IP Library › Patent Application 19334614

Patent Application

App. No. 19/334,614

QUINOLINONE AMIDE COMPOUNDS AND USES THEREOF

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App. No.: 19/334,614

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Abstract

The present disclosure generally relates to substituted quinolinone amide compounds or salts of Formula (I), (II-A), (IV), or (III) and pharmaceutical compositions thereof. The substituted quinolinone amide compounds or salts of Formula (I), (II-A), (IV), or (III) disclosed herein may be used to treat or prevent cardiac disease in an individual in need thereof.

Claims (218)

1 . A method of treating a cardiac disease or a related condition in an individual in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (III):

or a salt thereof, wherein:

X 1 , X 2 , X 3 , and X 4 are each independently selected from C(R) and N, wherein no more than two of X 1 , X 2 , X 3 , and X 4 are N;

each R is independently selected from:

hydrogen, halogen, —NO 2 , —CN, —N 3 , —OR 28 , —SR 28 , —N(R 28 ) 2 , —C(O)R 28 , —C(O)N(R 28 ) 2 , —N(R 28 )C(O)R 28 , —N(R 28 )C(O)N(R 28 ) 2 , —OC(O)N(R 28 ) 2 , —N(R 28 )C(O)OR 28 , —C(O)OR 28 , —OC(O)R 28 , —S(O)R 28 , and —S(O) 2 R 28 ;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28 , —SR 28 , —N(R 28 ) 2 , —C(O)R 28 , —C(O)N(R 28 ) 2 , —N(R 28 )C(O)R 28 , —C(O)OR 28 , —OC(O)R 28 , —N(R 28 )C(O)N(R 28 ) 2 , —OC(O)N(R 28 ) 2 , —N(R 28 )C(O)OR 28 , —S(O)R 28 , —S(O) 2 R 28 , —NO 2 , ═O, ═S, ═N(R 28 ), —CN, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C 3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 27 ; and

C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28 , —SR 28 , —N(R 28 ) 2 , —C(O)R 28 , —C(O)N(R 28 ) 2 , —N(R 28 )C(O)R 28 , —N(R 28 )C(O)N(R 28 ) 2 , —OC(O)N(R 28 ) 2 , —N(R 28 )C(O)OR 28 , —C(O)OR 28 , —OC(O)R 28 , —S(O)R 28 , —S(O) 2 R 28 , —NO 2 , ═O, ═S, ═N(R 28 ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from R 27 ;

R 21 is selected from:

hydrogen;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28a , —SR 28a , —N(R 28a ) 2 , —C(O)R 28a , —C(O)N(R 28a ) 2 , —N(R 28a )C(O)R 28a , —C(O)OR 28a , —OC(O)R 28a , —N(R 28a )C(O)N(R 28a ) 2 , —OC(O)N(R 28a ) 2 , —N(R 28a )C(O)OR 28a , —S(O)R 28a , —S(O) 2 R 28a , —NO 2 , ═O, ═S, ═N(R 28a ), —CN, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C 3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 27a ; and

C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28a , —SR 28a , —N(R 28a ) 2 , —C(O)R 28a , —C(O)N(R 28a ) 2 , —N(R 28a )C(O)R 28a , —N(R 28a )C(O)N(R 28a ) 2 , —OC(O)N(R 28a ) 2 , —N(R 28a )C(O)OR 28a , —C(O)OR 28a , —OC(O)R 28a , —S(O)R 28a , —S(O) 2 R 28a , —NO 2 , ═O, ═S, ═N(R 28a ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from R 27a ;

R 22 is selected from:

hydrogen;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28b , —SR 28b , —C(O)R 28b , —C(O)N(R 28b ) 2 , —N(R 28b )C(O)R 28b , —C(O)OR 28b , —OC(O)R 28b , —N(R 28b )C(O)N(R 28b ) 2 , —OC(O)N(R 28b ) 2 , —N(R 28b )C(O)OR 28b , —S(O)R 28b , —S(O) 2 R 28b , —NO 2 , ═O, ═S, ═N(R 28b ), —CN, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C 3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 27b ; and

