Bisamide Inhibitors of Hedgehog Signaling

• US 20080269215A1
• Filed: 11/14/2006
• Published: 10/30/2008
• Est. Priority Date: 11/14/2005
• Status: Active Grant

• Current Assignee: Curis, Inc., Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Olivero, Alan G., Sutherlin, Daniel P., Robarge, Kirk D., Goldsmith, Richard A.
• Granted Patent: US 8,101,610 B2
• Time in Patent Office: Days
• US Class Current: 514/235.5
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/433 Thidiazoles
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/4453 only substituted in position 1, e.g. propipocaine, diperodon
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61K 31/538 ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 213/82 : in position 3
• CPC Class Codes: C07D 231/14 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/06 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/28 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 265/36 : condensed with one six-membered ring
• CPC Class Codes: C07D 277/56 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 285/06 : 1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
• CPC Class Codes: C07D 295/155 : with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

The invention provides inhibitors of hedgehog signaling that are useful as a therapeutic agents for treating malignancies where the compounds have the general formula I:

wherein ring A, ring B, R₁, R₂, R₃, R₄, R₅, m and n are as defined herein.

Claims

1. A method for inhibiting hedgehog signaling in a cell comprising contacting said cell with a compound of formula I:

2. The method of claim 1, wherein R₅ is chloro.

3. The method of claim 1, wherein ring A is optionally substituted benzene, pyridine, pyrimidine, pyrazine, thiophene, thiazole, imidazole, pyrrole or pyrazole.

4. The method of claim 1, wherein ring A is benzene.

5. The method of claim 1, wherein ring B is aryl or heteroaryl.

6. The method of claim 1, wherein ring B is pyridine, pyrazine, pyrimidine, pyrazine, 1,2,4-triazine, thiophene, thiazole, imidazole, pyrrole or pyrazole.

7. The method of claim 1, wherein R₁ is alkyl, haloalkyl, aryl, a heterocycle or a heterocycloalkyl wherein said aryl, heterocycle and heterocycloalkyl is optionally substituted with hydroxy, halogen, alkyl, alkanoyl or hydroxyalkyl.

8. The method of claim 1, wherein R₁ is Me, CF₃, Ph, 4-F-phenyl, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-acetylpiperazin-1-yl, 3,5-dimethylpiperazine-1-yl, 4-(2-hydroxyethyl)-piperazin-1-yl, (4-methylpiperazin-1-yl)methyl, (4-ethylpiperazin-1-yl)methyl, (4-acetylpiperazin-1-yl)methyl, (3,5-dimethylpiperazine-1-yl)methyl, 4-hydroxypiperidin-1-yl, (piperidin-1-yl)methyl, (1-methylpiperidin-4-ylamino)methyl, morpholino, (3,5-dimethyl)morpholino, morpholinomethyl or 1H-1,2,4-triazol-1-yl.

9. The method of claim 1, wherein R₂ is H.

10. The method of claim 1, wherein In a particular embodiment, R₃ is halogen, alkyl, alkylsulfonyl, alkylsulfonylalkyl or a heterocycle.

11. The method of claim 1, wherein R₃ is Me, F, Cl, —

CH₂—

SO₂-Me, —

SO₂-Me, 1H-1,2,4-triazol-1-yl, 1H-imidazol-1-yl, morpholino, thiomorpholino-methyl (in which S is in the oxidized form SO₂), 1,2,3-thiadiazol-4-yl or N-methyl-piperizinyl.

12. The method of claim 1, wherein both R₄ groups are H.

20. The method of claim 1, wherein R₁ is Me, CF₃, Ph, 4-F-phenyl, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-acetylpiperazin-1-yl, 3,5-dimethylpiperazine-1-yl, 4-(2-hydroxyethyl)-piperazin-1-yl, (4-methylpiperazin-1-yl)methyl, (4-ethylpiperazin-1-yl)methyl, (4-acetylpiperazin-1-yl)methyl, (3,5-dimethylpiperazine-1-yl)methyl, 4-hydroxypiperidin-1-yl, (piperidin-1-yl)methyl, (1-methylpiperidin-4-ylamino)methyl, morpholino, (3,5-dimethyl)morpholino, morpholinomethyl or 1H-1,2,4-triazol-1-yl.

21. The method of claim 1, wherein R₂ is H.

22. The method of claim 1, wherein In a particular embodiment, R₃ is halogen, alkyl, alkylsulfonyl, alkylsulfonylalkyl or a heterocycle.

23. The method of claim 1, wherein R₃ is Me, F, Cl, —

CH₂—

SO₂-Me, —

SO₂-Me, 1H-1,2,4-triazol-1-yl, 1H-imidazol-1-yl, morpholino, thiomorpholino-methyl (in which S is in the oxidized form SO₂), 1,2,3-thiadiazol-4-yl or N-methyl-piperizinyl.

