Bicyclic 1,4-diazepanones and therapeutic uses thereof

Patent metadata

Field	Value
Publication number	US-12441691-B2
Application number	US-202418623812-A
Country	US
Kind code	B2
Filing date	Apr 1, 2024
Priority date	Nov 6, 2020
Publication date	Oct 14, 2025
Grant date	Oct 14, 2025

Abstract

Provided herein are compounds of formula (I):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 , X 2 , R y , R z , R 1 , R 2 , R 3 , and R 4 are as defined herein.

Also provided herein is a pharmaceutically acceptable composition comprising a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
Also provided herein are methods of using a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, to treat various diseases, disorders, and conditions responsive to the modulation of the contractility of the skeletal sarcomere.

First claim

The invention claimed is:

1. A method for treating a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related deficits, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, conditions of muscle wasting, muscular myopathies, muscle atrophy and fatigue, frailty, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, muscular myopathies, stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, muscle wasting caused by heart failure, cancer, or chronic kidney disease/dialysis, post-spinal cord injury (SCI) muscle dysfunction, post-stroke muscle dysfunction, facioscapulohumeral dystrophy, and Charcot-Marie-Tooth disease, in a subject, comprising administering to the subject an effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising any of the foregoing and a pharmaceutical carrier,
wherein:
X 1 and X 2 are each independently N or C—R x ;
each R x , R y , and R z is independently H, halo, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, or C 6-20 aryl;
R 1 is C 3-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, or

 wherein R w is C 1-12 alkyl;
R 2 is:
a) C(O)—R h , wherein R h is
(i) amino optionally substituted with one or more R q , wherein R q is C 1-12 alkyl, C 3-10 cycloalkyl, C 6-20 aryl, 3-15 membered heterocyclyl, or 5-20 membered heteroaryl, wherein the C 1-12 alkyl, C 3-10 cycloalkyl, C 6-20 aryl, 3-15 membered heterocyclyl, or 5-20 membered heteroaryl of R q is optionally substituted with one or more R p , wherein R p is OH, cyano, halo, oxo, —C(O)NH 2 , —C(O)NH(C 1-12 alkyl), —C(O)-(3-15 membered heterocyclyl), —S(O)—C 1-12 alkyl, —S(O) 2 —C 1-12 alkyl, —S(O) 2 —NH 2 , —N(C 1-12 alkyl) 2 , —NHC(O)—C 1-12 alkyl, —NHC(O)—NH 2 , C 6-20 aryl, 3-15 membered heterocyclyl, or 5-20 membered heteroaryl, wherein the C 6-20 aryl, 3-15 membered heterocyclyl, 5-20 membered heteroaryl, or the 3-15 membered heterocyclyl of the C(O)-(3-15 membered heterocyclyl) of R p is independently optionally substituted with one or more R v , wherein R v is OH, oxo, —C(O)NH 2 , —C(O)OH, or C 1-12 alkyl, wherein the C 1-12 alkyl of R v is further optionally substituted with one or more OH,
C 1-3 alkoxy,
C(O)NH 2 ,
C 3-10 cycloalkyl,
C 3-10 cycloalkenyl, wherein the C 3-10 cycloalkenyl is unsubstituted or substituted with one or more oxo,
C 6-20 aryl, wherein the C 6-20 aryl is unsubstituted or substituted with one or more OH, 5-20 membered heteroaryl, or —C(O)NH 2 ,
3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl is unsubstituted or substituted with one or more R j , wherein R j is OH, oxo, halo, NH 2 , —N(C 1-12 alkyl) 2 , —N(C 1-12 alkyl)-C(O)C 1-12 alkyl, —NH—SO 2 —C 1-12 alkyl, —SO 2 —C 1-12 alkyl, C 1-12 alkyl, C 1-12 alkoxy, —C(O)OH, —C(O)—C 1-12 alkoxy, —C(O)NH 2 , —C(O)NH(C 1-12 alkyl), —C(O)N(C 1-12 alkyl) 2 , 3-15 membered heterocyclyl, or 5-20 membered heteroaryl, wherein the C 1-12 alkyl, C 1-12 alkoxy, 3-15 membered heterocyclyl, or 5-20 membered heteroaryl of R j is independently further optionally substituted with one or more R k , wherein R k is OH, C 1-12 alkyl, —C(O)NH 2 , —C(O)NH(C 1-12 alkyl), —C(O)N(C 1-12 alkyl) 2 , C 6-20 aryl, or 5-20 membered heteroaryl, wherein the C 1-12 alkyl of R k is independently further optionally substituted with one or more OH, or
5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is unsubstituted or substituted with one or more R t , wherein R t is OH, NH 2 , C 1-12 alkyl, —C(O)OH, —C(O)—C 1-12 alkoxy, —C(O)NH 2 , —C(O)NH(C 1-12 alkyl), —C(O)N(C 1-12 alkyl) 2 , or —C(O)-(3-15 membered heterocyclyl), wherein the C 1-12 alkyl of R t , the 3-15 membered heterocyclyl of the —C(O)-(3-15 membered heterocyclyl) of R t , the C 1-12 alkyl of the —C(O)NH(C 1-12 alkyl) of R t , or the C 1-12 alkyl of the —C(O)N(C 1-12 alkyl) 2 of R′ is independently further optionally substituted with one or more OH, —C 1-12 alkoxy, or —C(O)NH 2 , or
(ii) C 1-12 alkyl, wherein the C 1-12 alkyl is unsubstituted or is substituted with one or more R n , wherein R n is OH, oxo, halo, cyano, —C(O)NH 2 , amino, sulfonyl, C 1-12 alkoxy, C 6-20 aryloxy, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, 3-15 membered heterocyclyl, or 5-20 membered heteroaryl, or

