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Publication numberUS20010027195 A1
Publication typeApplication
Application numberUS 09/731,304
Publication dateOct 4, 2001
Filing dateDec 6, 2000
Priority dateApr 21, 1998
Also published asUS6407103
Publication number09731304, 731304, US 2001/0027195 A1, US 2001/027195 A1, US 20010027195 A1, US 20010027195A1, US 2001027195 A1, US 2001027195A1, US-A1-20010027195, US-A1-2001027195, US2001/0027195A1, US2001/027195A1, US20010027195 A1, US20010027195A1, US2001027195 A1, US2001027195A1
InventorsDavid Nugiel, David Carini, Susan DiMeo, Eddy Yue
Original AssigneeNugiel David A., Carini David J., Dimeo Susan V., Yue Eddy W.
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Indeno [1,2-c]pyrazol-4-ones and their uses
US 20010027195 A1
Abstract
The present invention relates to the synthesis of a new class of indeno[1,2-c]pyrazol-4-ones of formula (I):
that are potent inhibitors of the class of enzymes known as cyclin dependent kinases, which relate to the catalytic subunits cdk1-9 and their regulatory subunits know as cyclins A-H.
This invention also provides a novel method of treating cancer or other proliferative diseases by administering a therapeutically effective amount of one of these compounds or a pharmaceutically acceptable salt form thereof. Alternatively, one can treat cancer or other proliferative diseases by administering a therapeutically effective combination of one of the compounds of the present invention and one or more other known anti-cancer or anti-proliferative agents.
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Claims(58)
What is claimed is:
1. A compound according to formula (I):
or stereoisomers, pharmaceutically acceptable salts, and prodrugs thereof, wherein:
X is selected from the groups: O, S, and NR;
R is selected from the groups: H, C1-4 alkyl, and NR5R5a;
R1 is selected from the groups: H, C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc, C2-10 alkynyl substituted with 0-3 Rc, —NHR4, C3-10 membered carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;
Ra is independently selected from the groups: R5 R5aN(CR6R6a)m, R5O(CR6R6a)m, halo, —CN, N3, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, ═O, OR3, SR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, NR3C(O)OR3, NR3C(O)R3, SO2NR3R3a, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;
alternatively, when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—;
Rb is independently selected from the groups: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CONR3R3a, CON(R6)((CH2)mR7), CO(CH2)mR7, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, and SO2R3b;
Rc is independently selected from the groups: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR5NR5R5a, NR3C(O)OR3, NR3C(O)R3, ═O, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2N3R3a, SO2R3b, C3-10 membered carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;
R2 is selected from the groups: H, C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc, C2-10 alkynyl substituted with 0-3 Rc, —(CF2)mCF3, C3-10 membered carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;
R3 is independently selected from the groups: H, halo, —CN, NO2, C1-4 haloalkyl, R5R5aN(CR6R6a)m, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, ═O, R5O(CR6R6a)m, COR5, CO2R5, CONR5R5a, NHC(O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C1-4 alkyl, phenyl, and benzyl;
R3a is independently selected from the groups: H, C1-4 alkyl, phenyl, and benzyl;
alternatively, R3 and R3a, together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom and substituted with 0-3 R3c;
R3b is independently selected from the groups: H, C1-4 alkyl, phenyl, and benzyl;
R3c is independently selected from the groups: halo, —CN N3, NO2, C1-4 alkyl, C3-8 cycloalkyl, C4-10 cycloalkylalkyl, C1-4 haloalkyl, NR3R3b, R5R5aN(CR6R6a)m, ═O, OR3, R5O(CR6 R6a)m, COR3, CO2R3, CONR3R3 b , NHC(O)NR3R3 b , NHC(S)NR3R3 b , NR3C(O)OR3, NR3C(O)R3, C(═NR5)R5a, C(═NR5)NR5aR5b, SO2NR3R3 b , SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;
R4 is independently selected from the groups: H, —CN, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, SO2R3b, C3-10 membered carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;
R5 is independently selected from the groups: H, C1-4 alkyl, phenyl and benzyl;
R5a is independently selected from the groups: H, C1-4 alkyl, phenyl and benzyl;
alternatively, R5 and R5a, together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom;
R5b is independently selected from the groups: H, C1-4 alkyl, phenyl and benzyl;
R6 is idependently selected from the groups: H, C1-4 alkyl;
R6a is independently selected from the groups: H, C1-4 alkyl;
R7 is independently selected from the groups: NR3R3a, C3-10 membered carbocycle substituted with 0-3 R3, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3; and
m is independently selected from 0, 1, 2, 3, and 4;
provided that: when R2 is a C1-4 unsubstituted, branched alkyl then R1 is not CH3; or when R1 is NHR4 and R4 is NR3R3a then R3 and R3a can not both be phenyl.
2. A compound according to
claim 1
, wherein
X is O or S;
R1 is H, C1-10 alkyl substituted with 0-3 Rc, —NHR4, C3-10 membered carbocycle substituted with 0-5 Ra, or 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5;
Rc is independently selected from the groups: halo, C3-10 membered carbocycle substituted with 0-5 Ra, 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3, NR3R3a;
R3 is H, C1-4 alkyl, phenyl, benzyl, or together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom and substituted with 0-3 R3c;
R4 is H, C1-4 alkyl, NR3R3a, C3-10 membered carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;
R2 is selected from the groups: C3-10 membered carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb, and C1-10 alkyl substituted with 0-3 Rc.
3. A compound according to
claim 1
, wherein
X is O or S;
R1 is C1-4 alkyl substituted with 0-3 Rc, wherein Rc is independently selected from the group consisting of: C3-6 membered carbocycle substituted with 0-5 Ra, 5-6 membered heterocycle substituted with 0-3 R3, NR3R3a, and OR3; C3-6 membered carbocycle substituted with 0-5 Ra, wherein Ra is independently selected from the group consisting of: R5R5aN(CR6R6a)m—, R5O(CR6R6a)m—, OR3, halo, C1-4 alkyl, —NR3C(O)R3, COR3, CO2R3, N3, NR3C(O)OR3, NR3R3a, CONR3R3a, and 5-6 membered heterocycle; or when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—; or 5-6 membered heterocycle and substituted with 0-5 Rb, wherein Rb is independently selected from the group: OR3, halo, COR , C1-4 alkyl, CO2R3, NR3C(O)R3, NR3C(O)OR3, NR3R3a, and CONR3R3a;
R2 is C3-6 membered carbocycle substituted with 0-5 Ra, wherein Ra is independently selected from the groups: R5R5aN(CR6R6a)m, R5O(CR6R6a)m, OR3, halo, C1-4 alkyl, NR3C(O)R3, COR3, CO2R3, N3, NR3C(O)OR3, NR3R3a, CONR3R3a, and 5-6 membered heterocycle, or when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—; 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb, wherein Rb is independently selected from the group: OR3 1 halo, COR3, C1-4 alkyl, CO2R3, NR3C(O)R3, NR3C(O)OR3, NR3R3a, and CONR3R3a; or C1-10 alkyl substituted with 0-3 Rc, wherein Rc is independently selected from the groups: C3-6 membered carbocycle substituted with 0-5 Ra, 5-6 membered heterocycle substituted with 0-3 R3, NR3R3a, and OR3.
4. A compound according to
claim 1
, wherein
X is O or S;
R1 is selected from the groups: H, —NHR4, C1-4 alkyl substituted with 0-3 Rc, C3-6 membered carbocycle substituted with 0-5 Ra, and 5-6 membered heterocycle and substituted with 0-5 Rb;
R2 is selected from the group: C3-6 membered carbocycle substituted with 0-5 Ra, 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb, and C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc;
R4 is independently selected from the groups: H, C1-4 alkyl, NR3R3a, 3-6 membered carbocycle substituted with 0-5 Ra, and 5-6 membered heterocycle substituted with 0-3 R3;
R3 is independently selected from the group: H, halo, COR5, CO2R5, R5R5aN(CR6R6a)m, R5O(CR6R6a)m, CONR5R5a, NR5C(O)OR5, NR5C(O)R5, C1-4 alkyl, phenyl, and benzyl;
R3a is independently selected from the group: H, C1-4 alkyl, phenyl, and benzyl; or R3 and R3a, together with the atoms to which they are attached, form a 5-6 membered heterocycle containing an additional 0-1 N, S, or O atom and substituted with 0-3 R3c;
Rc is independently selected from the groups: C3-6 membered carbocycle substituted with 0-5 Ra, 5-6 membered heterocycle substituted with 0-3 R3, NR3R3a, and OR3;
Ra is independently selected from the groups: R5 R5aN(CR6R6a)m, R5O(CR6R6a)m, OR3, halo, C1-4 alkyl,
NR3C(O)R3, COR3, CO2R3, N3, NR3C(O)OR3, NR3R3a, CONR3R3a, 5-6 membered heterocycle; or when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—;
Rb is independently selected from the group: OR3, halo, COR3, C1-4 alkyl, CO2R3, NR3C(O)R3, NR3C(O)OR3, NR3R3a, CONR3R3a;
R3c is independently selected from the groups: OR3, halo, COR3, R5R5aN(CR6R6a)m—, R5O)(CR6R6)m—, CO2R3, N3, NR3R3b, C1-4 alkyl, NR3C(O)R3, NR3C(O)OR3, N3, NR3R3b, CONR3R3b, and 5-6 membered heterocycle; and
m is independently selected from the group consisting of 1 2, 3 and 4.
5. A compound according to
claim 1
, wherein
R1 is selected from the group: —NHR4 and C1-2 alkyl substituted with 1 Rc.
6. A compound according to
claim 1
wherein
X is O or S; and
R1 is selected from the group: H, C1-4 alkyl substituted with 0-3 Rc, C2-4 alkenyl substituted with 0-3 Rc, C2-4 alkynyl substituted with 0-3 RC, —NHR4, C3-6 carbocycle substituted with 0-5 Ra, and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb.
7. A compound according to
claim 1
wherein
X is O or S; and
R1 is selected from the group: H, C1-4 alkyl substituted with 0-3 Rc, C2-4 alkenyl substituted with 0-3 Rc, C2-4 alkynyl substituted with 0-3 Rc, —NHR4, C3-6 carbocycle substituted with 0-5 Ra, and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;
Ra is independently at each occurrence selected from the group: —CH2N(CH3)2, —CH2NH2, —SH, —SCH3, —NR3C(O)R3, —N3, halo, C1-4 alkyl, NR3R3a, and OR3; alternatively, when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—;
Rb is independently at each occurrence selected from the group: halo, C1-4 alkyl, NR3R3a, OR3, COR3, and CO2R3;
Rc is independently at each occurrence selected from the group: halo, C1-4 alkyl, NR3R3a, C3-6 carbocycle substituted with 0-5 Ra, and 5-7 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;
R3a is H or C1-4 alkyl; and
R3 is selected from the group: H, —CH2CH2OH, —C(O)CH2NH2, —C(O)CH2N(CH3)2, —NR5R5a, —C1-4alkyl-NR5R5a, C1-4 alkyl, phenyl, and benzyl.
8. A compound according to
claim 1
wherein
X is O or S;
R1 is selected from the group: H, C1-4 alkyl substituted with 0-3 Rc, —NHR4, C3-6 carbocycle substituted with 0-5 Ra, and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;
Ra is independently at each occurrence selected from the group: —CH2N(CH3)2, —CH2NH2, —SH, —SCH3, halo, C1-4 alkyl, NR3R3a, and OR3; alternatively, when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O —;
Rb is independently at each occurrence selected from the group: halo, C1-4 alkyl, NR3R3a, OR3, COR3, and CO2R3;
Rc is independently at each occurrence selected from the group: —OH, chloro, C1-4 alkyl, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3, —NHCH2CH2OH, —N(CH3)2, phenyl substituted with 0-5 Ra, and 5-7 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R 3.
9. A compound according to
claim 1
wherein
R1 is selected from the group: H, C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc, C2-10 alkynyl substituted with 0-3 Rc;
R2 is selected from the group: H, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb; and
Rc is independently at each occurrence selected from the group: phenyl substituted with 0-5 Ra, and thiophenyl or pyridyl, which is substituted with 0-3 R3.
10. A compound according to
claim 1
wherein
R1 is selected from the group: H, C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc, C2-10 alkynyl substituted with 0-3 Rc;
R2 is selected from the group: H, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb; and
Rc is independently at each occurrence selected from the group: thiophenyl, piperazinyl, piperidinyl, thiomorpholinyl, morpholinyl, pyrrolidinyl, and pyridyl, which is substituted with 0-3 substituents indepently selected from the group consiting of CH3, CH2CH2OH, CH2CH2NH2, —C(═O)NH2, —OCH3, CH2NH2, NHCH2CH3,OH, NH2, halo, —CH2N(CH3)2, —OCH2CH2O—,—OCH2O—, —N(CH3)2, uridomethyl, and pyridyl.
11. A compound according to
claim 1
wherein
R1 is selected from the group: H, C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc, C2-10 alkynyl substituted with 0-3 Rc;
R2 is selected from the group: H, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb; and
Rc is phenyl substituted with 0-5 substituents indepently selected from the group consiting of CH3, CH2CH2OH, CH2CH2NH2, —C(═O)NH2, —OCH3, CH2NH2, NHCH2CH3, OH, NH2, halo, —CH2N(CH3)2, —OCH2CH2O—, —OCH2O—, —N(CH3)2, uridomethyl, and pyridyl.
12. A compound according to
claim 1
wherein
X is O or S;
R1 is —NHR4 or methylene substituted with 0-3 Rc;
Rc is NR3R3a;
R4 is selected from the group consisting of H, C1-4 alkyl, and NR3R3a; and
R3 and R3a, are independently hydrogen or C1-4alkyl, or R3 and R3a, together with the nitrogen atom to which they are attached, form a 4-8 membered heterocycle containing an additional 0-1 N, S, or O atom and substituted with 0-3 R3c.
13. A compound according to
claim 1
wherein
X is O or S;
R1 is —NHR4 or methylene substituted with 0-3 Rc;
Rc is NR3R3a;
R4 is selected from the group consisting of H, C1-4 alkyl, and NR3R3a; and
R3 and R3a, are independently hydrogen or C1-4alkyl, or R3 and R3a, together with the nitrogen atom to which they are attached, form a 4-8 membered heterocycle containing an additional 0-1 N, S, or O atom and substituted with with 0-3 substituents independently selected from the group consisting of methyl, —CH2OCH3, —C(CH3)2OCH3, —CH2CH2OH, —CH2OH, —CH2OCH2Phenyl, —CH2CH2NH2, —CH2NH2, —C(═NH)CH3, and NH2.
14. A compound according to
claim 1
wherein
X is O or S; and
R1 is selected from the group: methylene substituted with a substituent selected from the group consisting of: halo, NR3R3a, C3-6 carbocycle substituted with 0-5 Ra, and 5-7 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3.
15. A compound according to
claim 1
wherein
X is O or S;
R1 is selected from the group: methylene substituted with NR3R3a; and
R3 and R3a, together with the nitrogen atom to which they are attached, form pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thiomorpholinyl, pymorpholinyl, piperidinyl, piperazinyl, or piperadinyl, which is substituted with 0-3 R3c.
16. A compound according to
claim 1
wherein
R1 is —NHR4;
R4 is NR3R3a; and
R3 and R3a, together with the nitrogen atom to which they are attached, form pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thiomorpholinyl, pymorpholinyl, piperidinyl, piperazinyl, or piperadinyl, which is substituted with 0-3 R3c.
17. A compound according to
claim 1
wherein
R1 is —NHR4;
R4 is NR3R3a; and
R3 and R3a, together with the nitrogen atom to which they are attached, form pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thiomorpholinyl, pymorpholinyl, piperidinyl, piperazinyl, or piperadinyl, which is substituted with 0-3 substituents independently selected from the group consisting of methyl, —CH2OCH3, —C(CH3)2OCH3, —CH2CH2OH, —CH2OH, —CH2OCH2Phenyl, —CH2CH2NH2, —CH2NH2, —C(═NH)CH3, and NH2.
18. A compound according to
claim 1
, wherein
R2 is selected from the group: 5- to 7- membered monocyclic saturated, or partially saturated, heterocyclic ring substituted with 0-5 Rb.
19. A compound according to
claim 1
, wherein
R2 is selected from the group: 5- to 7- membered monocyclic aromatice heterocyclic ring substituted with 0-5 Rb.
20. A compound according to
claim 1
, wherein
R2 is selected from the group: C1-10 alkyl substituted with 0-3 Rc, C3-10 carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb.
21. A compound according to
claim 1
, wherein
R2 is selected from the group: C1-6 alkyl substituted with 0-3 Rc, C3-6 carbocycle substituted with 0-5 Ra, and 3-7 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb.
22. A compound according to
claim 1
, wherein
R2 is selected from the group: C1-6 alkyl substituted with C3-10 carbocycle substituted with 0-5 Ra, and C1-6 alkyl substituted with 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S.
23. A compound according to
claim 1
, wherein
R2 is selected from the group: phenyl substituted with 0-5 Ra, and cyclopropyl or cyclohexyl substituted with 0-2 Ra; and
Ra is independently at each occurrence selected from the group: —CH2N(CH3)2, —CH2NH2, —SR3 halo, —CN , N3, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, ═O, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, NR3C(O)OR3, NR3C(O)R3, SO2NR3R3a, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S.
24. A compound according to
claim 1
, wherein
R2 is selected from the group: phenyl substituted with 0-5 Ra, and cyclopropyl or cyclohexyl substituted with 0-2 Ra; and
Ra is independently at each occurrence selected from the group: C1-4 alkyl, COR3, CO2R3, and CONR3R3a;
R3a is H or C1-4 alkyl.
25. A compound according to
claim 1
, wherein
R2 is selected from the group: phenyl substituted with 0-5 Ra, and cyclopropyl or cyclohexyl substituted with 0-2 Ra;
Ra is independently at each occurrence selected from the group: C1-4 alkyl, COR3, CO2R3, and CONR3R3a;
R3a is H or C1-4 alkyl;
R3 is C1-4alkyl, C1-4alkyl-NR5R5a; and
R5 and R5a, together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom.
26. A compound according to
claim 1
, wherein
R2 is selected from the group: phenyl substituted with 0-5 Ra, and cyclopropyl or cyclohexyl substituted with 0-2 Ra;
Ra is independently at each occurrence selected from the group: C1-4 alkyl, COR3, CO2R3, and CONR3R3a; and
R3a is H or C1-4 alkyl.
27. A compound according to
claim 1
, wherein
R2 is phenyl substituted with NR3R3a, wherein R3 and R3a, together with the nitrogen atom to which they are attached, form a 4-8 membered heterocycle containing an additional 0-1 N, S, or O atom and substituted with 0-3 R3c.
28. A compound according to
claim 25
, wherein
R2 is phenyl substituted with NR3R3a; and
R3 and R3a, together with the nitrogen atom to which they are attached, form a pyrrolinyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, morpholinyl,thiomorpholinyl, homopiperazinyl or piperazinyl group, substituted with 0-3 R3c.
29. A compound according to
claim 25
, wherein
R2 is phenyl substituted with NR3R3a wherein R3 and R3a, together with the nitrogen atom to which they are attached, form a piperidinyl, homopiperazinyl or piperazinyl group, substituted with 0-3 R3c.
30. A compound according to
claim 25
, wherein
R2 is phenyl substituted with NR3R3a and
R3 and R3a, together with the nitrogen atom to which they are attached, form a piperidinyl, homopiperazinyl or piperazinyl group, substituted with 0-3 substituents independently selected from the group consisting of: —C(═NH)CH3, pyrrolinyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, morpholinyl,thiomorpholinyl, homopiperazinyl or piperazinyl group, pyridyl, C1-4 alkyl, —NR3R3b.
31. A compound according to
claim 1
which is selected from Table 1.
32. A compound according to
claim 1
which is selected from Table 2.
33. A compound according to
claim 1
which is selected from Table 3.
34. A compound according to
claim 1
which is selected from Table 4.
35. A compound according to
claim 1
, wherein the compound is selected from:
3-(4-methoxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-phenyl-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methylthiophenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methanesulfonylphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-(N,N-dimethylamino)phenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-(3-pyridyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(formamido)indeno[1,2-c]pyrazol-4-one;
3-(4-hydroxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-piperidinophenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-morpholinophenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-ethoxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-butylphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-ethylphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-n-propylphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((4-aminophenyl)acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-pyridyl)-5-(formamido)indeno[1,2-c]pyrazol-4-one;
3-(4-pyridyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((4-aminophenyl)acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((4-azidophenyl)acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((4-(methoxycarbonylamino)phenyl) acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((4-(aminomethylcarbonylamino)phenyl) acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((4-((N,N-dimethylamino)methylcarbonyl amino)phenyl)acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((4-acetamidophenyl)acetamido) indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(pyrrolidinoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(morpholinoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(thiomorpholinoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(ethylaminoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(4-(aminomethyl)piperidinoacetamido) indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(piperazinoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(4-methylpiperazinoacetamido) indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(4-(2-hydroxyethyl)piperazinoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(N,N-dimethylaminoacetamido) indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((2-hydroxyethyl)aminoacetamido) indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(aminoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((2-chlorophenyl) acetamido) indeno [1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((2,4-dichlorophenyl) acetamido) indeno [1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((3′,4-dichlorophenyl) acetamido) indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((2-methoxyphenyl) acetamnido) indeno[1,2-c]pyrazol-4-one;
3-(4-dimethoxyphenyl)-5-(3-thienylacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((3,4-methylenedioxyphenyl)acetamido) indeno[1,2-c]pyrazol-4-one;
3-(3,4-dimethoxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-(2-methoxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((2,5-dimethoxyphenyl)acetamido) indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((3,4-dimethoxyphenyl)acetamido) indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((4-methoxyphenyl)acetamido) indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((3-methoxyphenyl)acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((4-chlorophenyl)acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((butylcarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((4-aminobenzylcarbamoyl)amino)indeno [1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((4-pyridylcarbamoyl) amino)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((phenylcarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(cyclobutanecarboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(cyclopentanecarboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(butanamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(propanamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(phenylacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-methylpropanamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(cyclopropanecarboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(chloroacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(4-(aminomethyl)piperidinoacetamido)-indeno[1,2-c]pyrazol-4-one;
3-(4-(N,N-dimethylamino)phenyl)-5-(morpholinoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-(N,N-dimethylamino)phenyl)-5-(N,N-dimethylaminoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-(trifluoromethyl)phenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-(N,N-dimethylamino)phenyl)-5-(4-methyl-piperazinoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-(N,N-dimethylamino)phenyl)-5-(4-(aminomethyl)-piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-(N,N-dimethylamino)phenyl)-5-(4-hydroxy-piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-morpholinophenyl)-5-(morpholinoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-morpholinophenyl)-5-(4-methylpiperazinoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-morpholinophenyl)-5-(4-hydroxy-piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-morpholinophenyl)-5-(4-(aminomethyl)-piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-(morpholinoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-((N,N-dimethylamino)acetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-(4-methylpiperazinoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-(4-(aminomethyl)-piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-(aminocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-(morpholinocarbamoylamino)-indeno[1,2-c]pyrazol-4-one;
3-(4-(4-methylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-ethylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-isopropylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-t-butoxycarbonylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(N,N-dimethylamino)phenyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(c-propyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-(2-thienyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-(3-methyl-2-thienyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
3-(ethyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(n-propyl)-5-(carbamoylamino)aminoindeno[1,2-c]pyrazol-4-one;
3-(i-propyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(c-propyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(c-hexyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(3-methyl-2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-methyl-2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-carboethoxy-2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(3-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-methyl-3-pyrrolyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(2,5-dimethyl-3-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(2-furanyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(i-propyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
3-(c-propyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
3-(c-hexyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
3-(2-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
3-(5-methoxy-2-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
3-(5-methyl-2-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
3-(5-carboethoxy-2-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
3-(3-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
3-(5-chloro-3-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
3-(2,5-dimethyl-3-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
3-(2-furanyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
3-(i-propyl)-5-((4-carbamoylpiperidino)acetamido)indeno[1,2-c]pyrazol-4-one;
3-(c-hexyl)-5-((4-carbamoylpiperidino)acetamido)indeno[1,2-c]pyrazol-4-one;
3-(ethyl)-5-(4-(aminomethyl)piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;
3-(i-propyl)-5-(4-(aminomethyl)piperidinoacetamido) indeno[1,2-c]pyrazol-4-one;
3-(c-propyl)-5-(4-(aminomethyl)piperidinoacetamido) indeno[1,2-c]pyrazol-4-one;
3-(c-hexyl)-5-(4-(aminomethyl)piperidinoacetamido) indeno[1,2-c]pyrazol-4-one;
3-(i-propyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-carboethoxy-2-thienyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-carboxyl-2-thienyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(2,5-dimethyl-3-thienyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(i-propyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-methoxycarbonyl-4-piperidinyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-methyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-chloro-3-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(2,5-dimethyl-3-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-carboethoxy-2-thienyl)-5-(morpholinylcarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-carboxyl-2-thienyl)-5-(morpholinylcarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(benzylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-((4-methylpiperazino)carbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-((2-(1-methyl-2-pyrrolidinyl)ethyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-((N,N-dimethylamino)aminocarbonyl)-2-thienyl-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-((2-(N,N-dimethylamino)ethyl)aminocarbonyl)-2-thienyl-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(2-pyrrolidinoethyl)aminocarbonyl)-2-thienyl-5-(morpholinocarbamoylamino)indeno [1,2-c]pyrazol-4-one;
3-(5-(2-morpholinoethyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(morpholinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-((3-(2-pyrrolidon-1-yl)propyl)aminocarbonyl)-2-thienyl-5-(morpholinocarbamoylamino) indeno[1,2-c]pyrazol-4-one;
3-(5-((2-(3-pyridyl)ethyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino) indeno [17 2-c]pyrazo-1-4-one;
3-(5-((3-(1-imidazolyl)propyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;
3-(5-((2-(2-pyridyl)ethyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-((2-pyridyl)methyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-((2-piperidinoethyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-((N,N-dimethylamino)carbamoylamino)-indeno[1,2-c]pyrazol-4-one;
3-(4-(4-methylpiperazino)phenyl)-5-((N,N-dimethylamino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-((4-methylpiperazino)carbamoylamino)-indeno[1,2-c]pyrazol-4-one; 3-(4-(4-methylpiperazino)phenyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-ethylpiperazino)phenyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-isopropylpiperazino)phenyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinopheny)5((2,6-dimethylpiperidino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-((4-(2-hydroxyethyl)piperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-((2(R)-(methoxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-((2(S)-(methoxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-((2(R)-(1-methoxy-1-methylethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-((2(S)-(1-methoxy-1-methylethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-((2(R)-(hydroxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-((2(S)-(hydroxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-((2(R)-(benzyloxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-((2(S)-(benzyloxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(3-methylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(cis-3,5-dimethylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one; 3-(4-(cis-3,4,5-trimethylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-isopropylpiperazino)-2-methylphenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-homopiperazinophenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-methylhomopiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-ethylhomopiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-isopropylhomopiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-homopiperazino-2-methylphenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-ethylhomopiperazino)-2-methylphenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-isopropylhomopiperazino)-2-methylphenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-(N,N-dimethylamino)piperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-(N,N-diethylamino)piperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-piperidinopiperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-pyrrolidinopiperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-(N,N-diethylamino)piperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-((4-methylpiperazino)-thionocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-methyl-3-pyrrolyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-pyrrolidinoaminocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-piperidinoaminocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-piperidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-piperazinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-methylpiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-ethylpiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-(2-hydroxyethyl)piperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-(cyclopropylmethyl)piperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-(t-butoxycarbonyl)piperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-(2-pyridyl)piperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(((1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptyl)carbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(((1S,4S)-(+)-2-methyl-2,5-diazabicyclo[2.2.1]heptyl)carbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-(N,N-dimethylamino)piperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-pyrrolidinopiperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-piperidinopiperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-cyclohexylaminocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-piperidylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-((1-(t-butoxycarboxyl)piperidin-4-yl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-(1-methylpiperidin-4-yl)methylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(3-(N,N-dimethylamino)piperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(3-p-toluenesulfonylamino)piperidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(3-hydroxypiperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-((3-piperidyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-((3-quinuclidyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-((3-aminocyclohexyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-((3-(t-butoxycarbonylamino)cyclohexyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(2-(N,N-dimethylaminomethyl)piperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(2-(N,N-diethylaminomethyl)piperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-pyrrolidinocarbonyl-2-thienyl)-5-(morpholinocarbamnoylamino) indeno[1,2-c]pyrazol-4-one;
3-(5-(3-aininopyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamnoylamino) indeno [1,2-c]pyrazol-4-one;
3-(5(3(S)-N-methylamino)pyrrolidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(3(S)-acetamidopyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(3(S)-(N-methylacetamido)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5(3(S)-(N-methyl-t-butoxycarbonylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(3-(N,N-dimethylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(3(R)-(N,N-dimethylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(3(S)-(N,N-dimethylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-clpyrazol-4-one;
3-(5-((1-methylpyrrolidin-3-yl)methylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(2(R)-(pyrrolidinomethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(2(S)-(hydroxymethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(2(R)-(methoxymethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(2(S)-(phenylaminomethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(2(R)-(methoxymethyl)pyrrolidinoaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-homopiperidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-homopiperazinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-methylhomopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-ethylhomopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno(1,2-c]pyrazol-4-one;
3-(5-(4-(cyclopropylmethyl)homopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-(t-butoxycarbonyl)homopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-acetylhomopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-((4-methylaminophenyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-((4-acetamidophenyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-(diethylamino)phenylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-((1-methyl-3-cyclopropylpyrazo-5-yl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-methyl-3-pyrrolyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-carboethoxy-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-carboxyl-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-methylpiperazinocarbonyl)-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-piperazinocarbonyl-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-(t-butoxycarbonyl)piperazinocarbonyl)-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-methylhomopiperazinocarbonyl)-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-homopiperazinocarbonyl-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(5-(4-(t-butoxycarbonyl)homopiperazinocarbonyl)-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(c-propyl)-5-(4-carbamoylpiperidinoacetamido)indeno[1,2-c]pyrazol-4-one;
3-ethyl-5-(4-methylpiperazinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(c-propyl)-5-(4-methylpiperazinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;
3-(c-hexyl)-5-(4-methylpiperazinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;
3-ethyl-5-(morpholinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;
3-(c-propyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one; 3-(c-hexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-ethoxycarbonylpiperidin-4-yl)-5-(morpholinocarbamoylamino) indeno[1,2-c]pyrazol-4-one;
3-(1-phenoxycarbonylpiperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(imidazol-1-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(2-thienylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-carbamoylpiperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(ethylcarbamoyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(2-(1-methylpyrrolidin-2-yl) ethylaminocarbamoyl)piperidin-4-yl)-5-(morpholinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;
3-(1-(4-(dimethylamino)piperidinocarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(piperazinocarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino) indeno[1,2-c]pyrazol-4-one;
3-(1-(4-(-butoxycarbonyl)piperazinoarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;
3-(1-(((1S,4S)-(+)-2,5-diazabicyclo[2.2.1]hept-2-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(((1S,4S)-(+)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamnino) indeno [1,2-c]pyrazol-4-one;
3-(1-(3-aminopropylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno [1,2-c]pyrazol-4-one;
3-(1-(3-(dimethylamino)propylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(3-(t-butoxycarbonylamino)propylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylainino)indeno[1,2-c]pyrazol-4-one;
3-(1-(4-aminobutylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(4-(dimethylamino)butylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamnino)indeno[1,2-c]pyrazol-4-one;
3-(1-(4-(t-butoxycarbonylamino)butylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamnoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-((1-methylpiperidin-4-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamroylamino) indeno [1,2-c]pyrazol-4-one;
3-(1-((1-(t-butoxycarbonyl)piperidin-4-yl) carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;
3-(1-(cis-4-aminocyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;
3-(1-(4-aminocyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3(1-(cis-4-(dimethylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(4-(t-butoxycarbonylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(trans-4-(t-butoxycarbonylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;
3-(1-(piperidin-3-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(1-methylpiperidin-3-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(1-(t-butoxycarbonyl)piperidin-3-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(3-aminocyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(3-(dimethylamino) cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;
3-(1-(trans-4-methoxycyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(cis-4-methoxycyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(4-aminobenzylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(4-(dimethylamino)benzylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(4-(t-butoxycarbonylamino)benzylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(4-aminophenylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(4-(dimethylamino)phenylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(1-(4-(t-butoxycarbonylamino)phenylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(trans-4-carboxylcyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(trans-4-(methoxycarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(trans-4-(3-(dimethylamino)pyrrolidinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(trans-4-(piperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(trans-4-(4-methylpiperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(trans-4-(homopiperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one; 3-(trans-4-(4-methylhomopiperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
or pharmaceutically acceptable salt form thereof.
36. A compound according to
claim 1
, wherein the compound is selected from:
3-(4-piperazinophenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-methylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-ethylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-isopropylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-((N,N-dimethylamino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-methylpiperazino)phenyl)-5-((N,N-dimethylamino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-((4-methylpiperazino)carbamoylamino)-indeno[1,2-c]pyrazol-4-one;
3-(4-(4-methylpiperazino)phenyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-ethylpiperazino)phenyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-isopropylpiperazino)phenyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-((2(R)-(methoxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-piperazinophenyl)-5-((2(R)-(1-methoxy-1-methylethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-homopiperazinophenyl)-5-(morpholinocarbamoylamino)-indeno[1,2-c]pyrazol-4-one;
3-(4-(4-methylhomopiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-ethylhomopiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-isopropylhomopiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-(N,N-dimethylamino)piperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-(N,N-diethylamino)piperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-piperidinopiperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-pyrrolidinopiperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
or pharmaceutically acceptable salt form thereof.
37. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier, a compound according to
claim 1
or a pharmaceutically acceptable salt or prodrug form thereof, and a cytostatic or cytotoxic agent.
38. A method of treating a cell proliferative disease associated with CDK activity in a patient in need thereof,comprising administrering to said patient a pharmaceutically effective amount of a compound according to
claim 1
, or a pharmaceutically acceptable salt or prodrug form thereof, wherein the proliferative diseases is selected from the group consisting of: Alzheimer's disease, viral infections, auto-immune diseases, fungal disease, cancer, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis, neurodegenerative disorders and post-surgical stenosis and restenosis.
39. A method of treating cancer associated with CDK activity in a patient in need thereof, comprising administrering to said patient a pharmaceutically effective amount of a compound according to
claim 1
, or a pharmaceutically acceptable salt or prodrug form thereof, wherein the cancer is selected from the group consisting of: carcinoma such as bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
40. A method of treating a disease associated with apoptosis in a patient in need thereof, comprising administrering to said patient a pharmaceutically effective amount of a compound according to
claim 1
, or a pharmaceutically acceptable salt or prodrug form thereof, wherein the disease associated with apoptosis is selected from the group consisting of: cancer, viral infections, autoimmune diseases and neurodegenerative disorder.
41. A method of inhibiting tumor angiogenesis and metastasis in a patient in need thereof, comprising administrering to said patient a pharmaceutically effective amount of a compound according to
claim 1
, or a pharmaceutically acceptable salt or prodrug form thereof.
42. A method of modulating the level of cellular RNA and DNA synthesis in a patient in need thereof, comprising administering to said patient a CDK inhibitory effective amount of a compound according to
claim 1
, or a pharmaceutically acceptable salt or prodrug form thereof.
43. A method of treating viral infections in a patient in need thereof, comprising administering to said patient a CDK inhibitory effective amount of a compound according to
claim 1
, or a pharmaceutically acceptable salt or prodrug form thereof, wherein the viral infections is selected from the group consiting of HIV, human papilloma virus, herpesvirus, poxyirus, Epstein-Barr virus, Sindbis virus and adenovirus.
44. A method of chemopreventing cancer in a patient, comprising administering to said patient in need thereof, a CDK inhibitory effective amount of a compound according to
claim 1
, or a pharmaceutically acceptable salt or prodrug form thereof.
45. A method of inhibiting CDK activity comprising combining an effective amount of a compound according to
claim 1
, with a composition containing CDK.
46. A method of treating cancer associated with CDK activity in a patient in need thereof, comprising administrering to said patient a pharmaceutically effective amount of a compound according to
claim 1
, or a pharmaceutically acceptable salt or prodrug form thereof, in combination (administered together or sequentially) with known anti-cancer treatments such as radiation therapy or with cytostatic or cytotoxic agents, wherein such agents are selected from the group consisting of: DNA interactive agents, such as cisplatin or doxorubicin; topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents, such as paclitaxel, docetaxel or the epothilones; hormonal agents, such as tamoxifen; thymidilate synthase inhibitors, such as 5-fluorouracil; and anti-metabolites, such as methoxtrexate.
47. A method treating cell proliferative diseases associated with CDK activity in a patient in need thereof, comprising administrering to said patient a pharmaceutically effective amount of a compound according to
claim 1
, or a pharmaceutically acceptable salt or prodrug form thereof, in combination (administered together or sequentially) with known anti-proliferating agents selected from the group consisting of:, altretamine, busulfan, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, thiotepa, cladribine, fluorouracil, floxuridine, gemcitabine, thioguanine, pentostatin, methotrexate, 6-mercaptopurine, cytarabine, carmustine, lomustine, streptozotocin, carboplatin, cisplatin, oxaliplatin, iproplatin, tetraplatin, lobaplatin, JM216, JM335, fludarabine, aminoglutethimide, flutamide, goserelin, leuprolide, megestrol acetate, cyproterone acetate, tamoxifen, anastrozole, bicalutamide, dexamethasone, diethylstilbestrol, prednisone, bleomycin, dactinomycin, daunorubicin, doxirubicin, idarubicin, mitoxantrone, losoxantrone, mitomycin-c, plicamycin, paclitaxel, docetaxel, CPT-11, epothilones , topotecan, irinotecan, 9-amino camptothecan, 9-nitro camptothecan, GS-211, etoposide, teniposide, vinblastine, vincristine, vinorelbine, procarbazine, asparaginase, pegaspargase, methoxtrexate, octreotide, estramustine, and hydroxyurea.
48. A method of inhibiting CDKl activity, comprising adminsitering to a patient in need thereof an efective CDKl inhibitory amount of a compound according to
claim 1
, or a pharmaceutically acceptable salt or prodrug form thereof.
49. A method of inhibiting CDK2 activity, comprising adminsitering to a patient in need thereof an efective CDK2 inhibitory amount of a compound according to
claim 1
, or a pharmaceutically acceptable salt or prodrug form thereof.
50. A method of inhibiting CDK3 activity, comprising adminsitering to a patient in need thereof an efective CDK3 inhibitory amount of a compound according to
claim 1
, or a pharmaceutically acceptable salt or prodrug form thereof.
51. A method of inhibiting CDK4 activity, comprising adminsitering to a patient in need thereof an efective CDK4 inhibitory amount of a compound according to
claim 1
, or a pharmaceutically acceptable salt or prodrug form thereof.
52. A method of inhibiting CDK5 activity, comprising adminsitering to a patient in need thereof an efective CDK5 inhibitory amount of a compound according to
claim 1
, or a pharmaceutically acceptable salt or prodrug form thereof.
53. A method of inhibiting CDK6 activity, comprising adminsitering to a patient in need thereof an efective CDK6 inhibitory amount of a compound according to
claim 1
, or a pharmaceutically acceptable salt or prodrug form thereof.
54. A method of inhibiting CDK7 activity, comprising adminsitering to a patient in need thereof an efective CDK7 inhibitory amount of a compound according to
claim 1
, or a pharmaceutically acceptable salt or prodrug form thereof.
55. A method of inhibiting CDK8 activity, comprising adminsitering to a patient in need thereof, an efective CDK8 inhibitory amount of a compound according to
claim 1
, or a pharmaceutically acceptable salt or prodrug form thereof.
56. A method of inhibiting CDK9 activity, comprising adminsitering to a patient in need thereof an efective CDK9 inhibitory amount of a compound according to
claim 1
, or a pharmaceutically acceptable salt or prodrug form thereof.
57. A pharmaceutical kit for treating a cell proliferative disease associated with CDK activity, said kit comprising a plurality of separate containers, wherein at least one of said containers contains a compound accordig to
claim 1
, or a pharmaceutically acceptable salt or prodrug form thereof, and at least another of said containers contains one or more compounds selected from the group consisting of cytostatic or cytotoxic agents, such as for example, but not limited to, DNA interactive agents, such as carboplatin, cisplatin or doxorubicin; topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents, such as paclitaxel, taxane, docetaxel or the epothilones; hormonal agents, such as tamoxifen; thymidilate synthase inhibitors, such as 5-fluorouracil; and anti-metabolites, such as methoxtrexate, and said containers optionally contain a pharmaceutical carrier, which kit may be effectively utilized for carrying out combination therapies according to the invention.
58. A method of inhibiting the division of a cell which comprises contacting the cell with a composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of the formula (I):
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
X is selected from the group: O, S, and NR;
R is selected from the group: H, C1-4 alkyl, and NR5R5a;
R1 is selected from the group: H, C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc, C2-10 alkynyl substituted with 0-3 Rc, —NHR4, C3-10 carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;
Ra is independently at each occurrence selected from the group: halo, —CN , N3, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, ═O, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, NR3C(O)OR3, NR3C(O)R3, SO2NR3R3a, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;
alternatively, when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—;
Rb is independently at each occurrence selected from the group: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, and SO2R3b;
Rc is independently at each occurrence selected from the group: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR5NR5R5a, NR3C(O)OR3, NR3C(O)R3, ═O, OR3, COR3, CO2R3, CONR R3a, NHC(O)NR3R3a, NHC(S)NR R3a, SO2N R3a, SO2R3b, C3-10 carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;
R2 is selected from the group: H, C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc, C2-10 alkynyl substituted with 0-3 Rc, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;
R3 is selected from the group: H, halo, —CN, NO2, C1-4 haloalkyl, NR5R5a, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, ═O, OR5, COR5, CO2R5, CONR5R5a, NH(O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C1-4 alkyl, phenyl, and benzyl;
R3a is selected from the group: H, C1-4 alkyl, phenyl, and benzyl;
alternatively, R3 and R3a, together with the nitrogen atom to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom;
R3b is selected from the group: H, C1-4 alkyl, phenyl, and benzyl;
R4 is independently at each occurrence selected from the group:
H, —CN, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, SO2R3b, C3-10 carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;
R5 is independently selected from the group: H, C1-4 alkyl, phenyl and benzyl;
R5a is independently selected from the group: H, C1-4 alkyl, phenyl and benzyl;
R5b is independently selected from the group: H, C1-4 alkyl, phenyl and benzyl; and
m is selected from 0, 1, 2, and 3.,
provided that R2 my not be an unsubstituted branched alkyl group when R1 is CH3.
Description
    FIELD OF THE INVENTION
  • [0001]
    This invention relates generally to novel 5-substituted-indeno[1,2-c]pyrazol-4-ones which are useful as cyclin dependent kinase (cdk) inhibitors, pharmaceutical compositions comprising the same, methods for using the same for treating proliferative diseases, and intermediates and processes for making the same.
  • BACKGROUND OF THE INVENTION
  • [0002]
    One of the most important and fundamental processes in biology is the division of cells mediated by the cell cycle. This process ensures the controlled production of subsequent generations of cells with defined biological function. It is a highly regulated phenomenon and responds to a diverse set of cellular signals both within the cell and from external sources. A complex network of tumor promoting and suppressing gene products are key components of this cellular signaling process. Over expression of the tumor promoting components or the subsequent loss of the tumor suppressing products will lead to unregulated cellular proliferation and the generation of tumors (Pardee, Science 246:603-608, 1989).
  • [0003]
    Cyclin dependent kinases (cdks) play a key role in regulating the cell cycle machinery. These complexes consist of two components: a catalytic subunit (the kinase) and a regulatory subunit (the cyclin). To date, nine kinase subunits (cdk 1-9) have been identified along with several regulatory subunits (cyclins A-H).(A. M. Senderowicz and E. A. Sausville Journal of the National Cancer Institute (2000), 92 (5), 376-387; and S. Mani; C. Wang; K. Wu; R. Francis; R. Pestell Exp. Opin. Invest. Drugs (2000) 9(8), 1849-1870).
  • [0004]
    Each kinase associates with a specific regulatory partner and together make up the active catalytic moiety. Each transition of the cell cycle is regulated by a particular cdk complex: G1l/S by cdk2/cyclin E, cdk4/cyclin D1 and cdk6/cyclinD2; S/G2 by cdk2/cyclin A and cdkl/cyclin A; G2/M by cdk1/B. The coordinated activity of these kinases guides the individual cells through the replication process and ensures the vitality of each subsequent generation (Sherr, Cell 73:1059-1065, 1993; Draetta, Trends Biochem. Sci. 15:378-382, 1990)
  • [0005]
    An increasing body of evidence has shown a link between tumor development and cdk related malfunctions. Over expression of the cyclin regulatory proteins and subsequent kinase hyperactivity have been linked to several types of cancers (Jiang, Proc. Natl. Acad. Sci. USA 90:9026-9030, 1993; Wang, Nature 343:555-557, 1990). More recently, endogenous, highly specific protein inhibitors of cdks were found to have a major affect on cellular proliferation (Kamb et al, Science 264:436-440, 1994; Beach, Nature 336:701-704, 1993). These inhibitors include p16 INK4 (an inhibitor of cdk4/D1), p21 CIP1 (a general cdk inhibitor), and p27KIP1 (a specific cdk2/E inhibitor). A recent crystal structure of p27 bound to cdk2/A revealed how these proteins effectively inhibit the kinase activity through multiple interactions with the cdk complex (Pavletich, Nature 382:325-331, 1996). These proteins help to regulate the cell cycle through specific interactions with their corresponding cdk complexes. Cells deficient in these inhibitors are prone to unregulated growth and tumor formation.
  • [0006]
    Protein kinases, in particular, CDK, play a role in the regulation of cellular proliferation. Therefore, CDK inhibitors could be useful in the treatment of cell proliferative disorders such as cancer, familial adenomatosis polyposis, neuro-fibromatosis, psoriasis, fungal infections, endotoxic shock, trasplantaion rejection, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis (U.S. Pat. No. 6,114,365). CDKs are also known to play a role in apoptosis.
  • [0007]
    Therefore CDK inhibitors, could be useful in the treatment of useful of cancer; viral infections, for example, herpevirus, poxyirus, Epstein-Barr virus, Sindbis virus and adenovirus; prevention of AIDS development in HIV-infected individuals; autoimmune diseases, for example, systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus; neurodegenerative disorders, for example, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases, for example, chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system, for example, osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain (U.S. Pat. No. 6,107,305).
  • [0008]
    It has also been discovered that some cyclin-dependent kinase inhibitors can be used in combination therapy with some other anticancer agents. For example, the cytotoxic activity of the cyclin-dependent kinase inhibitor, flavopiridol, has been used with other anticancer agents in cancer combination therapy. Cancer Research, 57, 3375 (1997).
  • [0009]
    Also, it has recenly been disclosed that CDK inhibitors may be useful in the chemoprevention of cancer. Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse (U.S. Pat. No. 6,107,305).
  • [0010]
    Furthermore, it has recently been discovered that cdk5 is involved in the phosphorylation of tau protein, and therefore CDK inhibitors may be useful in the treatment of Alzheimer's disease (J. Biochem., 117, 741-749, 1995).
  • [0011]
    This body of evidence has led to an intense search for small molecule inhibitors of the cdk family as an approach to cancer chemotherapy. There are no known examples of molecules related to the current invention which describe 5-substituted-indeno[1,2-c]pyrazoles as cdk inhibitors. There is one case describing indeno[1,2-c]pyrazoles having anticancer activity. There are two other examples which describe indeno[1,2-c]pyrazoles having unrelated utilities and structures.
  • [0012]
    A series of indeno[1,2-c]pyrazoles having anticancer activity are described in JP 60130521 and JP 62099361 with the following generic structure:
  • [0013]
    No substitution is claimed on the indenophenyl portion of the molecule and the molecules are not indicated to be cdk inhibitors. In addition, we discovered that substitution at the 5-position was critical for cdk inhibitory activity.
  • [0014]
    A series of indeno[1,2-c]pyrazoles having herbicidal activity are described in GB 2223946 with the following generic structure:
  • [0015]
    The above compounds differ from the presently claimed invention in Xn is defined as halo, alkyl, haloalkyl, and haloalkoxy; n=0-2. In addition, R1 is defined as acyl and R2 is defined as alkyl or cycloalkyl.
  • [0016]
    A series of 1-(6′-substituted-4′-methylquinol-2′-yl)-3-methylindeno[1,2-c]pyrazoles having CNS activity are described by Quraishi, Farmaco 44:753-8, 1989 with the following generic structure:
  • [0017]
    Compounds of this series are not considered to be part of the presently claimed invention.
