Substituted pyrazolopyridines, compositions containing them, method for the production thereof, and their use

Abstract

The disclosure relates to substituted pyrazolo-pyridines, compositions containing them, methods for the production thereof, and to their use as medicaments, in particular, as anticancer agents.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       Formula (I) 
       in which:
 1) A is selected from the group consisting of: aryl, heteroaryl, substituted aryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; 
 2) L is selected from the group consisting of: bond, CO, NH, CO—NH, NH—CO, NH—SO, NH—SO 2 , SO 2 NH, NH—CH 2 , CH 2 —NH, CH 2 —CO—NH, NH—CO—CH 2 , NH—CH 2 —CO, CO—CH 2 —NH, NH—CO—NH, NH—CS—NH, NH—CO—O, and O—CO—NH; 
 3) A-L-Ar is 
 
       
         
           
           
               
               
           
         
          in which 
       
       X2 is C—CH 3 , CF or CH;
 4) one from X, Y, Z is chosen from N and NO and two others from Z, Y and X are C(R5) and C(R6); 
 5) R5 and R6 are independently selected from the group consisting of: H, halogen, R2, CN, O(R2), OC(O)(R2), OC(O)N(R2)(R3), OS(O 2 )(R2), N(R2)(R3), N═C(R2)(R3), N(R2)C(O)(R3), N(R2)C(O)O(R3), N(R4)C(O)N(R2)(R3), N(R4)C(S)N(R2)(R3), N(R2)S(O 2 )(R3), C(O)(R2), C(O)O(R2), C(O)N(R2)(R3), C(═N(R3))(R2), C(═N(OR3))(R2), S(R2), S(O)(R2), S(O 2 )(R2), S(O 2 )O(R2), and S(O 2 )N(R2)(R3); in which each R2, R3 and R4 is independently selected from the group consisting of H, alkyl, alkylene, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, substituted alkyl, substituted alkylene, substituted alkynyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted heterocyclyl, alkylene, substituted alkylene, and substituted alkynyl; in which R2 and R3 may be linked together to form a 4- to 8-membered ring containing from 1 to 3 hetero atoms chosen from O, N and S; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A compound according to  claim 1 , wherein R5 and R6 are independently selected from H, halogen, OMe and methyl. 
     
     
         3 . A compound according to  claim 2 , wherein R5 and R6 are selected from H and F. 
     
     
         4 . A compound according to  claim 1 , wherein L-A is chosen from NH—CO—NH-A and NH—SO 2 -A. 
     
     
         5 . A compound according to  claim 2 , wherein L-A is NH—CO—NH-A. 
     
     
         6 . A compound according to  claim 1 , wherein A is selected from the group consisting of phenyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, and benzothiazolyl; optionally substituted. 
     
     
         7 . A compound according to  claim 4 , wherein A is chosen from phenyl, pyrazolyl and isoxazolyl; optionally substituted. 
     
     
         8 . A compound according to  claim 2 , wherein A is substituted with a substituent selected from a first group consisting of (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkylene, (C2-C6)alkynyl, aryl, halogen, heteroaryl, O—(C1-C6)alkyl, O-Aryl, O-heteroaryl, S—(C1-C6)alkyl, S-Aryl and S-heteroaryl, each being optionally substituted with one or more substituents chosen from (C1-C3)alkyl, halogen and O—(C1-C3)alkyl. 
     
     
         9 . A compound according to  claim 5 , wherein A is substituted with a substituent selected from a first group consisting of (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkylene, (C2-C6)alkynyl, aryl, halogen, heteroaryl, O—(C1-C6)alkyl, O-Aryl, O-heteroaryl, S—(C1-C6)alkyl, S-Aryl and S-heteroaryl, each being optionally substituted with one or more substituents chosen from (C1-C3)alkyl, halogen and O—(C1-C3)alkyl. 
     
     
         10 . A compound according to  claim 2 , wherein A is substituted with a substituent selected from a second group consisting of F, Cl, Br, I, OH, SH, SO 3 M, COOM, CN, NO 2 , CON(R8)(R9), N(R8)CO(R9), (C1-C3)alkyl-OH, (C1-C3)alkyl-N(R8)(R9), (C1-C3)alkyl-(R10), (C1-C3)alkyl-COON and N(R8)(R9); in which R8 and R9 are independently chosen from H, (C1-C3)alkyl, (C1-C3)alkyl-OH, (C1-C3)alkyl-NH 2 , (C1-C3)alkyl-COOM, and (C1-C3)alkyl-SO 3 M; in which, when R8 and R9 are simultaneously other than H, they may be linked to form a 5- to 7-membered ring containing from 0 to 3 hetero atoms chosen from O, N and S; in which M is H or a cation of an alkali metal chosen from Li, Na and K; and in which R10 is H or an optionally substituted non-aromatic heterocycle, containing 2 to 7 carbon atoms and 1 to 3 hetero atoms chosen from N, O and S. 
     
