Inhibitors of human phosphatidylinositol 3-kinase delta

• US 8,138,195 B2
• Filed: 04/20/2005
• Issued: 03/20/2012
• Est. Priority Date: 04/25/2000
• Status: Active Grant

• Current Assignee: ICOS Corporation (Eli Lilly and Company)
• Original Assignee: ICOS Corporation (Eli Lilly and Company)
• Inventors: Sadhu, Chanchal, Treiberg, Jennifer, Sowell, C. Gregory, Kesicki, Edward A., Oliver, Amy, Dick, Kenneth O.
• Primary Examiner(s): Wilson, James O
• Assistant Examiner(s): Truong, Tamthom N
• Application Number:
  US11/110,204
• Publication Number:
  US 20050261317A1
• Time in Patent Office: 2,526 Days
• Field of Search: 514/263.1, 544/256
• US Class Current: 514/263.1
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/08 Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock artificial tears A61P27/04
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 233/66 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07D 233/66 : 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 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 473/00 : Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07D 473/16 : two nitrogen atoms
• CPC Class Codes: C07D 473/24 : one nitrogen and one sulfur atom
• CPC Class Codes: C07D 473/30 : attached in position 6, e.g. hypoxanthine
• CPC Class Codes: C07D 473/32 : Nitrogen atom
• CPC Class Codes: C07D 473/34 : attached in position 6, e.g. adenine
• CPC Class Codes: C07D 473/38 : attached in position 6
• CPC Class Codes: C07D 473/40 : with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C12N 9/1205 : Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases
• CPC Class Codes: C12N 9/99 : Enzyme inactivation by chemical treatment
• CPC Class Codes: C12Y 207/01137 : Phosphatidylinositol 3-kinase (2.7.1.137)

Abstract

Methods of inhibiting phosphatidylinositol 3-kinase delta isoform (PI3Kδ) activity, and methods of treating diseases, such as disorders of immunity and inflammation, in which PI3Kδ plays a role in leukocyte function are disclosed. Preferably, the methods employ active agents that selectively inhibit PI3Kδ, while not significantly inhibiting activity of other PI3K isoforms. Compounds are provided that inhibit PI3Kδ activity, including compounds that selectively inhibit PI3Kδ activity. Methods of using PI3Kδ inhibitory compounds to inhibit cancer cell growth or proliferation are also provided. Accordingly, the invention provides methods of using PI3Kδ inhibitory compounds to inhibit PI3Kδ-mediated processes in vitro and in vivo.

Claims

1. A compound of formula (I):

2. The compound of claim 1 wherein X is selected from the group consisting of CH₂, CH(CH₃), CH(CH₂CH₃), and C(CH₃)₂.

3. The compound of claim 1 wherein X is selected from the group consisting of CH₂, CH(CH₃), and CH(CH₂CH₃).

4. The compound of claim 1 wherein Y is null.

5. The compound of claim 1, wherein Y is NH.

6. The compound of claim 1 wherein the A ring system is optionally substituted with one to three substituents selected from the group consisting of N(R^a)₂, halo, C_1-3alkyl, S(C_1-3alkyl), and OR^a.

7. The compound of claim 1 wherein the A ring system is optionally substituted with one to three substituents selected from the group consisting of NH₂, NH(CH₃), N(CH₃)₂, NHCH₂C₆H₅, NH(C₂H₅), Cl, F, CH₃, SCH₃, and OH.

8. The compound according to claim 1 wherein the A ring system is optionally substituted with NH₂.

9. The compound of claim 1 wherein R¹ and R², independently, are selected from the group consisting of hydrogen, OR^a, halo, C_1-6alkyl, CF₃, NO₂, N(R^a)₂, NR^aC_1-3alkyleneN(R^a)₂, and OC_2-4alkyleneOR^a.

10. The compound of claim 1 wherein R¹ and R², independently, are selected from the group consisting of H, OCH₃, Cl, Br, F, CH₃, CF₃, NO₂, OH, N(CH₃)₂, O(CH₂)₂OCH₂C₆H₅, and

11. The compound according to claim 1 wherein R¹ and R², independently, are selected from the group consisting of H, F, Cl, or CH₃.

12. The compound of claim 1 wherein R³ is selected from the group consisting of optionally substituted C_1-6alkyl, aryl, heteroaryl, C_3-8cycloalkyl, and C_3-8heterocycloalkyl.

