Derivatives of azaindazole or diazaindazole type as medicament

Abstract

The present invention relates to a compound of following formula (I): or a pharmaceutically acceptable salt or solvate of same, a tautomer of same, or a stereoisomer or mixture of stereoisomers of same in any proportions, such as a mixture of enantiomers, notably a racemic mixture; as well as to the use of same as a drug, notably intended for the treatment of cancer, inflammation and neurodegenerative diseases such as Alzheimer's disease; to the use of same as a kinase inhibitor; to the pharmaceutical compositions comprising same; and to methods for the preparation of same.

1 - 22 . (canceled) 
     
     
         23 . A compound of following general formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate of same, a tautomer of same, or a stereoisomer or mixture of stereoisomers of same in any proportions, 
       wherein:
 Y 1  and Y 4  each represent, independently of each other, a CH group or a nitrogen atom, 
 Y 2  represents a C—X—Ar group and Y 3  represents a nitrogen atom or a C—W group, or Y 2  represents a nitrogen atom or a CH group and Y 3  represents a C—X—Ar group, on the condition that:
 at least one and at most two Y 1 , Y 2 , Y 3 , and Y 4  groups represent a nitrogen atom, and 
 Y 2  and Y 4  cannot represent a nitrogen atom at the same time, 
 
 Ar represents an aryl or heteroaryl group optionally substituted by one or more groups selected from a halogen atom, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )halothioalkoxy, CN, NO 2 , OR 11 , SR 12 , NR 13 R 14 , CO 2 R 15 , CONR 16 R 17 , SO 2 R 18 , SO 2 NR 19 R 20 , COR 21 , NR 22 COR 23 , NR 24 SO 2 R 25 , and R 26 NR 27 R 28  and/or optionally fused to a heterocycle, 
 X represents a divalent group selected from O, S, S(O), S(O) 2 , NR 4 , S(NR 4 ), S(O)(NR 4 ), S(O) 2 (NR 4 ), NR 4 S, NR 4 S(O), NR 4 S(O) 2 , CH 2 , CH 2 S, CH 2 S(O), CH 2 S(O) 2 , SCH 2 , S(O)CH 2 , S(O) 2 CH 2 , CH 2 CH 2 , CH═CH, CH 2 O, OCH 2 , NR 4 CH 2 , and CH 2 NR 4 , 
 W represents an R 5 , SR 5 , OR 5  or NR 5 R 6  group, 
 U represents a CH 2  or NH group, one or more hydrogen atoms which may be replaced by a (C 1 -C 6 )alkyl group, 
 V represents C(O), C(S) or CH 2 , 
 n represents 0 or 1, 
 R 1  represents a hydrogen atom, or an OR 7  or NR 7 R 8  group, 
 R 2  represents a hydrogen atom, an optionally substituted heterocycle, NO 2 , OR 9  or NR 9 R 10 , 
 R 3 , R 4 , R 11  to R 25  and R 27  to R 28  each represent, independently of each other, a hydrogen atom or a (C 1 -C 6 )alkyl group, 
 R 5  and R 6  each represent, independently of each other, a hydrogen atom or a (C 1 -C 6 )alkyl, optionally substituted aryl or optionally substituted benzyl group, 
 R 7 , R 8 , R 9  and R 10  each represent, independently of each other, a hydrogen atom or an optionally substituted (C 1 -C 6 )alkyl or (C 3 -C 12 )cycloalkyl group or an optionally substituted heterocycle, and 
 R 26  represents a (C 1 -C 6 )alkyl group. 
 
     
     
         24 . The compound according to  claim 23 , wherein:
 Y 1  and/or Y 4 =N,   Y 2 =CH or C—X—Ar, and   Y 3 =C—W or C—X—Ar.   
     
     
         25 . The compound according to  claim 23 , wherein X represents a divalent group selected from S, S(O), S(O) 2 , NR 4 , CH 2 , CH 2 S, CH 2 S(O), CH 2 S(O) 2 , CH 2 O, CH 2 NR 4 , NHS(O) 2 , SCH 2 , S(O)CH 2 , S(O) 2 CH 2 , S(O) 2 NH, OCH 2 , NR 4 CH 2 , CH 2 CH 2 , CH═CH, and C≡C, wherein the first atom of these groups is bound to atom C of chain C—X—Ar. 
     
