IP Library › Granted Patent US 12,240,839
Granted Patent B2
US 12,240,839 · App. 17/633,151 · Granted Mar 4, 2025

Cyclobutyl dihydroquinoline sulfonamide compounds

Inventors: Benjamin C Milgram (Cambridge, MA); Isaac E Marx (Arlington, MA); Haoxuan Wang (Somerville, MA); Alan H Cherney (Somerville, MA)
Assignee: AMGEN INC.
C07D413/12A61P25/04C07D215/36C07D401/12
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Quick Facts
Patent No.
US 12,240,839
App. No.
17/633,151
Granted
Mar 4, 2025
Kind
B2
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.

Claims (20)

1. A compound of Formula (Ia), or an enantiomer, diastereoisomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein: R 1a is fluoro, chloro, methyl, —O—CF 3 , or CF 3 ;

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 an enantiomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 1a is CF 3 ; the cyclobutyl ring is a trans isomer; and R 4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, or oxazolyl.

3. The compound according to claim 1 , or an enantiomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 1a is CF 3 ; the cyclobutyl ring is a cis isomer; R 2 is F; and R 4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, or oxazolyl.

4. The compound according to claim 1 , or an enantiomer, diastereoisomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said atropisomer, when present, is a P atropisomer.

5. The compound according to claim 1 , or an enantiomer, diastereoisomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 1a is F.

6. The compound according to claim 1 , or an enantiomer, diastereoisomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 1a is CF 3 or —O—CF 3 ; R 2 is H, F, or methyl; and R 4 is isoxazolyl or pyridazinyl.

7. The compound according to claim 1 , or an enantiomer, diastereoisomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 1a is CF 3 ; R 2 is F; and R 4 is isoxazolyl.

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is trans-(P)—N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is trans-(P)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide.

11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide.

12. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 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.

13. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 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.

14. A pharmaceutical composition comprising the compound according to claim 1 , or an enantiomer, diastereoisomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 4, 2022
From: MILGRAM, BENJAMIN C; MARX, ISAAC E; WANG, HAOXUAN; CHERNEY, ALAN H
To: AMGEN INC.
Reel/Frame 058956/0131 →
Continuity (2)
Provisional Application 63037001 · Jun 10, 2020
Related Publication 20220306604A1 · Sep 29, 2022
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