • NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is:
        • C1 to C6 alkyl; or
        • alkyl- or dialkyl-amino optionally substituted with halo; and
  • Figure US20100305100A1-20101202-C00085
  • Z is C1 to C6 alkyl;
    R is hydrogen;
    R1 is hydrogen;
    R2 is (O)-5 or 6 membered heterocyclo; and
    R3 is hydrogen.
    32. The compound of embodiment 31, wherein Y is C6 to C8 aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl optionally substituted with one or more substituents independently selected from C6 to C8 aryl optionally substituted with one or more halos and/or haloalkyls.
    33. The compound of embodiment 15, wherein:
    X is cyano;
    Y is C6 to C8 aryl substituted with one or more substituents independently selected from NRtCOORu, wherein Rt is hydrogen, and wherein R1 is C1 to C12 alkyl substituted with one or more halos;
    Z is C1 to C6 alkyl;
    R is hydrogen;
    • R1 is
      • hydrogen;
      • (O)-5 or 6 membered heterocyclo; or
      • 5 or 6 membered heterocyclo;
    R2 is:
      • alkoxy substituted with one or more substituents independently selected from:
        • halo;
        • alkoxy;
        • sulfonyl-C1 to C6 alkyl;
        • 5 to 7 membered heterocyclo;
        • 5 or 6 membered heteroaryl;
      • (O)-5 or 6 membered heterocyclo;
      • (O)-5 or 6 membered heteroaryl;
      • 5 or 6 membered heteroaryl;
      • 5 or 6 membered heterocyclo; or
      • ORkk, wherein Rkk is 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkoxys; and
        R3 is hydrogen.
        34. The compound of embodiment 33, wherein R1 is hydrogen, and R2 is alkoxy substituted with one or more halos.
        35. The compound of embodiment 33, wherein R1 is hydrogen; and R2 is alkoxy substituted with one or more alkoxys.
        36. The compound of embodiment 15, wherein:
        X is cyano;
        Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
      • NRqCONRqRr, wherein Rq is hydrogen; and wherein Rr is C6 to C8 aryl substituted with halo; and
      • NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl substituted with C6 to C8 aryl, which aryl is substituted with one or more halos and/or haloalkyls;
        Z is C1 to C6 alkyl;
        R is hydrogen;
        R1 is hydrogen;
    R2 is:
      • alkoxy substituted with one or more substituents independently selected from:
        • alkoxy; and
        • 5 or 6 membered heteroaryl;
      • (O)-5 or 6 membered heterocyclo; or
      • (O)-5 or 6 membered heteroaryl; and
        R3 is hydrogen.
        37. The compound of embodiment 36, wherein Y is C6 to C8 aryl substituted with NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is C6 to C8 aryl substituted with halo.
        38. The compound of embodiment 36, wherein Y is C6 to C8 aryl substituted with one or more substituents independently selected from NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl substituted with C6 to C8 aryl, which aryl is substituted with one or more halos and/or haloalkyls.
        39. A compound of formula IIb
  • Figure US20100305100A1-20101202-C00086
  • or a pharmaceutically acceptable salt thereof, wherein:
    X is cyano;
    Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
      • C1 to C6 alkyl;
      • amino substituted with C1 to C6 alkyl
      • NRtCOORu, wherein Rt is hydrogen, and wherein Ru, is C1 to C12 alkyl optionally substituted with one or more halos;
      • NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is C1 to C6 alkyl;
        Z is C1 to C6 alkyl;
        R is hydrogen;
        R1 is hydrogen;
    R2 is:
      • alkoxy substituted with one or more halos;
      • 5 or 6 membered heterocyclo;
      • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl; and
        • NO2,
      • C(O)-3 to 7 membered heterocyclo or —C(O)-5 membered heterocyclo; and
      • ORkk, wherein Rkk is:
      • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from cyano, and C1 to C6 alkyl; or
      • 5 or 6 membered heterocyclo optionally substituted with one or more ═O; and
        R3 is hydrogen.
        40. The compound of embodiment 39, wherein:
        X is a cyano group;
        Y is C6 to C8 aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru, is C1 to C12 alkyl substituted with one or more halos;
        Z is C1 to C6 alkyl;
        R is a hydrogen,
        R1 is a hydrogen;
        R2 is alkoxy substituted with one or more halos; and
        R3 is a hydrogen.
        41. The compound of embodiment 40, wherein the C6 to C8 aryl is phenyl.
        42. The compound of embodiment 41, wherein the phenyl is substituted at the para position.
        43. The compound of embodiment 41, wherein Ru is C1 to C12 alkyl substituted with fluoro.
        44. The compound of embodiment 39, wherein:
        X is cyano;
        Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
      • C1 to C6 alkyl;
      • amino substituted with C1 to C6 alkyl; and
      • NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is C1 to C6 alkyl;
        Z is C1 to C6 alkyl;
        R is hydrogen;
        R1 is hydrogen;
        R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with cyano; and
        R3 is hydrogen.
        45. The compound of embodiment 44, wherein Y is C6 to C8 aryl para substituted with NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is C1 to C6 alkyl.
        46. The compound of embodiment 44, wherein Y is C6 to C8 aryl para substituted with C1 to C6 alkyl and NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is C1 to C6 alkyl.
        47. The compound of embodiment 44, wherein Y is C6 to C8 aryl para substituted with amino substituted with C1 to C6 alkyl.
        48. The compound of embodiment 44, wherein R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with cyano at the ortho position.
        49. The compound of embodiment 39, wherein:
        X is cyano;
        Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
      • NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl; and
      • NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is C1 to C6 alkyl;
        Z is C1 to C6 alkyl;
        R is hydrogen;
        R1 is hydrogen;
        R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with C1 to C6 alkyl; and
        R3 is hydrogen.
        50. The compound of embodiment 49, wherein the C6 to C8 aryl is phenyl.
        51. The compound of embodiment 50, wherein Y is phenyl substituted at the para position with NRvSO2Rw, wherein Rv is hydrogen, and wherein R1 is C1 to C6 alkyl.
        52. The compound of embodiment 50, wherein Y is phenyl substituted at the para position with NRtCOORu, wherein Rt is hydrogen, and wherein Ru, is C1 to C12 alkyl.
        53. The compound of embodiment 39, wherein:
        X is cyano;
        Y is C6 to C8 aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl substituted with one or more halos;
        Z is C1 to C6 alkyl;
        R is hydrogen;
        R1 is hydrogen;
        R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl; and
        R3 is hydrogen.
        54. The compound of embodiment 53, wherein the C6 to C8 aryl is phenyl.
        55. The compound of embodiment 54, wherein the phenyl is substituted at the para position.
        56. The compound of embodiment 55, wherein Ru is C1 to C12 alkyl substituted with fluoro.
        57. The compound of embodiment 39, wherein:
        X is cyano;
        Y is C6 to C8 aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl optionally substituted with one or more halos;
        Z is C1 to C6 alkyl;
        R is hydrogen;
        R1 is hydrogen;
        R2 is 5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl; and
        R3 is hydrogen.
        58. The compound of embodiment 57, wherein the C6 to C8 aryl is phenyl.
        59. The compound of embodiment 58, wherein Y is phenyl substituted at the para position with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl.
        60. The compound of embodiment 58, wherein Y is phenyl substituted at the para position with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl substituted with one or more halos.
        61. The compound of embodiment 60, wherein Rt is C1 to C12 alkyl substituted with fluoro.
        62. The compound of embodiment 39, wherein:
        X is cyano;
        Y is C6 to C8 aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl;
        Z is C1 to C6 alkyl;
        R is hydrogen;
        R1 is hydrogen;
        R2 is ORkk, wherein Rkk is 5 or 6 membered heterocyclo; and
        R3 is hydrogen.
        63. The compound of embodiment 62, wherein the C6 to C8 aryl is phenyl.
        64. The compound of embodiment 63, wherein the phenyl is substituted at the para position.
        65. The compound of embodiment 39, wherein:
        X is cyano;
        Y is C6 to C8 aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl;
        Z is C1 to C6 alkyl;
        R is hydrogen;
        R1 is hydrogen;
        R2 is 5 or 6 membered heterocyclo; and
        R3 is hydrogen.
        66. The compound of embodiment 65, wherein the C6 to C8 aryl is phenyl.
        67. The compound of embodiment 66, wherein the phenyl is substituted at the para position.
        68. The compound of embodiment 39, wherein:
        X is cyano;
        Y is C6 to C8 aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl;
        Z is C1 to C6 alkyl;
        R is hydrogen;
        R1 is hydrogen;
        R2 is 5 or 6 membered heteroaryl substituted with NO2; and
        R3 is hydrogen.
        69. The compound of embodiment 68, wherein the C6 to C8 aryl is phenyl.
        70. The compound of embodiment 69, wherein the phenyl is substituted at the para position.
        71. The compound of embodiment 39, wherein:
        X is cyano;
        Y is C6 to C8 aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl;
        Z is C1 to C6 alkyl;
        R is hydrogen;
        R1 is hydrogen;
        R2 is —C(O)-3 to 7 membered heterocyclo or —C(O)-5 membered heterocyclo; and
        R3 is hydrogen.
        72. The compound of embodiment 71, wherein the C6 to C8 aryl is phenyl.
        73. The compound of embodiment 72, wherein the phenyl is substituted at the para position.
        74. The compound of embodiment 39, wherein:
        X is cyano;
        Y is C6 to C8 aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl;
        Z is C1 to C6 alkyl;
        R is hydrogen;
        R1 is hydrogen;
        R2 is ORkk, wherein Rkk is -5 or 6 membered heterocycle substituted with one or more ═O; and
        R3 is hydrogen.
        75. The compound of embodiment 74, wherein the C6 to C8 aryl is phenyl.
        76. The compound of embodiment 75, wherein the phenyl is substituted at the para position.
        77. A compound of formula IIc
  • Figure US20100305100A1-20101202-C00087
  • or a pharmaceutically acceptable salt thereof, wherein:
    X is cyano;
    Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
      • NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is C1 to C6 alkyl;
      • NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl optionally substituted with one or more substituents independently selected from:
        • C6 to C8 aryl optionally substituted with one or more halos;
        • halo; and
        • 5 or 6 membered heteroaryl; and
      • NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is C1 to C6 alkyl;
    Z is:
      • C1 to C6 alkyl; or
      • 5 or 6 membered heterocyclo;
        R is hydrogen;
    R1 is:
      • C1 to C6 alkoxy substituted with one or more substituents independently selected from:
        • 5 or 6 membered heterocyclo; and
        • 5 or 6 membered heteroaryl;
      • (O)-5 or 6 membered heterocyclo;
      • (O)-5 or 6 membered heteroaryl; or
      • 5 or 6 membered heterocyclo;
        R2 is hydrogen; and
        R3 is hydrogen;
        with the proviso that when R1 is C1 to C6 alkoxy substituted with a 5 or 6 membered heterocyclo or when R1 is a 5 or 6 membered heterocyclo, Y is a C6 to C8 aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is:
      • C1 to C12 alkyl substituted with one or more halos; or
      • aryl substituted with one or more halos.
        78. The compound of embodiment 77, wherein:
        Y is C6 to C8 aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl;
        Z is C1 to C6 alkyl; and
        R1 is C1 to C6 alkoxy substituted with 5 or 6 membered heteroaryl.
        79. The compound of embodiment 77, wherein R1 is C1 to C6 alkoxy substituted with 5 or 6 membered heteroaryl.
        80. The compound of embodiment 77, wherein R1 is (O)-5 or 6 membered heterocyclo.
        81. The compound of embodiment 77, wherein R1 is (O)-5 or 6 membered heteroaryl.
        82. The compound of embodiment 77, wherein Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, or cyclopentyl.
        83. A compound of formula IId
  • Figure US20100305100A1-20101202-C00088
  • or a pharmaceutically acceptable salt thereof, wherein:
    X is hydrogen;
    Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
      • NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is C1 to C6 alkyl; and
      • NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl optionally substituted with one or more halos;
        Z is C1 to C6 alkyl;
        R is hydrogen;
        R1 is hydrogen;
        R2 is ORkk, wherein Rkk is:
      • 5 or 6 membered heteroaryl;
      • 5 or 6 membered heterocyclo; or
      • 5 or 6 membered heteroaryl optionally substituted with one or more independently selected halos; and
        R3 is hydrogen.
        84. The compound of embodiment 83, wherein:
        X is hydrogen;
        Y is C6 to C8 aryl substituted with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl substituted with one or more halos;
        Z is C1 to C6 alkyl;
        R is hydrogen;
        R1 is hydrogen;
        R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl; and
        R3 is hydrogen.
        85. The compound of embodiment 84, wherein the C6 to C8 aryl is phenyl.
        86. The compound of embodiment 84, wherein Y is phenyl substituted at the para position with NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl substituted with fluoro.
        87. The compound of embodiment 84, wherein Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl.
        88. The compound of embodiment 83, wherein R2 is (O)-5 or 6 membered heterocyclo.
        89. A compound of formula IIe
  • Figure US20100305100A1-20101202-C00089
  • or a pharmaceutically acceptable salt thereof, wherein:
    • X is:
      • hydrogen;
      • cyano;
      • nitro;
      • formyl;
      • COOH;
      • CORx, wherein Rx is C1 to C6 alkyl;
      • CH═N—(C1 to C6 alkoxy);
      • CH═N-(amino optionally substituted with one or more C1 to C6 alkyls);
      • halo;
      • alkyl optionally substituted with one or more halos;
      • alkynyl optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos;
      • oximyl;
      • SO2Rx;
      • SO2NH2;
      • SO2NH(Rx);
      • SO2N(Rx)2;
      • amino optionally substituted with one or more independently selected C1 to C6 alkyls and/or —C(O)—C1 to C6 alkyls;
      • amido optionally substituted with one or more independently selected C1 to C6 alkyls;
      • 5 or 6 membered heterocyclo;
      • 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more halos; or
      • C6 to C8 aryl optionally substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more halos;
        • halo; and
        • cyano;
    Y is:
      • benzothiazolyl optionally substituted with amino, which amino is optionally substituted with one or more C1 to C6 alkyls;
      • indolyl optionally substituted on the nitrogen with —SO2Rx;
      • C6 to C8 aryl optionally substituted with one or more substituents independently selected from:
        • halo;
        • C1 to C6 alkyl;
        • alkoxy, optionally substituted with one or more substituents independently selected from:
          • halo;
          • 5 or 6 membered heterocyclo;
          • C(O)NH2 optionally substituted with C6 to C8 alkyl;
          • C(O)NH—(C1 to C6)-alkyl;
        • hydroxy;
        • haloalkyl;
        • cyano;
        • nitro;
        • COOH;
        • N═CHN(Rx)2,
        • amino optionally substituted with one or more substituents independently selected from:
          • SO2Rx;
          • 6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy;
          • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and C6 to C8 aryl optionally substituted with halo;
          • 5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, ═O, alkyl and haloalkyl;
          • C1 to C7 alkyl optionally substituted with one or more substituents independently selected from:
            • 5 or 6 membered heteroaryl optionally substituted with one more substituents independently selected from alkyl, halo, and haloalkyl;
            • C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo, and haloalkyl;
            • alkoxy; and
            • halo; and
          • PO2Rx;
        • OC(O)NHRx wherein Rx is optionally substituted with vinyl;
        • OC(O)N(Ru)2, wherein Ru is alkyl or C6 to C8 aryl, which alkyl or aryl is optionally substituted with dialkylamino;
        • OC(O)NH(ORuu), wherein Ruu is —C6 to C8 aryl optionally substituted with dialkylamino;
        • OC(O)NRx(ORx);
        • OC(O)N(ORx)2;
        • OC(O)Rab, wherein Rab is 5 or 6 membered heterocyclo optionally substituted with heteroaryl, which heteroaryl is optionally substituted with alkyl or haloalkyl;
        • NRoC(O)Rp, wherein Rp is:
          • C1 to C6 alkyl;
          • amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from C6 to C8 aryl and alkoxy; or
          • 5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from C1 to C6 alkyl and C6 to C8 aryl;
        • and wherein Ro is:
          • hydrogen; or
          • C1 to C6 alkyl;
        • NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is:
          • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
            • halo;
            • hydroxy;
            • alkoxy;
            • 5 or 6 membered heterocyclo;
            • 5 or 6 membered heteroaryl; and
            • C6 to C8 aryl optionally substituted with halo;
          • C2 to C6 alkenyl optionally substituted with one or more halos;
          • C1 to C6 alkoxy;
          • 5 or 6 membered heterocyclo; or
          • 5 to 6 membered heteroaryl optionally substituted with alkyl;
        • SO2Raa, wherein Raa is:
          • 5 or 6 heterocyclo optionally substituted with one or more substituents independently selected from:
            • hydroxy;
            • C1 to C6 alkoxy; and
            • C1 to C6 alkyl;
          • amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
            • alkoxy;
            • hydroxy;
            • halo;
        • CORm, wherein Rm is:
          • amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with 5 or 6 membered heterocyclo or C6 to C8 aryl, which heterocyclo or aryl is optionally substituted one or more substituents independently selected from halo and alkoxy;
          • heterocyclo optionally substituted with hydroxy;
          • 3 to 7 membered heterocyclo optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with dialkyl-amino;
        • NRtCOORu, wherein Rt is hydrogen, and wherein Ru is:
          • C1 to C12 alkyl optionally substituted with one or more substituents independently selected from:
            • C6 to C8 aryl optionally substituted with one or more halos and/or haloalkyls;
            • alkoxy optionally substituted with one or more alkoxys;
            • amino optionally substituted with one or more C1 to C6 alkyls;
            • halo;
            • SO2Rw;
            • SO2Rx;
            • 5 or 6 membered heteroaryl; and
            • 5 or 6 membered heterocyclo;
          • C2 to C6 alkenyl;
          • C6 to C8 aryl optionally substituted with halo;
          • 4 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
            • ═O;
            • SO2Rw;
            • CORp; and
            • (CO)O—(C1 to C4 alkyl)-O—(C1 to C4 alkyl);
        • NHRbb, wherein Rbb is:
          • C(═S)NH2;
          • C(═S)NHRx;
          • C(═S)NRxRx;
          • C(═N—CN)NHRx, or
          • PO(ORx)2;
        • N(CONHRw)2,
        • NH(SORw),
        • N(SO2Rw)2,
        • NRvSO2Rw, wherein Rv is hydrogen or alkyl optionally substituted with 4 to 7 membered heterocyclo;
        • and wherein Rw is:
          • C1 to C6 alkyl optionally substituted with C6 to C8 aryl, which aryl is optionally substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
          • C6 to C8 aryl;
          • C6 to C8 heteroaryl; or
          • amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, alkoxycarbonyl, (CO)O—(C1 to C6) alkyl), hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
  • Figure US20100305100A1-20101202-C00090
        • 5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
          • halo;
          • C1 to C6 alkyl;
          • alkoxy optionally substituted with one or more substituents independently selected from:
            • halo;
            • 5 or 6 membered heterocyclo; and
            • C(O)NH2 optionally substituted with C6 to C8 alkyl;
          • hydroxy;
          • haloalkyl;
          • cyano;
          • nitro;
          • COOH;
          • amino optionally substituted with one or more substituents independently selected from:
            • SO2Rx;
            • 6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy;
            • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and —C6 to C8 aryl optionally substituted with halo;
            • C5 to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; and
            • C1 to C7 alkyl optionally substituted with one or more substituents independently selected from:
            •  5 or 6 membered heteroaryl optionally substituted with one or more alkyls, halos, and/or haloalkyls;
            •  C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
            •  alkoxy; and
            •  halo;
        • NRoCORp, wherein Rp is:
          • C1 to C6 alkyl;
          • amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally and independently substituted with one or more C6 to C8 aryls and/or alkoxys; or
          • 5 or 6 membered heterocyclo optionally substituted with one or more C1 to C6 alkyls and/or C6 to C8 aryls;
        • and wherein Ro is:
          • hydrogen; or
          • C1 to C6 alkyl;
        • NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is:
          • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
            • halo;
            • hydroxy;
            • alkoxy;
            • 5 or 6 membered heterocyclo;
            • 5 or 6 membered heteroaryl; and
            • C6 to C8 aryl optionally substituted with halo;
          • C2 to C6 alkenyl optionally substituted with one or more halos;
          • C1 to C6 alkoxy;
          • 5 or 6 membered heterocyclo; or
          • 5 to 6 membered heteroaryl optionally substituted with alkyl;
        • NRtCOORu, wherein Rt is hydrogen, and wherein Ru is:
          • C1 to C12 alkyl optionally substituted with one or more substituents independently selected from:
            • C6 to C8 aryl optionally substituted with one or more halos and/or haloalkyls;
            • alkoxy optionally substituted with one or more alkoxys;
            • amino optionally substituted with one or more C1 to C6 alkyls;
            • halo;
            • SO2Rw;
            • SO2Rx;
            • 5 or 6 membered heteroaryl; and
            • 5 or 6 membered heterocyclo; and
        • NRvSO2Rw, wherein Rv is hydrogen or alkyl optionally substituted with 4 to 7 membered heterocyclo;
        • and wherein Rw is:
          • C1 to C6 alkyl optionally substituted with C6 to C8 aryl, which aryl is optionally substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
          • C6 to C8 aryl;
          • C6 to C8 heteroaryl;
          • amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
  • Figure US20100305100A1-20101202-C00091
    • Z is:
      • C1 to C6 alkyl optionally substituted with 5 or 6 membered heterocyclo; or
      • 5 or 6 membered heterocyclo;
        R is hydrogen;
    R1 is:
      • hydrogen;
      • a 5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
        • hydroxy;
        • C1 to C6 alkyl;
        • SO2Rx;
        • C(O)—C6 to C8 aryl;
        • CORp, and
        • C(O)ORx; or
      • 5 or 6 membered heteroaryl optionally substituted with one or more independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
        • alkoxy;
        • halo;
        • alkylthio;
        • haloalkyl;
        • cyano;
        • amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
        • heterocyclo;
        • nitro;
        • hydroxy;
        • COOH;
        • CO2Rx;
        • CORx;
        • C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
        • amido optionally substituted with one or more or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
      • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
        • amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys;
        • amido optionally substituted with C1 to C6 alkyl;
        • 5 or 6 membered heterocyclo optionally substituted with C1 to C6 alkyl;
        • 5 or 6 membered heteroaryl; and
        • C6 to C8 aryl;
        • SO2Rx,
      • C2 to C6 alkenyl optionally substituted with —SO2Rx;
      • C1 to C6 alkoxy optionally substituted with one or more substituents independently selected from:
        • halo;
        • hydroxy;
        • cyano;
        • alkoxy optionally substituted with alkoxy;
        • amino optionally substituted with one or more independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
          • 5 or 6 membered heterocyclo; and
          • amino optionally substituted with one or more alkyl;
        • amino optionally substituted with heterocyclo;
        • amido optionally substituted with C1 to C6 alkyl;
        • 5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy and C1 to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
          • C1 to C6 alkoxy; and
          • C6 to C8 aryl;
        • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
          • C1 to C6 alkyl; and
          • 4 to 7 membered heterocyclo;
        • alkoxy; and
        • C6 to C8 aryl;
      • (O)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
        • hydroxy;
        • C1 to C6 alkyl;
        • SO2Rx;
        • C(O)—C6 to C8 aryl;
        • CORp, and
        • C(O)ORx; or
      • (O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • alkoxy;
        • halo;
        • alkylthio;
        • haloalkyl;
        • cyano;
        • amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • heterocyclo;
        • nitro;
        • hydroxy;
        • COOH;
        • CO2Rx;
        • CORN;
        • C(O)NH2 optionally substituted with one or more substituents independently selected from:
          • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and
          • amido optionally substituted with one or more or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
      • C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
      • C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
        • C6 to C8 aryl;
        • 5 or 6 membered heteroaryl; and
        • C1 to C6 alkyl further optionally substituted with one or more substituted with hydroxys;
      • SO2Rx optionally substituted with one or more substituents independently selected from:
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and
        • 5 or 6 membered heteroaryl; or
      • alkylthio optionally substituted with one or more substituents independently selected from:
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and
        • 5 or 6 membered heteroaryl;
      • C6 to C8 aryl;
      • C(O)-5 or 6 membered heteroaryl;
      • C(O)—C6 to C8 aryl;
      • COOH; or
      • ORkk, wherein R is:
        • C6 to C8 aryl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl;
    R2 is:
      • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
        • 5 or 6 membered heterocyclo;
        • 5 or 6 membered heteroaryl;
        • C6 to C8 aryl;
        • amido optionally substituted with C1 to C6 alkyl; and
        • amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxy; and
        • SO2Rx,
      • C2 to C6 alkenyl optionally substituted with SO2Rx,
      • alkylthio optionally substituted with one or more substituents independently selected from:
        • 5 or 6 membered heteroaryl optionally substituted with alkyl;
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and
        • C1 to C6 alkyl;
      • SO2Rx optionally substituted with one or more substituents independently selected from:
        • 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls;
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and
        • C1 to C6 alkyl;
      • S(O)Rx optionally substituted with one or more substituents independently selected from:
        • 5 or 6 membered heteroaryl;
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and
        • C1 to C6 alkyl;
      • alkoxy optionally substituted with one or more substituents independently selected from:
        • halo;
        • hydroxy;
        • cyano;
        • alkoxy optionally substituted with alkoxy;
        • amino optionally substituted with one or more substituents independently selected from —SO2—C1 to C4 alkyl, 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
          • 5 or 6 membered heterocyclo; and
          • amino optionally substituted with one or more alkyls;
        • amido optionally substituted with C1 to C6 alkyl;
        • S-5 or 6 membered heterocyclo;
        • S-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
        • S—C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
          • C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloalkyl and halo; and
          • C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloalkyl and halo;
        • S—C6 to C8 aryl;
        • sulfinyl-5 or 6 membered heterocyclo;
        • sulfinyl-5 or 6 membered heteroaryl;
        • sulfinyl-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
          • C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloalkyl and halo; and
          • C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloalkyl and halo;
        • sulfinyl-C6 to C8 aryl;
        • sulfonyl-5 or 6 membered heterocyclo;
        • sulfonyl-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
        • sulfonyl-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
          • C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloalkyl and halo; and
          • C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloalkyl and halo;
        • sulfonyl-C6 to C8 aryl;
        • 5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, ═O, heterocyclo, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
          • C1 to C6 alkoxy; and
          • C6 to C8 aryl;
        • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
          • C1 to C6 alkyl optionally substituted with one or more alkoxys;
          • 4 to 7 membered heterocyclo; and
          • alkoxy; and
        • C6 to C8 aryl;
      • C6 to C8 aryl;
      • (O)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
        • hydroxy;
        • ═O;
        • C1 to C6 alkyl;
        • SO2Rx;
        • C(O)—C6 to C8 aryl;
        • CORp; and
        • C(O)ORx; or
      • (O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • alkoxy;
        • halo;
        • alkylthio;
        • haloalkyl;
        • cyano;
        • amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • heterocyclo;
        • nitro;
        • hydroxy;
        • COOH;
        • CO2Rx;
        • CORx;
        • C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • amido optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
      • C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
        • C6 to C8 aryl;
        • 5 or 6 membered heteroaryl; and
        • C1 to C6 alkyl optionally substituted with one or more hydroxys;
      • C(O)-5 or 6 membered heteroaryl;
      • C(O)—C6 to C8 aryl;
      • COOH;
      • C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
      • amido optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more C1 to C6 alkoxys;
      • amino optionally substituted with one or more substituents independently selected from:
        • SO2Rx;
        • 6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy;
        • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and —C6 to C8 aryl optionally substituted with halo;
        • C5 to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl;
        • C1 to C7 alkyl optionally substituted with one or more substituents independently selected from:
          • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
          • C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
          • alkoxy; and
          • halo;
      • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • alkoxy;
        • halo;
        • alkylthio;
        • haloalkyl;
        • cyano;
        • amino optionally substituted with one more alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • heterocyclo;
        • nitro;
        • hydroxy;
        • COOH;
        • CO2Rx;
        • CORN;
        • C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • amido optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
      • 5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
        • hydroxy;
        • ═O;
        • C1 to C6 alkyl;
        • SO2Rx;
        • C(O)—C6 to C8 aryl;
        • CORp, and
        • C(O)ORx;
      • ORkk, wherein Rkk is:
        • C6 to C8 aryl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl;
        • 5 to 6 membered heterocyclo optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with C6 to C8 aryl; or
        • 5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl;
        • SO2Rx; or
        • Si(Rx)3;
      • OC(O)NHRx wherein Rx is optionally substituted with —C6 to C8 aryl;
      • OC(O)N(Rx)2; or
  • Figure US20100305100A1-20101202-C00092
  • R3 is hydrogen; or nitro;
    with the proviso that at least one of X, Y, Z, R1, R2 and R3 is selected from the following:
    • X is:
      • CH═N—(C1 to C6 alkoxy);
      • CH═N-(amino optionally substituted with one or more C1 to C6 alkyls);
      • halo;
      • alkyl optionally substituted with one or more halos;
      • alkynyl optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos;
      • oximyl;
      • SO2Rx;
      • SO2NH2;
      • SO2NH(Rx);
      • SO2N(Rx)2;
      • amino optionally substituted with one or more independently selected C1 to C6 alkyls and/or —C(O)—C1 to C6 alkyls;
      • amido optionally substituted with one or more independently selected C1 to C6 alkyls;
      • 5 or 6 membered heterocyclo;
      • 5 or 6 membered heteroaryl substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more halos; or
      • C6 to C8 aryl substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more halos;
        • halo; and
        • cyano;
    Y is:
      • benzothiazolyl substituted with amino, which amino is optionally substituted with one or more C1 to C6 alkyls;
      • indolyl substituted on the nitrogen with —SO2Rx;
      • C6 to C8 aryl substituted with one or more substituents independently selected from:
        • alkoxy substituted with one or more substituents independently selected from:
          • C(O)NH2 optionally substituted with C6 to C8 alkyl; and
          • C(O)NH—(C1 to C6)-alkyl;
        • haloalkyl;
        • cyano;
        • COOH;
        • N═CHN(Rx)2,
        • amino substituted with one or more substituents independently selected from:
          • SO2Rx;
          • 6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy;
          • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and C6 to C8 aryl optionally substituted with halo;
          • 5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, ═O, alkyl and haloalkyl;
          • C1 to C7 alkyl substituted with one or more substituents independently selected from:
            • 5 or 6 membered heteroaryl optionally substituted with one more substituents independently selected from alkyl, halo, and haloalkyl;
            • C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo, and haloalkyl;
            • alkoxy; and
            • halo; and
          • PO2Rx;
        • OC(O)NHRx wherein Rx is optionally substituted with vinyl;
        • OC(O)N(Ru)2, wherein Ru is alkyl or C6 to C8 aryl, which alkyl or aryl is optionally substituted with dialkylamino;
        • OC(O)NH(ORuu), wherein Ruu is —C6 to C8 aryl optionally substituted with dialkylamino;
        • OC(O)NRx(ORx);
        • OC(O)N(ORx)2;
        • OC(O)Rab, wherein Rab is 5 or 6 membered heterocyclo optionally substituted with heteroaryl, which heteroaryl is optionally substituted with alkyl or haloalkyl;
        • NRoC(O)Rp, wherein Rp is:
          • amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from C6 to C8 aryl and alkoxy; or
          • 5 or 6 membered heterocyclo substituted with one or more substituents independently selected from C1 to C6 alkyl and C6 to C8 aryl;
        • NRqCONRqRr, wherein Rr is:
          • C1 to C6 alkyl substituted with one or more substituents independently selected from:
            • hydroxy;
            • alkoxy;
            • 5 or 6 membered heterocyclo;
            • 5 or 6 membered heteroaryl; and
            • C6 to C8 aryl substituted with halo;
          • C2 to C6 alkenyl optionally substituted with one or more halos;
          • C1 to C6 alkoxy;
          • 5 or 6 membered heterocyclo; or
          • 5 to 6 membered heteroaryl optionally substituted with alkyl;
        • SO2Raa, wherein Raa is:
          • 5 or 6 heterocyclo optionally substituted with one or more substituents independently selected from:
            • hydroxy;
            • C1 to C6 alkoxy; and
            • C1 to C6 alkyl;
          • amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
            • alkoxy;
            • hydroxy;
            • halo;
        • CORm, wherein Rm, is:
          • amino substituted with one or more C1 to C6 alkyls, which alkyls are substituted with 5 or 6 membered heterocyclo or C6 to C8 aryl, which heterocyclo is substituted with one or more halos and/or alkoxys, and which aryl is optionally substituted with one or more halos and/or alkoxys;
          • heterocyclo substituted with hydroxy;
        • NRtCOORu, wherein Ru is:
          • C1 to C12 alkyl substituted with one or more substituents independently selected from:
            • C6 to C8 aryl substituted with one or more halos and/or haloalkyls;
            • alkoxy substituted with one or more alkoxys;
            • amino optionally substituted with one or more C1 to C6 alkyls;
            • SO2Rw;
            • SO2Rx; and
            • 5 or 6 membered heteroaryl;
          • C2 to C6 alkenyl;
          • 4 to 7 membered heterocyclo substituted with one or more substituents independently selected from:
            • ═O;
            • SO2Rw;
            • CORp; and
            • (CO)O—(C1 to C4 alkyl)-O—(C1 to C4 alkyl);
          • 4 or 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
            • ═O;
            • SO2Rw;
            • CORp; and
            • (CO)O—(C1 to C4 alkyl)-O—(C1 to C4 alkyl);
        • NHRbb, wherein Rbb is:
          • C(═S)NHRx;
          • C(═S)NRxRx; or
          • C(═N—CN)NHRx;
        • N(CONHRw)2,
        • NH(SORw),
        • N(SO2Rw)2,
        • NRvSO2Rw, wherein Rv is alkyl substituted with 4 or 7 membered heterocyclo;
        • or wherein Rw is:
          • C1 to C6 alkyl substituted with C6 to C8 aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
          • amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, alkoxycarbonyl, (CO)O—(C1 to C6) alkyl), hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
  • Figure US20100305100A1-20101202-C00093
        • 5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
          • halo;
          • C1 to C6 alkyl;
          • alkoxy optionally substituted with one or more substituents independently selected from:
            • halo;
            • 5 or 6 membered heterocyclo; and
            • C(O)NH2 optionally substituted with C6 to C8 alkyl;
          • hydroxy;
          • haloalkyl;
          • cyano;
          • nitro;
          • COOH;
          • amino optionally substituted with one or more substituents independently selected from:
            • SO2Rx;
            • 6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy;
            • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and —C6 to C8 aryl optionally substituted with halo;
            • C5 to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; and
            • C1 to C7 alkyl optionally substituted with one or more substituents independently selected from:
            •  5 or 6 membered heteroaryl optionally substituted with one or more alkyls, halos, and/or haloalkyls;
            •  C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
            •  alkoxy; and
            •  halo;
        • NRoCORp, wherein Rp is:
          • amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally and independently substituted with one or more C6 to C8 aryls and/or alkoxys; or
          • 5 or 6 membered heterocyclo optionally substituted with one or more C1 to C6 alkyls and/or C6 to C8 aryls;
        • NRqCONRqRr, wherein Rr is:
          • C1 to C6 alkyl substituted with one or more substituents independently selected from:
            • hydroxy;
            • alkoxy;
            • 5 or 6 membered heterocyclo;
            • 5 or 6 membered heteroaryl; and
            • C6 to C8 aryl substituted with halo;
          • C2 to C6 alkenyl optionally substituted with one or more halos;
          • C1 to C6 alkoxy;
          • 5 or 6 membered heterocyclo; or
          • 5 to 6 membered heteroaryl optionally substituted with alkyl;
        • NRTCOORu, wherein RU is:
          • C1 to C12 alkyl substituted with one or more substituents independently selected from:
            • C6 to C8 aryl substituted with one or more halos and/or haloalkyls;
            • alkoxy substituted with one or more alkoxys;
            • amino optionally substituted with one or more C1 to C6 alkyls;
            • SO2Rw;
            • SO2Rx; and
            • 5 or 6 membered heteroaryl;
        • NRvSO2Rw, wherein Rv is alkyl substituted with 4 to 7 membered heterocyclo; or wherein R1 is:
          • C1 to C6 alkyl substituted with C6 to C8 aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
          • C6 to C8 aryl;
          • amino substituted with heterocyclo or alkyl, which heterocyclo is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl, and which alkyl is substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
  • Figure US20100305100A1-20101202-C00094
    • Z is:
      • C1 to C6 alkyl substituted with 5 or 6 membered heterocyclo; or
      • 5 or 6 membered heterocyclo;
    R1 is:
      • a 5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
        • hydroxy;
        • C1 to C6 alkyl;
        • SO2Rx;
        • C(O)—C6 to C8 aryl;
        • CORp, and
        • C(O)ORx; or
      • 5 or 6 membered heteroaryl substituted with one or more independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
        • alkoxy;
        • halo;
        • alkylthio;
        • haloalkyl;
        • cyano;
        • amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
        • heterocyclo;
        • nitro;
        • hydroxy;
        • COOH;
        • CO2Rx;
        • CORx;
        • C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
        • amido optionally substituted with one or more or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
      • C1 to C6 alkyl substituted with one or more substituents independently selected from:
        • amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is substituted with one or more alkoxys;
        • amido optionally substituted with C1 to C6 alkyl;
        • 5 or 6 membered heterocyclo substituted with C1 to C6 alkyl;
        • 5 or 6 membered heteroaryl; and
        • C6 to C8 aryl;
        • SO2Rx;
      • C2 to C6 alkenyl optionally substituted with —SO2Rx;
      • C1 to C6 alkoxy substituted with one or more substituents independently selected from:
        • hydroxy;
        • cyano;
        • alkoxy optionally substituted with alkoxy;
        • amino optionally substituted with one or more independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
          • 5 or 6 membered heterocyclo; and
          • amino optionally substituted with one or more alkyl;
        • amino optionally substituted with heterocyclo;
        • amido optionally substituted with C1 to C6 alkyl;
        • 5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and C1 to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
          • C1 to C6 alkoxy; and
          • C6 to C8 aryl;
        • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
          • C1 to C6 alkyl; and
          • 4 to 7 membered heterocyclo; and
        • alkoxy;
      • (O)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
        • hydroxy;
        • C1 to C6 alkyl;
        • SO2Rx;
        • C(O)—C6 to C8 aryl;
        • CORp, and
        • C(O)ORx; or
      • (O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • alkoxy;
        • halo;
        • alkylthio;
        • haloalkyl;
        • cyano;
        • amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • heterocyclo;
        • nitro;
        • hydroxy;
        • COOH;
        • CO2Rx;
        • CORx;
        • C(O)NH2 optionally substituted with one or more substituents independently selected from:
          • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and
          • amido optionally substituted with one or more or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
      • C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
      • C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
        • C6 to C8 aryl;
        • 5 or 6 membered heteroaryl; and
        • C1 to C6 alkyl further optionally substituted with one or more substituted with hydroxys;
      • SO2Rx optionally substituted with one or more substituents independently selected from:
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and
        • 5 or 6 membered heteroaryl; or
      • alkylthio optionally substituted with one or more substituents independently selected from:
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and
        • 5 or 6 membered heteroaryl;
      • C(O)-5 or 6 membered heteroaryl;
      • C(O)—C6 to C8 aryl;
      • COOH;
      • ORkk, wherein Rkk is:
        • C6 to C8 aryl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl;
    R2 is:
      • C1 to C6 alkyl substituted with one or more substituents independently selected from:
        • 5 or 6 membered heterocyclo;
        • 5 or 6 membered heteroaryl;
        • C6 to C8 aryl;
        • amido optionally substituted with C1 to C6 alkyl; and
        • amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxy; and
        • SO2Rx,
      • C2 to C6 alkenyl optionally substituted with SO2Rx,
      • alkylthio optionally substituted with one or more substituents independently selected from:
        • 5 or 6 membered heteroaryl optionally substituted with alkyl;
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and
        • C1 to C6 alkyl;
      • SO2Rx optionally substituted with one or more substituents independently selected from:
        • 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls;
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and
        • C1 to C6 alkyl;
      • S(O)Rx optionally substituted with one or more substituents independently selected from:
        • 5 or 6 membered heteroaryl;
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and
        • C1 to C6 alkyl;
      • alkoxy substituted with one or more substituents independently selected from:
        • halo;
        • hydroxy;
        • cyano;
        • alkoxy optionally substituted with alkoxy;
        • amino substituted with one or more substituents independently selected from —SO2—C1 to C4 alkyl and alkyl, which alkyl is substituted with one or more substituents independently selected from:
          • 5 or 6 membered heterocyclo; and
          • amino optionally substituted with one or more alkyls;
        • amido substituted with C1 to C6 alkyl;
        • S-5 or 6 membered heterocyclo;
        • S-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
        • S—C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
          • C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloalkyl and halo; and
          • C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloalkyl and halo;
        • S—C6 to C8 aryl;
        • sulfinyl-5 or 6 membered heterocyclo;
        • sulfinyl-5 or 6 membered heteroaryl;
        • sulfinyl-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
          • C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloalkyl and halo; and
          • C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloalkyl and halo;
        • sulfinyl-C6 to C8 aryl;
        • sulfonyl-5 or 6 membered heterocyclo;
        • sulfonyl-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
        • sulfonyl-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
          • C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloalkyl and halo; and
          • C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloalkyl and halo;
        • sulfonyl-C6 to C8 aryl;
        • 5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, ═O, heterocyclo, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
          • C1 to C6 alkoxy; and
          • C6 to C8 aryl;
        • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
          • C1 to C6 alkyl optionally substituted with one or more alkoxys;
          • 4 to 7 membered heterocyclo; and
          • alkoxy; and
        • C6 to C8 aryl;
      • C6 to C8 aryl;
      • (O)-5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
        • hydroxy;
        • ═O;
        • C1 to C6 alkyl;
        • SO2Rx;
        • C(O)—C6 to C8 aryl;
        • CORp, and
        • C(O)ORx; or
      • (O)-5 or 6 membered heteroaryl substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • alkoxy;
        • halo;
        • alkylthio;
        • haloalkyl;
        • cyano;
        • amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • heterocyclo;
        • nitro;
        • hydroxy;
        • COOH;
        • CO2Rx;
        • CORx;
        • C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • amido optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
      • C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
        • C6 to C8 aryl;
        • 5 or 6 membered heteroaryl; and
        • C1 to C6 alkyl optionally substituted with one or more hydroxys;
      • C(O)-5 or 6 membered heteroaryl;
      • C(O)—C6 to C8 aryl;
      • COOH;
      • C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
      • amido substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more C1 to C6 alkoxys;
      • amino substituted with one or more substituents independently selected from:
        • SO2Rx;
        • 6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy;
        • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and —C6 to C8 aryl optionally substituted with halo;
        • C5 to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl;
        • C1 to C7 alkyl optionally substituted with one or more substituents independently selected from:
          • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
          • C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
          • alkoxy; and
          • halo;
      • 5 or 6 membered heteroaryl substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • alkoxy;
        • halo;
        • alkylthio;
        • haloalkyl;
        • cyano;
        • amino optionally substituted with one more alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • heterocyclo;
        • nitro;
        • hydroxy;
        • COOH;
        • CO2Rx;
        • CORx;
        • C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • amido optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
      • 5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
        • hydroxy;
        • ═O;
        • C1 to C6 alkyl;
        • SO2Rx;
        • C(O)—C6 to C8 aryl;
        • CORp, and
        • C(O)ORx;
      • ORkk, wherein Rkk is:
        • C6 to C8 aryl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl;
        • 5 to 6 membered heterocyclo optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with C6 to C8 aryl; or
        • 5 to 6 membered heteroaryl substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl;
        • SO2Rx; or
        • Si(Rx)3;
      • OC(O)NHRx wherein Rx is optionally substituted with —C6 to C8 aryl;
      • OC(O)N(Rx)2; or
  • Figure US20100305100A1-20101202-C00095
  • R3 is nitro.
    90. The compound of embodiment 89, wherein:
    • X is:
      • CH═N—(C1 to C6 alkoxy);
      • CH═N-(amino optionally substituted with one or more C1 to C6 alkyls);
      • halo;
      • alkyl optionally substituted with one or more halos;
      • alkynyl optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos;
      • oximyl;
      • SO2Rx;
      • SO2NH2;
      • SO2NH(Rx);
      • SO2N(Rx)2;
      • amino optionally substituted with one or more independently selected C1 to C6 alkyls and/or —C(O)—C1 to C6 alkyls;
      • amido optionally substituted with one or more independently selected C1 to C6 alkyls;
      • 5 or 6 membered heterocyclo;
      • 5 or 6 membered heteroaryl substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more halos; or
      • C6 to C8 aryl substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more halos;
        • halo; and
        • cyano.
          91. The compound of embodiment 89, wherein:
    Y is:
      • benzothiazolyl substituted with amino, which amino is optionally substituted with one or more C1 to C6 alkyls;
      • indolyl substituted on the nitrogen with —SO2Rx; or
      • C6 to C8 aryl substituted with one or more substituents independently selected from:
        • alkoxy substituted with one or more substituents independently selected from:
          • C(O)NH2 optionally substituted with C6 to C8 alkyl; and
          • C(O)NH—(C1 to C6)-alkyl;
        • haloalkyl;
        • cyano;
        • COOH;
        • N═CHN(Rx)2,
        • amino substituted with one or more substituents independently selected from:
          • SO2Rx;
          • 6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy;
          • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and C6 to C8 aryl optionally substituted with halo;
          • 5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, ═O, alkyl and haloalkyl;
          • C1 to C7 alkyl substituted with one or more substituents independently selected from:
            • 5 or 6 membered heteroaryl optionally substituted with one more substituents independently selected from alkyl, halo, and haloalkyl;
            • C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo, and haloalkyl;
            • alkoxy; and
            • halo; and
          • PO2Rx;
        • OC(O)NHRx wherein Rx is optionally substituted with vinyl;
        • OC(O)N(Ru)2, wherein Ru is alkyl or C6 to C8 aryl, which alkyl or aryl is optionally substituted with dialkylamino;
        • OC(O)NH(ORuu), wherein Ruu is —C6 to C8 aryl optionally substituted with dialkylamino;
        • OC(O)NRx(ORx);
        • OC(O)N(ORx)2;
        • OC(O)Rab, wherein Rab is 5 or 6 membered heterocyclo optionally substituted with heteroaryl, which heteroaryl is optionally substituted with alkyl or haloalkyl;
        • NRoC(O)Rp, wherein Rp is:
          • amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from C6 to C8 aryl and alkoxy; or
          • 5 or 6 membered heterocyclo substituted with one or more substituents independently selected from C1 to C6 alkyl and C6 to C8 aryl;
        • NRqCONRqRr, wherein Rr is:
          • C1 to C6 alkyl substituted with one or more substituents independently selected from:
            • hydroxy;
            • alkoxy;
            • 5 or 6 membered heterocyclo;
            • 5 or 6 membered heteroaryl; and
            • C6 to C8 aryl substituted with halo;
          • C2 to C6 alkenyl optionally substituted with one or more halos;
          • C1 to C6 alkoxy;
          • 5 or 6 membered heterocyclo; or
          • 5 to 6 membered heteroaryl optionally substituted with alkyl;
        • SO2Raa, wherein Raa is:
          • 5 or 6 heterocyclo optionally substituted with one or more substituents independently selected from:
            • hydroxy;
            • C1 to C6 alkoxy; and
            • C1 to C6 alkyl;
          • amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
            • alkoxy;
            • hydroxy;
            • halo;
        • CORm, wherein Rm is:
          • amino substituted with one or more C1 to C6 alkyls, which alkyls are substituted with 5 or 6 membered heterocyclo or C6 to C8 aryl, which heterocyclo is substituted with one or more halos and/or alkoxys, and which aryl is optionally substituted with one or more halos and/or alkoxys;
          • heterocyclo substituted with hydroxy;
        • NRtCOORu, wherein Ru is:
          • C1 to C12 alkyl substituted with one or more substituents independently selected from:
            • C6 to C8 aryl substituted with one or more halos and/or haloalkyls;
            • alkoxy substituted with one or more alkoxys;
            • amino optionally substituted with one or more C1 to C6 alkyls;
            • SO2Rw;
            • SO2Rx; and
            • 5 or 6 membered heteroaryl;
          • C2 to C6 alkenyl;
          • 4 to 7 membered heterocyclo substituted with one or more substituents independently selected from:
            • ═O;
            • SO2Rw;
            • CORp; and
            • (CO)O—(C1 to C4 alkyl)-O—(C1 to C4 alkyl);
          • 4 or 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
            • ═O;
            • SO2Rw;
            • CORp; and
            • (CO)O—(C1 to C4 alkyl)-O—(C1 to C4 alkyl);
        • NHRbb, wherein Rbb is:
          • C(═S)NHRx;
          • C(═S)NRxRx; or
          • C(═N—CN)NHRx;
        • N(CONHRw)2,
        • NH(SORw),
        • N(SO2Rx)2,
        • NRvSO2Rw, wherein Rv is alkyl substituted with 4 or 7 membered heterocyclo; or wherein Rw is:
          • C1 to C6 alkyl substituted with C6 to C8 aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
          • amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, alkoxycarbonyl, (CO)O—(C1 to C6) alkyl), hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
  • Figure US20100305100A1-20101202-C00096
        • 5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
          • halo;
          • C1 to C6 alkyl;
          • alkoxy optionally substituted with one or more substituents independently selected from:
            • halo;
            • 5 or 6 membered heterocyclo; and
            • C(O)NH2 optionally substituted with C6 to C8 alkyl;
          • hydroxy;
          • haloalkyl;
          • cyano;
          • nitro;
          • COOH;
          • amino optionally substituted with one or more substituents independently selected from:
            • SO2Rx;
            • 6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy;
            • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and —C6 to C8 aryl optionally substituted with halo;
            • C5 to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; and
            • C1 to C7 alkyl optionally substituted with one or more substituents independently selected from:
            •  5 or 6 membered heteroaryl optionally substituted with one or more alkyls, halos, and/or haloalkyls;
            •  C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
            •  alkoxy; and
            •  halo;
        • NRoCORp, wherein Rp is:
          • amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally and independently substituted with one or more C6 to C8 aryls and/or alkoxys; or
          • 5 or 6 membered heterocyclo optionally substituted with one or more C1 to C6 alkyls and/or C6 to C8 aryls;
        • NRqCONRqRr, wherein Rr is:
          • C1 to C6 alkyl substituted with one or more substituents independently selected from:
            • hydroxy;
            • alkoxy;
            • 5 or 6 membered heterocyclo;
            • 5 or 6 membered heteroaryl; and
            • C6 to C8 aryl substituted with halo;
          • C2 to C6 alkenyl optionally substituted with one or more halos;
          • C1 to C6 alkoxy;
          • 5 or 6 membered heterocyclo; or
          • 5 to 6 membered heteroaryl optionally substituted with alkyl;
        • NRtCOORu, wherein Ru is:
          • C1 to C12 alkyl substituted with one or more substituents independently selected from:
            • C6 to C8 aryl substituted with one or more halos and/or haloalkyls;
            • alkoxy substituted with one or more alkoxys;
            • amino optionally substituted with one or more C1 to C6 alkyls;
            • SO2Rw;
            • SO2Rx; and
            • 5 or 6 membered heteroaryl; and
        • NRvSO2Rw, wherein Rv is alkyl substituted with 4 to 7 membered heterocyclo; or wherein Rw is:
          • C1 to C6 alkyl substituted with C6 to C8 aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
          • C6 to C8 aryl;
          • amino substituted with heterocyclo or alkyl, which heterocyclo is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl, and which alkyl is substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
  • Figure US20100305100A1-20101202-C00097
  • 92. The compound of embodiment 89, wherein:
    • Z is:
      • C1 to C6 alkyl substituted with 5 or 6 membered heterocyclo; or
      • 5 or 6 membered heterocyclo.
        93. The compound of embodiment 89, wherein:
    R1 is:
      • a 5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
        • hydroxy;
        • C1 to C6 alkyl;
        • SO2Rx;
        • C(O)—C6 to C8 aryl;
        • CORp, and
        • C(O)ORx; or
      • 5 or 6 membered heteroaryl substituted with one or more independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
        • alkoxy;
        • halo;
        • alkylthio;
        • haloalkyl;
        • cyano;
        • amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
        • heterocyclo;
        • nitro;
        • hydroxy;
        • COOH;
        • CO2Rx;
        • CORx;
        • C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
        • amido optionally substituted with one or more or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
      • C1 to C6 alkyl substituted with one or more substituents independently selected from:
        • amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is substituted with one or more alkoxys;
        • amido optionally substituted with C1 to C6 alkyl;
        • 5 or 6 membered heterocyclo substituted with C1 to C6 alkyl;
        • 5 or 6 membered heteroaryl; and
        • C6 to C8 aryl;
        • SO2Rx,
      • C2 to C6 alkenyl optionally substituted with —SO2Rx;
      • C1 to C6 alkoxy substituted with one or more substituents independently selected from:
        • hydroxy;
        • cyano;
        • alkoxy optionally substituted with alkoxy;
        • amino optionally substituted with one or more independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
          • 5 or 6 membered heterocyclo; and
          • amino optionally substituted with one or more alkyl;
        • amino optionally substituted with heterocyclo;
        • amido optionally substituted with C1 to C6 alkyl;
        • 5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and C1 to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
          • C1 to C6 alkoxy; and
          • C6 to C8 aryl;
        • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
          • C1 to C6 alkyl; and
          • 4 to 7 membered heterocyclo; and
        • alkoxy;
      • (O)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
        • hydroxy;
        • C1 to C6 alkyl;
        • SO2Rx;
        • C(O)—C6 to C8 aryl;
        • CORp, and
        • C(O)ORx; or
      • (O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • alkoxy;
        • halo;
        • alkylthio;
        • haloalkyl;
        • cyano;
        • amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • heterocyclo;
        • nitro;
        • hydroxy;
        • COOH;
        • CO2Rx;
        • CORx;
        • C(O)NH2 optionally substituted with one or more substituents independently selected from:
          • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and
          • amido optionally substituted with one or more or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
      • C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
      • C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
        • C6 to C8 aryl;
        • 5 or 6 membered heteroaryl; and
        • C1 to C6 alkyl further optionally substituted with one or more substituted with hydroxys;
      • SO2Rx optionally substituted with one or more substituents independently selected from:
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and
        • 5 or 6 membered heteroaryl; or
      • alkylthio optionally substituted with one or more substituents independently selected from:
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and
        • 5 or 6 membered heteroaryl;
      • C(O)-5 or 6 membered heteroaryl;
      • C(O)—C6 to C8 aryl;
      • COOH; or
      • ORkk, wherein Rkk is:
        • C6 to C8 aryl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl.
          94. The compound of embodiment 89, wherein:
    R2 is:
      • C1 to C6 alkyl substituted with one or more substituents independently selected from:
        • 5 or 6 membered heterocyclo;
        • 5 or 6 membered heteroaryl;
        • C6 to C8 aryl;
        • amido optionally substituted with C1 to C6 alkyl; and
        • amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxy; and
        • SO2Rx,
      • C2 to C6 alkenyl optionally substituted with SO2Rx,
      • alkylthio optionally substituted with one or more substituents independently selected from:
        • 5 or 6 membered heteroaryl optionally substituted with alkyl;
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and
        • C1 to C6 alkyl;
      • SO2Rx optionally substituted with one or more substituents independently selected from:
        • 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls;
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and
        • C1 to C6 alkyl;
      • S(O)Rx optionally substituted with one or more substituents independently selected from:
        • 5 or 6 membered heteroaryl;
        • 5 or 6 membered heterocyclo;
        • C6 to C8 aryl; and
        • C1 to C6 alkyl;
      • alkoxy substituted with one or more substituents independently selected from:
        • halo;
        • hydroxy;
        • cyano;
        • alkoxy optionally substituted with alkoxy;
        • amino substituted with one or more substituents independently selected from —SO2—C1 to C4 alkyl and alkyl, which alkyl is substituted with one or more substituents independently selected from:
          • 5 or 6 membered heterocyclo; and
          • amino optionally substituted with one or more alkyls;
        • amido substituted with C1 to C6 alkyl;
        • S-5 or 6 membered heterocyclo;
        • S-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
        • S—C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
          • C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloalkyl and halo; and
          • C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloalkyl and halo;
        • S—C6 to C8 aryl;
        • sulfinyl-5 or 6 membered heterocyclo;
        • sulfinyl-5 or 6 membered heteroaryl;
        • sulfinyl-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
          • C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloalkyl and halo; and
          • C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloalkyl and halo;
        • sulfinyl-C6 to C8 aryl;
        • sulfonyl-5 or 6 membered heterocyclo;
        • sulfonyl-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
        • sulfonyl-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
          • C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloalkyl and halo; and
          • C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloalkyl and halo;
        • sulfonyl-C6 to C8 aryl;
        • 5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, ═O, heterocyclo, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
          • C1 to C6 alkoxy; and
          • C6 to C8 aryl;
        • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
          • C1 to C6 alkyl optionally substituted with one or more alkoxys;
          • 4 to 7 membered heterocyclo; and
          • alkoxy; and
        • C6 to C8 aryl;
      • C6 to C8 aryl;
      • (O)-5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
        • hydroxy;
        • ═O;
        • C1 to C6 alkyl;
        • SO2Rx;
        • C(O)—C6 to C8 aryl;
        • CORp, and
        • C(O)ORx; or
      • (O)-5 or 6 membered heteroaryl substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • alkoxy;
        • halo;
        • alkylthio;
        • haloalkyl;
        • cyano;
        • amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • heterocyclo;
        • nitro;
        • hydroxy;
        • COOH;
        • CO2Rx;
        • CORx;
        • C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • amido optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
      • C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
        • C6 to C8 aryl;
        • 5 or 6 membered heteroaryl; and
        • C1 to C6 alkyl optionally substituted with one or more hydroxys;
      • C(O)-5 or 6 membered heteroaryl;
      • C(O)—C6 to C8 aryl;
      • COOH;
      • C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
      • amido substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more C1 to C6 alkoxys;
      • amino substituted with one or more substituents independently selected from:
        • SO2Rx;
        • 6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy;
        • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and —C6 to C8 aryl optionally substituted with halo;
        • C5 to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl;
        • C1 to C7 alkyl optionally substituted with one or more substituents independently selected from:
          • 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
          • C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
          • alkoxy; and
          • halo;
      • 5 or 6 membered heteroaryl substituted with one or more substituents independently selected from:
        • C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • alkoxy;
        • halo;
        • alkylthio;
        • haloalkyl;
        • cyano;
        • amino optionally substituted with one more alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • heterocyclo;
        • nitro;
        • hydroxy;
        • COOH;
        • CO2Rx;
        • CORx;
        • C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
        • amido optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
      • 5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
        • hydroxy;
        • ═O;
        • C1 to C6 alkyl;
        • SO2Rx;
        • C(O)—C6 to C8 aryl;
        • CORp, and
        • C(O)ORx;
      • ORkk, wherein Rkk is:
        • C6 to C8 aryl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl;
        • 5 to 6 membered heterocyclo optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with C6 to C8 aryl; or
        • 5 to 6 membered heteroaryl substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl;
        • SO2Rx; or
        • Si(Rx)3;
      • OC(O)NHRx wherein Rx is optionally substituted with —C6 to C8 aryl;
      • OC(O)N(Rx)2; or
  • Figure US20100305100A1-20101202-C00098
  • 95. The compound of embodiment 89, wherein R3 is nitro.
    96. The compound of embodiment 89, wherein:
    X is cyano or hydrogen;
    • Y is:
      • C6 to C8 aryl optionally substituted with one or more substituents independently selected from:
        • halo;
        • C1 to C6 alkyl;
        • amino optionally substituted with one or more substituents independently selected from:
          • SO2Rx;
          • 5 or 6 membered heteroaryl optionally substituted with one or more alkyl;
          • C1 to C7 alkyl;
        • NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl;
        • NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is C1 to C6 alkyl or amino optionally substituted with alkyl;
  • Figure US20100305100A1-20101202-C00099
  • Z is C1 to C6 alkyl;
    R is hydrogen;
    R1 is hydrogen;
    R2 is —(O)-5 or 6 membered heteroaryl substituted with cyano; and
    R3 is hydrogen.
    97. The compound of embodiment 96, wherein the C6 to C8 aryl is phenyl.
    98. The compound of embodiment 97, wherein:
    X is cyano;
    Y is phenyl para substituted with NRvSO2Rw, wherein Rv is hydrogen, and wherein R1 is C1 to C6 alkyl; and
    R2 is —(O)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.
    99. The compound of embodiment 97, wherein:
    X is cyano;
    Y is phenyl substituted with C1 to C6 alkyl and NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is C1 to C6 alkyl; and
    R2 is —(O)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.
    100. The compound of embodiment 97, wherein:
    X is cyano;
    Y is phenyl substituted with halo and NRvSO2Rw, wherein Rv is hydrogen, and wherein R1 is C1 to C6 alkyl; and
    R2 is —(O)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.
    101. The compound of embodiment 97, wherein:
    X is hydrogen;
    Y is phenyl is para substituted with —NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl;
    Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl; and
    R2 is —(O)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.
    102. The compound of embodiment 89, wherein:
    X is cyano;
    • Y is:
      • C6 to C8 aryl optionally substituted with one or more substituents independently selected from:
        • NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl optionally substituted with one or more halo; or
        • NRvSO2Rw, wherein Rv is hydrogen, and wherein Rw is C1 to C6 alkyl;
          Z is C1 to C6 alkyl;
          R is hydrogen;
          R1 is hydrogen;
          R2 is —(O)-5 or 6 membered heterocyclo substituted with one or more ═O; and
          R3 is hydrogen.
          103. A compound which is selected from the compound range: 1330-2128 and 2600-3348.
          104. The compound embodiment 103 selected from:
  • Figure US20100305100A1-20101202-C00100
    Figure US20100305100A1-20101202-C00101
    Figure US20100305100A1-20101202-C00102
    Figure US20100305100A1-20101202-C00103
    Figure US20100305100A1-20101202-C00104
  • 105. A composition comprising the compound of embodiment 1 and one or more pharmaceutically acceptable excipient(s).
    106. A composition comprising the compound of embodiment 39 and one or more pharmaceutically acceptable excipient(s).
    107. A composition comprising the compound of embodiment 77 and one or more pharmaceutically acceptable excipient(s).
    108. A composition comprising the compound of embodiment 83 and one or more pharmaceutically acceptable excipient(s).
    109. A composition comprising the compound of embodiment 89 and one or more pharmaceutically acceptable excipient(s).
    110. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 1 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 1.
    111. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 39 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 39.
    112. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 77 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 77.
    113. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 83 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 83.
    114. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 89 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 89.
    115. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 1 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 1.
    116. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 39 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 39.
    117. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 77 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 77.
    118. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 83 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 83.
    119. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 89 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 89.
  • In yet another embodiment, the present invention includes compounds of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Y is a —NRtCOORu group and Ru is a C1 to C6 alkyl. In an embodiment, compounds are provided wherein Y is a —NRtCOORu group and Ru is a C1 to C6 alkyl in the para position. In another embodiment, the present invention includes compounds of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Y is a —NRtCOORu group and Ru is a branched C1 to C6 alkyl. In an embodiment of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, Y is a —NRtCOORu group and R1 is a branched C1 to C6 alkyl in the para position. In another embodiment, the present invention includes compounds of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Y is a —NRtCOORu group and Ru is an isopropyl. In another embodiment, the present invention includes compounds of I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Y is a —NRtCOORu group and Ru is a methyl cyclopropyl. In another embodiment, the present invention includes compounds of I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Y is a —NRtCOORu group and R1 is an ethyl cyclopropyl.
  • In another embodiment, the present invention includes compounds of I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Y is a —NRvSO2Rw group, Rv is a hydrogen, and where Rw is a C1 to C6 alkyl. In a further embodiment, the present invention includes compounds wherein Y is a —NRvSO2Rw group and Rw is a propyl group.
