Carbazole derivatives

1 . A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein

X, R 1 , R 2 , and R 3 are each independently selected from H, halo, C 1 -C 6 alkyl, halo(C 1 -C 6 )-alkyl, C 1 -C 6 alkoxy, nitro, hydroxy, cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, thiol, amino, mono- or di-(C 1 -C 6 )alkylamino, mono C 3 -C 6 alkenylamino, carboxamide, aryl, heteroaryl, C 3 -C 7 cycloalkyl, and C 3 -C 7 cycloalkyl(C 1 -C 6 )alkyl, where each alkyl or cycloalkyl group is optionally substituted with aryl, heteroaryl, or 1-2 R 22 groups,

where each of the foregoing aryl and heteroaryl groups is optionally substituted with from 1-4 R 22 groups;

where R 22 at each occurrence is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, halogen, hydroxy, amino, mono- or di-(C 1 -C 6 )alkylamino, nitro, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, or carboxamide;

or R 2 and R 3 together with the atoms to which they are attached form a 5-12 membered mono-, bi-, or tricyclic ring system, where the 5-12 membered ring is partially unsaturated or aromatic and optionally contains one or two of oxygen, S(O) m where m is 0, 1, or 2, nitrogen, or NR 7 where R 7 is hydrogen or C 1 -C 6 alkyl, and wherein the 5-12 membered ring is optionally substituted with 1 or 2 R 22 groups;

or R 1 and X together with the atoms to which they are attached form a 5-12 membered mono-, bi-, or tricyclic ring system, where the 5-12 membered ring is partially unsaturated or aromatic and optionally contains one or two of oxygen, S(O) m where m is 0, 1, or 2, nitrogen, or NR 7 where R 7 is hydrogen or C 1 -C 6 alkyl, and wherein the 5-12 membered ring is optionally substituted with 1 or 2 R 22 groups;

Y is H, NR 7 R 7 ′, NR 7 (C 3 -C 6 )alkenyl, NR 7 CONHCOR 7 ′, C(=Z)NR 7 R 7 ′, NR 7 CONR 7 R 7 ′, NR 7 COR 7 ′, or —NR 7 —(C 1 -C 6 )alkyl-(C 1 -C 6 )alkoxy, where Z is O, S, or NOR 7 , and

R 7 and R 7 ′ at each occurrence are independently selected from H and C 1 -C 6 alkyl;

R 4 is H or C 1 -C 6 alkyl optionally substituted with 1-2 groups selected from oxo, aryl, heteroaryl, or R 22 ;

R 5 is OR 7 , NR 7 R 7 ′, NR 7 OR 7 ′, or C 1 -C 6 alkyl optionally substituted with 1-2 groups selected from oxo, aryl, heteroaryl, or R 22 ; or

R 4 and R 5 together with the atoms to which they are attached form a 5-12 membered mono-, bi-, or tricyclic ring system, where the 5-12 membered ring is partially unsaturated or aromatic and optionally contains one or two of oxygen, S(O) m where m is 0, 1, or 2, nitrogen, NOR 7 or NR 7 where R 7 is hydrogen or C 1 -C 6 alkyl, and wherein the 5-12 membered ring is optionally substituted with 1 or 2 R 22 groups;

n is 0, 1, 2, 3, or 4;

R 6 at each occurrence is independently halo, C 1 -C 6 alkyl, halo (C 1 -C 6 )-alkyl, C 1 -C 6 alkoxy, nitro, hydroxyl, cyano, alkenyl, alkynyl, thiol, amino, mono- or di-(C 1 -C 6 ) alkylamino, aryl, heteroaryl, C 3 -C 7 cycloalkyl, and C 3 -C 7 cycloalkyl(C 1 -C 6 )alkyl, where each alkyl or cycloalkyl group is optionally substituted with aryl, heteroaryl, or 1-2 R 22 groups,

where each of the foregoing aryl groups and heteroaryl groups is optionally substituted with from 1-4 R 22 groups;

or two R 6 groups on adjacent carbons, together with the atoms to which they are attached, form a 5-12 membered mono-, bi-, or tricyclic ring system fused to the ring to which Y is attached, where the 5-12 membered ring is partially unsaturated or aromatic and optionally contains one or two of oxygen, S(O) m where m is 0, 1, or 2, nitrogen, or NR 7 where R 7 is hydrogen or C 1 -C 6 alkyl, wherein the 5-12 membered ring is optionally substituted with 1 or 2 R 22 groups;

