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Publication numberUS20030236277 A1
Publication typeApplication
Application numberUS 10/352,279
Publication dateDec 25, 2003
Filing dateJan 27, 2003
Priority dateFeb 14, 2002
Also published asDE60317630D1, DE60317630T2, EP1474135A1, EP1474135A4, EP1474135B1, EP1474135B9, US7531552, US7714019, US20060287531, US20080096912, US20090186933, WO2003068221A1
Publication number10352279, 352279, US 2003/0236277 A1, US 2003/236277 A1, US 20030236277 A1, US 20030236277A1, US 2003236277 A1, US 2003236277A1, US-A1-20030236277, US-A1-2003236277, US2003/0236277A1, US2003/236277A1, US20030236277 A1, US20030236277A1, US2003236277 A1, US2003236277A1
InventorsJohn Kadow, Qiufen Xue, Tao Wang, Zhongxing Zhang, Nicholas Meanwell
Original AssigneeKadow John F., Xue Qiufen May, Tao Wang, Zhongxing Zhang, Meanwell Nicholas A.
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Indole, azaindole and related heterocyclic pyrrolidine derivatives
US 20030236277 A1
Abstract
This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with amido piperazine derivatives. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS.
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Claims(8)
What is claimed is:
1. A compound of Formula I, including pharmaceutically acceptable salts thereof
Q is selected from the group consisting of:
R1, R2, R3, R4, and R5, are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, COOR8, XR57, and B;
m is 1 or 2;
R7 is (CH2)nR44 wherein n is 0-6;
R6 is O or does not exist;
——represents a carbon-carbon bond or does not exist;
A is selected from the group consisting of C1-6alkoxy, phenyl and D; wherein D is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzoimidazolyl and benzothiazolyl; wherein said phenyl and D are independently optionally substituted with one or two of the same or different amino, halogen or trifluoromethyl;
B is selected from the group consisting of (C1-6)alkyl, (C3-6)cycloalkyl, C(O)NR40R41, phenyl and heteroaryl; wherein said (C1-6)alkyl, phenyl and heteroaryl are independently optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from F;
F is selected from the group consisting of (C1-6)alkyl, phenyl, hydroxy, (C1-6)alkoxy, halogen, benzyl, —NR42C(O)—(C1-6)alkyl, —NR42R43, COOR54 and —CONR42; wherein said (C1-6)alkyl is optionally substituted with one to three same or different halogen;
R8 is selected from the group consisting of hydrogen and (C1-6)alkyl;
R9 is selected from the group consisting of hydrogen and methyl;
X is selected from the group consisting of NR9, O and S;
R40 and R41 are independently selected from the group consisting of hydrogen, (C1-6)alkyl, (C1-6)alkoxy, phenyl and heteroaryl; wherein said phenyl and heteroaryl are independently optionally substituted with one to three same or different halogen, methyl, or CF3 groups;
R42 and R43 are independently selected from the group consisting of hydrogen and (C1-6)alkyl;
R44 is selected from the group consisting of H, (C1-6)alkyl, CO(C1-6)alkyl, C(O)-phenyl and —CONRaRb;
Ra and Rb are each independently H, (C1-6)alkyl or phenyl;
R54 is selected from the group consisting of hydrogen and (C1-6)alkyl;
R57 is (C1-6)alkyl; and
heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl and triazolyl.
2. The compound of claim 1, including pharmaceutically acceptable salts thereof of formula
wherein:
Z is
A is selected from the group consisting of phenyl and D; wherein D is selected from the group consisting of pyridinyl, furanyl and thienyl; wherein phenyl and D are independently optionally substituted with one or two of the same or different amino or halogen;
W is selected from the group consisting of
R1 is hydrogen; and
Q is a member selected from groups (A) and (B) consisting of
provided R2 and R3 are each independently hydrogen, methoxy or halogen; and R4 and R5 are selected from the group consisting of hydrogen, halogen, cyano, COOR8, C(O)NHCH3, C(O)NHheteroaryl, and heteroaryl; and
provided R2 is hydrogen, methoxy or halogen;
R3 and R4 are selected from the group consisting of hydrogen, halogen, methoxy, cyano, COOR8, C(O)NHCH3, C(O)NHheteroaryl and heteroaryl; and R6 does not exist;
and ——represents a carbon-carbon bond in (A) and (B).
3. A pharmaceutical composition which comprises an antiviral effective amount of a compound of Formula I, including pharmaceutically acceptable salts thereof, as claimed in any of claims 1-2, and one or more pharmaceutically acceptable carriers, excipients or diluents.
4. The pharmaceutical composition of claim 3, useful for treating infection by HIV, which additionally comprises an antiviral effective amount of an AIDS treatment agent selected from the group consisting of:
(a) an AIDS antiviral agent;
(b) an anti-infective agent;
(c) an immunomodulator; and
(d) HIV entry inhibitors.
5. A method for treating a mammal infected with a virus comprising administering to said mammal an antiviral effective amount of a compound of Formula I, including pharmaceutically accceptable salts thereof, as claimed in any of claims 1-2, and one or more pharmaceutically acceptable carriers, excipients or diluents.
6. The method of claim 5, comprising administering to said mammal an antiviral effective amount of a compound of Formula I in combination with an antiviral effective amount of an AIDS treatment agent selected from the group consisting of: an AIDS antiviral agent; an anti-infective agent; an immunomodulator; and an HIV entry inhibitor.
7. The method of claim 5 wherein said virus is HIV.
8. The method of claim 6 wherein said virus is HIV.
Description
REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 60/356,977 filed Feb. 14, 2002.

FIELD OF THE INVENTION

[0002] This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with new heterocyclic amidopiperazine derivatives that possess unique antiviral activity. More particularly, the present invention relates to compounds useful for the treatment of HIV and AIDS.

BACKGROUND ART

[0003] HIV-1 (human immunodeficiency virus-1) infection remains a major medical problem, with an estimated 33.6 million people infected worldwide. The number of cases of HIV and AIDS (acquired immunodeficiency syndrome) has risen rapidly. In 1999, 5.6 million new infections were reported, and 2.6 million people died from AIDS. Currently available drugs for the treatment of HIV include six nucleoside reverse transcriptase (RT) inhibitors (zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavir), three non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine and efavirenz), and six peptidomimetic protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir, amprenavir and lopinavir). Each of these drugs can only transiently restrain viral replication if used alone. However, when used in combination, these drugs have a profound effect on viremia and disease progression. In fact, significant reductions in death rates among AIDS patients have been recently documented as a consequence of the widespread application of combination therapy. However, despite these impressive results, 30 to 50% of patients ultimately fail combination drug therapies. Insufficient drug potency, non-compliance, restricted tissue penetration and drug-specific limitations within certain cell types (e.g. most nucleoside analogs cannot be phosphorylated in resting cells) may account for the incomplete suppression of sensitive viruses. Furthermore, the high replication rate and rapid turnover of HIV-1 combined with the frequent incorporation of mutations, leads to the appearance of drug-resistant variants and treatment failures when sub-optimal drug concentrations are present (Larder and Kemp; Gulick; Kuritzkes; Morris-Jones et al; Schinazi et al; Vacca and Condra; Flexner; Berkhout and Ren et al; (Ref. 6-14)). Therefore, novel anti-HIV agents exhibiting distinct resistance patterns, and favorable pharmacokinetic as well as safety profiles are needed to provide more treatment options.

[0004] Currently marketed HIV-1 drugs are dominated by either nucleoside reverse transcriptase inhibitors or peptidomimetic protease inhibitors. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have recently gained an increasingly important role in the therapy of HIV infections (Pedersen & Pedersen, Ref 15). At least 30 different classes of NNRTI have been described in the literature (De Clercq, Ref. 16) and several NNRTIs have been evaluated in clinical trials. Dipyridodiazepinone (nevirapine), benzoxazinone (efavirenz) and bis(heteroaryl) piperazine derivatives (delavirdine) have been approved for clinical use. However, the major drawback to the development and application of NNRTIs is the propensity for rapid emergence of drug resistant strains, both in tissue cell culture and in treated individuals, particularly those subject to monotherapy. As a consequence, there is considerable interest in the identification of NNRTIs less prone to the development of resistance (Pedersen & Pedersen, Ref 15). A recent overview of non-nucleoside reverse transcriptase inhibitors: perspectives on novel therapeutic compounds and strategies for the treatment of HIV infection. has appeared (Buckheit , reference 99). A review covering both NRTI and NNRTIs has appeared (De clercq, reference 100). An overview of the current state of the HIV drugs has been published (De clercq, reference 101)

[0005] Several indole derivatives including indole-3-sulfones, piperazino indoles, pyrazino indoles, and 5H-indolo[3,2-b][1,5]benzothiazepine derivatives have been reported as HIV-1 reverse transciptase inhibitors (Greenlee et al, Ref. 1; Williams et al, Ref. 2; Romero et al, Ref. 3; Font et al, Ref. 17; Romero et al, Ref. 18; Young et al, Ref. 19; Genin et al, Ref. 20; Silvestri et al, Ref. 21). Indole 2-carboxamides have also been described as inhibitors of cell adhesion and HIV infection (Boschelli et al, U.S. Pat. No. 5,424,329, Ref. 4). 3-substituted indole natural products (Semicochliodinol A and B, didemethylasterriquinone and isocochliodinol) were disclosed as inhibitors of HIV-1 protease (Fredenhagen et al, Ref. 22).

[0006] Structurally related aza-indole amide derivatives have been disclosed previously (Kato et al, Ref. 23; Levacher et al, Ref. 24; Dompe Spa, WO-09504742, Ref. 5(a); SmithKline Beecham PLC, WO-09611929, Ref. 5(b); Schering Corp., US-05023265, Ref. 5(c)). However, these structures differ from those claimed herein in that they are aza-indole mono-amide rather than unsymmetrical aza-indole piperazine diamide derivatives, and there is no mention of the use of these compounds for treating viral infections, particularly HIV. Indole and azaindole piperazine containing derivatives have been disclosed in three different PCT patent applications (Reference 93-95) None of these applications discloses pyrrolidine compounds such as described in this invention.

[0007] Nothing in these references can be construed to disclose or suggest the novel compounds of this invention and their use to inhibit HIV infection.

REFERENCES CITED

[0008] Patent Documents

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SUMMARY OF THE INVENTION

[0112] The present invention comprises compounds of Formula I, their pharmaceutical formulations, and their use in patients suffering from or susceptible to a virus such as HIV. The compounds of Formula I, which include nontoxic pharmaceutically acceptable salts and/or hydrates thereof, have the formula and meaning as described below. Each embodiment of a particular aspect of the invention depends from the preceding embodiment unless otherwise stated.

SUMMARY DESCRIPTION OF THE INVENTION

[0113] The present invention comprises compounds of Formula I, or pharmaceutically acceptable salts thereof, which are effective antiviral agents, particularly as inhibitors of HIV.

