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Claims for Patent: 6,949,535

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Claims for Patent: 6,949,535

Title: Inhibitors of human phosphatidyl-inositol 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 (Bothell, WA), Sowell; C. Gregory (Mukilteo, WA), Kesicki; Edward A. (Bothell, WA), Oliver; Amy (Bothell, WA)
Assignee: ICOS Corporation (Bothell, WA)
Application Number:10/697,912
Patent Claims: 1. A method of disrupting leukocyte function comprising a step of contacting leukocytes with a compound having a structure ##STR90## wherein A is an optionally substituted monocyclic 5-membered heterocyclic ring system containing two or three nitrogen atoms or a bicyclic ring system containing at least two nitrogen atoms, and at least one ring of the bicyclic system is aromatic; X is selected from the group consisting of C(R.sup.b).sub.2, CH.sub.2 CHR.sup.b, and CH.dbd.C(R.sup.b); Y is selected from the group consisting of null, S, SO, and SO.sub.2, NH, O, C(.dbd.O), OC(.dbd.O), C(.dbd.O)O, and NHC(.dbd.O)CH.sub.2 S; R.sup.1 and R.sup.2, independently, are selected from the group consisting of hydrogen, C.sub.1-6 alkyl, aryl, heteroaryl, halo, NHC(.dbd.O)C.sub.1-3 alkyleneN(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.a C(.dbd.O)C.sub.1-3 alkyleneC(.dbd.O)OR.sup.a, arylOC.sub.1-3 alkyleneN(R.sup.a).sub.2, arylOC(.dbd.O)R.sup.a, C.sub.1-4 alkyleneC(.dbd.O)OR.sup.a, OC.sub.1-4 alkyleneC(.dbd.O)OR.sup.a, C.sub.1-4 alkyleneOC.sub.1-4 alkyleneC(.dbd.O)--OR.sup.a, C(.dbd.O)NR.sup.a SO.sub.2 R.sup.a, C.sub.1-4 alkyleneN(R.sup.a).sub.2, C.sub.2-6 alkenylene-N(R.sup.a).sub.2, C(.dbd.O)NR.sup.a C.sub.1-4 alkyleneOR.sup.a, C(.dbd.O)NR.sup.a C.sub.1-4 alkyleneHet, OC.sub.2-4 alkyleneN(R.sup.a).sub.2, OC.sub.1-4 alkyleneCH(OR.sup.b)CH.sub.2 N(R.sup.a).sub.2, OC.sub.1-4 alkyleneHet, OC.sub.2-4 alkyleneOR.sup.a, OC.sub.2-4 alkyleneNR.sup.a C(.dbd.O)--OR.sup.a, NR.sup.a C.sub.1-4 alkyleneN(R.sup.a).sub.2, NR.sup.a C(.dbd.O)R.sup.a, NR.sup.a C(.dbd.O)N(R.sup.a).sub.2, N(SO.sup.2 C.sub.1-4 alkyl).sub.2, NR.sup.a (SO.sub.2 C.sub.1-4 alkyl), SO.sub.2 N(R.sup.a).sub.2, OSO.sub.2 CF.sub.3, C.sub.1-3 alkylenearyl, C.sub.1-4 alkyleneHet, C.sub.1-6 alkyleneOR.sup.b, C.sub.1-3 alkyleneN(R.sup.a).sub.2, C(.dbd.O)N(R.sup.a).sub.2, NHC(.dbd.O)C.sub.1 -C.sub.3 alkylenearyl, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocycloalkyl, arylOC.sub.1-3 