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 compound of the general formula I
or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein:
X 1 , X 2 , X 3 , X 4 are each carbon where one is substituted with Z and the rest independently with Y; or one of X 1 , X 2 , X 3 , X 4 is N, and the others are carbon where one carbon is substituted with Z and the rest independently with Y;
A is a ring selected from:
where D is selected from H, C 1-4 alkyl, halogen, amino;
Q is a bond, halogen, C 1-4 alkyl, O, S, SO, SO 2 , CO, CS;
W is:
(i) NR1R2 where R1 and R2 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 R1 and R2 are joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR3; and R3 is selected from H, C 1-4 alkyl, aryl, hetaryl, C 1-4 alkyl aryl, C 1-4 alkyl hetaryl, COR4 where R4 is selected from H, C 1-4 alkyl, aryl, 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, C 1-4 alkyl cyclohetalkyl;
Y is H, halogen, CN, CF 3 , nitro, OH, C 1-4 alkyl, C 1-4 alkylNR5R6, C 1-4 alkylhetaryl, OC 1-4 alkyl, OC 2-4 alkylOC 1-4 alkyl, OC 1-4 alkylNR5R6, OC 1-4 alkylhetaryl, OC 1-4 alkylcyclohetalkyl, SC 1-4 alkyl, SC 2-4 alkylOC 1-4 alkyl, SC 1-4 alkylNR5R6, NR5R6, NR5COR6, NR5SO 2 R6; and R5 and R6 are each independently H, C 1-4 alkyl, or may be joined to form an optionally substituted 3-6 membered ring optionally containing an atom selected from O, S, NR7 and R7 is selected from H, C 1-4 alkyl, aryl, hetaryl, C 1-4 alkylaryl, C 1-4 alkylhetaryl;
Z is selected from:
where R8 is selected from H, C 1-4 alkyl;
R9 and R10 are independently selected from H, C 1-4 alkyl, C 1-4 alkylNR12R13, C 1-4 alkylOR12, C 1-4 alkylhetaryl or may be joined to form a 5-8 membered ring containing an atom selected from SO, or SO 2 ;
R11 is selected from OH, OC 1-4 alkyl, NR12R13;
n is 0-4;
where R12 and R13 are independently selected from H, C 1-4 alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR14; and R14 is selected from H, C 1-4 alkyl.
2 . A compound according to claim 1 wherein the compound of formula I is a compound of formula II:
or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein:
X 1 , X 2 , X 3 , X 4 are each carbon where one is substituted with Z and the rest independently with Y; or one of X 1 , X 2 , X 3 , X 4 is N, and the others are carbon where one carbon is substituted with Z and the rest independently with Y;
A is a ring selected from:
where D is selected from H, C 1-4 alkyl, halogen, amino;
Q is a bond, halogen, C 1-4 alkyl, O, S, SO, SO 2 , CO, CS;
W is:
(i) NR1R2 where R1 and R2 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 R1 and R2 are joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR3; and R3 is selected from H, C 1-4 alkyl, aryl, hetaryl, C 1-4 alkyl aryl, C 1-4 alkyl hetaryl, COR4 where R4 is selected from H, C 1-4 alkyl, aryl, hetaryl; or
(ii) W is 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, C 1-4 alkyl cyclohetalkyl;
Y is H, halogen, CN, CF 3 , nitro, OH, C 1-4 alkyl, C 1-4 alkylNR5R6, C 1-4 alkylhetaryl, OC 1-4 alkyl, OC 2-4 alkylOC 1-4 alkyl, OC 1-4 alkylNR5R6, OC 1-4 alkylhetaryl, OC 1-4 alkylcyclohetalkyl, SC 1-4 alkyl, SC 2-4 alkylOC 1-4 alkyl, SC 1-4 alkylNR5R6, NR5R6, NR5COR6, NR5SO 2 R6; and R5 and R6 are each independently H, C 1-4 alkyl, or may be joined to form an optionally substituted 3-6 membered ring optionally containing an atom selected from O, S, NR7 and R7 is selected from H, C 1-4 alkyl, aryl, hetaryl, C 1-4 alkylaryl, C 1-4 alkylhetaryl;
Z is selected from:
where R8 is selected from H, C 1-4 alkyl;
R9 and R10 are independently selected from H, C 1-4 alkyl, C 1-4 alkylNR12R13, C 1-4 alkylOR12, C 1-4 alkylhetaryl or may be joined to form a 5-8 membered ring containing an atom selected from SO, or SO 2 ;
R11 is selected from OH, OC 1-4 alkyl, NR12R13;
n is 0-4;
where: R12 and R13 are independently selected from H, C 1-4 alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR14; and R14 is selected from H, C 1-4 alkyl.
3 . A compound selected from the group consisting of:
4 . A compound according to claim 1 , wherein the compound irreversibly inhibits JAK-3.
5 . A compound according to claim 1 , wherein the compound selectively inhibits JAK 3 with respect to JAK1 or JAK 2.
6 . A composition comprising a carrier and a compound according to claim 1 .
7 . A method of treating a tyrosine kinase-associated disease state, the method comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition thereof.
8 . (canceled)
9 . A method of suppressing the immune system of a subject, the method comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition thereof.
10 . A selective JAK 3 inhibitor comprising a functionality wherein the functionality is positioned to selectively interact with the Cysteine residue close to the front lip of the ATP-binding cavity of JAK3 (CYS909) whereby the inhibitor is selective for JAK3 with respect to JAK2 and JAK1.
11 . A selective JAK3 inhibitor according to claim 10 wherein the functionality irreversibly binds with the Cysteine residue.
12 . A selective JAK3 inhibitor according to claim 10 wherein the functionality is an alkylating group.
13 . A selective JAK3 inhibitor according to claim 10 , wherein the functionality is a Michael acceptor.