Substituted Ureas and Methods of Making and Using Same

Abstract

The invention relates to substituted ureas, and compositions comprising the same, which in certain embodiments are useful for treating and/or preventing pain in a subject in need thereof.

1 - 21 . (canceled) 
     
     
         22 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a salt, solvate, enantiomer, diastereoisomer, or tautomer thereof, 
         wherein one of the following applies: 
         (i) A is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         
           B 2  is H and B 1  is selected from the group consisting of 
         
       
       
         
           
           
               
               
           
         
         
            or 
           B 1  and B 2  are independently selected from the group consisting of —CH 3  and —CH 2 CH 3 , or 
           B 1  and B 2  combine to form a divalent substituent selected from the group consisting of —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 —, and —CH 2 CH 2 OCH 2 CH 2 —; 
           or 
         
         (ii) A is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
          and
 B 1  and B 2  are independently selected from the group consisting of —CH 3  and —CH 2 CH 3 , or 
 B 1  and B 2  combine to form a divalent substituent selected from the group consisting of —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 —, and —CH 2 CH 2 OCH 2 CH 2 —; 
 
         R 1  and R 2  are independently selected from the group consisting of H, CH 3 , and CH 3  substituted with at least one selected from the group consisting of fluoro, chloro, cyano, hydroxyl and nitro; 
         R 3  is selected from the group consisting of H and CH 3    
         X is selected from the group consisting of S, O, and N—R 3 ; 
         each occurrence of R is independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, hydroxyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, and substituted phenyl; 
         each occurrence of m is independently selected from the group consisting of 0, 1, 2, and 3; 
         n is selected from the group consisting of 1, 2, and 3; and 
         each occurrence of p is independently selected from the group consisting of 0, 1, 2, and 3. 
       
     
     
         23 . The compound of  claim 22 , wherein in (i) A is 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 22 , wherein in (i) A is 
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound of  claim 22 , wherein in (ii) A is 
       
         
           
           
               
               
           
         
       
     
     
         26 . The compound of  claim 22 , wherein in (ii) A is 
       
         
           
           
               
               
           
         
       
     
     
         27 . The compound of  claim 22 , wherein in (I) A is 
       
         
           
           
               
               
           
         
       
     
     
         28 . The compound of  claim 22 , wherein in (i) B 1  is 
       
         
           
           
               
               
           
         
       
     
     
         29 . The compound of  claim 22 , wherein (i) B 1  is 
       
         
           
           
               
               
           
         
       
     
     
         30 . The compound of  claim 22 , wherein A is selected from the group consisting of isoindolin-2-yl, 5-fluoroisoindolin-2-yl, 5-chloroisoindolin-2-yl, 5-methoxyisoindolin-2-yl, 5-methylisoindolin-2-yl, 5-hydroxyisoindolin-2-yl, 5-cyanoisoindolin-2-yl, 4-fluoroisoindolin-2-yl, 4-chloroisoindolin-2-yl, 4-methoxyisoindolin-2-yl, 4-methylisoindolin-2-yl, 4-hydroxyisoindolin-2-yl, 4-cyanoisoindolin-2-yl, 5,6-difluoroisoindolin-2-yl, 5,6-dichloroisoindolin-2-yl, 6-chloro-5-fluoroisoindolin-2-yl, 5-chloro-6-fluoroisoindolin-2-yl, 1,2,3,4-tetrahydroquinolin-1-yl, 5-fluoro-1,2,3,4-tetrahydroquinolin-1-yl, 6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl, 7-fluoro-1,2,3,4-tetrahydroquinolin-1-yl, 8-fluoro-1,2,3,4-tetrahydroquinolin-1-yl, 5-hydroxy-1,2,3,4-tetrahydroquinolin-1-yl, 6-hydroxy-1,2,3,4-tetrahydroquinolin-1-yl, 7-hydroxy-1,2,3,4-tetrahydroquinolin-1-yl, 8-hydroxy-1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, 5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl, 6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl, 7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl, 8-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl, 5-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl, 6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl, 7-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl, 8-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl, 5-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl, 6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl, 7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl, 8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl, 5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl, 6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl, 7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl, 8-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl, pyrrolidin-1-yl, and 3-phenyl-pyrrolidin-1-yl. 
     
     
         31 . The compound of  claim 22 , wherein in (I) B 2  is H and B 1  is selected from the group consisting of 3-thienyl and 2-thienyl. 
     
     
         32 . The compound of  claim 22 , wherein B 1  is CH 3  and B 2  is CH 3 . 
     