24. The method of claim 1, wherein both R₄ groups are H.

13. A method for treating a disease or condition associated with the hedgehog signaling in a mammal, comprising administering to said mammal an effective amount of a compound of formula I

14. The method of claim 13, wherein R₅ is chloro.

15. The method of claim 13, wherein ring A is optionally substituted benzene, pyridine, pyrimidine, pyrazine, thiophene, thiazole, imidazole, pyrrole or pyrazole.

16. The method of claim 13, wherein ring A is benzene.

17. The method of claim 13, wherein ring B is aryl or heteroaryl.

18. The method of claim 13, wherein ring B is pyridine, pyrazine, pyrimidine, pyrazine, 1,2,4-triazine, thiophene, thiazole, imidazole, pyrrole or pyrazole.

19. The method of claim 13, wherein R₁ is alkyl, haloalkyl, aryl, a heterocycle or a heterocycloalkyl wherein said aryl, heterocycle and heterocycloalkyl is optionally substituted with hydroxy, halogen, alkyl, alkanoyl or hydroxyalkyl.

25. The method of claim 13, wherein said disease or condition is cancer.

26. The method of claim 13, wherein said disease or condition is basal cell carcinoma, medulloblastoma, meningioma, hemangioma, glioblastoma, pancreatic adenocarcinoma, squamous lung carcinoma, small-cell lung carcinoma, non-small cell lung carcinoma, chondrosarcoma, breast carcinoma, rhabdomyosarcoma, oesophageal cancer, stomach cancer, biliary tract cancer, renal carcinoma or thyroid carcinoma.

27. A compound of formula II:

28. A method of treating cancer in a mammal, comprising administering to said mammal an effective amount of a compound of claim 27.

29. The method of claim 28, wherein said cancer is basal cell carcinoma, medulloblastoma, pancreatic adenocarcinoma, small-cell lung carcinoma, breast carcinoma, rhabdomyosarcoma, oesophageal cancer, stomach cancer, biliary tract cancer

30. A method of inhibiting angiogenesis in a mammal, comprising administering to said mammal an effective amount of a compound of claim 28.

31. A method of inhibiting hedgehog pathway signaling in a cell comprising contacting said cell with an effective amount of a compound of claim 28.

32. A compound selected from the group consisting of:

N-(4-chloro-3-nitrophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide;

N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide;

N-(3-benzamido-4-chlorophenyl)-4-methyl-6-(trifluoromethyl)nicotinamide;

N-(4-chloro-3-(2-chlorobenzamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide;

N-(4-chloro-3-(3-chlorobenzamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide;

N-(4-chloro-3-(4-chlorobenzamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide;

N-(4-chloro-3-(2-fluorobenzamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide;

N-(4-chloro-3-(3-fluorobenzamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide;

N-(4-chloro-3-(4-fluorobenzamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide;

N-(4-chloro-3-(3,4-difluorobenzamide)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide;

N-(4-chloro-3-(3-chloro-4-fluorobenzamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide;

N-(4-chloro-3-(2-morpholinobenzamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide;

N-(4-chloro-3-(4-(4-methylpiperazin-1-yl)benzamido)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide;

N-(4-chloro-3-(4-methoxybenzamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide;

N-(3-(4-(1,2,3-thiadiazol-4-yl)benzamido)-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide;

N-(3-(4-(1H-imidazol-1-yl)benzamido)-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide;

N-(3-(4-(1H-1,2,4-triazol-1-yl)benzamido)-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide;

N-(3-benzamido-4-chlorophenyl)-6-morpholinonicotinamide;

N-(3-benzamido-4-chlorophenyl)-2-methyl-4-phenylpyrimidin-5-carboxamide;

N-(3-benzamido-4-chlorophenyl)-1-(4-fluorophenyl)-4-methyl-1H-pyrazole-3-carboxamide;

N-(3-benzamido-4-chlorophenyl)-4-methyl-2-phenylpyrimidin-5-carboxamide;

N-(3-benzamido-4-chlorophenyl)-6-chloronicotinamide;

N-(3-benzamido-4-chlorophenyl)-6-((3S,5R)-3,5-dimethylpiperazine-1-yl)-nicotinamide;

N-(3-benzamido-4-chlorophenyl)-6-(4-ethylpiperazin-1-yl)nicotinamide;

N-(3-benzamido-4-chlorophenyl)-6-(4-(2-hydroxyethyl)piperazin-1-yl)-nicotinamide;

N-(3-benzamido-4-chlorophenyl)-6-(2,6-dimethylmorpholine)nicotinamide;

6-(4-acetylpiperazin-1-yl)-N-(3-benzamido-4-chlorophenyl)nicotinamide;

N-(3-benzamido-4-chlorophenyl)-6-(4-hydroxypiperidin-1-yl)nicotinamide;