[0114] A first embodiment of a first aspect of the invention are compounds of Formula I, including pharmaceutically acceptable salts thereof,

[0115] wherein:

[0116] Z is

[0117] Q is selected from the group consisting of:

[0118] R1, R2, R3, R4, and R5, are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, COOR8, XR57, and B;

[0119] m is 1 or 2;

[0120] R7 is (CH2)nR44 wherein n is 0-6;

[0121] R6 is O or does not exist;

[0122] ——represents a carbon-carbon bond or does not exist;

[0123] A is selected from the group consisting of C1-6alkoxy, phenyl and D; wherein D is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzoimidazolyl and benzothiazolyl; wherein said phenyl and D are independently optionally substituted with one or two of the same or different amino, halogen or trifluoromethyl;

[0124] —W— is

[0125] B is selected from the group consisting of (C1-6)alkyl, (C3-6)cycloalkyl, C(O)NR40R41, phenyl and heteroaryl; wherein said (C1-6)alkyl, phenyl and heteroaryl are independently optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from F; F is selected from the group consisting of (C1-6)alkyl, phenyl, hydroxy, (C1-6)alkoxy, halogen, benzyl, —NR42C(O)—(C1-6)alkyl, —NR42R43, COOR54 and —CONR42; wherein said (C1-6)alkyl is optionally substituted with one to three same or different halogen;

[0126] R8 is selected from the group consisting of hydrogen and (C1-6)alkyl;

[0127] R9 is selected from the group consisting of hydrogen and methyl;

[0128] X is selected from the group consisting of NR9, O and S;

[0129] R40 and R41 are independently selected from the group consisting of hydrogen, (C1-6)alkyl, (C1-6)alkoxy, phenyl and heteroaryl; wherein said phenyl and heteroaryl are independently optionally substituted with one to three same or different halogen, methyl, or CF3 groups;

[0130] R42 and R43 are independently selected from the group consisting of hydrogen and (C1-6)alkyl;

[0131] R44 is selected from the group consisting of H, (C1-6)alkyl, CO(C1-6)alkyl, C(O)-phenyl and —CONRaRb;

[0132] Ra and Rb are each independently H, (C1-6)alkyl or phenyl;

[0133] R54 is selected from the group consisting of hydrogen and (C1-6)alkyl;

[0134] R57 is (C1-6)alkyl; and

[0135] heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl and triazolyl.

[0136] A more preferred embodiment of a first aspect of the invention are compounds of Formula I, including pharmaceutically acceptable salts thereof,

[0137] wherein:

[0138] Z is

[0139] A is selected from the group consisting of phenyl and D; wherein D is selected from the group consisting of pyridinyl, furanyl and thienyl; wherein phenyl and D are independently optionally substituted with one or two of the same or different amino or halogen;

[0140] W is selected from the group consisting of

[0141] R1 is hydrogen; and

[0142] Q is a member selected from groups (A) and (B) consisting of

[0143] provided R2 and R3 are each independently hydrogen, methoxy or halogen; and R4 and R5 are selected from the group consisting of hydrogen, halogen, cyano, COOR8, C(O)NHCH3, C(O)NHheteroaryl, and heteroaryl; and

[0144] provided R2 is hydrogen, methoxy or halogen;

[0145] R3 and R4 are selected from the group consisting of hydrogen, halogen, methoxy, cyano, COOR8, C(O)NHCH3, C(O)NHheteroaryl and heteroaryl; and R6 does not exist;

[0146] and ——represents a carbon-carbon bond in (A) and (B).

[0147] Another embodiment of the present invention is a method for treating mammals infected with a virus, wherein said virus is HIV, comprising administering to said mammal an antiviral effective amount of a compound of Formula I, and one or more pharmaceutically acceptable carriers, excipients or diluents; optionally the compound of Formula I can be administered in combination with an antiviral effective amount of an AIDS treatment agent selected from the group consisting of: (a) an AIDS antiviral agent; (b) an anti-infective agent; (c) an immunomodulator; and (d) HIV entry inhibitors.

[0148] Another embodiment of the present invention is a pharmaceutical composition comprising an antiviral effective amount of a compound of Formula I and one or more pharmaceutically acceptable carriers, excipients, diluents and optionally in combination with an antiviral effective amount of an AIDS treatment agent selected from the group consisting of: (a) an AIDS antiviral agent; (b) an anti-infective agent; (c) an immunomodulator; and (d) HIV entry inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

[0149] Since the compounds of the present invention, may possess asymmetric centers and therefore occur as mixtures of diastereomers and enantiomers, the present invention includes the individual diastereoisomeric and enantiomeric forms of the compounds of Formula I in addition to the mixtures thereof.

Definitions

[0150] The term “C1-6 alkyl” as used herein and in the claims (unless specified otherwise) mean straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and the like.

[0151] “Halogen” refers to chlorine, bromine, iodine or fluorine.

[0152] An “aryl” group refers to an all carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, napthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted. When substituted the substituted group(s) is preferably one or more selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, amino and —NRxRy, wherein Rx and Ry are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, C-carboxy, sulfonyl, trihalomethyl, and, combined, a five- or six-member heteroalicyclic ring.

[0153] As used herein, a “heteroaryl” group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system. It should be noted that the term heteroaryl is intended to encompass an N-oxide of the parent heteroaryl if such an N-oxide is chemically feasible as is known in the art. Examples, without limitation, of heteroaryl groups are furyl, thienyl, benzothienyl, thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzoxazolyl, benzimidazolyl, indolyl, isoindolyl, pyrazinyl. diazinyl, pyrazine, triazinyltriazine, tetrazinyl, and tetrazolyl. When substituted the substituted group(s) is preferably one or more selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, amino, and —NRxRy, wherein Rx and Ry are as defined above.

[0154] As used herein, a “heteroalicyclic” group refers to a monocyclic or fused ring group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. Examples, without limitation, of heteroalicyclic groups are azetidinyl, piperidyl, piperazinyl, imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl, thiomorpholinyl and tetrahydropyranyl. When substituted the substituted group(s) is preferably one or more selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, silyl, guanyl, guanidino, ureido, phosphonyl, amino and —NRxRy, wherein Rx and Ry are as defined above.

[0155] An “alkyl” group refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms (whenever a numerical range; e.g., “1-20”, is stated herein, it means that the group, in this case the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms). More preferably, it is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more individually selected from trihaloalkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, and combined, a five- or six-member heteroalicyclic ring.

[0156] A “cycloalkyl” group refers to an all-carbon monocyclic or fused ring (i.e., rings which share and adjacent pair of carbon atoms) group wherein one or more rings does not have a completely conjugated pi-electron system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, cycloheptane, cycloheptatriene and adamantane. A cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more individually selected from alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy, thioheteroarylloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalo-methanesulfonamido, trihalomethanesulfonyl, silyl, guanyl, guanidino, ureido, phosphonyl, amino and —NRxRy with Rx and Ry as defined above.

[0157] An “alkenyl” group refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond.

[0158] An “alkynyl” group refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond.

[0159] A “hydroxy” group refers to an —OH group.

[0160] An “alkoxy” group refers to both an —O-alkyl and an —O-cycloalkyl group as defined herein.

[0161] An “aryloxy” group refers to both an —O-aryl and an —O-heteroaryl group, as defined herein.

[0162] A “heteroaryloxy” group refers to a heteroaryl-O— group with heteroaryl as defined herein.

[0163] A “heteroalicycloxy” group refers to a heteroalicyclic-O— group with heteroalicyclic as defined herein.

[0164] A “thiohydroxy” group refers to an —SH group.

[0165] A “thioalkoxy” group refers to both an S-alkyl and an —S-cycloalkyl group, as defined herein.

[0166] A “thioaryloxy” group refers to both an —S-aryl and an —S-heteroaryl group, as defined herein.

[0167] A “thioheteroaryloxy” group refers to a heteroaryl-S— group with heteroaryl as defined herein.

[0168] A “thioheteroalicycloxy” group refers to a heteroalicyclic-S— group with heteroalicyclic as defined herein.

[0169] A “carbonyl” group refers to a —C(═O)—R″ group, where R″ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), as each is defined herein.

[0170] An “aldehyde” group refers to a carbonyl group where R″ is hydrogen.

[0171] A “thiocarbonyl” group refers to a —C(═S)—R″ group, with R″ as defined herein.

[0172] A “Keto” group refers to a —CC(═O)C— group wherein the carbon on either or both sides of the C═O may be alkyl, cycloalkyl, aryl or a carbon of a heteroaryl or heteroaliacyclic group.

[0173] A “trihalomethanecarbonyl” group refers to a Z3CC(═O)— group with said Z being a halogen.

[0174] A “C-carboxy” group refers to a —C(═O)O—R″ groups, with R″ as defined herein.

[0175] An “O-carboxy” group refers to a R″C(—O)O-group, with R″ as defined herein.

[0176] A “carboxylic acid” group refers to a C-carboxy group in which R″ is hydrogen.

[0177] A “trihalomethyl” group refers to a —CZ3, group wherein Z is a halogen group as defined herein.

[0178] A “trihalomethanesulfonyl” group refers to an Z3CS(═O)2— groups with Z as defined above.

[0179] A “trihalomethanesulfonamido” group refers to a Z3CS(═O)2NRx— group with Z and RX as defined herein.

[0180] A “sulfinyl” group refers to a —S(═O)—R″ group, with R″ as defined herein and, in addition, as a bond only; i.e., —S(O)—.

[0181] A “sulfonyl” group refers to a —S(═O)2R″ group with R″ as defined herein and, in addition as a bond only; i.e., —S(O)2—.

[0182] A “S-sulfonamido” group refers to a —S(═O)2NRXRY, with RX and RY as defined herein.

[0183] A “N-Sulfonamido” group refers to a R″S(═O)2NRX— group with Rx as defined herein.

[0184] A “O-carbamyl” group refers to a —OC(═O)NRxRy as defined herein.

[0185] A “N-carbamyl” group refers to a RxOC(═O)NRy group, with Rx and Ry as defined herein.

[0186] A “O-thiocarbamyl” group refers to a —OC(═S)NRxRy group with Rx and Ry as defined herein.

[0187] A “N-thiocarbamyl” group refers to a RxOC(═S)NRy— group with Rx and Ry as defined herein.

[0188] An “amino” group refers to an —NH2 group.

[0189] A “C-amido” group refers to a —C(═O)NRxRy group with Rx and Ry as defined herein.

[0190] A “C-thioamido” group refers to a —C(═S)NRxRy group, with Rx and Ry as defined herein.

[0191] A “N-amido” group refers to a RxC(═O)NRy— group, with Rx and Ry as defined herein.

[0192] An “ureido” group refers to a —NRxC(═O)NRyRy2 group with Rx and Ry as defined herein and Ry2 defined the same as Rx and Ry.

[0193] A “guanidino” group refers to a —RxNC(═N)NRyRy2 group, with Rx, Ry and Ry2 as defined herein.

[0194] A “guanyl” group refers to a RxRyNC(═N)— group, with Rx and RY as defined herein.

[0195] A “cyano” group refers to a —CN group.

[0196] A “silyl” group refers to a —Si(R″)3, with R″ as defined herein.