     
         26 . The compound according to  claim 25 , wherein X represents a divalent group selected from S, S(O), S(O) 2 , NR 4 , CH 2 , SCH 2 , S(O)CH 2 , S(O) 2 CH 2 , S(O) 2 NH, CH 2 CH 2 , C≡C, OCH 2 , and NR 4 CH 2 , wherein the first atom of these groups is bound to atom C of chain C—X—Ar. 
     
     
         27 . The compound according to  claim 26 , wherein X represents a divalent group selected from S, S(O) 2 , CH 2 , SCH 2 , S(O) 2 CH 2 , S(O) 2 NH, CH 2 CH 2 , and C≡C, wherein the first atom of these groups is bound to atom C of chain C—X—Ar. 
     
     
         28 . The compound according to  claim 23 , wherein Ar represents an aryl group optionally substituted by one or more groups selected from a halogen atom, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )halothioalkoxy, CN, NO 2 , OR 11 , SR 12 , NR 13 R 14 , CO 2 R 15 , CONR 16 R 17 , SO 2 R 18 , SO 2 NR 19 R 20 , COR 21 , NR 22 COR 23  and NR 24 SO 2 R 25 ; or a pyridine group. 
     
     
         29 . The compound according to  claim 28 , wherein Ar represents a phenyl group optionally substituted by one or more groups selected from a halogen atom, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )halothioalkoxy, CN, NO 2 , OR 11 , SR 12 , NR 13 R 14 , CO 2 R 15 , CONR 16 R 17 , SO 2 R 18 , SO 2 NR 19 R 20 , COR 21 , NR 22 COR 23  and NR 24 SO 2 R 25 ; or a pyridine group. 
     
     
         30 . The compound according to  claim 28 , wherein Ar represents a group selected from the following groups: 
       
         
           
           
               
               
           
         
       
     
     
         31 . The compound according to  claim 23 , wherein W represents an R 5 , SR 5 , OR 5  or NR 5 R 6  group, with R 5  and R 6  representing, independently of each other, a hydrogen atom or a (C 1 -C 6 )alkyl group. 
     
     
         32 . The compound according to  claim 23 , wherein:
 R 3 =H,   U=CH 2  or NH,   V=C(O) or C(S), and   n=0 or 1.   
     
     
         33 . The compound according to  claim 32 , wherein V=C(O). 
     
     
         34 . The compound according to  claim 32 , wherein n=0. 
     
     
         35 . The compound according to  claim 23 , wherein R 1  represents a hydrogen atom or an NR 7 R 8  group, with R 7  representing a hydrogen atom and R 8  representing an optionally substituted (C 3 -C 12 )cycloalkyl group or an optionally substituted heterocycle. 
     
     
         36 . The compound according to  claim 35 , wherein R 1  represents one of the following groups: 
       
         
           
           
               
               
           
         
       
     
     
         37 . The compound according to  claim 23 , wherein R 2  represents NO 2 , NR 9 R 10  or a heterocycle optionally substituted by (C 1 -C 6 )alkyl or NH 2 . 
     
     
         38 . The compound according to  claim 37 , wherein R 2  represents one of the following groups: 
       NH 2 , NH(CH 2 ) 3 NMe 2 , NMe(CH 2 ) 3 NMe 2 , NO 2 , 
       
         
           
           
               
               
           
         
       
     
     
         39 . The compound according to  claim 23 , selected from the following compounds: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         40 . A method for treating cancer, inflammation and neurodegenerative diseases comprising the administration to a person in need thereof of an effective amount of a compound according to  claim 23 . 
     
     
         41 . The method according to  claim 40 , wherein the neurodegenerative disease is Alzheimer's disease. 
     
     
         42 . A method for inhibiting kinases comprising the administration to a person in need thereof of an effective amount of a compound according to  claim 23 . 
     
     
         43 . The method according to  claim 42 , wherein the kinase is ALK, Abl and/or c-Src. 
     
     
         44 . A method for treating a disease associated with a kinase comprising the administration to a person in need thereof of an effective amount of a compound according to  claim 23 . 
     
     
         45 . The method according to  claim 44 , wherein the kinase is ALK, Abl and/or c-Src. 
     
     
         46 . A pharmaceutical composition comprising at least one compound of formula (I) according to  claim 23  and at least one pharmaceutically acceptable excipient. 
     