  • In an embodiment of the present invention, compounds are provided wherein Y is a C6 to C8 aryl that is substituted. In an embodiment of the present invention, compounds are provided wherein Y is a phenyl that is substituted. In an embodiment of the present invention, compounds are provided wherein Y is a C6 to C8 aryl that has one, two, three, or four substituents. In another embodiment of the compounds of the present invention, Y is a C6 to C8 aryl that has one, two, or three substituents. In another embodiment, Y is a C6 to C8 aryl that has one or two substituents. In a further embodiment, Y is a C6 to C8 aryl that has three substituents. In a further embodiment, Y is a C6 to C8 aryl that has two substituents. In a further embodiment, Y is a C6 to C8 aryl that has one substituent.
  • In another embodiment of the present invention, compounds are provided wherein Y is a C6 to C8 aryl with at least one substituent in the ortho, meta, or para position. In a further embodiment, Y is a C6 to C8 aryl with at least one substituent in the meta or para position. In yet another embodiment, Y is a C6 to C8 aryl with a substituent in the para position.
  • In an embodiment of the present invention, compounds are provided wherein Y is a C6 to C8 aryl, optionally substituted with one of the following in the para position:
      • an alkoxy,
      • an amino optionally substituted with one or more of the following:
        • SO2Rx groups, or
        • C1 to C6 alkyl, the C1 to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group,
      • OC(O)NHRx,
      • OC(O)N(Rx)2,
      • OC(O)NH(ORx),
      • OC(O)NRx(ORx),
      • OC(O)N(ORx)2,
      • OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group,
      • a —NRoCORp group, where Rp is:
        • a C1 to C6 alkyl,
        • an amino group optionally substituted with one or more C1 to C6 alkyl groups where the C1 to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups,
        • a 5 or 6 membered heterocycle, optionally substituted with one or more C1 to C6 alkyl or C6 to C8 aryl groups, and where Ro is:
        • a hydrogen,
        • a C1 to C6 alkyl,
      • a —NRqCONRqRr group, where Rq is a hydrogen,
      • and where Rr is:
        • a C1 to C6 alkyl optionally substituted with one or more of the following:
          • a hydroxyl,
          • an alkoxy,
          • a 5 or 6 membered heterocycle,
          • a 5 or 6 membered heteroaryl, or
          • a C6 to C8 aryl optionally substituted with a halo,
        • a C2 to C6 alkylene group,
        • a C1 to C6 alkoxy group,
        • a 5 or 6 membered heterocycle group,
      • a —NRtCOORu group, where Ru is:
        • a C1 to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
          • a C6 to C8 aryl optionally substituted with halo,
          • an alkoxy group optionally substituted with one or more alkoxy groups,
          • an amino optionally substituted with one or more C1 to C6 alkyl,
          • halo, or
          • a 5 or 6 membered heteroaryl,
        • a C2 to C6 alkylene,
        • a C6 to C8 aryl, optionally substituted with halo,
      • and Rt is:
        • a hydrogen;
      • a —NHRbb group, where Rbb is:
        • a —C(═S)NH2 group, or
        • a —PO(ORx)2, where Rx is as defined above;
      • a —NRvSO2Rw group, where Rv is a hydrogen, and where Rw is a C1 to C6 alkyl,
  • Figure US20100305100A1-20101202-C00105
  • In some embodiments, Y is selected from the Y substituents of compounds 1330-2128, and 2600-3348.
  • In other embodiments of the present invention, compounds are provided wherein Y is selected from the group consisting of the following substituents:
  • Figure US20100305100A1-20101202-C00106
    Figure US20100305100A1-20101202-C00107
    Figure US20100305100A1-20101202-C00108
    Figure US20100305100A1-20101202-C00109
    Figure US20100305100A1-20101202-C00110
  • In other non-limiting embodiments of the present invention, compounds are provided wherein Y is selected from the group consisting of
  • Figure US20100305100A1-20101202-C00111
    Figure US20100305100A1-20101202-C00112
    Figure US20100305100A1-20101202-C00113
    Figure US20100305100A1-20101202-C00114
    Figure US20100305100A1-20101202-C00115
    Figure US20100305100A1-20101202-C00116
    Figure US20100305100A1-20101202-C00117
    Figure US20100305100A1-20101202-C00118
    Figure US20100305100A1-20101202-C00119
    Figure US20100305100A1-20101202-C00120
    Figure US20100305100A1-20101202-C00121
    Figure US20100305100A1-20101202-C00122
    Figure US20100305100A1-20101202-C00123
    Figure US20100305100A1-20101202-C00124
    Figure US20100305100A1-20101202-C00125
    Figure US20100305100A1-20101202-C00126
    Figure US20100305100A1-20101202-C00127
    Figure US20100305100A1-20101202-C00128
    Figure US20100305100A1-20101202-C00129
    Figure US20100305100A1-20101202-C00130
    Figure US20100305100A1-20101202-C00131
    Figure US20100305100A1-20101202-C00132
    Figure US20100305100A1-20101202-C00133
    Figure US20100305100A1-20101202-C00134
    Figure US20100305100A1-20101202-C00135
    Figure US20100305100A1-20101202-C00136
    Figure US20100305100A1-20101202-C00137
    Figure US20100305100A1-20101202-C00138
    Figure US20100305100A1-20101202-C00139
    Figure US20100305100A1-20101202-C00140
    Figure US20100305100A1-20101202-C00141
    Figure US20100305100A1-20101202-C00142
    Figure US20100305100A1-20101202-C00143
    Figure US20100305100A1-20101202-C00144
    Figure US20100305100A1-20101202-C00145
    Figure US20100305100A1-20101202-C00146
    Figure US20100305100A1-20101202-C00147
    Figure US20100305100A1-20101202-C00148
    Figure US20100305100A1-20101202-C00149
    Figure US20100305100A1-20101202-C00150
    Figure US20100305100A1-20101202-C00151
    Figure US20100305100A1-20101202-C00152
    Figure US20100305100A1-20101202-C00153
    Figure US20100305100A1-20101202-C00154
    Figure US20100305100A1-20101202-C00155
    Figure US20100305100A1-20101202-C00156
    Figure US20100305100A1-20101202-C00157
    Figure US20100305100A1-20101202-C00158
  • In an embodiment, the present invention includes compounds of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Z is a 5 or 6 membered heterocycle. In another embodiment of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, Z is a 5 membered heterocycle. In a further embodiment of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, Z is a 6 membered heterocycle. In another embodiment, the present invention includes compounds of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Z is a C1 to C6 alkyl optionally substituted with a 5 or 6 membered heterocycle. In another embodiment, the present invention includes compounds wherein Z is a C1 to C6 alkyl. In another embodiment, the present invention includes compounds wherein Z is a C1 alkyl. In another embodiment, the present invention includes compounds wherein Z is a C2 alkyl. In another embodiment, the present invention includes compounds wherein Z is a C3 alkyl. In another embodiment, the present invention includes compounds wherein Z is a C4 alkyl. In another embodiment, the present invention includes compounds wherein Z is a C5 alkyl. In another embodiment, the present invention includes compounds wherein Z is a C6 alkyl.
  • In another embodiment, the present invention includes compounds wherein Z is a straight chain C1 to C6 alkyl. In another embodiment, the present invention includes compounds wherein Z is a cyclic C1 to C6 alkyl. In another embodiment, the present invention includes compounds wherein Z is a C1 to C6 alkyl that is a combination of straight and cyclic. In yet another embodiment, the present invention includes compounds wherein Z is selected from the group consisting of cyclobutyl, cyclopropyl, cyclopropyl methyl, ethyl, cyclopentyl, and isopropyl. In a further embodiment, the present invention includes compounds wherein Z is cyclobutyl, cyclopropyl or ethyl. In a further embodiment, the present invention includes compounds wherein Z is cyclobutyl, cyclopropyl, or cyclopropyl methyl. In an embodiment, the present invention includes compounds wherein Z is cyclobutyl or cyclopropyl. In an embodiment of the present invention, a compound is provided wherein Z is cyclobutyl.
  • In some embodiments, Z is selected from the Z substituents of compounds 1330-2128, and 2600-3348.
  • In a non-limiting embodiment of the compounds of the present invention, Z is selected from the group consisting of
  • Figure US20100305100A1-20101202-C00159
  • In another non-limiting embodiment of the present invention, compounds are provided wherein Z is selected from the following:
  • Figure US20100305100A1-20101202-C00160
  • In some embodiments, the Z substituent is a hydrogen. In other embodiments, Z is a C1 to C6 alkyl optionally substituted with a five membered heterocycle. In other embodiments, Z is a C1 to C6 alkyl optionally substituted with a six membered heterocycle. In an embodiment of the present invention, compounds are provided wherein R2 is an alkoxy group. In an embodiment, the present invention provides compounds wherein R2 is a methoxy or an ethoxy group. In an embodiment of the compounds of the present invention, R2 is a methoxy group. In an embodiment of the compounds of the present invention, R2 is an ethoxy group. In an embodiment, the present invention provides compounds wherein R2 is an alkoxy group optionally substituted with one or more groups independently selected from the following:
      • a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected C1 to C6 alkyl, alkoxy, or hydroxy groups, or
      • a 5 or 6 membered heteroaryl group optionally substituted with one or more C1 to C6 alkyl groups.
  • In an embodiment, the present invention provides compounds wherein R2 is an alkoxy group substituted with an imidazole, a triazole, a thiazole. In another embodiment, R2 is an alkoxy group substituted with a hydroxy group and an imidazole, a triazole, or a thiazole.
  • In an embodiment, the present invention provides compounds wherein R2 is an —ORkk group, where Rkk is a 5 to 6 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl group.
  • In an embodiment of the present invention, compounds are provided wherein R2 is a C1 to C6 alkyl group, optionally substituted with one or more 5 or 6 membered heterocycle groups. In a further embodiment of the present invention, compounds are provided wherein R2 is a —C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups.
  • In some embodiments, R2 is selected from the R2 substituents of compounds 1330-2128, and 2600-3348.
  • In an embodiment of the present invention, compounds are provided wherein R2 is selected from the group consisting of the following substituents:
  • Figure US20100305100A1-20101202-C00161
    Figure US20100305100A1-20101202-C00162
  • In another embodiment, compounds of the present invention are provided wherein R2 is selected from the group consisting of the following substituents:
  • Figure US20100305100A1-20101202-C00163
    Figure US20100305100A1-20101202-C00164
    Figure US20100305100A1-20101202-C00165
    Figure US20100305100A1-20101202-C00166
  • In an embodiment of the present invention, Z is a C1 to C6 alkyl group, Y is a—NRtCOORu group, where Ru is—a C1 to C12 alkyl and Rt is—a hydrogen, and R2 is:
      • an alkoxy group optionally substituted with one or more groups independently selected from the following:
        • an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more 5 or 6 membered heterocycle,
        • a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C1 to C6 alkyl group, the C1 to C6 alkyl group optionally substituted with one or more independently selected C1 to C6 alkoxy group,
        • a 5 or 6 membered heteroaryl group optionally substituted with one or more C1 to C6 alkyl groups,
      • an —ORkk group, where Rkk is a 5 to 6 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl group.
  • In another embodiment of the present invention, Z is a C1 to C6 alkyl group, Y is a —NRtCOORu group, where Ru is—a C1 to C12 alkyl and Rt is—a hydrogen, and R2 is:
      • an alkoxy group optionally substituted with one or more groups independently selected from the following:
        • a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C1 to C6 alkyl group, the C1 to C6 alkyl group optionally substituted with one or more independently selected C1 to C6 alkoxy group,
        • a 5 or 6 membered heteroaryl group optionally substituted with one or more C1 to C6 alkyl groups,
      • an —ORkk group, where Rkk is a 5 to 6 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl group.
  • In another embodiment of the present invention, Z is a C1 to C6 alkyl group, Y is a —NRtCOORu group, where Ru is—a C1 to C12 alkyl and Rt is—a hydrogen, and R2 is:
      • an alkoxy group optionally substituted with one or more groups independently selected from the following:
        • a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C1 to C6 alkyl group, the C1 to C6 alkyl group optionally substituted with one or more independently selected C1 to C6 alkoxy group,
        • a 5 or 6 membered heteroaryl group optionally substituted with one or more C1 to C6 alkyl groups.
  • In another embodiment of the present invention, Z is a C1 to C6 alkyl group, Y is a —NRtCOORu group, where Ru is—a C1 to C12 alkyl and Rt is—a hydrogen, and R2 is:
      • an alkoxy group optionally substituted with one or more groups independently selected from the following:
        • a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C1 to C6 alkyl group, the C1 to C6 alkyl group optionally substituted with one or more independently selected C1 to C6 alkoxy group.
  • In another embodiment of the present invention, Z is a C1 to C6 alkyl group, Y is a —NRtCOORu group, where Ru is—a C1 to C12 alkyl and Rt is—a hydrogen, and R2 is:
      • an alkoxy group optionally substituted with one or more groups independently selected from the following:
  • Exemplary compounds include the following:
  • Figure US20100305100A1-20101202-C00167
    Figure US20100305100A1-20101202-C00168
    Figure US20100305100A1-20101202-C00169
    Figure US20100305100A1-20101202-C00170
    Figure US20100305100A1-20101202-C00171
    Figure US20100305100A1-20101202-C00172
    Figure US20100305100A1-20101202-C00173
    Figure US20100305100A1-20101202-C00174
    Figure US20100305100A1-20101202-C00175
    Figure US20100305100A1-20101202-C00176
    Figure US20100305100A1-20101202-C00177
    Figure US20100305100A1-20101202-C00178
    Figure US20100305100A1-20101202-C00179
    Figure US20100305100A1-20101202-C00180
    Figure US20100305100A1-20101202-C00181
    Figure US20100305100A1-20101202-C00182
    Figure US20100305100A1-20101202-C00183
    Figure US20100305100A1-20101202-C00184
    Figure US20100305100A1-20101202-C00185
    Figure US20100305100A1-20101202-C00186
    Figure US20100305100A1-20101202-C00187
    Figure US20100305100A1-20101202-C00188
    Figure US20100305100A1-20101202-C00189
    Figure US20100305100A1-20101202-C00190
    Figure US20100305100A1-20101202-C00191
    Figure US20100305100A1-20101202-C00192
    Figure US20100305100A1-20101202-C00193
    Figure US20100305100A1-20101202-C00194
    Figure US20100305100A1-20101202-C00195
    Figure US20100305100A1-20101202-C00196
    Figure US20100305100A1-20101202-C00197
    Figure US20100305100A1-20101202-C00198
    Figure US20100305100A1-20101202-C00199
    Figure US20100305100A1-20101202-C00200
    Figure US20100305100A1-20101202-C00201
    Figure US20100305100A1-20101202-C00202
    Figure US20100305100A1-20101202-C00203
    Figure US20100305100A1-20101202-C00204
    Figure US20100305100A1-20101202-C00205
    Figure US20100305100A1-20101202-C00206
    Figure US20100305100A1-20101202-C00207
    Figure US20100305100A1-20101202-C00208
    Figure US20100305100A1-20101202-C00209
    Figure US20100305100A1-20101202-C00210
    Figure US20100305100A1-20101202-C00211
    Figure US20100305100A1-20101202-C00212
    Figure US20100305100A1-20101202-C00213
    Figure US20100305100A1-20101202-C00214
    Figure US20100305100A1-20101202-C00215
    Figure US20100305100A1-20101202-C00216
    Figure US20100305100A1-20101202-C00217
    Figure US20100305100A1-20101202-C00218
    Figure US20100305100A1-20101202-C00219
    Figure US20100305100A1-20101202-C00220
    Figure US20100305100A1-20101202-C00221
    Figure US20100305100A1-20101202-C00222
    Figure US20100305100A1-20101202-C00223
    Figure US20100305100A1-20101202-C00224
    Figure US20100305100A1-20101202-C00225
    Figure US20100305100A1-20101202-C00226
    Figure US20100305100A1-20101202-C00227
    Figure US20100305100A1-20101202-C00228
    Figure US20100305100A1-20101202-C00229
    Figure US20100305100A1-20101202-C00230
    Figure US20100305100A1-20101202-C00231
    Figure US20100305100A1-20101202-C00232
    Figure US20100305100A1-20101202-C00233
    Figure US20100305100A1-20101202-C00234
    Figure US20100305100A1-20101202-C00235
    Figure US20100305100A1-20101202-C00236
    Figure US20100305100A1-20101202-C00237
    Figure US20100305100A1-20101202-C00238
    Figure US20100305100A1-20101202-C00239
    Figure US20100305100A1-20101202-C00240
    Figure US20100305100A1-20101202-C00241
    Figure US20100305100A1-20101202-C00242
    Figure US20100305100A1-20101202-C00243
    Figure US20100305100A1-20101202-C00244
    Figure US20100305100A1-20101202-C00245
    Figure US20100305100A1-20101202-C00246
    Figure US20100305100A1-20101202-C00247
    Figure US20100305100A1-20101202-C00248
    Figure US20100305100A1-20101202-C00249
    Figure US20100305100A1-20101202-C00250
    Figure US20100305100A1-20101202-C00251
    Figure US20100305100A1-20101202-C00252
    Figure US20100305100A1-20101202-C00253
    Figure US20100305100A1-20101202-C00254
    Figure US20100305100A1-20101202-C00255
    Figure US20100305100A1-20101202-C00256
    Figure US20100305100A1-20101202-C00257
    Figure US20100305100A1-20101202-C00258
    Figure US20100305100A1-20101202-C00259
    Figure US20100305100A1-20101202-C00260
    Figure US20100305100A1-20101202-C00261
    Figure US20100305100A1-20101202-C00262
    Figure US20100305100A1-20101202-C00263
    Figure US20100305100A1-20101202-C00264
    Figure US20100305100A1-20101202-C00265
    Figure US20100305100A1-20101202-C00266
    Figure US20100305100A1-20101202-C00267
    Figure US20100305100A1-20101202-C00268
    Figure US20100305100A1-20101202-C00269
    Figure US20100305100A1-20101202-C00270
    Figure US20100305100A1-20101202-C00271
    Figure US20100305100A1-20101202-C00272
    Figure US20100305100A1-20101202-C00273
    Figure US20100305100A1-20101202-C00274
    Figure US20100305100A1-20101202-C00275
    Figure US20100305100A1-20101202-C00276
    Figure US20100305100A1-20101202-C00277
    Figure US20100305100A1-20101202-C00278
    Figure US20100305100A1-20101202-C00279
    Figure US20100305100A1-20101202-C00280
    Figure US20100305100A1-20101202-C00281
    Figure US20100305100A1-20101202-C00282
    Figure US20100305100A1-20101202-C00283
    Figure US20100305100A1-20101202-C00284
    Figure US20100305100A1-20101202-C00285
    Figure US20100305100A1-20101202-C00286
    Figure US20100305100A1-20101202-C00287
    Figure US20100305100A1-20101202-C00288
    Figure US20100305100A1-20101202-C00289
    Figure US20100305100A1-20101202-C00290
    Figure US20100305100A1-20101202-C00291
    Figure US20100305100A1-20101202-C00292
    Figure US20100305100A1-20101202-C00293
    Figure US20100305100A1-20101202-C00294
    Figure US20100305100A1-20101202-C00295
    Figure US20100305100A1-20101202-C00296
    Figure US20100305100A1-20101202-C00297
  • Exemplary compounds include the following:
  • Figure US20100305100A1-20101202-C00298
    Figure US20100305100A1-20101202-C00299
    Figure US20100305100A1-20101202-C00300
    Figure US20100305100A1-20101202-C00301
    Figure US20100305100A1-20101202-C00302
    Figure US20100305100A1-20101202-C00303
    Figure US20100305100A1-20101202-C00304
    Figure US20100305100A1-20101202-C00305
    Figure US20100305100A1-20101202-C00306
    Figure US20100305100A1-20101202-C00307
    Figure US20100305100A1-20101202-C00308
    Figure US20100305100A1-20101202-C00309
    Figure US20100305100A1-20101202-C00310
    Figure US20100305100A1-20101202-C00311
    Figure US20100305100A1-20101202-C00312
    Figure US20100305100A1-20101202-C00313
    Figure US20100305100A1-20101202-C00314
    Figure US20100305100A1-20101202-C00315
    Figure US20100305100A1-20101202-C00316
    Figure US20100305100A1-20101202-C00317
    Figure US20100305100A1-20101202-C00318
    Figure US20100305100A1-20101202-C00319
    Figure US20100305100A1-20101202-C00320
    Figure US20100305100A1-20101202-C00321
    Figure US20100305100A1-20101202-C00322
    Figure US20100305100A1-20101202-C00323
    Figure US20100305100A1-20101202-C00324
    Figure US20100305100A1-20101202-C00325
    Figure US20100305100A1-20101202-C00326
    Figure US20100305100A1-20101202-C00327
    Figure US20100305100A1-20101202-C00328
    Figure US20100305100A1-20101202-C00329
    Figure US20100305100A1-20101202-C00330
    Figure US20100305100A1-20101202-C00331
    Figure US20100305100A1-20101202-C00332
    Figure US20100305100A1-20101202-C00333
    Figure US20100305100A1-20101202-C00334
    Figure US20100305100A1-20101202-C00335
    Figure US20100305100A1-20101202-C00336
    Figure US20100305100A1-20101202-C00337
    Figure US20100305100A1-20101202-C00338
    Figure US20100305100A1-20101202-C00339
    Figure US20100305100A1-20101202-C00340
    Figure US20100305100A1-20101202-C00341
    Figure US20100305100A1-20101202-C00342
    Figure US20100305100A1-20101202-C00343
    Figure US20100305100A1-20101202-C00344
    Figure US20100305100A1-20101202-C00345
    Figure US20100305100A1-20101202-C00346
    Figure US20100305100A1-20101202-C00347
    Figure US20100305100A1-20101202-C00348
    Figure US20100305100A1-20101202-C00349
    Figure US20100305100A1-20101202-C00350
    • B. Preparation of Compounds of the Invention
  • Indole compounds of the present invention can be obtained via standard, well-known synthetic methodology. Many of the indole starting materials can be prepared the routes described below or by those skilled in the art.
  • Compounds of formula I, represented by structure II can be prepared by the methodology depicted in Scheme A below:
  • An α-nitroketone derivative A2 can be derived from treatment of the anion of nitromethane, obtained from the treatment of nitromethane with a base, such as, e.g., sodium or potassium t-butoxide or sodium hydride, with an activated carboxylic acid derivative, e.g., the acyl imidazolide A1. Reaction of the α-nitroketone A2 with amine derivative A3 can afford the nitro enamine A4 by mixing the components A3 and A4 and heating in a suitable solvent such as an alcohol or an aprotic solvent. Treatment of the nitro enamine A4 with quinone A5 in a polar protic solvent such as acetic acid at or near ambient temperature gives the compound of formula II.
  • Compounds of formula I, represented by structure II can be prepared as shown in Scheme A below:
  • Treatment of nitromethane with base followed by reaction with an activated carboxylic acid, e.g., an imidazolide, such as compound A1 gives compounds of type A2. Treatment of compounds of type A2 with an amine of structure A3 gives the compound A4. Reaction of compound A4 with quinine in the presence of acid, e.g., acetic acid gives the hydroxyindoles of structure II.
  • Figure US20100305100A1-20101202-C00351
  • Compounds of formula I, represented by structure III can be prepared as shown in Scheme B below:
  • Treatment of B1 with a reactive alkyl or aryl group containing a leaving group L in a suitable solvent, with or without heat in the presence of a base, such an inorganic base, e.g., sodium or potassium carbonate or an organic base, e.g., triethylamine, can afford the compound of structure III. Examples of leaving groups include but are not limited to halogens (e.g., chlorine, bromine or iodine) or alkyl or arylsulfonates.
  • Figure US20100305100A1-20101202-C00352
  • Compounds of formula I, represented by structure IV can be prepared as shown in Scheme C below:
  • Compounds of structure IV can be obtained by nitrating an indole of structure C1, to give the 3-nitroindole C2. The nitration can be carried out by treatment of C1 with a nitrating agent, such as nitric acid or sodium nitrite in a solvent such as acetic acid, acetic anhydride, sulfuric acid or in a mixed solvent system containing an organic solvent such as dichloromethane. The reaction can be carried out a temperature of −30° C. to +50° C. Treatment of C2 with a reactive functional group R9 containing a suitable leaving group L (C3) can give compounds of structure IV. Reactive functional groups can consist of but are not limited to alkyl and aralkyl. L can represent a halide, particularly chloro, bromo or iodo or an alkylsulfonate. The reaction between C2 and C3 can be carried out in a suitable solvent in the presence of an inorganic base such as potassium carbonate or sodium hydride or an organic base such as a trialkylamine. Alternatively, the group R9 can represent an aryl or heteroaryl group and L can represent a halide, particularly chloro, bromo or iodo. The reaction can be carried out in a polar or nonpolar solvent at a temperature from ambient to 200° C. in the presence of a copper catalyst, e.g., CuI, a base such as Cs2CO3 or K3PO4, and optionally an amine ligand such as 1,2-bis(methylamino)ethane or 1,2-cyclohexanediamine
  • An alternative pathway is to convert C1 into C4 in similar fashion as described above and then carry out the nitration reaction to afford compounds of structure IV.
  • Figure US20100305100A1-20101202-C00353
  • Compounds of formula I, represented by structure V can be prepared as shown in Scheme D.
  • Treatment of β-ketoesters of structure D1 with amines D2 gives the amino crotonate derivatives D3 by heating in a suitable solvent such as an alcohol or an aprotic solvent. Reaction between D3 and quinone D4 in a polar protic solvent, such as acetic acid gives compounds of structure V.
  • Figure US20100305100A1-20101202-C00354
  • Compounds of the present invention, represented by structure VI compounds can be prepared by the chemistry described in scheme E below.
  • Indole-3-carboxylic esters E1 can be converted to indole-3-carboxylic acids E2 by treatment of compounds of structure E1 with, for example, either acid or base in aqueous or mixed aqueous-organic solvents at ambient or elevated temperature or by treatment with nucleophilic agents, for example, boron tribromide or trimethylsilyl iodide, in a suitable solvent. Compounds of type E2 can then be activated and treated with amines of type E3 to give compounds E4. Activation of the carboxylic acid can be carried out, for example, by any of the standard methods. For example, the acid E2 can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of the amine E3, or alternatively the acid can be activated as the acid chloride by treatment of the acid with, e.g., thionyl chloride or oxalyl chloride or as the acyl imidazolide, obtained by treatment of the acid with carbonyl diimidazole, followed by treatment of the amine E3. Compounds E4 can be converted to compounds of structure VI by treatment of E4 with a reactive functional group R9 containing a suitable leaving group L (E5) as described previously. Alternatively, compounds of type E1 can be converted to compounds of structure E6 by treatment with E5. Indole-3-carboxylic esters E6 can then be converted to indole-3-carboxylic acids E7 by the methods described above. Conversion of E7 to compounds of structure VI can be carried out by the activation and reaction with an amine E3 as described above.
  • Figure US20100305100A1-20101202-C00355
  • Compounds of the present invention, represented by structure VII compounds can be prepared by the chemistry described in scheme F below.
  • Indoles F1 can be formylated with reagents such as phosphorous oxychloride in the presence of DMF to give the indole-3-carboxaldehydes F2. Conversion to compounds of structure VII can be accomplished by treatment of F2 with compounds F3 as described previously. Alternatively, compounds of type F1 can first be converted to F4 and then be formylated to compounds of structure VII.
  • Figure US20100305100A1-20101202-C00356
  • Compounds of formula G, represented by structure VIII can be prepared as shown in Scheme G.
  • Indole-3-carboxaldehydes of structure G1 can be converted to the indole-3-carboxylic acid derivatives by oxidation with reagents such as potassium permanganate under aqueous conditions.
  • Figure US20100305100A1-20101202-C00357
  • Compounds of formula H, represented by structure IX can be prepared as shown in Scheme H.
  • Indole-3-carboxaldehydes of structure H1 can be converted to the indole-3-carbonitrile derivatives H2 by a variety of methods. Treatment of H1 with a nitroalkane, e.g., nitropropane, in the presence of an amine source, e g, ammonium hydrogen phosphate gives the indole-3-carbonitrile H2 derivative. An alternative pathway to compound H2 is via the intermediate H3. Conversion of H1 to the oxime derivative H3 can be followed by dehydration, e.g., treatment of the oxime with acetic anhydride and a base, or reaction of the oxime with thionyl chloride to give H2. The compound H2 can then be reacted with a reactive functional group R9 containing a suitable leaving group L (H4) as described previously to afford compounds of structure IX.
  • Alternatively, H1 can be reacted with a reactive functional group R9 containing a suitable leaving group L (H4) to give the intermediate H5, which can be reacted with a nitroalkane as above to give the indole-3-carbonitrile IX compound. Compound IX can also be obtained by conversion to the oxime H6 followed by a dehydration reaction as described above.
  • Figure US20100305100A1-20101202-C00358
  • Compounds of the present invention, represented by structure X can also be prepared as described in scheme I below.
  • Indoles I1 can be cyanated with an appropriate cyanating agent, e.g., chlorosulfonyl isocyanate (I2) or a dialkyl phosphoryl isocyanate in a suitable solvent or solvent mixture, e.g. DMF, CH3CN or dioxane, to afford compounds of structure I3. The compound I3 can then be reacted with a reactive functional group R9 containing a suitable leaving group L (I4) as described previously afford the compound X.
  • Alternatively, compound I1 can be reacted with a reactive functional group R9 containing a suitable leaving group L to give compounds of structure I5 that can then be cyanated as above to give compounds of formula X.
  • Figure US20100305100A1-20101202-C00359
  • Compounds of formula J, represented by structure XI can be prepared as shown in Scheme J.
  • Amino crotonates J1 can be reacted with amines J2 to give J3. Reaction of J3 with quinone in the presence of a polar, protic solvent, e.g., acetic acid, gives the compound of structure XI.
  • Figure US20100305100A1-20101202-C00360
  • Compounds of the present invention, represented by structure XII and XIII can be prepared as described in scheme K below.
  • Aldehydes of structure K1 can be reacted with an alkyl azidoacetate K2 by heating the components together in a suitable organic solvent, e.g., a protic or non-protic solvent, in the presence of an organic or inorganic base, to give the α-azidoacrylate K3. Heating K3 in the presence of a suitable non-reactive organic solvent, e.g., toluene or xylenes can give the 2-alkoxycarbonylindoles K4. Reduction of the ester functionality with a suitable reducing reagent, for example, lithium aluminum hydride, in a suitable solvent, e.g., ether or THF can give the intermediate K5. Reaction of K5 with a reactive functional group R9 containing a suitable leaving group L (K6) as described in previously affords the compound K7. Cyanation of K7 with a cyanating agent, e.g., chlorosulfonyl isocyanate as described previously can give compound XII. Alternatively, cyanation of K5 with chlorosulfonyl isocyanate gives K8, which can be reacted with a reactive functional group R9 containing a suitable leaving group L (K6) as described previously, affords, the compound XII.
  • An alternative use of intermediate K4 is exemplified below. Hydrolysis of the 2-alkoxycarbonyl group of the indole K4 either under acidic or basic conditions followed by decarboxylation can give the intermediate K9. Decarboxylation can be carried out thermally, i.e., heating in an appropriate solvent, e.g., toluene, xylenes, or quinoline. Alternatively, a source of copper can be added, for example, copper bronze, to facilitate decarboxylation. Reaction of K9 with a reactive functional group R9 containing a suitable leaving group L (K6) as described above can afford the compounds K10. Cyanation of K10 with a cyanating agent, e.g., chlorosulfonyl isocyanate as described previously can give compound XIII. Alternatively, cyanation of K9 with chlorosulfonyl isocyanate gives K11, which can be reacted with a reactive functional group R9 containing a suitable leaving group L (K6) as described in previously, affords the compound XIII.
  • Figure US20100305100A1-20101202-C00361
  • Compounds of formula L, represented by structure XIV can be prepared as shown in Scheme L.
  • Compounds of formula L1 can be halogenated on the 2-methyl group to give 2-bromomethyl or chloromethyl indoles L2. The halogenation reaction can be conducted with reagents, e.g., N-bromo- or chlorosuccinimide. The reaction can be conducted in a suitable solvent, such as chloroform, carbon tetrachloride, or THF and carried out in a range between ambient temperature and 80° C. Optionally, a radical initiator may be added, e.g., benzoyl peroxide or AIBN. The compound L2 can then be reacted with a nucleophile R5—W (L3) to give compounds of structure XIV. The reaction can be conducted in a suitable solvent, e.g., THF, CH2Cl2 or DMF, within a temperature range of 0° C. to 120° C. A base, e.g., an inorganic base, such as potassium carbonate or an organic base, such as a trialkylamine can be used to remove the acid formed in the reaction. The group W can refer to an N, O or S atom.
  • Figure US20100305100A1-20101202-C00362
  • Compounds of the present invention, represented by structure XV can be prepared as described in scheme M below.
  • Anilines of structure M1 can be diazotized and the resulting diazonium salt can be reduced to give the phenyl hydrazine compound M2. Reaction between the hydrazine M2 and a ketone M3 under acidic conditions can give the indole compound M4. The conditions for the cyclization reaction can be carried out under typical conditions utilized by one skilled in the art, for example, acidic conditions, utilizing acids such as a Bronstead acid, e.g., acetic acid, hydrochloric acid or polyphosphoric acid or a Lewis acid, e.g., zinc chloride. The reaction can be carried out in the presence of a co-solvent, e.g., CH2Cl2 or THF typically within a temperature range of 0° C. to 120° C. Reaction of M4 with a reactive functional group R9 containing a suitable leaving group L (M5) as described previously, can afford compounds M6. Cyanation of the indole M6 with a cyanating agent such as chlorosulfonyl isocyanate can give the compound of structure XV.
  • Alternatively, the indoles M4 can be cyanated to give compounds of structure M7. Reaction of M7 with a reactive functional group R9 containing a suitable leaving group L (M5) as described above can give compounds of structure XV.
  • Figure US20100305100A1-20101202-C00363
  • Compounds of formula I, represented by structure XVI can be prepared as shown in Scheme N.
  • Compounds of formula N1 can be reacted with a dialkylformamide dialkyl acetal, N2, e.g., dimethylformamide dimethyl acetal, optionally in the presence of a suitable solvent, e.g., DMF or dioxane, at a temperature range from ambient to 150° C. to give the compound of structure N3. Reduction of the nitro group of compounds of type N3 under standard conditions can give the indole compounds of structure N4. The reduction can be carried out via hydrogenation, using a sub-stoichiometric amount of a hydrogenation catalyst, e.g., platinum or palladium, in the presence of a hydrogen source in a protic or aprotic solvent. The reduction can be carried out in a temperature range of ambient to 80° C. Alternatively, the reduction can be carried out via chemical reduction, e.g., in the presence of stoichiometric amounts of Fe or Sn compounds in a suitable solvent at a temperature range of ambient to 100° C. The compound N4 can then be reacted with a reactive functional group R9 containing a suitable leaving group L (N5) as described previously to afford compounds of structure N6. Cyanation of N6 with a cyanating agent such as chlorosulfonyl isocyanate in a suitable solvent can give the compounds of structure XVI.
  • Alternatively, compounds of structure N4 can be cyanated to give compounds of structure N7. Reaction with N7 with a reactive functional group R9 containing a suitable leaving group L (N5) as described above can give compounds of structure XVI.
  • Figure US20100305100A1-20101202-C00364
  • Compounds of formula I, represented by structure XVII can be prepared as shown in Scheme O.
  • Compounds of structure O1 can be converted to 2-iodo- or bromoindoles O2. Typically, a strong base, such as n-butyllithium or s-butyllithium or lithium diisopropylamide or lithium or potassium hexamethyldisilazide is employed, with formation of the 2-indolyl anion generated in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them. The reaction is typically carried out in the range of −78° C. to ambient temperature. The 2-indolyl anion can then be quenched with an electrophilic source of halogen, including but not limited to iodine, bromine or N-bromosuccinimide to give compounds of structure O2. Reaction of 2-iodo- or bromoindoles O2 with a boronic acid (commonly referred to as a Suzuki reaction) or trialkyl stannane (commonly referred to as a Stille reaction) can give the compounds of structure XVII. The coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as tetrakis(triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand. The reactions are carried out in a suitable solvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at a temperature range of ambient to 150° C. For the Suzuki reaction, a base is usually added. The base can be in aqueous solution, e.g., aqueous sodium carbonate or sodium bicarbonate, or the base can be employed under anhydrous conditions, e.g., cesium or potassium fluoride. For the Stille reaction a copper co-catalyst, e.g., copper iodide, can be added.
  • Alternatively, indoles O1 can be converted to the indole-2-boronic acid or indole-2-trialkylstannane derivatives O3 by reacting the 2-indolyl anion described above with a trialkylborate or chlorotrialkyl stannane derivative, respectively. Compounds of type O3 can be reacted with aryl and heteroaryl bromides and iodides under similar conditions to those described above to form compounds of structure XVII.
  • Figure US20100305100A1-20101202-C00365
  • Compounds of formula I, represented by structure XVIII can be prepared as shown in Scheme P.
  • Compounds of structure P1 can be converted to compounds P3 by treatment of P1 with an aryl or heteroaryl halide (P2) in the presence of organometallic catalysis. Such catalyst combinations can include palladium catalysts, e.g., palladium acetate and a source of copper, e.g., copper iodide. The reaction can be carried out in the presence of a base, e.g., cesium carbonate. The reaction can be carried out within a temperature range of ambient temperature to 150° C.
  • Figure US20100305100A1-20101202-C00366
  • Compounds of the present invention, represented by structure XIX can be prepared as described in scheme Q below.
  • Compounds of structure XIX can be prepared by protecting an indole compound of structure Q1 as e.g., the N-Boc derivative Q2. Alternatively, other protecting groups that can be utilized but not limited to include, e.g., benzyl, alkyl or aryl sulfonyl, or trialkyl silyl. Treatment of Q2 with a strong base, e.g., lithium diisopropyl amide in an aprotic solvent, e.g., THF followed by quenching with a trialkylborate derivative can give the indolyl-2-boronic acid Q3. Reaction with an aryl or heteroaryl halide Q4 in the presence of palladium catalysis, e.g., tetrakis(triphenylphosphine) palladium (0), bis(triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand, can give the compound Q5. Removal of the protecting group can give Q6. Reaction with Q6 with a reactive functional group R9 containing a suitable leaving group L as described above can give compounds of structure Q7. Cyanation of compound Q7 can give the compounds of structure XIX.
  • Figure US20100305100A1-20101202-C00367
  • Compounds of formula I, represented by structure XX can be prepared as shown in Scheme R.
  • Compounds of structure R1 can be prepared by protecting an indole compound of structure R1 as e.g., the N-Boc derivative R2 as above. Compounds of structure R2 can be converted to 2-iodo- or bromoindoles R3. Typically, a strong base, such as n-butyllithium or s-butyllithium or lithium diisopropylamide or lithium or potassium hexamethyldisilazide is employed, with formation of the 2-indolyl anion generated in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them. The reaction is typically carried out in the range of −78° C. to ambient temperature. The 2-indolyl anion can then be quenched with an electrophilic source of halogen, including but not limited to iodine, bromine or N-bromosuccinimide to give compounds of structure R3. After removal of the protecting group, compounds of R4 can be reacted with aryl or heteroaryl boronic acids or esters (R5) (commonly referred to as a Suzuki reaction) to give compounds of structure R6. The coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as tetrakis(triphenylphosphine) palladium (0), bis(triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand. Reaction with R6 with a reactive functional group R9 containing a suitable leaving group L as described above can give compounds of structure XX.
  • Figure US20100305100A1-20101202-C00368
  • Compounds of the present invention, represented by structure XXI can be prepared as described in scheme S below.
  • 2-iodo- or bromoindoles of structure S1 can be reacted with alkenes in the presence of a palladium catalyst (commonly referred to as the Heck reaction) to give compounds of type XXI. The coupling reactions can be carried out by methods known to those skilled in the art. The choice of catalyst and solvents are similar to those described previously.
  • Figure US20100305100A1-20101202-C00369
  • Compounds of formula I, represented by structure XXII can be prepared as shown in Scheme T.
  • 2-Iodo- or 2-bromoindoles of structure T1 can be reacted with acetylenes in the presence of a palladium catalyst (commonly referred to as the Sonagashira reaction) to give compounds of type XXII. The coupling reactions can be carried out by methods known to those skilled in the art. A typical set of reaction conditions includes reacting the indoles of structure T1 with an acetylene compound T2 in the presence of a source of palladium, a copper co-catalyst and an amine source. The reaction is carried out in a suitably unreactive solvent and conducted within a temperature range from ambient to 150° C.
  • Figure US20100305100A1-20101202-C00370
  • Compounds of formula I, represented by structure XXIII can be prepared as shown in Scheme U.
  • Compounds of structure XXIII can be obtained from the reduction of compounds XXI and XXII. Conditions for the reduction can include, but are not limited to catalytic reduction, e.g., hydrogenation over a source of platinum or palladium in a suitable solvent, e.g., CH2Cl2, ether, THF, methanol or solvent combinations.
  • Figure US20100305100A1-20101202-C00371
  • Compounds of the present invention, represented by structure XXIV can be prepared as described in scheme V below.
  • Indoles of structure V1 can be reacted with a suitable base, such as lithium diisopropylamide or potassium hexamethyldisilazide to generate the 2-indolyl anion in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them. The reaction is typically carried out in the range of −78° C. to ambient temperature. The 2-indolyl anion can then be quenched with a source of zinc halide, e.g., zinc halide metal or solutions containing them to give organozinc compounds of structure V2. Reaction of V2 with an arylhalide (V3) in the presence of a palladium catalyst (commonly referred to as the Negishi reaction) gives compounds of structure XXIV. Alternatively, 2-iodo or bromoindoles of structure V4, prepared from compounds V1 as described previously, can be reacted with organozinc compounds of structure V5 in the presence of a suitable palladium catalyst to give compounds of structure XXIV. The organozinc compound V5 can be derived from, e.g., an alkyl or alkenyl halide after treatment with activated zinc or an aryl or heteroaryl lithium or magnesium compound after treatment with zinc halide. Furthermore, the reactions of V2 or V4 can be carried out in the presence of a palladium source, e.g., as tetrakis(triphenylphosphine) palladium (0) or bis(triphenylphosphine) palladium (II) dichloride in a suitable solvent and at a temperature range from ambient to 150° C.
  • Figure US20100305100A1-20101202-C00372
  • Compounds of formula I, represented by structure XXV-XXVIII can be prepared as shown in Scheme W.
  • 2-Iodo- or bromoindoles of structure W1 can be reacted with acetylenes of structure W2 in the presence of a palladium catalyst (commonly referred to as the Sonagashira reaction) to give compounds of type XXV. The coupling reactions can be carried out by methods known to those skilled in the art. A typical set of reaction conditions includes reacting the indoles of structure W1 with an acetylene compound W2 in the presence of a source of palladium, an optional copper co-catalyst and an amine source. The reaction is carried out in a suitably unreactive solvent and conducted within a temperature range from ambient to 150° C. Reaction with XXV with a reactive functional group R9 containing a suitable leaving group L as described above can give compounds of structure XXVI.
  • 2-iodo- or bromoindoles of structure W1 can also be reacted with alkenes in the presence of a palladium catalyst (commonly referred to as the Heck reaction) to give compounds of type XXVII. The coupling reactions can be carried out by methods known to those skilled in the art. The choice of catalyst and solvents are similar to those described previously. Reaction with XXVII with a reactive functional group R9 containing a suitable leaving group L as described above can give compounds of structure XXVIII.
  • Figure US20100305100A1-20101202-C00373
  • Compounds of formula I, represented by structure XXIX can be prepared as shown in Scheme X.
  • Indoles of structure X1 and be acylated with acyl halides of structure X2 to give compounds of structure XXIX. The reaction can be promoted with a Lewis acid. The choice of Lewis acid can be chosen from, but is not limited to aluminum chloride, ferric chloride, stannic chloride or diethyl aluminum. The reaction is typically carried out in a suitable non-reactive solvent including CH2Cl2, carbon disulfide or dichloroethane and is typically conducted within a temperature range of −20° C. to 80° C.
  • Figure US20100305100A1-20101202-C00374
  • Compounds of formula I, represented by structure XXX can be prepared as shown in Scheme Y.
  • 3-Cyanoindoles of structure Y1 can be converted to tetrazoles of structure Y2 by treatment with, e.g., sodium azide. Heating a mixture of Y2 and the reagent Y3 can give the 3-(1,2,4-oxadiazolyl)indole compound XXX. The reagent Y3 can be, e.g., an acyl halide or an acid derivative activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide. The reaction can be carried out in a variety of solvents, including e.g., toluene, dioxane, pyridine and dichloroethane and can be carried out by heating Y2 and Y3 at a temperature range of 30° to 130° C.
  • Figure US20100305100A1-20101202-C00375
  • Compounds of formula I, represented by structure XXXI can be prepared as shown in Scheme Z.
  • 3-Cyanoindoles of structure Z1 can be treated with hydroxylamine to give hydroxyamidine compounds of formula Z2. Reaction of hydroxyamidines of structure Z2 with compounds of structure Z3 can give O-acylhydroxyamidines Z4. Compounds Z3 can represent, for example, acyl halides or carboxylic acids activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide. Heating compounds of structure Z4 in a non-reactive organic solvent, e.g., toluene, dichloroethane or dioxane in a temperature range of 30° C. to 150° C. can give compounds of structure XXXI.
  • Figure US20100305100A1-20101202-C00376
  • Compounds of the present invention, represented by structure XXXII can be prepared as described in scheme AA below.
  • Ketoindoles of type AA1 can be converted to oximes of structure AA2 by heating the ketoindoles with hydroxylamine (free base or acid salt) in a suitable solvent. Bis-deprotonation of compounds of type AA2 with a strong organic base (e.g., n-butyllithium or sec-butyllithium or tert-butyllithium) followed by reaction with DMF can give compounds of formula XXXII.
  • Figure US20100305100A1-20101202-C00377
  • Compounds of formula I, represented by structure XXXIII can be prepared as shown in Scheme AB.
  • 3-Ketoindoles of structure AB 1 can be homologated to vinylogous amides of structure AB3 by reaction with dialkyl amide dialkyl acetals AB2. The dialkyl amides can include e.g., lower alkyl amides such as formamide, acetamide and propionamide. Examples would include dimethlformamide dimethyl acetal and dimethyl acetamide dimethyl acetal. The reaction can be conducted by reacting AB 1 and AB2 with or without additional solvent at a temperature from ambient to 150° C. Treatment of AB3 with hydroxylamine (free base or acid salt) in a suitable solvent can give compounds of structure XXXIII. The reaction is typically conducted within a temperature range from ambient to 120° C.
  • Figure US20100305100A1-20101202-C00378
  • Compounds of formula I, represented by structure XXXIV can be prepared as shown in Scheme AC.
  • Vinylogous amides of structure AC1 (as prepared above) can be treated with hydrazines AC2 in a suitable organic solvent (DMF, alcohol or acetic acid) at temperatures ranging from ambient temperature to 150° C. to give compounds of structure XXXIV.
  • Figure US20100305100A1-20101202-C00379
  • Compounds of the present invention, represented by structure XXXV can be prepared as described in scheme AD below.
  • Indole-3-carboxaldehydes of structure AD1 (as prepared in Scheme F) can be reacted with p-(toluenesulfonyl)methyl isocyanate (TOSMIC) in the presence of a base to give compounds of structure XXXV. Bases can include potassium carbonate or 1,8-diazabicyclo[5.4.0]undec-7-ene and the reaction can be carried out in a suitable organic solvent from ambient temperature to 150° C.
  • Figure US20100305100A1-20101202-C00380
  • Compounds of formula I, represented by structures XXXVI and XXXVII can be prepared as shown in Scheme AE.
  • 3-Indolecarboxylic acids of structure AE1 (from Scheme E) can be converted to amides of structure AE2. Compounds of structure AE2 can be activated by any of the standard methods. For example, the acid AE1 can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of ammonia. Alternatively, the acid can be activated as the acid chloride or as the acyl imidazolide as described previously, followed by treatment of ammonia.
  • The indole-3-carboxamides of structure AE2 can be reacted with substituted aldehydes or ketones (AE3) containing a suitable leaving group L, in a suitable solvent at temperatures above ambient and up to 200° C. The reaction can be performed with or without added base to afford oxazoles of structure XXXVI.
  • The indole-3-carboxamides of structure AE2 can also be converted to thioamides of structure AE4 by treating the primary amides with Lawesson's reagent or phosphorous pentasulfide at or above ambient temperature in a suitable organic solvent. The resulting thioamides AE4 can be reacted with substituted aldehydes or ketones containing a suitable leaving group L (AE3), in a suitable solvent at temperatures above ambient and up to 150° C. The reaction can be performed with or without added base to afford thiazoles of structure XXXVII.
  • Figure US20100305100A1-20101202-C00381
  • Compounds of the present invention, represented by structure XXXVIII and XXXIX can be prepared as described in scheme AF below.
  • 3-Ketoindoles of structure AF1 can be halogenated (e.g., brominated) to give compounds of structure AF3. Suitable brominating agents can include but are not limited to phenyltrimethylammonium tribromide (AF2), N-bromosuccinimide or bromine and can be carried out in a variety of organic solvents.
  • Treatment of compounds AF3 with amides of type AF4 in a suitable solvent at temperatures above ambient and up to 200° C. with or without added base can give oxazoles of structure XXXVIII.
  • Treatment of compounds AF3 with thioamides of type AF5 in a suitable solvent at temperatures above ambient and up to 150° C. with or without added base can give thiazoles of structure XXXIX.
  • Figure US20100305100A1-20101202-C00382
  • Compounds of formula I, represented by structure XL can be prepared as shown in Scheme AG.
  • Indoles of structure AG1 can be brominated or iodinated to give compounds of structure AG2. Brominating agents may include but are not limited to bromine or N-bromosuccinimide and iodinating reagents may include iodine monochloride or bis-trifluoroacetoxy iodobenzene. Reaction of 3-iodo- or bromoindoles AG2 with a boronic acid AG3 (commonly referred to as a Suzuki reaction) can give the compounds of structure XL. The coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as tetrakis(triphenylphosphine) palladium (0), bis(triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand. The reactions are carried out in a suitable solvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at a temperature range of ambient to 150° C. and typically in the presence of a base e.g., aqueous sodium carbonate or sodium bicarbonate, or the base can be employed under anhydrous conditions, e.g., cesium or potassium fluoride.
  • Alternatively, indole AG2 can be converted to the indole-3-boronic acid derivative AG5 by reacting the 3-haloindole AG2 with a strong organic base (alkyllithium or Grignard reagent) and reacting the resultant anion with a trialkylborate reagent AG4. Compounds of type AG5 can be reacted with aryl and heteroaryl bromides and iodides under similar conditions to those described above to form compounds of structure XL.
  • Figure US20100305100A1-20101202-C00383
  • Compounds of the present invention, represented by structure XLI can be prepared as described in scheme AH below.
  • 3-iodo- or bromoindoles of structure AH1 can be reacted with alkenes AH2 in the presence of a palladium catalyst (commonly referred to as the Heck reaction) to give compounds of type XLI. The coupling reactions can be carried out by methods known to those skilled in the art. The choice of catalyst and solvents are similar to those described in Scheme AG.
  • Figure US20100305100A1-20101202-C00384
  • Compounds of formula I, represented by structure XLII can be prepared as shown in Scheme AI.
  • 3-Iodo- or bromoindoles of structure All can be reacted with acetylenes AI2 in the presence of a palladium catalyst (commonly referred to as the Sonagashira reaction) to give compounds of type XLII. The coupling reactions can be carried out by methods known to those skilled in the art. A typical set of reaction conditions includes reacting the indole of structure All with an acetylene compound AI2 in the presence of a source of palladium, a copper co-catalyst and an amine source and carrying out the reaction at a temperature range of ambient to 150° C.
  • Figure US20100305100A1-20101202-C00385
  • Compounds of the present invention, represented by structure XLIII and XLIV can be prepared as described in scheme AJ below.
  • Nitroanilines of structure AJ1 can be converted to indoles of structure XLIII by condensation and cyclization with nitriles of structure AJ2. The reaction can be carried out in a suitable organic solvent, e.g., DMF or dioxane. Treatment of compounds of structure XLIII with a base followed by reaction with a reactive functional group R9 containing a suitable leaving group L can give the compounds of formula XLIV.
  • Figure US20100305100A1-20101202-C00386
  • Compounds of formula I, represented by structure XLV-XLVIII can be prepared as shown in Scheme AK.
  • 2-aminoindoles of structure XLV can be alkylated with a reactive functional group R15 containing a suitable leaving group L in the presence of a base, e.g., sodium hydride or potassium carbonate in a suitable organic solvent to give compounds of structure XLVI. A second alkylation utilizing a reactive functional group R′15 containing a suitable leaving group L similarly can give compounds of structure XLVII.
  • Acylation of compounds of structure XLV with acyl chlorides of structure AK1 can give compounds of structure XLVIII. The reaction is typically carried out in the presence of an organic base, e.g., a trialkylamine or an inorganic base, e.g., potassium carbonate in a suitable organic solvent.
  • Figure US20100305100A1-20101202-C00387
  • Compounds of the present invention, represented by structure XLIX can be prepared as described in scheme AL below.
  • Indole-3-carboxylic acids of structure AL1 can be activated to give compounds of structure AL2. Compounds of structure AL2 can represent, for example, acyl halides or carboxylic acids activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide. Reaction of compounds of structure AL2 with hydroxyamidines of structure AL3 can give O-acylhydroxyamidines AL4. Hydroxyamidines may be obtained commercially or by treatment of nitrile compounds with hydroxylamine. Heating compounds of structure AL4 in a non-reactive organic solvent, e.g., toluene, dichloroethane or dioxane in a temperature range of 30° C. to 150° C. can give compounds of structure XLIX.
  • Figure US20100305100A1-20101202-C00388
  • Compounds of formula I, represented by structure L can be prepared as shown in Scheme AM.
  • 3-Cyanoindoles of structure AM1 can be converted to tetrazoles of structure AM2 by treatment with, e.g., sodium azide. Heating a mixture of AM2 and the reagent AM3 can give the 3-(1,2,4-oxadiazolyl)indole compound L. The reagent AM3 can be, e.g., an acyl halide or an acid derivative activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide. The reaction can be carried out in a variety of solvents, including e.g., toluene, dioxane, pyridine and dichloroethane and can be carried out by heating AM2 and AM3 at a temperature range of 30° to 130° C.
  • Figure US20100305100A1-20101202-C00389
  • Compounds of formula I, represented by structure L1 can be prepared as shown in Scheme AN.
  • 3-Cyanoindoles of structure AN1 can be treated with hydroxylamine to give hydroxyamidine compounds of formula AN2. Reaction of hydroxyamidines of structure AN2 with compounds of structure AN3 can give O-acylhydroxyamidines AN4. Compounds AN3 can represent, for example, acyl halides or carboxylic acids activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide. Heating compounds of structure AN4 in a non-reactive organic solvent, e.g., toluene, dichloroethane or dioxane in a temperature range of 30° C. to 150° C. can give compounds of structure LI.
  • Figure US20100305100A1-20101202-C00390
  • Compounds of the present invention, represented by structure LII can be prepared as described in scheme AO below.
  • Ketoindoles of type AO1 can be converted to oximes of structure AO2 by heating the ketoindoles with hydroxylamine (free base or acid salt) in a suitable solvent. Bis-deprotonation of compounds of type AO2 with a strong organic base (e.g., n-butyllithium or sec-butyllithium or tert-butyllithium) followed by reaction with DMF can give compounds of formula LII.
  • Figure US20100305100A1-20101202-C00391
  • Compounds of formula I, represented by structure LIII can be prepared as shown in Scheme AP.
  • 3-Ketoindoles of structure AP1 can be homologated to vinylogous amides of structure AP3 by reaction with dialkyl amide dialkyl acetals AP2. The dialkyl amides can include e.g., lower alkyl amides such as formamide, acetamide and propionamide. Examples would include dimethlformamide dimethyl acetal and dimethyl acetamide dimethyl acetal. The reaction can be conducted by reacting AP1 and AP2 with or without additional solvent at a temperature from ambient to 150° C. Treatment of AP3 with hydroxylamine (free base or acid salt) in a suitable solvent can give compounds of structure LIII. The reaction is typically conducted within a temperature range from ambient to 120° C.
  • Figure US20100305100A1-20101202-C00392
  • Compounds of formula I, represented by structure LIV can be prepared as shown in Scheme AQ.
  • Vinylogous amides of structure AQ1 (as prepared above) can be treated with hydrazines AQ2 in a suitable organic solvent (DMF, alcohol or acetic acid) at temperatures ranging from ambient temperature to 150° C. to give compounds of structure LIV.
  • Figure US20100305100A1-20101202-C00393
  • Compounds of the present invention, represented by structure LV can be prepared as described in scheme AR below.
  • Indole-3-carboxaldehydes of structure AR1 (as prepared in Scheme F) can be reacted with p-(toluenesulfonyl)methyl isocyanate (TOSMIC, AR2) in the presence of a base to give compounds of structure LV. Bases can include potassium carbonate or 1,8-diazabicyclo[5.4.0]undec-7-ene and the reaction can be carried out in a suitable organic solvent from ambient temperature to 150° C.
  • Figure US20100305100A1-20101202-C00394
  • Compounds of formula I, represented by structures LVI and LVII can be prepared as shown in Scheme AS.
  • 3-Indolecarboxylic acids of structure AS1 (from Scheme F) can be converted to amides of structure AS2. Compounds of structure AS1 can be activated by any of the standard methods. For example, the acid AS1 can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of ammonia. Alternatively, the acid can be activated as the acid chloride or as the acyl imidazolide as described previously, followed by treatment of ammonia.
  • The indole-3-carboxamides of structure AS2 can be reacted with substituted aldehydes or ketones (AS3) containing a suitable leaving group L, in a suitable solvent at temperatures above ambient and up to 200° C. The reaction can be performed with or without added base to afford oxazoles of structure LVI.
  • The indole-3-carboxamides of structure AS2 can also be converted to thioamides of structure AS4 by treating the primary amides with Lawesson's reagent or phosphorous pentasulfide at or above ambient temperature in a suitable organic solvent. The resulting thioamides AS4 can be reacted with substituted aldehydes or ketones containing a suitable leaving group L (AS3), in a suitable solvent at temperatures above ambient and up to 150° C. The reaction can be performed with or without added base to afford thiazoles of structure LVII.
  • Figure US20100305100A1-20101202-C00395
  • Compounds of the present invention, represented by structure LVIII and LIX can be prepared as described in scheme AT below.
  • 3-Ketoindoles of structure AT1 can be halogenated (e.g., brominated) to give compounds of structure AT3. Suitable brominating agents can include but are not limited to phenyltrimethylammonium tribromide (AT2), N-bromosuccinimide or bromine and can be carried out in a variety of organic solvents.
  • Treatment of compounds AT3 with amides of type AT4 in a suitable solvent at temperatures above ambient and up to 200° C. with or without added base can give oxazoles of structure LVIII.
  • Treatment of compounds AT3 with thioamides of type AT5 in a suitable solvent at temperatures above ambient and up to 150° C. with or without added base can give thiazoles of structure LIX.
  • Figure US20100305100A1-20101202-C00396
  • Compounds of the present invention, represented by structure LX can be prepared as described in scheme AU below.
  • Indole-3-carboxylic acids of structure AU1 can be activated to give compounds of structure AU2. Compounds of structure AU2 can represent, for example, acyl halides or carboxylic acids activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide. Reaction of compounds of structure AU2 with hydroxyamidines of structure AU3 can give O-acylhydroxyamidines AU4. Hydroxyamidines may be obtained commercially or by treatment of nitrile compounds with hydroxylamine Heating compounds of structure AU4 in a non-reactive organic solvent, e.g., toluene, dichloroethane or dioxane in a temperature range of 30° C. to 150° C. can give compounds of structure LX.
  • Figure US20100305100A1-20101202-C00397
  • Compounds of formula I, represented by structure LXI can be prepared as shown in Scheme AV.
  • Reaction of 3-iodo- or bromoindoles AV1 with a boronic acid AV2 (commonly referred to as a Suzuki reaction) can give the compounds of structure LXI. The coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as tetrakis(triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand. The reactions are carried out in a suitable solvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at a temperature range of ambient to 150° C. and typically in the presence of a base e.g., aqueous sodium carbonate or sodium bicarbonate, or the base can be employed under anhydrous conditions, e.g., cesium or potassium fluoride.
  • Alternatively, indole AV1 can be converted to the indole-3-boronic acid derivative AV3 by reacting the 3-haloindole AV1 with a strong organic base (alkyllithium or Grignard reagent) and reacting the resultant anion with a trialkylborate reagent AV4. Compounds of type AV3 can be reacted with aryl and heteroaryl bromides and iodides AV6 under similar conditions to those described above to form compounds of structure LXI.
  • Figure US20100305100A1-20101202-C00398
  • Compounds of formula I, represented by structure LXII, can be prepared as shown in Scheme AW.
  • Compounds of formula AW1 can be reacted with a protecting group, e.g., di-tert-butyl dicarbonate, to form the boc-protected indole, in the presence of a suitable base and solvent at ambient temperature to give compounds of structure AW2. Treatment of compounds of structure AW2 with base in a polar aprotic solvent at temperatures from −78° C. to ambient temperature, followed by addition of a trialkyl borate would yield compounds of type AW3 upon hydrolytic workup. Reaction of reactive aryl halides or triflates (of the type AW4) with compounds of formula AW3 at or around ambient temperature, in a suitable solvent system containing base and catalytic amounts of palladium catalyst, can give compounds of formula AW5. Removal of the protecting group in compounds of structure AW5, e.g., acid treatment to remove the Boc group would yield compounds of structure AW6. Compounds of type AW6 can be alkylated at the indole nitrogen to give compounds of structure LXII. The alkylation can be carried out in the presence of a suitable alkylating agent and base in a polar solvent at temperatures ranging from ambient temperature to 150° C. to yield compounds of formula LXII.
  • Figure US20100305100A1-20101202-C00399
  • Compounds of formula I, represented by structure LXIII, can be prepared as shown in Scheme AX.
  • Compounds of formula AX1 can be fluorinated at the 3-position with an electrophilic fluorinating agent, e.g., N-fluorocollidine tetrafluoroborate, in a suitable non-polar solvent at temperatures ranging from −78° C. to 100° C. to yield compounds of structure LXIII.
  • Figure US20100305100A1-20101202-C00400
  • Compounds of formula I, represented by structure LIV, can be prepared as shown in Scheme AY.
  • Compounds of formula AY1 can be chlorinated at the 3-position with an electrophilic chlorinating agent, e.g., N-chlorosuccinimide or chlorine, in a suitable solvent at temperatures ranging from −78° C. to 100° C. to yield products of structure LXIV.
  • Figure US20100305100A1-20101202-C00401
  • Compounds of formula I, represented by structure LXV, can be prepared as shown in scheme AZ.
  • Compounds of formula AZ1 can be brominated at the 3-position with an electrophilic brominating agent, e.g., N-bromosuccinimide or bromine) in a suitable solvent at temperatures ranging from −78° C. to 100° C. to yield products of structure LXV.
  • Figure US20100305100A1-20101202-C00402
  • Compounds of formula I, represented by structure LXVI, can be prepared as shown in Scheme BA.
  • Compounds of formula BA1 can be iodinated at the 3-position with an electrophilic iodinating agent, e.g., N-iodosuccinimide, (bis-trifluoroacetoxy)iodobenzene, or ICl, in a suitable solvent at temperatures ranging from −78° C. to 100° C. to yield products of structure LXVI.
  • Figure US20100305100A1-20101202-C00403
  • Compounds of formula I, represented by structure LXVII can be prepared as shown in Scheme BB.
