PROTEIN KINASE INHIBITORS

• US 20120028966A1
• Filed: 12/23/2010
• Published: 02/02/2012
• Est. Priority Date: 06/23/2008
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Charrier, Jean-Damien, Durrant, Steve
• Granted Patent: US 8,278,297 B2
• Time in Patent Office: Days
• US Class Current: 514/221
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• 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: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

In one aspect, the invention provides compounds of Formula I

or pharmaceutically acceptable salts thereof. In another aspect, the invention provides methods for treatment of diseases or disorders mediated by a protein kinase, comprising administering a therapeutically effective amount of a compound of this invention.

Claims

1. A compound of Formula I

2. The compound of claim 1, wherein R² is alkyl.

3. The compound of claim 2, wherein R² is methyl.

4. The compound of claim 1, wherein Y is O.

5. The compound of claim 1, wherein each of R³ and R⁴ is independently H or alkyl.

6. The compound of claim 5, wherein each of R³ and R⁴ is independently H, methyl, or ethyl.

7. The compound of claim 1, wherein R⁷ is alkyl or cycloalkyl.

8. The compound of claim 7, wherein R⁷ is cycloalkyl.

9. The compound of claim 8, wherein R⁷ is cyclopentyl.

10. The compound of claim 1, wherein q is 1.

11. The compound of claim 10, wherein each of R⁵ and R⁶ is independently H or alkyl.

12. The compound of claim 11, wherein each of R⁵ and R⁶ is H.

13. The compound of claim 1, wherein R⁸ is optionally substituted alkyl.

14. The compound of claim 13, wherein R⁸ is methyl, ethyl, methoxymethyl, methoxyethyl, hydroxymethyl, or hydroxyethyl.

15. The compound of claim 14, wherein R⁸ is methyl.

16. The compound of claim 15, wherein the carbon atom to which R⁸ is attached is in the S configuration.

17. The compound of claim 1, wherein R¹ is optionally substituted phenyl, optionally substituted napthyl, optionally substituted pyridyl, optionally substituted furanyl or optionally substituted thiazolyl.

18. The compound of claim 17, wherein R¹ is phenyl optionally substituted with 1 to 3 substituents each independently selected from the group consisting of alkyl, halo, amino, alkoxy, haloalkyl, alkylsulfonyl, nitro, phenyl, 1-piperazinyl, and 4-alkylpiperazin-1-yl.

19. The compound of claim 18, wherein R¹ is phenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 4-(trifluoromethoxy)phenyl, 2-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-fluorophenyl, 3,5-difluorophenyl, 4-(4-methylpiperazin-1-yl)phenyl, 4-(piperazin-1-yl)phenyl, 4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl, 4-nitrophenyl, 4-(methylsulfonyl)phenyl, biphenyl-4-yl, naphthalenyl, 3-pyridinyl, 2-pyridinyl, 4-pyridinyl, 2-furanyl, 4-thiazolyl, or 2-methylthiazol-4-yl.

20. The compound of claim 1, wherein the compound is represented by Formula Ia.

21. The compound of claim 1, wherein the compound is

9-cyclopentyl-5,7,7-trimethyl-2-(1-phenylethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-5,7,7-trimethyl-2-(1-phenylpropylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-2-(2-methoxy-1-phenylethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-2-(2-hydroxy-1-phenylethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

2-(1-(4-bromophenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(piperazin-1-yl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-2-(1-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-5,7,7-trimethyl-2-(1-p-tolylethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

2-(1-(4-chlorophenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-2-(1-(4-fluorophenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-2-(1-(2-fluorophenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-2-(1-(3,5-difluorophenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-2-(1-(4-methoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-2-(1-(3-methoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-2-(1-(2-methoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-2-(1-(3,4-dimethoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(trifluoromethoxy)phenyl)ethyl amino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(trifluoromethyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-5,7,7-trimethyl-2-(1-(3-(trifluoromethyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

2-(1-(3,5-bis(trifluoromethyl)phenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-5,7,7-trimethyl-2-(1-(2-(trifluoromethyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-nitrophenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(methylsulfonyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

2-(1-(biphenyl-4-yl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-5,7,7-trimethyl-2-(1-(naphthalen-1-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-5,7,7-trimethyl-2-(1-(pyridin-3-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-5,7,7-trimethyl-2-(1-(pyridin-2-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-][1,4]diazepin-6(7H)-one;

9-cyclopentyl-5,7,7-trimethyl-2-(1-(pyridin-4-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

9-cyclopentyl-2-(1-(furan-2-yl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

or

9-cyclopentyl-5,7,7-trimethyl-2-(1-(2-methylthiazol-4-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one.

