Nicotinamide-based kinase inhibitors
A compound of the general formula (I) or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof is described. A method of treating tyrosine kinase-associated disease states in a subject using a compound of formula (I) is also described.
1. A compound of formula I
or a pharmaceutically acceptable salt or diastereomer thereof, wherein:
A is NR 1 , where R 1 is H or C 1-4 alkyl;
B is phenyl optionally substituted with 0-4 substituents independently selected from halogen, C 1-4 alkyl, CF 3 , CN, aryl, OH, OCF 3 , OC 1-4 alkyl, OC 2-5 alkylNR 2 R 3 , Oaryl, CO 2 R 2 , CONR 2 R 3 , NR 2 R 3 , NR 4 C 1-4 alkylNR 2 R 3 , NR 2 COR 3 , OC(O)NR 2 R 3 , NR 4 CONR 2 R 3 , and NR 2 SO 2 R 3 ;
wherein R 2 and R 3 are each independently H, C 1-4 alkyl, aryl, or C 1-4 alkyl aryl;
wherein R 4 is H or C 1-4 alkyl; and
wherein R 5 is H or C 1-4 alkyl;
Q is a bond when W is absent, and is C 1-4 alkyl when W is present;
W is selected from H, C 1-4 alkyl, and C 2-6 alkenyl; where C 1-4 alkyl or C 2-6 alkenyl may be optionally substituted with C 1-4 alkyl, OH, OC 1-4 alkyl, NR 6 C(O)R 7 , CONR 6 R 7 , OR 6 , or NR 6 R 7 ;
wherein R 6 and R 7 are each independently H, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, or aryl, and
Y is phenyl, optionally substituted with 0-3 substituents independently selected from halogen, C 1-4 alkyl, CF 3 , aryl, OH, OCF 3 , C 2-4 alkynyl, OC 1-4 alkyl, OC 2-5 alkylNR 9 R 10 , Oaryl, CONR 9 R 10 , C 1-4 alkylNR 9 R 10 , NR 11 C 1-4 alkylNR 9 R 10 , NR 9 COR 10 , NR 11 CONR 9 R 10 , and NR 9 SO 2 R 10 ;
wherein R 9 and R 10 are each independently H, C 1-4 alkyl, aryl, or C 1-4 alkyl aryl; and
wherein R 11 is H or C 1-4 alkyl.
2. A compound according to claim 1 or a pharmaceutically acceptable salt or diastereomer thereof, wherein:
W is selected from H, C 1-4 alkyl, and C 2-6 alkenyl; wherein C 1-4 alkyl or C 2-6 alkenyl may be optionally substituted with C 1-4 alkyl, OH, OC 1-4 alkyl, or NR 6 R 7 ;
wherein R 6 and R 7 are each independently H, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, aryl;
Y is phenyl optionally substituted with 0-3 substituents independently selected from halogen, C 1-4 alkyl, CF 3 , aryl, OH, OCF 3 , OC 1-4 alkyl, OC 2-5 alkylNR 9 R 10 , Oaryl, CONR 9 R 10 , C 1-4 alkylNR 9 R 10 , NR 11 C 1-4 alkylNR 9 R 10 , NR 9 COR 10 , NR 11 CONR 9 R 10 , and NR 9 SO 2 R 10 ;
wherein R 9 and R 10 are each independently H, C 1-4 alkyl, aryl, or C 1-4 alkyl aryl; and
wherein R 11 is H or C 1-4 alkyl.
3. A compound selected from the group consisting of:
and pharmaceutically acceptable salts or diastereomers thereof.
4. A pharmaceutical composition comprising a carrier and at least one compound of claim 1 .
5. A pharmaceutical composition comprising a carrier and at least one compound of claim 2 .
6. A pharmaceutical composition comprising a carrier and at least one compound of claim 3 .