Granted Patent B2

US 12,435,040 · App. 18/493,441 · Granted Oct 7, 2025

Inventors: Donglei Liu (Dover, MA); Julien Papillon (Somerville, MA); Stefan Peukert (Arlington, MA); James J. Powers (Waltham, MA)

Assignee: Bausch + Lomb Ireland Limited

C07D217/02C07D401/12C07D405/12C07D417/12

Abstract

Claims (134)

1. A method of treating pain or inflammation caused by TRPV1 activation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof,

wherein:

W is C(═O) or absent;

X is N or N oxide;

Y is N or CH;

Z is NH, O or S;

A is CH 2 or absent;

L is selected from 5- to 10-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, C 6 -C 10 aryl, and 6- to 10-membered partially saturated heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S;

R A is at each occurrence independently selected from halo, —CN, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, SF 5 , C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, —(CH 2 ) p —NR 3 R 4 and —C(═O)—O—(C 1 -C 6 alkyl),

wherein the C 3 -C 6 cycloalkyl and 4- to 6-membered heterocyclyl are each independently substituted with 0-4 R A1 ;

R A1 is at each occurrence independently selected from halo and C 1 -C 6 haloalkyl;

R 1 is at each occurrence independently selected from hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, halo, C 1 -C 6 haloalkyl and NR 3 R 4 ,

wherein the C 1 -C 6 alkyl and C 1 -C 6 haloalkyl are each independently substituted with 0-4 R 1a ;

R 1a is at each occurrence independently selected from hydroxyl, NR 3 R 4 and —C(═O)—OH;

R 2 is selected from hydrogen and C 1 -C 6 alkyl;

R 3 is at each occurrence independently selected from hydrogen and C 1 -C 6 alkyl;

R 4 is at each occurrence independently selected from —SO 2 R 5 , hydrogen, —C(═O)—(C 1 -C 6 alkyl) and C 1 -C 6 alkyl;

R 5 is at each occurrence independently selected from NH 2 and C 1 -C 6 alkyl;

n is 0, 1, 2, 3 or 4;

m is 0, 1, 2, 3, 4 or 5;

p is 0, 1 or 2.

2. The method of claim 1 , wherein

W is C(═O) or absent;

X is N or N oxide;

Y is CH;

Z is NH, O or S;

A is CH 2 or absent;

L is selected from 5- to 10-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, C 6 -C 10 aryl and 6- to 10-membered partially saturated heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S;

R A is at each occurrence independently selected from halo, —CN, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, SF 5 , C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S and —(CH 2 ) p —NR 3 R 4 ,

wherein the C 3 -C 6 cycloalkyl and 4- to 6-membered heteocyclyl are each independently substituted with 0-4 R A1 ;

R A1 is at each occurrence independently selected from halo and C 1 -C 6 haloalkyl;

R 1 is at each occurrence independently selected from C 1 -C 6 alkyl, halo, C 1 -C 6 aloalkyl and NR 3 R 4 ,

wherein the C 1 -C 6 alkyl and C 1 -C 6 haloalkyl are each independently substituted with 0-4 R 1a ;

R 1a is at each occurrence independently selected from hydroxyl, NR 3 R 4 and —C(═O)—OH;

R 2 is selected from hydrogen and C 1 -C 6 alkyl;

R 3 is at each occurrence independently selected from hydrogen and C 1 -C 6 alkyl;

R 4 is at each occurrence independently selected from —SO 2 R 5 , hydrogen, —C(═O)—(C 1 -C 6 alkyl) and C 1 -C 6 alkyl;

R 5 is at each occurrence independently selected from NH 2 and C 1 -C 6 alkyl;

n is 0, 1, 2, 3, 4;

m is 0, 1, 2, 3, 4 or 5;

p is 0, 1 or 2.

3. The method of claim 1 , wherein

W is C(═O) or absent;

X is N or N oxide;

Y is CH;

Z is NH, O or S;

A is CH 2 or absent;

L is selected from 5- to 10-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, C 6 -C 10 aryl and 6- to 10-membered partially saturated heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S;

R A is at each occurrence independently selected from halo, —CN, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S and —(CH 2 ) p —NR 3 R 4 ,

wherein the C 3 -C 6 cycloalkyl and 4- to 6-membered heteocyclyl are each independently substituted with 0-4 R A1 ;

R A1 is at each occurrence independently selected from halo and C 1 -C 6 haloalkyl;

R 1 is at each occurrence independently selected from C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl and NH 2 ,

wherein the C 1 -C 6 alkyl and C 1 -C 6 haloalkyl are each independently substituted with 0-4 R 1a ;

R 1a is at each occurrence independently selected from hydroxyl, NR 3 R 4 and —C(═O)—OH;

R 2 is selected from hydrogen and C 1 -C 3 alkyl;

R 3 is at each occurrence independently selected from hydrogen and C 1 -C 6 alkyl;

R 4 is at each occurrence independently selected from —SO 2 R 5 , hydrogen, —C(═O)—(C 1 -C 6 alkyl) and C 1 -C 6 alkyl;

R 5 is at each occurrence independently selected from NH 2 and C 1 -C 6 alkyl;

n is 0, 1, 2 or 3;

m is 0, 1, 2, 3 or 4;

p is 0, 1 or 2.

