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Claims for Patent: 8,138,195

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Claims for Patent: 8,138,195

Title:Inhibitors of human phosphatidylinositol 3-kinase delta
Abstract: Methods of inhibiting phosphatidylinositol 3-kinase delta isoform (PI3K.delta.) activity, and methods of treating diseases, such as disorders of immunity and inflammation, in which PI3K.delta. plays a role in leukocyte function are disclosed. Preferably, the methods employ active agents that selectively inhibit PI3K.delta., while not significantly inhibiting activity of other PI3K isoforms. Compounds are provided that inhibit PI3K.delta. activity, including compounds that selectively inhibit PI3K.delta. activity. Methods of using PI3K.delta. inhibitory compounds to inhibit cancer cell growth or proliferation are also provided. Accordingly, the invention provides methods of using PI3K.delta. inhibitory compounds to inhibit PI3K.delta.-mediated processes in vitro and in vivo.
Inventor(s): Sadhu; Chanchal (Bothell, WA), Dick; Kenneth O. (Bothell, WA), Treiberg; Jennifer (Bothell, WA), Sowell; C. Gregory (Mukilteo, WA), Kesicki; Edward A. (Bothell, WA), Oliver; Amy (Bothell, WA)
Assignee: ICOS Corporation (Bothell, WA)
Application Number:11/110,204
Patent Claims: 1. A compound of formula (I): ##STR00092## wherein A is an optionally substituted purinyl ring system; X is C(R.sup.b).sub.2; Y is null or NH; R.sup.1 and R.sup.2, independently, are selected from the group consisting of hydrogen, halo, NO.sub.2, CF.sub.3, and optionally substituted C.sub.1-6alkyl, OR.sup.a, N(R.sup.a).sub.2, OC.sub.2-4alkyleneOR.sup.a, and NR.sup.aC.sub.1-4alkyleneN(R.sup.a).sub.2; R.sup.3 is selected from the group consisting of optionally substituted, C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.3-8heterocycloalkyl, C.sub.1-4alkylenecycloalkyl, C.sub.2-6alkenyl, C.sub.1-3alkylenearyl, arylC.sub.1-3alkyl, C(.dbd.O)R.sup.a, aryl, heteroaryl, C.sub.1-4alkylenearyl substituted with one or more of SO.sub.2N(R.sup.a).sub.2, N(R.sup.a).sub.2, C(.dbd.O)OR.sup.a, NR.sup.aSO.sub.2CF.sub.3, C(.dbd.O)R.sup.a, OR.sup.a, C.sub.1-4alkyleneN(R.sup.a).sub.2, and OC.sub.1-4alkyleneN(R.sup.a).sub.2, C.sub.1-4alkyleneHet, C.sub.1-4alkyleneOR.sup.a, C.sub.1-4alkyleneOC.sub.1-4alkyleneOR.sup.a, and C.sub.1-4alkyleneN (R.sup.a).sub.2; wherein the optional substituents for R.sup.3 are selected from one to three substituents selected from the group consisting of halo, OR.sup.a, C.sub.1-6alkyl, aryl, heteroaryl, NO.sub.2, N(R.sup.a).sub.2, NR.sup.aSO.sub.2CF.sub.3, NR.sup.a(C.dbd.O)R.sup.a, C(.dbd.O)OR.sup.a, N(R.sup.a)C.sub.1-4alkylene (R.sup.a).sub.2, SO.sub.2N(R.sup.a).sub.2, CN, C(.dbd.O)R.sup.a, C.sub.1-4alkyleneN(R.sup.a).sub.2, OC.sub.1-4alkyleneC.dbd.CR.sup.a, OC.sub.1-4alkyleneC(O)N(R.sup.a).sub.2, OC.sub.1-4alkylenearyl, OC.sub.1-4alkyleneheteroaryl, OC.sub.1-4alkyleneHet, OC.sub.1-4alkyleneN(R.sup.a).sub.2, and N(R.sup.a)C.sub.1-4alkyleneN(R.sup.a).sub.2; each R.sup.a is independently selected from the group consisting of hydrogen, C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.3-8heterocycloalkyl, C.sub.1-3alkyleneN(R.sup.c).sub.2, aryl, arylC.sub.1-3alkyl, C.sub.1-3alkylenearyl, heteroaryl, heteroarylC.sub.1-3alkyl, and C.sub.1-3alkyleneheteroaryl; or two R.sup.a groups are taken together to form a 5- or 6-membered ring, optionally containing at least one heteroatom; each R.sup.b is independently selected from the group consisting of hydrogen, C.sub.1-6alkyl, heteroC.sub.1-3alkyl, C.sub.1-3alkyleneheteroC.sub.1-3alkyl, arylheteroC.sub.1-3alkyl, aryl, heteroaryl, arylC.sub.1-3alkyl, heteroarylC.sub.1-3alkyl, C.sub.1-3alkylenearyl, and C.sub.1-3alkyleneheteroaryl; each R.sup.c is independently selected from the group consisting of hydrogen, C.sub.1-6alkyl, C.sub.3-8cycloalkyl, aryl, and heteroaryl; Het is a 5- or 6-membered heterocyclic ring, saturated or partially or fully unsaturated, containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, and optionally substituted with C.sub.1-4alkyl or C(.dbd.O)OR.sup.a; or pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein X is selected from the group consisting of CH.sub.2, CH(CH.sub.3), CH(CH.sub.2CH.sub.3), and C(CH.sub.3).sub.2.