  • SUMMARY OF THE INVENTION
  • [0018]
    The present invention describes a novel class of indeno[1,2-c]pyrazol-4-ones or pharmaceutically acceptable salt forms thereof that are potent inhibitors of the class of enzymes known as cyclin dependent kinases, which relate to the catalytic subunits cdk 1-9 and their regulatory subunits know as cyclins A-H.
  • [0019]
    It is another object of this invention to provide a novel method of treating proliferative diseases associated with CDK activity by administering a therapeutically effective amount of one of the compounds of the invention or a pharmaceutically acceptable salt form thereof.
  • [0020]
    It is another object of this invention to provide a novel method of treating cancer associated with CDK activity by administering a therapeutically effective amount of one of the compounds of the invention or a pharmaceutically acceptable salt form thereof.
  • [0021]
    It is another object of this invention to provide a novel method of treating a proliferative disease, which comprises administering a therapeutically effective combination of one of the compounds of the present invention and one or more other known anti-cancer treatments such as radiation therapy, chemotoxic or chemostatic agents.
  • [0022]
    These and other objectives have been achieved by the inventors' discovery that compounds of formula (I):
  • [0023]
    wherein R1, R2 and X are defined below or pharmaceutically acceptable salts thereof are cyclin dependent kinase inhibitors.
  • DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
  • [0024]
    The invention pertains to novel cyclin dependent kinase inhibitors (cdks) and specifically, but not exclusively, as inhibitors of cdk/cyclin complexes. The inhibitors of this invention are indeno[1,2-c]pyrazol-4-one analogs. Certain analogs were selective for their activity against cdks and their cyclin bound complexes and were less active against other known serine/threonine kinases such as Protein Kinase A (PKA) and Protein Kinase C (PKC).
  • [0025]
    As described herein, the inhibitors of this invention are capable of inhibiting the cell-cycle machinery and consequently would be useful in modulating cell-cycle progression, which would ultimately control cell growth and differentiation. Such compounds would be useful for treating subjects having disorders associated with excessive cell proliferation, such as the treatment of cancer, psoriasis, immunological disorders involving unwanted leukocyte proliferation, in the treatment of restinosis and other smooth muscle cell disorders, and the like.
  • [0026]
    [1] The present invention, in a first embodiment, describes novel compounds of formula (I):
  • [0027]
    or stereoisomers, pharmaceutically acceptable salts, and prodrugs thereof, wherein:
  • [0028]
    X is selected from the groups: O, S, and NR;
  • [0029]
    R is selected from the groups: H, C1-4 alkyl, and NR5R5a;
  • [0030]
    R1 is selected from the groups: H, C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc, C2-10 alkynyl substituted with 0-3 Rc, —NHR4, C3-10 membered carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;
  • [0031]
    Ra is independently selected from the groups: R5
  • [0032]
    R5aN(CR6R6a)m, R5O(CR6R6a)m, halo, —CN , N3, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, ═O, OR3, SR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, NR3C(O)OR3, NR3C(O)R3, SO2NR3R3a, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;
  • [0033]
    alternatively, when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—;
  • [0034]
    Rb is independently selected from the groups: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, CON(R6)((CH2)mR7), CO(CH2)mR7, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, and SO2R3b;
  • [0035]
    Rc is independently selected from the groups: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR5NR5R5a, NR3C(O)OR3, NR3C(O)R3, ═O, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2N3R3a, SO2R3b, C3-10 membered carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;
  • [0036]
    R2 is selected from the groups: H, C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc, C2-10 alkynyl substituted with 0-3 Rc, —(CF2)mCF3, C3-10 membered carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;
  • [0037]
    R3 is independently selected from the groups: H, halo, —CN, NO2, C1-4 haloalkyl, R5R5aN(CR6R6a)m, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, ═O, R5O(CR6R6a)m, COR5, CO2R5, CONR5R5a, NHC(O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C1-4 alkyl, phenyl, and benzyl;
  • [0038]
    R3a is independently selected from the groups: H, C1-4 alkyl, phenyl, and benzyl;
  • [0039]
    alternatively, R3 and R3a, together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom and substituted with 0-3 R3c;
  • [0040]
    R3b is independently selected from the groups: H, C1-4 alkyl, phenyl, and benzyl;
  • [0041]
    R3c is independently selected from the groups: halo, —CN, N3, NO2, C1-4 alkyl, C3-8 cycloalkyl, C4-10 cycloalkylalkyl, C1-4 haloalkyl, NR3R3b, R5R5aN(CR6R6a)m, ═O, OR3, R5O(CR6R6a)m, COR3, CO2R3, CONR3R3 b , NHC(O)NR3R3 b , NHC(S)NR3R3 b , NR3C(O)OR3, NR3C(O)R3, C(═NR5)R5a, C(═NRS)NR5aR5b, SO2NR3R3 b , SO2R3 b , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;
  • [0042]
    R4 is independently selected from the groups: H, —CN, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, SO2R3b, C3-10 membered carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;
  • [0043]
    R5 is independently selected from the groups: H, C1-4 alkyl, phenyl and benzyl;
  • [0044]
    R5a is independently selected from the groups: H, C1-4 alkyl, phenyl and benzyl;
  • [0045]
    alternatively, R5 and R5a, together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom;
  • [0046]
    R5b is independently selected from the groups: H, C1-4 alkyl, phenyl and benzyl;
  • [0047]
    R6 is idependently selected from the groups: H, C1-4 alkyl;
  • [0048]
    R6a is independently selected from the groups: H, C1-4 alkyl;
  • [0049]
    R7 is independently selected from the groups: NR3R3a, membered carbocycle substituted with 0-3 R3, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3; and
  • [0050]
    m is independently selected from 0, 1, 2, 3, and 4;
  • [0051]
    provided that: when R2 is a C1-4 unsubstituted, branched alkyl then R1 is not CH3; or when R1 is NHR4 and R4 is NR3R3a then R3 and R3a can not both be phenyl.
  • [0052]
    [2] In another embodiment, the invention describes novel compounds of formula (I):
  • [0053]
    or stereoisomers, pharmaceutically acceptable salts, and prodrugs thereof, wherein:
  • [0054]
    X is selected from the groups: O, S, and NR;
  • [0055]
    R is selected from the groups: H, C1-4 alkyl, and NR5R5a;
  • [0056]
    R1 is selected from the groups: H, C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc, C2-10 alkynyl substituted with 0-3 Rc, —NHR4, C3-10 membered carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;
  • [0057]
    Ra is independently selected from the groups: halo, —CN, N3, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, ═O, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, NR3C(O)OR3, NR3C(O)R3, SO2NR3R3a, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;
  • [0058]
    alternatively, when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—;
  • [0059]
    Rb is independently selected from the groups: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, CON(R6)((CH2)mR7), CO(CH2)mR7, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, and SO2R3b;
  • [0060]
    Rc is independently selected from the groups: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR5NR5R5a, NR3C(O)OR3, NR3C(O)R3, ═O, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2N3R3a, SO2R3b, C3-10 membered carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;
  • [0061]
    R2 is selected from the groups: H, C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc, C2-10 alkynyl substituted with 0-3 Rc, —(CF2)mCF3, C3-10 membered carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;
  • [0062]
    R3 is independently selected from the groups: H, halo, —CN, NO2, C1-4 haloalkyl, R5R5aN(CR6R6a)m, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, ═O, R5O(CR5R6a)m, COR5, CO2R5, CONR5R5a, NHC(O)NR5R5a, NHC (S)NR5R5a, SO2NR5R5a, SO2R5b, C1-4 alkyl, phenyl, and benzyl;
  • [0063]
    R3a is independently selected from the groups: H, C1-4 alkyl, phenyl, and benzyl;
  • [0064]
    alternatively, R3 and R3a, together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom and substituted with 0-3 R3c;
  • [0065]
    R3b is independently selected from the groups: H, C1-4 alkyl, phenyl, and benzyl;
  • [0066]
    R3c is independently selected from the groups: halo, —CN, N3, NO2, C1-4 alkyl, C3-8 cycloalkyl, C4-10 cycloalkylalkyl, C1-4 haloalkyl, NR3R3b, R5R5aN(CR6R6a)m, ═O, OR3, R5 O(CR6R6a)m, COR3, CO2R3, CONR3R3b, NHC(O)NR3R3b, NHC(S)NR3R3b, NR3C(O)OR3, NR3C(O)R3, C(═NR5)R5a, C(═NR5)NR5aR5b, SO2NR3R3b, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;
  • [0067]
    R4 is independently selected from the groups: H, —CN, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, SO2R3b, C3-10 membered carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;
  • [0068]
    R5 is independently selected from the groups: H, C1-4 alkyl, phenyl and benzyl;
  • [0069]
    R5a is independently selected from the groups: H, C1-4 alkyl, phenyl and benzyl;
  • [0070]
    alternatively, R5 and R5a, together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom;
  • [0071]
    R5b is independently selected from the groups: H, C1-4 alkyl, phenyl and benzyl;
  • [0072]
    R6 is idependently selected from the groups: H, C1-4 alkyl;
  • [0073]
    R6a is independently selected from the groups: H, C1-4 alkyl;
  • [0074]
    R7 is independently selected from the groups: NR3R3a, C3-10 membered carbocycle substituted with 0-3 R3, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3; and
  • [0075]
    m is independently selected from 0, 1, 2, 3, and 4; provided that:
  • [0076]
    1) when R2 is a C1-4 unsubstituted, branched alkyl then R1 is not CH3; or
  • [0077]
    2)when R1 is NHR4 and R4 is NR3R3a then R3 and R3a can not both be phenyl.
  • [0078]
    R3 and R3a can not both be phenyl.
  • [0079]
    [3] In another embodiment, the invention describes novel compounds of embodiment [1], wherein X is O or S;
  • [0080]
    R1 is H, C1-10 alkyl substituted with 0-3 Rc, —NHR4, C3-10 membered carbocycle substituted with 0-5 , or 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5;
  • [0081]
    Rc is independently selected from the groups: halo, C3-10 membered carbocycle substituted with 0-5 Ra, 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3, NR3R3a;
  • [0082]
    R3 is H, C1-4 alkyl, phenyl, benzyl, or together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom and substituted with 0-3 R3c;
  • [0083]
    R4 is H, C1-4 alkyl, NR3R3a, C3-10 membered carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;
  • [0084]
    R2 is selected from the groups: C3-10 membered carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb, and C1-10 alkyl substituted with 0-3 Rc.
  • [0085]
    [4] In another embodiment, the invention describes novel compounds of embodiment [1], wherein X is O or S;
  • [0086]
    R1 is C1-4 alkyl substituted with 0-3 Rc, wherein Rc is independently selected from the group consisting of: C3-6 membered carbocycle substituted with 0-5 Ra, 5-6 membered heterocycle substituted with 0-3 R3, NR3R3a, and OR3; C3-6 membered carbocycle substituted with 0-5 Ra, wherein Ra is independently selected from the group consisting of:
  • [0087]
    R5R5aN(CR6R6a)m—, R5O(CR6R6a)m—, OR3, halo, C1-4 alkyl, —NR3O(O)R3, COR3, CO2R3, N3, NR3C(O)OR3, NR3R3aCONR3R3a, and 5-6 membered heterocycle; or when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—; or 5-6 membered heterocycle and substituted with 0-5 Rb, wherein Rb is independently selected from the group:
  • [0088]
    OR3, halo, COR3, C1-4 alkyl, CO2R3, NR3C(O)R3, NR3C(O)OR3, NR3R3a, and CONR3R3a;
  • [0089]
    R2 is C3-6 membered carbocycle substituted with 0-5 Ra, wherein Ra is independently selected from the groups:
  • [0090]
    R5R5aN(CR6R6a)m, R5O(CR6R6a)m, OR3, halo, C1-4 alkyl, NR3C(O)R3, COR3, CO2R3, N3, NR3C(O)OR3, NR3R3a, CONR3R3a, and 5-6 membered heterocycle, or when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—; 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb, wherein Rb is independently selected from the group:
  • [0091]
    OR3, halo, COR3, C1-4 alkyl, CO2R3, NR3C(O)R3, NR3C(O)OR3, NR3R3a, and CONR3R3a; or C1-10 alkyl substituted with 0-3 Rc, wherein Rc is independently selected from the groups:
  • [0092]
    C3-6 membered carbocycle substituted with 0-5 Ra, 5-6 membered heterocycle substituted with 0-3 R3, NR3R3a, and OR3.
  • [0093]
    [5] In another embodiment, the invention describes novel compounds of embodiment [1], wherein
  • [0094]
    X is O or S;
  • [0095]
    R1 is selected from the groups: H, —NHR4, C1-4 alkyl substituted with 0-3 Rc, 3-6 membered carbocycle substituted with 0-5 Ra, and 5-6 membered heterocycle and substituted with 0-5 Rb;
  • [0096]
    R2 is selected from the group: C3-6 membered carbocycle substituted with 0-5 Ra, 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb, and C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc;
  • [0097]
    R4 is independently selected from the groups: H, C1-4 alkyl, NR3R3a, C3-6 membered carbocycle substituted with 0-5 Ra, and 5-6 membered heterocycle substituted with 0-3 R3;
  • [0098]
    R3 is independently selected from the group: H, halo, COR5, CO2R5, R5R5aN(CR6R6a)m, R5O(CR6R6a)m, CONR5R5a, NR5C(O)OR5, NR5C(O)R5, C1-4 alkyl, phenyl, and benzyl;
  • [0099]
    R3a is independently selected from the group: H, C1-4 alkyl, phenyl, and benzyl; or
  • [0100]
    R3 and R3a, together with the atoms to which they are attached, form a 5-6 membered heterocycle containing an additional 0-1 N, S, or O atom and substituted with 0-3 R3c;
  • [0101]
    Rc is independently selected from the groups: C3-6 membered carbocycle substituted with 0-5 Ra, 5-6 membered heterocycle substituted with 0-3 R3, NR3R3a, and OR3;
  • [0102]
    Ra is independently selected from the groups: R5 R5aN(CR6R6)m, R5O(CR6R6a)m, OR3, halo, C1-4 alkyl, NR3C(O)R3, COR3, CO2R3, N3, NR3C(O)OR3, NR3R3a, CONR3R3a, 5-6 membered heterocycle; or when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—;
  • [0103]
    Rb is independently selected from the group: OR3, halo, COR3, C1-4 alkyl, CO2R3, NR3C(O)R3, NR3C(O)OR3, NR3R3a, CONR3R3a;
  • [0104]
    R3c is independently selected from the groups: OR3, halo, COR3, R5R5aN(CR6R6a)m−, R5O(CR6R6a)m−, CO2R3, N3, NR3R3a, C1-4 alkyl, NR3C(O)R3, NR3C(O)OR3, N3, NR3R3b, CONR3R3b, and 5-6 membered heterocycle; and
  • [0105]
    m is independently selected from the group consisting of 1 2, 3 and 4.
  • [0106]
    [6] In another embodiment, the invention describes novel compounds of embodiment [1], wherein
  • [0107]
    R1 is selected from the group: —NHR4 and C1-2 alkyl substituted with 1 Rc.
  • [0108]
    [7] In another embodiment, the invention describes novel compounds of embodiment [1], wherein X is O or S; and
  • [0109]
    R1 is selected from the group: H, C1-4 alkyl substituted with 0-3 Rc, C2-4 alkenyl substituted with 0-3 Rc, C2-4 alkynyl substituted with 0-3 Rc, —NHR4, C3-6 carbocycle substituted with 0-5 Ra, and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb.
  • [0110]
    [8] In another embodiment, the invention describes novel compounds of embodiment [1], wherein X is O or S; and
  • [0111]
    R1 is selected from the group: H, C1-4 alkyl substituted with 0-3 Rc, C2-4 alkenyl substituted with 0-3 Rc, C2-4 alkynyl substituted with 0-3 Rc, —NHR4, C3-6 carbocycle substituted with 0-5 Ra, and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;
  • [0112]
    Ra is independently at each occurrence selected from the group: —CH2N(CH3)2, —CH2NH2, —SH, —SCH3, —NR3C(O)R3, —N3, halo, C1-4 alkyl, NR3R3a, and OR3; alternatively, when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—;
  • [0113]
    Rb is independently at each occurrence selected from the group: halo, C1-4 alkyl, NR3R3a, OR3, COR3, and CO2R3;
  • [0114]
    Rc is independently at each occurrence selected from the group: halo, C1-4 alkyl, NR3R3a, C3-6 carbocycle substituted with 0-5 Ra, and 5-7 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;
  • [0115]
    R3a is H or C1-4 alkyl; and
  • [0116]
    R3 is selected from the group: H, —CH2CH2OH, —C(O)CH2NH2, —C(O)CH2N(CH3)2, —NR5R5a, —C1-4 alkyl, phenyl, and benzyl.
  • [0117]
    [9] In another embodiment, the invention describes novel compounds of embodiment [1], wherein X is O or S;
  • [0118]
    R1 is selected from the group: H, C1-4 alkyl substituted with 0-3 Rc, —NHR4, C3-6 carbocycle substituted with 0-5 Ra, and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;
  • [0119]
    Ra is independently at each occurrence selected from the group: —CH2N(CH3)2, —CH2NH2, —SH, —SCH3, halo, C1-4 alkyl, NR3R3a, and OR3; alternatively, when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—;
  • [0120]
    Rb is independently at each occurrence selected from the group: halo, C1-4 alkyl, NR3R3a, OR3, COR3, and CO2R3;
  • [0121]
    Rc is independently at each occurrence selected from the group: —OH, chloro, C1-4 alkyl, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3,—NHCH2CH2OH, —N(CH3)2, phenyl substituted with 0-5 Ra, and 5-7 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3.
  • [0122]
    [10] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R1 is selected from the group: H, C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc, C2-10 alkynyl substituted with 0-3 Rc;
  • [0123]
    R2 is selected from the group: H, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb; and
  • [0124]
    Rc is independently at each occurrence selected from the group: phenyl substituted with 0-5 Ra, and thiophenyl or pyridyl, which is substituted with 0-3 R3.
  • [0125]
    [11] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R1 is selected from the group: H, C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc, C2-10 alkynyl substituted with 0-3 Rc;
  • [0126]
    R2 is selected from the group: H, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb; and
  • [0127]
    Rc is independently at each occurrence selected from the group: thiophenyl, piperazinyl, piperidinyl, thiomorpholinyl, morpholinyl, pyrrolidinyl, and pyridyl, which is substituted with 0-3 substituents indepently selected from the group consiting of CH3, CH2CH2OH, CH2CH2NH2, —C(═O)NH2, —OCH3, CH2NH2, NHCH2CH3,OH, NH2, halo, —CH2N(CH3)2, —OCH2CH2O—, —OCH20—, —N(CH3)2, uridomethyl, and pyridyl.
  • [0128]
    [12] In another embodiment, the invention describes novel compounds of embodiment [1], wherein
  • [0129]
    R1 is selected from the group: H, C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc, C2-10 alkynyl substituted with 0-3 Rc;
  • [0130]
    R2 is selected from the group: H, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb; and
  • [0131]
    Rc is phenyl substituted with 0-5 substituents indepently selected from the group consiting of CH3, CH2CH2OH, CH2CH2NH2, —C(═O)NH2, —OCH3, CH2NH2, NHCH2CH3,OH, NH2, halo, —CH2N(CH3)2, —OCH2CH2O—, —OCH2O—, —N(CH3)2, uridomethyl, and pyridyl.
  • [0132]
    [13] In another embodiment, the invention describes novel compounds of embodiment [1], wherein X is O or S;
  • [0133]
    R1 is —NHR4 or methylene substituted with 0-3 Rc;
  • [0134]
    Rc is NR3 R3a;
  • [0135]
    R4 is selected from the group consisting of H, C1-4 alkyl, and NR3 R3a; and
  • [0136]
    R3 and R3a, are independently hydrogen or C1-4alkyl, or R3 and R3a, together with the nitrogen atom to which they are attached, form a 4-8 membered heterocycle containing an additional 0-1 N, S, or O atom and substituted with 0-3 R3c.
  • [0137]
    [14] In another embodiment, the invention describes novel compounds of embodiment [1], wherein X is O or S;
  • [0138]
    R1 is —NHR4 or methylene substituted with 0-3 Rc;
  • [0139]
    Rc is NR3R3a;
  • [0140]
    R4 is selected from the group consisting of H, C1-4 alkyl, and NR3R3a; and
  • [0141]
    R3 and R3a, are independently hydrogen or C1-4alkyl, or R3 and R3a, together with the nitrogen atom to which they are attached, form a 4-8 membered heterocycle containing an additional 0-1 N, S, or O atom and substituted with with 0-3 substituents independently selected from the group consisting of methyl, —CH2OCH3, —C(CH3)2OCH3, —CH2CH2OH, —CH2OH, —CH2OCH2Phenyl, —CH2CH2NH2, —CH2NH2, —C(═NH)CH3, and NH2.
  • [0142]
    [15] In another embodiment, the invention describes novel compounds of embodiment [1], wherein X is O or S; and
  • [0143]
    R1 is selected from the group: methylene substituted with a substituent selected from the group consisting of: halo, NR3R3a, C3-6 carbocycle substituted with 0-5 Ra, and 5-7 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3.
  • [0144]
    [16] In another embodiment, the invention describes novel compounds of embodiment [1], wherein X is O or S;
  • [0145]
    R1 is selected from the group: methylene substituted with NR3R3a; and
  • [0146]
    R3 and R3a, together with the nitrogen atom to which they are attached, form pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thiomorpholinyl, pymorpholinyl, piperidinyl, piperazinyl, or piperadinyl, which is substituted with 0-3 R3c.
  • [0147]
    [17] In another embodiment, the invention describes novel compounds of embodiment [1], wherein
  • [0148]
    R1 is —NHR4;
  • [0149]
    R4 is NR3R3a; and
  • [0150]
    R3 and R3a, together with the nitrogen atom to which they are attached, form pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thiomorpholinyl, pymorpholinyl, piperidinyl, piperazinyl, or piperadinyl, which is substituted with 0-3 R3c.
  • [0151]
    [18] In another embodiment, the invention describes novel compounds of embodiment [1], wherein
  • [0152]
    R1 is —NHR4;
  • [0153]
    R4 is NR3R3a; and
  • [0154]
    R3 and R3a, together with the nitrogen atom to which they are attached, form pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thiomorpholinyl, pymorpholinyl, piperidinyl, piperazinyl, or piperadinyl, which is substituted with 0-3 substituents independently selected from the group consisting of methyl, —CH2OCH3, —C(CH3)2OCH3, —CH2CH2OH, —CH2OH, —CH2OCH2Phenyl, —CH2CH2NH2, —CH2NH2, —C(═NH)CH3, and NH2.
  • [0155]
    [19] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R2 is selected from the group: 5- to 7- membered monocyclic saturated, or partially saturated, heterocyclic ring substituted with 0-5 Rb.
  • [0156]
    [20] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R2 is selected from the group: 5- to 7- membered monocyclic aromatice heterocyclic ring substituted with 0-5 Rb.
  • [0157]
    [21] In another embodiment, the invention describes 6novel compounds of embodiment [1], wherein R2 is selected from the group: C1-10 alkyl substituted with 0-3 Rc, C3-10 carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb.
  • [0158]
    [22] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R2 is selected from the group: C1-6 alkyl substituted with 0-3 Rc, C3-6 carbocycle substituted with 0-5 Ra, and 3-7 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb.
  • [0159]
    [23] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R2 is selected from the group: C1-6 alkyl substituted with C3-10 carbocycle substituted with 0-5 Ra, and C1-6 alkyl substituted with 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S.
  • [0160]
    [24] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R2 is selected from the group: phenyl substituted with 0-5 Ra, and cyclopropyl or cyclohexyl substituted with 0-2 Ra; and
  • [0161]
    Ra is independently at each occurrence selected from the group: —CH2N(CH3)2, —CH2NH2, —SR halo, —ON , N3, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, αO, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, NR3C(O)OR3, NR3C(O)R3, SO2NR3R3a, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S.
  • [0162]
    [25] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R2 is selected from the group: phenyl substituted with 0-5 Ra, and cyclopropyl or cyclohexyl substituted with 0-2 Ra; and
  • [0163]
    Ra is independently at each occurrence selected from the group: C1-4 alkyl, COR3, CO2R3, and CONR3R3a;
  • [0164]
    R3a is H or C1-4 alkyl.
  • [0165]
    [26] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R2 is selected from the group: phenyl substituted with 0-5 Ra, and cyclopropyl or cyclohexyl substituted with 0-2 Ra;
  • [0166]
    Ra is independently at each occurrence selected from the group: C1-4 alkyl, COR3, CO2R3, and CONR3R3a;
  • [0167]
    R3a is H or C1-4 alkyl;
  • [0168]
    R3 is C1-4alkyl, C1-4alkyl-NR5R5a; and
  • [0169]
    R5 and R5a, together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom.
  • [0170]
    [27] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R2 is selected from the group: phenyl substituted with 0-5 Ra, and cyclopropyl or cyclohexyl substituted with 0-2 Ra;
  • [0171]
    Ra is independently at each occurrence selected from the group: C1-4 alkyl, COR3, CO2R3, and CONR3R3a; and
  • [0172]
    R3a is H or C1-4 alkyl.
  • [0173]
    [28] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R2 is phenyl substituted with NR3R3a, wherein R3 and R3a together with the nitrogen atom to which they are attached, form a 4-8 membered heterocycle containing an additional 0-1 N, S, or O atom and substituted with 0-3 R3c.
  • [0174]
    [29] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R2 is phenyl substituted with NR3R3a; and
  • [0175]
    R3 and R3a, together with the nitrogen atom to which they are attached, form a pyrrolinyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, morpholinyl,thiomorpholinyl, homopiperazinyl or piperazinyl group, substituted with 0-3 R3c.
  • [0176]
    [30] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R2 is phenyl substituted with NR3R3a, wherein R3 and R3a, together with the nitrogen atom to which they are attached, form a piperidinyl, homopiperazinyl or piperazinyl group, substituted with 0-3 R3c.
  • [0177]
    [31] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R2 is phenyl substituted with NR3R3a; and
  • [0178]
    R3 and R3a, together with the nitrogen atom to which they are attached, form a piperidinyl, homopiperazinyl or piperazinyl group, substituted with 0-3 substituents independently selected from the group consisting of: —C(═NH)CH3, pyrrolinyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, morpholinyl,thiomorpholinyl, homopiperazinyl or piperazinyl group, pyridyl, C1-4 alkyl, —NR3R3b.
  • [0179]
    [32] In another embodiment, the invention describes novel compounds of embodiment [1], which is selected from Table 1.
  • [0180]
    [33] In another embodiment, the invention describes novel compounds of embodiment [1], which is selected from Table 2.
  • [0181]
    [34] In another embodiment, the invention describes novel compounds of embodiment [1], which is selected from Table 3.
  • [0182]
    [35] In another embodiment, the invention describes novel compounds of embodiment [1], which is selected from Table 4.
  • [0183]
    [36] In another embodiment, the invention describes novel compounds of embodiment [1], selected from:
  • [0184]
    3-(4-methoxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0185]
    3-phenyl-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0186]
    3-(4-methylthiophenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0187]
    3-(4-methanesulfonylphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0188]
    3-(4-(N,N-dimethylamino)phenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0189]
    3-(3-pyridyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0190]
    3-(4-methoxyphenyl)-5-(formamido)indeno[1,2-c]pyrazol-4-one;
  • [0191]
    3-(4-hydroxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0192]
    3-(4-piperidinophenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0193]
    3-(4-morpholinophenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0194]
    3-(4-ethoxyphenyl)-5-(acetamido) indeno[1,2-c]pyrazol-4-one;
  • [0195]
    3-(4-butylphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0196]
    3-(4-ethylphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0197]
    3-(4-n-propylphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0198]
    3-(4-methoxyphenyl)-5-((4-aminophenyl)acetamido)indeno[1,2-ac]pyrazol-4-one;
  • [0199]
    3-(4-pyridyl)-5-(formamido)indeno[1,2-c]pyrazol-4-one;
  • [0200]
    3-(4-pyridyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0201]
    3-(4-methoxyphenyl)-5-((4-aminophenyl)acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0202]
    3-(4-methoxyphenyl)-5-((4-azidophenyl)acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0203]
    3-(4-methoxyphenyl)-5-((4-(methoxycarbonylamino)phenyl) acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0204]
    3-(4-methoxyphenyl)-5-((4-(aminomethylcarbonylamino)phenyl) acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0205]
    3-(4-methoxyphenyl)-5-((4-((N,N-dimethylamino)methylcarbonyl amino)phenyl)acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0206]
    3-(4-methoxyphenyl)-5-((4-acetamidophenyl)acetamido) indeno[1,2-c]pyrazol-4-one;
  • [0207]
    3-(4-methoxyphenyl)-5-(pyrrolidinoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0208]
    3-(4-methoxyphenyl)-5-(morpholinoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0209]
    3-(4-methoxyphenyl)-5-(thiomnorpholinoacetainido)indeno[1,2-c]pyrazol-4-one;
  • [0210]
    3-(4-methoxyphenyl)-5-(ethylaminoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0211]
    3-(4-mnethoxyphenyl)-5-(piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0212]
    3-(4-mnethoxyphenyl)-5-(4-(aminomethyl)piperidinoacetamnido) indeno[1,2-c]pyrazol-4-one;
  • [0213]
    3-(4-methoxyphenyl)-5-(piperazinoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0214]
    3-(4-methoxyphenyl)-5-(4-methylpiperazinoacetamnido) indeno[1,2-c]pyrazol-4-one;
  • [0215]
    3-(4-methoxyphenyl)-5-(4-(2-hydroxyethyl)piperazinoacetamnido)indeno[1,2-c]pyrazol-4-one;
  • [0216]
    3-(4-methoxyphenyl)-5-(N,N-dimnethylaminoacetamnido) indeno [1,2-c]pyrazol-4-one;
  • [0217]
    3-(4-methoxyphenyl)-5-((2-hydroxyethyl) aminoacetamnido) indeno [1,2-c]pyrazol-4-one;
  • [0218]
    3-(4-methoxyphenyl)-5-(amninoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0219]
    3-(4-methoxyphenyl)-5-((2-chlorophenyl)acetamnido) indeno[1,2-c]pyrazol-4-one;
  • [0220]
    3-(4-methoxyphenyl)-5-((2,4-dichlorophenyl) acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0221]
    3-(4-methoxyphenyl)-5-((3, 4-dichlorophenyl) acetamido) indeno[1,2-c]pyrazol-4-one;
  • [0222]
    3-(4-methoxyphenyl)-5-((2-methoxyphenyl) acetamido) indeno[1,2-c]pyrazol-4-one;
  • [0223]
    3-(4-dimethoxyphenyl)-5-(3-thienylacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0224]
    3-(4-methoxyphenyl)-5-((3,4-methylenedioxyphenyl)acetamido) indeno[1,2-c]pyrazol-4-one;
  • [0225]
    3-(3,4-dimethoxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0226]
    3-(2-methoxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0227]
    3-(4-methoxyphenyl)-5-((2,5-dimethoxyphenyl)acetamido) indeno[1,2-c]pyrazol-4-one;
  • [0228]
    3-(4-methoxyphenyl)-5-((3,4-dimethoxyphenyl)acetamido) indeno[1,2-c]pyrazol-4-one;
  • [0229]
    3-(4-methoxyphenyl)-5-((4-methoxyphenyl)acetamido) indeno[1,2-c]pyrazol-4-one;
  • [0230]
    3-(4-methoxyphenyl)-5-((3-methoxyphenyl)acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0231]
    3-(4-methoxyphenyl)-5-((4-chlorophenyl)acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0232]
    3-(4-methoxyphenyl)-5-((butylcarbamoyl)amino)indeno[1,2]pyrazol-4-one;
  • [0233]
    3-(4-methoxyphenyl)-5-((4-aminobenzylcarbamoyl)amino)indeno [1,2-c]pyrazol-4-one;
  • [0234]
    3-(4-methoxyphenyl)-5-((4-pyridylcarbamoyl) amino)indeno[1,2-c]pyrazol-4-one;
  • [0235]
    3-(4-methoxyphenyl)-5-((phenylcarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
  • [0236]
    3-(4-methoxyphenyl)-5-(cyclobutanecarboxamido)indeno[1,2-c]pyrazol-4-one;
  • [0237]
    3-(4-methoxyphenyl)-5-(cyclopentanecarboxamido)indeno[1,2-c]pyrazol-4-one;
  • [0238]
    3-(4-methoxyphenyl)-5-(butanamido)indeno[1,2-c]pyrazol-4-one;
  • [0239]
    3-(4-methoxyphenyl)-5-(propanamido)indeno[1,2-c]pyrazol-4-one;
  • [0240]
    3-(4-methoxyphenyl)-5-(phenylacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0241]
    3-(4-methoxyphenyl)-5-(2-methylpropanamido)indeno[1,2-c]pyrazol-4-one;
  • [0242]
    3-(4-methoxyphenyl)-5-(cyclopropanecarboxamido)indeno[1,2-c]pyrazol-4-one;
  • [0243]
    3-(4-methoxyphenyl)-5-(chloroacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0244]
    3-(4-methoxyphenyl)-5-(4-(aminomethyl)piperidinoacetamido)-indeno[1,2-c]pyrazol-4-one;
  • [0245]
    3-(4-(N,N-dimethylamino)phenyl)-5-(morpholinoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0246]
    3-(4-(N,N-dimethylamino)phenyl)-5-(N,N-dimethylaminoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0247]
    3-(4-(trifluoromethyl)phenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0248]
    3-(4-(N,N-dimethylamino)phenyl)-5-(4-methyl-piperazinoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0249]
    3-(4-(N,N-dimethylamino)phenyl)-5-(4-(aminomethyl)-piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0250]
    3-(4-(N,N-dimethylamino)phenyl)-5-(4-hydroxy-piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0251]
    3-(4-morpholinophenyl)-5-(morpholinoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0252]
    3-(4-morpholinophenyl)-5-(4-methylpiperazinoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0253]
    3-(4-morpholinophenyl)-5-(4-hydroxy-piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0254]
    3-(4-morpholinophenyl)-5-(4-(aminomethyl)-piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0255]
    3-(4-piperazinophenyl)-5-(morpholinoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0256]
    3-(4-piperazinophenyl)-5-((N,N-dimethylamino)acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0257]
    3-(4-piperazinophenyl)-5-(4-methylpiperazinoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0258]
    3-(4-piperazinophenyl)-5(4-(aminomethyl)-piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0259]
    3-(4-piperazinophenyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0260]
    3-(4-piperazinophenyl)-5-(aminocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0261]
    3-(4-piperazinophenyl)-5-(morpholinocarbamoylamino)-indeno[1,2-c]pyrazol-4-one;
  • [0262]
    3-(4-(4-methylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0263]
    3-(4-(4-ethylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0264]
    3-(4-(4-isopropylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0265]
    3-(4-(4-t-butoxycarbonylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0266]
    3-(4-(N,N-dimethylamino)phenyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0267]
    3-(c-propyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0268]
    3-(2-thienyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0269]
    3-(3-methyl-2-thienyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0270]
    3-(ethyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0271]
    3-(n-propyl)-5-(carbamoylamino)aminoindeno[1,2-c]pyrazol-4-one;
  • [0272]
    3-(i-propyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0273]
    3-(c-propyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0274]
    3-(c-hexyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0275]
    3-(2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0276]
    3-(3-methyl-2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0277]
    3-(5-methyl-2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0278]
    3-(5-carboethoxy-2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0279]
    3-(3-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0280]
    3-(1-methyl-3-pyrrolyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0281]
    3-(2,5-dimethyl-3-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0282]
    3-(2-furanyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0283]
    3-(i-propyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
  • [0284]
    3-(c-propyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
  • [0285]
    3-(c-hexyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
  • [0286]
    3-(2-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
  • [0287]
    3-(5-methoxy-2-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
  • [0288]
    3-(5-methyl-2-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
  • [0289]
    3-(5-carboethoxy-2-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
  • [0290]
    3-(3-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
  • [0291]
    3-(5-chloro-3-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
  • [0292]
    3-(2,5-dimethyl-3-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
  • [0293]
    3-(2-furanyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;
  • [0294]
    3-(i-propyl)-5-((4-carbamoylpiperidino)acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0295]
    3-(c-hexyl)-5-((4-carbamoylpiperidino)acetamido)indeno[1,2-c]pyrazol-4-one;
  • [0296]
    3-(ethyl)-5-(4-(aminomethyl)piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0297]
    3-(i-propyl)-5-(4-(aminomethyl)piperidinoacetamido) indeno[1,2-c]pyrazol-4-one;
  • [0298]
    3-(c-propyl)-5-(4-(aminomethyl)piperidinoacetamido) indeno[1,2-c]pyrazol-4-one;
  • [0299]
    3-(c-hexyl)-5-(4-(aminomethyl)piperidinoacetamido) indeno[1,2-c]pyrazol-4-one;
  • [0300]
    3-(i-propyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0301]
    3-(5-carboethoxy-2-thienyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0302]
    3-(5-carboxyl-2-thienyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0303]
    3-(2,5-dimethyl-3-thienyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0304]
    3-(i-propyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0305]
    3-(1-methoxycarbonyl-4-piperidinyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0306]
    3-(5-methyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0307]
    3-(5-chloro-3-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0308]
    3-(2,5-dimethyl-3-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0309]
    3-(5-carboethoxy-2-thienyl)-5-(morpholinylcarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0310]
    3-(5-carboxyl-2-thienyl)-5-(morpholinylcarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0311]
    3-(5-(benzylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0312]
    3-(5-((4-methylpiperazino)carbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0313]
    3-(5-((2-(1-methyl-2-pyrrolidinyl)ethyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0314]
    3-(5-((N,N-dimethylamino)aminocarbonyl)-2-thienyl-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0315]
    3-(5-((2-(N,N-dimethylamino)ethyl)aminocarbonyl)-2-thienyl-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0316]
    3-(5-(2-pyrrolidinoethyl)aminocarbonyl)-2-thienyl-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0317]
    3-(5-(2-morpholinoethyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0318]
    3-(5-(morpholinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0319]
    3-(5-((3-(2-pyrrolidon-1-yl)propyl)aminocarbonyl)-2-thienyl-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0320]
    3-(5-((2-(3-pyridyl)ethyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0321]
    3-(5-((3-(1-imidazolyl)propyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0322]
    3-(5-((2-(2-pyridyl)ethyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0323]
    3-(5-((2-pyridyl)methyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0324]
    3-(5-((2-piperidinoethyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0325]
    3-(4-piperazinophenyl)-5-((N,N-dimethylamino)carbamoylamino)-indeno[1,2-c]pyrazol-4-one;
  • [0326]
    3-(4-(4-methylpiperazino)phenyl)-5-((N,N-dimethylamino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0327]
    3-(4-piperazinophenyl)-5-((4-methylpiperazino)carbamoylamino)-indeno[1,2-c]pyrazol-4-one;
  • [0328]
    3-(4-(4-methylpiperazino)phenyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0329]
    3-(4-(4-ethylpiperazino)phenyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0330]
    3-(4-(4-isopropylpiperazino)phenyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0331]
    3-(4-piperazinophenyl)-5-((2,6-dimethylpiperidino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0332]
    3-(4-piperazinophenyl)-5-((4-(2-hydroxyethyl)piperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0333]
    3-(4-piperazinophenyl)-5-((2(R)-(methoxymethyl)pyrrolidino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0334]
    3-(4-piperazinophenyl)-5-((2(S)-(methoxymethyl)pyrrolidino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0335]
    3-(4-piperazinophenyl)-5-((2(R)-(1-methoxy-1-methylethyl)-pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0336]
    3-(4-piperazinophenyl)-5-((2(S)-(1-methoxy-1-methylethyl)-pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0337]
    3-(4-piperazinophenyl)-5-((2(R)-(hydroxymethyl)-pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0338]
    3-(4-piperazinophenyl)-5-((2(S)-(hydroxymethyl)-pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0339]
    3-(4-piperazinophenyl)-5-((2(R)-(benzyloxymethyl)-pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0340]
    3-(4-piperazinophenyl)-5-((2(S)-(benzyloxymethyl)-pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0341]
    3-(4-(3-methylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0342]
    3-(4-(cis-3,5-dimethylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0343]
    3-(4-(cis-3,4,5-trimethylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0344]
    3-(4-(4-isopropylpiperazino)-2-methylphenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0345]
    3-(4-homopiperazinophenyl)-5-(morpholinocarbamoylamino)-indeno[1,2-c]pyrazol-4-one;
  • [0346]
    3-(4-(4-methylhomopiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0347]
    3-(4-(4-ethylhomopiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0348]
    3-(4-(4-isopropylhomopiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0349]
    3-(4-homopiperazino-2-methylphenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0350]
    3-(4-(4-ethylhomopiperazino)-2-methylphenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0351]
    3-(4-(4-isopropylhomopiperazino)-2-methylphenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0352]
    3-(4-(4-(N,N-dimethylamino)piperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0353]
    3-(4-(4-(N,N-diethylamino)piperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0354]
    3-(4-(4-piperidinopiperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0355]
    3-(4-(4-pyrrolidinopiperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0356]
    3-(4-(4-(N,N-diethylamino)piperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0357]
    3-(4-methoxyphenyl)-5-((4-methylpiperazino)-thionocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0358]
    3-(1-methyl-3-pyrrolyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0359]
    3-(5-pyrrolidinoaminocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0360]
    3-(5-piperidinoaminocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0361]
    3-(5-piperidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0362]
    3-(5-piperazinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0363]
    3-(5-(4-methylpiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0364]
    3-(5-(4-ethylpiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0365]
    3-(5-(4-(2-hydroxyethyl)piperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0366]
    3-(5-(4-(cyclopropylmethyl)piperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0367]
    3-(5-(4-(t-butoxycarbonyl)piperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0368]
    3-(5-(4-(2-pyridyl)piperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0369]
    3-(5-(((1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptyl)carbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0370]
    3-(5-(((1S,4S)-(+)-2-methyl-2,5-diazabicyclo[2.2.1]heptyl)carbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0371]
    3-(5-(4-(N,N-dimethylamino)piperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0372]
    3-(5-(4-pyrrolidinopiperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0373]
    3-(5-(4-piperidinopiperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0374]
    3-(5-cyclohexylaminocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0375]
    3-(5-(4-piperidylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0376]
    3-(5-((1-(t-butoxycarboxyl)piperidin-4-yl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0377]
    3-(5-(4-(1-methylpiperidin-4-yl)methylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0378]
    3-(5-(3-(N,N-dimethylamino)piperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0379]
    3-(5-(3-p-toluenesulfonylamino)piperidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0380]
    3-(5-(3-hydroxypiperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0381]
    3-(5-((3-piperidyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0382]
    3-(5-((3-quinuclidyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0383]
    3-(5-((3-aminocyclohexyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0384]
    3-(5-((3-(t-butoxycarbonylamino)cyclohexyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0385]
    3-(5-(2-(N,N-dimethylaminomethyl)piperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0386]
    3-(5-(2-(N,N-diethylaminomethyl)piperidinocarbonyl)-2--thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0387]
    3-(5-pyrrolidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0388]
    3-(5-(3-aminopyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0389]
    3-(5-(3(S)-N-methylamino)pyrrolidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0390]
    3-(5-(3(S)-acetamidopyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0391]
    3-(5-(3(S)-(N-methylacetamido)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0392]
    3-(5-(3(S)-(N-methyl-t-butoxycarbonylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0393]
    3-(5-(3-(N,N-dimethylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0394]
    3-(5-(3(R)-(N,N-dimethylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0395]
    3-(5-(3(S)-(N,N-dimethylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0396]
    3-(5-((1-methylpyrrolidin-3-yl)methylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0397]
    3-(5-(2(R)-(pyrrolidinomethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0398]
    3-(5-(2(S)-(hydroxymethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0399]
    3-(5-(2(R)-(methoxymethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0400]
    3-(5-(2(S)-(phenylaminomethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0401]
    3-(5-(2(R)-(methoxymethyl)pyrrolidinoaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0402]
    3-(5-homopiperidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0403]
    3-(5-homopiperazinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0404]
    3-(5-(4-methylhomopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0405]
    3-(5-(4-ethylhomopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0406]
    3-(5-(4-(cyclopropylmethyl)homopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0407]
    3-(5-(4-(t-butoxycarbonyl)homopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0408]
    3-(5-(4-acetylhomopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0409]
    3-(5-((4-methylaminophenyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0410]
    3-(5-((4-acetamidophenyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0411]
    3-(5-(4-(diethylamino)phenylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0412]
    3-(5-((1-methyl-3-cyclopropylpyrazo-5-yl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0413]
    3-(1-methyl-3-pyrrolyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0414]
    3-(5-carboethoxy-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0415]
    3-(5-carboxyl-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0416]
    3-(5-(4-methylpiperazinocarbonyl)-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0417]
    3-(5-piperazinocarbonyl-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0418]
    3-(5-(4-(t-butoxycarbonyl)piperazinocarbonyl)-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0419]
    3-(5-(4-methylhomopiperazinocarbonyl)-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0420]
    3-(5-homopiperazinocarbonyl-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0421]
    3-(5-(4-(t-butoxycarbonyl)homopiperazinocarbonyl)-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0422]
    3-(c-propyl)-5-(4-carbamoylpiperidinoacetamido)indeno[1,2-c]pyrazol-4-one;
  • [0423]
    3-ethyl-5-(4-methylpiperazinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0424]
    3-(c-propyl)-5-(4-methylpiperazinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0425]
    3-(c-hexyl)-5-(4-methylpiperazinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0426]
    3-ethyl-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0427]
    3-(c-propyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0428]
    3-(c-hexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0429]
    3-(1-ethoxycarbonylpiperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0430]
    3-(1-phenoxycarbonylpiperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0431]
    3-(1-(imidazol-1-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0432]
    3-(1-(2-thienylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0433]
    3-(1-carbamoylpiperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0434]
    3-(1-(ethylcarbamoyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0435]
    3-(1-(2-(1-methylpyrrolidin-2-yl)ethylaminocarbamoyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0436]
    3-(1-(4-(dimethylamino)piperidinocarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0437]
    3-(1-(piperazinocarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0438]
    3-(1-(4-(t-butoxycarbonyl)piperazinocarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0439]
    3-(1-(((lS,4S)-(+)-2,5-diazabicyclo[2.2.1]hept-2-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0440]
    3-(1-(((IS,4S)-(+)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0441]
    3-(1-(3-aminopropylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0442]
    3-(1-(3-(dimethylamino)propylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0443]
    3-(1-(3-(t-butoxycarbonylamino)propylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0444]
    3-(1-(4-aminobutylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0445]
    3-(1-(4-(dimethylamino)butylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0446]
    3-(1-(4-(t-butoxycarbonylamino)butylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0447]
    3-(1-((1-methylpiperidin-4-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0448]
    3-(1-((1-(t-butoxycarbonyl)piperidin-4-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0449]
    3-(1-(cis-4-aminocyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0450]
    3-(1-(4-aminocyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0451]
    3-(1-(cis-4-(dimethylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0452]
    3-(1-(4-(t-butoxycarbonylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0453]
    3-(1-(trans-4-(t-butoxycarbonylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0454]
    3-(1-(piperidin-3-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0455]
    3-(1-(1-methylpiperidin-3-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0456]
    3-(1-(1-(t-butoxycarbonyl)piperidin-3-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0457]
    3-(1-(3-aminocyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0458]
    3-(1-(3-(dimethylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0459]
    3-(1-(trans-4-methoxycyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0460]
    3-(1-(cis-4-methoxycyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0461]
    3-(1-(4-aminobenzylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0462]
    3-(1-(4-(dimethylamino)benzylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0463]
    3-(1-(4-(t-butoxycarbonylamino)benzylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0464]
    3-(1-(4-aminophenylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0465]
    3-(1-(4-(dimethylamino)phenylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0466]
    3-(1-(4-(t-butoxycarbonylamino)phenylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0467]
    3-(trans-4-carboxylcyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0468]
    3-(trans-4-(methoxycarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0469]
    3-(trans-4-(3-(dimethylamino)pyrrolidinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0470]
    3-(trans-4-(piperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0471]
    3-(trans-4-(4-methylpiperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0472]
    3-(trans-4-(homopiperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0473]
    3-(trans-4-(4-methylhomopiperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one; or pharmaceutically acceptable salt form thereof.
