1h-indazole-3-carboxamide compounds as glycogen synthase kinase 3 beta inhibitors

Abstract

The present invention relates to the 1H-indazole-3-carboxamide compounds as glycogen synthase kinase 3 beta (GSK-3β) inhibitors and to their use in the treatment of GSK-3β-related disorders such as, for example, (i) insulin-resistance disorders; (ii) neurodegenerative diseases; (iii) mood disorders; (iv) schizophrenic disorders; (v) cancerous disorders; (vi) inflammation, (vii) substance abuse disorders; (viii) epilepsies; and (ix) neuropathic pain.

1 - 23 . (canceled) 
     
     
         24 . A 1H-indazole-3-carboxamide compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R a ′ is a halogen atom; a hydroxy group; a C 1 -C 6  alkyl, a C 1 -C 6  alkoxy group; or a carbocyclic or heterocyclic ring selected from the group consisting of pyrimidinyl, isoxazolyl, 3,6-dihydro-2H-pyranyl, and cyclohexyl, said ring being optionally substituted by one or more C 1 -C 6  alkyl groups; 
         R a  is a hydrogen atom; a halogen atom; or a carbocyclic or heterocyclic ring selected from the group consisting of phenyl and pyridinyl, said ring being optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, —C(O)OH, and C(O)NR 1 R 2  group; 
         Y is a bond, a C 1 -C 6  alkyl group; 
         R b  is a C 1 -C 6  alkoxy, —C(O)OH, —C(O)OR 1 , or —NHC(O)R 1  group; 
         R 1  and R 2  are independently a C 1 -C 4  alkyl group, a C 2 -C 4  alkenyl group, a C 2 -C 4  alkynyl group, or a phenyl group; 
         or an addition salt with pharmaceutically acceptable organic acid, inorganic acid, or base. 
       
     
     
         25 . The 1H-indazole-3-carboxamide compound or salt according to  claim 24 , wherein R a ′ is a halogen atom selected from the group consisting of chlorine, bromine and iodine; a hydroxy group; a C 1 -C 3  alkyl, C 1 -C 3  alkoxy group; or a carbocyclic or heterocyclic ring selected from the group consisting of pyrimidinyl, isoxazolyl, 3,6-dihydro-2H-pyranyl, cyclohexyl, said ring being optionally substituted by one or more C 1 -C 3  alkyl group. 
     
     
         26 . The 1H-indazole-3-carboxamide compound or salt according to  claim 25 , wherein said ring is optionally substituted by one or more methyl groups. 
     
     
         27 . The 1H-indazole-3-carboxamide compound or salt according to  claim 24 , wherein R a  is a hydrogen atom; a halogen atom selected from the group consisting of chlorine, bromine and iodine; or a carbocyclic or heterocyclic ring selected from the group consisting of phenyl and pyridinyl, said ring being optionally substituted by C(O)NR 1 R 2 . 
     
     
         28 . The 1H-indazole-3-carboxamide compound or salt according to  claim 24 , wherein Y is a bond or a C 1 -C 3  alkyl group. 
     
     
         29 . The 1H-indazole-3-carboxamide compound or salt according to  claim 28 , wherein Y is a bond, an ethyl group, or a methyl group. 
     
     
         30 . The 1H-indazole-3-carboxamide compound or salt according to  claim 24 , wherein R b  is a C 1 -C 3  alkoxy or —C(O)OH group. 
     
     
         31 . The 1H-indazole-3-carboxamide compound or salt according to  claim 24 , wherein R b  is a methoxy or —C(O)OH group. 
     
     
         32 . The 1H-indazole-3-carboxamide compound or salt according to  claim 24 , wherein R 1  and R 2  are each a C 1 -C 3  alkyl group. 
     
     
         33 . The 1H-indazole-3-carboxamide compound or salt according to  claim 32 , wherein R 1  and R 2  are both a methyl group. 
     
     
         34 . A method of treatment of a pathological state arising from the uncontrolled activation and/or over-expression of GSK-3β, selected from the group consisting of (i) an insulin-resistance disorder; (ii) a neurodegenerative disease; (iii) a mood disorder; (iv) a schizophrenic disorder; (v) a cancerous disorder; (vi) inflammation, (vii) a substance abuse disorder; (viii) epilepsy; and (ix) neuropathic pain, said method comprising administering to a human being in need thereof of an effective amount of a 1H-indazole-3-carboxamide of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R a ′ is a halogen atom; a hydroxy group; a C 1 -C 6  alkyl, a C 1 -C 6  alkoxy group; or a carbocyclic or heterocyclic ring selected from the group consisting of pyrimidinyl, isoxazolyl, 3,6-dihydro-2H-pyranyl, and cyclohexyl, said ring being optionally substituted by one or more C 1 -C 6  alkyl groups; 
         R a  is a hydrogen atom; a halogen atom; or a carbocyclic or heterocyclic ring selected from the group consisting of phenyl and pyridinyl, said ring being optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, —C(O)OH, and C(O)NR 1 R 2  group; 
         Y is a bond or a C 1 -C 6  alkyl group; 
         R b  is a C 1 -C 6  alkoxy, —C(O)OH, —C(O)OR 1 , or —NHC(O)R 1  group; 
         R 1  and R 2  are independently a C 1 -C 4  alkyl group, a C 2 -C 4  alkenyl group, a C 2 -C 4  alkynyl group, or a phenyl group; 
         or an addition salt with a pharmaceutically acceptable organic acid, an inorganic acid, or a base. 
       
     
     
         35 . The method according to  claim 34 , wherein said insulin-resistance disorder is selected from the group consisting of type-2 diabete, syndrome X, obesity and polycystic ovary syndrome. 
     
     
         36 . The method according to  claim 34 , wherein said neurodegenerative disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease, and a spinal neurodegenerative disorder. 
     
     
         37 . The method according to  claim 36 , wherein said spinal neurodegenerative disorder is selected from the group consisting of amyotrophic lateral sclerosis, multiple sclerosis, spinal muscular atrophy, and neurodegeneration due to spinal cord injury. 
     
     
         38 . The method according to  claim 34 , wherein said mood disorder is selected from the group consisting of a bipolar disorder and a depressive disorder. 
     
     
         39 . The method according to  claim 38 , wherein said bipolar disorder is selected from the group consisting of bipolar I, bipolar II, cyclothymia and bipolar disorder not otherwise specified (BD-NOS). 
     
     
         40 . The method according to  claim 38 , wherein said depressive disorder is selected from the group consisting of major depressive disorder (MDD), atypical depression (AD), melancholic depression, psychotic major depression (PMD), catatonic depression, postpartum depression (PPD), seasonal affective disorder (SAD), dysthymia, and depressive disorder not otherwise specified (DD-NOS). 
     
     
         41 . The method according to  claim 34 , wherein said substance abuse disorder is an abuse disorder due to psychostimulants. 
     
     
         42 . The method according to  claim 34 , wherein said schizophrenic disorder is selected from the group consisting of paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, simple schizophrenia, residual schizophrenia, and undifferentiated schizophrenia. 
     
     
         43 . The method according to  claim 34 , wherein said cancerous disorder is selected from the group consisting of prostate cancer, pancreatic cancer, ovarian cancer, colon-rectal cancer, and MLL-associated leukaemia. 
     
     
         44 . A pharmaceutical composition, comprising an effective amount of at least one compound or salt according to claim  1  and at least one inert pharmaceutically acceptable excipient.