C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28b , —SR 28b , —N(R 28b ) 2 , —C(O)R 28b , —C(O)N(R 28b ) 2 , —N(R 28b )C(O)R 28b , —N(R 28b )C(O)N(R 28b ) 2 , —OC(O)N(R 28b ) 2 , —N(R 28b )C(O)OR 28b , —C(O)OR 28b , —OC(O)R 28b , —S(O)R 28b , —S(O) 2 R 28b , —NO 2 , ═O, ═S, ═N(R 28b ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from R 27b ; or

R 21 together with R 22 form a C 3-10 carbocycle or 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28a , —SR 28a , —N(R 28a ) 2 , —C(O)R 28a , —C(O)N(R 28a ) 2 , —N(R 28a )C(O)R 28a , —N(R 28a )C(O)N(R 28a ) 2 , —OC(O)N(R 28a ) 2 , —N(R 28a )C(O)OR 28a , —C(O)OR 28a , —OC(O)R 28a , —S(O)R 28a , —S(O) 2 R 28a , —NO 2 , ═O, ═S, ═N(R 28a ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from R 27b ;

R 23 is selected from:

hydrogen, halogen, —OR 28c , —SR 28c , —N(R 28c ) 2 , —NO 2 , and —CN; and

C 1-6 alkyl optionally substituted with one or more substituents independently selected from R 27c ; or

R 21 together with R 23 form a 3- to 10-membered heterocycle, which is optionally substituted with one or more substituents independently selected from halogen, —OR 28a , —SR 28a , —N(R 28a ) 2 , —C(O)R 28a , —C(O)N(R 28a ) 2 , —N(R 28a )C(O)R 28a , —N(R 28a )C(O)N(R 28a ) 2 , —OC(O)N(R 28a ) 2 , —N(R 28a )C(O)OR 28a , —C(O)OR 28a , —OC(O)R 28a , —S(O)R 28a , —S(O) 2 R 28a , —NO 2 , ═O, ═S, ═N(R 28a ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from R 27c ; or

R 22 together with R 23 form a 3- to 10-membered heterocycle, optionally substituted with one or more substituents independently selected from halogen, —OR 28a , —SR 28a , —N(R 28a ) 2 , —C(O)R 28a , —C(O)N(R 28a ) 2 , —N(R 28a )C(O)R 28a , —N(R 28a )C(O)N(R 28a ) 2 , —OC(O)N(R 28a ) 2 , —N(R 28a )C(O)OR 28a , —C(O)OR 28a , —OC(O)R 28a , —S(O)R 28a , —S(O) 2 R 28a , —NO 2 , ═O, ═S, ═N(R 28a ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from R 27c ; or

R 21 , R 22 , and R 23 together form a bicyclic heterocycle which is optionally substituted with one or more substituents independently selected from halogen, —OR 28a , —SR 28a , —N(R 28a ) 2 , —C(O)R 28a , —C(O)N(R 28a ) 2 , —N(R 28a )C(O)R 28a , —N(R 28a )C(O)N(R 28a ) 2 , —OC(O)N(R 28a ) 2 , —N(R 28a )C(O)OR 28a , —C(O)OR 28a , —OC(O)R 28a , —S(O)R 28a , —S(O) 2 R 28a , —NO 2 , ═O, ═S, ═N(R 28a ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from R 27c ;

R 24 is selected from:

hydrogen, halogen, —OR 28d , —SR 28d , —N(R 28d ) 2 , —NO 2 , and —CN; and

C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 28d , —SR 28d , —N(R 28d ) 2 , —NO 2 , —CN, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C 3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 27d ;

R 24′ is selected from:

hydrogen, halogen, —OR 28d , —SR 28d , —N(R 28d ) 2 , —NO 2 , and —CN; and

R 24 and R 24 ′ together form a C 3-10 carbocycle or 3- to 10-membered heterocycle, wherein the C 3-10 carbocycle or 3- to 10-membered heterocycle, is optionally substituted with one or more substituents independently selected from R 27d ;

R 25 is selected from:

hydrogen, halogen, —OR 28e , —SR 28e , —N(R 28e ) 2 , —NO 2 , —CN, C 1-6 alkyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C 1-6 alkyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 27e ;