  • [0474]
    [37] In another embodiment, the invention describes novel compounds of embodiment [1], selected from:
  • [0475]
    3-(4-piperazinophenyl)-5-(morpholinocarbamoylamino)-indeno[1,2-c]pyrazol-4-one;
  • [0476]
    3-(4-(4-methylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0477]
    3-(4-(4-ethylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0478]
    3-(4-(4-isopropylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0479]
    3-(4-piperazinophenyl)-5-((N,N-dimethylamino)carbamoylamino)-indeno[1,2-c]pyrazol-4-one;
  • [0480]
    3-(4-(4-methylpiperazino)phenyl)-5-((N,N-dimethylamino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0481]
    3-(4-piperazinophenyl)-5-((4-methylpiperazino)carbamoylamino)-indeno[1,2-c]pyrazol-4-one;
  • [0482]
    3-(4-(4-methylpiperazino)phenyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0483]
    3-(4-(4-ethylpiperazino)phenyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0484]
    3-(4-(4-isopropylpiperazino)phenyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0485]
    3-(4-piperazinophenyl)-5-((2(R)-(methoxymethyl)pyrrolidino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0486]
    3-(4-piperazinophenyl)-5-((2(R)-(1-methoxy-1-methylethyl)-pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0487]
    3-(4-homopiperazinophenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0488]
    3-(4-(4-methylhomopiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0489]
    3-(4-(4-ethylhomopiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0490]
    3-(4-(4-isopropylhomopiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0491]
    3-(4-(4-(N,N-dimethylamino)piperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0492]
    3-(4-(4-(N,N-diethylamino)piperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0493]
    3-(4-(4-piperidinopiperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0494]
    3-(4-(4-pyrrolidinopiperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0495]
    3-(2,4-dimethylthiazol-5-yl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0496]
    3-(2,4-dimethylthiazol-5-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0497]
    3-(2,4-dimethylthiazol-5-yl)-5-((1-methyl-1-phenylamino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;
  • [0498]
    3-(2,4-dimethylthiazol-5-yl)-5-((2,6-dimethylpiperidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one; and
  • [0499]
    3-(2,4-dimethylthiazol-5-yl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one; or pharmaceutically acceptable salt form thereof.
  • [0500]
    [38] In another embodiment, the invention describes a pharmaceutical composition, comprising a pharmaceutically acceptable carrier, a compound according to embodiment [1] or a pharmaceutically acceptable salt or prodrug form thereof, and a cytostatic or cytotoxic agent.
  • [0501]
    [39] In another embodiment, the invention describes a method of treating a cell proliferative disease associated with CDK activity in a patient in need thereof,comprising administrering to said patient a pharmaceutically effective amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof, wherein the proliferative diseases is selected from the group consisting of: Alzheimer's disease, viral infections, auto-immune diseases, fungal disease, cancer, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis, neurodegenerative disorders and post-surgical stenosis and restenosis.
  • [0502]
    [40] In another embodiment, the invention describes a method of treating cancer associated with CDK activity in a patient in need thereof,comprising administrering to said patient a pharmaceutically effective amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof, wherein the cancer is selected from the group consisting of: carcinoma such as bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
  • [0503]
    [41] In another embodiment, the invention describes a method of treating a disease associated with apoptosis in a patient in need thereof, comprising administrering to said patient a pharmaceutically effective amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof, wherein the disease associated with apoptosis is selected from the group consisting of: cancer, viral infections, autoimmune diseases and neurodegenerative disorder.
  • [0504]
    [42] In another embodiment, the invention describes a method of inhibiting tumor angiogenesis and metastasis in a patient in need thereof, comprising administrering to said patient a pharmaceutically effective amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.
  • [0505]
    [43] In another embodiment, the invention describes a method of modulating the level of cellular RNA and DNA synthesis in a patient in need thereof, comprising administering to said patient a CDK inhibitory effective amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.
  • [0506]
    [44] In another embodiment, the invention describes a method of treating viral infections in a patient in need thereof, comprising administering to said patient a CDK inhibitory effective amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof, wherein the viral infections is selected from the group consiting of HIV, human papilloma virus, herpesvirus, poxyirus, Epstein-Barr virus, Sindbis virus and adenovirus.
  • [0507]
    [45] In another embodiment, the invention describes a method of chemopreventing cancer in a patient, comprising administering to said patient in need thereof, a CDK inhibitory effective amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.
  • [0508]
    [46] In another embodiment, the invention describes a method of inhibiting CDK activity comprising combining an effective amount of a compound according to embodiment [1], with a composition containing CDK.
  • [0509]
    [47] In another embodiment, the invention describes a method of treating cancer associated with CDK activity in a patient in need thereof,comprising administrering to said patient a pharmaceutically effective amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof, in combination (administered together or sequentially) with known anti-cancer treatments such as radiation therapy or with cytostatic or cytotoxic agents, wherein such agents are selected from the group consisting of: DNA interactive agents, such as cisplatin or doxorubicin; topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents, such as paclitaxel, docetaxel or the epothilones; hormonal agents, such as tamoxifen; thymidilate synthase inhibitors, such as 5-fluorouracil; and anti-metabolites, such as methoxtrexate.
  • [0510]
    [48] In another embodiment, the invention describes a method treating cell proliferative diseases associated with CDK activity in a patient in need thereof, comprising administrering to said patient a pharmaceutically effective amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof, in combination (administered together or sequentially) with known anti-proliferating agents selected from the group consisting of:, altretamine, busulfan, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, thiotepa, cladribine, fluorouracil, floxuridine, gemcitabine, thioguanine, pentostatin, methotrexate, 6-mercaptopurine, cytarabine, carmustine, lomustine, streptozotocin, carboplatin, cisplatin, oxaliplatin, iproplatin, tetraplatin, lobaplatin, JM216, JM335, fludarabine, aminoglutethimide, flutamide, goserelin, leuprolide, megestrol acetate, cyproterone acetate, tamoxifen, anastrozole, bicalutamide, dexamethasone, diethylstilbestrol, prednisone, bleomycin, dactinomycin, daunorubicin, doxirubicin, idarubicin, mitoxantrone, losoxantrone, mitomycin-c, plicamycin, paclitaxel, docetaxel, CPT-11, epothilones , topotecan, irinotecan, 9-amino camptothecan, 9-nitro camptothecan, GS-211, etoposide, teniposide, vinblastine, vincristine, vinorelbine, procarbazine, asparaginase, pegaspargase, methoxtrexate, octreotide, estramustine, and hydroxyurea.
  • [0511]
    [49] In another embodiment, the invention describes a method of inhibiting CDK1 activity, comprising adminsitering to a patient in need thereof an efective CDKl inhibitory amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.
  • [0512]
    [50] In another embodiment, the invention describes a method of inhibiting CDK2 activity, comprising adminsitering to a patient in need thereof an efective CDK2 inhibitory amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.
  • [0513]
    [51] In another embodiment, the invention describes a method of inhibiting CDK3 activity, comprising adminsitering to a patient in need thereof an efective CDK3 inhibitory amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.
  • [0514]
    [52] In another embodiment, the invention describes a method of inhibiting CDK4 activity, comprising adminsitering to a patient in need thereof an efective CDK4 inhibitory amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.
  • [0515]
    [53] In another embodiment, the invention describes a method of inhibiting CDK5 activity, comprising adminsitering to a patient in need thereof an efective CDK5 inhibitory amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.
  • [0516]
    [54] In another embodiment, the invention describes a method of inhibiting CDK6 activity, comprising adminsitering to a patient in need thereof an efective CDK6 inhibitory amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.
  • [0517]
    [55] In another embodiment, the invention describes a method of inhibiting CDK7 activity, comprising adminsitering to a patient in need thereof an efective CDK7 inhibitory amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.
  • [0518]
    [56] In another embodiment, the invention describes a method of inhibiting CDK8 activity, comprising adminsitering to a patient in need thereof, an efective CDK8 inhibitory amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.
  • [0519]
    [57] In another embodiment, the invention describes a method of inhibiting CDK9 activity, comprising adminsitering to a patient in need thereof an efective CDK9 inhibitory amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.
  • [0520]
    [58] In another embodiment, the invention describes a pharmaceutical kit for treating a cell proliferative disease associated with CDK activity, said kit comprising a plurality of separate containers, wherein at least one of said containers contains a compound accordig to embodiment [1],, or a pharmaceutically acceptable salt or prodrug form thereof, and at least another of said containers contains one or more compounds selected from the group consisting of cytostatic or cytotoxic agents, such as for example, but not limited to, DNA interactive agents, such as carboplatin, cisplatin or doxorubicin; topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents, such as paclitaxel, taxane, docetaxel or the epothilones; hormonal agents, such as tamoxifen; thymidilate synthase inhibitors, such as 5-fluorouracil; and anti-metabolites, such as methoxtrexate, and said containers optionally contain a pharmaceutical carrier, which kit may be effectively utilized for carrying out combination therapies according to the invention.
  • [0521]
    It is a further object of the invention to provide a method of treating a patient having a disorder associated with excessive cell proliferation, comprising administering to the patient a therapeutically effective amount of a compound of embodiment [1], such that the excessive cell proliferation in the patient is reduced.
  • [0522]
    It is appreciated that certain feactures of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. For example, R1 of embodiment [6] may be combined with R2 of embodiment [19] to form a single embodiment. Conversely, various feactures of the invention which are, for brevity, described in the context of a single embodiment, may also be provided seperately or in any suitable subcombination.
  • DETAILED DESCRIPTION OF THE INVENTION
  • [0523]
    As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
  • Definitions
  • [0524]
    As used herein, the following terms and expressions have the indicated meanings.
  • [0525]
    The term “compounds of the invention”, and equivalent expressions, are meant to embrace compounds of the invention as herein before described i.e. compounds of formula (I), which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.
  • [0526]
    The term “derivative” means a chemically modified compound wherein the modification is considered routine by the ordinary skilled chemist, such as an ester or an amide of an acid, protecting groups, such as a benzyl group for an alcohol or thiol, and tert-butoxycarbonyl group for an amine.
  • [0527]
    The term “effective amount” means an amount of a compound/composition according to the present invention effective in producing the desired therapeutic effect.
  • [0528]
    The term “amine protecting group” means an easily removable group which is known in the art to protect an amino group against undesirable reaction during synthetic procedures and to be selectively removable. The use of amine protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991), incorporated herein by reference. Preferred amine protecting groups are acyl, including formyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl, acylisothiocyanate, aminocaproyl, benzoyl and the like, and acyloxy including methoxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethxoycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl (BOC), 1,1-dimethylpropynyloxycarbonyl, benzyloxycarbonyl (CBZ), p-nitrobenzyloxycarbony, 2,4-dichlorobenzyloxycarbonyl, and the like.
  • [0529]
    The term “acid labile amine protecting group” means an amine protecting group as defined above which is readily removed by treatment with acid while remaining relatively stable to other reagents. A preferred acid labile amine protecting group is tert-butoxycarbonyl (BOC).
  • [0530]
    The term “hydrogenation labile amine protecting group” means an amine protecting group as defined above which is readily removed by hydrogenation while remaining relatively stable to other reagents. A preferred hydrogenation labile amine protecting group is benzyloxycarbonyl (CBZ).
  • [0531]
    The term “hydrogenation labile acid protecting group” means an acid protecting group as defined above which is readily removed by hydrogenation while remaining relatively stable to other reagents. A preferred hydrogenation labile acid protecting group is benzyl.
  • [0532]
    The term “analogue” means a compound which comprises a chemically modified form of a specific compound or class thereof, and which maintains the pharmaceutical and/or pharmacological activities characteristic of said compound or class.
  • [0533]
    The term “patient” includes both human and other mammals.
  • [0534]
    The term “pharmaceutical composition” means a composition comprising a compound of formula (I) and at least one component selected from the group comprising pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. Examples of suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monosterate and gelatin. Examples of suitable carriers, diluents, solvents or vehicles include water, ethanol, polyols, suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Examples of excipients include lactose, milk sugar, sodium citrate, calcium carbonate, dicalcium phosphate phosphate. Examples of disintegrating agents include starch, alginic acids and certain complex silicates. Examples of lubricants include magnesium stearate, sodium lauryl sulphate, talc, as well as high molecular weight polyethylene glycols.
  • [0535]
    The term “solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, and the like.
  • [0536]
    The term “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. In addition, the term is intended to include both unsubstituted and substituted alkyl groups, the latter referring to alkyl moieties having one or more hydrogen substituents replaced by, but not limited to halogen, hydroxyl, carbonyl, alkoxy, ester, ether, cyano, phosphoryl, amino, imino, amido, sulfhydryl, alkythio, thioester, sulfonyl, nitro, heterocyclo, aryl or heteroaryl. It will also be understood by those skilled in the art that the substituted moieties themselves can be substituted as well when appropriate.
  • [0537]
    The terms “halo” or “halogen” as used herein refer to fluoro, chloro, bromo and iodo. The term “aryl” is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as, but not limited to phenyl, indanyl or naphthyl. The terms “cycloalkyl” and “bicycloalkyl” are intended to mean any stable ring system, which may be saturated or partially unsaturated. Examples of such include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]nonane, adamantly, or tetrahydronaphthyl (tetralin).
  • [0538]
    As used herein, “carbocycle” or “carbocyclic residue” is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,; [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
  • [0539]
    As used herein, the term “heterocycle” or “heterocyclic system” is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term “aromatic heterocyclic system” is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • [0540]
    Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
  • [0541]
    As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • [0542]
    The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, p. 1445, the disclosure of which is hereby incorporated by reference.
  • [0543]
    The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
  • [0544]
    The term “Pharmaceutically acceptable prodrugs” as used herein means those prodrugs of the compounds useful according to the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • [0545]
    The term “Prodrugs”, as the term is used herein, are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (i.e., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same, and compositions containing the same. Prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfydryl group, respectively. Functional groups which may be rapidly transformed, by metabolic cleavage, in vivo form a class of groups reactive with the carboxyl group of the compounds of this invention. They include, but are not limited to such groups as alkanoyl (such as acetyl, propionyl, butyryl, and the like), unsubstituted and substituted aroyl (such as benzoyl and substituted benzoyl), alkoxycarbonyl (such as ethoxycarbonyl), trialkylsilyl (such as trimethyl- and triethysilyl), monoesters formed with dicarboxylic acids (such as succinyl), and the like. Because of the ease with which the metabolically cleavable groups of the compounds useful according to this invention are cleaved in vivo, the compounds bearing such groups act as pro-drugs. The compounds bearing the metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group. A thorough discussion of prodrugs is provided in the following: Design of Prodrugs, H. Bundgaard, ed., Elsevier, 1985; Methods in Enzymology, K. Widder et al, Ed., Academic Press, 42, p.309-396, 1985; A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; “Design and Applications of Prodrugs” p.113-191, 1991; Advanced Drug Delivery Reviews, H. Bundgard, 8, p.1-38, 1992; Journal of Pharmaceutical Sciences, 77, p. 285, 1988; Chem. Pharm. Bull., N. Nakeya et al, 32, p. 692, 1984; Pro-drugs as Novel Delivery Systems, T. Higuchi and V. Stella, Vol. 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference.
  • [0546]
    “Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced.
  • [0547]
    The term “Treating” refers to:
  • [0548]
    (i) preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it;
  • [0549]
    (ii) inhibiting the disease, disorder or condition, i.e., arresting its development; and
  • [0550]
    (iii) relieving the disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
  • Preparation of Comounds of the Invention
  • [0551]
    It will be apparent to those skilled in the art that certain compounds of formula (I) can exhibit isomerism, for example geometrical isomerism, e.g., E or Z isomerism, and optical isomerism, e.g., R or S configurations. Geometrical isomers include the cis and trans forms of compounds of the invention having alkenyl moieties. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
  • [0552]
    Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are separately prepared from the appropriate isomers of their intermediates, for example by the application or adaptation of methods described herein.
  • [0553]
    The compounds of the present invention are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof. All forms are within the scope of the invention.
  • [0554]
    Where the compound of the present invention is substituted with a basic moiety, acid addition salts are formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on CDK inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures.
  • [0555]
    According to a further feature of the invention, acid addition salts of the compounds of this invention are prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
  • [0556]
    The acid addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
  • [0557]
    Where the compound of the invention is substituted with an acidic moiety, base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on CDK inherent in the free acid are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including for example alkali and alkaline earth-metal salts, within the scope of the invention are those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.
  • [0558]
    Metal salts of compounds of the present invention may be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the chosen metal in an aqueous or organic solvent with the free acid form of the compound. The aqueous solvent employed may be water or it may be a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate. Such reactions are normally conducted at ambient temperature but they may, if desired, be conducted with heating.
  • [0559]
    Amine salts of compounds of the present invention may be obtained by contacting an amine in an aqueous or organic solvent with the free acid form of the compound. Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitrites such as acetonitrile, or ketones such as acetone. Amino acid salts may be similarly prepared.
  • [0560]
    The base addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
  • [0561]
    Pharmaceutically acceptable salts also include quaternary lower alkyl ammonium salts. The quaternary salts are prepared by the exhaustive alkylation of basic nitrogen atoms in compounds, including nonaromatic and aromatic basic nitrogen atoms, according to the invention, i.e., alkylating the non-bonded pair of electrons of the nitrogen moieties with an alkylating agent such as methylhalide, particularly methyl iodide, or dimethyl sulfate. Quaternarization results in the nitrogen moiety becoming positively charged and having a negative counter ion associated therewith.
  • [0562]
    As will be self-evident to those skilled in the art, some of the compounds of this invention do not form stable salts. However, acid addition salts are more likely to be formed by compounds of this invention having a nitrogen-containing heteroaryl group and/or wherein the compounds contain an amino group as a substituent. Preferable acid addition salts of the compounds of the invention are those wherein there is not an acid labile group.
  • [0563]
    As well as being useful in themselves as active compounds, salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
  • [0564]
    Compounds according to the invention, for example, starting materials, intermediates or products, are prepared as described herein or by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature.
  • [0565]
    Compounds useful according to the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example those described by R. C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.
  • [0566]
    In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Green and P. G. M. Wuts in “Protective Groups in Organic Chemistry” John Wiley and Sons, 1991; J. F. W. McOmie in “Protective Groups in Organic Chemistry” Plenum Press, 1973.
  • [0567]
    Preferred methods of synthesizing the compounds of the invention include, but are not limited to, those methods described below. Each of the references cited below are hereby incorporated herein by reference.
  • [0568]
    An approach to preparing indeno[1,2-c]pyrazol-4-ones is presented in Scheme 1 and can be used to prepare compounds of the present invention. The nitro group of dimethyl 3-nitrophthalate was reduced to the amine using catalytic hydrogenation. The aniline was acylated using acetic anhydride and pyridine as a base. A mixture of the resulting acetamide 2 and an acetophenone were treated with a strong base in an appropriate solvent at elevated temperature to give the desired triketone 3. Additional means of preparing triketones are known to one skilled in the art as described in Kilgore et al, Industrial and Engineering Chemistry 34:494-497, 1946, the contents of which are hereby incorporated herein by reference. The triketone was treated with hydrazine at elevated temperature in an appropriate solvent to give the indeno[1,2-c]pyrazol-4-one ring system. Additional means of preparing indeno[1,2-c]pyrazol-4-ones are known to one skilled in the art as described in Lemke et al., J. Heterocyclic Chem. 19:1335-1340, 1982; Mosher and Soeder, J. Heterocyclic Chem. 8:855-59, 1971;Hrnciar and Svanygova Collect. Czech. Chem. Commun. 59:2734-40, 1994 the contents of which are hereby incorporated herein by reference. The amide was deacetylated by heating with a strong acid in an appropriate solvent to give aniline 4. This aniline was acylated under standard conditions using an acid chloride in an appropriate solvent to give the desired product 5.
  • [0569]
    An alternative method for making compounds of the present invention is shown in Scheme 2. The intermediate triketone 3 can be deacetylated with strong acid and reacylated with an appropriate acid chloride using methods known to those skilled in the art. Subsequently, triketone 6 can be converted to the indeno[1,2-c]pyrazol-4-ones using the same conditions described previously in Scheme 1.
  • [0570]
    Another method for preparing the triketones 6 of Scheme 2 employs the condensation of a 1,3-diketone 6a with 3-nitrophthalic anhydride as described in Rotberg and Qshkaya, Zh. Organ. Khim. 8:84-87, 1972; Zh. Organ. Khim. 9:2548-2550, 1973, the contents of which are hereby incorporated herein by reference. The 1,3-diketones, when not commercially available can be readily prepared by one skilled in the art by the acetylation or trifluoroacetylation of the requisite methyl ketone, R1COCH3. Reduction of the nitro derivative 6b to the aniline 6c can be accomplished in a variety of ways including catalyic hydrogenation, treatment with zinc or iron under acidic conditions, or treatment with other reducing agents such as sodium dithionite or stannous chloride. Subsequently the aniline 6c can be converted to the indeno[1,2-c]pyrazol-4-ones of this invention by acylation followed by treatment with hydrazine as described previously in Scheme 2.
  • [0571]
    Another method for making the indeno[1,2-c]pyrazol-4-one ring system is exemplified in Scheme 4. Dimethyl hydrazine was reacted with 3-acetylpyridine with no solvent to give the hydrazone 7. This was treated in a similar fashion as described in Scheme 1 to give the desired intermediate 8. Additional means of preparing similar intermediates are known to one skilled in the art as described in Rappoport, J. Org. Chem. 49:2948-2953, 1984, the contents of which are hereby incorporated herein by reference. This intermediate was carried through the sequence in a similar fashion as described in Scheme 1.
  • [0572]
    The ureas and semicarbazides (R1═NHR4, X═O) of this invention can be prepared by treating the aniline intermediates in Schemes 1-4, for example 4 or 6c, with an isocyanate (RNCO) or an aminoisocyanate (RR′NNCO). These reagents are readily prepared in advance by one skilled in the art, or they can be generated in situ employing a precursor, such as an O-phenylcarbamate (RNHCO2Ph or RR′NNHCO2Ph), in the presense of base. Alternatively, the ureas and semicarbazides can be prepared by treatment of the anilines intermediates above with phenyl chloroformate in the presense of base to give an intermediate phenyl carbamate, followed by exposure of the phenyl carbamate to an amine or a hydrazine at elevated temperatures in an appropriate solvent.
  • [0573]
    The thioureas and thiosemicarbazides (X═S) of this invention can be prepared as described above by treating the aniline intermediates with phenyl thionochloroformate, followed by exposure of the resulting phenyl thiocarbamate to the appropriate amine or hydrazine derivative. The thioamides, thioureas, and thiosemicarbazides can also be prepared from the corresponding amides, ureas, and semicarbazides by treatment with a reagent such as phosphorous pentasulfide or Lawesson's reagent.
  • [0574]
    The amidines and guanidines (X═NR) of this invention can be prepared as described in Schemes 1-4 by treatment of the intermediate anilines with a wide variety of reagents known to one skilled in the art. These reagents include, but are not limited to, imidates and iminoyl chlorides for the production of amidines and isothioures and carbodiimides for the production of guanidines. Alternatively, the amidines and guanidines of this invention can be prepared from the corresponding thioamides, thioureas, and thiosemicarbazides. For example, a thiourea can be S-alkylated by treatment with an akylating agent such as methyl iodide or methyl triflate to provide the corresponding isothiourea. Treatment of this intermediate with the requisite amine or hydrazine at elevated temperatures in an appropriate solvent then provides the desired quanidine derivative.
  • [0575]
    Many of the compounds of this invention are synthesized from the indeno[1,2-c]pyrazol-4-ones prepared in Schemes 1-4 by the further synthetic elaboration of the R1 and R2 groups. As required the pyrazole ring can be protected by a wide range of protecting groups known to one skilled in the art with the selection of a protecting depending on the chemistry to be employed.
  • [0576]
    Other features of the invention will become apparent during the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.
  • EXAMPLES
  • [0577]
    Abbreviations used in the Examples are defined as follows: “°C” for degrees Celsius, “CIMS” for chemical ionization mass spectroscopy, “eq” for equivalent or equivalents, “g” for gram or grams, “h” for hour or hours, “mg” for milligram or milligrams, “mL” for milliliter or milliliters, “mmol” for millimolar, “M” for molar, “min” for minute or minutes, “p-TsOH” for para-toluenesulphonic acid, “DMF” for dimethylformamide, and “TFA” for trifluoroacetic acid.
  • Example I Preparation of 3-(4-methoxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one
  • [0578]
    [0578]
  • [0579]
    Step 1. Synthesis of 2 from Dimethyl 3-nitrophthalate.
  • [0580]
    A solution of dimethyl 3-nitrophthalate (25 g, 105 mmol) in methanol (100 mL) was treated with 5% Pd/C (2.5 g) and hydrogenated on a Parr Shaker at 50 psi for 2 h. The solution was filtered (Celite), the filtrate collected and the solvent removed at reduced pressure. The residue was dissolved in acetic anhydride (20 mL) treated with pyridine (0.05 mL) and heated to 80° C. for 1 min. The reaction was cooled and stirred at 25° C. for 2 h. The solvent was removed at reduced pressure and the residue recrystallized from ethanol to give the product as a white solid (21 g, 79%). mp 104-105° C.; CIMS m/e calc'd for C12H14NO5: 252.0872, found 252.0888; Analysis calc'd for C12H13NO5: C, 57.37; H, 5.22; N, 5.58; found: C, 57.67; H, 5.29; N, 5.77.
  • [0581]
    Step 2. Synthesis of Triketone 11 from 2.
  • [0582]
    A solution of 2 (1 g, 4.0 mmol) in dry DMF (2 mL) was treated with sodium hydride (0.15 g, 60% suspension in oil, 0.4 mmol) in one portion. After 1 h, 4-methoxyacetophenone (0.6 g, 4.0 mmol) was added in one portion and the reaction heated to 90° C. A second portion of sodium hydride (0.15 g, 60% suspension in oil, 0.4 mmol) was added and the exothermic reaction turns deep red. After 20 min, the reaction was cooled to 25° C., diluted with water (20 mL), extracted with EtOAc (10 mL) and the aqueous phase separated. The aqueous phase was acidified with 2 N HCl to pH 2 and the crude product collected. Recrystalization with ethanol gave the desired product as a yellow solid (0.4 g, 30%). mp 174-175° C.; CIMS m/e calc'd for C19H16NO5: 338.1028, found 338.1022; Analysis calc'd for C19H15NO5: C, 67.65;H, 4.48; N, 4.15; found: C, 67.87;H, 4.29; N, 3.99.
  • [0583]
    Step 3. Synthesis of 12 from 11.
  • [0584]
    A solution of 11 (0.2 g, 0.6 mmol) in EtOH (5 mL) was treated with hydrazine hydrate (0.1 mL, 1.8 mmol) and p-TsOH (3 mg). The reaction was heated to reflux and stirred for 2 h. The reaction was cooled to 25° C. and the product collected as a yellow solid (0.1 g, 50%). mp 268° C.; CIMS m/e calc'd for C19H16N3O3: 334.1192, found: 334.1168; Analysis calc'd for C19H15N3O3: C, 68.46;H, 4.54; N, 12.61; found: C, 68.81;H, 4.39; N, 12.45.
  • Example II Preparation of 3-(4-methoxyphenyl)-5-(chloroacetamido)indeno[1,2-c]pyrazol-4-one
  • [0585]
    [0585]
  • [0586]
    Step 1. Synthesis of 13 from 12.
  • [0587]
    A suspension of 12 (1.0 g, 3.0 mmol) in MeOH (10 mL) was treated with conc. HCl (1 mL) and heated to reflux. After 2 h, the reaction was cooled and the product was collected as a greenish solid (0.7 g, 81%). mp 273° C.; CIMS m/e calc'd for C17H14N3O2: 292.1086, found: 292.1080; Analysis calc'd for C17H13N3O2: C, 69.85;H, 4.83; N, 14.37; found: C, 69.99;H, 4.59; N, 14.44.
  • [0588]
    Step 2. Synthesis of 14 from 13.
  • [0589]
    A suspension of 13 (20 mg, 0.07 mmol) in dioxane (2 mL) was treated with aqueous sat. NaHCO3 (1 mL) and chloroacetyl chloride (30 mL, 0.21 mmol). The reaction was heated to 50° C. and stirred for 2 h. The reaction was cooled, poured into water (2 mL), extracted with EtOAc (10 mL), the organic layer separated, dried (MgSO4) and the solvent removed at reduced pressure. The solid residue was recrystallized from EtOH to give the product as a yellow solid (9 mg, 35%). mp 274° C.; CIMS m/e calc'd for C19H15N3O3Cl: 368.0802, found: 368.0818.
  • Example III Preparation of 3-(4-methoxyphenyl)-5-(cyclopropanecarboxamido)indeno[1,2-c]pyrazol-4-one
  • [0590]
    Prepared in a similar fashion as described for example II using cyclopropanecarboxoyl chloride as the starting material. mp 289° C.; CIMS m/e calc'd for C21H18N3O3: 360.1348, found: 360.1330.
  • Example IV Preparation of 3-(4-methoxyphenyl)-5-(2-methylpropanamido)indeno[1,2-c]pyrazol-4-one
  • [0591]
    Prepared in a similar fashion as described for example II using 2-methylpropanoyl chloride as the starting material. mp 288° C.; CIMS m/e calc'd for C21H20N3O3: 362.1505, found: 362.1535.
  • Example V Preparation of 3-(4-methoxyphenyl)-5-(propanamido)indeno[1,2-c]pyrazol-4-one
  • [0592]
    Prepared in a similar fashion as described for example II using propionyl chloride as the starting material. mp 287° C.; CIMS m/e calc'd for C20H18N3O3: 348.1348, found: 348.1313.
  • Example VI Preparation of 3-(4-methoxyphenyl)-5-(cyclopentanecarboxamido)indeno[1,2-c]pyrazol-4-one
  • [0593]
    Prepared in a similar fashion as described for example II using cyclopentanecarboxoyl chloride as the starting material. mp 267° C.; CIMS m/e calc'd for C23H22N3O3: 388.1661, found: 388.1626.
  • Example VII Preparation of 3-(4-methoxyphenyl)-5-(cyclobutanecarboxamido)indeno[1,2-c]pyrazol-4-one
  • [0594]
    Prepared in a similar fashion as described for example II using cyclobutanecarboxoyl chloride as the starting material. mp 297° C.; CIMS m/e calc'd for C22H20N3O3: 374.1505, found: 374.1530.
  • Example VIII Preparation of 3-(4-methoxyphenyl)-5-(phenylacetamido)indeno[1,2-c]pyrazol-4-one
  • [0595]
    Prepared in a similar fashion as described for example II using phenylacetyl chloride as the starting material. mp 280° C.; CIMS m/e calc'd for C25H20N3O3: 410.1505, found: 410.1533.
  • Example IX Preparation of 3-(4-methoxyphenyl)-5-(butanamido)indeno[1,2-c]pyrazol-4-one
  • [0596]
    Prepared in a similar fashion as described for example II using butyryl chloride as the starting material. mp 282° C.; CIMS m/e calc'd for C21H20N3O3: 362.1505, found: 362.1500.
  • Example X Preparation of 3-(4-methoxyphenyl)-5-((4-chlorophenyl)acetamido)indeno[1,2-c]pyrazol-4-one
  • [0597]
    Prepared in a similar fashion as described for example II using 4-chlorophenylacetyl chloride as the starting material. mp 238° C.; CIMS m/e calc'd for C25H19N3O3Cl: 444.1115, found: 444.1110.
  • Example XI Preparation of 3-(4-methoxyphenyl)-5-((3-methoxyphenyl)acetamido)indeno[1,2-c]pyrazol-4-one
  • [0598]
    Prepared in a similar fashion as described for example II using 3-methoxyphenylacetyl chloride as the starting material. mp >300° C.; CIMS m/e calc'd for C26H22N3O4: 440.1610, found: 440.1620.
  • Example XII Preparation of 3-(4-methoxyphenyl)-5-((4-methoxyphenyl)acetamido)indeno[1,2-c]pyrazol-4-one
  • [0599]
    Prepared in a similar fashion as described for example II using 4-methoxyphenylacetyl chloride as the starting material. mp 280° C.; CIMS m/e calc'd for C26H22N3O4: 440.1610, found: 440.1630.
  • Example XIII Preparation of 3-(4-methoxyphenyl)-5-((3,4-dimethoxyphenyl)acetamido)indeno[1,2-c]pyrazol-4-one
  • [0600]
    Prepared in a similar fashion as described for example II using 3,4-dimethoxyphenylacetyl chloride as the starting material. mp >300° C.; CIMS m/e calc'd for C27H24N3O5: 470.1716, found: 470.1731.
  • Example XIV Preparation of 3-(4-methoxyphenyl)-5-((2,5-dimethoxyphenyl)acetamido)indeno[1,2-c]pyrazol-4-one
  • [0601]
    Prepared in a similar fashion as described for example II using 2,5-dimethoxyphenylacetyl chloride as the starting material. mp 226° C.; CIMS m/e calc'd for C27H24N3O5: 470.1716, found: 470.1739.
  • Example XV Preparation of 3-(2-methoxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one
  • [0602]
    Prepared in a similar fashion as described for example I using 2-methoxyacetophenone as the starting material. mp 276° C.; CIMS m/e calc'd for C19H16N3O3: 334.1192, found: 334.1169.
  • Example XVI Preparation of 3-(3,4-dimethoxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one
  • [0603]
    Prepared in a similar fashion as described for example I using 3,4-dimethoxyacetophenone as the starting material. mp >300° C.; CIMS m/e calc'd for C20H18N3O4: 364.1297, found: 364.1288.
  • Example XVII Preparation of 3-(4-methoxyphenyl)-5-((3,4-methylenedioxyphenyl)acetamido)indeno[1,2-c]pyrazol-4-one
  • [0604]
    [0604]
  • [0605]
    Step 1. Synthesis of 15 from 11.
  • [0606]
    A suspension of 11 (5 g, 14.8 mmol) in MeOH (50 mL) was treated with conc. HCl (3 mL) and heated to reflux. After stirring for 2 h, the reaction was cooled to 0° C. and the product collected as a yellow solid (4.2 g, 96%). mp 173° C.; CIMS m/e calc'd for C17H14NO4: 296.0923, Found: 296.0901.
  • [0607]
    Step 2. Synthesis of 16 from 15.
  • [0608]
    A suspension of 15 (20 mg, 0.07 mmol) in acetone (2 mL) was treated with NaHCO3 (10 mg) and the acid chloride of (3,4-methylenedioxyphenyl)acetic acid (prepared by heating the acid in a benzene:thionyl chloride 4:1 mixture at 50° C. for 2 h, removing the volatile components at reduced pressure, and using the crude acid chloride without further purification). The reaction was heated to 50° C. and stirred for 2 h. The reaction was cooled, poured into water (4 mL), extracted with EtOAc (10 mL), dried (MgSO4), filtered and concentrated. The crude triketone was suspended in EtOH (2 mL), treated with hydrazine hydrate (0.05 mL) and p-TsOH (1 mg) and heated to reflux for 2 h. The reaction was cooled to 0° C. and the product filtered to give a yellow solid (6.5 mg, 20%). mp 297° C.; CIMS m/e calc'd for C26H20N3O5: 454.1403, Found: 454.1398.
  • Example XVIII Preparation of 3-(4-dimethoxyphenyl)-5-(3-thienylacetamido)indeno[1,2-c]pyrazol-4-one
  • [0609]
    Prepared in a similar fashion as described for example XVII using the acid chloride of 3-thiopheneacetic acid as the starting material. mp 293° C.; CIMS m/e calc'd for C23H18N3O3S: 416.1069, found: 416.1088.
  • Example XIX Preparation of 3-(4-methoxyphenyl)-5-((2-methoxyphenyl)acetamido)indeno[1,2-c]pyrazol-4-one
  • [0610]
    Prepared in a similar fashion as described for example XVII using the acid chloride of 2-methoxyphenylacetic acid as the starting material. mp 255° C.; CIMS m/e calc'd for C26H22N3O4: 440.1610, found: 440.1622.
  • Example XX Preparation of 3-(4-methoxyphenyl)-5-((3,4-dichlorophenyl)acetamido)indeno[1,2-c]pyrazol-4-one
  • [0611]
    Prepared in a similar fashion as described for example XVII using the acid chloride of 3,4-dichlorophenylacetic acid as the starting material. mp 299° C.; CIMS m/e calc'd for C25H18N3O3Cl2: 478.0725, found: 478.0744.
  • Example XXI Preparation of 3-(4-methoxyphenyl)-5-((2,4-dichlorophenyl)acetamido)indeno[1,2-c]pyrazol-4-one
  • [0612]
    Prepared in a similar fashion as described for example XVII using the acid chloride of 2,4-dichlorophenylacetic acid as the starting material. mp 286° C.; CIMS m/e calc'd for C25H18N3O3Cl2: 478.0725, found: 478.0734.
  • Example XXII Preparation of 3-(4-methoxyphenyl)-5-((2-chlorophenyl)acetamido)indeno[1,2-c]pyrazol-4-one
  • [0613]
    Prepared in a similar fashion as described for example XVII using the acid chloride of 2-chlorophenylacetic acid as the starting material. mp 300° C.; CIMS m/e calc'd for C25H19N3O3Cl: 444.1115, found: 444.1111.
  • Example XXIII Preparation of 3-(4-methoxyphenyl)-5-(aminoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0614]
    [0614]
  • [0615]
    A suspension of 14 (15 mg, 0.04 mol) in EtOH (1 mL) was treated with conc. NH4OH (1 mL), placed in a sealed tube and heated to 80° C. for 3 h. The reaction was cooled and the solvent removed at reduced pressure. The residue was recrystallized from EtOH to give the product as a yellow solid (9 mg, 62%). mp >300° C.; CIMS m/e calc'd for C20H19N4O3: 363.1457, Found: 363.1431.
  • Example XXIV Preparation of 3-(4-methoxyphenyl)-5-((2-hydroxyethyl)aminoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0616]
    Prepared in a similar fashion as described for example XXIII using hydroxylamine as the starting material. mp 243° C.; CIMS m/e calc'd for C21H21N4O4: 393.1563, found: 393.1539.
  • Example XXV Preparation of 3-(4-methoxyphenyl)-5-(N,N-dimethylaminoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0617]
    Prepared in a similar fashion as described for example XXIII using dimethylamine as the starting material. mp 279 ° C.; CIMS m/e calc'd for C21H21N4O3: 377.1614, found: 377.1640.
  • Example XXVI Preparation of 3-(4-methoxyphenyl)-5-(piperazinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0618]
    Prepared in a similar fashion as described for example XXIII using piperazine as the starting material. mp 277° C.; CIMS m/e calc'd for C23H24N5O3: 418.1879, found: 418.1899.
  • Example XXVII Preparation of 3-(4-methoxyphenyl)-5-(4-methylpiperazinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0619]
    Prepared in a similar fashion as described for example XXIII using 4-methylpiperizine as the starting material. mp >300° C.; CIMS m/e calc'd for C24H26N5O3: 432.2036, found: 432.2030.
  • Example XXVIII Preparation of 3-(4-methoxyphenyl)-5-(4-(2-hydroxyethyl)piperazinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0620]
    Prepared in a similar fashion as described for example XXIII using 4-hydroxyethylpiperizine as the starting material. mp >300° C.; CIMS m/e calc'd for C25H28N5O4: 462.2141, found: 462.2128.
  • Example XXIX Preparation of 3-(4-methoxyphenyl)-5-(piperidinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0621]
    Prepared in a similar fashion as described for example XXIII using piperidine as the starting material. mp 291° C.; CIMS m/e calc'd for C24H25N4O3: 417.1927, found: 417.1955.
  • Example XXX Preparation of 3-(4-methoxyphenyl)-5-(4-(aminomethyl)piperidinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0622]
    Prepared in a similar fashion as described for example XXIII using 4-aminomethylpiperidine as the starting material. mp >300° C.; CIMS m/e calc'd for C25H28N5O3: 446.2192, found: 446.2166.
  • Example XXXI Preparation of 3-(4-methoxyphenyl)-5-(ethylaminoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0623]
    Prepared in a similar fashion as described for example XXIII using ethylamine as the starting material. mp 250° C.; CIMS m/e calc'd for C21H21N4O3: 377.1614, found: 377.1644.
  • Example XXXII Preparation of 3-(4-methoxyphenyl)-5-(thiomorpholinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0624]
    Prepared in a similar fashion as described for example XXIII using thiomorpholine as the starting material. mp 298 IC; CIMS m/e calc'd for C23H23N4O3S: 435.1491, found: 435.1477.
  • Example XXXIII Preparation of 3-(4-methoxyphenyl)-5-(morpholinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0625]
    Prepared in a similar fashion as described for example XXIII using morpholine as the starting material. mp 295° C.; CIMS m/e calc'd for C23H23N4O4: 419.1719, found: 419.1744.
  • Example XXXIV Preparation of 3-(4-methoxyphenyl)-5-(pyrrolidinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0626]
    Prepared in a similar fashion as described for example XXIII using pyyrolidine as the starting material. mp 279° C.; CIMS m/e calc'd for C23H23N4O3: 403.1770, found: 403.1761.
  • Example XXXV Preparation of 3-(4-methoxyphenyl)-5-((4-pyridinylmethylaminoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0627]
    Prepared in a similar fashion as described for example XXIII using 4-aminomethylpyridine as the starting material. mp >300° C.; CIMS m/e calc'd for C25H22N5O3: 440.1723, found: 440.1762.
  • Example XXXVI Preparation of 3-(4-methoxyphenyl)-5-((4-acetamidophenyl)acetamido)indeno[1,2-c]pyrazol-4-one
  • [0628]
    [0628]
  • [0629]
    A suspension of 18 (10 mg, 0.02 mmol) in dioxane (1 mL) was treated with aqueous sat. NaHCO3 (0.5 mL) and acetyl chloride (0.01 mL) and heated at 50° C. for 1 h. The reaction was cooled, poured into water (5 mL), extracted with EtOAc (10 mL), the organic layer separated, dried (MgSO4) and the solvent removed at reduced pressure. The residue was recrystallized from EtOH to give the product as a yellow solid (5.6 mg, 61%). mp 268° C.; CIMS m/e calc'd for C27H23N4O4: 467.1719, Found: 467.1730.
  • Example XXXVII Preparation of 3-(4-methoxyphenyl)-5-((4-(methoxycarbonylamino)phenyl)acetamido) indeno[1,2-c]pyrazol-4-one
  • [0630]
    Prepared in a similar fashion as described for example XXXII using methylchloroformate as the starting material. mp 257° C.; CIMS m/e calc'd for C27H23N4O5: 483.1668, found: 483.1633.
  • Example XXXVIII Preparation of 3-(4-methoxyphenyl)-5-((4-(aminomethylcarbonylamino)phenyl)acetamido) indeno[1,2-c]pyrazol-4-one
  • [0631]
    Prepared in a similar fashion as described for example XXIII and XXXII using chloroacetyl chloride and conc. NH4OH as the starting materias. mp 228° C.; CIMS m/e calc'd for C27H24N5O4: 482.1828, found: 482.1844.
  • Example XXXIX Preparation of 3-(4-methoxyphenyl)-5-((4-((N,N-dimethylamino)methylcarbonylamino)phenyl)acetamido) indeno[1,2-c]pyrazol-4-one
  • [0632]
    Prepared in a similar fashion as described for example XXIII and XXXII using chloroacetyl chloride and dimethyl amine as the starting materias. mp >300° C.; CIMS m/e calc'd for C29H28N5O4: 510.2141, found: 510.2121.
  • Example XL Preparation of 3-(4-methoxyphenyl)-5-((4-azidophenyl)acetamido)indeno[1,2-c]pyrazol-4-one
  • [0633]
    A solution of example XXXVI (20 mg, 0.04 mmol) in DMF (2 mL) was treated with 5% palladium on carbon (5 mg) and hydrogentaed at atmospheric pressure using a hydrogen baloon. After 2 h, the solution was filtered (Celite), and the solvent removed at reduced pressure. The residue was recrystallized from EtOH to give the product as a yellow solid (15 mg, 78%). mp >300° C.; CIMS m/e calc'd for C25H19N6O3: 451.1519, found: 451.1544.
  • Example XLI Preparation of 3-(4-methoxyphenyl)-5-((4-aminophenyl)acetamido)indeno[1,2-c]pyrazol-4-one
  • [0634]
    Prepared in a similar fashion as described for example XXVII using the acid chloride of 4-azidophenylacetic acid as the starting material. mp 283° C.; CIMS m/e calc'd for C25H21N4O3: 425.1614, found: 425.1643.
  • Example XLII Preparation of 3-(4-methoxyphenyl)-5-((phenylcarbamoyl)amino)indeno [1,2-c]pyrazol-4-one
  • [0635]
    [0635]
  • [0636]
    Step 1. Synthesis of 20 from 15.
  • [0637]
    A suspension of 15 (0.5 g, 1.7 mmol) in acetone (10 mL) was treated with NaHCO3 (0.5 g) and phenyl chloroformate. The mixture was heated to 50° C. for 2 h. The reaction was cooled, poured into water (20 mL), extracted with EtOAc (40 mL), the organic layer separated, dried (MgSO4) and the solvent removed at reduced pressure. The residue was suspended in EtOH (10 mL) and treated with hydrazine hydrate (0.16 mL, 5.1 mmol) and p-TsOH (10 mg). The mixture was heated to reflux and stirred for 3 h. The reaction was cooled to 0° C. and the product collected as a yellow solid (0.25 g, 36%). mp 195° C.; CIMS m/e calc'd for C24H18N3O4: 412.1297, Found: 412.1308.
  • [0638]
    Step 2. Synthesis of 21 from 20.
  • [0639]
    A solution of 20 (20 mg, 0.05 mmol) in DMSO (2 mL) was treated with aniline (20 mL, mmol) and dimethylaminopyridine (1 mg). The mixture was heated to 80° C. for 2 h. The reaction was cooled, poured into water (4 mL), extracted with EtOAc (15 mL), the organic layer separated, dried (MgSO4) and the solvent removed at reduced pressure. The residue was recrystallized from EtOH to give the product as a yellow solid (9 mg, 44%). mp >300° C.; CIMS m/e calc'd for C24H19N4O3: 411.1457, Found: 411.1432.
  • Example XLIII Preparation of 3-(4-methoxyphenyl)-5-((butylcarbamoyl)amino)indeno[1,2-c]pyrazol-4-one
  • [0640]
    Prepared in a similar fashion as described for example XLII using butyl amine as the starting material. mp 252° C.; CIMS m/e calc'd for C21H21N4O3: 377.1614, found: 377.1633.
  • Example XLIV Preparation of 3-((4-methoxyphenyl)-5-(4-aminobenzylcarbamoyl)amino)indeno[1,2-c]pyrazol-4-one
  • [0641]
    Prepared in a similar fashion as described for example XLII using 4-aminobenzyl amine as the starting material. mp >300° C.; CIMS m/e calc'd for C25H22N5O3: 440.1723, found: 440.1700.
  • Example XLV Preparation of 3-(4-methoxyphenyl)-5-((4-pyridylcarbamoyl)amino)indeno[1,2-c]pyrazol-4-one
  • [0642]
    Prepared in a similar fashion as described for example XLII using 4-aminomethylpyridine as the starting material. mp >300° C.; CIMS m/e calc'd for C24H20N5O3: 426.1566, found: 426.1533.
  • Example XLVI Preparation of 3-(4-hydroxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one
  • [0643]
    [0643]
  • [0644]
    A suspension of 12 (20 mg, 0.07 mmol) in CH2Cl2 (2 mL) was treated with excess BBr3 (1.0 mL, 1.0 M in CH2Cl2) and stirred for 20 h. The reaction was slowly poured into aqueous sat. NaHCO3 (5 mL), extracted with EtOAc (10 mL), dried (MgSO4) and concentrated. The residue was recrystallized from EtOH to give the desired product as a yellow solid (7.5 mg, 33%). mp >300° C.; CIMS m/e calc'd for C18H14N3O3: 320.1035, Found: 320.1050.
  • Example XLVII Preparation of 3-(4-methoxyphenyl)-5-(formamido)indeno[1,2-c]pyrazol-4-one
  • [0645]
    [0645]
  • [0646]
    A suspension of 13 (20 mg, 0.06 mmol) in formic acid (2 mL) was heated to 100° C. for 2 h. The reaction mixture was cooled and the solvent removed at reduced pressure. The residue was recrystallized from EtOH to give the desired product as a yellow solid (12 mg, 63%). mp 280° C.; CIMS m/e calc'd for C18H14N3O3: 320.1035, Found: 320.1040.
  • Example XLVIII Preparation of 3-(3-pyridyl)-5-(acetamido)indeno [1,2-c]pyrazol-4-one
  • [0647]
    [0647]
  • [0648]
    Step 1. Synthesis of 24 from 3-acetylpyridine.
