Inhibitors of AKT activity
View Patent ↗The instant invention provides for substituted fused pyrimidine compounds of Formula A that inhibit Akt activity: In particular, the compounds disclosed selectively inhibit one or two of the Akt isoforms. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting Akt activity by administering the compound to a patient in need of treatment of cancer.
1. A compound according to Formula B:
wherein,
a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; n is 0, 1 or 2;
R 1 is independently selected from H, (C═O) a O b (C 1 -C 10 )alkyl, (C═O) a O b (C 1 -C 10 )alkenyl, (C═O) a O b (C 1 -C 10 )alkynyl, (C═O) a O b (C 3 -C 10 )cycloalkyl, (C═O) a O b -aryl, (C═O) a O b -heteroaryl, (C═O) a O b -heterocyclyl, halo, OH, CF 3 , CO 2 H, CN, NR 7 R 8 , (C═O)NR 7 R 8 , S(O) m NR 7 R 8 , S(O) m (C 1 -C 10 )alkyl, S(O) m (C 1 -C 10 )alkenyl, S(O) m (C 1 -C 10 )alkynyl, S(O) m (C 3 -C 8 )cycloalkyl, S(O) m -aryl, S(O) m -heteroaryl, and S(O) m -heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents selected from R 6 ;
R 3 and R 3 ′ are H; or R 3 and R 3 ′ can be taken together to form a (C 3 -C 10 )cycloalkyl, said cycloalkyl is optionally substituted with one or more substituents selected from (C 1 -C 10 )alkyl, (C 1 -C 10 )alkenyl, (C 1 -C 10 )alkynyl, (C 3 -C 10 )cycloalkyl, aryl, heteroaryl, heterocycicyl, (C═O)NR 7 R 8 , halo, OH, CF 3 , CO 2 H, CN, and NH 2 , said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are further optionally substituted with one or more substituents selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkenyl, (C 1 -C 4 )alkynyl, (C 3 -C 5 )cycloalkyl, halo, OH, CF 3 , CO 2 H, CN, phenyl and NR 7 R 8 ;
R 6 is selected from (C═O) a O b (C 1 -C 6 )alkyl, (C═O) a O b (C 1 -C 6 )alkenyl, (C═O) a O b (C 1 -C 6 )alkynyl, (C═O) a O b (C 3 -C 8 )cycloalkyl, (C═O) a O b -aryl, (C═O) a O b -heteroaryl, (C═O) a O b -heterocyclyl, halo, OH, CF 3 , CO 2 H, CN, NR 7 R 8 , (C═O)NR 7 R 8 , S(O) m NR 7 R 8 , S(O) m (C 1 -C 4 )alkyl, S(O) m (C 1 -C 4 )alkenyl, S(O) m (C 1 -C 4 )alkynyl, S(O) m (C 3 -C 8 )cycloalkyl, S(O) m -aryl, S(O) m -heteroaryl, and S(O) m -heterocyclyl said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents selected from R 6a ;
R 6a is selected from (C═O) a O b (C 1 -C 6 )alkyl, (C═O) a O b (C 1 -C 6 )alkenyl, (C═O) a O b (C 1 -C 6 )alkynyl, (C═O) a O b (C 3 -C 8 )cycloalkyl, (C═O) a O b -aryl, (C═O) a O b -heteroaryl, (C═O) a O b -heterocyclyl, halo, OH, CF 3 , CO 2 H, CN and NH 2 , said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, halo, OH, CF 3 , CO 2 H, CN, phenyl and NH 2 ;
R 7 and R 8 are independently selected from H, (C═O) a O b (C 1 -C 6 )alkyl, (C═O) a O b (C 1 -C 6 )alkenyl, (C═O) a O b (C 1 -C 6 )alkynyl, (C═O) a O b (C 3 -C 8 )cycloalkyl, (C═O) a O b -aryl, (C═O) a O b -heteroaryl, (C═O) a O b -heterocyclyl, halo, OH, CF 3 , CO 2 H, CN, N(R b ) 2 , (C═O)N(R b ) 2 , (C═S)N(R b ) 2 , S(O) m N(R b ) 2 , S(O) m (C 1 -C 6 )alkyl, S(O) m (C 1 -C 6 )alkenyl, S(O) m (C 1 -C 6 )alkynyl, S(O) m (C 3 -C 8 )cycloalkyl, S(O) m -aryl, S(O) m -heteroaryl, and S(O) m -heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents selected from R 6a , or R 7 and R 8 can be taken together to form a (C 3 -C 10 )cycloalkyl, said cycloalkyl is optionally substituted with one or more substituents selected from H, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkenyl, (C 1 -C 10 )alkynyl, (C 3 -C 10 )cycloalkyl, aryl, heteroaryl, heterocycicyl, (C═O)NR 7 R 8 , halo, OH, CF 3 , CO 2 H, CN, and NR 7 R 8 ; and
R b is independently selected from H, (C═O) a O b (C 1 -C 6 )alkyl, (C═O) a O b (C 1 -C 6 )alkenyl, (C═O) a O b (C 1 -C 6 )alkynyl, (C═O) a O b (C 3 -C 8 )cycloalkyl, (C═O) a O b -aryl, (C═O) a O b -heteroaryl and (C═O) a O b -heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, halo, OH, CF 3 , CO 2 H, CN, phenyl and NH 2 ;
or a tautomer thereof;
or a pharmaceutically acceptable salt or a stereoisomer thereof.