R 26 is selected from:

hydrogen, halogen, —OR 28f , —SR 28f , —N(R 28f ) 2 , —NO 2 , and —CN; and

C 1-6 alkyl optionally substituted with one or more substituents independently selected from R 27f ;

each R 27 , R 27a , R 27b , R 27c , R 27d , R 27e , and R 27f is independently selected from:

halogen, —OR 28g , —SR 28g , —N(R 28g ) 2 , —C(O)R 28g , —C(O)N(R 28g ) 2 , —N(R 28g )C(O)R 28g , —N(R 28g )C(O)N(R 28g ) 2 , —OC(O)N(R 28g ) 2 , —N(R 28g )C(O)OR 28g , —C(O)OR 28g , —OC(O)R 28g , —S(O)R 28g , —S(O) 2 R 28g , —NO 2 , ═O, ═S, ═N(R 28g ), and —CN; and

C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28g , —SR 28g , —N(R 28g ) 2 , —C(O)R 28g , —C(O)N(R 28g ) 2 , —N(R 28g )C(O)R 28g , —N(R 28g )C(O)N(R 28g ) 2 , —OC(O)N(R 28g ) 2 , —N(R 28g )C(O)OR 28g , —C(O)OR 28g , —OC(O)R 28g , —S(O)R 28g , —S(O) 2 R 28g , —NO 2 , ═O, ═S, ═N(R 28g ), and —CN; and

each R 28 , R 28a , R 28b , R 28c , R 28d , R 28e , R 28f , and R 28g is independently selected from:

hydrogen and halogen;

C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , ═O, ═S, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —N(C 1-6 alkyl) 2 , —NH(C 1-6 alkyl), C 3-10 carbocycle, and 3- to 10-membered heterocycle; and

C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , ═O, ═S, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —SO 2 —C 1-6 alkyl, —N(C 1-6 alkyl) 2 , —NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, and C 1-6 haloalkyl;

provided the compound of Formula (III) is not

2 . The method of claim 1 , wherein X 1 , X 2 , X 3 , and X 4 are each independently selected from C(R) and N; and at least one of X 1 , X 2 , X 3 , or X 4 is N.

3 . The method of claim 1 , wherein X 1 , X 2 , X 3 , and X 4 are each independently selected from C(R).

4 . The method of claim 1 , wherein the compound or salt of Formula (III) is a compound of Formula (II-A):

or a salt thereof, wherein:

X 11 is selected from C(R 17a ) and N;

X 12 is selected from C(R 17b ) and N;

X 13 is selected from C(R 17c ) and N;

Y 11 is selected from C(R 17d ) and N;

Y 12 is selected from C(R 17c ) and N;

R 11a , R 11b , R 11c , and R 11d are each independently selected from:

hydrogen, halogen, —NO 2 , —CN, —N 3 , —OR 19a , —SR 19a , —N(R 19a ) 2 , —C(O)R 19a , —C(O)N(R 19a ) 2 , —N(R 19a )C(O)R 19a , —N(R 19a )C(O)N(R 19a ) 2 , —OC(O)N(R 19a ) 2 , —N(R 19a )C(O)OR 19a , —C(O)OR 19a , —OC(O)R 19a , —S(O)R 19a , and —S(O) 2 R 19a ;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 19a , —SR 19a , —N(R 19a ) 2 , —C(O)R 19a , —C(O)N(R 19a ) 2 , —N(R 19a )C(O)R 19a , —C(O)OR 19a , —OC(O)R 19a , —N(R 19a )C(O)N(R 19a ) 2 , —OC(O)N(R 19a ) 2 , —N(R 19a )C(O)OR 19a , —S(O)R 19a , —S(O) 2 R 19a , —NO 2 , ═O, ═S, ═N(R 19a ), —CN, C 3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C 3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 18a ; and