  • 3-Iodo- or bromoindoles of structure BB1 can be reacted with acetylenes BB2 in the presence of a palladium catalyst (commonly referred to as the Sonagashira reaction) to give compounds of type LXVII. The coupling reactions can be carried out by methods known to those skilled in the art. A typical set of reaction conditions includes reacting the indole of structure BB1 with an acetylene compound BB2 in the presence of a source of palladium, a copper co-catalyst and an amine and carrying out the reaction at a temperature range of ambient to 150° C.
  • Figure US20100305100A1-20101202-C00404
  • Compounds of formula I, represented by structure LXVIII, can be prepared as shown in Scheme BC.
  • Compounds of formula BC1 can react with a mixture of POCl3 and DMF at temperatures ranging from ambient to 140° C. to yield 3-carboxaldehydes of structure LXVIII after hydrolysis of the intermediate iminium salt with aqueous NaOH.
  • Figure US20100305100A1-20101202-C00405
  • Compounds of formula I, represented by structure LXIX, can be prepared as shown in Scheme BD.
  • Carboxaldehydes of formula BD1 can be treated with a fluorinating reagent, e.g., (diethylammonium sulfur trifluoride) in a suitable solvent at temperatures ranging from 0° C. to 80° C. to yield compounds of formula LXIX.
  • Figure US20100305100A1-20101202-C00406
  • Compounds of formula I, represented by structure LXX, can be prepared as shown in Scheme BE.
  • Carboxaldehydes of formula BE1 can react with hydroxylamines of structure BE2 in the presence of a suitable polar solvent system and base at temperatures ranging from ambient to 100° C. to yield compounds of formula LXX.
  • Figure US20100305100A1-20101202-C00407
  • Compounds of formula I, represented by structure LXXI, can be prepared as shown in Scheme BF.
  • Carboxaldehydes of formula BF1 can react with hydrazines of structure BF2, in the presence of a suitable solvent and base at temperatures ranging from ambient to 100° C. to yield compounds of formula LXXI.
  • Figure US20100305100A1-20101202-C00408
  • Compounds of formula I, represented by structure LXXII, can be prepared as shown in Scheme BG.
  • Indolecarboxaldehydes of formula BG1 can be oxidized to carboxylic acids of formula LXXII, using reagents known to those skilled in the art, e.g., KMnO4 or chromic acid. The oxidation can usually be carried out in aqueous or mixed-aqueous/organic solvent systems and carried out at ambient or elevated temperature.
  • Figure US20100305100A1-20101202-C00409
  • Compounds of formula I, represented by structure LXXIII, can be prepared as shown in Scheme BH.
  • Carboxylic acids of formula BH1 can be converted to amides by treatment of the carboxylic acid with a suitable activating reagent (thionyl chloride, oxalyl chloride or carbonyldiimidazole) and then treated with amines of formula BH2 to give compounds of formula LXXIII.
  • Figure US20100305100A1-20101202-C00410
  • Compounds of formula I, represented by structure LXXIV, can be prepared as shown in Scheme BI.
  • Carboxylic acids of formula BI1 can be converted to hydrazides and N-alkoxyamides by treatment of the carboxylic acid with a suitable activating reagent (thionyl chloride, oxalyl chloride or carbonyldiimidazole) and then treating the activated carboxylic acids with hydrazines and alkoxylamines of formula BI2 to give compounds of formula LXXIV.
  • Figure US20100305100A1-20101202-C00411
  • Compounds of formula I, represented by structure LXXV, can be prepared as shown in Scheme BJ.
  • Carboxaldehydes of formula BJ1 can be treated with the appropriate alkyllithium or Grignard reagent of formula BJ2 at temperatures between −78° C. to ambient temperature in a suitable aprotic solvent to produce secondary alcohols of formula LXXV. An alternative reduction of the carboxaldehydes with an appropriate hydride reducing agent at −78° C. to ambient temperatures can produce primary alcohols of formula LXXV.
  • Figure US20100305100A1-20101202-C00412
  • Compounds of formula I, represented by structure LXXVI, can be prepared as shown in Scheme BK.
  • Compounds of structure BK1 can be sulfonated at the 3-position with sulfur trioxide or some similar sulfuric acid equivalent to produce compounds of formula BK2. Compounds of formula BK2 can be treated with reagents such as, but not limited to, POCl3 at temperatures from 50° C. to 100° C. to convert them into sulfonyl chlorides of formula BK3. Alternatively, treatment of compounds of structure BK1 with reagents such as chlorosulfonic acid can directly afford compounds of structure BK3. Compounds BK3 can react with amines of formula BK4 at ambient temperature in the presence of a suitable base and solvent to produce sulfonamides of formula LXXVI.
  • Figure US20100305100A1-20101202-C00413
  • Compounds of formula I, represented by structure LXXVII, can be prepared as shown in Scheme BL.
  • Iodides or bromides of structure BL1 can be transformed into 3-thioalkyl indoles using an appropriate copper catalyst, e.g., CuI, and a suitable thiol or disulfide. The reaction can generally be carried out at temperatures between ambient and 150° C. to yield compounds of structure BL2. Compounds of structure BL2 can be oxidized to sulfones of formula LXXVII, using oxidizing agents such as, but not limited to, m-CPBA in chloroform at ambient or elevated temperatures.
  • Figure US20100305100A1-20101202-C00414
  • Compounds of formula I, represented by structure LXXVIII, can be prepared as shown in Scheme BM.
  • Iodides or bromides of structure BM1 can be transformed into 3-thioalkyl indoles using an appropriate copper catalyst, e.g., CuI, and a suitable thiol or disulfide. The reaction can generally be carried out at temperatures between ambient and 150° C. to yield compounds of structure BM2. Compounds of structure BM2 can be selectively oxidized to sulfoxides of formula LXXVIII, using oxidizing agents such as, but not limited to, sodium periodate in methanol at ambient temperature.
  • Figure US20100305100A1-20101202-C00415
  • Compounds of formula I, represented by structure LXXIX, can be prepared as shown in Scheme BN.
  • Compounds of structure BN1 can be converted to ketones of formula LXXIX via a Friedel-Crafts reaction using an acid chloride of formula BN2. The reaction can typically be carried out in a non-polar solvent such as dichloromethane or CS2 in the presence of a suitable Lewis acid, e.g., AlCl3 or FeCl3 and carried out in a temperature range of 0° C. to 100° C.
  • Figure US20100305100A1-20101202-C00416
  • Compounds of formula I, represented by structure LXXX, can be prepared as shown in Scheme BO.
  • Compounds of structure BO1 can be selectively nitrated at the 3-position using stoichiometric amounts of nitric acid under mild reaction conditions to produce compounds of formula LXXX. These conditions may include, but are not limited to, the use of nitric acid in acetic anhydride at a temperature range of −40° C. to room temperature.
  • Figure US20100305100A1-20101202-C00417
  • Compounds of formula I, represented by structure LXXXI, can be prepared in several ways, as shown in Scheme BP.
  • 3-Nitroindoles of structure BP1 can be reduced to 3-aminoindoles of structure BP2 using any number of standard conditions familiar to chemist skilled in the art, such as hydrogenation or iron reduction. Compounds of formula BP2 can be further elaborated by mono- or di-alkylation of the amino group, using the appropriate alkylating agent, solvent, and base at temperatures ranging from ambient to 150° C. to yield compounds of formula LXXXI.
  • Alternatively, 3-haloindoles of structure BP3 can undergo Buchwald coupling with mono- or di-alkylamines of formula BP4 in the presence of copper or palladium catalysts, using conditions familiar to chemists skilled in the art, to produce compounds of formula LXXXI.
  • Figure US20100305100A1-20101202-C00418
  • Compounds of formula I, represented by structure LXXXII, can be prepared as shown in BQ.
  • 3-Aminoindoles of structure BQ1 can be reacted with acyl halides or anhydrides of formula BQ2 in the presence of a suitable base and solvent at ambient temperature to yield amides of structure LXXXII.
  • Figure US20100305100A1-20101202-C00419
  • Compounds of formula I, represented by structure LXXXIII, can be prepared as shown in Scheme BR.
  • 3-Aminoindoles of structure BR1 can react with chloroformates or carbonates or dicarbonates of formula BR2 in the presence of a suitable base and solvent at ambient or elevated temperature to yield carbamates of structure LXXXIII. Alternative conditions involve the synthesis of a reactive carbamoyl intermediate of compounds BR1, e.g., by treatment of the amine BR1 with p-nitrophenyl chloroformate or phosgene, followed by reaction of the activated carbamoyl intermediate with alcohols of formula BR3 at temperatures ranging from ambient to 100° C. in a suitable solvent to form carbamates of formula LXXXIII.
  • Figure US20100305100A1-20101202-C00420
  • Compounds of formula I, represented by structure LXXXIV, can be prepared as shown in Scheme BS.
  • 3-Aminoindoles of structure BS1 can react with isocyanates of formula BS2 in the presence of a suitable base and solvent at ambient or elevated temperature to yield ureas of structure LXXXIV. Alternative conditions involve the synthesis of a reactive carbamoyl intermediate of compounds BS1, e.g., by treatment of the amine BS1 with p-nitrophenyl chloroformate or phosgene, followed by reaction of the activated carbamoyl intermediate with amines of formula BS3 at ambient temperature to form ureas of structure LXXXIV.
  • Figure US20100305100A1-20101202-C00421
  • Compounds of formula I, represented by structure LXXXV, can be prepared as shown in Scheme BT.
  • 3-Aminoindoles of structure BT1 can be reacted with sulfonyl chlorides of formula BT2 in the presence of a suitable base and solvent and reacted at temperatures in the range of −20° C. to 50° C. to yield sulfonamides of structure LXXXV.
  • Figure US20100305100A1-20101202-C00422
  • Compounds of formula I, represented by structure LXXXVI can be prepared as shown in Scheme BU.
  • 3-Iodo- or bromoindoles of structure BU1 can be reacted with alkenes BU2 in the presence of a palladium catalyst (commonly referred to as the Heck reaction) to give compounds of structure LXXXVI. The coupling reactions can be carried out by methods known to those skilled in the art. The choice of catalyst and solvents are similar to those described in Scheme AG.
  • Figure US20100305100A1-20101202-C00423
  • Compounds of formula I, represented by structure LXXXVII can be prepared as shown in Scheme BV.
  • Hydrazines of structure BV1 can react with 3,3,3-trifluoropropanal to form hydrazone intermediates. Heating the hydrazone intermediates in a suitable solvent and at temperatures from ambient to 150° C. can form indoles of formula BV2. Typically, a Lewis acid catalyst is used, e.g., AlCl3, TiCl4 or ZnCl4. Compounds of formula BV2 can be reacted with a protecting group, e.g., di-tert-butyl dicarbonate, to prepare the Boc derivative BV3. Treatment of compounds of structure BV3 with a strong base, e.g., lithium diisopropyl amide, in an aprotic solvent, e.g., THF or DME at temperatures from −78° C. to ambient temperature, followed by addition of a trialkyl borate can yield compounds BV4 upon hydrolytic workup. Reaction of compounds BV4 with reactive aryl halides or triflates, e.g., BV5 at temperatures in the range of −20° C. to 100° C., in a suitable solvent system containing base and sub-stoichiometric amounts of a palladium catalyst, can give compounds of formula BV6. Proteolytic cleavage of the Boc group of compounds of type BV6 can give compounds of structure BV7. The indole BV7 can be alkylated in the presence of a suitable alkylating agent and base in a suitable solvent at temperatures ranging from 0° C. to 150° C. to yield indoles of formula LXXXVII.
  • Figure US20100305100A1-20101202-C00424
    Figure US20100305100A1-20101202-C00425
  • Compounds of formula I, represented by structure LXXXVIII can be prepared as shown in Scheme BW.
  • Compounds of structure BW1 are commercially available, or can be prepared by well-known methodology, e.g., from the hydrolysis of substituted phenylacetonitriles. BW1 can then be activated, e.g., using peptide coupling reagents, or converted to an acid halide, and then reacted with amines (BW2) to provide substituted acetamides BW3. Compounds of type BW3 can undergo cyclization in the presence of a base, such as potassium carbonate or sodium hydride, and a catalyst, such as Cut or CuBr to form compounds of structure BW4. Reduction of compounds BW4 with a reducing agent, such as DIBALH or lithium aluminum hydride can furnish indoles of type BW5. Compounds of type BW5 can then be cyanated with a reagent such as chlorosulfonyl isocyanate (BW6) to afford compounds of type BW7. Treatment of compounds BW7 with a base, e.g., lithium diisopropyl amide in a solvent such as THF or DME and a trialkyl borate can give a 2-indolylboronic acid intermediate. Reaction of the 2-indolylboronic acid intermediate with a group L-R12 in the presence of a palladium catalyst can afford compounds of structure LXXXVIII.
  • Figure US20100305100A1-20101202-C00426
  • Compounds of formula I, represented by structure LXXXIX can be prepared as shown in Scheme BX.
  • Indoles BX1 can be cyanated with an appropriate cyanating agent, e.g., chlorosulfonyl isocyanate (BX2) or a dialkyl phosphoryl isocyanate in a suitable solvent or solvent mixture, e.g. DMF, CH3CN or dioxane, and carrying out the reaction at or above ambient temperature to afford compounds of structure BX3. Treatment of BX3 with a reactive functional group Z containing a suitable leaving group L (BX4) can give compounds of structure BX5. L can represent a halide, particularly chloro, bromo or iodo or an alkylsulfonate. The reaction between BX3 and BX4 can be carried out in a suitable solvent in the presence of an inorganic base such as potassium carbonate or sodium hydride or an organic base such as a trialkylamine to afford compounds of formula BX5.
  • Compounds of structure BX5 can be converted to indolyl-2-boronic acids BX6. Typically, a strong base, such as lithium diisopropylamide or lithium or potassium hexamethyldisilazide is employed in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them. The reaction is typically carried out in the range of −78° C. to ambient temperature. Quenching with a trialkylborate derivative can give the indolyl-2-boronic acid BX6. Reaction of the indolyl-2-boronic acid BX6 with an aryl or heteroaryl halide BX7 (commonly referred to as a Suzuki reaction) can give the compounds of structure BX8. The coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as 1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex. The reactions are carried out in a suitable solvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at a temperature range of ambient to 150° C. in the presence of a base. The base can be in aqueous solution, e.g., aqueous sodium carbonate or sodium bicarbonate, or the base can be employed under anhydrous conditions, e.g., cesium or potassium fluoride.
  • Compounds BX8 can be de-methylated to give compounds of structure BX9. Suitable de-methylating reagents can include, but are not limited to boron tribromide, boron trichloride or iodotrimethylsilane in a variety of organic solvents, such as methylene chloride. Indoles of structure BX9 can be alkylated with an electrophile, L(CH2)nOP (BX10), to give compounds of structure BX11. L can represent a halide, particularly chloro, bromo or iodo or an alkylsulfonate. N can be equal 2, 3 or 4. P can represent any acid-labile protecting group, such as tert-butyldimethylsilyl, triethylsilyl or tetrahydropyranyl. The reaction can be conducted in a suitable solvent, e.g., THF, CH2Cl2 or DMF, within a temperature range of 20° C. to 100° C. A base, e.g., an inorganic base, such as potassium or cesium carbonate or an organic base, such as a trialkylamine can be used to remove the acid formed in the reaction. Compounds BX11 can be deprotected to give compounds of structure BX12. Suitable deprotecting reagents can include, but are not limited to any mild organic acid, such as para-toluenesulfonic acid or pyridinium para-toluenesulfonate or an inorganic acid, such as acetic or hydrochloric acid in a variety of organic solvents, such as methylene chloride, THF or methanol.
  • Oxidation of compounds BX12 to carboxylic acids with structure BX13 can be accomplished with various oxidating reagents such as potassium permanganate or pyridinium dichromate. Compounds of type BX13 can then be activated and treated with amines of type BX14 to form compounds of structure LXXXIX. Activation of the carboxylic acid can be carried out by any of the standard methods. For example, the acid BX13 can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of the amine BX14, or alternatively the acid can be activated as the acid chloride by treatment of the acid with, e.g., thionyl chloride or oxalyl chloride or as the acyl imidazolide, obtained by treatment of the acid with carbonyl diimidazole, followed by treatment of the amine BX14.
  • Figure US20100305100A1-20101202-C00427
    Figure US20100305100A1-20101202-C00428
  • Compounds of the present invention represented by structure XC and XCI can be prepared by the methodology depicted in Scheme BY below, wherein p is an integer between 2 and 6.
  • A compound of formula BY1 is treated with a reagent of structure BY2, wherein L and L′ represent leaving groups (halogen, arylsulfonate, etc.) and can be the same or different. If different, the more reactive of the two will be displaced by the phenol oxygen atom to give compound BY3. Conditions for this reaction include solvents such as, but not limited to, acetonitrile, acetone, 2-butanone or dimethylformamide; bases such as sodium carbonate, potassium carbonate, cesium carbonate, tertiary amine bases or sodium hydride; and reaction temperatures from ambient to the reflux temperature of the chosen solvent. The remaining leaving group in this molecule may be displaced by a reagent of formula R18SH (BY4),
  • wherein R18 may be alkyl, aryl or heteroaryl to give compounds of structure XC. The conditions for this reaction may be similar but not necessarily the same as used for the transformation of BY1 to BY3.
  • Oxides of the resulting sulfide group in compound XC may be prepared, utilizing oxidizing reagents, such as m-chloroperbenzoic acid, potassium permanganate, potassium peroxymonosulfate or dimethyldioxirane, in stoichiometries chosen to optimize the particular oxidation state, using solvents such as dichloromethane, ethanol, methanol or acetone, and at temperatures ranging from −30° C. to 120° C. to afford compounds of structure XCI.
  • Figure US20100305100A1-20101202-C00429
  • Compounds of this invention represented by structure XCII can be prepared by the methodology depicted in Scheme BZ below, wherein p is 1-6:
  • A compound of formula BZ1 is treated with a reagent of structure BZ2, wherein L and L′ represent leaving groups (halogen, arylsulfonate, etc.) and can be the same or different. The resulting compounds of formula BZ3 may be alkylated by an amine of formula R18R19NH to prepare compounds of formula XCII. Conditions for this alkylation reaction may include solvents such as ethanol, tetrahydrofuran or dimethylformamide. The presence of a basic reagent, such as pyridine, diisopropylethylamine or potassium carbonate, may be utilized.
  • Figure US20100305100A1-20101202-C00430
  • Compounds of this invention represented by structure XCIII can be prepared by the methodology depicted in Scheme CA below.
  • A phenol compound, CAL can be reacted with an alkylating agent CA3, which can be derived from a compound of structure CA2. Compounds of structure CA2, wherein R19 taken together with the hydroxyl-bearing carbon atom to which R19 is attached, represent a 4-7 membered ring. Such atoms may be all carbon, but may also include up to two heteroatoms, chosen from N, O, S or SO2. A reagent of the formula CA2 may be purchased from commercial sources or be prepared by means familiar to those skilled in the art of organic synthesis and is then converted to compounds of structure CA3, wherein L represents a leaving group. Compound CA3 is then used in an alkylation reaction with the phenol compound CAL employing the usual alkylation reaction conditions discussed above, to give the compound of formula XCIII.
  • Figure US20100305100A1-20101202-C00431
  • Compounds of this invention represented by structure XCIV and XCV can be prepared by the methodology depicted in Scheme CB below.
  • Compounds of structure CB1 can be prepared starting from bromo-substituted indoles using the methodology discussed elsewhere in this invention (introduction of the Z group, installation of the cyano group at C-3 of the indole ring, and cross-coupling of the indole with an aryl reagent to give the corresponding 2-aryl group). Alternatively, the bromide may be introduced at a later stage by bromination of the indole ring, employing brominating reagents such as bromine, N-bromosuccinimide or HOBr. The bromide compound can be then subjected to a metal-halogen exchange reaction to generate an organometallic compound CB2, which is not isolated but taken on directly to the next reaction, wherein M is a metal atom such as magnesium or lithium. Organomagnesium reagents may be prepared from aryl bromides by treating with magnesium metal in refluxing ether-like solvents, or treatment with other organomagnesium reagents such as isopropyl magnesium chloride. Organolithium reagents may be prepared from aryl bromides by treating with lithium metal in refluxing solvents, or by treatment with other organolithium reagents such as sec- or tert-butyllithium. The metallated indole may then be treated in situ with a thionating reagent to afford compounds such as XCIV or CB3. If the group R18—(CH2)p— is relatively simple, it may prove convenient to employ a reagent of the structure R18—(CH2)p—S—S—(CH2)p—R18, which will give sulfide compound XCIV directly. Otherwise, it may be more efficient to react compound CB2 with a reagent such as atomic sulfur (S8), which will afford a thiol compound CB3. The thiol group may be alkylated with a reagent of structure CB4, where L represents a suitable leaving group. Typical alkylation conditions known to those skilled in the art can be employed.
  • Oxides of the resulting sulfide group in compound XCV can be prepared using oxidizing reagents, such as m-chloroperbenzoic acid, potassium permanganate, potassium peroxymonosulfate or dimethyldioxirane in stoichiometries chosen to optimize the particular oxidation state desired, in solvents such as dichloromethane, ethanol, methanol or acetone, and at temperatures ranging from −30° C. to 120° C.
  • Figure US20100305100A1-20101202-C00432
  • Compounds of this invention represented by structures XCVI and XCVII can be prepared by the methodology depicted in Scheme CC below.
  • A compound of formula CC1 may be nitrated at the indole C-5 position with reagents such as concentrated nitric acid optionally with solvents such as acetic acid or sulfuric acid. The resulting nitro group in compound CC2 may be reduced to the amino compounds of structure CC3 with the use of reducing reagents such as hydrogen (with a catalyst such as palladium on carbon), tin dichloride (in the presence of HCl), sodium thiosulfate (in the presence of ammonia) or iron powder. The amino and hydroxyl groups of compound CC3 may be used to construct a ring; for example, cyclocondensation of CC3 with a reagent CC4, such as phosgene, carbonyldiimidazole or trichloromethyl chloroformate in the presence of a basic reagent to afford compounds of structure CC5. Alternatively, reacting compounds of structure CC3 with compounds of structure CC6 in the presence of a base gives compounds of structure CC7. Compounds CC5 and CC7 can be alkylated with groups of structure L-R21 to give compounds XCVI and XCVII.
  • Figure US20100305100A1-20101202-C00433
  • Compounds of this invention represented by structures CXVIII, XCIX and C can be prepared by the methodology depicted in Scheme CD, below.
  • Commercially available 5,6-dihydroxyindole may be protected on the phenol groups with group P to give compound CD1. Suitable protecting groups include e.g., tert-butyldimethylsilyl, benzyl, or tetrahydropyranyl, and their synthesis and subsequent removal are well known to those skilled in the art. Functionalization of the indole nitrogen to give compound CD2, followed by cyanation of CD2 to give CD3, and aryl cross-coupling of CD3 to give CD4 have been discussed elsewhere in this invention. The protecting groups on the phenol oxygen atoms may then be removed, and the oxygens used in various cyclocondensation reactions. For example, reaction with a reagent of structure CD6 in the presence of a suitable base can afford the dioxanyl-fused ring system of compound XCIX. Treatment of CD5 with phosgene or a phosgene equivalent (CD7) can give compounds of structure XCVIII. Condensation of CD5 with ketones of formula CD8 or ketal derivatives of the ketone CD8 can afford the cyclic ketal compounds of structure C.
  • Figure US20100305100A1-20101202-C00434
  • Compounds of formula I, represented by structure CI can be prepared by the methodology depicted in Scheme CE below.
  • Treatment of CE1 with a reactive heteroaryl group containing a leaving group L in a suitable solvent, with or without heat in the presence of a base, such an inorganic base, e.g., sodium or potassium carbonate or an organic base, e.g., a trialkylamine, can afford the compound of structure CI. The leaving group L can be a halide, particularly choro, bromo or iodo. R18 can be an alkyl, aryl or heteroaryl group.
  • Figure US20100305100A1-20101202-C00435
  • Compounds of formula I, represented by structure CII can be prepared by the methodology depicted in Scheme CF below.
  • Treatment of CF1 with the compound CF2 containing leaving groups L and L′ in a suitable solvent, with or without heat in the presence of a base, such an inorganic base, e.g., sodium or potassium carbonate or an organic base, e.g., triethylamine, can afford the compound of structure CF3. L and L′ independently represent a leaving group, including but are not limited to halogens (e.g., chlorine, bromine or iodine) or alkyl or arylsulfonates, and p is an integer between 1 and 6. The reactive heterocycle or heteroaryl compound CF4 can be reacted with the compound CF3 in a suitable solvent, with or without heat in the presence of a base, such an inorganic base, e.g., sodium or potassium carbonate or an organic base, e.g., triethylamine, diisopropylamine, to afford the compound of structure CII.
  • Alternatively, the compound CF1 can be treated with a reactive compound CF5 containing a suitable leaving group L as described above to afford the compound of structure CII.
  • Figure US20100305100A1-20101202-C00436
  • Compounds of formula I, represented by structure CIII can be prepared by the methodology depicted in Scheme CG below:
  • Indoles CG1 can be cyanated with an appropriate cyanating agent, e.g., chlorosulfonyl isocyanate (CG2) or a dialkyl phosphoryl isocyanate in a suitable solvent or solvent mixture, e.g. DMF, CH3CN or dioxane, carrying out the reaction at a temperature between −20° C. and 80° C. to afford compounds of structure CG3. The compounds CG3 can then be reacted with a reactive functional group Z containing a suitable leaving group L (CG4) as described previously to afford the compound CG6. Alternatively, compound CG1 can be reacted with a reactive functional group Z containing a suitable leaving group L to give compounds of structure CG5, which can then be cyanated as above to give compounds of formula CG6.
  • Compounds of structure CG6 can be converted to indolyl-2-boronic acid CG7. Typically, a strong base, such as lithium diisopropylamide or lithium or potassium hexamethyldisilazide is employed in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them. The reaction is typically carried out in the range of −78° C. to ambient temperature. Quenching with a trialkylborate derivative can give the indolyl-2-boronic acid CG7. Reaction of indolyl-2-boronic acid CG7 with aryl or heteroaryl halide CG8 (commonly referred to as a Suzuki reaction) can give the compounds of structure CG9. The coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as 1,1′-bis(diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex. The reactions are carried out in a suitable solvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at a temperature range of ambient to 150° C. in the presence of a base. The base can be in aqueous solution, e.g., aqueous sodium carbonate or sodium bicarbonate, or the base can be employed under anhydrous conditions, e.g., cesium or potassium fluoride.
  • Indole-carboxylic esters CG9 can be converted to indole-carboxylic acids CG10 by treatment of compounds of structure CG9 with, for example, either acid or base in aqueous or mixed aqueous-organic solvents at ambient or elevated temperature or by treatment with nucleophilic agents, for example, boron tribromide or trimethylsilyl iodide, in a suitable solvent. Compounds of type CG10 can then be activated and treated with amines of type CG11 to form compounds of structure CIII. Activation of the carboxylic acid can be carried out by any of the standard methods. For example, the acid CG10 can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of the amine CG11, or alternatively the acid can be activated as the acid chloride by treatment of the acid with, e.g., thionyl chloride or oxalyl chloride or as the acyl imidazolide, obtained by treatment of the acid with carbonyl diimidazole, followed by treatment with amines CG11.
  • Figure US20100305100A1-20101202-C00437
  • Compounds of formula I, represented by structure CIV can be prepared as shown in Scheme CH.
  • Compounds of formula CH1 can be reduced at the 6-ester group to give 6-hydroxymethyl indoles CH2. The reduction reaction can be carried out using a hydride regent such as lithium borohydride, in an ethereal solvent such as THF, ethyl ether or DME at temperatures ranging from ambient to reflux to give the alcohol CH2. The benzylic alcohol group in CH2 can be converted to a leaving group L (halogen, aryl sulfonate or alkyl sulfonate) by treatment with reagents such as thionyl chloride, phosphorous trichloride, thionyl bromide, methane sulfonyl chloride or toluenesulfonyl chloride in a solvent such as but not limited to dichloromethane, 1,2-dichloroethane or chloroform. The leaving group L in compounds of formula CH3 can be displaced by a reagent of formula R18H to afford compounds of formula CIV, wherein R18 maybe a heterocycle or a heteroaryl compound. Conditions for this reaction include solvents such as but not limited to acetonitrile, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide; bases such as potassium carbonate, cesium carbonate or sodium hydride; and reaction temperatures ranting from ambient to reflux.
  • Figure US20100305100A1-20101202-C00438
  • Compounds of formula I, represented by structure CV can be prepared as shown in Scheme CI
  • Compounds of formula CI1 in which V represents bromide or iodide, can undergo reaction with alkyl vinyl ethers such as ethyl vinyl ether in the presence of palladium catalysts such as but not limited to palladium acetate, palladium (tetrakis)triphenylphosphine, in solvents such as but not limited to dimethyl formamide or dimethoxyethane to give the addition products of formula CI2. Vinyl ethers of formula CI2 can be hydrolyzed to aldehydes of formula CI3 using aqueous acids, such as but not limited to, hydrochloric acid, sulfuric acid or acetic acid. Compounds of formula CI3 can be reduced to the alcohol using hydrides such as lithium borohydride or sodium borohydride, in solvents such as methanol or tetrahydrofuran to give primary alcohols CI4.
  • The alcohol group in CI4 can be converted to a leaving group L (halogen or aryl sulfonate or alkyl sulfonate) by treatment with reagents such as thionyl chloride, phosphorous trichloride, thionyl bromide, methane sulfonyl chloride or toluenesulfonyl chloride in a solvent such as but not limited to dichloromethane, 1,2-dichloroethane or chloroform. The leaving group L in compounds of formula CI5 can be displaced by a reagent of formula R18H to afford compounds of formula CV, wherein R18 maybe a heterocycle or a heteroaryl group. Conditions for this reaction include using solvents such as but not limited to acetonitrile, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide; bases such as potassium carbonate, cesium carbonate or sodium hydride; and reaction temperatures ranging from ambient to reflux.
  • Figure US20100305100A1-20101202-C00439
  • Compounds of formula I, represented by structure CVI can be prepared as shown in Scheme CJ.
  • Compounds of formula CJ1 in which V represents iodine or bromine, can undergo reaction with acrylic esters in the presence of palladium catalysts such as palladium acetate, palladium (tetrakis)triphenylphosphine or palladium (bis)-triphenylphosphinedichloride, and ligands such as triphenylphosphine or tri-ortho-tolylphosphine, in solvents such as but not limited to, dimethyl formamide, dimethoxyethane or toluene to give compounds of structure CJ2. Hydrogenation of compounds of type CJ2 can give products of type CJ3 by addition of hydrogen in the presence of a catalyst such a palladium or platinum in a solvent such as, but not limited to, methanol, ethanol or acetic acid at pressures ranging from 1-5 atmospheres. Reduction of the ester group in compounds CJ3 can be accomplished using hydride reagents such as lithium borohydride to give the alcohols CJ4. Conversion of the alcohol in CJ4 to a leaving group L (halogen or aryl sulfonate or alkyl sulfonate) can be accomplished by treatment with reagents such as thionyl chloride, phosphorous trichloride, thionyl bromide, methane sulfonyl chloride or toluenesulfonyl chloride in a solvent such as but not limited to dichloromethane, 1,2-dichloroethane or chloroform. The leaving group L in compounds of formula CJ5 can be displaced by a reagent of formula R181-1 to afford compounds of formula CVI, wherein R18 maybe a heterocycle or a heteroaryl group. Conditions for this reaction include solvents such, as but not limited to, acetonitrile, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide; bases such as potassium carbonate, cesium carbonate or sodium hydride; and reaction temperatures ranging from ambient to reflux.
  • Figure US20100305100A1-20101202-C00440
  • Compounds of formula I, represented by structure CVII can be prepared as shown in Scheme CK.
  • Compounds of formula CK1 (in which L is a leaving group such as chloride, bromide, iodide or sulfonate and n is 0 or 1) can undergo reaction with triphenylphosphine in a solvent such as but not limited to tetrahydrofuran, toluene or dichloromethane; at a temperature ranging from ambient or to reflux to give the phosphonium salt CK2. Phosphonium salt CK2 can be converted to olefin compounds of type CK3 by treatment with a base such as butyllithium, sodium hydride, sodium amide or potassium t-butoxide in a solvent such as tetrahydrofuran, ethyl ether or DME followed by addition of an aldehyde R18CHO (in which R18 is an aryl, heterocycle or heteroaryl) at temperatures ranging from ambient to reflux. Hydrogenation of compounds of type CK3 can be accomplished in the presence of a catalyst such a palladium or platinum in a solvent such as but not limited to methanol, ethanol or acetic acid at pressures ranging from ambient to 100° C. under a hydrogen atmosphere to give compounds of formula CVII.
  • Figure US20100305100A1-20101202-C00441
  • Compounds of formula I, represented by structure CVIII can be prepared as shown in Scheme CL.
  • Compounds of formula CL1 (in which L represents iodide, bromide or chloride or methanesulfonate) can undergo reaction with boronic acids of structure R18B(OH)2 (in which R18 is an aryl or heteroaryl) in the presence of palladium catalysts such as palladium acetate, palladium tetrakis triphenylphosphine or palladium dichloride; and ligands such as triphenylphosphine or tri-ortho-tolylphosphine in solvents such as but not limited to acetone, dimethyl formamide or toluene at temperatures from ambient to reflux to give the addition product CVIII.
  • Figure US20100305100A1-20101202-C00442
  • Compounds of formula I, represented by structure CIX can be prepared as shown in Scheme CM.
  • Compounds of formula CM1 (in which L represents iodide, bromide or chloride or methanesulfonate) can undergo reaction with metal sulfinates (in which R18 is an alkyl, aryl or heteroaryl) in solvents such as but not limited to acetone, dimethylformamide or toluene at temperatures from ambient to reflux to give the addition product CIX.
  • Figure US20100305100A1-20101202-C00443
  • Compounds of formula I, represented by structure CX can be prepared as shown in Scheme CN.
  • Compounds of formula CL1 (in which R17, defined above, is 1-3 substituents placed on the indole ring) when treated with a base such as potassium hydride, sodium hydride or the like, and then an alkyl lithium such as tert-butyl lithium form a carbanion that reacts with disulfide R18SS R18 (in which R18 is an alkyl, aryl or heteroaryl) in solvents such as but not limited to THF, diethyl ether, or toluene at temperatures from −78° C. to ambient to provide intermediate. Cyanation (CN3), alkylation of the indole nitrogen (CN4) and metal coupling to form product CX are described above.
  • Figure US20100305100A1-20101202-C00444
  • Compounds of formula I, represented by structure CXI, can be prepared as shown in Scheme CO.
  • Compounds of formula CO1 (in which R17, defined above, is 1-3 substituents placed on the indole) when treated with a base, copper (I) iodide and a substituted amine (Z—NH2 where Z is defined above) to provide compounds of formula CO2. Acylation with 2-chloroacetyl chloride and a base such as triethylamine in solvents such as but not limited to dichloromethane, tetrahydrofuran or toluene at temperatures from ambient to reflux provides intermediate CO3 which is subsequently cyclized to form compounds of structure CO4 employing palladium (II) acetate as catalyst, a phosphine ligand and a base such as triethylamine in solvents such as but not limited to tetrahydrofuran, dimethylformamide or toluene at temperatures from ambient to reflux. Reduction and elimination with a hydride source such as DIBAL-H in solvents such as but not limited to dichloromethane, tetrahydrofuran or toluene at temperatures from 0° C. to reflux provides intermediate CO5. The subsequent steps leading to product CXI are described above.
  • Figure US20100305100A1-20101202-C00445
  • Compounds of formula I, represented by structure CXII can be prepared as shown in Scheme CP.
  • Compounds of formula CP1 was elaborated using conditions as described above provide CP3 which can be subsequently hydrogenated using a metal such as palladium on carbon and a source of hydrogen such as hydrogen gas or ammonium formate to provide the aniline intermediate CP4. Bis-alkylation using CP5 where X can be CH2, S, SO, SO2, O, C═O, etc. and n=0 to 3, with two leaving groups (L), as described above, and an appropriate base such as triethylamine or potassium hydroxide in solvents such as but not limited to tetrahydrofuran, dimethylformamide or toluene at temperatures from ambient to reflux will provide intermediate CP6. Employing conditions described above then provides product CXII.
  • Figure US20100305100A1-20101202-C00446
  • Compounds of formula I, represented by structure CXIII, can be prepared as shown in Scheme CQ.
  • Compounds of formula CQ1 can be elaborated using conditions described above to provide product CXIII.
  • Figure US20100305100A1-20101202-C00447
  • Compounds of formula I, represented by structure CXIV, can be prepared as shown in Scheme CR.
  • Compounds of formula CR1 can be elaborated using conditions described above to provide intermediate CR4. Treatment of indole CR4 with a halogen source, such as halogen substituted succinimides, in solvents such as but not limited to tetrahydrofuran, dimethylformamide or toluene at temperatures from ambient to reflux provide halogen substituted product CXIV.
  • Figure US20100305100A1-20101202-C00448
  • Compounds of formula I, represented by structure CXV, can be prepared as shown in Scheme CS.
  • Compounds of formula CS1 can be treated with a triflate source, such as triflic anhydride, and a base, such as pyridine, in solvents such as but not limited to tetrahydrofuran, dichloromethane or toluene at temperatures from ambient to reflux to provide intermediate CS2. CS2 can either be directly reacted with palladium (0) and a R12 substituted trialkyl tin compound in the presence of cesium fluoride and copper (I) iodide in solvents such as but not limited to tetrahydrofuran, dimethylformamide or toluene at temperatures from ambient to reflux to provide product CXV or reacted in a two step sequence of coupling with a pinacol borane source such as bis-pinacol diborane in the presence of palladium (II) and a base, such as potassium acetate, in solvents such as but not limited to tetrahydrofuran, dioxane or toluene at temperatures from ambient to reflux and then a second palladium coupling with palladium (0), cesium fluoride and an appropriate R12L compound in solvents such as but not limited to tetrahydrofuran, dimethoxy ethane or toluene at temperatures from ambient to reflux to provide CXV.
  • Figure US20100305100A1-20101202-C00449
    • C. Methods of the Invention
  • Another aspect of the invention relates to a method for treating Hepatitis C viral (HCV) infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, or a pharmaceutical composition comprising an effective amount of one of more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, as described above.
  • As used herein, the term “treating” refers to: (i) preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; (ii) inhibiting a disease, disorder or condition, i.e., arresting its development; and/or (iii) relieving a disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
  • As used herein, the term “subject” refers to an animal or any living organism having sensation and the power of voluntary movement, and which requires for its existence oxygen and organic food. Nonlimiting examples include members of the human, equine, porcine, bovine, murine, canine and feline species. In some embodiments, the subject is a mammal or a warm-blooded vertebrate animal. In other embodiments, the subject is a human. As used herein, the term “patient” may be used interchangeably with “human”.
  • Without being limited to any particular theory, it is believed that the compounds of the present invention inhibit IRES-mediated initiation, elongation and termination, i.e., translation by interfering with function of the IRES directly and/or with the interaction of the IRES and a cellular and/or viral factor. Thus, another aspect of the invention relates to a method for treating an infection by a wild type virus or a virus that is resistant to a currently available antiviral agent, in a subject in need thereof, wherein the wild type or resistant virus comprises an internal ribosome entry site (IRES), comprising administering to the subject an effective amount of one or more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, or a pharmaceutical composition comprising an effective amount of one of more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, as described above. Nonlimiting examples of such virus include viruses of the picornavirus genus, such as poliovirus, hepatitis A virus, coxsackievirus and rhinovirus; viruses of the coronaviridae genus, such as SARS; viruses of the arbovirus genus; viruses of the flavivirus genus, such as yellow fever, dengue, and West Nile virus; herpesviruses, such as herpes simplex virus and Kaposi's sarcoma-associated herpesvirus, and other viruses with a similar mode of replication; and HIV, human leukemia viruses (HTLV) and other viruses with a similar mode of translation.
  • Yet another aspect of the invention relates to a method for inhibiting HCV IRES-mediated initiation and/or translation in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, or a pharmaceutical composition comprising an effective amount of one of more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, as described above.
  • As used herein, the term “effective amount” refers to the amount required to produce a desired effect. For example, the effective amount may be the amount required to treat a Hepatitis C viral (HCV) infection, the amount required to treat an infection by a virus which comprises an internal ribosome entry site (IRES), the amount required to inhibit HCV IRES-mediated initiation and/or translation, or the amount required to inhibit viral replication or infectivity, in a subject or, more specifically, in a human. In some instances, the desired effect can be determined by analyzing (1) the presence of HCVRNA; (2) the presence of anti-HCV antibodies; (3) the level of serum alanine amino transferase (ALT) and aspartate aminotransferase (AST) (ALT and AST are elevated in patients chronically infected with HCV); (4) hepatocellular damage resulting from HCV infection, including steatosis, fibrosis and cirrhosis; (5) hepatocellular carcinoma as a result of chronic HCV infection; and (5) extrahepatic sequelae (non-limiting examples include pruritis, encephalopathies, mental disorders such as anxiety or depression) of infection with HCV or other viruses which contain an IRES element. The effective amount for a subject will depend upon various factors, including the subject's body weight, size and health. Effective amounts for a given patient can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • For any compound, the effective amount can be estimated initially either in cell culture assays or in relevant animal models, such as marmosets and tarmarins. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, ED50/LD50. In some embodiments, the effective amount is such that a large therapeutic index is achieved. In further embodiments, the dosage is within a range of circulating concentrations that include an ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
  • More specifically, the concentration-biological effect relationships observed with regard to the compound(s) of the present invention indicate an initial target plasma concentration ranging from approximately 0.1 μg/ml to approximately 100 μg/mL, from approximately 1 μg/mL to approximately 50 μg/mL, from approximately 5 μg/mL to approximately 50 μg/mL, or from approximately 10 μg/mL to approximately 25 μg/mL. To achieve such plasma concentrations, the compounds of the invention may be administered at doses that vary from 0.1 μg to 100,000 mg, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and is generally available to practitioners in the art. In general, the dose will be in the range of about 1 mg/day to about 10 g/day, or about 0.1 g to about 3 g/day, or about 0.3 g to about 3 g/day, or about 0.5 g to about 2 g/day, in single, divided, or continuous doses for a patient weighing between about 40 to about 100 kg (which dose may be adjusted for patients above or below this weight range, particularly children under 40 kg).
  • The exact dosage will be determined by the practitioner, in light of factors related to the subject. Dosage and administration may be adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.
  • The compounds and compositions of the present invention may be administered to the subject via any drug delivery route known in the art. Nonlimiting examples include oral, ocular, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intraveneous (bolus and infusion), intracerebral, transdermal, and pulmonary routes of administration.
    • D. Metabolites of the Compounds of the Invention
  • Also falling within the scope of the present invention are the in vivo metabolic products of the compounds described herein. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammalian tissue or a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radio-labeled (e.g. C14 or H3) compound of the invention, administering it in a detectable dose (e.g., greater than about 0.5 mg/kg) to a mammal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating its conversion products from urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis. In general, analysis of metabolites may be done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no biological activity of their own.
    • E. Pharmaceutical Compositions of the Invention
  • Yet another aspect of the invention relates to a pharmaceutical composition comprising: (i) an effective amount of one or more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, or a pharmaceutical composition comprising an effective amount of one of more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, as described above.
  • A pharmaceutical composition of the present invention may be formulated to achieve a physiologically compatible pH, ranging from a pH of about 3 to a pH of about 11. In some embodiments, the pharmaceutical composition is formulated to achieve a pH of about 3 to a pH of about 7. In other embodiments, the pharmaceutical composition is formulated to achieve a pH of about 5 to a pH of about 8.
  • The pharmaceutical composition may comprise a combination of compounds of the present invention, or may include a second active ingredient useful in the treatment of viral infections, such as anti-viral agents that include, but are not limited to: pegylated interferon, including by way of non-limiting example pegylated α-interferon; un-pegylated interferon, including by way of non-limiting example, un-pegylated α-interferon; ribavirin or prodrugs or derivatives thereof; a glucosidase inhibitor; protease inhibitors; polyermase inhibitors; p7 inhibitors; entry inhibitors, including fusion inhibitors such as Fuzeon™ (Trimeris); helicase inhibitors; a Toll-like receptor agonist, a caspase inhibitor, anti-fibrotics; drugs that target IMPDH (inosine monophosphate dehydrogenase inhibitors), such as Merimepadib™ (Vertex Pharmaceuticals Inc.); synthetic thymosin alpha 1 (ZADAXIN™, SciClone Pharmaceuticals Inc.); a glycosidase inhibitor; therapeutic viral vaccines, such as those produced by Chiron and Immunogenics; and immunomodulators, such as histamine.
  • The term “pharmaceutically acceptable excipient” refers to an excipient for administration of a pharmaceutical agent, such as the compounds of the present invention. The term refers to any pharmaceutical excipient that may be administered without undue toxicity. Pharmaceutically acceptable excipients may be determined in part by the particular composition being administered, as well as by the particular mode of administration and/or dosage form. Nonlimiting examples of pharmaceutically acceptable excipients include carriers, solvents, stabilizers, adjuvants, diluents, etc. Accordingly, there exist a wide variety of suitable formulations of pharmaceutical compositions of the present invention (see, e.g., Remington's Pharmaceutical Sciences).
  • Suitable excipients may be carrier molecules that include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles. Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA; carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid; liquids such as oils, water, saline, glycerol and ethanol; wetting or emulsifying agents; pH buffering substances; and the like. Liposomes are also included within the definition of pharmaceutically acceptable excipients.
  • The pharmaceutical compositions of the invention may be formulated in any form suitable for the intended method of administration. Suitable formulations for oral administration include solids, liquid solutions, emulsions and suspensions, while suitable inhalable formulations for pulmonary administration include liquids and powders. Alternative formulations include syrups, creams, ointments, tablets, and lyophilized solids which can be reconstituted with a physiologically compatible solvent prior to administration.
  • When intended for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, non-aqueous solutions, dispersible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Pharmaceutically acceptable excipients suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as croscarmellose sodium, cross-linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with non-aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.
  • In other embodiments, pharmaceutical compositions of the invention may be formulated as suspensions comprising one or more compound(s) of the present invention in admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension. In yet other embodiments, pharmaceutical compositions of the invention may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of one or more excipient(s).
  • Excipients suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickening agents, such as carbomer, beeswax, hard paraffin or cetyl alcohol. The suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth; naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • Additionally, the pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension. Such emulsion or suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,2-propane-diol. The sterile injectable preparation may also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • The compounds of the invention may be substantially insoluble in water and sparingly soluble in most pharmaceutically acceptable protic solvents and vegetable oils, but generally soluble in medium-chain fatty acids (e.g., caprylic and capric acids) or triglycerides and in propylene glycol esters of medium-chain fatty acids. Thus, contemplated in the invention are compounds which have been modified by substitutions or additions of chemical or biochemical moieties which make them more suitable for delivery (e.g., increase solubility, bioactivity, palatability, decrease adverse reactions, etc.), for example by esterification, glycosylation, PEGylation, etc.
  • In some embodiments, the compound of the invention is formulated for oral administration in a lipid-based composition suitable for low solubility compounds. Lipid-based formulations can generally enhance the oral bioavailability of such compounds. As such, pharmaceutical compositions of the invention may comprise a effective amount of one or more compound(s) of the invention, together with at least one pharmaceutically acceptable excipient selected from medium chain fatty acids or propylene glycol esters thereof (e.g., propylene glycol esters of edible fatty acids such as caprylic and capric fatty acids) and pharmaceutically acceptable surfactants, such as polyoxyl 40 hydrogenated castor oil.
  • In alternative embodiments, the pharmaceutical composition may further comprise one or more aqueous solubility enhancer(s), such as a cyclodextrin. Nonlimiting examples of cyclodextrin include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of α-, β-, and γ-cyclodextrin, and hydroxypropyl-β-cyclodextrin (HPBC). In some embodiments, the pharmaceutical composition further comprises about 0.1% to about 20% hydroxypropyl-β-cyclodextrin, about 1% to about 15% hydroxypropyl-β-cyclodextrin, or about 2.5% to about 10% hydroxypropyl-β-cyclodextrin. The amount of solubility enhancer employed may depend on the amount of the compound of the present invention in the composition.
    • F. Combination Therapy
  • It is also possible to combine any compound of the present invention with one or more other active ingredients useful in the treatment of HCV infection, including compounds, in a unitary dosage form, or in separate dosage forms intended for simultaneous or sequential administration to a patient in need of treatment. When administered sequentially, the combination may be administered in two or more administrations. In an alternative embodiment, it is possible to administer one or more compounds of the present invention and one or more additional active ingredients by different routes.
  • The skilled artisan will recognize that a variety of active ingredients may be administered in combination with the compounds of the present invention that may act to augment or synergistically enhance the viral inhibiting activity of the compounds of the invention. Such active ingredients include anti-HCV agents. Anti-HCV agents include agents that target the virus as well as agents that have an immunomodulatory effect. For example, anti-HCV agents include, but are not limited to, interferon, including, for example without limitation, IFN-α, ribavirin or prodrugs or derivatives thereof; a glucosidase inhibitor, protease inhibitors, polymerase inhibitors, helicase inhibitors, a Toll-like receptor agonist, a caspase inhibitor and a glycosidase inhibitor. Furthermore, the compounds of the invention may also be administered in combination with other compounds that affect IRES activity.
  • According to the methods of the invention, the combination of active ingredients may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art. When delivered in alternation therapy, the methods of the invention may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in simultaneous therapy, effective dosages of two or more active ingredients are administered together. Various sequences of intermittent combination therapy may also be used.
  • To assist in understanding the present invention, the following Examples are included. The experiments relating to this invention should not, of course, be construed as specifically limiting the invention and such variations of the invention, now known or later developed, which would be within the purview of one skilled in the art are considered to fall within the scope of the invention as described herein and hereinafter claimed.
  • It will be apparent to those skilled in the art that specific embodiments of the present invention may be directed to one, some or all of the above-indicated aspects as well as other aspects, and may encompass one, some or all of the above- and below-indicated embodiments, as well as other embodiments.
  • Other than in the working examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified by the term “about”. Accordingly, unless indicated to the contrary, such numbers are approximations that may vary depending upon the-desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding techniques.
  • While the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the working examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
    • EXAMPLES
  • The present invention is described in more detail with reference to the following non-limiting examples, which are offered to more fully illustrate the invention, but are not to be construed as limiting the scope thereof. The examples illustrate the preparation of certain compounds of the invention, and the testing of these compounds in vitro or in vivo or both in vitro and in vivo. Those of skill in the art will understand that the techniques described in these examples represent techniques described by the inventors to function well in the practice of the invention, and as such constitute preferred modes for the practice thereof. However, it should be appreciated that those of skill in the art should in light of the present disclosure, appreciate that many changes can be made in the specific methods that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
    • Example 1 Preparation of Compounds of the Invention Example 1A Preparation of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (compound 5)
  • Figure US20100305100A1-20101202-C00450
  • Step A: A solution of 6-methoxyindole (10.0 g, 68.0 mmol) in DMF (120 mL) is cooled to 0° C. and treated with chlorosulfonyl isocyanate (7.72 mL, 88.4 mmol). After the addition, the reaction mixture is stirred at this temperature for 1 h. The dark solution is poured into ice water (600 mL) and the light brown solid is collected by filtration, washed with additional H2O and dried to afford 9.9 g (85%) of 6-methoxy-1H-indole-3-carbonitrile as a light brown solid.
  • Step B: To a solution of 6-methoxy-1H-indole-3-carbonitrile (9.9 g, 57.6 mmol) in DMF (150 mL) is added NaH (60% dispersion in mineral oil, 3.45 g, 86.3 mmol). The reaction mixture is stirred for 15 min and then ethyl iodide (5.53 mL, 69.1 mmol) is added and the mixture is stirred at room temperature overnight. The reaction mixture is then diluted with H2O and extracted with EtOAc (2×). The organic phases are washed with H2O (3×) and saturated NaCl and then dried and concentrated to a semi-solid. The crude product is purified via column chromatography on silica gel (200 g) using CH2Cl2/hexanes (50-100%) as eluent to yield 6-methoxy-1-ethyl-1H-indole-3-carbonitrile as a tan solid.
  • Utilizing steps A and B above and substituting different indoles and alkyl halides gives the following compounds: Compounds 43, 45, 51, 52, 108, 109, 115, 118, 120, 123, 126, 179 and 714.
    • Example 1B Preparation of 6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (compound 9)
  • Figure US20100305100A1-20101202-C00451
  • Step A: To a solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (2.85 g, 14.2 mmol), prepared by example 1A, step B, in CH2Cl2 (40 mL) is added a 1M solution of BBr3 in CH2Cl2 (28.5 mL, 28.5 mmol) at 0° C. The mixture is allowed to warm to room temperature and kept for 2.5 h. The dark reaction mixture is then poured onto ice and sufficient 1M NaOH is added until the pH is 8-9. The product is extracted with CH2Cl2 (3×) and the combined organic phases are washed with saturated NaHCO3, H2O and saturated NaCl. After drying over MgSO4, the solution is concentrated and the product is purified by chromatography (EtOAc/CH2Cl2, 0-10%) to afford 2.15 g (82%) of 6-hydroxy-1-ethyl-1H-indole-3-carbonitrile as a yellow solid.
  • Step B: To a solution 6-hydroxy-1-ethyl-1H-indole-3-carbonitrile (80 mg, 0.43 mmol) in 5 mL of methyl ethyl ketone is added anhydrous K2CO3 (71 mg, 0.52 mmol) and iodomethane (0.05 mL, 0.60 mmol). After stirring overnight at reflux, the reaction mixture is cooled, diluted with H2O and extracted with EtOAc (3×). The combined organic phases are dried and concentrated. Flash chromatography (CH2Cl2) gives 94 mg (100%) of 6-ethoxy-1-ethyl-1H-indole-3-carbonitrile as a white wax.
  • In similar fashion, following steps A and B, above, the following compounds are also prepared: Compounds 6, 10, 11, 12 and 24.
    • Example 1C Preparation of 5-(4-methoxyphenyl)-5H-[1,3]dioxolo[4,5-f]indole-7-carbonitrile (compound 44)
  • Figure US20100305100A1-20101202-C00452
  • A mixture of p-iodoanisole (85 mg, 0.36 mmol), anhydrous K3PO4 (102 mg, 0.48 mmol), CuI (4.6 mg, 0.024 mmol) and N,N′-Dimethyl cyclohexane-1,2-diamine (14 mg, 0.096 mmol) is added to 5H-[1,3]dioxolo[4,5-f]indole-7-carbonitrile (45 mg, 0.24 mmol), prepared as described by the method of example 1A, step A, in anhydrous toluene (0.4 mL). After heating at reflux for 24 h, the solvent is evaporated under vacuum. The residue is dissolved with CH2Cl2 (5 mL) and the mixture is filtered. The filtrate is concentrated to afford crude product, which is purified by silica gel chromatography using EtOAc/petroleum ether (1:4) as eluent to yield 5-(4-methoxyphenyl)-5H-[1,3]dioxolo[4,5-f]indole-7-carbonitrile.
  • Utilizing the procedure above and substituting different aryl iodides gives the following compounds: Compounds 4, 8, 102, 103, 111, 112, 117, 119, 124, 125, 127, 154.
    • Example 1D Preparation of 1-ethyl-6-(pyrazin-2-yloxy)-1H-indole-3-carbonitrile (compound 13)
  • Figure US20100305100A1-20101202-C00453
  • To a solution of 1-ethyl-6-hydroxy-1H-indole-3-carbonitrile (60 mg, 0.32 mmol) prepared as described in example 1A, step A, in DMF (5 mL) is added K2CO3 (55 mg, 0.40 mmol) and 2-chloropyridazine (45 mg, 0.40 mmol). The mixture is heated at 110° C. for 18 h. After cooling to room temperature, the reaction mixture is diluted with H2O and extracted with EtOAc (3×). The combined organic phases are washed with H2O and saturated NaCl, dried and concentrated. The product is isolated by chromatography (EtOAc/CH2Cl2, 1-3%) over silica gel to afford 76 mg (96%) of the title compound, 1-ethyl-6-(pyrazin-2-yloxy)-1H-indole-3-carbonitrile, as an off-white solid.
    • Example 1E Preparation of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid phenylamide (compound 15)
  • Figure US20100305100A1-20101202-C00454
  • Step A: A solution of methyl 3-cyano-1-ethyl-1H-indole-6-carboxylate (1.60 g, 7.02 mmol), prepared by the method described in example 1A from methyl 1H-indole-6-carboxylate, in THF (35 mL) is treated with 1N NaOH (7.7 mL, 7.7 mmol) and heated at reflux for 2.5 h. After cooling to room temperature, most of the THF is removed and the solution is diluted with H2O and extracted with ether (2×). The ether extracts are discarded. The aqueous phase is then acidified with 6N HCl to pH 2 and then extracted with EtOAc (3×). The EtOAc layers are combined, washed with saturated NaCl and then dried and concentrated to afford 1.43 g (95%) of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid as a white solid.
  • Step B: A suspension of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid (0.42 g, 1.96 mmol) in CH2Cl2 (15 mL) is cooled to 0° C. The suspension is treated with DMF (2 drops) and then oxalyl chloride (0.34 mL, 3.92 mmol) is added via syringe during 2 minutes after which the ice bath is removed and the reaction mixture is allowed to warm to ambient temperature during 1.5 h during which time the reaction became a yellow solution. The solution is then concentrated in vacuo to afford 0.46 g (quantitative yield) of 3-cyano-1-ethyl-1H-indole-6-carbonyl chloride as a yellow solid.
  • Step C: A suspension of 3-cyano-1-ethyl-1H-indole-6-carbonyl chloride (70 mg, 0.30 mmol) in THF (5 mL) is cooled to 0° C. and treated with aniline (0.08 mL, 0.90 mmol). After the addition the reaction is warmed to ambient temperature and after stirring for an additional 16 hours, the reaction mixture is diluted with H2O and extracted with EtOAc (2×). The combined organic phases are washed with saturated NaCl and then dried and concentrated to afford the product. Chromatography (EtOAc/CH2Cl2, 2/98) over silica gel gives 44 mg (51%) of 3-cyano-1-ethyl-1H-indole-6-carb oxylic acid phenylamide. Utilizing essentially the procedure above gives the following compound: Compound 89.
    • Example 1F Preparation of t-butyl (3-cyano-1-ethyl-1H-indol-6-yl)-carbamate (compound 16)
  • Figure US20100305100A1-20101202-C00455
  • A solution of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid (0.60 g, 2.80 mmol) from Example 1E, step A, in t-butanol (20 mL) is treated with Et3N (0.46 mL, 3.36 mmol) and diphenylphosphoryl azide (0.73 mL, 3.36 mmol) and then heated at reflux for 4 h. After cooling to room temperature, most of the t-butanol is removed in vacuo to give an oil, which is then dissolved in EtOAc. After washing with H2O, the organic phase is back-extracted with EtOAc and the organic layers are combined and washed sequentially with additional H2O, saturated NaHCO3 and saturated NaCl. The organic phase is dried, concentrated and the resulting crude product is purified by chromatography over silica gel using EtOAc/CH2Cl2 (0-1%) to afford 0.52 g (65%) of t-butyl (3-cyano-1-ethyl-1H-indol-6-yl)-carbamate as a white solid.
  • The following compound is made in similar fashion: Compound 90.
    • Example 1Ga Preparation of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile via Suzuki route (compound 55)
  • Figure US20100305100A1-20101202-C00456
  • Step A: A 2M solution of lithium diisopropyl amide in THF/hexanes (Acros) (3.9 mL, 7.8 mmol) is diluted with THF (5 mL) in a flame-dried flask. After cooling the reaction to −30° C., a solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.30 g, 6.5 mmol) in THF (10 mL) is added dropwise during 10 min, maintaining the temperature at −30° C. After stirring for an additional 30 min at this temperature, a solution of iodine (2.31 g, 9.1 mmol) in THF (5 mL) is added during 10 min. After the addition, the reaction is warmed to ambient temperature during 1 h. The reaction is then diluted with ice-H2O and extracted with EtOAc (2×). The combined organic phases are washed with 1M sodium thiosulfate and saturated NaCl and then concentrated to a brown solid. Chromatography (CH2Cl2/hexanes, 1/1) over silica gel gives 1.31 g (62%) of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile as an off-white solid.
  • Step B: A mixture of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile (1.25 g, 3.83 mmol), 4-(4,4,5,5-tetramethyl)-1,3-2-dioxaboralanyl-2-yl-aniline (0.96 g, 4.90 mmol), CsF (1.46 g, 9.58 mmol) and Pd(PPh3)2Cl2 (110 mg, 0.15 mmol) in DME (20 mL) is added to a flask and alternatively evacuated and flushed with N2. The reaction is then heated at reflux for 24 h and then cooled to room temperature. The reaction mixture is diluted with H2O and extracted with EtOAc (2×). The combined organic phases are washed with H2O and saturated NaCl and then dried over MgSO4 and concentrated. The crude reaction mix is purified by flash chromatography on silica gel using EtOAc/CH2Cl2 (5/95) as eluent to afford 765 mg (69%) of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile as a yellow solid.
  • Utilizing essentially the same procedure described above and substituting different boronic acids gives the following compounds: Compounds 19, 20, 21, 22, 53, 63, 70, 71, 74, 76, 77, 79, 80, 100, 110, 229, 239, 240, 247, 250, 254, 255, 256, 257, 258, 259, 260, 281, 282, 283, 284, 286, 335, 336, 337, 338, 339, 347, 348, 426, 427, 428, 429, 476, 543, 578, 758.
    • Example 1Gb Preparation of 2-(4-aminophenyl)-1-butyl-6-methoxy-1H-indole-3-carbonitrile via alternative Suzuki route
  • Figure US20100305100A1-20101202-C00457
  • To a solution of (i-Pr)2NH (1.35 mL, 9.65 mmol) in THF (30 mL) cooled to −78° C. is added n-BuLi (3.7 mL, 2.5M in hexanes, 9.21 mmol) in one portion. The acetone/dry ice bath is exchanged for ice/water bath and the solution is stirred further for 40 min. The solution is cooled to −78° C. and solution of 1-butyl-6-methoxy-1H-indole-3-carbonitrile, prepared as in example 1A (2.0 g, 8.77 mmol) in THF (10 mL) is added dropwise. This solution is stirred for 15 min at −78° C., following by 20 min at −20° C. Trimethyl borate (1.0 mL, 8.77 mmol) is added, the reaction mixture is stirred for 15 min at −20° C. after which the cooling bath is removed and this solution is stirred further at room temperature for 1 h. A solution of K3PO4 is added (11.7 mL, 3M aqueous solution, 35.1 mmol) followed by a solution of 4-iodoaniline (2.5 g, 11.40 mmol) and PdCl2dppf catalyst (640 mg, 0.88 mmol) in DMF (40 mL, plus a 5 mL rinse). The reaction mixture is stirred overnight (ca. 18 h) and then water (80 mL) is added and the product is extracted with EtOAc (3×50 mL). The combined organic fractions are dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified via flush chromatography on silica gel (5→60% EtOAc/Hexanes as eluant) to afford the desired 2-(4-aminophenyl)-1-butyl-6-methoxy-1H-indole-3-carbonitrile as a tan solid (2.4 g, 86% yield).
  • The following compounds are prepared in similar fashion utilizing other indole and aryl and heteroaryl bromides and iodides: Compounds 656, 659, 660, 661, 682, 683, 712, 731, 732, 733, 806, 807, 808, 809, 810, 811, 812, 813, 814, 827.
