US 11,299,479 B1 · Bisamide sarcomere activating compounds and uses thereof

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising a compound of the invention, a method for manufacturing compounds of the invention and therapeutic uses thereof.

A method of treating heart disease in a mammal comprising administering to the mammal a therapeutically effective amount of at least one compound, or pharmaceutically acceptable salt thereof, according to Formula (I):

wherein
Q is
X1 is CR2;
X2, X4 and X5 are each independently CR3;
X3 is CR3a;
R1a is selected from the group consisting of hydrogen, C1-C6alkyl and halogen;
R1 is selected from the group consisting of 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 at each occurrence 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;
R3a is C1-C6alkyl, haloC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C3-C7cycloalkylC1-C4alkyl, C1-C6alkoxy, haloC1-C6alkoxy, or 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;
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 with halogen, 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 carbocycle or a 4 to 6 member heterocycle having a ring heteroatom 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;
R13a is hydrogen or C1-C6alkyl;
R13 and R14, taken in combination with the interposed C and N atoms, form a saturated 5 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, 0-C(O)pyridine substituted with C1-C4alkyl and haloC1-C4alkyl;
and
R15 is hydrogen or halogen;
with the proviso that
(1) when R4 is halogen, trifluoromethyl, or cyano and R6 is hydrogen or halogen, then R2 is not hydrogen or R1 is not methyl,
(2) when R5 is C1-C6alkoxy, then R4 is not hydrogen or halogen, and
(3) when R4 is C1-C6alkoxy or C1-C6alkyl, then R2 is not hydrogen.

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Bisamide sarcomere activating compounds and uses thereof

Life of this patent

Bisamide sarcomere activating compounds and uses thereof

Life of this patent

Abstract

Claims23