13. The compound of claim 1 wherein R³ is selected from the group consisting of optionally substituted

14. The compound of claim 1 wherein R³ is optionally substituted

15. The compound of claim 1 wherein R³ is substituted with a substituent selected from the group consisting of halo, OR^a, C_1-6alkyl, aryl, heteroaryl, NO₂, N(R^a)₂, NR^aSO₂CF₃, NR^aC(═

O)R^a, C(═

O)OR^a, SO₂N(R^a)₂, CN, C(═

O)R^a, C_1-4alkyleneN(R^a)₂, OC_1-4alkyleneC(═

O)N(R^a)₂, OC_1-4alkylenearyl, OC_1-4alkyleneheteroaryl, OC_1-4alkyleneHet, OC_1-4alkyleneN(R^a)₂, and N(R^a)C_1-4alkyleneN(R^a)₂.

16. The compound of claim 1 wherein R³ is substituted with a substituent selected from the group consisting of Cl, F, CH₃, CH(CH₃)₂, and OH.

17. A method to treat a condition selected from the group consisting of an arthritic disorder and leukemia, said method comprising administering an effective amount of a compound of claim 1 to a subject in need of such treatment.

18. The method of claim 17 wherein the compound is selected from the group consisting of:

2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-6,7-dimethoxy-3H-quinazolin-4-one;

2- (6-aminopurin-9-ylmethyl)-6-bromo-3- (2-chlorophenyl)-3H-quinazolin-4-one;

2- (6-aminopurin-9-ylmethyl)-6-bromo-3- (2-chlorophenyl)-7-fluoro-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-6-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-fluoro-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-8-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-biphenyl-2-yl-5-chloro-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-fluorophenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-isopropylphenyl)-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-chloro-3-o-tolyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-methoxyphenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-cyclopropylmethyl-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-cyclopentyl-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-chloropyridin-3-yl)-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-cyclopropyl-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-cyclohexyl-5-methyl-3H-quinazolin-4-one;

3-(2-chlorophenyl)-5-fluoro-2-[(9H-purin-6-ylamino)-methyl]-3H-quinazolin-4-one;

2-[(2-amino-9H-purin-6-ylamino)methyl]-3-(2-chloro-phenyl)-5-fluoro-3H-quinazolin-4-one;

5-methyl-2-[(9H-purin-6-ylamino)methyl]-3-o-tolyl-3H-quinazolin-4-one;

2-[(2-amino-9H-purin-6-ylamino)methyl]-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

2-[(2-fluoro-9H-purin-6-ylamino)methyl]-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

2-[1-(2-fluoro-9H-purin-6-ylamino)ethyl]-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-3-o-tolyl-3H-quinazolin-4-one;

2-(6-dimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-(2-methyl-6-oxo-1,6-dihydro-purin-7-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-(2-methyl-6-oxo-1,6-dihydro-purin-9-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one;

2-(6-amino-2-dimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-purin-7-ylmethyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-purin-9-ylmethyl-3-o-tolyl-3H-quinazolin-4-one;

2-(2-amino-6-chloro-purin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

2-(6-aminopurin-7-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-(6-methylaminopurin-9-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one;

2-(6-benzylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one; and

2-(2,6-diaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one and pharmaceutically acceptable salts thereof.

39. The compound according to claim 3, wherein Y is null.

40. The compound according to claim 39, wherein the compound is selected from the group consisting of 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-6,7-dimethoxy-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-6-bromo-3-(2-chlorophenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-6-bromo-3-(2-chlorophenyl)-7-fluoro-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-6-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-fluoro-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-8-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-biphenyl-2-yl-5-chloro-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-fluorophenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-isopropylphenyl)-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-chloro-3-o-tolyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-methoxyphenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-cyclopropylmethyl-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-cyclopentyl-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-chloropyridin-3-yl)-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-cyclopropyl-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-cyclohexyl-5-methyl-3H-quinazolin-4-one;

2-(6-dimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-(2-methyl-6-oxo-1,6-dihydro-purin-7-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-(2-methyl-6-oxo-1,6-dihydro-purin-9-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one;

2-(6-amino-2-dimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-purin-7-ylmethyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-purin-9-ylmethyl-3-o-tolyl-3H-quinazolin-4-one;

2-(2-amino-6-chloro-purin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

2-(6-aminopurin-7-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-(6-methylaminopurin-9-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one;

2-(6-benzylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one; and

2-(2,6-diaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

and pharmaceutically acceptable salts thereof.

41. The compound according to claim 14, wherein R³ is unsubstituted

42. The compound according to claim 14, wherein R³ is substituted with one to three halo.

43. The method according to claim 17, wherein the condition is an arthritic disorder.

44. The method according to claim 43, wherein the arthritic disorder is selected from the group consisting of rheumatoid arthritis, monoarticular arthritis, osteoarthritis and gouty arthritis.

