IP Library › Granted Patent US 12,187,712
Granted Patent B2
US 12,187,712 · App. 17/255,379 · Granted Jan 7, 2025

Cardiac sarcomere inhibitors

Inventors: Bradley P. Morgan (South San Francisco, CA); Mark Vanderwal (Oakland, CA); Chihyuan Chuang (Millbrae, CA)
Assignee: CYTOKINETICS, INC.
C07D413/14C07D271/06C07D413/12
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Quick Facts
Patent No.
US 12,187,712
App. No.
17/255,379
Granted
Jan 7, 2025
Kind
B2
Abstract

Provided are compounds of Formula (I): or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , Y 1 , Y 2 , L 1 , and G 1 are as defined herein. Also provided is a pharmaceutically acceptable composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also provided are methods of using a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

Claims (182)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H or halo;

G 1 is —N— or —C(R b )—, wherein R b is H or halo;

R 2 is H or —CH 3 ;

L 1 , Y 1 , and Y 2 are defined by (i) or (ii):

(i) L 1 is absent;

Y 1 is R x ; and

Y 2 is R z ;

or

(ii) L 1

 wherein L 2 is absent, —O—, —NH—, or —OCH 2 —*, and wherein * indicates the attachment to Y 2 ;

Y 1 is

 wherein R 1aa is H, alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; and

Y 2 is —CH 3 , phenyl, or R z ;

R x is

R 1a , R 1b , R 1c1 , R 1c2 , R 1f , R 1g , R 1h1 , and R 1h2 are each independently H, alkyl, alkenyl, alkynyl, haloalkyl, —C(O)O-alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;

R 1d1 , R 1d2 , and R 1d3 are each independently alkyl, alkenyl, alkynyl, —C(O)O— alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;

R 1e1 and R 1e2 are each independently H, alkyl, alkenyl, alkynyl, haloalkyl, —C(O)O-alkyl, or a cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, or heteroaryl ring;

R z is

R 2a , R 2b1 , R 2b2 , R 2c , R 2d1 , R 2g2 , R 2h , R 2i , and R 2j are each independently selected from the group consisting of H, halo, —OH, —CN, —NR c R d , alkyl, alkenyl, alkynyl, —O-alkyl, haloalkyl, cycloalkyl, and —C(O)NR c R d ;

R 2e , R 2f , R 2g1 , and R 2g2 are each independently selected from the group consisting of halo, —OH, —CN, —NR c R d , alkyl, alkenyl, alkynyl, —O-alkyl, haloalkyl, cycloalkyl, and —C(O)NR c R d ; and

R c and R d are each independently H or alkyl;

wherein, when Y 1 is

 at least one of (a)-(c) applies:

(a) R 2 is —CH 3 ;

(b) R 1 is halo; and

(c) G 1 is —C(R b )—, wherein R b is halo; and

when Y 1 is

 and Y 2 is

 R 2b1 is selected from the group consisting of H, halo, —OH, —CN, —NR c R d , alkyl, alkenyl, alkynyl, —O—C 2 -C 6 alkyl, haloalkyl, cycloalkyl, and —C(O)NR c R d .

2. The compound of claim 1 , wherein the compound is of Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H or halo;

G 1 is —N— or —C(R b )—, wherein R b is H or halo;

R 2 is H or —CH 3 ;

Y 1 is R x ;

R x is

R 1a , R 1b , R 1c1 , R 1c2 , R 1f , R 1g , R 1h1 , and R 1h2 are each independently H, alkyl, alkenyl, alkynyl, —C(O)O-alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;

R 1d1 , R 1d2 , and R 1d3 are each independently alkyl, alkenyl, alkynyl, —C(O)O— alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;

R 1e1 and R 1e2 are each independently H, alkyl, alkenyl, alkynyl, haloalkyl, —C(O)O-alkyl, or a cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, or heteroaryl ring;

Y 2 is R z ;

R z is

R 2a , R 2b1 , R 2b2 , R 2c , R 2d1 , R 2d2 , R 2h , R 2i , and R 2j are each independently selected from the group consisting of H, halo, —OH, —CN, —NR c R d , alkyl, alkenyl, alkynyl, —O-alkyl, haloalkyl, cycloalkyl, and —C(O)NR c R d ;

R 2e , R 2f , R 2g , and R 2g2 are each independently selected from the group consisting of halo, —OH, —CN, —NR c R d , alkyl, alkenyl, alkynyl, —O-alkyl, haloalkyl, cycloalkyl, and —C(O)NR c R d ; and

R c and R d are each independently H or alkyl;

wherein, when Y 1 is

 at least one of (a)-(c) applies:

(a) R 2 is —CH 3 ;

(b) R 1 is halo; and

(c) G 1 is —C(R b )—, wherein R b is halo; and

when Y 1 is

and Y 2 is

R 2b1 is selected from the group consisting of H, halo, —OH, —CN, —NR c R d , alkyl, alkenyl, alkynyl, —O—C 2 -C 6 alkyl, haloalkyl, cycloalkyl, and —C(O)NR c R d .