[0197] A “phosphonyl” group refers to a P(═O)(ORx)2 with Rx as defined herein.

[0198] A “hydrazino” group refers to a —NRxNRyRy2 group with Rx, Ry and Ry2 as defined herein.

[0199] Any two adjacent R groups may combine to form an additional aryl, cycloalkyl, heteroaryl or heterocyclic ring fused to the ring initially bearing those R groups.

[0200] It is known in the art that nitogen atoms in heteroaryl systems can be “participating in a heteroaryl ring double bond”, and this refers to the form of double bonds in the two tautomeric structures which comprise five-member ring heteroaryl groups. This dictates whether nitrogens can be substituted as well understood by chemists in the art. The disclosure and claims of the present invention are based on the known general principles of chemical bonding. It is understood that the claims do not encompass structures known to be unstable or not able to exist based on the literature.

[0201] Physiologically acceptable salts and prodrugs of compounds disclosed herein are within the scope of this invention. The term “pharmaceutically acceptable salt” as used herein and in the claims is intended to include nontoxic base addition salts. Suitable salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, sulfinic acid, citric acid, maleic acid, fumaric acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, and the like. The term “pharmaceutically acceptable salt” as used herein is also intended to include salts of acidic groups, such as a carboxylate, with such counterions as ammonium, alkali metal salts, particularly sodium or potassium, alkaline earth metal salts, particularly calcium or magnesium, and salts with suitable organic bases such as lower alkylamines (methylamine, ethylamine, cyclohexylamine, and the like) or with substituted lower alkylamines (e.g. hydroxyl-substituted alkylamines such as diethanolamine, triethanolamine or tris(hydroxymethyl)-aminomethane), or with bases such as piperidine or morpholine.

[0202] In the method of the present invention, the term “antiviral effective amount” means the total amount of each active component of the method that is sufficient to show a meaningful patient benefit, i.e., healing of acute conditions characterized by inhibition of the HIV infection. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously. The terms “treat, treating, treatment” as used herein and in the claims means preventing or ameliorating diseases associated with HIV infection.

[0203] The present invention is also directed to combinations of the compounds with one or more agents useful in the treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, antiinfectives, or vaccines, such as those in the following table.

Drug Name Manufacturer Indication
ANTIVIRALS
097 Hoechst/Bayer HIV infection,
AIDS, ARC
(non-nucleoside
reverse trans-
criptase (RT)
inhibitor)
Amprenivir Glaxo Wellcome HIV infection,
141 W94 AIDS, ARC
GW 141 (protease inhibitor)
Abacavir (1592U89) Glaxo Wellcome HIV infection,
GW 1592 AIDS, ARC
(RT inhibitor)
Acemannan Carrington Labs ARC
(Irving, TX)
Acyclovir Burroughs Wellcome HIV infection, AIDS,
ARC, in combination
with AZT
AD-439 Tanox Biosystems HIV infection, AIDS,
ARC
AD-519 Tanox Biosystems HIV infection, AIDS,
ARC
Adefovir dipivoxil Gilead Sciences HIV infection
AL-721 Ethigen ARC, PGL
(Los Angeles, CA) HIV positive, AIDS
Alpha Interferon Glaxo Wellcome Kaposi's sarcoma,
HIV in combination
w/Retrovir
Ansamycin Adria Laboratories ARC
LM 427 (Dublin, OH)
Erbamont
(Stamford, CT)
Antibody which Advanced Biotherapy AIDS, ARC
Neutralizes pH Concepts
Labile alpha aberrant (Rockville, MD)
Interferon
AR177 Aronex Pharm HIV infection, AIDS,
ARC
Beta-fluoro-ddA Nat'l Cancer Institute AIDS-associated
diseases
BMS-232623 Bristol-Myers Squibb/ HIV infection,
(CGP-73547) Novartis AIDS, ARC
(protease inhibitor)
BMS-234475 Bristol-Myers Squibb/ HIV infection,
(CGP-61755) Novartis AIDS, ARC
(protease inhibitor)
CI-1012 Warner-Lambert HIV-1 infection
Cidofovir Gilead Science CMV retinitis,
herpes, papillomavirus
Curdlan sulfate AJI Pharma USA HIV infection
Cytomegalovirus MedImmune CMV retinitis
Immune globin
Cytovene Syntex Sight threatening
Ganciclovir CMV
peripheral CMV
retinitis
Delaviridine Pharmacia-Upjohn HIV infection,
AIDS, ARC
(RT inhibitor)
Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV
Ind. Ltd. (Osaka, positive
Japan) asymptomatic
ddC Hoffman-La Roche HIV infection, AIDS,
Dideoxycytidine ARC
ddI Bristol-Myers Squibb HIV infection, AIDS,
Dideoxyinosine ARC; combination
with AZT/d4T
DMP-450 AVID HIV infection,
(Camden, NJ) AIDS, ARC
(protease inhibitor)
Efavirenz DuPont Merck HIV infection,
(DMP 266) AIDS, ARC
(-)6-Chloro-4-(S)- (non-nucleoside RT
cyclopropylethynyl- inhibitor)
4(S)-trifluoro-
methyl-1,4-dihydro-
2H-3,1-benzoxazin-
2-one, STOCRINE
EL10 Elan Corp, PLC HIV infection
(Gainesville, GA)
Famciclovir Smith Kline herpes zoster,
herpes simplex
FTC Emory University HIV infection,
AIDS, ARC
(reverse transcriptase
inhibitor)
GS 840 Gilead HIV infection,
AIDS, ARC
(reverse transcriptase
inhibitor)
HBY097 Hoechst Marion HIV infection,
Roussel AIDS, ARC
(non-nucleoside
reverse transcriptase
inhibitor)
Hypericin VIMRx Pharm. HIV infection, AIDS,
ARC
Recombinant Human Triton Biosciences AIDS, Kaposi's
Interferon Beta (Almeda, CA) sarcoma, ARC
Interferon alfa-n3 Interferon Sciences ARC, AIDS
Indinavir Merck HIV infection, AIDS,
ARC, asymptomatic
HIV positive, also in
combination with
AZT/ddI/ddC
ISIS 2922 ISIS Pharmaceuticals CMV retinitis
KNI-272 Nat'l Cancer Institute HIV-assoc. diseases
Lamivudine, 3TC Glaxo Wellcome HIV infection,
AIDS, ARC
(reverse
transcriptase
inhibitor); also
with AZT
Lobucavir Bristol-Myers Squibb CMV infection
Nelfinavir Agouron HIV infection,
Pharmaceuticals AIDS, ARC
(protease inhibitor)
Nevirapine Boeheringer HIV infection,
Ingleheim AIDS, ARC
(RT inhibitor)
Novapren Novaferon Labs, Inc. HIV inhibitor
(Akron, OH)
Peptide T Peninsula Labs AIDS
Octapeptide (Belmont, CA)
Sequence
Trisodium Astra Pharm. CMV retinitis, HIV
Phosphonoformate Products, Inc. infection, other CMV
infections
PNU-140690 Pharmacia Upjohn HIV infection,
AIDS, ARC
(protease inhibitor)
Probucol Vyrex HIV infection, AIDS
RBC-CD4 Sheffield Med. HIV infection,
Tech (Houston, TX) AIDS, ARC
Ritonavir Abbott HIV infection,
AIDS, ARC
(protease inhibitor)
Saquinavir Hoffmann- HIV infection,
LaRoche AIDS, ARC
(protease inbitor)
Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS,
Didehydrodeoxy- ARC
thymidine
Valaciclovir Glaxo Wellcome Genital HSV & CMV
infections
Virazole Viratek/ICN asymptomatic HIV
Ribavirin (Costa Mesa, CA) positive, LAS, ARC
VX-478 Vertex HIV infection, AIDS,
ARC
Zalcitabine Hoffmann-LaRoche HIV infection, AIDS,
ARC, with AZT
Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS,
ARC, Kaposi's
sarcoma, in
combination with
other therapies
IMMUNOMODULATORS
AS-101 Wyeth-Ayerst AIDS
Bropirimine Pharmacia Upjohn Advanced AIDS
Acemannan Carrington Labs, Inc. AIDS, ARC
(Irving, TX)
CL246,738 American Cyanamid AIDS, Kaposi's
Lederle Labs sarcoma
EL10 Elan Corp, PLC HIV infection
(Gainesville, GA)
FP-21399 Fuki ImmunoPharm Blocks HIV fusion
with CD4+ cells
Gamma Interferon Genentech ARC, in combination
w/TNF (tumor
necrosis factor)
Granulocyte Genetics Institute AIDS
Macrophage Colony Sandoz
Stimulating Factor
Granulocyte Hoechst-Roussel AIDS
Macrophage Colony Immunex
Stimulating Factor
Granulocyte Schering-Plough AIDS,
Macrophage Colony combination
Stimulating Factor w/AZT
HIV Core Particle Rorer Seropositive HIV
Immunostimulant
IL-2 Cetus AIDS, in combination
Interleukin-2 w/AZT
IL-2 Hoffman-LaRoche AIDS, ARC, HIV, in
Interleukin-2 Immunex combination w/AZT
IL-2 Chiron AIDS, increase in
Interleukin-2 CD4 cell counts
(aldeslukin)
Immune Globulin Cutter Biological Pediatric AIDS, in
Intravenous (Berkeley, CA) combination w/AZT
(human)
IMREG-1 Imreg AIDS, Kaposi's
(New Orleans, LA) sarcoma, ARC, PGL
IMREG-2 Imreg AIDS, Kaposi's
(New Orleans, LA) sarcoma, ARC, PGL
Imuthiol Diethyl Merieux Institute AIDS, ARC
Dithio Carbamate
Alpha-2 Schering Plough Kaposi's sarcoma
Interferon w/AZT, AIDS
Methionine- TNI Pharmaceutical AIDS, ARC
Enkephalin (Chicago, IL)
MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma
Muramyl-Tripeptide
Granulocyte Amgen AIDS, in combination
Colony Stimulating w/AZT
Factor
Remune Immune Response Immunotherapeutic
Corp.
rCD4 Genentech AIDS, ARC
Recombinant
Soluble Human CD4
rCD4-IgG AIDS, ARC
hybrids
Recombinant Biogen AIDS, ARC
Soluble Human CD4
Interferon Hoffman-La Roche Kaposi's sarcoma
Alfa 2a AIDS, ARC,
in combination w/AZT
SK&F106528 Smith Kline HIV infection
Soluble T4
Thymopentin Immunobiology HIV infection
Research Institute
(Annandale, NJ)
Tumor Necrosis Genentech ARC, in combination
Factor; TNF w/gamma Interferon
ANTI-INFECTIVES
Clindamycin with Pharmacia Upjohn PCP
Primaquine
Fluconazole Pfizer Cryptococcal
meningitis,
candidiasis
Pastille Squibb Corp. Prevention of
Nystatin Pastille oral candidiasis
Ornidyl Merrell Dow PCP
Eflornithine
Pentamidine LyphoMed PCP treatment
Isethionate (IM & IV) (Rosemont, IL)
Trimethoprim Antibacterial
Trimethoprim/sulfa Antibacterial
Piritrexim Burroughs Wellcome PCP treatment
Pentamidine Fisons Corporation PCP prophylaxis
Isethionate for
Inhalation
Spiramycin Rhone-Poulene Cryptosporidial
diarrhea
Intraconazole- Janssen-Pharm. Histoplasmosis;
R51211 cryptococcal
meningitis
Trimetrexate Wamer-Lambert PCP
Daunorubicin NeXstar, Sequus Kaposi's sarcoma
Recombinant Human Ortho Pharm. Corp. Severe anemia
Erythropoietin assoc. with AZT
therapy
Recombinant Human Serono AIDS-related
Growth Hormone wasting, cachexia
Megestrol Acetate Bristol-Myers Squibb Treatment of
anorexia assoc.
W/AIDS
Testosterone Alza, Smith Kline AIDS-related wasting
Total Enteral Norwich Eaton Diarrhea and
Nutrition Pharmaceuticals malabsorption
related to AIDS

[0204] Additionally, the compounds of the invention herein may be used in combination with another class of agents for treating AIDS which are called HIV entry inhibitors. Examples of such HIV entry inhibitors are discussed in DRUGS OF THE FUTURE 1999, 24(12), pp. 1355-1362; CELL, Vol. 9, pp. 243-246, Oct. 29, 1999; and DRUG DISCOVERY TODAY, Vol. 5, No. 5, May 2000, pp. 183-194.