    • Example 1Gc Preparation of 2-(4-aminophenyl)-6-methoxy-1-propyl-1H-indole-3-carbonitrile via Negishi route
  • Figure US20100305100A1-20101202-C00458
  • A nitrogen-purged flask fitted with a septum and a nitrogen needle is charged with dry THF (all additions performed by syringe) (20 mL). Diisopropylamine (Aldrich Sure-Seal, 2.00 mL, 14.3 mmol) is added, and the solution is cooled to 0° C. n-Butyllithium (8.50 mL of 1.6 M solution in hexane, 13.6 mmol) is added slowly. The flask is allowed to warm to room temperature briefly, and then is cooled to −78° C. A concentrated THF solution of 6-methoxy-1-propyl-1H-indole-3-carbonitrile (2.77 g, 12.9 mmol; prepared analogously to compound 5 of Example 1A) is added slowly, and the resulting solution is maintained at −78° C. for 30 min. The flask is then transferred to a water-ice bath and allowed to come to 0° C. for about 15 minutes. The solution is once again cooled to −78° C., and ZnCl2 (0.5 M solution in THF, 27.0 mL, 13.5 mmol) is slowly added. A precipitate is observed at this point, which may be the bis(indole)zinc compound, but the solution becomes homogeneous when the entire volume of zinc chloride solution is added. After about 10 minutes, the solution is allowed to come to room temperature, and a THF solution (5 mL) of 4-iodoaniline (3.47 g, 15.8 mmol) and triphenylphosphine (338 mg, 1.29 mmol) is added. The septum is removed, and solid Pd2(dba)3 (295 mg, 0.322 mmol) is added. A reflux condenser is fitted to the flask, and the solution is degassed by three successive cycles of vacuum pumping/N2 purging. The solution is then heated to reflux overnight. After cooling to room temperature, the solution is poured into 4 volumes of water, and 4 volumes of ethyl acetate are added. The resulting mixture is vigorously stirred for 30 minutes, then filtered through celite (with ethyl acetate washing) to remove solid Zn- and Pd-containing material. The phases are separated, and the aqueous phase is extracted with more ethyl acetate. The organic phases are washed in sequence with saturated brine, combined, dried over anhydrous sodium sulfate, filtered and evaporated. A solid precipitate forms at this point, which is sufficiently pure product and is collected by trituration with ether and filtration. The remaining material is purified by column chromatography (eluting 1:2 ethyl acetate-hexane on silica gel 60). Total yield of the product, 2-(4-amino-phenyl)-6-methoxy-1-propyl-1H-indole-3-carbonitrile, is 2.75 g (8.99 mmol, 70%).
  • The following compounds are made using essentially the same procedure and substituting other aryl or heteroaryl iodides or bromides: Compounds 393, 408, 430, 431, 436, 437, 438, 459, 460, 461, 462, 483, 484, 632, 633, 634, 635, 636, 650, 651.
    • Example 1Gd Preparation of 1-ethyl-2-(3-hydroxyphenyl)-6-methoxy-1H-indole-3-carbonitrile (Compound 288)
  • Figure US20100305100A1-20101202-C00459
  • Step A: A solution of THF (60 mL) and diisopropylamine (5.5 mL, 39 mmol) is cooled to −78° C. n-Butyllithium (14.5 mL, 2.5M in hexanes, 36.2 mmol) is added dropwise over 5 minutes. The LDA mixture is stirred at −78° C. for 10 minutes, and then at 0° C. for 20 minutes. The solution is re-cooled to −78° C. 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (5.0 g, 25 mmol), prepared as in example 1A, is taken up in THF (30 mL) and added dropwise to the LDA mixture over 15 minutes. The reaction is stirred at −78° C. for 10 minutes, and at 0° C. for 30 minutes. Once again, the reaction mixture is cooled to −78° C. Tributyltin iodide (10 mL, 35 mmol) is added dropwise. This is stirred at −78° C. for 15 minutes, and then at 0° C. for 30 minutes. The reaction mixture is absorbed onto silica gel and concentrated. Purification by chromatography (CH2Cl2) yields 1-ethyl-6-methoxy-2-tributylstannanyl-1H-indole-3-carbonitrile (12.05 g, 98%).
  • Step B: 1-Ethyl-6-methoxy-2-tributylstannanyl-1H-indole-3-carbonitrile (1.0 g, 2.05 mmol), prepared in step A, is combined with 3-iodophenol (474 mg, 2.15 mmol), Pd(PPh3)2Cl2 (67 mg, 0.102 mmol), CuI (75 mg, 0.39 mmol) and THF (4.0 mL). This mixture is heated at 65° C. overnight. The reaction mixture is diluted in EtOAc, and is filtered through celite. The filtrate is concentrated and the residue is purified by silica gel chromatography (4:1, CH2Cl2/EtOAc) to yield crude product. Ether trituration yields 1-ethyl-2-(3-hydroxy-phenyl)-6-methoxy-1H-indole-3-carbonitrile (430 mg, 72%) as a yellow-white solid.
  • The following compounds are prepared similarly as above, using other commercially available iodides and bromides, or using iodides derived from a one step amidation of p-iodophenylsulfonyl chloride: Compounds 275, 276, 277, 278, 331, 363, 364, 373, 374, 375, 474, 475, 678.
    • Example 1Ge Preparation of ethanesulfonic acid [4-(3-cyano-6-difluoromethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-amide via Heck route (compound 519)
  • Figure US20100305100A1-20101202-C00460
  • Step A: A solution of 6-difluoromethoxy-1-ethyl-1H-indole (402.8 mg, 2.04 mmol), ethanesulfonic acid (4-iodo-phenyl)-amide (712.1 mg, 2.29 mmol), cesium carbonate (733.2 mg, 3.82 mmol), triphenylphosphine (33.1 mg, 0.13 mmol) and palladium acetate (5.7 mg, 0.025 mmol) in DMA (5 ml) is heated to 135° C. for 48 h. The reaction mixture is diluted with water and extracted with EtOAc (2×10 mL). The combined organic phases are washed with brine, dried over MgSO4, and then concentrated. The residue is purified via column chromatography on silica gel (25 g) using EtOAc/Hexanes (10-20%) as eluent to afford 298.2 mg (37.1% yield) of ethanesulfonic acid [4-(6-difluoromethoxy-1-ethyl-1H-iodo-2-yl)-phenyl]-amide, compound 516, as a light brown solid.
  • Step B: Following the procedure 1A, step A, ethanesulfonic acid [4-(6-difluoromethoxy-1-ethyl-1H-iodo-2-yl)-phenyl]-amide is converted to ethanesulfonic acid [4-(3-cyano-6-difluoromethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-amide, compound 519.
  • Following steps A and B above, the following compounds are prepared in similar fashion: Compounds 343, 344, 345, 346, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 515, 517, 518, 520, 521, 522, 523, 524, 575, 577, 579, 580, 611, 612, 613, 614
    • Example 1H Preparation of 1-ethyl-2-(4-fluorophenylethynyl)-6-methoxy-1H-indole-3-carbonitrile (compound 67)
  • Figure US20100305100A1-20101202-C00461
  • A mixture of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile (150 mg, 0.46 mmol), prepared as described in example 1Ga, step A, 4-fluorophenylacetylene (80 mg, 0.0.69 mmol), bis(triphenylphosphine) palladium (II) dichloride (6 mg, 0.009 mmol) and CuI (4 mg, 0.018 mmol) is added to a sealable tube and alternatively evacuated and flushed with N2. To the tube is then added DMF (4 mL) and Et3N (0.25 mL, 1.84 mmol) and the reaction is heated at 80° C. for 20 h and then cooled to room temperature. The reaction mixture is diluted with H2O and extracted with EtOAc (2×). The combined organic phases are washed with H2O (3×) and saturated NaCl and then dried over MgSO4 and concentrated. The crude reaction mix is absorbed on silica gel (0.6 g) and chromatographed over silica gel using EtOAc/hexanes (10-20%) as eluent to afford 120 mg (82%) of 1-ethyl-2-(4-fluorophenylethynyl)-6-methoxy-1H-indole-3-carbonitrile as a yellow solid.
  • Utilizing essentially the same procedure described above and substituting different acetylene derivatives gives the following compounds: Compounds 64, 65, 66, 68, 69, 91, 92, 93, 94, 95, 96, 133, 134, 135, 136, 137, 143, 144, 145, 146, 147, 148, 149, 150, 151, 158, 159, 160, 161, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 184, 185, 186, 187, 188, 196, 197, 198, 199, 200, 201, 202, 223, 230, 231, 232, 233, 234, 235, 236, 237, 238.
    • Example 1I Preparation of 1-ethyl-3-(5-ethyl-[1,2,4]oxadiazol-3-yl)-6-methoxy-1H-indole (compound 28)
  • Figure US20100305100A1-20101202-C00462
  • Step A: A solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.00 g, 5.00 mmol) in MeOH (10 mL) is treated with a 50% aqueous solution of hydroxylamine (0.38 mL, 6.25 mmol) and heated at reflux for 18 h. After cooling to room temperature, the heterogeneous mixture is filtered to afford 525 mg of desired product as a tan solid. The filtrate is concentrated to an oil, which is then dissolved in CH2Cl2 and chromatographed over silica gel using EtOAc/CH2Cl2 (15-50%) to afford an additional 295 mg of product as a tan solid. Total yield of 1-ethyl-N-hydroxy-6-methoxy-1H-indole-3-carboxamidine is 820 mg (70%).
  • Step B: The N-hydroxycarboxamidine above (50 mg, 0.21 mmol), polystyrene-diisopropylethylamine 165 mg, 3.90 mmol/g loading) and propionyl chloride (0.03 mL, 0.32 mmol) in CH2Cl2 (10 mL) are placed in a tube and rotated for 22 h at room temperature. After this time, trisamine resin (77 mg, 2.71 mmol/g loading) is then added and the tube rotated for an additional 30 min at room temperature. Solids are filtered and then the filtrate is concentrated and diluted with toluene (5 mL) and heated at 110° C. overnight. The crude reaction mixture is concentrated and purified by chromatography (EtOAc/CH2Cl2, 2/98) to afford 27 mg (46%) of 1-ethyl-3-(5-ethyl-[1,2,4]oxadiazol-3-yl)-6-methoxy-1H-indole as a white solid.
  • The following compound is prepared utilizing the above procedure with substitution of the appropriate acyl halide: Compound 29.
    • Example 1J Preparation of 1-ethyl-6-methoxy-3-(5-ethyl-[1,3,4]oxadiazol-2-yl)-1H-indole (compound 54)
  • Figure US20100305100A1-20101202-C00463
  • Step A: A mixture of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.00 g, 5.00 mmol) in toluene (30 mL) is treated with triethylamine hydrochloride (1.03 g, 7.50 mmol) and sodium azide (0.49 g, 7.50 mmol) and is heated at reflux for 16 h. After cooling to room temperature, the reaction mixture is diluted with saturated NaHCO3 and extracted with EtOAc. The organic layer is then washed with additional NaHCO3 (2×). The combined aqueous phases are acidified to pH 2 with 6N HCl. The resultant thick precipitate is extracted with hot EtOAc (3×) and the combined organic phases are washed with saturated NaCl and dried and concentrated to give 0.55 g (45%) of 1-ethyl-6-methoxy-3-(1H-tetrazol-5-yl)-1H-indole as a yellow solid.
  • Step B: A suspension of the tetrazole above (50 mg, 0.21 mmol) and propionyl chloride (0.03 mL, 0.31 mmol) in dichloroethane (5 mL) is heated at reflux for 21 h. After cooling the reaction mixture to room temperature, polystyrene trisamine resin (70 mg, 3.4 meq/g) is added and the reaction is rotated for 4 h at room temperature. After filtering off the resin, and removal of the solvent, the crude product is absorbed on silica gel and the product is isolated by silica gel chromatography (EtOAc/CH2Cl2, 5-10%) to afford 30 mg (53%) of 1-ethyl-6-methoxy-3-(5-ethyl-[1,3,4]oxadiazol-2-yl)-1H-indole as a tan solid.
    • Example 1K Preparation of ethyl 5-difluoromethoxy-1-(4-methoxyphenyl)-2-methyl-1H-indole-3-carboxylate (compound 49)
  • Figure US20100305100A1-20101202-C00464
  • Freon-22 (HCF2Cl) gas is bubbled into a solution of ethyl 5-hydroxy-1-(4-methoxyphenyl)-2-methyl-1H-indole-3-carboxylate (250 mg, 0.77 mmol) in CH2Cl2 (5 mL) at 0° C. containing a small amount of tetrabutylammonium bromide as a phase transfer catalyst. A 50% solution of NaOH is added dropwise at 0° C. After the addition, the mixture is stirred at 0° C. for 2 h. After the addition of H2O, the organic phase is separated and washed with brine and dried over Na2SO4. The solvent is then concentrated and the residue is purified by column chromatography over silica gel using EtOAc/petroleum ether (1/2) as eluent to yield the desired product in 40% yield.
  • The following compounds are prepared utilizing the above procedure with substitution of the appropriate hydroxyindole: Compounds 18, 46, and 50.
    • Example 1L Preparation of 1-[5-methoxy-1-(4-methoxyphenyl)-1-H-indol-3-yl]-ethanone (compound 42)
  • Figure US20100305100A1-20101202-C00465
  • 5-Methoxy-1-(4-methoxyphenyl)-1-H-indole (50 mg, 0.2 mmol), prepared by the method of example 1C, is dissolved in 1 mL of CH2Cl2 at 0° C. Et2AlCl (300 μL, 1M in hexanes, 0.3 mmol) is then added. After stirring at 0° C. for 30 min, a solution of acetyl chloride (22 μL, 0.3 mmol) in 1 mL of CH2Cl2 is added dropwise. This is stirred at 0° C. for a further 90 min. The reaction mixture is quenched with H2O and is extracted with CH2Cl2 and concentrated in vacuo. Purification by column chromatography on silica gel EtOAc/CH2Cl2 (5/95) yields the title compound as a white solid (42 mg, 71%).
  • Utilizing essentially the same procedure described above and substituting different acyl chlorides, the following compounds are prepared: Compounds 32, 33, 34, 37, 38, 39, 47, 48.
    • Example 1M Preparation of 1-ethyl-3-isoxazol-3-yl-6-methoxy-1-H-indole (compound 57)
  • Figure US20100305100A1-20101202-C00466
  • Step A: A mixture of 1-(1-ethyl-6-methoxy-1-H-indole-3-yl)ethanone (200 mg, 0.92 mmol), prepared from 1-ethyl-6-methoxy-1H-indole by the procedure described in example 1L, hydroxylamine hydrochloride (128 mg, 1.84 mmol), NaOAc (151 mg, 1.84 mmol) and EtOH (7 mL) is heated at 85° C. for 4 h. The reaction mixture is then partitioned between H2O and EtOAc. The organic phase is dried and concentrated in vacuo. Purification by column chromatography using EtOAc/CH2Cl2 (1/9) yields 1-(1-ethyl-6-methoxy-1-H-indole-3-yl)ethanone oxime as a white solid (189 mg, 92%).
  • Step B: 1-(1-Ethyl-6-methoxy-1-H-indole-3-yl)ethanone oxime (100 mg, 0.43 mmol) is dissolved in THF (900 μL) at 0° C. n-BuLi (450 μL, 2.5 M in hexanes, 1.12 mol) is added dropwise, resulting in instant precipitation of solids. DMF (70 μL, 0.9 mol) in 260 μL of is then added dropwise. This is stirred at 0° C. for 1 h, then at room temperature for 1 h. The reaction mixture is pipetted into a mixture containing 1 mL of H2O, 1 mL of THF, and 100 μL of concentrated H2SO4. This mixture is heated at 75° C. for 1 h and then is partitioned between H2O and EtOAc. The organic phase is dried and concentrated. Purification by column chromatography (CH2Cl2) yields 1-ethyl-3-isoxazol-3-yl-6-methoxy-1-H-indole product as a white solid (13 mg, 12%).
    • Example 1N Preparation of 1-ethyl-3-isoxazol-5-yl-6-methoxy-1H-indole (compound 58)
  • Figure US20100305100A1-20101202-C00467
  • 1-(1-Ethyl-6-methoxy-1H-indol-3-yl)ethanone (100 mg, 0.46 mmol), prepared from 1-ethyl-6-methoxy-1H-indole by the procedure described in example 1L, is heated with 1.5 mL of dimethylformamide dimethylacetal and 100 μL of pyrrolidine at 110° C. overnight. The dimethylformamide dimethylacetal is then concentrated in vacuo. The residue is redissolved in 1.25 mL of EtOH and 250 μL of H2O, and is treated with hydroxylamine hydrochloride (66 mg, 0.95 mmol) and heated at 80° C. for 2 h. Partitioning between H2O and EtOAc and drying and concentration of the organic phase followed by purification by silica gel chromatography (EtOAc/CH2Cl2, 5/95) gives 1-ethyl-3-isoxazol-5-yl-6-methoxy-1H-indole as a white solid (72 mg, 66%).
  • Utilizing essentially the same procedure described above, the following compound is prepared: Compound 60.
    • Example 1O Preparation of 1-ethyl-6-methoxy-3-(2H-pyrazol-3-yl)-1H-indole (compound 59)
  • Figure US20100305100A1-20101202-C00468
  • 1-(1-Ethyl-6-methoxy-1H-indol-3-yl)-ethanone (100 mg, 0.46 mmol), prepared from 1-ethyl-6-methoxy-1H-indole by the procedure described in example 1L, is heated with 1.5 mL of dimethylformamide dimethyl acetal and 100 μL pyrrolidine at 110° C. overnight. The DMF dimethyl acetal is removed in vacuo. The residue is redissolved in 3 mL of acetic acid, hydrazine hydrate (70 μL, 1.38 mmol) is added, and the mixture is heated to 100° C. for 2 h. The acetic acid is removed in vacuo, and the residue is partitioned between EtOAc and saturated NaHCO3. The organic phase is dried and concentrated and the product purified by silica gel chromatography (EtOAc/Hex, 1/1) to give 59 mg of 1-ethyl-6-methoxy-3-(2H-pyrazol-3-yl)-1H-indole (54%) as a colorless semisolid. Trituration in Et2O gives a white crystalline powder.
  • The following compound is prepared utilizing the above procedure: Compound 61.
    • Example 1P Preparation of methyl 1-ethyl-3-oxazol-5-yl-1H-indole-6-carboxylate (compound 72)
  • Figure US20100305100A1-20101202-C00469
  • Step A: 1-Ethyl-1H-indole-6-carboxylic acid methyl ester (900 mg, 4.45 mmol) is dissolved in DMF (3.3 mL). This is added dropwise to an ice-cold solution of POCl3 (430 μL, 4.5 mmol) in DMF (1.5 mL). The reaction mixture is stirred at room temperature for 90 minutes. The reaction mixture is then treated with 6N NaOH (3.5 ml). The mixture is then partitioned between H2O and ethyl acetate. Purification by silica gel chromatography (5-10% EtOAc/CH2Cl2) yields 1-ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (985 mg, 96%) as a white solid.
  • Step B: 1-Ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (100 mg, 0.42 mmol), TOSMIC (100 mg, 0.52 mmol), K2CO3 (178 mg, 1.29 mmol), and MeOH (800 μL) are heated at 80° C. overnight. The reaction mixture is then partitioned between H2O and ether. After drying and concentrating the organic phase, the product is purified by silica gel chromatography (EtOAc/CH2Cl2, 10/90) to give methyl 1-ethyl-3-oxazol-5-yl-1H-indole-6-carboxylate (26 mg, 23%) as an off-white solid.
    • Example 1Q Preparation of methyl 1-ethyl-3-oxazol-2-yl-1H-indole-6-carboxylate (compound 75)
  • Figure US20100305100A1-20101202-C00470
  • Step A: 1-Ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (800 mg, 3.5 mmol), prepared as shown in example 1P, step A, is dissolved in acetone (98 mL). A solution of KMnO4 (655 mg, 4.15 mmol) in H2O (31 mL) is added. The reaction mixture is stirred at room temperature for 90 minutes. Another addition of KMnO4 (108 mg) in H2O (6 mL), followed by stirring for another 45 minutes is required to drive the reaction to completion. The reaction mixture is then quenched with 10% H2O2 (1.5 mL). The mixture is filtered through celite. The filtrate is stripped down under vacuum to roughly 1/3 of the volume. The residue is acidified with 6N HCl, and is extracted into ethyl acetate. The solids isolated from the ethyl acetate layer are triturated with acetone to yield 1-ethyl-1H-indole-3,6-dicarboxylic acid 6-methyl ester (696 mg, 79%) as a light orange solid.
  • Step B: 1-Ethyl-1H-indole-3,6-dicarboxylic acid 6-methyl ester (600 mg, 2.43 mmol) is suspended in a solution of CH2Cl2(27 ml) and DMF (20 μL). Oxalyl chloride (470 μL, 5.38 mmol) is added, and the reaction mixture is stirred for 1 hour at room temperature. This mixture is then slowly poured into a rapidly stirring solution of concentrated NH4OH (10 mL). This is then partitioned in H2O and EtOAc. The residue from the ethyl acetate layer is triturated with acetone to yield 6-methoxycarbonyl-1-ethyl-1H-indole-3-carboxamide (511 mg, 85%) as a white solid.
  • Step C: A mixture of 150 mg (0.61 mmol) of 6-methoxycarbonyl-1-ethyl-1H-indole-3-carboxamide in diglyme (3.6 mL), and bromoacetaldehyde dimethyl acetal (430 μL, 3.7 mmol) is heated at 125° C. for 2 h. The reaction mixture is cooled and partitioned in H2O and EtOAc. The organic phase is dried and concentrated and the product is purified by silica gel chromatography (EtOAc/CH2Cl2 5-10%). The product containing fractions are combined and concentrated and the solid is triturated with hexanes to yield methyl 1-ethyl-3-oxazol-2-yl-1H-indole-6-carboxylate (75 mg, 46%) as a yellow solid.
    • Example 1R Preparation of 1-ethyl-6-methoxy-3-thiazol-2-yl-1H-indole (compound 73)
  • Figure US20100305100A1-20101202-C00471
  • Step A: 1-Ethyl-6-methoxy-1H-indole (900 mg, 5.14 mmol) is dissolved in DMF (1.5 mL). This is added dropwise to an ice-cold solution of POCl3 (500 μL, 5.2 mmol) in DMF (1.75 ml). After stirring at room temperature for 90 minutes, the reaction mixture is re-cooled in an ice bath and is slowly quenched with 6N NaOH (4 mL). The reaction mixture is partitioned between EtOAc and H2O. Purification by silica gel chromatography (EtOAc/CH2Cl2, 5/95) yields 1-ethyl-6-methoxy-1H-indole-3-carbaldehyde (849 mg, 81%) as a yellow solid.
  • Step B: 1-Ethyl-6-methoxy-1H-indole-3-carbaldehyde (600 mg, 2.95 mmol) is dissolved in acetone (85 mL). A solution of KMnO4 (450 mg, 2.85 mmol) in H2O (28 mL) is added. This is stirred at room temperature for 5 hours. Another solution of KMnO4 (450 mg, 2.85 mmol) in H2O (25 mL) is then added. After stirring for another hour at room temperature, the reaction is complete. The reaction mixture is quenched with 10% H2O2 (1.5 mL), and is then filtered through celite. The filtrate is stripped down under vacuum to roughly 1/3 of the volume. The residue is acidified with 6N HCl, and is extracted into ethyl acetate. Purification by silica gel column (hexanes/acetone/acetic acid, 70/30/1) yields crude product. Trituration with ether yields pure 1-ethyl-6-methoxy-1H-indole-3-carboxylic acid (365 mg, 56%) as a yellow solid.
  • Step C: 1-Ethyl-6-methoxy-1H-indole-3-carboxylic acid (250 mg, 1.14 mmol) is suspended in a solution of CH2Cl2 (12.5 mL) and DMF (10 μL). Oxalyl chloride (230 μL, 2.64 mmol) is added, and the reaction mixture is stirred for 1 hour at room temperature. This mixture is then slowly poured into a rapidly stirring solution of concentrated NH4OH (5 mL). This is then partitioned in H2O and EtOAc. The residue from the ethyl acetate layer is triturated with acetone to yield 1-ethyl-6-methoxy-1H-indole-3-carboxamide (134 mg, 54%) as a white solid.
  • Step D: 1-Ethyl-6-methoxy-1H-indole-3-carboxamide (120 mg, 0.55 mmol), Lawesson's reagent (240 mg, 0.6 mmol), and toluene (2 mL) are heated at 90° C. for 90 min. The reaction mixture is concentrated and purified by silica gel chromatography (EtOAc/CH2Cl2, 1/9) to yield 1-ethyl-6-methoxy-1H-indole-3-thiocarboxamide as a yellow solid (92 mg, 71%).
  • Step E: 1-Ethyl-6-methoxy-1H-indole-3-thiocarboxamide (83 mg, 0.36 mmol), glyme (3.6 mL) and bromoacetaldehyde dimethyl acetal (220 μL, 1.86 mmol) are heated at 80° C. for 16 h. More bromoacetaldehyde dimethyl acetal (250 μL is added. This is heated at 80° C. for 2 h. Addition of 250 μL more bromoacetaldehyde dimethyl acetal is followed by heating for another 2 hours. The reaction mixture is cooled to room temperature, absorbed onto silica and purified by silica gel chromatography (hexanes/EtOAc, 7/3) to afford 1-ethyl-6-methoxy-3-thiazol-2-yl-1H-indole as a brown oil (44 mg, 47%).
  • The following compounds are prepared following the procedure described above: Compounds 78, 101, 104, 105 and 106.
    • Example 1S Preparation of 1-ethyl-6-methoxy-2-phenoxymethyl-1H-indole-3-carbonitrile (compound 99)
  • Figure US20100305100A1-20101202-C00472
  • Step A: To a suspension of LiAlH4 (7.6 g, 0.2 mol) in dioxane (100 mL) is added dropwise a solution of methyl 6-methoxy-1H-indole-2-carboxylate (8.2 g, 0.04 mol) in dioxane (50 mL) at 0° C. After the addition, the mixture is stirred at room temperature for 1 h and then heated at reflux for 5 h. After cooling to 0° C., the reaction is quenched by water (dropwise) and then 15% aqueous NaOH. After stirring at room temperature for 1 h, the mixture is filtered through Celite. The solid is washed with a large amount of EtOAc. The solvent is washed with brine, dried over Na2SO4 and evaporated under vacuum. The residue is purified by flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 61% of 6-methoxy-2-methyl-1H-indole.
  • Step B: To a solution of 6-methoxy-2-methyl-1H-indole (3.9 g, 24 mmol) in acetonitrile (200 mL) and DMF (20 mL) is added dropwise a solution of ClSO2NCO (4 mL, 1.3 eq.) in acetonitrile (31 mL) at 0° C. After the addition, the mixture is stirred at room temperature for 3 h. Then it is poured into ice water and saturated NaHCO3 is added to it until it becomes basic. The aqueous phase is extracted with CH2Cl2 and then evaporated. The residue is purified with flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 81% of 6-methoxy-2-methyl-1H-indole-3-carbonitrile.
  • Step C: To a suspension of NaH (0.6 g, 2 eq.) in DMF (7 mL) is added a solution of 6-methoxy-2-methyl-1H-indole-3-carbonitrile (1.3 g, 7.0 mmol) in DMF (8 mL) followed by ethyl iodide (1.2 mL, 2 eq.) at 0° C. After stirring for 1 h, the mixture is poured into ice water and the mixture is extracted with CH2Cl2. The organic layer is washed with brine and dried with Na2SO4. The solvent is evaporated under vacuum and purified with flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 92% of 1-ethyl-6-methoxy-2-methyl-1H-indole-3-carbonitrile.
  • Step D: To a solution of 1-ethyl-6-methoxy-2-methyl-1H-indole-3-carbonitrile (1.38 g, 6.45 mmol) in benzene (130 mL) is added benzoyl peroxide (226 mg) and NBS (1.21 g, 1.05 eq.). Then the mixture is heated to reflux for 3 h. After cooling and filtering, the filtrate is concentrated under vacuum. The crude 2-bromomethyl-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.6 g, 86%) is used without further purification.
  • Step E: To a solution of NaH (44 mg, 4 eq.) in DMF (0.5 mL) is added 2-bromomethyl-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (80 mg, 0.274 mmol) and phenol (2 eq.). After stirring for 20 h, the mixture is poured into ice water and extracted with CH2Cl2. The organic layer is washed with brine and dried with Na2SO4. The solvent is evaporated under vacuum and purified with flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 1-ethyl-6-methoxy-2-phenoxymethyl-1H-indole-3-carbonitrile, compound 99.
    • Example 1T Preparation of 6-nitro-2-pyrrol-1-yl-1H-indole-3-carbonitrile (compound 7)
  • Figure US20100305100A1-20101202-C00473
  • Step A: A solution of 2-fluoro-5-nitroaniline (11.7 g, 74.9 mmol) in dimethylformamide (120 mL) is treated with malononitrile (5.28 g, 80.0 mmol) and potassium carbonate (11.05 g, 80.0 mmol) (Modification of Chem. Heterocyclic Cpd. (Engl. Trans., 9, 37 (2001). The resulting heterogeneous mixture is heated to gentle reflux for 3 h, then cooled and poured into water (500 mL). The resulting precipitate is collected by filtration and taken up into ethyl acetate (300 mL). This solution is dried over Na2SO4, filtered and partially evaporated to give a precipitate, which is collected by filtration. Further evaporation and filtration gives a second crop. The two crops are combined and dried under vacuum to give 2-amino-1-ethyl-6-nitro-1H-indole-3-carbonitrile (7.90 g, 52%) as an orange powder.
  • Step B: A solution of 2-amino-6-nitro-1H-indole-3-carbonitrile (362 mg, 1.79 mmol) in acetic acid (5 mL) is treated with 2,5-dimethoxytetrahydrofuran (0.30 mL, 2.27 mmol), and the solution is heated to reflux for 14 h. After cooling to ambient temperature, the solution is poured into water (100 mL), and solid sodium bicarbonate is added until CO2 evolution ceased. The mixture is extracted with EtOAc (2×100 mL), and the extracts are washed with saturated brine, combined, dried over MgSO4, filtered and concentrated. The residual material is separated by silica gel chromatography (EtOAc/hexanes, 1/4) to afford 6-nitro-2-pyrrol-1-yl-1H-indole-3-carbonitrile, compound 5, as a yellow solid (232 mg, 51%).
    • Example 1U Preparation of N-(3-cyano-1-ethyl-6-nitro-1H-indol-2-yl)acetamide (compound 25)
  • Figure US20100305100A1-20101202-C00474
  • Step A: Sodium hydride (42 mg, 1.05 mmol, 60% w/w suspension in mineral oil) is washed with hexane and taken up in dimethylsulfoxide (1 mL). A solution of 2-amino-6-nitro-1H-indole-3-carbonitrile, prepared in procedure 1T) in dimethylsulfoxide (1 mL) is added by syringe, and the resulting mixture is stirred for 20 min. Then, iodoethane (77 μL, 0.96 mmol) is added by syringe, and the mixture is stirred for 14 h. The reaction is then poured into EtOAc (50 mL), and this solution is washed with water (3×50 mL) and saturated brine (40 mL). The aqueous phases are back-extracted with EtOAc, and the organic extracts are combined, dried over Na2SO4, filtered and evaporated. The residual material is separated by column chromatography over silica gel (EtOAc/hexanes, 1/1) to afford first a small amount of a dialkylated analog, then the desired compound, 2-amino-1-ethyl-6-nitro-1H-indole-3-carbonitrile (114 mg, 52%), and finally unreacted starting material. The desired product is isolated as an orange powder.
  • Step B: Sodium hydride (44 mg, 1.10 mmol, 60% w/w in mineral oil) is washed with hexanes and suspended in 1,4-dioxane (3 mL). A solution of 2-amino-1-ethyl-6-nitro-1H-indole-3-carbonitrile (120 mg, 0.521 mmol), prepared in step B, above, in dioxane (2 mL) is added, and the resulting mixture is allowed to stir for 30 min. Then, acetyl chloride (45 μL, 0.63 mmol) is added by syringe, and the solution is stirred for an additional 12 h. The reaction is partitioned between water and EtOAc (20 mL each), and the organic phase is washed with brine. The aqueous phases are back-extracted in sequence with ethyl acetate, and the organic extracts are combined, dried over MgSO4, filtered and evaporated. The resulting solid is triturated with Et2O, collected by filtration and dried under vacuum to afford N-(3-cyano-1-ethyl-6-nitro-1H-indol-2-yl)-acetamide (100 mg, 71%), compound 25, as an off-white powder.
  • Using this procedure and substituting the appropriate acid chlorides or chloroformates gives the following compounds: Compounds 23, 26, 35, 36, 203, 204, 214, 215, 216.
    • Example 1V Preparation of N-ethyl-3-phenyl-5-nitroindole (compound 41)
  • Figure US20100305100A1-20101202-C00475
  • Step A: To a solution of 5-nitroindole (5.00 g, 30.8 mmol) in pyridine (200 mL) at −4° C. is added a solution of pyridinium bromide perbromide (10.99 g, 34.3 mmol) in pyridine (200 mL) dropwise under nitrogen with stirring. After complete addition, the reaction mixture is stirred for 5 min at 0° C. The reaction mixture is diluted in 0° C. water (200 mL) and extracted with 200 mL of Et2O. The organic layer is washed with 6 M HCl (300 mL), 5% NaHCO3 (300 mL), and brine (300 mL). The organic phase is dried over MgSO4 and solvent is removed to give 3-bromo-5-nitroindole as a yellow powder, 80% pure with 20% 5-nitroindole (6.80 g, 74% yield).
  • Step B: A solution of 3-bromo-5-nitroindole from above (625 mg, 2.1 mmol), phenylboronic acid (381 mg, 3.13 mmol), triphenylphosphine (109.3 mg, 0.417 mmol) in dimethoxyethane (4.16 mL) is degassed. To this mixture 2N sodium carbonate (6.25 mL) is added, and reaction mixture is degassed again. To the reaction is added palladium (II) acetate (23.4 mg, 0.104 mmol), and the reaction is refluxed under dry nitrogen with stirring for 8 hours. The reaction mixture is then diluted with 1 M HCl (100 mL), and extracted with ethyl acetate (100 mL). The organic phase is washed with water (100 mL), and brine (100 mL). The organic phase is dried over MgSO4 and concentrated in vacuo. The crude product is purified by chromatography over silica gel (EtOAc/hexanes, 10/90) to afford 3-phenyl-5-nitroindole as an orange powder (45 mg, 9% yield).
  • Step C: To a mixture of 60% NaH in mineral oil (8.7 mg, 0.630 mmol) and DMF (1.0 mL) is added dropwise a solution of 3-phenyl-5-nitroindole (40.0 mg, 2.1 mmol) in DMF (0.75 mL). The reaction mixture is stirred for 20 min at 0° C. under N2. Ethyl iodide (14.8 μL, 0.185 mmol) is added dropwise and the reaction mixture is stirred for an additional 3 hours. The reaction mixture is diluted with water (250 mL), and extracted with EtOAc (30 mL). The organic phase is washed with water (250 mL) and is then dried over MgSO4 and the solvent is removed in vacuo. The desired N-ethyl-3-phenyl-5-nitroindole is obtained as a yellow powder (40.0 mg, 89.5% yield).
  • In similar fashion the following compound is prepared: Compound 40.
    • Example 1W Preparation of [3-Cyano-1-(4-methoxyphenyl)-1H-indol-6-yl]-carbamic acid propyl ester (compound 97)
  • Figure US20100305100A1-20101202-C00476
  • 6-Amino-1-(4-methoxyphenyl)-1H-indole-3-carbonitrile (30 mg, 0.12 mmol), is suspended in EtOH (300 μL). Propyl chloroformate (168 μL, 1.5 mmol) is added, and this mixture is stirred at room temperature overnight. The addition of triethylamine (300 μL), followed by another hour of stirring at room temperature, completes the reaction. This reaction mixture is loaded directly onto a silica column, and is eluted with CH2Cl2. Another silica column (3/2, ether/hexanes) is needed to fully purify the product, [3-cyano-1-(4-methoxy-phenyl)-1H-indol-6-yl]-carbamic acid propyl ester (19 mg, 45%), as a white solid.
    • Example 1X Preparation of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-methanesulfonamide (compound 130)
  • Figure US20100305100A1-20101202-C00477
  • 2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (50 mg, 0.16 mmol), prepared as described by the method of Example 1H, is dissolved in pyridine (550 μL) at room temperature. Methanesulfonyl chloride (17 μL, 0.21 mmol) is added dropwise. This is stirred overnight at room temperature. The reaction mixture is then diluted in ethyl acetate and is washed with aqueous HCl, followed by brine. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2Cl2/EtOAc) yields N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-methanesulfonamide (58 mg, 92%) as an off-white solid.
  • The following compounds are made using the procedure shown above, by substituting the appropriate aminophenylethynyl indoles and sulfonyl chlorides: Compounds 131, 132, 208, 209, and 210.
    • Example 1Y Preparation of N-[4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-methanesulfonamide (compound 129)
  • Figure US20100305100A1-20101202-C00478
  • A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in Example 1Ga, step B in THF (3 mL) is cooled to 0° C. and treated with triethylamine (0.04 mL, 0.31 mmol) and methanesulfonylchloride (0.02 mL, 0.29 mmol) and stirred, warming to room temperature overnight. The reaction mixture is then diluted with H2O and extracted with ethyl acetate (3×). The organic phase is washed with H2O and saturated NaCl, dried and concentrated and purified by flash chromatography using EtOAc/hexanes (30-50%) to afford 60 mg (68%) of N-[4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-methanesulfonamide as a tan solid.
  • Using essentially the same procedure as above and substituting the appropriate aminophenylindole and sulfonyl chloride or carrying out the reaction in pyridine as both base and solvent gives the following compounds: Compounds 83, 85, 86, 87, 88, 243, 251, 252, 272, 273, 287, 289, 365, 366, 367, 368, 369, 370, 371, 394, 439, 440, 448, 449, 451, 452, 477, 487, 488, 495, 505, 510, 548, 549, 550, 551, 552, 562, 563, 598, 599, 601, 602, 608, 609, 610, 615, 616, 617, 621, 622, 623, 629, 630, 631, 639, 655, 657, 658, 662, 669, 670, 671, 674, 675, 701, 702, 703, 706, 707, 708, 709, 710, 711, 713, 715, 720, 789, 790, 791, 850, 851, 867, 868, 890, 891, 912, 919, 920, 921, 922, 923, 924, 932, 933, 934, 935, 941, 953, 968, 982, 988, 990, 995, 996, 997, 998, 1035, 1038, 1041, 1103, 1105, 1115, 1116, 1117, 1123, 1140, 1141, 1155, 1160, 1161, 1170, 1175, 1181, 1182, 1188, 1189, 1228, 1229, 1230, 1231, 1280.
    • Example 1Za Preparation of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-acetamide (compound 138)
  • Figure US20100305100A1-20101202-C00479
  • 2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (95 mg, 0.29 mmol), prepared as described in Example 1H, is dissolved in THF (1.4 mL). Triethylamine (84 μL, 0.6 mmol) is added, followed by dropwise addition of acetyl chloride (44 μL, 0.5 mmol). This is stirred at room temperature for 1 h. The reaction mixture is partitioned between H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica chromatography (9/1, CH2Cl2/EtOAc) yields N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-acetamide (103 mg, 96%) as a yellow solid.
  • The following compounds are prepared by the procedure shown above, substituting the appropriate aminophenylethynyl indoles and acid chlorides: Compounds 82, 139, 152, 153, 162, 163, 165, 167, 205, 206, 207, 211, 212, 213, 219, 224, 225, 228.
    • Example 1Zb Preparation of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-formamide (compound 241)
  • Figure US20100305100A1-20101202-C00480
  • Acetic anhydride (2.5 mL) and 98% formic acid (1.0 mL) are heated at 65° C. for 1 hour. This is cooled to 0° C. 2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as in example 1H, is taken up in THF (1.2 mL) and added to the formic acetic anhydride mixture. This is stirred at 0° C. for 30 minutes. The reaction mixture is then partitioned between H2O and EtOAc. The EtOAc layer is washed with saturated NaHCO3, followed by saturated brine. The organic layer is dried and concentrated. Purification by silica gel chromatography (4/1, CH2Cl2/EtOAc) yields N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-formamide (105 mg, 96%) as a yellow solid.
  • The following compound is prepared similarly as described above: Compound 218.
    • Example 1AA Preparation of N-[4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-acetamide (compound 128)
  • Figure US20100305100A1-20101202-C00481
  • A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in Example 1Ga, step B in THF (3 mL) is cooled to 0° C. and treated with triethylamine (0.04 mL, 0.31 mmol) and acetyl chloride (0.02 mL, 0.29 mmol) and stirred, warming to room temperature overnight. The reaction mixture is then diluted with H2O and extracted with ethyl acetate (3×). The organic phase is washed with H2O and saturated NaCl, dried and concentrated and purified by flash chromatography using EtOAc/hexanes (30-50%) to afford 57 mg (71%) of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]acetamide as a tan solid.
  • Using essentially the same procedure as above and substituting appropriate aminophenyl indoles and the acid chlorides, the following compounds are prepared: Compounds 81, 242, 244, 324, 325, 326, 327, 328, 329, 330, 383, 420, 421, 422, 423, 424, 425, 544, 558, 559, 560, 561, 565, 566 567, 644, 645, 646, 755, 756, 757, 759, 760, 761, 762, 763, 764, 765, 766, 798, 799, 801, 802, 803, 804, 854, 855, 856, 857, 858, 859, 895, 896, 897, 898, 899, 900, 901, 913, 914, 915, 916, 983.
    • Example 1AB Preparation of 1-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)phenyl]-3-ethyl urea (compound 220)
  • Figure US20100305100A1-20101202-C00482
  • 2-(3-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as described in Example 1H, is dissolved in pyridine (670 μL). Ethyl isocyanate (62 μL, 0.75 mmol) is added. The reaction mixture is then heated at 100° C. for 2 h. The mixture is then diluted in EtOAc, and is washed with aqueous HCl, followed by brine. The organic layer is dried and concentrated. Purification by silica chromatography (4/1, CH2Cl2/EtOAc), followed by trituration with hexanes/acetone (1/1), yields 1-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-3-ethyl urea (44 mg, 36%) as a white solid.
    • Example 1AC Preparation of 1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]urea (compound 156)
  • Figure US20100305100A1-20101202-C00483
  • 2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as described in Example 1H, is suspended in toluene (600 μL). 2-Chloroethyl isocyanate (32 μL, 0.37 mmol) is added, and the mixture is heated at 100° C. for 5 h. The reaction mixture is then cooled, diluted in acetone, and absorbed onto silica. Purification by column chromatography (5-10% EtOAc in CH2Cl2) yields 1-(2-chloro-ethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]urea (73 mg, 54%) as a yellow solid.
  • The following compound is prepared using the procedure above: Compound 221.
    • Example 1AD Preparation of Ethanesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]methyl amide (compound 157)
  • Figure US20100305100A1-20101202-C00484
  • N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)phenyl]ethanesulfonamide (70 mg, 0.17 mmol), prepared as in Example 1×, is combined with K2CO3 (49 mg, 0.35 mmol), and DMF (1.0 mL). Iodomethane (16 μL, 0.26 mmol) is added, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is then diluted in EtOAc, and is washed with H2O and then brine. The organic layer is dried and concentrated. Purification by silica chromatography (95/5, CH2Cl2/EtOAc) yields a light tan solid. Trituration gives ethanesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]methyl amide (61 mg, 85%) as an orange-white solid.
  • The following compounds are prepared using the procedure above, substituting the appropriate sulfonamide: Compound 182, 652, 840.
    • Example 1AE Preparation of 1-ethyl-5-methoxy-2-[4-(morpholine-4-carbonyl)-phenyl]-1H-indole-3-carbonitrile (compound 245)
  • Figure US20100305100A1-20101202-C00485
  • Step A: Methyl 4-(3-cyano-1-ethyl-5-methoxy-1H-indol-2-yl)-benzoate (350 mg, 1.05 mmol), prepared as described in Example 1Ga step B, is combined with NaOH (40 mg, 1 mmol), H2O (0.8 mL), and THF (3.4 mL) and is heated at 80° C. for 1 hour. The reaction mixture is diluted in H2O and is then ether-washed. The aqueous layer is acidified with aqueous HCl, and is extracted into EtOAc. The organic layer is dried and concentrated to yield 4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-benzoic acid (311 mg, 92%) as a pure white solid.
  • Step B: 4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-benzoic acid (50 mg, 0.16 mmol) is suspended in CH2Cl2 (2.2 mL) and catalytic DMF (2 μL). Oxalyl chloride (22 μL, 0.25 mmol) is added. The reaction mixture is stirred at room temperature for 1 hour, at which time full dissolution occurs. This reaction mixture is pipetted dropwise into a vigorously stirring solution of morpholine (1.0 mL) in CH2Cl2 (5 ml). After addition is complete, the reaction mixture is washed with aqueous HCl solution. The organic layer is dried and concentrated. Purification by silica column (1:1 CH2Cl2/EtOAc) yields 1-ethyl-6-methoxy-2-[4-(morpholine-4-carbonyl)-phenyl]-1H-indole-3-carbonitrile (56 mg, 90%) as a white solid.
  • The following compounds are prepared similarly as described above: Compounds 113, 114, 246, 270, 271 290, 291, 292, 323, 377, 378, 379, 380, 381, 382, 384, 385, 386, 387, 388, 389, 390, 391, 392, 432, 433, 564, 568, 569, 570, 571, 572, 573, 647, 648, 853, 860, 861, 862.
    • Example 1AF Preparation of cyclopropanecarboxylic acid [4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-ylethynyl)-phenyl]amide (compound 194)
  • Figure US20100305100A1-20101202-C00486
  • Cyclopropanecarboxylic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-amide (60 mg, 0.16 mmol), prepared as described in Example 1Za, is stirred in BBr3 (800 μL, 1M in CH2Cl2, 0.8 mmol) at room temperature for 1 hour. The reaction mixture is quenched with H2O, and is extracted with CH2Cl2. The organic layer is dried and concentrated. Purification by silica chromatography (EtOAC) gives impure product. This crude product is triturated with 1/1 hexanes/acetone to yield cyclopropanecarboxylic acid [4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-ylethynyl)-phenyl]-amide (32 mg, 54%) as an off-white solid.
  • The following compounds are prepared using the procedure above, substituting the appropriate sulfonamides (from Example 1X) or amides (from Example 1Z): Compounds 164, 168, 183, 193, 195.
    • Example 1AG Preparation of 1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenylethynyl]-1H-indole-3-carbonitrile (compound 166)
  • Figure US20100305100A1-20101202-C00487
  • 1-(2-Chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]urea (55 mg, 0.13 mmol), prepared as in Example 1AC, is combined with K2CO3 (50 mg, 0.36 mmol) and DMF (550 μL). This mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted in EtOAc, and is washed with H2O, and then with brine. The organic layer is dried and concentrated. Purification by silica chromatography (10-50%, EtOAc/CH2Cl2) yields 1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenylethynyl]-1H-indole-3-carbonitrile (47 mg, 94%) as a white solid.
  • The following compound is prepared using the above procedure, substituting the appropriate urea: Compound 222.
    • Example 1AH Preparation of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-dimethylphosphinic amide (compound 227)
  • Figure US20100305100A1-20101202-C00488
  • 2-(3-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as described in Example 1H, is dissolved in pyridine (300 μL) at 0° C. Dimethylphosphinic chloride (60 mg, 0.53 mmol) in THF (300 μL) is added. The reaction is stirred at room temperature for 2 hours. The reaction mixture is diluted in EtOAc, and is washed with aqueous HCl followed by brine. The organic layer is dried and concentrated. Purification by silica chromatography (acetone) yields N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-dimethylphosphinic amide (65 mg, 52%), compound 227, as a pure white solid. The silica column is then flushed with 9/1 CH2Cl2/MeOH to yield 9 mg of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-bis-(dimethylphosphinic) amide as a by-product.
    • Example 1AI Preparation of 1-ethyl-6-methoxy-3-[5-(4-methoxyphenyl)-isoxazol-3-yl]-1H-indole (compound 116)
  • Figure US20100305100A1-20101202-C00489
  • Step A: A mixture of 1-ethyl-6-methoxy-1H-indole-3-carbaldehyde oxime (0.20 g, 0.92 mmol), prepared from the aldehyde precursor in example 1R, in dichloroethane (3 mL) is treated with N-chlorosuccinimide (0.12 g, 0.92 mmol) and pyridine (0.04 mL, 0.46 mmol) and stirred at room temperature for 1 h. The reaction mixture is then poured into H2O and acidified with 1N HCl until the pH is 2. The mixture is extracted with EtOAc and the organic phases are washed with H2O and saturated NaCl and dried and concentrated to a mixture of chlorooximes, which are used in the next step without further purification.
  • Step B: The mixture of chlorooximes prepared above is dissolved in CH2Cl2 (5 mL) and to this is added 4-methoxyphenylacetylene (0.24 g, 1.84 mmol) and triethylamine (0.25 mL, 1.84 mmol) at 0° C. and the reaction is then stirred overnight warming to room temperature. The reaction is then diluted with H2O and extracted with EtOAc (3×). The organic phases are washed with H2O and saturated NaCl and dried and concentrated. Chromatography over silica gel (EtOAc/hexanes, 10-20%) gives 76 mg (24%) of 1-ethyl-6-methoxy-3-[5-(4-methoxy-phenyl)-isoxazol-3-yl]-1H-indole as a tan solid.
    • Example 1AJ Preparation of [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester (compound 121)
  • Figure US20100305100A1-20101202-C00490
  • A biphasic mixture of 2-(4-amino-phenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in example 1Ga step B, and ethyl chloroformate (0.03 mL, 0.29 mmol) in EtOAc (3 mL) and saturated NaHCO3 (3 mL) is prepared at 0° C. and then allowed to warm to room temperature and stirred for 24 h. The reaction is then diluted with H2O and extracted with EtOAc (2×). The organic phases are washed with H2O and saturated NaCl and then dried and concentrated. Flash chromatography (EtOAc/hexanes 20-40%) gives 48 mg (55%) of [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester as an off-white solid.
  • The following compounds are prepared in similar fashion: Compound 122, 293, 294, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 372, 434, 435, 450, 453, 454, 455, 457, 485, 486, 489, 490, 500, 501, 502, 503, 506, 507, 508, 509, 545, 546, 547, 553, 554, 555, 556, 557, 581, 582, 583, 584, 585, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 603, 604, 605, 606, 607, 618, 619, 624, 625, 637, 640, 641, 664, 665, 676, 677, 721, 722, 723, 734, 735, 736, 737, 738, 739, 744, 745, 746, 747, 787, 788, 792, 793, 794, 795, 796, 797, 819, 822, 823, 824, 825, 826, 849, 925, 926, 945, 946, 947, 948, 949, 950, 951, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 981, 984, 985, 986, 991, 992, 993, 1015, 1020, 1021, 1022, 1029, 1030, 1031, 1032, 1033, 1034, 1037, 1040, 1042, 1044, 1055, 1056, 1057, 1058, 1059, 1062, 1063, 1064, 1065. 1071, 1073, 1074, 1075, 1077, 1078, 10791107, 1109, 1111, 1112, 1113, 1114, 1122, 1127, 1128, 1129, 1145, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1169, 1174, 1176, 1177, 1178, 117911801186, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1211, 1222, 1232, 1233, 1300, 1302.
    • Example 1AK Preparation of 1-ethyl-5-thiophen-3-yl-1H-indole-3-carbonitrile (compound 141)
  • Figure US20100305100A1-20101202-C00491
  • A tube is charged with a mixture of 5-bromo-1-ethyl-1H-indole-3-carbonitrile (100 mg, 0.40 mmol), thiophene-3-boronic acid (72 mg, 0.56 mmol), PdCl2(PPh3)2 (11 mg, 0.016 mmol) and CsF (152 mg, 1 mmol) and then alternately evacuated and filled with nitrogen (3×) and diluted with dimethoxyethane (3 mL) and then heated to 90° C. for 19 h. After cooling, the crude reaction mixture is diluted with saturated NaHCO3 and extracted with EtOAc (2×). The combined organic phases are washed with saturated NaCl and dried and concentrated. Flash chromatography over silica gel (CH2Cl2/hexanes, 40/60) gives 25 mg (25%) of 1-ethyl-5-thiophen-3-yl-1H-indole-3-carbonitrile as a white solid.
  • The following compounds are prepared in similar fashion: Compounds 140 and 142.
    • Example 1AL Preparation of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-methyl methanesulfonamide (compound 180)
  • Figure US20100305100A1-20101202-C00492
  • A solution of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide (130 mg, 0.35 mmol), prepared as in Example 1Y, in DMF (10 mL) is treated with NaH (21 mg, 0.53 mmol), and stirred at room temperature for 10 min. Iodomethane (0.03 mL, 0.53 mmol) is added, and the mixture is stirred at room temperature for 18 h. The reaction mixture is then diluted with H2O, and extracted with EtOAc (2×). The organic phases are washed with H2O and saturated NaCl and then dried and concentrated. Purification by flash chromatography over silica gel (EtOAc/CH2Cl2, 0-1%) gives 60 mg (45%) of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-methyl methanesulfonamide as a white solid.
  • In similar fashion the following compounds are prepared: Compounds 181, 642, 643, 672, 673, 816, 852, 1002, 1003, 1004, 1005, 1006, 1007.
    • Example 1AM Preparation of N-[4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-methanesulfonamide (compound 189)
  • Figure US20100305100A1-20101202-C00493
  • A solution of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide (85 mg, 0.23 mmol) in CH2Cl2 (2 mL) is cooled to −5° C. A solution of boron tribromide (1.15 mL, 1.15 mmol, 1M solution in CH2Cl2) is added and the reaction mixture is allowed to warm to 10° C. over 4 h. The reaction mixture is poured into H2O and extracted with EtOAc (3×). The combined organic phases are washed with H2O and saturated NaCl and dried and concentrated. Chromatography over silica gel (EtOAc/CH2Cl2, 5-10%) gives 18 mg (22%) of N-[4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]methanesulfonamide as a tan solid.
  • The following compounds are made similarly: Compounds 190, 191, 192.
    • Example 1AN Preparation of methyl 3-[5-(3-cyano-6-methoxy-1H-indol-2-yl)-[1,2,4]oxadiazol-3-yl]benzoate (compound 226)
  • Figure US20100305100A1-20101202-C00494
  • Step A: To a mixture of 6-methoxy-1H-indole-3-carbonitrile (5.88 g, 40 mmol), prepared as described in the previous examples, and (Boc)2O (9.59 g, 44.0 mmol) in DCM (50 mL) is added DMAP (0.10 g, 0.8 mmol). The mixture is stirred at room temperature for 48 h, then treated with water (30 mL) and dried over anhydrous Na2SO4. The crude product is chromatographed over silica gel (hexanes/EtOAc, 7/1) to furnish the desired intermediate, 3-cyano-6-methoxyindole-1-carboxylic acid tert-butyl ester (8.48 g, 86%).
  • Step B: The above intermediate (2.72 g, 10.0 mmol) is dissolved in anhydrous THF (20 mL), and cooled at −78° C., followed by the addition of LDA (1.5 M monoTHF in cyclohexane, 10.0 mL, 15 mmol). After stirring for 45 min, CO2 gas is introduced for 2 h. The mixture is then brought to room temperature and the solvent is removed in vacuo, and the residue is treated with water and acidified to pH=2 with 6 N HCl. The precipitate is collected and washed with water and dried to provide the acid intermediate, 3-cyano-6-methoxy-indole-1,2-dicarboxylic acid 1-tert-butyl ester (2.40 g, 73%).
  • Step C: To a solution of 3-cyano-6-methoxyindole-1,2-dicarboxylic acid 1-tert-butyl ester (474 mg, 1.5 mmol) prepared above, and HOBt (200 mg, 1.5 mmol) in DCE/DMF (10 mL/1 mL), is added DCC (310 mg, 1.5 mmol), followed by 3-(N-hydroxycarbamimidoyl)benzoic acid methyl ester (291 mg, 1.5 mmol). The mixture is stirred at room temperature for 2 h and filtered. The filtrate is collected and the solvent is replaced with chlorobenzene, followed by the heating at 150° C. for 48 h. After cooling to room temperature, the solvent is removed in vacuo and the residue is chromatographed (silica gel, CH2Cl2/EtOAc, 8/2) to furnish the intermediate, 3-cyano-6-methoxy-2-[3-(3-methoxycarbonylphenyl)-[1,2,4]oxadiazol-5-yl]-indole-1-carboxylic acid tert-butyl ester, which is treated with 50% TFA in DCM (10.0 mL) at room temperature for 1 h. After removal of the volatiles in vacuo, the residue is suspended in water and neutralized with K2CO3 to provide the desired product, methyl 3-[5-(3-cyano-6-methoxy-1H-indol-2-yl-)[1,2,4]oxadiazol-3-yl]benzoate, compound 226 (350 mg, 62%).
    • Example 1AO Preparation of 1-ethyl-2-(4-methanesulfonylphenyl)-6-methoxy-1H-indole-3-carbonitrile (compound 265)
  • Figure US20100305100A1-20101202-C00495
  • A solution of 1-ethyl-6-methoxy-2-(4-methylsulfanylphenyl)-1H-indole-3-carbonitrile (0.12 g, 0.37 mmol) in CH2Cl2 (5 mL) is treated with m-chloroperbenzoic acid (Aldrich, <77%, 0.26 g) in one portion and the reaction is stirred for 10 h at room temperature. The reaction is then diluted with H2O and saturated NaHCO3 and extracted twice with EtOAc. The organic phases are washed with NaHCO3 (2×) and saturated NaCl and dried and concentrated to a dark semi-solid. The crude product is purified by flash chromatography (EtOAc/CH2Cl2, 0-3%) through a 5 gram silica cartridge topped with 1 gram of basic alumina to give 72 mg (55%) of 1-ethyl-6-methoxy-2-(4-methylsulfanylphenyl)-1H-indole-3-carbonitrile as an off-white solid.
    • Example 1AP Preparation of N-{4-[3-cyano-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-phenyl}methanesulfonamide (compound 478)
  • Figure US20100305100A1-20101202-C00496
  • A solution of N-{4-[6-(2-chloroethoxy)-3-cyano-1-ethyl-1H-indol-2-yl]-phenyl}methanesulfonamide (90 mg, 0.21 mmol), morpholine (0.06 mL, 0.65 mmol), NaI (32 mg, 0.21 mmol) and diisopropyl ethylamine (0.06 mL, 0.32 mmol) in CH3CN (2 mL) is heated in a sealed tube at 100° C. for 25 h. The reaction mixture is cooled to room temperature, diluted with H2O and extracted with EtOAc (3×). The combined organic phases are washed with saturated NaCl, dried and concentrated. The crude solid is triturated with EtOAc and filtered to give 41 mg (41%) of N-{4-[3-cyano-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-phenyl}methanesulfonamide as a tan solid.
  • The following compounds are made similarly: Compounds 479, 480, 481, 482, 496, 497 and 498.
    • Example 1AQ Preparation of 2-morpholin-4-yl-ethanesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide (compound 653)
  • Figure US20100305100A1-20101202-C00497
  • Step A: A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile, prepared by example 1Ga step B, (0.82 mg, 2.82 mmol), in pyridine (10 mL) is treated dropwise with chloroethyl sulfonylchloride (0.38 mL, 3.66 mmol) at room temperature. After stirring for 4 h, the reaction mixture is quenched with ice-water and enough 6N HCl is added until the pH is lowered to 2. The suspension is extracted with hot EtOAc (3×). The organic phases are then washed sequentially with 1N HCl, H2O and saturated NaCl and dried and concentrated to give ethenesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide as a pale orange solid which is used directly in the next step without further purification.
  • Step B: A suspension of ethenesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide, prepared above, (70 mg, 0.18 mmol), morpholine (0.05 mL, 0.55 mmol) in CH3CN (1.5 mL) is heated at reflux for 1.5 h. After cooling to room temperature, the reaction is concentrated and the residue is purified by flash chromatography (acetone/EtOAc, 2/98) over silica gel to afford 89 mg (100%) of 2-morpholin-4-yl-ethanesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide as a tan foam.
  • The following compound is made similarly: Compound 654.
    • Example 1AR Preparation of 2-morpholin-4-yl-ethanesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methyl amide (compound 668)
  • Figure US20100305100A1-20101202-C00498
  • A solution of 2-morpholin-4-yl-ethanesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide, prepared in example 1AQ (60 mg, 0.13 mmol) in DMF (3 mL) is treated with K2CO3 (35 mg, 0.26 mmol) and methyl iodide (0.02 mL, 0.26 mmol). After stirring at room temperature for 1.5 h, the reaction mixture is diluted with H2O and extracted with EtOAc (2×). The organic phases are then washed with H2O (3×) and saturated NaCl, and then dried and concentrated to afford a residue. Flash chromatography over silica gel (acetone/EtOAc, 0-2%) gives 31 mg (50%) of 2-morpholin-4-yl-ethanesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methyl amide as an off white solid.
  • The following compounds are made similarly: Compounds 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698.
    • Example 1AS Preparation of 2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (compound 84)
  • Figure US20100305100A1-20101202-C00499
  • Step A: A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile, prepared by example 1Ga step B, (2.78 g, 9.55 mmol) in pyridine (40 mL) is treated dropwise with 3-chloropropanesulfonyl chloride (1.45 mL, 11.9 mmol) and the reaction is stirred for 4 h at room temperature. The reaction is diluted with water and enough 6N HCl to lower the pH to 2. The reaction mixture is extracted with EtOAc (3×) and the combined organic layers are washed sequentially with 1N HCl, water and saturated NaCl and then dried and concentrated to give 3.9 g (95%), of 3-chloropropane-1-sulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide as a brown foam which is used directly in the next step.
  • Step B: A solution of 3-chloropropane-1-sulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide, prepared above (3.65 g, 2.33 mmol) in DMF (100 mL) is treated with K2CO3 and heated at 70° C. for 2 h. After cooling to room temperature, the reaction mixture is diluted with H2O and extracted 3× with hot EtOAc. The hot organic layers are washed with warm H2O (3×) and saturated NaCl and dried and concentrated to a solid. Trituration (CH2Cl2/hexanes) gives 2.27 g (68%) of 2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile as a light brown solid.
  • The following compounds are made in similar fashion: Compound 649, 775, 809, 969, 980.
    • Example 1AT Preparation of 2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (compound 666)
  • Figure US20100305100A1-20101202-C00500
  • Step A: Following the procedure in example 1B step A, 2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile is treated with 1M BBr3 solution in CH2Cl2 at −15° C. for 1.5 h and then poured into ice-water and filtered and dried to afford 2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-hydroxy-1H-indole-3-carbonitrile in nearly quantitative yield.
  • Step B: Following the procedure in example 1B step B, 2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-hydroxy-1H-indole-3-carbonitrile, K2CO3, 2-iodopropane and methyl ethyl ketone are heated at reflux to give, after flash chromatography (EtOAc/CH2Cl2, 0-2%), 61% of 2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-isopropoxy-1H-indole-3-carbonitrile as an off-white solid.
  • The following compounds are made similarly: Compounds 667, 699
    • Example 1AU Preparation of 2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-phenyl]-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indole-3-carbonitrile (compound 729)
  • Figure US20100305100A1-20101202-C00501
  • A mixture of 2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-hydroxy-1H-indole-3-carbonitrile, prepared in example 1AT above (70 mg, 0.25 mmol), K2CO3 (75 mg, 0.51 mmol), sodium iodide (27 mg, 0.18 mmol), 4-(2-chloroethyl) morpholine hydrochloride (42 mg, 0.25 mmol) in methyl ethyl ketone (3 mL) is heated in a sealed tube at 100° C. After 13 hours, DMF (3 mL) is added and the reaction is heated for an additional 6 h. After this time, an additional 42 mg of 4-(2-chloroethyl) morpholine hydrochloride and 135 mg of K2CO3 is added and the reaction is heated for an additional 6 h to complete the reaction. The reaction mixture is cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic phases are washed with water (2×) and saturated NaCl and dried and concentrated. Pure 2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-phenyl]-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indole-3-carbonitrile is obtained by flash chromatography (MeOH/CH2Cl2, 0-6%) to give 29 mg (34%) of a tan solid.
