Inhibitors of human phosphatidyl-inositol 3-kinase delta
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.
1. A method of disrupting leukocyte function comprising a step of contacting leukocytes with a compound having a structure
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 b ) 2 , CH 2 CHR b , and CH═C(R b );
Y is selected from the group consisting of null, S, SO, and SO 2 , NH, O, C(═O), OC(═O), C(═O)O, and NHC(═O)CH 2 S;
R 1 and R 2 , independently, are selected from the group consisting of hydrogen, C 1-6 alkyl, aryl, heteroaryl, halo, NHC(═O)C 1-3 alkyleneN(R a ) 2 , NO 2 , OR a , CF 3 , OCF 3 , N(R a ) 2 , CN, OC(═O)R a , C(═O)R a , C(═O)OR a , arylOR b , Het, NR a C(═O)C 1-3 alkyleneC(═O)OR a , arylOC 1-3 alkyleneN(R a ) 2 , arylOC(═O)R a , C 1-4 alkyleneC(═O)OR a , OC 1-4 alkyleneC(═O)OR a , C 1-4 alkyleneOC 1-4 alkyleneC(═O)—OR a , C(═O)NR a SO 2 R a , C 1-4 alkyleneN(R a ) 2 , C 2-6 alkenylene-N(R a ) 2 , C(═O)NR a C 1-4 alkyleneOR a , C(═O)NR a C 1-4 alkyleneHet, OC 2-4 alkyleneN(R a ) 2 , OC 1-4 alkyleneCH(OR b )CH 2 N(R a ) 2 , OC 1-4 alkyleneHet, OC 2-4 alkyleneOR a , OC 2-4 alkyleneNR a C(═O)—OR a , NR a C 1-4 alkyleneN(R a ) 2 , NR a C(═O)R a , NR a C(═O)N(R a ) 2 , N(SO 2 C 1-4 alkyl) 2 , NR a (SO 2 C 1-4 alkyl), SO 2 N(R a ) 2 , OSO 2 CF 3 , C 1-3 alkylenearyl, C 1-4 alkyleneHet, C 1-6 alkyleneOR b , C 1-3 alkyleneN(R a ) 2 , C(═O)N(R a ) 2 , NHC(═O)C 1 -C 3 alkylenearyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, arylOC 1-3 alkylene-N(R a ) 2 , arylOC(═O)R b , NHC(═O)C 1-3 alkyleneC 3-8 heterocyclo-alkyl, NHC(═O)C 1-3 alkyleneHet, OC 1-4 alkyleneOC 1-4 alkylene-C(═O)OR b , C(═O)C 1-4 alkyleneHet, and NHC(═O)haloC 1-6 alkyl;
or R 1 and R 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 3 is selected from the group consisting of optionally substituted hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 1-4 alkylenecycloalkyl, C 2-6 alkenyl, C 1-3 alkylenearyl, arylC 1-3 alkyl, C(═O)R a , aryl, heteroaryl, C(═O)OR a , C(═O)N(R a ) 2 , C(═S)N(R a ) 2 , SO 2 R a , SO 2 N(R a ) 2 , S(═O)R a , S(═O)N(R a ) 2 , C(═O)NR a C 1-4 alkyleneOR a , C(═O)NR a C 1-4 alkyleneHet, C(═O)C 1-4 alkylenearyl, C(═O)C 1-4 alkyleneheteroaryl, C 1-4 alkylenearyl substituted with one or more of SO 2 N(R a ) 2 , N(R a ) 2 , C(═O)OR a , NR a SO 2 CF 3 , CN, NO 2 , C(═O)R a , OR a , C 1-4 alkyleneN(R a ) 2 , and OC 1-4 alkyleneN(R a ) 2 , C 1-4 alkyleneheteroaryl, C 1-4 alkyleneHet, C 1-4 alkyleneC(═O) C 1-4 alkylenearyl, C 1-4 alkyleneC(═O)—C 1-4 alkyleneheteroaryl, C 1-4 alkyleneC(═O)Het, C 1-4 alkyleneC(═O)N(R a ) 2 , C 1-4 alkyleneOR a , C 1-4 alkyleneNR a C(═O)R a , C 1-4 alkyleneOC 1-4 alkyleneOR a , C 1-4 alkyleneN(R a ) 2 , C 1-4 alkyleneC(═O)OR a , and C 1-4 alkyleneOC 1-4 alkyleneC(═O)OR a ;
R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 1-3 alkyleneN(R c ) 2 , aryl, arylC 1-3 alkyl, C 1-3 alkylenearyl, heteroaryl, heteroarylC 1-3 alkyl, and C 1-3 alkyleneheteroaryl;