45. The method according to claim 17, wherein the condition is leukemia.

46. The method according to claim 45, wherein leukemia is chronic myeloid leukemia (CML) or lymphocytic leukemia.

57. A method to treat a condition selected from the group consisting of an arthritic disorder and leukemia, said method comprising administering an effective amount of a compound of claim 40 to a subject in need of such treatment.

58. The method according to claim 57, wherein the condition is an arthritic disorder.

59. The method according to claim 58, wherein arthritic disorder is selected from the group consisting of rheumatoid arthritis, monoarticular arthritis, osteoarthritis and gouty arthritis.

60. The method according to claim 57, wherein the condition is leukemia.

61. The method according to claim 60, wherein leukemia is selected from chronic myeloid leukemia (CML) and lymphocytic leukemia.

19. A compound of formula (I):

20. The compound of claim 19 wherein Y is null.

21. The compound of claim 19 wherein Y is NH.

22. The compound according to claim 19 wherein the A ring system is substituted with one or two substituents.

23. The compound of claim 19 wherein the A ring system is optionally substituted with one to three substituents selected from the group consisting of NH₂, NH(CH₃), N(CH₃)₂, NH(C₂H₅), Cl, F, CH₃, SCH₃, and OH.

24. The compound according to claim 19 wherein the A ring system is substituted with NH₂.

25. The compound according to claim 19 wherein the A ring system is optionally substituted with NH₂.

26. The compound according to claim 19 wherein R¹ and R², independently, are selected from the group consisting of H, F, Cl, and CH₃.

27. The compound according to claim 25 wherein R¹ and R², independently, are selected from the group consisting of H, F, Cl, and CH₃.

28. The compound of claim 19 wherein R³ is optionally substituted

29. The compound of claim 27 wherein R³ is optionally substituted

30. The compound of claim 19 wherein R³ is substituted with a substituent selected from the group consisting of Cl, F, CH₃, CH(CH₃)₂, OH, OCH₃, OCH₂C₆H₅, O(CH₂)₃N(CH₃)₂, OCH₂C═

CH, OCH₂C(═

O)NH₂, C₆H₅, NO₂, NH₂, NHC(═

O)CH₃, CO₂H, N(CH₃)CH₂CH₂N(CH₃)₂, and

31. The compound of claim 29 wherein R³ is substituted with a substituent selected from the group consisting of Cl, F, CH₃, CH(CH₃)₂, OH, OCH₃, OCH₂C₆H₅, O(CH₂)₃N(CH₃)₂, OCH₂C═

CH, OCH₂C(═

O)NH₂, C₆H₅, NO₂, NH₂, NHC(═

O)CH₃, CO₂H, N(CH₃)CH₂CH₂N(CH₃)₂, and

32. The compound of claim 19, wherein A is optionally substituted with 1-2substituents selected from NH₂, NH(CH₃), N(CH₃)₂, NH(C₂H₅), Cl, F, CH₃, SCH₃, and OH.

37. A method to treat an arthritic disorder, which comprises administering to a subject in need thereof an effective amount of a compound of claim 19.

38. The method of claim 37, wherein the arthritic disorder is selected from rheumatoid arthritis, monoarticular arthritis, osteoarthritis and gouty arthritis.

47. The compound according to claim 29, wherein R³ is unsubstituted

48. The compound according to claim 47, wherein Y is NH.

49. The compound according to claim 48, wherein A is unsubstituted.

50. The compound according to claim 29, wherein R³ is substituted with up to three substituents selected from the group consisting of Cl, F, and OH.

51. The compound according to claim 50, wherein Y is NH.

52. The compound according to claim 51, wherein A is unsubstituted.

62. A method to treat a condition selected from the group consisting of an arthritic disorder and leukemia, said method comprising administering an effective amount of a compound of claim 47 to a subject in need of such treatment.

63. The method according to claim 62, wherein the condition is an arthritic disorder.

64. The method according to claim 63, wherein arthritic disorder is selected from the group consisting of rheumatoid arthritis, monoarticular arthritis, osteoarthritis and gouty arthritis.

65. The method according to claim 62, wherein the condition is leukemia.

66. The method according to claim 65, wherein leukemia is selected from chronic myeloid leukemia (CML) and lymphocytic leukemia

67. A method to treat a condition selected from the group consisting of an arthritic disorder and leukemia, said method comprising administering an effective amount of a compound of claim 50 to a subject in need of such treatment.

