CARDIAC SARCOMERE INHIBITORS

Abstract

Compounds of formula (I) are provided: (see Formula) Formula (I) or a pharmaceutically acceptable salt thereof, wherein A, Z, B, R1, R2, R3, G1, G2, and G3 are as defined herein. A pharmaceutically acceptable composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof is also provided. Methods for using a compound of formula (I), or a pharmaceutically acceptable salt thereof, are also provided.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: (I), wherein: G is CR4R5 or O; G2 is a bond or -CR6R7; G3 is -CR- or -N-; R1, R3, R4, R5, R6, R7 and R8 are each independently H, C1-C6 alkyl, halo or hydroxyl; R2 is H, C2-C6 alkyl, halo or hydroxyl; Z is selected from the group consisting of a bond, C6-C6 alkyl, -O-, -N(R9)-, -RXO-, -ORy- and -RZS-; R9 is H, C6-alkyl or cycloalkyl; A is selected from the group consisting of substituted C2 alkynyl, unsubstituted C2 alkynyl, substituted phenyl, unsubstituted phenyl, and 5- or 6-membered heteroaryl comprising at least one ring N atom, wherein the 5- or 6-membered heteroaryl is either unsubstituted or substituted with one or more R10 substituents;each R10 is independently selected from the group consisting of substituted or unsubstituted Ci-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl and -C(O)ORa; B is selected from the group consisting of H, Ci-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, wherein the Ci-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is either unsubstituted or substituted with one or more R11 substituents;each R11 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 C1-C6 alkyl, C1-C6 alkyl substituted with one or more R12 substituents, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, halo, -ORb, -C(O)RC, -C(O)ORd, oxo and -NReRf; each R12 is independently selected from the group consisting of halo, -ORb, -C(O)R8, -C(O)ORh and C(O)NR'RJ; 298 each Ra, Rb, Rc, Rd, Re, Rr, Rs, Rh, R1 and RJ is independently H or CpCe alkyl; and Rx, Ry and Rz are each Cj-Cé alkyl, wherein when A is unsubstituted phenyl or 5-trifluoromethyl-l,2,4-oxadiazolyl, the -ZB moiety is not OC(CH3)3 or l-ethyl-3-hydroxy-l,5-dihydro-2H-pyrrole-2-onyl.; 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 claim 2, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7 and R8 are each H.

4. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein Gj is -CR4R'-.

5. The compound of any of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Gi is -CH2-.

6. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein Gi is O.

7. The compound of any of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein G2 is a bond.

8. The compound of any of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein G2 is - CR6R7-.

9. The compound of any of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein G2 is -CH2-.

10. The compound of any of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein G3 is -CR8-.

11. The compound of any of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein G3 is -CH-.

12. The compound of any of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein G3 is -N-.

13. The compound of any of claims 1 to 12, wherein R', R2 and R3 are each H.

14. The compound of any of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein Z is a bond.

15. The compound of any of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein Z is O. 299 16. The compound of any of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein Z is -N(R9)-.

17. The compound of any of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of substituted phenyl, unsubstituted phenyl and 5- or 6-membered heteroaryl comprising at least one ring N atom, wherein the 5- or 6-membered heteroaryl is either unsubstituted or substituted with one or more R10 substituents.

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of phenyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, tetrazolyl, triazolyl, thiazolyl, pyrimidinyl, pyridinyl, pyrazinyl and pyridazinyl, which are either unsubstituted or substituted with one or more R10 substituents.

19. The compound of any of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein A is oxadiazolyl or isoxazolyl, which are either unsubstituted or substituted with one or more R10 substituents.

20. The compound of any of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of: IVIA / a / ZUZZ / UI or I are substituted with one or more R10 substituents.

21. The compound of any of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein each C]-C6 alkyl, cycloalkyl or heterocycloalkyl of R10 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of —ORk and -OC(O)Rm, wherein Rk and Rm are each independently H or Ci-Cg alkyl.

22. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein each R10 is independently selected from the group consisting of C(O)OCH3, methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl, cyclobutyl, and oxethanyl, wherein each methyl, ethyl, and isopropyl of R10 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OCH3, -OH, and OC(O)CH3.

23. The compound of any of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein A is oxadiazolyl, which is unsubstituted or substituted with a substituent selected from the group consisting of methyl, methyl substituted with -OCH3, -OH or -OC(O)CH3, ethyl, ethyl substituted with -OCH3, -OH or -OC(O)CH3, isopropyl, isopropyl substituted with -OCH3, -OH or -OC(O)CH3, difluoromethyl, cyclopropyl, cyclobutyl, oxethanyl and -C(O)OCH3.

24. The compound of any of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein A is oxadiazolyl, which is unsubstituted or substituted with a substituent selected from the group consisting of methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl, and cyclobutyl.