N-(3-benzamido-4-chlorophenyl)-6-(3-methylpiperazin-1-yl)nicotinamide;

(R)—

N-(3-benzamido-4-chlorophenyl)-6-(3-methylpiperazin-1-yl)nicotinamide;

(S)—

N-(3-benzamido-4-chlorophenyl)-6-(3-methylpiperazin-1-yl)nicotinamide;

N-(3-benzamido-4-chlorophenyl)-6-(piperazin-1-yl)nicotinamide;

N-(3-benzamido-4-chlorophenyl)-6-chloro-2-methylnicotinamide;

N-(3-benzamido-4-chlorophenyl)-6-((3S,5R)-3,5-dimethylpiperazine-1-yl)-2-methyl-nicotinamide;

N-(3-benzamido-4-chlorophenyl)-6-(bromomethyl)nicotinamide;

N-(3-benzamido-4-chlorophenyl)-6-(morpholinomethyl)nicotinamide;

N-(3-benzamido-4-chlorophenyl)-6-(piperidin-1-ylmethyl)nicotinamide;

N-(3-benzamido-4-chlorophenyl)-6-((4-methylpiperazin-1-yl)methyl)nicotinamide;

N-(3-benzamido-4-chlorophenyl)-2-phenylthiazole-4-carboxamide;

N-(2-chloro-5-(2-chloro-4-(methylsulfonyl)benzamido)phenyl)nicotinamide;

6-chloro-N-(4-chloro-3-(4-fluorobenzamido)phenyl)nicotinamide;

N-(4-chloro-3-(4-fluorobenzamido)phenyl)-6-((3S,5R)-3,5-dimethylpiperazine-1-yl)nicotinamide;

N-(4-chloro-3-(4-fluorobenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)nicotinamide;

6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(4-fluorobenzamido)phenyl)nicotinamide;

6-(4-methylsulfonylpiperazine-1-yl-N-(4-chloro-3-(4-fluorobenzamido)phenyl-nicotinamide;

N-(3-(4-fluorobenzamido)-4-chlorophenyl)-6-(4-propionylpiperazin-1-yl)pyridine-3-carboxamide;

6-(4-(3-methylbutanoyl)piperazin-1-yl)-N-(3-(4-fluorobenzamido)-4-chlorophenyl)pyridine-3-carboxamide;

N-(3-(4-fluorobenzamido)-4-chlorophenyl)-6-(4-cyclopropylcarbonylpiperazin-1-yl)pyridine-3-carboxamide;

N-(4-chloro-3-(4-fluorobenzamido)phenyl)-6-(4-ethylpiperazin-1-yl)nicotinamide;

N-(4-chloro-3-(4-fluorobenzamido)phenyl)-6-(piperazin-1-yl)nicotinamide;

N-(4-chloro-3-(4-fluorobenzamido)phenyl)-6-(3-methylpiperazin-1-yl)nicotinamide;

(R)—

N-(4-chloro-3-(4-fluorobenzamido)phenyl)-6-(3-methylpiperazin-1-yl)-nicotinamide;

(S)—

N-(4-chloro-3-(4-fluorobenzamido)phenyl)-6-(3-methylpiperazin-1-yl)-nicotinamide;

6-chloro-N-(4-chloro-3-(4-fluorobenzamido)phenyl)-2-methylnicotinamide;

N-(4-chloro-3-(4-fluorobenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)-2-methylnicotinamide;

N-(4-chloro-3-(4-fluorobenzamido)phenyl)-6-(3,5-dimethylpiperazine-1-yl)-2-methylnicotinamide;

6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(4-fluorobenzamido)phenyl)-2-methylnicotinamide;

N-(2-chloro-5-(4-(methylsulfonylmethyl)benzamido)phenyl)nicotinamide;

N-(5-(4-(1H-1,2,4-triazol-1-yl)benzamido)-2-chlorophenyl)-3-chlorobenzamido;

6-chloro-N-(4-chloro-3-(3-chlorobenzamido)phenyl)nicotinamide;

N-(4-chloro-3-(3-chlorobenzamido)phenyl)-6-((3S,5R)-3,5-dimethylpiperazine-1-yl)nicotinamide;

N-(4-chloro-3-(3-chlorobenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)-nicotinamide;

6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(3-chlorobenzamido)phenyl)nicotinamide;

N-(4-chloro-3-(3-chlorobenzamido)phenyl)-6-(4-ethylpiperazin-1-yl)nicotinamide;

N-(4-chloro-3-(3-chlorobenzamido)phenyl)-6-(piperazin-1-yl)nicotinamide;

N-(4-chloro-3-(3-chlorobenzamido)phenyl)-6-(4-(2-hydroxyethyl)piperazin-1-yl)-nicotinamide;