b) C 1-12 alkyl, wherein the C 1-12 alkyl is unsubstituted or is substituted with one or more R m , wherein
R m is OH, halo, cyano, oxo, C 1-12 alkyl, C 1-3 alkoxy, C 6-20 aryloxy, —C(O)NH 2 , —C(O)NH(C 1-12 alkyl), —C(O)N(C 1-12 alkyl) 2 , —C(O)OH, —C(O)—C 1-12 alkoxy, —C(O)-(3-15 membered heterocyclyl), NH 2 , —NH(C 1-12 alkyl), —N(C 1-12 alkyl) 2 , —NHC(O)—C 1-12 alkyl, —NHC(O)—NH 2 , —NH—SO 2 —C 1-12 alkyl, —S(O)—C 1-12 alkyl, —S(O) 2 —C 1-12 alkyl, —S(O) 2 —NH 2 , C 3-10 cycloalkyl, or 3-15 membered heterocyclyl, wherein the C 1-12 alkyl, C 6-20 aryloxy, the C 1-12 alkyl of —C(O)NH(C 1-12 alkyl), the C 1-12 alkyl of —C(O)N(C 1-12 alkyl) 2 , —C(O)OH, —C(O)—C 1-12 alkoxy, the 3-15 membered heterocyclyl of —C(O)-(3-15 membered heterocyclyl), NH 2 , the C 1-12 alkyl of —NH(C 1-12 alkyl), the C 1-12 alkyl of —N(C 1-12 alkyl) 2 , the C 1-12 alkyl of —NHC(O)—C 1-12 alkyl, —NHC(O)—NH 2 , the C 1-12 alkyl of —NH—SO 2 —C 1-12 alkyl, the C 1-12 alkyl of —S(O)—C 1-12 alkyl, the C 1-12 alkyl of —S(O) 2 —C 1-12 alkyl, —S(O) 2 —NH 2 , C 3-10 cycloalkyl, or 3-15 membered heterocyclyl of R m is further optionally substituted by one or more OH, halo, cyano, oxo, C 1-12 alkyl, C 1-12 alkoxy, —C(O)NH 2 , —C(O)NH(C 1-12 alkyl), —C(O)N(C 1-12 alkyl) 2 , C(O)OH, NH 2 , —NH(C 1-12 alkyl), —N(C 1-12 alkyl) 2 , C 3-10 cycloalkyl, C 6-20 aryl, 3-15 membered heterocyclyl, or 5-20 membered heteroaryl, or

c) C 3-10 cycloalkenyl, wherein the C 3-10 cycloalkenyl is unsubstituted or is substituted with one or more R i , wherein R i is oxo, NH 2 , —NH(C 1-12 alkyl), —N(C 1-12 alkyl) 2 , or 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R i , the C 1-12 alkyl of the —NH(C 1-12 alkyl) of R i , or the C 1-12 alkyl of the —N(C 1-12 alkyl) 2 of R i is independently optionally substituted with one or more OH or C 1-12 alkoxy, or
d) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is unsubstituted or substituted with one or more OH, oxo, NH 2 , or C 1-12 alkyl, or
e) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl is unsubstituted or substituted with one or more OH, oxo, NH 2 , or C 1-12 alkyl, or
f) amidinyl, wherein the amidinyl is unsubstituted or substituted with one or more R s , wherein R s is OH, cyano, C 1-12 alkyl, —C(O)—C 1-12 alkyl, —C(O)—C 1-12 alkoxy, C 6-20 aryloxy, or —SO 2 —C 1-12 alkyl, or
g) optionally substituted sulfonyl, wherein the sulfonyl is unsubstituted or substituted with one or more R u , wherein R u is C 1-12 alkyl, NH 2 , —NH(C 1-12 alkyl), —N(C 1-12 alkyl) 2 , or C 6-20 aryl, wherein the C 1-12 alkyl or C 6-20 aryl of R u is independently further optionally substituted with one or more halo or C 1-12 alkoxy, or
h) cyano, and

R 3 is H, C 1-12 alkyl, C(O)NH 2 , or C(O)—C 1-12 alkoxy; or
R 2 and R 3 are taken together with the atoms to which they are attached to form a 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl independently comprises two or more annular

Assignees

• Cytokinetics Inc

Inventors

• Morgan Bradley P
• Evans Chris
• Lu Pu-Ping
• Yamasaki Makoto
• Wang Wenyue
• Collibee Scott
• Makino Takuya
• Tsuchiya Kazuyuki
• Kurosaki Toshio
• Yamaki Susumu
• Honjo Eriko
• Koizumi Yuka
• Katoh Naoto
• Sekioka Ryuichi
• Kuriwaki Ikumi

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/10

  Spiro-condensed systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title