[0205] It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives, HIV entry inhibitors or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.

[0206] Preferred combinations are simultaneous or alternating treatments of with a compound of the present invention and an inhibitor of HIV protease and/or a non-nucleoside inhibitor of HIV reverse transcriptase. An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. A preferred inhibitor of HIV protease is indinavir, which is the sulfate salt of N-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-N′-(t-butylcarboxamido)-piperazinyl))-pentaneamide ethanolate, and is synthesized according to U.S. Pat. No. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day. Other preferred protease inhibitors are nelfinavir and ritonavir. Another preferred inhibitor of HIV protease is saquinavir which is administered in a dosage of 600 or 1200 mg tid. Preferred non-nucleoside inhibitors of HIV reverse transcriptase include efavirenz. The preparation of ddC, ddI and AZT are also described in EPO 0,484,071. These combinations may have unexpected effects on limiting the spread and degree of infection of HIV. Preferred combinations include those with the following (1) indinavir with efavirenz, and, optionally, AZT and/or 3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/or ddI and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3) stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5) zidovudine and lamivudine.

[0207] In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

Abbreviations

[0208] The following abbreviations, most of which are conventional abbreviations well known to those skilled in the art, are used throughout the description of the invention and the examples. Some of the abbreviations used are as follows:

h = hour(s)
rt = room temperature
mol = mole(s)
mmol = millimole(s)
g = gram(s)
mg = milligram(s)
mL = milliliter(s)
TFA = Trifluoroacetic Acid
DCE = 1,2-Dichloroethane
CH2Cl2 = Dichloromethane
TPAP = tetrapropylammonium perruthenate
THF = Tetrahydofuran
DEPBT = 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-
one
DMAP = 4-dimethylaminopyridine
P-EDC = Polymer supported 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide
EDC = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
DMF = N,N-dimethylformamide
Hunig's Base = N,N-Diisopropylethylamine
mCPBA = meta-Chloroperbenzoic Acid
azaindole = 1H-Pyrrolo-pyridine
4-azaindole = 1H-pyrrolo[3,2-b]pyridine
5-azaindole = 1H-Pyrrolo[3,2-c]pyridine
6-azaindole = 1H-pyrrolo[2,3-c]pyridine
7-azaindole = 1H-Pyrrolo[2,3-b]pyridine
PMB = 4-Methoxybenzyl
DDQ = 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
OTf = Trifluoromethanesulfonoxy
NMM = 4-Methylmorpholine
PIP-COPh = 1-Benzoylpiperazine
NaHMDS = Sodium hexamethyldisilazide
EDAC = 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
TMS = Trimethylsilyl
DCM = Dichloromethane
DCE = Dichloroethane
MeOH = Methanol
THF = Tetrahrdrofuran
EtOAc = Ethyl Acetate
LDA = Lithium diisopropylamide
TMP-Li = 2,2,6,6-tetramethylpiperidinyl lithium
DME = Dimethoxyethane
DIBALH = Diisobutylaluminum hydride
HOBT = 1-hydroxybenzotriazole
CBZ = Benzyloxycarbonyl
PCC = Pyridinium chlorochromate

[0209] Chemistry

[0210] The present invention comprises compounds of Formula I, their pharmaceutical formulations, and their use in patients suffering from or susceptible to HIV infection. The compounds of Formula I include pharmaceutically acceptable salts thereof.

[0211] The synthesis procedures and anti-HIV-1 activities of indoleoxoacetic pyrrolidine containing analogs are below. Procedures for making Z are described herein or in many cases references of Blair, Wang, Wallace, references 93-95 respectively.

[0212] Additional general procedures to construct substituted azaindole Q and Z of Formula I and intermediates useful for their synthesis are described in the following Schemes 1-16.

[0213] Step A in Scheme 1 depicts the synthesis of an aza indole intermediate, 2, via the well known Bartoli reaction in which vinyl magnesium bromide reacts with an aryl or heteroaryl nitro group, such as in 1, to form a five-membered nitrogen containing ring as shown. Some references for the above transformation include: Bartoli et al. a) Tetrahedron Lett. 1989, 30, 2129. b) J. Chem. Soc. Perkin Trans. 1 1991, 2757. c) J. Chem. Soc. Perkin Trans. II 1991, 657. d) Synthesis (1999), 1594. In the preferred procedure, a solution of vinyl Magnesium bromide in THF (typically 1.0M but from 0.25 to 3.0M) is added dropwise to a solution of the nitro pyridine in THF at −78 under an inert atmosphere of either nitrogen or Argon. After addition is completed, the reaction temperature is allowed to warm to −20 and then is stirred for approximately 12 h before quenching with 20% aq ammonium chloride solution. The reaction is extracted with ethyl acetate and then worked up in a typical manner using a drying agent such as anhydrous magnesium sulfate or sodium sulfate. Products are generally purified using chromatography over Silica gel. Best results are generally achieved using freshly prepared vinyl Magnesium bromide. In some cases, vinyl Magnesium chloride may be substituted for vinyl Magnesium bromide.

[0214] Substituted azaindoles may be prepared by methods described in the literature or may be available from commercial sources. Thus there are many methods for carrying out step A in the literature and the specific examples are too numerous to even list. A review on the synthesis of 7-azaindoles has been published (Merour et. al. reference 102). Alternative syntheses of aza indoles and general methods for carrying out step A include, but are not limited to, those described in the following references (a-k below): a) Prokopov, A. A.; Yakhontov, L. N. Khim.-Farm. Zh. 1994, 28(7), 30-51; b) Lablache-Combier, A. Heteroaromatics. Photoinduced Electron Transfer 1988, Pt. C, 134-312; c) Saify, Zafar Said. Pak. J. Pharmacol. 1986, 2(2), 43-6; d) Bisagni, E. Jerusalem Symp. Quantum Chem. Biochem. 1972, 4, 439-45; e) Yakhontov, L. N. Usp. Khim. 1968, 37(7), 1258-87; f) Willette, R. E. Advan. Heterocycl. Chem. 1968, 9, 27-105; g) Mahadevan, I.; Rasmussen, M. Tetrahedron 1993, 49(33), 7337-52; h) Mahadevan, I.; Rasmussen, M. J. Heterocycl. Chem. 1992, 29(2), 359-67; i) Spivey, A. C.; Fekner, T.; Spey, S. E.; Adams, H. J. Org. Chem. 1999, 64(26), 9430-9443; j) Spivey, A. C.; Fekner, T.; Adams, H. Tetrahedron Lett. 1998, 39(48), 8919-8922; k) Advances in Heterocyclic Chemistry (Academic press) 1991, Vol. 52, pg 235-236 and references therein.

[0215] Step B. Intermediate 3 can be prepared by reaction of aza-indole, intermediate 2, with an excess of ClCOCOOMe in the presence of AlCl3 (aluminum chloride) (Sycheva et al, Ref. 26, Sycheva, T. V.; Rubtsov, N. M.; Sheinker, Yu. N.; Yakhontov, L. N. Some reactions of 5-cyano-6-chloro-7-azaindoles and lactam-lactim tautomerism in 5-cyano-6-hydroxy-7-azaindolines. Khim. Geterotsikl. Soedin., 1987, 100-106). Typically an inert solvent such as CH2Cl2 is used but others such as THF, Et2O, DCE, dioxane, benzene, or toluene may find applicability either alone or in mixtures. Other oxalate esters such as ethyl or benzyl mono esters of oxalic acid could also suffice for either method shown above. More lipophilic esters ease isolation during aqueous extractions. Phenolic or substituted phenolic (such as pentafluorophenol) esters enable direct coupling of the HW(C═O)A group, such as a piperazine, in Step D without activation. Lewis acid catalysts, such as tin tetrachloride, titanium IV chloride, and aluminum chloride are employed in Step B with aluminum chloride being most preferred. Alternatively, the azaindole is treated with a Grignard reagent such as MeMgI (methyl magnesium iodide), methyl magnesium bromide or ethyl magnesium bromide and a zinc halide, such as ZnCl2 (zinc chloride) or zinc bromide, followed by the addition of an oxalyl chloride mono ester, such as ClCOCOOMe (methyl chlorooxoacetate) or another ester as above, to afford the aza-indole glyoxyl ester (Shadrina et al, Ref. 25). Oxalic acid esters such as methyl oxalate, ethyl oxalate or as above are used. Aprotic solvents such as CH2Cl2, Et2O, benzene, toluene, DCE, or the like may be used alone or in combination for this sequence. In addition to the oxalyl chloride mono esters, oxalyl chloride itself may be reacted with the azaindole and then further reacted with an appropriate amine, such as a piperazine derivative (See Scheme 52, for example).

[0216] Step C. Hydrolysis of the methyl ester, (intermediate 3, Scheme 1) affords a potassium salt of intermediate 4, which is coupled with mono-benzoylated piperazine derivatives as shown in Step D of Scheme 1. Some typical conditions employ methanolic or ethanolic sodium hydroxide followed by careful acidification with aqueous hydrochloric acid of varying molarity but 1M HCl is preferred. The acidification is not utilized in many cases as described above for the preferred conditions. Lithium hydroxide or potassium hydroxide could also be employed and varying amounts of water could be added to the alcohols. Propanols or butanols could also be used as solvents. Elevated temperatures up to the boiling points of the solvents may be utilized if ambient temperatures do not suffice. Alternatively, the hydrolysis may be carried out in a non polar solvent such as CH2Cl2 or THF in the presence of Triton B. Temperatures of −78 C. to the boiling point of the solvent may be employed but −10 C. is preferred. Other conditions for ester hydrolysis are listed in reference 41 and both this reference and many of the conditions for ester hydrolysis are well known to chemists of average skill in the art.