22. The compound of claim 1, wherein q is 0.

23. The compound of claim 22, wherein each of R³ and R⁴ is independently H or alkyl.

24. The compound of claim 23, wherein each of R³ and R⁴ is independently H, methyl, or ethyl.

25. The compound of claim 24, wherein R³ is ethyl and R⁴ is H.

26. The compound of claim 25, wherein the carbon atom to which R³ and R⁴ are attached is in the R configuration.

27. The compound of claim 22, wherein R¹ is optionally substituted aryl or optionally substituted heteroaryl.

28. The compound of claim 27, wherein R¹ is phenyl optionally substituted with 1 to 3 of alkyl, halo, amino, alkoxy, haloalkyl, alkylsulfonyl, nitro, phenyl, 1-piperazinyl, or 4-methylpiperazin-1-yl.

29. The compound of claim 22, wherein R⁸ is optionally substituted alkyl or optionally substituted cycloalkyl.

30. The compound of claim 29, wherein R⁸ is optionally substituted alkyl.

31. The compounds of claim 30, wherein R⁸ is methyl, ethyl, methoxymethyl, methoxyethyl, hydroxymethyl, or hydroxyethyl.

32. The compound of claim 31, wherein R⁸ is methyl.

33. The compound of claim 32, wherein the carbon to which R⁸ is attached is in the S configuration.

34. The compound of claim 22, wherein the compound is represented by Formula Ib.

35. The compound of claim 1, wherein the compound is 8-cyclopentyl-7-ethyl-5-methyl-2-(1-phenylethylamino)-7,8-dihydropteridin-6(5H)-one.

36. The compound of claim 1, wherein Y is NR⁹.

37. The compound of claim 36, wherein R² and R⁹, together with the atoms to which they are attached, form a 5- to 8-membered monocyclic ring containing additional 0-2 hetero atoms each independently selected from O, N, and S, wherein said monocyclic ring is optionally substituted with 0 to 4 groups each independently being halo or alkyl.

38. The compound of claim 36, wherein q is 0.

39. The compound of claim 36, wherein each of R³ and R⁴ is independently H or alkyl.

40. The compound of claim 39, wherein R³ is ethyl and R⁴ is H.

41. The compound of claim 36, wherein R⁷ is cycloalkyl.

42. The compound of claim 41, wherein R⁷ is cyclopentyl.

43. The compound of claim 36, wherein R⁷ is aryl.

44. The compound of claim 43, wherein R⁷ is phenyl.

45. The compound of claim 36, wherein R¹ is optionally substituted aryl or optionally substituted heteroaryl.

46. The compound of claim 45, wherein R¹ is optionally substituted aryl.

47. The compound of claim 46, wherein R¹ is phenyl, p-bromophenyl, or 4-methylpiperazin-1-yl.

48. The compound of claim 36, wherein R⁸ is alkyl.

49. The compound of claim 48, wherein R⁸ is methyl, ethyl, methoxymethyl, methoxyethyl, hydroxymethyl, or hydroxyethyl.

50. The compound of claim 49, wherein R⁸ is methyl.

51. The compound of claim 50, wherein the carbon to which R⁸ is attached is in the S configuration.

52. The compound of claim 36, wherein the compound is represented by Formula Ic:

53. The compound of claim 1, wherein the compound is

5-cyclopentyl-4-ethyl-N-(1-phenylethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridi N-(1-(4-bromophenyl)ethyl)-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;

5-cyclopentyl-4-ethyl-N-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;

5-cyclopentyl-4-ethyl-N-(1-(4-(piperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;

or

4-ethyl-5-phenyl-N-(1-phenylethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine.

54. The compound of claim 1, wherein the compound is

5-cyclopentyl-4-ethyl-N-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine, or

5-cyclopentyl-4-ethyl-N-(1-(4-(piperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine.

55. The compound of claim 1, wherein the compound is:

(R)-5-cyclopentyl-4-ethyl-N—

((S)-1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;

or

(R)-5-cyclopentyl-4-ethyl-N—

((S)-1-(4-(piperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine.

