Amide derivatives as lysophosphatidic acid receptor antagonists

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, formula (I) wherein R 1 , X, m, R 2 , Y, R 3 , Z, n, R 4 , A and B are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

1 .- 18 . (canceled) 
     
     
         19 . A method of treating a condition whose development or symptoms are linked to LPAR5 activity comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound selected from 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid, 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid, 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid, and a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         20 . The method according to  claim 19 , wherein the condition is chosen from fibrosis, liver diseases, atherosclerosis, inflammatory diseases, gastrointestinal tract diseases, and pain disorders. 
     
     
         21 . The method according to  claim 19 , wherein the compound is 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid. 
     
     
         22 . The method according to  claim 19 , wherein the compound is 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         23 . The method according to  claim 19 , wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid. 
     
     
         24 . The method according to  claim 19 , wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The method according to  claim 19 , wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid. 
     
     
         26 . The method according to  claim 19 , wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The method according to  claim 19 , further comprising administering at least one additional therapeutic agent. 
     
     
         28 . The method according to  claim 27 , wherein the at least one additional therapeutic agent is selected from opioid agonists, partial agonists or antagonists; antidepressants; anxiolytics; anticonvulsants; migraine therapies; stroke therapies; urinary incontinence therapies; neuropathic pain therapies; and nociceptive pain therapies. 
     
     
         29 . A method of treating a condition whose development or symptoms are linked to LPAR1 activity comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound selected from 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid, 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid, 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid, and a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         30 . The method according to  claim 29 , wherein the condition is chosen from fibrosis, liver diseases, atherosclerosis, inflammatory diseases, gastrointestinal tract diseases, and pain disorders. 
     
     
         31 . The method according to  claim 29 , wherein the compound is 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid. 
     
     
         32 . The method according to  claim 29 , wherein the compound is 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         33 . The method according to  claim 29 , wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid. 
     
     
         34 . The method according to  claim 29 , wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         35 . The method according to  claim 29 , wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid. 
     
     
         36 . The method according to  claim 29 , wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         37 . The method according to  claim 29 , further comprising administering at least one additional therapeutic agent. 
     
     
         38 . The method according to  claim 37 , wherein the at least one additional therapeutic agent is selected from opioid agonists, partial agonists or antagonists; antidepressants; anxiolytics; anticonvulsants; migraine therapies; stroke therapies; urinary incontinence therapies; neuropathic pain therapies; and nociceptive pain therapies. 
     
     
         39 . A method of treating a condition chosen from pain disorders and gastrointestinal tract diseases comprising administering to a patient in need thereof a therapeutically effective amount of a compound selected from 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid, 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid, 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid, and a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         40 . The method according to  claim 39 , wherein the compound is 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid. 
     
     
         41 . The method according to  claim 39 , wherein the compound is 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         42 . The method according to  claim 39 , wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid. 
     
     
         43 . The method according to  claim 39 , wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         44 . The method according to  claim 39 , wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid. 
     
     
         45 . The method according to  claim 39 , wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         46 . The method according to  claim 39 , further comprising administering at least one additional therapeutic agent. 
     
     
         47 . The method according to  claim 46 , wherein the at least one additional therapeutic agent is selected from opioid agonists, partial agonists or antagonists; antidepressants; anxiolytics; anticonvulsants; migraine therapies; stroke therapies; urinary incontinence therapies; neuropathic pain therapies; and nociceptive pain therapies.