[0217] Alternative Procedures for Step B and C:

[0218] Imidazolium Chloroaluminate:

[0219] We found that ionic liquid 1-alkyl-3-alkylimidazolium chloroaluminate is generally useful in promoting the Friedel-Crafts type acylation of indoles and azaindoles. The ionic liquid is generated by mixing 1-alkyl-3-alkylimidazolium chloride with aluminium chloride at room temperature with vigorous stirring. 1:2 or 1:3 molar ratio of 1-alkyl-3-alkylimidazolium chloride to aluminium chloride is preferred. One particular useful imidazolium chloroaluminate for the acylation of azaindole with methyl or ethyl chlorooxoacetate is the 1-ethyl-3-methylimidazolium chloroaluminate. The reaction is typically performed at ambient temperature and the azaindoleglyoxyl ester can be isolated. More conveniently, we found that the glyoxyl ester can be hydrolyzed in situ at ambient temperature on prolonged reaction time (typically overnight) to give the corresponding glyoxyl acid for amide formation (Scheme 2).

[0220] A representative experimental procedure is as follows: 1-ethyl-3-methylimidazolium chloride (2 equiv.; purchased from TCI; weighted under a stream of nitrogen) was stirred in an oven-dried round bottom flask at r.t. under a nitrogen atmosphere, and added aluminium chloride (6 equiv.; anhydrous powder packaged under argon in ampules purchased from Aldrich preferred; weighted under a stream of nitrogen). The mixture was vigorously stirred to form a liquid, which was then added azaindole (1 equiv.) and stirred until a homogenous mixture resulted. The reaction mixture was added dropwise ethyl or methyl chlorooxoacetate (2 equiv.) and then stirred at r.t. for 16 h. After which time, the mixture was cooled in an ice-water bath and the reaction quenched by carefully adding excess water. The precipitates were filtered, washed with water and dried under high vacuum to give the azaindoleglyoxyl acid. For some examples, 3 equivalents of 1-ethyl-3-methylimidazolium chloride and chlorooxoacetate may be required.

[0221] Related references: (1) Welton, T. Chem Rev. 1999, 99, 2071; (2) Surette, J. K. D.; Green, L.; Singer, R. D. Chem. Commun. 1996, 2753; (3) Saleh, R. Y. WO 0015594.

[0222] Step D. The acid intermediate, 4, from step C of Scheme 1 is coupled with an amine A(C═O)WH preferably in the presence of DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) and N,N-diisopropylethylamine, commonly known as Hunig's base, to provide azaindole piperazine diamides. DEPBT was prepared according to the procedure of Ref. 28, Li, H.; Jiang, X.; Ye, Y. -H.; Fan, C.; Romoff, T.; Goodman, M. Organic Lett., 1999, 1, 91-93. Typically an inert solvent such as DMF or THF is used but other aprotic solvents could be used. The group W as referred to herein is described below.

[0223] The amide bond construction reaction could be carried out using the preferred conditions described above, the EDC conditions described below, other coupling conditions described in this application, or alternatively by applying the conditions or coupling reagents for amide bond construction described later in this application for construction of substituents R1-R4. Some specific nonlimiting examples are given in this application.

[0224] It should be noted that in many cases reactions are depicted for only one position of an intermediate, such as the R5 position, for example. It is to be understood that such reactions could be used at other positions, such as R2-R4, of the various intermediates. Reaction conditions and methods given in the specific examples are broadly applicable to compounds with other substitution and other tranformations in this application. Schemes 1 and 2 describe general reaction schemes for taking appropriately substituted Q (indoles and azaindoles) and converting them to compounds of Formula I. While these schemes are very general, other permutations such as carrying a precursor or precursors to substituents R2 through R5 through the reaction scheme and then converting it to a compound of Formula I in the last step are also contemplated methods of this invention. Nonlimiting examples of such strategies follow in subsequent schemes.

[0225] The amide coupling with amine H—W—C(O)A is shown in Scheme 3, step a3. The group W as referred to herein is either

[0226] One preferred method for carrying out this reaction is the use of the peptide coupling reagent 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) and an amine H—W—C(O)A in DMF solvent containing a tertiary amine such as N,N-diisopropylethylamine. Commonly used amide bond coupling conditions, e.g. EDC with HOBT or DMAP, are also employed in some examples. Typical stoichiometries are given in the specific examples but these ratios may be modified.

[0227] The amide bond construction reactions depicted in step a3 or step a5 of Schemes 3 and 4 respectively could be carried out using the specialized conditions described herein or alternatively by applying the conditions or coupling reagents for amide bond construction described in Wallace, reference 95. Some specific nonlimiting examples are given in this application.

[0228] Additional procedures for synthesizing, modifying and attaching groups: WC(O)—A are contained in references 93-95 or described below except that the piperazine intermediates are replaced by the pyrrolidines described herein.

[0229] Scheme 4a provides a more specific example of the transformations previously described in Scheme 1. Intermediates 6-10 are prepared by the methodologies as described for intermediates 1a-5a in Scheme 1. Scheme 5 is another embodiment of the transformations described in Schemes 1 and 4a. Conversion of the phenol to the chloride (Step S, Scheme 5) may be accomplished according to the procedures described in Reimann, E.; Wichmann, P.; Hoefner, G.; Sci. Pharm. 1996, 64(3), 637-646; and Katritzky, A. R.; Rachwal, S.; Smith, T. P.; Steel, P. J.; J. Heterocycl. Chem. 1995, 32(3), 979-984. Step T of Scheme 5 can be carried out as described for Step A of Scheme 3. The bromo intermediate can then be converted into alkoxy, chloro, or fluoro intermediates as shown in Step U of Scheme 5. Scheme 2A describes the preferred method for preparing intermediate 6c or other closely related compounds containing a 4 methoxy group in the 6-azaindole system. When step U is the conversion of the bromide into alkoxy derivatives, the conversion may be carried out by reacting the bromide with an excess of sodium methoxide in methanol with cuprous salts, such as copper I bromide, copper I iodide, and copper I cyanide. The temperature may be carried out at temperatures of between ambient and 175 but most likely will be around 115 C. or 100 C. The reaction may be run in a pressure vessel or sealed tube to prevent escape of volatiles such as methanol. The preferred conditions utilize 3 UUq of sodium methoxide in methanol, CuBr as the reaction catalyst (0.2 to 3 equivalents with the preferred being 1 eq or less), and a reaction temperature of 115 C. The reaction is carried out in a sealed tube or sealed reaction vessel. The conversion of the bromide into alkoxy derivatives may also be carried out according to procedures described in Palucki, M.; Wolfe, J. P.; Buchwald, S. L.; J. Am. Chem. Soc. 1997, 119(14), 3395-3396; Yamato, T.; Komine, M.; Nagano, Y.; Org. Prep. Proc. Int. 1997, 29(3), 300-303; Rychnovsky, S. D.; Hwang, K.; J. Org. Chem. 1994, 59(18), 5414-5418. Conversion of the bromide to the fluoro derivative (Step U, Scheme 2A) may be accomplished according to Antipin, I. S.; Vigalok, A. I.; Konovalov, A. I.; Zh. Org. Khim. 1991, 27(7), 1577-1577; and Uchibori, Y.; Umeno, M.; Seto, H.; Qian, Z.; Yoshioka, H.; Synlett. 1992, 4, 345-346. Conversion of the bromide to the chloro derivative (Step U, Scheme 2A) may be accomplished according to procedures described in Gilbert, E. J.; Van Vranken, D. L.; J. Am. Chem. Soc. 1996, 118(23), 5500-5501; Mongin, F.; Mongin, O.; Trecourt, F.; Godard, A.; Queguiner, G.; Tetrahedron Lett. 1996, 37(37), 6695-6698; and O'Connor, K. J.; Burrows, C. J.; J. Org. Chem. 1991, 56(3), 1344-1346. Steps V, W and X of Scheme 2A are carried out according to the procedures previously described for Steps B, C, and D of Scheme 1, respectively. The steps of Scheme 5 may be carried out in a different order as shown in Scheme 6 and Scheme 7.

[0230] Scheme 8 shows the synthesis of 4-azaindole derivatives 1b-5b, 5-azaindole derivatives 1c-5c, and 7-azaindole derivatives 1d-5d. The methods used to synthesize 1b-5b, 1c-5c, and 1d-5d are the same methods described for the synthesis of 1a-5a as described in Scheme 3. It is understood, for the purposes of Scheme 8, that 1b is used to synthesize 2b-5b, 1c provides 2c-5c and 1d provides 2d-5d.

[0231] The compounds where there is a single carbonyl between the azaindole and group W can be prepared by the method of Kelarev, V. I.; Gasanov, S. Sh.; Karakhanov, R. A.; Polivin, Yu. N.; Kuatbekova, K. P.; Panina, M. E.; Zh. Org. Khim 1992, 28(12), 2561-2568. In this method azaindoles are reacted with trichloroacetyl chloride in pyridine and then subsequently with KOH in methanol to provide the 3-carbomethoxy azaindoles shown in Scheme 4 which can then be hydrolyzed to the acid and carried through the coupling sequence with HW(C═O)A to provide the compounds of Formula I wherein a single carbonyl links the azaindole moiety and group W.

[0232] An alternative method for carrying out the sequence outlined in steps B-D (shown in Scheme 8) involves treating an azaindole, such as 11, obtained by procedures described in the literature or from commercial sources, with MeMgI and ZnCl2, followed by the addition of ClCOCOCl (oxalyl chloride) in either THF or Et2O to afford a mixture of a glyoxyl chloride azaindole, 12a, and an acyl chloride azaindole, 12b. The resulting mixture of glyoxyl chloride azaindole and acyl chloride azaindole is then coupled with mono-benzoylated piperazine derivatives under basic conditions to afford the products of step D as a mixture of compounds, 13a and 13b, where either one or two carbonyl groups link the azaindole and group W. Separation via chromatographic methods which are well known in the art provides the pure 13a and 13b. This sequence is summarized in Scheme 10, below.

[0233] Scheme 11 depicts a general method for modifying the substituent A. Coupling of H—W—C(O)OtBu using the conditions described previously for W in Scheme 1, Step D provides Boc protected intermediate, 15. Intermediate 15 is then deprotected by treatment with an acid such as TFA, hydrochloric acid or formic acid using standard solvents or additives such as CH2Cl2, dioxane, or anisole and temperatures between −78 C. and 100 C. Other acids such as aq hydrochloric or perchloric may also be used for deprotection. Alternatively other nitrogen protecting groups on W such as Cbz or TROC, may be utilized and could be removed via hydrogenation or treatment with zinc respectively. A stable silyl protecting group such as phenyl dimethylsilyl could also be employed as a nitrogen protecting group on W and can be removed with fluoride sources such as tetrabutylammonium fluoride. Finally, the free amine is coupled to acid A—C(O)OH using standard amine-acid coupling conditions such as those used to attach group W or as shown below for amide formation on positions R1-R4 to provide compound 16.