56. The compound of claim 1, wherein the compound is:

(S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-phenylethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-phenylpropylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(R)-9-cyclopentyl-2-(2-methoxy-1-phenylethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(R)-9-cyclopentyl-2-(2-hydroxy-1-phenylethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(S)-2-(1-(4-bromophenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-p-tolylethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(S)-2-(1-(4-chlorophenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(S)-9-cyclopentyl-2-(1-(4-fluorophenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(S)-9-cyclopentyl-2-(1-(4-methoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(S)-9-cyclopentyl-2-(1-(3-methoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(S)-9-cyclopentyl-2-(1-(2-methoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(2-(trifluoromethyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-nitrophenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-][1,4]diazepin-6(7H)-one;

(RS)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(methylsulfonyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-][1,4]diazepin-6(7H)-one;

(RS)-2-(1-(biphenyl-4-yl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-][1,4]diazepin-6(7H)-one;

(RS)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(naphthalen-1-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-][1,4]diazepin-6(7H)-one;

(RS)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(pyridin-3-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(RS)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(pyridin-4-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(RS)-9-cyclopentyl-2-(1-(furan-2-yl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(RS)-9-cyclopentyl-2-(1-(3,4-dimethoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-][1,4]diazepin-6(7H)-one;

(RS)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(trifluoromethoxy)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(R)—

N—

((S)-1-(4-bromophenyl)ethyl)-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;

(R)-5-cyclopentyl-4-ethyl-N—

((S)-1-phenylethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;

(R)-8-cyclopentyl-7-ethyl-5-methyl-2-((S)-1-phenylethylamino)-7,8-dihydropteridin-6(5H)-one;

(S)-9-cyclopentyl-2-(1-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(R,S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(2-methylthiazol-4-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(3-(trifluoromethyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(R,S)-9-cyclopentyl-2-(1-(2-fluorophenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(R,S)-9-cyclopentyl-2-(1-(3,5-difluorophenyl)ethylamino)-5,7,7-trimethyl-8dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(trifluoromethyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(S)-2-(1-(3,5-bis(trifluoromethyl)phenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;

(R)-4-ethyl-5-phenyl-N—

((S)-1-phenylethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;

(R)—

N—

((S)-1-(4-bromophenyl)ethyl)-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;

(R)-5-cyclopentyl-4-ethyl-N—

((S)-1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;

or

(R)-5-cyclopentyl-4-ethyl-N—

((S)-1-(4-(piperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine.

57. A composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

58. A method of inhibiting protein kinase in a patient comprising administering to said patient in need thereof a pharmaceutically effective amount of a compound of claim 1 or a composition of claim 57.

59. The method of claim 58, wherein the protein kinase is a PLK.

60. The method of claim 59, wherein said protein kinase is PLK1.

61. A method of inhibiting protein kinase in a biological sample comprising contacting said biological sample with a pharmaceutically effective amount of a compound of claim 1 or a composition of claim 57.

62. The method of claim 61, wherein the protein kinase is a PLK.

63. The method of claim 62, wherein the protein kinase is PLK1.

64. A method of treating a proliferative disorder, a neurodegenerative disorder, an autoimmune disorder, an inflammatory disorder, or an immunologically mediated disorder in a patient, comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of claim 1 or a composition of claim 57.

65. The method of claim 64, further comprising administering to the patient a chemotherapeutic agent, an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, an immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorder, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorder, an agent for treating diabetes, or an agent for treating immunodeficiency disorder.

66. A method of treating melanoma, myeloma, leukemia, lymphoma, neuroblastoma, colon cancer, breast cancer, gastric cancer, ovarian cancer, cervical cancer, lung cancer, central nervous system cancer, renal cancer, prostate cancer, bladder cancer, or pancreatic cancer, in a patient, comprising administering to the patient in need thereof a pharmaceutically effective amount of a compound of claim 1 or a composition of claim 57.

67. A method of treating cancer in a patient, comprising administering to the patient in need thereof a pharmaceutically effective amount of a compound of claim 1 or a composition of claim 57.

68. The method of claim 67, wherein the method comprises disrupting mitosis of the cancer cells by inhibiting a PLK with the compound of claim 1 or the composition of claim 57.