3. The compound of claim 1 , wherein the compound is of Formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein:

R 1aa is H, alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;

R 1 is H or halo;

G 1 is —N— or —C(R b )—, wherein R b is H or halo;

R 2 is H or —CH 3 ;

L 2 is absent, —O—, —NH—, or —OCH 2 —*; wherein * indicates the attachment to Y 2 ;

Y 2 is CH 3 , phenyl, or R z ;

R z is

R 2a , R 2b1 , R 2b2 , R 2c , R 2d1 , R 2g2 , R 2h , R 2i , and R 2j are each independently selected from the group consisting of H, halo, —OH, —CN, —NR c R d , alkyl, alkenyl, alkynyl, —O-alkyl, haloalkyl, cycloalkyl, and —C(O)NR c R d ;

R 2e , R 2f , R 2g1 , and R 2g2 are each independently selected from the group consisting of halo, —OH, —CN, —NR c R d , alkyl, alkenyl, alkynyl, —O-alkyl, haloalkyl, cycloalkyl, and —C(O)NR c R d ; and

R c and R d are each independently H or alkyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is halo.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 1 is —N—.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 1 is —C(R b )—, and R b is H or halo.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —CH 3 .

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 1 is

and R 1a is H, alkyl, haloalkyl, —C(O)O-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 1 is

and R 1b is H, alkyl, haloalkyl, —C(O)O-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 1 is

and R 1c1 and R 1c2 are each independently H, alkyl, haloalkyl, —C(O)O-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 1 is

and R 1d1 , R 1d2 , and R 1d3 are each independently alkyl, alkenyl, alkynyl, —C(O)O-alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 1 is

and R 1e1 and R 1e2 are each independently H, alkyl, alkenyl, alkynyl, haloalkyl, —C(O)O-alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, or heteroaryl.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 1 is

and R 1f and R 1g are each independently H, alkyl, alkenyl, alkynyl, haloalkyl, —C(O)O-alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 1 is

and R 1h1 and R 1h2 are each independently H, alkyl, haloalkyl, —C(O)O-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 1 is selected from the group consisting of

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 1 is

and R 1aa is alkyl.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is absent.

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is —O—.

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is —NH—.

22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is —OCH 2 —*, wherein * indicates the attachment to Y 2 .

23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 2 is

and R 2a , R 2b1 , and R 2b2 are each independently selected from the group consisting of H, halo, —OH, —CN, —NR c R d , alkyl, alkenyl, alkynyl, —O-alkyl, haloalkyl, cycloalkyl, and —C(O)NR c R d .

24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 2 is

and R 2c , R 2d1 , and R 2d2 are each independently selected from the group consisting of H, halo, —OH, —CN, —NR c R d , alkyl, alkenyl, alkynyl, —O-alkyl, haloalkyl, cycloalkyl, and —C(O)NR c R d .

25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 2 is

and R 2e , R 2f , R 2g1 , and R 2g2 are each independently selected from the group consisting of halo, —OH, —CN, —NR c R d , alkyl, alkenyl, alkynyl, —O-alkyl, haloalkyl, cycloalkyl, and —C(O)NR c R d .

26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 2 is

and R 2h and R 2i are each independently selected from the group consisting of H, halo, —OH, —CN, —NR c R d , alkyl, alkenyl, alkynyl, —O-alkyl, haloalkyl, cycloalkyl, and —C(O)NR c R d .

27. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 2 is

and R 2j is selected from the group consisting of H, halo, —OH, —CN, —NR c R d , alkyl, alkenyl, alkynyl, —O-alkyl, haloalkyl, cycloalkyl, and —C(O)NR c R d .

28. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 2 is selected from the group consisting of

29. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 2 is CH 3 or phenyl.

30. A compound selected from the group consisting of

6-chloro-N-(4-(5-methyl- 1,2,4-oxadiazol-3- yl)benzyl)pyrazin-2-amine;

N-(4-(5-methyl-1,2,4- oxadiazol-3- yl)benzyl)pyrazin-2-amine;

N-(4-(5-methyl-1,2,4- oxadiazol-3- yl)benzyl)pyrimidin-4- amine;

6-methyl-N-(4-(5-methyl- 1,2,4-oxadiazol-3- yl)benzyl)pyrimidin-4- amine;

N-(4-(5-methyl-1,2,4- oxadiazol-3-yl)benzyl)-6- (trifluoromethyl)pyrimidin- 4-amine;

6-cyclopropyl-N-(4-(5- methyl-1,2,4-oxadiazol-3- yl)benzyl)pyrimidin-4- amine;