  • The following compounds are made similarly: Compounds 728 and 730.
    • Example 1AV Preparation of 2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (compound 779)
  • Figure US20100305100A1-20101202-C00502
  • Step A: A solution of 2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (585 mg, 1.92 mmol) in 10 mL of 1,4-dioxane is treated with ethyl isocyanatoacetate (0.25 mL, 2.12 mmol), and the resulting solution is heated to reflux overnight. The solution is allowed to cool, and the solvent is removed by rotary evaporation. The residual material is triturated with ether, and the resulting precipitate is collected by filtration and dried under vacuum to afford compound 773 (587 mg, 1.35 mmol, 70%).
  • A similar procedure is used to prepare methyl 2-{3-[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-ureido}-3-phenyl-propionate (compound 777)
  • Step B: A solution of ethyl {3-[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-ureido}-acetate (compound 773, 101 mg, 0.232 mmol) in THF (10 mL) is treated with a solution of potassium tert-butoxide in tert-butanol (0.30 mL, 1.0 M, 0.30 mmol), and the resulting mixture is allowed to stir overnight. The reaction mixture is partitioned between water and ethyl acetate (50 mL each), and the organic phase is washed with saturated brine. The aqueous phases are extracted with more ethyl acetate, and the extracts are combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is separated by column chromatography (eluting 2/1 ethyl acetate/hexane on silica gel 60) to afford 2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile, compound 779, which is purified further by trituration with ether, collection by filtration and drying under high vacuum (76 mg, 0.196 mmol, 84%).
    • Example 1AW Preparation of 2-[4-(2,4-dioxo-imidazolidin-1-yl)phenyl]-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (compound 776)
  • Figure US20100305100A1-20101202-C00503
  • A solution of 2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (319 mg, 1.04 mmol) in 1,4-dioxane (3 mL) is treated with chloroacetyl isocyanate (0.10 mL, 1.17 mmol), and the resulting solution is warmed to 60° C. overnight. The solution is cooled, and DBU (0.20 mL, 1.31 mmol) is added. This mixture is stirred at ambient temperature overnight, and then is partitioned between water and ethyl acetate (50 mL each). The organic layer is washed with saturated brine, and then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is triturated with ether, and the resulting solid is collected by filtration and dried under high vacuum to afford the title product (319 mg, 0.821 mmol, 79%).
    • Example 1AX Preparation of N,N-Dimethyl-2-[4-(3,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)-phenyl]-6-ethoxy-1-ethyl-1H-indole-3-carboxamide (compound 780) and N,N-Dimethyl-6-ethoxy-1-ethyl-2-[4-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carboxamide (compound 781)
  • Figure US20100305100A1-20101202-C00504
  • Step A. A solution of ethyl {3-[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-ureido}acetate (compound 773, 325 mg, 0.748 mmol), prepared in procedure 1AV, step A, in acetone (5 mL) is treated with HCl (3 mL, 6 N), and the resulting solution is heated to reflux overnight. The reaction mixture is cooled, and the resulting precipitate is collected by filtration, washed with ether and dried under high vacuum to afford the product, 6-ethoxy-1-ethyl-2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carboxamide (264 mg, 0.650 mmol, 87%).
  • Step B. Sodium hydride dispersion in mineral oil (75 mg) is washed with a small portion of hexane, and the hexane layer is decanted off. A solution of 6-ethoxy-1-ethyl-2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carboxamide (190 mg, 0.468 mmol) in dimethylformamide (2 mL) is added, and the mixture is stirred for 1 hour. Then, methyl iodide (0.10 mL, 1.61 mmol) is added by syringe. The resulting mixture is allowed to stir at ambient temperature overnight and then is poured into 50 mL of ethyl acetate. The organic phase is washed with water (3×50 mL) and saturated brine (20 mL), then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is separated by column chromatogaphy (1/1 ethyl acetate/hexane, eluting on silica gel 60) to afford the title products, compounds 780 and 781.
    • Example 1AY Preparation of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-(2-hydroxyethyl)-methanesulfonamide (compound 828)
  • Figure US20100305100A1-20101202-C00505
  • Step A: Sodium hydride dispersion in mineral oil (108 mg) is washed with a small portion of hexane, and the hexane layer is decanted off. A solution of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide (compound 129, 500 mg, 1.35 mmol) in DMF (5 mL) is slowly added. After gas evolution is complete, 2-bromoethyl acetate (0.30 mL, 2.64 mmol) and sodium iodide (20 mg) are added. The mixture is stirred at ambient temperature overnight, and then is poured into 50 mL of ethyl acetate. This is washed with water (3×50 mL) and saturated brine (20 mL), then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is separated by column chromatogaphy (1/1 ethyl acetate/hexane, eluting on silica gel 60) to afford compound 815 (364 mg, 0.799 mmol, 59%).
  • Step B: A mixture of N-(2-acetoxyethyl)-N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide (compound 815, 164 mg, 0.360 mmol) and lithium hydroxide hydrate (45 mg, 1.07 mmol) in 5 mL THF/1 mL water is warmed to 60° C. overnight. The mixture is cooled and poured into ethyl acetate (50 mL). This is washed with water (50 mL) and brine (20 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to afford a solid. The solid is triturated with ether, collected by filtration and dried under high vacuum to afford N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-(2-hydroxyethyl) methanesulfonamide, compound 828 (137 mg, 0.331 mmol, 92%).
    • Example 1AZ Preparation of 1-ethyl-6-methoxy-2-[4-(2-methoxyethoxy)-phenyl]-1H-indole-3-carbonitrile (compound 248)
  • Figure US20100305100A1-20101202-C00506
  • 1-Ethyl-2-(4-hydroxy-phenyl)-6-methoxy-1H-indole-3-carbonitrile (40 mg, 0.14 mmol), prepared as in example 1Ga step B, is combined with K2CO3 (77 mg, 0.56 mmol), bromoethyl methyl ether (26 μL, 0.28 mmol), and DMF (450 μL). This is stirred at room temperature for 1 hour, and then at 75° C. for 3 hours. The reaction mixture is then partitioned between H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2, 0-5% EtOAc) yields 1-ethyl-6-methoxy-2-[4-(2-methoxyethoxy)-phenyl]-1H-indole-3-carbonitrile (44 mg, 90%) as a white solid.
  • The following compound is prepared similarly as above: Compound 249.
    • Example 1BA Preparation of 1-ethyl-6-methoxy-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-1H-indole-3-carbonitrile (compound 261)
  • Figure US20100305100A1-20101202-C00507
  • Step A: 1-Ethyl-6-methoxy-2-[4-(2-hydroxyethoxy)-phenyl]-1H-indole-3-carbonitrile (450 mg, 1.34 mmol), prepared as in example 1AZ, is combined with PPh3 (878 mg, 3.35 mmol) in CH2Cl2 (32 mL) at 0° C. N-bromosuccinimide (600 mg, 3.37 mmol) is added in one portion. The reaction mixture is stirred at room temperature for 30 minutes. The reaction mixture is washed with aqueous NaHCO3. The organic layer is dried and concentrated, and purified by silica gel chromatography (CH2Cl2) to yield 2-[4-(2-bromoethoxy)-phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (506 mg, 95%), compound 253 as a white solid.
  • Step B: 2-[4-(2-bromoethoxy)-phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (40 mg, 0.1 mmol), prepared as in step A above, is combined with morpholine (50 μL, 0.58 mmol) and acetonitrile (1.0 mL). This is heated at 85° C. for 2 h. The reaction mixture is then partitioned between CH2Cl2 and H2O. The organic layer is dried and concentrated. Purification by silica gel chromatography (6/4, acetone/hexanes) yields 1-ethyl-6-methoxy-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-1H-indole-3-carbonitrile (39 mg, 96%) as a white solid.
  • The following compounds are prepared similarly as above, using different amines Compounds 262, 263, 264.
    • Example 1BB Preparation of N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-ethyl}methanesulfonamide (compound 268)
  • Figure US20100305100A1-20101202-C00508
  • Step A: 2-[4-(2-Bromoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (258 mg, 0.65 mmol), prepared in example 1BA, step A, is combined with NaN3 (144 mg, 2.2 mmol), and MeOH (3.2 mL). This is heated overnight at 75° C. The reaction mixture is then partitioned between CH2Cl2 and H2O. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2) yields 2-[4-(2-azidoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (187 mg, 80%), compound 266 as a white solid.
  • Step B: 2-[4-(2-Azidoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (410 mg, 1.14 mmol), prepared as in step A, above, is suspended in a solution of MeOH (20 mL) and concentrated HCl (500 μL). Pd/C (150 mg, 10%) is added, and this mixture is hydrogenated at 30 p.s.i. for 1 h. This is filtered and the filtrate is concentrated. The filtrate residue is partitioned between EtOAc and 0.5N NaOH. The organic layer is dried and concentrated. Purification by silica gel chromatography (10-30%, MeOH/CH2Cl2) yields 2-[4-(2-aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (298 mg, 78%), compound 267, as a white solid.
  • Step C: 2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared in step B, above, is dissolved in pyridine (300 μL). Methanesulfonyl chloride (8 μL, 0.1 mmol) is added. This is stirred at room temperature for 45 minutes. More methansulfonyl chloride (4 μL, 0.05 mmol) is added. Stirring continues for another hour. The reaction mixture is partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated. Purification by silica gel chromatography (1/1 CH2Cl2/EtOAc) yields N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]ethyl}methanesulfonamide, compound 268 (32 mg, 86%) as a white solid.
  • The following compound is prepared similarly as above: Compound 269.
    • Example 1BC Preparation of N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-ethyl}acetamide (compound 274)
  • Figure US20100305100A1-20101202-C00509
  • 2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared as in example 1BB, step B, is dissolved in THF (400 μL), and Et3N (24 μL, 0.17 mmol). Acetyl chloride (10 μL, 0.14 mmol) is added, and the reaction mixture is stirred at room temperature for 2 h. The reaction mixture is partitioned between EtOAc and H2O. The organic layer is dried and concentrated. Purification by silica gel chromatography (EtOAc) yields N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]ethyl}acetamide (33 mg, 97%) as a white solid.
    • Example 1BD Preparation of 1-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]ethyl}-3-ethyl-urea (Compound 279)
  • Figure US20100305100A1-20101202-C00510
  • 2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared as in example 1BB, is combined with ethyl isocyanate (18 μL, 0.21 mmol) and pyridine (300 μL). This mixture is stirred at room temperature for 90 minutes, and is then partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated. Purification by silica gel chromatography (EtOAc) yields 1-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-ethyl}-3-ethyl-urea (34 mg, 93%) as a white solid.
    • Example 1BE Preparation of N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]ethyl}formamide (compound 280)
  • Figure US20100305100A1-20101202-C00511
  • Acetic anhydride (700 μL) and 98% formic acid (280 μL) are heated at 65° C. for 1 h. This is cooled to 0° C. 2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared as in example 1BB, is taken up in THF (400 μL), and added to the mixed anhydride. This is stirred at 0° C. for 45 minutes. The mixture is then portioned between EtOAc and aqueous NaHCO3. The organic layer is dried and concentrated. Purification by silica gel chromatography (4/1, CH2Cl2/acetone) yields N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]-ethyl}formamide (28 mg, 86%) as a white solid.
    • Example 1BF Preparation of 1-ethyl-2-{4-[2-(3-hydroxypyrrolidin-1-yl)-2-oxo-ethoxy]phenyl}-6-methoxy-1H-indole-3-carbonitrile (compound 285)
  • Figure US20100305100A1-20101202-C00512
  • Step A: 1-Ethyl-2-(4-hydroxyphenyl)-6-methoxy-1H-indole-3-carbonitrile (559 mg, 1.91 mmol), is used to prepare [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-acetic acid tert-butyl ester (780 mg, 100%) utilizing essentially the same procedure as example 1AZ.
  • Step B: [4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-acetic acid tert-butyl ester (745 mg, 1.83 mmol) is stirred in 20% TFA in CH2Cl2 at room temperature for 3 hours. This is concentrated and the residue is partitioned between H2O and EtOAc. The organic layer is dried and concentrated. The residue is triturated with CH2Cl2 to yield [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-acetic acid (634 mg, 99%) as a white solid.
  • Step C: [4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-acetic acid (40 mg, 0.12 mmol) is suspended in CH2Cl2 (1.65 mmol) and DMF (2 μL). Oxalyl chloride (17 μL, 0.19 mmol) is added. This is stirred at room temperature for 30 minutes. The resulting solution is then pipetted into a stirring solution of S-3-hydroxypyrrolidine (150 μL) and CH2Cl2 (3.0 mL). The mixture is washed with aqueous HCl. The organic layer is dried and concentrated. Purification by silica gel chromatography (3/2 CH2Cl2/acetone) yields 1-ethyl-2-{4-[2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-phenyl}-6-methoxy-1H-indole-3-carbonitrile (40 mg, 79%), compound 285 as a white solid.
    • Example 1BG Preparation of 1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-1H-indole-3-carbonitrile (Compound 332)
  • Figure US20100305100A1-20101202-C00513
  • Step A: 1-Ethyl-2-(4-hydroxy-3-nitrophenyl)-6-methoxy-1H-indole-3-carbonitrile (369 mg, 1.1 mmol), prepared as in example 1Gd, is combined with EtOAc (20 mL) and Pd/C (150 mg, 10%). This mixture is hydrogenated at 30 p.s.i. for 1 h. This is filtered through celite. The filtrate is concentrated and triturated with ether to yield 2-(3-amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (307 mg, 91%), compound 322, as a white solid.
  • Step B: 2-(3-Amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.33 mmol), prepared as in step A, is combined with CDI (83 mg, 0.51 mmol), and THF (1.1 mL). This is heated at 65° C. for 1 hour. The reaction mixture is partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2Cl2/EtOAc) yields 1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-1H-indole-3-carbonitrile (89 mg, 81%) as a white solid.
    • Example 1BH Preparation of 1-ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (compound 334)
  • Figure US20100305100A1-20101202-C00514
  • Step A: Bromoacetic acid (52 mg, 0.37 mmol) is combined with EDCI hydrochloride (62 mg, 0.4 mmol) and acetonitrile (900 μL) to form a homogeneous solution. 2-(3-Amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.33 mmol), prepared as in example 1BG, step B, is added to the solution. A thick paste soon forms. Another 1.1 mL of acetonitrile is added and the mixture is then stirred at room temperature for 2 hours. The reaction mixture is then partitioned between H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (4/1, CH2Cl2/EtOAc) yields 2-chloro-N-[5-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-2-hydroxyphenyl]acetamide (82 mg, 60%), compound 333, as a white solid.
  • Step B: 2-Chloro-N-[5-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-2-hydroxy-phenyl]acetamide (57 mg, 0.13 mmol), prepared in step A, is combined with K2CO3 (55 mg, 0.4 mmol), and DMF (400 μL). This is heated at 80° C. for 1 hour. The reaction mixture is then partitioned between H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2Cl2/EtOAc) yields 1-ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (45 mg, 90%) as a white solid.
    • Example 1BI Preparation of 1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-1H-indole-3-carbonitrile (Compound 340)
  • Figure US20100305100A1-20101202-C00515
  • Step A: 4-Aminosalicylic acid (4.0 g, 26 mmol) is suspended in H2SO4 (26 mL, 2.7M) at −5° C. Sodium nitrite (1.8 g, 26.1 mmol) in H2O (6.5 mL) is cooled to ice bath temperature and is added dropwise to the aminosalicylic acid mixture over 5 minutes. The resulting suspension is stirred at −5° C. for 15 minutes. A solution of KI (6.8 g, 41 mmol) in H2SO4 (13 mL, 1M) is added dropwise to the diazonium salt, with considerable evolution of N2. The reaction mixture is heated at 70° C. for 20 minutes. The reaction mixture is then partitioned between H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (7/3, hexanes/acetone, 1% acetic acid) yields 4-iodosalicylic acid (5.33 g, 85-90% pure).
  • Step B: Crude 4-Iodosalicylic acid (1.0 g, 3.8 mmol) is dissolved in THF (28 mL) and Et3N (1.15 mL, 8.2 mmol). DPPA (1.7 mL, 7.8 mmol) is added. This is heated at 70° C. overnight. The reaction mixture is then partitioned between H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2Cl2/EtOAc) yields 472 mg crude intermediate. Trituration with ether yields 6-iodo-3H-benzooxazol-2-one (369 mg, 37%) as a white solid.
  • Step C: 6-Iodo-3H-benzooxazol-2-one (118 mg, 0.45 mmol) is used to prepare 1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-1H-indole-3-carbonitrile, compound 340 (75 mg, 55%), utilizing essentially the same procedure as in example 1Gd.
    • Example 1BJ Preparation of 1-ethyl-6-methoxy-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (compound 339)
  • Figure US20100305100A1-20101202-C00516
  • 1-Ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (20 mg, 0.058 mmol), prepared as in example 1BH, is combined with NaH (14 mg, 60% suspension in oil, 0.35 mmol). THF (300 μL) is added. This is stirred at room temperature for 5 minutes. A solution of methyl iodide (4.4 μL) in THF (100 μL) is added. This is stirred at room temperature for 1 hour. The reaction mixture is partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2Cl2/EtOAc) yields 1-ethyl-6-methoxy-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (16 mg, 76%) as a white solid.
  • The following compound is prepared similarly: Compound 341.
    • Example 1BK Preparation of 1-ethyl-2-iodo-6-methoxy-5-nitro-1H-indole-3-carbonitrile (compound 499)
  • Figure US20100305100A1-20101202-C00517
  • 1-Ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile (50 mg, 0.15 mmol), prepared as in example 1Ga, Step A, is suspended in acetic acid (620 μL) at 0° C. Nitric acid (4.25M in AcOH) is added. This is stirred at room temperature for 2 hours. The reaction mixture is then partitioned between CH2Cl2 and H2O. The organic layer is washed with aqueous NaHCO3, and then is dried and concentrated. Purification by silica gel chromatography (6/4, CH2Cl2/hexanes), followed by ether trituration, yields 1-ethyl-2-iodo-6-methoxy-5-nitro-1H-indole-3-carbonitrile (16 mg, 29%) as a yellow solid.
    • Example 1BL Preparation of 1′-ethanesulfonyl-1-ethyl-6-methoxy-2′,3′-dihydro-1H,1H′-[2,6′]biindolyl-3-carbonitrile (compound 753)
  • Figure US20100305100A1-20101202-C00518
  • Step A: 6-Nitroindoline (3.0 g, 18.3 mmol) is dissolved in THF (45 mL) and Et3N (3.4 mL, 24.4 mmol) at 0° C. Acetyl chloride (1.5 mL, 21 mmol) is added dropwise. The mixture is stirred at room temperature for 30 minutes. The mixture is partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated to yield 1-acetyl-6-nitroindoline (3.8 g, 100%) as a yellow solid.
  • Step B: 1-Acetyl-6-nitroindoline (3.8 g, 18.3 mmol) is suspended in EtOAc (200 mL). Pd/C (650 mg, 10%) is added, and the mixture is hydrogenated at 40-55 p.s.i. for 2 hours. The mixture is then filtered through celite. The filtrate is concentrated, and the residue is triturated with ether to yield 1-acetyl-6-aminoindoline (3.18 g, 99%) as an orange solid.
  • Step C: 1-Acetyl-6-aminoindoline (1.5 g, 8.5 mmol) is used to prepare 1-acetyl-6-iodoindoline (1.06 g, 43%), utilizing essentially the same procedure in example 1BI, Step A.
  • Step D: 1-Acetyl-6-iodoindoline (1.06 g, 3.7 mmol), NaOH (1.16 g, 29 mmol), EtOH (8 mL), and H2O (6 mL) are heated at 90° C. overnight. The reaction mixture is then partitioned between H2O and EtOAc. The organic layer is extracted into aqueous HCl. The aqueous layer is in turn basified with NaOH, and is extracted with EtOAc. The organic layer is dried and concentrated. Hexane trituration yields 6-iodoindoline (577 mg, 64%) as a brown solid.
  • Step E: 1-Iodoindoline (600 mg, 2.45 mmol) is used to prepare 1-ethyl-6-methoxy-2′,3′-dihydro-1H,1H′[2,6′]biindolyl-3-carbonitrile (535 mg, 67%), utilizing essentially the same procedure as in example 1Gd, Step B.
  • Step F: 1-Ethyl-6-methoxy-2′,3′-dihydro-1H,1H′-[2,6′]biindolyl-3-carbonitrile (30 mg, 0.095 mmol) is used to prepare 1′-Ethanesulfonyl-1-Ethyl-6-methoxy-2′,3′-dihydro-1H,1H′-[2,6′]biindolyl-3-carbonitrile (24 mg, 62%), utilizing the procedure in example 1Y.
  • The following compounds are prepared similarly as above: Compounds 752 and 754.
    • Example 1BM Preparation of 5-acetyl-1-ethyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile (compound 844)
  • Figure US20100305100A1-20101202-C00519
  • 1-Ethyl-6-methoxy-2-(4-nitrophenyl)-1H-indole-3-carbonitrile (100 mg, 0.3 mmol), prepared by the method of example 1Gc, is suspended in 1,2-dichloroethane (500 μL) at 0° C. Acetyl chloride (50 μL, 0.69 mmol) is added, followed by AlCl3 (55 mg, 0.4 mmol) in one portion. This is stirred at 0° C. for 1 hour, at room temperature for 4 hours, and at 45° C. overnight. The reaction mixture is then partitioned between CH2Cl2 and H2O. The organic layer is dried and concentrated. Purification by silica gel chromatography (195:5 CH2Cl2/EtOAc) yields 5-acetyl-1-ethyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile (33 mg, 29%) as an orange solid.
    • Example 1BN Preparation of 1-ethyl-6-methoxy-5-morpholin-4-ylmethyl-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile (compound 845)
  • Figure US20100305100A1-20101202-C00520
  • Step A: 1-Ethyl-6-methoxy-2-(4-nitrophenyl)-1H-indole-3-carbonitrile (100 mg, 0.3 mmol), prepared by the method of example 1Gc, is combined with 1,3,5-trioxane (64 mg, 0.71 mmol) and acetic acid (2.0 mL). 33% HBr in acetic acid (2.0 mL) is added. This is stirred at room temperature for 4 hours. The reaction mixture is then partitioned between CH2Cl2 and H2O. The organic layer is washed with aqueous NaHCO3, and is subsequently dried and concentrated. The crude material is carried through to the next step.
  • Step B: Crude 6-bromomethyl-1-ethyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile (0.3 mmol) is heated with morpholine (150 μL, 1.75 mmol) and DCE (1.0 mL) at 90° C. overnight. The reaction mixture is then partitioned between H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (50-100%, EtOAc/CH2Cl2), followed by trituration with 1/1 hexane/acetone yields 1-ethyl-6-methoxy-5-morpholin-4-ylmethyl-2-(4-nitrophenyl)-1H-indole-3-carbonitrile (57 mg, 44% overall yield) as a yellow solid.
    • Example 1BO 2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-1-cyclopropylmethyl-6-methoxy-1H-indole-3-carbonitrile (compound 716)
  • Figure US20100305100A1-20101202-C00521
  • Step A: To a solution of 6-methoxyindole (5.88 g, 40.0 mmol) and di-tert-butyl dicarbonate (9.59 g, 44.0 mmol) in DCM (50 mL) is added, at 40° C. while stirring, DMAP (0.10 g). After stirring overnight, the mixture is washed sequentially with 0.1 N HCl, water and brine and dried over anhydrous Na2SO4. The solvent is evaporated and the residue is chromatographed (silica gel, EtOAc/hexanes, 1/7) to provide tert-butyl 6-methoxy-1H-indole-1-carboxylate (8.48 g, 86%).
  • Step B: The above Boc-indole (3.08 g, 12.5 mmol) and isopropylborate (4.83 mL, 21.9 mmol) are dissolved in anhydrous THF (20 mL) and the solution is cooled at 0° C. While stirring, LDA (12.5 mL, 1.5 M mono-THF complex in cyclohexane, 18.7 mmol) is added dropwise. The mixture is stirred at 0° C. for 15 min and then room temperature for 0.5 h, followed by the addition of HCl (6 N, 3.0 mL, 18 mmol) in an ice-water bath. The organic solvent is removed in vacuo and the residue is suspended in H2O (100 mL) and acidified with HCl (6 N) to pH 4˜5. The precipitate is collected via filtration and washed with water and hexanes and dried in air to provide 1-Boc-6-mehoxyindole-2-boronic acid (3.38 g, 93%).
  • Step C: To a solution of 4-iodoanilline (3.18 g, 14.5 mmol) in pyridine (15 mL) at 0° C., is added 3-chloropropanesulfonyl chloride (2.3 mL, 18.9 mmol). After the addition, the mixture is stirred for 2 hr at room temperature, and poured into ice-water (200 mL). The organic is separated and the aqueous layer is extracted with DCM (2×50 mL). The combined organics are washed with HCl (2 N, 2×15 mL), water (2×50 mL) and brine (20 mL) consecutively and dried over anhydrous Na2SO4. The solvent is then evaporated and the residue is chromatographed to furnish 3-chloro-N-(4-iodophenyl)propane-1-sulfonamide (4.68 g, 90%). The chlorosulfonamide obtained (3.47 g, 9.6 mmol) is then treated with K2CO3 (3.33 g, 24.1 mmol) in DMF (50 mL) at 50° C. for 2 h. The mixture is poured into ice-water (300 mL) and the precipitate is collected and dried in air to provide essentially pure 2-(4-iodophenyl)isothiazolidine-1,1-dioxide (3.11 g, 100%).
  • Step D: To a mixture of 1-Boc-6-mehoxyindole-2-boronic acid prepared in step B above (0.36 g, 1.25 mmol), 2-(4-iodophenyl)isothiazolidine-1,1-dioxide (0.32 g, 1.0 mmol) and PdCl2(dppf) (0.037 g, 0.05 mmol) in DMF (4.0 mL), is added aqueous K2CO3 solution (1.5 mL, 2.0 M, 3.0 mmol). The mixture is stirred at room temperature overnight and then poured into ice-water (100 mL). The precipitate is collected and washed with water and purified by flash column chromatography (silica gel, DCM/EtOAc, 9/1) to furnish 1-Boc-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxy-1H-indole (0.43 g, 98%).
  • The following compound is made similarly: Compound 768
  • Step E: 1-Boc-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxy-1H-indole (1.63 g, 3.7 mmol) is treated with TFA (25 mL) in DCM (25 mL) at room temperature for 4 h. After the removal of the volatiles, the residue is carefully stirred with saturated NaHCO3 for 0.5 h. The precipitate is collected via filtration and washed with water thoroughly and dried to provide essentially pure 1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole (1.17 g, 92%).
  • At 0° C., 1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole (0.95 g, 2.8 mmol) is dissolved in DMF (10 mL) and treated with chlorosulfonyl isocyanate (0.36 mL, 4.2 mmol). The mixture is then stirred at room temperature overnight and poured into ice-water (150 mL) then stirred for 0.5 h. The precipitate is collected via filtration and washed thoroughly with water and dried in air to furnish 1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole-3-carbonitrile (0.89 g, 87%).
  • The following compound is prepared in the same fashion as described above: Compound 829
  • Step F: To a solution of 1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole-3-carbonitrile (73 mg, 0.2 mmol) and K2CO3 (69 mg, 0.5 mmol) in DMF (3.0 mL) is added cyclopropylmethyl iodide (0.029 mL, 0.3 mmol). The mixture is stirred at 50° C. overnight and poured into ice-water (10 mL). The precipitate is collected via filtration, washed with water and purified by column chromatography to provide 2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxy-1-cyclopropylmethylindole-3-carbonitrile, compound 716 (73 mg, 87%).
  • The following compounds are prepared in the same fashion as described above: Compounds 717, 718, 719, 782, 783, 784.
    • Example 1BP Preparation of 2-[4-(1,1′-dioxo-1λ6-isothiazolidin-2-yl)-6-methoxy-3-oxazol-5-yl-1-propyl-1H-indole (compound 805)
  • Figure US20100305100A1-20101202-C00522
  • Step A: 2-[4-(1,1′-Dioxo-1λ6-isothiazolidin-2-yl)-6-methoxy-indole (900 mg, 2.62 mmol), prepared in example 1BO, step D is used to prepare 2-[4-(1,1′-dioxo-1λ6-isothiazolidin-2-yl)-6-methoxy-1-propyl-1H-indole (608 mg, 60%), utilizing essentially the same procedure as example 1A, Step B.
  • Step B: 2-[4-(1,1′-Dioxo-1λ6-isothiazolidin-2-yl)-6-methoxy-1-propyl-1H-indole (50 mg, 0.13 mmol) is used to prepare 2-[4-(1,1′-dioxo-1λ6-isothiazolidin-2-yl)-6-methoxy-3-oxazol-5-yl-1-propyl-1H-indole (9 mg, 15% overall yield) according to the protocol in example 1P.
    • Example 1BQ Preparation of 2-[4-(cyclopropylsulfonyl)piperazin-1-yl]-1-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (compound 842)
  • Figure US20100305100A1-20101202-C00523
  • Step A: To a solution of 1-ethyl-6-trifluoromethylindole-3-carbonitrile (2.54 g, 10.0 mmol), prepared by the method of procedure 1A, in anhydrous THF (20.0 mL), at −78° C. is added LDA (8.3 mL, 1.5 M mono-THF in cyclohexane, 12.5 mmol) dropwise. The mixture is continued for 0.5 hr after the addition, followed by the addition of hexachloroethane and the mixture is then brought to room temperature slowly and stirred for 0.5 hr. The solvent is then evaporated and the residue is treated with water. The organics are extracted with dichloromethane, washed with water and brine and dried over anhydrous Na2SO4. The crude product obtained after the removal of the solvent is chromatographed (silica gel, dichloromethane/hexanes, 3/2) to provide 2-chloro-1-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (1.75 g, 64%).
  • Step B: The chloroindole obtained above (0.27 g, 1.0 mmol), K2CO3 (0.35 g, 2.5 mmol) and N-Boc-piperazine (0.28 g, 1.5 mmol) are stirred at 70° C. in DMF (5.0 mL) for 3 days and then poured into water (50 mL). The precipitate is collected via filtration and washed with water. Chromatography of this crude product (silica gel, dichloromethane/ethyl acetate, 9/1) provides 4-(3-cyano-1-ethyl-6-trifluoromethyl-1H-indol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester, compound 785 (0.30 g, 71%).
  • The following compounds are prepared in the same fashion as described above, by using other amines: Compounds 514, 785, 786.
  • Step C: 4-(3-cyano-1-ethyl-6-trifluoromethyl-1H-indol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.26 g, 6.1 mmol) is treated with TFA (5 mL) in dichloromethane (5 mL) for 1 hr at room temperature. After the removal of the volatiles, the residue is treated with saturated NaHCO3 and the precipitate is collected via filtration, washed with water thoroughly and dried in air to furnish essentially pure 1-ethyl-2-piperazin-1-yl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (0.20 g, 100%).
  • Step D: To a solution of 1-ethyl-2-piperazin-1-yl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (32 mg, 0.1 mmol), pyridine (0.1 mL) in dichloromethane (1.0 mL) is added cyclopropanesulfonyl chloride (28 mg, 0.2 mmol) and the mixture is stirred at room temperature overnight. This is then diluted with dichloromethane (5 mL), washed with HCl (2 N, 2×2 mL), water (2×5 mL) and brine (5 mL) and chromatographed over silica gel (dichloromethane/ethyl acetate, 9/1) to provide 2-[4-(cyclopropylsulfonyl)piperazin-1-yl]-1-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile, compound 842 (30 mg, 70%).
  • The following compounds are prepared in the same fashion as described above, using corresponding sulfonyl chlorides: Compounds 841, 843.
    • Example 1BR Ethanesulfonic acid [3-cyano-2-(4-ethoxyphenyl)-1-ethyl-1H-indol-6-yl]-amide (compound 835)
  • Figure US20100305100A1-20101202-C00524
  • Step A: 6-Bromo-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (0.74 g, 2.0 mmol), compound 831, prepared from 6-bromoindole as described in example 1 Gb, is mixed with K2CO3 (0.55 g, 4.0 mmol), CuI (0.02 g, 0.1 mmol), tert-butyl carbamate (0.35 g, 3.0 mmol), N,N′-dimethylcyclohexane-1,2-diamine ligand (0.028 g, 0.2 mmol) and anhydrous toluene (5.0 mL) in a sealed tube. The reaction system is flushed with nitrogen and then stirred at 110° C. overnight. After cooling, the solvent is replaced with dichloromethane and chromatographed (silica gel, dichloromethane) to provide [3-cyano-2-(4-ethoxy-phenyl)-1-ethyl-H-indol-6-yl]-carbamic acid tert-butyl ester (0.68 g, 84%), compound 832.
  • Step B: Compound 832 prepared in step A above (0.63 g, 1.56 mmol) is treated with TFA/DCM (7.5 mL/7.5 mL) at room temperature for 2 h, and the volatiles are removed in vacuum. The residue is treated with saturated NaHCO3 and the precipitate is collected via filtration and washed thoroughly with water, dried in air to provide 6-amino-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (0.45 g, 96%), compound 833.
  • Step C: The above amine (31 mg, 0.1 mmol) is treated with ethanesulfonyl chloride (19 mg, 0.15 mmol) in pyridine (1.0 mL) at room temperature overnight to provide, after purification using column chromatography, ethanesulfonic acid [3-cyano-2-(4-ethoxy-phenyl)-1-ethyl-1H-indol-6-yl]-amide (83%), compound 835.
  • The following compounds are prepared in the same fashion as described above: Compounds 830, 834, 836 and 837.
    • Example 1BS Preparation of [3-cyano-2-(4-ethoxyphenyl)-1-ethyl-1H-indol-6-yl]-carbamic acid ethyl ester (compound 838)
  • Figure US20100305100A1-20101202-C00525
  • 6-Amino-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (31 mg, 0.1 mmol), compound 833, prepared in example 1BR, step B is treated with ethyl chloroformate (16 mg, 0.15 mmol) in pyridine (1.0 mL) at room temperature overnight to furnish, after purification using column chromatography, [3-cyano-2-(4-ethoxyphenyl)-1-ethyl-1H-indol-6-yl]-carbamic acid ethyl ester (30 mg, 79%).
    • Example 1BT Preparation of 1-[3-cyano-2-(4-ethoxyphenyl)-1-ethyl-1H-indol-6-yl]-3-ethyl-urea (compound 839)
  • Figure US20100305100A1-20101202-C00526
  • 6-Amino-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (31 mg, 0.1 mmol) is treated with ethyl isocyanate (14 mg, 0.2 mmol) in dichloromethane (1.0 mL) at 40° C. overnight. The precipitate is collected via filtration, washed with dichloromethane and dried in air to furnish 1-[3-cyano-2-(4-ethoxy-phenyl)-1-ethyl-1H-indol-6-yl]-3-ethyl-urea (36 mg, 95%).
    • Example 1BU Preparation of 1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-urea (compound 442)
  • Figure US20100305100A1-20101202-C00527
  • To a solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (50 mg, 0.172 mmol) in THF (2 mL) is added 2-chloroethyl isocyanate (22 uL, 0.258 mmol) at room temperature. After stirring overnight at reflux, the reaction mixture is concentrated in vacuo and the residue is diluted with ethyl acetate. The resulting semi-solid is triturated with hexane and the precipitate collected is collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford (62 mg, 91%) of 1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-urea.
  • Utilizing essentially the same procedure, the following compounds are prepared: Compounds 295, 362, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 443, 444, 445, 446, 511, 512, 513, 600, 620, 626, 627, 628, 679, 680, 681, 740, 741, 742, 743, 748, 749, 750, 751, 774, 817, 818, 846, 847, 848, 954, 955, 956, 957, 958, 987, 999, 1000, 1001, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1016, 1017, 1018, 1019, 1023, 1024, 1027, 1036, 1039, 1043, 1045, 1060, 1061, 1066, 1067, 1070, 1080, 1092, 1094, 1095, 1096, 1097, 1098, 1099, 1100, 1101, 1102, 1106, 1108, 1118, 1120, 1124, 1125, 1126, 1136, 1137, 1138, 1139, 1143, 1144, 1156, 1157, 1162, 1163, 1164, 1165, 1171, 1172, 11731197, 1190, 1214, 1221, 1223, 1224, 1225, 1225, 1227, 1256, 1279, 1301, 1303, 1304, 1305.
    • Example 1BV Preparation of 1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carbonitrile (compound 771)
  • Figure US20100305100A1-20101202-C00528
  • To a solution of 1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-urea (100 mg, 0.252 mmol) in MeOH (10 mL) is added aqueous 1M KOH (504 uL) and then stirred at 49° C. for 24 h. The solvents are removed under reduced pressure. The residue is diluted with ethyl acetate and then washed with water. The organic layer is dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue is diluted with ethyl acetate and then triturated with hexane and the precipitate collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford 1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carbonitrile (56 mg, 62%).
  • Using essentially the same procedure, the following compounds are prepared: Compounds 770, 778.
    • Example 1BW Preparation of 1-ethyl-6-isopropoxy-2-[4-(2-oxo-oxazolidin-3-yl)-phenyl]-1H-indole-3-carbonitrile (compound 638)
  • Figure US20100305100A1-20101202-C00529
  • To a solution of [4-(3-cyano-1-ethyl-6-isopropoxy-1H-indol-2-yl)-phenyl]-carbamic acid 2-chloro-ethyl ester (30 mg, 0.07 mmol) in DMF (1 mL) is added aqueous K2CO3 (10 mg) and then stirred at 50° C. for 18 h. The reaction mixture is poured into cold water and the precipitate collected by filtration and washed with hexane and dried in vacuo to afford the title compound (21 mg, 81%).
  • The following compounds are made in similar fashion: Compounds 820, 821, 863, 864.
    • Example 1BX Preparation of {3-[3-cyano-1-ethyl-6-(3-pyrrolidin-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamic acid ethyl ester (compound 530)
  • Figure US20100305100A1-20101202-C00530
  • Step A: To a solution of [3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester (1.65 g, 4.37 mmol) in DCM (20 mL) is added 1M BBr3 in DCM (13.12 mL) over a period of 20 min. The reaction mixture is stirred further 1 h at room temperature and then the solvents are removed under reduced pressure. The residue is dissolved in MeOH and then poured into cold water. The precipitate is collected by filtration and washed with hexane and dried in vacuo to afford [3-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester (1.5 g, 98%).
  • Step B: To a solution of [3-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester (1.2 g, 2.91 mmol) in DMF (10 mL) is added K2CO3 (538 mg, 3.9 mmol) and 3-bromo-1-chloroproane (383 uL, 3.9 mmol) and the reaction is stirred for overnight at 50° C. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with hexane and dried in vacuo to afford 1.1 g, 89% of the desired product.
  • Step C: To a solution of {3-[3-cyano-1-ethyl-6-(3-pyrrolidin-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamic acid ethyl ester (50 mg, 0.12 mmol) in CH3CN (2 mL) is added DIEA (31 uL, 0.18 mmol), sodium iodide (20 mg, 0.132 mmol) and pyrrolidine (30 uL, 0.36 mmol). The resulting mixture is stirred at reflux temperature for overnight. The solvent is evaporated and the residue is diluted with ethyl acetate and then triturated with hexane and the precipitate collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford 1-ethyl-6-isopropoxy-2-[4-(2-oxo-oxazolidin-3-yl)-phenyl]-1H-indole-3-carbonitrile, compound 638 (46 mg, 85%).
  • The following compounds are made in similar fashion following steps A-C, above: Compounds 441, 447, 491, 492, 493, 504, 525, 526, 527, 528, 529, 531, 532, 533, 534, 535, 536, 537, 538, 539.
    • Example 1BY Preparation of [3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea (Compound 767)
  • Figure US20100305100A1-20101202-C00531
  • Step A: The starting material 2-(3-amino-phenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (187 mg, 0.642 mmol) is dissolved in anhydrous acetone (3.0 mL). Benzoyl isothiocyanate (107 mg, 0.656 mmol) is added to the solution at room temperature and the mixture is stirred for 17 h during which time a precipitate forms. The precipitate is filtered, washed with acetone and dried to give 264 mg of 1-benzoyl-3-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea (90% yield) as a light yellow solid.
  • Step B: A suspension of 1-benzoyl-3-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea (241 mg, 0.530 mmol) in methyl alcohol (2.0 ml) and water (0.5 mL) is stirred at room temperature as sodium hydroxide (31 mg, 0.78 mmol) is added. The reaction mixture is heated to 50° C. for 17 h. The reaction mixture is concentrated to remove methyl alcohol. Water is added to the mixture and the solid is filtered, washed with water and dried to give 179 mg of [3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea, compound 767 (96% yield) as a white solid.
    • Example 1BZ Preparation of 1-ethyl-6-methoxy-2-[4-(2-phenylquinazolin-4-ylamino)-phenyl]-1H-indole-3-carbonitrile (Compound 458)
  • Figure US20100305100A1-20101202-C00532
  • A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.343 mmol), 4-chloro-2-phenyl-quinazoline (83 mg, 0.34 mmol) and diisopropylethylamine (0.10 mL, 0.57 mmol) in absolute ethanol (3 mL) is heated to reflux overnight. The solution is cooled and evaporated, and the residue taken up in ethyl acetate (50 mL). This is washed with water and saturated brine (50 mL each), then dried over anhydrous sodium sulfate, filtered and evaporated. The resulting solid is triturated with ether, collected by filtration and dried under vacuum to afford 1-ethyl-6-methoxy-2-[4-(2-phenylquinazolin-4-ylamino)-phenyl]-1H-indole-3-carbonitrile (139 mg, 0.280 mmol, 82%).
    • Example 1CA Preparation of diethyl[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-phosphoramidate (compound 772)
  • Figure US20100305100A1-20101202-C00533
  • A solution of 2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (148 mg, 0.484 mmol), diethyl chlorophosphate (0.086 mL, 0.58 mmol) and diisopropylethylamine (0.10 mL, 0.57 mmol) in 1,4-dioxane (5 mL) is stirred at ambient temperature for 12 hours, then heated to 80° C. for an additional 24 hours. The solution is cooled and poured into 50 mL of ethyl acetate. This is washed with water and saturated brine (50 mL each), then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is separated by flash chromatography (eluting 2/1 ethyl acetate/hexane on silica gel 60) to afford diethyl[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-phosphoramidate (108 mg, 0.245 mmol, 51%) as a white powder after evaporation.
  • The following examples are made in similar fashion: Compounds 936, 937, 942, 943, 944, 1081.
    • Example 1CB Preparation of 1-ethyl-6-methoxy-2-[4-(5-methyl-1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-indole-3-carbonitrile (compound 726)
  • Figure US20100305100A1-20101202-C00534
  • Step A: To a solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (202 mg, 0.693 mmol) in pyridine (2.0 mL) is added the N-β-(chloroethylamino)sulfonyl chloride (222 mg, 1.39 mmol). The mixture is stirred at room temperature for 17 h then water (12.0 mL) is added and the mixture is extracted with ethyl acetate (3×2 mL). The extract is washed with 10% aqueous HCl (2×2 mL), water (2×2 mL), dried over MgSO4, filtered and concentrated on a rotary evaporator. The crude product is purified by flash chromatography (0-5%, ethyl acetate/methylene chloride) to give 217 mg of N-(2-chloro-ethyl)-N′-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenyl]sulfamide, compound 724, as a tan solid (75% yield).
  • In similar fashion the following compounds are prepared: Compounds 540, 541, 542, 574, 576, 704.
  • Step B: To a solution of N-(2-chloro-ethyl)-N′-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenyl]sulfamide (100 mg, 0.241 mmol) in anhydrous DMF (1.25 mL), is added potassium carbonate (71.0 mg, 0.514 mmol). The mixture is stirred at room temperature for 17 h, then diluted with water (7.5 mL). The reaction mixture is extracted with ethyl acetate (3×2 mL) and the extract is washed with water (2×2 mL), dried over MgSO4 and concentrated to give 2-[4-(1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile, compound 725, as a white solid (84 mg, 88% yield).
  • In similar fashion the following compound is prepared: Compound: 705.
  • Step C: To a solution of 2-[4-(1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (34 mg, 0.086 mmol) in anhydrous DMF (1.0 mL) is added potassium carbonate (25 mg, 0.18 mmol) and iodomethane (20.4 mg, 0.144 mmol). The mixture is stirred at room temperature for 2 h and then diluted with water (6.0 mL) to give a precipitate. The precipitate is filtered, washed with water and dried to give 1-ethyl-6-methoxy-2-[4-(5-methyl-1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-indole-3-carbonitrile, compound 726, as a white solid (35 mg, 98% yield).
  • In similar fashion the following compounds are prepared: Compound 727, 1110.
    • Example 1CC Preparation of [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-2-fluorophenyl]-carbamic acid propyl ester (compound 877)
  • Figure US20100305100A1-20101202-C00535
  • A biphasic mixture of 2-(4-amino-3-fluorophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (74 mg, 0.24 mmol), prepared as described in example 1 Gb, and propyl chloroformate (0.033 mL, 0.29 mmol) in EtOAc (3 mL) and saturated NaHCO3 (3 mL) is prepared at 0° C. and then allowed to warm to room temperature and stirred for 24 h. The reaction is then diluted with H2O and extracted with EtOAc (2×). The organic phases are washed with H2O and saturated NaCl and then dried and concentrated. Flash chromatography (EtOAc/hexanes 10-40%) gives 60 mg (63%) of [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-2-fluorophenyl]-carbamic acid propyl ester as an off-white solid.
  • The following compounds are prepared in a similar fashion: Compounds 875, 876, 878, 879. By utilizing 2-(4-amino-3-methylphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile, the following compounds are prepared: Compounds: 963, 964, 965. Utilizing the same starting material and procedures described in examples 1Y, the following compounds are prepared: Compounds 871, 872, 873, 874. In similar fashion, utilizing 2-(4-amino-3-methylphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile, the following compounds are prepared: Compounds 959, 960, 961, 962.
  • Utilizing the same starting material and procedures described in examples 1BU, the following compounds are prepared: 909, 910, 911. In a similar fashion, utilizing 2-(4-amino-3-methylphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile, the following compounds are prepared: Compound: 966, 967.
    • Example CD Preparation of cyclopropanecarboxylic acid {4-[3-cyano-1-ethyl-6-(2-imidazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-amide (compound 1183)
  • Figure US20100305100A1-20101202-C00536
  • Step A: To a solution of compound 2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (3.66 g, 12 mmol), prepared as described in example 1 Gb, in 20 mL of THF is added Et3N (3.37 ml) and cyclopropanecarbonyl chloride (1.6 mL, 18 mmol). The mixture is stirred for 3 h at room temperature. Then water and ethyl acetate are added to the reaction mixture. The organic layer is separated, washed with brine (2×), dried over anhydrous Na2SO4, filtered and concentrated. The residue is recrystallized with ethyl acetate and hexane to yield 99% of cyclopropanecarboxylic acid [4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-amide.
  • Step B: To a solution of cyclopropanecarboxylic acid [4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-amide (4.4 g, 11.8 mmol) in 60 mL of DCM is added BBr3 (6.65 mL, 70 mmol) at −10° C. After the addition, the mixture is stirred for 3 h at 0° C. Then aqueous NaHCO3 is added to the mixture carefully until it becomes basic. The crude solid is collected by filtration to give 91% of cyclopropanecarboxylic acid [4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-amide and is used for the next step without further purification.
  • Step C: To a solution of cyclopropanecarboxylic acid [4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-amide (4 g, 11.6 mmol) in 15 mL of MEK is added K2CO3 (8 g, 58 mmol) and 1-bromo-2-chloro-ethane (6.7 mL, 70 mmol). Then the mixture is heated at reflux overnight. After it is cooled to room temperature, water and ethyl acetate are added. The organic layer is separated, washed with brine (2×), dried over anhydrous Na2SO4, filtered and concentrated to yield 81% of the crude cyclopropanecarboxylic acid {4-[6-(2-chloroethoxy)-3-cyano-1-ethyl-1H-indol-2-yl]-phenyl}-amide.
  • Step D: To a solution of cyclopropanecarboxylic acid {4-[6-(2-chloroethoxy)-3-cyano-1-ethyl-1H-indol-2-yl]-phenyl}-amide (102 mg, 0.25 mmol) in 1.5 mL of acetonitrile are added NaI (46 mg, 0.275 mmol), K2CO3 (138 mg, 1 mmol) and imidazole (51 mg, 0.75 mmol) in a sealed tube. Then the mixture is heated to 90° C. and stirred overnight. After it is cooled to room temperature, water and ethyl acetate are added. The organic layer is separated, washed with brine (2×), dried over anhydrous Na2SO4, filtered and concentrated. The crude compound is purified by preparative HPLC to give 71% of cyclopropanecarboxylic acid {4-[3-cyano-1-ethyl-6-(2-imidazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-amide.
  • Using the same procedure and substituting the appropriate nucleophilic reagents gives the following compounds: Compounds 952, 1025, 1054, 1090, 1091, 1092, 1093, 1184, 1394, 1395, 1413, 1414.
    • Example CE Preparation of ethanesulfonic acid [4-(3-cyano-1-ethyl-6-trifluoromethoxyindol-2-yl)phenyl]amide (compound 881)
  • Figure US20100305100A1-20101202-C00537
  • Step A: To a suspension of t-BuONO (8.01 mL, 67.5 mmol) and CuCl2 (7.26 g, 54 mmol) in acetonitrile (50 mL), at 61° C. with gentle stirring, is added 2-nitro-4-trifluoromethoxyaniline (10.0 g, 45.0 mmol) portionwise. The mixture is stirred at this temperature for 2 h after the addition. The solvent is removed on a rotovap and the residue is treated with HCl (6 N, 200 mL), and extracted with dichloromethane (3×100 mL). The extracts are combined, dried over anhydrous Na2SO4, and passed through a short silica gel pad. The solvent is removed and the residue is added to a suspension of benzyl cyanoacetate (7.88 g, 45 mmol) and K2CO3 (12.42 g, 90 mmol) in DMF (100 mL). This mixture is then stirred at 45° C. overnight and poured into ice-water (700 mL), and extracted with dichloromethane (3×100 mL). The organics are dried over anhydrous Na2SO4 and again passed through a short silica gel pad, eluting with ethyl acetate. The solvent is then replaced with EtOH (160 mL), acetic acid (16 mL) and water (16 mL), and the reaction mixture is hydrogenated over 5% Pd/C (2.80 g) at 50 psi overnight. The mixture is filtered over Celite and the volatiles are removed in vacuo. The residue is dissolved in dichloromethane (200 mL), washed with Na2CO3 (2 M, 2×50 mL), water (2×50 mL), brine (50 mL) and dried over anhydrous Na2SO4. The crude product, obtained after the removal of the solvent, is chromatographed (silica gel, DCM/Hexanes, 1/1) to provide 6-trifluoromethoxyindole (5.70 g, 63% based on 2-nitro-4-trifluoromethoxyaniline).
  • Step B: To a solution of 6-trifluoromethoxyindole (2.68 g, 13.3 mmol) in dry DMF (10 mL) at 0° C., is added chlorosulfonylisocyanate (2.35 g, 1.44 mL, 16.6 mmol). The mixture is then brought to room temperature slowly and stirred for 1 h. The mixture is poured into ice (100 mL) and stirred for 1 h. The precipitate is collected by filtration and washed thoroughly with water and dried in vacuo, which is then dissolved in DMF (15 mL). To the solution is added K2CO3 and EtI (2.59 g, 1.34 mL, 16.6 mmol), and the mixture is stirred at 50° C. overnight. It is then poured into ice-water (200 mL). The precipitate is collected by filtration and washed with water, dried in air and purified by chromatography (silica gel, DCM) to furnish 1-ethyl-6-trifluoromethoxyindole-3-carbonitrile (2.90 g, 86%).
  • Step C: To a solution of the intermediate (2.03 g, 8.0 mmol) obtained above, triisopropylborate (2.16 g, 2.65 mL, 12.0 mmol) in dry THF (15 mL) at −78° C. is added LDA (6.7 mL, 1.5 M, 10.0 mmol). The mixture is stirred at −78° C. for 15 min after the addition, then slowly brought to room temperature and stirred for 30 min. It is then cooled at −78° C. and followed by the addition of 4-iodoaniline (2.10 g, 9.6 mmol), PdCl2(dppf) (0.29 g, 0.4 mmol), DMF (30 mL) and K2CO3 (12.0 mL, 2.0 M, 24.0 mmol). The mixture is brought to room temperature slowly and stirred overnight and poured into ice-water (400 mL). The precipitate is collected and washed with water, chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to furnish 2-(4-aminophenyl)-1-ethyl-6-trifluoromethoxyindole-3-carbonitrile (1.99 g, 72%).
  • Step D: To a solution of the compound obtained in step C (31 mg, 0.1 mmol) in dry pyridine (1.0 mL) is added ethanesulfonyl chloride (14 μL, 0.15 mmol). The mixture is stirred at room temperature overnight and diluted with water (5 mL). The organic is extracted with DCM (5 mL) and washed with HCl (2N, 2×3 mL), water (2×4 mL) and brine (3 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the product, ethanesulfonic acid [4-(3-cyano-1-ethyl-6-trifluoromethoxyindol-2-yl)phenyl]amide (33 mg, 83%).
  • Compounds 882, 883, 884, 885, 886, 887, 888, 889 are prepared utilizing the above route using either the appropriate alkylsulfonyl chlorides (procedure 1Y) or chloroformates (procedure 1AJ).
    • Example 1CF Preparation of 2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-1-ethyl-6-(trifluoromethoxy)indole-3-carbonitrile (compound 903)
  • Figure US20100305100A1-20101202-C00538
  • Step A: To a solution of 6-trifluoromethoxyindole (3.01 g, 15.0 mmol) and di-tert-butyl dicarbonate (3.59 g, 16.5 mmol) in DCM (30 mL) at 40° C. is added DMAP (0.04 g) while stirring. After stirring overnight, the mixture is washed sequentially with 0.1 N HCl, water and brine and dried over anhydrous Na2SO4. The solvent is evaporated and the residue is chromatographed (silica gel, EtOAc/Hexanes, 1/9) to provide tert-butyl 6-trifluoromethoxy-1H-indole-1-carboxylate.
  • Step B: The above Boc-indole and triisopropylborate (4.73 g, 5.8 mL, 26.3 mmol) are dissolved in anhydrous THF (20 mL) and the solution is cooled to 0° C. While stirring, LDA (15.0 mL, 1.5 M mono-THF complex in cyclohexane, 22.5 mmol) is added dropwise. The mixture is stirred at 0° C. for 15 min and then room temperature for 0.5 h, followed by the addition of HCl (6 N, 3.75 mL, 22.5 mmol) in an ice-water bath. The organic solvent is removed in vacuo and the residue is suspended in H2O (100 mL) and acidified with HCl (6 N) to pH 4-5. The precipitate is collected via filtration and washed with water and hexanes and dried in air to provide 1-Boc-6-trifluoromehoxyindole-2-boronic acid (2.56 g, 49%).
  • Step C: To a mixture of 1-Boc-6-trifluoromehoxyindole-2-boronic acid prepared above (0.74 g, 2.1 mmol), 2-(4-iodophenyl)isothiazolidine-1,1-dioxide (0.76 g, 2.4 mmol), and PdCl2(dppf) (0.08 g, 0.1 mmol) in DMF (6.0 mL), is added K2CO3 solution (3.2 mL, 2.0 M, 6.4 mmol). The mixture is stirred at room temperature overnight and then poured into ice-water (100 mL). The precipitate is collected and washed with water and purified by flash column chromatography (silica gel, DCM/EtOAc, 9/1) to furnish 1-Boc-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole, which is treated with 50% TFA in DCM (15 mL) at room temperature for 1 h. After the removal of the volatiles, the residue is carefully stirred with saturated NaHCO3 for 0.5 h. The precipitate is collected via filtration and washed thoroughly with water and dried to provide essentially pure 1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-trifluoromethoxyindole.
  • Step D: At 0° C., a solution of the intermediate obtained above in dry DMF (10 mL) is treated with chlorosulfonyl isocyanate (0.38 g, 0.23 mL, 2.68 mmol). The mixture is then stirred at room temperature overnight and poured into ice-water (150 mL) then stirred for 0.5 h. The precipitate is collected via filtration and washed thoroughly with water and dried in air to furnish 1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-trifluoromethoxyindole-3-carbonitrile (0.81 g, 90%).
  • Step E: To a solution of 1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-trifluoromethoxyindole-3-carbonitrile (63 mg, 0.15 mmol) and K2CO3 (62 mg, 0.45 mmol) in DMF (2.0 mL) is added ethyl iodide (36 μL, 0.45 mmol). The mixture is stirred at 50° C. overnight and poured into ice-water (10 mL). The precipitate is collected via filtration, washed with water and purified by column chromatography to provide 2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-trifluoromethoxy-1-ethylindole-3-carbonitrile (59 mg, 88%).
  • The following compounds are prepared in the same fashion as described above: Compounds 902, 904, 905, 906.
    • Example 1CG Preparation of [4-(3-cyano-1-cyclopropyl-6-methoxyindol-2-yl)phenyl]carbamic acid isopropyl ester (compound 1234)
  • Figure US20100305100A1-20101202-C00539
  • Step A: To a suspension of 2-bromo-4-methoxyphenylacetic acid (24.5 g, 100 mmol) in DCM (100 mL), while stirring, is added DMF (˜10 mL) until all the solid disappeared, which is followed by the addition of DCC (22.66 g, 110 mmol) and HOBt (14.85 g, 110 mmol). After stirring at RT for 10 min, cyclopropylamine (8.55 g, 10.4 mL, 150 mmol) is added to the mixture, and the resulting mixture is stirred at room temperature for 4 h. The solid is filtered and washed thoroughly with DCM (300 mL). The filtrate is cooled to −10° C. and gently stirred for 1 h and filtered again to remove additional urea by-product. The filtrate is passed through a silica gel pad and eluted with DCM/EtOAc, 8/2). After the removal of the solvent, the cyclopropyl amide intermediate is obtained as white solid (28.34 g, 100%).
  • Step B: A mixture of above amide (14.2 g, 50.0 mmol), K2CO3 (13.8 g, 100 mmol), CuI (0.74 g, 5.0 mmol) and N,N′-dimethylcyclohexanediamine (1.42 g, 1.57 mL, 10.0 mmol) in toluene (150 mL) is stirred at 110° C. under N2 atmosphere for 48 h. After cooling to room temperature, the mixture is filtered over Celite and washed thoroughly with DCM. The filtrate is evaporated under reduced pressure to dryness and the residue is chromatographed (DCM/EtOAc, 9.5/0.5) to provide the product, 1-cyclopropyl-6-methoxyoxindole as pale yellow solid (4.30 g, 42%).
  • Step C: To a solution of the oxindole obtained above (5.0 g, 24.6 mmol) in dry DCM (25 mL), at 0° C., is added DIBAL-H (1.0 M in DCM, 35.0 mL, 35.0 mmol). After the addition, the mixture is stirred at room temperature for 4 h and re-cooled to 0° C., followed by the addition of HCl (2 N) dropwise. The DCM layer is washed with HCl (2 N, 10 mL) water and brine and dried over anhydrous Na2SO4. The crude product obtained after the removal of the solvent is chromatographed (hexanes/EtOAc, 9.5/0.5) to provide the 1-cyclopropyl-6-methoxyindole as a colorless oil (4.52 g, 98%).
  • Step D: To a solution of 1-cyclopropyl-6-methoxylindole (3.29 g, 17.6 mmol) in dry DMF (30 mL), at 0° C., is added chlorosulfonyl isocyanate (3.11 g, 1.91 mL, 22.0 mmol). After the addition, the mixture is stirred at room temperature for 2 h, followed by aqueous work-up. Chromatography (silica gel, hexanes/EtOAc, 9/1) furnishes 3-cyano-1-cyclopropyl-6-methoxyindole (3.05 g, 82%).
  • Step E: To a solution of the intermediate (2.65 g, 12.5 mmol) obtained above and triisopropyl borate (3.38 g, 4.14 mL, 18.8 mmol) in dry THF (18 mL) at −78° C. is added LDA (10 mL, 1.5 M, 15.0 mmol). The mixture is stirred at −78° C. for 15 min after the addition, then slowly brought to room temperature and stirred for 30 min. It is then cooled at −78° C. and followed by the addition of 4-iodoaniline (3.29 g, 15.0 mmol), PdCl2(dppf) (0.46 g, 0.6 mmol), DMF (40 mL) and K2CO3 (18.8 mL, 2.0 M, 37.6 mmol). The mixture is brought to room temperature slowly and stirred overnight and then poured into ice-water (400 mL). The precipitate is collected and washed with water, and after drying, is chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to furnish 2-(4-aminophenyl)-1-cyclopropyl-6-methoxyindole-3-carbonitrile (2.84 g, 75%).
  • Step F: To a solution of the compound obtained in step E (61 mg, 0.2 mmol) in dry pyridine (2.0 mL) is added isopropylchloroformate (0.3 mL, 1.0 M, 0.3 mmol) in toluene. The mixture is stirred at room temperature overnight and diluted with water (10 mL). The organic layer is extracted with DCM (10 mL) and washed with HCl (2N, 2×3 mL), water (2×4 mL) and brine (3 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the product, [4-(3-cyano-1-cyclopropyl-6-methoxyindol-2-yl)phenyl]carbamic acid isopropyl ester (66 mg, 85%).
  • Compounds 1235 and 1236 are prepared by utilizing the above chemistry.
    • Example 1CH Preparation of 1-allyl-6-methoxy-2-[4-(2-oxopyrrolidin-1-yl)-phenyl]-1H-indole-3-carbonitrile (compound 938)
  • Figure US20100305100A1-20101202-C00540
  • Utilizing the procedure described in Example 1 Gb, substituting 1-allyl-6-methoxy-1H-indole-3-carbonitrile (92.3 mg, 0.43 mmol) and 1-(4-iodophenyl)-pyrrolidin-2-one gives 99.0 mg (61.3% yield) of compounds 938.
    • Example 1CI Preparation of 6-cyclopropoxy-2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-phenyl]-1-ethyl-1H-indole-3-carbonitrile (compound 1046)
  • Figure US20100305100A1-20101202-C00541
  • Step A: To a solution of 6-hydroxy-1-ethyl-1H-indole-3-carbonitrile (503.9 mg, 2.70 mmol) in 5 mL of DMF is added anhydrous K2CO3 (1.12 g, 8.12 mmol) and 1-bromo 2-fluoroethane (413.7 mg, 3.29 mmol). The resulting mixture is stirred at 80° C. until complete consumption of the starting material as determined by TLC. The reaction mixture is cooled, potassium tert-butoxide (1M solution in THF, 5.5 ml, 5.43 mmol) is added, and stirring is continued at 80° C. overnight. The mixture is partitioned between EtOAc (30 mL) and 1N HCl (20 mL). The organic phase is washed with saturated NaHCO3, saturated NaCl and dried and concentrated. The product is isolated by chromatography (EtOAc/hexanes, 10-25%) over silica gel to afford 430.2 mg (74.9%) 1-ethyl-6-vinyloxy-1H-indole-3-carbonitrile as a white solid.
  • Step B: Via a syringe, diethyl zinc is added to a mixture of 1-ethyl-6-vinyloxy-1H-indole-3-carbonitrile (288.1 mg, 1.36 mmol), chloroiodomethane (268.9 mg, 1.53 mmol) and 5 ml of 1,2-dichloroethane over a period of 10 min, maintaining the temperature at −10° C. The mixture is warmed to 20-25° C. for 20 min, and then cooled back to 0° C. Saturated NH4Cl (15 mL), concentrated ammonium hydroxide (15 mL), and ethyl acetate (15 mL) are added in sequence at this temperature, and stirred for 10 min. After the phases are separated, the aqueous phase is back-extracted with ethyl acetate (10 mL). The combined organic phases are washed with saturated NH4Cl (10 mL), dried over MgSO4 and then the solution is concentrated and the product is purified by chromatography, eluting with 15-30% ethyl acetate/hexanes to afford 140.5 mg (45.7% yield) of 6-cyclopropoxy-1-ethyl-1H-indole-3-carbonitrile as a yellow solid.
