Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same

Abstract

Compounds are disclosed that have a formula represented by the following: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, traumatic injury, and others.

1 . A method for preventing, treating, ameliorating or managing a disease or condition which comprises administering to a patient in need of such prevention, treatment, amelioration or management, a prophylactically or therapeutically effective amount of a compound having a formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, and stereoisomers and tautomers thereof, wherein:  
         each of W, Z, Y and X is independently N or CR 4 ;  
         L is substituted or unsubstituted cyclopropyl;  
         R 1  is substituted or unsubstituted aryl, heteroaryl, bicycloaryl or bicycloheteroaryl;  
         R 3  is substituted or unsubstituted alkyl, heteroalkyl, aryl, cycloalkyl, cycloheteroalkyl, heteroaryl, aralkyl, heteroaralkyl, or a hetero group; each R 4  is independently hydrogen, substituted or unsubstituted alkyl, acyl, acylamino, alkylamino, alkylthio, alkoxy, alkoxycarbonyl, alkylarylamino, arylalkyloxy, amino, aryl, arylalkyl, sulfo, sulfonyl, sulfanyl, aminosulfonyl, arylsulfonyl, sulfonic acid, sulfonic acid ester, azido, carbamoyl, carboxyl, cyano, cycloheteroalkyl, dialkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxyl, nitro or thiol.  
       
     
     
         2 . (canceled)  
     
     
         3 . A method according to  claim 1  wherein L is cyclopropyl substituted with H, halo, C 1 -C 6  alkyl, halo C 1 -C 6  alkyl, or hydroxy C 1 -C 6  alkyl.  
     
     
         4 . A method according to  claim 1  wherein the compound is of the formula  
       
         
           
           
               
               
           
         
         and wherein W, X, Y, Z and R 1  are as described in  claim 1  and A is CR 5 R 6 ; each of R 3 , R 3′  R 5 , R 5′  and R 6  is independently selected from hydrogen, substituted or unsubstituted alkyl, heteroalkyl, aryl, cycloalkyl, cycloheteroalkyl, heteroaryl, aralkyl, heteroaralkyl, or a hetero group.  
       
     
     
         5 . A method according to  claim 1  wherein the compound is of the formula  
       
         
           
           
               
               
           
         
         and wherein W, X, Y, Z and R 1  are as described in  claim 1  and A is CR 5 R 6 ; each of R 3′ , R 5 , R 5′  and R 6  is independently selected from H, halo, C 1 -C 6  alkyl, halo C 1 -C 6  alkyl, or hydroxy C 1 -C 6  alkyl; and R 3  is independently selected from halo, C 1 -C 6  alkyl, halo C 1 -C 6  alkyl, or hydroxy C 1 -C 6  alkyl.  
       
     
     
         6 . A method according to  claim 5  wherein each of R 5 , R 5′  and R 6  is independently H; R 3′  selected from H, halo, C 1 -C 6  alkyl, halo C 1 -C 6  alkyl, or hydroxy C 1 -C 6  alkyl; and R 3  is independently selected from halo, C 1 -C 6  alkyl, halo C 1 -C 6  alkyl, or hydroxy C 1 -C 6  alkyl.  
     
     
         7 . A method according to  claim 5  wherein each of R 5 , R 5′  and R 6  is independently H; R 3′  selected from H, and halo; and R 3  is independently selected from halo, C 1 -C 6  alkyl, halo C 1 -C 6  alkyl, or hydroxy C 1 -C 6  alkyl.  
     
     
         8 . A method according to  claim 5  wherein each of R 5 , R 5′  and R 6  is independently H; and each of R 3  and R 3′  is Cl.  
     
     
         9 . A method according to  claim 5  wherein each of R 3′  R 5 , R 5′  and R 6  is independently H; and R 3  is independently selected from halo, C 1 -C 6  alkyl, halo C 1 -C 6  alkyl, or hydroxy C 1 -C 6  alkyl.  
     
     
         10 . A method according to  claim 5  wherein each of R 3′  R 5 , R 5′  and R 6  is independently H; and R 3  is independently selected t-Bu and CF 3 .  
     
     
         11 . A method according to claim S wherein R 1  is substituted or unsubstituted is aryl, heteroaryl, bicycloaryl or bicycloheteroaryl and the substitution is selected from H, halo, C 1 -C 6  alkyl, halo C 1 -C 6  alkyl, hydroxy C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxy, halo C 1 -C 6  alkoxyamino, C 1 -C 6  alkylamino, C 1 -C 6  dialkylamino, aryl, SO 2  C 1 -C 6  alkyl, SO 2  halo C 1 -C 6  alkyl, SO 2 N(C 1 -C 6  alkyl) 2 , and carboxy.  
     
