Compounds for the treatment of pain

Abstract

Provided herein are compounds that are useful in the treatment of pain in a subject.

1 - 23 . (canceled) 
     
     
         24 . A compound of Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is C 1-2  alkoxy, wherein the C 1-2  alkoxy is optionally substituted with 1, 2, or 3 halo substituents; 
         R 2  is hydrogen, C 1-6  alkyl, C 3-10  cycloalkyl, 4- to 12-membered heterocycloalkyl, C 1-4  alkylene-CF 3 , C 1-4  alkylene-(C 3-10  cycloalkyl), C 1-4  alkylene-(4- to 12-membered heterocycloalkyl), C 1-6  alkenyl, C 1-4  alkylene-(C 6-14  aryl), C 1-4  alkylene-(5- to 14-membered heteroaryl), (C 3-10  cycloalkylene)-(C 6-14  aryl), (C 3-10  cycloalkylene)-(5- to 14-membered heteroaryl), (4- to 12-membered heterocycloalkylene)-(C 6-14  aryl), or (4- to 12-membered heterocycloalkylene)-(5- to 14-membered heteroaryl); 
         wherein each of the C 1-6  alkyl, C 3-10  cycloalkyl, 4- to 12-membered heterocycloalkyl, C 1-4  alkylene, C 1-6  alkenyl, C 3-10  cycloalkylene, 4- to 12-membered heterocycloalkylene, C 6-14  aryl, and 5- to 14-membered heteroaryl of R 2  is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of —OH, halo, C 1-4  alkyl, C 1-4  alkoxy, —C(═O)—(C 1-4  alkyl), —S(═O)—(C 1-4  alkyl) and —S(═O) 2 —(C 1-4  alkyl); 
         wherein the C 3-10  cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 12-membered heterocycloalkyl of R 2  are each optionally substituted with 1, 2, or 3 oxo moieties; and 
         R 3  is hydrogen, OH, halo, C 1-4  alkyl, or C 1-4  alkoxy. 
       
     
     
         25 . The compound of  claim 24 , wherein R 1  is unsubstituted C 1-2  alkoxy. 
     
     
         26 . The compound of  claim 24 , wherein R 1  is —OCH 3 . 
     
     
         27 . The compound of  claim 24 , wherein R 3  is halo. 
     
     
         28 . The compound of  claim 24 , wherein R 3  is OH. 
     
     
         29 . The compound of  claim 24 , wherein R 3  is hydrogen. 
     
     
         30 . The compound of  claim 24 , wherein the compound of Formula (II) has the structure of Formula (IIa): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is C 1-2  alkoxy, wherein the C 1-2  alkoxy is optionally substituted with 1, 2, or 3 halo substituents; 
         R 2  is hydrogen, C 1-6  alkyl, C 3-10  cycloalkyl, 4- to 12-membered heterocycloalkyl, C 1-4  alkylene-CF 3 , C 1-4  alkylene-(C 3-10  cycloalkyl), C 1-4  alkylene-(4- to 12-membered heterocycloalkyl), C 1-6  alkenyl, C 1-4  alkylene-(C 6-14  aryl), C 1-4  alkylene-(5- to 14-membered heteroaryl), (C 3-10  cycloalkylene)-(C 6-14  aryl), (C 3-10  cycloalkylene)-(5- to 14-membered heteroaryl), (4- to 12-membered heterocycloalkylene)-(C 6-14  aryl), or (4- to 12-membered heterocycloalkylene)-(5- to 14-membered heteroaryl); 
         wherein each of the C 1-6  alkyl, C 3-10  cycloalkyl, 4- to 12-membered heterocycloalkyl, C 1-4  alkylene, C 1-6  alkenyl, C 3-10  cycloalkylene, 4- to 12-membered heterocycloalkylene, C 6-14  aryl, and 5- to 14-membered heteroaryl of R 2  is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of —OH, halo, C 1-4  alkyl, C 1-4  alkoxy, —C(═O)—(C 1-4  alkyl), —S(═O)—(C 1-4  alkyl) and —S(═O) 2 —(C 1-4  alkyl); and 
         wherein the C 3-10  cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 12-membered heterocycloalkyl of R 2  are each optionally substituted with 1, 2, or 3 oxo moieties. 
       
     
     
         31 . The compound of  claim 30 , wherein R 1  is unsubstituted C 1-2  alkoxy. 
     
     
         32 . The compound of  claim 30 , wherein R 1  is —OCH 3 . 
     
     
         33 . The compound of  claim 30 , wherein R 2  is hydrogen, C 1-6  alkyl, C 3-10  cycloalkyl, or 4- to 12-membered heterocycloalkyl. 
     
     
         34 . The compound of  claim 30 , wherein R 2  is C 3-10  cycloalkyl, 4- to 12-membered heterocycloalkyl, C 1-4  alkylene-(C 3-10  cycloalkyl), or C 1-4  alkylene-(4- to 12-membered heterocycloalkyl). 
     
     
         35 . The compound of  claim 30 , wherein R 2  is hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, 4- to 10-membered heterocycloalkyl, C 1-4  alkylene-(C 3-7  cycloalkyl), or C 1-4  alkylene-(4- to 10-membered heterocycloalkyl). 
     
     
         36 . The compound of  claim 30 , wherein R 2  is C 1-4  alkylene-(C 3-10  cycloalkyl) or C 1-4  alkylene-(4- to 12-membered heterocycloalkyl). 
     
     
         37 . The compound of  claim 30 , wherein R 2  is C 3-10  cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 12-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 oxo moieties. 
     
     
         38 . The compound of  claim 30 , wherein R 2  is C 1-4  alkylene-(C 3-10  cycloalkyl) or C 1-4  alkylene-(4- to 12-membered heterocycloalkyl, wherein C 3-10  cycloalkyl and 4- to 12-membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 oxo moieties. 
     
     
         39 . The compound of  claim 30 , wherein R 2  is C 1-6  alkyl, C 3-10  cycloalkyl, or 4- to 12-membered heterocycloalkyl, each of which is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of —OH, halo, C 1-4  alkyl, C 1-4  alkoxy, —C(═O)—(C 1-4  alkyl), —S(═O)—(C 1-4  alkyl) and —S(═O) 2 —(C 1-4  alkyl). 
     
     
         40 . The compound of  claim 24 , wherein the compound of Formula II is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         41 . A pharmaceutical composition comprising the compound of  claim 24  and a pharmaceutically acceptable carrier. 
     
     
         42 . A method of treating pain in a subject in need thereof comprising administering to the subject the compound of  claim 24 . 
     
     
         43 . The method of  claim 42 , wherein the pain is inflammatory pain, thermal pain, acute pain, chronic pain, traumatic pain, chemical pain, ischemic pain, centrally mediated pain, peripherally mediated pain, prickling pain, visceral pain, progressive disease pain, musculoskeletal pain and neuropathic pain. 
     
     
         44 . The method of  claim 43 , wherein the pain is inflammatory pain, thermal pain, acute pain, chronic pain, musculoskeletal pain, and neuropathic pain. 
     
     
         45 . The method of  claim 43 , wherein the pain is chronic pain. 
     
     
         46 . The method of  claim 43 , wherein the pain is musculoskeletal pain.