alkylene-N(R.sup.a).sub.2, arylOC(.dbd.O)R.sup.b, NHC(.dbd.O)C.sub.1-3 alkyleneC.sub.3-8 heterocyclo-alkyl, NHC(.dbd.O)C.sub.1-3 alkyleneHet, OC.sub.1-4 alkyleneOC.sub.1-4 alkylene-C(.dbd.O)OR.sup.b, C(.dbd.O)C.sub.1-4 alkyleneHet, and NHC(.dbd.O)haloC.sub.1-6 alkyl; 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 selected from the group consisting of optionally substituted hydrogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocycloalkyl, C.sub.1-4 alkylenecycloalkyl, C.sub.2-6 alkenyl, C.sub.1-3 alkylenearyl, arylC.sub.1-3 alkyl, 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.2 R.sup.a, SO.sub.2 N(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.a C.sub.1-4 alkyleneOR.sup.a, C(.dbd.O)NR.sup.a C.sub.1-4 alkyleneHet, C(.dbd.O)C.sub.1-4 alkylenearyl, C(.dbd.O)C.sub.1-4 alkyleneheteroaryl, C.sub.1-4 alkylenearyl substituted with one or more of SO.sub.2 N(R.sup.a).sub.2, N(R.sup.a).sub.2, C(.dbd.O)OR.sup.a, NR.sup.a SO.sub.2 CF.sub.3, CN, NO.sub.2, C(.dbd.O)R.sup.a, OR.sup.a, C.sub.1-4 alkyleneN(R.sup.a).sub.2, and OC.sub.1-4 alkyleneN(R.sup.a).sub.2, C.sub.1-4 alkyleneheteroaryl, C.sub.1-4 alkyleneHet, C.sub.1-4 alkyleneC(.dbd.O) C.sub.1-4 alkylenearyl, C.sub.1-4 alkyleneC(.dbd.O)--C.sub.1-4 alkyleneheteroaryl, C.sub.1-4 alkyleneC(.dbd.O)Het, C.sub.1-4 alkyleneC(.dbd.O)N(R.sup.a).sub.2, C.sub.1-4 alkyleneOR.sup.a, C.sub.1-4 alkyleneNR.sup.a C(.dbd.O)R.sup.a, C.sub.1-4 alkyleneOC.sub.1-4 alkyleneOR.sup.a, C.sub.1-4 alkyleneN(R.sup.a).sub.2, C.sub.1-4 alkyleneC(.dbd.O)OR.sup.a, and C.sub.1-4 alkyleneOC.sub.1-4 alkyleneC(.dbd.O)OR.sup.a ; R.sup.a is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocycloalkyl, C.sub.1-3 alkyleneN(R.sup.c).sub.2, aryl, arylC.sub.1-3 alkyl, C.sub.1-3 alkylenearyl, heteroaryl, heteroarylC.sub.1-3 alkyl, and C.sub.1-3 alkyleneheteroaryl; 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.1-6 alkyl, heteroC.sub.1-3 alkyl, C.sub.1-3 alkyleneheteroC.sub.1-3 alkyl, arylheteroC.sub.1-3 alkyl, and aryl, heteroaryl, arylC.sub.1-3 alkyl, heteroarylC.sub.1-3 alkyl, C.sub.1-3 alkylenearyl, and C.sub.1-3 alkyleneheteroaryl; R.sup.c is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, 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, 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.1-4 alkyl or C(.dbd.O)OR.sup.a ; and pharmaceutically acceptable salts or solvates, in an amount sufficient to inhibit phosphatidylinositol 3-kinase delta activity in said leukocytes.

