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Details for Patent: 8,653,077

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Details for Patent: 8,653,077

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; Kennith O. (Bothell, WA), Treiberg; Jennifer (Redmond, WA), Sowell; C. Gregory (Mukilteo, WA), Kesicki; Edward A. (Bothell, WA), Oliver; Amy (Bothell, WA)
Assignee: ICOS Corporation (Indianapolis, IN)
Filing Date:Sep 28, 2011
Application Number:13/247,962
Claims:1. A compound of formula (I): ##STR00093## wherein A is a triazolyl ring optionally substituted with up 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), OR.sup.a, and ##STR00094## X is selected from the group consisting of C(R.sup.b).sub.2, CH.sub.2CHR.sup.b, and CH.dbd.C(R.sup.b); Y is selected from the group consisting of a single bond, S, SO, SO.sub.2, NH, O, C(.dbd.O), OC(.dbd.O), C(.dbd.O)O, and NHC(.dbd.O)CH.sub.2S; R.sup.1 and R.sup.2, independently, are selected from the group consisting of hydrogen and C.sub.1-6alkyl, aryl, heteroaryl, halo, NHC(.dbd.O)C.sub.1-3alkyleneN(R.sup.a).sub.2, NO.sub.2, OR.sup.a, CF.sub.3, OCF.sub.3, N(R.sup.a).sub.2, CN, OC(.dbd.O)R.sup.a, C(.dbd.O)R.sup.a, C(.dbd.O)OR.sup.a, arylOR.sup.b, Het, NR.sup.aC(.dbd.O)C.sub.1-3alkyleneC(.dbd.O)OR.sup.a, arylOC.sub.1-3alkyleneN(R.sup.a).sub.2, arylOC(.dbd.O)R.sup.a, C.sub.1-4alkyleneC(.dbd.O)OR.sup.a, OC.sub.1-4alkyleneC(.dbd.O)OR.sup.a, C.sub.1-4alkyleneOC.sub.1-4alkyleneC(.dbd.O)OR.sup.a, C(.dbd.O)NR.sup.aSO.sub.2R.sup.a, C.sub.1-4alkyleneN(R.sup.a).sub.2, C.sub.2-6alkenyleneN(R.sup.a).sub.2, C(.dbd.O)NR.sup.aC.sub.1-4alkyleneOR.sup.a, C(.dbd.O)NR.sup.aC.sub.1-4alkyleneHet, OC.sub.2-4alkyleneN(R.sup.a).sub.2, OC.sub.1-4alkyleneCH(OR.sup.b)CH.sub.2N(R.sup.a).sub.2, OC.sub.1-4alkyleneHet, OC.sub.2-4alkyleneOR.sup.a, OC.sub.2-4alkyleneNR.sup.aC(.dbd.O)OR.sup.a, NR.sup.aC.sub.1-4alkyleneN(R.sup.a).sub.2, NR.sup.aC(.dbd.O)R.sup.a, NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, N(SO.sub.2C.sub.1-4alkyl).sub.2, NR.sup.a(SO.sub.2C.sub.1-4 alkyl), SO.sub.2N(R.sup.a).sub.2, OSO.sub.2CF.sub.3, C.sub.1-3alkylenearyl, C.sub.1-4alkyleneHet, C.sub.1-6alkyleneOR.sup.b, C.sub.1-3alkyleneN(R.sup.a).sub.2, C(.dbd.O)N(R.sup.a).sub.2, NHC(.dbd.O)C.sub.1-C.sub.3alkylenearyl, C.sub.3-8cycloalkyl, C.sub.3-8heterocycloalkyl, arylOC.sub.1-3alkyleneN(R.sup.a).sub.2, arylOC(.dbd.O)R.sup.b, NHC(.dbd.O)C.sub.1-3alkyleneC.sub.3-8heterocycloalkyl, NHC(.dbd.O)C.sub.1-3alkyleneHet, OC.sub.1-4alkyleneOC.sub.1-4alkyleneC(.dbd.O)OR.sup.b, C(.dbd.O)C.sub.1-4alkyleneHet, and NHC(.dbd.O)haloC.sub.1-6alkyl, each of which is optionally substituted with a substituent selected from the group consisting of OCH.sub.3, Cl, Br, F, CH.sub.3, CF.sub.3, NO.sub.2, OH, N(CH.sub.3).sub.2, ##STR00095## and O(CH.sub.2).sub.2OCH.sub.2C.sub.6H.sub.5; or R.sup.1 and R.sup.2 are taken together to form a 3- or 4-membered alkylene or alkenylene chain component of a 5- or 6-membered fused ring, optionally containing at least one heteroatom; R.sup.3 is selected from the group consisting of hydrogen, C.sub.1-4alkylenearyl substituted with one or more substituents selected from the group consisting 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, CN, NO.sub.2, 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, and 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(.dbd.O)OR.sup.a, C(.dbd.O)N(R.sup.a).sub.2, C(.dbd.S)N(R.sup.a).sub.2, SO.sub.2R.sup.a, SO.sub.2N(R.sup.a).sub.2, S(.dbd.O)R.sup.a, S(.dbd.O)N(R.sup.a).sub.2, C(.dbd.O)NR.sup.aC.sub.1-4alkyleneOR.sup.a, C(.dbd.O)NR.sup.aC.sub.1-4alkyleneHet, C(.dbd.O)C.sub.1-4alkylenearyl, C(.dbd.O)C.sub.1-4alkyleneheteroaryl, C.sub.1-4alkyeneheteroaryl, C.sub.1-4alkyleneHet, C.sub.1-4alkyleneC(.dbd.O)C.sub.1-4alkylene-aryl, C.sub.1-4alkyleneHet, C.sub.1-4alkyleneC(.dbd.O)C.sub.1-4alkylene-aryl, C.sub.1-4alkyleneC(.dbd.O)C.sub.1-4alkyleneheteroaryl, C.sub.1-4alkyleneC(.dbd.O)Het, C.sub.1-4alkyleneC(.dbd.O)N(R.sup.a).sub.2, C.sub.1-4alkyleneOR.sup.a, C.sub.1-4alkyleneNR.sup.aC(.dbd.O)R.sup.a, C.sub.1-4alkyleneOC.sub.1-4alkyleneOR.sup.a, C.sub.1-4alkyleneN(R.sup.a).sub.2, C.sub.1-4alkyleneC(.dbd.O)OR.sup.a, and C.sub.1-4alkyleneOC.sub.1-4alkyleneC(.dbd.O)OR.sup.a, each of which is optionally 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.ident.CR.sup.a, 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; 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 saturated or unsaturated heterocyclic ring, containing at least one heteroatom, and optionally substituted with C.sub.1-4alkyl or C(.dbd.O)OR.sup.a; wherein each heteroatom is independently selected from the group consisting of oxygen, nitrogen, and sulfur, or pharmaceutically acceptable salts or solvates thereof.