3. The compound of claim 1 wherein X is selected from the group consisting of CH.sub.2, CH(CH.sub.3), and CH(CH.sub.2CH.sub.3).

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.sup.a).sub.2, halo, C.sub.1-3alkyl, S(C.sub.1-3alkyl), and OR.sup.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 NH.sub.2, NH(CH.sub.3), N(CH.sub.3).sub.2, NHCH.sub.2C.sub.6H.sub.5, NH(C.sub.2H.sub.5), Cl, F, CH.sub.3, SCH.sub.3, and OH.

8. The compound according to claim 1 wherein the A ring system is optionally substituted with NH.sub.2.

9. The compound of claim 1 wherein R.sup.1 and R.sup.2, independently, are selected from the group consisting of hydrogen, OR.sup.a, halo, C.sub.1-6alkyl, CF.sub.3, NO.sub.2, N(R.sup.a).sub.2, NR.sup.aC.sub.1-3alkyleneN(R.sup.a).sub.2, and OC.sub.2-4alkyleneOR.sup.a.

10. The compound of claim 1 wherein R.sup.1 and R.sup.2, independently, are selected from the group consisting of H, OCH.sub.3, Cl, Br, F, CH.sub.3, CF.sub.3, NO.sub.2, OH, N(CH.sub.3).sub.2, O(CH.sub.2).sub.2OCH.sub.2C.sub.6H.sub.5, and ##STR00093##

11. The compound according to claim 1 wherein R.sup.1 and R.sup.2, independently, are selected from the group consisting of H, F, Cl, or CH.sub.3.

12. The compound of claim 1 wherein R.sup.3 is selected from the group consisting of optionally substituted C.sub.1-6alkyl, aryl, heteroaryl, C.sub.3-8cycloalkyl, and C.sub.3-8heterocycloalkyl.

13. The compound of claim 1 wherein R.sup.3 is selected from the group consisting of optionally substituted ##STR00094##

14. The compound of claim 1 wherein R.sup.3 is optionally substituted ##STR00095##

15. The compound of claim 1 wherein R.sup.3 is substituted with a substituent selected from the group consisting of halo, OR.sup.a, C.sub.1-6alkyl, aryl, heteroaryl, NO.sub.2, N(R.sup.a).sub.2, NR.sup.aSO.sub.2CF.sub.3, NR.sup.aC(.dbd.O)R.sup.a, C(.dbd.O)OR.sup.a, SO.sub.2N(R.sup.a).sub.2, CN, C(.dbd.O)R.sup.a, C.sub.1-4alkyleneN(R.sup.a).sub.2, OC.sub.1-4alkyleneC(.dbd.O)N(R.sup.a).sub.2, OC.sub.1-4alkylenearyl, OC.sub.1-4alkyleneheteroaryl, OC.sub.1-4alkyleneHet, OC.sub.1-4alkyleneN(R.sup.a).sub.2, and N(R.sup.a)C.sub.1-4alkyleneN(R.sup.a).sub.2.

