Cardiac sarcomere inhibitors

Patent metadata

Field	Value
Publication number	US-10836755-B2
Application number	US-201916252483-A
Country	US
Kind code	B2
Filing date	Jan 18, 2019
Priority date	Jan 19, 2018
Publication date	Nov 17, 2020
Grant date	Nov 17, 2020

Abstract

Provided are compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein A, Z, B, R 1 , R 2 , R 3 , G 1 , G 2 , and G 3 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.

First claim

The invention claimed is:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:

wherein:
G 1 is —CR 4 R 5 ;
G 2 is a bond;
G 3 is —CR 8 ;
R 1 , R 3 , R 4 , R 5 , and R 8 are each independently H, C 1 -C 6 alkyl, halo, or hydroxyl;
R 2 is H, C 2 -C 6 alkyl, halo, or hydroxyl;
Z is a bond
A is 5- or 6-membered heteroaryl comprising at least one annular N atom, wherein the 5- or 6-membered heteroaryl is unsubstituted or substituted with one or more R 10 substituents;
each R 10 is independently selected from the group consisting of substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, and —C(O)OR a ;
B is heteroaryl, wherein the heteroaryl of B is unsubstituted or substituted with one or more R 11 substituents;
each R 11 is independently selected from the group consisting of substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with one or more R 12 substituents, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, halo, —OR b , —C(O)R c , —C(O)OR d , oxo, and —NR e R f ;
each R 12 is independently selected from the group consisting of halo, —OR b , —C(O)R g , —C(O)OR h , and —C(O)NR i R j ; and
each R a , R b , R c , R d , R e , R f , R g , R h , R i , and R j is independently H or C 1 -C 6 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (If):

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 8 are each H.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 1 is —CH 2 —.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 3 is —CH—.

6. The compound of claim 1 , wherein R 1 , R 2 , and R 3 are each H.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is 5-membered heteroaryl comprising at least one annular N atom, wherein the 5-membered heteroaryl is unsubstituted or substituted with one or more R 10 substituents.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, tetrazolyl, triazolyl, thiazolyl, pyrimidinyl, pyridinyl, pyrazinyl, and pyridazinyl, each of which is unsubstituted or substituted with one or more R 10 substituents.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is oxadiazolyl or isoxazolyl, each of which is unsubstituted or substituted with one or more R 10 substituents.

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

each of which is unsubstituted or substituted with one or more R 10 substituents.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl of R 10 is independently unsubstituted or substituted with one more substituents independently selected from the group consisting of —OR k and —OC(O)R m , wherein R k and R m are each independently H or C 1 -C 6 alkyl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 10 is independently selected from the group consisting of —C(O)OCH 3 , methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl, cyclobutyl, and oxetanyl,
wherein each methyl, ethyl and isopropyl of R 10 is independently unsubstituted or substituted with one more substituents independently selected from the group consisting of —OCH 3 , —OH, and —OC(O)CH 3 .

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is oxadiazolyl, which is unsubstituted or substituted with one substituent selected from the group consisting of methyl, methyl substituted with —OCH 3 , —OH, or —OC(O)CH 3 , ethyl, ethyl substituted with —OCH 3 , —OH, or —OC(O)CH 3 , isopropyl, isopropyl substituted with —OCH 3 , —OH, or —OC(O)CH 3 , difluoromethyl, cyclopropyl, cyclobutyl, oxetanyl, and —C(O)OCH 3 .

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is oxadiazolyl, which is unsubstituted or substituted with one substituent selected from the group consisting of methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl, and cyclobutyl.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is isoxazolyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of methyl, ethyl, and difluoromethyl.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is isoxazolyl, which is unsubstituted or substituted with one substituent selected from the group consisting of methyl, ethyl, and difluoromethyl.

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

wherein each R 13 is independently selected from the group consisting of H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, and —C(O)OR a ; and R a is H or C 1 -C 6 alkyl.

18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein each R 13 is independently selected from the group consisting of H, —C(O)OCH 3 , methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl, cyclobutyl, and oxetanyl,
wherein each methyl, ethyl and isopropyl of R 13 is independently unsubstituted or substituted with one more substituents independently selected from the group consisting of —OCH 3 , —OH, and —OC(O)CH 3 .

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl of B is unsubstituted or substituted with one or more R 11 substituents;
each R 11 is independently selected from the group consisting of heterocycloalkyl, heteroaryl, cycloalkyl, aryl, C 1 -C 6 alkyl, halo, fluoroalkyl, —OR b , —C(O)R c , —C(O)OR d , oxo, and —NR e R f , wherein each heterocycloalkyl and heteroaryl of R 11 is unsubstituted or substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, —C(O)R n , —C(O)OR p , and —C(O)NR q R r ; and
each R b , R c , R d , R e , R f , R n , R p , R q , and R r is independently H or C 1 -C 6 alkyl.

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is 5- or 6-membered monocyclic heteroaryl comprising at least one annular N atom or 8- or 9-membered bicyclic heteroaryl comprising at least one annular N atom, each of which is substituted or unsubstituted.

Assignees

• Cytokinetics Inc

Inventors

• Chuang Chihyuan
• Morgan Bradley P
• Vanderwal Mark
• Wang Wenyue
• Ashcraft Luke W

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• C07D403/12

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

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title