Cyclopropyl dihydroquinoline sulfonamide compounds

Patent metadata

Field	Value
Publication number	US-11807634-B2
Application number	US-202117344939-A
Country	US
Kind code	B2
Filing date	Jun 10, 2021
Priority date	Jun 10, 2020
Publication date	Nov 7, 2023
Grant date	Nov 7, 2023

Abstract

The present invention provides a 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 (I):

an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a cyclopropyl ring; or a 4-, 5-, 6-, 7-, or 8-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S; and wherein said cyclopropyl 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, —N(C 1-4 alk)C 1-4 alk, 3-, 4-, or 5-membered cycloalkyl, or 6-membered aryl;
R 2 is H, halo, CN, 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, —O-cyclopropyl, or —O-cyclobutyl;
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,
wherein the compound is not

or a salt or tautomer thereof.

2. The compound according to claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1a is selected from halo, C 1-8 alk, —O—C 1-4 alk, C 1-8 haloalk, cyclopropyl, or phenyl; 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 R 1 is a cyclopropyl ring; or a 4-, 5-, or 6-membered bicyclic ring; wherein said bicyclic ring contains 0 N, O, and S atoms; and wherein said cyclopropyl ring or bicyclic ring is substituted by 1, 2 or 3 R 1a groups selected from F, —CF 3 , —O—CF 3 , —C(CH 3 ) 3 , cyclopropyl, or phenyl.

4. The compound according to claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is a cyclopropyl ring or bicyclo[1.1.0]butan-1-yl ring; wherein each ring is substituted by 1 or 2 F or —CF 3 substituents.

5. The compound according to claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is a cyclopropyl ring substituted by 1 or 2 F or —CF 3 ; wherein said cyclopropyl ring is a trans isomer.

6. The compound according to claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is a bicyclo[1.1.0]butan-1-yl ring substituted by 1 or 2 F or —CF 3 .

7. 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, CN, methyl, CF 3 , CHF 2 , or CH 2 F.

8. 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, CN, or methyl.

9. 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 or fluoro.

10. 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.

11. 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 5-membered heteroaryl.

12. 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 6-membered heteroaryl.

13. The compound according to claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl.

14. 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 5d is F; and each of R 5a ; R 5b ; R 5c ; and R 5e is hydrogen.

15. 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 of Formula (Ia):

wherein each R 1a is independently fluoro, methyl, —O—CF 3 , CF 3 , cyclopropyl, or phenyl.

16. The compound according to claim 15 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1a is CF 3 or methyl; the cyclopropyl ring is a trans isomer; R 2 is H or F; R 4 is isoxazolyl, pyridazinyl, thiazolyl, or thiadiazolyl; and R 5a is H or F.

17. The compound according to claim 15 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1a is CF 3 or methyl; the cyclopropyl ring is a cis isomer; R 2 is H or F; R 4 is isoxazolyl, pyridazinyl, thiazolyl, or thiadiazolyl; and R 5a is H or F.

18. The compound according to claim 15 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1a is CF 3 ; the cyclopropyl ring is a trans isomer; R 2 is H; R 4 is isoxazolyl, pyridazinyl, thiazolyl, or thiadiazolyl; and 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 R 1a is CF 3 ; the cyclopropyl ring is a trans isomer; R 2 is F; R 4 is isoxazolyl, pyridazinyl, thiazolyl, or thiadiazolyl; and R 5a is H.

20. The compound according to claim 18 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is isoxazolyl.

21. The compound according to claim 19 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is isoxazolyl.

22. The compound according to claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said compound is an atropisomer and is the P atropisomer.

23. The compound according to claim 1 , an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
a) (P)-1-(5-fluoro-2-methoxy-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
b) (P)-1-(5-fluoro-2-methoxy-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
c) (P)-1-(5-f

Assignees

• Amgen Inc

Inventors

• Milgram Benjamin C
• Marx Isaac E
• Stellwagen John
• Zhao Wei
• Cherney Alan H

Classifications

• C07D413/12 Primary

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

• C07D401/12 Primary

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

• C07D417/12

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

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title