[0234] Scheme 12 a preferred method for preparing H—W—C(O)—A. Specific details are contained in the experimental section. Additional examples of the preparation of 3-amino and 3-aminomethyl pyrrolidines are described in Patane et al PCT Patent Application WO 98/57640. Scheme 13 depicts a specific route to compounds of the invention Q in which Q is an indole with a dicarbonyl at the 3 position and W is an aminomethyl pyrollidine attached to Q via the primary amine. A specific procedure where A is phenyl is contained in the experimental. Q could also be alternative indoles and azaindoles and A other substituents as needed to prepare compounds of the invention. Scheme 14 describes a similar sequence except that the amino methyl pyrrolidine, W is attached to the dicarbonyl via the secondary ring nitrogen and A is —OtBu. As shown, acidic removal of the tertbutoxycarbonyl group provides a free primary amine or amine hydrochloride which may be reacted with acyl chlorides or chloroformates to give additional compounds of the invention with various A groups. The example where A is phenyl is described in detail in the experimental section. Scheme 15 describes similar chemistry but shows how the 7-position of the indole may be funtionalized by an aldehyde, carboxylic acid, or methyl carboxamide. This sequence is also described in the experimental section. A chemist skilled in the art can recognize how this chemistry could be utilized on other examples where Q, W, and A are modified.

[0235] As shown below in Scheme 16, step a13, suitable substituted indoles, such as the bromoindole intermediate, 10, may undergo metal mediated couplings with aryl groups, heterocycles, or vinyl stannanes to provide compounds within Formula I wherein R5 is aryl, heteroaryl, or heteroalicyclic for example. The bromoindole intermediates, 10 (or indole triflates or iodides) may undergo Stille-type coupling with heteroarylstannanes as shown in Scheme 17, step a14. Conditions for this reaction are well known in the art and references 72-74 as well as reference 91 provide numerous conditions in addition to the specific examples provided in Scheme 17 and in the specific embodiments. It can be well recognized that an indole stannane could also couple to a heterocyclic or aryl halide or triflate to construct compounds of Formula I. Suzuki coupling (reference 71) between the bromo intermediate, 10, and a suitable boronate could also be employed and some specific examples are contained in this application. Other Suzuki conditions, partners, and leaving groups have utility. Suzuki couplings between chloro intermediates are also feasible. If standard conditions fail new specialized catalysts and conditions can be employed. Procedures describing catalysts which are useful for coupling boronates with aryl and heteroaryl chlorides are known in the art (reference 100 a-g). The boronate could also be formed on the indole and then subjected to Suzuki coupling conditions. The same coupling methodologies may be used in the case where Q contains azaindoles rather than indoles.

[0236] Chemistry

[0237] All Liquid Chromatography (LC) data were recorded on a Shimadzu LC-10AS liquid chromatograph using a SPD-10AV UV-Vis detector with Mass Spectrometry (MS) data determined using a Micromass Platform for LC in electrospray mode.

[0238] LC/MS Method (i.e., Compound Identification)

[0239] Note: column A is used unless otherwise indicated in the preparation of intermediates or examples.

Column A: YMC ODS-A S7 3.0 50 mm column
Column B: PHX-LUNA C18 4.6 30 mm column
Column C: XTERRA ms C18 4.6 30 mm column
Column D: YMC ODS-A C18 4.6 30 mm column
Column E: YMC ODS-A C18 4.6 33 mm column
Column F: YMC C18 S5 4.6 50 mm column
Column G: XTERRA C18 S7 3.0 50 mm column
Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/
100% Solvent
Rt in min. 2 minutes
Gradient time:
Hold time 1 minute
Flow rate: 5 mL/min
Detector Wavelength: 220 nm
Solvent A: 10% MeOH/90% H2O/0.1% Trifluoroacetic Acid
Solvent B: 10% H2O/90% MeOH/0.1% Trifluoroacetic Acid

[0240] Compounds purified by preparative HPLC were diluted in MeOH (1.2 mL) and purified using the following methods on a Shimadzu LC-10A automated preparative HPLC system or on a Shimadzu LC-8A automated preparative HPLC system with detector (SPD-10AV UV-VIS) wavelength and solvent systems (A and B) the same as above.

[0241] Preparative HPLC Method (i.e., Compound Purification)

[0242] Purification Method: Initial gradient (40% B, 60% A) ramp to final gradient (100% B, 0% A) over 20 minutes, hold for 3 minutes (100% B, 0% A)

Solvent A: 10% MeOH/90% H2O/0.1% Trifluoroacetic Acid
Solvent B: 10% H2O/90% MeOH/0.1% Trifluoroacetic Acid
Column: YMC C18 S5 20 100 mm column
Detector Wavelength: 220 nm

[0243] Intermediate 1

[0244] Methanesulfonic acid 1-benzyl-pyrrolidin-3-ylmethyl ester

[0245] This tranformation was carried out via the method in J. L. Marco et.al. reference 96. Methanesulfonyl chloride (0.10 mol, 7.8 mL) was added slowly to a solution of racemic 1-benzyl-pyrolidin-3-ol (0.085 mol, 15 g) in 150 mL of dichloromethane which was stirring under a nitogen atmosphere at a temperature of −20 C. The reaction was stirred for an additional 1.5 h after addition was completed. The reaction was poured into a separatory funnel containing additional dichloromethane and washed with five thirty mL portions of saturated aqueous sodium bicarbonate. The organic layer was washed with one portion of water and then one portion of saturated aq NaCl. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide 22.75 g of crude mesylate which was used directly following characterization by proton NMR and LC/MS.

[0246] Intermediate 2

[0247] 1-Benzyl-pyrrolidine-3-carbonitrile

[0248] This tranformation was carried out using the method described in C. Thomas et. al. reference 97. The mesylate of racemic 1-benzyl-pyrrolidin-3-ol (0.039 mol, 10 g), prepared as described above, sodium cyanide (0.24 mol, 15 g) and tetrabutylammonium cyanide (10 g, 0.037 mol) in 75 mL of DMSO was stirred at 80-85 C. for 16 h. The reaction mixture was partitioned between diethyl ether and sat. aq sodium bicarbonate. The aqueous layer was extracted twice with ether and the combined organic layer was washed successively with sodium bicarbonate, water, and sat aq. NaCl. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by flash chromatography over silica gel using a gradient of 20 to 30% ethyl acetate in hexane to afford 5.5 g of the desired product.

[0249] Intermediate 3

[0250] C-(1-Benzyl-pyrrolidin-3-yl)-methylamine

[0251] This reaction was carried out according to the procedure in M. R. Pavia et.al. reference 98. The nitrite (0.03 mol, 5.5 g) was dissolved in THF and cooled to 0 C. Lithium aluminum hydride (0.03 mol, 1.14 g) was added into the solution in one portion. After the addition was finished, the colling bath was removed and the reaction was stirred at ambient temperature for 18 h. The reaction was filtered and the filtrate was aconcentrated in vacuo to provide the crude product which was used directly in the next reaction.

[0252] Intermediate 4

[0253] (1-Benzyl-pyrrolidin-3-ylmethyl)-carbamic acid tert-butyl ester

[0254] A mixture of crude amine (0.028 mol, 5.3 g), triethylamine (0.034 mol, 4.7 mL), and and ditertbutyl dicarbonate (0.034 mol, 7.4 g) in dichloromethane was stirred at ambient temperature for 3 h. The reaction was diluted with dichloromethane, and then washed with water and then sat aq NaCl. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification via flash chromatography over silica gel provided 4.2 g of the desired carbamate. 1H NMR (300 MHz, CDCl3): 7.32˜7.30(m, 5H), 3.59˜3.58(m, 2H), 3.17˜3.02(m, 2H), 2.73˜2.28(m, 5H), 2.04˜1.90(m, 1H), 1.60˜1.48(m,1H), 1.45(s,9H).

[0255] Intermediate 5

[0256] Pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester

[0257] The benzyl amine (4.2 g) and 2.1 g of 10% Pd/C in methanol was shaken under 50PSI of hydrogen on a Parr apparatus for 20 h. The reaction mixture was filtered through celite and concentrated in vacuo to give a residue which was used directly without further purification. 1H NMR (300 MHz, CDCl3): 3.15˜1.82(m, 8H), 1.55˜1.45(m, 1H), 1.43(s,9H).

[0258] Intermediate 6

[0259] (1-Benzoyl-pyrrolidin-3-ylmethyl)-carbamic acid tert-butyl ester

[0260] The amine (14.65 mmol, 2.93 g) was dissolved in dichloromethane and treated with DMAP (14.65 mmol, 1.79 g), EDC (14.65 mmol, 2.80 g), and then benzoic acid (13.18 mmol, 0.9 eq). The reaction was stirred for 16 h at ambient temperature and then diluted with dichloromethane. The organic layer was washed with water and sat aq. NaCl and dried over anhydrous sodium sulfate. The solution was filtered and concentrated in vacuo to provide a residue which was purified by by flash chromatography over silica gel to provide 3.06 g of the desired benzamide. 1H NMR (300 MHz, CDCl3): 7.55˜7.34(m, 5H), 3.80˜3.10(m, 6H), 2.55˜1.58(m, 3), 1.40(s,9H).

[0261] Intermediate 7

[0262] (3-Aminomethyl-pyrrolidin-1-yl)-phenyl-methanone

[0263] The carbamate was stirred in 20 mL of 4N HCl in dioxane for 20 h. The reaction mixture was concentrated on a rotary evaporator and dried under vacuum to provide the hydrochloride salt which was used directly without further purification.

EXAMPLE 1 N-(1-Benzoyl-pyrrolidin-3-ylmethyl)-2-(4-fluoro-1H-indol-3-yl)-2-oxo-acetamide

[0264]

[0265] The acid chloride (1 mmol, 225 mg) was added to a solution of the amine hydrochloride (1 mmol, 240 mg) and diisopropyl ethyl amine (10 mmol, 1.74 mL) in 5 mL of anhydrous TUF under a nitrogen atmosphere. The reaction was stirred for 16 h at ambient temperature and then poured into ethyl acetate. The organic layer was washed with water and then sat aq NaCl and then dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo provided a crude product which was purified by flash chromatography over silica gel to provide 208 mg of the desired N-(1-Benzoyl-pyrrolidin-3-ylmethyl)-2-(4-fluoro-1H-indol-3-yl)-2-oxo-acetamide.

[0266] 1H NMR (500 MHz, CD3OD): 8.69 (s), 8.56 (s), 1H. 7.55˜7.40 (m, 5H), 7.31˜7.20 (m, 2H), 6.96˜6.87 (m, 1H), 3.81˜3.29 (m, 6H), 2.70˜1.73 (m, 3H).

[0267] LC/MS: (ES+) m/z (M+H)+=394, RT=1.06.

