Compounds

Abstract

The present invention relates to substituted triazole compounds of the formula (I): and salts thereof, to pharmaceutical compositions containing them and their use in medicine. In particular, the invention relates to compounds for inhibiting SCD activity.

1 . A method for treating and/or preventing diseases or conditions caused by or associated with an abnormal plasma lipid profile with an effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
       wherein:
 X represents —CONH—, —NHCO— or —CH 2 NH—; 
 R 1  represents:
 —C 6-10 aryl optionally substituted by one, two or three groups independently selected from:
 —C 1-3 alkyl, —C 1-6 alkoxy, —C 1-6 haloalkyl, —OC 1-6 haloalkyl, —OC 3-6 cycloalkyl or halogen; 
 
 
 R 2  represents hydrogen, —C 1-6 alkyl or —C 1-3 alkylOC 1-3 alkyl; 
 R 3  represents:
 —C 5-9 heteroaryl optionally substituted by one, two or three groups independently selected from: —C 1-3 alkyl, —C 1-6 alkoxy, —CO 2 R 4 , —C(═O)NR 5 R 6 , —C(═O)NHC 1-3 alkylNR 7 R 8 , —C(═O)NHC 1-3 alkylOC 1-3 alkyl, —C(═O)NHC 1-3 alkylOH, —C(═O)R 9 , —C 1-6 alkylOH, —C═O, —CHO, —C 1-3 alkylCO 2 C 1-3 alkyl, —C 1-3 alkylOC 1-3 alkyl, —C 1-6 haloalkyl, —OC 1-6 haloalkyl, —OC 3-6 cycloalkyl, —C 3-6 cycloalkyl, or halogen; 
 
 R 4  represents —H or —C 1-3 alkyl; 
 R 5  represents —H or —C 1-3 alkyl; 
 R 6  represents —H or —C 1-6 alkyl; 
 R 7  represents —H or —C 1-3 alkyl; 
 R 8  represents —H or —C 1-3 alkyl; and 
 R 9  represents —C 6 heterocycle which is optionally substituted by a group independently selected from: —C 1-6 alkyl; 
 or a pharmaceutically acceptable salt thereof, 
 with the proviso that the compound of formula (I) is not 
 N-1,3-benzodioxol-5-yl-1-[(4-flurophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide 
 
       
         
           
           
               
               
           
         
       
       or N-(6-acetyl-1,3-benzodioxol-5-yl)-1-[(4-methylphenyl)methyl]-1H-1,2,3-triazole-4-carboxamide 
       
         
           
           
               
               
           
         
       
       and further provided that R3 is not an optionally substituted tetrahydronapthyridine when X is —NHCO or —CONH
 in a human in need thereof with an effective amount of a compound of Formula (I) wherein said disease or condition is selected from the group dyslipidemia, hypoalphalipoproteinemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, atherosclerosis, obesity, Type I diabetes, Type II diabetes, insulin resistance, hyperinsulinaemia and metabolic syndrome; peripheral vascular disease, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, thrombosis, hepatic steatosis, non-alcoholic steatohepatitis (NASH) and other diseases related to accumulation of lipids in the liver; eczema, acne, psoriasis, skin ageing, keloid scar formation or prevention, and diseases related to production or secretions from mucous membranes; cancer, neoplasia, malignancy, metastases, tumours (benign or malignant), carcinogenesis, hepatomas and the like; mild cognitive impairment (MCI), Alzheimer's Disease (AD), cerebral amyloid angiopathy (CAA) or dementia associated with Down Syndrome (DS) and other neurodegenerative diseases characterized by the formation or accumulation of amyloid plaques comprising Aβ42. 
 
     
     
         2 . The method according to  claim 1  wherein the disease or condition is selected from acne, psoriasis, skin ageing, dyslipidemia, hypertriglyceridemia, atherosclerosis, obesity, Type II diabetes, insulin resistance, hyperinsulinaemia, hepatic steatosis and non-alcoholic steatohepatitis (NASH). 
     
     
         3 . The method according to  claim 1  wherein the disease or condition is for treatment or prevention of acne. 
     
     
         4 . The method according to  claim 1  wherein X represents —CONH—. 
     
     
         5 . The method according to  claim 1  wherein X represents —NHCO—. 
     
