Bisamide sarcomere activating compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-10899746-B2
Application number	US-202016833336-A
Country	US
Kind code	B2
Filing date	Mar 27, 2020
Priority date	Sep 13, 2017
Publication date	Jan 26, 2021
Grant date	Jan 26, 2021

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.

First claim

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 C 1 -C 6 alkyl and halo C 1 -C 6 alkyl;
A is absent, oxygen, N(H), N(C 1 -C 6 alkyl) or CR 11 R 11a ;
X 1 is N or CR 2 ;
X 2 , X 3 , X 4 and X 5 are each independently selected from N and CR 3 provided that 0, 1, or 2 of X 1 , X 2 , X 3 , X 4 and X 5 are N and the remainder are CR 2 or CR 3 ;
R 1a is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and halogen;
R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl optionally substituted with 1 or 2 groups selected from hydroxy, halogen, and C 1 -C 4 alkyl, hydroxy C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylC 1 -C 4 alkyl, hydroxy C 3 -C 7 cycloalkylC 1 -C 4 alkyl, 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 C 1 -C 4 alkyl;
R 2 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylC 1 -C 4 alkyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkoxy and SF 5 ;

or
R 1 and R 2 , taken in combination, form a divalent group selected from —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —OCH 2 —, —CH 2 OCH 2 —, —OCH 2 CH 2 , —CH 2 N(H)CH 2 — and —CH 2 N(C 1 -C 4 alkyl)CH 2 —, each of which is optionally substituted with C 1 -C 4 alkyl or hydroxyC 1 -C 4 alkyl and wherein the oxygen of —OCH 2 CH 2 — or —OCH 2 — is attached to the CR 2 carbon;
R 3 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylC 1 -C 4 alkyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkoxy and SF 5 ;
R 8 is C 1 -C 6 alkyl, NR 8d R 8e , C 3 -C 7 cycloalkyl, haloC 1 -C 6 alkyl or benzyl, wherein each alkyl, cycloalkyl or haloalkyl is optionally substituted with hydroxy, CO 2 H, CO 2 C 1 -C 6 alkyl or C(O)NH 2 ; or
R 8 is a group of the formula:

wherein
p is 1 or 2;
R 8a is hydrogen, C 1 -C 6 alkyl, benzyl, or phenyl optionally substituted with C 1 -C 6 alkyl or halogen;
R 8b is hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxyC 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, cyano, amino, N(H)C(O)C 1 -C 6 alkyl, N(H)C(O)C 3 -C 7 cycloalkyl, N(H)C(O)haloC 1 -C 6 alkyl, CO 2 H, C(O)NH 2 , C(O)NH(C 1 -C 6 alkyl), C(O)N(C 1 -C 6 alkyl) 2 , C(O)C 1 -C 6 alkyl, C(O)haloC 1 -C 6 alkyl, SO 2 C 1 -C 6 alkyl, phenyl optionally substituted with halogen, C 1 -C 4 alkyl or haloC 1 -C 4 alkyl, 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 C 1 -C 6 alkyl, and wherein the alkoxy is optionally substituted with halogen, phenyl or halogen-substituted phenyl;
R 8c is hydrogen, halogen, hydroxy or C 1 -C 6 alkyl; or
CR 8b R 8c , taken in combination, forms a spirocyclic 3 to 6 member carboxycle or a 4 to 6 member heterocycle having a ring heteroatom selected from N, O and S, which spirocycle is optionally substituted with hydroxy, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl or C 1 -C 4 alkoxy;
R 8d is hydrogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 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, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;
R 8e is hydrogen or C 1 -C 6 alkyl; or
NR 8d R 8e , 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, C 1 -C 6 alkyl, C 1 -C 6 alkoxy 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 NR 8d R 8e , taken in combination, forms a 5 or 6 member heteroaryl optionally comprising 1 additional ring heteroatom selected from N, O and S;
R 9 is hydrogen or C 1 -C 6 alkyl;
R 10 and R 10a are each independently selected from the group consisting of hydrogen, halogen and C 1 -C 6 alkyl; or
R 9 and R 10 taken in combination form a divalent bridge selected from O, CH 2 , and CH 2 CH 2 and R 10a is hydrogen;
R 11a is hydrogen or halogen;
R 12 is hydrogen or halogen;
R 11 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, N(H)C 1 -C 6 alkyl and N(H)C 3 -C 7 cycloalkyl; or
R 11 and R 12 , taken in combination, form a double bond;
R 13a is hydrogen or C 1 -C 6 alkyl;
R 13 is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkylC 1 -C 6 alkyl;
R 14 is C 1 -C 5 alkyl, C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkylC 1 -C 6 alkyl; or
R 13 and R 14 , 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, haloC 1 -C 5 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, O-A C(O)pyridine substituted with C 1 -C 4 alkyl and haloC 1 -C 4 alkyl.

2. The compound or salt of claim 1 , wherein
X 1 is CR 2 , X 2 is N or CR 3 , X 3 is CR 3 a, X 4 is N or CR 3 and X 5 is CR 3 ;
R 2 is hydrogen, halogen, C 1 -C 4 alkyl, cyclopropyl, haloC 1 -C 4 alkyl, C 1 -C 4 alkoxy or haloC 1 -C 4 alkoxy;
R 3 is independently selected at each occurrence from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, cyclopropyl, haloC 1 -C 4 alkyl, C 1 -C 4 alkoxy and haloC 1 -C 4 alkoxy; and
R 3a is halogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylC 1 -C 4 alkyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkoxy or SF 5 .

3. The compound or salt of claim 1 , wherein
X 1 is CR 2 ;
R 2 is hydrogen, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy;
X 2 is CH or N;
X 3 is CR 3a ;
R 3 is halogen, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, haloC 1 -C 6 alkoxy or SF 5 ;
X 4 is CR 3 or N;
R 3 is hydrogen or halogen; and
X 5 is CH.

4. The compound or salt of claim 1 , wherein
X 1 is CR 2 ;
R 2 is hydrogen, halogen, methyl, ethyl, methoxy or ethoxy;
X 2 and X 5 are each CH;
X 3 is CR 3a ;
R 3a

Assignees

• Amgen Inc
• Cytokinetics Inc

Inventors

• Ashcraft Luke
• Boezio Alessandro
• Butler John
• Chandra Aroop
• Chuang Chihyuan
• Collibee Scott E
• Debenedetto Mikkel V
• Dimassa Vincent
• Graceffa Russell
• Malinowski Justin
• Moebius David
• Morgan Bradley Paul
• Payette Joshua
• Romero Antonio
• St Jean Jr David
• Vargas Richard
• Yeoman John
• Zhang Hanmo
• Cheng Alan
• Gonzalez Lopez De Turiso Felix
• Johnson Michael Garrett

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D413/12

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

• C07D405/12

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

• C07D403/14

  containing three or more hetero rings · CPC title