R 8 is H; and

R 9 is OH;

or R 8 and R 9 together are Q, wherein Q is ═O or ═NOR 7 , provided that when the 5-12 membered ring formed by R 4 and R 5 is aromatic, one of R 8 and R 9 is absent.

2 . A compound according to claim 1 wherein X, R 1 , R 2 , and R 3 are each independently selected from H, halo, C 1 -C 6 alkyl, halo (C 1 -C 6 )-alkyl, C 1 -C 6 alkoxy, nitro, hydroxy, cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, thiol, amino, mono- or di-(C 1 -C 6 ) alkylamino, aryl, heteroaryl, C 3 -C 7 cycloalkyl, and C 3 -C 7 cycloalkyl(C 1 -C 6 )alkyl, where each alkyl or cycloalkyl group is optionally substituted with aryl or heteroaryl, where each of the foregoing aryl groups and heteroaryl groups is optionally substituted with from 1-4 R 22 groups.

3 . A compound according to claim 1 wherein R 1 , R 2 , and R 3 are each hydrogen, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy. and X is H, halo, C 1 -C 6 alkyl, halo(C 1 -C 6 )-alkyl, C 1 -C 6 alkoxy, nitro, hydroxy, cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, thiol, amino, or mono- or di-(C 1 -C 6 )alkylamino.

4 . A compound according to claim 1 wherein R 4 is H or C 1 -C 6 alkyl and R 5 is OR 7 , NR 7 R 7 , NR 7 OR 7 , or C 1 -C 6 alkyl.

5 . A compound according to claim 1 wherein n is 0.

6 . A compound according to claim 1 wherein n is 1 and R 6 is halo, C 1 -C 6 alkyl, halo(C 1 -C 6 )-alkyl, C 1 -C 6 alkoxy, nitro, hydroxyl, cyano, alkenyl, alkynyl, thiol, amino, mono- or di-(C 1 -C 6 )alkylamino, aryl, heteroaryl, C 3 -C 7 cycloalkyl, and C 3 -C 7 cycloalkyl(C 1 -C 6 )alkyl, where each alkyl or cycloalkyl group is optionally substituted with aryl or heteroaryl.

7 . A compound according to claim 1 of the formula:

wherein

m is 1, 2, or 3; and

Q is O or NOR 7 .

8 . A compound according to claim 7 wherein X, R 1 , R 2 , and R 3 are each independently selected from H, halo, C 1 -C 6 alkyl, halo (C 1 -C 6 )-alkyl, C 1 -C 6 alkoxy, nitro, hydroxy, cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, thiol, amino, mono- or di-(C 1 -C 6 ) alkylamino, aryl, heteroaryl, C 3 -C 7 cycloalkyl, and C 3 -C 7 cycloalkyl(C 1 -C 6 )alkyl, where each alkyl or cycloalkyl group is optionally substituted with aryl or heteroaryl, where each of the foregoing aryl groups and heteroaryl groups is optionally substituted with from 1-4 R 22 groups.

9 . A compound according to claim 7 wherein R 1 , R 2 , and R 3 are each hydrogen, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy. and X is H, halo, C 1 -C 6 alkyl, halo(C 1 -C 6 )-alkyl, C 1 -C 6 alkoxy, nitro, hydroxy, cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, thiol, amino, or mono- or di-(C 1 -C 6 )alkylamino.

10 . A compound according to claim 7 wherein m is 2.

