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1. WO2019055590 - BISAMIDE SARCOMERE ACTIVATING COMPOUNDS AND USES THEREOF

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

What is Claimed:

1. A compound or pharmaceutically acceptable salt thereof, according to Formula (I):

wherein

Q is
or a 5-member heteroaryl having 1 or 2 ring heteroatoms independently selected from N, O, and S which is optionally substituted with 1 or 2 groups selected from C1-C6alkyl and halo C1-C6alkyl;

A is absent, oxygen, N(H), N(C1-C6alkyl) or CR11R11a;

X1 is N or CR2;

X2, X3, X4 and X5 are each independently selected from N and CR3 provided that 0, 1, or 2 of X1, X2, X3, X4 and X5 are N and the remainder are CR2 or CR3;

R1a is selected from the group consisting of hydrogen, C1-C6alkyl and halogen;

R1 is selected from the group consisting of hydrogen, C1-C6alkyl, halo C1-C6alkyl, hydroxy C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl optionally substituted with 1 or 2 groups selected from hydroxy, halogen, and C1-C4alkyl, hydroxy C3-C7cycloalkyl, C3-C7cycloalkylC1-C4alkyl, hydroxy C3-C7cycloalkylC1-C4alkyl,and 4 to 7 member heterocycloalkyl having 1 or 2 ring heteroatoms independently selected from N, O and S, which heterocycloalkyl is optionally substituted with 1 or 2 groups selected from oxo, hydroxy, halogen and C1-C4alkyl;

R2 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, haloC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C3-C7cycloalkylC1-C4alkyl, C1-C6alkoxy, haloC1-C6alkoxy and SF5;

or

R1 and R2, taken in combination, form a divalent group selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -OCH2-, -CH2OCH2-, -OCH2CH2, -CH2N(H)CH2- and -CH2N(C1-C4alkyl)CH2-, each of which is optionally substituted with C1-C4alkyl or hydroxyC1-C4alkyl and wherein the oxygen of– OCH2CH2- or–OCH2- is attached to the CR2 carbon;

R3 is independently selected from the group consisting of hydrogen, halogen, C1-C6alkyl, haloC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C3-C7cycloalkylC1-C4alkyl, C1-C6alkoxy, haloC1-C6alkoxy and SF5;

Z1 is N or CR5;

Z2 is N or CR6;

Z3 is N or CR7, wherein 0, 1, or 2 of Z1, Z2 and Z3 can be N;

R4 is hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, C3-C7cycloalkyl, cyano, benzoyl, SO2-R8 or 4 to 7 member heterocycloalkyl having a ring heteroatom selected from N, O and S which heterocycloalkyl is substituted with 0, 1 or 2 groups independently selected from the group consisting of halogen, oxo, C1-C6alkyl, C(O)C1-C6alkyl, and SO2-R8, and wherein when R4 is C1-C6alkyl, haloC1-C6alkyl, or C3-C7cycloalkyl, it is optionally substituted with one or two groups independently selected from hydroxy, cyano, CO2H, CO2C1-C6alkyl and C(O)NH2;

R5 is hydrogen, C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxy, amino, mono- or di-C1-C6alkylamino, C3-C7cycloalkylamino or -N(H)C(O)C1-C4alkyl, where each alkyl or cycloalkyl is optionally substituted with hydroxy;

R6 is hydrogen, C1-C6alkyl, haloC1-C6alkyl or halogen; or

R5 and R6, taken in combination with the interposed atoms, form a 5- or 6- memebred heteroaryl having 1 or 2 ring heteroatoms selected from N, O, and S;

R7 and R8 taken in combination form a divalent group selected from–CH2CH2- and–

CH2CH2CH2-; or

R7 is hydrogen, C1-C6alkyl, or SO2C1-C6alkyl;

R8 is C1-C6alkyl, NR8dR8e, C3-C7cycloalkyl, haloC1-C6alkyl or benzyl, wherein each alkyl, cycloalkyl or haloalkyl is optionally substituted with hydroxy, CO2H, CO2C1-C6alkyl or C(O)NH2; or R8 is a group of the formula:

wherein

p is 1 or 2;

