Organic Compounds and Their Uses

• US 20100093776A1
• Filed: 12/20/2007
• Published: 04/15/2010
• Est. Priority Date: 12/22/2006
• Status: Abandoned Application

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Beckwith, Rohan Eric John
• Application Number:
  US12/520,764
• Publication Number:
  US 20100093776A1
• Time in Patent Office: Days
• US Class Current: 514/275
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present application describes organic compounds that are useful for the treatment, prevention and/or amelioration of diseases.

Claims

1. A compound represented by the Formula I:

and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof;

wherein

the dashed line indicates a single or double bond;

m is 0 or 1;

n is 0 or 1;

A¹, A², A³, A⁴, A⁵ and A⁶ are each, independently, C, C(H) or N;

R¹ is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted aryl and substituted or unsubstituted C_3-7-cycloalkyl; and

R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each, independently, selected from the group consisting of hydrogen, halogen, substituted or unsubstituted amino, substituted or unsubstituted C_1-6-alkyl, substituted or unsubstituted C_1-6-alkoxy, thioether, sulfoxide, sulfone and substituted or unsubstituted C_3-7-cycloalkyl.

2. The compound of claim 1, wherein

the dashed line is a double bond;

n is 0 or 1;

A¹, A², A³, A⁴, A⁵ and A⁶ are each, independently, C, C(H) or N;

R¹ is selected from the group consisting of substituted-aryl, substituted-C_1-6-alkyl, and substituted or unsubstituted C_3-7-cycloalkyl;

R³ is selected from the group consisting of hydrogen, C_1-6-alkyl, substituted-C_1-6-alkyl, C_1-6-alkoxy, and alkyl-amino;

R⁶ and R⁷ are each, independently, selected from the group consisting of hydrogen, substituted or unsubstituted amino, C_1-6-alkyl, C_1-6-alkoxy and halogen; and

R², R⁴, R⁵ and R⁸ are each hydrogen.

3. The compound of claim 1, wherein

A¹ is C, n is 1, and R⁷ is C_1-6-alkyl, C_1-6-alkoxy, halogen or substituted or unsubstituted amino.

4. The compound of claim 1, wherein n is 1, A'"'"', A³, A⁴, A⁵ and A⁶ are C, and A² is C(H).

5. The compound of claim 1, wherein the dashed line is a double bond, m is 0, n is 1, A¹ is C, A² is N, A³ and A⁴ are C, A⁵ is N and A⁶ is C.

6. The compound of claim 1, wherein the dashed line is a double bond, m is 1, n is 1, A¹ is C, A² is N, A³ and A⁴ are C, and A⁵ and A⁶ are C.

7. The compound of claim 1, wherein the dashed line is a double bond, m is 1, n is 0, A¹ and A² are N, A³ and A⁴ are C, and A⁵ and A⁶ are C.

8. The compound of claim 1, wherein the dashed line is a single bond, m is 1, n is 1, A¹ is C, A² is N, A³ and A⁴ are C(H), and A⁵ and A⁶ are C.

9. The compound of claim 1, wherein the dashed line is a double bond, m is 1, n is 1, A¹ is C, A² is N, A³ and A⁴ are N, and A⁵ and A⁶ are C.

10. The compound of claim 1, wherein the dashed line is a double bond, m is 1, n is 1, A¹ is C, A² and A³ are N, A⁴ is C, and A⁵ and A⁶ are C.

11. The compound of claim 1, wherein R² is selected from the group consisting of H, C_1-6-alkyl substituted by substituted or unsubstituted amino, substituted or unsubstitued C_1-6-alkoxy, substituted or unsubstitued aryl and substituted or unsubstitued heterocycle.

12. The compound of claim 1, wherein R⁸ is H.

13. The compound of claim 1, wherein Formula I is represented by a compound of Formula II:

and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof;

wherein

R¹ is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6-alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted C_3-7-cycloalkyl; and

R³, R⁶, and R⁷ are each, independently, selected from the group consisting of hydrogen, halogen, substituted or unsubstituted amino, substituted or unsubstituted C_1-6-alkyl, substituted or unsubstituted C_1-6-alkoxy, and substituted or unsubstituted C_3-7-cycloakyl.

14. The compound of claim 13, wherein

R³ and R⁶ are each, independently, selected from the group consisting of hydrogen, halogen, substituted or unsubstituted amino, substituted or unsubstituted C_1-6-alkyl, substituted or unsubstituted C_1-6-alkoxy, and substituted or unsubstituted C_3-7-cycloalkyl;

and

R⁷ is selected from the group consisting of halogen, substituted or unsubstituted amino, substituted or unsubstituted C_1-6-alkyl, substituted or unsubstituted C_1-6-alkoxy, and substituted or unsubstituted C_3-7-cycloalkyl.

15. The compound of claim 13, wherein

R¹ is selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted C_1-6-alkyl;

R³ is selected from the group consisting of hydrogen, C_1-6-alkyl, substituted-C_1-6-alkyl, C_1-6-alkoxy, and substituted or unsubstituted amino; and

R⁶ and R⁷ are each, independently, selected from the group consisting of hydrogen, substituted or unsubstituted amino, C_1-6-alkyl, C_1-6-alkoxy and halogen.

