Cyclobutyl dihydroquinoline sulfonamide compounds

Patent metadata

Field	Value
Publication number	US-12240839-B2
Application number	US-202117633151-A
Country	US
Kind code	B2
Filing date	Jun 10, 2021
Priority date	Jun 10, 2020
Publication date	Mar 4, 2025
Grant date	Mar 4, 2025

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.

First claim

What is claimed is:

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.

Assignees

• Amgen Inc

Inventors

• Milgram Benjamin C
• Marx Isaac E
• Wang Haoxuan
• Cherney Alan H

Classifications

• C07D215/36 Primary

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

• C07D401/12

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

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P17/04

  Antipruritics · CPC title

• A61P11/14

  Antitussive agents · CPC title