2. The method according to claim 1 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-o-ylmethyl)-6-bromo-3-(2-chlorophenyl)-3H-quinazolin-4-one 2-(6-aminopurin-o-ylmethyl)-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-o-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 5-chloro-2-(9H-purin-6-ylsulfanylmethyl)-3-o-tolyl-3H-quinazolin-4-one 5-chloro-3-(2-fluorophenyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4 -one 2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-fluorophenyl)-3H-quinazolin-4-one 3-biphenyl-2-yl-5-chloro-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-on e 5-chloro-3-(2-methoxyphenyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin- 4-one 3-(2-chlorophenyl)-5-fluoro-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4 -one 3-(2-chlorophenyl)-6,7-dimethoxy-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazo lin-4-one 6-bromo-3-(2-chlorophenyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4- one 3-(2-chlorophenyl)-8-trifluoromethyl-2-(9H-purin-6-ylsulfanylmethyl)-3H-qui nazolin-4-one 3-(2-chlorophenyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-benzo[g]quinazolin-4- one 6-chloro-3-(2-chlorophenyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4 -one 8-chloro-3-(2-chlorophenyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4 -one 3-(2-chlorophenyl)-7-fluoro-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4 -one 3-(2-chlorophenyl)-7-nitro-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4- one 3-(2-chlorophenyl)-6-hydroxy-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin- 4-one 5-chloro-3-(2-chlorophenyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4 -one 3-(2-chlorophenyl)-5-methyl-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4 -one 3-(2-chlorophenyl)-6,7-difluoro-2-(9H-purin-6-ylsullfanylmethyl)-3H-quinazo lin-4-one 3-(2-chlorophenyl)-6-fluoro-2-(9H-purin-6-ylsulfanylmethyl)-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 3-(2-fluorophenyl)-5-methyl-2-(9H-purin-6-ylsulfanylmethyl)-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-on e 2-(2-amino-9H-purin-6-ylsulfanylmethyl)-3-cyclopropyl-5-methyl-3H-quinazoli n-4-one 3-cyclopropylmethyl-5-methyl-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin- 4-one 2-(6-aminopurin-9-ylmethyl)-3-cyclopropylmethyl-5-methyl-3H-quinazolin-4-on e 2-(2-amino-9H-purin-6-ylsulfanylrnethyl)-3-cyclopropylmethyl-5-methyl-3H-qu inazolin-4-one 5-methyl-3-phenethyI-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one 2-(2-amino-9H-purin-6-ylsulfanylmethyl)-5-methyl-3-phenethyl-3H-quinazolin- 4-one 3-cyclopentyl-5-methyl-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one 2-(6-aminopurin-9-ylmethyl)-3-cyclopentyl-5-methyl-3H-quinazolin-4-one 3-(2-chloropyridin-3-yl)-5-methyl-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinaz olin-4-one 2-(6-aminopurin-9-ylmethyl)-3-(2-chloropyridin-3-yl)-5-methyl-3H-quinazolin -4-one 3-methyl-4-[5-methyl-4-oxo-2-(9H-purin-6-ylsulfanylmethyl)-4H-quinazolin-3- yl]-benzoic acid 3-cyclopropyl-5-methyl-2-(9H-purin-6-ylsulfanylinethyl)-3H-quinazolin-4-one 2-(6-aminopurin-9-ylmethyl)-3-cyclopropyl-5-methyl-3H-quinazolin-4-one 5-methyl-3-(4-nitrobenzyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4- one 3-cyclohexyl-5-methyl-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one 2-(6-aminopurin-9-ylmethyl)-3-cyclohexyl-5-methyl-3H-quinazolin-4-one 2-(2-amino-9H-purin-6-ylsulfanylmethyl)-3-cyclchexyl-5-methyl-3H-quinazolin -4-one 5-methyl-3-(E-2-phenylcyclopropyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quina zolin-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-chlorophenyl)-5-fluoro-3H-quina zolin-4-one 5-methyl-2-[(9H-purin-6-ylamino)methyl]-3-o-tolyl-3H-quinazolin-4-one 2-[(2-amino-9H-purin-6-ylaminomethyl]-5-methyl-3-o-tolyl-3H-quinazolin-4-on e 2-[(2-fluoro-9H-purin-6-ylamino)methyl]-5-methyl-3-o-tolyl-3H-quinazolin-4- one (2-chlorophenyl)-dimethylamino-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin- 4-one 5-(2-benzyloxyethoxy)-3-(2-chlorophenyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H -quinazolin-4-one 6-aminopurine-9-carboxylic acid 3-(2-chlorophenyl)-5-fluoro-4-oxo-3,4-dihydro-quinazolin-2-ylmethyl ester N-[3-(2-chlorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-2-(9 H-purin-6-ylsulfanyl)-acetamide 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-quina zolin-4-one 5-methyl-2-(2-methyl-6-oxo-1,6-dihydro-purin-9-ylmethyl)-3-o-tolyl-3H-quina zolin-4-One 2-(amino-dimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4- one 2-(2-amino-9H-purin-6-ylsulfanylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4- one 2-(4-amino-1,3,5-triazin-2-ylsulfanylmethyl)-5-methyl-3-o-tolyl-3H-quinazol in-4-one 5-methyl-2-(7-methyl-7H-purin-6-ylsulfanylmethyl)-3-o-tolyl-3H-quinazolin-4 -one 5-methyl-2-(2-oxo-1,2-dihydro-pyrimidin-4-ylsulfanylmethyl)-3-o-tolyl-3H-qu inazolin-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 5-methyl-2-(9-methyl-9H-purin-6-ylsulfanylmethyl)-3-o-tolyl-3H-quinazolin-4 -one 2-(2,6-Diamino-pyrimidin-4-ylsulfanylniethyl)-5-methyl-3-o-tolyl-3H-quinazo lin-4-one 5-methyl-2-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidifl-7-ylsulfanylmethyl)-3 -o-tolyl-3H-quinazolin-4-one 5-methyl-2-(2-methylsulfanyl-9H-purin-6-ylsulfanylmethyl)-3-o-tolyl-3H-quin azolin-4-one 2-(2-hydroxy-9H-purin-6-ylsulfanylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin- 4-one 5-methyl-2-(1-methyl-1H-imidazol-2-ylsulfanylmethyl)-3-o-tolyl-3H-quinazoli n-4-one 5-methyl-3-o-tolyl-2-(1H-[1,2,4]triazol-3-ylsulfanylmethyl)-3H-quinazolin-4 -one 2-(2-amino- 6-chloro-purin-9-yimethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one 2-(6-aminopurin-7-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one 2-(7-amino-1,2,3-triazolo[4,5-d]pyrimidin-3-ylmethyl)-5-methyl-3-o-tolyl-3H -quinazolin-4-one 2-(7-amino-1,2,3-triazolo[4,5-d]pyrimidin-1-ylmethyl)-5-methyl-3-o-tolyl-3H -quinazolin-4-one 2-(6-amino-9H-purin-2-ylsulfanylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4- one 2-(2-amino-6-ethylamino-pyrimidin-4-ylsulfanylmethyl)-5-methyl-3-o-tolyl-3H -quinazolin-4-one 2-(3-amino-5-methylsulfanyl-1,2,4-triazol-1-ylmethyl)-5-methyl-3-o-tolyl-3H -quinazolin-4-one 2-(5-amino-3-methylsulfanyl-1,2,4-triazol-1-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-yimethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one 2-(2,6-diaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one 5-methyl-2-(9H-purin-6-ylsulfanylmethyl)-3-o-tolyl-3H-quinazolin-4-one 3-isobutyl-5-methyl-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one N-{2-[5-Methyl-4-oxo-2-(9H-purin-6-ylsulfanylmethyl)-4H-quinazolin-3-yl]-ph enyl}-acetamide 5-methyl-3-(E-2-methyl-cyclohexyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quina zolin-4-one 2-[5-methyl-4-oxo-2-(9H-purin-6-ylsulfanylmethyl)-4H-quinazolin-3-yl]-benzo ic acid 3-{2-[(2-dimethylaminoethyl)methylamino]phenyl}-5-methyl-2-(9H-purin-6-ylsu lfanylmethyl)-3H-quinazolin-4-one 3-(2-chlorophenyl)-5-methoxy-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin- 4-one 3-(2-chlorophenyl)-5-(2-morpholin-4-yl-ethylamino)-2-(9H-purin-6-ylsulfanyl methyl)-3H-quinazolin-4-one 3-benzyl-5-methoxy-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one 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-on e; 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; 2-(2-benzyloxy-1-(9H-purin-6-ylamino)ethyl)-5-methyl-3-o-tolyl-3H-quinazoli n-4-one; 2-(6-aminopurin-9-ylmethyl)-5-methyl-3-{2-(2-(1-methylpyrrolidin-2-yl)-etho xy)-phenyl}-3H-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-(3-dimethylaminopropoxy)-phenyl)-5-methyl- 3H-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-5-methyl-3-(2-prop-2-ynyloxyphenyl)-3H-quinazol in-4-one; and 2-{2-(1-(6-aminopurin-9-ylmethyl)-5-methyl-4-oxo-4H-quinazolin-3-yl[-phenox y}-acetamide.