4. The method of claim 1 , wherein

W is absent;

X is N;

Y is CH;

Z is NH, O or S;

A is absent;

L is selected from 5- to 10-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, C 6 -C 10 aryl, and 6- to 10-membered partially saturated heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S;

R A is at each occurrence independently selected from halo, —CN, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkoxyl, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S and —(CH 2 ) p —NR 3 R 4 ,

wherein the C 3 -C 6 cycloalkyl and 4- to 6-membered heteocyclyl are each independently substituted with 0-4 R A 1;

R A1 is at each occurrence independently selected from halo and C 1 -C 6 haloalkyl;

R 1 is at each occurrence independently selected from C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl,

wherein the C 1 -C 6 alkyl and C 1 -C 6 haloalkyl are each independently substituted with 0-4 R 1a ;

R 1a is at each occurrence independently selected from hydroxyl, NR 3 R 4 and —C(═O)—OH;

R 2 is selected from hydrogen and C 1 -C 6 alkyl;

R 3 is at each occurrence independently selected from hydrogen and C 1 -C 6 alkyl;

R 4 is at each occurrence independently selected from —SO 2 R 5 , hydrogen, —C(═O)—(C 1 -C 6 alkyl) and C 1 -C 6 alkyl;

R 5 is at each occurrence independently selected from NH 2 and C 1 -C 6 alkyl;

n is 0, 1, 2 or 3;

m is 0, 1, 2, 3 or 4;

p is 0, 1 or 2.

5. The method of claim 1 ,

wherein R A is selected from fluoro, chloro, —CN, C 1 -C 6 fluoroalkyl (e.g., C 1 -C 3 fluoroalkyl), C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 fluoroalkoxyl and 4-membered heterocyclyl having 1 oxygen atom,

wherein the C 3 -C 6 cycloalkyl and the 4-membered oxygen containing heterocyclyl are each independently substituted with 0-3 R A1 , and

wherein R A1 is at each occurrence independently selected from halo and C 1 -C 6 haloalkyl.

6. The method of claim 1 ,

wherein L is selected from C 6 -C 10 aryl, 6- to 10-membered partially saturated heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S, and 5- to 10-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S selected from

wherein the C 6 -C 10 aryl, 6- to 10-membered partially saturated heterocyclyl and 5- to 10-membered heteroaryl are each independently substituted with 0-4 R A , and wherein R A is defined according to claim 1 .

7. The method of claim 1 ,

wherein L is selected from 6- to 10-membered partially saturated heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S, 5- to 10-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, and C 6 -C 10 aryl selected from phenyl and naphthyl,

wherein the 6- to 10-membered partially saturated heterocyclyl, 5- to 10-membered heteroaryl, phenyl and naphthyl are each independently substituted with 0-4 R A , and wherein R A is defined according to claim 1 .

8. The method of claim 1 , wherein L is selected from 5- to 10-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, C 6 -C 10 aryl and 6- to 10-membered partially saturated heterocyclyl selected from

wherein the 5- to 10-membered heteroaryl, C 6 -C 10 aryl and 6- to 10-membered partially saturated heterocyclyl are each independently substituted with 0-4 R A , and wherein R A is defined according to claim 1 .

9. The method of claim 1 ,

wherein R 1 is at each occurrence independently selected from C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl and NH 2 ,

wherein the C 1 -C 6 alkyl and C 1 -C 6 haloalkyl are each independently substituted with 0-4 R 1a ,

wherein R 1a is at each occurrence independently selected from hydroxyl and NR 3 R 4 .

10. The method of claim 1 , wherein

W is absent;

X is N;

Y is CH;

Z is O;

A is absent;

L is C 6 -C 10 aryl;

R A is at each occurrence independently selected from halo, —CN, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl;

R 1 is at each occurrence independently selected from C 1 -C 6 alkyl, halo and C 1 -C 6 haloalkyl,

wherein the C 1 -C 6 alkyl and C 1 -C 6 haloalkyl are each independently substituted with 0-4 R 1a ;

R 1a is at each occurrence independently selected from hydroxyl and NR 3 R 4 ;

R 2 is selected from hydrogen and C 1 -C 6 alkyl;

R 3 is at each occurrence independently selected from hydrogen and C 1 -C 6 alkyl;

R 4 is at each occurrence independently selected from —SO 2 R 5 , hydrogen and C 1 -C 6 alkyl;

R 5 is at each occurrence independently selected from NH 2 and C 1 -C 6 alkyl;

n is 1, 2 or 3;

m is 0, 1, 2 or 3.

11. The method of claim 1 , wherein R 1 is at each occurrence independently selected from

fluoro and NH 2 ,

wherein R 1b is hydrogen or C 1 -C 6 alkyl,

wherein the C 1 -C 6 alkyl is substituted with 0-3 hydroxyl.

12. The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Ia)

wherein W, L, R 1 , R 2 , R A , n and m are defined according to claim 1 .

13. The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Ib)

wherein W, L, R 1 , R 2 , R A , n and m are defined according to claim 1 .

14. The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Ic)

wherein L, R 1 , R 2 , R A , n and m are defined according to claim 1 .

15. The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Id)

wherein L, R 1 , R 2 , R A , n and m are defined according to claim 1 .

16. The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Ie)

wherein L, R 1 , R 2 , R A and m are defined according to claim 1 .

17. The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (If)

wherein L, R 1 , R 2 , R A and m are defined according to claim 1 .

18. The method of claim 1 , wherein the compound of Formula (I) is a compound selected from:

19. The method of claim 1 , wherein the compound of Formula (I) is a compound selected from:

(R)-1-(6-fluoro-5-((((1r,3R)-3-(4-fluoro-3-(trifluoromethyl) phenoxy)cyclobutyl)amino)methyl) isoquinolin-8-yl)ethane-1,2-diol; or

(S)-1-(6-fluoro-5-((((1r,3S)-3-(4-fluoro-3-(trifluoromethyl) phenoxy)cyclobutyl)amino)methyl) isoquinolin-8-yl)ethane-1,2-diol.

Assignments (4)

Continuity (3)

References Cited (12)