Cyclobutyl dihydroquinoline sulfonamide compounds

Abstract

The present invention provides a cyclobutyl dihydroquinoline sulfonamide compound of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, that inhibits 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 the compounds of the present invention. Also further provided is an atropi-selective preparation of said compounds of Formula (I), and intermediate thereof.

What is claimed is: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof; 
         wherein: R 1  is a saturated or partially-saturated 4-membered monocyclic ring; or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring; wherein said monocyclic ring or bicyclic ring contains 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S; and wherein said monocyclic ring or bicyclic ring is substituted by 0, 1, 2 or 3 R 1a  groups selected from hydroxy, halo, C 1-8 alk, C 1-8 haloalk, —O—C 1-4 alk, —O—C 1-8 haloalk, —C(═O)C 1-4 alk, —O—C(═O)C 1-4 alk, —NH 2 , —NHC 1-4 alk, or —N(C 1-4 alk)C 1-4 alk; 
         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 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 1a  group is selected from halo, C 1-8 alk, —O—C 1-4 alk, or C 1-8 haloalk, wherein said C 1-8 haloalk is C 1-8 fluoroalkyl. 
     
     
         3 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 1  is a cyclobutyl ring; or a 5-, or 6-membered bicyclic ring; wherein said cyclobutyl ring or bicyclic ring contains 0 N, O, and S atoms; and wherein said cyclobutyl ring or bicyclic ring is substituted by 1, 2 or 3 R 1a  groups selected from F, —CF 3 , —O—CF 3 , or —C(CH 3 ) 3 . 
     
     
         4 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 1  is a cyclobutyl ring or bicyclo[1.1.1]pentan-1-yl ring; wherein each ring is substituted by 1 or 2 F or —CF 3 . 
     
     
         5 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 1  is a cyclobutyl ring substituted by 1 or 2 F or —CF 3 . 
     
     
         6 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 1  is a cyclobutyl ring substituted by 1 or 2 —CF 3 . 
     
     
         7 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 1  is a cyclobutyl ring substituted by 1 or 2 F. 
     
     
         8 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 1  is a bicyclo[1.1.1]pentan-1-yl ring substituted by 1 or 2 F or —CF 3 . 
     
     
         9 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 2  is H, fluoro, chloro, methyl, CF 3 , CHF 2 , or CH 2 F. 
     
     
         10 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 2  is H, fluoro, chloro, or methyl. 
     
     
         11 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 2  is H or fluoro. 
     
     
         12 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 3  is methoxy. 
     
     
         13 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 4  is a 5-membered heteroaryl. 
     
     
         14 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 4  is a 6-membered heteroaryl. 
     
     
         15 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 4  is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl. 
     
     
         16 . The compound according to  claim 15 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 4  is isoxazolyl. 
     
     
         17 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein (a) each of R 5a ; R 5b ; R 5c ; R 5d ; and R 5e  is hydrogen; (b) R 5a  is F; and each of R 5b ; R 5c ; R 5d ; and R 5e  is hydrogen; or (c) R 5c  is F; and each of R 5a ; R 5b ; R 5d ; and R 5e  is hydrogen. 
     
     
         18 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 5a  is F. 
     
     
         19 . The compound according to  claim 15 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each of R 5a ; R 5b ; R 5c ; R 5d ; and R 5e  is hydrogen. 
     
     
         20 . The compound according to  claim 15 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 5a  is F; and each of R 5b ; R 5c ; R 5d ; and R 5e  is hydrogen. 
     
     
         21 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula (I) is selected from compounds of Formula (Ia), (Ib), or (Ic): 
       
         
           
           
               
               
           
         
         wherein each R 1a  in said compounds of Formula (Ia), (Ib), or (Ic) is independently fluoro, chloro, methyl, —O—CF 3 , or CF 3 . 
       
     
     
         22 . The compound according to  claim 21 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula (I) is a compound of Formula (Ia); wherein said R 1a  is CF 3 ; the cyclobutyl ring is a trans isomer; and R 4  is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, or oxazolyl. 
     