R8a is hydrogen, C1-C6alkyl, benzyl, or phenyl optionally substituted with C1-C6alkyl or halogen; R8b is hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, haloC1-C6alkyl, C1-C6alkoxy, C1-C6alkoxyC1-C4alkyl, C3-C7cycloalkyl, cyano, amino, N(H)C(O)C1-C6alkyl, N(H)C(O)C3-C7cycloalkyl, N(H)C(O)haloC1-C6alkyl, CO2H, C(O)NH2, C(O)NH(C1-C6alkyl), C(O)N(C1-C6alkyl)2, C(O)C1-C6alkyl, C(O)haloC1-C6alkyl, SO2C1-C6alkyl, phenyl optionally substituted with halogen, C1-C4alkyl or haloC1-C4alkyl, benzyl optionally substituted withhalogen, phenoxy optionally substituted with halogen, 4 to 7 member heterocycloalkyl having 1 or 2 ring heteroatoms selected from N, O and S, or 5 or 6 member heteroaryl having 1 ring heteroatom selected from N, O or S and 0, 1 or 2 additional ring nitrogen atoms, which heteroaryl is optionally substituted with 1 or 2 C1-C6alkyl, and wherein the alkoxy is optionally substituted with halogen, phenyl or halogen-substituted phenyl;

R8c is hydrogen, halogen, hydroxy or C1-C6alkyl; or

CR8bR8c, taken in combination, forms a spirocyclic 3 to 6 member carboxycle or a 4 to 6 member heterocycle having a ring heteratom selected from N, O and S, which spirocycle is optionally substituted with hydroxy, C1-C4alkyl, haloC1-C4alkyl or C1-C4alkoxy;

R8d is hydrogen, C1-C6alkyl, haloC1-C6alkyl, C3-C7cycloalkyl, or 4 to 7 member

heterocycloalkyl having 1 ring heteroatoms selected from N, O and S and 0 or 1 additional ring nitrogen atoms, which heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from hydroxy, halogen, oxo, C1-C6alkyl, and C1-C6alkoxy;

R8e is hydrogen or C1-C6alkyl; or

NR8dR8e, taken in combination, forms a 4 to 7 member heterocycloalkyl optionally comprising an additional ring heteroatom selected from N, O and S, which heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from hydroxy, halogen, oxo, C1-C6alkyl, C1-C6alkoxy and heteroaryl, which heteroaryl has 5 or 6 ring atoms and has one ring heteroatom selected from N, O and S and 0 or 1 additional ring nitrogen atom, or

NR8dR8e, taken in combination, forms a 5 or 6 member heteroaryl optionally comprising 1 additional ring heteroatom selected from N, O and S;

R9 is hydrogen or C1-C6alkyl;

R10 and R10a are each independently selected from the group consisting of hydrogen, halogen and C1-C6alkyl; or

R9 and R10 taken in combination form a divalent bridge selected from O, CH2, and CH2CH2 and R10a is hydrogen;

R11a is hydrogen or halogen;

R12 is hydrogen or halogen;

R11 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, N(H)C1-C6alkyl and N(H)C3-C7cycloalkyl; or

R11 and R12, taken in combination, form a double bond;

R13a is hydrogen or C1-C6alkyl;

R13 is C1-C6alkyl, C3-C7cycloalkyl or C3-C7cycloalkylC1-C6alkyl;

R14 is C1-C6alkyl, C3-C7cycloalkyl or C3-C7cycloalkylC1-C6alkyl; or

R13 and R14, taken in combination with the interposed C and N atoms, form a saturated or partially unsaturated 4 to 7 member heterocycle which heterocycle further comprises 0 or 1 additional ring heteroatoms selected from N, O and S, which heterocycle is optionally fused to a benzo ring or to a saturated carbocycle having 3 to 7 ring atoms, or which heterocycle is optionally taken together with a saturated carbocyle having 3 to 7 ring atoms to form a spirocyclic ring, and wherein the heterocycle is optionally substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, haloC1-C6alkyl, C1-C6alkoxy, C3-C7cycloalkyl, O-C(O)pyridine substituted with C1-C4alkyl and haloC1-C4alkyl; and

