5-(pyrimidin-4-yl)thiazol-2-yl urea derivatives as therapeutic agents

Abstract

A novel class of inhibitors of protein kinases useful in the treatment of proliferative cell diseases and conditions including cancers, and especially those characterised by over-expression of CDK8 and/or one or more aberrant CDK8 activity, including certain cancers of lung, breast, brain, ovary, prostate, colorectal cancer and leukaemias. The inhibitors have the general structure I.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are each independently selected from the group consisting of H, alkyl, alkyl-R 10 , aralkyl, aralkyl-R 10 , heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aryl-R 10 , heteroaryl, halogen, NO 2 , CHO, CN, CHF 2 , CF 3 , OH, O, O—CHF 2 , O—CF 3 , O-alkyl, O-alkyl-R 10 , O-heteroalkyl, O-cycloalkyl, O-heterocycloalkyl, O-aryl, O-heteroaryl, O—R 10 , NH 2 , NH-alkyl, NH-alkyl-R 10 , NH-heteroalkyl, NH-cycloalkyl, NH-heterocycloalkyl, NH-aryl, NH-heteroaryl, NH—R 10 , N-(alkyl) 2 , N-(heteroalkyl) 2 , N-(cycloalkyl) 2 , N-(heterocycloalkyl) 2 , N-(aryl) 2 , N-(heteroaryl) 2 , N—(R 10 )(R 11 ), N-(alkyl)(R 10 ), N-(alkyl)(aryl), N-(heteroalkyl)(R 10 ), N-(cycloalkyl)(R 10 ), N-(heterocycloalkyl)(R 10 ), N-(aryl)(R 10 ), N-(heteroaryl)(R 10 ), SH-alkyl, SH-alkyl-R 10 , SH-heteroalkyl, SH-cycloalkyl, SH-heterocycloalkyl, SH-aryl, SH-heteroaryl, S-(alkyl) 2 , S-heteroalkyl, S—C 1-6  alkyl, S—CF 3 , SO 2 CF 3 , S-(cycloalkyl) 2 , S-(heterocycloalkyl) 2 , S-(aryl) 2 , S-(heteroaryl) 2 , S-(alkyl)(aryl), SH—R 10 , S—(R 10 )(R 11 ), S-(alkyl)(R 10 ), S-(heteroaryl)(R 10 ), S-(cycloalkyl)(R 10 ), S-(heterocycloalkyl)(R 10 ), S-(aryl)(R 10 ), S-(heteroaryl)(R 10 ), COOH, CONH 2 , CONH-alkyl, CONH-aryl, CON-(alkyl)(R 10 ), CON(aryl)(R 10 ), CON(heteroaryl)(R 10 ), CONH—R 10 , CON—(R 10 )(R 11 ), SO 3 H, SO 2 -alkyl, SO 2 -alkyl-R 10 , SO 2 -aryl, SO 2 -aryl-R 10 , SO 2 NH 2 , SO 2 NH—R 10 , SO 2 N—(R 10 )(R 11 )CO-alkyl, CO-alkyl-R 10 , CO-aryl, CO-aryl-R 10 , CO—R 10 , COOR 10 , and R 12 , 
         and wherein R 10  and R 11  are each independently selected from the group consisting of H, alkyl, alkyl-R 13 , heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halogen, NO 2 , CN, CF 3 , OH, O-alkyl, O-alkyl-R 13 , O-heteroalkyl, O-cycloalkyl, O-heterocycloalkyl, O-aryl, O-heteroaryl, O—R 13 , NH 2 , NH-alkyl, NH-alkyl-R 13 , NH-heteroalkyl, NH-cycloalkyl, NH-heterocycloalkyl, NH-aryl, NH-heteroaryl, NH—R 13 , N-(alkyl) 2 , N-(heteroalkyl) 2 , N-(cycloalkyl) 2 , N-(heterocycloalkyl) 2 , N-(aryl) 2 , N-(heteroaryl) 2 , N—(R 13 )(R 14 ), N-(alkyl)(R 13 ), N-(heteroalkyl)(R 13 ), N-(cycloalkyl)(R 13 ), N-(heterocycloalkyl)(R 13 ), N-(aryl)(R 13 ), N-(heteroaryl)(R 13 ), SH-alkyl, SH-alkyl-R 13 , SH-heteroalkyl, SH-cycloalkyl, SH-heterocycloalkyl, SH-aryl, SH-heteroaryl, S-(alkyl) 2 , S-(cycloalkyl) 2 , S-(heterocycloalkyl) 2 , S-(aryl) 2 , S-(heteroaryl) 2 , S-(alkyl)(aryl), SH—R 13 , S—(R 13 )(R 14 ), S-(alkyl)(R 13 ), S-(heteroaryl)(R 13 ), S-(cycloalkyl)(R 13 ), S-(heterocycloalkyl)(R 13 ), S-(aryl)(R 13 ), S-(heteroaryl)(R 13 ), COOH, COO-alkyl, CONH 2 , CONH-alkyl, CONH-aryl, CON-(alkyl)(R 13 ), CON(aryl)(R 13 ), CON(heteroaryl)(R 13 ), CONH—R 13 , CON—(R 13 )(R 14 ), SO 3 H, SO 2 -alkyl, SO 2 -alkyl-R 13 , SO 2 -aryl, SO 2 -aryl-R 13 , SO 2 NH 2 , SO 2 NH—R 13 , SO 2 N—(R 13 )(R 14 ), CO-alkyl, CO-alkyl-R 13 , CO-aryl, CO-aryl-R 13 , CO—R 13 , COOR 13 , and R 12 , 
         and wherein said heterocycloalkyl and heteroaryl groups comprise at least one but no more than two heteroatoms selected from N, S and O, and wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aralkyl, aryl and heteroaryl groups may be optionally substituted with one or more groups selected from halogen, CN, OH, O-methyl, C 1-6  alkyl, NH 2 , N—(C 1-6  alkyl) 2 , COOH, CO—C 1-6  alkyl, CONH 2 , SO 2 —C 1-6  alkyl, CF 3 ; and 
         R 12 , R 13  and R 14  are independently selected from water solubilising groups; 
         or a pharmaceutically acceptable salt, solvate or prodrug thereof; 
         and wherein the compound is not N-[5-(2-methyl-4-pyrimidinyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-N′-phenylurea. 
       
