Benzimidazoles as selective kinase inhibitors
A compound of the general formula (I) or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein A represents a variety of six membered nitrogen containing heterocyclic rings, Q is a bond, halogen, C 1-4 alkyl, O, S, SO 2 , CO or CS and X 1 , X 2 , X 3 and X 4 are optionally substituted by 9 specific substituents or one can be nitrogen. Compositions comprising a carrier and at least one compound of formula (I) are also provided. Further provided are methods of treating tyrosine kinase-associated disease states by administering a compound of formula (I) and methods of suppressing the immune system of a subject by administering a compound of formula (I).
1. A Janus kinase inhibitor compound of formula I
or a pharmaceutically acceptable salt or diastereomer thereof, wherein:
one carbon of ring B is substituted with Z and the rest of the carbons are independently substituted with Y;
A is a ring selected from:
where D is selected from H, C 1-4 alkyl, halogen, and amino;
W is:
(i) NR 1 R 2 where R 1 and R 2 are independently H, C 1-4 alkyl, C 1-4 alkylCF 3 , aryl, hetaryl, C 1-4 alkylaryl, C 1-4 alkylhetaryl, C 3-8 cycloalkyl, C 2-6 alkenyl, cyclohetalkyl, C 1-4 alkylcycloalkyl, C 1-4 alkyl cyclohetalkyl, or R 1 and R 2 are joined to form a 3-8 membered ring optionally containing an atom selected from O, S, and NR 3 ; and R 3 is selected from H, C 1-4 alkyl, aryl, hetaryl, C 1-4 alkyl aryl, C 1-4 alkyl hetaryl, and COR 4 where R 4 is selected from H, C 1-4 alkyl, aryl, and hetaryl; or
(ii) H, C 1-4 alkyl, aryl, hetaryl, C 3-8 cycloalkyl, cyclohetalkyl, C 1-4 alkylaryl, C 1-4 alkylhetaryl, C 3-8 cycloalkyl, C 1-4 alkylcycloalkyl, or C 1-4 alkyl cyclohetalkyl;
Y is H, halogen, CN, CF 3 , nitro, OH, C 1-4 alkyl, C 1-4 alkylNR 5 R 6 , C 1-4 alkylhetaryl, OC 1-4 alkyl, OC 2-4 alkylOC 1-4 alkyl, OC 1-4 alkylNR 5 R 6 , OC 1-4 alkylhetaryl, OC 1-4 alkylcyclohetalkyl, SC 1-4 alkyl, SC 2-4 alkylOC 1-4 alkyl, SC 1-4 alkylNR 5 R 6 , NR 5 R 6 , NR 5 COR 6 , or NR 5 SO 2 R 6 ; and R 5 and R 6 are each independently H, C 1-4 alkyl, or may be joined to form a 3-6 membered ring optionally containing an atom selected from O, S, and NR 7 and R 7 is selected from H, C 1-4 alkyl, aryl, hetaryl, C 1-4 alkylaryl, and C 1-4 alkylhetaryl;
Z is selected from:
where R 8 is selected from H and C 1-4 alkyl;
R 9 and R 10 are independently selected from H, C 1-4 alkyl, C 1-4 alkylNR 12 R 13 , C 1-4 alkylOR 12 , and C 1-4 alkylhetaryl or may be joined to form a 5-8 membered ring containing an atom selected from SO, or SO 2 ;
R 11 is selected from OH, OC 1-4 alkyl, and NR 12 R 13 ;
n is 0, 1, 2, 3, or 4;
where R 12 and R 13 are independently selected from H and C 1-4 alkyl, or may be joined to form a 3-8 membered ring optionally containing an atom selected from O, S, and NR 14 ; and R 14 is selected from H and C 1-4 alkyl.
2. A compound according to claim 1 wherein Z is selected from:
3. A pharmaceutical composition comprising a carrier and a compound according to claim 1 .
4. A compound selected from the group consisting of:
and pharmaceutically acceptable salts and diastereomers thereof.