     
         47 . The pharmaceutical composition according to  claim 46 , further comprising at least one other active ingredient. 
     
     
         48 . The pharmaceutical composition according to  claim 47 , wherein the other active ingredient is an anticancer agent. 
     
     
         49 . A pharmaceutical composition comprising:
 (i) at least one compound of formula (I) according to  claim 23 , and   (ii) at least one other active ingredient,   
       as a combination product for simultaneous, separate or sequential use. 
     
     
         50 . The pharmaceutical composition according to  claim 49 , wherein the other active ingredient is an anticancer agent. 
     
     
         51 . A method for the preparation of a compound of formula (I) according to  claim 23 , wherein V=C(O) or C(S), comprising the following successive steps:
 (a1) coupling between a compound of following formula (A):   
       
         
           
           
               
               
           
         
         
           wherein Y 1 , Y 2 , Y 3  and Y 4  are as defined in  claim 23 , and R 29  represents a hydrogen atom or an N-protecting group, 
           with a compound of following formula (B): 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 1 , R 2 , U and n are as defined in  claim 23 , V=C(O) or C(S), and R 30 =OH or a leaving group such as Cl, 
           to yield a compound of following formula (C): 
         
       
       
         
           
           
               
               
           
         
         
           wherein Y 1 , Y 2 , Y 3 , Y 4 , R 1 , R 2 , U and n are as defined in  claim 23 , R 29  is as defined above and V=C(O) or C(S), 
         
         (b1) optionally substitution of the nitrogen atom bound to V of the compound of formula (C) obtained in the preceding step with an R 3  group other than H and/or deprotection of the nitrogen atom carrying an R 29  group representing an N-protecting group to yield a compound of formula (I) with V=C(O) or C(S), 
         (c1) optionally forming of a salt of the compound of formula (I) obtained in the preceding step to yield a pharmaceutically acceptable salt of same. 
       
     
     
         52 . A method for the preparation of a compound of formula (I) according to  claim 23 , wherein V=CH 2 , comprising the following successive steps:
 (a2) reducing amination reaction between a compound of following formula (A):   
       
         
           
           
               
               
           
         
         
           wherein Y 1 , Y 2 , Y 3  and Y 4  are as defined in  claim 23 , and R 29  represents a hydrogen atom or an N-protecting group, 
           and an aldehyde of following formula (D): 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 1 , R 2 , U and n are as defined in  claim 23 , 
           to yield a compound of following formula (E): 
         
       
       
         
           
           
               
               
           
         
         
           wherein Y 1 , Y 2 , Y 3 , Y 4 , R 1 , R 2 , U and n are as defined in  claim 23  and R 29  is as defined above, 
         
         (b2) optionally deprotection of the nitrogen atom carrying an R 29  group representing an N-protecting group and/or substitution of the nitrogen atom bound to V with an R 3  group other than H of the compound of formula (E) obtained in the preceding step to yield a compound of formula (I) with V=CH 2 , and 
         (c2) optionally forming of a salt of the compound of formula (I) obtained in the preceding step to yield a pharmaceutically acceptable salt of same. 
       
     
     
         53 . A method for the preparation of a compound of formula (I) according to any one of  claim 23  wherein V=C(O) or C(S), n=1 and U=NH, comprising the following successive steps:
 (a3) coupling between a compound of following formula (A): 
 
       
         
           
           
               
               
           
         
         
           wherein Y 1 , Y 2 , Y 3  and Y 4  are as defined in  claim 23 , and R 29  represents a hydrogen atom or an N-protecting group, 
           and a compound of following formula (F): 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 1  and R 2  are as defined in  claims 23  and Z=O or S, 
           to yield a compound of following formula (G): 
         
       
       
         
           
           
               
               
           
         
         
           wherein Y 1 , Y 2 , Y 3 , Y 4 , R 1  and R 2  are as defined in  claim 23 , R 29  is as defined above and Z is as defined above, 
         
         (b3) optionally deprotection of the nitrogen atom carrying an R 29  group representing an N-protecting group and/or substitution of the nitrogen atom bound to V with an R 3  group other than H of the compound of formula (G) obtained in the preceding step to yield a compound of formula (I) with V=C(O) or C(S), n=1 and U=NH, and 
         (c3) optionally forming of a salt of the compound of formula (I) obtained in the preceding step to yield a pharmaceutically acceptable salt of same.