16. The compound of claim 1 wherein R.sup.3 is substituted with a substituent selected from the group consisting of Cl, F, CH.sub.3, CH(CH.sub.3).sub.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-quinazoli- n-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-o- ne; 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-quinazol- in-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-methyl-3H-quina- zolin-4-one; 2-(6-aminopurin-9-ylmethyl)-8-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-o- ne; 2-(6-aminopurin-9-ylmethyl)-3-biphenyl-2-yl-5-chloro-3H-quinazolin-4-o- ne; 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-quina- zolin-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-quinazoli- n-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-qu- inazolin-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-fluor- o-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-quinaz- olin-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-qui- nazolin-4-one; 2-(6-amino-2-dimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazo- lin-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-on- e and pharmaceutically acceptable salts thereof.

19. A compound of formula (I): ##STR00096## wherein A is an optionally substituted ##STR00097## where A can be substituted with up to three substituents selected from N(R.sup.a).sub.2, halo, C.sub.1-3alkyl, S(C.sub.1-3alkyl), OR.sup.a, and ##STR00098## X is selected from CH.sub.2, CH(CH.sub.3), CH(CH.sub.2CH.sub.3), and C(CH.sub.3).sub.2; Y is selected from the group consisting of null, and NH; R.sup.1 and R.sup.2, independently, are selected from the group consisting of hydrogen, C.sub.1-6alkyl, OR.sup.a, CF.sub.3, NO.sub.2, N(R.sup.a).sub.2, halo, NR.sup.a--C.sub.1-3alkylene-N(R.sup.a).sub.2, and OC.sub.1-3alkylene-OR.sup.a; R.sup.3 is selected from the group consisting of ##STR00099## each of which is optionally substituted with up to three substituents selected from the group consisting of Cl, F, CH.sub.3, CH(CH.sub.3).sub.2, OH, OCH.sub.3, OCH.sub.2C.sub.6H.sub.5, O(CH.sub.2).sub.3N(CH.sub.3).sub.2, OCH.sub.2C.dbd.CH, OCH.sub.2C(.dbd.O)NH.sub.2, C.sub.6H.sub.5, NO.sub.2, NH.sub.2, NHC(.dbd.O)CH.sub.3, CO.sub.2H, N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2, and ##STR00100## each R.sup.a is independently selected from the group consisting of hydrogen and C.sub.1-6alkyl; or two R.sup.a groups are taken together to form a 5- or 6-membered ring, optionally containing at least one heteroatom; or a pharmaceutically acceptable salt thereof.

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 NH.sub.2, NH(CH.sub.3), N(CH.sub.3).sub.2, NH(C.sub.2H.sub.5), Cl, F, CH.sub.3, SCH.sub.3, and OH.

24. The compound according to claim 19 wherein the A ring system is substituted with NH.sub.2.

25. The compound according to claim 19 wherein the A ring system is optionally substituted with NH.sub.2.

26. The compound according to claim 19 wherein R.sup.1 and R.sup.2, independently, are selected from the group consisting of H, F, Cl, and CH.sub.3.

27. The compound according to claim 25 wherein R.sup.1 and R.sup.2, independently, are selected from the group consisting of H, F, Cl, and CH.sub.3.