11 . A compound according to claim 7 wherein n is 0.

12 . A compound according to claim 7 wherein n is 1 and R 6 is halo, C 1 -C 6 alkyl, halo(C 1 -C 6 )-alkyl, C 1 -C 6 alkoxy, nitro, hydroxyl, cyano, alkenyl, alkynyl, thiol, amino, mono- or di-(C 1 -C 6 )alkylamino, aryl, heteroaryl, C 3 -C 7 cycloalkyl, and C 3 -C 7 cycloalkyl(C 1 -C 6 )alkyl, where each alkyl or cycloalkyl group is optionally substituted with aryl or heteroaryl.

13 . A compound according to claim 7 wherein Q is O.

14 . A compound according to claim 7 wherein Q is NOH.

15 . A compound according to claim 7 of the formula:

wherein R 6 ′ is H, halo, C 1 -C 6 alkyl, halo(C 1 -C 6 )-alkyl, C 1 -C 6 alkoxy, nitro, hydroxyl, cyano, alkenyl, alkynyl, thiol, amino, mono- or di-(C 1 -C 6 )alkylamino, aryl, heteroaryl, C 3 -C 7 cycloalkyl, and C 3 -C 7 cycloalkyl(C 1 -C 6 )alkyl, where each alkyl or cycloalkyl group is optionally substituted with aryl, heteroaryl, or 1-2 R 22 groups,

where each of the foregoing aryl and heteroaryl groups is optionally substituted with from 1-4 R 22 groups.

16 . A compound according to claim 7 of the formula:

wherein R 6 ′ is H, halo, C 1 -C 6 alkyl, halo(C 1 -C 6 )-alkyl, C 1 -C 6 alkoxy, nitro, hydroxyl, cyano, alkenyl, alkynyl, thiol, amino, mono- or di-(C 1 -C 6 )alkylamino, aryl, heteroaryl, C 3 -C 7 cycloalkyl, and C 3 -C 7 cycloalkyl(C 1 -C 6 )alkyl, where each alkyl or cycloalkyl group is optionally substituted with aryl, heteroaryl, or 1-2 R 22 groups,

where each of the foregoing aryl and heteroaryl groups is optionally substituted with from 1-4 R 22 groups.

17 . A compound according to claim 7 of the formula:

and pharmaceutically acceptable salts thereof, wherein

R 6 ′ is H, halo, C 1 -C 6 alkyl, halo(C 1 -C 6 )-alkyl, C 1 -C 6 alkoxy, nitro, hydroxyl, cyano, alkenyl, alkynyl, thiol, amino, mono- or di-(C 1 -C 6 )alkylamino, aryl, heteroaryl, C 3 -C 7 cycloalkyl, and C 3 -C 7 cycloalkyl(C 1 -C 6 )alkyl, where each alkyl or cycloalkyl group is optionally substituted with aryl, heteroaryl, or 1-2 R 22 groups,

where each of the foregoing aryl and heteroaryl groups is optionally substituted with from 1-4 R 22 groups.

18 . A compound according to claim 7 of the formula:

wherein R 6 ′ is H, halo, C 1 -C 6 alkyl, halo(C 1 -C 6 )-alkyl, C 1 -C 6 alkoxy, nitro, hydroxyl, cyano, alkenyl, alkynyl, thiol, amino, mono- or di-(C 1 -C 6 )alkylamino, aryl, heteroaryl, C 3 -C 7 cycloalkyl, and C 3 -C 7 cycloalkyl(C 1 -C 6 )alkyl, where each alkyl or cycloalkyl group is optionally substituted with aryl, heteroaryl, or 1-2 R 22 groups,

where each of the foregoing aryl and heteroaryl groups is optionally substituted with from 1-4 R 22 groups.