3. A method of inhibiting kinase activity of a phosphatidylinositol 3-kinase delta polypeptide comprising a step of contacting the polypeptide with a compound having a structure ##STR91## wherein A is an optionally substituted monocyclic 5-membered heterocyclic ring system containing two or three nitrogen atoms or a bicyclic ring system containing at least two nitrogen atoms, and at least one ring of the bicyclic system is aromatic; X is selected from the group consisting of C(R.sup.b).sub.2, CH.sub.2 CHR.sup.b, and CH.dbd.C(R.sup.b); Y is selected from the group consisting of null, S, SO, and SO.sub.2, NH, O, C(.dbd.O), OC(.dbd.O), C(.dbd.O)O, and NHC(.dbd.O)CH.sub.2 S; R.sup.1 and R.sup.2, independently, are selected from the group consisting of hydrogen, C.sub.1-6 alkyl, aryl, heteroaryl, halo, NHC(.dbd.O)C.sub.1-3 alkyleneN(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.a C(.dbd.O)C.sub.1-3 alkyleneC(.dbd.O)OR.sup.a, arylOC.sub.1-3 alkyleneN(R.sup.a).sub.2, arylOC(.dbd.O)R.sup.a, C.sub.1-4 alkyleneC(.dbd.O)OR.sup.a, OC.sub.1-4 alkyleneC(.dbd.O)OR.sup.a, C.sub.1-4 alkyleneOC.sub.1-4 alkyleneC(.dbd.O)OR.sup.a, C(.dbd.O)NR.sup.a SO.sub.2 R.sup.a, C.sub.1-4 alkyleneN(R.sup.a).sub.2, C.sub.2-6 alkenyleneN(R.sup.a).sub.2, C(.dbd.O)NR.sup.a C.sub.1-4 alkyleneOR.sup.a, C(.dbd.O)NR.sup.a C.sub.1-4 alkyleneHet, OC.sub.2-4 alkyleneN(R.sup.a).sub.2, OC.sub.1-4 alkyleneCH(OR.sup.b)CH.sub.2 N(R.sup.a).sub.2, OC.sub.1-4 alkyleneHet, OC.sub.2-4 alkyleneOR.sup.a, OC.sub.2-4 alkyleneNR.sup.a C(.dbd.O)OR.sup.a, NR.sup.a C.sub.1-4 alkyleneN(R.sup.a).sub.2, NR.sup.a C(.dbd.O)R.sup.a, NR.sup.a C(.dbd.O)--N(R.sup.a).sub.2, N(SO.sup.2 C.sub.1-4 alkyl).sub.2, NR.sup.a (SO.sub.2 C.sub.1-4 alkyl), SO.sub.2 N(R.sup.a).sub.2, OSO.sub.2 CF.sub.3, C.sub.1-3 alkylenearyl, C.sub.1-4 alkyleneHet, C.sub.1-6 alkyleneOR.sup.b, C.sub.1-3 alkyleneN(R.sup.a).sub.2, C(.dbd.O)N(R.sup.a).sub.2, NHC(.dbd.O)C.sub.1 -C.sub.3 alkylenearyl, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocycloalkyl, arylOC.sub.1-3 alkyleneN(R.sup.a).sub.2, arylOC(.dbd.O)R.sup.b, NHC(.dbd.O)C.sub.1-3 alkyleneC.sub.3-8 heterocycloalkyl, NHC(.dbd.O)C.sub.1-3 alkyleneHet, OC.sub.1-4 alkyleneOC.sub.1-4 alkyleneC(O)OR.sup.b, C(.dbd.O)C.sub.1-4 alkyleneHet, and NRC(.dbd.O)haloC.sub.1-6 alkyl; 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-mernbered ring, optionally containing at least one heteroatom; R.sup.3 is selected from the group consisting of optionally substituted hydrogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocycloalkyl, C.sub.1-4 alkylenecycloalkyl, C.sub.2-6 alkenyl, C.sub.1-3 alkylenearyl, arylC.sub.1-3 alkyl, 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.2 R.sup.a, SO.sub.2 N(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.a C.sub.1-4 alkyleneOR.sup.a, C(.dbd.O)NR.sup.a C.sub.1-4 alkyleneHet, C(.dbd.O)C.sub.1-4 alkylenearyl, C(.dbd.O)C.sub.1-4 alkyleneheteroaryl, C.sub.1-4 alkylenearyl substituted with one or more of SO.sub.2 N(R.sup.a).sub.2, N(R.sup.a).sub.2, C(.dbd.O)OR.sup.a, NR.sup.a SO.sub.2 CF.sub.3, CN, NO.sub.2, C(.dbd.O)R.sup.a, OR.sup.a, C.sub.1-4 alkyleneN(R.sup.a).sub.2, and OC.sub.1-4 alkyleneN(R.sup.a).sub.2, C.sub.1-4 alkyleneheteroaryl, C.sub.1-4 alkyleneHet, C.sub.1-4 alkyleneC(.dbd.O)C.sub.1-4 alkylenearyl, C.sub.1-4 alkyleneC(.dbd.O)C.sub.1-4 alkyleneheteroaryl, C.sub.1-4 alkyleneC(.dbd.O)Het, C.sub.1-4 alkyleneC(.dbd.O)N(R.sup.a).sub.2, C.sub.1-4 alkyleneOR.sup.a, C.sub.1-4 alkyleneNR.sup.a C(.dbd.O)R.sup.a, C.sub.1-4 alkyleneOC.sub.1-4 alkyleneOR.sup.a, C.sub.1-4 alkyleneN(R.sup.a).sub.2, C.sub.1-4 alkyleneC(.dbd.O)OR.sup.a, and C.sub.1-4 alkyleneOC.sub.1-4 alkyleneC(.dbd.O) OR.sup.a ; R.sup.a is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocycloalkyl, C.sub.1-3 alkyleneN(R.sup.c).sub.2, aryl, arylC.sub.1-3 alkyl, C.sub.1-3 alkylenearyl, heteroaryl, heteroarylC.sub.1-3 alkyl, and C.sub.1-3 alkyleneheteroaryl; 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.1-6 alkyl, heteroC.sub.1-3 alkyl, C.sub.1-3 alkyleneheteroC.sub.1-3 alkyl, arylheteroC.sub.1-3 alkyl, and aryl, heteroaryl, arylC.sub.1-3 alkyl, heteroarylC.sub.1-3 alkyl, C.sub.1-3 alkylenearyl, and C.sub.1-3 alkyleneheteroaryl; R.sup.c is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, aryl, and heteroaryl; Het is a 5- or 6-menibered heterocyclic ring, saturated or partially or fully unsaturated, containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; 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 2,4-dioxane, and optionally substituted with C.sub.1-4 alkyl or C(.dbd.O)OR.sup.a ; and pharmaceutically acceptable salts or solvates thereof.