  • [0649]
    A solution of 3-acetylpyridine (1.0 g, 8.3 mmol) in benzene (3 mL) was treated with 1,1-dimethylhydrazine (0.62 mL, 8.3 mmol) and p-TsOH (5 mg). The mixture was heated to 85° C. and stirred for 3 h. The reaction was cooled and the solvent removed at reduced pressure. This crude hydrazone was treated with 1.0 M NaN(TMS)2 in THF (16.6 mL, 16.6 mmol) at 25° C. over 5 min. After 30 min dimethyl 3-acetamidophthalate (2.1 g, 8.3 mmol) was added in one portion and the reaction heated to reflux. Stirring was continued for 6 h. The reaction was cooled and quenched by the slow addition of TFA. The solvent was removed at reduced pressure and the residue chromatographed (silica, 2.5-5% MeOH/CH2Cl2) to give the product as a yellow solid (0.35 g, 14%). mp 265° C.; CIMS m/e calc'd for C17H13N2O4: 309.0875, Found: 309.0888.
  • [0650]
    Step 2. Synthesis of 25 from 24.
  • [0651]
    A suspension of 24 (30 mg, 0.09 mmol) in EtOH (2 mL) was treated with hydrazine hydrate (0.05 mL) and p-TsOH (1 mg) and heated to reflux. After stirring for 2 h. the reaction was cooled and the product filtered to give a yellow solid (12 mg, 44%). mp >300° C.; CIMS m/e calc'd for C17H13N4O2: 305.1039, Found: 305.1048.
  • Example XLIX Preparation of 3-(4-pyridyl)-5-(acetamido)indeno [1,2-c]pyrazol-4-one
  • [0652]
    Prepared in a similar fashion as described for example XLVIII using 4-acetylpyridine as the starting material. mp >300° C.; CIMS m/e calc'd for C17H13N4O2: 305.1039, found: 305.1046.
  • Example L Preparation of 3-(4-pyridyl)-5-(formamido)indeno [1,2-c]pyrazol-4-one
  • [0653]
    Prepared in a similar fashion as described for example XLVII using 4-acetylpyridine as the starting material. mp >300° C.; CIMS m/e calc'd for C16H11N4O2: 291.0882, found: 291.0882.
  • Example LI Preparation of 3-phenyl-5-(acetamido)indeno [1,2-c]pyrazol-4-one
  • [0654]
    Prepared in a similar fashion as described for example I using acetophenone as the starting material. mp >300° C.; CIMS m/e calc'd for C18H13N3O2: 304.1065, found: 304.1086.
  • Example LII Preparation of 3-(4-methylthiophenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one
  • [0655]
    Prepared in a similar fashion as described for example I using 4′-methylthioacetophenone as the starting material. mp 283° C.; CIMS m/e calc'd for C19H15N3O2S: 350.0956, found: 350.0963.
  • Example LIII Preparation of 3-(4-methanesulphonylphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one
  • [0656]
    Prepared by oxidation of the product of example LII. mp >300° C.; CIMS m/e calc'd for C19H15N3O4S: 382.0860, found: 382.0862.
  • Example LIV Preparation of 3-(4-(N,N-dimethylamino)phenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one
  • [0657]
    Prepared in a similar fashion as described for example I using 4′-(N,N-dimethylamino)acetophenone as the starting material. mp >300° C.; CIMS m/e calc'd for C20H18N4O2: 347.1496, found: 347.1508.
  • Example LV Preparation of 3-(4-(N,N-dimethylamino)phenyl)-5-(morpholinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0658]
    Prepared in a similar fashion as described for examples II and XXIII employing the product of example LIV and morpholine as the starting materials. mp >300° C.; CIMS m/e calc'd for C24H26N5O3: 432.2036, found: 432.2020.
  • Example LVI Preparation of 3-(4-(N,N-dimethylamino)phenyl)-5-(N,N-dimethylaminoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0659]
    Prepared in a similar fashion as described for examples II and XXIII employing the product of example LIV and dimethylamine as the starting materials. mp >300° C.; CIMS m/e calc'd for C22H24N5O2: 390.1930, found: 390.1948.
  • Example LVII Preparation of 3-(4-piperidinophenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one
  • [0660]
    Prepared in a similar fashion as described for example I using 41-(1-piperidinyl)acetophenone as the starting material. mp 291° C.; CIMS m/e calc'd for C23H22N4O2: 387.1801, found: 387.1821.
  • Example LVIII Preparation of 3-(4-morpholinophenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one
  • [0661]
    Prepared in a similar fashion as described for example I using 4′-morpholinylacetophenone as the starting material. mp >300° C.; CIMS m/e calc'd for C22H20N4O3: 388.1528, found: 388.1535.
  • Example LIX Preparation of 3-(4-ethoxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one
  • [0662]
    Prepared in a similar fashion as described for example I using 4′-ethoxyacetophenone as the starting material. mp 288° C.; CIMS m/e calc'd for C20H17N3O3: 348.1325, found: 348.1348.
  • Example LX Preparation of 3-(4-butylphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one
  • [0663]
    Prepared in a similar fashion as described for example I using 4′-butylacetophenone as the starting material. mp 259° C.; CIMS m/e calc'd for C22H21N3O2: 360.1701, found: 360.1712.
  • Example LXI Preparation of 3-(4-ethylphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one
  • [0664]
    Prepared in a similar fashion as described for example I using 4′-ethylacetophenone as the starting material. mp 294° C.; CIMS m/e calc'd for C20H17N3O2: 331.1310, found: 331.1321.
  • Example LXII Preparation of 3-(4-n-propylphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one
  • [0665]
    Prepared in a similar fashion as described for example I using 4′-n-propylacetophenone as the starting material. mp 269° C.; CIMS m/e calc'd for C21H19N3O2: 346.1555, found: 346.1554.
  • Example LXIII Preparation of 3-(4-methoxyphenyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0666]
    Prepared in a similar fashion as described for example XLII using concentrated ammonium hydroxide as the starting material. mp >300° C.; CIMS m/e calc'd for C18H15N4O3: 335.1144, found: 335.1113.
  • Example LXIV Preparation of 3-(4-methoxyphenyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one
  • [0667]
    Prepared in a similar fashion as described for example XLII using dimethylamino hydrazine as the starting material. mp >300° C.; CIMS m/e calc'd for C20H20N5O3: 378.1566, found: 378.1555.
  • Example LXV Preparation of 3-(4-methoxyphenyl)-5-((methylcarbamoyl)amino)indeno[1,2-c]pyrazol-4-one
  • [0668]
    Prepared in a similar fashion as described for example XLII using methylamine as the starting material. mp >300° C.; CIMS m/e calc'd for C19H17N4O3: 349.1300, found: 349.1311.
  • Example LXVI Preparation of 3-(4-methoxyphenyl)-5-((morpholinocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one
  • [0669]
    Prepared in a similar fashion as described for example XLII using N-aminomorpholine as the starting material. mp >300° C.; CIMS m/e calc'd for C22H22N5O4: 420.1671, found: 420.1655.
  • Example LXVII Preparation of 3-(4-methoxyphenyl)-5-((cis-2-aminocyclohexylcarbamoyl)amino)indeno[1,2-c]pyrazol-4-one
  • [0670]
    Prepared in a similar fashion as described for example XLII using cis-1,2-diaminocyclohexane as the starting material. mp >300° C.; CIMS m/e calc'd for C24H26N5O3: 432.2035, found: 432.2020.
  • Example LXVIII Preparation of 3-(4-methoxyphenyl)-5-((4-methylpiperazinocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one
  • [0671]
    Prepared in a similar fashion as described for example XLII using (4-amino)methylpiperazine as the starting material. mp >300° C.; CIMS m/e calc'd for C23H25N6O3: 433.1987, found: 433.1999.
  • Example LXIX Preparation of 3-(4-methoxyphenyl)-5-(4-(uridomethyl)piperidinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0672]
    Prepared in a similar fashion as described for example XXIII using example XXX as the starting material. mp >300° C.; CIMS m/e calc'd for C26H29N6O4: 489.2250, found: 489.2209.
  • Example LXX Preparation of 3-(4-methoxyphenyl)-5-(4-(2-pyridyl)piperazinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0673]
    Prepared in a similar fashion as described for example XXIII using 4-(2-pyridyl)piperazine as the starting material. mp >300° C.; CIMS m/e catc'd for C28H27N6O3: 495.2144, found: 495.2111.
  • Example LXXI Preparation of 3-(4-methoxyphenyl)-5-(4-(aminoethyl)piperazinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0674]
    Prepared in a similar fashion as described for example XXIII using 4-(aminoethyl)piperazine as the starting material. mp >300° C.; CIMS m/e calc'd for C25H29N6O3: 461.2300, found: 461.2333.
  • Example LXXII Preparation of 3-(4-methoxyphenyl)-5-(4-carbamoylpiperidinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0675]
    Prepared in a similar fashion as described for example XXIII using isonipecotamide as the starting material. mp >300° C.; CIMS m/e calc'd for C25H26N5O4: 460.1984, found: 460.1998.
  • Example LXXIII Preparation of 3-(4-methoxyphenyl)-5-(4-hydroxypiperidinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0676]
    Prepared in a similar fashion as described for example XXIII using 4-hydroxypiperidine as the starting material. mp >300° C.; CIMS m/e calc'd for C24H25N4O4: 433.1875, found: 433.1844.
  • Example LXXIV Preparation of 3-(4-methoxyphenyl)-5-(4-(hydroxmethyl)piperidinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0677]
    Prepared in a similar fashion as described for example XXIII using 4-(hydroxmethyl)piperidine as the starting material. mp >300° C.; CIMS m/e calc'd for C25H27N4O4: 447.2032, found: 447.2002.
  • Example LXXV Preparation of 3-(4-methoxyphenyl)-5-(4-amidopiperazinylacetamido)indeno[1,2-c]pyrazol-4-one
  • [0678]
    Prepared in a similar fashion as described for example XXIII using 4-amidopiperazine as the starting material. mp >300° C.; CIMS m/e calc'd for C24H25N6O6: 493.1835, found: 493.1802.
  • Example LXXVI Preparation of 3-(4-methoxyphenyl)-5-(4-(N,N-dimethylamino)piperidinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0679]
    Prepared in a similar fashion as described for example XXIII using 4-dimethylaminopiperidine as the starting material. mp >300° C.; CIMS m/e calc'd for C26H30N5O5: 492.2246, found: 492.2220.
  • Example LXXVII Preparation of 3-(4-methoxyphenyl)-5-(4-aminopiperidinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0680]
    Prepared in a similar fashion as described for example XXIII using 4-aminopiperidine as the starting material. mp >300° C.; CIMS m/e calc'd for C24H26N5O5: 464.1933, found: 464.1975.
  • Example LXXVIII Preparation of 3-(4-(dimethylamino)phenyl)-5-((4-methylpiperazino)acetamido)indeno[1,2-c]pyrazol-4-one
  • [0681]
    Prepared in a similar fashion as described for examples II and XXIII employing the product of example LIV and 1-methylpiperazine as the starting materials. mp >300° C.; ESI-MS m/e calc'd for C25H29N6O2: 445.2352, found: 445.2359.
  • Example LXXIX Preparation of 3-(4-(N,N-dimethylamino)phenyl)-5-(4-(aminomethyl)piperidinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0682]
    Prepared in a similar fashion as described for examples II and XXIII employing the product of example LIV and 4-(aminomethyl)piperidine as the starting materials. ESI-MS m/e calc'd for C26H31N6O2: 459.2508, found: 459.2508.
  • Example LXXX Preparation of 3-(4-(N,N-dimethylamino)phenyl)-5-(4-hydroxypiperidinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0683]
    Prepared in a similar fashion as described for examples II and XXIII employing the product of example LIV and 4-hydroxypiperidine as the starting materials. mp 267° C.; ESI-MS m/e calc'd for C25H28N5O3: 446.2192, found: 446.2206.
  • Example LXXXI Preparation of 3-(4-morpholinophenyl)-5-(morpholinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0684]
    Prepared in a similar fashion as described for examples II and XXIII employing the product of example LVIII and morpholine as the starting materials. mp 258° C.; ESI-MS m/e calc'd for C26H28N5O4: 474.2141, found: 474.2151.
  • Example LXXXII Preparation of 3-(4-morpholinophenyl)-5-((4-methylpiperazinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0685]
    Prepared in a similar fashion as described for examples II and XXIII employing the product of example LVIII and 1-methylpiperazine as the starting materials. mp 258° C.; ESI-MS m/e calc'd for C27H31N6O3: 487.2457, found: 487.2447.
  • Example LXXXIII Preparation of 3-(4-(4-morpholinyl)phenyl)-5-((4-hydroxy-1-piperidinyl)acetamido)indeno[1,2-c]pyrazol-4-one
  • [0686]
    Prepared in a similar fashion as described for examples II and XXIII employing the product of example LVIII and 4-hydroxypiperidine as the starting materials. mp 245° C.; ESI-MS m/e calc'd for C27H30N5O4: 488.2298, found: 488.2290.
  • Example LXXXIV Preparation of 3-(4-morpholinophenyl)-5-(4-(aminomethyl)piperidinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0687]
    Prepared in a similar fashion as described for examples II and XXIII employing the product of example LVIII and 4-(aminomethyl)piperidine as the starting materials. mp 240 ° C.; ESI-MS m/e calc'd for C28H33N6O3: 501.2614, found: 501.2619.
  • Example LXXXV Preparation of 3-(4-(N,N-dimethylamino)phenyl)-5-(4-methylpiperazinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0688]
    Prepared in a similar fashion as described for examples I, XXVII, and XLII employing the 4-(dimethylamino) acetophenone and 1-amino-4-methylpiperazine as the starting materials. mp >300° C.; ESI-MS m/e calc'd for C24H28N7O2: 446.2304, found: 446.2310.
  • Example LXXXVI Preparation of 3-(4-methoxyphenyl)-5-((4-methylpiperazino)thionocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0689]
    Prepared in a similar fashion as described for example XLII using phenylthionochloroformate and 1-amino-4-methylpiperazine as the starting materials. mp >300° C.; CIMS m/e calc'd for C23H25N6O2S: 449.1760, found: 449.1777.
  • Example LXXXVII Preparation of 3-(2-thienyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one
  • [0690]
    [0690]
  • [0691]
    Step 1. Synthesis of 26 from 3-nitrophthalic Anhydride.
  • [0692]
    A solution of 3-nitrophthalic anhydride (2.5 g, 13 mmol) and 2-thenoyltrifluoroacetone (2.87 g, 13 mmol) in acetic anhydride (7.3 mL, 78 mmol) was treated with triethylamine (3.6 mL, 26 mmol) and stirred at 25° C. for 12 h. The solution was diluted with 1 N HCl (25 mL) and the precipate collected and washed with 0.1 M HCl (2×25 mL) and hexane (3×25 mL) to give the product as a yellow solid (1.5 g, 38%). mp 140-141° C.; APIMS (M+H) calc'd for C14H8NO5S: 302.29, found: 302.20.
  • [0693]
    Step 2. Synthesis of Triketone 27 from 26.
  • [0694]
    A solution of 26 (1 g, 3.3 mmol) in EtOH (12 mL) and water (12 mL) was treated with zinc (7.1 g, 110 mmol) and calcium chloride (240 mg, 2.2 mmol) and heated to reflux for 1.5 h. The reaction was filtered (Celite) and washed with EtOH/H20 (1:1, 3×200 mL), EtOAc (3×100 mL), MeOH (2×100 mL), and i-PrOH (2×100 mL). The filtrate was concentrated at reduced pressure to give an aqueous residue which was extracted with EtOAc (4×200 mL). The combined organic extracts were separated, dried (Na2SO4), filtered, and concentrated at reduced pressure to give a reddish foam (˜0.9 g, 100%). mp >300° C.; ESIMS (M−H) calc'd for C14H8NO3S: 270.29, found: 270.20.
  • [0695]
    Step 3. Synthesis of 28 from 27.
  • [0696]
    A solution of 27 (900 mg, 3.3 mmol) in acetic anhydride (20 mL) was refluxed for 1.5 h. The reaction mixture was treated heptane and the solvents were concentrated at reduced pressure to give a dark residue which was diluted with EtOAc (100 mL) and washed with H2O (3×75 mL) and brine (2×50 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated at reduced pressure to give a reddish-brown foam. Purification (SiO2, 1:1 EtOAc/hexane) gave the product as a red oil (600 mg, 58%). mp >300° C.; ESIMS (M−H) calc'd for C16H10NO4S: 313.33, found: 313.10.
  • [0697]
    Step 4. Synthesis of LXXXVII from 28.
  • [0698]
    A solution of 28 (200 mg, 0.64 mmol) in EtOH (2 mL) was treated with hydrazine hydrate (0.04 mL, 1.3 mmol) and p-TsOH (6 mg, 0.032 mmol). The reaction was heated to reflux and stirred for 12 h. The reaction was cooled to 25° C. and the solid filtered. Purification by reverse phase HPLC (CH3CN/H2O) gave the product (16 mg, 9%). mp 269° C.; CIMS (M+H) calc'd for C16H12N3O2S: 310.0650, found: 310.0635.
  • Example LXXXVIII Preparation of 3-(c-propyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one
  • [0699]
    Prepared in a similar fashion as described for example LXXXVII using 1-cyclopropyl-4,4,4-trifluoro-1,3-butanedione as the starting material. mp 220-221° C.; CIMS (M+H) calc'd for C15H14N3O2: 268.1086, found: 268.1078.
  • Example LXXXVIX Preparation of 3-(1-methyl-3-pyrrolyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0700]
    Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 1-methyl-3-pyrrolyl analog of 15 as the starting materials. mp >300° C.; ESIMS (M+H) calc'd for C16H14N5O2: 308.1148, found: 308.1166.
  • Example XC Preparation of 3-(3-methyl-2-thienyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one
  • [0701]
    Prepared in a similar fashion as described for example LXXXVII and XLII using the 3-methyl-2-thienyl analog of 26 as the starting material. mp 275° C.; ESIMS (M+H) calc'd for C17H14N3O2S: 324.0811, found: 324.0807.
  • Example XCI Preparation of 3-(ethyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0702]
    Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the ethyl analog of 15 as the starting materials. mp >250° C.; CIMS (M+H) calc'd for C13H13N4O2: 257.1039, found: 257.1033.
  • Example XCII Preparation of 3-(n-propyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0703]
    Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the n-propyl analog of 15 as the starting materials. mp 187-189° C.; CIMS (M+H) calc'd for C14H15N4O2: 271.1195, found: 271.1187.
  • Example XCIII Preparation of 3-(i-propyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0704]
    Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 1-propyl analog of 15 as the starting materials. mp >250° C.; CIMS (M+H) calc'd for C14H15N4O2: 271.1195, found: 271.1196.
  • Example XCIV Preparation of 3-(c-propyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0705]
    Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the c-propyl analog of 15 as the starting materials. mp 252-253° C.; ESIMS (M−H) calc'd for C14H11N4O2: 267.0881, found: 267.0884.
  • Example XCV Preparation of 3-(c-hexyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0706]
    Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the c-hexyl analog of 15 as the starting materials. mp 178-179° C.; ESIMS (M+H) calc'd for C17H19N4O2: 311.1507, found: 311.1500.
  • Example XCVI Preparation of 3-(2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0707]
    Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 2-thienyl analog of 15 as the starting materials. mp 214° C.; CIMS m+ calc'd for C15H10N4O2S: 310.0517, found: 310.0524.
  • Example XCVII Preparation of 3-(3-methyl-2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0708]
    Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 3-methyl-2-thienyl analog of 15 as the starting materials. mp 270° C.; ESIMS (M+H) calc'd for C16H13N4O2S: 325.0759, found: 325.0744.
  • Example XCVIII Preparation of 3-(5-methyl-2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0709]
    Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 5-methyl-2-thienyl analog of 15 as the starting materials. mp >280° C.; ESIMS (M+H) calc'd for C16H13N4O2S: 325.0759, found: 325.0761.
  • Example XCIX Preparation of 3-(5-carboethoxy-2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0710]
    Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 5-ethylcarboxyl-2-thienyl analog of 15 as the starting materials. mp >280° C.; ESIMS (M+H) calc'd for C18H15N4O4S: 383.0813, found: 383.0788.
  • Example C Preparation of 3-(3-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0711]
    Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 3-thienyl analog of 15 as the starting materials. mp >280° C.; ESIMS (M+H) calc'd for C15H11N4O2S: 311.0603, found: 311.0594.
  • Example CI Preparation of 3-(5-chloro-3-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0712]
    Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 5-chloro-3-thienyl analog of 15 as the starting materials. mp >300° C.; ESIMS (M+H) calc'd for C15H10N4O2SCl: 345.0209, found: 345.0213.
  • Example CII Preparation of 3-(2,5-dimethyl-3-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0713]
    Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 2,5-dimethyl-3-thienyl analog of 15 as the starting materials. mp >280° C.; ESIMS (M+H) calc'd for C17H15N4O2S: 339.0916, found: 339.0905.
  • Example CIII Preparation of 3-(2-furanyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0714]
    Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 2-furanyl analog of 15 as the starting materials. mp 278° C.; ESIMS (M+H) calc'd for C15H11N4O3: 295.0831, found: 295.0838.
  • Example CIV Preparation of 3-(i-propyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno [1,2-c]pyrazol-4-one
  • [0715]
    Prepared in a similar fashion as described for example LXXXVII and XLII using 1,1-dimethylhydrazine and the i-propyl analog of 15 as the starting materials. mp 231-233° C.; ESIMS (M+H) calc'd for C16H20N5O2: 314.1616, found: 314.1599.
  • Example CV Preparation of 3-(c-propyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno [1,2-c]pyrazol-4-one
  • [0716]
    Prepared in a similar fashion as described for example LXXXVII and XLII using 1,1-dimethylhydrazine and the c-propyl analog of 15 as the starting materials. mp XXX° C.; ESIMS (M+H) calc'd for C16H18N5O2: 312.1460, found: 312.1487.
  • Example CVI Preparation of 3-(c-hexyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno [1,2-c]pyrazol-4-one
  • [0717]
    Prepared in a similar fashion as described for example LXXXVII and XLII using 1,1-dimethylhydrazine and the c-hexyl analog of 15 as the starting materials. mp 229-231° C.; ESIMS (M+H) calc'd for C19H24N5O2: 354.1929, found: 354.1932.
  • Example CVII Preparation of 3-(2-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno [1,2-c]pyrazol-4-one
  • [0718]
    Prepared in a similar fashion as described for example LXXXVII and XLII using 1,1-dimethylhydrazine and the 2-thienyl analog of 15 as the starting materials. mp 279° C.; ESIMS (M+H) calc'd for C17H16N5O2S: 354.1024, found: 354.1025.
  • Example CVIII Preparation of 3-(5-methoxy-2-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno [1,2-c]pyrazol-4-one
  • [0719]
    Prepared in a similar fashion as described for example LXXXVII and XLII using 1,1-dimethylhydrazine and the 5-methoxy-2-thienyl analog of 15 as the starting materials. mp 280° C.; ESIMS (M+H) calc'd for C18H18N5O3S: 384.1130, found: 384.1119.
  • Example CIX Preparation of 3-(5-methyl-2-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno [1,2-c]pyrazol-4-one
  • [0720]
    Prepared in a similar fashion as described for example LXXXVII and XLII using 1,1-dimethylhydrazine and the 5-methyl-2-thienyl analog of 15 as the starting materials. mp >280° C.; ESIMS (M+H) calc'd for C18H18N5O2S: 368.1181, found: 368.1171.
  • Example CX Preparation of 3-(5-carboethoxy-2-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno [1,2-c]pyrazol-4-one
  • [0721]
    Prepared in a similar fashion as described for example LXXXVII and XLII using 1,1-dimethylhydrazine and the 5-ethylcarboxyl-2-thienyl analog of 15 as the starting materials. mp 252° C.; ESIMS (M+H) calc'd for C20H20N5O4S: 426.1236, found: 426.1251.
  • Example CXI Preparation of 3-(3-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno [1,2-c]pyrazol-4-one
  • [0722]
    Prepared in a similar fashion as described for example LXXXVII and XLII using 1,1-dimethylhydrazine and the 3-thienyl analog of 15 as the starting materials. mp 202° C.; ESIMS (M+H) calc'd for C17H16N5O2S: 354.1025, found: 354.1031.
  • Example CXII Preparation of 3-(1-methyl-3-pyrrolyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0723]
    Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 1-methyl-3-pyrrolyl analog of 15 as the starting materials. mp >300° C.; ESIMS (M+H) calc'd for C16H14N5O2: 308.1147, found: 308.1166.
  • Example CXIII Preparation of 3-(2,5-dimethyl-3-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno [1,2-c]pyrazol-4-one
  • [0724]
    Prepared in a similar fashion as described for example LXXXVII and XLII using 1,1-dimethylhydrazine and the 2,5-dimethyl-3-thienyl analog of 15 as the starting materials. mp 252° C.; ESIMS (M+H) calc'd for C19H20N5O2S: 382.1338, found: 382.1357.
  • Example CXIV Preparation of 3-(2-furanyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno [1,2-c]pyrazol-4-one
  • [0725]
    Prepared in a similar fashion as described for example LXXXVII and XLII using 1,1-dimethylhydrazine and the 2-furanyl analog of 15 as the starting materials. mp 202° C.; ESIMS (M+H) calc'd for C17H16N5O3: 338.1253, found: 338.1248.
  • Example CXV Preparation of 3-(i-propyl)-5-((4-carbamoylpiperidino)acetamido)indeno [1,2-c]pyrazol-4-one
  • [0726]
    Prepared in a similar fashion as described for example XXIII using isonipecotamide and the 1-propyl analog of 14 as the starting materials. mp 224-225° C.; ESIMS (M+H) calc'd for C21H26N5O3: 396.2035, found: 396.2036.
  • Example CXVI Preparation of 3-(c-hexyl)-5-((4-carbamoylpiperidino)acetamido)indeno [1,2-c]pyrazol-4-one
  • [0727]
    Prepared in a similar fashion as described for example XXIII using isonipecotamide and the c-hexyl analog of 14 as the starting materials. mp 228-229° C.; ESIMS (M+H) calc'd for C24H30N5O3: 436.2348, found: 436.2345.
  • Example CXVII Preparation of 3-(ethyl)-5-(4-(aminomethyl)piperidinoacetamido)indeno [1,2-c]pyrazol-4-one
  • [0728]
    Prepared in a similar fashion as described for example XXIII using 4-(aminomethyl)piperidine and the ethyl analog of 14 as the starting materials. mp 174-176° C.; ESIMS (M+H) calc'd for C20H26N5O2: 368.2086, found: 368.2078.
  • Example CXVIII Preparation of 3-(i-propyl)-5-(4-(aminomethyl)piperidinoacetamido)indeno [1,2-c]pyrazol-4-one
  • [0729]
    Prepared in a similar fashion as described for example XXIII using 4-(aminomethyl)piperidine and the 1-propyl analog of 14 as the starting materials. mp 218-220° C.; ESIMS (M+H) calc'd for C21H28N5O2: 382.2242, found: 382.2227.
  • Example CXIX Preparation of 3-(c-propyl)-5-(4-(aminomethyl)piperidinoacetamido)indeno [1,2-c]pyrazol-4-one
  • [0730]
    Prepared in a similar fashion as described for example XXIII using 4-(aminomethyl)piperidine and the c-propyl analog of 14 as the starting materials. mp 138-140° C.; ESIMS (M+H) calc'd for C21H26N5O2: 380.2086, found: 380.2079.
  • Example CXX Preparation of 3-(c-hexyl)-5-(4-(aminomethyl)piperidinoacetamido)indeno [1,2-c]pyrazol-4-one
  • [0731]
    Prepared in a similar fashion as described for example XXIII using 4-(aminomethyl)piperidine and the c-hexyl analog of 14 as the starting materials. mp 196-198° C.; ESIMS (M+H) calc'd for C24H32N5O2: 422.2555, found: 422.2540.
  • Example CXXI Preparation of 3-(i-propyl)-5-((4-methylpiperazino)carbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0732]
    Prepared in a similar fashion as described for example LXXXVII and XLII using 1-amino-4-methylpiperazine and the i-propyl analog of 15 as the starting materials. mp 231-233° C.; ESIMS (M+H) calc'd for C19H25N6O2: 369.2038, found: 369.2039.
  • Example CXXII Preparation of 3-(5-carboethoxy-2-thienyl)-5-((4-methylpiperazino)carbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0733]
    Prepared in a similar fashion as described for example LXXXVII and XLII using 1-amino-4-methylpiperazine and the 5-ethylcarboxyl-2-thienyl analog of 15 as the starting materials. mp 249° C.; ESIMS (M+H) calc'd for C23H25N6O4S: 481.1657, found: 481.1642.
  • Example CXXIII Preparation of 3-(5-carboxyl-2-thienyl)-5-((4-methylpiperazino)carbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0734]
    [0734]
  • [0735]
    A solution of CXXII (30 mg, 0.05 mmol) in 3:1 THF/water (2 mL) was treated with LiOH (23 mg, 0.5 mmol) and the reaction was stirred at 25° C. for 12 h and then heated to reflux for 1 h. The organic solvent was removed at reduced pressure and the residue was partioned between EtOAc (5 mL) and water (5 mL). The organic layer was separated and the aqueous phase was adjusted to pH=2 with 1 M HCl and re-extracted with EtOAc (5 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated at reduced pressure to give a crude residue. Purification by reverse phase HPLC gave the product as a yellow solid (10.4 mg, 46%). mp 270° C.; ESIMS (M+H) calc'd for C21H21N6O4S: 453.1344, found: 453.1353.
  • Example CXXIV Preparation of 3-(2,5-dimethyl-3-thienyl)-5-((4-methylpiperazino)carbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0736]
    Prepared in a similar fashion as described for example LXXXVI using 1-amino-4-methylpiperazine and the 2,5-dimethyl-3-thienyl analog of 15 as the starting materials. mp 250° C.; ESIMS (M+H) calc'd for C22H25N6O2S: 437.1760, found: 437.1771.
  • Example CXXV Preparation of 3-(i-propyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0737]
    Prepared in a similar fashion as described for example LXXXVI using 4-aminomorpholine and the 1-propyl analog of 15 as the starting materials. mp 256-258° C.; ESIMS (M−H) calc'd for C18H20N5O3: 354.1566, found: 354.1543.
  • Example CXXVI Preparation of 3-(1-methoxycarbonyl-4-piperidinyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0738]
    [0738]
  • [0739]
    Step 1. Synthesis of 29A from 4-acetylpiperidine hydrochloride.
  • [0740]
    A solution of 4-acetylpiperidine hydrochloride (8.18 g, 0.05 mol) in THF (100 mL) at 0° C. was treated with triethylamine (13.93 mL, 0.1 mol) and stirred for 15 min. The reaction mixture was treated with a solution of di-t-butyldicarbonate (10.91 g, 0.05 mol) in THF (50 mL) and stirred at 25° C. for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated at reduced pressure to give a pale yellow oil (10.7 g, 94%). The 4-acetyl-N-BOC-piperidine in EtOH (20 mL) was added dropwise to a solution of ethyl trifluoroacetate (6.25 g, 0.044 mol) and sodium ethoxide [freshly prepared from sodium (1.Olg, 0.044 mol) and EtOH (100 mL)] and stirred at 25° C. for 16 h. The solution was quenched with aqueous H2SO4 (50 mls, 0.044 mol) and extracted with EtOAc (200 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated at reduced pressure to give a pale yellow liquid (14.8 g, 92%). CI-MS (M+H) calc'd for C14H20F3NO4: 323.1344, found: 323.1337.
  • [0741]
    Step 2. Synthesis of 29B from 29A.
  • [0742]
    Prepared in a similar fashion as described for example LXXXVII, Step 1, using 3-nitrophthalic anhydride and 29A as the starting materials. mp 132-134° C.; ESI-MS (M+H) calc'd for C20H23N2O7: 403.1505, found: 403.1521.
  • [0743]
    Step 3. Synthesis of 29C from 29B.
  • [0744]
    Prepared in a similar fashion as described for example LXXXVII, Step 2, using 29B as the starting material. mp 187-189° C.; ESI-MS (M+H) calc'd for C20H25N2O5: 373.1763, found: 373.1777.
  • [0745]
    Step 4. Synthesis of 29D from 29C.
  • [0746]
    A suspension of C (8.0 g, 21.5 mmol) in acetone (200 mL) was treated with NaHCO3 (16.0 g) and phenyl chloroformate (4.04 g, 25.8 mol) and heated to 50° C. for 16 h. The reaction mixture was cooled, poured into water (200 mL), and extracted with EtOAc (400 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated at areduced pressure to give a crude residue. Trituration with hexane gave the product as a pale yellow solid (1.1 g, 79%). mp 121-123° C.; ESI-MS (M+H) calc'd for C27H29N2O7: 493.1975, found: 493.1982.
  • [0747]
    Step 5. Synthesis of 29E from 29D.
  • [0748]
    A solution of 29D (4.93 g, 0.01 mol) in dimethylsulfoxide (30 mL) was treated with 4-aminomorpholine (2.04 g, 0.02 mol) and heated to 90° C. in a sealed tube for 6 hours. The solvent was removed at reduced pressure and the residue was taken up in water (30 mL). The solid was filtered to give the product as a yellow solid (5.0 g, 99%). mp 164-166° C.; ESI-MS (M+H) calc'd for C25H33N4O7: 501.2349, found: 501.2357.
  • [0749]
    Step 6. Synthesis of 29F from 29E.
  • [0750]
    Prepared in a similar fashion as described for example LXXXVII, Step 4, using 29E (5.0 g, 0.01 mol) as the starting material to give the product as a yellow solid (3.8 g, 77%). mp 201-203° C.; ESI-MS (M−H) calc'd for C25H31N6O5: 495.2356, found: 495.2383.
  • [0751]
    Step 7. Synthesis of 29G from 29F.
  • [0752]
    A solution of 29F (1.8 g, 3.6 mmol) in methylene chloride (25 mL) was treated with trifluoroacetic acid (2.8 mL, 36 mmol) and stirred at 25° C. for 3 h. The organic solvent was removed at reduced pressure and rediluted with methylene chloride (25 mL). Removal of the organic solvent again at reduced pressure gave a solid which was treated with ether (25 mL) and stirred at 25° C. for 16 h. The solid was filtered to give the product as a yellow solid (1.8 g, 98%). mp 282-284° C.; ESI-MS (M+H) calc'd for C20H25N6O3: 397.1988, found: 397.1993.
  • [0753]
    Step 8. Synthesis of CXXVI from 29G.
  • [0754]
    A suspension of 29G (0.03 g, 0.059 mmol) in acetone (1 mL) was treated with NaHCO3 (0.06 g) and methyl chloroformate (6.69 mg, 0.071 mmol) and heated to 50° C. for 2 h. The reaction was cooled, poured into water (20 mL), and extracted with EtOAc (40 mL). The organic layer was separated, dried (MgSO4), filtered, and the concentrated at reduced pressure to give a yellow solid. Purification using reverse phase HPLC (CH3CN/water) gave the product as an off-white solid (7.7 mg, 23%). mp 216-218° C.; ESI-MS (M+H) calc'd for C22H27N6O5: 455.2043, found: 455.2036.
  • Example CXXVII Preparation of 3-(5-methyl-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0755]
    Prepared in a similar fashion as described for example LXXXVII and XLII using 4-aminomorpholine and the 5-methyl-2-thienyl analog of 15 as the starting materials. mp 261° C.; ESIMS (M+H) calc'd for C20H20N5O3S: 410.1287, found: 410.1308.
  • Example CXXVIII Preparation of 3-(5-chloro-3-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0756]
    Prepared in a similar fashion as described for example LXXXVII and XLII using 4-aminomorpholine and the 5-chloro-3-thienyl analog of 15 as the starting materials. mp 259° C.; ESIMS (M+H) calc'd for C19H17N5O3SCl: 430.0741, found: 430.0757.
  • Example CXXIX Preparation of 3-(2,5-dimethyl-3-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0757]
    Prepared in a similar fashion as described for example LXXXVII and XLII using 4-aminomorpholine and the 2,5-dimethyl-3-thienyl analog of 15 as the starting materials. mp >280° C.; ESIMS (M+H) calc'd for C21H22N5O3S: 424.1443, found: 424.1431.
  • Example CXXX Preparation of 3-(5-carboethoxy-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0758]
    Prepared in a similar fashion as described for example LXXXVII and XLII using 4-aminomorpholine and the 5-ethylcarboxyl-2-thienyl analog of 15 as the starting materials. mp 258° C.; ESIMS (M+H) calc'd for C22H22N5O5S: 468.1341, found: 468.1331.
  • Example CXXXI Preparation of 3-(5-carboxyl-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0759]
    Prepared in a similar fashion as described for example CXXIII using CXXX as starting material. mp 273° C.; ESIMS (M+H) calc'd for C20H18N5O5S: 440.1028, found: 440.1026.
  • Example CXXXII Preparation of 3-(5-benzylaminocarbonyl-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0760]
    [0760]
  • [0761]
    A solution of benzylamine (0.01 mL, 0.09 mmol) in DMF (1 mL) was treated with acid CXXXI (40 mg, 0.09 mmol) and stirred at 25° C. The reaction was treated with TBTU (29 mg, 0.09 mmol) and stirred at 25° C. for 30 min. Triethylamine (0.01 mL, 0.09 mmol) was added and the reaction stirred at 25° C. for 12 h. After adding more TBTU (15 mg, 0.045 mmol) and triethylamine (0.01 mL, 0.09 mmol) the reaction was stirred at 25° C. for an additional 4 h. The reaction was diluted with EtOAc (10 mL) and water (10 mL) and the aqueous layer was extracted with EtOAc (5×10 mL). The combined organic layers were dried (Na2SO4), filtered, and the solvent removed at reduced pressure. Purification of the residue using reverse phase HPLC gave the product as a yellow solid (21 mg, 42%). mp 275° C.; ESIMS (M+H) calc'd for C27H25N5O4S: 529.1659, found: 529.1682.
  • Example CXXXIII Preparation of 3-(5-((4-methylpiperazino) carbonyl)-2-thienyl)-5-(morpholinylcarbamoyl)aminoindeno [1,2-c]pyrazol-4-one
  • [0762]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-amino-4-methylpiperazine as the starting materials. mp 190° C. (TFA salt); ESIMS (M+H) calc'd for C25H29N8O4S: 537.2032, found: 537.2055.
  • Example CXXXIV Preparation of 3-(5-((2-(1-methyl-2-pyrrolidinyl)ethyl) aminocarbonyl)-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0763]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 2-(2-aminoethyl)-1-methylpyrrolidine as the starting materials. mp 235° C. (TFA salt); ESIMS (M+H) calc'd for C27H32N7O4S: 550.2236, found: 550.2229.
  • Example CXXXV Preparation of 3-(5-((N,N-dimethylamino) aminocarbonyl)-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0764]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and l,l-dimethylhydrazine as the starting materials. mp 201° C. (TFA salt); ESIMS (M+H) calc'd for C22H24N7O4S: 482.1610, found: 482.1588.
  • Example CXXXVI Preparation of 3-(5-(2-((N,N-dimethylamino)ethyl) aminocarbonyl)-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0765]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and N,N-dimethylethylenediamine as the starting materials. mp 190° C. (TFA salt); ESIMS (M+H) calc'd for C24H28N7O4S: 510.1923, found: 510.1922.
  • Example CXXXVII Preparation of 3-(5-((2-pyrrolidinoethyl) aminocarbonyl)-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0766]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-(2-aminoethyl)pyrrolidine as the starting materials. mp 224° C. (TFA salt); ESIMS (M+H) calc'd for C26H30N7O4S: 536.2080, found: 536.2091.
  • Example CXXXVIII Preparation of 3-(5-((2-morpholinoethyl) aminocarbonyl)-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0767]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-(2-aminoethyl)morpholine as the starting materials. mp 241° C. (TFA salt); ESIMS (M+H) calc'd for C26H30N7O5S: 552.2029, found: 552.2043.
  • Example CXXXIX Preparation of 3-(5-(morpholinoaminocarbonyl)-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0768]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-aminomorpholine as the starting materials. mp 271° C. (TFA salt); ESIMS (M+H) calc'd for C24H26N7O5S: 524.1716, found: 524.1719.
  • Example CXL Preparation of 3-(5-((3-(2-pyrrolidon-1-yl)propyl) aminocarbonyl)-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0769]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-(3-aminopropyl)-2-pyrrolidinone as the starting materials. mp 260° C. (TFA salt); ESIMS (M+H) calc'd for C27H30N7O5S: 564.2029, found: 564.2031.
  • Example CXLI Preparation of 3-(5-((2-(3-pyridyl)ethyl) aminocarbonyl)-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0770]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 3-(2-aminoethyl)pyridine as the starting materials. mp 203° C. (TFA salt); ESIMS (M+H) calc'd for C27H26N7O4S: 544.1766, found: 544.1760.
  • Example CXLII Preparation of 3-(5-((3-(1-imidazolyl)propyl) aminocarbonyl)-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0771]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-(3-aminopropyl)imidazole as the starting materials. mp 263° C. (TFA salt); ESIMS (M+H) calc'd for C26H27N8O4S: 547.1875, found: 547.1872.
  • Example CXLIII Preparation of 3-(5-((2-(2-pyridyl)ethyl) aminocarbonyl)-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0772]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 2-(2-aminoethyl)pyridine as the starting materials. mp >280° C. (TFA salt); ESIMS (M+H) calc'd for C27H26N7O4S: 544.1767, found: 544.1778.
  • Example CXLIV Preparation of 3-(5-(((2-pyridyl)methyl) aminocarbonyl)-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0773]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 2-(aminomethyl)pyridine as the starting materials. mp 239° C. (TFA salt); ESIMS (M+H) calc'd for C26H24N7O4S: 530.1610, found: 530.1603.
  • Example CXLV Preparation of 3-(5-((2-piperidinoethyl) aminocarbonyl)-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0774]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-(2-aminoethyl)piperidine as the starting materials. mp 228° C. (TFA salt); ESIMS (M+H) calc'd for C27H32N7O4S: 550.2236, found: 550.2236.
  • Example CXLVI Preparation of 3-(5-pyrrolidinoaminocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0775]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-aminopyrrolidine as the starting materials. mp 213-215° C. (TFA salt); ESI-MS (M+H) calc'd for C24H26N7O4S: 508.1764, found: 508.1774.
  • Example CXLVII Preparation of 3-(5-piperidinoaminocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0776]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-aminopiperidine as the starting materials. mp 189-191° C. (TFA salt); ESI-MS (M+H) calc'd for C25H28N7O4S: 522.1923, found: 522.1920.
  • Example CXLVIII Preparation of 3-(5-piperidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0777]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and piperidine as the starting materials. ESI-MS (M+H) calc'd for C25H27N6O4S: 507.1815, found: 507.1833.
  • Example CXLIX Preparation of 3-(5-piperazinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0778]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and piperazine as the starting materials. mp 241-242° C. (TFA salt); ESI-MS (M+H) calc'd for C24H26N7O4S: 508.5732, found: 508.1758.
  • Example CL Preparation of 3-(5-(4-methylpiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0779]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-methylpiperazine as the starting materials. mp 186-187° C. (TFA salt); ESI-MS (M+H) calc'd for C25H28N7O4S: 522.1923, found: 522.1928.
  • Example CLI Preparation of 3-(5-(4-ethylpiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0780]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-ethylpiperazine as the starting materials. mp 186-188° C. (TFA salt); ESI-MS (M+H) calc'd for C26H30N7O4S: 536.2080, found: 536.2081.
  • Example CLII Preparation of 3-(5-(4-(2-hydroxyethyl)piperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0781]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-(2-hydroxyethyl)piperazine as the starting materials. mp 186-187° C. (TFA salt); ESI-MS (M+H) calc'd for C26H30N7O5S: 552.2029, found: 552.2032.
  • Example CLIII Preparation of 3-(5-(4-(cyclopropylmethyl)piperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0782]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-(cyclopropylmethyl)piperazine as the starting materials. mp 211-212° C. (TFA salt); ESI-MS (M+H) calc'd for C28H32N7O4S: 562.2236, found: 562.2249.
  • Example CLIV Preparation of 3-(5-(4-(t-butoxycarbonyl)piperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0783]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-t-butoxycarbonylpiperazine as the starting materials. mp 225-226° C. (TFA salt); ESI-MS (M+H) calc'd for C29H34N7O6S: 608.2290, found: 608.2320.
  • Example CLV Preparation of 3-(5-(4-(2-pyridyl)piperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0784]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-(2-pyridyl)piperazine as the starting materials. mp 201-202° C. (TFA salt); ESI-MS (M+H) calc'd for C29H29N8O4S: 585.2032, found: 585.2002.
  • Example CLVI Preparation of 3-(5-(((1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptyl)carbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0785]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and (1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C25H26N7o4S: 520.1767, found: 520.1765.
  • Example CLVII Preparation of 3-(5-(((1S,4S)-(+)-2-methyl-2,5-diazabicyclo[2.2.l]heptyl)carbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0786]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and (lS,4S)-(+)-2-methyl-2,5-diazabicyclo[2.2.1]heptane as the starting materials. mp 224-225° C. (TFA salt); ESI-MS (M+H) calc'd for C26H28N7O4S: 534.1923, found: 534.1934.
  • Example CLVIII Preparation of 3-(5-(4-(N,N-dimethylamino)piperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0787]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-(N,N-dimethylamino)piperidine as the starting materials. mp 185-186° C. (TFA salt); ESI-MS (M+H) calc'd for C27H32N7O4S: 550.2240, found: 550.2250.
  • Example CLIX Preparation of 3-(5-(4-pyrrolidinopiperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0788]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-pyrrolidinopiperidine as the starting materials. mp 228° C. (TFA salt); ESI-MS (M+H) calc'd for C29H34N7O4S: 576.2393, found: 576.2410.
  • Example CLX Preparation of 3-(5-(4-piperidinopiperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0789]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-piperidinopiperidine as the starting materials. ESI-MS (M+H) calc'd for C30H36N7O4S: 590.2549, found: 590.2536.
  • Example CLXI Preparation of 3-(5-cyclohexylaminocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0790]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and cyclohexylamine as the starting materials. mp 264-267° C. (TFA salt); ESI-MS (M+H) calc'd for C26H29N6O4S: 521.1971, found: 521.1971.
  • Example CLXII Preparation of 3-(5-(4-piperidylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0791]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-aminopiperidine as the starting materials. mp 224-226° C. (TFA salt); ESI-MS (M+H) calc'd for C25H28N7O4S: 522.1923, found: 522.1933.
  • Example CLXIII Preparation of 3-(5-((1-(t-butoxycarboxyl)piperidin-4-yl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0792]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-amino-1-(t-butoxycarbonyl)piperidine as the starting materials. mp 229-230° C. (TFA salt); ESI-MS (M+H) calc'd for C30H34N7O4S: 620.2291, found: 620.2304.
  • Example CLXIV Preparation of 3-(5-(4-(1-methylpiperidin-4-yl)methylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0793]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-methyl-4-(methylamino)piperidine as the starting materials. mp 230° C. (TFA salt); ESI-MS (M+H) calc'd for C27H32N7O4S: 550.2236, found: 550.2241.
  • Example CLXV Preparation of 3-(5-(3-(N,N-dimethylamino)piperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0794]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 3-(N,N-dimethylamino)piperidine as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C27H32N7O4S: 550.2236, found: 550.2232.
  • Example CLXVI Preparation of 3-(5-(3-p-toluenesulfonylamino)piperidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0795]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 3-(p-toluenesulfonylamino)piperidine as the starting materials. mp 193-194° C. (TFA salt); ESI-MS (M+H) calc'd for C32H34N7O6S: 676.2018, found: 676.2025.
  • Example CLXVII Preparation of 3-(5-(3-hydroxypiperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0796]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 3-hydroxypiperidine as the starting materials. ESI-MS (M+H) calc'd for C25H27N6O5S: 523.1764, found: 523.1765.
  • Example CLXVIII Preparation of 3-(5-((3-piperidyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0797]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 3-aminopiperidine as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C25H28N7O4S: 522.1923, found: 522.1934.
  • Example CLXIX Preparation of 3-(5-((3-quinuclidyl)aminocarbonyl)-2-thienyl)-S-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0798]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and (S)-(−)-3-aminoquinuclidine as the starting materials. mp 245-246° C. (TFA salt); ESI-MS (M+H) calc'd for C27H30N7O4S: 548.2080, found: 548.2084.
  • Example CLXX Preparation of 3-(5-((3-aminocyclohexyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0799]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1,3-diaminocyclohexane as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C26H30N7O4S: 536.2080, found: 536.2078.
  • Example CLXXI Preparation of 3-(5-((3-(t-butoxycarbonylamino)cyclohexyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0800]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-amino-3-(t-butoxycarbonylamino)cyclohexane as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C31H38N706S: 636.2604, found: 636.2625.
  • Example CLXXII Preparation of 3-(5-(2-(N,N-dimethylaminomethyl)piperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0801]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 2-(dimethylaminomethyl)piperidine as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C28H34N7O4S: 564.2393, found: 564.2388.