C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 19a , —SR 19a , —N(R 19a ) 2 , —C(O)R 19a , —C(O)N(R 19a ) 2 , —N(R 19a )C(O)R 19a , —N(R 19a )C(O)N(R 19a ) 2 , —OC(O)N(R 19a ) 2 , —N(R 19a )C(O)OR 19a , —C(O)OR 19a , —OC(O)R 19a , —S(O)R 19a , —S(O) 2 R 19a , —NO 2 , ═O, ═S, ═N(R 19a ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from R 8a ;

wherein when R 11a , R 11b , and R 11c are each hydrogen; then R 11d is not hydrogen;

wherein when R 1 b is —OCH 3 , then R 11c is not —OMe;

R 12 is selected from:

hydrogen, halogen, —NO 2 , —CN, —OR 19b , —SR 19b , —N(R 19b ) 2 , —C(O)R 19b , —C(O)N(R 19b ) 2 , —N(R 19b )C(O)R 19b , —N(R 19b )C(O)N(R 19b ) 2 , —OC(O)N(R 19b ) 2 , —N(R 19b )C(O)OR 19b , —C(O)OR 19b , —OC(O)R 19b , —S(O)R 19b , and —S(O) 2 R 19b ;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 19b , —SR 19b , —N(R 19b ) 2 , —C(O)R 19b , —C(O)N(R 19b ) 2 , —N(R 19b )C(O)R 19b , —C(O)OR 19b , —OC(O)R 19b , —N(R 19b )C(O)N(R 19b ) 2 , —OC(O)N(R 19b ) 2 , —N(R 19b )C(O)OR 19b , —S(O)R 19b , —S(O) 2 R 19b , —NO 2 , ═O, ═S, ═N(R 19b ), —CN, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C 3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 18b ; and

C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 19b , —SR 19b , —N(R 19b ) 2 , —C(O)R 19b , —C(O)N(R 19b ) 2 , —N(R 19b )C(O)R 19b , —N(R 19b )C(O)N(R 19b ) 2 , —OC(O)N(R 19b ) 2 , —N(R 19b )C(O)OR 19b , —C(O)OR 19b , —OC(O)R 19b , —S(O)R 19b , —S(O) 2 R 19b , —NO 2 , ═O, ═S, ═N(R 19b ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from R 18b ;

R 13 is selected from:

hydrogen, halogen, —OR 19c , —SR 19c , —N(R 19c ) 2 , —NO 2 , and —CN;

C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 19c , —SR 19c , —N(R 19c ) 2 , —NO 2 , and —CN; and

C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from —OR 19c , —SR 19c , —N(R 19c ) 2 , —C(O)R 19c , —C(O)N(R 19c ) 2 , —N(R 19c )C(O)R 19c , —N(R 19c )C(O)N(R 19c ) 2 , —OC(O)N(R 19c ) 2 , —N(R 19c )C(O)OR 19c , —C(O)OR 19c , —OC(O)R 19c , —S(O)R 19c , —S(O) 2 R 19c , —NO 2 , and —CN;

R 14 is selected from:

hydrogen, halogen, —OR 19d , —SR 19d , —N(R 19d ) 2 , —NO 2 , and —CN;

C 1-6 alkyl which is optionally substituted with one or more substituents independently selected from halogen, —OR 19d , —SR 19d , —N(R 19d ) 2 , —NO 2 , and —CN; and

C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 19d , —SR 19d , —N(R 19d ) 2 , —C(O)R 19d , —C(O)N(R 19d ) 2 , —N(R 19d )C(O)R 19d , —N(R 19d )C(O)N(R 19d ) 2 , —OC(O)N(R 19d ) 2 , —N(R 19d )C(O)OR 19d , —C(O)OR 19d , —OC(O)R 19d , —S(O)R 19d , —S(O) 2 R 19d , —NO 2 , ═O, ═S, ═N(R 19d ), and —CN;

R 14′ is selected from:

hydrogen, halogen, —OR 19d , —SR 19d , —N(R 19d ) 2 , —NO 2 , and —CN; and

C 1-6 alkyl which is optionally substituted with one or more substituents independently selected from halogen, —OR 19d , —SR 19d , —N(R 19d ) 2 , —NO 2 , and —CN; and