4. A compound having a general structural formula ##STR92## wherein A is an optionally substituted monocyclic 5-membered heterocyclic ring system containing two or three nitrogen atoms or a bicyclic ring system containing at least two nitrogen atoms, and at least one ring of the cyclic system is aromatic; X is selected from the group consisting of C(R.sup.b).sub.2, CH.sub.2 CHR.sup.b, and CH.dbd.C(R.sup.b); Y is selected from the group consisting of null, S, SO, and SO.sub.2, NH, O, C(.dbd.O), OC(.dbd.O), C(.dbd.O)O, and NHC(.dbd.O)CH.sub.2 S; R.sup.1 and R.sup.2, independently, are selected from the group consisting of hydrogen, C.sub.1-6 alkyl, aryl, heteroaryl, halo, NHC(.dbd.O)C.sub.1-3 alkyleneN(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.a C(.dbd.O)C.sub.1-3 alkyleneC(.dbd.O)OR.sup.a, arylOC.sub.1-3 alkyleneN(R.sup.a).sub.2, arylOC(.dbd.O)R.sup.a, C.sub.1-4 alkyleneC(.dbd.O)OR.sup.a, OC.sub.1-4 alkyleneC(.dbd.O) OR.sup.a, C.sub.1-4 alkyleneOC.sub.1-4 alkyleneC(.dbd.O)OR.sup.a, C(.dbd.O)--NR.sup.a SO.sub.2 R.sup.a, C.sub.1-4 alkyleneN(R.sup.a).sub.2, C.sub.2-6 alkenyleneN(R.sup.a).sub.2, C(.dbd.O)--NR.sup.a C.sub.1-4 alkyleneOR.sup.a, C(.dbd.O)NR.sup.a C.sub.1-4 alkyleneHet, OC.sub.2-4 alkyleneN(R.sup.a).sub.2, OC.sub.1-4 alkyleneCH(OR.sup.b)CH.sub.2 N(R.sup.a).sub.2, OC.sub.1-4 alkyleneHet, OC.sub.2-4 alkyleneOR.sup.a, OC.sub.2-4 alkyleneNR.sup.a C(.dbd.O)OR.sup.a, NR.sup.a C.sub.1-4 alkyleneN(R.sup.a).sub.2, NR.sup.a C(.dbd.O)R.sup.a, NR.sup.a C(.dbd.O)N(R.sup.a).sub.2, N(SO.sub.2 C.sub.1-4 alkyl).sub.2, NR.sup.a (SO.sub.2 C.sub.1-4 alkyl), SO.sub.2 N (R.sup.a).sub.2, OSO.sub.2 CF.sub.3, C.sub.1-3 alkylenearyl, C.sub.1-4 alkyleneHet, C.sub.1-6 alkyleneOR.sup.b, C.sub.1-3 alkyleneN(R.sup.a).sub.2, C(.dbd.O)N(R.sup.a).sub.2, NHC(.dbd.O)C.sub.1 -C.sub.3 alkylenearyl, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocycloalkyl, arylOC.sub.1-3 alkyleneN(R.sup.a).sub.2, arylOC(.dbd.O)R.sup.b, NHC(.dbd.O)C.sub.1-3 alkyleneC.sub.3-8 heterocycloalkyl, NHC(.dbd.O) C.sub.1-3 alkyleneHet, OC.sub.1-4 alkyleneOC.sub.1-4 alkyleneC(.dbd.O)OR.sup.b, C(.dbd.O)C.sub.1-4 alkyleneHet, and NHC(.dbd.O)haloC.sub.1-6 alkyl; 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 selected from the group consisting of optionally substituted hydrogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocycloalkyl, C.sub.1-4 