68. The method according to claim 67, wherein the condition is an arthritic disorder.

69. The method according to claim 68, wherein arthritic disorder is selected from the group consisting of rheumatoid arthritis, monoarticular arthritis, osteoarthritis and gouty arthritis.

70. The method according to claim 67, wherein the condition is leukemia.

71. The method according to claim 70, wherein leukemia is selected from chronic myeloid leukemia (CML) and lymphocytic leukemia.

72. The compound according to claim 20, wherein the compound is selected from the group consisting of 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-6,7-dimethoxy-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-6-bromo-3-(2-chlorophenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-6-bromo-3-(2-chlorophenyl)-7-fluoro-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-6-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-fluoro-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-8-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-biphenyl-2-yl-5-chloro-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-fluorophenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-isopropylphenyl)-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-chloro-3-o-tolyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-methoxyphenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-cyclopropylmethyl-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-cyclopentyl-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-chloropyridin-3-yl)-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-cyclopropyl-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-cyclohexyl-5-methyl-3H-quinazolin-4-one;

2-(6-dimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-(2-methyl-6-oxo-1,6-dihydro-purin-7-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-(2-methyl-6-oxo-1,6-dihydro-purin-9-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one;

2-(6-amino-2-dimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-purin-7-ylmethyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-purin-9-ylmethyl-3-o-tolyl-3H-quinazolin-4-one;

2-(2-amino-6-chloro-purin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

2-(6-aminopurin-7-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-(6-methylaminopurin-9-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one;

2-(6-benzylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one; and

2-(2,6-diaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

and pharmaceutically acceptable salts thereof.

33. A compound selected from the group consisting of:

2-(6-aminopurin-9-ylmethyl)-5-methyl-3-{2-(2-(1-methylpyrrolidin-2-yl)-ethoxy)-phenyl}-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-methyl-3-(2-prop-2-ynyloxyphenyl)-3H-quinazolin-4-one; and

2-{2-(1-(6-aminopurin-9-ylmethyl)-5-methyl-4-oxo-4H-quinazolin-3-yl]-phenoxy}-acetamide;

and pharmaceutically acceptable salts thereof.

34. A compound selected from the group consisting of:

2-(6-aminopurin-9-ylmethyl)-3-(2-benzyloxyphenyl)-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-hydroxyphenyl)-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-(3-dimethylamino-propoxy)-phenyl)-5-methyl-3H-quinazolin-4-one;

2-(1-(2-amino-9H-purin-6-ylamino)ethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-[1-(9H-purin-6-ylamino)propyl]-3-o-tolyl-3H-quinazolin-4-one;

2-(1-(2-fluoro-9H-purin-6-ylamino)propyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

2-(1-(2-amino-9H-purin-6-ylamino)propyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one; and

2-(2-benzyloxy-1-(9H-purin-6-ylamino)ethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

and pharmaceutically acceptable salts thereof.

35. A pharmaceutical composition comprising:

a);

an effective amount of a compound of formula (I);

53. The composition according to claim 35, wherein Y is null.

54. The composition according to claim 53, wherein the compound is selected from the group consisting of 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-6,7-dimethoxy-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-6-bromo-3-(2-chlorophenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-6-bromo-3-(2-chlorophenyl)-7-fluoro-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-6-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-fluoro-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-8-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-biphenyl-2-yl-5-chloro-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-fluorophenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-isopropylphenyl)-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-chloro-3-o-tolyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-methoxyphenyl)-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-cyclopropylmethyl-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-cyclopentyl-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-(2-chloropyridin-3-yl)-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-cyclopropyl-5-methyl-3H-quinazolin-4-one;

2-(6-aminopurin-9-ylmethyl)-3-cyclohexyl-5-methyl-3H-quinazolin-4-one;

2-(6-dimethylaminopurin-9-ylmethyl)- 5-methyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-(2-methyl-6-oxo-1,6-dihydro-purin-7-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-(2-methyl-6-oxo-1,6-dihydro-purin-9-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one;

2-(6-amino-2-dimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-purin-7-ylmethyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-purin-9-ylmethyl-3-o-tolyl-3H-quinazolin-4-one;

2-(2-amino-6-chloro-purin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

2-(6-aminopurin-7-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-(6-methylaminopurin-9-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one;

2-(6-benzylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one; and

2-(2,6-diaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

and pharmaceutically acceptable salts thereof.

55. The composition according to claim 35, wherein Y is NH.

56. The composition according to claim 55, wherein R³ is unsubstituted aryl.

36. A pharmaceutical composition comprising:

a) an effective amount of a compound of formula (I);