19 . A compound according to claim 7 of the formula:

20 . A compound according to claim 7 of the formula:

21 . A compound according to claim 7 of the formula:

22 . A compound according to claim 7 of the formula:

23 . A compound according to claim 1 , of the formula,

or pharmaceutically acceptable salts thereof, wherein

R 4 is H or C 1 -C 6 alkyl;

R 5 is C 1 -C 6 alkyl; and

R 6 ′ is H, halo, C 1 -C 6 alkyl, halo(C 1 -C 6 )-alkyl, C 1 -C 6 alkoxy, nitro, hydroxyl, cyano, alkenyl, alkynyl, thiol, amino, mono- or di-(C 1 -C 6 )alkylamino, aryl, heteroaryl, C 3 -C 7 cycloalkyl, and C 3 -C 7 cycloalkyl(C 1 -C 6 )alkyl, where each alkyl or cycloalkyl group is optionally substituted with aryl, heteroaryl, or 1-2 R 22 groups,

where each of the foregoing aryl and heteroaryl groups is optionally substituted with from 1-4 R 22 groups.

24 . A compound according to claim 23 , wherein

X, R 1 , R 2 , and R 3 are each independently selected from H, halo, C 1 -C 6 alkyl, halo(C 1 -C 6 )-alkyl, C 1 -C 6 alkoxy, nitro, hydroxy, cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, thiol, amino, or mono- or di-(C 1 -C 6 )alkylamino.

25 . A compound according to claim 23 , wherein

R 1 , R 2 , and R 3 are each hydrogen, halo, or C 1 -C 6 alkoxy and X is H, halo, nitro, C 1 -C 6 alkyl, halo(C 1 -C 6 )-alkyl or C 1 -C 6 alkoxy.

26 . A compound according to claim 23 , of the formula,

27 . A compound according to claim 26 , wherein

R 1 , R 2 , and R 3 are each hydrogen, halo, or C 1 -C 6 alkoxy; and

X is H, halo, C 1 -C 6 alkyl, halo(C 1 -C 6 )-alkyl, C 1 -C 6 alkoxy, nitro, hydroxy, cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, thiol, amino, or mono- or di-(C 1 -C 6 )alkylamino.

28 . A compound according to claim 27 , wherein

R 1 , R 2 , and R 3 are each hydrogen; and

X is H, halo or halo(C 1 -C 6 )-alkyl.

29 . A compound according to claim 26 , wherein

Q is O or N—OH.

30 . A compound according to claim 23 , of the formula,

31 . A compound according to claim 30 , wherein

R 1 , R 2 , and R 3 are each hydrogen, halo, or C 1 -C 6 alkoxy; and

X is H, halo, C 1 -C 6 alkyl, halo(C 1 -C 6 )-alkyl, C 1 -C 6 alkoxy, nitro, hydroxy, cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, thiol, amino, or mono- or di-(C 1 -C 6 )alkylamino.

32 . A compound according to claim 31 , wherein

R 1 , R 2 , and R 3 are each hydrogen; and

X is H, halo or halo(C 1 -C 6 )-alkyl.

33 . A compound according to claim 30 , wherein

Q is O or N—OH.

34 . A compound according to claim 1 which is

2-Allylamino-4-(4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-benzamide;

3-Bromo-4-(4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-benzamide;

9-[4-(Amino-hydroxyamino-methyl)-2-bromo-phenyl]-1,2,3,9-tetrahydro-carbazol-4-one;

3-Chloro-4-(4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-benzamide;

4-(4-Oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-2-[(pyridin-4-ylmethyl)-amino]-benzamide;

3-Chloro-4-(1-oxo-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-benzamide;

3-Chloro-4-(6-methoxy-4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-benzamide;

4-(6-Bromo-4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-3-chloro-benzamide;

3-Fluoro-4-(4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-benzamide;

3-Methoxy-4-(4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-benzamide;

3-Methyl-4-(4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-benzamide;

3-Bromo-4-(4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-thiobenzamide;

3-Chloro-4-(6-chloro-4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-benzamide;

3-Bromo-4-(4-hydroxyimino-1,2,3,4-tetrahydro-carbazol-9-yl)-benzamide;