R15 is hydrogen or halogen;

with the proviso that

(1) when R4 is SO2CH3, then at least one occurrence of R1, R2 or R3 is not hydrogen,

(2) when R4 is halogen, trifluoromethyl or cyano and R6 is hydrogen or halogen, then at least one occurrence of R1 or R2 is not hydrogen or R1 is not methyl,

(3) when R5 is C1-C6alkoxy, then R4 is not hydrogen or halogen, and

(4) when R4 is C1-C6alkoxy or C1-C6alkyl, then R2 is not hydrogen.

2. The compound of claim 1, wherein Q is
.

3. The compound of claim 1 or claim 2, wherein

X1 is CR2, X2 is N or CR3, X3 is CR3a, X4 is N or CR3 and X5 is CR3;

R2 is hydrogen, halogen, C1-C4alkyl, cyclopropyl, haloC1-C4alkyl, C1-C4alkoxy or haloC1-C4alkoxy;

R3 is independently selected at each occurrence from the group consisting of hydrogen, halogen, C1-C4alkyl, cyclopropyl, haloC1-C4alkyl, C1-C4alkoxy and haloC1-C4alkoxy; and

R3a is halogen, C1-C6alkyl, haloC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C3-C7cycloalkylC1-C4alkyl, C1-C6alkoxy, haloC1-C6alkoxy or SF5.

4. The compound of any one of claims 1 to 3, wherein

X1 is CR2;

R2 is hydrogen, halogen, C1-C4alkyl or C1-C4alkoxy;

X2 is CH or N;

X3 is CR3a;

R3a is halogen, C1-C4alkyl, haloC1-C4alkyl, haloC1-C6alkoxy or SF5;

X4 is CR3 or N;

R3 is hydrogen or halogen; and

X5 is CH.

5. The compound of any one of claims 1 to 4, wherein

X1 is CR2;

R2 is hydrogen, halogen, methyl, ethyl, methoxy or ethoxy;

X2 and X5 are each CH;

X3 is CR3a;

R3a is halogen, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, or SF5;

X4 is CR3; and

R3 is hydrogen or halogen.

6. The compound of any one of claims 1 to 5, wherein R1 is selected from the group consisting of hydrogen, C1-C6alkyl, halo C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkylmethyl, and 4 to 6 member heterocycloalkyl having a ring heteroatom selected from N and O, which heterocycloalkyl is optionally substituted with 1 or 2 groups selected from oxo, halogen, and hydroxy, and wherein the alkyl or cycloalkyl is optionally substituted with hydroxy.

7. The compound of any one of claims 1 to 6, wherein R1 is C1-C4alkyl, trifluoromethyl, C3-C5cycloalkyl, C3-C5cycloalkylmethyl, oxetanyl, tetrahydrofuryl, or azetidinyl, wherein each alkyl, cycloalkyl, oxetanyl or azetidinyl is optionally substituted with hydroxy or halogen.

8. The compound of any one of claims 1 to 7, wherein R1 is methyl, isopropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, oxetanyl, difluoromethyl, 1-hydroxycyclopropyl, 3-hydroxycyclobutyl, 3-hydroxy-3-methylcyclobutyl, 3-fluorooxetanyl or oxopyrrolidinyl.

9. The compound of any one of claims 1 to 8, wherein

R13 and R14 are each independently selected from the group consisting of C1-C4alkyl, C3-C5cycloalkyl and C3-C5cycloalkylmethyl; and

R13a is hydrogen.

10. The compound of any one of claims 1 to 9, wherein R13 and R14 are each methyl and R13a is hydrogen.

11. The compound of any one of claims 1 to 8, wherein R13a is hydrogen; and R13 and R14, taken in combination with the interposed C and N atoms, form a saturated or partially unsaturated 4 to 6 member heterocycle, which heterocycle further comprises 0 or 1 additional ring heteroatoms selected from N, O and S, wherein the heterocycle is optionally fused to a saturated carbocycle having 3 to 7 ring atoms, or which heterocycle is optionally taken together with a saturated carbocyle having 3 to 7 ring atoms to form a spirocyclic ring, and wherein the heterocycle is optionally substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxy, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy and C3-C7cycloalkyl.

