Pyrazinopyrazines and Derivatives as Kinase Inhibitors

Abstract

This invention relates to compounds of the general formula: in which the variable groups are as defined herein, and to their preparation and use.

1 . A compound of Formula I, a tautomer, a pharmaceutically acceptable salt and a solvate thereof: 
       
         
           
           
               
               
           
         
         wherein 
         W 1  represents an aryl, a 3- to 8-membered carbocyclyl, a 5-, 6- or 7-membered heterocyclic or heteroaryl ring comprising carbon atoms and 1-4 heteroatoms independently selected from O, N, P(O) and S(O) r  and W 1  is optionally substituted with 1-5 R a  groups; 
         W 2  represents an aryl or a 5- or 6-membered heteroaryl ring comprising carbon atoms and 1-3 heteroatoms independently selected from O, N, P(O) and S(O) r , and W 2  is optionally substituted with 1-5 R b  groups; 
         Q is N or CR c ; 
         L 1  and L 2  are independently selected from the group consisting of a bond, C 1-6 -alkyl, O—C 0-6 -alkyl, NR 1 —C 0-6 -alkyl, C(O)NR 1 —C 0-6 -alkyl, NR 1 C(O)—C 0-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 0-6 -alkyl-S(O) r , C 0-6 -alkyl-S(O) 2 NR 1 , C 0-6 -alkyl-NR 1 S(O) 2 , C(O)—C 0-6 -alkyl, OC(O)NR 1 —C 0-6 -alkyl, NR 1 C(O)O—C 0-6 -alkyl, NR 1 C(O)NR 1 —C 0-6 -alkyl; and the linkers L 1  and L 2  can be included in either direction; 
         R a  and R b  are independently selected from the group consisting of halo, —CN, —NO 2 , —R 1 , —OR 2 , —O—NR 1 R 2 , —NR 1 R 2 , —NR 1 —NR 1 R 2 , —NR 1 —OR 2 , —C(O)YR 2 , —OC(O)YR 2 , —NR 1 C(O)YR 2 , —SC(O)YR 2 , —NR 1 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 1 )YR 2 , —YC(═N—OR 1 )YR 2 , —YC(═N—NR 1 R 2 )YR 2 , —YP(═O)(YR 3 )(YR 3 ), —Si(R 3 ) 3 , —NR 1 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 1 R 2  and NR 1 SO 2 NR 1 R 2 ; alternatively two adjacent R a  or two adjacent R b  can form with the atoms to which they are attached, a 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-3 heteroatoms selected from N, O, P(O) and S(O) r ; 
         R c  is selected from the group consisting of halo, —R 3 , —OR 2  and —SR 2 ; 
         wherein each Y is independently a bond, —O—, —S— or —NR 1 —; 
         r is 0, 1 or 2; 
         n is 1 or 2; 
         each occurrence of R 1  and R 2  is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; 
         each occurrence of R 3  is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; 
         alternatively, each NR 1 R 2  moiety may be a 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 additional heteroatoms selected from N, O, P(O) and S(O) r ; and 
         each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclic moiety is optionally substituted. 
       
     
     
         2 . A compound of  claim 1  in which n is 1. 
     
     
         3 . A compound of  claim 1  in which n is 2. 
     
     
         4 . A compound of any of  claims 1  to  3  in which Q is N. 
     
     
         5 . A compound of any of  claims 1  to  3  in which Q is CR c . 
     
     
         6 . A compound of  claim 5  in which R c  is an alkyl. 
     
     
         7 . A compound of  claim 5  in which R c  is halo. 
     
     
         8 . A compound of any of  claims 1  to  3  in which L 1  is a bond. 
     
     
         9 . A compound of any of  claims 1  to  3  in which L 1  is C(O)C 0-6 alkyl. 
     
     
         10 . A compound of any of  claims 1  to  3  in which L 1  is C(O)NHC 0-6 alkyl 
     
     
         11 . A compound of any of  claims 1  to  3  and  8  to  10  in which W 1  is aryl. 
     
     
         12 . A compound of any of  claims 1  to  3  and  8  to  10  in which W 1  is 5- or 6-membered heteroaryl. 
     
     
         13 . A compound of any of  claims 1  to  3  and  8  to  10  in which W 1  is a 5-, 6- or 7-membered heterocyclyl. 
     
     
         14 . A compound of any of  claims 1  to  3  and  8  to  10  in which W 1  is a 3- to 8-membered carbocyclyl. 
     
     
         15 . A compound of any of  claims 1  to  3  in which L 2  is CH 2  or CH(CH 3 ). 
     
     
         16 . A compound of  claim 15  in which L 2  is CH 1 . 
     
     
         17 . A compound of  claim 15  having the following formulae: 
       
         
           
           
               
               
           
         
         in which R is CH 3  or H. 
       
     
     
         18 . A compound of  claim 15  having the following formulae: 
       
         
           
           
               
               
           
         
       
     
     
         19 . A compound of  claim 17  having the formulae: 
       
         
           
           
               
               
           
         
       
     
     
         20 . A compound of  claim 19  in which Q is N. 
     
     
         21 . A compound of  claim 19  in which Q is CR c . 
     
     
         22 . A compound of  claim 21  in which R c  is a lower alkyl or halo. 
     
     
         23 . A compound of  claim 19  in which n is 1. 
     
     
         24 . A compound of  claim 19  in which n is 2. 
     
     
         25 . A compound of  claim 19  in which W 1  and W 2  are aryl optionally substituted with 1-5 R a  and 1-5 R b  respectively; and R is H. 
     
     
         26 . A compound of  claim 19  in which W 1  is a 5- or 6-membered heteroaryl optionally substituted with 1-5 R a  and W 2  is an aryl optionally substituted with 1-5 R b  respectively; and R is H. 
     
     
         27 . A compound of any of  claims 1  to  3  in which L 2  is C(O)C 0-6 alkyl. 
     
     
         28 . A compound of  claim 27  in which L 2  is C(O). 
     
     
         29 . A compound of  claim 27  in which L 2  is C(O)CH 2 . 
     
     
         30 . A compound of  claim 27  having the following formulae: 
       
         
           
           
               
               
           
         
       
     
     
         31 . A compound of  claim 30  in which W 1  and W 2  are aryl optionally substituted with 1-5 R a  and 1-5 R b  respectively. 
     
     
         32 . A compound of  claim 30  in which W 1  is a 5- or 6-membered heteroaryl optionally substituted with 1-5 R a , W 2  is an aryl optionally substituted with 1-5 R b . 
     
     
         33 . A compound of  claim 30  in which Q is N. 
     
     
         34 . A compound of  claim 30  in which Q is CR c . 
     
     
         35 . A compound of  claim 34  in which R c  is a lower alkyl or halo. 
     
     
         36 . A compound of  claim 30  in which n is 1. 
     
     
         37 . A compound of  claim 30  in which n is 2. 
     
     
         38 . A method for treating cancer in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of any of the  claims 1  to  37 ; or a pharmaceutically acceptable salt, solvate or hydrate thereof. 
     
     
         39 . A method of  claim 38  in which the cancer is non-small-cell lung cancer, gliosblastoma, neuroblastoma, esophageal carcinomas, diffuse large B-cell lymphomas, breast cancer, rhabdomyosarcomas, anaplastic large-cell lymphomas and inflammatory myofibroblastic tumors. 
     
     
         40 . A composition comprising a compound of any of  claims 1  to  37 ; or a pharmaceutically acceptable salt, solvate or hydrate thereof and a pharmaceutical carrier, diluent or vehicle.