     
         23 . The compound according to  claim 21 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula (I) is a compound of Formula (Ia); wherein said R 1a  is cis CF 3 ; the cyclobutyl ring is a cis isomer; R 2  is F; and R 4  is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, or oxazolyl. 
     
     
         24 . The compound according to  claim 21 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula (I) is a compound of Formula (Ib); wherein each R 1a  is fluoro; R 2  is F; and R 4  is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl. 
     
     
         25 . The compound according to  claim 21 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula (I) is a compound of Formula (Ib); wherein each R 1a  is fluoro; R 5a  is F; and R 4  is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl. 
     
     
         26 . The compound according to  claim 21 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula (I) is a compound of Formula (Ic); wherein each R 1a  is CF 3 . 
     
     
         27 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
 a) cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;   b) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;   c) cis-(P)-1-(5-chloro-2-methoxy-4-((1S,3S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;   d) trans-(P)-1-(5-chloro-2-methoxy-4-((1S,3S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;   e) trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;   f) trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;   g) trans-(P)—N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;   h) trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;   i) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;   j) (P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;   k) (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;   l) cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;   m) trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;   n) trans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or   o) trans (P)-1-(5-chloro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.   
     
     
         28 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
 a) (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;   b) (P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;   c) trans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;   d) cis-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;   e) cis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;   f) trans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;   g) (P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or   h) (P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.   
     
     
         29 . The compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
 a) (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or   b) (P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide.   
     
     
         30 . 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. 
     
     
         31 . A pharmaceutical composition comprising a compound according to  claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         32 . 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 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof. 
     
     
         33 . The method according to  claim 32 ; wherein the pain is selected from chronic pain, acute pain, neuropathic pain, pain associated with rheumatoid arthritis, pain associated with osteoarthritis, pain associated with cancer, peripheral diabetic neuropathy, and neuropathic low back pain. 
     
     
         34 . The method according to  claim 32 ; wherein the cough is selected from post viral cough, viral cough, or acute viral cough. 
     
     
         35 . A method of preparation of a compound of Formula (A): 
       
         
           
           
               
               
           
         
       
       wherein R is halo;
 comprising: 
 (1) reacting a trans olefin compound of Formula (B): 
 
       
         
           
           
               
               
           
         
       
       wherein R is halo; and R 1  is C 1 -C 6 alkyl;
 with a UV light or near UV light; to form a cis olefin compound (C); and 
 (2) reacting said compound (C) with a chiral acid in an organic solvent to form said compound of Formula (A). 
 
     
     
         36 . The method of  claim 35 , wherein said chiral acid is a phosphorus chiral acid. 
     
     
         37 . The method of  claim 35  wherein said chiral acid is (S)-TRIP having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         38 . The method of  claim 35 , wherein said organic solvent is dichloromethane. 
     
     
         39 . The method of  claim 35 , wherein said R is bromo. 
     
     
         40 . The method of  claim 35 , wherein said R 1  is ethyl. 
     
     
         41 . The method of  claim 35 , wherein in reaction (2), a P atropisomer of said compound of Formula (A) is selectively formed. 
     
     
         42 . The method of  claim 35 , wherein said compound of Formula (A) is used as an intermediate compound in preparation of a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein: 
 R 1  is a saturated or partially-saturated 4-membered monocyclic ring; or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring; wherein said monocyclic ring or bicyclic ring contains 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S; and wherein said monocyclic ring or bicyclic ring is substituted by 0, 1, 2 or 3 R 1a  groups selected from hydroxy, halo, C 1-8 alk, C 1-8 haloalk, —O—C 1-4 alk, —O—C 1-8 haloalk, —C(═O)C 1-4 alk, —O—C(═O)C 1-4 alk, —NH 2 , —NHC 1-4 alk, or —N(C 1-4 alk)C 1-4 alk; 
 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; and 
 Wherein a P atropisomer of said compound of Formula (I) is selectively formed.