  • Step C: Utilizing the same procedure described in Example 1 Gb substituting 4-iodoaniline with 2-(4-iodo-phenyl)-isothiazolidine 1,1-dioxide gives the title compound.
  • In similar fashion, following steps A to C, above, compound 1047 is also prepared.
    • Example CJ Propane-1-sulfonic acid [4-(3-cyano-6-difluoromethoxy-1-ethyl-1H-indole-2-yl)-phenyl]-amide (compound 928)
  • Figure US20100305100A1-20101202-C00542
  • Step A: A solution of 6-difluoromethoxy-1-ethyl-1H-indole-3-carbonitrile (316.3 mg, 1.34 mmol) and triisopropyl borate (402.9 mg, 2.14 mmol) in THF (15 mL) is cooled to −78° C. and treated with LDA (1.5 M mono-THF in cyclohexane, 1.07 mL, 1.61 mmol). After the addition, the acetone/dry ice bath is exchanged for an ice water bath and the solution is stirred further for 30 min. The solution is cooled to −78° C. and a solution of 4-iodoaniline (299.5 mg, 1.37 mmol) in DMF (8 mL), K2CO3 (2M, 2.01 mL, 6.02 mmol) and PdCl2dppf (51.3 mg, 0.07 mmol) are added in sequence. The mixture is degassed by three successive cycles of vacuum pumping/N2 purging and is stirred overnight (ca. 16 h). The reaction mixture is poured into 4 volumes of water, and 4 volumes of ethyl acetate are added. The phases are separated, and the aqueous phase is extracted with more ethyl acetate. The organic phases are washed by water, saturated NaCl and then dried over anhydrous MgSO4, filtered and evaporated. The remaining material is purified by column chromatography, eluting with 5-15% ethyl acetate/hexanes on silica gel to yield 304.5 mg (70%) of the aniline intermediate as a white solid.
  • Step B: Utilizing the same procedure described in Example 1Y and substituting n-propylsulfonyl chloride gives the title compound.
  • The following compounds are made using essentially the same procedure and substituting other sulfonyl chlorides: Compounds 929, 930, 931.
    • Example 1CK [4-(3-cyano-6-difluoromethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-carbamic acid methyl ester (compound 1130)
  • Figure US20100305100A1-20101202-C00543
  • A solution of 2-(4-aminophenyl)-6-difluoromethoxy-1-ethyl-1H-indole-3-carbonitrile (200 mg, 0.611 mmol) and methyl chloroformate (95 μL, 1.23 mmol) in ethyl acetate (2 mL) is treated with 2 M aqueous potassium carbonate solution (0.370 mL, 0.74 mmol), and the resulting mixture is stirred vigorously overnight. Saturated brine solution (1 mL) is added, and the mixture is stirred for 10 minutes. The organic layer is removed, dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting solid is triturated with 1/1 ether-hexane, collected by filtration and dried under vacuum to afford the title product as a white solid.
  • Similarly prepared from appropriate reagents are: Compounds 1131, 1132, 1133, 1134, 1135.
    • Example 1CL 1-[4-(3-cyano-6-difluoromethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-3-propyl-urea (Compound 893)
  • Figure US20100305100A1-20101202-C00544
  • A solution of 2-(4-aminophenyl)-6-difluoromethoxy-1-ethyl-1H-indole-3-carbonitrile (200 mg, 0.611 mmol) in 1,2-dichloroethane (2 mL) is treated with n-propylisocyanate (115 mL, 1.23 mmol) and triethylamine (170 mL, 1.22 mmol). The resulting solution is stirred at ambient temperature for 12 hours, and then concentrated. The residual material is separated by silica gel chromatography (1/2 ethyl acetate-hexane) to afford the title product as a solid. Similarly prepared from appropriate reagents are: Compounds 892, 894.
    • Example 1CM Preparation of morpholine-4-carboxylic acid [4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-amide (compound 1166)
  • Figure US20100305100A1-20101202-C00545
  • Step A: 6-Ethoxy-1H-indole-3-carbonitrile (2.8 g, 15 mmol), prepared as shown in example 1A, step A, is combined with Cs2CO3 (11.6 g, 35.6 mmol), DMF (21 mL), and cyclobutyl bromide (1.73 mL, 17.9 mmol) in a capped tube. The reaction mixture is heated at 80° C. for 8 h. This is then quenched with H2O (200 mL) and is extracted with EtOAc. The EtOAc layer is backwashed with H2O, and then with brine. The organic phase is dried and concentrated. Purification by silica gel chromatography (hexanes/CH2Cl2, 50-100%) yields 1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (3.00 g, 83%) as a white solid.
  • Step B: Following essentially the procedure in example 1 Gb, 1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (3.0 g, 12.4 mmol) is converted via Suzuki coupling to yield 2-(4-aminophenyl)-1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (2.60 g, 68%) as an off-white solid.
  • Step C: 2-(4-aminophenyl)-1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (40 mg, 0.12 mmol), 4-nitrophenyl chloroformate (60 mg, 0.30 mmol), CH2Cl2 (400 μL), and pyridine (25 μL, 0.31 mmol) are stirred at room temperature for 1 hour. Morpholine (60 μL, 0.70 mmol) is added. After stirring at room temperature for an additional 30 minutes, the reaction mixture is diluted in CH2Cl2 and is washed with dilute aqueous NaOH to remove the yellow nitrophenol byproduct. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2/EtOAc, 7/3) yields morpholine-4-carboxylic acid [4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-amide (53 mg, 100%) as a white solid.
  • The following compounds are prepared in a similar fashion, using the appropriate amine in the final step: Compounds 1087, 1088, 1089, 1119, 1159, 1168, 1191, 1266, 1288, 1324, 1325, 1326.
    • Example 1CN Preparation of rac-[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (compound 1147)
  • Figure US20100305100A1-20101202-C00546
  • 2-(4-Aminophenyl)-1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (50 mg, 0.15 mmol), prepared as in example 1CM, step B, is combined with 4-nitrophenyl chloroformate (76 mg, 0.38 mmol), DCE (0.5 mL), and pyridine (30 μL, 0.37 mmol). This suspension is stirred at room temperature for 1 h. Rac-cyclopropyl methyl carbinol (100 μL, 0.98 mmol) is added. This mixture is heated at 75° C. overnight. The reaction mixture is then diluted in CH2Cl2 and is washed with dilute aqueous NaOH to remove the yellow nitrophenol byproduct. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2) yields rac-[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (40 mg, 60%) as a white solid.
  • The following compounds are prepared in a similar fashion, using the appropriate alcohols: Compounds 1146, 1158, 1167, 1192, 1208, 1209, 1210, 1215, 1216, 1240, 1241, 1242, 1243, 1244, 1246, 1247, 1248, 1249, 1250, 1264, 1265, 1267, 1268, 1281, 1282, 1283, 1286, 1287, 1289, 1290, 1291, 1292, 1294, 1295, 1296, 1297, 1298, 1299, 1312, 1313.
    • Example 1CO Preparation of 1-cyclobutyl-6-ethoxy-2-(4-ethylaminophenyl)-1H-indole-3-carbonitrile (compound 1239)
  • Figure US20100305100A1-20101202-C00547
  • Step A: 2-(4-Aminophenyl)-1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (600 mg, 1.81 mmol), prepared as in example 1CM, step B, is suspended in CH2Cl2 (18 mL), and Et3N (390 μL, 2.7 mmol). Trifluoroacetic anhydride (310 μL, 2.2 mmol) is added dropwise. The reaction mixture is stirred at room temperature for 30 minutes, after which time dissolution is complete. The reaction mixture is then washed with saturated NaHCO3 solution. The organic layer is dried and concentrated to yield N-[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-2,2,2-trifluoro-acetamide (802 mg, 100%) as a yellow solid.
  • Step B: N-[4-(3-Cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-2,2,2-trifluoro-acetamide (800 mg, 1.8 mmol) is dissolved in DMF (10 mL). NaH (140 mg, 60% oil suspension, 3.5 mmol) is added. This is stirred at room temperature for a few minutes, after which ethyl iodide (176 μL, 2.2 mmol) is added. This is stirred at room temperature overnight, and then at 75° C. for 6 h. Additional portions of NaH (200 mg, 5.0 mmol) and iodoethane (200 μL, 2.5 mmol) are necessary to push the reaction further. This is heated overnight at 75° C. Additional ethyl iodide (200 μL, 2.5 mmol) is added. This is heated for another 2 h. The reaction mixture is then diluted in H2O and is extracted into EtOAc. The EtOAc layer is dried and concentrated. Silica gel chromatography (CH2Cl2) yields 384 mg of an inseparable mixture of expected N-[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-N-ethyl-2,2,2-trifluoro-acetamide and hydrolyzed 1-cyclobutyl-6-ethoxy-2-(4-ethylamino-phenyl)-1H-indole-3-carbonitrile.
  • Step C: The crude mixture from the previous step is dissolved in methanol (5 mL). 6N NaOH (1.0 mL, 6 mmol) is added, and the mixture is heated at 80° C. for 1 h. The reaction mixture is then diluted in H2O and is extracted into CH2Cl2. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2) yields pure 1-cyclobutyl-6-ethoxy-2-(4-ethylaminophenyl)-1H-indole-3-carbonitrile (343 mg, 53% over two steps) as a white solid.
  • 1-Cyclobutyl-2-(4-diethylamino-phenyl)-6-ethoxy-1H-indole-3-carbonitrile (compound 1217, 77 mg, 11%) is isolated as a byproduct of the reaction described in example 1CO, step B.
    • Example 1CP Preparation of [4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-ethyl-carbamic acid cyclopentyl ester (compound 1251)
  • Figure US20100305100A1-20101202-C00548
  • 1-Cyclobutyl-6-ethoxy-2-(4-ethylaminophenyl)-1H-indole-3-carbonitrile (35 mg, 0.10 mmol), prepared as in example 1CO, step C, is dissolved in pyridine (300 μL). Cyclopentyl chloroformate (25 μL, 0.17 mmol) is added. The reaction mixture is stirred at room temperature for 2.5 h. More chloroformate (10 μL, 0.07 mmol) is added to drive the reaction to completion. After an additional 90 min of stirring, the reaction mixture is partitioned between aqueous HCl and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography yields [4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-ethyl-carbamic acid cyclopentyl ester (41 mg, 87%) as a white solid.
  • Compound 1252 is prepared similarly using the appropriate chloroformate.
    • Example 1CQ Preparation of {4-[3-cyano-1-cyclobutyl-6-(3-[1,2,4]triazol-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (compound 1255)
  • Figure US20100305100A1-20101202-C00549
  • Step A: To a solution [4-(3-cyano-1-cyclobutyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (950 mg, 2.35 mmol) in DCM (10 mL) is added BBr3 (556 uL, 5.9 mmol) over a period of 20 min. The reaction mixture is stirred further for 1 h at room temperature and then water (1 mL) is added. The solvents are removed under reduced pressure. The residue is dissolved in MeOH and then poured into cold water. The precipitate is collected by filtration and washed with hexane and dried in vacuo to afford [4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (650 mg, 71%).
  • Step B: To a solution of [4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (340 mg, 0.87 mmol) in DMF (2 mL) is added K2CO3 (132 mg, 0.96 mmol) and 3-bromo-1-chloroproane (172 uL, 1.75 mmol) and the reaction is stirred for 5 h at 60° C. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with hexane and dried in vacuo to afford 370 mg (92%) of the desired product.
  • Step C: To a solution of {4-[6-(3-chloro-propoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (37 mg, 0.08 mmol) in CH3CN (1 mL) is added sodium iodide (71 mg, 0.48 mmol). The resulting mixture is stirred at reflux temperature overnight. The solvent is then evaporated and the residue is diluted with anhydrous DMF (1 mL) and then treated with the sodium salt of 1,2,4-triazole (0.16 mmol) at room temperature overnight. The solvent is removed under reduced pressure and the residue is diluted with ethyl acetate and then washed with water. The organic layer is concentrated and triturated with hexane and the precipitate is collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford {4-[3-cyano-1-cyclobutyl-6-(3-[1,2,4]triazol-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester, compound 1255 (31 mg, 78%).
  • The following compounds are made in similar fashion following steps A-C, above: Compounds 1253, 1254, 1260, 1261, 1262, 1427, 1430.
    • Example 1CR Preparation of {4-[3-cyano-1-cyclobutyl-6-(2-[1,2,4]triazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (compound 1276)
  • Figure US20100305100A1-20101202-C00550
  • Step A: To a solution of [4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (390 mg, 1.0 mmol) in CH3CN (5 mL) is added K2CO3 (414 mg, 3.0 mmol) and 3-bromo-1-chloroethane (250 uL, 3.0 mmol) and the reaction is stirred for 18 h at 80° C. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with hexane and dried in vacuo to afford 420 mg, 93% of the desired product.
  • Step B: To a solution of {4-[6-(3-chloroethoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (42 mg, 0.09 mmol) in CH3CN (1 mL) is added sodium iodide (56 mg, 0.37 mmol). The resulting mixture is stirred at reflux temperature overnight. The solvent is evaporated and the residue is diluted with anhydrous DMF (1 mL) and then treated with the sodium salt of 1,2,4-triazole (0.18 mmol) at room temperature for overnight. The solvent is removed under reduced pressure and the residue is diluted with ethyl acetate and then washed with water. The organic layer is concentrated and triturated with hexane. The precipitate is collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford {4-[3-cyano-1-cyclobutyl-6-(3-[1,2,4]triazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester, compound 1276 (28 mg, 64%).
  • The following compounds are made in similar fashion following steps A and B, above: Compounds 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278, 1434, 1435.
    • Example 1CS Preparation of {4-[3-cyano-1-cyclobutyl-6-(2-[1,2,4]triazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (compound 1329)
  • Figure US20100305100A1-20101202-C00551
  • Step A: To a solution 2-(4-aminophenyl)-1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile (909 mg, 3 mmol) in pyridine (5 mL) is added 4-nitrophenyl chloroformate (6 mmol) at room temperature and then stirred for 2 h at room temperature. To the reaction is added cyclopropyl methyl carbinol and then stirred for 8 h at 80° C. The reaction mixture is diluted with 1N HCl and then extracted with ethyl acetate. The organic layer is concentrated and the residue is dissolved in EtOAc and triturated with hexane. The precipitate is collected by filtration and washed with hexane and dried in vacuo to afford [4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (996 mg, 80%).
  • Step B: To a solution of [4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (1.5 g, 3.61 mmol) in CH3CN (8 mL) is added K2CO3 (1.5 g, 10.8 mmol) and 2-bromo-1-chloroethane (895 uL, 10.8 mmol) and the reaction is stirred for 18 h at 80° C. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with hexane and dried in vacuo to afford 1.46 g, 84% of the desired product.
  • Step C: To a solution of {4-[6-(2-chloroethoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (1.46 g, 3.05 mmol) in CH3CN (10 mL) is added sodium iodide (1.84 g, 12.22 mmol). The resulting mixture is stirred at reflux temperature overnight. The solvent is evaporated and the residue is diluted with anhydrous DMF (20 mL) and then used without further purification. To 1 mL of the DMF solution containing the iodoethyl intermediate (0.153 mmol) is added the sodium salt of 1,2,4-triazole (0.31 mmol) and the reaction is stirred at room temperature overnight. The reaction mixture is diluted with 0.5 mL DMF and the desired product is purified by preparative LC to give {4-[3-cyano-1-cyclobutyl-6-(2-[1,2,4]triazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester, compound 1329 (23 mg, 29%).
  • The following compounds are made in similar fashion following steps A-C, above: Compounds 1327, 1328.
    • Example 1CT Preparation of 1-{4-[3-cyano-1-cyclobutyl-6-(3-[1,2,4]triazol-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-3-isopropyl-urea (compound 1314)
  • Figure US20100305100A1-20101202-C00552
  • Step A: To a solution of 1-[4-(3-cyano-1-cyclobutyl-6-methoxy-1H-indol-2-yl)-phenyl]-3-isopropyl-urea (2.21 g, 5.49 mmol in CH2Cl2 (30 mL) is added a 1M solution of BBr3 in CH2Cl2 (16.5 mL, 16.5 mmol) at 0° C. The mixture is allowed to warm to room temperature and kept for 1 h. The reaction mixture is then poured onto ice and aqueous 1M NaHCO3 is added until the pH is 7-8. The product is extracted with 100 mL of ethyl acetate (3×) and the organic phases are washed with 100 mL of saturated NaCl. The organic phases are combined and dried over MgSO4. Solvent is removed to recover 1.95 g (92%) of 1-[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-3-isopropyl-urea, as a tan solid.
  • Step B: To a solution of 1-[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-3-isopropyl-urea (750 mg, 1.93 mmol) in 10 mL of acetonitrile is added anhydrous K2CO3 (800 mg, 5.79 mmol) and 1-bromo-3-chloropropane (382 μL, 3.86 mmol). After stirring overnight at 80° C., the reaction mixture is cooled and solvent is removed. The reaction is re-suspended in 100 mL of ethyl acetate. The organic phase is washed with 200 mL of H2O, and the aqueous phase is re-extracted 2× with 100 mL of ethyl acetate. The organic phases are combined, dried over MgSO4 and the solvent is removed to afford 769 mg (86%) of 1-{4-[6-(3-chloropropoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-3-isopropyl-urea as a tan powder.
  • Step C: To a solution of 1-{4-[6-(3-chloropropoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-3-isopropyl-urea (400 mg, 0.860 mmol) in 8 mL of acetonitrile/DMF, (4/1) is added anhydrous NaI (258 mg, 1.72 mmol). After stirring overnight at 60° C., the reaction shows conversion to product by LCMS-UV. The reaction mixture is cooled, the solvent is removed and redissolved in DMF to 14.0 mL total volume.
  • Step D: To 1 mL of the DMF solution above, 1-{4-[3-cyano-1-cyclobutyl-6-(3-iodopropoxy)-1H-indol-2-yl]-phenyl}-3-isopropyl-urea (34 mg, 0.062 mmol) is added anhydrous 1,2,4-triazole, sodium salt (10.0 mg, 0.110 mmol). After stirring overnight at rt, the reaction mixture is filtered and purified by preparatory LC/UV purification. The solvent is removed to obtain 12.3 mg (40%) of 1-{4-[3-cyano-1-cyclobutyl-6-(3-[1,2,4]triazol-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-3-isopropyl-urea (compound 1314), as a white powder.
  • The following compounds are prepared following the above procedure: Compounds 1306, 1307, 1308, 1309, 1315, 1316, 1317, 1318, 1319, 1320, 1321, 1323 and 1324.
    • Example 1CU Preparation of 1-ethyl-1′-methanesulfonyl-6-methoxy-1H,1′H-[2,5′]biindolyl-3-carbonitrile (compound 1330)
  • Figure US20100305100A1-20101202-C00553
  • A solution of 1-ethyl-6-methoxy-1H,1′H-[2,5′]biindolyl-3-carbonitrile (70 mg, 0.22 mmol), prepared as described in Example 1 Gb, in pyridine (2 mL) is treated with methanesulfonyl chloride (0.034 mL, 0.44 mmol) and stirred overnight. The reaction mixture is then diluted with H2O and extracted with ethyl acetate (3×). The organic phase is washed with H2O and saturated NaCl, dried and concentrated and purified by flash chromatography using EtOAc/hexanes (30-80%) to afford 70 mg (81%) of 1-ethyl-1′-methanesulfonyl-6-methoxy-1H,1′H-[2,5]biindolyl-3-carbonitrile as a tan solid.
  • Using the same procedure as above and substituting the appropriate ethanesulfonyl chloride gives the following compound: Compound 1331.
    • Example 1CV Preparation of 3-cyano-1-ethyl-2-[4-(propane-1-sulfonylamino)-phenyl]-1H-indole-6-carboxylic acid diethylamide (compound 1360)
  • Figure US20100305100A1-20101202-C00554
  • Step A: 3-Cyano-1-ethyl-2-[4-(propane-1-sulfonylamino)-phenyl]-1H-indole-6-carboxylic acid methyl ester (1.25 g, 3.04 mmol), prepared by the method described in example 1Y from methyl 2-(4-aminophenyl)-3-cyano-1-ethyl-1H-indole-6-carboxylate, is treated with 0.5N KOH (30 mL, 15.2 mmol) and heated at reflux for 2.5 h. After cooling to room temperature, the aqueous phase is acidified with 3N HCl to pH 2 and the resultant precipitate is filtered, washed with water (2×) and dried until constant weight to afford 1.15 g (96%) of 3-cyano-1-ethyl-2-[4-(propane-1-sulfonylamino)-phenyl]-1H-indole-6-carboxylic acid as a white solid.
  • Step B: To a sample of PS-HOBt resin (2.84 g, 1.02 mmol/g loading) is added a solution of DMAP in DCM (0.045M, 39 mL) followed by a solution of 3-cyano-1-ethyl-2-[4-(propane-1-sulfonylamino)-phenyl]-1H-indole-6-carboxylic acid in DMF (0.38M, 7.5 mL). This mixture is stirred for 15 min., then a solution of diisopropylcarbodiimide in DCM (1.65M, 7.9 mL) is added and the reaction mixture is stirred for 18 h at room temperature. The resin is filtered and washed with DMF (3×50 mL), DCM (3×50 mL) and THF (3×50 mL) and then dried under vacuum for 4 h to afford 4.1 g of active ester resin. The loading of this resin is determined by combining a small aliquot of the active ester resin with benzyl amine in CDCl3 directly in NMR tube, shaking the resultant mixture at room temperature overnight, and then comparing the integration of protons of unreacted benzyl amine with the protons of resultant amide.
  • Step C: The above active ester resin (400 mg, 0.551 mmol/g loading), DIEA (0.036 mL, 0.22 mmol) and THF (3 mL) are combined and diethylamine (0.03 mL, 0.15 mmol) is added to the mixture. The tube is sealed and the reaction mixture is shaken overnight. The resin is filtered, washed with THF (2×5 mL), DCM (2×5 mL) and the combined organic fractions are concentrated. The crude product is purified by preparative HPLC to afford 50 mg (71% yield) of 3-cyano-1-ethyl-2-[4-(propane-1-sulfonylamino)-phenyl]-1H-indole-6-carboxylic acid diethylamide.
  • The following compounds are prepared utilizing the above procedure with substitution of the appropriate amine: Compounds 1361, 1362, 1363, 1364.
    • Example 1CW Preparation of isopropyl-methyl-carbamic acid 4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl ester (compound 1349)
  • Figure US20100305100A1-20101202-C00555
  • Step A: To a solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (2.5 g, 12.5 mmol) in 21 mL of THF is added LDA (23 mL, 22.5 mmol) at −78° C. After warming to 0° C. and stirring for 10 min, the mixture is re-cooled to −78° C. and B(O-iPr)3 (4.35 mL, 18.8 mmol) is added. After the addition, the reaction is allowed to warm to room temperature and stirred for about 1 h. 4-iodophenol (2.89 g, 13.1 mmol), PdCl2(dppf) (510 mg, 0.625 mmol), aqueous K2CO3 (25 mL, 50 mmol) and DMF (42 mL) is added and the reaction mixture is stirred at room temperature overnight. The organic solvent is evaporated under reduced pressure. The residue is washed with water and the mixture is filtered. The filtrate is concentrated to afford crude solid which is purified via column chromatography on silica gel using EtOAc/petrolum ether (1/5 to 2/1) as eluant to yield 73% of 1-ethyl-2-(4-hydroxyphenyl)-6-methoxy-1H-indole-3-carbonitrile.
  • Step B: To a solution of 1-ethyl-2-(4-hydroxyphenyl)-6-methoxy-1H-indole-3-carbonitrile (58 mg, 0.2 mmol) in 4 mL of Et3N and CH2Cl2 (1/1) is added p-nitrophenyl chloroformate (100 mg, 0.5 mmol) at room temperature. After the mixture is stirred for about 1 h, N-isopropylmethylamine (0.062 mL, 0.6 mmol) is added. The mixture is stirred for 3 h and then water and ethyl acetate are added to the reaction mixture. The organic layer is separated, washed with aqueous HCl (1N) and brine, dried over anhydrous Na2SO4, and filtered and concentrated. The crude solid is purified by preparative HPLC to afford 70% of isopropyl-methyl-carbamic acid 4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl ester.
  • The following compounds are prepared utilizing the above procedure with substitution of the appropriate amines: Compounds 1348, 1350, 1351, 1385.
    • Example 1CX Preparation of N-{4-[3-cyano-6-difluoromethoxy-1-(tetrahydro-furan-2-ylmethyl)-1H-idole-2-yl]-phenyl}-methanesulfonamide (compound 1334)
  • Figure US20100305100A1-20101202-C00556
  • Step A: Utilizing the procedure described in Example 1A (Step B) substituting iodo ethane with 2-bromomethyl tetrahydrofuran affords 6-difluoromethoxy-1-(tetrahydrofuran-2-ylmethyl)-1H-indole-3-carbonitrile.
  • Step B: A solution of 6-difluoromethoxy-1-ethyl-1H-indole-3-carbonitrile (516.2 mg, 1.77 mmol) and tri-isopropyl borate (532.7 mg, 2.83 mmol) in THF (15 mL) is cooled to −78° C. and treated with LDA (1.5 M mono-THF in cyclohexane, 1.43 ml, 2.04 mmol). After the addition, the acetone/dry ice bath is exchanged for ice/water bath and the solution is stirred further for 30 min. The solution is cooled to −78° C. and a solution of 4-iodoaniline (390.2 mg, 1.78 mmol) in DMF (8 mL), K2CO3 (2M, 2.7 ml, 5.31 mmol) and PdCl2dppf (67.4 mg, 0.09 mmol) are added in sequence. The mixture is degassed by three successive cycles of vacuum pumping/N2 purging and is stirred overnight (ca. 16 h), after which it is poured into 4 volumes of water, and 4 volumes of ethyl acetate are added. The phases are separated, and the aqueous phase is extracted with more ethyl acetate. The organic phases are washed by water, saturated NaCl, dried over anhydrous MgSO4, filtered and evaporated. The remaining material is purified by column chromatography, eluting with 5-15% ethyl acetate/hexanes on silica gel to yield 367.5 mg (55.0% yield) of 2-(4-aminophenyl)-6-difluoromethoxy-1-(tetrahydrofuran-2-ylmethyl)-1H-indole-3-carbonitrile as a white solid.
  • Step C: Utilizing the same procedure described in Example 1Y gives the title compound, N-{4-[3-cyano-6-difluoromethoxy-1-(tetrahydro-furan-2-ylmethyl)-1H-idole-2-yl]-phenyl}-methanesulfonamide (compound 1334).
  • The following compounds are made using essentially the same procedure and substituting other sulfonyl chlorides: Compounds 1335, 1336.
    • Example 1CY Preparation of 1-cyclobutyl-6-ethoxy-2-[4-(2-oxo-[1,3]oxazinan-3-yl)-phenyl]-1H-indole-3-carbonitrile (compound 1346)
  • Figure US20100305100A1-20101202-C00557
  • Step A: To a suspension of 2-(4-aminophenyl)-1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (50.0 mg, 0.15 mmol), K2CO3 (2N, 0.45 mL, 0.45 mmol) and 5 mL of ethyl acetate is added 3-chloropropylchlorofromate (35.6 mg, 0.23 mmol). The resulting mixture is stirred at room temperature until complete consumption of the starting material as determined by TLC. The phases are separated and the organic phase is washed by saturated NaCl, dried over MgSO4 and concentrated. The residual oil is crystallized from diethyl ether/hexanes to afford [4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indole-2-yl)-phenyl]-carbamic acid 3-chloro-propyl ester as a white solid.
  • Step B: To a solution of [4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indole-2-yl)-phenyl]-carbamic acid 3-chloro-propyl ester in 5 mL of DMF is added anhydrous K2CO3. The resulting mixture is stirred at 80° C. until complete consumption of the starting material is determined by TLC. After cooling, 10 mL of water is added to the reaction mixture to afford a solid precipitation which is collected by filtration, followed by washing with ether. The desired 1-cyclobutyl-6-ethoxy-2-[4-(2-oxo-[1,3]oxazinan-3-yl)-phenyl]-1H-indole-3-carbonitrile is obtained as a white powder (76.2 mg, 91.8% yield).
    • Example 1CZ Preparation of {4-[3-cyano-1-cyclobutyl-6-(2-methoxy-ethoxy)-1H-indole-2-yl]-phenyl}-carbamic acid ethyl ester (compound 1397)
  • Figure US20100305100A1-20101202-C00558
  • Step A: Utilizing the same procedure described in Example 1CW (Step B) gives 2-(4-aminophenyl)-1-cyclobutyl-6-methoxy-1H-indole-3-carbonitrile.
  • Step B: Utilizing the procedure described in Example 1B (Step A) gives 2-(4-aminophenyl)-1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile.
  • Step C: To a suspension of 2-(4-aminophenyl)-1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile (519.2 mg, 1.71 mmol), K2CO3, 10 mL of methyl ethyl ketone, and 2 mL of DMF is added 2-bromoethyl methyl ether. The resulting mixture is stirred at 85° C. for 8 h. The mixture is concentrated and the residue is partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous phase is extracted with additional ethyl acetate (20 mL). The combined organic phases are washed with saturated NaCl, dried over MgSO4, and then the solution is concentrated and the product is washed with diethyl ether to afford 505.0 mg (81.7% yield) of 2-(4-aminophenyl)-1-cyclobutyl-6-(2-methoxy-ethoxy)-1H-indole-3-carbonitrile as a yellow solid.
  • Step D: Utilizing the same procedure described in Example 1AJ gives the desired title compound, {4-[3-cyano-1-cyclobutyl-6-(2-methoxy-ethoxy)-1H-indole-2-yl]-phenyl}-carbamic acid ethyl ester (compound 1397) as a white solid.
  • In similar fashion, following steps A to D above, the following compounds are prepared: Compounds 1365, 1366, 1367, 1368, 1369, 1370, 1371, 1372, 1373, 1398, 1399, 1400, 1401, 1402, 1407, 1431.
  • In similar fashion, substituting the procedure described in example 1BU for step D above, gives the following urea derivatives: Compounds 1403, 1404, 1405, 1406, 1412.
    • Example 1DA Preparation of [4-(3-cyano-1-cyclobutyl-6-(2-methoxyethoxy)-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (compound 1423)
  • Figure US20100305100A1-20101202-C00559
  • To a solution of 2-(4-aminophenyl)-1-cyclobutyl-6-(2-methoxy-ethoxy)-1H-indole-3-carbonitrile (76.0 mg, 0.21 mmol), pyridine (36.5 mg, 0.46 mmol) in 10 mL of 1,1 dichloroethane is added 4-nitrophenyl chloroformate (93.2 mg, 0.46 mmol). The resulting mixture is stirred at room temperature for 2 h. Then α-methylcyclopropane methanol (54.3 mg, 0.63 mmol) is added. The reaction mixture is heated to 70° C. for 5 h. After cooling, the reaction is partitioned between ethyl acetate (10 mL) and saturated K2CO3 (10 mL). The organic phase is washed with additional saturated K2CO3 (2×10 mL), water, and saturated NaCl. The colorless solution is dried over MgSO4, filtered and evaporated. The remaining solid is washed with diethyl ether to yield the title compound, of [4-(3-cyano-1-cyclobutyl-6-(2-methoxyethoxy)-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (compound 1423) as a white solid.
    • Example 1DB Preparation of 4-[3-cyano-2-(4-ethoxyphenyl)-1-ethylindol-6-yl]piperazine-1-carboxylic acid tert-butyl ester (compound 1337)
  • Figure US20100305100A1-20101202-C00560
  • Step A: 6-Bromo-2-(4-ethoxyphenyl)-1-ethyl-indole-3-carbonitrile (0.37 g, 1.0 mmol), prepared from 6-bromoindole using the procedure described in example 1 Gb, is mixed with NaO t-Bu (0.13 g, 1.4 mmol), Pd2(dba)3 (0.009 g, 0.01 mmol), BINAP (0.019 g, 0.03 mmol), 1-Boc-piperazine (0.22 g, 1.2 mmol) and dry toluene (3.0 mL). The mixture is stirred at 80° C. for 6 h. After cooling, the solvent is replaced with dichloromethane and chromatographed (silica gel, DCM/EtOAc, 9.5/0.5) to provide 4-[3-cyano-2-(4-ethoxyphenyl)-1-ethylindol-6-yl]piperazine-1-carboxylic acid tert-butyl ester (0.41 g, 86%).
  • Compound 1338 is prepared in the same fashion as described above.
    • Example 1DC Preparation of {N-{4-[3-cyano-1-ethyl-6-(4-methylpiperazin-1-yl)-indol-2-yl]phenyl}propionamide (compound 1341)
  • Figure US20100305100A1-20101202-C00561
  • Step A: 6-chloro-1-ethylindole-3-carbonitrile (1.02 g, 5.0 mmol), prepared from 6-chloroindole using the procedures described in example 1A, is mixed with K3PO4 (1.48 g, 7.0 mmol), Pd2(dba)3 (0.11 g, 0.12 mmol), biphenyl-2-yldicyclohexylphosphane (0.17 g, 0.48 mmol), 1-methylpiperazine (0.60 g, 0.67 mL 6.0 mmol) and dry DME (10.0 mL). The mixture is stirred at 100° C. overnight. After cooling, the solvent is replaced with dichloromethane and chromatographed (silica gel, DCM, then EtOAc, finally DCM/MeOH, 9/1) to provide 1-ethyl-6-(4-methylpiperazin-1-yl)indole-3-carbonitrile (0.96 g, 72%).
  • Step B: To a solution of 1-ethyl-6-(4-methylpiperazin-1-yl)indole-3-carbonitrile (0.81 g, 3.0 mmol) obtained above and triisopropylborate (0.81 g, 0.99 mL, 4.50 mmol) in dry THF (5 mL) at −78° C. is added LDA (2.5 mL, 1.5 M, 3.75 mmol). The mixture is stirred at −78° C. for 15 min after the addition, then slowly brought to room temperature and stirred for an additional 30 min. The reaction is then cooled to −78° C. followed by the addition of 4-iodoaniline (0.78 g, 3.6 mmol), PdCl2(dppf) (0.11 g, 0.15 mmol), DMF (10 mL) and K2CO3 (4.5 mL, 2.0 M, 9.0 mmol). The mixture is brought to room temperature slowly and stirred overnight and then poured into ice-water (200 mL). The precipitate is collected and washed with water, chromatographed (silica gel, EtOAc/DCM/Et3N, 6/4/0.02) to furnish 2-(4-aminophenyl)-1-ethyl-6-(4-methylpiperazin-1-yl)indole-3-carbonitrile (0.90 g, 83%).
  • Step C: To a solution of the compound obtained in step B (54 mg, 0.15 mmol) in dry pyridine (1.5 mL) is added propionyl chloride (26 μL, 0.30 mmol). The mixture is stirred at room temperature overnight and the solvent is removed in vacuo. The residue is dissolved with DCM (5 mL) and washed with water (2×4 mL) and chromatographed (silica gel, MeOH/DCM, 0.5/9.5) to provide product, {N-{4-[3-cyano-1-ethyl-6-(4-methylpiperazin-1-yl)indol-2-yl]phenyl}propionamide (45 mg, 73%).
  • Compounds 1339 and 1340 are prepared by utilizing the above procedure using ethyl chloroformate and cyclopropane carbonylchloride.
    • Example 1DD Preparation of {4-[3-cyano-1-cyclopropyl-6-(2-methoxyethoxy)indol-2-yl]phenyl}carbamic acid 1-cyclopropylethyl ester (compound 1436)
  • Figure US20100305100A1-20101202-C00562
  • Step A: To a solution of 2-(4-aminophenyl)-1-cyclopropyl-6-methoxyindole-3-carbonitrile (2.02 g, 6.7 mmol), prepared in example 1CG, step E, in dry DCM (30 mL), at −30° C., is added boron tribromide (8.35 g, 3.15 mL, 33.3 mmol). The mixture is stirred at −30° C. ˜−15° C. for 1.5 h and then brought to ambient temperature and stirred for 15 min. The mixture is poured into saturated NaHCO3 and ice and stirred for 1 h. The volatiles are removed on a rotovap and the precipitate is collected via filtration and washed with water and then dried under a stream of N2 to provide 2-(4-aminophenyl)-1-cyclopropyl-6-hydroxyindole-3-carbonitrile in quantitative yield.
  • Step B: The intermediate obtained above (0.29 g, 1.0 mmol) is mixed with Cs2CO3 (0.98 g, 3.0 mmol), 2-methoxyethyl bromide (0.21 g, 0.14 mL, 1.5 mmol) and acetonitrile (5 mL) and the mixture is stirred at 85° C. overnight. The solvent is removed in vacuum and the residue is treated with DCM and chromatographed (silica gel, DCM/EtOAc, 9/1) to provide 2-(4-aminophenyl)-1-cyclopropyl-6-(2-methoxyethoxy)indole-3-carbonitrile (0.16 g, 46%).
  • Step C: A mixture of 2-(4-aminophenyl)-1-cyclopropyl-6-(2-methoxyethoxy)indole-3-carbonitrile (35 mg, 0.1 mmol), 4-nitrophenylchloroformate (50 mg, 0.25 mmol) in pyridine (2.0 mL) is stirred at 35° C. for 2 h, followed by the addition of 1-cyclopropylethanol (98 μL, 1.0 mmol). The mixture is then stirred at 60° C. overnight and diluted with water (10 mL) and DCM (5 mL). The organic is washed with water (3×5 mL), HCl (2N, 3×5 mL), saturated NaHCO3 (3×5 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the title compound, {4-[3-cyano-1-cyclopropyl-6-(2-methoxyethoxy)indol-2-yl]phenyl}carbamic acid 1-cyclopropylethyl ester (22 mg, 48%).
  • Compounds 1437, 1438 and 1439 are prepared by utilizing the above chemistry.
    • Example 1DE Preparation of {4-[3-cyano-1-cyclopropyl-6-(tetrahydrofuran-2-yloxy)-2-yl]-phenyl}carbamic acid 1-cyclopropylethyl ester (compound 1444)
  • Figure US20100305100A1-20101202-C00563
  • Step A: 2-(4-aminophenyl)-1-cyclopropyl-6-hydroxyindole-3-carbonitrile (0.29 g, 1.0 mmol), prepared in example 1DD, step A, is mixed with K2CO3 (0.35 g, 2.5 mmol), toluene-4-sulfonic acid tetrahydrofuran-2-yl ester (0.36 g, 1.5 mmol) and acetonitrile (5 mL) and the mixture is stirred at 80° C. overnight. The solvent is removed in vacuum and the residue is treated with DCM and chromatographed (silica gel, DCM/EtOAc, 9/1) to provide 2-(4-aminophenyl)-1-cyclopropyl-6-(tetrahydrofuran-2-yloxy)indole-3-carbonitrile (0.27 g, 75%).
  • Step B: A mixture of 2-(4-aminophenyl)-1-cyclopropyl-6-(tetrahydrofuran-2-yloxy)indole-3-carbonitrile (36 mg, 0.1 mmol), 4-nitrophenylchloroformate (50 mg, 0.25 mmol) in pyridine (2.0 mL) is stirred at 35° C. for 2 h, followed by the addition of 1-cyclopropylethanol (98 μL, 1.0 mmol). The mixture is then stirred at 60° C. overnight and diluted with water (10 mL) and DCM (5 mL). The organic is washed with water (3×5 mL), HCl (2N, 3×5 mL), saturated NaHCO3 (3×5 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the title compound, {4-[3-cyano-1-cyclopropyl-6-(tetrahydrofuran-2-yloxy)indol-2-yl]phenyl}carbamic acid 1-cyclopropylethyl ester (32 mg, 68%).
  • In similar fashion, the following compounds are prepared following the procedure described above: Compounds 1445, 1446, 1447, 1448, 1449, 1453, 1454, 1455, 1456, 1457, 1458, 1459, 1460, 1461.
    • Example 1DF Preparation of 4-Methyl-piperidine-1-carboxylic acid {4-[3-cyano-1-cyclobutyl-6-(2-methoxy-ethoxy)-1H-indol-2-yl]-phenyl}-amide (compound 1377)
  • Figure US20100305100A1-20101202-C00564
  • Step A: To a solution 2-(4-aminophenyl)-1-cyclobutyl-6-(2-methoxyethoxy)-1H-indole-3-carbonitrile (530 mg, 1.58 mmol) in EtOAc (10 mL) is added 2M aqueous K2CO3 (556 uL, 5.9 mmol) and 4-methoxyphenyl chloroformate over a period of 5 min. The reaction mixture is stirred further for 3 h at room temperature. The reaction mixture is diluted with EtOAc (20 mL) and then washed with water (5 mL). The solvents are removed under reduced pressure and the residue is dissolved in EtOAc and then triturated with hexane. The precipitate is collected by filtration and washed with 50% EtOAc/hexane and dried in vacuo to afford {4-[3-cyano-1-cyclobutyl-6-(2-methoxy-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid 4-methoxy-phenyl ester (761 mg, 98%).
  • Step B: To a solution of {4-[3-cyano-1-cyclobutyl-6-(2-methoxy-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid 4-methoxy-phenyl ester (40 mg, 0.082 mmol) in DCM (4 mL) is added 4-methylpiperidine (0.16 mmole) and the reaction is stirred for 18 h at reflux temperature. The solvent is removed under reduced pressure. The residue is dissolved in EtOAc and then triturated with hexane. The precipitate is collected by filtration and washed with 50% EtOAc/hexane and dried in vacuo to afford 4-methyl-piperidine-1-carboxylic acid {4-[3-cyano-1-cyclobutyl-6-(2-methoxyethoxy)-1H-indol-2-yl]-phenyl}-amide, compound 1377, (26 mg, 68%).
  • The following compounds are made in similar fashion following steps A and B, above: Compounds 1378, 1379, 1380, 1381, 1382, 1383, 1384.
    • Example 1DG Preparation of {4-[3-Cyano-1-cyclobutyl-6-(2-hydroxy-3-[1,2,4]triazol-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (compound 1420)
  • Figure US20100305100A1-20101202-C00565
  • Step A: To a solution of [4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (1.0 g, 2.57 mmol) in DMF (10 mL) is added K2CO3 (710 mg, 5.13 mmole) and epibromohydrin (436 uL, 5.13 mmole) and the reaction is stirred for 42 h at ambient temperature. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with hexane and dried in vacuo to afford 960 mg, 84% of the desired product.
  • Step B: To a solution of [4-(3-cyano-1-cyclobutyl-6-oxiranylmethoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (40 mg, 0.09 mmole) in DMF (1 mL) is added the sodium salt of 1,2,4-triazole (30 mg). The resulting mixture is stirred at 60° C. overnight. The solvent is removed under reduced pressure and the residue is diluted with ethyl acetate and then washed with water. The organic layer is concentrated and triturated with hexane. The precipitate is collected by filtration and washed well with 1/1 ethyl acetate/hexane and dried in vacuo to afford {4-[3-cyano-1-cyclobutyl-6-(2-hydroxy-3-[1,2,4]triazol-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester, compound 1420, (29 mg, 63%).
  • The following compounds are made in similar fashion following steps A and B, above: Compounds 1418, 1419.
  • Following the chemistry described above the urea derivative, compound 1421 is prepared similarly.
    • Example 1DH Preparation of {4-[3-cyano-1-cyclobutyl-6-(3,4-dihydroxy-butoxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (compound 1429)
  • Figure US20100305100A1-20101202-C00566
  • Step A: To a solution of [4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (100 mg, 0.26 mmol) in DMF (3 mL) is added K2CO3 (43.2 mg, 0.312 mmole) and 4-nitrobenzenesulfonic acid 2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester (129 mg, 0.39 mmole) and the reaction is stirred for 18 h at ambient temperature. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with EtOAc/hexane and dried in vacuo to afford 96 mg, 84% of the desired product, (4-{3-cyano-1-cyclobutyl-6-[2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-1H-indol-2-yl}-phenyl)-carbamic acid isopropyl ester, compound 1428.
  • Step B: To a solution of (4-{3-cyano-1-cyclobutyl-6-[2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-1H-indol-2-yl}-phenyl)-carbamic acid isopropyl ester (70 mg, 0.135 mmole) in DCM (2 mL) is added TFA (10 uL). The resulting mixture is stirred at ambient temperature for 2 h. The solvent is removed under reduced pressure and the residue is diluted with ethyl acetate and triturated with hexane and the precipitate collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford {4-[3-cyano-1-cyclobutyl-6-(3,4-dihydroxy-butoxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester, compound 1429, 45 mg, (70%).
    • Example 1DI Preparation of 1-[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-3-(2-hydroxy-ethyl)-urea (compound 1408)
  • Figure US20100305100A1-20101202-C00567
  • 2-(4-Aminophenyl)-1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (40 mg, 0.12 mmol), prepared as in example 1CM, step B, is combined with 4-nitrophenyl chloroformate (60 mg, 0.30 mmol), CH2Cl2 (400 μL), and pyridine (25 μL, 0.31 mmol). This suspension is stirred at room temperature for 1 hour. Ethanolamine (42 μL, 0.70 mmol) is added. After stirring at room temperature for an additional 30 min, the reaction mixture is diluted in CH2Cl2 and is washed with dilute aqueous NaOH to remove the yellow nitrophenol by-product. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2/Acetone, 7/3) yields 1-[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-3-(2-hydroxy-ethyl)-urea (40 mg, 80%) as a white solid.
  • The following compounds are prepared in a similar fashion, using the appropriate amine and aniline coupling partner: Compounds 1375, 1390, 1391, 1392, 1396, 1409, 1440, and 1441.
    • Example 1DJ Preparation of [4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-carbamic acid 2-(2-methoxyethoxy)-ethyl ester (compound 1424)
  • Figure US20100305100A1-20101202-C00568
  • 2-(4-Aminophenyl)-1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (40 mg, 0.12 mmol), prepared as in example 1CM, step B, is combined with 4-nitrophenyl chloroformate (60 mg, 0.30 mmol), DCE (0.4 mL), and pyridine (25 μL, 0.31 mmol). This suspension is stirred at room temperature for 1 h. 2-(2-methoxyethoxy)ethanol (150 μL, 1.25 mmol) is added. This mixture is heated at 80° C. overnight. The reaction mixture is then diluted in CH2Cl2 and is washed with dilute aqueous NaOH to remove the yellow nitrophenol by-product. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2) yields [4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-carbamic acid 2-(2-methoxy-ethoxy)-ethyl ester (51 mg, 89%) as a white solid.
  • The following compounds are prepared in a similar fashion, using the appropriate alcohol: Compounds 1416, 1426, 1432.
    • Example 1DK Preparation of 1-[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-3-cyclopenyl-1-ethyl-urea (compound 1425)
  • Figure US20100305100A1-20101202-C00569
  • 1-Cyclobutyl-6-ethoxy-2-(4-ethylaminophenyl)-1H-indole-3-carbonitrile, prepared in example 1CO, step C, (35 mg, 0.10 mmol) is dissolved in pyridine (300 μL). Cyclopentyl isocyanate (130 μL, 1.08 mmol) is added. The reaction mixture is heated at 110° C. for 2 h. The reaction mixture is then partitioned between aqueous HCl and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography using hexanes/EtOAc (6/4) followed by a second chromatography using CH2Cl2/EtOAc (95/5) is required to remove the dicyclopentyl urea impurity, affording pure 1-[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-3-cyclopenyl-1-ethyl-urea (39 mg, 82%) as an off-white solid.
    • Example 1DL Preparation of 1-cyclobutyl-6-ethoxy-2-[4-(2-pyridin-2-yl-ethylamino)-phenyl]-1H-indole-3-carbonitrile (compound 1433)
  • Figure US20100305100A1-20101202-C00570
  • 2-(4-Aminophenyl)-1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (40 mg, 0.12 mmol), prepared as in example 1CM, step B, is combined with 4-nitrophenyl chloroformate (60 mg, 0.30 mmol), DCE (0.4 mL), and pyridine (25 μL, 0.31 mmol). This suspension is stirred at room temperature for 1 h. 2-(2-methoxyethoxy)ethanol (150 μL, 1.25 mmol) is added. This mixture is heated at 75° C. overnight. The reaction mixture is then diluted in CH2Cl2 and is washed with dilute aqueous NaOH to remove the yellow nitrophenol by-product. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2/EtOAc, 4/1), followed by trituration with hexanes/acetone (2/1) yields 1-cyclobutyl-6-ethoxy-2-[4-(2-pyridin-2-yl-ethylamino)-phenyl]-1H-indole-3-carbonitrile (23 mg, 42%) as a white solid.
    • Example 1DM Preparation of 2-(2-Diethylaminobenzothiazol-6-yl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (compound 1343)
  • Figure US20100305100A1-20101202-C00571
  • Step A: tert-butyl 6-methoxy-1H-indole-1-carboxylate, from example 1BO, (2.50 g, 8.6 mmol) is dissolved in anhydrous dimethoxyethane (21.5 mL). To the solution is added 2-chloro-6-iodobenzothiazole (2.42 g, 8.2 mmol), cesium fluoride (2.53 g, 16.7 mmol) and PdCl2(PPh3)2 (0.23 g, 0.33 mmol). The reaction mixture is heated at reflux. After 17 h the reaction mixture is cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (4×20 mL). The extract is washed with saturated aqueous NaHCO3 (20 mL), dried over MgSO4 and concentrated under vacuum to give tert-butyl 2-(2-chlorobenzothiazol-6-yl)-6-methoxy-indole-1-carboxylate (2.95 g, 83%) as a hard foam.
  • Step B: The above Boc indole (2.87 g, 6.9 mmol) is dissolved in anhydrous CH2Cl2 (13 mL). To the solution is added trifluoroacetic acid (3.0 mL, 38.9 mmol) at room temperature. The reaction mixture is stirred at room temperature for 17 h. Water (20 mL) is added and the mixture is extracted with CH2Cl2 (3×10 mL). The extract is washed with water (1×15 mL), saturated aqueous NaHCO3 (20 mL), dried over MgSO4 and concentrated using a rotary evaporator to give the crude product. The product is purified by silica gel chromatography (1-50% ethyl acetate/hexane) to give 2-chloro-6-(-methoxy-1H-indol-2-yl)-benzothiazole (0.40 g, 18%).
  • Step C: The above indole is dissolved in anhydrous DMF (3.0 mL) and cooled in an ice bath. Chlorosulfonyl isocyanate (0.12 mL, 1.4 mol) is added and the mixture stirred for 2 h in an ice bath. Water (15 mL) is added and the mixture stirred at room temperature for 30 minutes. The precipitate is filtered, washed with water and dried to give 2-(2-chlorobenzothiazol-6-yl)-6-methoxy-1H-indole-3-carbonitrile (0.39 g, 95%).
  • Step D: The above indole (373 mg, 1.1 mmol) is dissolved in anhydrous DMF (2.2 mL) and stirred at room temperature as iodoethane (0.20 g, 1.3 mmol) and potassium carbonate (0.31 g, 2.2 mmol) are added. The mixture is stirred at 50° C. for 22 h. The mixture is diluted with water (15 mL) and stirred at room temperature for 15 minutes. The solid is filtered, washed with water and dried to give 2-(2-chlorobenzothiazol-6-yl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (0.39 g, 96%).
  • Step E: The above indole (46 mg, 0.13 mmol) is dissolved in 15% water/isopropyl alcohol (1.5 mL). Diethyl amine (25 mg, 0.34 mmol) is added followed by sodium bicarbonate (43 mg, 0.51 mmol). The reaction mixture is heated at reflux for 21 hours. The reaction mixture is cooled to room temperature, and diluted with water (5 mL). The precipitate is filtered, washed with water and dried to give 2-(2-diethylaminobenzothiazol-6-yl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (40 mg, 79%).
    • Example 1DN Preparation of Ethanesulfonic acid [4-(3-cyano-6-diethylaminomethyl-1-ethyl-1H-indol-2-yl)-phenyl]-amide (compound 1352)
  • Figure US20100305100A1-20101202-C00572
  • Step A: A solution of methyl 3-cyano-1-ethyl-1H-indole-6-carboxylate (4.11 g, 18.0 mmol), prepared by the method described in example 1A from methyl 1H-indole-6-carboxylate, in anhydrous THF (36 mL) is cooled in a dry ice/ether bath. Lithium diisopropylamide (1.5 M solution in cyclohexane, 14.4 mL, 21.6 mmol) is added at a rate to keep the reaction temperature below −60° C. After the addition, the reaction mixture is stirred at −60° C. for 30 minutes. Trimethylborate (3.1 mL, 27.8 mmol) is added to the reaction and the mixture is stirred at −60° C. for 30 minutes. The reaction mixture is allowed to warm to room temperature and DMF (60 mL), 4-iodoaniline (4.00 g, 18.3 mmol), PdCl2(dppf) (735 mg, 0.90 mmol) and aqueous K2CO3 (2M, 36 mL) are added. The mixture is stirred at 40° C. for 17 h. The mixture is cooled to room temperature and concentrated to remove THF. Water is added to a volume of 500 mL and the mixture is extracted with ethyl acetate (3×50 mL). The extract is washed with water (3×50 mL), dried over MgSO4 and concentrated to give the product as a semi-solid. The product is crystallized from ethyl acetate to give methyl 2-(4-aminophenyl)-3-cyano-1-ethyl-1H-indole-6-carboxylate (2.53 g, 44%) as a tan solid.
  • Step B: The indole product from above (1.26 g, 3.95 mmol) is dissolved in anhydrous pyridine (6 mL). To the solution is added ethanesulfonyl chloride (0.63 g, 4.90 mmol). The mixture is heated to 50° C. for 17 hours. The reaction mixture is cooled to room temperature and water (30 mL) is added. The mixture is extracted with ethyl acetate (3×5 mL). The extract is washed with 10% aqueous hydrochloric acid (5 mL), water (2×10 mL), dried over MgSO4 and concentrated using a rotary evaporator to give 3-cyano-2-(4-ethanesulfonylamino-phenyl)-1-ethyl-1H-indole-6-carboxylic acid methyl ester (1.47 g, 90%).
  • Step C: The indole product from above (0.72 g, 1.76 mmol) is suspended in anhydrous THF (3.3 mL). A solution of lithium borohydride (2.6 mL, 5.2 mmol, 2M in THF) is added at room temperature. The mixture is heated at reflux for 20 h. The mixture is cooled to room temperature and water (4 mL) is added. The pH is adjusted to 4 by addition of 10% aqueous hydrochloric acid. The mixture is extracted with methylene chloride (4×2 mL). The extract is washed with water (2.2 mL), dried over MgSO4 and concentrated to give ethanesulfonic acid[4-(3-cyano-1-ethyl-6-hydroxymethyl-1H-indol-2-yl)-phenyl]-amide (595 mg, 88%) as a tan solid.
  • Step D: The indole product from above (471 mg, 1.23 mmol) is suspended in anhydrous methylene chloride (6 mL). Thionyl chloride (0.135 mL, 1.85 mmol) is added and the mixture stirred at room temperature for 2 h. The mixture is concentrated on a rotary evaporator to give ethanesulfonic acid [4-(6-chloromethyl-3-cyano-1-ethyl-1H-indol-2-yl)-phenyl]-amide (493 mg, 99%).
  • Step E: The indole product from above (50 mg, 0.124 mmol) is dissolved in anhydrous acetonitrile (1.0 mL). Diethylamine (28.1 mg, 0.38 mmol) is added and the mixture is heated at 80° C. for 17 hours. The mixture is cooled to room temperature, concentrated on a rotary evaporator and purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to give ethanesulfonic acid [4-(3-cyano-6-diethylaminomethyl-1-ethyl-1H-indol-2-yl)-phenyl]-amide (33.6 mg, 62%).
    • Example 1DO {4-[3-Cyano-1-cyclobutyl-6-(2-methanesulfonyl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (compound 2695)
  • Figure US20100305100A1-20101202-C00573
  • Step A: To a solution of 2-(4-aminophenyl)-1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile (3.43 g, 11.3 mmol) in CH3CN (8 mL) was added Cs2CO3 (4.30 g, 73.2 mmol) and 2-chloroethyl-p-tosylate (2.39 mL, 13.2 mmol) and the reaction mixture was stirred for 18 h at 40° C. in a sealed tube. An aqueous workup was performed in 0.5M HCl (500 mL) and the mixture extracted with EtOAc (2×500 mL). Organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified over silica gel column in 10% EtOAc/CH2Cl2. Solvent was removed to provide 4.06 g (98% yield) of 2-(4-Amino-phenyl)-6-(2-chloro-ethoxy)-1-cyclobutyl-1H-indole-3-carbonitrile, as a white solid.
  • Step B: 2-(4-Amino-phenyl)-6-(2-chloro-ethoxy)-1-cyclobutyl-1H-indole-3-carbonitrile (800 mg, 2.19 mmol) was dissolved in phosgene in toluene (2M, 10 mL, 5.00 mmol) and stirred for 2 h at 80° C. in a sealed tube. Solvent was removed and the white solid obtained was suspended in 1 ml of DCE. To this solution was added (R)-1-cyclopropylethanol (400 uL, 5.28 mmol) and DMAP (268 mg, 2.19 mmol). Solution was stirred in a sealed tube for 16 h at room temperature. An aqueous workup was performed in 0.5M HCl (200 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, dried over MgSO4 and concentrated. Solid product was triturated with ether to generate 800 mg (77% yield) of {4-[6-(2-Chloro-ethoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester, as a white solid.
  • Step C: To a solution of {4-[6-(2-Chloro-ethoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (800 mg, 1.67 mmol) in 1:4 DMF/CH3CN (8 mL) is added sodium iodide (2.50 g, 16.7 mmol). The resulting mixture was refluxed overnight. An aqueous workup was performed in 0.5M HCl (200 mL) and extracted with EtOAc (2×100 mL). Organic layers were combined, dried over MgSO4 and concentrated. Solid product was triturated with ether and used without further purification. To 4 mL of a DMF solution containing the iodoethyl intermediate (0.56 mmol) was added the sodium methane sulfinate (113 mg, 1.11 mmol), and the reaction was stirred at room temperature overnight. An aqueous workup was performed in 0.5M HCl (200 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, dried over MgSO4 and concentrated. The mixture was purified over silica gel column (CH2Cl2) to provide 100 mg (35% yield) of {4-[3-Cyano-1-cyclobutyl-6-(2-methanesulfonyl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropylethyl ester, as an off-white powder.
    • Example 1DP Preparation of [4-(1-cyclopropylmethyl-6-ethoxy-3-iodo-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (compound 2634)
  • Figure US20100305100A1-20101202-C00574
  • Step A: To a solution 6-Ethoxy-1-H-indole (5.0 g, 31 mmol) in CH3CN (31 mL) was added di-tert-butyldicarbonate (7.2 g, 33 mmol) and DMAP (480 mg, 3.9 mmol). The mixture was stirred overnight at room temperature, concentrated and the residue purified by silica gel chromatography (1:1 CH2Cl2/hexane) provided 6-ethoxy-indole-1-carboxylic acid tert-butyl ester (7.67 g, 95%) as a tan oil.
  • Step B: A solution of 6-ethoxy-indole-1-carboxylic acid tert-butyl ester (8 g, 30 mmol) and B(OiPr)3 (12 mL, 52 mmol) in THF (48 mL) was cooled to 0° C. and LDA (1.5 M in THF-cyclohexane, 30 mL, 45 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 20 minutes, and then at room temperature for 30 minutes. HCl (7.5 mL, 6 M) was added and the mixture concentrated to roughly 30 mL of solution. This concentrate was acidified with aqueous HCl to pH 1-2. The solids were filtered, washed with H2O, and dried at 50° C. at reduced pressure for 30 minutes. The product, 2-(6-ethoxy-indole-1-tert-butoxy-carbonyl-indole)-boronic acid trihydrate (10.32 g, 96%) was isolated as a white solid.
  • Step C: To a mixture of 2-(6-ethoxy-indole-1-tert-butoxy-carbonyl-indole)-boronic acid trihydrate (5.1 g, 14.2 mmol), 1-iodo-4-nitrobenzene (3.6 g, 14.4 mmol), Pd(dppf)Cl2—CH2Cl2 (205 mg, 0.25 mmol) and DMF (45 mL) was added aq. K2CO3 (2M, 20 mL, 40 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H2O and was extracted with EtOAc. The EtOAc layer was washed with H2O, and then with brine. The organic layer was dried, concentrated and purified by silica gel chromatography (1:1 CH2Cl2/hexane), followed by trituration with 1:1 hexane/ether to provide 6-ethoxy-2-(4-nitro-phenyl)-indole-1-carboxylic acid tert-butyl ester (3.63 g, 67%) as a yellow solid.
  • Step D: To a solution of 6-ethoxy-2-(4-nitro-phenyl)-indole-1-carboxylic acid tert-butyl ester (8.1 g, 21.2 mmol) in CH2Cl2 (8 mL) was added TFA (8 mL). This mixture was stirred at room temperature for 2 h and concentrated. The residue was diluted in EtOAc and washed with sat. aq. NaHCO3. The organic layer was concentrated and purified by silica gel chromatography (7:3 CH2Cl2/hexane, followed by 100% CH2Cl2) to provide 6-ethoxy-2-(4-nitro-phenyl)-1H-indole (4.5 g, 68%) as an orange-red solid.
  • Step E: 6-Ethoxy-2-(4-nitro-phenyl)-1H-indole (4.5 g, 16 mmol), Cs2CO3 (7.8 g, 24 mmol), DMF (23 mL), and bromomethylcyclopropane (1.8 mL, 18 mmol) were stirred at 80° C. in a sealed tube for 16 hours. The reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried and concentrated. Purification by silica gel chromatography (1:1 CH2Cl2/hexane) provided 1-cyclopropylmethyl-6-ethoxy-2-(4-nitro-phenyl)-1H-indole (4.73 g, 88%) as an orange solid.
  • Step F: To 1-cyclopropylmethyl-6-ethoxy-2-(4-nitro-phenyl)-1H-indole (800 mg, 2.38 mmol) in DMF (8.6 mL) at room temperature was added a solution of N-iodosuccinimide (585 mg, 2.6 mmol) in DMF (5.6 mL) dropwise. The reaction mixture was stirred at room temperature for 2 h, diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O, and then with sat. aq. NaHCO3 and then dried and concentrated. The residue was triturated with hexane to provide 1-cyclopropylmethyl-6-ethoxy-3-iodo-2-(4-nitro-phenyl)-1H-indole (1.061 g, 96%) as an orange solid.
  • Step G: A mixture of 1-Cyclopropylmethyl-6-ethoxy-3-iodo-2-(4-nitro-phenyl)-1H-indole (990 mg, 2.14 mmol), iron powder (690 mg, 11.8 mmol), NH4Cl (690 mg, 12.9 mmol), ethanol (22 mL), and H2O (8 mL) were heated at 80° C. for 90 minutes. The reaction mixture was diluted with H2O and extracted with CH2Cl2. The organic layer was dried, concentrated and purified by silica gel chromatography (CH2Cl2). Product containing fractions were used immediately in the next reaction. The compound in CH2Cl2 (80 mL) was treated with pyridine (15 mL) and isopropylchloroformate (1M in toluene, 2.5 mL, 2.5 mmol) and stirred at room temperature for 15 minutes. The reaction mixture was concentrated and extracted with a mixture of EtOAc and aq. HCl. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (CH2Cl2/hexane, 1:1 to 3:1) to provide [4-(1-cyclopropylmethyl-6-ethoxy-3-iodo-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (644 mg, 58%) as a white solid.