     
         6 . The method according to  claim 1  wherein X represents —CH 2 NH—. 
     
     
         7 . The method according to  claim 1  wherein R 1  represents phenyl substituted by two groups independently selected from halogen. 
     
     
         8 . The method according to  claim 1  wherein R 2  represents hydrogen or —C 1-3 alkyl. 
     
     
         9 . The method according to  claim 1  wherein R 3  represents —C 5 heteroaryl containing 5 ring-atoms 1, 2, 3 or 4 of which are hetero-atoms independently selected from nitrogen, oxygen or sulphur and the remaining ring-atoms are carbon, optionally substituted by one, two or three groups independently selected from: —C 1-3 alkyl, —C 1-6 alkoxy, —CO 2 R 4 , —C(═O)NR 5 R 6 , —C(═O)NHC 1-3 alkylNR 7 R 8 , —C(═O)NHC 1-3 alkylOC 1-3 alkyl, —C(═O)NHC 1-3 alkylOH, —C(═O)R 9 , —C 1-6 alkylOH, —C(═O), —CHO, —C 1-3 alkylCO 2 C 1-3 alkyl, —C 1-3 alkylOC 1-3 alkyl, —C 1-6 haloalkyl, —OC 1-6 haloalkyl, —OC 3-6 cycloalkyl, —C 3-6 cycloalkyl or halogen. 
     
     
         10 . The method according to  claim 1  wherein R 3  represents —C 9 heteroaryl containing 9 ring-atoms 1, 2, 3 or 4 of which are hetero-atoms independently selected from nitrogen or sulphur and the remaining ring-atoms are carbon, optionally substituted by one, two or three groups independently selected from: —C 1-3 alkyl, —C 1-6 alkoxy, —CO 2 R 4 , —C(═O)NR 5 R 6 , —C(═O)NHC 1-3 alkylNR 7 R 8 , —C(═O)NHC 1-3 alkylOC 1-3 alkyl, —C(═O)NHC 1-3 alkylOH, —C(═O)R 9 , —C 1-6 alkylOH, —C(═O), —CHO, —C 1-3 alkylCO 2 C 1-3 alkyl, —C 1-3 alkylOC 1-3 alkyl, —C 1-6 haloalkyl, —OC 1-6 haloalkyl, —OC 3-6 cycloalkyl, —C 3-6 cycloalkyl or halogen. 
     
     
         11 . The method according to  claim 1  wherein R 3  represents —C 6 heteroaryl optionally substituted by one, two or three groups independently selected from: —C 1-3 alkyl, —C 1-6 alkoxy, —CO 2 R 4 , —C(═O)NR 5 R 6 , —C(═O)NHC 1-3 alkylNR 7 R 8 , —C(═O)NHC 1-3 alkylO—C 1-3 alkyl, —C(═O)NHC 1-3 alkylOH, —C(═O)R 9 , —C 1-6 alkylOH, —C(═O), —CHO, —C 1-3 alkylCO 2— C 1-3 alkyl, —C 1-3 alkylOC 1-3 alkyl, —C 1-6 haloalkyl, —OC 1-6 haloalkyl, —OC 3-6 cycloalkyl, —C 3-6 cycloalkyl or halogen. 
     
     
         12 . The method according to  claim 1  wherein the C 5-9 heteroaryl is a monocyclic or bicyclic ring system including an aromatic cyclic group containing 5 to 9 ring-atoms 1, 2, 3 or 4 of which are hetero-atoms independently selected from nitrogen, oxygen and sulphur and the remaining ring-atoms are carbon. 
     
     
         13 . The method according to  claim 12  wherein the bicyclic structure contains at least one ring which is aromatic. 
     
     
         14 . The method according to  claim 1  wherein the C 5-9 heteroaryl is an isoxazole, oxazole, thiazolopyrimidine, imidazole, thiazole, benzothiazole, thiadiazole, oxadiazole or pyridine. 
     
     
         15 . The method according to  claim 1  wherein the C 5-9 heteroaryl is a thiazole, benzothiazole, thiadiazole, oxazole, pyridine or thiazolopyrimidine. 
     