     
         12 . A method according to  claim 5  wherein R 1  is substituted or unsubstituted is phenyl, and the substitution is selected from H, halo, C 1 -C 6  alkyl, halo C 1 -C 6  alkyl, hydroxy C 1 -C 6  alkyl, C 1 -C 6  alkoxy.  
     
     
         13 . A method according to  claim 5  wherein R 1  is substituted or unsubstituted is pyridyl, and the substitution is selected from H, halo, C 1 -C 6  alkyl, halo C 1 -C 6  alkyl, hydroxy C 1 -C 6  alkyl, C 1 -C 6  alkoxy.  
     
     
         14 . A method according to  claim 5  wherein R 1  is:  
       
         
           
           
               
               
           
         
         wherein each of A 1 , A 2 , A 3 , A 4 , B1 and B2 is independently CR 4  and N;  
         and each of R 4′  is independently H, C 1 -C 6  alkyl, halo, or hydroxy C 1 -C 6  alkyl.  
       
     
     
         15 . A method according to  claim 5  wherein R 1  is:  
       
         
           
           
               
               
           
         
         wherein each of A 5  and A 8  is independently CR 4′ R 4 , NR 4 , O, S, SO or SO 2 ;  
         each of A 6  and A 7  is independently CR 4 , NR 4 , CR 4′ R 4  or CO; each of B 3  and B 4  is independently CR 4′ ; when R 4′  is attached to C, each of R 4′  is independently H, C 1 -C 6  alkyl, halo, or hydroxy C 1 -C 6  alkyl, and when R 4  is attached to N, each of R 4′  is independently H or C 1 -C 6  alkyl; and the dotted bond represents a single or a double bond.  
       
     
     
         16 . A method according to  claim 5  wherein R 1  is:  
       
         
           
           
               
               
           
         
         wherein each of A 9 , A 10  and A 11  is independently CR 4 , CR 4 , R 4 , CO, CS, N, NR, O, S, SO or SO 2 ; each of B 5  and B 6  is independently CR 4 ;  
         when R 41  is attached to C, each of R 4′  is independently H, C 1 -C 6  alkyl, halo, or hydroxy C 1 -C 6  alkyl, and when R 4  is attached to N, each of R 4  is independently H, or C 1 -C 6  alkyl; and  
         each of the dotted bonds independently represents a single or a double bond.  
       
     
     
         17 . A method according to  claim 5  wherein R 1  is  
       
         
           
           
               
               
           
         
         wherein, the ring may be further substituted with R 4′ , and R 4′  is as described in  claim 4;  and  
         when feasible, the ring N can further be substituted with H or C 1 -C 6  alkyl.  
       
     
     
         18 . A method according to  claim 5  wherein R 1  is  
       
         
           
           
               
               
           
         
         wherein each of A 1 , A 2 , A 3 , A 4 , B 1  and B 2  is independently CH and N;  
         and R 4′  is C 1 -C 6  alkyl or hydroxy C 1 -C 6  alkyl.  
       
     
     
         19 . A method according to  claim 5  wherein R 1  is  
       
         
           
           
               
               
           
         
         wherein each of A 5  and A 8  is independently CH 2 , CHMe, NH, NMe, O, S, SO or SO 2 ;  
         and R 4  is C—C 6  alkyl or hydroxy C—C 6  alkyl.  
       
     
     
         20 . A method according to  claim 5  wherein R 1  is  
       
         
           
           
               
               
           
         
         wherein each of A 9 , A 10  and A 11  is independently CH, CH 2 , N, NH, O, or S; each of B 5  and B 6  is independently CH and N;  
         each of R 4′  is independently H, C 1 -C 6  alkyl or hydroxy C 1 -C 6  alkyl; and  
         each of the dotted bonds independently represents a single or a double bond.  
       
     
     
         21 . A method according to  claim 5  wherein R 1  is  
       
         
           
           
               
               
           
         
         and wherein R 4′  is independently H, C 1 -C 6  alkyl or hydroxy C 1 -C 6  alkyl.  
       
     
     
         22 . A method to any one of claims  17 - 21  wherein R 4′  is hydroxy C 1 -C 6  alkyl.  
     
     
         23 . A method according to  claim 22  wherein R 4′  is —(CH 2 ) n —OH; and wherein n is selected from 1-3.  
     
     
         24 . A method according to  claim 23  wherein R 4′  is CH 2 OH.  
     