     
         33 . The compound of  claim 22 , which is selected from the group consisting of:
 N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-isoindoline-2-carboxamide;   N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamide;   (−)-ent-N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamide;   (+)-ent-N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamide;   N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-4-fluoroisoindoline-2-carboxamide;   5-Chloro-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;   N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methoxyisoindoline-2-carboxamide;   N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5,6-difluoroisoindoline-2-carboxamide;   N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-6-fluoro-3,4-dihydroquinoline-1(2H)-carboxamide;   N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-7-fluoro-3,4-dihydroquinoline-1(2H)-carboxamide;   N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-3,4-dihydroquinoline-1(2H)-carboxamide;   N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methylisoindoline-2-carboxamide;   (R)-3-Phenyl-pyrrolidine-1-carboxylic acid (2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;   (S)-3-Phenyl-pyrrolidine-1-carboxylic acid (2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;   4-Cyano-1,3-dihydro-isoindole-2-carboxylic acid (2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;   5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid (1-dimethylamino-cyclohexylmethyl)-amide hydrochloride;   7-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid (2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;   6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid (2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;   1,3-Dihydro-isoindole-2-carboxylic acid (1-dimethylamino-cyclohexylmethyl)-amide;   (R)-1-((1-(Dimethylamino)cyclohexyl)methyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea;   (S)-1-((1-(Dimethylamino)cyclohexyl)methyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea;   5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid (4-dimethylamino-tetrahydro-pyran-4-ylmethyl)-amide;   5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid (2-dimethylamino-2-methyl-propyl)-amide;   5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid (1-dimethylamino-cyclopentylmethyl)-amide;   1,3-Dihydro-isoindole-2-carboxylic acid (1-dimethylamino-cyclopentylmethyl)-amide;   1-(1-Dimethylamino-cyclopentylmethyl)-3-(S)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;   (R)—N—((R)-3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-3-phenylpyrrolidine-1-carboxamide;   (S)—N—((R)-3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-3-phenylpyrrolidine-1-carboxamide;   (S)—N—((S)-3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-3-phenylpyrrolidine-1-carboxamide;   (−)-N-(2-(Methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;   (+)—N-(2-(Methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;   (−)-4-Fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;   (+)-4-Fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;   (R)—N-(3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamide;   (S)—N-(3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamide;   N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-hydroxyisoindoline-2-carboxamide; and   5-Fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide.   
     
     
         34 . A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one compound of  claim 22 . 
     
     
         35 . A method of treating, ameliorating, or preventing pain in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of  claim 22 . 
     
     
         36 . The method of  claim 35 , wherein the at least one compound is selected from the group of:
 N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-isoindoline-2-carboxamide;   N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamide;   (−)-ent-N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamide;   (+)-ent-N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamide;   N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-4-fluoroisoindoline-2-carboxamide;   5-Chloro-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;   N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methoxyisoindoline-2-carboxamide;   N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5,6-difluoroisoindoline-2-carboxamide;   N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-6-fluoro-3,4-dihydroquinoline-1(2H)-carboxamide;   N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-7-fluoro-3,4-dihydroquinoline-1(2H)-carboxamide;   N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-3,4-dihydroquinoline-1(2H)-carboxamide;   N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methylisoindoline-2-carboxamide;   (R)-3-Phenyl-pyrrolidine-1-carboxylic acid (2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;   (S)-3-Phenyl-pyrrolidine-1-carboxylic acid (2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;   4-Cyano-1,3-dihydro-isoindole-2-carboxylic acid (2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;   5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid (1-dimethylamino-cyclohexylmethyl)-amide hydrochloride;   7-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid (2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;   6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid (2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;   1,3-Dihydro-isoindole-2-carboxylic acid (1-dimethylamino-cyclohexylmethyl)-amide;   (R)-1-((1-(Dimethylamino)cyclohexyl)methyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea;   (S)-1-((1-(Dimethylamino)cyclohexyl)methyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea;   5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid (4-dimethylamino-tetrahydro-pyran-4-ylmethyl)-amide;   5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid (2-dimethylamino-2-methyl-propyl)-amide;   5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid (1-dimethylamino-cyclopentylmethyl)-amide;   1,3-Dihydro-isoindole-2-carboxylic acid (1-dimethylamino-cyclopentylmethyl)-amide;   1-(1-Dimethylamino-cyclopentylmethyl)-3-(S)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;   (R)—N—((R)-3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-3-phenylpyrrolidine-1-carboxamide;   (S)—N—((R)-3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-3-phenylpyrrolidine-1-carboxamide;   (S)—N—((S)-3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-3-phenylpyrrolidine-1-carboxamide;   (−)-N-(2-(Methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;   (+)—N-(2-(Methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;   (−)-4-Fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;   (+)-4-Fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;   (R)—N-(3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamide;   (S)—N-(3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamide;   N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-hydroxyisoindoline-2-carboxamide; and   5-Fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide.   
     
     
         37 . The method of  claim 35 , wherein the at least one compound is a MOR agonist. 
     
     
         38 . The method of  claim 35 , wherein the at least one compound decreases cyclic adenosine monophosphate (cAMP) levels in the subject. 
     
     
         39 . The method of  claim 35 , wherein the at least one compound does not significantly induce recruitment, binding to, or association with a β-arrestin. 
     
     
         40 . The method of  claim 35 , wherein the at least one compound does not significantly cause at least one side effect selected from the group consisting of tachyphylaxis, respiratory depression, constipation, nausea, emesis, withdrawal, dependence, and addiction. 
     
     
         41 . The method of  claim 35 , wherein the pain comprises at least one of chronic pain, neuropathic pain, nociceptive pain, hyperalgesia, or allodynia.