R 14 together with R 14′ form a C 3-10 carbocycle, or 3- to 10-membered heterocycle, wherein the C 3-10 carbocycle or 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 18c ;

R 15 is selected from:

hydrogen, halogen, —OR 19 , —SR 19 , —N(R 19e ) 2 , —NO 2 , and —CN; and

C 1-6 alkyl optionally substituted with one or more substituents independently selected from R 18d ; or

R 15 together with R a form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 18f ; or

R 15 together with R 17b form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 18f ; or

R 15 , R 16 , and R 17b together form a bridged heterocycle, wherein the bridged heterocycle is optionally substituted with one or more substituents independently selected from R 18f ;

R 16 is selected from:

hydrogen, halogen, —OR 19f , —SR 19f , —N(R 19f ) 2 , —NO 2 , and —CN; and

C 1-6 alkyl optionally substituted with one or more substituents independently selected from R 18e ; or

R 16 together with R 17a form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 18f ; or

R 16 together with R 17b form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 18f ; or

R 15 , R 16 , and R 17b together form a bridged heterocycle, wherein the bridged heterocycle is optionally substituted with one or more substituents independently selected from R 18f ;

R 17a , R 17b , R 17c , R 17d , and R 17e are each independently selected from:

hydrogen, halogen, —OR 19g , —SR 19g , —N(R 19g ) 2 , —NO 2 , —CN, and —N 3 ; and

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from R 18f ; or

R 15 together with R 17a form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 18f ; or

R 15 together with R 17b form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 18f ; or

R 16 together with R 17a form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 18f ; or

R 16 together with R 17b form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 18f ; or

R 15 , R 16 , and R 17b together form a bridged heterocycle, wherein the bridged heterocycle is optionally substituted with one or more substituents independently selected from R 18f ;

each R 18a , R 18b , R 18c , R 18d , R 18e , and R 18f is independently selected from:

halogen, —OR 19h , —SR 19h , —N(R 19h ) 2 , —C(O)R 19h , —C(O)N(R 19h ) 2 , —N(R 19h )C(O)R 19h , —N(R 19h )C(O)N(R 19h ) 2 , OC(O)N(R 19h ) 2 , —N(R 19h )C(O)OR 19h , —C(O)OR 19h , —OC(O)R 19h , —S(O)R 19h , —S(O) 2 R 19h , —NO 2 , ═O, ═S, ═N(R 19h ), and —CN; and

C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 19h , —SR 19h , —N(R 19h ) 2 , —C(O)R 19h , —C(O)N(R 19h ) 2 , —N(R 19h )C(O)R 19h , —N(R 19h )C(O)N(R 19h ) 2 , —OC(O)N(R 19h ) 2 , —N(R 19h )C(O)OR 19h , —C(O)OR 19h , —OC(O)R 19h , —S(O)R 19h , —S(O) 2 R 19h , —NO 2 , ═O, ═S, ═N(R 19h ), and —CN; and

each R 19a , R 19b , R 19c , R 19d , R 19e , R 19f , R 19g , and R 19h is independently selected from:

hydrogen;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , ═O, ═S, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —N(C 1-6 alkyl) 2 , —NH(C 1-6 alkyl), C 3-10 carbocycle, and 3- to 10-membered heterocycle; and

C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , ═O, ═S, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —N(C 1-6 alkyl) 2 , —NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, and C 1-6 haloalkyl.

5 . The method of claim 1 , wherein each R 21 is selected from:

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28 , —SR 28 , —N(R 28 ) 2 , —C(O)R 28 , —S(O)R 28 , —S(O) 2 R 28 , —NO 2 , —CN, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C 3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, —C(O)R 28g , —CN, and C 1-3 alkyl.

6 . The method of claim 1 , wherein each R 22 is selected from:

hydrogen;

C 1-6 alkyl and C 2-6 alkenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28b , —SR 28b , N(R 28b ) 2 , —C(O)R 28b , —S(O)R 28b , —S(O) 2 R 28b , —NO 2 , —CN, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C 3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 27b ; and

C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28b , —SR 28b , —N(R 28b ) 2 , —C(O)R 28b , —S(O)R 28b , —S(O) 2 R 28b , —NO 2 , —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from R 27b .