28. The compound of claim 19 wherein R.sup.3 is optionally substituted ##STR00101##

29. The compound of claim 27 wherein R.sup.3 is optionally substituted ##STR00102##

30. The compound of claim 19 wherein R.sup.3 is substituted with a substituent selected from the group consisting of Cl, F, CH.sub.3, CH(CH.sub.3).sub.2, OH, OCH.sub.3, OCH.sub.2C.sub.6H.sub.5, O(CH.sub.2).sub.3N(CH.sub.3).sub.2, OCH.sub.2C.dbd.CH, OCH.sub.2C(.dbd.O)NH.sub.2, C.sub.6H.sub.5, NO.sub.2, NH.sub.2, NHC(.dbd.O)CH.sub.3, CO.sub.2H, N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2, and ##STR00103##

31. The compound of claim 29 wherein R.sup.3 is substituted with a substituent selected from the group consisting of Cl, F, CH.sub.3, CH(CH.sub.3).sub.2, OH, OCH.sub.3, OCH.sub.2C.sub.6H.sub.5, O(CH.sub.2).sub.3N(CH.sub.3).sub.2, OCH.sub.2C.dbd.CH, OCH.sub.2C(.dbd.O)NH.sub.2, C.sub.6H.sub.5, NO.sub.2, NH.sub.2, NHC(.dbd.O)CH.sub.3, CO.sub.2H, N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2, and ##STR00104##

32. The compound of claim 19, wherein A is optionally substituted with 1-2substituents selected from NH.sub.2, NH(CH.sub.3), N(CH.sub.3).sub.2, NH(C.sub.2H.sub.5), Cl, F, CH.sub.3, SCH.sub.3, and OH.

33. A compound selected from the group consisting of: 2-(6-aminopurin-9-ylmethyl)-5-methyl-3-{2-(2-(1-methylpyrrolidin-2-yl)-et- hoxy)-phenyl}-3H-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-5-methyl-3-(2-prop-2-ynyloxyphenyl)-3H-quinaz- olin-4-one; and 2-{2-(1-(6-aminopurin-9-ylmethyl)-5-methyl-4-oxo-4H-quinazolin-3-yl]-phen- oxy}-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-quinazo- lin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-(3-dimethylamino-propoxy)-phen- yl)-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-quin- azolin-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-quinazo- lin-4-one; and pharmaceutically acceptable salts thereof.

35. A pharmaceutical composition comprising: a): an effective amount of a compound of formula (I): ##STR00105## wherein A is an optionally substituted purinyl ring system; X is C(R.sup.b).sub.2; Y is selected from the group consisting of null and NH; R.sup.1 and R.sup.2, independently, are selected from the group consisting of hydrogen, N(R.sup.a).sub.2, halo, C.sub.1-3alkyl, S(C.sub.1-3alkyl), and OR.sup.a; R.sup.3 is selected from the group consisting of optionally substituted aryl and heteroaryl; each R.sup.a is independently selected from the group consisting of hydrogen and C.sub.1-6alkyl; or two R.sup.a groups are taken together to form a 5- or 6-membered ring, optionally containing at least one heteroatom; and each R.sup.b is independently selected from the group consisting of hydrogen and C.sub.1-6alkyl; and pharmaceutically acceptable salts thereof; and b): a pharmaceutically acceptable excipient.

36. A pharmaceutical composition comprising: a) an effective amount of a compound of formula (I): ##STR00106## wherein A is an optionally substituted ##STR00107## where A can be substituted with up to three substituents selected from N(R.sup.a).sub.2, halo, C.sub.1-3alkyl, S(C.sub.1-3alkyl), OR.sup.a, and ##STR00108## X is selected from CH.sub.2, CH(CH.sub.3), CH(CH.sub.2CH.sub.3), and C(CH.sub.3).sub.2; Y is selected from the group consisting of null, and NH; R.sup.1 and R.sup.2, independently, are selected from the group consisting of hydrogen, methyl, OR.sup.a, CF.sub.3, NO.sub.2, N(R.sup.a).sub.2, halo, NR.sup.a--C.sub.1-3alkylene-N(R.sup.a).sub.2, and OC.sub.1-3alkylene-OR.sup.a; R.sup.3 is selected from the group consisting of ##STR00109## each of which is optionally substituted with up to three substituents selected from the group consisting of Cl, F, CH.sub.3, CH(CH.sub.3).sub.2, OH, OCH.sub.3, OCH.sub.2C.sub.6H.sub.5, O(CH.sub.2).sub.3N(CH.sub.3).sub.2, OCH.sub.2C.dbd.CH, OCH.sub.2C(.dbd.O)NH.sub.2, C.sub.6H.sub.5, NO.sub.2, NH.sub.2, NHC(.dbd.O)CH.sub.3, CO.sub.2H, N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2, and ##STR00110## each R.sup.a is independently selected from the group consisting of hydrogen and C.sub.1-6alkyl; or two R.sup.a groups are taken together to form a 5- or 6-membered ring, optionally containing at least one heteroatom; or a pharmaceutically acceptable salt thereof.