or two R a groups are taken together to form a 5- or 6-membered ring, optionally containing at least one heteroatom;
R b is selected from the group consisting of hydrogen, C 1-6 alkyl, heteroC 1-3 alkyl, C 1-3 alkyleneheteroC 1-3 alkyl, arylheteroC 1-3 alkyl, and aryl, heteroaryl, arylC 1-3 alkyl, heteroarylC 1-3 alkyl, C 1-3 alkylenearyl, and C 1-3 alkyleneheteroaryl;
R c is selected from the group consisting of hydrogen, C 1-6 alkyl, C 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 1-4 alkyl or C(═O)OR 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-one
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-quinazolin-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-quinazolin-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-quinazolin-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-one
2-(2-amino-9H-purin-6-ylsulfanylmethyl)-3-cyclopropyl-5-methyl-3H-quinazolin-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-one
2-(2-amino-9H-purin-6-ylsulfanylrnethyl)-3-cyclopropylmethyl-5-methyl-3H-quinazolin-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-quinazolin-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-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-chlorophenyl)-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-ylaminomethyl]-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-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-(9H-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-quinazolin-4-one
5-methyl-2-(2-methyl-6-oxo-1,6-dihydro-purin-9-ylmethyl)-3-o-tolyl-3H-quinazolin-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-quinazolin-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-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
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-quinazolin-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-quinazolin-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-quinazolin-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]-phenyl}-acetamide
5-methyl-3-(E-2-methyl-cyclohexyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
2-[5-methyl-4-oxo-2-(9H-purin-6-ylsulfanylmethyl)-4H-quinazolin-3-yl]-benzoic acid
3-{2-[(2-dimethylaminoethyl)methylamino]phenyl}-5-methyl-2-(9H-purin-6-ylsulfanylmethyl)-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-ylsulfanylmethyl)-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-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;
2-(2-benzyloxy-1-(9H-purin-6-ylamino)ethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;
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)-3-(2-(3-dimethylaminopropoxy)-phenyl)-5-methyl-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.
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
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 b ) 2 , CH 2 CHR b , and CH═C(R b );
Y is selected from the group consisting of null, S, SO, and SO 2 , NH, O, C(═O), OC(═O), C(═O)O, and NHC(═O)CH 2 S;
