Azaspiro derivatives as trpm8 antagonists

Abstract

The present invention relates to azaspiro derivatives of the formula (I) or a pharmaceutically acceptable salt thereof or a prodrug thereof, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders which are mediated via the TRPM8 receptor,

1 . A compound of the following formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         A is selected from the group consisting of: phenyl, pyridine, pyridazine, pyrazine, pyrimidine, triazine, thiophene, furan, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, and triazole; 
         B is phenyl, 5 to 6 membered heteroaryl, or 9 to 10 membered bicyclic heteroaryl 
         wherein, when A is phenyl, B is not phenyl; 
         L is independently selected from the group consisting of: a chemical bond, oxygen, and —NR 4 —; 
         X is independently selected from the group consisting of: —CH 2 —, oxygen, and NH; 
         R A  and R B  are independently selected from the group consisting of: (1) hydrogen and (3) (C 1 -C 6 )alkyl; or R A  and R B  form an oxo group (═O); 
         R 1  is independently selected from the group consisting of: (1) hydrogen and (6) (C 1 -C 6 ) alkyl; or 
         alternatively, two R 1  on the same carbon or different carbons form a 3 to 8 membered cycloalkyl ring; 
         R 2  is independently selected from the group consisting of: (1) hydrogen, (2) fluorine, (3) chlorine, (4) iodine, (7) hydroxyl, (10) (C 1 -C 6 )alkyl, (12) (C 1 -C 6 )alkoxy, (13) (C 1 -C 6 )haloalkyl, and (14) (C 1 -C 6 )haloalkoxy; 
         R 3  is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) cyano, (5) hydroxyl, (8) (C 1 -C 6 )alkylsulfonyl, (9) —NR 5 R 6 , (10) —C(═O)NR 5 R 6 , (12) (C 1 -C 6 )alkyl, (14) (C 1 -C 6 )alkoxy(C 0 -C 6 )alkyl, and (16) —C(═O)(C 1 -C 6 )alkyl; wherein the (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy(C 0 -C 6 )alkyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) cyano, and (9) —NR 6 R 5 ; 
         wherein R 5  and R 6  together with nitrogen atom to which they are attached, may form a 3 to 7 membered ring which may contain an atom selected from oxygen and nitrogen; and the 3 to 7 membered ring is optionally substituted with a substituent independently selected from the group consisting of: (1) hydrogen, (3) hydroxyl, and (7) (C 1 -C 6 )alkoxy; 
         R 4  is independently selected from the group consisting of: (1) hydrogen and (2) (C 1 -C 6 )alkyl; 
         R 5  and R 6  are independently selected from the group consisting of: (1) hydrogen, (2) (C 1 -C 6 )alkyl, (5) hydroxyl(C 1 -C 6 )alkyl, (6) (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, and (7) H 2 N—(C 1 -C 6 )alkyl; 
         p is 1, 2, 3 or 4; 
         q is 1, 2, 3, or 4, and when q is 2 or more than 2, R 1  is the same or different; 
         r is 1 or 2, and when r is 2, R 2  is the same or different; 
         s is 1 or 2, when s is 2, R 3  is the same or different; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound according to  claim 1 , which is selected from the group consisting of:
 3-(2-(2,5-dimethyl-1-phenyl-1H-imidazol-4-yl)-2-oxoethyl)-1-oxa-3-azaspiro[4.5]decane-2,4-dione;   3-(2-(2,5-dimethyl-1-(m-tolyl)-1H-imidazol-4-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   3-(2-(1,4-dimethyl-5-phenyl-1H-pyrazol-3-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   3-(2-([2,3′-bipyridin]-5-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   3-(2-(4-(2-methyl-1H-benzo[d]imidazol-1-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.6]undecane-2,4-dione;   3-(2-oxo-2-(4-(pyridin-2-yloxy)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   3-(2-(4-(2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.6]undecane-2,4-dione;   3-(2-(4-(2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   3-(2-oxo-2-(4-(pyridazin-3-yl oxy)phenyl)ethyl)-1,3-diazaspiro[4.6]undecane-2,4-dione;   3-(2-(4-(2-methylpyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   3-(2-(4-(4-methylpyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   3-(2-(4-(3-methylthiophen-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   3-(2-(4-(3,6-dimethylpyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   6-(4-(2-(2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)picolinonitrile;   3-(4-(2-(2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)picolinonitrile;   3-(2-(4-(4-(hydroxymethyl)pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   3-(2-(4-(3-(hydroxymethyl)pyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   3-(2-(4-(3-methylpyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   3-(2-(4′-methyl-[2,3′-bipyridin]-5-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   3-(2-(2′-methyl-[2,3′-bipyridin]-5-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   3-(2-oxo-2-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   3-(2-(2-fluoro-4-(pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   3-(2-(4-methyl-5-(pyridin-3-yl)thiophen-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   3-(2-(4-methyl-5-(4-methylpyridin-3-yl)thiophen-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; and   3-(2-(6-(methyl(pyridin-2-yl)amino)pyridin-3-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   or a pharmaceutically acceptable salt thereof.   
     
     
         3 . A method of antagonizing a TRPM8 receptor in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         4 . A method for treating a condition or disorder, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein the condition or disorder is at least one selected from the group consisting of a pain disease or disorder, ischemia, irritable bowel syndrome, Raynaud's syndrome, neurodegeneration, fibromyalgia, stroke, itch, a psychiatric disorder, an inflammatory disorder, anxiety, and a urological disease or disorder. 
     
     
         5 . A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to  claim 1 , and a pharmaceutically acceptable carrier or excipient. 
     
     
         6 . The pharmaceutical composition according to  claim 5 , which further comprises another pharmacologically active agent. 
     
     
         7 . A process for preparing a pharmaceutical composition comprising mixing a compound according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. 
     
     
         8 . The method according to  claim 3 , wherein the mammal is a human. 
     
     
         9 . The method according to  claim 4 , wherein the pain disease or disorder is at least one selected from the group consisting of chronic pain, neuropathic pain, postoperative pain, osteoarthritis, rheumatoid arthritic pain, cancer pain, neuralgia, neuropathies, algesia, dentin hypersensitivity, nerve injury, migraine, cluster, and a tension headache. 
     
     
         10 . The method according to  claim 9 , wherein the neuropathic pain is at least one selected from the group consisting of cold allodynia and diabetic neuropathy. 
     
     
         11 . The method according to  claim 4 , wherein the psychiatric disorder is at least one selected from the group consisting of anxiety and depression. 
     
     
         12 . The method according to  claim 4 , wherein the inflammatory disorder is at least one selected from the group consisting of asthma, chronic obstructive pulmonary, airways disease, COPD, and pulmonary hypertension. 
     
     
         13 . The method according to  claim 4 , wherein the urological disease or disorder is at least one selected from the group consisting of detrusor overactivity, overactive bladder, urinary incontinence, neurogenic detrusor overactivity, detrusor hyperflexia, idiopathic detrusor overactivity, detrusor instability, benign prostatic hyperplasia, and a lower urinary tract symptom.