Alkyl dihydroquinoline sulfonamide compounds

Abstract

and pharmaceutically acceptable salts thereof, that are inhibitors of voltage-gated sodium channels, in particular Nav1.7. The compounds are useful for the treatment of diseases associated with the activity of sodium channels such as pain disorders, cough, and itch. Also provided are pharmaceutical compositions containing compounds of the present invention.

1 . A compound of Formula I, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is (a) C 1-8 alk wherein said C 1-8 alk is substituted by 0, 1, 2 or 3 groups selected from hydroxy, —OC 1-4 alk, —NH 2 , —NHC 1-4 alk, —OC(═O)C 1-4 alk, or —N(C 1-4 alk)C 1-4 alk; or (b) C 1-8 haloalk; 
 R 2  is H, halo, C 1-6 alk, or C 1-6 haloalk; 
 R 3  is C 1-6 alk, C 1-6 haloalk, —O—C 1-6 alk, or —CN; 
 R 4  is a 5- to 6-membered heteroaryl; 
 Each of R 6  and R 7  is hydrogen; and 
 Each of R 5a ; R 5b ; R 5c ; R 5d ; and R 5e  is independently hydrogen or halo. 
 
     
     
         2 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is C 4-8 alk or C 1-6 haloalk, wherein said C 1-6 haloalk is C 1-6 fluoroalkyl. 
     
     
         3 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is selected from —CH 2 —CF 3 , —CH 2 —CH 2 —CF 3 , —CH 2 —CH 2 —CH 2 —CF 3 , —CH 2 —CH(CH 3 )—CF 3 , —CH 2 —CF 2 —CF 3 , —CH 2 —C(CH 3 ) 2 —CF 3 , —C(CH 3 ) 2 —CH 2 —CF 3 , —CF 2 —CH 2 —CF 3 , or —CH 2 —CH 2 —CHF 2 . 
     
     
         4 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is H, fluoro, chloro, methyl, CF 3 , CHF 2 , or CH 2 F. 
     
     
         5 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is fluoro. 
     
     
         6 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  is methoxy. 
     
     
         7 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4  is a 5-membered heteroaryl. 
     
     
         8 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4  is a 6-membered heteroaryl. 
     
     
         9 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4  is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl. 
     
     
         10 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of R 5a ; R 5b ; R 5c ; R 5d ; and R 5e  is hydrogen. 
     
     
         11 . (canceled) 
     
     
         12 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said atropisomer is a P atropisomer. 
     
     
         13 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         14 . A method of treating pain, cough, or itch, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The method according to  claim 14 ; wherein the pain is selected from chronic pain, acute pain, neuropathic pain, pain associated with rheumatoid arthritis, pain associated with osteoarthritis, or pain associated with cancer. 
     
     
         16 . The method according to  claim 14 ; wherein the cough is selected from post viral cough, viral cough, or acute viral cough.