alkylenecycloalkyl, C.sub.2-6 alkenyl, C.sub.1-3 alkylenearyl, arylC.sub.1-3 alkyl, 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.2 R.sup.a, SO.sub.2 N(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.a C.sub.1-4 alkyleneOR.sup.a, C(.dbd.O)NR.sup.a C.sub.1-4 alkyleneHet, C(.dbd.O)C.sub.1-4 alkylenearyl, C(.dbd.O)C.sub.1-4 alkyleneheteroaryl, C.sub.1-4 alkylenearyl substituted with one or more of SO.sub.2 N(R.sup.a).sub.2, N(R.sup.a).sub.2, C(.dbd.O)OR.sup.a, NR.sup.a SO.sub.2 CF.sub.3, CN, NO.sub.2, C(.dbd.O)R.sup.a, OR.sup.a, C.sub.1-4 alkyleneN(R.sup.a).sub.2, and OC.sub.1-4 alkyleneN(R.sup.a).sub.2, C.sub.1-4 alkyleneheteroaryl, C.sub.1-4 alkyleneHet, C.sub.1-4 alkyleneC(.dbd.O)C.sub.1-4 alkylenearyl, C.sub.1-4 alkyleneC(O)--C.sub.1-4 alkyleneheteroaryl, C.sub.1-4 alkyleneC(.dbd.O) Het, C.sub.1-4 alkyleneC(.dbd.O)N(R.sup.a).sub.2, C.sub.1-4 alkyleneOR.sup.a, C.sub.1-4 alkyleneNR.sup.a C(.dbd.O)R.sup.a, C.sub.1-4 alkyleneOC.sub.1-4 alkyleneOR.sup.a, C.sub.1-4 alkyleneN(R.sup.a).sub.2, C.sub.1-4 alkyleneC(.dbd.O)OR.sup.a, and C.sub.1-4 alkyleneOC.sub.1-4 alkyleneC(.dbd.O)OR.sup.a ; R.sup.d is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocycloalkyl, C.sub.1-3 alkyleneN(R.sup.c).sub.2, aryl, arylC.sub.1-3 alkyl, C.sub.1-3 alkylenearyl, heteroaryl, heteroarylC.sub.1-3 alkyl, and C.sub.1-3 alkyleneheteroaryl; 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.1-6 alkyl, heteroC.sub.1-3 alkyl, C.sub.1-3 alkyleneheteroC.sub.1-3 alkyl, arylheteroC.sub.1-3 alkyl, and aryl, heteroaryl, arylC.sub.1-3 alkyl, heteroarylC.sub.1-3 alkyl, C.sub.1-3 alkylenearyl, and C.sub.1-3 alkyleneheteroaryl; R.sup.c is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, 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, selected from the group consisting of 1,3-dioxolane, 2-pyrazoline, pyrazolidine, pyrrolidirie, piperazine, pyrroline, 2H-pyran, 4H-pyran, morpholine, thiomorpholine, piperidine, 1,4-dithiane, and 1,4-dioxane, and optionally substituted with C.sub.1-4 alkyl or C(.dbd.O)OR.sup.a ; and pharmaceutically acceptable salts or solvates thereof, with the provisos that if X--Y is CH.sub.2 S, then R.sup.3 is different from ##STR93## and if X--Y is CH.sub.2 S, then R.sup.3 is different from --CH.sub.2 CH(OH)CH.sub.2 OH substituted phenyl.