2. A compound according to Formula B of claim 1 , wherein,
is
a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; n is 0, 1 or 2;
R 1 is independently selected from (C═O) a O b (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 3 -C 8 )cycloalkyl, O b -aryl, O b -heteroaryl, (C═O) a O b -heterocyclyl, halo, OH, CF 3 , CO 2 H, CN, NR 7 R 8 , (C═O)NR 7 R 8 , S(O) m (C 1 -C 4 )alkyl, said alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents selected from R 6 ;
R 3 and R 3 ′ are H, or R 3 and R 3 ′ can be taken together to form cyclobutyl, said cyclobutyl is optionally substituted with one or more substituents selected from H, OH, methyl and cyclopropyl;
R 6 is selected from O b (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, O b -aryl, halo, OH, CF 3 , NR 7 R 8 , said alkyl and cycloalkyl are optionally substituted with one or more substituents selected from R 6a ;
R 6a is selected from O b (C 1 -C 6 )alkyl, aryl, OH and NH 2 , said alkyl and aryl are optionally substituted with one or more substituents selected from halo;
R 7 and R 8 are independently selected from H, (C═O) a O b (C 1 -C 6 )alkyl, (C═O) a (C 3 -C 8 )cycloalkyl, (C═O) a -aryl, heterocyclyl, (C═O)N(R b ) 2 , (C═S)N(R b ) 2 , S(O) m (C 1 -C 6 )alkyl, and S(O) m -aryl, said alkyl, cycloalkyl, aryl and heterocyclyl are optionally substituted with one or more substituents selected from R 6a ; and
R b is independently selected from H, (C 1 -C 6 )alkyl and aryl;
or a tautomer thereof;
or a pharmaceutically acceptable salt or a stereoisomer thereof.
3. A compound of claim 1 which is selected from:
1-[4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]cyclobutanamine;
1-[4-(3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]cyclobutanamine;
3-amino-3-[4-(3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]-1-methylcyclobutanol;
3-amino-1-methyl-3-[4-(2-methyl-3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]cyclobutanol;
1-[4-(2-methyl-3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]cyclobutanamine;
1-[4-(3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]methanamine;
3-Amino-1-cyclopropyl-3-[4-(6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutanol;
1-[4-(6-Phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;
1-[4-(3-Bromo-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;
1-[4-(6-Phenyl-3-vinyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;
1-{4-[3-(2-Methoxy-phenyl)-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutylamine;
7-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-imidazo[1,2-a]pyrimidine-3-carbonitrile;
7-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-imidazo[1,2-a]pyrimidine-3-carboxylic acid amide;
1-[4-(3-Chloro-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;
1-[4-(3-Methyl-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;
1-{4-[3-(2-Cyclopropyl-vinyl)-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutylamine;
1-[4-(2,6-Diphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;
1-[4-(3-Bromo-2,6-diphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;
1-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-2,6-diphenyl-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutylamine;
1-[4-(2,6-Diphenyl-3-vinyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;
1-[4-(2-Ethyl-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;
1-[4-(6-Phenyl-2-trifluoromethyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;
7-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-imidazo[1,2-a]pyrimidine-2-carboxylic acid ethyl ester;
7-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-imidazo[1,2-a]pyrimidine-2-carboxylic acid;
7-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-imidazo[1,2-a]pyrimidine-2-carboxylic acid methyl ester;
1-{4-[2-(4-Fluoro-phenyl)-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutylamine;
1-[4-(6-Phenyl-2-p-tolyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;
1-[4-(3-Bromo-6-phenyl-2-trifluoromethyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;
1-[4-(3-Methyl-2,6-diphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine
1-[4-(2,3,6-Triphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;
1-[4-(3-Cyclopropyl-2,6-diphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;
1-{4-[2,6-Diphenyl-3-(2,3,4-trifluoro-phenyl)-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutylamine;
1-[4-(2,6-Diphenyl-3-propenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;
or a tautomer thereof;
or a pharmaceutically acceptable salt or stereoisomer thereof.
4. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 1 .