  • Example CLXXIII Preparation of 3-(5-(2-(N,N-diethylaminomethyl)piperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0802]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 2-(diethylaminomethyl)piperidine as the starting materials. mp 210-212° C. (TFA salt); ESI-MS (M+H) calc'd for C30H38N7O4S: 592.2706, found: 592.2706.
  • Example CLXXIV Preparation of 3-(5-pyrrolidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0803]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and pyrrolidine as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C24H25N6O4S: 493.1658, found: 493.1679.
  • Example CLXXV Preparation of 3-(5-(3-aminopyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0804]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 3-aminopyrrolidine as the starting materials. mp 201-202° C. (TFA salt); ESI-MS (M+H) calc'd for C24H26N7O4S: 508.5793, found: 508.1775.
  • Example CLXXVI Preparation of 3-(5-(3(S)-N-methylamino)pyrrolidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0805]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and (S)-3-N-methylaminopyrrolidine as the starting materials. ESI-MS (M+H) calc'd for C25H28N7O4S: 522.1920, found: 522.1920.
  • Example CLXXVII Preparation of 3-(5-(3(S)-acetamidopyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0806]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and (S)-3-N-acetamidopiperidine as the starting materials. mp 264-265° C. (TFA salt); ESI-MS (M+H) calc'd for C26H28N7O5S: 550.1873, found: 550.1896.
  • Example CLXXVIII Preparation of 3-(5-(3(S)-(N-methylacetamido)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0807]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and (S)-3-(N-acetyl-N-methylamino)piperidine as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C27H30N7O5S: 564.2029, found: 564.2054.
  • Example CLXXIX Preparation of 3-(5-(3(S)-(N-methyl-t-butoxycarbonylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0808]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and (S)-3-(N-t-butoxycarbonyl-N-methylamino)piperidine as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C30H36N7O6S: 622.2448, found: 622.2472.
  • Example CLXXX Preparation of 3-(5-(3-(N,N-dimethylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0809]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 3-(N,N-dimethylamino)pyrrolidine as the starting materials. mp 216-217° C. (TFA salt); ESI-MS (M+H) calc'd for C26H30N7O4S: 536.2079, found: 536.2070.
  • Example CLXXXI Preparation of 3-(5-(3(R)-(N,N-dimethylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0810]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and (R)-3-(N,N-dimethylamino)pyrrolidine as the starting materials. mp 265° C. (TFA salt); ESI-MS (M+H) calc'd for C26H30N7O4S: 536.298, found: 536.2105.
  • Example CLXXXII Preparation of 3-(5-(3(S)-(N,N-dimethylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0811]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and (S)-3-(N,N-dimethylamino)pyrrolidine as the starting materials. mp 264-265° C. (TFA salt); ESI-MS (M+H) calc'd for C26H30N7O4S: 536.2980, found: 536.2096.
  • Example CLXXXIII Preparation of 3-(5-((1-methylpyrrolidin-3-yl)methylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0812]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-methyl-3-(methylamino)pyrrolidine as the starting materials. mp 151-153° C. (TFA salt); ESI-MS (M+H) calc'd for C26H30N7O4S: 536.2080, found: 536.2088.
  • Example CLXXXIV Preparation of 3-(5-(2(R)-(pyrrolidinomethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0813]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and (R)-2-(pyrrolidinomethyl)pyrrolidine as the starting materials. mp 166-167° C. (TFA salt); ESI-MS (M+H) calc'd for C29H34N7O4S: 536.2393, found: 576.2416.
  • Example CLXXXV Preparation of 3-(5-(2(S)-(hydroxymethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0814]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and (S)-2-(hydroxymethyl)pyrrolidine as the starting materials. mp 267-268° C. (TFA salt); ESI-MS (M+H) calc'd for C25H27N6O5S: 523.1764, found: 523.1754.
  • Example CLXXXVI Preparation of 3-(5-(2(R)-(methoxymethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0815]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and (R)-2-(methoxymethyl)pyrrolidine as the starting materials. mp 262° C. (TFA salt); ESI-MS (M+H) calc'd for C26H29N6O4S: 537.1920, found: 537.1936.
  • Example CLXXXVII Preparation of 3-(5-(2(S)-(phenylaminomethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0816]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and (S)-2-(phenylaminomethyl)pyrrolidine as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C31H32N7O4S: 598.2236, found: 598.2225.
  • Example CLXXXVIII Preparation of 3-(5-(2(R)-(methoxymethyl)pyrrolidinoaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0817]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and (R)-1-amino-2-(methoxymethyl)pyrrolidine as the starting materials. mp 266-267° C. (TFA salt); ESI-MS (M+H) calc'd for C26H30N7O5S: 552.2029, found: 552.2036.
  • Example CLXXXIX Preparation of 3-(5-homopiperidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0818]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and homopiperidine as the starting materials. ESI-MS (M+H) calc'd for C26H29N6O4S: 521.1971, found: 521.1943.
  • Example CXC Preparation of 3-(5-homopiperazinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0819]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and homopiperazine as the starting materials. mp 209° C. (TFA salt); ESI-MS (M+H) calc'd for C25H28N7O4S: 522.1923, found: 522.1901.
  • Example CXCI Preparation of 3-(5-(4-methylhomopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0820]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-methylhomopiperazine as the starting materials. mp 207-208° C. (TFA salt); ESI-MS (M+H) calc'd for C26H30N7O4S: 536.2080, found: 536.2086.
  • Example CXCII Preparation of 3-(5-(4-ethylhomopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0821]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-ethylhomopiperazine as the starting materials. mp 192-193° C. (TFA salt); ESI-MS (M+H) calc'd for C27H32N7O4S: 550.2237, found: 550.2241.
  • Example CXCIII Preparation of 3-(5-(4-(cyclopropylmethyl)homopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0822]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-(cyclopropylmethyl)homopiperazine as the starting materials. mp 194-196° C. (TFA salt); ESI-MS (M+H) calc'd for C29H34N7O4S: 576.2393, found: 576.2410.
  • Example CXCIV Preparation of 3-(5-(4-(t-butoxycarbonyl)homopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0823]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-t-butoxycarbonylhomopiperazine as the starting materials. mp 210-211° C. (TFA salt); ESI-MS (M+H) calc'd for C30H36N7O6S: 622.2488, found: 622.2450.
  • Example CXCV Preparation of 3-(5-(4-acetylhomopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0824]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-acetylhomopiperazine as the starting materials. mp 274-275° C. (TFA salt); ESI-MS (M+H) calc'd for C27H30N7O5S: 564.2029, found: 564.2056.
  • Example CXCVI Preparation of 3-(5-((4-methylaminophenyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0825]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-(methylamino)aniline as the starting materials. mp 230° C. (TFA salt); ESI-MS (M+H) calc'd for C27H26N7O4S: 544.1767, found: 544.1772.
  • Example CXCVII Preparation of 3-(5-((4-acetamidophenyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0826]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-(acetamido)aniline as the starting materials. mp 253-254° C. (TFA salt); ESI-MS (M+H) calc'd for C30H28N4O6S: 572.1730, found: 572.1723.
  • Example CXCVIII Preparation of 3-(5-(4-(diethylamino)phenylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0827]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-(diethylamino)aniline as the starting materials. mp 198-199° C. (TFA salt); ESI-MS (M+H) calc'd for C30H32N7O4S: 586.2236, found: 586.2224.
  • Example CXCIX Preparation of 3-(5-((1-methyl-3-cyclopropylpyrazo-5-yl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0828]
    Prepared in a similar fashion as described for example CXXXII using CXXXI and 5-amino-3-cyclopropyl-1-methylpyrazole as the starting materials. mp 290° C. (TFA salt); ESI-MS (M+H) calc'd for C27H27N8O4S: 559.1876, found: 559.1849.
  • Example CC Preparation of 3-(1-methyl-3-pyrrolyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0829]
    Prepared in a similar fashion as described for example LXXXVII and XLII using 4-aminomorpholine and the 1-methyl-3-pyrrolyl analog of 15 as the starting materials. mp 301° C.; ESI-MS (M+H) calc'd for C20H21N6O3: 393.1675, found: 393.1669.
  • Example CCI Preparation of 3-(5-carboethoxy-2-thienyl)-5-(2 (R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0830]
    Prepared in a similar fashion as described for example LXXXVII and XLII using 1-amino-2(R)-(methoxymethyl)pyrrolidine and the 5-carboethoxy-2-thienyl analog of 15 as the starting materials. mp 221-222° C.; ESI-MS (M+H) calc'd for C24H26N5O5S: 496.1655, found: 496.1658.
  • Example CCII Preparation of 3-(5-carboxyl-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0831]
    Prepared in a similar fashion as described for example CXXIII using CCI as the starting material. mp 258-259° C. (TFA salt); ESI-MS (M+H) calc'd for C22H22N5O5S: 468.1342, found: 468.1346.
  • Example CCIII Preparation of 3-(5-(4-methylpiperazinocarbonyl)-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0832]
    Prepared in a similar fashion as described for example CXXXII using 1-methylpiperazine and CCII as the starting materials. mp 181-183° C. (TFA salt); ESI-MS (M+H) calc'd for C27H32N7O4S: 550.2236, found: 550.2251.
  • Example CCIV Preparation of 3-(5-piperazinocarbonyl-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0833]
    Prepared in a similar fashion as described for example CXXXII using piperazine and CCII as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C26H31N7O4S: 536.2080, found: 536.2091.
  • Example CCV Preparation of 3-(5-(4-(t-butoxycarbonyl)piperazinocarbonyl)-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0834]
    Prepared in a similar fashion as described for example CXXXII using 1-t-butoxycarbonylpiperazine and CCII as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C31H38N7O6S: 636.2604, found: 636.2633.
  • Example CCVI Preparation of 3-(5-(4-methylhomopiperazinocarbonyl)-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0835]
    Prepared in a similar fashion as described for example CXXXII using 1-methylhomopiperazine and CCII as the starting materials. mp 176-177° C. (TFA salt); ESI-MS (M+H) calc'd for C28H34N7O4S: 564.2393, found: 564.2388.
  • Example CCVII
  • [0836]
    Preparation of 3-(5-homopiperazinocarbonyl-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0837]
    Prepared in a similar fashion as described for example CXXXII using homopiperazine and CCII as the starting materials. mp 185-186° C. (TFA salt); ESI-MS (M+H) calc'd for C27H32N7O4S: 550.2236, found: 550.2231.
  • Example CCVIII Preparation of 3-(5-(4-(t-butoxycarbonyl)homopiperazinocarbonyl)-2-thienyl)-5-(2 (R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0838]
    Prepared in a similar fashion as described for example CXXXII using 1-t-butoxycarbonylhomopiperazine and CCII as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C32H40N7O6S: 650.2761, found: 650.2753.
  • Example CCIX Preparation of 3-(4-(trifluoromethyl)phenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one
  • [0839]
    Prepared in a similar fashion as described for example LXXXVI employing 1-(4-(trifluoromethyl)phenyl)-4,4,4-trifluoro-1,3-butanedione as the starting material. mp >300 ° C.; ESI -MS m/e calc'd for C19H11N3O2: 370.0804, found: 370.0809.
  • Example CCX Preparation of 3-(4-(4-t-butoxycarbonylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0840]
    [0840]
  • [0841]
    Step 1. Synthesis of 30
  • [0842]
    To a suspension of 139 g (680 mmol) of 4-piperazinoacetophenone in 700 mL of tetrahydrofuran at 25° C. was added slowly over 20 min. a solution of 157 g (720 mmol) of di-tert-butyl dicarbonate in 300 mL of tetrahydrofuran. The resulting mixture was refluxed for 15 h. After cooling the mixture was filtered, and the filtrate was concentrated under vacuum to provide an off-white solid. This crude product was recrystallized from diethyl ether/hexane to afford 192 g of the 30 as a white solid. NMR (CDCl3) δ 7.89 (d, 2H, J=9 Hz), 6.87 (d, 2H, J=9 Hz), 3.59 (m, 4H), 3.33 (m, 4H), 2.53 (s, 3H), 1.49 (s, 9H).
  • [0843]
    Step 2. Synthesis of 31 from 30
  • [0844]
    To a solution of 192 g (630 mmol) of 30 and 90 mL (750 mmol) of ethyl trifluoroacetate in 1000 mL of tetrahydrofuran at 25° C. was added slowly over 15 min. 280 mL (750 mmol) of 21% sodium ethoxide in ethanol, and the resulting solution then was stirred at 25° C. for 16 h. The reaction mixture was diluted with 500 mL of water, and to this mixture was added 45 mL of acetic acid. The resulting precipitate was recovered by filtration. The solids were washed with diethyl ether/hexane and dried to furnish 236 g of 31 as an orange solid. NMR (CDCl3) δ 7.87 (d, 2H, J=9 Hz), 6.87 (d, 2H, J=9 Hz), 6.45 (s, 1H), 3.60 (m, 4H), 3.41 (m, 4H), 1.48 (s, 9H).
  • [0845]
    Step 3. Synthesis of 32 from 31
  • [0846]
    A suspension of 117 g (610 mmol) of 3-nitrophthalic anhydride in 560 mL of acetic anhydride was heated until the mixture became homogeneous, and the solution then was allowed to cool to room temperature. To this solution was added 236 g (590 mmol) of 31. The resulting mixture was cooled to 0° C., and 165 mL (1200 mmol) of triethylamine was added slowly over 10 min. The mixture was allowed to warm to 25° C., was stirred at 25° C. for 1 h, and then was heated to 65° C. for 0.5 h. After cooling to room temperature, the reaction mixture was poured into a well-stirred solution of 1200 mL of 1.0 N hydrochloric acid and 2000 mL of ethanol. The resulting precipitate was recovered by filtration, washed with ethanol, and dried to provide 140 g of 32 as an orange solid. NMR (acetone-d6) δ 8.34 (d, 2H, J=9 Hz), 8.05 (m, 3H), 7.07 (d, 2H, J=9 Hz), 3.59 (br s, 8H), 1.48 (s, 9H).
  • [0847]
    Step 4. Synthesis of 33 from 32
  • [0848]
    To a solution of 12.00 g (25 mmol) of 32 in 500 mL of ethanol and 50 mL of conc. ammonium hydroxide at 25° C. was added 500 mL of water, followed by 15.3 g (88 mmol) of sodium dithionite. The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was filtered, and the filtrate was reduced to ˜½ the original volume under vacuum. This solution was adjusted to pH 3 employing hydrochloric acid and then extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over anhyd. sodium sulfate, filtered, and concentrated. The resulting solids were recrystallized from ethanol/water to provide 8.40 g of 33 as a green solid. NMR (DMSO-d6) δ 8.20 (d, 2H, J=9 Hz), 7.44 (t, 1H, J=8 Hz), 7.02 (d, 2H, J=9 Hz), 6.96 (d, 1H, J=8 Hz), 6.91 (d, 1H, J=8 Hz), 6.70 (br s, 2H), 3.46 (br s, 8H), 1.43 (s, 9H).
  • [0849]
    Step 5. Synthesis of 35 from 33 and 34.
  • [0850]
    A solution of 4.50 g (10 mmol) of 33, 4.45 g (20 mmol) of 34, 3.68 g (30 mmol) of 4-dimethylaminopyridine, and 80 mL of DMSO was stirred at 90° C. for 2.5 h. After cooling to room temperature the reaction mixture was poured into a well-stirred solution of 80 mL of ethanol and 30 mL of 1N hydrochloric acid. The resulting solution was diluted further by the slow addition of 120 mL of water. A precipitate formed. It was recovered by filtration, washed with 50% aqueous ethanol, and dried to provide 3.83 g of 35 as an orange solid. NMR (DMSO-d6) δ 10.95 (br s, 1H), 8.60 (d, 1H, J=8.5 Hz), 8.38 (br s, 1H), 8.24 (d, 2H, J=9 Hz), 7.69 (t, 1H, J=8.5 Hz), 7.32 (d, 1H, J=8.5 Hz), 7.04 (d, 2H, J=9 Hz), 3.86 (m, 4H), 3.74 (m, 4H), 2.91 (m, 4H), 2.73 (m, 4H), 1.44 (s, 9H).
  • [0851]
    Step 6. Synthesis of CCX from 35.
  • [0852]
    A mixture of 3.82 g (6.6 mmol) of 35, 0.64 mL (13.2 mmol) of hydrazine monohydrate, 0.090 g (1.32 mmol) of hydrazine hydrochloride, and 130 mL of ethanol was refluxed for 18 h. While still at reflux the solution was diluted by the dropwise addition of 30 mL of water. The mixture then was allowed to cool to room temperature. The resulting precipitate was recovered by filtration, washed with 80% aqueous ethanol, and dried to afford 1.80 g of CCX as a yellow solid. mp 242° C.; ESI-MS m/e calc'd for C30H36N7O5: 574.2778, found: 574.2762.
  • Example CCXI Preparation of 3-(4-piperazinophenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0853]
    A solution of CCX (0.58 g, 1.0 mmol) in 20 mL of trifluoroacetic acid was stirred at 25° C. for 2 h. The reaction mixture was concentrated under vacuum, and the residue was recrystallized from ethanol to provide 0.53 g of the yellow product as its TFA-salt. mp 263° C.; ESI-MS m/e calc'd for C25H28N7O3: 474.2254, found: 474.2280.
  • Example CCXII Preparation of 3-(4-piperazinophenyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0854]
    Prepared in a similar fashion as described for examples CCX and CCXI employing 2-(4-(4-t-butoxycarbonyl-1-piperazinyl)benzoyl)-4-amino-1,3-indanedione obtained in example CCX and ammonia as the starting materials. mp 257° C. (TFA salt); ESI-MS m/e calc'd for C21H21N6O2: 389.1726, found: 389.1724.
  • Example CCXIII Preparation of 3-(4-piperazinophenyl)-5-(aminocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0855]
    Prepared in a similar fashion as described for examples CCX and CCXI employing 2-(4-(4-t-butoxycarbonylpiperazino)benzoyl)-4-amino-1,3-indanedione obtained in example CCX and hydrazine as the starting materials. mp 257° C. (TFA salt); ESI-MS m/e calc'd for C21H22N7O2: 404.1835, found: 404.1834.
  • Example CCXIV Preparation of 3-(4-piperazinophenyl)-5-((N,N-dimethylamino)acetamido)indeno[1,2-c]pyrazol-4-one
  • [0856]
    Prepared employing 2-(4-(4-t-butoxycarbonylpiperazino)benzoyl)-4-amino-1,3-indanedione obtained in example CCX as the starting material. Chloroacetylation and treatment with dimethylamine in a similar fashion as described for examples II and XXIII, followed by treatment with hydrazine and removal of the t-butoxycarbonyl group in a similar fashion as described for examples I and CCXI, afforded the example compound. mp 243° C. (TFA salt); ESI-MS m/e calc'd for C24H27N6O2: 431.2196, found: 431.2198.
  • Example CCXV Preparation of 3-(4-piperazinophenyl)-5-(morpholinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0857]
    Prepared employing 2-(4-(4-t-butoxycarbonylpiperazino)benzoyl)-4-amino-1,3-indanedione obtained in example CCX as the starting material. Chloroacetylation and treatment with morpholine in a similar fashion as described for examples II and XXIII, followed by treatment with hydrazine and removal of the t-butoxycarbonyl group in a similar fashion as described for examples I and CCXI, afforded the example compound. mp 259° C. (TFA salt); ESI-MS m/e calc'd for C26H29N6O3: 473.2301, found: 473.2302.
  • Example CCXVI Preparation of 3-(4-piperazinophenyl)-5-((4-methylpiperazino)acetamido)indeno[1,2-c]pyrazol-4-one
  • [0858]
    Prepared employing 2-(4-(4-t-butoxycarbonylpiperazino)benzoyl)-4-amino-1,3-indanedione obtained in example CCX as the starting material. Chloroacetylation and treatment with 1-methylpiperazine in a similar fashion as described for examples II and XXIII, followed by treatment with hydrazine and removal of the t-butoxycarbonyl group in a similar fashion as described for examples I and CCXI, afforded the example compound. ESI-MS m/e calc'd for C27H32N7O2: 486.2618, found: 486.2608.
  • Example CCXVII Preparation of 3-(4-piperazinophenyl)-5-(4-(aminomethyl)piperidinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0859]
    Prepared employing 2-(4-(4-t-butoxycarbonylpiperazino)benzoyl)-4-amino-1,3-indanedione obtained in example CCX as the starting material. Chloroacetylation and treatment with 4-(aminomethyl)piperidine in a similar fashion as described for examples II and XXIII, followed by treatment with hydrazine and removal of the t-butoxycarbonyl group in a similar fashion as described for examples I and CCXI, afforded the example compound. mp 239° C. (TFA salt); ESI-MS m/e calc'd for C28H34N7O2: 500.2774, found: 500.2772.
  • Example CCXVIII Preparation of 3-(4-(4-methylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0860]
    [0860]
  • [0861]
    To a solution of CCXI (0.17 g, 0.29 mmol) in 10 mL of methanol and 2 mL of water at 25° C. was added sequentially 37% aqueous formaldehyde (0.45 g, 5.8 mmol), sodium cyanoborohydride (0.18 g, 2.9 mmol), and 4 drops of acetic acid. The resulting solution was stirred at 25° C. for 16 h. The mixture was diluted with water. It then was made acidic (˜pH 1) with conc. hydrochloric acid and stirred for 10 min. The solution next was made basic (˜pH 13) with 50% aqueous sodium hydroxide and finally adjusted to pH 10 with 1 N hydrochloric acid. The mixture was extracted with 4:1 chloroform/isopropanol. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. To the filtrate was added excess trifluoroacetic acid, and the solution was concentrated under vacuum. The residue was recrystallized from isopropanol to furnish 0.16 g (92%) of the yellow product as its TFA-salt. mp 245° C.; ESI-MS m/e calc'd for C26H30N7O3: 488.2410, found: 488.2420.
  • Example CCXIX Preparation of 3-(4-(4-ethylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0862]
    Prepared in a similar fashion as described for example CCXVIII employing CCXI and acetaldehyde as the starting materials. mp 245° C. (TFA salt); ESI-MS m/e calc'd for C27H32N7O3: 502.2567, found: 502.2555.
  • Example CCXX Preparation of 3-(4-(4-isopropylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0863]
    Prepared in a similar fashion as described for example CCXVIII employing CCXI and acetone as the starting materials. mp 253° C. (TFA salt); ESI-MS m/e calc'd for C28H34N7O3: 516.2723, found: 516.2726.
  • Example CCXXI Preparation of 3-(4-piperazinophenyl)-5-((N,N-dimethylamino)carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0864]
    Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1,1-dimethylhydrazine as the starting materials. mp 238° C. (TFA salt); ESI-MS m/e calc'd for C23H26N7O2: 432.2148, found: 432.2150.
  • Example CCXXII Preparation of 3-(4-(4-methylpiperazino)phenyl)-5-((N,N-dimethylamino)carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0865]
    Prepared in a similar fashion as described for example CCXVIII employing CCXI as the starting material. mp 192° C. (TFA salt); ESI-MS m/e calc'd for C24H28N7O2: 446.2305, found: 446.2313.
  • Example CCXXIII Preparation of 3-(4-piperazinophenyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0866]
    Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-4-methylpiperazine as the starting materials. mp 254° C. (TFA salt); ESI-MS m/e calc'd for C26H31N8O2: 487.2570, found: 487.2574.
  • Example CCXXIV Preparation of 3-(4-(4-methylpiperazino)phenyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0867]
    Prepared in a similar fashion as described for example CCXVIII employing CCXXIII as the starting material. mp 293° C. (TFA salt); ESI-MS m/e calc'd for C27H33N8 O 2: 501.2727, found: 501.2731.
  • Example CCXXV Preparation of 3-(4-(4-ethylpiperazino)phenyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0868]
    Prepared in a similar fashion as described for example CCXVIII employing CCXXIII and acetaldehyde as the starting materials. ESI-MS m/e calc'd for C28H35N8O2: 515.2883, found: 515.2894.
  • Example CCXXVI Preparation of 3-(4-(4-isopropylpiperazino)phenyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0869]
    Prepared in a similar fashion as described for example CCXVIII employing CCXXIII and acetone as the starting materials. mp 272° C. (TFA salt); ESI-MS m/e calc'd for C27H33N8O2: 529.3039, found: 529.3053.
  • Example CCXXVII Preparation of 3-(4-piperazinophenyl)-5-((2,6-dimethylpiperidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0870]
    Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-2,6- dimethylpiperidine as the starting materials. mp 270° C. (TFA salt); ESI-MS m/e calc'd for C28H34N7O2: 500.2774, found: 500.2786.
  • Example CCXXVIII Preparation of 3-(4-piperazinophenyl)-5-((4-(2-hydroxyethyl)piperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0871]
    Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-4-(2-hydroxyethyl)piperazine as the starting materials. mp 279° C. (TFA salt); ESI-MS m/e calc'd for C27H33N8O3: 517.2676, found: 517.2865.
  • Example CCXXIX Preparation of 3-(4-piperazinophenyl)-5-((2(R)-(methoxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c] pyrazol-4-one
  • [0872]
    Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-2(R)-(methoxymethyl)pyrrolidine as the starting materials. ESI-MS m/e calc'd for C27H32N703: 502.2567, found: 502.2574.
  • Example CCXXX Preparation of 3-(4-piperazinophenyl)-5-((2(S)-(methoxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0873]
    Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-2(S)-(methoxymethyl)pyrrolidine as the starting materials. ESI-MS m/e calc'd for C27H32N7O3: 502.2566, found: 502.2570.
  • Example CCXXXI Preparation of 3-(4-piperazinophenyl)-5-((2(R)-(1-methoxy-1-methylethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0874]
    Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-2(R)-(1-methoxy-1-methylethyl)pyrrolidine as the starting materials. mp 221° C. (TFA salt); ESI-MS m/e calc'd for C29H36N7O3: 530.2879, found: 530.2878.
  • Example CCXXXII Preparation of 3-(4-piperazinophenyl)-5-((2(S)-(1-methoxy-1methylethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0875]
    Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-2(S)-(1-methoxy-1-methylethyl)pyrrolidine as the starting materials. mp 218° C. (TFA salt); ESI-MS m/e calc'd for C29H36N7O3: 530.2880, found: 530.2895.
  • Example CCXXXIII Preparation of 3-(4-piperazinophenyl)-5-((2(R)-(hydroxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0876]
    Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-2(R)-(hydroxymethyl)pyrrolidine as the starting materials. mp 193° C. (TFA salt); ESI-MS m/e calc'd for C26H30N7O3: 488.2411, found: 488.2380.
  • Example CCXXXIV Preparation of 3-(4-piperazinophenyl)-5-((2(S)-(hydroxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c] pyrazol-4-one
  • [0877]
    Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and I-amino-2(S)-(hydroxymethyl)pyrrolidine as the starting materials. mp 190 ° C. (TFA salt); ESI-MS m/e calc'd for C26H30N7O3: 488.2410, found: 488.2401.
  • Example CCXXXV Preparation of 3-(4-piperazinophenyl)-5-((2(R)-(benzyloxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-a] pyrazol-4-one
  • [0878]
    Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-2(R)-(benzyloxymethyl)pyrrolidine as the starting materials. mp 207° C. (TFA salt); ESI-MS m/e calc'd for C33H36N7O3: 578.2880, found: 578.2889.
  • Example CCXXXVI Preparation of 3-(4-piperazinophenyl)-5-((2(S)-(benzyloxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c] pyrazol-4-one
  • [0879]
    Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-2(S)-(benzyloxymethyl)pyrrolidine as the starting materials. ESI-MS m/e calc'd for C33H36N7O3: 578.2879, found: 578.2897.
  • Example CCXXXVII Preparation of 3-(4-(3-methylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0880]
    Prepared in a similar fashion as described for example CCXI and CCX employing 4-(4-tert-butoxycarbonyl-3-methylpiperazino)acetophenone as the starting materials. mp 230° C. (TFA salt); ESI-MS m/e calc'd for C26H30N7O3: 488.2410, found: 488.2416.
  • Example CCXXXVIII Preparation of 3-(4-(cis-3,5-dimethylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0881]
    Prepared in a similar fashion as described for example CCXI and CCX employing 4-(cis-4-tert-butoxycarbonyl-3,5-dimethylpiperazino)acetophenone as the starting materials. mp 237° C. (TFA salt); ESI-MS m/e calc'd for C27H32N7O3: 502.2567, found: 502.2571.
  • Example CCXXXIX Preparation of 3-(4-(cis-3,4,5-trimethylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0882]
    Prepared in a similar fashion as described for example CCXVIII employing CCXXXVIII as the starting material. mp 240° C. (TFA salt); ESI-MS m/e calc'd for C28H34N7O3: 516.2723, found: 516.2734.
  • Example CCXL Preparation of 3-(4-(4-isopropylpiperazino)-2-methylphenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0883]
    Prepared in a similar fashion as described for example CCXVIII, CCXI, and CCX employing 4-(4-tert-butoxycarbonylpiperazino)-2-methylacetophenone as the starting materials. ESI-MS m/e calc'd for C29H36N7O3: 530.2879, found: 530.2893.
  • Example CCXLI Preparation of 3-(4-homopiperazinophenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0884]
    Prepared in a similar fashion as described for example CCXI and CCX employing 4-(4-tert-butoxycarbonylhomopiperazino)acetophenone as the starting materials. mp 253° C. (TFA salt); ESI-MS m/e calc'd for C26H30N7O3: 488.2410, found: 488.2406.
  • Example CCXLII Preparation of 3-(4-(4-methylhomopiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0885]
    Prepared in a similar fashion as described for example CCXVIII employing CCXLI as the starting material. ESI-MS m/e calc'd for C27H32N7O3: 502.2567, found: 502.2581.
  • Example CCXLIII Preparation of 3-(4-(4-ethylhomopiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0886]
    Prepared in a similar fashion as described for example CCXVIII employing CCXLI and acetaldehyde as the starting materials. mp 240° C. (TFA salt); ESI-MS m/e calc'd for C28H34N7O3: 516.2723, found: 516.2732.
  • Example CCXLIV Preparation of 3-(4-(4-isopropylhomopiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0887]
    Prepared in a similar fashion as described for example CCXVIII employing CCXLI and acetone as the starting materials. mp 245° C. (TEA salt); ESI-MS mie calc'd for C29H36N7O3: 530.2880, found: 530.2876.
  • Example CCXLV Preparation of 3-(4-homopiperazino-2-methylphenyl)-5-(morpholinocarbamoylamino) indeno[1,2-c] pyrazol-4-one
  • [0888]
    Prepared in a similar fashion as described for example CCXI and CCX employing 4-(4-tert-butoxycarbonylhomopiperazino)-2-methylacetophenone as the starting materials. mp 209° C. (TFA salt); ESI-MS m/e calc'd for C27H32N7O3: 502.2566, found: 502.2580.
  • Example CCXLVI Preparation of 3-(4-(4-ethylhomopiperazino)-2-methylphenyl)-5-(morpholinocarbamoylamino)indeno [1,2-c]pyrazol-4-one
  • [0889]
    Prepared in a similar fashion as described for example CCXVIII employing CCXLV and acetaldehyde as the starting materials. mp 217° C. (TFA salt); ESI-MS m/e calc'd for C29H36N7O3:530.2880, found: 530.2891.
  • Example CCXLVII Preparation of 3-(4-(4-isopropylhomopiperazino)-2-methylphenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0890]
    Prepared in a similar fashion as described for example CCXVIII employing CCXLV and acetone as the starting materials. mp 197° C. (TFA salt); ESI-MS m/e calc'd for C30H38N7O3: 544.3036, found: 544.3059.
  • Example CCXLVIII Preparation of 3-(4-(4-(N,N-dimethylamino)piperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0891]
    [0891]
  • [0892]
    Step 1. Synthesis of 36.
  • [0893]
    Prepared in a similar fashion as described for example CCX employing 4-(4,4-ethylenedioxypiperidino)acetophenone as starting material.
  • [0894]
    Step 2. Synthesis of 37 from 36.
  • [0895]
    A mixture of 12.40 g (23.4 mmol) of 36, 500 mL of acetone, 125 mL of water, and 25 mL of trifluoroacetic acid was refluxed for 24 h. After cooling to room temperature the mixture was concentrated under vacuum. The residue was slurried in 95% aqueous ethanol, and the mixture was adjusted to pH 7 employing aqueous sodium hydroxide solution. The resulting mixture was filtered. The recovered solids were washed with 95% aqueous ethanol and dried to afford 10.68 g of 37 as a yellow solid. NMR (DMSO-d6) δ 13.46 (br s, 1H), 10.96 (br s, 1H), 8.30 (d, 1H, J=9 Hz), 8.27 (s, 1H), 8.14 (d, 2H, J=9 Hz), 7.43 (t, 1H, J=9 Hz), 7.18 (d, 2H, J=9 Hz), 7.10 (d, 1H, J=9 Hz), 3.90-3.75 (m, 8H), 3.34 (s, 8H), 2.92 (m, 2H), 2.72 (m, 2H), 2.45 (t, 4H, J=6 Hz).
  • [0896]
    Step 3. Synthesis of CCXLVIII from 37.
  • [0897]
    To a mixture of 1.00 g (2 mmol) of 37, 200 mL of 2M dimethylamine in methanol, 200 mL of acetonitrile, and 1 mL of acetic acid at 25° C. was added 2.60 g (40 mmol) of sodium cyanoborohydride, and the reaction mixture was stirred at 25° C. for 20 h. The mixture was diluted with 200 mL of water and then acidified (pH<2) employing conc. hydrochloric acid. After 30 min. gas evolution had ceased, and the solution was made strongly basic (pH>12) employing conc. aqueous sodium hydroxide solution. The solution was stirred for 20 min. and then was adjusted to pH 10 by the addition of 1N hydrochloric acid. The resulting precipitate was recovered by filtration, washed with water, and dried. These solids were dissolved in 10 mL of trifluoroacetic acid, and the solution was diluted with 50 mL of anhydrous ethanol. A yellow precipitate formed, was recovered by filtration, and was dried under vacuum to provide 0.41 g of the product as its TFA-salt. mp 258° C.; ESI-MS m/e calc'd for C28H34N7O3: 516.2723, found: 516.2737.
  • Example CCXLIX Preparation of 3-(4-(4-morpholinopiperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0898]
    Prepared in a similar fashion as described for example CCXLVIII employing 37, morpholine, and methanesulfonic acid as the starting materials. mp 249° C. (MSOH salt); ESI-MS m/e calc'd for C30H36N7O4: 558.2828, found: 558.2817.
  • Example CCL Preparation of 3-(4-(4-piperidinopiperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0899]
    Prepared in a similar fashion as described for example CCXLVIII employing 37 and piperidine as the starting materials. mp 233° C. (TFA salt); ESI-MS m/e calc'd for C31H38N7O3: 556.3036, found: 556.3039.
  • Example CCLI Preparation of 3-(4-(4-pyrrolidinopiperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0900]
    Prepared in a similar fashion as described for example CCXLVIII employing 37 and pyrrolidine as the starting materials. mp 247° C. (TFA salt); ESI-MS m/e calc'd for C30H36N7O3: 542.2879, found: 542.2860.
  • Example CCLII Preparation of 3-(4-(4-(N,N-diethylamino)piperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0901]
    Prepared in a similar fashion as described for example CCXLVIII employing 37 and diethylamine as the starting materials. mp 251° C. (TFA salt); ESI-MS m/e calc'd for C30H38N7O3: 544.3036, found: 544.3035.
  • Example CCLIII Preparation of 3-(4-(4-(1-iminoethyl)piperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0902]
    [0902]
  • [0903]
    Step 1. Synthesis of 38 from 35.
  • [0904]
    A mixture of 4.43 g (7.7 mmol) of 35 (example CCX), 3.15 g (20.7 mnmol) of 4-methoxybenzylhydrazine, 0.29 g (1.50 mmol) of 4-methoxybenzylhydrazine hydrochloride, and 150 mL of ethanol was refluxed for 22 h. While the reaction mixture was maintained at reflux 30 mL of water was added dropwise, and the mixture then was allowed to cool to room temperature. The resulting precipitate was recovered by filtration, washed with 95% aqueous ethanol, and dried to furnish 1.40 g of 38. NMR (CDCl3) δ 11.04 (s, 1H), 8.32 (d, 1H, J=9 Hz), 8.19 (d, 2H, J=9 Hz), 7.28 (d, 2H, J=9 Hz), 7.24 (t, 1H, J=9 Hz), 7.02 (d, 2H, J=9 Hz), 6.88 (d, 2H, J=9 Hz), 6.68 (d, 1H, J=9 Hz), 5.52 (s, 1H), 5.38 (s, 2H), 4.00 (m, 4H), 3.78 (s, 3H), 3.62 (m, 4H), 3.27 (m, 4H), 3.08 (m, 2H), 2.72 (m, 2H), 1.49 (s, 9H).
  • [0905]
    Step 2. Synthesis of 39 from 38.
  • [0906]
    A solution of 1.38 g of 38 in 20 mL of trifluoroacetic acid was stirred at 25° C. for 0.5 h. The excess trifluoroacetic acid was removed under vacuum, and the residue was recyrstallized from ethanol to afford 1.25 g of 39 as its TFA-salt. ESI-MS m/e=594 (M+H)+.
  • [0907]
    Step 3. Synthesis of 40 from 39.
  • [0908]
    A solution of 0.18 g (0.25 mmol) of 39, 0.27 g (2.5 mmol) of methyl acetimidate hydrochloride, 0.31 g (2.5 mmol) of 4-dimethylaminopyridine, and 10 mL of methanol was refluxed for 48 h. To the hot solution was added 2 mL of water, and the miture was allowed to cool to room temperature. The resulting precipitate was washed with 95% aqueous ethanol and dried to provide 0.125 g of 40 as an orange solid.
  • [0909]
    Step 4. Synthesis of CCLIII from 40.
  • [0910]
    A solution of 0.122 g of 40 in 10 mL of trifluoroacetic acid was stirred at 25° C. for 120 h and then concentrated under vacuum. The residue was purified by reverse-phase preparative HPLC to afford 0.045 g of CCLIII as its TFA-salt. mp 240° C.; ESI-MS m/e calc'd for C27H31N8O3: 515.2519, found: 515.2529.
  • Example CCLIV Preparation of 3-(4-(4-(2-pyridinyl)piperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0911]
    Prepared in a similar fashion as described for example CCLIII employing 39 and 2-bromopyridine as the starting materials. ESI-MS m/e calc'd for C30H31N8O3: 551.2519, found: 551.2514.
  • Example CCLV Preparation of 3-(c-propyl)-5-(4-carbamoylpiperidinoacetamido)indeno[1,2-c]pyrazol-4-one
  • [0912]
    Prepared in a similar fashion as described for example XXIII using isonipecotamide and the c-propyl analog of 14 as the starting materials. mp 178-180° C. (TFA salt); ESI-MS (M+H) calc'd for C21H24N5O3: 394.1879, found: 394.1876.
  • Example CCLVI Preparation of 3-ethyl-5-(4-methylpiperazinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0913]
    Prepared in a similar fashion as described for example XLII using 1-amino-4-methylpiperazine and the ethyl analog of 15 as the starting materials. mp 244-246° C. (TFA salt); ESI-MS (M+H) calc'd for C18H23N6O2: 355.1882, found: 355.1858.
  • Example CCLVII Preparation of 3-(c-propyl)-5-(4-methylpiperazinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0914]
    Prepared in a similar fashion as described for example XLII using 1-amino-4-methylpiperazine and the c-propyl analog of 15 as the starting materials. mp 215-217° C. (TFA salt); ESI-MS (M+H) calc'd for C19H23N6O2: 367.1882, found: 367.1862.
  • Example CCLVIII Preparation of 3-(c-hexyl)-5-(4-methylpiperazinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0915]
    Prepared in a similar fashion as described for example XLII using 1-amino-4-methylpiperazine and the c-hexyl analog of 15 as the starting materials. mp 241-242° C. (TFA salt); ESI-MS (M+H) calc'd for C22H29N6O2: 409.2352, found: 409.2371.
  • Example CCLIX Preparation of 3-ethyl-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0916]
    Prepared in a similar fashion as described for example XLII using 4-aminomorpholine and the ethyl analog of 15 as the starting materials. mp 253-254° C. (TFA salt); ESI-MS (M+H) calc'd for C17H20N5O3: 342.1566, found: 342.1555.
  • Example CCLX Preparation of 3-(c-propyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0917]
    Prepared in a similar fashion as described for example XLII using 4-aminomorpholine and the c-propyl analog of 15 as the starting materials. ESI-MS (M+H) calc'd for C18H20N5O3: 354.1566, found: 354.1548.
  • Example CCLXI Preparation of 3-(c-hexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0918]
    Prepared in a similar fashion as described for example XLII using 4-aminomorpholine and the c-hexyl analog of 15 as the starting materials. mp >260° C. (TFA salt); ESI-MS (M+H) calc'd for C21H26N5O3: 396.2036, found: 396.2021.
  • Example CCLXII Preparation of 3-(1-ethoxycarbonylpiperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0919]
    Prepared in a similar fashion as described for example CXXVI using ethylchloroformate and 29G as the starting materials. mp 206-207° C. (TFA salt); ESI-MS (M+H) calc'd for C23H29N6O5: 469.2199, found: 469.2170.
  • Example CCLXIII Preparation of 3-(1-phenoxycarbonylpiperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0920]
    Prepared in a similar fashion as described for example CXXVI using phenylchloroformate and 29G as the starting materials. mp 250-252° C. (TFA salt); ESI-MS (M+H) calc'd for C27H29N6O5: 517.2199, found: 517.2182.
  • Example CCLXIV Preparation of 3-(1-(imidazol-1-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0921]
    [0921]
  • [0922]
    A solution of 29G (0.255 g, 0.5 mmol) in dimethylformamide (10 mL) was treated with carbonyldiimidazole (0.16 g, 1 mmol) and stirred at 50° C. for 2 h. The reaction mixture was cooled, poured into water (20 mL), and extracted with EtOAc (40 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated at reduced pressure to give a yellow oil. Purification using reverse phase HPLC (CH3CN/water) gave the product as a yellow solid (18.5 mg, 6%). mp 202-204° C. (TFA salt); ESI-MS (M+H) calc'd for C24H27N8O4: 491.2155, found: 491.2138.
  • Example CCLXV Preparation of 3-(1-(2-thienylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0923]
    Prepared in a similar fashion as described for example CXXXII using 29G and 2-thiophenecarboxylic acid as the starting materials. mp 218-220° C. (TFA salt); ESI-MS (M+H) calc'd for C25H27N6O4S: 507.1815, found: 507.1822.
  • Example CCLXVI Preparation of 3-(1-carbamoylpiperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0924]
    [0924]
  • [0925]
    Step 1. Synthesis of 29H from 29G
  • [0926]
    Prepared in a similar fashion as described for example CXXVI using 29G and 4-nitrophenylchloroformate as the starting materials to give the product as a tan solid (1.22 g, 72%). mp 255-257° C.; ESI-MS (M+H) calc'd for C27H28N7O7: 562.2050, found: 562.2032.
  • [0927]
    Step 2. Synthesis of CCLXVI from 29H.
  • [0928]
    A suspension of 29H (0.20 g, 0.36 mmol) in dimethylsulfoxide (1 mL) was treated with conc. NH4OH (0.048 mL, 0.72 mmol) and heated to 90° C. for 6 h. The reaction mixture was cooled and the solvent removed at reduced pressure to give an yellow oil. Purification using reverse phase HPLC (CH3CN/water) gave the product as a pale yellow solid (11.3 mg, 57%). mp 258-259° C. (TFA salt); ESI-MS (M+H) calc'd for C21H26N7O4: 440.2046, found: 440.2068.
  • Example CCLXVII Preparation of 3-(1-(ethylcarbamoyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0929]
    Prepared in a similar fashion as described for example CCLXVI using 29H and ethylamine as the starting materials. mp 215-216° C. (TFA salt); ESI-MS (M−H) calc'd for C23H28N7O4: 466.2203, found: 466.2208.
  • Example CCLXVIII Preparation of 3-(1-(2-(1-methylpyrrolidin-2-yl)ethylaminocarbamoyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0930]
    Prepared in a similar fashion as described for example CCLXVI using 29H and 2-(2-aminoethyl)-1-methylpyrrolidine as the starting materials. mp 91-93° C. (TFA salt); ESI-MS (M+H) calc'd for C28H39N8O4: 551.3094, found: 551.3095.
  • Example CCLXIX Preparation of 3-(1-(4-(dimethylamino)piperidinocarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0931]
    Prepared in a similar fashion as described for example CCLXVI using 29H and 4-(dimethylamino)piperidine as the starting materials. mp 172-174° C. (TFA salt); ESI-MS (M+H) calc'd for C28H39N8O4: 551.3109, found: 551.3109.
  • Example CCLXX Preparation of 3-(1-(piperazinocarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0932]
    Prepared in a similar fashion as described for example CXXVI, step 7, using CCLXXI as the starting material. mp 195-197° C. (TFA salt); ESI-MS (M+H) calc'd for C25H33N8O4: 509.2625, found: 509.2635.
  • Example CCLXXI Preparation of 3-(1-(4-(t-butoxycarbonyl)piperazinocarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0933]
    Prepared in a similar fashion as described for example CCLXVI using 29H and 1-(t-butoxycarbonyl)piperazine as the starting materials. mp 231-232° C. (TFA salt); ESI-MS (M+H) calc'd for C30H41N8O6: 609.3149, found: 609.3123.
  • Example CCLXXII Preparation of 3-(1-(((1S,4S)-(+)-2,5-diazabicyclo[2.2.1]hept-2-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0934]
    Prepared in a similar fashion as described for example CXXVI, step 7, using the 3-(1-((5-t-butoxycarbonyl-(1S,4S)-(+)-2,5-diazabicyclo[2.2.1]hept-2-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one as the starting material. mp 196-198° C. (TFA salt); ESI-MS (M+H) calc'd for C26H33N8O4: 521.2613, found: 521.2613.
  • Example CCLXXIII Preparation of 3-(1-(((1S,4S)-(+)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0935]
    Prepared in a similar fashion as described for example CCLXVI using 29H and (1S,4S)-(+)-2-methyl-2,5-diazabicyclo[2.2.1]heptane as the starting materials. mp 224-225° C. (TFA salt); ESI-MS (M+H) calc'd for C27H5N8O4: 535.2781, found: 535.2783.
  • Example CCLXXIV Preparation of 3-(1-(3-aminopropylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0936]
    Prepared in a similar fashion as described for example CXXVI, step 7, using CCLXXVI as the starting material. mp 172-174° C. (TFA salt); ESI-MS (M+H) calc'd for C24H32N7O4: 482.2516, found: 482.2497.
  • Example CCLXXV Preparation of 3-(1-(3-(dimethylamino)propylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0937]
    Prepared in a similar fashion as described for example CXXXII using 29G and 4-(dimethylamino)butyric acid as the starting materials. mp 145-147° C. (TFA salt); ESI-MS (M+H) calc'd for C26H35N7O4: 510.2829, found: 510.2830.
  • Example CCLXXVI Preparation of 3-(1-(3-(t-butoxycarbonylamino)propylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0938]
    Prepared in a similar fashion as described for example CXXXII using 29G and 5-(t-butoxycarbonylamino)butyric acid as the starting materials. mp 73-75° C.; ESI-MS (M+H) calc'd for C29H40N7O6: 582.3040, found: 582.3050.
  • Example CCLXXVII Preparation of 3-(1-(4-aminobutylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0939]
    Prepared in a similar fashion as described for example CXXVI, step 7, using CCLXXIX as the starting material. mp 103-105° C. (TFA salt); ESI-MS (M+H) calc'd for C25H34N7O4: 496.2672, found: 496.2648.
  • Example CCLXXVIII Preparation of 3-(1-(4-(dimethylamino)butylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0940]
    Prepared in a similar fashion as described for example CXXXII using 29G and 5-(dimethylamino)valeric acid as the starting materials. mp 68-70° C. (TFA salt); ESI-MS (M+H) calc'd for C27H38N7O4: 524.2985, found: 524.2978.
  • Example CCLXXIX Preparation of 3-(1-(4-(t-butoxycarbonylamino)butylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0941]
    Prepared in a similar fashion as described for example CXXXII using 29G and 5-(t-butoxycarbonylamino)valeric acid as the starting material. mp 98-99° C. (TFA salt); ESI-MS (M+H) calc'd for C30H42N7O6: 596.3197, found: 596.3182.
  • Example CCLXXX Preparation of 3-(1-((1-methylpiperidin-4-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0942]
    Prepared in a similar fashion as described for example CXXXII using 29G and 1-methylpiperidine-4-carboxylic acid as the starting materials. mp 148-150° C. (TFA salt); ESI-MS (M+H) calc'd for C27H36N7O4: 522.2829, found: 522.2840.