    • Example 1DQ Preparation of [4-(1-Cyclopropylmethyl-6-ethoxy-3-fluoro-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (compound 2640)
  • Figure US20100305100A1-20101202-C00575
  • Step A: To 1-cyclopropylmethyl-6-ethoxy-2-(4-nitro-phenyl)-1H-indole (600 mg, 1.79 mmol) in CH2Cl2 (4 mL) was added 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (418 mg, 1.85 mmol). The reaction mixture was stirred at room temperature for 3 days and then diluted in CH2Cl2 and washed with aq. NaHCO3. The organic layer was dried, concentrated and purified by silica gel chromatography (1:1 CH2Cl2/hexane) to provide 1-cyclopropylmethyl-6-ethoxy-3-fluoro-2-(4-nitro-phenyl)-1H-indole (161 mg, 25%) as a yellow solid.
  • Step B: A mixture of 1-cyclopropylmethyl-6-ethoxy-3-fluoro-2-(4-nitro-phenyl)-1H-indole (161 mg, 0.45 mmol), iron powder (170 mg), NH4Cl (170 mg, 3.2 mmol), ethanol (4 mL) and H2O (1.5 mL) were heated at 80° C. for 90 minutes. The reaction mixture was diluted with H2O and was extracted with CH2Cl2. The organic layer was dried and concentrated to provide 4-(1-cyclopropylmethyl-6-ethoxy-3-fluoro-1H-indol-2-yl)-phenylamine (122 mg, 83%) as a white solid.
  • Step C: A mixture of 4-(1-cyclopropylmethyl-6-ethoxy-3-fluoro-1H-indol-2-yl)-phenyl amine (30 mg, 0.093 mmol), pyridine (300 μL), and isopropylchloroformate (1 M in toluene, 110 μL, 0.11 mmol) was stirred at room temperature for 90 minutes. The residue was extracted with a mixture of EtOAc and aqueous HCl. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (CH2Cl2/Hex, 1:1) to provide [4-(1-cyclopropylmethyl-6-ethoxy-3-fluoro-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (35 mg, 92%) as a white solid.
    • Example 1DR Preparation of [4-(3-cyclopropylethynyl-1-cyclopropylmethyl-6-ethoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (compound 2635)
  • Figure US20100305100A1-20101202-C00576
  • [4-(1-Cyclopropylmethyl-6-ethoxy-3-iodo-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (100 mg, 0.19 mmol), cyclopropylacetylene (50 μL, 70% in toluene, 0.4 mmol), Pd(PPh3)2Cl2 (6.7 mg, 0.0096 mmol), CuI (5 mg, 0.026 mmol), triethylamine (600 μL), and DMF (600 μL) was stirred at room temperature for 5 h. Additional Pd(PPh3)2Cl2 (5 mg), and cyclopropylacetylene (30 μL) was then added and the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc and washed with H2O and aq. HCl. The organic layer was dried, concentrated and purified by silica gel chromatography (3:1 CH2Cl2/hexane), followed by a second chromatography (7:3 hexane/ether) to provide [4-(3-cyclopropylethynyl-1-cyclopropylmethyl-6-ethoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (21 mg, 24%) as a white solid.
    • Example 1DS Preparation of [4-(3-bromo-1-cyclopropylmethyl-6-ethoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (compound 2691)
  • Figure US20100305100A1-20101202-C00577
  • Step A: To 1-cyclopropylmethyl-6-ethoxy-2-(4-nitro-phenyl)-1H-indole (200 mg, 0.6 mmol) in DMF (2.5 mL) was added a solution of N-bromosuccinimide (107 mg, 0.6 mmol) in DMF (1.5 mL) dropwise. The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was diluted in H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (1:1 CH2Cl2/hexane) to provide 3-bromo-1-cyclopropylmethyl-6-ethoxy-2-(4-nitro-phenyl)-1H-indole (219 mg, 88%) as a yellow solid.
  • Step B: Following Example 1DP step B, 3-bromo-1-cyclopropylmethyl-6-ethoxy-2-(4-nitro-phenyl)-1H-indole (205 mg, 0.5 mmol) was reduced to provide 4-(3-bromo-1-cyclopropylmethyl-6-ethoxy-1H-indol-2-yl)-phenylamine (164 mg, 85%) as yellowish solid.
  • Step C: Following Example 1DP step C, 4-(3-bromo-1-cyclopropylmethyl-6-ethoxy-1H-indol-2-yl)-phenylamine (30 mg, 0.078 mmol) was carbamoylated to provide [4-(3-bromo-1-cyclopropylmethyl-6-ethoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (25 mg, 68%) as a white solid.
    • Example 1DT Preparation of [4-(3-chloro-1-cyclopropylmethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (compound 2804)
  • Figure US20100305100A1-20101202-C00578
  • Step A: 2-(6-Methoxy-indole-1-tert-butoxy-carbonyl-indole)-boronic acid (14 g, 48 mmol) was combined with N-(4-iodophenyl)-isopropylcarbamate (15.25 g, 50 mmol), Pd(dppf)Cl2 (678 mg, 0.92 mmol), aq. K2CO3 (2M, 66 mL, 132 mmol), and DMF (150 mL). The reaction mixture was stirred overnight at room temperature then diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (CH2Cl2), followed by trituration with 2:1 hexane/ether to provide 2-(4-isopropoxycarbonylamino-phenyl)-6-methoxy-indole-1-carboxylic acid tert-butyl ester (15.6 g, 76%) as a gray solid.
  • Step B: A mixture of 2-(4-Isopropoxycarbonylamino-phenyl)-6-methoxy-indole-1-carboxylic acid tert-butyl ester (17.4 g, 41 mmol), CH2Cl2 (50 mL), and TFA (50 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated, diluted in CH2Cl2, and washed with sat. aq. NaHCO3. The organic layer was dried, concentrated, and triturated with ether to provide [4-(6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (11.4 g, 86%) as a grayish solid.
  • Step C: To [4-(6-Methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (11.3 g, 34.9 mmol) in DMF (50 mL) was added a solution of N-chlorosuccinimide (5 g, 37.4 mmol) dropwise over 20 minutes and the mixture stirred at room temperature for 1 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried, concentrated and triturated with ether to provide [4-(3-chloro-6-Methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (10.65 g, 85%) as a tan solid.
  • Step D: A mixture of [4-(3-Chloro-6-Methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (50 mg, 0.14 mmol), Cs2CO3 (95 mg, 0.29 mmol), bromomethylcyclopropane (18 μL, 0.18 mmol), and DMF (200 μL) was stirred at 60° C. for 4 h. The reaction mixture was then stirred at room temperature for 1 h, diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (7:3 CH2Cl2/hexane) to provide [4-(3-chloro-1-cyclopropylmethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (19 mg, 33%) as a white solid.
    • Example 1DU Preparation of (R)-[4-(3-cyano-1-cyclobutyl-6-methanesulfonylmethoxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (compound 2988)
  • Figure US20100305100A1-20101202-C00579
  • Step A: [4-(3-Cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid tert-butyl ester (1.6 g, 4 mmol) was combined with Cs2CO3 (2.6 g, 8 mmol), methyl chloromethyl sulfide (410 μL, 5 mmol), and DMF (16 mL). The reaction mixture was stirred overnight at room temperature, diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (CH2Cl2) to provide [4-(3-cyano-1-cyclobutyl-6-methanesulfanylmethoxy-1H-indol-2-yl)-phenyl]-carbamic acid tert-butyl ester (1.72 g, 93%) as an off-white solid.
  • Step B: To [4-(3-Cyano-1-cyclobutyl-6-methanesulfanylmethoxy-1H-indol-2-yl)-phenyl]-carbamic acid tert-butyl ester (1.35 g, 2.9 mmol) in CHCl3 (20 mL) was added 3-Chloroperoxybenzoic acid (1.5 g, 8.7 mmol) in one portion. After 10 minutes the reaction mixture was washed with dilute NaHCO3 solution, dried, concentrated and purified by silica gel chromatography (95:5 CH2Cl2/EtOAc) to yield [4-(3-cyano-1-cyclobutyl-6-methanesulfonylmethoxy-1H-indol-2-yl)-phenyl]-carbamic acid tert-butyl ester (1.11 g, 77%) as an off-white solid.
  • Step C: To [4-(3-Cyano-1-cyclobutyl-6-methanesulfonylmethoxy-1H-indol-2-yl)-phenyl]-carbamic acid tert-butyl ester (1.21 g, 2.47 mmol) in CH2Cl2 (6 mL) was added TFA (2 mL) and stirred at room temperature for 1 h. The reaction mixture was diluted in CH2Cl2, washed with aq. NaHCO3, dried and concentrated. Trituration with acetone (5 mL) provided 2-(4-amino-phenyl)-1-cyclobutyl-6-methansulfonylmethoxy-1H-indole-3-carbonitrile (891 mg, 91%) as a light pink solid.
  • Step D: 2-(4-Amino-phenyl)-1-cyclobutyl-6-methansulfonylmethoxy-1H-indole-3-carbonitrile (100 mg, 0.25 mmol) was combined with p-nitrophenyl chloroformate (120 mg, 0.6 mmol), DCE (1 mL), and pyridine (60 μL, 0.75 mmol) and stirred at room temperature for 1 h. To this mixture was added (R)-1-Cyclopropylethanol (90 μL, 0.92 mmol) and then heated at 80° C. for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with dilute aqueous NaOH solution. The organic layer was dried, concentrated and purified by silica gel chromatography (95:5 CH2Cl2/EtOAc) to provide (R)-[4-(3-cyano-1-cyclobutyl-6-methanesulfonylmethoxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (105 mg, 83%) as a white solid.
    • Example 1DV Preparation of [4-(3-cyano-1-cyclobutyl-6-morpholin-4-yl-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (compound 2800)
  • Figure US20100305100A1-20101202-C00580
  • Step A: To a solution of 6-nitroindole (16.2 g, 100 mmol) in DMF (60 mL) at 0° C. was added chlorosulfonylisocyanate (10.9 mL, 125.0 mmol). The mixture was then stirred at room temperature overnight, poured into ice-water (1.0 L) and stirred for 3 h. The precipitate was filtered, washed with water and dried in air to provide 3-cyano-6-nitroindole (17.63 g, 94%).
  • Step B: A mixture of 3-cyano-6-nitroindole (3.74 g, 20.0 mmol), cyclobutylbromide (2.27 mL, 24.0 mmol), Cs2CO3 (13.04 g, 40.0 mmol) in DMF (20 mL) was stirred at 90° C. in a sealed tube for 3 days. After cooling, the mixture was poured into ice-water (200 mL) and the precipitate was filtered, washed with water and transferred to a Paar hydrogenator. The hydrogenation was carried out with 5% Pd/C (1.0 g), in MeOH (50 mL) and EtOAc (50 mL) at 60 psi of H2 for 24 h. The mixture was filtered through Celite, washed with MeOH and concentrated to dryness to provide 6-amino-1-cyclobutyl-3-cyanoindole (3.13 g, 74%).
  • Step C: A mixture of 6-amino-1-cyclobutyl-3-cyanoindole (4.60 g, 21.8 mmol), bromoethylether (6.07 g, 26.16 mmol), DIEA (10.79 mL, 65.4 mmol) in DMF (100 mL) was stirred at 90° C. overnight and then poured into ice-water (1.0 L). The precipitate was filtered, washed with water, and purified on silica gel (CH2Cl2/EtOAc, 9:1) to provide 1-cyclobutyl-6-morpholin-4-yl-1H-indole-3-carbonitrile (5.24 g, 85%).
  • Step D: To a solution of 1-cyclobutyl-6-morpholin-4-yl-1H-indole-3-carbonitrile (1.20 g, 4.27 mmol), triisopropylborate (1.28 mL, 5.55 mmol) in THF (15 mL) at −78° C. was added LDA (1.5M mono THF in cyclohexane, 3.27 mL, 4.91 mmol) with stirring. The mixture was stirred at −78° C. for 10 minutes and at room temperature for 30 min followed by the addition of 4-iodoaniline (1.03 g, 4.70 mmol) and PdCl2(dppf) (0.16 g, 0.2 mmol). The reaction system was cooled to −78° C., flushed with nitrogen followed by the addition of DMF (30 mL) and aq. K2CO3 (2.0M, 6.4 mL, 12.8 mmol). The cooling bath was removed and the mixture was stirred overnight and poured into ice water (500 mL). The precipitate was filtered, washed with water, dried in air and purified on silica gel (CH2Cl2/EtOAc, 9:1) to give 2-(4-amino-phenyl)-1-cyclobutyl-6-morpholin-4-yl-1H-indole-3-carbonitrile (1.49 g, 94%).
  • Step E: A solution of 2-(4-amino-phenyl)-1-cyclobutyl-6-morpholin-4-yl-1H-indole-3-carbonitrile (0.112 g, 0.3 mmol), pyridine (1.0 mL) in CH2Cl2 (2.0 mL) was treated with isopropylchloroformate (1.0 M in toluene, 0.6 mL, 0.6 mmol). The mixture was stirred at room temperature for 5 h and diluted with CH2Cl2 (5 mL). The organic layer was separated, washed with HCl (1.0 N, 3×2 mL), water (5 mL×2) and brine (5 mL), and purified on silica gel (CH2Cl2/EtOAc, 9:1) to provide [4-(3-cyano-1-cyclobutyl-6-morpholin-4-yl-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (0.12 g, 87%).
    • Example 1DW Preparation of {4-[3-cyano-1-cyclobutyl-6-(tetrahydro-pyran-4-yloxy)-1H-indole-2-yl]-phenyl}-carbamic acid isopropyl ester (compound 2616)
  • Figure US20100305100A1-20101202-C00581
  • Step A: A mixture of 6-hydroxyindole (1.47 g, 6.93 mmol), toluene-4-sulfonic acid tetrahydro-pyran-4-yl ester (2.65 g, 10.42 mmol), K2CO3 (2.87 g, 20.77 mmol) and DMF (15 ml) was stirred at 80° C. overnight. After cooling, the reaction mixture was poured into ice-water (60 ml) to afford precipitate, which was collected by filtration, washed with water and ether/hexanes (1:1). The solid was dried under vacuum to obtain the product (1.76 g, 86%) as a brown solid.
  • Step B: A solution of 1-cyclobutyl-6-(tetrahydro-pyran-4-yloxy)-1H-indole-3-carbonitrile (1.68 g, 5.68 mmol) and triisopropyl borate (1.39 g, 7.38 mmol) in THF (15 mL) was cooled to −78° C. whereupon LDA (1.5 M in THF-cyclohexane, 4.73 mL, 7.10 mmol) was added dropwise. The reaction mixture was allowed to warm up to room temperature and continued stirring for 30 minutes. The reaction mixture was cooled to −78° C. 4-iodoaniline (1.31 g, 5.96 mmol) in DMF (10 mL), K2CO3 (2 M, 8.5 mL, 17.0 mmol), and PdCl2dppf (208 mg, 0.29 mmol) were added to it in sequence. The mixture was de-gassed, back-filled with N2 and then stirred at room temperature for 3 h. The reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous phase was washed with more EtOAc (40 mL). The combined organic phase was washed with water (2×30 mL), brine and dried over Mg2SO4, concentrated and purified on silica gel (EtOAc/hexanes, 10% to 50%) to afford the product (1.81 g, 83%) as a brown solid.
  • Step C: To a mixture of 2-(4-amino-phenyl)-1-cyclobutyl-6-(tetrahydro-pyran-4-yloxy)-1H-indole-3-carbonitrile (897.8 mg, 2.32 mmol), K2CO3 (7 mL), and ethyl acetate (7 mL) was added iPrOCOCl (6.9 mL, 1 M in toluene, 6.96 mmol). The resulting mixture was stirred at room temperature overnight. The organic layer was washed with brine, dried over Mg2SO4, concentrated and purified on silica gel (EtOAc/hexanes, 10% to 30%) to provide the product (1.01 g, 92%) as white solid.
    • Example 1DX Preparation of [4-(3-cyano-1-cyclobutyl-6-ethylsulfanyl-1H-indole-2-yl)-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (compound 2720)
  • Figure US20100305100A1-20101202-C00582
  • Step A: To a mixture of potassium hydride (30% wt. in mineral oil, 2.71 g, 20.2 mmol) and THF (30 mL) was added a solution of 6-bromoindole (3.98 g, 20.3 mmol) in THF (10 mL) at 0° C. After 15 minutes the solution was cooled to −78° C., and tert-butyllithium (1.5 M in pentane, 27.07 mL, 40.60 mmol) was added via syringe. The mixture was stirred at −78° C. for 10 min then ethyl disulfide (4.97 g, 40.6 mmol) in THF (10 mL) was added. The reaction mixture was allowed to warm to room temperature, poured into ice-sat. aq. NH4Cl (150 mL), and then extracted with EtOAc (150 mL). The organic phase was washed with water (150 mL), brine (150 mL), dried over Mg2SO4, concentrated, and purified on silica gel (EtOAc/hexane 5% to 15%), to provide 6-ethylsulfanyl-1H-indole (2.75 g, 77%) as a clear liquid.
  • Step B: To a mixture of 6-ethylsulfanyl-1H-indole (2.75 g, 15.54 mmol) in DMF (20 mL) was added chlorosulfonyl isocyante dropwise at −30° C. The temperature was raised to 0° C. after addition and stirred for 30 minutes. The mixture was partitioned between EtOAc and water. The organic layer was washed with water, brine, dried over Mg2SO4, concentrated and purified on silica gel (CH2Cl2) to provide 6-ethylsulfanyl-1H-indole-3-carbonitrile (3.25 g, 84%) as a white solid.
  • Step C: A mixture of 6-ethylsulfanyl-1H-indole-3-carbonitrile (2.13 g, 10.5 mmol) Cs2CO3 (6.9 g, 21 mmol), cyclobutyl bromide (1.78 g, 13.2 mmol) and DMF (20 mL) was heated to 85° C. overnight and, after cooling, partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over Mg2SO4, concentrated and purified on silica gel (EtOAc/hexane 5% to 30%) to provide 1-cyclobutyl-6-ethylsulfanyl-/H-indole-3-carbonitrile (2.58 g, 96%) as a light-yellow oil.
  • Step D: To a solution of 1-cyclobutyl-6-ethylsulfanyl-1H-indole-3-carbonitrile (2.58 g, 10.08 mmol), triisopropyl borate (2.47 g, 13.13 mmol) in THF (25 mL) was slowly added LDA (1.5 M in THF-cyclohexane, 9.41 mL, 14.1 mmol). The reaction mixture was allowed to warm to room temperature and continued stirring for 30 minutes. The reaction mixture was then cooled to −78° C. and 4-iodoaniline (2.42 g, 11.09 mmol) in DMF (10 mL), K2CO3 (15.5 mL, 31.00 mmol), and PdCl2dppf (368.0 mg, 0.50 mmol) were added. The mixture was degassed, back-filled with N2, stirred at room temperature for 3 h and then partitioned between EtOAc (40 mL) and water (40 mL). The aqueous phase was washed with more ethyl acetate (30 mL) and the combined organics were washed with water (2×40 mL), brine, dried over Mg2SO4, and then concentrated. A precipitate was collected by filtration, washed with water and ether afford 1.45 g of product. The filtrate was condensed and purified on silica gel (EtOAc/hexane 5% to 40) to afford a further 1.65 g of 2-(4-amino-phenyl)-1-cyclobutyl-6-ethylsulfanyl-/H-indole-3-carbonitrile (3.10 g, 89%) as a solid.
  • Step E: To 2-(4-amino-phenyl)-1-cyclobutyl-6-ethylsulfanyl-1H-indole-3-carbonitrile (230.0 mg, 0.66 mmol) was combined with p-nitrophenyl chloroformate (266 mg, 1.32 mmol), DCE (3.0 mL), and pyridine (104.7 mg, 1.32 mmol) and stirred at room temperature for 2 h. (R)-1-Cyclopropylethanol (115.0, 1.34 mmol) was added and mixture was heated at 80° C. for 2 h. The reaction mixture was diluted with EtOAc and washed with sat. aq. K2CO3 (2×15 mL), water, and brine. The organic layer was dried, concentrated and purified on silica gel (EtOAc/hexane 10%),) to provide (R)-[4-(3-cyano-1-cyclobutyl-6-ethylsulfanyl-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (209 mg, 69%) as a white solid.
    • Example 1DY Preparation of {4-[1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indole-2-yl]-phenyl}-carbamic acid 2,2,2-trifluoro-1-methyl-ethyl ester (compound 2888)
  • Figure US20100305100A1-20101202-C00583
  • Step A: To a solution of 6-methoxyindole (18.32 g, 124.0 mmol), di-(tert-butyl)dicarbonate (35.3 g, 162.2 mmol) in CH2Cl2 (120 mL) was added DMAP (200 mg, 1.64 mmol) at 0° C. The resulting mixture was stirred at room temperature for 16 h, concentrated and partitioned between EtOAc and water. The organic layer was washed with water, brine, dried, concentrated and purified on silica gel (EtOAc/hexane 5%) to provide 6-methoxy-indole-1-carboxylic acid t-butyl ester (30.4 g, 99%) as a solid.
  • Step B: To a solution of 6-methoxy-indole-1-carboxylic acid tert-butyl ester (14.33 g, 57.90 mmol) triisopropyl borate (15.25 g, 81.06 mmol) in THF (80 mL) at −78° C. was added LDA slowly. The resulting mixture was stirred at room temperature for 1 h, concentrated to half of its original volume, poured into ice-water (100 mL) and acidified with 1N HCl. A precipitate was collected by filtration, washed with water and hexanes to provide 2-Boronic acid 6-methoxy-indole-1-carboxylic acid t-butyl ester (14.2 g, 85% yield) as a brown solid.
  • Step C: To a solution of indole 2-boronic acid from Step B (5.98 g, 20.5 mmol) and 1-iodo-4-nitrobenzene (5.37 g, 21.6 mmol) in DMF (60 mL) was added aq. K2CO3 (2M, 30.8 mL, 61.6 mmol) dropwise at 0° C. and then PdCl2dppf (375.4 mg, 0.51 mmol). The mixture was degassed by three successive cycles of vacuum pumping/N2 backfilling, then stirred at room temperature for 5 h and partitioned between EtOAc and water. The organic layer was washed with water, brine, dried and concentrated. The residue was suspended in hexanes and a precipitate collected by filtration and washed with hexanes to afford the product (7.20 g, 95%) as a red solid.
  • Step D: To a solution of 6-methoxy-2-(4-nitro-phenyl)-indole-1-carboxylic acid tert-butyl ester (7.20 g, 19.55 mmol) in CH2Cl2 (50 mL) was added TFA (22 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature for 3 h, concentrated and suspended in ether to afford a solid, which was collected by filtration, washed with ether to provide 2.43 g of a red solid as the first crop product. The filtrate was condensed, and the residue was purified on silica gel (EtOAc/hexane 5% to 20%), to provide 1.55 g of a second crop of 6-methoxy-2-(4-nitro-phenyl)-1H-indole (combined: 3.98 g, 76% yield) as a red solid.
  • Step E: A mixture of 6-methoxy-2-(4-nitro-phenyl)-1H-indole (2.12 g, 7.90 mmol), Cs2CO3 (5.15 g, 15.80 mmol), cyclobutyl bromide (1.28 g, 9.48 mmol) and DMF (20 mL) was heated at 85° C. for 2 days. After cooling, the reaction mixture was partitioned between EtOAc and water. The organic phase was washed with water, brine, dried, concentrated and purified on silica gel (EtOAc/hexane 5% to 20 to provide the product (0.96 g, 37%) as a yellow solid.
  • Step F: A mixture of 1-cyclobutyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole (0.83 g, 2.60 mmol), iron powder (0.84 mg, 15.0 mmol), ammonium chloride (0.96 g, 18.0 mmol), and EtOH/water (25 mL/8 mL) was stirred at 80° C. for 1 h and concentrated. The residue was suspended in DMF (20 mL) and MeOH/CH2Cl2 (1:1, 20 mL). The mixture was passed through a Celite pad, washed with MeOH/CH2Cl2 (1:1), concentrated and water was added to afford a precipitate which was collected by filtration and washed with water. The solid was dissolved in CH2Cl2, dried over MgSO4, concentrated and purified on silica gel (EtOAc/hexane 20%) to provide 4-(1-cyclobutyl-6-methoxy-1H-indole-2-yl)-phenylamine (0.57 mg, 75%) as a white solid.
  • Step G: To a solution of 4-(1-cyclobutyl-6-methoxy-1H-indole-2-yl)-phenylamine (518.5 mg, 1.77 mmol) in CH2Cl2 (15 mL) was added borontribromide (1.33 g, 5.31 mmol) at −30° C. The resulting mixture was stirred at 0° C. for 2 h, poured into ice-water, neutralized with aq KHCO3 and then extracted with EtOAc. The aqueous phase was washed with more EtOAc and the combined organics were washed with water, brine, dried, concentrated and purified on silica gel (EtOAc/hexane 20%) to afford the product (480 mg, 98%) as a white solid.
  • Step H: A mixture of 2-(4-amino-phenyl)-1-cyclobutyl-1H-indole-6-ol (480 mg, 1.72 mmol), Cs2CO3 (1.12 g, 3.45 mmol), 2-chloropyridine (296 mg, 2.60 mmol) and DMF (3 mL) was stirred at 50° C. overnight. After cooling, the mixture was partitioned between EtOAc and water. The aqueous phase was washed with more ethyl acetate and the combined organics were washed with water, brine, dried, concentrated and purified on silica gel (EtOAc/hexane 25%) to afford the product the product (567 mg, 92% yield) as a white sold.
  • Step I: Prepared as in Example 1DX, step E.
    • Example 1DZ Preparation of {4-[3-cyano-1-cyclobutyl-6-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yloxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (compound 3182)
  • Figure US20100305100A1-20101202-C00584
  • Step A: To tetrahydrothiopyran-4-one in CH3CN (50 mL) and H2O (35 mL) at 0° C. was added in portions over 1 hour a mixture of oxone (70.5 g, 115 mmol) and NaHCO3 (29.9 g, 356 mmol). The reaction mixture was then stirred at room temperature for 1 h, diluted in CH3CN (250 mL) and filtered. The filtrate was concentrated, suspended in acetone and filtered. 1,1-Dioxo-tetrahydrothiopyran-4-one (6.3 g, quantitative yield) was obtained as a white solid.
  • Step B: To 1,1-dioxo-tetrahydrothiopyran-4-one (6.3 g, 36 mmol) in H2O (55 mL) was added, in portions, sodium borohydride (720 mg, 18.9 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then the pH was adjusted to 4 with aq. HCl. The reaction mixture was concentrated and suspended in acetone and filtered. The filtrate was concentrated and triturated with ether/hexane to provide 1,1-dioxo-tetrahydrothiopyran-4-ol (5.63 g, 90%) as a white solid.
  • Step C: 1,1-Dioxo-tetrahydrothiopyran-4-ol (1.0 g, 6.6 mmol), pyridine (10 mL), and tosyl chloride (1.6 g, 8.4 mmol) were combined and stirred at room temperature overnight. The reaction mixture was concentrated, diluted in EtOAc and washed with aqueous HCl and brine. The organic layer was dried, concentrated and triturated with hexane to yield O-tosyl-1,1-dioxo-tetrahydrothiopyran-4-ol (1.073 g, 53%) as a white solid.
  • Step D: [4-(3-Cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (90 mg, 0.23 mmol) was combined with Cs2CO3 (156 mg, 0.48 mmol), DMF (0.9 mL), and O-tosyl-1,1-dioxo-tetrahydrothiopyran-4-ol (96 mg, 0.32 mmol). The reaction mixture was heated overnight at 80° C., diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (95:5 CH2Cl2/EtOAc) to provide 4-[3-cyano-1-cyclobutyl-6-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yloxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (66 mg, 56%) as a white solid.
    • Example 1EA Preparation of 1-cyclobutyl-2-[4-(4-methyl-thiazol-2-ylamino)-phenyl]-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile (compound 3180)
  • Figure US20100305100A1-20101202-C00585
  • Step A: Prepared as in Example 1EA, step H.
  • Step B: 1. A solution of 6-pyrimidin-indole aniline (2.25 g, 5.90 mmol) prepared in Step A, Fmoc-NCS (1.74 g, 6.19 mmol) and CH2Cl2 (15 mL) was stirred at room temperature for 2 h, concentrated and washed with ethyl ether to afford Fmoc-indole-urea used without further purification. To the above solid was added CH2Cl2 (30 mL) and piperidine (5 mL). The resulting mixture was stirred at room temperature for 14 h, concentrated, washed with ether, dried and concentrated to afford the product (2.5 g, 96%) as a light-brown solid.
  • Step D: To a mixture of indole thiourea obtained in step C (150 mg, 0.34 mmol), DIPEA (88 mg, 0.68 mmol), isopropanol (3.5 mL) and DMSO (2.0 mL) was added 1-chloro-propan-2-one (92.5 mg, 47.6 mmol). The resulting mixture was stirred at 70° C. for 2 days. After cooling, the reaction mixture was partitioned between EtOAc and water and the organic layer was washed with water, brine, dried over MgSO4, and purified on silica gel (EtOAc/hexane 25%) the product (102 mg, 63% yield) as a brown solid.
    • Example 1EB Preparation of 1-cyclobutyl-2-[4-(2,5-dimethyl-2H-pyrazol-3-ylamino)-phenyl]-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile (compound 3285)
  • Figure US20100305100A1-20101202-C00586
  • Step A: A mixture of 2,5-dimethyl-2H-pyrazol-3-ylamine (2.53 g, 22.8 mmol), acetic anhydride (2.67 g, 26.2 mmol) and acetic acid (10 mL) was stirred at 50° C. for 3 h. After cooling, the mixture was treated with sat. aq. NaHCO3 to afford a precipitate, which was collected by filtration, washed with water and hexanes, and dried to provide the product (3.43 g, quant.) as a white solid.
  • Step B: To N-(2,5-dimethyl-2H-pyrazol-3-yl)-acetamide (2.01 g, 13.1 mmol), 1,4-diiodobenzene (5.20 g, 15.8 mmol), K3PO4 (5.57 g, 26.2 mmol), CuI (125 mg, 0.66 mmol), and dioxane (50 mL), was added N,N-dimethyl-cyclohexane-1,2-diamine The mixture was degassed by three successive cycles of vacuum pumping/N2 backfilling, then stirred at reflux for 14 h. After cooling, the mixture was partitioned between EtOAc and water and the organic layer was washed with water, brine, dried over Mg2SO4, concentrated and purified on silica gel (EtOAc/CH2Cl2 20%) to afford the product (4.91 g, 69%) as a white solid.
  • Step C. Prepared N-[4-cyano-1-cyclobutyl-6-hydroxy-1H-indole-yl)-phenyl]-N-(2,5-dimethyl-2H-pyrazol-3-yl)-acetamide (2.12 g, 86% yield) as in Example 1EI, Step D.
  • Step D. A mixture of N-[4-cyano-1-cyclobutyl-6-hydroxy-1H-indole-yl)-phenyl]-N-(2,5-dimethyl-2H-pyrazol-3-yl)-acetamide (1.54 g, 3.50 mmol) and HCl (6N, 6 mL) was stirred at 80° C. for 15 h. After cooling, the reaction mixture was partitioned between EtOAc and water and organic layer was washed with sat. aq. NaHCO3, water, brine, dried over MgSO4, and concentrated. The residual solid was washed with ether to afford the product (1.27 g, 92% yield) as a brown solid.
  • Step E: 1-cyclobutyl-2-[4-(2,5-dimethyl-2H-pyrazol-3-ylamino)-phenyl]-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile (PS102656) was prepared as in Example 3, step H.
    • Example 1EC {4-[3-Cyano-1-cyclobutyl-6-(2-methanesulfonyl-vinyloxy)-1H-indol-2-yl]-phenyl}-carbamic acid tert-butyl ester (compound 3301)
  • Figure US20100305100A1-20101202-C00587
  • To a solution of the indole triflate (1.07 g, 2.00 mmol) in DMF (2 mL) was added methyl vinyl sulfone (432 mg, 3.99 mmol), bis(triphenylphosphine)palladium(II) chloride (72 mg, 0.103 mmol) and Et3N (0.84 mL, 6.03 mmol). The mixture was purged with nitrogen and heated at 90° C. for 20 h then additional methyl vinyl sulfone (106 mg, 1 mmol) and bis(triphenylphosphine)palladium (72 mg, 0.10 mmol) were added. The mixture was heated for 20 h at 90° C. then cooled to room temperature. Water (14 mL) was added and the solid was filtered, washed with water, dried and purified on silica gel (EtOAc/1:1 CH2Cl2-hexanes 0-10%) to give the product (250 mg, 26%) as a tan solid.
    • Example 1ED Preparation of (R)-{4-[3-cyano-1-cyclopropyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropylethyl ester (compound 3321)
  • Figure US20100305100A1-20101202-C00588
  • Step A: To a solution of 1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile (4.24 g, 20 mmol) in THF (60.0 mL) at −78° C. was added LDA (30.7 mL, 46.0 mmol) and iodine (7.62 g, 30.0 mmol). The mixture was stirred at −78° C. for 10 min, warmed to room temperature and stirred for 3 h. The reaction mixture was poured into ice-water (500 mL) and the precipitate was filtered and washed with water and CH2Cl2. After drying in air the crude iodide obtained (3.99 g) was taken up in DMF (25 mL) and Cs2CO3 (9.78 g, 30.0 mmol) and 2-chloropyrimidine (2.18 g, 19.0 mmol) were added to this solution. The mixture was stirred at 70° C. for 30 min, poured into ice water (200 mL) and the precipitate was collected on a filter, washed with water and purified on silica gel (CH2Cl2/EtOAc, 9.75:0.25) to provide 1-cyclobutyl-2-iodo-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile (1.52 g, 47%).
  • Step B: The iodide obtained in Step A (0.83 g, 2.0 mmol), 5-(4,4,5,5-eetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (0.48 g, 2.2 mmol), PdCl2(dppf) (0.07 g, 0.1 mmol) were mixed with DMF (10.0 mL), followed by the addition of aq. K2CO3 (2.0 M, 3.0 mL, 6.0 mmol). The mixture was stirred at 80° C. overnight and poured into ice-water (100 mL). The precipitate was filtered, washed with water and purified on silica gel (CH2Cl2/EtOAc/MeOH, 5:5:0.2) to furnish 2-(6-amino-pyridin-3-yl)-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile (0.61 g, 80%).
  • Step C: A mixture of 2-(6-amino-pyridin-3-yl)-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile (115 mg, 0.3 mmol), 4-nitrophenylchloroformate (91 mg, 0.45 mmol) in pyridine (1.0 mL) was stirred at 30° C. for 2 h, followed by the addition of (R)-1-cyclopropylethanol (150 μL, 1.5 mmol). The mixture was stirred at 80° C. overnight and diluted with water (10 mL) and CH2Cl2 (5 mL). The organic layer was washed with water (3×5 mL), HCl (2N, 3×5 mL), sat. aq. NaHCO3 (3×5 mL) and purified on silica gel (CH2Cl2/EtOAc, 1:9) to provide (R)-{4-[3-cyano-1-cyclopropyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropylethyl ester (25 mg, 17%).
    • Example 2 Screening of Low Molecular Weight Compounds Using a Cell-Based HCV IRES Monocistronic Translation Assay
  • Chemical libraries are screened using a cell-based monocistronic HCV IRES-regulated translation assay designed to closely mimic natural HCV mRNA translation and then compound analogs are made based on hits in the chemical libraries and screened as well. A DNA construct is prepared, termed pHCVIRESmono, in which HCV IRES sequences (HCV 2b, nucleotides 18-347) are inserted between a promoter and the firefly luciferase (Fluc) reporter gene. A stably transfected HepG 2 (hepatoblastoma) cell line (termed HepGmono-4) or a Huh7 cell line (termed Huhmono 7), or a Hela-cell line (termed Helamono), are established by transfection with the pHCVIRESmono DNA by selecting for resistance to hygromycin.
    • Example 3 Determination of Selectivity for HCV IRES-Regulated Translation Using the Cell-Based Cap-Dependent Translation Assays
  • Since translation assays are used to screen HCV IRES inhibitors, the selected hits may specifically act on HCV IRES-driven translation or may modulate general protein synthesis in mammalian cells. The compounds that act on general translation will most likely have significant toxicity. To address this possibility, various cell-based cap-dependent translation assays are established for the further evaluation of all selected compounds. Plasmid DNAs containing 130 nucleotides of vector sequence 5′ to Fluc are constructed. This construct is referred to herein as pLuc. A stable cell line is established in cap-dependent translation assays using 293T cells (a human embryonic kidney cell line). HepGmono-4 and pLuc are treated with compound for 20 hours and activity is determined by quantifying the Fluc signal. A five-fold selectivity between the HCV IRES and cap-dependent translation is considered to be desirable. Using these cell-based cap-dependent translation assays, compounds are identified that show IC50 values that are at least 5-fold greater in the cap-dependent translation assays than in the HCV IRES translation assay.
  • Western blotting assays are used to further demonstrate that compounds selectively inhibit HCV IRES-driven translation. Both HepGmono-4 and pLuc cells are treated with the compounds as described above, following treatment with the test compounds for 20 hours, cells are collected and lysed in Laminin buffer containing 0.5% SDS. Proteins are separated on a 10% SDS-PAGE, then transferred onto a nitrocellulose membrane, and blotted using antibodies against Fluc (RDI) and β-actin (Oncogene). For example, some compounds of the present invention are tested in this manner.
  • Testing conditions for these cell lines are optimized and the effects of mRNA level on activity of the compounds are controlled by quantitating Fluc mRNA levels by RT real-time PCR. For example, some of the compounds of the present invention are tested in this manner.
    • Example 4 Evaluation of the Selectivity for HCV IRES-Driven Translation Using Cellular IRES-mediated translation assays
  • A number of human mRNAs have been shown to harbor IRES elements (18, 19, 39, 44, 45, 91, 126, 130). Although the primary sequences and secondary structures of the HCV IRES are different from those of cellular IRESs, an important test for selectivity is to determine whether the selected compounds are active against cellular IRESs. The VEGF IRES has poor initiation activity in in vitro assays, but demonstrates substantial activity in cell-based translation assays (18, 45). For example, some of the compounds of the present invention are tested
    • Example 5 Evaluation of Cytotoxicity
  • Effects on cell proliferation are a critical issue for any drug discovery effort. Therefore, a cell proliferation/cytotoxicity assay is used to eliminate any compounds that affect mammalian cell growth. The effects of the selected hits on cell proliferation are tested in human cell lines 293 T and Huh7 (a human hepatoblastoma cell line). Cells are grown in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, L-glutamine, penicillin, and streptomycin. Cells in log phase are treated with test compounds for three days, with 250 μM being the highest concentration of test compound used. The effect of the compounds on cell proliferation is assessed by using the CellTiter 96 AQueous One Solution Cell Proliferation Assay (Promega, Madison, Wis.). Compounds that have at least 5-fold higher CC50 values relative to IC50 values in HepGmono-4 are considered to have a sufficient window between activity and cytotoxicity and are selected for further evaluation.
    • Example 6 Evaluation of the Efficacy of the Compounds in the HCV Replicon System
  • The lack of reliable and readily accessible cell-culture and small animal models permissive for HCV replication has limited the development of new anti-HCV agents. Self-replicating subgenomic HCV systems, termed HCV replicons, have recently been described and have been widely used to assess the efficacy of anti-HCV inhibitors (8, 70, 104). Interferon (IFN) α and inhibitors of the HCV protease and polymerase have been reported to be active in the HCV replicon system (8, 17, 32, 68, 69, 117).
  • HCV replicons that include bicistronic and monocistronic systems are identified and assays for testing the HCV IRES inhibitors are established. In the bicistronic replicons, the HCV IRES directs the expression of the selective marker (Neo and/or a Fluc reporter), and the EMCV IRES mediates the expression of viral non-structural proteins. In the monocistronic replicon, the HCV IRES directly mediates viral protein synthesis. The HCV IRES inhibitors are analyzed in the bicistronic replicon by quantitating the Fluc reporter signal. Replicon-containing cells are cultured with the compounds of the invention for 2 days or for 3 days. Interferon (IFN) α is used as a positive control. For example, some compounds of the present invention are tested in this manner.
  • In the following table (Table 1A),
      • *=replicon or HCV-PV IC50>2 uM
      • **=replicon or HCV-PV IC50 between 0.5 uM and 2 uM
      • ***=replicon or HCV-PV IC50<0.5 uM
        Replicon IC50 values are determined by firefly luciferase signal.
        HCV-PV IC50 values are determined by viral RNA reduction.
  • TABLE 1A
    Mass Replicon Replicon
    Melting Spec IC50μM IC50μM
    Compound Point (° C.) [M + H] 2-day 3-day 1H NMR Data
    1330 148-151 394.18 **
    1331 157-160 408.20 **
    1332 213-215 440.2 **
    1333 160-164 482.2 **
    1334 87-88 460.25 (M − H+) ** ***
    1335 179-180 488.31 **
    1336 173-176 488.31 (M − H+) **
    1337 183-184 **
    1338 186-187 389.4 **
    1339 177-178 432.3 **
    1340 249-250 428.3 ***
    1341 170-171 416.3 **
    1342 232-234 498.17 *** ***
    1343 155-158 405.24 **
    1344 294-296 398.15 *
    1345 201-203 401.21 (M − H+) *** ***
    1346 226-228 416.29 *
    1347 Foam 437.10 **
    1348 134.2-139.5 392.1 ** (CDCl3, 300 MHz), δ 7.63 (d, J = 8.7 Hz,
    1H), 7.53 (d, J = 8.7 Hz, 2H), 7.32 (d,
    J = 8.7 Hz, 2H), 6.96 (dd, J = 2.1 Hz and
    8.7 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H),
    4.14 (q, J = 6.9 Hz, 2H), 3.90 (s, 3H),
    3.49-3.40 (m, 4H), 1.36-1.21 (m, 9H).
    1349 111.3-116.5 423.4 ** (CDCl3, 300 MHz), δ 7.63 (d, J = 8.7 Hz,
    1H), 7.52 (d, J = 8.4 Hz, 2H), 7.31 (d,
    J = 7.8 Hz, 2H), 6.96 (dd, J = 2.1 Hz and
    8.7 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H),
    4.61-4.43 (m, 1H), 4.14 (q, J = 7.5 Hz, 2H),
    3.90 (s, 3H), 2.97-2.90 (m, 3H), 1.34 (t,
    J = 7.2 Hz, 3H), 1.30-1.16 (m, 6H).
    1350 173.6-182.1 435.5 ** (CDCl3, 300 MHz), δ 7.63 (d, J = 8.1 Hz,
    1H), 7.52 (d, J = 8.4 Hz, 2H), 7.30 (d,
    J = 8.4 Hz, 2H), 6.97 (d, J = 7.5 Hz, 1H),
    6.87 (s, 1H), 4.14 (q, J = 6.6 Hz, 2H), 3.90 (s,
    3H), 3.64-3.48 (m, 4H), 1.72-1.62 (m,
    6H), 1.34 (t, J = 6.3 Hz, 3H).
    1351 197.1-205.3 421.5 ** (CDCl3, 300 MHz), δ 7.63 (d, J = 8.7 Hz,
    1H), 7.52 (d, J = 8.7 Hz, 2H), 7.33 (d,
    J = 8.4 Hz, 2H), 6.96 (dd, J = 1.8 Hz and
    8.4 Hz, 1H), 6.88 (s, 1H), 4.14 (q,
    J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.60 (t,
    J = 6.6 Hz, 2H), 3.51 (t, J = 6.6 Hz, 2H),
    2.04-1.91 (m, 4H), 1.34 (t, J = 6.9 Hz, 3H).
    1352 Foam 439.25 **
    1353 Foam 441.24 **
    1354 110-115 488.3 **
    1355 163-164 400.26 (M − H+) **
    1356 251-252 550.4 ** ***
    1357 278-280 554.3 ** **
    1358 260-261 554.3 ***
    1359 254-256 504.3 **
    1360 163-165 453.22 *** **
    1361 238-241 467.22 **
    1362 236-238 542.27 **
    1363 168-171 451.21 ** **
    1364 128-131 451.21 **
    1365 112-114 436.3 *** **
    1366 168-169 336.3 **
    1367 191-194 394.2 *** **
    1368 175-177 408.2 *** ***
    1369 154-156 422.2 *** ***
    1370 145-148 436.2 *** ***
    1371 166-168 426.2 *** ***
    1372 107-109 470.2 *** ***
    1373 148-151 442.1 **
    1374 158-161 514.3 **
    1375 108-120 418.2 **
    1376 165-167 391.2 **
    1377 161-163 417.2 **
    1378 147-150 435.3 **
    1379 152-155 461.4 **
    1380 216-218 447.3 **
    1381 151-154 433.3 **
    1382 110-114 495.4 **
    1383 196-198 524.4 **
    1384 175-176 483.3 **
    1385 122-127 408.0 ** (CDCl3, 300 MHz), δ 7.63 (d, J = 8.7 Hz,
    1H), 7.54-7.51 (m, 2H), 7.34-7.29 (m,
    2H), 6.96 (dd, J = 2.4 Hz and 8.7 Hz, 1H),
    6.87 (d, J = 2.1 Hz, 1H), 4.13 (q, J = 7.2 Hz,
    2H), 3.90 (s, 3H), 3.64-3.56 (m, 4H),
    3.40 (d, J = 1.8 Hz, 3H), 3.14 (d, J = 29.7 Hz, 3H),
    1.34 (t, J = 7.2 Hz, 3H).
    1386 213-214 405.34 ** 1H NMR (300 MHz, DMSO-d6): δ
    8.44 (1H, s), 7.72 (2H, d, J = 8.8 Hz),
    7.50 (1H, d, J = 8.8 Hz), 7.44 (2H, d, J = 8.8 Hz,),
    7.24 (1H, d, J = 2.0 Hz), 6.91 (1H,
    dd, J = 8.8, 2.0 Hz), 4.15 (2H, t, J = 7.2 Hz),
    3.84 (3H, s), 3.36 (4H, q, J = 7.0 Hz),
    1.56 (2H, hx, J = 7.0 Hz), 1.10 (6H, t, J = 7.0 Hz),
    0.64 (3H, t, J = 7.2 Hz).
    1387 65-70 477.38 * 1H NMR (300 MHz, DMSO-d6): δ
    8.54 (1H, s), 7.40 (2H, d, J = 8.8 Hz),
    7.28 (1H, d, J = 8.5 Hz), 7.24 (2H, d, J = 8.8 Hz),
    6.89 (1H, d, J = 2.0 Hz), 6.62 (1H,
    dd, J = 8.5, 2.0 Hz), 6.06 (1H, t, J = 5.7 Hz),
    3.98-3.91 (2H, m), 2.85 (2H, q, J = 6.1 Hz),
    1.30-1.20 (2H, m), 0.76 (9H, s),
    0.67 (3H, t, J = 7.3 Hz), 0.00 (6H, s).
    1388 161-164 429.25 **
    1389 171-173 500.2 ***
    1390 217-223 No **
    ionization
    1391 195-200 433.25 **
    1392 193-197 478.39 (ES−) ***
    1393 193-197 478.39 (ES−) ***
    1394  96.5-100.6 502.2 *** (MeOD, 300 MHz), δ 7.78 (d, J = 8.4 Hz,
    2H), 7.52-7.45 (m, 3H), 7.17 (s, 1H),
    7.02 (dd, J = 1.8 Hz and 8.4 Hz, 1H), 4.40 (t,
    J = 4.2 Hz, 2H), 4.19 (q, J = 6.9 Hz, 2H),
    3.89 (t, J = 4.2 Hz, 4H), 3.63-3.59 (m, 4H),
    3.45 (t, J = 6.3 Hz, 2H), 3.29-3.23 (m, 4H),
    1.85-1.77 (m, 1H), 1.25 (t, J = 7.2 Hz, 3H),
    0.98-0.86 (m, 4H).
    1395 95.9-99   486.3 ** *** (MeOD, 300 MHz), δ 7.79 (d, J = 8.4 Hz,
    2H), 7.54-7.48 (m, 3H), 7.19 (s, 1H),
    7.02 (d, J = 7.8 Hz, 1H), 4.46-4.41 (m, 2H),
    4.21 (q, J = 6.9 Hz, 2H), 3.84-3.79 (m, 4H),
    3.66-3.61 (m, 4H), 3.51 (br, 2H), 2.96 (s, 3H),
    2.32 (br, 2H), 1.81-1.79 (m, 1H), 1.26 (t,
    J = 7.2 Hz, 3H), 0.97-0.87 (m, 4H).
    1396 192-198 455.30 *** ***
    1397 170-171 434.27 *** ***
    1398 166-167 448.27 *** ***
    1399 125-126 448.27 *** ***
    1400 168-169 474.26 **
    1401 182-183 516.25 *** ***
    1402 144-145 494.20 (M − H+) *** ***
    1403 168-171 483.1 ***
    1404 174-176 407.2 ***
    1405 182-185 421.3 *** ***
    1406 141-144 422.3 *** ***
    1407 137-140 448.3 **
    1408 199-203 419.41 ***
    1409 152-155 447.26 ***
    1410 153-155 486.7 ***
    1411 173-174 506.3 *** ***
    1412 198-200 446.00 (M − H+) ** 1H NMR (300 MHz, CDCl3): δ 7.61 (1H, d,
    J = 8.8 Hz), 7.50 (2H, d, J = 8.6 Hz),
    7.36 (2H, d, J = 8.6 Hz), 7.29 (1H, d, J = 1.9 Hz),
    7.03 (1H, s), 6.99 (1H, dd, J = 8.0, J = 2.2 Hz),
    4.95 (2H, m), 4.23 (2H, t, J = 4.7 Hz),
    4.00 (1H, m), 2.81 (2H, t, J = 4.7 Hz),
    3.49 (3H, s), 2.82 (2H, m), 2.35 (2H,
    m), 1.80 (2H, m), 1.20 (6H, d, J = 6.3 Hz).
    1413 90.2-95.4 474.1 ** (CD3CN, 300 MHz), δ 9.04 (s, 1H),
    7.80 (d, J = 8.7 Hz, 2H), 7.57 (d, J = 8.4 Hz, 1H),
    7.50 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 1.5 Hz,
    1H), 6.99 (dd, J = 1.5 Hz and 8.7 Hz, 1H),
    4.44 (t, J = 4.2 Hz, 2H), 4.15 (q, J = 7.2 Hz,
    2H), 3.59-3.51 (m, 6H), 2.90 (s, 3H),
    2.84 (s, 6H), 1.78-1.72 (m, 1H), 1.25 (t,
    J = 7.2 Hz, 3H), 0.93-0.82 (m, 4H).
    1414 163.9-168.8 516.5 ** (CD3CN, 300 MHz), δ 8.90 (s, 1H),
    7.79 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 8.7 Hz, 1H),
    7.50 (d, J = 8.7 Hz, 2H), 7.11 (d, J = 1.5 Hz,
    1H), 6.96 (dd, J = 1.8 Hz and 8.7 Hz, 1H),
    4.43 (t, J = 4.2 Hz, 2H), 4.15 (q, J = 7.2 Hz,
    2H), 3.71-3.68 (m, 8H), 3.70-3.67 (m,
    2H), 3.54 (br, 2H), 3.32-3.29 (m, 5H),
    1.95-1.92 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H),
    0.90-0.82 (m, 4H).
    1415 220-222 474.22 *** 1H NMR (300 MHz, DMSO-d6): δ
    8.75 (1H, s), 7.62-7.39 (7H, m), 6.98 (1H, d, J = 8.8 Hz),
    6.27 (1H, t, J = 5.4 Hz),
    5.19 (2H, s), 4.18 (2H, q, J = 7.3 Hz),
    3.05 (2H, q, J = 6.4 Hz), 2.65 (3H, s),
    1.44 (2H, hx, J = 7.3 Hz), 1.18 (3H, t, J = 7.0 Hz),
    0.87 (3H, t, J = 7.5 Hz).
    1416 115-121 489.35 **
    1417 192-193 466.28 ***
    1418 183-185 533.4 *** ***
    1419 121-123 514.5 *** ***
    1420 209-215 515.6 *** ***
    1421 138-140 513.3 **
    1422 201-203 516.6 *** ***
    1423 192-193 474.36 *** **
    1424 65-72 476.33 (ES−) **
    1425 153-160 471.48 *** ***
    1426 159-164 468.37 *** ***
    1427 211-213 517.3 *** **
    1428 141-145 518.4 ***
    1429 132-134 478.4 ***
    1430 122-125 487.3 ***
    1431 136-138 432.3 (ES−) ***
    1432 187-194 467.47 ***
    1433 153-156 437.50 ***
    1434 221-223 487.6 ***
    1435 161-165 503.5 ***
    1436 76-79 463.4 ***
    1437 74-76 522.4 ***
    1438 76-79 496.4 ***
    1439 74-76 514.4 **
    1440 232-236 459.43 ***
    1441 192-196 447.40 **
    1442 144-145 549.2 **
    1443 199-201 360.1 ***
    1444 189-191 472.4 ***
    1445 112-115 508.4 ***
    1446 207-208 474.4 ***
    1447 220-222 488.4 ***
    1448 182-184 525.4 ***
    1449 180-181 446.3 ***
    1450 162-163 468.41 **
    1451 163-164 453.41 ***
    1452 183-184 460.44 ***
    1453 183-184 486.49 ***
    1454 183-184 514.53 (M − H+) ***
    1455 183-184 472.45 ***
    1456 183-184 520.43 (M − H+) ***
    1457 183-184 514.43 ***
    1458 183-184 500.49 (M − H+) ***
    1459 183-184 500.43 (M − H+) ***
    1460 183-184 512.34 (M − H+) ***
    1461 183-184 472.31 (M − H+) **
    1462 183-184 459.43 **
    1463 482.35 **
    1464 496.41 ***
    1465 418.31 ***
    1466 223-224 434.3 ***
    2600 200-202 446.3 ***
    2601 191-193 432.3 ***
    2602 202-204 458.3 ***
    2603 167-169 480.3 ***
    2604 256 562.5 **
    (decomp.)
    2605 204-205 497.4 ***
    2606 148-150 496.4 ***
    2607 209-211 496.4 ***
    2608 153-155 436.4 ***
    2609 165-166 448.4 ***
    2610 181-183 464.4 ***
    2611 115-116 462 *** 1H NMR (300 MHz, CDCl3): δ 7.62 (1H, d,
    J = 8.8 Hz), 7.55 (2H, d, J = 8.8 Hz),
    7.42 (2H, d, J = 8.8 Hz), 7.27 (1H, d, J = 2.0 Hz),
    6.98 (1H, dd, J = 8.8, 2.0 Hz),
    6.73 (1H, s), 5.05 (1H, hp, J = 6.4 Hz),
    4.93 (1H, p, J = 8.8 Hz), 4.25-4.21 (2H, m),
    3.87-3.83 (2H, m), 3.64 (2H, q, J = 7.0 Hz),
    2.91-2.78 (2H, m), 2.40-2.28 (2H,
    m), 2.00-1.89 (1H, m), 1.88-1.77 (1H, m),
    1.32 (6H, d, J = 6.4 Hz), 1.28 (3H, t, J = 7.0 Hz).
    2612 148-150 461 *** 1H NMR (300 MHz, CDCl3): δ 7.62 (1H, d,
    J = 8.8 Hz), 7.49 (2H, d, J = 8.8 Hz),
    7.38 (2H, d, J = 8.8 Hz), 7.29 (1H, d, J = 2.3 Hz),
    6.99 (1H, dd, J = 8.8, 2.3 Hz),
    6.75 (1H, s), 4.96 (1H, p, J = 8.9 Hz),
    4.75 (1H, d, J = 7.9 Hz), 4.25-4.21 (2H, m),
    4.02 (1H, m, J = 7.3 Hz), 3.90-3.86 (2H,
    m), 3.64 (2H, q, J = 7.0 Hz),
    2.90-2.78 (2H, m), 2.40-2.28 (2H, m),
    1.98-1.88 (1H, m), 1.87-1.77 (1H, m), 1.28 (3H, t, J = 7.0 Hz),
    1.21 (6H, d, J = 6.6 Hz).
    2613 141-142 488 *** 1H NMR (300 MHz, CDCl3): δ 7.62 (1H, d,
    J = 8.8 Hz), 7.55 (2H, d, J = 8.8 Hz),
    7.42 (2H, d, J = 8.8 Hz), 7.27 (1H, d, J = 2.0 Hz),
    6.97 (1H, dd, J = 8.8, 2.0 Hz),
    6.75 (1H, s), 4.93 (1H, p, J = 8.7 Hz),
    4.34 (1H, dq, J = 8.4, 6.4 Hz), 4.27-4.23 (2H,
    m), 3.88-3.84 (2H, m), 3.64 (2H, q, J = 7.0 Hz),
    2.88-2.76 (2H, m), 2.39-2.27 (2H,
    m), 2.01-1.91 (1H, m), 1.90-1.80 (1H, m),
    1.38 (3H, d, J = 6.4 Hz), 1.27 (3H, t, J = 7.0 Hz),
    1.08-0.98 (1H, m), 0.62-0.42 (3H,
    m), 0.37-0.27 (1H, m).
    2614 181-182 464.4 **
    2615 118-120 500.4 ***
    2616 197-199 474.4 ***
    2617 127-129 502.4 ***
    2618 96-98 534.3 (M − 1) ***
    2619 102-103 534.3 (M − 1) ***
    2620 146-147 488.4 ***
    2621 145-146 486.4 (M − 1) ***
    2622 198-200 527.8 (M − 1) ***
    2623 190-192 486.4 ***
    2624 160-161 514.4 (M − 1) ***
    2625 187-189 473.4 ***
    2626 130-132 485.4 ***
    2627 523.1 **
    2628 575.2 *
    2629 194-195 483.4 ***
    2630 182-184 390.2 ***
    2631 185-188 482.4 ***
    2632 155-161 427.1 ***
    2633 170-175 426.3 ***
    2634 135-140 519.2 ***
    2635 175-180 457.3 ***
    2636 122-124 516 *** 1H NMR (300 MHz, CDCl3): δ 7.63 (1H, d,
    J = 8.8 Hz), 7.57 (2H, d, J = 8.8 Hz),
    7.45 (2H, d, J = 8.8 Hz), 7.27 (1H, dd, J = 8.8,
    2.3 Hz), 6.98 (1H, d, J = 2.3 Hz),
    6.93 (1H, br s), 5.35 (1H, hp, J = 6.6 Hz),
    4.92 (1H, p, J = 8.9 Hz), 4.23 (2H, m),
    3.86 (2H, m), 3.64 (2H, q, J = 7.0 Hz),
    2.89-2.72 (2H, m), 2.40-2.29 (2H, m),
    2.00-1.78 (2H, m), 1.49 (3H, d, J = 6.7 Hz),
    1.28 (3H, t, J = 7.0 Hz). 19F NMR (282 MHz,
    CDCl3): δ −79.17 (3F, d, J = 7.9 Hz).
    2637 485.4 ***
    2638 196-197 458.3 (M − 1) ***
    2639 101-109 325.4 **
    2640 178-184 411.3 ***
    2641 191-197 410.3 ***
    2642 93-95 592.5 ***
    2643 168-169 567.3 ***
    2644 108-110 593.5 ***
    2645 118-120 629.2 ***
    2646 187-189 530.3 ***
    2647 130-133 486.4 ***
    2648 203-205 502.3 ***
    2649 207-209 514.4 ***
    2650 540.4 ***
    2651 590.4 ***
    2652 576.4 ***
    2653 189-192 539.4 ***
    2654 100-104 453.3 ***
    2655 121-122 554.3 (M − 1) ***
    2656 270-272 592.4 ***
    2657 202-205 584.3 **
    2658 471.4 ***
    2659 102-105 489.4 ***
    2660 487.4 ***
    2661 195-202 464.3 * (CDCl3, 400 MHz), δ 7.91 (d, J = 8.4 Hz,
    2H), 7.68-7.64 (m, 3H), 7.18 (d, J = 2.0 Hz,
    1H), 7.00 (dd, J = 8.8 Hz and 1.6 Hz, 1H),
    4.91-4.87 (m, 1H), 4.14 (q, J = 7.2 Hz, 2H),
    3.09 (t, J = 4.8 Hz, 4H), 2.78-2.70 (m, 2H),
    2.38-2.31 (m, 2H), 1.96-1.80 (m, 2H),
    1.69-1.65 (m, 4H), 1.51-1.48 (m, 5H).
    2662 505.4 ***
    2663 491.3 ***
    2664 509.4 ***
    2665 507.3 ***
    2666 186-191 498.4 (M − 1) ***
    2667 184-190 517.4 (M + NH4) ***
    2668 195-197 528.3 ***
    2669 128-131 464.4 ***
    2670 204-205 478.4 ***
    2671 148-150 444.3 ***
    2672 510.4 ***
    2673 509.4 ***
    2674 510.5 ***
    2675 511.3 ***
    2676 494.3 ***
    2677 190-192 495.4 ***
    2678 530.3 ***
    2679 531.4 ***
    2680 531.4 ***
    2681 545.4 ***
    2682 544.3 ***
    2683 545.4 ***
    2684 221-223 481.3 ***
    2685 205-206 482.4 ***
    2686 162-165 490.2 ***
    2687  89-112 516.3 ***
    2688 150-155 552.4 ***
    2689 180-183 480.0 * (CDCl3, 300 MHz), δ 8.01 (d, J = 8.4 Hz,
    2H), 7.69-7.65 (m, 3H), 7.17 (d, J = 2.1 Hz,
    1H), 6.99 (dd, J = 8.7 Hz and 1.8 Hz, 1H),
    4.92-4.83 (m, 1H), 4.14 (q, J = 7.2 Hz, 2H),
    3.77-3.71 (m, 3H), 3.77-3.69 (m, 1H),
    3.58-3.51 (m, 1H), 2.80-2.67 (m, 2H),
    2.37-2.34 (m, 2H), 2.00-1.79 (m, 5H),
    1.70-1.61 (m, 1H), 1.57 (t, J = 7.2 Hz, 3H).
    2690 170-172 480.0 *** (CDCl3, 400 MHz), δ 8.01 (d, J = 8.4 Hz,
    2H), 7.68-7.65 (m, 3H), 7.18 (d, J = 2.0 Hz,
    1H), 6.99 (d, J = 8.8 Hz and 2.0 Hz, 1H),
    4.91-4.87 (m, 1H), 4.14 (q, J = 7.2 Hz, 2H),
    3.77-3.70 (m, 3H), 3.58-3.52 (m, 1H),
    3.37-3.31 (m, 1H), 2.76-2.71 (m, 2H),
    2.36-2.34 (m, 2H), 2.08-1.76 (m, 5H),
    1.62-1.56 (m, 1H), 1.47 (t, J = 7.2 Hz, 3H).
    2691 128-132 473.1 ***
    2692 176-183 472.2 ***
    2693  78-110 499.2 ***
    2694 155-160 536.4 *** 1H-NMR (CDCl3) δ 7.63 (d, 1H), 7.55 (m,
    2H), 7.43 (d, 2H), 7.18 (d, 1H), 6.91 (dd,
    1H), 6.78 (s, 1H), 4.94 (q, 1H), 4.34 (m,
    1H), 4.21 (t, 2H), 3.32 (t, 2H), 2.93 (s,
    3H), 2.81 (m, 2H), 2.41 (m, 4H),
    1.93-1.40 (m, 4H), 1.40 (t, 3H), 1.03 (m, 1H),
    0.59-0.48 (m, 3H), 0.32 (m, 1H).
    2695 135-140 522.32 ***
    2696 126-128 500.4 ***
    2697 145-146 527.4 ** 1H NMR (300 MHz, CDCl3): δ 8.45 (1H,
    ddd, J = 5.0, 1.9, 1.0 Hz), 7.63 (1H, d, J = 8.8 Hz),
    7.55 (2H, d, J = 8.5 Hz),
    7.54-7.45 (1H, m), 7.42 (2H, d, J = 8.5 Hz),
    7.25-7.21 (2H, m), 7.05-7.00 (2H, m),
    6.70 (1H, s), 5.05 (1H, hp, J = 6.3 Hz),
    4.93 (1H, p, J = 8.9 Hz), 4.35 (2H, t, J = 6.7 Hz),
    3.64 (2H, t, J = 6.7 Hz),
    2.85-2.70 (2H, m), 2.37-2.27 (2H, m),
    1.97-1.86 (1H, m), 1.83-1.73 (1H, m),
    1.32 (6H, d, J = 6.3 Hz).