EXAMPLE 2 {1-[2-(4-Fluoro-1H-indol-3-yl)-2-oxo-acetyl]-pyrrolidin-3-ylmethyl}-carbamic acid tert-butyl ester

[0268]

[0269] The acid chloride (2 mmol, 453 mg) was added to a solution of the amine hydrochloride (2 mmol, 400 mg) and diisopropyl ethyl amine (4 mmol, 0.7 mL) in 12 mL of anhydrous THF under a nitrogen atmosphere. The reaction was stirred for 18 h at ambient temperature and then poured into ethyl acetate. The organic layer was washed with water and then sat aq NaCl and then dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo provided a crude product which was purified by flash chromatography over silica gel to provide 475 mg of the desired 3-{[2-(4-Fluoro-1H-indol-3-yl)-2-oxo-acetylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester.

[0270] 1H NMR (500 MHz, CD3OD): 8.17(s), 8.14(S), 1H. 7.32˜7.24(m, 2H), 6.97˜6.93(m, 1H), 3.73˜3.04(m, 6H), 2.46˜2.43(m, 1H), 2.09˜2.01(m, 1H), 1.74˜1.73(m, 1H), 1.44(s, 9H).

[0271] Intermediate 8

[0272] The carbamate was stirred in 15 mL of 4N HCl in dioxane for 20 h. The reaction mixture was concentrated on a rotary evaporator and dried under vacuum to provide the hydrochloride salt which was used directly without further purification.

EXAMPLE 3 N-{1-[2-(4-Fluoro-1H-indol-3-yl)-2-oxo-acetyl]-pyrrolidin-3-ylmethyl}-benzamide and Example 4 N-{1-[2-(1-Benzoyl-4-fluoro-1H-indol-3-yl)-2-oxo-acetyl]-pyrrolidin-3-ylmethyl}-benzamide

[0273]

[0274] Benzoyl chloride (0.46 mmol, 54 μL) and then diisopropyl ethyl amine (0.92 mmol, 0.16 mL) were added to a stirring solution of amine hydrochloride (0.46 mmol, 150 mg) in 5 mL of THF under an atmosphere of nitrogen at ambient temperature. The reaction was stirred for 18 h and then the THF was removed in vacuo. The residue was dissolved in ethyl acetate and washed with water and then sat aq NaCl. The organic extract was dried, filtered, concentrated, and purified via flash chromatography to the desired product of example 3:

[0275] 1H NMR (500 MHz, CD3OD): 8.18 (s), 8.14 (s), 1H. 7.85˜7.82 (m, 1H), 7.72˜7.68 (m, 1H), 7.54˜7.24 (m, 5H), 6.97˜6.90 (m, 1H), 3.80˜3.29 (m, 6H), 2.67˜2.61 (m, 1H), 2.20˜2.05(m, 1H), 1.87˜1.81(m, 1H).

[0276] LC/MS: (ES+) m/z (M+H)+=394, RT=1.74. and the bis benzylated product Example 4 which resulted from a second benzylation of the indole nitrogen:

[0277] LC/MS: (ES+) m/z (m+H)+=498; RT=1.46

EXAMPLE 5 N-(1-Benzoyl-pyrrolidin-3-ylmethyl)-2-(4-fluoro-7-formyl-1H-indol-3-yl)-2-oxo-acetamide

[0278]

[0279] DEPBT (2.13 mmol, 514 mg) was added to a stirring solution of the aldehyde acid (prepared as described in WO 00/76521, 2.13 mmol, 500 mg), amine hydrochloride (2.13 mmol, 514 mg), and diisopropyl ethylamine (4.26 mmol, 0.74 mL) in 5 mL of DMF at ambient temperature. The reaction was stirred for 16 h and then the DMF was removed in vacuo. The residue was dissolved in ethyl acetate and water was added. After separation the water layer was reextracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, concentrated and chromatographed over silica gel to provide the desired product.

[0280] 1H NMR (300 MHz, CD3OD): 10.06 (s, 1H); 8.79 (s), 8.72 (s), 1H; 7.89˜7.84 (m, 1H); 7.53˜7.40 (m, 5H); 7.15˜7.06 (m, 1H); 3.81˜3.29 (m, 6H); 2.68˜2.51 (m,1H); 2.17˜2.00 (m, 1H); 1.87˜1.72 (m, 1H).

[0281] LC/MS: (ES+) m/z (m+H)+=422; RT=1.29.

EXAMPLE 6 N-(1-Benzoyl-pyrrolidin-3-ylmethyl)-2-oxo-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-acetamide

[0282]

[0283] DEPBT (1.32 mmol, 395 mg) was added to a stirring solution of the potassium salt (prepared as described in WO 01/62255, 1.32 mmol, 300 mg), amine hydrochloride (1.32 mmol, 318 mg), and diisopropyl ethylamine (2.64 mmol, 0.46 mL) in 3 mL of DMF at ambient temperature. The reaction was stirred for 16 h and then the DMF was removed in vacuo. The residue was dissolved in ethyl acetate and water was added. After separation the water layer was reextracted with ethyl acetate. The combined organic extracts were washed with sat aq NaCl, dried over anhydrous magnesium sulfate, concentrated and chromatographed over silica gel to provide 268 mg of the desired product.

[0284] 1H NMR (500 MHz, CD3OD): 8.92˜8.89 (m), 8.81˜8.79 (m), 1H; 8.68˜8.60 (m, 1H); 8.34˜8.8.32 (m, 1H); 7.54˜7.43 (m, 5H); 7.33˜7.7.26 (m, 1H); 3.96˜3.26 (m, 6H); 2.66˜2.52 (m, 1H); 2.16˜2.05 (m,1H); 1.85˜1.74 (m, 1H).

[0285] LC/MS: (ES+) m/z (m+H)+=377; RT=1.18

EXAMPLE 7 3-(1-Benzoyl-pyrrolidin-3-ylmethyl)-aminooxalyl)-4-fluoro-1H-indole-7-carboxylic acid

[0286]

[0287] Silver nitrate (AgNO3, 1.48 mmol, 252 mg) was dissolved in 2 mL of water. A solution of NaOH (2.96 mmol, 118 mg) in 2 mL of methanol and 2 mL of water was added to the silver nitrate solution and a brown precipitate formed. The aldehyde (0.74 mmol, 313 mg) was added into the solution/precipitate in one portion. The reaction was heated to 90 C. and stirred for 15 h. After coiling to ambient temperature, the reaction was filtered through celite using ethyl acetate washes. The filtrate was extracted with ethyl acetate. The aqueous layer was acidified with 2N HCl to about PH 2. The resulting solid was collected by filtration to give the desired acid. 1H NMR (500 MHz, CD3OD): 8.79 (s), 8.70 (s), 1H; 8.05˜7.92 (m, 1H); 7.53˜7.44 (m, 5H); 7.05˜6.93 (m, 1H); 3.78˜3.26 (m, 6H); 2.66˜2.53 (m, 1H); 2.17˜2.06 (m, 1H); 1.84˜1.75 (m, 1H).

[0288] LC/MS: (ES+) m/z (m+H)+=438; RT=1.33.

EXAMPLE 8 3-(1-Benzoyl-pyrrolidin-3-ylmethyl)-aminooxalyl)-4-fluoro-1H-indole-7-carboxylic acid methylamide

[0289]

[0290] The acid (19 mg,1 equivalent) was dissolved in 1 mL of DMF and 1.5 equivalents of 1,1-carbonyl diimidazole was added. The reaction was stirred at ambient temperature for 15 min and then 4 equivalents (0.1 ml) of 2N methyl amine in THF was added. The reaction was stirred overnight and then the DMF was removed in vacuo. The residue was chromatographed to afford 12 mg of the desired methyl amide.

[0291] LC/MS: (ES+) m/z (m+H)+=451; RT=1.26

EXAMPLE 9 N-{1-[2-(7-Bromo-4-fluoro-1H-indol-3-yl)-2-oxo-acetyl]-pyrrolidin-3-ylmethyl}-benzamide

[0292]

[0293] The ketoacid (0.97 mmol, 280 mg), the amine (0.97 mmol, 200 mg) and diisopropyl ethyl amine (0.34 mL) and DEPBT (0.97 mmol, 292 mg) were dissolved in 2 mLof dry DMF under an atmosphere of nitrogen. The reaction was stirred for 36 h at ambient temperature and then poured into 10 mL of ethyl acetate. The organic layer was washed with two 10 mL portions of water and then the aqueous layer was back extracted with 10 mL of EtOAc. The combined organic extracts were dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo provided a crude product which was purified by flash chromatography over silica gel using gradients of 50 to 100% EtOAc: Hexane then 2 to 5% MeOH/EtOAc to provide 29 mg of the desired amide as a light brown solid.

[0294] 1H NMR (500 MHz, CD3OD): 8.43 (s), 8.38 (s), 1H; 8.01˜7.97 (m, 1H); 7.83˜7.79 (m, 1H); 7.69˜7.34 (m, 4H); 4.13˜1.20 (m, 9H).

[0295] LC/MS: (ES+) m/z (m+H)+=475; RT=1.27.

EXAMPLE 10 N-{1-[2-(7-Bromo-4-fluoro-1H-indol-3-yl)-2-oxo-acetyl]-pyrrolidin-3-ylmethyl}-benazmide

[0296]

[0297] The ketoacid (0.97 mmol, 280 mg), the amine (0.97 mmol, 200 mg) and diisopropyl ethyl amine (0.34 mL) and DEPBT (0.97 mmol, 292 mg) were dissolved in 2 mLof dry DMF under an atmosphere of nitrogen. The reaction was stirred for 36 h at ambient temperature and then poured into 10 mL of ethyl acetate. The organic layer was washed with two 10 mL portions of water and then the aqueous layer was back extracted with 10 mL of EtOAc. The combined organic extracts were dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo provided a crude product which was purified by flash chromatography over silica gel using gradients of 50 to 100% EtOAc: Hexane then 2 to 5% MeOH/EtOAc to provide 108 mg of the desired amide as a yellow solid.

[0298] 1H NMR (500 MHz, CD3OD): 8.43 (s), 8.39 (s), 1H; 8.02˜7.97 (m, 1H); 7.84˜7.81 (m, 1H); 7.69˜7.66 (m, 1H); 7.54˜7.35 (m, 3H); 4.13˜1.21 (m, 9H)

[0299] LC/MS: (ES+) m/z (m+H)+=475; RT=1.19, 1.27.

EXAMPLE 11 N-(1-{2-[4-Fluoro-7-(1H-pyrazol-3-yl)-1H-indol-3-yl]-2-oxo-acetyl}-pyrrolidin-3-ylmethyl)-benz Amide

[0300]

[0301] The bromide (0.12 mmol, 59 mg), the pyrazole stannane (0.24 mmol, 86 mg), and palladium tetrakis triphenyl phosphine (0.012 mmol, 14 mg) were dissolved in 0.5 mLof dry dioxane and heated in a sealed tube at 140 to 145 C. for 17 h. After cooling to room temperature, the reaction was filtered through filter paper and the filtrate concentrated by rotary evaporation. The residue was dissolved in 2 mL of MeOH and purified using preparative thin layer chromatography to provide 12.6 mg of the desired pyrazole as a light yellow solid.