     
         25 . A method according to  claim 1  wherein the compound is depicted by a formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, and stereoisomers and tautomers thereof, wherein:  
         each of W, Z, Y and X is independently N or CR 4 ;  
         each of A 1 , A 2 , A 3 , A 4 , B 1  and B 2  is independently N or CR 4 ;  
         R 3  is t-Bu or CF 3 ;  
         each R 4  is independently hydrogen, substituted or unsubstituted alkyl, acyl, acylamino, alkylamino, alkylthio, alkoxy, alkoxycarbonyl, alkylarylamino, arylalkyloxy, amino, aryl, arylalkyl, sulfo, sulfonyl, sulfanyl, aminosulfonyl, arylsulfonyl, sulfonic acid, sulfonic acid ester, azido, carbamoyl, carboxyl, cyano, cycloheteroalkyl, dialkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxyl, nitro or thiol;  
         and R 4′  is C 1 -C 6  alkyl or hydroxyl C 1 -C 6  alkyl.  
       
     
     
         26 . A method according to  claim 1  wherein the compound is depicted by a formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, and stereoisomers and tautomers thereof, wherein:  
         wherein each of A 5  and A 8  is independently CR 4′ R 4″ , NR 4 , O, S, SO or SO 2 ;  
         each of A 6  and A 7  is independently CR 4 , NR 4 , CR 4′  R 4′  or CO; each of B3 and B4 is independently CH; when R 4′  is attached to C, each of R 4′  is independently H, C 1 -C 6  alkyl, halo, or hydroxy C 1 -C 6  alkyl, and when R 4′  is attached to N, each of R 4′  is independently H or C 1 -C 6  alkyl; and the dotted bond represents a single or a double bond;  
         R 3  is t-Bu or CF 3 ;  
         each R 4  is independently hydrogen, substituted or unsubstituted alkyl, acyl, acylamino, alkylamino, alkylthio, alkoxy, alkoxycarbonyl, alkylarylamino, arylalkyloxy, amino, aryl, arylalkyl, sulfo, sulfonyl, sulfanyl, aminosulfonyl, arylsulfonyl, sulfonic acid, sulfonic acid ester, azido, carbamoyl, carboxyl, cyano, cycloheteroalkyl, dialkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxyl, nitro or thiol;  
         and R 4′  is C 1 -C 6  alkyl or hydroxyl C 1 -C 6  alkyl.  
       
     
     
         27 . A method according to  claim 1  wherein the compound is depicted by a formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, and stereoisomers and tautomers thereof, wherein:  
         each of A 9 , A 10  and A 11  is independently CH, CH 2 , N, NH, O, or S; each of B 5  and B 6  is independently CH;  
         each of R 4′  is independently H, C 1 -C 6  alkyl or hydroxy C 1 -C 6  alkyl; and  
         each of the dotted bonds independently represents a single or a double bond;  
         R 3  is t-Bu or CF 3 ;  
         each R 4  is independently hydrogen, substituted or unsubstituted alkyl, acyl, acylamino, alkylamino, alkylthio, alkoxy, alkoxycarbonyl, alkylarylamino, arylalkyloxy, amino, aryl, arylalkyl, sulfo, sulfonyl, sulfanyl, aminosulfonyl, arylsulfonyl, sulfonic acid, sulfonic acid ester, azido, carbamoyl, carboxyl, cyano, cycloheteroalkyl, dialkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxyl, nitro or thiol;  
         and R 4′  is C 1 -C 6  alkyl or hydroxyl C 1 -C 6  alkyl.  
       
     
     
         28 . A method according to  claim 1  wherein the compound is depicted by a formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, and stereoisomers and tautomers thereof, wherein:  
         each of W, Z, Y and X is independently N or CR 4 ;  
         each of B 7 , B 8  and B 9  is independently CR 4 ;  
         R 3  is t-Bu or CF 3 ;  
         each R 4  is independently hydrogen, substituted or unsubstituted alkyl, acyl, acylamino, alkylamino, alkylthio, alkoxy, alkoxycarbonyl, alkylarylamino, arylalkyloxy, amino, aryl, arylalkyl, sulfo, sulfonyl, sulfanyl, aminosulfonyl, arylsulfonyl, sulfonic acid, sulfonic acid ester, azido, carbamoyl, carboxyl, cyano, cycloheteroalkyl, dialkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxyl, nitro or thiol;  
         and R 4′  is C 1 -C 6  alkyl or hydroxyl C 1 -C 6  alkyl.  
       
     
     
         29 . A method according to any one of claims  5 ,  25 - 28 , wherein each of W, X, Y and Z is CR 4 .  
     
     
         30 . A method according to any one of claims  5 ,  25 - 28  wherein one of W, X, Y and Z is N and the rest are independently CR 4 .  
     
     
         31 . A method according to any one of claims  5 ,  25 - 28  wherein W is N and each of X, Y and Z is CR 4 .  
     