7 . The method of claim 1 , wherein R 21 together with R 22 form a C 3-10 carbocycle or 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28a , —SR 28a , —N(R 28a ) 2 , —C(O)R 28a , —NO 2 , —CN, and C 1-6 alkyl, wherein each C 1-6 alkyl is optionally substituted with one or more substituents independently selected from R 27b .

8 . The method of claim 1 , wherein the compound is

of any one thereof.

9 . The method of claim 1 , wherein the cardiovascular disease or related condition is selected from: heart failure with preserved ejection fraction (HFpEF), heart failure with mid-ranged ejection fraction (HFmrEF), heart failure with reduced ejection fraction (HFrEF), cardiomyopathy, cardiac transplant allograft vasculopathy, valve disease, left ventricular (LV) hypertrophy, right ventricular (RV) hypertrophy, acute myocardial infarction, and acute revascularization.

10 . The method of claim 1 , wherein the patient exhibits arrhythmia, stroke, ischemia, or angina.

11 . The method of claim 1 , wherein the patient exhibits myocarditis.

12 . The method of claim 9 , wherein the cardiovascular disease or related condition is selected from left ventricular (LV) hypertrophy.

13 . The method of claim 12 , wherein the left ventricular (LV) hypertrophy is malignant left ventricular (LV) hypertrophy.

14 . The method of claim 9 , wherein the cardiovascular disease or related condition is HFpEF.

15 . The method of claim 14 , wherein said HFpEF comprises disorders of relaxation.

16 . The method of claim 14 , wherein said HFpEF comprises disorders of chamber stiffness.

17 . The method of claim 14 , wherein said HFpEF comprises diabetic HFpEF.

18 . The method of claim 14 , wherein the patient exhibits aortic valvular disease.

19 . The method of claim 9 , wherein the cardiovascular disease or related condition is HFrEF.

20 . The method of claim 9 , wherein the cardiovascular disease or related condition is HFmrEF.

21 . The method of claim 9 , wherein the cardiovascular disease or related condition is valve disease.

22 . The method of claim 9 , wherein the cardiovascular disease or related condition is cardiomyopathy.

23 . The method of claim 22 , wherein the cardiomyopathy is ischemic cardiomyopathy, toxic cardiomyopathy, restrictive cardiomyopathy, or dilated cardiomyopathy.

24 . The method of claim 23 , wherein the restrictive cardiomyopathy comprises Loefilers Endocarditis, Endomyocardial fibrosis (EMF), hemochromatosis, Fabry cardiomyopathy, glycogen storage disease, a pressure-overloaded right ventricle (RV), Tetralogy of Fallot, pulmonic stenosis, amyloidosis, sarcoidosis, heart conditions related to chest radiation therapy, heart conditions related to mutations in the gene encoding Troponin I (beta myosin HC) mutations, heart conditions related to mutations in a gene encoding Troponin T (alpha cardiac actin), or heart conditions related to mutations in a desmin gene.

25 . The method of claim 1 , wherein the cardiovascular disease or related condition is hypertrophic cardiomyopathy.

26 . The method of claim 1 , wherein the cardiovascular disease or related condition is obstructive hypertrophic cardiomyopathy.

27 . The method of claim 1 , wherein the cardiovascular disease or related condition is non-obstructive hypertrophic cardiomyopathy.

28 . The method of claim 1 , wherein the cardiovascular disease or the related condition comprises heart attack, heart infection, endocarditis, myocarditis, pericarditis, abnormal heart rhythms, aorta disease, Marfan syndrome, congenital heart disease, coronary artery disease, rhematic heart disease, peripheral vascular disease, heart valve disease, pericardial disease, deep vein thrombosis, or pulmonary embolism.

29 . The method of claim 1 , wherein the cardiovascular disease comprises heart failure.

30 . The method of claim 1 , wherein the cardiovascular disease comprises a hypertrophy.

31 . The method of claim 1 , wherein the cardiovascular disease comprises left ventricular stiffness.

32 . The method of claim 1 , further comprising administering an additional active agent.

