Pyrazolopyridinone compounds

Abstract

The invention relates to new pyrazolopyridinone compounds, to pharmaceutical compositions comprising said compounds, to processes for the preparation of said compounds and to the use of said compounds as FGFR (fibroblast growth factor receptor) inhibitors and to their use in the treatment of diseases, e.g. cancer.

What is claimed is: 
     
         1 . A method for the prophylaxis or treatment of a disease state or condition mediated by a FGFR kinase, which method comprises administering to a subject in need thereof a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a tautomeric or stereochemically isomeric form thereof, wherein:
 A 1 , A 2 , A 3  and A 4  are each, independently, CH, CR a1 , CR a2  or N; provided that when one or more of A 1 , A 2 , A 3  and A 4  is a substituted carbon atom, at least one of said substituted carbon atoms is CR a1 , and provided that maximum three of A 1 , A 2 , A 3  and A 4  are CR a1  or CR a2 ; 
 C1 is hydrogen or C 1-4 alkyl; 
 C2 is hydrogen, C 1-4 alkyl, hydroxyl or C 1-4 alkoxy; 
 or C1 and C2 are taken together to form a C 3-6 cycloalkyl together with the carbon atom to which they are attached; 
 each R a1  independently is halo, C 1-6 alkyl, haloC 1-6 alkyl, cyano, —OR c , —N(R c ), —C(═O)—N(R c ) 2 , —S(═O)—C 1-6 alkyl, —S(═O) 2 —C 1-6 alkyl or C 3-6 cycloalkyl; 
 each R a2  independently is C 1-6 alkyl, haloC 1-6 alkyl, halo, C 1-6 alkoxy, carboxyl, C 1-6 alkyloxycarbonyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano, cyanoC 1-6 alkyl, hydroxyC 1-6 alkyl, —C(═O)—NH 2 , —C(═O)—NH(C 1-4 alkyl), —C(═O)—N(C 1-4 alkyl) 2 , or a 3 to 6 membered monocyclic saturated heterocyclyl containing at least one heteroatom that is N, O or S; 
 R c  is hydrogen, C 1-4 alkyl or C 1-4 alkyloxyC 1-4 alkyl; 
 R b  is hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyloxycarbonyl, C 2-6 alkenyl, C 2-6 alkynyl, cyanoC 1-6 alkyl, hydroxyC 1-6 alkyl, —C(═O)—NH 2 , —C(═O)—NH(C 1-4 alkyl), —C(═O)—N(C 1-4 alkyl) 2 , C 3-6 cycloalkyl, phenyl, a 3 to 6 membered monocyclic heterocyclyl containing at least one heteroatom that is N, O or S, or C 1-6 alkyl substituted with C 3-6 cycloalkyl, phenyl, a 3 to 6 membered monocyclic heterocyclyl containing at least one heteroatom that is N, O or S; 
 B is a 3 to 12 membered carbocyclyl or a 3 to 12 membered heterocyclyl containing at least one heteroatom that is N, O or S, wherein said carbocyclyl and heterocyclyl are each optionally substituted with 1 to 5 R substituents; 
 each R independently is C 1-6 alkyl, cyano, halo, C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyl, hydroxyC 1-6 alkyl, haloC 1-6 alkyl, oxo, —SO 2 —NH 2 , —SO 2 —NH(C 1-4 alkyl), —SO 2 —N(C 1-4 alkyl) 2 , —NH—C(═O)—C 2-6 alkenyl, —C(═O)—C 1-6 alkyl, —C(═O)—C 2-6 alkenyl, C 1-6 alkyl-O—C(═O)—, C 3-6 cycloalkyl, phenyl, or a 3 to 6 membered monocyclic heterocyclyl containing at least one heteroatom that is N, O or S; 
 
         or a pharmaceutically acceptable salt thereof or a solvate thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the compound is of formula (I-a): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 1 , wherein each R a1  independently is halo, —OR c , —N(R c ) 2 , or —C(═O)—N(R c ) 2 . 
     
     
         4 . The method of  claim 3 , wherein R a1  is, independently, —OR c , —N(R c ) 2 , or —C(═O)—N(R c ) 2 . 
     
     
         5 . The method of  claim 1 , wherein the compound is of formula (I-A) or (I-A-a): 
       
         
           
           
               
               
           
         
         wherein n is an integer equal to 0, 1 or 2. 
       