     
         16 . The method according to  claim 1  wherein the compound is selected from: 
       1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-[6-(methyloxy)-1,3-benzothiazol-2-yl]-1H-1,2,3-triazole-4-carboxamide, 
       Ethyl 2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-methyl-1,3-thiazole-5-carboxylate, 
       Ethyl 5-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3,4-thiadiazole-2-carboxylate, 
       Methyl 2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-thiazole-5-carboxylate, 
       1-[(3,4-Dichlorophenyl)methyl]-N-(5-formyl-1,3-thiazol-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-{5-[(methyloxy)methyl]-1,3,4-thiadiazol-2-yl}-1H-1,2,3-triazole-4-carboxamide, 
       Methyl {2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-thiazol-4-yl}acetate, 
       Ethyl 2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-(trifluoromethyl)-1,3-thiazole-5-carboxylate, 
       1-[(3,4-Dichlorophenyl)methyl]-N-(4,5-dimethyl-1,3-thiazol-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide, 
       Ethyl 2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-benzothiazole-6-carboxylate, 
       Ethyl {2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-5-methyl-1,3-thiazol-4-yl}acetate, 
       1-[(3,4-Dichlorophenyl)methyl]-N-(5,7-dioxo-4,5,6,7-tetrahydro[1,3]thiazolo[4,5-d]pyrimidin-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide, 
       Methyl 6-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-3-pyridinecarboxylate, 
       Methyl 2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-pyridinecarboxylate, 
       2-[({1-[(3,4-Dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-methyl-1,3-thiazole-5-carboxylic acid, 
       2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-oxazole-5-carboxylic acid, 
       1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-{4-methyl-5-[(methylamino)carbonyl]-1,3-thiazol-2-yl}-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-(4-methyl-5-{[(3-methylbutyl)amino]carbonyl}-1,3-thiazol-2-yl)-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-(4-methyl-5-{[(1-methylethypamino]carbonyl}-1,3-thiazol-2-yl)-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-N-{5-[(ethylamino)carbonyl]-4-methyl-1,3-thiazo1-2-yl}-5-methyl-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-N-[5-({[2-(dimethylamino)ethyl]amino}carbonyl)-4-methyl-1,3-thiazol-2-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-(5-{[(3-methylbutyl)amino]carbonyl}-1,3-thiazol-2-yl)-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-[4-methyl-5-(4-morpholinylcarbonyl)-1,3-thiazol-2-yl]-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-{4-methyl-5-[(4-methyl-1-piperazinyl)carbonyl]-1,3-thiazol-2-yl}-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-[4-methyl-5-({[2-(methyloxy)ethyl]amino}carbonyl)-1,3-thiazol-2-yl]-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-N-(5-{[(2-hydroxyethyl)amino]carbonyl}-4-methyl-1,3-thiazol-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-N-{5-[(dimethylamino)carbonyl]-4-methyl-1,3-thiazol-2-yl}-5-methyl-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-{5-[(methylamino)carbonyl]-1,3-thiazol-2-yl}-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-N-{5-[(dimethylamino)carbonyl]-1,3-thiazol-2-yl}-5-methyl-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-N-(5-{[(2-hydroxyethyl)amino]carbonyl}-1,3-thiazol-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide, 
       2-[({1-[(3,4-Dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-N-methyl-4-pyridinecarboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-N-{5-[(ethylamino)carbonyl]-4-methyl-1,3-thiazol-2-yl}-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-N-{4-methyl-5-[(methylamino)carbonyl]-1,3-thiazol-2-yl}-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-N-(5-{[(2-hydroxyethyl)amino]carbonyl}-1,3-thiazol-2-yl)-1H-1,2,3-triazole-4-carboxamide, 
       N-[5-(Aminocarbonyl)-1,3-thiazol-2-yl]-1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide, 
       N-[5-(Aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-1,3,4-thiadiazol-2-yl-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-N-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-N-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-5-[(methyloxy)methyl]-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-N-[5-(hydroxymethyl)-4-methyl-1,3-thiazol-2-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-N-[5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-N-[4-(2-hydroxyethyl)-1,3-thiazol-2-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide, 
       1-[(3,4-Dichlorophenyl)methyl]-N-[4-(hydroxymethyl)-2-pyridinyl]-5-methyl-1H-1,2,3-triazole-4-carboxamide, 
       N-{1-[(3,4-Dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}-6-(methyloxy)-1,3-benzothiazole-2-carboxamide, or 
       {2-[({1-[(3,4-Dichlorophenyl)methyl]-1H-1,2,3-triazol-4-yl}methypamino]-1,3-thiazol-5-yl}methanol, 
       or a pharmaceutically acceptable salt thereof. 
     
