Alkynyl dihydroquinoline sulfonamide compounds
The present invention provides compounds of Formula I, 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, an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is an ethynyl substituted by an C 4-8 alk or a cyclopropyl, cyclobutyl, or cyclohexyl ring; wherein said C 4-8 alk is substituted by 1, 2, 3, or 4 halo; and wherein said cyclopropyl, cyclobutyl, or cyclohexyl ring is substituted by 1, 2, 3, or 4 halo or C 1-4 haloalk;
R 2 is H, halo, C 1-6 alk, or C 1-6 haloalk;
R 3 is C 1-6 alk, C 1-4 haloalk, —O—C 1-6 alk, or —CN;
R 4 is isoxazolyl or pyrimidinyl;
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 R 1 is selected from —C≡C—CF 3 , —C≡C—C(CH 3 ) 2 —CF 3 , —C≡C— cyclopropyl-CF 3 , —C≡C-cyclopentyl (wherein said cyclopentyl is unsubstituted or is substituted by —O—CH 2 —CF 3 ), or —C≡C-cyclohexyl- (wherein said cyclohexyl is substituted by 2 F atoms).
3. The compound according to claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is H, fluoro, chloro, methyl, CF 3 , CHF 2 , or CH 2 F.
4. The compound according to claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is methoxy.
5. The compound according to claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is an isoxazolyl.
6. The compound according to claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is a pyrimidinyl.
7. The compound according to claim 1 , 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.
8. The compound according to claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of
9. 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.
10. 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.
11. A method of treating pain, cough, or itch mediated by Nav 1.7, 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.
12. The method according to claim 11 ; 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.
13. The method according to claim 11 ; wherein the cough is selected from post viral cough, viral cough, or acute viral cough.
14. The compound according to claim 8 , an enantiomer, diastereoisomer, atropisomer thereof, or a pharmaceutically acceptable salt thereof, which is
15. The compound according to claim 8 , an enantiomer, diastereoisomer, atropisomer thereof, or a pharmaceutically acceptable salt thereof, which is
16. The compound according to claim 8 , an enantiomer, diastereoisomer, atropisomer thereof, or a pharmaceutically acceptable salt thereof, which is
17. The compound according to claim 8 , an enantiomer, diastereoisomer, atropisomer thereof, or a pharmaceutically acceptable salt thereof, which is
18. The compound according to claim 8 , an enantiomer, diastereoisomer, atropisomer thereof, or a pharmaceutically acceptable salt thereof, which is
19. The compound according to claim 8 , an enantiomer, diastereoisomer, atropisomer thereof, or a pharmaceutically acceptable salt thereof, which is
20. The compound according to claim 8 , an enantiomer, diastereoisomer, atropisomer thereof, or a pharmaceutically acceptable salt thereof, which is