4-(4-Oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-3-trifluoromethyl-benzamide;

3-Nitro-4-(4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-benzamide;

3-(4-Oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-4-trifluoromethyl-benzamide;

9-(4-Amino-2-chloro-phenyl)-1,2,3,9-tetrahydro-carbazol-4-one;

4-(3-Acetyl-indol-1-yl)-3-chloro-benzamide;

[3-Chloro-4-(4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-phenyl]-urea;

3-Chloro-4-[3-(1-hydroxyimino-ethyl)-indol-1-yl]-benzamide;

9-[4-(2-Methoxy-ethylamino)-2-trifluoromethyl-phenyl]-1,2,3,9-tetrahydro-carbazol-4-one;

[3-Chloro-4-(4-hydroxyimino-1,2,3,4-tetrahydro-carbazol-9-yl)-phenyl]-urea;

3-Chloro-4-(3-isobutyryl-indol-1-yl)-benzamide;

[4-(3-Acetyl-indol-1-yl)-3-chloro-phenyl]-urea;

1-[3-Chloro-4-(4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-phenyl]-3-ethyl-urea;

[3-Chloro-4-(1-oxo-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-phenyl]-urea;

3-Chloro-4-[3-(1-hydroxy-ethyl)-indol-1-yl]-benzamide;

4-(3-Acetyl-indol-1-yl)-2-bromo-benzamide;

4-(3-Acetyl-indol-1-yl)-2-(2-methoxy-ethylamino)-benzamide;

N-[3-Chloro-4-(4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-phenyl]-acetamide;

[4-(4-Oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-phenyl]-urea;

1-[1-(4-Amino-2-bromo-phenyl)-1H-indol-3-yl]-ethanone;

1-[1-(4-Amino-2-chloro-phenyl)-5-chloro-1H-indol-3-yl]-ethanone;

1-[1-(4-Amino-2-chloro-phenyl)-6-chloro-1H-indol-3-yl]-ethanone;

9-(4-Allylamino-2-trifluoromethyl-phenyl)-1,2,3,9-tetrahydro-carbazol-4-one;

[4-(3-Acetyl-5-chloro-indol-1-yl)-3-chloro-phenyl]-urea;

[4-(3-Acetyl-6-chloro-indol-1-yl)-3-chloro-phenyl]-urea;

N-[3-Chloro-4-(4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-phenyl]-propionamide;

1-Acetyl-3-[3-chloro-4-(4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-phenyl]-urea;

[3-Chloro-4-(6-chloro-4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-phenyl]-urea;

4-(3-Acetyl-indol-1-yl)-3-methoxy-benzamide; 4-(3-Acetyl-indol-1-yl)-2-methoxy-benzamide;

4-(3-Acetyl-6-chloro-indol-1-yl)-3-chloro-benzamide;

4-(3-Acetyl-5-bromo-indol-1-yl)-3-chloro-benzamide;

4-(3-Acetyl-6-chloro-indol-1-yl)-2-methoxy-benzamide; or

4-(3-Acetyl-6-fluoro-indol-1-yl)-3-chloro-benzamide.

35 . A pharmaceutical composition comprising at least one compound or salt according to claim 1 and a pharmaceutically acceptable solvent, carrier, excipient, adjuvant or a combination thereof.

36 . A method of treating diseases and/or conditions related to cell proliferation and/or abnormal cell mitosis, such as cancer, inflammation and inflammation-associated disorders, and conditions associated with angiogenesis, the method comprising administering to a patient in need of such treatment a pharmaceutically acceptable amount of a compound or salt according to claim 1 .

37 . A method of treating diseases and/or conditions related to cell proliferation and/or abnormal cell mitosis, such as cancer, inflammation and inflammation-associated disorders, and conditions associated with angiogenesis, the method comprising administering to a patient in need of such treatment a pharmaceutically acceptable amount of a compound or salt according to claim 1 .

38 . A package comprising a compound of claim 1 in a container with instructions on how to use the compound.