  • Example CCLXXXI Preparation of 3-(1-((1-(t-butoxycarbonyl)piperidin-4-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0943]
    Prepared in a similar fashion as described for example CXXXII using 29G and 1-(t-butoxycarbonyl)piperidine-4-carboxylic acid as the starting materials. mp 220-222° C.; ESI-MS (M+H) calc'd for C31H42N7O6: 608.3197, found: 608.3174.
  • Example CCLXXXII Preparation of 3-(1-(cis-4-aminocyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0944]
    Prepared in a similar fashion as described for example CXXVI, step 7, using CCLXXXV as the starting material. mp 212-214° C. (TFA salt); ESI-MS (M+H) calc'd for C27H36N7O4: 522.2829, found: 522.2818.
  • Example CCLXXXIII Preparation of 3-(1-(4-aminocyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0945]
    Prepared in a similar fashion as described for example CXXVI, step 7, using CCLXXXVI as the starting material. mp 202-204° C. (TFA salt); ESI-MS (M+H) calc'd for C27H36N7O4: 522.2829, found: 522.2857.
  • Example CCLXXXIV Preparation of 3-(1-(cis-4-(dimethylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0946]
    Prepared in a similar fashion as described for example CXXXII using 29G and 4-(dimethylamino)cyclohexane carboxylic acid as the starting materials. mp 123-125° C. (TFA salt); ESI-MS (M+H) calc'd for C29H39N7O4: 550.3142, found: 550.3148.
  • Example CCLXXXV Preparation of 3-(1-(4-(t-butoxycarbonylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0947]
    Prepared in a similar fashion as described for example CXXXII using 29G and 4-(t-butoxycarbonylamino)cyclohexane carboxylic acid as the starting materials. mp 210-212° C. (TFA salt); ESI-MS (M+H) calc'd for C32H44N7O6: 622.3353, found: 622.3340.
  • Example CCLXXXVI Preparation of 3-(1-(trans-4-(t-butoxycarbonylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0948]
    Prepared in a similar fashion as described for example CXXXII using 29G and 4-(t-butoxycarbonylamino)cyclohexane carboxylic acid as the starting materials. mp 178-180° C.; ESI-MS (M+H) calc'd for C32H44N7O6: 622.3353, found: 622.3349.
  • Example CCLXXXVII Preparation of 3-(1-(piperidin-3-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0949]
    Prepared in a similar fashion as described for example CXXVI, step 7, using CCLXXXIX as the starting material. mp 169-170° C. (TFA salt); ESI-MS (M+H) calc'd for C26H34N7O4: 508.2672, found: 508.2669.
  • Example CCLXXXVIII Preparation of 3-(1-(1-methylpiperidin-3-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0950]
    Prepared in a similar fashion as described for example CXXXII using 29G and 1-methylpiperidine-3-carboxylic acid as the starting materials. mp 158-160° C. (TFA salt); ESI-MS (M+H) calc'd for C27H36N7O4: 522.2829, found: 522.2842.
  • Example CCLXXXIX Preparation of 3-(1(1-(t-butoxycarbonyl)piperidin-3-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0951]
    Prepared in a similar fashion as described for example CXXXII using 29G and 1-t-butoxycarbonylpiperidine-3-carboxylic acid as the starting materials. mp 196-198° C.; ESI-MS (M+H) calc'd for C31H41N7O6: 608.3197, found: 608.3198.
  • Example CCXC Preparation of 3-(1-(3-aminocyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0952]
    Prepared in a similar fashion as described for example CXXVI, step 7, using 3-(1-(3-t-butoxycarbonylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one as the starting material. mp 201-203° C. (TFA salt); ESI-MS (M+H) calc'd for C27H36N7O4: 522.2829, found: 522.2815.
  • Example CCXCI Preparation of 3-(1-(3-(dimethylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0953]
    Prepared in a similar fashion as described for example CXXXII using 29G and 1-(dimethylamino)cyclohexane-3-carboxylic acid as the starting materials. mp 153-155° C. (TFA salt); ESI-MS (M+H) calc'd for C29H40N7O4: 550.3142, found: 550.3131.
  • Example CCXCII Preparation of 3-(1-(trans-4-methoxycyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0954]
    Prepared in a similar fashion as described for example CXXXII using 29G and 4-trans-methoxycyclohexane carboxylic acid as the starting materials. mp 246-248° C. (TFA salt); ESI-MS (M+H) calc'd for C28H37N6O5: 537.2825, found: 537.2841.
  • Example CCXCIII Preparation of 3-(1-(cis-4-methoxycyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0955]
    Prepared in a similar fashion as described for example CXXXII using 29G and 4-cis-methoxycyclohexane carboxylic acid as the starting materials. mp 178-180° C. (TFA salt); ESI-MS (M+H) calc'd for C28H37N6O5: 537.2825, found: 537.2828.
  • Example CCXCIV Preparation of 3-(1-(4-aminobenzylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0956]
    Prepared in a similar fashion as described for example CXXVI, step 7, using CCXCVI as the starting material. mp 177-179° C. (TFA salt); ESI-MS (M+H) calc'd for C28H32N7O4: 530.2516, found: 530.2519.
  • Example CCXCV Preparation of 3-(1-(4-(dimethylamino)benzylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0957]
    Prepared in a similar fashion as described for example CXXXII using 29G and 4-(dimethylamino)phenyl acetic acid as the starting materials. mp 107-109° C. (TFA salt); ESI-MS (M+H) calc'd for C30H36N7O4: 558.2829, found: 558.2834.
  • Example CCXCVI Preparation of 3-(1-(4-(t-butoxycarbonylamino)benzylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0958]
    Prepared in a similar fashion as described for example CXXXII using 29G and 4-(t-butoxycarbonylamino)phenyl acetic acid as the starting materials. mp 177-178° C.; ESI-MS (M+H) calc'd for C33H40N7O6: 630.3040, found: 630.3040.
  • Example CCXCVII Preparation of 3-(1-(4-aminophenylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0959]
    Prepared in a similar fashion as described for example CXXVI, step 7, using CCXCIX as the starting material. mp 198-200° C. (TFA salt); ESI-MS (M+H) calc'd for C27H30N7O4: 516.2359, found: 516.2376.
  • Example CCXCVIII Preparation of 3-(1-(4-(dimethylamino)phenylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0960]
    Prepared in a similar fashion as described for example CXXXIII using 29G and 4-(dimethylamino)benzoic acid as the starting materials. mp 189-191° C. (TFA salt); ESI-MS (M+H) calc'd for C29H34N7O4: 544.2672, found: 544.2647.
  • Example CCXCIX Preparation of 3-(1-(4-(t-butoxycarbonylamino)phenylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0961]
    Prepared in a similar fashion as described for example CXXXIII using 29G and 4-(t-butoxycarbonylamino)benzoic acid as the starting materials. mp 212-214° C.; ESI-MS (M+H) calc'd for C32H38N7O6: 616.2884, found: 616.2884.
  • Example CCC Preparation of 3-(trans-4-carboxylcyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0962]
    Prepared in a similar fashion as described for example CXXIII using CCCI as the starting material. mp 264-266° C. (TFA salt); ESI-MS (M+H) calc'd for C22H26N5O5: 440.1934, found: 440.1905.
  • Example CCCI Preparation of 3-(trans-4-(methoxycarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0963]
    Prepared in a similar fashion as described for example XLII using 4-aminomorpholine and the trans-4-(methoxycarbonyl)cyclohexyl analog of 15 as the starting materials. mp 259-261° C. (TFA salt); ESI-MS (M+H) calc'd for C23H28N5O5: 454.2090, found: 454.2100.
  • Example CCCII Preparation of 3-(trans-4-(3-(dimethylamino)pyrrolidinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0964]
    Prepared in a similar fashion as described for example CXXXII using 3-(dimethylamino)pyrrolidine and acid CCC as the starting materials. mp 191-193° C. (TFA salt); ESI-MS (M+H) calc'd for C28H38N7O4: 536.2985, found: 536.2970.
  • Example CCCIII Preparation of 3-(trans-4-(piperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0965]
    Prepared in a similar fashion as described for exampleCXXVI, step 7, using 3-(trans-4-(4-(t-butoxycarbonyl)piperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one as the starting material. mp 247-248° C. (TFA salt); ESI-MS (M+H) calc'd for C26H34N7O4: 508.2672, found: 508.2670.
  • Example CCCIV Preparation of 3-(trans-4-(4-methylpiperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0966]
    Prepared in a similar fashion as described for example CXXXII using 1-methylpiperazine and CCC as the starting materials. mp 228-230° C. (TFA salt); ESI-MS (M+H) calc'd for C27H36N7O4: 522.2829, found: 522.2844.
  • Example CCCV Preparation of 3-(trans-4-(homopiperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0967]
    Prepared in a similar fashion as described for example CXXVI, step 7, using 3-(trans-4-(4-(t-butoxycarbonyl)homopiperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one as the starting material. mp >265° C. (TFA salt); ESI-MS (M+H) calc'd for C27H36N7O4: 522.2829, found: 522.2833.
  • Example CCCVI Preparation of 3-(trans-4-(4-methylhomopiperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0968]
    Prepared in a similar fashion as described for example CXXXIII using 1-methylhomopiperazine and CCC as the starting materials. mp 218-220° C. (TFA salt); ESI-MS (M+H) calc'd for C28H38N7O4: 536.2985, found: 536.2988.
  • Example CCCVII Preparation of 3-(2,4-dimethylthiazol-5-yl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0969]
    [0969]
  • [0970]
    Step 1. Synthesis of Nitrotriketone 4a from 1a.
  • [0971]
    Ethyl trifluoroacetate (22.9 g, 161 mmol) and 2,4-dimethyl-5-acetylthiazole (25.0 g, 161 mmol) were added to a solution sodium ethoxide, freshly prepared from sodium (3.71 g, 161 mmol) and ethanol (500 mL), and stirred at 23° C. for 12 h. Half of the volume of organic solvent was concentrated in vacuo and the reaction mixture was diluted with 6 M HCl (400 mL) and extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with brine (2×300 mL), dried (MgSO4), filtered, and concentrated in vacuo to give 1,3-diketone 2a as an orange oil which was used without purification.
  • [0972]
    3-Nitrophthalic anhydride (31.1 g, 161 mmol) was added to a solution of diketone 2a in acetic anhydride (91.2 mL, 968 mmol). The reaction mixture was cooled to 0° C. and triethylamine (67.3 mL, 484 mmol) was added dropwise over 1 h. The reaction mixture was warmed to 23° C. and stirred for 12 h, heated to 50° C. for 30 min, and then cooled to 23° C. The reaction mixture was slowly poured into 1 M HCl (484 mL, diluted with 1 L of water). The solid which precipitated was filtered and washed repeatedly with water (3×150 mL) to give a brown solid (24.4 g, 46%, 2 steps). ESI-MS (M−H) found for C15H9N2O5S: 329.
  • [0973]
    Step 2. Synthesis of Aniline 5a from 4a.
  • [0974]
    A solution of nitrotriketone 4a (24.4 g, 73.9 mmol), zinc powder (160 g, 2.4 mol), and calcium chloride (5.3 g, 48 mmol) in 4:1 ethanol/water (370 mL) was heated to reflux for 1 h. The reaction mixture was filtered over celite and washed with methanol (3×150 mL) and ethyl acetate (3×150 mL). The filtrate was concentrated in vacuo to give a crude brown solid. Purification by flash column chromatography (silica, chloroform→2% methanol/chloroform→5% methanol/chloroform→7% methanol/chloroform) gave aniline 5a (13.0 g, 59%) as a brown solid. ESI-MS (M−H) found for C15H11N2O3S: 299.
  • [0975]
    Step 3. Synthesis of Carbamate 6a from 5a.
  • [0976]
    A solution of aniline 5a (840 mg, 2.8 mmol), phenyl chloroformate (0.42 mL, 3.4 mmol), and sodium carbonate (1.6 g) in acetone (14 mL) was heated to 50° C. for 4 h. The reaction mixture was cooled to 23° C. and diluted with water (20 mL) and ethyl acetate (20 mL). The organic layer was separated and washed with brine (20 mL), dried (MgSO4), filtered, and concentrated in vacuo to give a crude brown solid. Trituration with ether gave carbamate 6a (1.18 g, 99%) as a brown solid. ESI-MS (M−H) found for C22H15N2O5S: 419.
  • [0977]
    Step 4. Synthesis of Urea 15a from 6a.
  • [0978]
    A solution of carbamate 6a (1.18 g, 2.8 mmol) and ammonium hydroxide (0.47 mL, 3.4 mmol) in N,N-dimethylformamide (5 mL) was heated to 90° C. for 1 h. The solvent was concentrated in vacuo to give a crude residue. Purification using reverse phase HPLC (acetonitrile/water/trifluoroacetic acid) gave the product as a yellow solid (117 mg, 12%). ESI-MS (M−H) found for C16H12N3O4S: 342.
  • [0979]
    Step 5. Synthesis of Pyrazole 16a from 15a.
  • [0980]
    A solution of urea 15a (117 mg, 0.34 mmol), hydrazine (21 μL, 0.68 mmol), and p-toluenesulfonic acid (3.2 mg, 17 μmol) in ethanol (1.7 mL) was refluxed for 4 h. The reaction mixture was cooled to 23° C. and concentrated in vacuo to give a crude residue. Purification using reverse phase HPLC (acetonitrile/water/trifluoroacetic acid) gave the product as its TFA-salt (10 mg, 9%). ESI-MS (M+H) calc'd for C16H14N5O2S: 340.0868, found: 340.0895.
  • Example CCCVIII Preparation of 3-(2,4-dimethylthiazol-5-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0981]
    [0981]
  • [0982]
    Prepared in a similar fashion as described for example CCCVII using 6a and morpholine as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C20H21N6O3S: 425.1396, found: 425.1424.
  • Example CCCIX Preparation of 3-(2,4-dimethylthiazol-5-yl)-5-((1-methyl-1-phenylamino)carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0983]
    [0983]
  • [0984]
    Step 1. Synthesis of Acetamide 8a from 5a.
  • [0985]
    A solution of aniline 5a (3.3 g, 10.8 mmol) in N,N-dimethylformamide (54 mL) was treated with acetyl chloride (0.81 mL, 11.4 mmol) and triethylamine (1.7 mL, 11.9 mmol) and refluxed for 4 h. The reaction mixture was cooled to 23° C. and diluted with ethyl acetate (100 mL) and water (100 mL). The aqueous layer was separated and washed with ethyl acetate (100 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4), filtered, and concentrated in vacuo to give a crude brown solid. The solid was dissolved in a small amount of methylene chloride (˜10 mL) and treated with ether. The solid which precipatated was filtered and washed with ether (3×100 mL) to give a brown solid (1.6 g, 43%). ESI-MS (M—H) found for C17H13N2O4S: 341.
  • [0986]
    Step 2. Synthesis of pyrazole 9a from 8a.
  • [0987]
    A solution of triketone 8a (1.6 g, 4.7 mmol), hydrazine (0.71 mL, 9.4 mmol), and p-toluenesulfonic acid (44 mg, 0.23 mmol) in ethanol (23 mL) was refluxed for 4 h. The reaction mixture was cooled to 23° C. and the solid was filtered and washed with ethanol (20 mL) and ether (20 mL). Recrystalization of the precipatate from ethanol gave the product as a brown solid (400 mg, 25%). ESI-MS (M—H) found for C17H13N4O2S: 337.
  • [0988]
    Step 3. Synthesis of aniline 10a from 9a.
  • [0989]
    A solution of pyrazole 9a (400 mg, 1.2 mmol) and concentrated hydrochloric acid (2 mL) in methanol was refluxed for 3 h. The reaction mixture was cooled to 23° C. and concentrated in vacuo to give the product as a yellow solid (350 mg, 99%). ESI-MS (M−H) found for C15H11N4OS: 295.
  • [0990]
    Step 4. Synthesis of aniline 11a from 10a.
  • [0991]
    A solution of aniline 10a (350 mg, 1.2 mmol) in dioxane (6 mL) was treated with triethylamine (0.69 mL, 5 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.52 mL, 3 mmol) and heated to reflux for 3 h. The reaction mixture was cooled to 23° C. and diluted with EtOAc (20 mL) and water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated in vacuo to give a yellow solid. The yellow solid was treated with methylene chloride (50 mL) and methanol (50 mL) and filtered. The filtrate was concentrated in vacuo to give a crude brown residue. Purification by flash column chromatography (silica, 10% ethyl acetate/hexane→20% ethyl acetate/hexane≦40% ethyl acetate/hexane→80% ethyl acetate/hexane) gave aniline 11a (235 mg, 47%) as a brown solid. ESI-MS (M+H) found for C21H27N4O2SSi: 427.
  • [0992]
    Step 5. Synthesis of carbamate 12a from 11a.
  • [0993]
    Prepared in a similar fashion as described for example 1, step 3, using aniline 11a as the starting material. ESI-MS (M+H) found for C28H31N40 4SSi: 547.
  • [0994]
    Step 6. Synthesis of pyrazole 17a from 12a.
  • [0995]
    A solution of carbamate 12a (167 mg, 0.3 mmol) and 1-methyl-1-phenylhydrazine (72 μL, 0.6 mmol) in dimethyl sulfoxide (2 mL) was heated to 90° C. for 1 h. The solvent was concentrated in vacuo to give a crude residue which was diluted with 1:1 acetonitrile/water (3 mL). The solid which precipitated was filtered to give the product as a yellow solid (110 mg, 63%). ESI-MS (M+H) found for C29H35N6O3SSi: 574.
  • [0996]
    Step 7. Synthesis of pyrazole 18a from 17a.
  • [0997]
    A solution of 17a (110 mg, 0.2 mmol) in ethanol (10 mL) was treated with 4M hydrochloric acid in dioxane (10 mL) and heated to 70° C. for 1 h. The reaction mixture was cooled to 23° C. and the solid which precipitated was filtered to give the product as its HCl-salt (50 mg, 59%). mp=250° C.; ESI-MS (M+H) calc'd for C23H21N6O2S: 445.1447, found: 445.1432.
  • Example CCCX Preparation of 3-(2,4-dimethylthiazol-5-yl)-5-((2,6-dimethylpiperidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [0998]
    [0998]
  • [0999]
    Prepared in a similar fashion as described for example 3 using 12a and 1-amino-2,6-dimethylpiperidine as the starting materials. ESI-MS (M+H) found for C23H37N6O2S: 451.
  • Example CCCXI Preparation of 3-(2,4-dimethylthiazol-5-yl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one
  • [1000]
    [1000]
  • [1001]
    Step 1. Synthesis of semicarbazide 19a from aniline 5a.
  • [1002]
    A solution of aniline 5a (13.0 g, 43.3 mmol), N-(4-methylpiperazinyl)-O-(phenyl)carbamate (20.4 g, 86.7 mmol), and triethylamine (18.1 mL, 130 mmol) in dimethylsulfoxide (217 mL) was heated to 90° C. for 1 h. The reaction mixture was cooled to 23° C. and diluted with water (500 mL). The solid which precipitated was collected and washed with water (300 mL), ethanol (300 mL), and ether (300 mL) and dried to give a brown solid (15.6 g, 82%). ESI-MS (M+H) calc'd for C21H24N5O4S: 442.1549, found: 442.1531.
  • [1003]
    Step 2. Synthesis of pyrazole 20a from semicarbazide 19a.
  • [1004]
    A solution of semicarbazide 19a (15.6 g, 35.3 mmol), hydrazine (6.7 mL, 212 mmol), and acetic acid (4.0 mL, 71 mmol) was refluxed in ethanol (354 mL) for 84 h. The reaction mixture was cooled to 23° C., filtered, washed with ethanol (300 mL) and ether (300 mL), and dried to give a yellow solid which was dissolved in 10% acetic acid in water (20 mL). The solution was adjusted to pH=7 with 10% sodium hydroxide. The solid which precipitated was filtered and dried to give the free base (6.8 g, 29%) as a yellow solid. The free base was dissolved in 1M hydrochloric acid (31 mL) and the water was removed with a lyophilizer to give the product as a light brown powder (7.9 g, 99% from the free base). mp=278° C.; ESI-MS (M+H) calc'd for C21H24N7O2S: 438.1712, found: 438.1714.
  • [1005]
    The compounds in the following tables are produced by suitabl methods from among the methods of the above examples.
    TABLE 1
    Example mass mp
    # R1 R2 (M + H)+ (° C.)
    I Methyl 4-MeOC6H4 334  268
    II ClCH2 4-MeOC6H4 382  274
    III cyclopropyl 4-MeOC6H4 360  289
    IV isopropyl 4-MeOC6H4 362  288
    V ethyl 4-MeOC6H4 348  287
    VI cyclopentyl 4-MeOC6H4 388  267
    VII cyclobutyl 4-MeOC6H4 374  297
    VIII benzyl 4-MeOC6H4 410  280
    IX n-propyl 4-MeOC6H4 362  282
    X 4-ClC6H4CH2 4-MeOC6H4 444  238
    XI 3-MeOC6H4CH2 4-MeOC6H4 440 >300
    XII 4-MeOC6H4CH2 4-MeOC6H4 440  280
    XIII 3,4-diMeOC6H4CH2 4-MeOC6H4 470 >300
    XIV 2,5-diMeOC6H4CH2 4-MeOC6H4 470  226
    XV Methyl 2-MeOC6H4 334  276
    XVI Methyl 3,4-diMeOC6H4 364 >300
    XVII 3,4-(OCH2O)C6H4CH2 4-MeOC6H4 454  297
    XVIII 3-thiophenylCH2 4-MeOC6H4 416  293
    XIX 2-MeOC6H4CH2 4-MeOC6H4 440  255
    XX 3,4-diClOC6H4CH2 4-MeOC6H4 479  299
    XXI 2,4-diClOC6H4CH2 4-MeOC6H4 479  286
    XXII 2-ClC6H4CH2 4-MeOC6H4 444  300
    XXIII H2NCH2 4-MeOC6H4 349 >300
    XXIV HOCH2CH2NHCH2 4-MeOC6H4 393  243
    XXV Me2NCH2 4-MeOC6H4 377  279
    XXVI PiperazinoCH2 4-MeOC6H4 418  277
    XXVII 4-Me-piperazinoCH2 4-MeOC6H4 432 >300
    XXVIII 4-HOCH2CH2-pipierazino-CH2 4-MeOC6H4 462 >300
    XXIX piperisinoCH2 4-MeOC6H4 417  291
    XXX 4-NH2CH2-piperidinoCH2 4-MeOC6H4 446 >300
    XXXI CH3CH2NHCH2 4-MeOC6H4 377  250
    XXXII thiomorpholinoCH2 4-MeOC6H4 435  298
    XXXIII morpholinoCH2 4-MeOC6H4 419  295
    XXXIV pyrrolidinoCH2 4-MeOC6H4 403  279
    XXXV 4-pyridylCH2NHCH2 4-MeOC6H4 440 >300
    XXXVI 4-CH3CONHC6H4CH2 4-MeOC6H4 467  268
    XXXVII 4-CH3OCONHC6H4CH2 4-MeOC6H4 483  257
    XXXVIII 4-NH2CH2CONHC6H4CH2 4-MeOC6H4 482  228
    XXXIX 4-Me2NCH2CONHC6H4CH2 4-MeOC6H4 510 >300
    XL 4-N3C6H4CH2 4-MeOC6H4 451 >300
    XLI 4-NH2C6H4CH2 4-MeOC6H4 425  283
    XLII C6H5NH 4-MeOC6H4 411 >300
    XLIII CH3CH2CH2NH 4-MeOC6H4 377  252
    XLIV 4-NH2C6H4CH2NH 4-MeOC6H4 440 >300
    XLV 4-pyridylCH2NH 4-MeOC6H4 426 >300
    XLVI Methyl 4-HOC6H4 320 >300
    XLVII H 4-MeOC6H4 320  280
    XLVII Methyl 3-pyridyl 305 >300
    XLIX Methyl 4-pyridyl 305 >300
    L H 4-pyridyl 291 >300
    LI Methyl C6H5 305 >300
    LII Methyl 4-MeSC6H4 351  283
    LIII Methyl 4-MeSO2C6H4 383 >300
    LVI Methyl 4-Me2NC6H4 348 >300
    LV morpholinoCH2 4-Me2NC6H4 432 >300
    LVI Me2NCH2 4-Me2NC6H4 390 >300
    LVII Methyl 4-(piperidino)C6H4 388  291
    LVIII Methyl 4-(morpholino)C6H4 389 >300
    LIX Methyl 4-CH3CH2OC6H4 349  288
    LX Methyl 4-CH3CH2CH2CH2C6H4 361  259
    LXI Methyl 4-CH3CH2C6H4 332  294
    LXII Methyl 4-CH3CH2CH2C6H4 347  269
    LXIII NH2 4-MeOC6H4 335 >300
    LXIV Me2NNH 4-MeOC6H4 378 >300
    LXV MeNH 4-MeOC6H4 349 >300
    LXVI morpholinoNH 4-MeOC6H4 420 >300
    LXVII cis-1,2- 4-MeOC6H4 432 >300
    diaminocyclohexanyl
    LXVIII 4-methylpiperazinoNH 4-MeOC6H4 433 >300
    LXVIX 4-uridomethylpiperidino- 4-MeOC6H4 489 >300
    CH2
    LXX 4-(2-pyridyl)piperazinol- 4-MeOC6H4 495 >300
    CH2
    LXXI 4- 4-MeOC6H4 461 >300
    (aminoethyl)piperazinoCH2
    LXXII 4-carbamoylpiperidinoCH2 4-MeOC6H4 460 >300
    LXXIII 4-hydroxypiperidinoCH2 4-MeOC6H4 433 >300
    LXXIV 4- 4-MeOC6H4 447 >300
    hydroxymethylpiperidino-
    CH2
    LXXV 4-amidopiperazinoCH2 4-MeOC6H4 493 >300
    LXXVI 4- 4-MeOC6H4 492 >300
    dimethylaminopiperidino-
    CH2
    LXXVII 4-aminopiperidinoCH2 4-MeOC6H4 464 >300
    LXXVIII 4-Me-piperazinoCH2 4-Me2NC6H4 445 >300
    LXXIX 4-NH2CH2-piperidinoCH2 4-Me2NC6H4 459 NA
    LXXX 4-OH-piperidinoCH2 4-Me2NC6H4 446  267
    LXXXI morpholinoCH2 4-(morpholino)C6H4 474  258
    LXXXII 4-Me-piperazinoCH2 4-(morpholino)C6H4 487  258
    LXXXIII 4-OH-pipieridinoCH2 4-(morpholino)C6H4 488  245
    LXXXIV 4-NH2CH2-piperidinoCH2 4-(morpholino)C6H4 501  240
    LXXXV 4-Me-piperazinoNH 4-Me2NC6H4 446 >300
    LXXXVI 4-Me-piperazinoNH(X = S) 4-MeOC6H4 449 >300
    LXXXVII Methyl c-propyl 268  220
    LXXXVIII NH2 1-Me-3-pyridyl 308 >300
    LXXXIX Methyl 2-thienyl 310  269
    XC Methyl 3-Me-2-thienyl 324  275
    XCI NH2 Ethyl 257 >250
    XCII NH2 n-propyl 271  187
    XCIII NH2 i-propyl 271 >250
    XCIV NH2 c-propyl 267  252
    (M − H)
    XCV NH2 c-hexyl 311  178
    XCVI NH2 2-thienyl 310  214
    (M+)
    XCVII NH2 3-Me-2-thienyl 325  270
    XCVIII NH2 5-Me-2-thienyl 325 >280
    XCIX NH2 5-CO2Et-2-thienyl 383 >280
    C NH2 3-thienyl 311 >280
    CI NH2 5-Cl-3-thienyl 345 >300
    CII NH2 2,5-diMe-3-thienyl 339 >280
    CIII NH2 2-furanyl 295  278
    CIV Me2NNH i-propyl 314  231
    CV Me2NNH c-propyl 312 NA
    CVI Me2NNH c-hexyl 354  229
    CVII Me2NNH 2-thienyl 354  279
    CVIII Me2NNH 5-MeO-2-thienyl 384  280
    CIX Me2NNH 5-Me-2-thienyl 368 >280
    CX Me2NNH 5-CO2Et-2-thienyl 426  252
    CXI Me2NNH 3-thienyl 354  202
    CXII NH2 1-methyl-3-pyrrolyl 308 >300
    CXIII Me2NNH 2,5-diMe-3-thienyl 382  252
    CXIV Me2NNH 2-furanyl 338  202
    CXV 4-NH2CO-piperidinylCH2 i-propyl 396  224
    CXVI 4-NH2CO-piperidinylCH2 c-hexyl 436  228
    CXVII 4-NH2CH2-piperidinolCH2 ethyl 368  174
    CXVIII 4-NH2CH2-piperidinoCH2 i-propyl 382  218
    CXVIX 4-NH2CH2-piperidinoCH2 c-propyl 380  138
    CXX 4-NH2CH2-piperidinoCH2 c-hexyl 422  196
    CXXI 4-CH3-piperazinoNH i-propyl 369  231
    CXXII 4-CH3-piperazinoNH 5-CO2Et-2-thienyl 481  249
    CXXIII 4-CH3-piperazinoNH 5-CO2H-2-thienyl 453  270
    CXXIV 4-CH3-piperazinoNH 2,5-diMe-3-thienyl 437  250
    CXXV morpholinoNH i-propyl 354  256
    (M − H)
    CXXVI morpholinoNH 1-CO2Me-4-piperidinyl 455  216
    CXXVII morpholinoNH 5-Me-2-thienyl 410  261
    CXXVIII morpholinoNH 5-Cl-3-thienyl 430  259
    CXXIX morpholinoNH 2,5-diMe-3-thienyl 424 >280
    CXXX morpholinoNH 5-CO2Et-2-thienyl 468  258
    CXXXI morpholinoNH 5-CO2H-2-thienyl 440  273
    CXXXII morpholinoNH 5-CONHBn-2-thienyl 529  275
    CXXXIII morpholinoNH 5-CO(4-Me-piperazino)- 537  190
    2-thienyl
    CXXXIV morpholinoNH 5-CONHCH2CH2(1-Me-2- 550  235
    pyrrolidinyl)-2-thienyl
    CXXXV morpholinoNH 5-CONHNMe2-2-thienyl 482  201
    CXXXVI morpholinoNH 5-CONHCH2CH2NMe2-2- 510  190
    thienyl
    CXXXVII morpholinoNH 5- 536  224
    CONHCH2CH2(pyrrolidino)-
    2-thienyl
    CXXXVIII morpholinoNH 5- 552  241
    CONHCH2CH2(morpholino)-
    2-thienyl
    CXXXIX morpholinoNH 5-CONH(morpholino)-2- 524  271
    thienyl
    CXL morpholinoNH 5-CONHCH2CH2CH2(1- 564  260
    pyrrolidonyl)-2-thienyl
    CXLI morpholinoNH 5-CONHCH2CH2(3- 544  203
    pyridyl)-2-thienyl
    CXLII morpholinoNH 5-CONHCH2CH2CH2(1- 547  263
    imidazolyl)-2-thienyl
    CXLIII morpholinoNH 5-CONHCH2CH2(2- 544 >280
    pyridyl)-2-thienyl
    CXLIV morpholinoNH 5-CONHCH2(2-pyridyl)-2- 530  239
    thienyl
    CXLV morpholinoNH 5-CONHCH2CH2(piper- 550  228
    idino)-2-thienyl
    CXLVI morpholinoNH 5-pyrrolidino- 508  213*
    aminocarbonyl-2-thienyl
    CXLVII morpholinoNH 5-piperidino- 522  189*
    aminocarbonyl-2-thienyl
    CXLVIII morpholinoNH 5-piperidino-carbonyl- 507 N/A
    2-thienyl
    CXLIX morpholinoNH 5-piperazino-carbonyl- 508  241*
    2-thienyl
    CL morpholinoNH 5-(4-Me- 522  186*
    piperazino)carbonyl-2-
    thienyl
    CLI morpholinoNH 5-(4-Et- 536  186*
    piperazino)carbonyl-2-
    thienyl
    CLII morpholinoNH 5-((4-CH2CH2OH)- 552  186*
    piperazino)carbonyl-2-
    thienyl
    CLIII morpholinoNH 5-(4-cyclopropylmethyl- 562  211*
    piperazino)carbonyl-2-
    thienyl
    CLIV morpholinoNH 5-(4-t-CO2t-Bu- 608  225*
    piperazino)carbonyl-2-
    thienyl
    CLV morpholinoNH 5-(4-(2-pyridyl)- 585  202*
    piperazino)carbonyl-2-
    thienyl
    CLVI morpholinoNH 5-(1S,4S)-2,5- 520 >300*
    diazobicyclo[2.2.1]hept-
    yl)carbonyl-2-thienyl
    CLVII morpholinoNH 5-((1S,4S)-2-Me-2,5- 534  244*
    dizaobicyclo[2.2.1]hept-
    yl)carbonyl-2-thienyl
    CLVIII morpholinoNH 5-(4-NMe2- 550  185*
    piperidino)carbonyl-2-
    thienyl
    CLIX morpholinoNH 5-(4-pyrrolidino- 576  228*
    piperidino)carbonyl-2-
    thienyl
    CLX morpholinoNH 5-(4-piperidino- 590 N/A
    piperidino)carbonyl-2-
    thienyl
    CLXI morpholinoNH 5-(cyclohexyl- 521  264*
    aminocarbonyl)-2-thienyl
    CLXII morpholinoNH 5-(4-piperidyl- 522  224*
    aminocarbonyl)-2-thienyl
    CLXIII morpholinoNH 5-((1-CO2t-Bu-4- 620  229*
    piperidyl)amino-
    carbonyl)-2-thienyl
    CLXIV morpholinoNH 5-(N-(1-Me-4- 550  230*
    piperidyl)-N-methyl-
    aminocarbonyl)-2-
    thienyl
    CLXV morpholinoNH 5-(3-NMe2- 550 >300*
    piperidinocarbonyl)-2-
    thienyl
    CLXVI morpholinoNH 5-(3-(p- 676  193*
    toluenesulfonyl-
    amino)piperidino-
    carbonyl)-2-thienyl
    CLXVII morpholinoNH 5-(3-OH-piperidino- 523 N/A
    carbonyl)-2-thienyl
    CLXVIII morpholinoNH 5-((3-piperidyl)- 522 >300*
    aminocarbonyl)-2-
    thienyl
    CLXIX morpholinoNH 5-((3-quinuclidyl)- 548  245*
    aminocarbonyl)-2-
    thienyl
    CLXX morpholinoNH 5-(3-(aminocyclohexyl)- 536 >300*
    aminocarbonyl)-2-
    thienyl
    CLXXI morpholinoNH 5-(3-(t-butoxy- 636 >300*
    carbonylaminocyclo-
    hexyl)aminocarbonyl)-2-
    thienyl
    CLXXII morpholinoNH 5-(2-(Me2NCH2)- 564 >300*
    piperidinocarbonyl)-2-
    thienyl
    CLXXIII morpholinoNH 5-(2-Et2NCH2)- 592  210*
    piperidinocarbonyl)-2-
    thienyl
    CLXXIV morpholinoNH 5-pyrrolidino- 493 >300*
    carbonyl)-2-thienyl
    CLXXV morpholinoNH 5-(3-NH2- 508  201*
    pyrrolidinocarbonyl)-2-
    thienyl
    CLXXVI morpholinoNH 5-(3(S)- 522 N/A
    (NHMe)pyrrolidino-
    carbonyl)-2-thienyl
    CLXXVII morpholinoNH 5-(3(S)-(NHCOCH3)- 550  264*
    pyrrolidinocarbonyl)-2-
    thienyl
    CLXXVIII morpholinoNH 5-(3(S)-(N(Me)COCH3)- 564 >300*
    pyrrolidinocarbonyl)-2-
    thienyl
    CLXXIX morpholinoNH 5-(3(S)-(N(Me)CO2t- 622 >300*
    Bu)pyrrolidino-
    carbonyl)-2-thienyl
    CLXXX morpholinoNH 5-(3-NMe2- 536  216*
    pyrrolidinocarbonyl)-2-
    thienyl
    CLXXXI morpholinoNH 5-(3(R)-(NMe2)- 536  265*
    pyrrolidinocarbonyl)-2-
    thienyl
    CLXXXII morpholinoNH 5-(3(S)-(NMe2)- 536  264*
    pyrrolidinocarbonyl)-2-
    thienyl
    CLXXXIII morpholinoNH 5-((1-Me-3- 536  151*
    pyrrolidinyl)methylamino-
    carbonyl)-2-thienyl
    CLXXXIV morpholinoNH 5-(2(R)- 576  166*
    (pyrrolidinomethyl)pyrro-
    lidino-carbonyl)-2-
    thienyl
    CLXXXV morpholinoNH 5-(2(S)- 523  267*
    (CH2OH)pyrrolidino-
    carbonyl)-2-thienyl
    CLXXXVI morpholinoNH 5-(2(R)-(CH3OCH2)- 537  262*
    pyrrolidinocarbonyl)-2-
    thienyl
    CLXXXVII morpholinoNH 5-(2(S)- 598 >300*
    (phenylaminomethyl)-
    pyrrolidinocarbonyl)-2-
    thienyl
    CLXXXVIII morpholinoNH 5-(2(R)-(CH3OCH2)- 552  266*
    pyrrolidinoamino-
    carbonyl)-2-thienyl
    CLXXXIX morpholinoNH 5-homopiperidino- 521 N/A
    carbonyl-2-thienyl
    CXC morpholinoNH 5-homopiperazino- 522  209*
    carbonyl-2-thienyl