     
     
         2 . A compound according to  claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are each independently selected from the group consisting of H, alkyl, alkyl-R 10 , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halogen, NO 2 , CHF 2 , CF 3 , CHO, CN, OH, O, O—CHF 2 , O—CF 3 , O-alkyl, O-heteroalkyl, O—C 3-8  cycloalkyl, O-aryl, O-heteroaryl, NH 2 , NH-alkyl, NH-heteroalkyl, NH-cycloalkyl, NH-heterocycloalkyl, NH-aryl, NH-heteroaryl, N(alkyl) 2 , N(cycloalkyl) 2 , N(heterocycloalkyl) 2 , N-(alkyl)(aryl), SH-alkyl, SH-aryl, SH-heteroaryl, S-heteroalkyl, S—C 1-6  alkyl, S—CF 3 , SO 2 CF 3 , S—(C 3-8  cycloalkyl) 2 , and R 12 . 
     
     
         3 . A compound according to  claim 1 , wherein R 1  is CH(C 1-6  alkyl) 2 , NH 2 , NH—C 1-6  alkyl or N(C 1-6  alkyl) 2 , or S—C 1-6  alkyl. 
     
     
         4 . A compound according to  claim 1 , wherein any one or more of R 2 , R 3  and R 4  is H. 
     
     
         5 . A compound according to  claim 1 , wherein R 3  is H, halogen or CN. 
     
     
         6 . A compound according to  claim 1 , wherein R 5  is selected from H, NH 2 , C 1-6  alkyl, halogen, O—C 1-3  alkyl, CHF 2 , CF 3  and CHO. 
     
     
         7 . A compound according to  claim 1 , wherein R 5  is selected from H and CF 3 . 
     
     
         8 . A compound according to  claim 1 , wherein R 6  is selected from H, NH 2 , C 1-6  alkyl, halogen, O—C 1-3  alkyl, CHF 2 , CF 3  and CHO. 
     
     
         9 . A compound according to  claim 1 , wherein R 6  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         10 . A compound according to  claim 1 , wherein R 7  is selected from H, NH 2 , NO 2 , C 1-6  alkyl, halogen, O—C 1-3  alkyl, CHF 2 , O—CHF 2 , CF 3 , O—CF 3 , S—C 1-3  alkyl, SCF 3 , SO 2 CF 3 , CN and CHO. 
     
     
         11 . A compound according to  claim 1 , wherein R 8  is selected from H, NH 2 , C 1-6  alkyl, halogen, O—C 1-3  alkyl, CHF 2 , CF 3  and CHO. 
     
     
         12 . A compound according to  claim 1 , wherein R 9  is selected from H, NH 2 , C 1-6  alkyl, halogen, O—C 1-3  alkyl, CHF 2 , CF 3  and CHO. 
     
     
         13 . A compound according to  claim 1 , wherein R 9  is H or a C 1-6  alkyl. 
     
     
         14 . A compound according to  claim 1 , wherein any one or more of R 2 , R 4  and R 8  is H. 
     
     
         15 . (canceled) 
     
     
         16 . A method of treating cancer or another proliferative cell disease or condition in a subject, the method comprising administering to said subject a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt, solvate or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier, diluent and/or excipient. 
     
     
         17 . (canceled) 
     
     
         18 . A pharmaceutical composition or medicament comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier, diluent and/or excipient. 
     
     
         19 . A method for modulating protein kinase activity in a cell, comprising introducing to or contacting said cell with an effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt, solvate or prodrug thereof. 
     
     
         20 . (canceled) 
     
     
         21 . A method of treating a disease or condition in a subject characterised by over-expression of CDK8 and/one or more aberrant CDK8 activity, the method comprising administering to said subject a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt, solvate or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier, diluent and/or excipient. 
     
     
         22 . (canceled)