6-((4-(5-methyl-1,2,4- oxadiazol-3- yl)benzyl)amino)pyrimidine- 4-carbonitrile;

6-ethyl-N-(4-(5-methyl- 1,2,4-oxadiazol-3- yl)benzyl)pyrimidin-4- amine;

6-chloro-N-(4-(5-methyl- 1,2,4-oxadiazol-3- yl)benzyl)pyrimidin-4- amine;

5-((4-(5-methyl-1,2,4- oxadiazol-3- yl)benzyl)amino)pyrazine-2- carbonitrile;

6-((4-(5-ethyl-1,2,4- oxadiazol-3- yl)benzyl)amino)pyrimidine- 4-carbonitrile;

2-chloro-N-(4-(5-methyl- 1,2,4-oxadiazol-3- yl)benzyl)pyrimidin-4- amine;

5-chloro-N-(4-(5-methyl- 1,2,4-oxadiazol-3- yl)benzyl)pyrazin-2-amine;

6-((4-(5-methyl-1,2,4- oxadiazol-3- yl)benzyl)amino)nicotinonitrile;

2-((4-(5-methyl-1,2,4- oxadiazol-3- yl)benzyl)amino)isonicotinonitrile;

N-(4-(5-methyl-1,2,4- oxadiazol-3-yl)benzyl)-5- (trifluoromethyl)pyrazin-2- amine;

6-(((5-(5-methyl-1,2,4- oxadiazol-3-yl)pyridin-2- yl)methyl)amino)pyrimidine- 4-carbonitrile;

6-chloro-N-(4-(3-methyl- 1,2,4-oxadiazol-5- yl)benzyl)pyrimidin-4- amine;

2-((4-(5-methyl-1,2,4- oxadiazol-3- yl)benzyl)amino)isonicotinamide;

5-chloro-N-(4-(5-methyl- 1,2,4-oxadiazol-3- yl)benzyl)pyridin-2-amine;

6-chloro-N-(1-(4-(5-methyl- 1,2,4-oxadiazol-3- yl)phenyl)ethyl)pyrimidin-4- amine;

N-(4-(5-cyclopropyl-1,2,4- oxadiazol-3- yl)benzyl)pyrazin-2-amine;

N-(4-(5-cyclobutyl-1,2,4- oxadiazol-3- yl)benzyl)pyrazin-2-amine;

N-(4-(5-(difluoromethyl)- 1,2,4-oxadiazol-3- yl)benzyl)pyrazin-2-amine;

N-(4-(5-(fluoromethyl)- 1,2,4-oxadiazol-3- yl)benzyl)pyrazin-2-amine;

N-(1-(4-(5-methyl-1,2,4- oxadiazol-3- yl)phenyl)ethyl)pyrazin-2- amine;

6-chloro-N-(4-(5- methyloxazol-2- yl)benzyl)pyrimidin-4- amine;

(R)-N-(1-(4-(5-methyl-1,2,4- oxadiazol-3- yl)phenyl)ethyl)pyrazin-2- amine;

N-(4-(4-methyl-1H-pyrazol- 1-yl)benzyl)pyrazin-2-amine;

methyl 3-(4-((pyrazin-2- ylamino)methyl)phenyl)- 1,2,4-oxadiazole-5- carboxylate;

(R)-N-(1-(4-(5-cyclopropyl- 1,2,4-oxadiazol-3- yl)phenyl)ethyl)pyrazin-2- amine;

(R)-N-(1-(4-(5-cyclobutyl- 1,2,4-oxadiazol-3- yl)phenyl)ethyl)pyrazin-2- amine;

(R)-N-(1-(4-(5- (difluoromethyl)-1,2,4- oxadiazol-3- yl)phenyl)ethyl)pyrazin-2- amine;

(R)-N-(1-(4-(5- (trifluoromethyl)-1,2,4- oxadiazol-3- yl)phenyl)ethyl)pyrazin-2- amine;

(R)-N-(1-(4-(5-isopropyl- 1,2,4-oxadiazol-3- yl)phenyl)ethyl)pyrazin-2- amine;

(R)-N-(1-(4-(5-(tert-butyl)- 1,2,4-oxadiazol-3- yl)phenyl)ethyl)pyrazin-2- amine;

(R)-N-(1-(4-(5-(3- methylisoxazol-5-yl)-1,2,4- oxadiazol-3- yl)phenyl)ethyl)pyrazin-2- amine;

(R)-N-(1-(4-(5-(furan-2-yl)- 1,2,4-oxadiazol-3- yl)phenyl)ethyl)pyrazin-2- amine;

(R)-N-(1-(4-(5-(thiophen-2- yl)-1,2,4-oxadiazol-3- yl)phenyl)ethyl)pyrazin-2- amine;

N-(3-fluoro-4-(5-methyl- 1,2,4-oxadiazol-3- yl)benzyl)pyrazin-2-amine;