12. The compound of any one of claims 1 to 8 and 11, wherein R13a is hydrogen; and R13 and R14, taken in combination with the interposed C and N atoms, form a heterocyclic ring selected from the group consisting of azetidine, pyrrolidine, thiazolidine, piperidine and morpholine, wherein the heterocyclic ring is optionally fused to a cyclopropyl ring and the heterocyclic ring is further optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, hydroxy, methyl, hydroxymethyl, methoxy and cyclopropyl.

13. The compound of any one of claims 1 to 8, 11 and 12, wherein R13a is hydrogen; and R13 and R14, taken in combination with the interposed C and N atoms, form a pyrrolidine ring, wherein the pyrrolidine ring is optionally fused to a cyclopropyl ring and the pyrrolidine ring is further optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, hydroxy, methyl, hydroxymethyl and cyclopropyl.

14. The compound of any one of claims 1 to 13, wherein

Q is

Z2 is N or CR6; Z3 is N or CR7, wherein 0 or 1 of Z2 and Z3 can be N;

R4 is C1-C4alkyl, C1-C4alkoxy, cyano, SO2-R8, or 4 to 7 member heterocycloalkyl having a ring heteroatom selected from N, O and S which heterocycloalkyl is substituted with 0, 1 or 2 groups independently selected from the group consisting of halogen, oxo, C1-C6alkyl, C(O)C1-C6alkyl, and SO2R8 and wherein each alkyl or cycloalkyl is optionally substituted with hydroxy, cyano, CO2H or C(O)NH2;

R5 is hydrogen, C1-C4alkyl, amino, mono- or di-C1-C4alkylamino, C3-C6cycloalkylamino or -N(H)C(O)C1-C4alkyl, where each alkyl or cycloalkyl is optionally substituted with hydroxy;

R6 is hydrogen, C1-C4alkyl, haloC1-C6alkyl or halogen;

R7 is hydrogen or C1-C4alkyl; and

R8 is C1-C6alkyl, NR8dR8e, C3-C7cycloalkyl or haloC1-C6alkyl, wherein each alkyl, cycloalkyl or haloalkyl is optionally substituted with hydroxy, CO2H, CO2C1-C6alkyl or C(O)NH2; or

R8 is a group of the formula:

p is 1 or 2;

R8a is hydrogen, C1-C6alkyl or phenyl substituted with halogen;

R8b is hydrogen, halogen, C1-C4alkyl, haloC1-C4alkyl, C1-C4alkoxy, C3-C5cycloalkyl, cyano, amino or SO2C1-C6alkyl;

R8c is hydrogen, halogen, hydroxy or C1-C6alkyl; or

CR8bR8c, taken in combination, forms a spirocyclic 3 to 6 member carboxycle or a 4 to 6 member heterocycle having a ring heteratom selected from N, O and S, which spirocycle is optionally substituted with hydroxy, C1-C4alkyl, haloC1-C4alkyl or C1-C4alkoxy;

R8d is hydrogen, C1-C6alkyl, haloC1-C6alkyl, C3-C7cycloalkyl, or 4 to 7 member

heterocycloalkyl having a ring heteroatoms selected from N, O and S and 0 or 1 additional ring nitrogen atoms, which heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from hydroxy, halogen, oxo, C1-C6alkyl, and C1-C6alkoxy;

R8e is hydrogen or C1-C6alkyl; or

NR8dR8e, taken in combination, forms a 4 to 7 member heterocycloalkyl optionally comprising 1 additional ring heteroatom selected from N, O and S, which heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from hydroxy, halogen, oxo, C1-C6alkyl, C1-C6alkoxy and heteroaryl, which heteroaryl has 5 or 6 ring atoms and has one ring heteroatom selected from N, O and S and 0 or 1 additional ring nitrogen atom, or

NR8dR8e, taken in combination, forms a 5 or 6 member heteroaryl, which heteroaryl optionally comprises 1 additional ring heteroatom selected from N, O and S.