R 1 and R 2 , independently, are selected from the group consisting of hydrogen, C 1-6 alkyl, aryl, heteroaryl, halo, NHC(═O)C 1-3 alkyleneN(R a ) 2 , NO 2 , OR a , CF 3 , OCF 3 , N(R a ) 2 , CN, OC(═O)R a , C(═O)R a , C(═O)OR a , arylOR b , Het, NR a C(═O)C 1-3 alkyleneC(═O)OR a , arylOC 1-3 alkyleneN(R a ) 2 , arylOC(═O)R a , C 1-4 alkyleneC(═O)OR a , OC 1-4 alkyleneC(═O)OR a , C 1-4 alkyleneOC 1-4 alkyleneC(═O)OR a , C(═O)NR a SO 2 R a , C 1-4 alkyleneN(R a ) 2 , C 2-6 alkenyleneN(R a ) 2 , C(═O)NR a C 1-4 alkyleneOR a , C(═O)NR a C 1-4 alkyleneHet, OC 2-4 alkyleneN(R a ) 2 , OC 1-4 alkyleneCH(OR b )CH 2 N(R a ) 2 , OC 1-4 alkyleneHet, OC 2-4 alkyleneOR a , OC 2-4 alkyleneNR a C(═O)OR a , NR a C 1-4 alkyleneN(R a ) 2 , NR a C(═O)R a , NR a C(═O)—N(R a ) 2 , N(SO 2 C 1-4 alkyl) 2 , NR a (SO 2 C 1-4 alkyl), SO 2 N(R a ) 2 , OSO 2 CF 3 , C 1-3 alkylenearyl, C 1-4 alkyleneHet, C 1-6 alkyleneOR b , C 1-3 alkyleneN(R a ) 2 , C(═O)N(R a ) 2 , NHC(═O)C 1 -C 3 alkylenearyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, arylOC 1-3 alkyleneN(R a ) 2 , arylOC(═O)R b , NHC(═O)C 1-3 alkyleneC 3-8 heterocycloalkyl, NHC(═O)C 1-3 alkyleneHet, OC 1-4 alkyleneOC 1-4 alkyleneC(O)OR b , C(═O)C 1-4 alkyleneHet, and NRC(═O)haloC 1-6 alkyl;
or R 1 and R 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 3 is selected from the group consisting of optionally substituted hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 1-4 alkylenecycloalkyl, C 2-6 alkenyl, C 1-3 alkylenearyl, arylC 1-3 alkyl, C(═O)R a , aryl, heteroaryl, C(═O)OR a , C(═O)N(R a ) 2 , C(═S)N(R a ) 2 , SO 2 R a , SO 2 N(R a ) 2 , S(═O)R a , S(═O)N(R a ) 2 , C(═O)NR a C 1-4 alkyleneOR a , C(═O)NR a C 1-4 alkyleneHet, C(═O)C 1-4 alkylenearyl, C(═O)C 1-4 alkyleneheteroaryl, C 1-4 alkylenearyl substituted with one or more of SO 2 N(R a ) 2 , N(R a ) 2 , C(═O)OR a , NR a SO 2 CF 3 , CN, NO 2 , C(═O)R a , OR a , C 1-4 alkyleneN(R a ) 2 , and OC 1-4 alkyleneN(R a ) 2 , C 1-4 alkyleneheteroaryl, C 1-4 alkyleneHet, C 1-4 alkyleneC(═O)C 1-4 alkylenearyl, C 1-4 alkyleneC(═O)C 1-4 alkyleneheteroaryl, C 1-4 alkyleneC(═O)Het, C 1-4 alkyleneC(═O)N(R a ) 2 , C 1-4 alkyleneOR a , C 1-4 alkyleneNR a C(═O)R a , C 1-4 alkyleneOC 1-4 alkyleneOR a , C 1-4 alkyleneN(R a ) 2 , C 1-4 alkyleneC(═O)OR a , and C 1-4 alkyleneOC 1-4 alkyleneC(═O) OR a ;
R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 1-3 alkyleneN(R c ) 2 , aryl, arylC 1-3 alkyl, C 1-3 alkylenearyl, heteroaryl, heteroarylC 1-3 alkyl, and C 1-3 alkyleneheteroaryl;
or two R a groups are taken together to form a 5-or 6-membered ring, optionally containing at least one heteroatom;
R b is selected from the group consisting of hydrogen, C 1-6 alkyl, heteroC 1-3 alkyl, C 1-3 alkyleneheteroC 1-3 alkyl, arylheteroC 1-3 alkyl, and aryl, heteroaryl, arylC 1-3 alkyl, heteroarylC 1-3 alkyl, C 1-3 alkylenearyl, and C 1-3 alkyleneheteroaryl;
R c is selected from the group consisting of hydrogen, C 1-6 alkyl, C 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 1-4 alkyl or C(═O)OR a ;
and pharmaceutically acceptable salts or solvates thereof.