     
         11 . A compound according to  claim 6 , wherein A is substituted with a substituent selected from a second group consisting of F, Cl, Br, I, OH, SH, SO 3 M, COOM, CN, NO 2 , CON(R8)(R9), N(R8)CO(R9), (C1-C3)alkyl-OH, (C1-C3)alkyl-N(R8)(R9), (C1-C3)alkyl-(R10), (C1-C3)alkyl-COON and N(R8)(R9); in which R8 and R9 are independently chosen from H, (C1-C3)alkyl, (C1-C3)alkyl-OH, (C1-C3)alkyl-NH 2 , (C1-C3)alkyl-COOM, and (C1-C3)alkyl-SO 3 M; in which, when R8 and R9 are simultaneously other than H, they may be linked to form a 5- to 7-membered ring containing from 0 to 3 hetero atoms chosen from O, N and S; in which M is H or a cation of an alkali metal chosen from Li, Na and K; and in which R10 is H or an optionally substituted non-aromatic heterocycle, containing 2 to 7 carbon atoms and 1 to 3 hetero atoms chosen from N, O and S. 
     
     
         12 . A compound according to  claim 2 , wherein A is phenyl or isoxazolyl substituted with halogen, (C1-C4)alkyl, (C1-C3)haloalkyl, O—(C1-C4)alkyl, S—(C1-C4)alkyl, O—(C1-C4)haloalkyl or S—(C1-C4)haloalkyl. 
     
     
         13 . A compound according to  claim 6 , wherein A is phenyl or isoxazolyl substituted with halogen, (C1-C4)alkyl, (C1-C3)haloalkyl, O—(C1-C4)alkyl, S—(C1-C4)alkyl, O—(C1-C4)haloalkyl or S—(C1-C4)haloalkyl. 
     
     
         14 . A compound according to  claim 2 , wherein A is substituted with one or more substituents, which may be identical or different, independently selected from the group consisting of F, Cl, Br, I, OH, SH, SO 3 M, COOM, CN, NO 2 , CON(R8)(R9), N(R8)CO(R9), (C1-C3)alkyl-OH, (C1-C3)alkyl-N(R8)(R9), (C1-C3)alkyl-(R10), (C1-C3)alkyl-COOH, N(R8)(R9), (C1-C6)alkyl, (C2-C6)alkylene, (C2-C6)alkynyl, aryl, heteroaryl, O—(C1-C6)alkyl, O-Aryl, O-heteroaryl, S—(C1-C6)alkyl, S-Aryl and S-heteroaryl, each being optionally substituted with one or more substituents chosen from (C1-C3)alkyl, halogen, and O—(C1-C3)alkyl; in which R8 and R9 are independently chosen from H, (C1-C3)alkyl, (C1-C3)alkyl-OH, (C1-C3)alkyl-NH 2 , (C1-C3)alkyl-COOM, and (C1-C3)alkyl-SO 3 M; in which, when R8 and R9 are simultaneously other than H, they may be linked to form a 5- to 7-membered ring containing from 0 to 3 hetero atoms chosen from O, N and S; in which M is H or a cation of an alkali metal chosen from Li, Na and K; and in which R10 is H or an optionally substituted non-aromatic heterocycle, containing 2 to 7 carbon atoms and 1 to 3 hetero atoms chosen from N, O and S. 
     
     
         15 . A compound according to  claim 6 , wherein A is substituted with one or more substituents, which may be identical or different, independently selected from the group consisting of F, Cl, Br, I, OH, SH, SO 3 M, COOM, CN, NO 2 , CON(R8)(R9), N(R8)CO(R9), (C1-C3)alkyl-OH, (C1-C3)alkyl-N(R8)(R9), (C1-C3)alkyl-(R10), (C1-C3)alkyl-COOH, N(R8)(R9), (C1-C6)alkyl, (C2-C6)alkylene, (C2-C6)alkynyl, aryl, heteroaryl, O—(C1-C6)alkyl, O-Aryl, O-heteroaryl, S—(C1-C6)alkyl, S-Aryl and S-heteroaryl, each being optionally substituted with one or more substituents chosen from (C1-C3)alkyl, halogen, and O—(C1-C3)alkyl; in which R8 and R9 are independently chosen from H, (C1-C3)alkyl, (C1-C3)alkyl-OH, (C1-C3)alkyl-NH 2 , (C1-C3)alkyl-COOM, and (C1-C3)alkyl-SO 3 M; in which, when R8 and R9 are simultaneously other than H, they may be linked to form a 5- to 7-membered ring containing from 0 to 3 hetero atoms chosen from O, N and S; in which M is H or a cation of an alkali metal chosen from Li, Na and K; and in which R10 is H or an optionally substituted non-aromatic heterocycle, containing 2 to 7 carbon atoms and 1 to 3 hetero atoms chosen from N, O and S. 
     
