Selective Kinase Inhibitors

Abstract

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.