15. The compound of any one of claims 1 to 14, wherein


;

Z2 is CH or N;

Z3 is CH or N; and

R8 is C1-C6alkyl, C3-C7cycloalkyl or haloC1-C6alkyl; or

R8 is a group of the formula:
;

R8b is halogen, C1-C4alkyl, haloC1-C4alkyl, C1-C4alkoxy, C3-C5cycloalkyl, cyano, or amino; R8c is hydrogen, halogen, hydroxy or C1-C6alkyl; or

CR8bR8c, taken in combination, forms a spirocyclic 3 to 4 member carboxycle or a 4 or 5 member heterocycle having a ring heteratom selected from N, O and S, which spirocycle is optionally substituted with hydroxy, C1-C4alkyl, haloC1-C4alkyl or C1-C4alkoxy.

16. The compound of any one of claims 1 to 4, according to the formula:

wherein

R1 is selected from the group consisting of hydrogen, C1-C6alkyl, halo C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkylmethyl, and 4 to 6 member heterocycloalkyl having a ring heteroatom selected from N and O, which heterocycloalkyl is optionally substituted with 1 or 2 groups selected from oxo or hydroxy, and wherein the alkyl or cycloalkyl is optionally substituted with hydroxy;

R2 is hydrogen, halogen, C1-C4alkyl or C1-C4alkoxy;

R3a is halogen, C1-C4alkyl, haloC1-C4alkyl or SF5;

X4 is CR3 or N;

R3 is hydrogen or halogen;

Z2 is CH or N;

Z3 is CH or N;

R8 is C1-C6alkyl, C3-C7cycloalkyl or haloC1-C6alkyl; or

R8 is a group of the formula:
;

R8b is halogen, C1-C4alkyl, haloC1-C4alkyl, C1-C4alkoxy, C3-C5cycloalkyl, cyano, or amino; R8c is hydrogen, halogen, hydroxy or C1-C6alkyl; or

CR8bR8c, taken in combination, forms a spirocyclic 3 to 4 member carboxycle or a 4 or 5 member heterocycle having a ring heteratom selected from N, O and S, which spirocycle is optionally substituted with hydroxy, C1-C4alkyl, haloC1-C4alkyl or C1-C4alkoxy;

W is a bond, CH2, CH2CH2 or CH2O, where the oxygen is adjacent to CR15aR15b; and

R15a and R15b are independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-C4alkyl, hydroxyC1-C4alkyl, C1-C4alkoxy and C3-C6cycloalkyl; or

R15a and R15b, taken in combination with the carbon atom to which they are attached, form a spirocyclic cyclopropyl ring; and

R16 is hydrogen; or

R15a and R16, taken in combination with the carbon atoms to which they are attached, form a fused cyclopropyl ring.

17. The compound of claim 16, wherein

X4 is CR3;

R3 is hydrogen or halogen;

W is CH2;

Z2 is N; and

Z3 is CH.

18. The compound of any one of claims 1 to 13, wherein


;

A is oxygen, N(H), or CHR11;

R8 is C1-C6alkyl, NR8dR8e, C3-C7cycloalkyl, haloC1-C6alkyl or benzyl, and wherein each alkyl, cycloalkyl or haloalkyl is optionally substituted with hydroxy, CO2H, CO2C1-C6alkyl or C(O)NH2; or

R8 is a group of the formula:
;

R8b is hydrogen, C1-C4alkyl, halo C1-C4alkyl, C1-C4alkoxy, C3-C6cycloalkyl, cyano, or amino; R8c is hydrogen, hydroxy or C1-C6alkyl;

R8d is hydrogen, C1-C6alkyl, haloC1-C6alkyl, or C3-C7cycloalkyl;

R8e is hydrogen or C1-C6alkyl;

R9 is hydrogen;

R10 is hydrogen; or

R9 and R10, taken in combination, form a divalent methylene bridge; and

R11 is hydrogen or C1-C6alkyl.