    CXCI morpholinoNH 5-(4-Me-homopiperazino- 536  207*
    carbonyl)-2-thienyl
    CXCII morpholinoNH 5-(4-Et-homopiperazino- 550  192*
    carbonyl)-2-thienyl
    CXCIII morpholinoNH 5-((4- 576  194*
    (cyclohexylmethyl)-
    homopiperazino)-
    carbonyl)-2-thienyl
    CXCIV morpholinoNH 5-(4-(CO2t-Bu)- 622  210*
    homopiperazino-
    carbonyl)-2-thienyl
    CXCV morpholinoNH 5-(4-(COCH3)- 564  274*
    homopiperazino-
    carbonyl)-2-thienyl
    CXCVI morpholinoNH 5-((4-methylamino- 544  230*
    phenyl)aminocarbonyl)-
    2-thienyl
    CXCVII morpholinoNH 5-((4-acetamidophenyl)- 572  253*
    aminocarbonyl)-2-
    thienyl
    CXCVIII morpholinoNH 5-(4-(NEt2)- 586  198*
    phenylaminocarbonyl)-2-
    thienyl
    CXCIX morpholinoNH 5-(1-Me-3-cyclopropyl- 559  290*
    5-pyrazolyl)amino-
    carbonyl-1-thienyl
    CC morpholinoNH 1-Me-3-pyrrolyl 393  301
    CCI 2(R)-(CH3OCH2)- 5-CO2Et-2-thienyl 496  221
    pyrrolidinoNH
    CCII 2(R)-(CH3OCH2)- 5-CO2H-2-thienyl 468  258*
    pyrrolidinoNH
    CCIII 2(R)-(CH3OCH2)- 5-(4-Me-piperazino- 550  181*
    pyrrolidinoNH carbonyl)-2-thienyl
    CCIV 2(R)-(CH3OCH2)- 5-piperazino-carbonyl- 536 >300*
    pyrroldinoNH 2-thienyl
    CCV 2(R)-(CH3OCH2)- 5-(4-(CO2t-Bu)- 636 >300*
    pyrrolidinoNH piperazinocarbonyl)-2-
    thienyl
    CCVI 2(R)-(CH3OCH2)- 5-(4-Me-homopiperazino- 564  176*
    pyrrolidinoNH carbonyl)-2-thienyl
    CCVII 2(R)-(CH3OCH2)- 5-homopiperazino- 550  185*
    pyrrolidinoNH carbonyl-2-thienyl
    CCVIII 2(R)-(CH3OCH2)- 5-(4-(CO2t-Bu)- 650 >300*
    pyrrolidinoNH homopiperazino-
    carbonyl)-2-thienyl
    CCIX Methyl 4-CF3C6H4 370 >300
    (M − H)
    CCX morpholinoNH 4-(4-Boc- 574  242
    piperazino)C6H4
    CCXI morpholinoNH 4-(piperazino)C6H4 474  263*
    CCXII NH2 4-(piperazino)C6H4 389  257*
    CCXIII NH2NH 4-(piperazino)C6H4 404  257*
    CCXIV Me2NCH2 4-(piperazino)C6H4 431  243*
    CCXV morpholinylCH2 4-(piperazino)C6H4 473  259*
    CCXVI 4-Me-piperazinoCH2 4-(piperazino)C6H4 486 NA
    CCXVII 4-NH2CH2-piperidinoCH2 4-(piperazino)C6H4 500  239*
    CCXVIII morpholinoNH 4-(4-Me-piperazino)C6H4 488  245*
    CCXIX morpholinoNH 4-(4-Et-piperazino)C6H4 502  245*
    CCXX morpholinoNH 4-(4-i-Pr- 516  253*
    piperazino)C6H4
    CCXXI Me2NNH 4-(piperazino)C6H4 432  238*
    CCXXII Me2NNH 4-(4-Me-piperazino)C6H4 446  192*
    CCXXIII 4-CH3-piperazinoNH 4-(piperazino)C6H4 487  254*
    CCXXIV 4-CH3-piperazinoNH 4-(4-Me-piperazino)C6H4 501  293*
    CCXXV 4-CH3-piperazinoNH 4-(4-Et-piperazino)C6H4 515 NA
    CCXXVI 4-CH3-piperazinoNH 4-(4-i-Pr- 529  272*
    piperazino)C6H4
    CCXXVII 2,6-diCH3-piperidinoNH 4-(piperazino)C6H4 500  270*
    CCXXVIII 4-HOCH2CH2-piperazino-NH 4-(piperazino)C6H4 517  279*
    CCXXIX 2(R)-CH3OCH2- 4-(piperazino)C6H4 502 NA
    pyrrolidinoNH
    CCXXX 2(S)-CH3OCH2- 4-(piperazino)C6H4 502 NA
    pyrrolidinoNH
    CCXXXI 2(R)-CH3OC(CH3)2- 4-(piperazino)C6H4 530  221*
    pyrrolidinoNH
    CCXXXII 2(S)-CH3OC(CH3)2- 4-(piperazino)C6H4 530  218*
    pyrrolidinoNH
    CCXXXIII 2(R)-HOCH2-pyrrolidinoNH 4-(piperazino)C6H4 488  193*
    CCXXXIV 2(S)-HOCH2-pyrrolidinoNH 4-(piperazino)C6H4 488  190*
    CCXXXV 2(R)-PhOCH2- 4-(piperazino)C6H4 578  207*
    pyrrolidinoNH
    CCXXXVI 2(S)-PhOCH2- 4-(piperazino)C6H4 578 NA
    pyrrolidinoNH
    CCXXXVII morpholinoNH 4-(3-Me-piperazino)C6H4 488  230*
    CCXXXVIII morpholinoNH 4-(cis-3,5-diMe- 502  237*
    piperazino)C6H4
    CCXXX morpholinoNH 4-(cis-3,4,5-triMe- 516  240*
    piperazino)C6H4
    CCXXXI morpholinoNH 4-(4-i-Pr-piperazino)- 530 NA
    2-Me—C6H4
    CCXLI morpholinoNH 4-(homopiperazino)-C6H4 488  253*
    CCXLII morpholinoNH 4-(4-Me- 502 NA
    homopiperazino)-C6H4
    CCXLIII morpholinoNH 4-(4-Et- 516  240*
    homopiperazino)-C6H4
    CCXLIV morpholinoNH 4-(4-i-Pr- 530  245*
    homopiperazino)-C6H4
    CCXLV morpholinoNH 4-(homopiperazino)-2- 502  209*
    Me—C6H4
    CCXLVI morpholinoNH 4-(4-Et- 530  217*
    homopiperazino)-2-Me-
    C6H4
    CCXLVII morpholinoNH 4-(4-i-Pr- 544  197*
    homopiperazino)-2-
    Me—C6H4
    CCXLVIII morpholinoNH 4-(4-Me2N- 516  258*
    piperidino)C6H4
    CCXLIX morpholinoNH 4-(4-morpholino- 558  249#
    piperidino)C6H4
    CCL morpholinoNH 4-(4-piperidino- 556  233*
    piperidino)C6H4
    CCLI morpholinoNH 4-(4-pyrrolidino- 542  247*
    piperidino)C6H4
    CCLII morpholinoNH 4-(4-Et2N- 544  251*
    piperidino)C6H4
    CCLIII morpholinoNH 4-(4-C(═NH)CH3- 515  240*
    piperazino)C6H4
    CCLIV morpholinoNH 4-(4-(2-pyridinyl)- 551 NA
    piperazino)C6H4
    CCLV 4-NH2CO-piperidinoCH2 c-propyl 394  178*
    CCLVI 4-CH3-piperazinoNH ethyl 355  244*
    CCVLVII 4-CH3-piperazinoNH c-propyl 367  215*
    CCLVIII 4-CH3-piperazinoNH c-hexyl 409  241*
    CCLIX morpholinoNH ethyl 342  253*
    CCLX morpholinoNH c-propyl 354 N/A
    CCLXI morpholinoNH c-hexyl 396 >260*
    CCLXII morpholinoNH 1-CO2Et-piperidin-4-yl 469  206*
    CCLXIII morpholinoNH 1-CO2Ph-piperidin-4-yl 517  250*
    CCLXIV morpholinoNH 1-Coimidazolyl- 491  202*
    piperidin-4-yl
    CCLXV morpholinoNH 1-(2- 507  218*
    thienylcarbonyl)piperidin-
    4-yl
    CCLXVI morpholinoNH 1-CONH2-piperidin-4-yl 440  258*
    CCLXVII morpholinoNH 1-CONHEt-piperidin-4-yl 466  215*
    CCLXVIII morpholinoNH 1-(2-(1-Me-pyrrolidin- 551  91*
    2-
    yl)ethylaminocarbamoyl)-
    piperidin-4-yl
    CCLXIX morpholinoNH 1-(4-Nme2- 551  172*
    piperidinocarbonyl)-
    piperidin-4-yl
    CCLXX morpholinoNH 1-(piperazinocarbonyl)- 509  195*
    piperidin-4-yl
    CCLXXI morpholinoNH 1-(4-(CO2t-Bu)- 609  231
    piperiazinocarbonyl)-
    piperidin-4-yl
    CCLXXII morpholinoNH 1-((1S,4S)-(+)-2,5- 521  196*
    diazabicyclo[2.2.1]hept-
    yl)carbonyl)-piperidin-
    4-yl
    CCLXXIII morpholinoNH 1-((1S,4S)-(+)-2- 535  225*
    methyl-2,5-
    diazabicyclo[2.2.1]hept-
    yl)carbonyl)-pipieridin-
    4-yl
    CCLXXIV morpholinoNH 1-(CO(CH2)3NH2)- 483  172*
    piperidin-4-yl
    CCLXXV morpholinoNH 1-(CO(CH2)3Nme2)- 482  172*
    piperidin-4-yl
    CCLXXVI morpholinoNH 1-(CO(CH2)3NHCO2t-Bu)- 582  73
    piperidin-4-yl
    CCLXXVII morpholinoNH 1-(CO(CH2)4NH2)- 496  103*
    piperidin-4-yl
    CCLXXVIII morpholinoNH 1-(CO(CH2)4Nme2)- 524  68*
    piperidin-4-yl
    CCLXXIX morpholinoNH 1-(CO(CH2)4NHCO2t-Bu)- 596  98*
    piperidin-4-yl
    CCLXXX morpholinoNH 1-(1-e-piperidin-4- 522  148*
    ylcarbonyl)piperidin-4-
    yl
    CCLXXXI morpholinoNH 1-(1-CO2t-Bu-piperidin- 608  220
    4-yl-
    carbonyl)piperidin-4-yl
    CCLXXXII morpholinoNH 1-(cis-4-NH2- 522  212*
    cyclohexylcarbonyl)piper-
    idin-4-yl
    CCLXXXIII morpholinoNH 1-(4-NH2- 522  202*
    cyclohexylcarbonyl)piper-
    idin-4-yl
    CCLXXXIV morpholinoNH 1-(cis-4-Nme2- 522  202*
    cyclohexylcarbonyl)piper-
    idin-4-yl
    CCLXXXV morpholinoNH 1-(4-NHCO2t-Bu)- 622  210*
    cyclohexylcarbonyl)piper-
    idin-4-yl
    CCLXXXVI morpholinoNH 1-(trans-4-(NHCO2t- 622  178
    Bu)cyclohexylcar-
    bonyl)piperidin-4-yl
    CCLXXXVII morpholinoNH 1-(piperidin-3- 508  169*
    ylcarbonyl)piperidin-4-
    yl
    CCLXXXVIII morpholinoNH 1-(1-Me-piperidin-3- 522  158*
    ylcarbonyl)piperidin-4-
    yl
    CCLXXXIX morpholinoNH 1-(1-CO2t-Bu-piperidin- 608  196
    3-ylcarbonyl)piperidin-
    4-yl
    CCXC morpholinoNH 1-(3-NH2- 522  201*
    cyclohexylcarbonyl)piper-
    idin-4-yl
    CCXCI morpholinoNH 1-(3-Nme2- 550  153*
    cyclohexylcarbonyl)piper-
    idin-4-yl
    CCXCII morpholinoNH 1-(trans-4-Ome- 537  246*
    cyclohexylcarbonyl)piper-
    idin-4-yl
    CCXCIII morpholinoNH 1-(cis-4-Ome- 537  178*
    cyclohexylcarbonyl)pipre-
    idin-4-yl
    CCXCIV morpholinoNH 1-(4-NH2- 530  177*
    benzylcarbonyl)piper-
    idin-4-yl
    CCXCV morpholinoNH 1-(4-Nme2- 558  107*
    benzylcarbonyl)piper-
    idin-4-yl
    CCXCVI morpholinoNH 1-(4-NHCO2C(CH3)3- 630  177
    benzylcarbonyl)piper-
    idin-4-yl
    CCXCVII morpholinoNH 1-(4-NH2- 516  198*
    phenylcarbonyl)piper-
    idin-4-yl
    CCXCVIII morpholinoNH 1-(4-Nme2- 544  189*
    phenylcarbonyl)piper-
    idin-4-yl
    CCXCIX morpholinoNH 1-(4-(NHCO2t-Bu)- 616  212
    phenylcarbonyl)piper-
    idin-4-yl
    CCC morpholinoNH trans-4-CO2H-cyclohexyl 440  264*
    CCCI morpholinoNH trans-4-CO2Me- 454  259*
    cyclohexyl
    CCCII morpholinoNH trans-4-(3-Nme2- 536  191*
    pyrrolidinocarbonyl)-
    cyclohexyl
    CCCIII morpholinoNH trans-4- 508  248*
    (piperazinocarbonyl)-
    cyclohexyl
    CCCIV morpholinoNH trans-4-(4-Me- 522  228*
    piperazinocarbonyl)-
    cyclohexyl
    CCCV morpholinoNH trans-4- 522 >265*
    (homopiperazinocar-
    bonyl)cyclohexyl
    CCCVI morpholinoNH trans-4-(4- 536  220*
    methylhomopiperazinocar-
    bonyl)cyclohexyl
  • [1006]
    [1006]
    TABLE 2
    Example
    Number R1 R2
    100 2-pyridylmethyl 4-MeOC6H4
    101 2-pyridylmethyl 3-MeOC6H4
    102 2-pyridylmethyl 4-NH2C6H4
    103 2-pyridylmethyl 3-NH2C6H4
    104 2-pyridylmethyl 2-NH2C6H4
    105 2-pyridylmethyl 4-Me2NC6H4
    106 2-pyridylmethyl 3-Me2NC6H4
    107 2-pyridylmethyl 2-Me2NC6H4
    108 2-pyridylmethyl 4-pyridyl
    109 2-pyridylmethyl 3-pyridyl
    110 2-pyridylmethyl 2-pyridyl
    111 2-pyridylmethyl 2-thiazolyl
    112 2-pyridylmethyl 2-pyrazolyl
    113 2-pyridylmethyl 5-isoquinolyl
    114 2-pyridylmethyl 3,4-methylenedioxyC6H3
    115 2-pyridylmethyl 3,4-ethylenedioxyC6H3
    116 2-pyridylmethyl 2-imidazolyl
    117 2-pyridylmethyl 4-isoxazolyl
    119 2-pyridylmethyl 4-HOC6H4
    120 2-pyridylmethyl 3-HOC6H4
    121 2-pyridylmethyl 3,4-diHOC6H4
    122 2-pyridylmethyl 4-NH2CH2C6H4
    123 2-pyridylmethyl 3-NH2CH2C6H4
    124 3-pyridylmethyl 4-MeOC6H4
    125 3-pyridylmethyl 3-MeOC6H4
    126 3-pyridylmethyl 4-NH2C6H4
    127 3-pyridylmethyl 3-NH2C6H4
    128 3-pyridylmethyl 2-NH2C6H4
    129 3-pyridylmethyl 4-Me2NC6H4
    130 3-pyridylmethyl 2-Me2NC6H4
    132 3-pyridylmethyl 4-pyridyl
    133 3-pyridylmethyl 2-pyridyl
    135 3-pyridylmethyl 2-thiazolyl
    136 3-pyridylmethyl 2-pyrazolyl
    137 3-pyridylmethyl 5-isoquinolyl
    138 3-pyridylmethyl 3,4-methylenedioxyC6H3
    139 3-pyridylmethyl 3,4-ethylenedioxyC6H3
    140 3-pyridylmethyl 2-imidazolyl
    141 3-pyridylmethyl 2-oxazolyl
    142 3-pyridylmethyl 4-isoxazolyl
    143 3-pyridylmethyl 4-HOC6H4
    144 3-pyridylmethyl 3-HOC6H4
    145 3-pyridylmethyl 3,4-diHOC6H4
    146 3-pyridylmethyl 4-NH2CH2C6H4
    147 3-pyridylmethyl 3-NH2CH2C6H4
    148 4-pyridylmethyl 4-MeOC6H4
    149 4-pyridylmethyl 3-MeOC6H4
    150 4-pyridylmethyl 4-NH2C6H4
    151 4-pyridylmethyl 3-NH2C6H4
    152 4-pyridylmethyl 2-NH2C6H4
    153 4-pyridylmethyl 4-Me2NC6H4
    154 4-pyridylmethyl 3-Me2NC6H4
    155 4-pyridylmethyl 2-Me2NC6H4
    156 4-pyridylmethyl 4-pyridyl
    157 4-pyridylmethyl 3-pyridyl
    158 4-pyridylmethyl 2-pyridyl
    159 4-pyridylmethyl 2-thiazolyl
    160 4-pyridylmethyl 2-pyrazolyl
    161 4-pyridylmethyl 5-isoquinolyl
    162 4-pyridylmethyl 3,4-methylenedioxyC6H3
    163 4-pyridylmethyl 3,4-ethylenedioxyC6H3
    164 4-pyridylmethyl 2-imidazolyl
    165 4-pyridylmethyl 2-oxazolyl
    166 4-pyridylmethyl 4-isoxazolyl
    167 4-pyridylmethyl 4-HOC6H4
    168 4-pyridylmethyl 3-HOC6H4
    169 4-pyridylmethyl 3,4-diHOC6H4
    170 4-pyridylmethyl 4-NH2CH2C6H4
    171 4-pyridylmethyl 3-NH2CH2C6H4
    172 2-NH2C6H4CH2 4-MeOC6H4
    173 2-NH2C6H4CH2 3-MeOC6H4
    174 2-NH2C6H4CH2 4-NH2C6H4
    175 2-NH2C6H4CH2 3-NH2C6H4
    176 2-NH2C6H4CH2 2-NH2C6H4
    177 2-NH2C6H4CH2 4-Me2NC6H4
    178 2-NH2C6H4CH2 3-Me2NC6H4
    179 2-NH2C6H4CH2 2-Me2NC6H4
    180 2-NH2C6H4CH2 4-pyridyl
    181 2-NH2C6H4CH2 3-pyridyl
    182 2-NH2C6H4CH2 2-pyridyl
    183 2-NH2C6H4CH2 2-thiazolyl
    184 2-NH2C6H4CH2 2-pyrazolyl
    185 2-NH2C6H4CH2 5-isoquinolyl
    186 2-NH2C6H4CH2 3,4-methylenedioxyC6H3
    187 2-NH2C6H4CH2 3,4-ethylenedioxyC6H3
    188 2-NH2C6H4CH2 2-imidazolyl
    189 2-NH2C6H4CH2 2-oxazolyl
    190 2-NH2C6H4CH2 4-isoxazolyl
    191 2-NH2C6H4CH2 4-HOC6H4
    192 2-NH2C6H4CH2 3-HOC6H4
    193 2-NH2C6H4CH2 3,4-diHOC6H4
    194 2-NH2C6H4CH2 4-NH2CH2C6H4
    195 2-NH2C6H4CH2 3-NH2CH2C6H4
    196 3-NH2C6H4CH2 3-MeOC6H4
    197 3-NH2C6H4CH2 4-NH2C6H4
    198 3-NH2C6H4CH2 3-NH2C6H4
    199 3-NH2C6H4CH2 2-NH2C6H4
    200 3-NH2C6H4CH2 4-Me2NC6H4
    201 3-NH2C6H4CH2 3-Me2NC6H4
    202 3-NH2C6H4CH2 2-Me2NC6H4
    203 3-NH2C6H4CH2 4-pyridyl
    204 3-NH2C6H4CH2 3-pyridyl
    205 3-NH2C6H4CH2 2-pyridyl
    206 3-NH2C6H4CH2 2-thiazolyl
    207 3-NH2C6H4CH2 2-pyrazolyl
    208 3-NH2C6H4CH2 5-isoquinolyl
    209 3-NH2C6H4CH2 3,4-methylenedioxyC6H3
    210 3-NH2C6H4CH2 3,4-ethylenedioxyC6H3
    211 3-NH2C6H4CH2 2-imidazolyl
    212 3-NH2C6H4CH2 2-oxazolyl
    213 3-NH2C6H4CH2 4-isoxazolyl
    214 3-NH2C6H4CH2 4-HOC6H4
    215 3-NH2C6H4CH2 3-HOC6H4
    216 3-NH2C6H4CH2 3,4-diHOC6H4
    217 3-NH2C6H4CH2 4-NH2CH2C6H4
    218 3-NH2C6H4CH2 3-NH2CH2C6H4
    219 4-NH2C6H4CH2 3-MeOC6H4
    220 4-NH2C6H4CH2 4-NH2C6H4
    221 4-NH2C6H4CH2 3-NH2C6H4
    222 4-NH2C6H4CH2 2-NH2C6H4
    223 4-NH2C6H4CH2 4-Me2NC6H4
    224 4-NH2C6H4CH2 3-Me2NC6H4
    225 4-NH2C6H4CH2 2-Me2NC6H4
    226 4-NH2C6H4CH2 4-pyridyl
    227 4-NH2C6H4CH2 3-pyridyl
    228 4-NH2C6H4CH2 2-pyridyl
    229 4-NH2C6H4CH2 2-thiazolyl
    230 4-NH2C6H4CH2 2-pyrazolyl
    231 4-NH2C6H4CH2 5-isoquinolyl
    232 4-NH2C6H4CH2 3,4-methylenedioxyC6H3
    233 4-NH2C6H4CH2 2-imidazolyl
    235 4-NH2C6H4CH2 2-oxazolyl
    236 4-NH2C6H4CH2 4-isoxazolyl
    237 4-NH2C6H4CH2 4-HOC6H4
    238 4-NH2C6H4CH2 3-HOC6H4
    239 4-NH2C6H4CH2 3,4-diHOC6H4
    240 4-NH2C6H4CH2 4-NH2CH2C6H4
    241 4-NH2C6H4CH2 3-NH2CH2C6H4
    242 2-MeOC6H4CH2 3-MeOC6H4
    243 2-MeOC6H4CH2 4-NH2C6H4
    244 2-MeOC6H4CH2 3-NH2C6H4
    245 2-MeOC6H4CH2 2-NH2C6H4
    246 2-MeOC6H4CH2 4-Me2NC6H4
    247 2-MeOC6H4CH2 3-Me2NC6H4
    248 2-MeOC6H4CH2 2-Me2NC6H4
    249 2-MeOC6H4CH2 4-pyridyl
    250 2-MeOC6H4CH2 3-pyridyl
    251 2-MeOC6H4CH2 2-pyridyl
    252 2-MeOC6H4CH2 2-thiazolyl
    253 2-MeOC6H4CH2 2-pyrazolyl
    254 2-MeOC6H4CH2 5-isoquinolyl
    255 2-MeOC6H4CH2 3,4-ethylenedioxyC6H3
    257 2-MeOC6H4CH2 2-imidazolyl
    258 2-MeOC6H4CH2 2-oxazolyl
    259 2-MeOC6H4CH2 4-isoxazolyl
    260 2-MeOC6H4CH2 4-HOC6H4
    261 2-MeOC6H4CH2 3-HOC6H4
    262 2-MeOC6H4CH2 3,4-diHOC6H4
    263 2-MeOC6H4CH2 4-NH2CH2C6H4
    264 2-MeOC6H4CH2 3-NH2CH2C6H4
    265 3-MeOC6H4CH2 3-MeOC6H4
    266 3-MeOC6H4CH2 4-NH2C6H4
    267 3-MeOC6H4CH2 3-NH2C6H4
    268 3-MeOC6H4CH2 2-NH2C6H4
    269 3-MeOC6H4CH2 4-Me2NC6H4
    270 3-MeOC6H4CH2 3-Me2NC6H4
    271 3-MeOC6H4CH2 2-Me2NC6H4
    272 3-MeOC6H4CH2 4-pyridyl
    273 3-MeOC6H4CH2 3-pyridyl
    274 3-MeOC6H4CH2 2-pyridyl
    275 3-MeOC6H4CH2 2-thiazolyl
    276 3-MeOC6H4CH2 2-pyrazolyl
    277 3-MeOC6H4CH2 5-isoquinolyl
    278 3-MeOC6H4CH2 3,4-methylenedioxyC6H3
    279 3-MeOC6H4CH2 3,4-ethylenedioxyC6H3
    280 3-MeOC6H4CH2 2-imidazolyl
    281 3-MeOC6H4CH2 2-oxazolyl
    282 3-MeOC6H4CH2 4-isoxazolyl
    283 3-MeOC6H4CH2 4-HOC6H4
    284 3-MeOC6H4CH2 3-HOC6H4
    285 3-MeOC6H4CH2 3,4-diHOC6H4
    286 3-MeOC6H4CH2 4-NH2CH2C6H4
    287 3-MeOC6H4CH2 3-NH2CH2C6H4
    288 4-MeOC6H4CH2 3-MeOC6H4
    289 4-MeOC6H4CH2 4-NH2C6H4
    290 4-MeOC6H4CH2 3-NH2C6H4
    291 4-MeOC6H4CH2 2-NH2C6H4
    292 4-MeOC6H4CH2 4-Me2NC6H4
    293 4-MeOC6H4CH2 3-Me2NC6H4
    294 4-MeOC6H4CH2 2-Me2NC6H4
    295 4-MeOC6H4CH2 4-pyridyl
    296 4-MeOC6H4CH2 3-pyridyl
    297 4-MeOC6H4CH2 2-pyridyl
    298 4-MeOC6H4CH2 2-thiazolyl
    299 4-MeOC6H4CH2 2-pyrazolyl
    300 4-MeOC6H4CH2 5-isoquinolyl
    301 4-MeOC6H4CH2 3,4-methylenedioxyC6H3
    302 4-MeOC6H4CH2 3,4-ethylenedioxyC6H3
    303 4-MeOC6H4CH2 2-imidazolyl
    304 4-MeOC6H4CH2 2-oxazolyl
    305 4-MeOC6H4CH2 4-isoxazolyl
    306 4-MeOC6H4CH2 4-HOC6H4
    307 4-MeOC6H4CH2 3-HOC6H4
    308 4-MeOC6H4CH2 3,4-diHOC6H4
    309 4-MeOC6H4CH2 4-NH2CH2C6H4
    310 4-MeOC6H4CH2 3-NH2CH2C6H4
    311 2-HOC6H4CH2 4-MeOC6H4
    312 2-HOC6H4CH2 3-MeOC6H4
    313 2-HOC6H4CH2 4-NH2C6H4
    314 2-HOC6H4CH2 3-NH2C6H4
    315 2-HOC6H4CH2 2-NH2C6H4
    316 2-HOC6H4CH2 4-Me2NC6H4
    317 2-HOC6H4CH2 3-Me2NC6H4
    318 2-HOC6H4CH2 2-Me2NC6H4
    319 2-HOC6H4CH2 4-pyridyl
    320 2-HOC6H4CH2 3-pyridyl
    321 2-HOC6H4CH2 2-pyridyl
    322 2-HOC6H4CH2 2-thiazolyl
    323 2-HOC6H4CH2 2-pyrazolyl
    324 2-HOC6H4CH2 5-isoquinolyl
    325 2-HOC6H4CH2 3,4-methylenedioxyC6H3
    326 2-HOC6H4CH2 3,4-ethylenedioxyC6H3
    327 2-HOC6H4CH2 2-imidazolyl
    328 2-HOC6H4CH2 2-oxazolyl
    329 2-HOC6H4CH2 4-isoxazolyl
    330 2-HOC6H4CH2 4-HOC6H4
    331 2-HOC6H4CH2 3-HOC6H4
    332 2-HOC6H4CH2 3,4-diHOC6H4
    333 2-HOC6H4CH2 4-NH2CH2C6H4
    334 2-HOC6H4CH2 3-NH2CH2C6H4
    335 3-HOC6H4CH2 4-MeOC6H4
    336 3-HOC6H4CH2 3-MeOC6H4
    337 3-HOC6H4CH2 4-NH2C6H4
    338 3-HOC6H4CH2 3-NH2C6H4
    339 3-HOC6H4CH2 2-NH2C6H4
    340 3-HOC6H4CH2 4-Me2NC6H4
    341 3-HOC6H4CH2 3-Me2NC6H4
    342 3-HOC6H4CH2 2-Me2NC6H4
    343 3-HOC6H4CH2 4-pyridyl
    344 3-HOC6H4CH2 3-pyridyl
    345 3-HOC6H4CH2 2-pyridyl
    346 3-HOC6H4CH2 2-thiazolyl
    347 3-HOC6H4CH2 2-pyrazolyl
    348 3-HOC6H4CH2 5-isoquinolyl
    349 3-HOC6H4CH2 3,4-methylenedioxyC6H3
    350 3-HOC6H4CH2 3,4-ethylenedioxyC6H3
    351 3-HOC6H4CH2 2-imidazolyl
    352 3-HOC6H4CH2 2-oxazolyl
    353 3-HOC6H4CH2 4-isoxazolyl
    354 3-HOC6H4CH2 4-HOC6H4
    355 3-HOC6H4CH2 3-HOC6H4
    356 3-HOC6H4CH2 3,4-diHOC6H4
    357 3-HOC6H4CH2 4-NH2CH2C6H4
    358 3-HOC6H4CH2 3-NH2CH2C6H4
    359 4-HOC6H4CH2 4-MeOC6H4
    360 4-HOC6H4CH2 3-MeOC6H4
    361 4-HOC6H4CH2 4-NH2C6H4
    362 4-HOC6H4CH2 3-NH2C6H4
    363 4-HOC6H4CH2 2-NH2C6H4
    364 4-HOC6H4CH2 4-Me2NC6H4
    365 4-HOC6H4CH2 3-Me2NC6H4
    366 4-HOC6H4CH2 2-Me2NC6H4
    367 4-HOC6H4CH2 4-pyridyl
    368 4-HOC6H4CH2 3-pyridyl
    369 4-HOC6H4CH2 2-pyridyl
    370 4-HOC6H4CH2 2-thiazolyl
    371 4-HOC6H4CH2 2-pyrazolyl
    372 4-HOC6H4CH2 5-isoquinolyl
    373 4-HOC6H4CH2 3,4-methylenedioxyC6H3
    374 4-HOC6H4CH2 3,4-ethylenedioxyC6H3
    375 4-HOC6H4CH2 2-imidazolyl
    376 4-HOC6H4CH2 2-oxazolyl
    377 4-HOC6H4CH2 4-isoxazolyl
    378 4-HOC6H4CH2 4-HOC6H4
    379 4-HOC6H4CH2 3-HOC6H4
    380 4-HOC6H4CH2 3,4-diHOC6H4
    381 4-HOC6H4CH2 4-NH2CH2C6H4
    382 4-HOC6H4CH2 3-NH2CH2C6H4
    383 4-ClC6H4CH2 3-MeOC6H4
    384 4-ClC6H4CH2 4-NH2C6H4
    385 4-ClC6H4CH2 3-NH2C6H4
    386 4-ClC6H4CH2 2-NH2C6H4
    387 4-ClC6H4CH2 4-Me2NC6H4
    388 4-ClC6H4CH2 3-Me2NC6H4
    389 4-ClC6H4CH2 2-Me2NC6H4
    390 4-ClC6H4CH2 4-pyridyl
    391 4-ClC6H4CH2 3-pyridyl
    392 4-ClC6H4CH2 2-pyridyl
    393 4-ClC6H4CH2 2-thiazolyl
    394 4-ClC6H4CH2 2-pyrazolyl
    395 4-ClC6H4CH2 5-isoquinolyl
    396 4-ClC6H4CH2 3,4-methylenedioxyC6H3
    397 4-ClC6H4CH2 3,4-ethylenedioxyC6H3
    398 4-ClC6H4CH2 2-imidazolyl
    399 4-ClC6H4CH2 2-oxazolyl
    400 4-ClC6H4CH2 4-isoxazolyl
    401 4-ClC6H4CH2 4-HOC6H4
    402 4-ClC6H4CH2 3-HOC6H4
    403 4-ClC6H4CH2 3,4-diHOC6H4
    404 4-ClC6H4CH2 4-NH2CH2C6H4
    405 4-ClC6H4CH2 3-NH2CH2C6H4
    406 2-NH2CH2C6H4CH2 4-MeOC6H4
    407 2-NH2CH2C6H4CH2 3-MeOC6H4
    408 2-NH2CH2C6H4CH2 4-NH2C6H4
    409 2-NH2CH2C6H4CH2 3-NH2C6H4
    410 2-NH2CH2C6H4CH2 2-NH2C6H4
    411 2-NH2CH2C6H4CH2 4-Me2NC6H4
    412 2-NH2CH2C6H4CH2 3-Me2NC6H4
    413 2-NH2CH2C6H4CH2 2-Me2NC6H4
    414 2-NH2CH2C6H4CH2 4-pyridyl
    415 2-NH2CH2C6H4CH2 3-pyridyl
    416 2-NH2CH2C6H4CH2 2-pyridyl
    417 2-NH2CH2C6H4CH2 2-thiazolyl
    418 2-NH2CH2C6H4CH2 2-pyrazolyl
    419 2-NH2CH2C6H4CH2 5-isoquinolyl
    420 2-NH2CH2C6H4CH2 3,4-methylenedioxyC6H3
    421 2-NH2CH2C6H4CH2 3,4-ethylenedioxyC6H3
    422 2-NH2CH2C6H4CH2 2-imidazolyl
    423 2-NH2CH2C6H4CH2 2-oxazolyl
    424 2-NH2CH2C6H4CH2 4-isoxazolyl
    425 2-NH2CH2C6H4CH2 4-HOC6H4
    426 2-NH2CH2C6H4CH2 3-HOC6H4
    427 2-NH2CH2C6H4CH2 3,4-diHOC6H4
    428 2-NH2CH2C6H4CH2 4-NH2CH2C6H4
    429 2-NH2CH2C6H4CH2 3-NH2CH2C6H4
    430 3-NH2CH2C6H4CH2 4-MeOC6H4
    431 3-NH2CH2C6H4CH2 3-MeOC6H4
    432 3-NH2CH2C6H4CH2 4-NH2C6H4
    433 3-NH2CH2C6H4CH2 3-NH2C6H4
    434 3-NH2CH2C6H4CH2 2-NH2C6H4
    435 3-NH2CH2C6H4CH2 4-Me2NC6H4
    436 3-NH2CH2C6H4CH2 3-Me2NC6H4
    437 3-NH2CH2C6H4CH2 2-Me2NC6H4
    438 3-NH2CH2C6H4CH2 4-pyridyl
    439 3-NH2CH2C6H4CH2 3-pyridyl
    440 3-NH2CH2C6H4CH2 2-pyridyl
    441 3-NH2CH2C6H4CH2 2-thiazolyl
    442 3-NH2CH2C6H4CH2 2-pyrazolyl
    443 3-NH2CH2C6H4CH2 5-isoquinolyl
    444 3-NH2CH2C6H4CH2 3,4-methylenedioxyC6H3
    445 3-NH2CH2C6H4CH2 3,4-ethylenedioxyC6H3
    446 3-NH2CH2C6H4CH2 2-imidazolyl
    447 3-NH2CH2C6H4CH2 2-oxazolyl
    448 3-NH2CH2C6H4CH2 4-isoxazolyl
    449 3-NH2CH2C6H4CH2 4-HOC6H4
    450 3-NH2CH2C6H4CH2 3-HOC6H4
    451 3-NH2CH2C6H4CH2 3,4-diHOC6H4
    452 3-NH2CH2C6H4CH2 4-NH2CH2C6H4
    453 3-NH2CH2C6H4CH2 3-NH2CH2C6H4
    454 4-NH2CH2C6H4CH2 4-MeOC6H4
    455 4-NH2CH2C6H4CH2 3-MeOC6H4
    456 4-NH2CH2C6H4CH2 4-NH2C6H4
    457 4-NH2CH2C6H4CH2 3-NH2C6H4
    458 4-NH2CH2C6H4CH2 2-NH2C6H4
    459 4-NH2CH2C6H4CH2 4-Me2NC6H4
    460 4-NH2CH2C6H4CH2 3-Me2NC6H4
    461 4-NH2CH2C6H4CH2 2-Me2NC6H4
    462 4-NH2CH2C6H4CH2 4-pyridyl
    463 4-NH2CH2C6H4CH2 3-pyridyl
    464 4-NH2CH2C6H4CH2 2-pyridyl
    465 4-NH2CH2C6H4CH2 2-thiazolyl
    466 4-NH2CH2C6H4CH2 2-pyrazolyl
    467 4-NH2CH2C6H4CH2 5-isoquinolyl
    468 4-NH2CH2C6H4CH2 3,4-methylenedioxyC6H3
    469 4-NH2CH2C6H4CH2 3,4-ethylenedioxyC6H3
    470 4-NH2CH2C6H4CH2 2-imidazolyl
    471 4-NH2CH2C6H4CH2 2-oxazolyl
    472 4-NH2CH2C6H4CH2 4-isoxazolyl
    473 4-NH2CH2C6H4CH2 4-HOC6H4
    474 4-NH2CH2C6H4CH2 3-HOC6H4
    475 4-NH2CH2C6H4CH2 3,4-diHOC6H4
    476 4-NH2CH2C6H4CH2 4-NH2CH2C6H4
    477 4-NH2CH2C6H4CH2 3-NH2CH2C6H4
    478 2-Me2NCH2C6H4CH2 4-MeOC6H4
    479 2-Me2NCH2C6H4CH2 3-MeOC6H4
    480 2-Me2NCH2C6H4CH2 4-NH2C6H4
    481 2-Me2NCH2C6H4CH2 3-NH2C6H4
    482 2-Me2NCH2C6H4CH2 2-NH2C6H4
    483 2-Me2NCH2C6H4CH2 4-Me2NC6H4
    484 2-Me2NCH2C6H4CH2 3-Me2NC6H4
    485 2-Me2NCH2C6H4CH2 2-Me2NC6H4
    486 2-Me2NCH2C6H4CH2 4-pyridyl
    487 2-Me2NCH2C6H4CH2 3-pyridyl
    488 2-Me2NCH2C6H4CH2 2-pyridyl
    489 2-Me2NCH2C6H4CH2 2-thiazolyl
    490 2-Me2NCH2C6H4CH2 2-pyrazolyl
    491 2-Me2NCH2C6H4CH2 5-isoquinolyl
    492 2-Me2NCH2C6H4CH2 3,4-methylenedioxyC6H3
    493 2-Me2NCH2C6H4CH2 3,4-ethylenedioxyC6H3
    494 2-Me2NCH2C6H4CH2 2-imidazolyl
    495 2-Me2NCH2C6H4CH2 2-oxazolyl
    496 2-Me2NCH2C6H4CH2 4-isoxazolyl
    497 2-Me2NCH2C6H4CH2 4-HOC6H4
    498 2-Me2NCH2C6H4CH2 3-HOC6H4
    499 2-Me2NCH2C6H4CH2 3,4-diHOC6H4
    500 2-Me2NCH2C6H4CH2 4-NH2CH2C6H4
    501 2-Me2NCH2C6H4CH2 3-NH2CH2C6H4
    502 3-Me2NCH2C6H4CH2 4-MeOC6H4
    503 3-Me2NCH2C6H4CH2 3-MeOC6H4
    504 3-Me2NCH2C6H4CH2 4-NH2C6H4
    505 3-Me2NCH2C6H4CH2 3-NH2C6H4
    506 3-Me2NCH2C6H4CH2 2-NH2C6H4
    507 3-Me2NCH2C6H4CH2 4-Me2NC6H4
    508 3-Me2NCH2C6H4CH2 3-Me2NC6H4
    509 3-Me2NCH2C6H4CH2 2-Me2OC6H4
    510 3-Me2NCH2C6H4CH2 4-pyridyl
    511 3-Me2NCH2C6H4CH2 3-pyridyl
    512 3-Me2NCH2C6H4CH2 2-pyridyl
    513 3-Me2NCH2C6H4CH2 2-thiazolyl
    514 3-Me2NCH2C6H4CH2 2-pyrazolyl
    515 3-Me2NCH2C6H4CH2 5-isoquinolyl
    516 3-Me2NCH2C6H4CH2 3,4-methylenedioxyC6H3
    517 3-Me2NCH2C6H4CH2 3,4-ethylenedioxyC6H3
    518 3-Me2NCH2C6H4CH2 2-imidazolyl
    519 3-Me2NCH2C6H4CH2 2-oxazolyl
    520 3-Me2NCH2C6H4CH2 4-isoxazolyl
    521 3-Me2NCH2C6H4CH2 4-HOC6H4
    522 3-Me2NCH2C6H4CH2 3-HOC6H4
    523 3-Me2NCH2C6H4CH2 3,4-diHOC6H4
    524 3-Me2NCH2C6H4CH2 4-NH2CH2C6H4
    525 3-Me2NCH2C6H4CH2 3-NH2CH2C6H4
    526 4-Me2NCH2C6H4CH2 4-MeOC6H4
    527 4-Me2NCH2C6H4CH2 3-MeOC6H4
    528 4-Me2NCH2C6H4CH2 4-NH2C6H4
    529 4-Me2NCH2C6H4CH2 3-NH2C6H4
    530 4-Me2NCH2C6H4CH2 2-NH2C6H4
    531 4-Me2NCH2C6H4CH2 4-Me2NC6H4
    532 4-Me2NCH2C6H4CH2 3-Me2NC6H4
    533 4-Me2NCH2C6H4CH2 2-Me2NC6H4
    534 4-Me2NCH2C6H4CH2 4-pyridyl
    535 4-Me2NCH2C6H4CH2 3-pyridyl
    536 4-Me2NCH2C6H4CH2 2-pyridyl
    537 4-Me2NCH2C6H4CH2 2-thiazolyl
    538 4-Me2NCH2C6H4CH2 2-pyrazolyl
    539 4-Me2NCH2C6H4CH2 5-isoquinolyl
    540 4-Me2NCH2C6H4CH2 3,4-methylenedioxyC6H3
    541 4-Me2NCH2C6H4CH2 3,4-ethylenedioxyC6H3
    542 4-Me2NCH2C6H4CH2 2-imidazolyl
    543 4-Me2NCH2C6H4CH2 2-oxazolyl
    545 4-Me2NCH2C6H4CH2 4-isoxazolyl
    546 4-Me2NCH2C6H4CH2 4-HOC6H4
    547 4-Me2NCH2C6H4CH2 3-HOC6H4
    548 4-Me2NCH2C6H4CH2 3,4-diHOC6H4
    549 4-Me2NCH2C6H4CH2 4-NH2CH2C6H4
    550 4-Me2NCH2C6H4CH2 3-NH2CH2C6H4
    551 H 3-MeOC6H4
    552 H 4-NH2C6H4
    553 H 3-NH2C6H4
    554 H 2-NH2C6H4
    555 H 4-Me2NC6H4
    556 H 3-Me2NC6H4
    557 H 2-Me2NC6H4
    558 H 3-pyridyl
    559 H 2-pyridyl
    560 H 2-thiazolyl
    561 H 2-pyrazolyl
    562 H 4-isoquinolyl
    563 H 3,4-methylenedioxyC6H3
    564 H 3,4-ethylenedioxyC6H3
    565 H 2-imidazolyl
    566 H 2-oxazolyl
    567 H 4-isoxazolyl
    568 4-HOC6H4
    569 H 3-HOC6H4
    570 H 3,4-diHOC6H4
    571 H 4-NH2CH2C6H4
    572 H 3-NH2CH2C6H4
    573 Me 3-MeOC6H4
    574 Me 4-NH2C6H4
    575 Me 3-NH2C6H4
    576 Me 2-NH2C6H4
    577 Me 4-Me2NC6H4
    578 Me 3-Me2NC6H4
    579 Me 2-Me2NC6H4
    580 Me 3-pyridyl
    581 Me 2-pyridyl
    582 Me 2-thiazolyl
    583 Me 2-pyrazolyl
    584 Me 5-isoquinolyl
    585 Me 3,4-ethylenedioxyC6H3
    586 Me 2-imidazolyl
    587 Me 2-oxazolyl
    588 Me 4-isoxazolyl
    589 Me 3-HOC6H4
    590 Me 3,4-diHOC6H4
    591 Me 4-NH2CH2C6H4
    592 Me 3-NH2CH2C6H4
    593 Et 3-MeOC6H4
    594 Et 4-NH2C6H4
    595 Et 3-NH2C6H4
    596 Et 2-NH2C6H4
    597 Et 4-Me2NC6H4
    598 Et 3-Me2NC6H4
    599 Et 2-Me2NC6H4
    600 Et 4-pyridyl
    601 Et 3-pyridyl
    601 Et 2-pyridyl
    603 Et 2-thiazolyl
    604 Et 2-pyrazolyl
    605 Et 5-isoquinolyl
    606 Et 3,4-methylenedioxyC6H3
    607 Et 3,4-ethylenedioxyC6H3
    608 Et 2-imidazolyl
    609 Et 2-oxazolyl
    610 Et 4-isoxazolyl
    611 Et 4-HOC6H4
    612 Et 3-HOC6H4
    613 Et 3,4-diHOC6H4
    614 Et 4-NH2CH2C6H4
    615 Et 3-NH2CH2C6H4
    616 Me2NCH2 3-MeOC6H4
    617 Me2NCH2 4-NH2C6H4
    618 Me2NCH2 3-NH2C6H4
    619 Me2NCH2 2-NH2C6H4
    620 Me2NCH2 4-Me2NC6H4
    621 Me2NCH2 3-Me2NC6H4
    622 Me2NCH2 2-Me2NC6H4
    623 Me2NCH2 4-pyridyl
    624 Me2NCH2 3-pyridyl
    625 Me2NCH2 2-pyridyl
    626 Me2NCH2 2-thiazolyl
    627 Me2NCH2 2-pyrazolyl
    628 Me2NCH2 5-isoquinolyl
    629 Me2NCH2 3,4-methylenedioxyC6H3
    630 Me2NCH2 3,4-ethylenedioxyC6H3
    631 Me2NCH2 2-imidazolyl
    632 Me2NCH2 2-oxazolyl
    633 Me2NCH2 4-isoxazolyl
    634 Me2NCH2 4-HOC6H4
    635 Me2NCH2 3-HOC6H4
    636 Me2NCH2 3,4-diHOC6H4
    637 Me2NCH2 4-NH2CH2C6H4
    638 Me2NCH2 3-NH2CH2C6H4
    639 EtNHCH2 3-MeOC6H4
    640 EtNHCH2 4-NH2C6H4
    641 EtNHCH2 3-NH2C6H4
    642 EtNHCH2 2-NH2C6H4
    643 EtNHCH2 4-Me2NC6H4
    644 EtNHCH2 3-Me2NC6H4
    645 EtNHCH2 2-Me2NC6H4
    646 EtNHCH2 4-pyridyl
    647 EtNHCH2 3-pyridyl
    648 EtNHCH2 2-pyridyl
    649 EtNHCH2 2-thiazolyl
    650 EtNHCH2 2-pyrazolyl
    651 EtNHCH2 5-isoquinolyl
    652 EtNHCH2 3,4-methylenedioxyC6H3
    653 EtNHCH2 3,4-ethylenedioxyC6H3
    654 EtNHCH2 2-imidazolyl
    655 EtNHCH2 2-oxazolyl
    656 EtNHCH2 4-isoxazolyl
    657 EtNHCH2 4-HOC6H4
    658 EtNHCH2 3-HOC6H4
    659 EtNHCH2 3,4-diHOC6H4
    660 EtNHCH2 4-NH2CH2C6H4
    661 EtNHCH2 3-NH2CH2C6H4
    662 HOCH2CH2NHCH2 3-MeOC6H4
    663 HOCH2CH2NHCH2 4-NH2C6H4
    664 HOCH2CH2NHCH2 3-NH2C6H4
    665 HOCH2CH2NHCH2 2-NH2C6H4
    666 HOCH2CH2NHCH2 4-Me2NC6H4
    667 HOCH2CH2NHCH2 3-Me2NC6H4
    668 HOCH2CH2NHCH2 2-Me2NC6H4
    669 HOCH2CH2NHCH2 4-pyridyl
    670 HOCH2CH2NHCH2 3-pyridyl
    671 HOCH2CH2NHCH2 2-pyridyl
    672 HOCH2CH2NHCH2 2-thiazolyl
    673 HOCH2CH2NHCH2 2-pyrazolyl
    674 HOCH2CH2NHCH2 5-isoquinolyl
    675 HOCH2CH2NHCH2 3,4-methylenedioxyC6H3
    676 HOCH2CH2NHCH2 3,4-ethylenedioxyC6H3
    677 HOCH2CH2NHCH2 2-imidazolyl
    678 HOCH2CH2NHCH2 2-oxazolyl
    679 HOCH2CH2NHCH2 4-isoxazolyl
    680 HOCH2CH2NHCH2 4-HOC6H4
    681 HOCH2CH2NHCH2 3-HOC6H4
    682 HOCH2CH2NHCH2 3,4-diHOC6H4
    683 HOCH2CH2NHCH2 4-NH2CH2C6H4
    684 HOCH2CH2NHCH2 3-NH2CH2C6H4
    685 H2NCH2CH2NHCH2 4-MeOC6H4
    686 H2NCH2CH2NHCH2 3-MeOC6H4
    687 H2NCH2CH2NHCH2 4-NH2C6H4
    688 H2NCH2CH2NHCH2 3-NH2C6H4
    689 H2NCH2CH2NHCH2 2-NH2C6H4
    690 H2NCH2CH2NHCH2 4-Me2NC6H4
    691 H2NCH2CH2NHCH2 3-Me2NC6H4
    692 H2NCH2CH2NHCH2 2-Me2NC6H4
    693 H2NCH2CH2NHCH2 4-pyridyl
    694 H2NCH2CH2NHCH2 3-pyridyl
    695 H2NCH2CH2NHCH2 2-pyridyl
    696 H2NCH2CH2NHCH2 2-thiazolyl
    697 H2NCH2CH2NHCH2 2-pyrazolyl
    698 H2NCH2CH2NHCH2 5-isoquinolyl
    699 H2NCH2CH2NHCH2 3,4-methylenedioxyC6H3
    700 H2NCH2CH2NHCH2 3,4-ethylenedioxyC6H3
    701 H2NCH2CH2NHCH2 2-imidazolyl
    702 H2NCH2CH2NHCH2 2-oxazolyl
    703 H2NCH2CH2NHCH2 4-isoxazolyl
    704 H2NCH2CH2NHCH2 4-HOC6H4
    705 H2NCH2CH2NHCH2 3-HOC6H4
    706 H2NCH2CH2NHCH2 3,4-diHOC6H4
    707 H2NCH2CH2NHCH2 4-NH2CH2C6H4
    708 H2NCH2CH2NHCH2 3-NH2CH2C6H4
    709 Me2NCH2CH2NHCH2 4-MeOC6H4
    710 Me2NCH2CH2NHCH2 3-MeOC6H4
    711 Me2NCH2CH2NHCH2 4-NH2C6H4
    712 Me2NCH2CH2NHCH2 3-NH2C6H4
    713 Me2NCH2CH2NHCH2 2-NH2C6H4
    714 Me2NCH2CH2NHCH2 4-Me2NC6H4
    715 Me2NCH2CH2NHCH2 3-Me2NC6H4
    716 Me2NCH2CH2NHCH2 2-Me2NC6H4
    717 Me2NCH2CH2NHCH2 4-pyridyl
    718 Me2NCH2CH2NHCH2 3-pyridyl
    719 Me2NCH2CH2NHCH2 2-pyridyl
    720 Me2NCH2CH2NHCH2 2-thiazolyl
    721 Me2NCH2CH2NHCH2 2-pyrazolyl
    722 Me2NCH2CH2NHCH2 5-isoquinolyl
    723 Me2NCH2CH2NHCH2 3,4-methylenedioxyC6H3
    724 Me2NCH2CH2NHCH2 3,4-ethylenedioxyC6H3
    725 Me2NCH2CH2NHCH2 2-imidazolyl
    726 Me2NCH2CH2NHCH2 2-oxazolyl
    727 Me2NCH2CH2NHCH2 4-isoxazolyl
    728 Me2NCH2CH2NHCH2 4-HOC6H4
    729 Me2NCH2CH2NHCH2 3-HOC6H4
    730 Me2NCH2CH2NHCH2 3,4-diHOC6H4
    731 Me2NCH2CH2NHCH2 4-NH2CH2C6H4
    732 Me2NCH2CH2NHCH2 3-NH2CH2C6H4
    733 1-morpholinylmethyl 3-MeOC6H4
    734 1-morpholinylmethyl 4-NH2C6H4
    735 1-morpholinylmethyl 3-NH2C6H4
    736 1-morpholinylmethyl 2-NH2C6H4
    737 1-morpholinylmethyl 4-Me2NC6H4
    738 1-morpholinylmethyl 3-Me2NC6H4
    739 1-morpholinylmethyl 2-Me2NC6H4
    740 1-morpholinylmethyl 4-pyridyl