2. The compound of claim 1 wherein X is selected from the group consisting of CH.sub.2, CH.sub.2CH.sub.2, CH.dbd.CH, CH(CH.sub.3), CH(CH.sub.2CH.sub.3), CH.sub.2CH(CH.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 selected from the group consisting of a single bond, O, S, and NH.

5. The compound of claim 1 wherein Y is a single bond, O or NH.

6. The compound of claim 3 wherein Y is a single bond, O or NH.

7. The compound of claim 1 wherein A is 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.

8. The compound of claim 1 wherein A 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.

9. The compound according to claim 1 wherein A is optionally substituted with NH.sub.2.

10. 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, and NR.sup.aC.sub.1-3alkyleneN(R.sup.a).sub.2, or R.sup.1 and R.sup.2 are taken together to form a fused five- or six-membered ring.

11. 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 ##STR00096##

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

13. The compound of claim 1 wherein R.sup.3 is selected from the group consisting of C.sub.1-6alkyl, aryl, heteroaryl, C.sub.3-8cycloalkyl, C.sub.3-8heterocycloalkyl, C(.dbd.O)OR.sup.a, C.sub.1-4alkyleneHet, C.sub.1-4alkylenecycloalkyl, C.sub.1-4alkyleneC(.dbd.O)C .sub.1-4alkylenearyl, C.sub.1-4alkyleneC(.dbd.O)OR.sup.a, C.sub.1-4alkyleneC(.dbd.O)N(R.sup.a).sub.2, C.sub.1-4alkyleneC(.dbd.O)Het, C.sub.1-4alkyleneN(R.sup.a).sub.2, and C.sub.1-4alkyleneNR.sup.aC(.dbd.O)R.sup.a, each of which is optionally substituted.

14. The compound of claim 1 wherein R.sup.3 is selected from the group consisting of ##STR00097## each of which optionally substituted.

15. The compound of claim 1 wherein R.sup.3 is optionally substituted ##STR00098##

16. 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.ident.CR.sup.a, 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.

17. 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, 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.ident.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 ##STR00099##

18. A compound of formula (I): ##STR00100## wherein A is a triazolyl ring optionally 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 ##STR00101## X is selected from CH.sub.2, CH.sub.2CH.sub.2, CH.dbd.CH, CH(CH.sub.3), CH(CH.sub.2CH.sub.3), CH.sub.2CH(CH.sub.3), and C(CH.sub.3).sub.2; Y is selected from the group consisting of a single bond, O, S and NH; R.sup.1 and R.sup.2, independently, are selected from the group consisting of hydrogen, 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; and R.sup.3 is selected from the group consisting of ##STR00102## 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.ident.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## 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 selected from the group consisting of oxygen, nitrogen, and sulfur; or a pharmaceutically acceptable salt thereof.

19. The compound of claim 18 wherein X is selected from the group consisting of CH.sub.2, CH(CH.sub.3), and CH(CH.sub.2CH.sub.3).

20. The compound of claim 19 wherein Y is a single bond.

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

22. The compound of claim 19 wherein Y is O.

23. The compound according to claim 18 wherein A is substituted with one or two substituents.

24. The compound of claim 18 wherein A 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.

25. The compound according to claim 18 wherein A is substituted with NH.sub.2.

26. The compound according to claim 18 wherein R.sup.1 and R.sup.2, independently, are selected from the group consisting of H, Cl, and CH.sub.3.

27. The compound of claim 18 wherein R.sup.3 is optionally substituted ##STR00104##

28. The compound of claim 18 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.ident.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 ##STR00105##

29. The compound of claim 28, wherein A is optionally substituted with 1-2substituents selected from 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.

30. A pharmaceutical composition comprising: a) an effective amount of a compound of formula (I): ##STR00106## wherein A is a triazolyl ring optionally 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 ##STR00107## X is selected from CH.sub.2, CH.sub.2CH.sub.2, CH.dbd.CH, CH(CH.sub.3), CH(CH.sub.2CH.sub.3), CH.sub.2CH(CH.sub.3), and C(CH.sub.3).sub.2; Y is selected from the group consisting of a single bond, O, S and NH; R.sup.1 and R.sup.2, independently, are selected from the group consisting of hydrogen, 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 ##STR00108## 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.ident.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 ##STR00109## 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 selected from the group consisting of oxygen, nitrogen, and sulfur; and or a pharmaceutically acceptable salt thereof.
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