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.

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-quinazoli- n-4-one; 2-(6-aminopurin-9-ylmethyl)-6-bromo-3-(2-chlorophenyl)-3H-quinazo- lin-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-o- ne; 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-quinazol- in-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-methyl-3H-quina- zolin-4-one; 2-(6-aminopurin-9-ylmethyl)-8-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-o- ne; 2-(6-aminopurin-9-ylmethyl)-3-biphenyl-2-yl-5-chloro-3H-quinazolin-4-o- ne; 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-quina- zolin-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-quinazoli- n-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-qu- inazolin-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-on- e; 5-methyl-2-(2-methyl-6-oxo-1,6-dihydro-purin-7-ylmethyl)-3-o-tolyl-3H-q- uinazolin-4-one; 5-methyl-2-(2-methyl-6-oxo-1,6-dihydro-purin-9-ylmethyl)-3-o-tolyl-3H-qui- nazolin-4-one; 2-(6-amino-2-dimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazo- lin-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-on- e; and pharmaceutically acceptable salts thereof.

41. The compound according to claim 14, wherein R.sup.3 is unsubstituted ##STR00111##

42. The compound according to claim 14, wherein R.sup.3 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.

47. The compound according to claim 29, wherein R.sup.3 is unsubstituted ##STR00112##

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 R.sup.3 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.

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-quinazoli- n-4-one; 2-(6-aminopurin-9-ylmethyl)-6-bromo-3-(2-chlorophenyl)-3H-quinazo- lin-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-o- ne; 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-quinazol- in-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-methyl-3H-quina- zolin-4-one; 2-(6-aminopurin-9-ylmethyl)-8-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-o- ne; 2-(6-aminopurin-9-ylmethyl)-3-biphenyl-2-yl-5-chloro-3H-quinazolin-4-o- ne; 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-quina- zolin-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-quinazoli- n-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-qu- inazolin-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-qui- nazolin-4-one; 5-methyl-2-(2-methyl-6-oxo-1,6-dihydro-purin-9-ylmethyl)-3-o-tolyl-3H-qui- nazolin-4-one; 2-(6-amino-2-dimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazo- lin-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-on- e; and pharmaceutically acceptable salts thereof.

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

56. The composition according to claim 55, wherein R.sup.3 is unsubstituted aryl.

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.

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-quinazoli- n-4-one; 2-(6-aminopurin-9-ylmethyl)-6-bromo-3-(2-chlorophenyl)-3H-quinazo- lin-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-o- ne; 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-quinazol- in-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-methyl-3H-quina- zolin-4-one; 2-(6-aminopurin-9-ylmethyl)-8-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-o- ne; 2-(6-aminopurin-9-ylmethyl)-3-biphenyl-2-yl-5-chloro-3H-quinazolin-4-o- ne; 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-quina- zolin-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-quinazoli- n-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-qu- inazolin-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-on- e; 5-methyl-2-(2-methyl-6-oxo-1,6-dihydro-purin-7-ylmethyl)-3-o-tolyl-3H-q- uinazolin-4-one; 5-methyl-2-(2-methyl-6-oxo-1,6-dihydro-purin-9-ylmethyl)-3-o-tolyl-3H-qui- nazolin-4-one; 2-(6-amino-2-dimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazo- lin-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-on- e; and pharmaceutically acceptable salts thereof.
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