     
         32 . A method according to any one of claims  5 ,  25 - 28  wherein each of W and X is CR 4 ; and each of Y and Z is CR 4″  and wherein R 4″  is independently selected from hydrogen, C 1 -C 6  alkyl, trihalo C 1 -C 6  alkyl and halo.  
     
     
         33 . A method according to  claim 32  wherein each of R 4″  is independently H, CH 3 , CF 3 , Cl, or F.  
     
     
         34 . A method according to any one of claims  5 ,  25 - 28  wherein each of W, X, and Z is CH; and Y is C—CH 3 , C—Cl, or C—F.  
     
     
         35 . A method according to  claim 32  wherein R 4  is H.  
     
     
         36 . A method according to  claim 1  wherein the compound is selected from the group consisting of: 
 4-cyclopropyl-N-(3-methoxyphenyl)-2-methylbenzamide;    N-(4-tert-butylphenyl)-4-cyclopropyl-2-methylbenzamide;    4-(2,2-dichlorocyclopropyl)-N-(quinolin-3-yl)benzamide;    4-(2,2-dichlorocyclopropyl)-N-(3-methoxyphenyl)benzamide;    4-cyclopropyl-2-methyl-N-(quinolin-3-yl)benzamide;    4-(2,2-dichlorocyclopropyl)-N-(2-methylbenzo[d]thiazol-5-yl)benzamide;    4-cyclopropyl-2-methyl-N-(2-methylbenzo[d]thiazol-5-yl)benzamide;    N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methyl-4-(2-(trifluoromethyl)cyclopropyl)benzamide;    2-methyl-N-(5,6,7,8-tetrahydronaphthalen-1-yl)-4-(2-(trifluoromethyl)cyclopropyl)benzamide;    N-(6-methoxypyridin-3-yl)-2-methyl-4-(2-(trifluoromethyl)cyclopropyl)benzamide;    2-methyl-N-(2-methylbenzo[d]thiazol-5-yl)-4-(2-(trifluoromethyl)cyclopropyl)benzamide;    2-methyl-N-(2-methylbenzo[d]thiazol-5-yl)-4-(2-(trifluoromethyl)cyclopropyl)benzamide;    N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methyl-4-(2-(trifluoromethyl)cyclopropyl)benzamide;    N-(4-tert-butylphenyl)-2-methyl-4-(2-(trifluoromethyl)cyclopropyl)benzamide;    N-(2-hydroxymethyl)benzo[d]thiazol-5-yl)-2-methyl-4-(2-(trifluoromethyl)cyclopropyl)benzamide;    N-(3-methoxyphenyl)-2-methyl-4-(2-(trifluoromethyl)cyclopropyl)benzamide;    (1R,2R) 2-methyl-N-(quinolin-3-yl)-4-(2-(trifluoromethyl)cyclopropyl)benzamide;    (1R,2S) 2-methyl-N-(quinolin-3-yl)-4-(2-(trifluoromethyl)cyclopropyl)benzamide;    (1S,2R) 2-methyl-N-(quinolin-3-yl)-4-(2-(trifluoromethyl)cyclopropyl)benzamide; and    (1S,2S) 2-methyl-N-(quinolin-3-yl)-4-(2-(trifluoromethyl)cyclopropyl)benzamide.    
     
     
         37 . (canceled)  
     
     
         38 . (canceled)  
     
     
         39 . (canceled)  
     
     
         40 . (canceled)  
     
     
         41 . (canceled)  
     
     
         42 . (canceled)  
     
     
         43 . A method according to  claim 1  wherein the disease is selected from acute cerebral ischemia, pain, chronic pain, acute pain, nociceptive pain, neuropathic pain, inflammatory pain, post herpetic neuralgia, neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve injury, rheumatoid arthritic pain, osteoarthritic pain, burns, back pain, visceral pain, cancer pain, dental pain, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain, menstrual pain, bladder disease, such as incontinence, micturition disorder, renal colic and cystitis, inflammation, such as burns, rheumatoid arthritis and osteoarthritis, neurodegenerative disease, such as stroke, post stroke pain and multiple sclerosis, pulmonary disease, such as asthma, cough, chronic obstructive pulmonary disease (COPD) and broncho constriction, gastrointestinal disorders, such as gastroesophageal reflux disease (GERD), dysphagia, ulcer, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colitis and Crohn's disease, ischemia, such as cerebrovascular ischemia, emesis, such as cancer chemotherapy-induced emesis and obesity.  
     
     
         44 . A method of treatment of a mammal, including a human being, to treat a disease for which a VR1 antagonist is indicated, including treating said mammal with an effective amount of a compound or with a pharmaceutically acceptable salt, solvate or composition thereof, as defined in  claim 1 .  
     
     
         45 . (canceled)