     
         17 . A method of treating and/or preventing a disease or a condition susceptible to amelioration by an SCD inhibitor in a human in need thereof with an effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
       wherein:
 X represents —CONH—, —NHCO— or —CH 2 NH—; 
 R 1  represents:
 —C 6-10 aryl optionally substituted by one, two or three groups independently selected from:
 —C 1-3 alkyl, —C 1-6 alkoxy, —C 1-6 haloalkyl, —OC 1-6 haloalkyl, —OC 3-6 cycloalkyl or halogen; 
 
 
 R 2  represents hydrogen, —C 1-6 alkyl or —C 1-3 alkylOC 1-3 alkyl; 
 R 3  represents:
 —C 5-9 heteroaryl optionally substituted by one, two or three groups independently selected from: —C 1-3 alkyl, —C 1-6 alkoxy, —CO 2 R 4 , —C(═O)NR 5 R 6 , —C(═O)NHC 1-3 alkylNR 7 R 8 , —C(═O)NHC 1-3 alkylOC 1-3 alkyl, —C(═O)NHC 1-3 alkylOH, —C(═O)R 9 , —C 1-6 alkylOH, —C═O, —CHO, —C 1-3 alkylCO 2 C 1-3 alkyl, —C 1-3 alkylOC 1-3 alkyl, —C 1-6 haloalkyl, —OC 1-6 haloalkyl, —OC 3-6 cycloalkyl, —C 3-6 cycloalkyl, or halogen; 
 
 R 4  represents —H or —C 1-3 alkyl; 
 R 5  represents —H or —C 1-3 alkyl; 
 R 6  represents —H or —C 1-6 alkyl; 
 R 7  represents —H or —C 1-3 alkyl; 
 R 8  represents —H or —C 1-3 alkyl; and 
 R 9  represents —C 6 heterocycle which is optionally substituted by a group independently selected from: —C 1-6 alkyl; 
 or a pharmaceutically acceptable salt thereof, 
 with the proviso that the compound of formula (I) is not 
 N-1,3-benzodioxol-5-yl-1-[(4-flurophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide 
 
       
         
           
           
               
               
           
         
       
       or N-(6-acetyl-1,3-benzodioxol-5-yl)-1-[(4-methylphenyl)methyl]-1H-1,2,3-triazole-4-carboxamide 
       
         
           
           
               
               
           
         
       
       and further provided that R3 is not an optionally substituted tetrahydronapthyridine when X is —NHCO or —CONH. 
     
     
         18 . A method according to  claim 17  wherein the disease or conditions susceptible to amelioration by an SCD inhibitior is selected from the group consisting of dyslipidemia, hypoalphalipoproteinemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, atherosclerosis, obesity, Type I diabetes, Type II diabetes, insulin resistance, hyperinsulinaemia and metabolic syndrome; peripheral vascular disease, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, thrombosis, hepatic steatosis, non-alcoholic steatohepatitis (NASH) and other diseases related to accumulation of lipids in the liver; eczema, acne, psoriasis, skin ageing, keloid scar formation or prevention, and diseases related to production or secretions from mucous membranes; cancer, neoplasia, malignancy, metastases, tumours (benign or malignant), carcinogenesis, hepatomas and the like; mild cognitive impairment (MCI), Alzheimer's Disease (AD), cerebral amyloid angiopathy (CAA), dementia associated with Down Syndrome (DS) and any other neurodegenerative diseases characterized by the formation or accumulation of amyloid plaques comprising Aβ42. 
     
     
         19 . The method according to  claim 18  wherein the disease or condition is selected fromacne, psoriasis, skin ageing, dyslipidemia, hypertriglyceridemia, atherosclerosis, obesity, Type II diabetes, insulin resistance, hyperinsulinaemia, hepatic steatosis and non-alcoholic steatohepatitis (NASH). 
     
     
         20 . The method according to  claim 18  wherein the disease or condition is for the treatment and/or prevention of acne.