    741 1-morpholinylmethyl 3-pyridyl
    742 1-morpholinylmethyl 2-pyridyl
    743 1-morpholinylmethyl 2-thiazolyl
    744 1-morpholinylmethyl 2-pyrazolyl
    745 1-morpholinylmethyl 5-isoquinolyl
    746 1-morpholinylmethyl 3,4-methylenedioxyC6H3
    747 1-morpholinylmethyl 3,4-ethylenedioxyC6H3
    748 1-morpholinylmethyl 2-imidazolyl
    749 1-morpholinylmethyl 2-oxazolyl
    750 1-morpholinylmethyl 4-isoxazolyl
    751 1-morpholinylmethyl 4-HOC6H4
    752 1-morpholinylmethyl 3-HOC6H4
    753 1-morpholinylmethyl 3,4-diHOC6H4
    754 1-morpholinylmethyl 4-NH2CH2C6H4
    755 1-morpholinylmethyl 3-NH2CH2C6H4
    756 1-thiomorpholinylmethyl 3-MeOC6H4
    757 1-thiomorpholinylmethyl 4-NH2C6H4
    758 1-thiomorpholinylmethyl 3-NH2C6H4
    759 1-thiomorpholinylmethyl 2-NH2C6H4
    760 1-thiomorpholinylmethyl 4-Me2NC6H4
    761 1-thiomorpholinylmethyl 3-Me2NC6H4
    762 1-thiomorpholinylmethyl 2-Me2NC6H4
    763 1-thiomorpholinylmethyl 4-pyridyl
    764 1-thiomorpholinylmethyl 3-pyridyl
    765 1-thiomorpholinylmethyl 2-pyridyl
    766 1-thiomorpholinylmethyl 2-thiazolyl
    767 1-thiomorpholinylmethyl 2-pyrazolyl
    768 1-thiomorpholinylmethyl 5-isoquinolyl
    769 1-thiomorpholinylmethyl 3,4-methylenedioxyC6H3
    771 1-thiomorpholinylmethyl 2-imidazolyl
    772 1-thiomorpholinylmethyl 2-oxazolyl
    773 1-thiomorpholinylmethyl 4-isoxazolyl
    774 1-thiomorpholinylmethyl 4-HOC6H4
    775 1-thiomorpholinylmethyl 3-HOC6H4
    776 1-thiomorpholinylmethyl 3,4-diHOC6H4
    777 1-thiomorpholinylmethyl 4-NH2CH2C6H4
    778 1-thiomorpholinylmethyl 3-NH2CH2C6H4
    779 1-piperazinylmethyl 3-MeOC6H4
    780 1-piperazinylmethyl 4-NH2C6H4
    781 1-piperazinylmethyl 3-NH2C6H4
    782 1-piperazinylmethyl 2-NH2C6H4
    783 1-piperazinylmethyl 4-Me2NC6H4
    784 1-piperazinylmethyl 3-Me2NC6H4
    785 1-piperazinylmethyl 2-Me2NC6H4
    786 1-piperazinylmethyl 4-pyridyl
    787 1-piperazinylmethyl 3-pyridyl
    788 1-piperazinylmethyl 2-pyridyl
    789 1-piperazinylmethyl 2-thiazolyl
    790 1-piperazinylmethyl 2-pyrazolyl
    791 1-piperazinylmethyl 5-isoquinolyl
    792 1-piperazinylmethyl 3,4-methylenedioxyC6H3
    793 1-piperazinylmethyl 3,4-ethylenedioxyC6H3
    794 1-piperazinylmethyl 2-imidazolyl
    795 1-piperazinylmethyl 2-oxazolyl
    796 1-piperazinylmethyl 4-isoxazolyl
    797 1-piperazinylmethyl 4-HOC6H4
    798 1-piperazinylmethyl 3-HOC6H4
    799 1-piperazinylmethyl 3,4-diHOC6H4
    800 1-piperazinylmethyl 4-NH2CH2C6H4
    801 1-piperazinylmethyl 3-NH2CH2C6H4
  • [1007]
    [1007]
    Example
    Number R1 R2
    802 2-pyridylmethyl 4-MeOC6H4
    803 2-pyridylmethyl 3-MeOC6H4
    804 2-pyridylmethyl 4-NH2C6H4
    805 2-pyridylmethyl 3-NH2C6H4
    806 2-pyridylmethyl 2-NH2C6H4
    807 2-pyridylmethyl 4-Me2NC6H4
    808 2-pyridylmethyl 3-Me2NC6H4
    809 2-pyridylmethyl 2-Me2NC6H4
    810 2-pyridylmethyl 4-pyridyl
    811 2-pyridylmethyl 3-pyridyl
    812 2-pyridylmethyl 2-pyridyl
    813 2-pyridylmethyl 2-thiazolyl
    814 2-pyridylmethyl 2-pyrazolyl
    815 2-pyridylmethyl 5-isoquinolyl
    816 2-pyridylmethyl 3,4-methylenedioxyC6H3
    817 2-pyridylmethyl 3,4-ethylenedioxyC6H3
    818 2-pyridylmethyl 2-imidazolyl
    819 2-pyridylmethyl 2-oxazolyl
    820 2-pyridylmethyl 4-isoxazolyl
    821 2-pyridylmethyl 4-HOC6H4
    822 2-pyridylmethyl 3-HOC6H4
    823 2-pyridylmethyl 3,4-diHOC6H4
    824 2-pyridylmethyl 4-NH2CH2C6H4
    825 2-pyridylmethyl 3-NH2CH2C6H4
    826 3-pyridylmethyl 4-MeOC6H4
    827 3-pyridylmethyl 3-MeOC6H4
    828 3-pyridylmethyl 4-NH2C6H4
    829 3-pyridylmethyl 3-NH2C6H4
    830 3-pyridylmethyl 2-NH2C6H4
    831 3-pyridylmethyl 4-Me2NC6H4
    832 3-pyridylmethyl 3-Me2NC6H4
    833 3-pyridylmethyl 2-Me2NC6H4
    834 3-pyridylmethyl 4-pyridyl
    835 3-pyridylmethyl 3-pyridyl
    836 3-pyridylmethyl 2-pyridyl
    837 3-pyridylmethyl 2-thiazolyl
    838 3-pyridylmethyl 2-pyrazolyl
    839 3-pyridylmethyl 5-isoquinolyl
    840 3-pyridylmethyl 3,4-methylenedioxyC6H3
    841 3-pyridylmethyl 3,4-ethylenedioxyC6H3
    842 3-pyridylmethyl 2-imidazolyl
    843 3-pyridylmethyl 2-oxazolyl
    844 3-pyridylmethyl 4-isoxazolyl
    845 3-pyridylmethyl 4-HOC6H4
    846 3-pyridylmethyl 3-HOC6H4
    847 3-pyridylmethyl 3,4-diHOC6H4
    848 3-pyridylmethyl 4-NH2CH2C6H4
    849 3-pyridylmethyl 3-NH2CH2C6H4
    850 4-pyridylmethyl 4-MeOC6H4
    851 4-pyridylmethyl 3-MeOC6H4
    852 4-pyridylmethyl 4-NH2C6H4
    853 4-pyridylmethyl 3-NH2C6H4
    854 4-pyridylmethyl 2-NH2C6H4
    855 4-pyridylmethyl 4-Me2NC6H4
    856 4-pyridylmethyl 3-Me2NC6H4
    857 4-pyridylmethyl 2-Me2NC6H4
    858 4-pyridylmethyl 4-pyridyl
    859 4-pyridylmethyl 3-pyridyl
    860 4-pyridylmethyl 2-pyridyl
    861 4-pyridylmethyl 2-thiazolyl
    862 4-pyridylmethyl 2-pyrazolyl
    863 4-pyridylmethyl 5-isoquinolyl
    864 4-pyridylmethyl 3,4-methylenedioxyC6H3
    865 4-pyridylmethyl 3,4-ethylenedioxyC6H3
    866 4-pyridylmethyl 2-imidazolyl
    867 4-pyridylmethyl 2-oxazolyl
    868 4-pyridylmethyl 4-isoxazolyl
    869 4-pyridylmethyl 4-HOC6H4
    870 4-pyridylmethyl 3-HOC6H4
    871 4-pyridylmethyl 3,4-diHOC6H4
    872 4-pyridylmethyl 4-NH2CH2C6H4
    873 4-pyridylmethyl 3-NH2CH2C6H4
    874 2-NH2C6H4 4-MeOC6H4
    875 2-NH2C6H4 3-MeOC6H4
    876 2-NH2C6H4 4-NH2C6H4
    877 2-NH2C6H4 3-NH2C6H4
    878 2-NH2C6H4 2-NH2C6H4
    879 2-NH2C6H4 4-Me2NC6H4
    880 2-NH2C6H4 3-Me2NC6H4
    881 2-NH2C6H4 2-Me2NC6H4
    882 2-NH2C6H4 4-pyridyl
    883 2-NH2C6H4 3-pyridyl
    884 2-NH2C6H4 2-pyridyl
    885 2-NH2C6H4 2-thiazolyl
    886 2-NH2C6H4 2-pyrazolyl
    887 2-NH2C6H4 5-isoquinolyl
    888 2-NH2C6H4 3,4-methylenedioxyC6H3
    889 2-NH2C6H4 3,4-ethylenedioxyC6H3
    890 2-NH2C6H4 2-imidazolyl
    891 2-NH2C6H4 2-oxazolyl
    892 2-NH2C6H4 4-isoxazolyl
    893 2-NH2C6H4 4-HOC6H4
    894 2-NH2C6H4 3-HOC6H4
    895 2-NH2C6H4 3,4-diHOC6H4
    896 2-NH2C6H4 4-NH2CH2C6H4
    897 2-NH2C6H4 3-NH2CH2C6H4
    898 3-NH2C6H4 4-MeOC6H4
    899 3-NH2C6H4 3-MeOC6H4
    900 3-NH2C6H4 4-NH2C6H4
    901 3-NH2C6H4 3-NH2C6H4
    902 3-NH2C6H4 2-NH2C6H4
    903 3-NH2C6H4 4-Me2NC6H4
    904 3-NH2C6H4 3-Me2NC6H4
    905 3-NH2C6H4 2-Me2NC6H4
    906 3-NH2C6H4 4-pyridyl
    907 3-NH2C6H4 3-pyridyl
    908 3-NH2C6H4 2-pyridyl
    909 3-NH2C6H4 2-thiazolyl
    910 3-NH2C6H4 2-pyrazolyl
    911 3-NH2C6H4 5-isoquinolyl
    912 3-NH2C6H4 3,4-methylenedioxyC6H3
    913 3-NH2C6H4 3,4-ethylenedioxyC6H3
    914 3-NH2C6H4 2-imidazolyl
    915 3-NH2C6H4 2-oxazolyl
    916 3-NH2C6H4 4-isoxazolyl
    917 3-NH2C6H4 4-HOC6H4
    918 3-NH2C6H4 3-HOC6H4
    919 3-NH2C6H4 3,4-diHOC6H4
    920 3-NH2C6H4 4-NH2CH2C6H4
    921 3-NH2C6H4 3-NH2CH2C6H4
    922 4-NH2C6H4 4-MeOC6H4
    923 4-NH2C6H4 3-MeOC6H4
    924 4-NH2C6H4 4-NH2C6H4
    925 4-NH2C6H4 3-NH2C6H4
    926 4-NH2C6H4 2-NH2C6H4
    927 4-NH2C6H4 4-Me2NC6H4
    928 4-NH2C6H4 3-Me2NC6H4
    930 4-NH2C6H4 2-Me2NC6H4
    931 4-NH2C6H4 4-pyridyl
    932 4-NH2C6H4 3-pyridyl
    933 4-NH2C6H4 2-pyridyl
    934 4-NH2C6H4 2-thiazolyl
    935 4-NH2C6H4 2-pyrazolyl
    936 4-NH2C6H4 5-isoquinolyl
    937 4-NH2C6H4 3,4-methylenedioxyC6H3
    938 4-NH2C6H4 3,4-ethylenedioxyC6H3
    939 4-NH2C6H4 2-imidazolyl
    940 4-NH2C6H4 2-oxazolyl
    941 4-NH2C6H4 4-isoxazolyl
    942 4-NH2C6H4 4-HOC6H4
    943 4-NH2C6H4 3-HOC6H4
    944 4-NH2C6H4 3,4-diHOC6H4
    945 4-NH2C6H4 4-NH2CH2C6H4
    946 4-NH2C6H4 3-NH2CH2C6H4
    947 2-MeOC6H4 4-MeOC6H4
    948 2-MeOC6H4 3-MeOC6H4
    949 2-MeOC6H4 4-NH2C6H4
    950 2-MeOC6H4 3-NH2C6H4
    951 2-MeOC6H4 2-NH2C6H4
    952 2-MeOC6H4 4-Me2NC6H4
    953 2-MeOC6H4 3-Me2NC6H4
    954 2-MeOC6H4 2-Me2NC6H4
    955 2-MeOC6H4 4-pyridyl
    956 2-MeOC6H4 3-pyridyl
    957 2-MeOC6H4 2-pyridyl
    958 2-MeOC6H4 2-thiazolyl
    959 2-MeOC6H4 2-pyrazolyl
    960 2-MeOC6H4 5-isoquinolyl
    961 2-MeOC6H4 3,4-methylenedioxyC6H3
    962 2-MeOC6H4 3,4-ethylenedioxyC6H3
    963 2-MeOC6H4 2-imidazolyl
    964 2-MeOC6H4 2-oxazolyl
    965 2-MeOC6H4 4-isoxazolyl
    966 2-MeOC6H4 4-HOC6H4
    967 2-MeOC6H4 3-HOC6H4
    968 2-MeOC6H4 3,4-diHOC6H4
    969 2-MeOC6H4 4-NH2CH2C6H4
    970 2-MeOC6H4 3-NH2CH2C6H4
    971 3-MeOC6H4 4-MeOC6H4
    972 3-MeOC6H4 3-MeOC6H4
    973 3-MeOC6H4 4-NH2C6H4
    974 3-MeOC6H4 3-NH2C6H4
    975 3-MeOC6H4 2-NH2C6H4
    976 3-MeOC6H4 4-Me2NC6H4
    977 3-MeOC6H4 3-Me2NC6H4
    978 3-MeOC6H4 2-Me2NC6H4
    979 3-MeOC6H4 4-pyridyl
    980 3-MeOC6H4 3-pyridyl
    981 3-MeOC6H4 2-pyridyl
    982 3-MeOC6H4 2-thiazolyl
    983 3-MeOC6H4 2-pyrazolyl
    984 3-MeOC6H4 5-isoquinolyl
    985 3-MeOC6H4 3,4-methylenedioxyC6H3
    986 3-MeOC6H4 3,4-ethylenedioxyC6H3
    987 3-MeOC6H4 2-imidazolyl
    988 3-MeOC6H4 2-oxazolyl
    989 3-MeOC6H4 4-isoxazolyl
    990 3-MeOC6H4 4-HOC6H4
    991 3-MeOC6H4 3-HOC6H4
    992 3-MeOC6H4 3,4-diHOC6H4
    993 3-MeOC6H4 4-NH2CH2C6H4
    994 3-MeOC6H4 3-NH2CH2C6H4
    995 4-MeOC6H4 4-MeOC6H4
    996 4-MeOC6H4 3-MeOC6H4
    997 4-MeOC6H4 4-NH2C6H4
    998 4-MeOC6H4 3-NH2C6H4
    999 4-MeOC6H4 2-NH2C6H4
    1000 4-MeOC6H4 4-Me2NC6H4
    1001 4-MeOC6H4 3-Me2NC6H4
    1002 4-MeOC6H4 2-Me2NC6H4
    1003 4-MeOC6H4 4-pyridyl
    1004 4-MeOC6H4 3-pyridyl
    1005 4-MeOC6H4 2-pyridyl
    1006 4-MeOC6H4 2-thiazolyl
    1007 4-MeOC6H4 2-pyrazolyl
    1008 4-MeOC6H4 5-isoquinolyl
    1009 4-MeOC6H4 3,4-methylenedioxyC6H3
    1010 4-MeOC6H4 3,4-ethylenedioxyC6H3
    1011 4-MeOC6H4 2-imidazolyl
    1012 4-MeOC6H4 2-oxazolyl
    1013 4-MeOC6H4 4-isoxazolyl
    1014 4-MeOC6H4 4-HOC6H4
    1015 4-MeOC6H4 3-HOC6H4
    1016 4-MeOC6H4 3,4-diHOC6H4
    1017 4-MeOC6H4 4-NH2CH2C6H4
    1018 4-MeOC6H4 3-NH2CH2C6H4
    1019 2-HOC6H4 4-MeOC6H4
    1020 2-HOC6H4 3-MeOC6H4
    1021 2-HOC6H4 4-NH2C6H4
    1022 2-HOC6H4 3-NH2C6H4
    1023 2-HOC6H4 2-NH2C6H4
    1024 2-HOC6H4 4-Me2NC6H4
    1025 2-HOC6H4 3-Me2NC6H4
    1026 2-HOC6H4 2-Me2NC6H4
    1027 2-HOC6H4 4-pyridyl
    1028 2-HOC6H4 3-pyridyl
    1029 2-HOC6H4 2-pyridyl
    1030 2-HOC6H4 2-thiazolyl
    1031 2-HOC6H4 2-pyrazolyl
    1032 2-HOC6H4 5-isoquinolyl
    1033 2-HOC6H4 3,4-methylenedioxyC6H3
    1034 2-HOC6H4 3,4-ethylenedioxyC6H3
    1035 2-HOC6H4 2-imidazolyl
    1036 2-HOC6H4 2-oxazolyl
    1037 2-HOC6H4 4-isoxazolyl
    1038 2-HOC6H4 4-HOC6H4
    1039 2-HOC6H4 3-HOC6H4
    1040 2-HOC6H4 3,4-diHOC6H4
    1041 2-HOC6H4 4-NH2CH2C6H4
    1042 2-HOC6H4 3-NH2CH2C6H4
    1043 3-HOC6H4 4-MeOC6H4
    1044 3-HOC6H4 3-MeOC6H4
    1045 3-HOC6H4 4-NH2C6H4
    1046 3-HOC6H4 3-NH2C6H4
    1047 3-HOC6H4 2-NH2C6H4
    1048 3-HOC6H4 4-Me2NC6H4
    1049 3-HOC6H4 3-Me2NC6H4
    1050 3-HOC6H4 2-Me2NC6H4
    1051 3-HOC6H4 4-pyridyl
    1052 3-HOC6H4 3-pyridyl
    1053 3-HOC6H4 2-pyridyl
    1054 3-HOC6H4 2-thiazolyl
    1055 3-HOC6H4 2-pyrazolyl
    1056 3-HOC6H4 5-isoquinolyl
    1057 3-HOC6H4 3,4-methylenedioxyC6H3
    1058 3-HOC6H4 3,4-ethylenedioxyC6H3
    1059 3-HOC6H4 2-imidazolyl
    1060 3-HOC6H4 2-oxazolyl
    1061 3-HOC6H4 4-isoxazolyl
    1062 3-HOC6H4 4-HOC6H4
    1063 3-HOC6H4 3-HOC6H4
    1064 3-HOC6H4 3,4-diHOC6H4
    1065 3-HOC6H4 4-NH2CH2C6H4
    1066 3-HOC6H4 3-NH2CH2C6H4
    1067 4-HOC6H4 4-MeOC6H4
    1068 4-HOC6H4 3-MeOC6H4
    1069 4-HOC6H4 4-NH2C6H4
    1070 4-HOC6H4 3-NH2C6H4
    1071 4-HOC6H4 2-NH2C6H4
    1072 4-HOC6H4 4-Me2NC6H4
    1073 4-HOC6H4 3-Me2NC6H4
    1074 4-HOC6H4 2-Me2NC6H4
    1075 4-HOC6H4 4-pyridyl
    1076 4-HOC6H4 3-pyridyl
    1077 4-HOC6H4 2-pyridyl
    1078 4-HOC6H4 2-thiazolyl
    1079 4-HOC6H4 2-pyrazolyl
    1080 4-HOC6H4 5-isoquinolyl
    1081 4-HOC6H4 3,4-methylenedioxyC6H3
    1082 4-HOC6H4 3,4-ethylenedioxyC6H3
    1083 4-HOC6H4 2-imidazolyl
    1084 4-HOC6H4 2-oxazolyl
    1085 4-HOC6H4 4-isoxazolyl
    1086 4-HOC6H4 4-HOC6H4
    1087 4-HOC6H4 3-HOC6H4
    1088 4-HOC6H4 3,4-diHOC6H4
    1089 4-HOC6H4 4-NH2CH2C6H4
    1090 4-HOC6H4 3-NH2CH2C6H4
    1091 4-ClC6H4 4-MeOC6H4
    1092 4-ClC6H4 3-MeOC6H4
    1093 4-ClC6H4 4-NH2C6H4
    1094 4-ClC6H4 3-NH2C6H4
    1095 4-ClC6H4 2-NH2C6H4
    1096 4-ClC6H4 4-Me2NC6H4
    1097 4-ClC6H4 3-Me2NC6H4
    1098 4-ClC6H4 2-Me2NC6H4
    1099 4-ClC6H4 4-pyridyl
    1100 4-ClC6H4 3-pyridyl
    1101 4-ClC6H4 2-pyridyl
    1102 4-ClC6H4 2-thiazolyl
    1103 4-ClC6H4 2-pyrazolyl
    1104 4-ClC6H4 5-isoquinolyl
    1105 4-ClC6H4 3,4-methylenedioxyC6H3
    1106 4-ClC6H4 3,4-ethylenedioxyC6H3
    1107 4-ClC6H4 2-imidazolyl
    1108 4-ClC6H4 2-oxazolyl
    1109 4-ClC6H4 4-isoxazolyl
    1110 4-ClC6H4 4-HOC6H4
    1111 4-ClC6H4 3-HOC6H4
    1112 4-ClC6H4 3,4-diHOC6H4
    1113 4-ClC6H4 4-NH2CH2C6H4
    1114 4-ClC6H4 3-NH2CH2C6H4
    1115 2-NH2CH2C6H4 4-MeOC6H4
    1116 2-NH2CH2C6H4 3-MeOC6H4
    1117 2-NH2CH2C6H4 4-NH2C6H4
    1118 2-NH2CH2C6H4 3-NH2C6H4
    1119 2-NH2CH2C6H4 2-NH2C6H4
    1120 2-NH2CH2C6H4 4-Me2NC6H4
    1121 2-NH2CH2C6H4 3-Me2NC6H4
    1122 2-NH2CH2C6H4 2-Me2NC6H4
    1123 2-NH2CH2C6H4 4-pyridyl
    1124 2-NH2CH2C6H4 3-pyridyl
    1125 2-NH2CH2C6H4 2-pyridyl
    1126 2-NH2CH2C6H4 2-thiazolyl
    1127 2-NH2CH2C6H4 2-pyrazolyl
    1128 2-NH2CH2C6H4 5-isoquinolyl
    1129 2-NH2CH2C6H4 3,4-methylenedioxyC6H3
    1130 2-NH2CH2C6H4 3,4-ethylenedioxyC6H3
    1131 2-NH2CH2C6H4 2-imidazolyl
    1132 2-NH2CH2C6H4 2-oxazolyl
    1133 2-NH2CH2C6H4 4-isoxazolyl
    1134 2-NH2CH2C6H4 4-HOC6H4
    1135 2-NH2CH2C6H4 3-HOC6H4
    1136 2-NH2CH2C6H4 3,4-diHOC6H4
    1137 2-NH2CH2C6H4 4-NH2CH2C6H4
    1138 2-NH2CH2C6H4 3-NH2CH2C6H4
    1139 3-NH2CH2C6H4 4-MeOC6H4
    1140 3-NH2CH2C6H4 3-MeOC6H4
    1141 3-NH2CH2C6H4 4-NH2C6H4
    1142 3-NH2CH2C6H4 3-NH2C6H4
    1143 3-NH2CH2C6H4 2-NH2C6H4
    1144 3-NH2CH2C6H4 4-Me2NC6H4
    1145 3-NH2CH2C6H4 3-Me2NC6H4
    1146 3-NH2CH2C6H4 2-Me2NC6H4
    1147 3-NH2CH2C6H4 4-pyridyl
    1148 3-NH2CH2C6H4 3-pyridyl
    1149 3-NH2CH2C6H4 2-pyridyl
    1150 3-NH2CH2C6H4 2-thiazolyl
    1151 3-NH2CH2C6H4 2-pyrazolyl
    1152 3-NH2CH2C6H4 5-isoquinolyl
    1153 3-NH2CH2C6H4 3,4-methylenedioxyC6H3
    1154 3-NH2CH2C6H4 3,4-ethylenedioxyC6H3
    1155 3-NH2CH2C6H4 2-imidazolyl
    1156 3-NH2CH2C6H4 2-oxazolyl
    1157 3-NH2CH2C6H4 4-isoxazolyl
    1158 3-NH2CH2C6H4 4-HOC6H4
    1159 3-NH2CH2C6H4 4-HOC6H4
    1160 3-NH2CH2C6H4 3,4-diHOC6H4
    1161 3-NH2CH2C6H4 4-NH2CH2C6H4
    1162 3-NH2CH2C6H4 3-NH2CH2C6H4
    1163 4-NH2CH2C6H4 4-MeOC6H4
    1164 4-NH2CH2C6H4 3-MeOC6H4
    1165 4-NH2CH2C6H4 4-NH2C6H4
    1166 4-NH2CH2C6H4 3-NH2C6H4
    1167 4-NH2CH2C6H4 2-NH2C6H4
    1168 4-NH2CH2C6H4 4-Me2NC6H4
    1169 4-NH2CH2C6H4 3-Me2NC6H4
    1170 4-NH2CH2C6H4 2-Me2NC6H4
    1171 4-NH2CH2C6H4 4-pyridyl
    1172 4-NH2CH2C6H4 3-pyridyl
    1173 4-NH2CH2C6H4 2-pyridyl
    1174 4-NH2CH2C6H4 2-thiazolyl
    1175 4-NH2CH2C6H4 2-pyrazolyl
    1176 4-NH2CH2C6H4 5-isoquinolyl
    1177 4-NH2CH2C6H4 3,4-methylenedioxyC6H3
    1178 4-NH2CH2C6H4 3,4-ethylenedioxyC6H3
    1179 4-NH2CH2C6H4 2-imidazolyl
    1180 4-NH2CH2C6H4 2-oxazolyl
    1181 4-NH2CH2C6H4 4-isoxazolyl
    1182 4-NH2CH2C6H4 4-HOC6H4
    1183 4-NH2CH2C6H4 3-HOC6H4
    1184 4-NH2CH2C6H4 3,4-diHOC6H4
    1185 4-NH2CH2C6H4 4-NH2CH2C6H4
    1186 4-NH2CH2C6H4 3-NH2CH2C6H4
    1187 2-Me2NCH2C6H4 4-MeOC6H4
    1188 2-Me2NCH2C6H4 3-MeOC6H4
    1189 2-Me2NCH2C6H4 4-NH2C6H4
    1190 2-Me2NCH2C6H4 3-NH2C6H4
    1191 2-Me2NCH2C6H4 2-NH2C6H4
    1192 2-Me2NCH2C6H4 4-Me2NC6H4
    1193 2-Me2NCH2C6H4 3-Me2NC6H4
    1194 2-Me2NCH2C6H4 2-Me2NC6H4
    1195 2-Me2NCH2C6H4 4-pyridyl
    1196 2-Me2NCH2C6H4 3-pyridyl
    1197 2-Me2NCH2C6H4 2-pyridyl
    1198 2-Me2NCH2C6H4 2-thiazolyl
    1199 2-Me2NCH2C6H4 2-pyrazolyl
    1200 2-Me2NCH2C6H4 5-isoquinolyl
    1201 2-Me2NCH2C6H4 3,4-methylenedioxyC6H3
    1202 2-Me2NCH2C6H4 3,4-ethylenedioxyC6H3
    1203 2-Me2NCH2C6H4 2-imidazolyl
    1204 2-Me2NCH2C6H4 2-oxazolyl
    1205 2-Me2NCH2C6H4 4-isoxazolyl
    1206 2-Me2NCH2C6H4 4-HOC6H4
    1207 2-Me2NCH2C6H4 3-HOC6H4
    1208 2-Me2NCH2C6H4 3,4-diHOC6H4
    1209 2-Me2NCH2C6H4 4-NH2CH2C6H4
    1210 2-Me2NCH2C6H4 3-NH2CH2C6H4
    1211 3-Me2NCH2C6H4 4-MeOC6H4
    1212 3-Me2NCH2C6H4 3-MeOC6H4
    1213 3-Me2NCH2C6H4 4-NH2C6H4
    1214 3-Me2NCH2C6H4 3-NH2C6H4
    1215 3-Me2NCH2C6H4 2-NH2C6H4
    1216 3-Me2NCH2C6H4 4-Me2NC6H4
    1217 3-Me2NCH2C6H4 3-Me2NC6H4
    1218 3-Me2NCH2C6H4 2-Me2NC6H4
    1219 3-Me2NCH2C6H4 4-pyridyl
    1220 3-Me2NCH2C6H4 3-pyridyl
    1221 3-Me2NCH2C6H4 2-pyridyl
    1222 3-Me2NCH2C6H4 2-thiazolyl
    1223 3-Me2NCH2C6H4 2-oyrazolyl
    1224 3-Me2NCH2C6H4 5-isoquinolyl
    1225 3-Me2NCH2C6H4 3,4-methylenedioxyC6H3
    1226 3-Me2NCH2C6H4 3,4-ethylenedioxyC6H3
    1227 3-Me2NCH2C6H4 2-imidazolyl
    1228 3-Me2NCH2C6H4 2-oxazolyl
    1229 3-Me2NCH2C6H4 4-isoxazolyl
    1230 3-Me2NCH2C6H4 4-HOC6H4
    1231 3-Me2NCH2C6H4 3-HOC6H4
    1232 3-Me2NCH2C6H4 3,4-diHOC6H4
    1233 3-Me2NCH2C6H4 4-NH2CH2C6H4
    1234 3-Me2NCH2C6H4 3-NH2CH2C6H4
    1235 4-Me2NCH2C6H4 4-MeOC6H4
    1236 4-Me2NCH2C6H4 3-MeOC6H4
    1237 4-Me2NCH2C6H4 4-NH2C6H4
    1238 4-Me2NCH2C6H4 3-0NH2C6H4
    1239 4-Me2NCH2C6H4 2-NH2C6H4
    1240 4-Me2NCH2C6H4 4-Me2C6H4
    1241 4-Me2NCH2C6H4 3-Me2NC6H4
    1242 4-Me2NCH2C6H4 2-Me2NC6H4
    1243 4-Me2NCH2C6H4 4-pyridyl
    1244 4-Me2NCH2C6H4 3-pyridyl
    1245 4-Me2NCH2C6H4 2-pyridyl
    1246 4-Me2NCH2C6H4 2-thiazolyl
    1247 4-Me2NCH2C6H4 2-pyrazolyl
    1248 4-Me2NCH2C6H4 5-isoquinolyl
    1249 4-Me2NCH2C6H4 3,4-methylenedioxyC6H3
    1250 4-Me2NCH2C6H4 3,4-ethylenedioxyC6H3
    1251 4-Me2NCH2C6H4 2-imidazolyl
    1252 4-Me2NCH2C6H4 2-oxazolyl
    1253 4-Me2NCH2C6H4 4-isoxazolyl
    1254 4-Me2NCH2C6H4 4-HOC6H4
    1255 4-Me2NCH2C6H4 3-HOC6H4
    1256 4-Me2NCH2C6H4 3,4-diHOC6H4
    1257 4-Me2NCH2C6H4 4-NH2CH2C6H4
    1258 4-Me2NCH2C6H4 3-NH2CH2C6H4
    1259 H 4-MeOC6H4
    1260 H 3-MeOC6H4
    1261 H 4-NH2C6H4
    1262 H 3-NH2C6H4
    1263 H 2-NH2C6H4
    1264 H 4-Me2NC6H4
    1265 H 3-Me2NC6H4
    1266 H 2-Me2NC6H4
    1267 H 4-pyridyl
    1268 H 3-pyridyl
    1269 H 2-pyridyl
    1270 H 2-thiazolyl
    1271 H 2-pyrazolyl
    1272 H 5-isoquinolyl
    1273 H 3,4-methylenedioxyC6H3
    1274 H 3,4-ethylenedioxyC6H3
    1275 H 2-imidazolyl
    1276 H 2-oxazolyl
    1277 H 4-isoxazolyl
    1278 H 4-HOC6H4
    1279 H 3-HOC6H4
    1280 H 3,4-diHOC6H4
    1281 H 4-NH2CH2C6H4
    1282 H 3-NH2CH2C6H4
    1283 Me 4-MeOC6H4
    1284 Me 3-MeOC6H4
    1285 Me 4-NH2C6H4
    1286 Me 3-NH2C6H4
    1287 Me 2-NH2C6H4
    1288 Me 4-Me2C6H4
    1289 Me 3-Me2NC6H4
    1290 Me 2-Me2NC6H4
    1291 Me 4-pyridyl
    1292 Me 3-pyridyl
    1293 Me 2-pyridyl
    1294 Me 2-thiazolyl
    1295 Me 2-pyrazolyl
    1296 Me 5-isoquinolyl
    1297 Me 3,4-methylenedioxyC6H3
    1298 Me 3,4-ethylenedioxyC6H3
    1299 Me 2-imidazolyl
    1300 Me 2-oxazolyl
    1301 Me 4-isoxazolyl
    1302 Me 4-HOC6H4
    1303 Me 3-HOC6H4
    1304 Me 3,4-diHOC6H4
    1305 Me 4-NH2CH2C6H4
    1306 Me 3-NH2CH2C6H4
    1307 Et 3-MeOC6H4
    1309 Et 4-NH2C6H4
    1310 Et 2-NH2C6H4
    1311 Et 4-Me2NC6H4
    1313 Et 3-Me2NC6H4
    1314 Et 2-Me2NC6H4
    1315 Et 4-pyridyl
    1316 Et 3-pyridyl
    1317 Et 2-pyridyl
    1318 Et 2-thiazolyl
    1319 Et 2-pyrazolyl
    1320 Et 5-isoquinolyl
    1321 Et 3,4-methylenedioxC6H3
    1322 Et 3,4-ethylenedioxyC6H3
    1323 Et 2-imidazolyl
    1324 Et 2-oxazolyl
    1325 Et 4-isoxazolyl
    1326 Et 4-HOC6H4
    1327 Et 3-HOC6H4
    1328 Et 3,4-diHOC6H4
    1329 Et 4-NH2CH2C6H4
    1330 Et 3-NH2CH2C6H4
    1331 2-NH2C6H4CH2 4-MeOC6H4
    1332 2-NH2C6H4CH2 3-MeOC6H4
    1333 2-NH2C6H4CH2 4-NH2C6H4
    1334 2-NH2C6H4CH2 3-NH2C6H4
    1335 2-NH2C6H4CH2 2-NH2C6H4
    1336 2-NH2C6H4CH2 4-Me2NC6H4
    1337 2-NH2C6H4CH2 3-Me2NC6H4
    1338 2-NH2C6H4CH2 2-Me2NC6H4
    1339 2-NH2C6H4CH2 4-pyridyl
    1340 2-NH2C6H4CH2 3-pyridyl
    1341 2-NH2C6H4CH2 2-pyridyl
    1342 2-NH2C6H4CH2 2-thiazolyl
    1343 2-NH2C6H4CH2 2-pyrazolyl
    1344 2-NH2C6H4CH2 5-isoquinolyl
    1345 2-NH2C6H4CH2 3,4-methylenedioxyC6H3
    1346 2-NH2C6H4CH2 3,4-ethylenedioxyC6H3
    1347 2-NH2C6H4CH2 2-imidazolyl
    1348 2-NH2C6H4CH2 2-oxazolyl
    1349 2-NH2C6H4CH2 4-isoxazolyl
    1350 2-NH2C6H4CH2 4-HOC6H4
    1351 2-NH2C6H4CH2 3-HOC6H4
    1352 2-NH2C6H4CH2 3,4-diHOC6H4
    1353 2-NH2C6H4CH2 4-NH2CH2C6H4
    1354 2-NH2C6H4CH2 3-NH2CH2C6H4
    1355 3-NH2C6H4CH2 4-MeOC6H4
    1356 3-NH2C6H4CH2 3-MeOC6H4
    1357 3-NH2C6H4CH2 4-NH2C6H4
    1358 3-NH2C6H4CH2 3-NH2C6H4
    1359 3-NH2C6H4CH2 2-NH2C6H4
    1360 3-NH2C6H4CH2 4-Me2NC6H4
    1361 3-NH2C6H4CH2 3-MNe2NC6H4
    1362 3-NH2C6H4CH2 2-Me2NC6H4
    1363 3-NH2C6H4CH2 4-pyridyl
    1364 3-NH2C6H4CH2 3-pyridyl
    1365 3-NH2C6H4CH2 2-pyridyl
    1366 3-NH2C6H4CH2 2-thiazolyl
    1367 3-NH2C6H4CH2 2-pyrazolyl
    1367 3-NH2C6H4CH2 5-isoquinolyl
    1369 3-NH2C6H4CH2 3,4-methylenedioxyC6H3
    1370 3-NH2C6H4CH2 3,4-ethylenedioxyC6H3
    1371 3-NH2C6H4CH2 2-imidazolyl
    1372 3-NH2C6H4CH2 2-oxazolyl
    1373 3-NH2C6H4CH2 4-isoxazolyl
    1374 3-NH2C6H4CH2 4-HOC6H4
    1375 3-NH2C6H4CH2 3-HOC6H4
    1376 3-NH2C6H4CH2 3,4-diHOC6H4
    1377 3-NH2C6H4CH2 4-NH2CH2C6H4
    1378 3-NH2C6H4CH2 3-NH2CH2C6H4
    1379 4-NH2C6H4CH2 4-MeOC6H4
    1380 4-NH2C6H4CH2 3-MeOC6H4
    1381 4-NH2C6H4CH2 4-NH2C6H4
    1382 4-NH2C6H4CH2 3-NH2C6H4
    1383 4-NH2C6H4CH2 2-NH2C6H4
    1384 4-NH2C6H4CH2 4-Me2NC6H4
    1385 4-NH2C6H4CH2 3-Me2NC6H4
    1386 4-NH2C6H4CH2 2-Me2NC6H4
    1387 4-NH2C6H4CH2 4-pyridyl
    1388 4-NH2C6H4CH2 3-pyridyl
    1389 4-NH2C6H4CH2 2-pyridyl
    1390 4-NH2C6H4CH2 2-thiazolyl
    1391 4-NH2C6H4CH2 2-pyrazolyl
    1392 4-NH2C6H4CH2 5-isoquinolyl
    1393 4-NH2C6H4CH2 3,4-methylenedioxyC6H3
    1394 4-NH2C6H4CH2 3,4-ethylenedioxyC6H3
    1395 4-NH2C6H4CH2 2-imidazolyl
    1396 4-NH2C6H4CH2 2-oxazolyl
    1397 4-NH2C6H4CH2 4-isoxazolyl
    1398 4-NH2C6H4CH2 4-HOC6H4
    1399 4-NH2C6H4CH2 3-HOC6H4
    1400 4-NH2C6H4CH2 3,4-diHOC6H4
    1401 4-NH2C6H4CH2 4-NH2CH2C6H4
    1402 4-NH2C6H4CH2 3-NH2CH2C6H4
    1403 2-MeOC6H4CH2 3-MeOC6H4
    1405 2-MeOC6H4CH2 4-NH2C6H4
    1406 2-MeOC6H4CH2 3-NH2C6H4
    1407 2-MeOC6H4CH2 2-NH2C6H4
    1408 2-MeOC6H4CH2 4-Me2NC6H4
    1409 2-MeOC6H4CH2 3-Me2NC6H4
    1410 2-MeOC6H4CH2 2-Me2NC6H4
    1411 2-MeOC6H4CH2 4-pyridyl
    1412 2-MeOC6H4CH2 3-pyridyl
    1413 2-MeOC6H4CH2 2-pyridyl
    1414 2-MeOC6H4CH2 2-thiazolyl
    1415 2-MeOC6H4CH2 2-pyrazolyl
    1416 2-MeOC6H4CH2 5-isoquinolyl
    1417 2-MeOC6H4CH2 3,4-methylenedioxyC6H3
    1418 2-MeOC6H4CH2 3,4-ethylenedioxyC6H3
    1419 2-MeOC6H4CH2 2-imidazolyl
    1420 2-MeOC6H4CH2 2-oxazolyl
    1421 2-MeOC6H4CH2 4-isoxazolyl
    1422 2-MeOC6H4CH2 4-HOC6H4
    1423 2-MeOC6H4CH2 3-HOC6H4
    1424 2-MeOC6H4CH2 3,4-diHOC6H4
    1425 2-MeOC6H4CH2 4-NH2CH2C6H4
    1426 2-MeOC6H4CH2 3-NH2CH2C6H4
    1427 3-MeOC6H4CH2 4-MeOC6H4
    1428 3-MeOC6H4CH2 3-MeOC6H4
    1429 3-MeOC6H4CH2 4-NH2C6H4
    1430 3-MeOC6H4CH2 3-NH2C6H4
    1431 3-MeOC6H4CH2 2-NH2C6H4
    1432 3-MeOC6H4CH2 4-Me2NC6H4
    1433 3-MeOC6H4CH2 3-Me2NC6H4
    1434 3-MeOC6H4CH2 2-Me2NC6H4
    1435 3-MeOC6H4CH2 4-pyridyl
    1436 3-MeOC6H4CH2 3-pyridyl
    1437 3-MeOC6H4CH2 2-pyridyl
    1438 3-MeOC6H4CH2 2-thiazolyl
    1439 3-MeOC6H4CH2 2-pyrazolyl
    1440 3-MeOC6H4CH2 5-isoquinolyl
    1441 3-MeOC6H4CH2 3,4-methylenedioxyC6H3
    1442 3-MeOC6H4CH2 3,4-ethylenedioxyC6H3
    1443 3-MeOC6H4CH2 2-imidazolyl
    1444 3-MeOC6H4CH2 2-oxazolyl
    1445 3-MeOC6H4CH2 4-isoxazolyl
    1446 3-MeOC6H4CH2 4-HOC6H4
    1447 3-MeOC6H4CH2 3-HOC6H4
    1448 3-MeOC6H4CH2 3,4-diHOC6H4
    1449 3-MeOC6H4CH2 4-NH2CH2C6H4
    1450 3-MeOC6H4CH2 3-NH2CH2C6H4
    1451 4-MeOC6H4CH2 4-MeOC6H4
    1452 4-MeOC6H4CH2 3-MeOC6H4
    1453 4-MeOC6H4CH2 4-NH2C6H4
    1454 4-MeOC6H4CH2 3-NH2C6H4
    1455 4-MeOC6H4CH2 2-NH2C6H4
    1456 4-MeOC6H4CH2 4-Me2NC6H4
    1457 4-MeOC6H4CH2 3-Me2NC6H4
    1458 4-MeOC6H4CH2 2-Me2NC6H4
    1459 4-MeOC6H4CH2 4-pyridyl
    1460 4-MeOC6H4CH2 3-pyridyl
    1461 4-MeOC6H4CH2 2-pyridyl
    1462 4-MeOC6H4CH2 2-thiazolyl
    1463 4-MeOC6H4CH2 2-pyrazolyl
    1464 4-MeOC6H4CH2 5-isoquinolyl
    1465 4-MeOC6H4CH2 3,4-methylenedioxyC6H3
    1466 4-MeOC6H4CH2 3,4-ethylenedioxyC6H3
    1467 4-MeOC6H4CH2 2-imidazolyl
    1468 4-MeOC6H4CH2 2-oxazolyl
    1469 4-MeOC6H4CH2 4-isoxazolyl
    1470 4-MeOC6H4CH2 4-HOC6H4
    1471 4-MeOC6H4CH2 3-HOC6H4
    1472 4-MeOC6H4CH2 3,4-diHOC6H4
    1473 4-MeOC6H4CH2 4-NH2CH2C6H4
    1474 4-MeOC6H4CH2 3-NH2CH2C6H4
    1475 2-HOC6H4CH2 4-MeOC6H4
    1476 2-HOC6H4CH2 3-MeOC6H4
    1477 2-HOC6H4CH2 4-NH2C6H4
    1478 2-HOC6H4CH2 3-NH2C6H4
    1479 2-HOC6H4CH2 2-NH2C6H4
    1480 2-HOC6H4CH2 4-Me2NC6H4
    1481 2-HOC6H4CH2 3-Me2NC6H4
    1482 2-HOC6H4CH2 2-Me2NC6H4
    1483 2-HOC6H4CH2 4-pyridyl
    1484 2-HOC6H4CH2 3-pyridyl
    1485 2-HOC6H4CH2 2-pyridyl
    1486 2-HOC6H4CH2 2-thiazolyl
    1487 2-HOC6H4CH2 2-pyrazolyl
    1488 2-HOC6H4CH2 5-isoquinolyl
    1489 2-HOC6H4CH2 3,4-methylenedioxyC6H3
    1490 2-HOC6H4CH2 3,4-ethylenedioxyC6H3
    1491 2-HOC6H4CH2 2-imidazolyl
    1492 2-HOC6H4CH2 2-oxazolyl
    1493 2-HOC6H4CH2 4-isoxazolyl
    1494 2-HOC6H4CH2 4-HOC6H4
    1495 2-HOC6H4CH2 3-HOC6H4
    1496 2-HOC6H4CH2 3,4-diHOC6H4
    1497 2-HOC6H4CH2 4-NH2CH2C6H4
    1498 2-HOC6H4CH2 3-NH2CH2C6H4
    1499 3-HOC6H4CH2 4-MeOC6H4
    1500 3-HOC6H4CH2 3-MeOC6H4
    1501 3-HOC6H4CH2 4-NH2C6H4
    1502 3-HOC6H4CH2 3-NH2C6H4
    1503 3-HOC6H4CH2 2-NH2C6H4
    1504 3-HOC6H4CH2 4-Me2NC6H4
    1505 3-HOC6H4CH2 3-Me2NC6H4
    1506 3-HOC6H4CH2 2-Me2NC6H4
    1507 3-HOC6H4CH2 4-pyridyl
    1508 3-HOC6H4CH2 3-pyridyl
    1509 3-HOC6H4CH2 2-pyridyl
    1510 3-HOC6H4CH2 2-thiazolyl
    1511 3-HOC6H4CH2 2-pyrazolyl
    1512 3-HOC6H4CH2 5-isoquinolyl
    1513 3-HOC6H4CH2 3,4-methylenedioxyC6H3
    1514 3-HOC6H4CH2 3,4-ethylenedioxyC6H3
    1514 3-HOC6H4CH2 2-imidazolyl
    1515 3-HOC6H4CH2 2-oxazolyl
    1517 3-HOC6H4CH2 4-isoxazolyl
    1518 3-HOC6H4CH2 4-HOC6H4
    1519 3-HOC6H4CH2 3-HOC6H4
    1520 3-HOC6H4CH2 3,4-diHOC6H4
    1521 3-HOC6H4CH2 4-NH2CH2C6H4
    1522 3-HOC6H4CH2 3-NH2CH2C6H4
    1523 4-HOC6H4CH2 4-MeOC6H4
    1524 4-HOC6H4CH2 3-MeOC6H4
    1525 4-HOC6H4CH2 4-NH2C6H4
    1526 4-HOC6H4CH2 3-NH2C6H4
    1527 4-HOC6H4CH2 2-NH2C6H4
    1528 4-HOC6H4CH2 4-Me2NC6H4
    1529 4-HOC6H4CH2 3-Me2NC6H4
    1530 4-HOC6H4CH2 2-Me2NC6H4
    1531 4-HOC6H4CH2 4-pyridyl
    1532 4-HOC6H4CH2 3-pyridyl
    1533 4-HOC6H4CH2 2-pyridyl
    1534 4-HOC6H4CH2 2-thiazolyl
    1535 4-HOC6H4CH2 2-pyrazolyl
    1536 4-HOC6H4CH2 5-isoquinolyl
    1537 4-HOC6H4CH2 3,4-methylenedioxyC6H3
    1538 4-HOC6H4CH2 3,4-ethylenedioxyC6H3
    1539 4-HOC6H4CH2 2-imidazolyl
    1540 4-HOC6H4CH2 2-oxazolyl
    1541 4-HOC6H4CH2 4-isoxazolyl
    1542 4-HOC6H4CH2 4-HOC6H4
    1543 4-HOC6H4CH2 3-HOC6H4
    1544 4-HOC6H4CH2 3,4-diHOC6H4
    1545 4-HOC6H4CH2 4-NH2CH2C6H4
    1546 4-HOC6H4CH2 3-NH2CH2C6H4
    1547 4-ClC6H4CH2 4-MeOC6H4
    1548 4-ClC6H4CH2 3-MeOC6H4
    1549 4-ClC6H4CH2 4-NH2C6H4
    1550 4-ClC6H4CH2 3-NH2C6H4
    1551 4-ClC6H4CH2 2-NH2C6H4
    1552 4-ClC6H4CH2 4-Me2NC6H4
    1553 4-ClC6H4CH2 3-Me2NC6H4
    1554 4-ClC6H4CH2 2-Me2NC6H4
    1555 4-ClC6H4CH2 4-pyridyl
    1556 4-ClC6H4CH2 3-pyridyl
    1557 4-ClC6H4CH2 2-pyridyl
    1558 4-ClC6H4CH2 2-thiazolyl
    1559 4-ClC6H4CH2 2-pyrazolyl
    1560 4-ClC6H4CH2 5-isoquinolyl
    1561 4-ClC6H4CH2 3,4-methylenedioxyC6H3
    1562 4-ClC6H4CH2 3,4-ethylenedioxyC6H3
    1563 4-ClC6H4CH2 2-imidazolyl
    1564 4-ClC6H4CH2 2-oxazolyl
    1565 4-ClC6H4CH2 4-isoxazolyl
    1566 4-ClC6H4CH2 4-HOC6H4
    1567 4-ClC6H4CH2 3-HOC6H4
    1568 4-ClC6H4CH2 3,4-diHOC6H4
    1569 4-ClC6H4CH2 4-NH2CH2C6H4
    1570 4-ClC6H4CH2 3-NH2CH2C6H4
    1571 2-NH2CH2C6H4CH2 3-MeOC6H4
    1573 2-NH2CH2C6H4CH2 4-NH2C6H4
    1574 2-NH2CH2C6H4CH2 3-NH2C6H4
    1575 2-NH2CH2C6H4CH2 2-NH2C6H4
    1576 2-NH2CH2C6H4CH2 4-Me2NC6H4
    1577 2-NH2CH2C6H4CH2 3-Me2NC6H4
    1578 2-NH2CH2C6H4CH2 2-Me2NC6H4
    1579 2-NH2CH2C6H4CH2 4-pyridyl
    1580 2-NH2CH2C6H4CH2 3-pyridyl
    1581 2-NH2CH2C6H4CH2 2-pyridyl
    1582 2-NH2CH2C6H4CH2 2-thiazolyl
    1583 2-NH2CH2C6H4CH2 2-pyrazolyl
    1584 2-NH2CH2C6H4CH2 5-isoquinolyl
    1585 2-NH2CH2C6H4CH2 3,4-methylenedioxyC6H3
    1586 2-NH2CH2C6H4CH2 3,4-ethylenedioxyC6H3
    1587 2-NH2CH2C6H4CH2 2-imidazolyl
    1588 2-NH2CH2C6H4CH2 2-oxazolyl
    1589 2-NH2CH2C6H4CH2 4-isoxazolyl
    1590 2-NH2CH2C6H4CH2 4-HOC6H4
    1591 2-NH2CH2C6H4CH2 3-HOC6H4
    1592 2-NH2CH2C6H4CH2 3,4-diHOC6H4
    1593 2-NH2CH2C6H4CH2 4-NH2CH2C6H4
    1594 2-NH2CH2C6H4CH2 3-NH2CH2C6H4
    1595 3-NH2CH2C6H4CH2 4-MeOC6H4
    1596 3-NH2CH2C6H4CH2 3-MeOC6H4
    1597 3-NH2CH2C6H4CH2 4-NH2C6H4
    1598 3-NH2CH2C6H4CH2 3-NH2C6H4
    1599 3-NH2CH2C6H4CH2 2-NH2C6H4
    1600 3-NH2CH2C6H4CH2 4-Me2NC6H4
    1601 3-NH2CH2C6H4CH2 3-Me2NC6H4
    1602 3-NH2CH2C6H4CH2 2-Me2NC6H4
    1603 3-NH2CH2C6H4CH2 4-pyridyl
    1604 3-NH2CH2C6H4CH2 3-pyridyl
    1605 3-NH2CH2C6H4CH2 2-pyridyl
    1606 3-NH2CH2C6H4CH2 2-thiazolyl
    1607 3-NH2CH2C6H4CH2 2-pyrazolyl
    1608 3-NH2CH2C6H4CH2 5-isoquinolyl
    1609 3-NH2CH2C6H4CH2 3,4-methylenedioxyC6H3
    1610 3-NH2CH2C6H4CH2 3,4-ethylenedioxyC6H3
    1611 3-NH2CH2C6H4CH2 2-imidazolyl
    1612 3-NH2CH2C6H4CH2 2-oxazolyl
    1613 3-NH2CH2C6H4CH2 4-isoxazolyl
    1614 3-NH2CH2C6H4CH2 4-HOC6H4
    1615 3-NH2CH2C6H4CH2 3-HOC6H4
    1616 3-NH2CH2C6H4CH2 3,4-diHOC6H4
    1617 3-NH2CH2C6H4CH2 4-NH2CH2C6H4
    1618 3-NH2CH2C6H4CH2 3-NH2CH2C6H4
    1619 4-NH2CH2C6H4CH2 4-MeOC6H4
    1620 4-NH2CH2C6H4CH2 3-MeOC6H4
    1621 4-NH2CH2C6H4CH2 4-NH2C6H4
    1622 4-NH2CH2C6H4CH2 3-NH2C6H4
    1623 4-NH2CH2C6H4CH2 2-NH2C6H4
    1624 4-NH2CH2C6H4CH2 4-Me2NC6H4
    1625 4-NH2CH2C6H4CH2 3-Me2NC6H4
    1626 4-NH2CH2C6H4CH2 2-Me2NC6H4
    1627 4-NH2CH2C6H4CH2 4-pyridyl
    1628 4-NH2CH2C6H4CH2 3-pyridyl
    1629 4-NH2CH2C6H4CH2 2-pyridyl
    1630 4-NH2CH2C6H4CH2 2-thiazolyl
    1631 4-NH2CH2C6H4CH2 2-pyrazolyl
    1632 4-NH2CH2C6H4CH2 5-isoquinolyl
    1633 4-NH2CH2C6H4CH2 3,4-methylenedioxyC6H3
    1634 4-NH2CH2C6H4CH2 3,4-ethylenedioxyC6H3
    1635 4-NH2CH2C6H4CH2 2-imidazolyl
    1636 4-NH2CH2C6H4CH2 2-oxazolyl
    1637 4-NH2CH2C6H4CH2 4-isoxazolyl
    1638 4-NH2CH2C6H4CH2 4-HOC6H4
    1639 4-NH2CH2C6H4CH2 3-HOC6H4
    1640 4-NH2CH2C6H4CH2 3,4-diHOC6H4
    1641 4-NH2CH2C6H4CH2 4-NH2CH2C6H4