33 . A method of modulating myosin, the method comprising administering to a subject in need thereof a compound of Formula (III):

or a salt thereof, wherein:

X 1 , X 2 , X 3 , and X 4 are each independently selected from C(R) and N, wherein no more than two of X 1 , X 2 , X 3 , and X 4 are N;

each R is independently selected from:

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28 , —SR 28 , —N(R 28 ) 2 , —C(O)R 28 , —C(O)N(R 28 ) 2 , —N(R 28 )C(O)R 28 , —C(O)OR 28 , —OC(O)R 28 , —N(R 28 )C(O)N(R 28 ) 2 , —OC(O)N(R 28 ) 2 , —N(R 28 )C(O)OR 28 , —S(O)R 28 , —S(O) 2 R 28 , —NO 2 , ═O, ═S, ═N(R 28 ), —CN, C 3-10 carbocycle and 3- to 10-membered heterocycle, wherein the C 3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from R 27 ; and

C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28 , —SR 28 , —N(R 28 ) 2 , —C(O)R 28 , —C(O)N(R 28 ) 2 , —N(R 28 )C(O)R 28 , —N(R 28 )C(O)N(R 28 ) 2 , —OC(O)N(R 28 ) 2 , —N(R 28 )C(O)OR 28 , —C(O)OR 28 , —OC(O)R 28 , —S(O)R 28 , —S(O) 2 R 28 , —NO 2 , ═O, ═S, ═N(R 28 ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with one or more substituents independently selected from R 27 ;

R 21 is selected from:

hydrogen;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28a , —SR 28a , —N(R 28a ) 2 , —C(O)R 28a , —C(O)N(R 28a ) 2 , —N(R 28a )C(O)R 28a , —C(O)OR 28a , —OC(O)R 28a , —N(R 28a )C(O)N(R 28a ) 2 , —OC(O)N(R 28a ) 2 , —N(R 28a )C(O)OR 28a , —S(O)R 28a , —S(O) 2 R 28a , —NO 2 , ═O, ═S, ═N(R 28a ), —CN, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein the C 3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from R 27a ; and

C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28a , —SR 28a , —N(R 28a ) 2 , —C(O)R 28a , —C(O)N(R 28a ) 2 , —N(R 28a )C(O)R 28a , —N(R 28a )C(O)N(R 28a ) 2 , —OC(O)N(R 28a ) 2 , —N(R 28a )C(O)OR 28a , —C(O)OR 28a , —OC(O)R 28a , —S(O)R 28a , —S(O) 2 R 28a , —NO 2 , ═O, ═S, ═N(R 28a ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with one or more substituents independently selected from R 27a ;

R 22 is selected from:

hydrogen;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28b , —SR 28b , —C(O)R 28b , —C(O)N(R 28b ) 2 , —N(R 28b )C(O)R 28b , —C(O)OR 28b , —OC(O)R 28b , —N(R 28b )C(O)N(R 28b ) 2 , —OC(O)N(R 28b ) 2 , —N(R 28b )C(O)OR 28b , —S(O)R 28b , —S(O) 2 R 28b , —NO 2 , ═O, ═S, ═N(R 28b ), —CN, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein the C 3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from R 27b ; and

C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28b , —SR 28b , —N(R 28b ) 2 , —C(O)R 28b , —C(O)N(R 28b ) 2 , —N(R 28b )C(O)R 28b , —N(R 28b )C(O)N(R 28b ) 2 , —OC(O)N(R 28b ) 2 , —N(R 28b )C(O)OR 28b , —C(O)OR 28b , —OC(O)R 28b , —S(O)R 28b , —S(O) 2 R 28b , —NO 2 , ═O, ═S, ═N(R 28b ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with one or more substituents independently selected from R 27b ; or

R 21 together with R 22 form a C 3-10 carbocycle or 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28a , —SR 28a , —N(R 28a ) 2 , —C(O)R 28a , —C(O)N(R 28a ) 2 , —N(R 28a )C(O)R 28a , —N(R 28a )C(O)N(R 28a ) 2 , —OC(O)N(R 28a ) 2 , —N(R 28a )C(O)OR 28a , —C(O)OR 28a , —OC(O)R 28a , —S(O)R 28a , —S(O) 2 R 28a , —NO 2 , ═O, ═S, ═N(R 28a ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with one or more substituents independently selected from R 27b ;