[0302]1H NMR (500 MHz, CD3OD): 8.62˜8.57 (m, 1H), 8.32˜8.30 (m, 1H); 7.92˜7.15 (m, 10H); 4.05˜1.82 (m, 9H)

[0303] LC/MS: (ES+) m/z (m+H)+=475; RT=1.01, 1.10.

EXAMPLE 12 N-(1-{2-[4-Fluoro-7-(1H-pyrazol-3-yl)-1H-indol-3-yl]-2-oxo-acetyl}-pyrrolidin-3-ylmethyl)-benz amide

[0304]

[0305] The bromide (0.046 mmol, 22 mg), the pyrazole stannane (0.092 mmol, 33 mg), and palladium tetrakis triphenyl phosphine (10 mg) were dissolved in 0.5 mLof dry dioxane and heated in a sealed tube at 140 to 145 C. for 17 h. After cooling to room temperature, the reaction was filtered through filter paper and the filtrate concentrated by rotary evaporation. The residue was dissolved in 2 mL of MeOH and purified using preparative thin layer chromatography to provide 4.8 mg of the desired pyrazole as a light yellow solid.

[0306] 1H NMR (500 MHz, CD3OD): 8.60˜8.54 (m, 1H), 8.29˜8.28 (m, 1H); 7.91˜7.15 (m, 10H); 4.06˜1.80 (m, 9H)

[0307] LC/MS: (ES+) m/z (m+H)+=475; RT=1.01, 1.10.

EXAMPLE 13 2-(N-benzoylaminoethyl)-1-[(indol-3-yl)-2-oxoacetyl]-pyrrolidine

[0308]

[0309] Preparation of compound C, 2-(N-benzoylaminoethyl)-1-[(indol-3-yl)-2-oxoacetyl]-pyrrolidine:

[0310] Tri-ethylamine (1 ml) was added into a solution of indole-3-glyoxylyl chloride, intermediate 9 (50 mg, purchased from Lancaster) and intermediate 10 2-(N-benzoylaminoethyl)-pyrrolidine (49 mg, Wang, et al, Tetrahedron Lett. 1999, 40, 6745-6747) in THF (5 ml). After the reaction was stirred for 10 hours, the solvents were removed under vaccum to afford a residue which was purified using Shimadzu automated preparative HPLC System to give 2-(N-benzoylaminoethyl)-1-[(indol-3-yl)-2-oxoacetyl]-pyrrolidine (20 mg). Start %=0

[0311] Final %=100

[0312] Gradient time=2 minute

[0313] Flow Rate=5 ml/min

[0314] Wavelength=220

[0315] Column: XTERRA ms C18 4.630 mm

[0316] Rf=1.57 minute

[0317] MS (M+H) for C22H22N3O3

[0318] Cald=376.17

[0319] Obsd=376.23

EXAMPLE 14 1H-Indole-3-carboxylic acid (1-benzoyl-pyrrolidin-3-yl)-methyl-amide

[0320]

[0321] The procedure is the same as the following one, which was described in Blair et. al. PCT WO 00/76521

[0322] Indole 3-carboxylic acid, (2.0 g) was dissolved in 5 ml of SOCl2. The mixture was heated to reflux for 30 minutes. Removal of excess of SOCl2 under vaccum provided intermediate 9, indole 3-carbonyl chloride, which was carried to the next step without further purification.

[0323] A mixture of indole 3-carbonyl chloride, intermediate 9 (50 mg), N-Benzoyl-3-methylamino-pyrrolidine, intermediate 10, (57 mg), pyridine (44 mg) in THF (5 ml) was stirred at room temperature for 10 hours. Solvents were removed under vaccum, and the residue was purified using a Shimadzu automated preparative HPLC System to give 78 mg of the compound of example 14, N-Benzoyl-3-[N-(indol-3-yl-carbonyl)-N-methyl]amino-pyrrolidine:

[0324] MS m/z: (M+H)+ calcd for C21H19FN3O3: 348.17; found 348.22. HPLC retention time: 1.40 p minutes (column A).

[0325] Biology

[0326] “μM” means micromolar;

[0327] “mL” means milliliter;

[0328] “μl” means microliter;

[0329] “mg” means milligram;

[0330] The materials and experimental procedures used to obtain the results reported in Tables 1-2 are described below.

[0331] Cells:

[0332] Virus production—Human embryonic Kidney cell line, 293, propagated in Dulbecco's Modified Eagle Medium (Life Technologies, Gaithersburg, Md.) containing 10% fetal Bovine serum (FBS, Sigma, St. Louis, Mo.).

[0333] Virus infection-Human epithelial cell line, HeLa, expressing the HIV-1 receptors CD4 and CCR5 was propagated in Dulbecco's Modified Eagle Medium (Life Technologies, Gaithersburg, Md.) containing 10% fetal Bovine serum (FBS, Sigma, St. Louis , Mo.) and supplemented with 0.2 mg/mL Geneticin (Life Technologies, Gaithersburg, Md.) and 0.4 mg/mL Zeocin (Invitrogen, Carlsbad, Calif.).

[0334] Virus—Single-round infectious reporter virus was produced by co-transfecting human embryonic Kidney 293 cells with an HIV-1 envelope DNA expression vector and a proviral cDNA containing an envelope deletion mutation and the luciferase reporter gene inserted in place of HIV-1 nef sequences (Chen et al, Ref. 41). Transfections were performed using lipofectAMINE PLUS reagent as described by the manufacturer (Life Technologies, Gaithersburg, Md.).

[0335] Experiment

[0336] 1. Compound was added to HeLa CD4 CCR5 cells plated in 96 well plates at a cell density of 1103 cells per well in 100 μl Dulbecco's Modified Eagle Medium containing 10% fetal Bovine serum at a concentration of <20 μM.

[0337] 2. 100 μl of single-round infectious reporter virus in Dulbecco's Modified Eagle Medium was then added to the plated cells and compound at an approximate multiplicity of infection (MOI) of 0.01, resulting in a final volume of 200 μl per well and a final compound concentration of <10 μM.

[0338] 3. Samples were harvested 72 h after infection.

[0339] 4. Viral infection was monitored by measuring luciferase expression from viral DNA in the infected cells using a luciferase reporter gene assay kit (Roche Molecular Biochemicals, Indianapolis, Ind.). Infected cell supernatants were removed and 50 μl of Dulbecco's Modified Eagle Medium (without phenol red) and 50 μl of luciferase assay reagent reconstituted as described by the manufacturer (Roche Molecular Biochemicals, Indianapolis, Ind.) was added per well. Luciferase activity was then quantified by measuring luminescence using a Wallac microbeta scintillation counter.

[0340] 5. The percent inhibition for each compound was calculated by quantifying the level of luciferase expression in cells infected in the presence of each compound as a percentage of that observed for cells infected in the absence of compound and subtracting such a determined value from 100.

[0341] 6. An EC50 provides a method for comparing the antiviral potency of the compounds of this invention. The effective concentration for fifty percent inhibition (EC50) was calculated with the Microsoft Excel Xlfit curve fitting software. For each compound, curves were generated from percent inhibition calculated at 10 different concentrations by using a four paramenter logistic model (model 205). The EC50 data for the compounds is shown in Tables 2-4. Table 1 is the key for the data in Table 2.

[0342] Results

TABLE 1
Biological Data Key for EC50s
Compounds with
EC50 >50 nM but
Compounds not yet tested at Compounds
Compounds* with EC50s >1 higher with
with EC50s >5 μM μM but <5 μM concentrations EC50 <1 μM
Group C Group B Group A′ Group A

[0343] In Tables 2-5, X2, X4 etc. indicates the point of attachment.

TABLE 2
Examples
EC50
Table Entry Group
(Example from
Number.) Z W A Table 1
1 (Example 1) A
2 (Example 2) C
3 (Example 3) A
4 (Example 4) A
5 (Example 5) B
6 (Example 6) C
7 (Example 7) B
8 (Example 8) A
9 (Example 9) A
10 (Example 10) A
11 (Example 11) A
12 (Example 12) A
13 (Example 13) A
14 (Example 14) C
15 (Example 15) C
16 (Example 16) A′

[0344] The compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and diluents.

[0345] Thus, in accordance with the present invention, there is further provided a method of treating and a pharmaceutical composition for treating viral infections such as HIV infection and AIDS. The treatment involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of the present invention.

[0346] The pharmaceutical composition may be in the form of orally administrable suspensions or tablets; nasal sprays, sterile injectable preparations, for example, as sterile injectable aqueous or oleagenous suspensions or suppositories.

[0347] When administered orally as a suspension, these compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweetners/flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents, and lubricants known in the art.

[0348] The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

[0349] The compounds of this invention can be administered orally to humans in a dosage range of 1 to 100 mg/kg body weight in divided doses. One preferred dosage range is 1 to 10 mg/kg body weight orally in divided doses. Another preferred dosage range is 1 to 20 mg/kg body weight in divided doses. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US6900323 *Jul 16, 2003May 31, 2005Bristol-Myers Squibb CompanyAntiviral azaindole derivatives
US7534809Sep 16, 2005May 19, 2009Idenix Pharmaceuticals, Inc.Phospho-indoles as HIV inhibitors
US7807671Apr 10, 2007Oct 5, 2010Bristol-Myers Squibb CompanyDiketo-piperazine and piperidine derivatives as antiviral agents
US7807676Oct 23, 2007Oct 5, 2010Bristol-Myers Squibb CompanyDiketo-Piperazine and Piperidine derivatives as antiviral agents
US7829711May 19, 2009Nov 9, 2010Bristol-Myers Squibb CompanyCrystalline materials of 1-(4-benzoyl-piperazin-1-yl)-2-[4-methoxy-7-(3-methyl-[1,2,4]triazol-1-yl)-1H-pyrrolo[2,3-C]pyridine-3-yl]-ethane-1,2-dione
US7851476Dec 11, 2006Dec 14, 2010Bristol-Myers Squibb CompanyCrystalline forms of 1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-YL)-1-[(phosphonooxy)methyl]-1H-pyrrolo[2,3-C]pyridin-3-YL]-1,2-dioxoethyl]-piperazine
US7960428Sep 28, 2007Jun 14, 2011Idenix Pharmaceuticals, Inc.Enantiomerically pure phosphoindoles as HIV inhibitors
US8044091Nov 21, 2008Oct 25, 2011Idenix Pharmaceuticals, Inc.Phospho-indoles as HIV inhibitors
US8486991Jun 2, 2011Jul 16, 2013Idenix Pharmaceuticals, Inc.Enantiomerically pure phosphoindoles as HIV inhibitors
EP2256124A1Sep 16, 2005Dec 1, 2010IDENIX Pharmaceuticals, Inc.Phospho-indoles as HIV inhibitors
Classifications
U.S. Classification514/300, 514/414, 546/113, 548/465
International ClassificationC07D471/04, C07D403/14, C07D403/06, C07D403/12
Cooperative ClassificationC07D403/06, C07D403/14, C07D403/12, C07D403/04, C07D471/04
European ClassificationC07D403/04, C07D403/06, C07D403/12, C07D403/14, C07D471/04