     
     
         6 . The method of  claim 1 , wherein the compound is of formula (I-B) or (I-B-a): 
       
         
           
           
               
               
           
         
         wherein n is an integer equal to 0, 1 or 2. 
       
     
     
         7 . The method of  claim 1 , wherein the compound is of formula (I-C) or (I-C-a): 
       
         
           
           
               
               
           
         
         wherein n is an integer equal to 0, 1 or 2. 
       
     
     
         8 . The method of  claim 1 , wherein the co R und is of formula I-D or I-D-a 
       
         
           
           
               
               
           
         
         wherein n is an integer equal to 0, 1 or 2. 
       
     
     
         9 . The method of  claim 1 , wherein each R a2  independently is halo or C 1-6 alkoxy. 
     
     
         10 . The method of  claim 1 , wherein the compound is of formula (I-E) or (I-E-a) 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 1 , wherein C 1  is hydrogen and C 2  is C 1-4 alkyl. 
     
     
         12 . The method of  claim 1 , wherein C 1  and C 2  are hydrogen. 
     
     
         13 . The method of  claim 1 , wherein C 1  and C 2  are C 1-4 alkyl. 
     
     
         14 . The method of  claim 1 , wherein R b  is C 1-4 alkyl. 
     
     
         15 . The method of  claim 1 , wherein B is a 5 or 6 membered heterocyclyl containing at least one heteroatom that is N, O or S, wherein said heterocyclyl is optionally substituted with 1 to 5 R substituents. 
     
     
         16 . The method of  claim 15 , wherein B is an aromatic heterocyclyl. 
     
     
         17 . The method of  claim 1 , wherein:
 A 1 , A 2 , A 3  and A 4  are each, independently, CH, CR a1 , CR a2 ; or one of A 1 , A 2 , A 3  and A 4  is N and the remaining A substituents are each, independently, CH, CR a1  or CR a2 ;   C1 is hydrogen or C 1-4 alkyl;   C2 is hydrogen or C 1-4 alkyl or C 1-4 alkoxy;   or C1 and C2 are taken together to form a C 3-6 cycloalkyl together with the carbon atom to which they are attached;   each R a1  independently is halo, —OR c , —N(R c ) 2 , or —C(═O)—N(R c ) 2 ;   each R a2  independently is halo or C 1-6 alkoxy;   R b  is C 1-6 alky;   B is a 5 or 6 membered aromatic monocyclic heterocyclyl containing at least one heteroatom that is N, O or S, wherein said heterocyclyl is optionally substituted with 1 R substituent; or   B is an unsubstituted 5 or 6 membered aromatic monocyclic heterocyclyl containing at least one heteroatom that is N, O or S.   
     
     
         18 . The method of  claim 17 , wherein:
 C1 is hydrogen or methyl; or   C2 is hydrogen, methyl or methoxy; or   C1 and C2 are taken together to form a cyclopropyl; or   R a1  is, independently, halo, —O—C 1-4 alkyl, —O—C 1-4 alkyloxyC 1-4 alkyl, —NH 2 , —N(C 1-4 alkyl) 2 , —C(═O)—NH 2  or —C(═O)—N(C 1-4 alkyl) 2 ; or   R a2  is, independently, halo or C 1-4 alkoxy; or   R b  is C 1-4 alkyl; or   B is pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl, or oxazolyl.   
     
     
         19 . The method of  claim 18 , wherein B is pyridyl, pyrimidinyl or oxazolyl. 
     
     
         20 . The method of  claim 17 , wherein B is an unsubstituted 5 or 6 membered aromatic monocyclic heterocyclyl containing at least one heteroatom that is N, O or S. 
     
     
         21 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof or a solvate thereof. 
       
     
     
         22 . The method of  claim 21 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof or a solvate thereof. 
       
     
     
         23 . The method of  claim 21 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof or a solvate thereof. 
       
     
     
         24 . The method of  claim 21 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof or a solvate thereof. 
       
     
     
         25 . The method of  claim 21 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof or a solvate thereof. 
       
     
     
         26 . The method of  claim 21 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof or a solvate thereof. 
       
     
     
         27 . The method of  claim 1 , wherein the disease state or condition is cancer. 
     
     
         28 . The method of  claim 27 , wherein the cancer is a cancer harboring FGFR3 V555M.