    2698 69-72 528.4 *** 1H NMR (300 MHz, CDCl3): δ 8.54 (2H, d,
    J = 4.7 Hz), 7.63 (1H, d, J = 8.8 Hz),
    7.55 (2H, d, J = 8.8 Hz), 7.42 (2H, d, J = 8.8 Hz),
    7.24 (1H, d, J = 2.0 Hz), 7.03 (1H,
    dd, J = 8.8, 2.0 Hz), 7.01 (1H, t, J = 4.7 Hz),
    6.71 (1H, s), 5.05 (1H, hp, J = 6.3 Hz),
    4.93 (1H, p, J = 8.7 Hz), 4.37 (1H, t,
    J = 6.8 Hz), 3.60 (1H, t, J = 6.8 Hz),
    2.89-2.70 (2H, m), 2.40-2.29 (2H, m),
    2.00-1.89 (1H, m), 1.88-1.77 (1H, m),
    1.32 (6H, d, J = 6.3 Hz).
    2699 150-151 549.6 *** 1H NMR (300 MHz, CDCl3): δ 7.63 (1H, d,
    J = 8.8 Hz), 7.55 (2H, d, J = 8.8 Hz),
    7.42 (2H, d, J = 8.8 Hz), 7.23 (1H, d, J = 2.0 Hz),
    6.96 (1H, dd, J = 8.8, 2.0 Hz),
    6.71 (1H, s), 5.05 (1H, hp, J = 6.3 Hz),
    4.94 (1H, p, J = 8.6 Hz), 4.46 (2H, t, J = 6.2 Hz),
    3.76 (2H, t, J = 6.2 Hz),
    2.80-2.68 (2H, m), 2.74 (3H, s), 2.40-2.29 (2H, m),
    2.00-1.90 (1H, m), 1.89-1.73 (1H, m),
    1.32 (6H, d, J = 6.3 Hz).
    2700 132-133 464.3 *** 1H NMR (300 MHz, CDCl3): δ 7.63 (1H, d,
    J = 8.8 Hz), 7.55 (2H, d, J = 8.5 Hz),
    7.42 (2H, d, J = 8.5 Hz), 7.22 (1H, d, J = 2.0 Hz),
    6.96 (1H, dd, J = 8.8, 2.0 Hz),
    6.71 (1H, s), 5.05 (1H, hp, J = 6.3 Hz),
    4.94 (1H, p, J = 8.7 Hz), 4.26 (2H, t, J = 6.8 Hz),
    2.95 (2H, t, J = 6.8 Hz),
    2.89-2.73 (2H, m), 2.40-2.30 (2H, m), 2.25 (3H, s),
    2.00-1.90 (1 H, m), 1.88-1.78 (1H, m),
    1.33 (6H, d, J = 6.3 Hz).
    2701 foam 496.1 ***
    2702 116-117 474.4 ***
    2703 166-168 486.4 ***
    2704 133-140 444.0 ***
    2705 180-183 479.1 (M − 1) ***
    2706 180-183 481.2 ***
    2707 211-213 522.3 ***
    2708 200-202 548.4 ***
    2709 246-248 584.4 ***
    2710 240-242 547.4 ***
    2711 157-159 459.4 ***
    2712 149-151 486.4 ***
    2713 150-152 432.4 (M − 1) ***
    2714 165-168 450.1 ***
    2715 123-125 494.1 ***
    2716 173-175 548.1 ***
    2717 foam 566.3 ***
    2718 188-191 504.2 ***
    2719  88-100 462.3 ***
    2720 120-122 458.1 (M − 1) ***
    2721 126-128 476.2 ***
    2722 179-181 522.3 ***
    2723 182-184 524.3 ***
    2724 178-180 536.3 ***
    2725 188-190 538.3 ***
    2726 229-231 544.3 ***
    2727 232-234 495.3 **
    2728 137-138 523.3 ***
    2729 172-173 525.3 ***
    2730 149-150 537.3 ***
    2731 171-172 539.4 ***
    2732 215-217 545.4 ***
    2733 206-208 561.4 ***
    2734 206-208 561.3 ***
    2735 173-174 496.3 ***
    2736 161-164 524.5 ***
    2737 glass 530.2 ***
    2738 glass 516.7 (M − 1) ***
    2739 179-183 498.5 ***
    2740 glass 500.6 (M − 1) ***
    2741 208-210 488.3 ***
    2742 189-192 474.3 ***
    2743 151-153 474.3 ***
    2744 195-197 524.3 ***
    2745 207-209 480.6 ***
    2746 185-187 494.2 ***
    2747 202-204 492.5 ***
    2748 211-213 494.5 ***
    2749 224-226 492.5 ***
    2750 221-225 497.5 ***
    2751 glass 604.4 (M − 1) ***
    2752 136-138 446.3 ** (CDCl3, 300 MHz), δ7.66 (d, J = 8.7 Hz,
    1H), 7.56-7.49 (m, 4H), 7.32 (d, J = 2.1 Hz,
    1H), 7.01 (dd, J = 8.7 Hz and 2.4 Hz, 1H),
    4.94-4.88 (m., 1H), 4.25-4.22 (m, 2H),
    3.84-3.81 (m, 2H), 3.58-3.55 (m, 2H),
    3.50 (s, 3H), 3.43-3.35 (m, 2H),
    2.89-2.82 (m, 2H), 2.31 (q, J = 8.4 Hz, 2H),
    1.97-1.79 (m, 2H), 1.28-1.14 (m, 6H).
    2753 202-204 432.2 ** (MeOD, 300 MHz), δ 7.98 (d, J = 8.4 Hz,
    2H), 7.64 (d, J = 8.1 Hz, 2H), 7.56 (d,
    J = 8.7 Hz, 1H), 7.31 (d, J = 2.1 Hz, 1H),
    7.01 (dd, J = 8.7 Hz and 2.1 Hz, 1H),
    5.07-4.98 (m, 1H), 4.29-4.20 (m, 2H), 3.82-3.79 (m,
    2H), 3.37 (s, 3H), 2.68-2.58 (m, 2H),
    2.42-2.34 (m, 2H), 1.92-1.81 (m, 2H),
    1.28 (d, J = 6.6 Hz, 6H).
    2754 148-150 460.2 ** (CDCl3, 400 MHz), δ 7.66 (d, J = 8.8 Hz,
    1H), 7.59-7.53 (m, 4H), 7.31 (s, 1H),
    7.01 (dd, J = 8.4 Hz and 2.0 Hz, 1H),
    4.92-4.88 (m, 1H), 4.24 (t, J = 4.4 Hz, 2H),
    3.84-3.49 (m, 13H), 2.87-2.82 (m, 2H),
    2.36-2.31 (m, 2H), 1.97-1.80 (m, 2H).
    2755 166-168 430.2 ** (CDCl3, 400 Hz) δ 7.78 (d, J = 8.0 Hz, 2H),
    7.65 (d, 8.8 Hz, 2H), 7.53 (d, J = 8.0 Hz,
    2H), 7.29 (d, J = 2.0 Hz, 1H), 7.01 (d,
    J = 8.4 Hz, 1H), 4.92-4.88 (m, 1H),
    4.37-4.33 (m, 4H), 4.24 (t, J = 4.4 Hz, 2H),
    3.82 (t, J = 4.8 Hz, 2H), 3.50 (s, 3H),
    2.83-2.77 (m, 2H), 2.44-2.29 (m, 4H), 1.95-1.82 (m,
    2H).
    2756 162-164 444.2 ** (CDCl3, 400 MHz), δ7.13-7.09 (m, 3H),
    6.97 (d, J = 8.0 Hz, 2H), 6.76 (s, 1H),
    6.46 (d, J = 8.8 Hz, 1H), 4.38-4.34 (m, 1H),
    3.71-3.68 (m, 2H), 3.27 (t, J = 4.4 Hz, 2H),
    3.14-3.11 (m, 2H), 2.98-2.95 (m, 5H),
    2.31-2.26 (m, 2H), 1.78-1.76 (m, 2H),
    1.44-1.25 (m, 6H).
    2757 155-158 458.3 *** (CDCl3, 400 MHz), δ 7.66 (d, J = 8.4 Hz,
    1H), 7.59-7.50 (m, 4H), 7.32 (s, 1H),
    7.01 (d, J = 8.8 Hz, 1H), 4.93-4.86 (m, 1H),
    4.25 (t, J = 4.0 Hz, 2H), 3.83 (t, J = 4.4 Hz, 2H),
    3.76 (b, 2H), .3.50 (s, 3H), 3.43 (b, 2H),
    2.91-2.81 (m, 2H), 2.32 (q, J = 8.8 Hz, 2H),
    2.00-1.72 (m, 8H).
    2758 194-196 456.2 ** (CDCl3, 300 MHz), δ 7.97 (dd, J = 6.9 Hz
    and 2.1 Hz, 2H), 7.63 (dd, J = 6.9 Hz and
    2.1 Hz, 2H), 7.55 (d, J = 8.7 Hz, 1H),
    7.31 (d, J = 1.8 Hz, 1H), 7.02 (dd, J = 9.0 Hz and
    2.4 Hz, 1H), 5.07-5.01 (m, 1H),
    4.38-4.33 (m, 1H), 4.24-4.21 (m, 2H), 3.82-3.79 (m,
    2H), 3.52 (s, 3H), 2.68-2.58 (m, 2H),
    2.43-2.33 (m, 2H), 2.07-2.01 (m, 2H),
    1.92-1.76 (m, 8H).
    2759 199-200 444.1 ** (MeOH, 300 MHz), δ 7.99 (dd, J = 6.9 Hz
    and 1.8 Hz, 2H), 7.64 (dd, J = 6.6 Hz and
    2.1 Hz, 2H), 7.56 (d, J = 8.7 Hz, 1H),
    7.31 (d, J = 2.1 Hz, 1H), 7.02 (dd, J = 8.7 Hz and
    2.1 Hz, 1H), 5.07-5.01 (m, 1H),
    4.57-4.51 (m, 1H), 4.25-4.21 (m, 2H), 3.82-3.79 (m,
    2H), 3.46 (s, 3H), 2.68-2.61 (m, 2H),
    2.43-2.35 (m, 4H), 2.18-2.11 (m, 2H),
    1.91-1.80 (m, 4H).
    2760 228-230 430.0 ** (CDCl3, 400 MHz) δ 7.88 (dd, J = 8.0 Hz,
    2H), 7.64 (dd, J = 9.2 Hz, 1H), 7.55 (dd,
    J = 7.6 Hz, 2H), 7.01 (dd, J = 8.8 Hz, 1H),
    6.31 (s, 1H), 4.94-4.88 (m, 1H), 4.23 (t,
    J = 4.4 Hz, 2H), 3.82 (t, J = 4.4 Hz, 2H),
    3.50 (s, 3H), 2.95 (b, 1H), 2.82-2.72 (m, 2H),
    2.32 (q, J = 8.8 Hz, 2H), 1.97-1.76 (m, 2H),
    0.92 (q, J = 6.0 Hz, 2H), 0.66 (q, J = 6.0 Hz,
    2H).
    2761 240-245 481.5 **
    2762 264-269 501.9 **
    2763 225-231 519.2 ***
    2764 218-220 472.9 ***
    2765 glass 504.4 ***
    2766 195-196 449.4 ***
    2767 glass 538.4 ***
    2768  99-102 492.3 ***
    2769 glass 606.5 ***
    2770 glass 554.3 (M − 1) ***
    2771 glass 530.3 ***
    2772 glass 488.3 ***
    2773 glass 488.3 ***
    2774 glass 518.3 **
    2775 199-203 494.3 **
    2776 183-184 494.4 (M − 1) ***
    2777 191 488.8 ***
    (decomp.)
    2778 222-225 444.4 ***
    2779 146-150 518.5 (M − 1) **
    2780 155-156 477.4 (M + NH4) ***
    2781 147-148 491.4 (M + NH4) ***
    2782 161-163 474.4 ***
    2783 146-147 505.5 (M + NH4) ***
    2784 169-171 500.4 ***
    2785 158-160 514.4 ***
    2786 183-185 509.4 ***
    2787 148-150 511.4 ***
    2788 124-127 497.4 ***
    2789 133-134 473.4 **
    2790 188-189 519.4 (M + NH4) *
    2791 96-98 515.4 ***
    2792 90-94 515.4 ***
    2793 148-151 529.4 ***
    2794 75-77 559.4 ***
    2795 548.4 ***
    2796 217-221 396.4 ***
    2797 glass 496.3 ***
    2798 glass 554.3 (M − 1) ***
    2799 162-169 530.2 ***
    2800 206-208 458.8 *** 1H NMR (300 MHz, CDCl3): δ 1.33 (d,
    6H), 1.73-1.99 (m, 2H), 2.27-2.46 (m,
    2H), 2.68-2.88 (m, 2H), 3.16-3.29 (4H),
    3.88-4.00 (4H), 4.89-5.13 (m, 2H),
    6.69 (s, br, 1H), 7.01-7.04 (dd, 1H), 7.15 (d,
    1H), 7.39-7.46 (m, 2H), 7.51-7.59 (m,
    2H), 7.64 (d, 1H)
    2801 220-220 479.3 ***
    2802 222-224 476.8 ***
    2803 203-204 479.4 ***
    2804 171-177 413.9 ***
    2805 174-175 591.8 ***
    2806 175-176 589.9 (M − 1) ***
    2807 205-207 477.4 (M + NH4) ***
    2808 153-154 491.4 (M + NH4) ***
    2809 185-186 491.4 (M + NH4) ***
    2810 137-138 505.4 (M + NH4) ***
    2811 168-169 517.4 (M + NH4) ***
    2812 187-188 514.4 ***
    2813 174-175 488.4 ***
    2814 178-179 519.4 (M + NH4) ***
    2815 179-181 503.4 (M + NH4) ***
    2816 137-138 488.4 ***
    2817 179-181 475.4 ***
    2818 185-187 402.5 ***
    2819 150 547.3 ***
    (decomp.)
    2820 152 547.3 ***
    (decomp.)
    2821 509.2 ***
    2822 247-249 503.3 **
    2823 209-211 489.3 ***
    2824 201-203 507.3 ***
    2825 125-128 505.3 **
    2826 205-207 521.3 ***
    2827 115-120 437.4 ***
    2828 225-230 550 ***
    2829 163-168 539.6 ***
    2830 161-162 567.4 ***
    2831 103-104 567.4 ***
    2832 197-202 512.5 ***
    2833 218-220 481.2 ***
    2834 199-201 495.3 ***
    2835 196-198 523.5 ***
    2836 193-195 537.5 ***
    2837 210-212 521.4 ***
    2838 179-181 535.4 ***
    2839 glass 505.3 (ES−) ***
    2840 508.4 ***
    2841 508.4 ***
    2842 203-212 512.5 ***
    2843 203-205 479.6 ***
    2844 169-170 503.2 ** (CDCl3, 8.8 MHz) δ 8.00 (b, 1H), 7.65 (d,
    J = 8.8 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H),
    7.29 (s, 1H), 7.01 (s, 1H), 4.94-4.90 (m, 1H),
    4.24 (t, J = 4.4 Hz, 2H) 3.86-3.82 (m, 4H),
    3.70-3.68 (m, 2H), 3.50 (s, 3H),
    2.84-2.69 (m, 6H), 2.33 (q, J = 8.0 Hz, 2H),
    1.98-1.77 (m, 2H), 1.68-1.48 (m, 4H).
    2845 glass 536.4 (M − 1) ***
    2846 202-204 447.3 ***
    2847 217-218 484.3 *
    2848 206-207 486.3 **
    2849 225-227 486.3 **
    2850 161-163 498.3 **
    2851 140-145 465.4 ***
    2852 205-207 522.3 ***
    2853 189-190 514.3 ***
    2854 113-116 516.3 ***
    2855 264 444.4 **
    2856 220-227 445.4 ***
    2857 176-179 471.5 ***
    2858 230-232 456.4 ***
    2859 200-201 502.2 (M − 1) ***
    2860 197-198 488.4 ***
    2861 221-232 516.2 (M − 1) ***
    decomposed
    2862 234-235 458.3 ***
    2863 172 470.4 ***
    (decomp.)
    2864 220-222 513.3 ***
    2865 163-165 539.3 ***
    2866 194-195 485.3 ***
    2867 198-200 494.3 ***
    2868 100-104 506.4 (M − 1) ***
    2869 108-111 538.4 (M − 1) ***
    2870 glass 554.2 (M − 1) ***
    2871 198-199 514.2 (M − 1) ***
    2872 215-216 488.4 ***
    2873 170-180 495.4 ***
    2874 glass 502.3 ***
    2875 151-153 495.6 ***
    2876 170-230 470.4 ***
    2877 241-243 463.6 ***
    2878 196-199 472.4 ***
    2879 198-200 490.3 ***
    2880 161-162 492.1 (M − 1) **
    2881 197-203 498.4 ***
    2882 210-212 475.4 ***
    2883 glass 554.5 (M − 1) ***
    2884 glass 530.4 ***
    2885 189-190 530.4 ***
    2886 179-780 492.6 ***
    2887 165-166 580.7 ***
    2888 99-101 497.5 ***
    2889 129-130 488.6 ***
    2890 186-189 479.6 ***
    2891 170-180 459.6 ***
    2892 145-148 457.5 ***
    2893 glass 474.6 (M − 1) ***
    2894 208-210 476.6 ***
    2895 185-187 494.7 ***
    2896 217-219 508.7 ***
    2897 247-249 **
    2898 220-222 ***
    2899 169-171 506 ***
    2900 198-200 ***
    2901 210-212 520 ***
    2902 223-227 502.6 ***
    2903 172-174 500.5 ***
    2904 182-186 532.6 ***
    2905 248-250 477.6 ***
    2906 208-213 479.7 ***
    2907 127-132 483.7 ***
    2908 191-194 475.5 ***
    2909 201-202 508.7 ***
    2910 162-164 515.1 ***
    2911 205-207 452.8 ***
    2912 212-214 466.9 ***
    2913 172-174 508.9 ***
    2914 290-292 477.7 **
    2915 269-271 451.7 **
    2916 235-236 465.7 ***
    2917 175-177 510.6 ***
    2918 195-196 520.2 (M − 1) ***
    2919 200-204 508.5 ***
    2920 196-198 496.4 ***
    2921 241-245 477.5 **
    2922 108-118 510.4 ***
    2923 158-160 522.8 ***
    2924 119-121 562.9 ***
    2925 231-233 522.9 ***
    2926 247-248 451.8 **
    2927 260-265 463.6 **
    2928 216-217 494.9 **
    2929 221-223 496.6 ***
    2930 227-229 522.8 ***
    2931 227-230 502.9 ***
    2932 224-225 489.7 **
    2933 167-173 485.7 ***
    2934 192-195 447.7 ***
    2935 216-217 541.8 **
    2936 209-210 507.6 ***
    2937 183-184 508.6 ***
    2938 191-193 488.8 ***
    2939 239-241 488.7 ***
    2940 222-227 466.8 **
    2941 219-224 478.6 **
    2942 191-193 473.7 ***
    2943 215-217 508.0 ***
    2944 234-239 488.8 *
    2945 173-175 521.6 ***
    2946 144-146 537.0 ***
    2947 130 523.0 ***
    (decomp.)
    2948 206-208 549.0 ***
    2949 181-183 534.9 **
    2950 224-226 435.1 ***
    2951 196-197 443.1 ***
    2952 148-150 501.1 ***
    2953 231-234 527.3 ***
    2954 241-244 443.2 ***
    2955 229-234 463.6 ***
    2956 198-200 490.8 ***
    2957 203-204 528.0 *
    2958 206-208 564.5 ***
    2959 220-222 505.0 ***
    2960 258-260 461.1 **
    2961 246-249 497.3 ***
    2962 244-250 449.4 **
    2963 189-194 477.1 ***
    2964 248-250 519.2 ***
    2965 212-214 533.3 ***
    2966 glass 487.0 **
    2967 208-213 456 ***
    2968 233-235 477.3 ***
    2969 181-183 502.1 **
    2970 183-185 508.4 ***
    2971 208-210 511.4 ***
    2972 235-237 504.9 ***
    2973 220-229 493.9 (M − 1) ***
    2974 203-205 463.6 ***
    2975 256-261 463.6 ***
    2976 168-173 443.5 ***
    2977 112-117 490.9 ***
    2978 210-212 484.9 ***
    2979 glass 569.3 ***
    2980 167-170 515.9 **
    2981 174-177 570.2 *
    2982 198-202 491 ***
    2983 232-238 475.6 ***
    2984 229-233 449.5 **
    2985 205-210 469 ***
    2986 197-202 455.5 ***
    2987 266-273 501.8 **
    2988 218-223 508.0 ***
    2989 234-238 500.0 **
    2990 114-143 536.3 ***
    2991 221-225 516.0 ***
    2992 211-213 481.9 ***
    2993 231-237 514.0 **
    2994 84-94 539.1 ***
    2995 206-208 493.8 ***
    2996 200-202 493.9 ***
    2997 90-98 544.7 ***
    2998 490.9 ***
    2999 226-228 491.0 ***
    3000 208-210 511.0 ***
    3001 111-122 511.0 ***
    3002  88-102 491.0 ***
    3003 223-225 552.7 ***
    3004 188-190 440.8 **
    3005 171-173 490.9 ***
    3006 173-175 437.6 ***
    3007 154-156 497.0 ***
    3008 197-200 546.7 ***
    3009 173-175 546.8 ***
    3010 172-174 518.9 ***
    3011 196-199 492.8 ***
    3012 181-184 483.6 ***
    3013 176-179 477.6 ***
    3014 90-91 497.3 ***
    3015 270 501.0 **
    (decomp.)
    3016 499.6 ***
    3017 120-125 561.8 ***
    3018 155-157 545.9 ***
    3019 227-229 542.8 ***
    3020 118-124 607.7 ***
    3021 195-196 535.7 ***
    3022 165-168 524.8 ***
    3023 158-160 515.9 **
    3024 171-174 569.8 **
    3025 214-220 493.7 (M − 1) ***
    3026 187-190 481.9 ***
    3027 186-189 507.9 ***
    3028 536.0 ***
    3029 110-113 580.4 ***
    3030 128-131 518.6 ***
    3031 82-88 468.8 ***
    3032 452.1 ***
    3033 466.1 ***
    3034 80-81 578.0 ***
    3035 94-96 552.0 **
    3036 144-154 503.8 ***
    3037 529.9 ***
    3038 236-243 502.9 ***
    3039 150-155 469.8 (M − 1) ***
    3040 176-180 498.0 ***
    3041 224-229 471.1 ***
    3042 555.4 **
    3043 505.6 (M − 1) ***
    3044 490.0 ***
    3045 484.0 ***
    3046 195-197 480.1 ***
    3047 225 495.1 ***
    (decomp.)
    3048 120 480.1 ***
    (decomp.)
    3049 154-155 521.8 ***
    3050 141-142 525.8 ***
    3051 184-185 539.7 (M − 1) ***
    3052 166-187 467.8 ***
    3053 203-208 493.8 ***
    3054 190-196 521.9 ***
    3055 72-73 496.8 ***
    3056 85-94 533.5 ***
    3057 95-112 521.8 ***
    3058 181-185 535.8 ***
    3059  97-109 542.1 ***
    3060 205-212 553.8 ***
    3061 77-78 510.9 ***
    3062 75-76 564.2 ***
    3063 74-75 536.2 ***
    3064 192-193 509.9 ***
    3065 218-220 521.3 ***
    3066 237-241 507.7 (M − 1) ***
    3067 265-271 496.0 ***
    3068 218-224 521.9 ***
    3069 207-211 559.5 ***
    3070 237-242 551.5 ***
    3071 236-241 563.5 ***
    3072 211-215 501.5 **
    3073 185-190 561.5 ***
    3074 274 526.5 **
    (decomp.)
    3075 513.4 *
    3076 513.4 *
    3077 109-110 448 *** 1H NMR (300 MHz, CDCl3): δ 7.60 (1H, d,
    J = 8.8 Hz), 7.29 (2H, d, J = 8.8 Hz), 7.27
    1H (d, J = 2.2 Hz), 6.96 (1H, dd, J = 8.8,
    2.2 Hz), 6.73 (2H, d, J = 8.8 Hz),
    4.97 (1H, p, J = 8.9 Hz), 4.36 (1H, br),
    4.24-4.21 (2H, m), 3.87-3.84 (2H, m),
    3.70-3.53 (6H, m), 3.37-3.34 (2H, m),
    2.92-2.81 (2H, m), 2.37-2.28 (2H, m),
    1.99-1.89 (1H, m), 1.88-1.77 (1H, m),
    1.28 (3H, t, J = 7.0 Hz), 1.25 (3H, t, J = 7.0 Hz).
    3078 180-182 516.2 * (CDCl3, 400 MHz), δ7.64 (d, J = 8.4 Hz,
    2H), 7.56 (d, J = 8.4 Hz, 2H), 7.40 (d,
    J = 8.8 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H),
    7.01 (dd, J = 9.2 Hz and 2.4 Hz, 1H), 4.12 (q,
    J = 6.8 Hz, 2H), 4.04 (d, J = 6.4 Hz, 2H),
    3.65 (q, J = 7.2 Hz, 4H), 1.68-1.46 (m, 9H),
    1.07-0.98 (m, 1H), 0.48 (q, J = 9.6 Hz, 2H),
    0.11-0.05 (m, 2H).
    3079 194-195 482 * 1H NMR (300 MHz, DMSO-d6): δ
    10.09 (1H, s), 7.66 (2H, d, J = 8.8 Hz),
    7.51 (1H, d, J = 8.8 Hz), 7.48 (2H, d, J = 8.8 Hz),
    7.20 (1H, d, J = 2.1 Hz), 6.93 (1H,
    dd, J = 8.8, 2.1 Hz), 4.97 (1H, p, J = 8.7 Hz),
    4.47 (2H, t, J = 5.7 Hz), 4.11 (2H, q,
    J = 7.0 Hz), 3.55 (2H, t, J = 5.7 Hz),
    3.08 (3H, s), 2.59-2.41 (2H, m), 2.37-2.26 (2H,
    m), 1.83-1.65 (2H, m), 1.36 (3H, t, J = 7.0 Hz).
    3080 187-192 427.1 (M − 1) ***
    3081 500.4 ***
    3082 520.4 **
    3083 192-205 556.4 **
    3084 156-162 516.1 **
    3085 195-196 466.3 ** (CDCl3, 400 MHz), δ 7.99 (d, J = 8.0 Hz,
    2H), 7.65-7.63 (m, 3H), 7.18 (s, 1H),
    6.99 (d, J = 8.8 Hz and 1.6 Hz, 1H),
    4.94-4.85 (m, 1H), 4.44 (s, 1H), 4.13 (q, J = 6.8 Hz,
    2H), 3.50-3.46 (m, 3H), 3.36 (d,
    J = 11.2 Hz, 1H), 2.79-2.71 (m, 2H),
    2.41-2.30 (m, 2H), 2.05-1.83 (m, 4H), 1.49 (t,
    J = 6.8 Hz, 3H).
    3086 194-196 466.0 ** (CDCl3, 400 MHz), δ 7.99 (d, J = 8.4 Hz,
    2H), 7.66-7.64 (m, 3H), 7.18 (d, J = 2.0 Hz,
    1H), 6.99 (d, J = 8.8 Hz and 1.6 Hz, 1H),
    4.92-4.87 (m, 1H), 4.44-4.43 (m, 1H),
    4.13 (q, J = 6.8 Hz, 2H), 3.50-3.46 (m, 3H),
    3.36 (d, J = 11.2 Hz, 1H), 2.77-2.72 (m,
    2H), 2.41-2.30 (m, 2H), 2.05-1.83 (m,
    4H), 1.49 (t, J = 6.8 Hz, 3H).
    3087 275 532.4 ***
    (decomp.)
    3088 140 526.1 **
    (decomp.)
    3089 172-177 540.6 ***
    3090 196-201 514 **
    3091 231-233 528.7 ***
    3092 238-243 513.2 **
    3093 112-119 481.0 (M − 1) **
    3094 236-237 465.2 ** (CDCl3, 400 MHz), δ 7.81-7.77 (m, 2H),
    7.48-7.46 (m, 3H), 7.34 (d, J = 8.4 Hz, 2H),
    6.76 (s, 1H), 5.00-4.96 (m, 1H),
    3.23-3.13 (m, 8H), 2.83-2.76 (m, 2H), 2.37 (q,
    J = 8.0 Hz, 2H), 2.00-1.82 (m, 4H), 1.09 (t,
    J = 7.6 Hz, 3H).
    3095 133-134 493.2 ** (CDCl3, 400 MHz), δ 7.78-7.76 (m, 2H),
    7.46 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 9.2 Hz,
    1H), 7.33 (d, J = 8.4 Hz, 2H), 6.80 (s, 1H),
    4.99-4.95 (m, 1H), 3.61 (b, 2H), 3.36 (b,
    2H), 3.20 (t, J = 8.0 Hz, 2H), 2.84-2.78 (m,
    2H), 2.38 (q, J = 9.6 Hz, 2H), 2.00-1.87 (m,
    4H), 1.27-1.18 (m, 6H), 1.09 (t, J = 7.2 Hz,
    3H).
    3096 138-139 479.2 ** (CDCl3, 400 MHz), δ7.80-7.77 (m, 2H),
    7.48-7.42 (m, 3H), 7.34 (d, J = 8.4 Hz, 2H),
    6.66 (s, 1H), 4.99-4.95 (m, 1H),
    3.62-3.32 (m, 2H), 3.23-3.19 (m, 2H), 3.08-3.07 (m,
    3H), 2.84-2.79 (m, 2H), 2.42-2.35 (m,
    2H), 2.00-1.85 (m, 4H), 1.25-1.22 (m,
    3H), 1.10 (t, J = 7.6 Hz, 3H).
    3097 200-202 491.2 *** (CDCl3, 400 MHz), δ7.93 (s, 1H),
    7.78-7.76 (m, 1H), 7.58-7.56 (m, 1H), 7.51 (s,
    1H), 7.45-7.43 (m, 2H), 7.38-7.36 (m,
    2H), 4.99-4.95 (m, 1H), 3.71 (s, 2H),
    3.55 (s, 2H), 3.21-3.17 (m, 2H), 2.82-2.77 (m,
    2H), 2.39-2.37 (m, 2H), 1.99-1.84 (m,
    7H), 1.07 (t, J = 8.4 Hz, 3H).
    3098 128-129 507.2 ** (CDCl3, 400 MHz), δ7.81-7.78 (m, 2H),
    7.48-7.43 (m, 3H), 7.35 (d, J = 8.4 Hz, 2H),
    6.75 (s, 1H), 5.00-4.96 (m, 1H),
    4.85-3.62 (m, 8H), 4.29 (s, 2H), 3.23-3.19 (m, 2H),
    2.83-2.75 (m, 2H), 2.41-2.36 (m, 2H),
    2.01-1.83 (m, 4H), 1.10 (t, J = 7.2 Hz, 3H).
    3099 149-152 467.5 **
    3100 201-203 633.9 *
    3101 461.7 ***
    3102 244 505.4 **
    (decomp.)
    3103 187 531.6 *
    (decomp.)
    3104 166-168 491.4 (M − C5H8O) ***
    3105 187-189 489.4 (M + NH4) ***
    3106 104-106 526.4 ***
    3107 156-158 513.4 ***
    3108 150-153 525.4 ***
    3109 152-153 488.5 *
    3110 167-168 472.3 ***
    3111 165-166 551.5 ***
    3112 167-169 539.4 (M + NH4) ***
    3113 179-180 646.5 ***
    3114 124-127 518.3 **
    3115 175-178 551.5 ***
    3116 214-217 537.3 ***
    3117 208-210 551.6 ***
    3118 105-108 506.3 ***
    3119 157-159 520.3 **
    3120 180-181 496.4 ***
    3121 168-172 492.5 ***
    3122 104-107 506.5 ***
    3123 175-177 484.2 ***
    3124 238-241 489.1 ***
    3125 171-175 482.4 ***
    3126 182-185 496.4 ***
    3127 185-188 506.5 ***
    3128 207-210 494.4 ***
    3129 108-110 548.4 ***
    3130 460.2 *** (CDCl3, 400 MHz), δ 7.72-7.64 (m, 3H),
    7.53 (d, J = 7.6 Hz, 2H), 7.31 (s, 1 H),
    7.01 (d, J = 9.2 Hz, 1H), 4.93-4.88 (m, 1H),
    4.64-4.51 (m, 1H), 4.24 (t, J = 4.0 Hz, 2H),
    3.89-3.79 (m, 4H), 3.73-3.60 (m, 2H), 3.50 (s,
    3H), 2.88-2.78 (m, 2H), 2.34-2.32 (m,
    2H), 2.17-1.91 (m, 3H), 1.85-1.74 (m,
    2H).
    3131 149-152 494.0 ** (CDCl3, 400 MHz), δ 7.91 (d, J = 8.4 Hz,
    2H), 7.64 (d, J = 9.2 Hz, 1H), 7.56 (d,
    J = 8.0 Hz, 2H), 7.43-7.39 (m, 4H), 7.32 (d,
    J = 2.0 Hz, 1H), 7.00 (d, J = 6.8 Hz, 1H),
    5.40-5.34 (m, 1H), 4.95-4.88 (m, 1H),
    4.23 (t, J = 4.4 Hz, 2H), 3.82 (t, J = 4.4 Hz,
    2H), 3.49 (s, 3H), 2.80-2.72 (m, 2H),
    2.33 (q, J = 8.8 Hz, 2H), 1.97-1.76 (m, 2H),
    1.65 (d, J = 6.8 Hz, 3H).
    3132 169-170 512.0 *** (CDCl3, 400 MHz), δ 7.91 (d, J = 8.0 Hz,
    2H), 7.64 (d, J = 8.8 Hz, 1H), 7.56 (dd,
    J = 8.4 Hz, 2H), 7.41-7.37 (m, 2H),
    7.09-7.04 (m, 2H), 7.01 (dd, J = 8.8 Hz and
    1.2 Hz, 1H), 6.35 (d, J = 8.4 Hz, 1H),
    5.38-5.31 (m, 1H), 4.93-4.88 (m, 1H), 4.23 (t,
    J = 4.4 Hz, 2H), 3.82 (t, J = 4.4 Hz, 2H),
    3.50 (s, 3H), 2.82-2.72 (m, 2H), 2.33 (q,
    J = 8.4 Hz, 2H), 1.94-1.76 (m, 2H), 1.62 (d,
    J = 6.8 Hz, 3H).
    3133 156-157 524.8 *** (CDCl3, 400 MHz), δ 7.91 (d, J = 8.0 Hz,
    2H), 7.64 (d, J = 8.8 Hz, 1H), 7.55 (d,
    J = 8.0 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H),
    7.00 (d, J = 7.2 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H),
    6.32 (d, J = 7.6 Hz, 1H), 5.36-5.29 (m, 1H),
    4.92-4.86 (m, 1H), 4.23 (t, J = 4.4 Hz, 2H),
    3.83-3.82 (m, 5H), 3.50 (s, 3H),
    2.82-2.75 (m, 2H), 2.33 (q, J = 8.8 Hz, 2H),
    1.96-1.76 (m, 2H), 1.63 (d, J = 6.8 Hz, 3H).
    3134 154-160 498.1 *** (CDCl3, 400 MHz), δ 7.94 (d, J = 8.0 Hz,
    2H), 7.65 (d, J = 8.8 Hz, 1H), 7.57 (d,
    J = 8.4 Hz, 2H), 7.38-7.33 (m, 2H),
    7.09-7.04 (m, 2H), 7.03 (d, J = 8.8 Hz, 1H),
    7.46 (t, J = 6.8 Hz, 1H), 4.95-4.86 (m, 1H),
    4.66 (d, J = 6.0 Hz, 2H), 4.23 (t, J = 4.4 Hz, 2H),
    3.82 (t, J = 4.4 Hz, 2H), 3.50 (s, 3H),
    2.83-2.72 (m, 2H), 2.32 (q, J = 8.8 Hz, 2H),
    1.97-1.79 (m, 2H).
    3135 216-218 493.9 * (CDCl3, 400 MHz), δ7.90 (d, J = 8.0 Hz,
    2H), 7.64 (d, J = 8.8 Hz, 1 H), 7.55 (d,
    J = 8.4 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H),
    7.18 (d, J = 1.6 Hz, 1H), 6.91 ((d, J = 8.4 Hz, 1H),
    6.44 (d, J = 7.6 Hz, 1H), 5.34-5.30 (m, 1H),
    4.93-4.88 (m, 1H), 4.12 (q, J = 2.8 Hz, 2H),
    3.81 (s, 3H), 2.81-2.71 (m, 2H),
    2.35-2.30 (m, 2H), 1.94-1.76 (m, 2H), 1.63 (d,
    J = 6.8 Hz, 3H), 1.49 (t, J = 6.8 Hz, 3H).
    3136 250 472.3 ** (CDCl3, 400 MHz), δ 7.76-7.72 (m, 3H),
    (decomp.) 7.34 (d, J = 8.0 Hz, 1H), 6.77-6.73 (m, 4H),
    4.84-4.80 (m, 1H), 4.00 (t, J = 6.8 Hz, 1H),
    3.65 (b, 2H), 3.46 (b, 2H), 2.63-2.58 (m,
    2H), 2.32-2.28 (m, 2H), 1.90-1.75 (m,
    2H), 1.36-1.23 (m, 12H)
    3137 477.2 ** (CDCl3, 400 MHz), δ7.99 (s, 1H),
    7.79-7.77 (m, 1H), 7.73-7.71 (m, 1H), 7.48 (d,
    J = 8.0 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H),
    6.71 (s, 1H), 4.96 (m, 1H), 4.41 (s, 2H),
    4.29 (s, 2H), 3.23-3.19 (m, 2H), 2.84-2.76 (m,
    2H), 2.40-2.37 (m, 4H), 2.01-1.83 (m,
    4H), 1.10 (t, J = 7.2 Hz, 3H).
    3138 463.2 ** (CDCl3, 400 MHz), δ8.37 (s, 1H),
    8.15-8.13 (m, 1H), 7.80 (d, J = 4.4 Hz, 1H),
    7.48 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H),
    7.00 (s, 1H), 5.02-4.93 (m, 1H),
    4.63-4.59 (m, 2H), 4.20-4.16 (m, 2H), 4.23-4.19 (m,
    2H), 2.85-2.75 (m, 2H), 2.40-2.36 (m,
    2H), 2.18-1.84 (m, 4H), 1.09 (t, J = 6.8 Hz,
    3H).
    3139 458.2 *** (CDCl3, 400 MHz), δ7.76-7.73 (m, 2H),
    7.39-7.32 (m, 2H), 6.88-6.86 (m, 4H),
    4.91-4.82 (m, 1H), 4.05-3.97 (m, 1H),
    3.75-3.59 (m, 2H), 3.15 (s, 3H),
    2.66-2.56 (m, 2H), 2.35-2.29 (m, 2H), 1.95-1.82 (m,
    2H), 1.32-1.22 (m, 9H).
    3140 470.2 *** (CDCl3, 400 MHz), δ7.87 (s, 1H),
    7.76-7.73 (m, 1H), 7.51-7.46 (m, 1H),
    7.34-7.32 (m, 1H), 7.00 (s, 4H), 4.91-4.85 (m,
    1H), 4.03-3.99 (m, 1H), 3.80-3.72 (m,
    2H), 3.62-3.59 (m, 2H), 2.74-2.61 (m,
    2H), 2.33-2.30 (m, 2H), 2.10-1.94 (m,
    6H), 1.24 (d, J = 8.4 Hz, 6H).
    3141 496.1 ** (CDCl3, 400 MHz), δ7.78-7.75 (m, 2H),
    7.42-7.38 (m, 1H), 7.10 (s, 4H), 5.24 (s,
    1H), 4.94-4.88 (m, 1H), 4.03-3.77 (m,
    9H), 2.72-2.61 (m, 2H), 2.35-2.29 (m,
    2H), 1.94-1.81 (m, 2H), 1.22 (d, J = 7.6 Hz,
    6H).
    3142 444.2 ** (CDCl3, 400 MHz), δ7.78-7.75 (m, 2H),
    7.42-7.39 (m, 2H), 6.93-6.86 (m, 4H),
    5.62 (s, 1H), 4.88-4.82 (m, 1H),
    4.02-3.98 (m, 1H), 3.20-3.16 (m, 6H), 2.67-2.60 (m,
    2H), 2.35-2.26 (m, 2H), 1.92-1.81 (m,
    2H), 1.23 (d, J = 8.8 Hz, 6H).
    3143 488.1 ** (CDCl3, 400 MHz), δ7.83-7.71 (m, 2H),
    7.48 (s, 1H), 7.41-7.38 (m, 1H), 6.87 (s,
    4H), 5.65 (s, 1H), 4.87-4.81 (m, 1H),
    3.80-3.74 (m, 2H), 3.64-3.55 (m, 2H),
    3.44-3.36 (m, 3H), 3.20 (s, 3H),
    2.66-2.59 (m, 2H), 2.34-2.25 (m, 2H), 1.91-1.81 (m,
    2H), 1.22 (d, J = 8.8 Hz, 6H).
    3144 500.1 ** (DMSO, 400 MHz), δ8.65 (s, 1H), 7.88 (d,
    J = 7.6 Hz, 1H), 7.76 (s, 1H), 7.59-7.57 (m,
    2H), 7.44-7.42 (m, 2H), 6.14 (d, J = 8.0 Hz,
    1H), 5.04-4.99 (m, 1H), 4.18-4.16 (m,
    1H), 3.78-3.74 (m, 1H), 3.57-3.46 (m,
    3H), 3.04-3.01 (m, 1H), 2.60-2.55 (m,
    2H), 2.32-2.30 (m, 1H), 1.91-1.65 (m,
    6H), 1.09 (d, J = 6.8 Hz, 6H).
    3145 225-226 473.3 *** (CDCl3, 400 MHz), δ 7.76 (dd, J = 7.6 Hz
    and 1.6 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H),
    7.45 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.8 Hz,
    1H), 6.76 (s, 1H), 5.09-4.97 (m, 2H),
    3.60-3.36 (m, 6H), 2.87-2.76 (m, 2H),
    2.38 (q, J = 8.8 Hz, 2H), 1.34-1.21 (m,
    12H).
    3146 136-138 445.2 ** (CDCl3, 400 MHz), δ 7.81 (d, J = 1.2 Hz,
    1H), 7.77 (d, J = 8.8 Hz, 1H), 7.58 (d,
    J = 8.4 Hz, 2H), 7.46-7.43 (m, 3H), 6.74 (s,
    1H), 5.09-4.98 (m, 2H), 3.14-3.09 (m,
    6H), 2.87-2.79 (m, 2H), 2.38 (q, J = 8.8 Hz,
    2H), 2.01-1.82 (m, 2H), 1.34 (d, J = 6.4 Hz,
    6H).
    3147 459.2 *** (CDCl3, 400 MHz), δ 7.79-7.75 (m, 2H),
    7.58 (d, J = 8.4 Hz, 2H), 7.46-7.40 (m, 3H),
    6.76 (s, 1H), 5.09-4.98 (m, 2H),
    3.63-3.37 (m, 2H), 3.09 (b, 3H), 2.86-2.76 (m, 2H),
    2.38 (q, J = 8.4 Hz, 2H), 3.01-1.80 (m, 2H),
    1.34-1.18 (m, 9H).
    3148 204-205 471.3 ** (CDCl3, 400 MHz), δ 7.92 (s, 1H), 7.76 (d,
    J = 8.4 Hz, 1H), 7.59-7.55 (m, 3H), 7.45 (d,
    J = 8.8 Hz, 2H), 6.73 (s, 1H), 5.07-5.00 (m,
    2H), 3.70 (t, J = 6.4 Hz, 2H), 3.54 (t,
    J = 5.6 Hz, 2H), 2.84-2.78 (m, 2H), 2.38 (q,
    J = 10 Hz, 2H), 2.01-1.89 (m, 6H), 1.33 (d,
    J = 6.0 Hz, 6H).
    3149 487.2 *** (CDCl3, 400 MHz), δ 7.80-7.77 (m, 2H),
    7.59 (d, J = 8.8 Hz, 2H), 7.46-7.41 (m, 3H),
    6.74 (s, 1H), 5.09-4.98 (m, 2H), 3.73 (b,
    8H), 2.85-2.77 (m, 2H), 2.38 (q, J = 8.8 Hz,
    2H), 2.01-1.80 (m, 2H), 1.34 (d, J = 6.4 Hz,
    6H).
    3150 136-138 557.4 ***
    3151 246-248 527.5 **
    3152 215-217 485.5 ***
    3153 269-271 565.5 ***
    3154 182-185 556.5 ***
    3155 164-166 506.2 ***
    3156 168-169 550.4 ***
    3157 137-138 515.4 ***
    3158 129-130 489.3 ***
    3159 195-201 508.4 ***
    3160 125-128 498.3 ***
    3161 174-179 512.4 ***
    3162 148-152 506.4 ***
    3163 211-212 465.3 ***
    3164 225-227 466.4 ***
    3165 210-212 463.4 (M − 1) ***
    3166 209-213 466.5 ***
    3167 168-169 467.4 ***
    3168 167-170 467.4 **
    3169 147-149 466.4 **
    3170 192-194 487.3 ***
    3171 174-177 501.3 ***
    3172 213-216 541.5 ***
    3173 203-206 563.5 ***
    3174 202-205 501.4 ***
    3175 171-175 538.6 ***
    3176 209-211 537.5 ***
    3177 250-252 539.4 ***
    3178 224-225 562.6 ***
    3179 240-241 521.7 ***
    3180 223-225 479.7 ***
    3181 218-220 513.6 ***
    3182 245-249 522.6 ***
    3183 222-224 484.4 **
    3184 259-264 528.5 **
    3185 279-285 538.8 (M − 1) ***
    3186 226-231 548.7 ***
    3187 243-249 577.1 ***
    3188 137-138 547.6 *
    3189 241-245 533.5 ***
    3190 192-193 533.6 *
    3191 227-229 519.7 ***
    3192 201-203 512.6 *** 1H NMR (300 MHz) δ, 8.32 (dd, 1 H, J = 1.8,
    4.8 Hz), 8.05 (dd, 1H, J = 1.8, 7.8 Hz),
    7.80 (d, 1H, J = 8.7 Hz), 7.58 (d, 1H,
    J = 1.8 Hz), 7.10-7.49 (m, 6H), 6.73 (s,
    1H), 4.95 (m, 1H), 3.21 (t, 2H, J = 7.8 Hz),
    2.74-2.82 (m, 2H), 2.33-2.37 (m,
    2H), 1.83-1.97 (m, 4H), 1.10 (t, 3H, 7.5 Hz).
    3193 189-191 475.7 **
    3194 210-212 499.7 ***
    3195 193-194 498.8 ***
    3196 232-236 485.6 **
    3197 215-217 512.6 ***
    3198 279-282 477.8 ***
    3199 205-210 535.1 ***
    3200 208-212 487.0 ***
    3201 181-184 555.7 ***
    3202 240-242 501.3 ***
    3203 241-242 474.3 **
    3204 174-177 488.0 ***
    3205 199-201 447.9 **
    3206 234-236 527.1 ***
    3207 116-118 501.1 ***
    3208 243-245 485.9 ***
    3209 219-221 528.2 *** 1H NMR (300 MHz, CDCl3): δ 1.21 (d,
    6H), 1.73-2.00 (m, 2H), 2.27-2.44 (m,
    2H), 2.66-2.86 (m, 2H), 3.57-3.75 (m,
    1H), 3.39 (d, 1H), 4.85-5.06 (m, 1H),
    6.62 (d, br, 1H), 7.12-7.15 (m, 1H),
    7.27-7.34 (m, 2H), 7.43-7.50 (m, 2H), 7.58 (d,
    1H), 7.82 (d, 1H), 8.30 (d, 1H), 8.43 (d,
    1H)
    3210 269-271 511.8 *** 1H NMR (300 MHz, CDCl3): δ 1.21 (d,
    6H), 1.73-2.00 (m, 2H), 2.27-2.44 (m,
    2H), 2.66-2.86 (m, 2H), 3.57-3.75 (m,
    1H), 3.39 (d, 1H), 4.85-5.06 (m, 1H),
    6.62 (d, br, 1H), 7.12-7.15 (m, 1H),
    7.27-7.34 (m, 2H), 7.43-7.50 (m, 2H), 7.58 (d,
    1H), 7.82 (d, 1H), 8.30 (d, 1H), 8.43 (d,
    1H)
    3211 189-191 525.9 ***
    3212 224-226 435.1 ***
    3213 195-197 434.1 ***
    3214 262-268 491.3 **
    3215 260-271 479.1 *
    3216 251-256 486.2 **
    3217 212-223 500.2 *
    3218 180-187 506.4 **
    3219 203-212 492.2 **
    3220 187-196 500.3 *
    3221 249-250 386.2 **
    3222 233-235 464.0 **
    3223 250-251 416.2 **
    3224 178-180 513.3 ***
    3225 194-197 527.3 ***
    3226 193-194 535.4 ***
    3227 148-150 373.5 **
    3228 92-95 537.8 ***
    3229 88-91 551.8 ***
    3230 253-257 496.1 **
    3231 189-196 522.2 **
    3232 278-282 508.1 **
    3233 193-198 548.5 ***
    3234 243-247 522.1 **
    3235 249-256 536.2 **
    3236 173-190 510.1 *
    3237 512.4 *
    3238 205-208 539.2 ***
    3239 193-196 511.1 ***
    3240 121-124 468.4 ***
    3241 169-173 446.0 ***
    3242 242-245 512.2 ***
    3243 183-185 502.3 ***
    3244 223-225 495.9 **
    3245 243-250 562.3 ***
    3246 223-227 536.2 ***
    3247 199-201 522.0 ***
    3248 238-241 527.0 ***
    3249 235-239 526.0 ***
    3250 232-235 511.8 ***
    3251 212-213 427.6 **
    3252 223-224 409.5 *
    3253 glass 516.8 (M − 1) ***
    3254 214-215 508.0 ***
    3255 209-211 527.9 **
    3256 217-218 517.9 **
    3257 205-208 507.9 ***
    3258 250-252 546.3 ***
    3259 203-208 520.2 ***
    3260 202-204 447.8 ***
    3261 207-209 448.6 ***
    3262 223 504.9 ***
    (decomp.)
    3263 183-185 503.9 ***
    3264 245-247 443.9 **
    3265 172-174 469.8 **
    3266 159-162 527.1 ***
    3267 181-212 558.5 ***
    3268 223-225 465.0 ***
    3269 240-246 543.9 **
    3270 193-195 481.9 ***
    3271 80-83 541.1 ***
    3272 79-81 556.1 *
    3273 227-230 526.1 ***
    3274 222-225 527.0 ***
    3275 130 552.8 ***
    (decomp.)
    3276 209-212 553.9 ***
    3277   267-268.5 467.0 ***
    3278 165-169 529.8 ***
    3279 542.5 (M − 1) ***
    3280 543.9 ***
    3281 211-213 529.7 ***
    3282 181-182 468.8 ***
    3283 145-147 494.9 ***
    3284  99-101 522.9 ***
    3285 236-238 476.9 ***
    3286 233-235 501.9 **
    3287 166-168 490.9 **
    3288 215-217 526.7 ***
    3289 177-178 540.6 ***
    3290 176-180 527.7 ***
    3291 168-172 537.3 (M − 1) ***
    3292 159-161 432.0 ***
    3293 232-250 513.6 ***
    3294 187-192 527.3 (M − 1) *
    3295 236-238 524.8 ***
    3296 215-216 548.8 *
    3297 112-119 442.1 ***
    3298 126-139 496.8 ***
    3299 178-179 563.9 **
    3300 215-216 470.8 **
    3301 253 489.8 (M − 1) ***
    (decomp.)
    3302 175-179 545.8 ***
    3303 138-142 525.8 ***
    3304 222-226 512.4 ***
    3305 225-228 513.4 ***
    3306 218-220 546.0 ***
    3307 243-246 547.0 ***
    3308 138-142 559.1 **
    3309 219-221 526.0 *
    3310 272-274 561.9 **
    3311 191-194 529.1 ***
    3312 206-208 425.1 ***
    3313 244-246 423.0 ***
    3314 198-199 519.9 ***
    3315 237-238 493.0 ***
    3316 244-245 520.9 ***
    3317 225 495.1 ***
    (decomp.)
    3318 235 505.1 ***
    (decomp.)
    3319 545.9 ***
    3320 546.9 ***
    3321 233 494.9 ***
    (decomp.)
    3322 227-229 522.8 ***
    3323 114-300 492.7 **
    3324 117-300 518.8 ***
    3325 173-181 491.8 ***
    3326 98-99 460.9 ***
    3327 213-215 426.0 ***
    3328 227-229 424.0 ***
    3329 237-238 438.0 ***
    3330 230-231 452.0 ***
    3331 217-218 466.0 ***
    3332 140 483.2 ***
    (decomp.)
    3333 108-115 ***
    3334 108-116 531.6 ***
    3335 227-230 540.0 ***
    3336 257-259 541.0 ***
    3338 280-281 507.0 ***
    3337 227-230 560.0 ***
    3339 284-285 481.0 ***
    3340 290-291 515.4 ***
    3341 265-266 535.0 ***
    3342   266-267.5 480.0 ***
    3343 109-110 466.0 ***
    3344 227-230 541.9 ***
    3345 167-169 561.8 ***
    3346 113-116 529.9 ***
    3347 160-162 549.9 ***
    3348 229-231 436.9 ***
    2150 170-172 402.4 ***
    2186 189-191 473.4 ***
    2194 493.4 ***
    2249 155-156 487.3 ** 1H NMR (CDCl3, 400 MHz), δ7.65 (d,
    J = 8.8 Hz, 1H), 7.58-7.52 (m, 4H), 7.23 (s,
    1H), 6.98 (dd, J = 8.8 Hz and 2.4 Hz, 1H),
    4.93-4.88 (m, 1H), 4.14 (q, J = 7.2 Hz, 2H),
    3.87 (b, 2H), 3.55 (b, 4H), 3.37 (s, 3H),
    2.87-2.82 (m, 2H), 2.70-2.44 (m, 6H),
    2.34-2.32 (m, 2H) 2.01-2.80 (m, 2H),
    1.49 (t, J = 6.8 Hz, 3H).
    2250 194-195 465.2 ** 1H NMR (CDCl3, 400 MHz), δ8.61 (d,
    J = 5.2 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H),
    7.85 (b, 1H), 7.78-7.74 (m, 1H), 7.64 (d,
    J = 8.8 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H),
    7.33-7.29 (m, 2H), 7.20 (s, 1H), 6.97 (d,
    J = 6.8 Hz, 1H), 4.94-4.90 (m, 1H), 4.14 (q,
    J = 7.2 Hz, 2H), 3.94 (q, J = 5.4 Hz, 2H),
    3.22 (t, J = 6.0 Hz, 2H), 2.83-2.72 (m, 2H),
    2.37-2.31 (m, 2H), 1.96-1.77 (m, 2H), 1.49 (t,
    J = 6.8 Hz, 3H).
    2251 172-173 430.2 ** 1H NMR (CDCl3, 400 MHz), δ
    7.69-7.64 (m, 3H), 7.53 (d, J = 8.0 Hz, 2H), 7.22 (s,
    1H), 6.98 (dd, J = 8.8 Hz and 1.2 Hz, 1H),
    4.93-4.89 (m, 1H), 4.63-4.52 (m, 1H),
    4.14 (q, J = 6.8 Hz, 2H), 3.83-3.49 (m, 4H),
    2.85-2.80 (m, 2H), 2.35-2.31 (m, 2H),
    2.04-1.78 (m, 5H), 1.49 (t, J = 7.2 Hz, 3H).
    2271 160-163 527.4 ***
    2272 166-168 499.4 ***
    2273 118-121 499.4 ***
    2274 201-203 585.4 ***
    2275 114-117 485.4 ***
    2276 118-120 471.4 ***
    2277 217-221 396.4 ***
    2293 199-201 519.4 ***
    2294 205-207 491.4 ***
    2295 105-107 491.4 ***
    2296 202-205 477.3 ***
    2297 235-237 463.3 ***
    2312 203-204 467.4 **
    • Example 7 Evaluation of the Activity of Compounds Using an HCV-Poliovirus Chimera
  • In an HCV-poliovirus (HCV-PV) chimera, the PV 5′ UTR is replaced by the HCV 5′ UTR and partial (the first 123 amino acids) core coding sequences (nucleotides 18 to 710 of HCV 1b) (140). As a consequence, the expression of poliovirus proteins is under regulation of the HCV IRES. Poliovirus is a picornavirus in which protein translation initiation is mediated by an IRES element located in the 5′ UTR. At the 5′ end of the HCV-PV chimeric genome, there is the cloverleaf-like RNA structure of PV, an essential cis-acting replication signal ending with the genome-linked protein VPg. Replication kinetics of the HCV-PV chimera matches that of the parental poliovirus (Mahoney) and can result in cytopathic effects (CPE) in cell culture. Heptazyme, a ribozyme that targets the HCV IRES, was shown to be active against the chimeric virus in cell culture (76, 77).
  • To evaluate compounds for activity against the chimeric virus, HeLa cells are seeded and incubated at 37° C. under 5% CO2 for 24 hours. The cells are then infected with HCV-PV at a multiplicity of infection (MOI) at 0.1 for 30 min and then treated with compound for 1 day (treatment time will be optimized). The activity of compounds is determined by a change in cytopathic effect, plaque assay, and/or viral RNA production (see e.g., Tables 1A and 1B).
    • Example 8 Evaluation of the Activity of Compounds Against a Wild-Type Poliovirus (WT-PV) and the Poliovirus IRES Translation Assay (WT-PV Mono Luc)
  • A DNA construct is prepared, termed pPVIRESmono, in which PV IRES sequences are inserted (nucleotide number 1-742) between a promoter and the firefly luciferase (Flue) reporter gene. A stably transfected 293 T cell line, is established by transfection with the pPVIRESmono DNA by selecting for resistance to hygromycin. As previously described, cells are treated with compounds for 20 hours, and activity is determined by quantifying the Flue signal. Additionally, to evaluate compounds activity against wild-type poliovirus, Hela cells are seeded and incubated at 37° C. under 5% CO2 for 24 hours. Cells are then infected with wild-type poliovirus at a MOI at 0.1 for 30 minutes, and then treated with compound for one day. The activity of compounds is determined by changes in cytopathic effect, plaque assay, and RT-PCR using poliovirus IRES primers and probes (see e.g., Table 2).
  • Furthermore, if compounds are active against the poliovirus and other virus IRESs, then the compounds are useful for treating viral infection by any virus containing an IRES.
  • TABLE 2
    Com-
    pound WT-PV CPE WT-PV CPE WT-PV CPE WTPV mono luc
    No. (100 μM) * (10 μM)* (1 μM)* IC50 (μM)
    4 3 2 1 0.8
    5 3 2 1 9
    9 3 2 2 >100
    10 3 2 2 >100
    19 3 2 1 15
    24 3 2 2 1.5
    • Example 9 In Vitro Translation Assay
  • In vitro translation assays can be used to distinguish between the compounds that act on HCV IRES RNA or cellular translation factors. In exemplary assays, the mRNA that will direct translation is a transcribed runoff product from the T7 RNA polymerase promoter of the pHCVIRESmono plasmid DNA generated with Ambion RNA MegaTranscript kit (Ambion, Inc., Austin, Tex.). In vitro translation is performed using HeLa cell lysates using methods known to one of skill in the art. Preliminary results indicate that one or more of the compounds of the present invention has significantly higher activity against HCV IRES regulated translation after preincubating the compound with the HCV IRES RNA transcripts than after preincubating with HeLa cell lysate for 30 min at 37° C. or without preincubation (data not shown). This suggests that this compound may interact with the HCV IRES RNA in the in vitro translation assay. To demonstrate whether the compounds selectively act on the HCV IRES, pLuc is used together with cellular IRES mRNA transcripts as controls for in vitro translation.
  • All publications and patent applications cited herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
  • Although certain embodiments have been described in detail above, those having ordinary skill in the art will clearly understand that many modifications are possible in the embodiments without departing from the teachings thereof. All such modifications are intended to be encompassed within the claims of the invention.
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Claims (4)

1.-119. (canceled)
120. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of:
Figure US20100305100A1-20101202-C00589
Figure US20100305100A1-20101202-C00590
Figure US20100305100A1-20101202-C00591
Figure US20100305100A1-20101202-C00592
Figure US20100305100A1-20101202-C00593
Figure US20100305100A1-20101202-C00594
Figure US20100305100A1-20101202-C00595
Figure US20100305100A1-20101202-C00596
Figure US20100305100A1-20101202-C00597
Figure US20100305100A1-20101202-C00598
Figure US20100305100A1-20101202-C00599
Figure US20100305100A1-20101202-C00600
Figure US20100305100A1-20101202-C00601
Figure US20100305100A1-20101202-C00602
Figure US20100305100A1-20101202-C00603
Figure US20100305100A1-20101202-C00604
Figure US20100305100A1-20101202-C00605
Figure US20100305100A1-20101202-C00606
Figure US20100305100A1-20101202-C00607
Figure US20100305100A1-20101202-C00608
Figure US20100305100A1-20101202-C00609
Figure US20100305100A1-20101202-C00610
Figure US20100305100A1-20101202-C00611
Figure US20100305100A1-20101202-C00612
Figure US20100305100A1-20101202-C00613
Figure US20100305100A1-20101202-C00614
Figure US20100305100A1-20101202-C00615
Figure US20100305100A1-20101202-C00616
Figure US20100305100A1-20101202-C00617
Figure US20100305100A1-20101202-C00618
Figure US20100305100A1-20101202-C00619
Figure US20100305100A1-20101202-C00620
Figure US20100305100A1-20101202-C00621
Figure US20100305100A1-20101202-C00622
Figure US20100305100A1-20101202-C00623
Figure US20100305100A1-20101202-C00624
Figure US20100305100A1-20101202-C00625
Figure US20100305100A1-20101202-C00626
Figure US20100305100A1-20101202-C00627
Figure US20100305100A1-20101202-C00628
Figure US20100305100A1-20101202-C00629
Figure US20100305100A1-20101202-C00630
Figure US20100305100A1-20101202-C00631
Figure US20100305100A1-20101202-C00632
Figure US20100305100A1-20101202-C00633
Figure US20100305100A1-20101202-C00634
Figure US20100305100A1-20101202-C00635
Figure US20100305100A1-20101202-C00636
Figure US20100305100A1-20101202-C00637
Figure US20100305100A1-20101202-C00638
Figure US20100305100A1-20101202-C00639
Figure US20100305100A1-20101202-C00640
Figure US20100305100A1-20101202-C00641
Figure US20100305100A1-20101202-C00642
Figure US20100305100A1-20101202-C00643
Figure US20100305100A1-20101202-C00644
Figure US20100305100A1-20101202-C00645
Figure US20100305100A1-20101202-C00646
Figure US20100305100A1-20101202-C00647
Figure US20100305100A1-20101202-C00648
Figure US20100305100A1-20101202-C00649
Figure US20100305100A1-20101202-C00650
121. A pharmaceutical composition comprising the compound of claim 120 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
122. A method for treating a viral infection in a subject in need thereof comprising administering an effective amount of the compound of claim 120 or a pharmaceutically acceptable salt thereof to the subject, wherein said viral infection is a Hepatitis C viral infection.
US12/828,597 2004-07-14 2010-07-01 Methods for treating hepatitis c Abandoned US20100305100A1 (en)

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