Triazolopyridine carboxamide derivatives, preparation thereof and therapeutic use thereof

Abstract

The invention relates to the triazolopyridine carboxamide derivatives of general formula (I): Wherein X, A, R 1 and R 2 are as defined herein. The invention further relates to preparation methods and therapeutic use thereof.

1 . A compound of the formula (I): 
       
         
           
           
               
               
           
         
         in which: 
         X is hydrogen, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, S(O) m R″, hydroxyl or cyano; 
         A is oxygen, sulfur, NR, C(O)NR′ or SO 2 NR′; 
         R 1  and R 2  are, independently of one another, one or more groups selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkoxy, halogen, cyano, C(O)R′, C(O)OR′, C(O)NR 10 R 20 , NO 2 , NR 10 R 20  and NR 10 C(O)—R 20  group, wherein (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy are optionally substituted with one or more groups selected, independently of one another, from halogen, hydroxyl, amino and NR 10 R 20 ; 
         R is selected from hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, C(O)R′, SO 2 R″, CO 2 R″ and C(O)NR 10 R 20 ; 
         R′ is selected from hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl and (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl; 
         R″ is selected from (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl and (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl; and 
         R 10  and R 20  are, independently of one another, selected from hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl and (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl; or 
         R 10  and R 20  form a saturated or partially unsaturated ring containing from 5 to 7 carbon atoms and optionally containing a heteroatom chosen from O, N or S(O) m ; wherein 
         m represents 0, 1 or 2; or 
         a salt thereof. 
       
     
     
         2 . The compound of formula (I) according to  claim 1 , wherein:
 X is hydrogen or halogen; or   a salt thereof.   
     
     
         3 . A pharmaceutical composition comprising a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. 
     
     
         4 . A pharmaceutical composition comprising a compound of formula (I) according to  claim 2  or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. 
     
     
         5 . A method of treating a pathological condition in a patient in which endogenous 2-arachidonoylglycerol (2-AG) and endogenous 1(3)-arachidonoylglycerol or any other substrate metabolized by the MGL enzyme are involved comprising administering to said patient a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         in which: 
         X is hydrogen, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, S(O) m R″, hydroxyl or cyano; 
         A is absent or else is a bond, oxygen, sulfur, NR, C(O)NR′ or SO 2 NR′, (C 1 -C 2 )alkylene or (C 2 )alkenyl group; 
         when A is absent the attachment is a benzhydryl group; 
         R 1  and R 2  are, independently of one another, one or more groups selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkoxy, halogen, cyano, C(O)R′, C(O)OR′, C(O)NR 10 R 20 , NO 2 , NR 10 R 20  and NR 10 C(O)—R 20  group, wherein (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy are optionally substituted with one or more groups selected, independently of one another, from halogen, hydroxyl, amino and NR 10 R 20 ; 
         R is selected from hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, C(O)R′, SO 2 R″, CO 2 R″ and C(O)NR 10 R 20 ; 
         R′ is selected from hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl and (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl; 
         R″ is selected from (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl and (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl; and 
         R 10  and R 20  are, independently of one another, selected from hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl and (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl; or 
         R 10  and R 20  form a saturated or partially unsaturated ring containing from 5 to 7 carbon atoms and optionally containing a heteroatom chosen from O, N or S(O) m ; wherein 
         m represents 0, 1 or 2; or 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         6 . A method of treating a disease selected from the group consisting of acute or chronic pain, an inflammatory disease, dizziness, vomiting, nausea, eating disorders, metabolic syndrome, dyslipidemia, epilepsy, a sleep disorder, osteoporosis, ocular condition, pulmonary condition, gastrointestinal disease, urinary incontinence and bladder inflammation, comprising administering to said patient a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         in which: 
         X is hydrogen, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, S(O) m R″, hydroxyl or cyano; 
         A is absent or else is a bond, oxygen, sulfur, NR, C(O)NR′ or SO 2 NR′, (C 1 -C 2 )alkylene or (C 2 )alkenyl group; 
         when A is absent the attachment is a benzhydryl group; 
         R 1  and R 2  are, independently of one another, one or more groups selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkoxy, halogen, cyano, C(O)R′, C(O)OR′, C(O)NR 10 R 20 , NO 2 , NR 10 R 20  and NR 10 C(O)—R 20  group, wherein (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy are optionally substituted with one or more groups selected, independently of one another, from halogen, hydroxyl, amino and NR 10 R 20 ; 
         R is selected from hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, C(O)R′, SO 2 R″, CO 2 R″ and C(O)NR 10 R 20 ; 
         R′ is selected from hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl and (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl; 
         R″ is selected from (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl and (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl; and 
         R 10  and R 20  are, independently of one another, selected from hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl and (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl; or 
         R 10  and R 20  form a saturated or partially unsaturated ring containing from 5 to 7 carbon atoms and optionally containing a heteroatom chosen from O, N or S(O) m ; wherein 
         m represents 0, 1 or 2; or 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 . The method according to  claim 6 , wherein the disease is selected from the group consisting of acute or chronic pain and an inflammatory disease. 
     
     
         8 . The method according to  claim 6  wherein the disease is selected from the group consisting of dizziness, vomiting, nausea, eating disorders, metabolic syndrome and dyslipidemia. 
     
     
         9 . The method according to  claim 6  wherein the disease is selected from the group consisting of epilepsy and a sleep disorder. 
     
     
         10 . The method according to  claim 6  wherein the disease is selected from the group consisting of osteoporosis, ocular condition, pulmonary condition, gastrointestinal disease, urinary incontinence and bladder inflammation.