5. The compound of claim 4 wherein X is selected from the group consisting of CH.sub.2, CH.sub.2 CH.sub.2, CH.dbd.CH, CH(CH.sub.3), CH(CH.sub.2 CH.sub.3), and CH.sub.2 CH(CH.sub.3), and C(CH.sub.3).sub.2.

6. The compound of claim 5 wherein Y is selected from the group consisting of null, S, and NH.

7. The compound of claim 5 wherein the A ring system is selected from the group consisting of ##STR94##

8. The compound of claim 7 wherein the A ring system is substituted with one to three substituents selected from the group consisting of N(R.sup.a).sub.2, halo, C.sub.1-3 alkyl, S(C.sub.1-3 alkyl), OR.sup.a, and ##STR95##

9. The compound of claim 8 wherein the A ring system is 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.2 C.sub.6 H.sub.5, NH(C.sub.2 H.sub.5), Cl, F, CH.sub.3, SCH.sub.3, OH, and ##STR96##

10. The compound of claim 5 wherein R.sup.1 and R.sup.2, independently, are selected from the group consisting of hydrogen, OR.sup.a, halo, C.sub.1-6 alkyl, CF.sub.3, NO.sub.2, N(R.sup.a).sub.2, NR.sup.a C.sub.1-3 alkyleneN(R.sup.a).sub.2, and OC.sub.1-3 alkyleneOR.sup.a, specific substituents include, but are not limited to, H, OCH.sub.3, Cl, Br, F, CH.sub.3, CF.sub.3, NO.sub.2, OH, N(CH.sub.3).sub.2, ##STR97##

and O(CH.sub.2).sub.2 OCH.sub.2 C.sub.6 H.sub.5, or R.sup.1 and R.sup.2 are taken together to form a five- or six-membered ring.

11. The compound of claim 5 wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkyl, aryl, heteroaryl, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocycloalkyl, C(.dbd.O)OR.sup.a, C.sub.1-4 alkyleneHet, C.sub.1-4 alkylenecycloalkyl, C.sub.1-4 alkylenearyl, C.sub.1-4 alkyleneC(.dbd.O)C.sub.1-4 alkylenearyl, C.sub.1-4 alkyleneC(.dbd.O) OR.sup.a, C.sub.1-4 alkyleneC(.dbd.O)N(R.sup.a).sub.2, C.sub.1-4 alkyleneC(.dbd.O)Het, C.sub.1-4 alkyleneN(R.sup.a).sub.2, and C.sub.1-4 alkyleneNR.sup.a C(.dbd.O) R.sup.a.

12. The compound of claim 5 wherein R.sup.3 is selected from the group consisting of OR.sup.a, C.sub.1-6 alkyl, aryl, heteroaryl, NO.sub.2, N(R.sup.a).sub.2, NR.sup.a C(.dbd.O)R.sup.a, C(.dbd.O)OC.sub.2 H.sub.5, CH.sub.2 CH(CH.sub.3).sub.2, ##STR98##

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

14. The compound of claim 4 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, OCR.sup.3, OCH.sub.2 C.sub.6 H.sub.5, O(CH.sub.2).sub.3 N(CH.sub.3).sub.2, OCH.sub.2 C.ident.CH, OCH.sub.2 C(.dbd.O)NH.sub.2, C.sub.6 H.sub.5, NO.sub.2, NH.sub.2, NHC(.dbd.O)CH.sub.3, CO.sub.2 H, and N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2, and ##STR99##

15. The compound of claim 4 selected from the group consisting of: 2-(6-aminopurin-9ylmethyl)-3-(2-benzyloxyphenyl)-5-methyl-3H-quinazolin-4-o ne; 2-(6-aminopurin-9-ylmethyl)-3-(2-hydroxyphenyl)-5-methyl-3H-quinazolin-4-on e; 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-6ylamino)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; 2-(2-benzyloxy-1-(9H-purin-6-ylamino)ethyl)-5-methyl-3-o-tolyl-3H-quinazoli n-4-one; 2-(6-aminopurin-9-ylmethyl)-5-methyl-3-{2-(2-(1-methylpyrrolidin-2-yl)-etho xy)-phenyl}-3H-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-3-(2-(3-dimethylaminopropoxy)-phenyl)-5-methyl- 3H-quinazolin-4-one; 2-(6-aminopurin-9-ylmethyl)-5-methyl-3-(2-prop-2-ynyloxyphenyl)-3H-quinazol in-4-one; and 2-{2-(1-(6-aminopurin-9-ylmethyl)-5-methyl-4-oxo-4H-quinazolin-3-yl)-phenox y}-acetamide.
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