N-(3-fluoro-4-(5- (trifluoromethyl)-1,2,4- oxadiazol-3- yl)benzyl)pyrazin-2-amine;

(R)-N-(1-(4-(5-(thiophen-3- yl)-1,2,4-oxadiazol-3- yl)phenyl)ethyl)pyrazin-2- amine;

2-chloro-N-(4-(5-methyl- 1,2,4-oxadiazol-3- yl)benzyl)pyridin-4-amine;

N-(2-fluoro-4-(5- (trifluoromethyl)-1,2,4- oxadiazol-3- yl)benzyl)pyrazin-2-amine;

N-(2-fluoro-4-(5-methyl- 1,2,4-oxadiazol-3- yl)benzyl)pyrazin-2-amine;

N-(4-(5-cyclopropyl-1,2,4- oxadiazol-3-yl)-2- fluorobenzyl)pyrazin-2- amine;

N-(4-(5-methylthiazol-2- yl)benzyl)pyrazin-2-amine;

N-(4-(5-methyloxazol-2- yl)benzyl)pyrazin-2-amine;

N-(4-(5-methyl-1,2,4- oxadiazol-3- yl)benzyl)benzamide;

N-(4-(5-methylisoxazol-3- yl)benzyl)pyrazin-2-amine;

N-(4-(3-methylisoxazol-5- yl)benzyl)pyrazin-2-amine;

methyl (4-(5-methyl-1,2,4- oxadiazol-3- yl)benzyl)carbamate;

1-(4-(5-methyl-1,2,4- oxadiazol-3-yl)benzyl)-3- phenylurea;

benzyl (4-(5-methyl-1,2,4- oxadiazol-3- yl)benzyl)carbamate;

phenyl (4-(5-methyl-1,2,4- oxadiazol-3- yl)benzyl)carbamate;

2-amino-N-(4-(5-methyl- 1,2,4-oxadiazol-3- yl)benzyl)isonicotinamide;

6-((4-(5-methylisoxazol-3- yl)benzyl)amino)pyridin- 2(1H)-one;

N-(4-(5-methylisoxazol-3- yl)benzyl)-1H-pyrazol-3- amine;

3-hydroxy-N-(4-(5-methyl- 1,2,4-oxadiazol-3- yl)benzyl)isonicotinamide;

1-methyl-N-(4-(5- methylisoxazol-3-yl)benzyl)- 1H-pyrazol-3-amine;

6-((4-(5-methylisoxazol-3- yl)benzyl)amino)pyrimidin- 4(3H)-one;

6-methoxy-N-(4-(5- methylisoxazol-3- yl)benzyl)pyrimidin-4- amine;

5-methoxy-N-(4-(5- methylisoxazol-3- yl)benzyl)pyrazin-2-amine;

2-((4-(5-methylisoxazol-3- yl)benzyl)amino)pyridin- 4(1H)-one;

N-(4-(4-methyloxazol-2- yl)benzyl)pyrazin-2-amine; and

6-methoxy-N-[[4-(5-methyl- 1,2-oxazol-3- yl)phenyl]methyl]pyridin-2- amine;

or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

32. A method of treating heart disease in a subject in need thereof, comprising administering to the subject a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

33. The method of claim 32 , wherein the heart disease is hypertrophic cardiomyopathy.

34. The method of claim 33 , wherein the hypertrophic cardiomyopathy is obstructive or nonobstructive or is caused by sarcomeric and/or non-sarcomeric mutations.

35. The method of claim 32 , wherein the heart disease is heart failure with preserved ejection fraction.

36. The method of claim 32 , wherein the heart disease is selected from the group consisting of diastolic dysfunction, primary or secondary restrictive cardiomyopathy, myocardial infarction and angina pectoris, left ventricular outflow tract obstruction, hypertensive heart disease, congenital heart disease, cardiac ischemia, coronary heart disease, diabetic heart disease, congestive heart failure, right heart failure, cardiorenal syndrome, and infiltrative cardiomyopathy.

37. The method of claim 32 , wherein the heart disease is or is related to one or more conditions selected from the group consisting of cardiac senescence, diastolic dysfunction due to aging, left ventricular hypertrophy and concentric left ventricular remodeling.

38. A method of treating a disease or condition that is associated with small left ventricular cavity, cavity obliteration, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis in a subject in need thereof, comprising administering to the subject a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

39. A method of inhibiting the cardiac sarcomere, comprising contacting the cardiac sarcomere with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 13, 2021
From: MORGAN, BRADLEY P.; VANDERWAL, MARK; CHUANG, CHIHYUAN
To: CYTOKINETICS, INC.
Reel/Frame 057779/0169 →
Continuity (2)
Provisional Application 62690249 · Jun 26, 2018
Related Publication 20210276991A1 · Sep 9, 2021
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