16. The compound of claim 13, wherein

R¹ is aryl, which is independently substituted one or more times with halogen, C_1-6-alkyl, C_1-6-alkoxy, substituted or unsubstituted amino, aryl, heteroaryl, hydroxy, thoether, electron-withdrawing groups or electron-withdrawing atoms;

R³ is selected from the group consisting of hydrogen, C_1-6-alkyl, C_1-6alkyl-C(O)O—

C_1-6-alkyl, C_1-6-alkyl-Ph, C_1-6-alkoxy, (CH₂)_1-6amino, and (CH₂)_1-6C(O)amino; and

R⁶ and R⁷ are each, independently, selected from the group consisting of hydrogen, substituted or unsubstituted amino, C_1-6-alkyl, C_1-6-alkoxy and halogen.

17. The compound of claim 13, wherein R¹ is benzothiazole, indazole, benzimidazole, benzoxazole or aryl, wherein the benzothiazole, indazole, benzimidazole, benzoxazole or aryl groups are independently substituted one or more times with halogen, nitro, hydroxy, nitrile, substituted or unsubstituted amino, ether, ester, carboxylic acid, amide, sulfone, sulfonamide, phenyl or heterocycle.

18. The compound of claim 13, wherein

R¹ is aryl, which may be are independently substituted one or more times with nitrile, substituted or unsubstituted amino, ether, ester, carboxylic acid, substituted or unsubstituted amide, substituted or unsubstituted sulfone, substituted or unsubstituted sulfonamide, substituted or unsubstituted phenyl or substituted or unsubstituted heterocycle;

R³ is selected from the group consisting of hydrogen, C_1-6-alkyl, C_1-6-alkyl-C(O)O—

C_1-6-alkyl, C_1-6-alkyl-Ph, C_1-6-alkoxy, (CH₂)_1-6amino, and (CH₂)_1-6C(O)amino; and

R⁶ and R⁷ are each, independently, selected from the group consisting of hydrogen, substituted or unsubstituted amino, C_1-6-alkyl, C_1-6-alkoxy and halogen.

19. The compound of claim 13, wherein R³ is selected from the group consisting of (CH₂)_1-6N(R¹⁰)R¹¹ and (CH₂)_1-6C(O)N(R¹⁰)R¹¹;

wherein R¹⁰ and R¹¹ are each, independently, selected from the group consisting of H and (C_1-6alkyl)_0-1G, wherein G is selected from the group consisting of H, COOH, NH₂, phenyl, N(H)C(O)C_1-6alkyl, N(C_1-6alkyl)C(O)C_1-6alkyl, N(H)C_1-6alkyl, OH, OC(O)C_1-6alkyl, N(H)-substituted phenyl, C(O)OC₁-C₆-alkyl, C(O)C_1-6alkyl-COOH, C(O)C₁-C₄-alkyl, C(O)-aryl, morpholino, imidazole, pyrrolidine and pyrrolidin-2-one;

or R¹⁰ and R¹¹ can together form a piperazine or piperadine ring, wherein the piperazine or piperadine rings may be substituted.

20. The compound of claim 13, wherein

R¹ is selected from the group consisting of chlorophenyl, methanesulfonyl-phenyl, and sulfonamidephenyl;

R³ is selected from the group consisting of hydrogen, CH₃, CH₂CH₃, CH₂C(O)OCH₂CH₃, CH₂Ph, CH₂CH₂OH, CH₂CH₂—

N-morpholino, CH₂CH₂N(CH₃)₂, CH₂C(O)N(H)CH₂CH₃, CH₂C(O)N(CH₃)₂, CH₂C(O)N(H)C(CH₃)₃, CH₂C(O)N(H)CH₂C(CH₃)₂, CH₂C(O)N(H)CH₂Ph, CH₂C(O)N(H)(CH₂)₂OH, CH₂C(O)N(H)(CH₂)₂NH₂, CH₂C(O)-piperazine, CH₂C(O)-piperidine-NH₂, CH₂C(O)N(H)CH₂-pyrrolidine, CH₂C(O)N(H)(CH₂)₂-pyrrolidine and CH₂CO₂H;

R⁶ is selected from the group consisting of hydrogen and CH₃; and

R⁷ is selected from the group consisting of hydrogen, CH₃, methoxy and fluoro.

21. The compound of claim 1, wherein the compound of Formula I is represented by a compound selected from Table A, Table B, or Table C.

22-27. -27. (canceled)

28. A method of treating a protein kinase-associated disorder comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound such that the protein kinase-associated disorder is treated, wherein the compound is a compound of the Formula I or Formula II.

29. The method of claim 28, wherein the compound is selected from the group consisting of compounds listed in Table A, Table B, or Table C.

30. The method of claim 28, wherein the protein kinase is selected from the group consisting of CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9.

31. The method of claim 28, wherein the protein kinase-associated disorder is cancer.

32. The method of claim 31, wherein the cancer is selected from the group consisting of bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, hematopoetic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal and pancreatic cancer.

33-50. -50. (canceled)