4. A compound having a general structural formula
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 b ) 2 , CH 2 CHR b , and CH═C(R b );
Y is selected from the group consisting of null, S, SO, and SO 2 , NH, O, C(═O), OC(═O), C(═O)O, and NHC(═O)CH 2 S;
R 1 and R 2 , independently, are selected from the group consisting of hydrogen, C 1-6 alkyl, aryl, heteroaryl, halo, NHC(═O)C 1-3 alkyleneN(R a ) 2 , NO 2 , OR a , CF 3 , OCF 3 , N(R a ) 2 , CN, OC(═O)R a , C(═O)R a , C(═O)OR a , arylOR b , Het, NR a C(═O)C 1-3 alkyleneC(═O)OR a , arylOC 1-3 alkyleneN(R a ) 2 , arylOC(═O)R a , C 1-4 alkyleneC(═O)OR a , OC 1-4 alkyleneC(═O) OR a , C 1-4 alkyleneOC 1-4 alkyleneC(═O)OR a , C(═O)—NR a SO 2 R a , C 1-4 alkyleneN(R a ) 2 , C 2-6 alkenyleneN(R a ) 2 , C(═O)—NR a C 1-4 alkyleneOR a , C(═O)NR a C 1-4 alkyleneHet, OC 2-4 alkyleneN(R a ) 2 , OC 1-4 alkyleneCH(OR b )CH 2 N(R a ) 2 , OC 1-4 alkyleneHet, OC 2-4 alkyleneOR a , OC 2-4 alkyleneNR a C(═O)OR a , NR a C 1-4 alkyleneN(R a ) 2 , NR a C(═O)R a , NR a C(═O)N(R a ) 2 , N(SO 2 C 1-4 alkyl) 2 , NR a (SO 2 C 1-4 alkyl), SO 2 N (R a ) 2 , OSO 2 CF 3 , C 1-3 alkylenearyl, C 1-4 alkyleneHet, C 1-6 alkyleneOR b , C 1-3 alkyleneN(R a ) 2 , C(═O)N(R a ) 2 , NHC(═O)C 1 -C 3 alkylenearyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, arylOC 1-3 alkyleneN(R a ) 2 , arylOC(═O)R b , NHC(═O)C 1-3 alkyleneC 3-8 heterocycloalkyl, NHC(═O) C 1-3 alkyleneHet, OC 1-4 alkyleneOC 1-4 alkyleneC(═O)OR b , C(═O)C 1-4 alkyleneHet, and NHC(═O)haloC 1-6 alkyl;
or R 1 and R 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 3 is selected from the group consisting of optionally substituted hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 1-4 alkylenecycloalkyl, C 2-6 alkenyl, C 1-3 alkylenearyl, arylC 1-3 alkyl, C(═O)R a , aryl, heteroaryl, C(═O)OR a , C(═O)N(R a ) 2 , C(═S)N(R a ) 2 , SO 2 R a , SO 2 N(R a ) 2 , S(═O)R a , S(═O)N(R a ) 2 , C(═O)NR a C 1-4 alkyleneOR a , C(═O)NR a C 1-4 alkyleneHet, C(═O)C 1-4 alkylenearyl, C(═O)C 1-4 alkyleneheteroaryl, C 1-4 alkylenearyl substituted with one or more of SO 2 N(R a ) 2 , N(R a ) 2 , C(═O)OR a , NR a SO 2 CF 3 , CN, NO 2 , C(═O)R a , OR a , C 1-4 alkyleneN(R a ) 2 , and OC 1-4 alkyleneN(R a ) 2 , C 1-4 alkyleneheteroaryl, C 1-4 alkyleneHet, C 1-4 alkyleneC(═O)C 1-4 alkylenearyl, C 1-4 alkyleneC(O)—C 1-4 alkyleneheteroaryl, C 1-4 alkyleneC(═O) Het, C 1-4 alkyleneC(═O)N(R a ) 2 , C 1-4 alkyleneOR a , C 1-4 alkyleneNR a C(═O)R a , C 1-4 alkyleneOC 1-4 alkyleneOR a , C 1-4 alkyleneN(R a ) 2 , C 1-4 alkyleneC(═O)OR a , and C 1-4 alkyleneOC 1-4 alkyleneC(═O)OR a ;
R d is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 1-3 alkyleneN(R c ) 2 , aryl, arylC 1-3 alkyl, C 1-3 alkylenearyl, heteroaryl, heteroarylC 1-3 alkyl, and C 1-3 alkyleneheteroaryl;
or two R a groups are taken together to form a 5-or 6-membered ring, optionally containing at least one heteroatom;
R b is selected from the group consisting of hydrogen, C 1-6 alkyl, heteroC 1-3 alkyl, C 1-3 alkyleneheteroC 1-3 alkyl, arylheteroC 1-3 alkyl, and aryl, heteroaryl, arylC 1-3 alkyl, heteroarylC 1-3 alkyl, C 1-3 alkylenearyl, and C 1-3 alkyleneheteroaryl;
R c is selected from the group consisting of hydrogen, C 1-6 alkyl, C 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 1-4 alkyl or C(═O)OR a ;
and pharmaceutically acceptable salts or solvates thereof,
with the provisos that if X—Y is CH 2 S, then R 3 is different from
and if X—Y is CH 2 S, then R 3 is different from —CH 2 CH(OH)CH 2 OH substituted phenyl.