     
         16 . A compound according to  claim 8 , wherein A is 2-fluoro-5-trifluoromethylphenyl or 2-methoxy-5-trifluoromethylphenyl. 
     
     
         17 . A compound according to  claim 1 , selected from the group consisting of:
 1-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(2-fluoro-5-trifluoro-methylphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(2-methoxy-5-trifluoromethylphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(2-methylcarbonylamino-5-trifluoromethylphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(2-ethoxy-5-trifluoro-methylphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(2-fluoro-5-methyl-phenyl)urea;   3-{3-[4-(3-amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]ureido}-4-methoxybenzoic acid;   1-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(2-hydroxy-5-trifluoro-methylphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(3,4-dimethylphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(2-methoxy-5-tert-butylphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(3-trifluoromethyl-4-methylphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(3-chloro-4-methylphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(3-ethylphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-1,3-benzodioxol-5-yl-urea;   1-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(3-chloro-4-methoxyphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(2-methoxy-5-chlorophenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(2-ethoxyphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(2-methoxy-5-methylphenyl)urea; and   N-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-2,3-dichlorobenzene-sulfonamide;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         18 . A compound according to  claim 1 , selected from the group consisting of:
 1-[4-(3-Amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]-3-(phenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]-3-(2-methoxy-5-trifluoromethylphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]-3-(2-methylcarbonylamino-5-trifluoromethylphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]-3-(2,4-dimethoxyphenyl)urea;   N-[4-(3-Amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]-2,3-dichlorobenzene-sulfonamide;   1-[4-(3-Amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]-3-(2-methoxy-5-tert-butylphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]-3-(3,4-dimethylphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]-3-(3-trifluoromethyl-4-methylphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]-3-(2,5-difluorophenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]-3-(3-chloro-4-methylphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]-3-(2-methyl-5-fluorophenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]-3-(2,4-dimethoxy-5-chlorophenyl)urea; and   1-[4-(3-Amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]-3-(3-trifluoromethylsulfanylphenyl)urea;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . A compound according to  claim 1 , selected from the group consisting of:
 1-[4-(3-Amino-1H-pyrazolo[3,4-c]pyrid-4-yl)phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea;   1-[4-(3-Amino-1H-pyrazolo[3,4-c]pyrid-4-yl)phenyl]-3-(2-methoxy-5-trifluoromethylphenyl)urea; and   N-[4-(3-Amino-1H-pyrazolo[3,4-c]pyrid-4-yl)phenyl]-2,3-dichlorobenzenesulfonamide;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         20 . A compound according to  claim 1 , characterized in that it is:
 a. in achiral form, or   b. in racemic form, or   c. enriched in one stereoisomer, or   d. enriched in one enantiomer;   
       and in that it is optionally salified. 
     
     
         21 . A pharmaceutical composition comprising a compound according to  claim 1 , in combination with a pharmaceutically acceptable excipient. 
     
     
         22 . A pharmaceutical composition comprising a compound according to  claim 17  in combination with a pharmaceutically acceptable excipient. 
     
     
         23 . A pharmaceutical composition comprising a compound according to  claim 18 , in combination with a pharmaceutically acceptable excipient. 
     
     
         24 . A method for inhibiting a reaction catalysed by a kinase comprising contacting said kinase with an effective amount of a compound according to  claim 1 . 
     
     
         25 . The method according to  claim 24 , wherein the kinase is chosen from FAK, KDR and Tie2. 
     
     
         26 . A method for treating a pathological condition, comprising administering to a patient in need of such treatment an effective amount of a compound according to  claim 1 . 
     
     
         27 . The method according to  claim 26 , wherein the pathological condition is cancer. 
     
     
         28 . The method according to  claim 27 , wherein said compound is administered in combination with another anticancer agent.