6-(bromomethyl)-N-(4-chloro-3-(3-chlorobenzamido)phenyl)nicotinamide;

N-(4-chloro-3-(3-chlorobenzamido)phenyl)-6-((4-ethylpiperazin-1-yl)methyl)-nicotinamide;

N-(4-chloro-3-(3-chlorobenzamido)phenyl)-6-((4-methylpiperazin-1-yl)methyl)-nicotinamide;

N-(4-chloro-3-(3-chlorobenzamido)phenyl)-6-((1-methylpiperidin-4-ylamino)methyl)nicotinamide;

6-((4-acetylpiperazin-1-yl)methyl)-N-(4-chloro-3-(3-chlorobenzamido)phenyl)-nicotinamide;

N-(4-chloro-3-(3-chlorobenzamido)phenyl)-6-(((3S,5R)-3,5-dimethylpiperazine-1-yl)methyl)nicotinamide;

6-chloro-N-(4-chloro-3-(3-chlorobenzamido)phenyl)-2-methylnicotinamide;

N-(4-chloro-3-(3-chlorobenzamido)phenyl)-6-((3S,5R)-3,5-dimethylpiperazine-1-yl)-2-methylnicotinamide;

N-(4-chloro-3-(3-chlorobenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)-2-methylnicotinamide;

6-chloro-N-(4-chloro-3-(3-chlorobenzamido)phenyl)-2-methylnicotinamide;

N-(4-chloro-3-(3-chlorobenzamido)phenyl)-6-((3S,5R)-3,5-dimethylpiperazine-1-yl)-2-methylnicotinamide;

N-(4-chloro-3-(3-chlorobenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)-2-methylnicotinamide;

6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(3-chlorobenzamido)phenyl)-2-methyl-nicotinamide;

6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(2-chlorobenzamido)phenyl)nicotinamide;

6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(2-fluorobenzamido)phenyl)nicotinamide;

6-chloro-N-(4-chloro-3-(3-fluorobenzamido)phenyl)nicotinamide;

N-(4-chloro-3-(3-fluorobenzamido)phenyl)-6-((3S,5R)-3,5-dimethylpiperazine-1-yl)-nicotinamide;

N-(4-chloro-3-(3-fluorobenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)-nicotinamide;

6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(3-fluorobenzamido)phenyl)nicotinamide;

6-chloro-N-(4-chloro-3-(2-fluorobenzamido)phenyl)nicotinamide;

N-(4-chloro-3-(2-fluorobenzamido)phenyl)-6-((3S,5R)-3,5-dimethylpiperazine-1-yl)nicotinamide;

N-(4-chloro-3-(2-fluorobenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)-nicotinamide;

6-chloro-N-(4-chloro-3-(4-chlorobenzamido)phenyl)nicotinamide;

N-(4-chloro-3-(4-chlorobenzamido)phenyl)-6-((3S,5R)-3,5-dimethylpiperazine-1-yl)nicotinamide;

N-(4-chloro-3-(4-chlorobenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)-nicotinamide;

6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(4-chlorobenzamido)phenyl)nicotinamide;

6-chloro-N-(4-chloro-3-(2-chlorobenzamido)phenyl)nicotinamide;

N-(4-chloro-3-(2-chlorobenzamido)phenyl)-6-((3S,5R)-3,5-dimethylpiperazine-1-yl)nicotinamide;

N-(4-chloro-3-(2-chlorobenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)-nicotinamide;

6-chloro-N-(4-chloro-3-(4-methylbenzamide)phenyl)nicotinamide;

N-(4-chloro-3-(4-methylbenzamide)phenyl)-6-((3S,5R)-3,5-dimethylpiperazine-1-yl)nicotinamide;

N-(4-chloro-3-(4-methylbenzamide)phenyl)-6-(4-hydroxypiperidin-1-yl)-nicotinamide;

6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(4-methylbenzamide)phenyl)-nicotinamide;

6-chloro-N-(4-chloro-3-(2-methylbenzamide)phenyl)nicotinamide;

N-(4-chloro-3-(2-methylbenzamide)phenyl)-6-((3S,5R)-3,5-dimethylpiperazine-1-yl)nicotinamide;

N-(4-chloro-3-(2-methylbenzamide)phenyl)-6-(4-hydroxypiperidin-1-yl)-nicotinamide;

6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(2-methylbenzamide)phenyl)-nicotinamide;

6-chloro-N-(4-chloro-3-(3-methylbenzamide)phenyl)nicotinamide;

N-(4-chloro-3-(3-methylbenzamide)phenyl)-6-((3S,5R)-3,5-dimethylpiperazine-1-yl)nicotinamide;

N-(4-chloro-3-(3-methylbenzamide)phenyl)-6-(4-hydroxypiperidin-1-yl)-nicotinamide; and

6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(3-methylbenzamide)phenyl)-nicotinamide.