Claims for Patent: 8,637,533

Summary for Patent: 8,637,533

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; Ken (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)
Application Number:	13/399,828
Patent Claims:	1. A compound having a general structural formula ##STR00093## wherein A is optionally substituted purinyl; X is C(R.sup.b).sub.2; Y is selected from the group consisting of null, 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, 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.1-4alkyl), 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(.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; 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 ring, optionally containing at least one heteroatom; R.sup.3 is hydrogen, or R.sup.3 is selected from the group consisting of 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.1-4alkyleneheteroaryl, 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, or R.sup.3 is 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, 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; 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 selected from the group consisting of 1,3-dioxolane, 2-pyrazoline, pyrazolidine, pyrrolidine, piperazine, pyrroline, 2H-pyran, 4H-pyran, morpholine, thiomorpholine, piperidine, 1,4-dithiane, and 1,4-dioxane, and optionally substituted with C.sub.1-4alkyl or C(.dbd.O)OR.sup.a; and 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, or a pharmaceutically acceptable salt thereof. 3. The compound of claim 2 wherein Y is selected from the group consisting of null and NH, or a pharmaceutically acceptable salt thereof. 4. The compound of claim 2 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.1-4alkyleneN(R.sup.a).sub.2, and OC.sub.2-4alkyleneOR.sup.a, or a pharmaceutically acceptable salt thereof. 5. The compound of claim 4, 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, ##STR00094## 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 five- or six-membered ring, or a pharmaceutically acceptable salt thereof. 6. The compound of claim 2 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.1-4alkylenearyl, 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, or a pharmaceutically acceptable salt thereof. 7. The compound of claim 2 wherein R.sup.3 is selected from the group consisting of C.sub.1-6alkyl, aryl, heteroaryl, C(.dbd.O)OC.sub.2H.sub.5, CH.sub.2CH(CH.sub.3).sub.2, ##STR00095## each of which is optionally substituted, or a pharmaceutically acceptable salt thereof. 8. 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, or a pharmaceutically acceptable salt thereof. 9. 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, and N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2, and ##STR00096## or a pharmaceutically acceptable salt thereof. 10. A compound having a general structural formula ##STR00097## wherein A is optionally substituted purinyl; X is CHR.sup.b; Y is selected from the group consisting of null, 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, 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, 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.1-4-alkyleneC(.dbd.O)OR.sup.a, OC.sub.1-4alkyleneC(.dbd.O)OR.sup.a, C.sub.1-4-alkyleneOC.sub.1-4-alkylene-C(.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.1-4-alkyleneHet, OC.sub.2-4alkyleneN(R.sup.a).sub.2, OC.sub.1-4-alkyleneCH(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.1-4-alkyleneN(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.1-4-alkyleneHet, 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(.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; 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 ring, optionally containing at least one heteroatom; R.sup.3 is hydrogen, or R.sup.3 is selected from the group consisting of 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.1-4-alkyleneheteroaryl, C.sub.1-4alkyleneheteroaryl, C.sub.1-4alkyleneHet, C.sub.1-4alkyleneC(.dbd.O)C.sub.1-4alkylenearyl, C.sub.1-4alkyleneC(.dbd.O)C.sub.1-4alkyleneheteroaryl, C.sub.1-4alkylene-C(.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.1-4alkyl-eneOC.sub.1-4alkyleneC(.dbd.O)OR.sup.a, each of which is optionally substituted, or R.sup.3 is C.sub.1-4alkylenearyl substituted with one or more of halo, 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; 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.a).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; R.sup.b is selected from the group consisting of hydrogen, C.sub.1-6alkyl, aryl, heteroaryl, arylC.sub.1-3alkyl, heteroarylC.sub.1-3alkyl, C.sub.1-3alkylenearyl, and C.sub.1-3alkyleneheteroaryl; Het is a 5- or 6-membered saturated or unsaturated heterocyclic ring, 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; and pharmaceutically acceptable salts thereof. 11. The compound of claim 10 wherein X is selected from the group consisting of CH.sub.2, CH(CH.sub.3), and C(CH.sub.3).sub.2, or a pharmaceutically acceptable salt thereof. 12. The compound of claim 10 wherein Y is null or NH, or a pharmaceutically acceptable salt thereof. 13. The compound of claim 10 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, NO.sub.2, N(R.sup.a).sub.2, NR.sup.aC.sub.1-4alkyleneN(R.sup.a).sub.2, and OC.sub.2-4alkyleneOR.sup.a, or a pharmaceutically acceptable salt thereof. 14. The compound of claim 13 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, NO.sub.2, OH, N(CH.sub.3).sub.2, ##STR00098## and O(CH.sub.2).sub.2OCH.sub.2C.sub.6H.sub.5, or a pharmaceutically acceptable salt thereof. 15. The compound of claim 10 wherein R.sup.3 is selected from the group consisting of C.sub.1-6alkyl, aryl, heteroaryl, C.sub.3-8cycloalkyl, C.sub.3-8heterocyclo alkyl, C(.dbd.O)OR.sup.a, C.sub.1-4alkyleneHet, C.sub.1-4alkylenecycloalkyl, C.sub.1-4alkylenearyl, 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, or a pharmaceutically acceptable salt thereof. 16. The compound of claim 10 wherein R.sup.3 is selected from the group consisting of C.sub.1-6alkyl, aryl, heteroaryl, NO.sub.2, N(R.sup.a).sub.2, C(.dbd.O)OC.sub.2H.sub.5, CH.sub.2CH(CH.sub.3).sub.2, ##STR00099## each of which is optionally substituted, or a pharmaceutically acceptable salt thereof. 17. The compound of claim 10 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.1-4alkyleneN(R.sup.a).sub.2, and N(R.sup.a)C.sub.1-4alkyleneN(R.sup.a).sub.2, or a pharmaceutically acceptable salt thereof. 18. The compound of claim 10 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, OCH.sub.3, C.sub.6H.sub.5, NO.sub.2, NH.sub.2, NHC(.dbd.O)CH.sub.3, CO.sub.2H, and N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2, or a pharmaceutically acceptable salt thereof.