5. The compound of claim 4 wherein X is selected from the group consisting of CH 2 , CH 2 CH 2 , CH═CH, CH(CH 3 ), CH(CH 2 CH 3 ), and CH 2 CH(CH 3 ), and C(CH 3 ) 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
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 a ) 2 , halo, C 1-3 alkyl, S(C 1-3 alkyl), OR a , and
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 2 , NH(CH 3 ), N(CH 3 ) 2 , NHCH 2 C 6 H 5 , NH(C 2 H 5 ), Cl, F, CH 3 , SCH 3 , OH, and
10. The compound of claim 5 wherein R 1 and R 2 , independently, are selected from the group consisting of hydrogen, OR a , halo, C 1-6 alkyl, CF 3 , NO 2 , N(R a ) 2 , NR a C 1-3 alkyleneN(R a ) 2 , and OC 1-3 alkyleneOR a , specific substituents include, but are not limited to, H, OCH 3 , Cl, Br, F, CH 3 , CF 3 , NO 2 , OH, N(CH 3 ) 2 ,
and O(CH 2 ) 2 OCH 2 C 6 H 5 , or R 1 and R 2 are taken together to form a five- or six-membered ring.
11. The compound of claim 5 wherein R 3 is selected from the group consisting of C 1-6 alkyl, aryl, heteroaryl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C(═O)OR a , C 1-4 alkyleneHet, C 1-4 alkylenecycloalkyl, C 1-4 alkylenearyl, C 1-4 alkyleneC(═O)C 1-4 alkylenearyl, C 1-4 alkyleneC(═O) OR a , C 1-4 alkyleneC(═O)N(R a ) 2 , C 1-4 alkyleneC(═O)Het, C 1-4 alkyleneN(R a ) 2 , and C 1-4 alkyleneNR a C(═O) R a .
12. The compound of claim 5 wherein R 3 is selected from the group consisting of OR a , C 1-6 alkyl, aryl, heteroaryl, NO 2 , N(R a ) 2 , NR a C(═O)R a , C(═O)OC 2 H 5 , CH 2 CH(CH 3 ) 2 ,
13. The compound of claim 4 wherein R 3 is substituted with a substituent selected from the group consisting of halo, OR a , C 1-6 alkyl, aryl, heteroaryl, NO 2 , N(R a ) 2 , NR a SO 2 CF 3 , NR a C(═O)R a , C(═O)OR a , SO 2 N(R a ) 2 , CN, C(═O)R a , C 1-4 alkyleneN(R a ) 2 , OC 1-4 alkyleneC≡CR a , OC 1-4 alkyleneC(═O)N(R a ) 2 , OC 1-4 alkylenearyl, OC 1-4 alkyleneheteroaryl, OC 1-4 alkyleneHet, OC 1-4 alkyleneN(R a ) 2 , and N(R a )C 1-4 alkyleneN(R a ) 2 .
14. The compound of claim 4 wherein R 3 is substituted with a substituent selected from the group consisting of Cl, F, CH 3 , CH(CH 3 ) 2 , OH, OCR 3 , OCH 2 C 6 H 5 , O(CH 2 ) 3 N(CH 3 ) 2 , OCH 2 C≡CH, OCH 2 C(═O)NH 2 , C 6 H 5 , NO 2 , NH 2 , NHC(═O)CH 3 , CO 2 H, and N(CH 3 )CH 2 CH 2 N(CH 3 ) 2 , and
15. The compound of claim 4 selected from the group consisting of:
2-(6-aminopurin-9ylmethyl)-3-(2-benzyloxyphenyl)-5-methyl-3H-quinazolin-4-one;
2-(6-aminopurin-9-ylmethyl)-3-(2-hydroxyphenyl)-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-6ylamino)propyl)-5-methyl-3-o-tolyl-3H-quinazolin-4one;
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-quinazolin-4-one;
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)-3-(2-(3-dimethylaminopropoxy)-phenyl)-5-methyl-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.