Alkynyl dihydroquinoline sulfonamide compounds

Patent metadata

Field	Value
Publication number	US-10729684-B2
Application number	US-201616062602-A
Country	US
Kind code	B2
Filing date	Dec 19, 2016
Priority date	Dec 18, 2015
Publication date	Aug 4, 2020
Grant date	Aug 4, 2020

Abstract

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.

First claim

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 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

Assignees

• Amgen Inc

Inventors

• Weiss Matthew
• Dineen Thomas
• Vaida Karina R

Classifications

• C07D241/44

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D215/36

  Sulfur atoms (C07D215/24 takes precedence) · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title