25. The compound of any of claims 1 to 17, 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.

26. The compound of any of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein A is isoxazolyl, which is unsubstituted or substituted with a substituent selected from the group consisting of methyl, ethyl, and difluoromethyl.

27. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of: wherein each R13 is independently selected from the group consisting of H, substituted or unsubstituted C]-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl and C(O)ORa; and Ra is H or CrC6 alkyl.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein each R13 is independently selected from the group consisting of H, -C(O)OCH3, methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl, cyclobutyl, and oxethanyl, wherein each methyl, ethyl, and isopropyl of R13 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OCH3, -OH, and OC(O)CH3.

29. The compound of any of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl of B is either unsubstituted or substituted with one or more substituents R1, and each R11 is independently selected from the group consisting of heterocycloalkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, halo, fluoroalkyl, -ORb, -C(O)RC, -C(O)ORd, oxo, and -NReRf, wherein each heterocycloalkyl and heteroaryl of R11 is either unsubstituted or substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, -C(O)Rn, -C(O)ORP, and -C(O)NRqRr; and each Rb, Rc, Rd, Re, Rf, Rn, Rp, Rq and R1 is independently H or CrC6 alkyl.

30. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of CrC4 alkyl, C3-C5 cycloalkyl, 6- to 10-membered aryl, 4- to 6-membered heterocycloalkyl comprising at least one ring N or O atom, 5- or 6-membered monocyclic heteroaryl comprising at least one ring N atom, and 8- or 9-membered bicyclic heteroaryl comprising at least one ring N atom, which are either substituted or unsubstituted.

31. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of C1-C4 alkyl, C3-C5 cycloalkyl, 6- to 10-membered aryl, 4- to 6-membered heterocycloalkyl comprising at least one ring N or O atom, 5- or 6-membered monocyclic heteroaryl comprising at least one ring N atom, or 8- or 9-membered bicyclic heteroaryl comprising at least one ring N atom, which are either unsubstituted or substituted with one or more R11 substituents;each R11 is independently selected from the group consisting of heterocycloalkyl, heteroaryl, cycloalkyl, aryl, Ci-Cg alkyl, halo, fluoroalkyl, -ORb, -C(O)RC, -C(O)ORd, oxo, and -NReRf, wherein each heterocycloalkyl and heteroaryl of R11 is either unsubstituted or substituted with one or more substituents selected from the group consisting of Ci-Ce alkyl, -C(O)Rn, -C(O)ORP, and -C(O)NRqRr, and wherein each Ci-C6 alkyl of R11 is either unsubstituted or substituted with -ORb; and each Rb, Rc, Rd, Re, Rf, Rn, Rp, Rq, and R1 is independently H or CrC6 alkyl.

32. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, terebutyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, indanyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, triazolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, indanyl, pyrrolopyrazolyl, and benzimidazolyl, which are either unsubstituted or substituted with one or more R11 substituents;each R11 is independently selected from the group consisting of heterocycloalkyl, heteroaryl, cycloalkyl, aryl, C1-C6 alkyl, halo, fluoroalkyl, -ORb, -C(O)RC, -C(O)ORd, oxo, and -NReRf, wherein each heterocycloalkyl and heteroaryl of R11 is either unsubstituted or substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, -C(O)Rn, -C(O)ORP, and -C(O)NRqRr, and wherein each C1-C6 alkyl of R11 is either unsubstituted or substituted with -ORb; and each Rb, Rc, Rd, Re, Rf, R, Rp, Rq, and Rr is independently H or C1-C6 alkyl.

33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein each R11 is independently selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, oxo, -C(O)CH3, -C(O)OtBu, -OCH3, -OH, -NH2, Cl, oxethanyl, oxadiazolyl, and azetidinyl, wherein each oxadiazolyl and azetidinyl of R11 is either unsubstituted or substituted with one or more substituents selected from the group consisting of ethyl, -C(O)CH3, C(O)OtBu, -C(O)OCH3, -C(O)NHCH3, -C(O)NH2, and -OCH3, and wherein each methyl, ethyl, and isopropyl of R11 is either unsubstituted or substituted with -OH.

34. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein B is methyl, pyrazolyl, oxazolyl, tetrazolyl, isoxazolyl, thiazolyl, imidazolyl, or pyridinyl, which are either unsubstituted or substituted with one or more R11 substituents; each R11 being independently selected from the group consisting of heterocycloalkyl, heteroaryl, halo, C1-C6 alkyl, C1-C6 alkyl substituted with one or two R12 substituents, cycloalkyl, cycloalkyl substituted with one or two R12 substituents, fluoroalkyl, -ORb, -C(O)RC, -C(O)ORd, oxo, and -NReRf; each R12 being independently selected from the group consisting of halo, -ORb, -C(O)Rg, -C(O)ORh, and C(O)NR'Rj; and each Rb, Rc, Rd, Re and Rf, Rg, Rh, R1 and R1 is independently H or C|-C6 alkyl.

35. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein B is pyrazolyl, oxazolyl, tetrazolyl, isoxazolyl, thiazolyl, imidazolyl, or pyridinyl, which are either unsubstituted or substituted with one or more R11 substituents; each R11 is independently selected from the group consisting of heterocycloalkyl, heteroaryl, halo, CrC6 alkyl, C1-C6 alkyl substituted with one or two R12 substituents, cycloalkyl, cycloalkyl substituted with one or two R12 substituents, fluoroalkyl, -ORb, oxo, and -NReRf; each R12 is independently selected from the group consisting of halo, -ORb, and -QOjNR'R'; and each Rb, Re, Rf, R1, and RJ is independently H or CrC6 alkyl.

36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein Rb is H.

37. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of: 303 are substituted or are substituted with one or more R11 substituents; each R11 is independently selected from the group consisting of heterocycloalkyl, heteroaryl, halo, CrC6 alkyl, CrC6 alkyl substituted with one or two R12 substituents, cycloalkyl, cycloalkyl substituted with one or two R12 substituents, fluoroalkyl, -ORb, -C(O)RC, -C(O)ORd, oxo and -NReRf; each R12 is independently selected from the group consisting of halo, -ORb, -C(O)Rg, -C(O)ORh and C(O)NR'RJ; and each Rb, Rc, Rd, Re and Rf, R8, Rh, R1 and Rj is independently H or alkyl Cj-Cé- 38. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of: R14 304 MA / a / ZUZZ / UI ¿M1 z wherein each R14 is independently selected from the group consisting of heterocycloalkyl, heteroaryl, cycloalkyl, cycloalkyl substituted with one or two R12 substituents, aryl, CpCe alkyl, CpCe alkyl substituted with one or two R12 substituents, halo, fluoroalkyl, -ORb, -C(O)Rc, -C(O)ORd, oxo and -NReRf, wherein each heterocycloalkyl and heteroaryl of R14 is unsubstituted or substituted with one or more substituents selected from the group consisting of CrC6 alkyl, -C(O)Rn, -C(O)ORP and -C(O)NRqRr; Each R12 is independently selected from the group consisting of halo, -ORb, -C(O)Rg, -C(O)ORh and C(O)NR'RJ; and each Rb, Rc, Rd, Re, Rf, Rg, Rh, R¡ and RJ, Rn, Rp, Rq and Rr is independently H or CrC6 alkyl.

39. A compound selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt of these.

40. A pharmaceutical composition comprising a compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

41. A method for treating heart disease in a subject in need, comprising administering to the subject a compound of any of claims 1-39, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 40.

42. The method of claim 41, wherein the heart disease is hypertrophic cardiomyopathy (HCM).

43. The method of claim 42, wherein the HCM is obstructive or non-obstructive or is associated with a sarcomeric and / or non-sarcomeric mutation.

44. The method of claim 41, wherein the heart disease is heart failure with preserved ejection fraction (HFpEF).

45. The method of claim 41, 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.

46. ​​The method of claim 41, 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.

47. A method for treating a disease or condition associated with HCM in a subject in need, comprising administering to the subject a compound of any of claims 1-39, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 40.

48. The method of claim 47, wherein the disease or condition is selected from the group consisting of Fabry disease, Danon disease, mitochondrial cardiomyopathies, and Noonan syndrome.

49. A method for treating a disease or condition that is associated with secondary left ventricular wall thickening in a subject in need, comprising administering to the subject a compound of any of claims 1-39, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 40.

50. The method of claim 49, wherein the disease or condition is selected from the group consisting of hypertension, valvular heart diseases (aortic stenosis, mitral valve regurgitation), metabolic syndromes (diabetes, obesity), end-stage renal disease, scleroderma, sleep apnea, amyloidosis, Fabry disease, Friedreich's ataxia, Danon disease, Noonan syndrome, and Pompe disease.

51. A method for treating a disease or condition that is associated with small left ventricular cavity and cavity obliteration, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis in a subject in need, comprising administering to the subject a compound of any of claims 1-39, or a pharmaceutically acceptable salt of 306 MA / a / ZUZZ / UI 4 or I z this, or a pharmaceutical composition of claim 40.

52. A method for treating a selected disease or condition of muscular dystrophies and glycogen storage diseases in a subject in need thereof, comprising administering to the subject a compound of any of claims 1-39, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 40.

53. A method for inhibiting the cardiac sarcomere, comprising contacting the cardiac sarcomere with a compound of any of claims 1-39, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 40.