19. The compound of any one of claims 1 to 4, according to the formula:

wherein

R1 is selected from the group consisting of hydrogen, C1-C6alkyl, halo C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkylmethyl, and 4 to 6 member heterocycloalkyl having a ring heteroatom selected from N and O, which heterocycloalkyl is optionally substituted with 1 or 2 groups selected from oxo and hydroxy, and wherein the alkyl or cycloalkyl is optionally substituted with hydroxy;

R2 is hydrogen, halogen, C1-C4alkyl or C1-C4alkoxy;

R3a is halogen, C1-C4alkyl, haloC1-C4alkyl or SF5;

X4 is CR3 or N;

R3 is hydrogen or halogen;

Z2 is CH or N;

Z3 is CH or N;

R8 is C1-C6alkyl, C3-C7cycloalkyl or haloC1-C6alkyl; or

R8 is a group of the formula:
;

R8b is halogen, C1-C4alkyl, haloC1-C4alkyl, C1-C4alkoxy, C3-C5cycloalkyl, cyano, or amino; R8c is hydrogen, halogen, hydroxy or C1-C6alkyl; or

CR8bR8c, taken in combination, forms a spirocyclic 3 to 4 member carboxycle or a 4 or 5 member heterocycle having a ring heteratom selected from N, O and S, which spirocycle is optionally substituted with hydroxy, C1-C4alkyl, haloC1-C4alkyl or C1-C4alkoxy;

W is a bond, CH2, CH2CH2 or CH2O, where the oxygen is adjacent to CR15aR15b; and

R15a and R15b are independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-C4alkyl, hydroxyC1-C4alkyl, C1-C4alkoxy and C3-C6cycloalkyl; or

R15a and R15b, taken in combination with the carbon to which they are attached, form a spirocyclic cyclopropyl ring; and

R16 is hydrogen; or

R15a and R16, taken in combination with the carbon atoms to which they are attached, form a fused cyclopropyl ring, and R15b is selected from the group consisting of hydrogen, halogen, hydroxy, C1-C4alkyl, hydroxyC1-C4alkyl, C1-C4alkoxy and C3-C6cycloalkyl.

20. A compound, which is recited in Table A, or a pharmaceutically acceptable salt thereof.

21. A compound, which is recited in Table B, or a pharmaceutically acceptable salt thereof.

22. A compound, which is recited in Table C, or a pharmaceutically acceptable salt thereof.

23. The compound of any one of claims 1 to 22 in the form of a pharmaceutically acceptable salt.

24. A pharmaceutical composition comprising a pharmaceutically acceptable excipient, carrier or adjuvant and at least one compound of any one of claims 1 to 23.

25. The pharmaceutical composition of claim 24, wherein the composition is formulated in a form selected from the group consisting of an injectable fluid, an aerosol, a tablet, a pill, a capsule, a syrup, a cream, a gel and a transdermal patch.

26. A packaged pharmaceutical composition, comprising a pharmaceutical composition of claim 24 or 25 and instructions for using the composition to treat a patient suffering from a heart disease.

27. The packaged pharmaceutical composition of claim 26, wherein the heart disease is heart failure.

28. A method of treating heart disease in a mammal which method comprises

administering to the mammal a therapeutically effective amount of at least one compound of any one of claims 1 to 23, or a pharmaceutical salt thereof or a pharmaceutical composition thereof.

29. The method of claim 28, wherein the heart disease is heart failure.

30. The method of claim 29, wherein the heart failure is congestive heart failure.

31. The method of claim 29, wherein the heart failure is systolic heart failure.

32. A method for modulating the cardiac sarcomere in a mammal which method comprises administering to the mammal an amount of at least one compound of any one of claims 1 to 23 or a pharmaceutical salt thereof or a pharmaceutical composition thereof to modulate the cardiac sarcomere in the mammal.

33. A method for potentiating cardiac myosin in a mammal which method comprises administering to the mammal an amount of at least one compound of any one of claims 1 to 23 or a

pharmaceutical salt thereof or a pharmaceutical composition thereof to potentiate cardiac myosin in the mammal.

34. A compound of any one of claims 1 to 23 for use as a medicament.

35. A compound of any one of claims 1 to 23 for use in the manufacture of a medicament for treating heart failure.