R 23 is selected from:

hydrogen, halogen, —OR 28c , —SR 28c , —N(R 28c ) 2 , —NO 2 , and —CN; and

C 1-6 alkyl optionally substituted with one or more substituents independently selected from R 27c ; or

R 21 together with R 23 form a 3- to 10-membered heterocycle, which is optionally substituted with one or more substituents independently selected from halogen, —OR 28a , —SR 28a , —N(R 28a ) 2 , —C(O)R 28a , —C(O)N(R 28a ) 2 , —N(R 28a )C(O)R 28a , —N(R 28a )C(O)N(R 28a ) 2 , —OC(O)N(R 28a ) 2 , —N(R 28a )C(O)OR 28a , —C(O)OR 28a , —OC(O)R 28a , —S(O)R 28a , —S(O) 2 R 28a , —NO 2 , ═O, ═S, ═N(R 28a ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with one or more substituents independently selected from R 27c ; or

R 22 together with R 23 form a 3- to 10-membered heterocycle, optionally substituted with one or more substituents independently selected from halogen, —OR 28a , —SR 28a , —N(R 28a ) 2 , —C(O)R 28a , —C(O)N(R 28a ) 2 , —N(R 28a )C(O)R 28a , —N(R 28a )C(O)N(R 28a ) 2 , —OC(O)N(R 28a ) 2 , —N(R 28a )C(O)OR 28a , —C(O)OR 28a , —OC(O)R 28a , —S(O)R 28a , —S(O) 2 R 28a , —NO 2 , ═O, ═S, ═N(R 28a ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with one or more substituents independently selected from R 27c ; or

R 21 , R 22 , and R 23 together form a bicyclic heterocycle which is optionally substituted with one or more substituents independently selected from halogen, —OR 28a , —SR 28a , —N(R 28a ) 2 , —C(O)R 28a , —C(O)N(R 28a ) 2 , —N(R 28a )C(O)R 28a , —N(R 28a )C(O)N(R 28a ) 2 , —OC(O)N(R 28a ) 2 , —N(R 28a )C(O)OR 28a , —C(O)OR 28a , —OC(O)R 28a , —S(O)R 28a , —S(O) 2 R 28a , —NO 2 , ═O, ═S, ═N(R 28a ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with one or more substituents independently selected from R 27c ;

R 24 is selected from:

hydrogen, halogen, —OR 28d , —SR 28d , —N(R 28d ) 2 , —NO 2 , and —CN; and

C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 28d , —SR 28d , —N(R 28d ) 2 , —NO 2 , —CN, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein the C 3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from R 27d ;

R 24′ is selected from:

hydrogen, halogen, —OR 28d , —SR 28d , —N(R 28d ) 2 , —NO 2 , and —CN; and

C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 28d , —SR 28d , —N(R 28d ) 2 , —NO 2 , —CN, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein the C 3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from R 27d ;

or R 24 and R 24 ′ together form a C 3-10 carbocycle or 3- to 10-membered heterocycle, wherein the C 3-10 carbocycle or 3- to 10-membered heterocycle, is optionally substituted with one or more substituents independently selected from R 27d ;

R 25 is selected from:

hydrogen, halogen, —OR 28e , —SR 28e , —N(R 28e ) 2 , —NO 2 , —CN, C 1-6 alkyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein the C 1-6 alkyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from R 27e ;

R 26 is selected from:

hydrogen, halogen, —OR 28f , —SR 28f , —N(R 28f ) 2 , —NO 2 , —CN; and

C 1-6 alkyl optionally substituted with one or more substituents independently selected from R 27f ;

each R 27 , R 27a , R 27b , R 27c , R 27d , R 27e , and R 27f is independently selected from:

each R 28 , R 28a , R 28b , R 28c , R 28d , R 28e , R 28f , and R 28g is independently selected from:

hydrogen and halogen;

provided the compound of Formula (III) is not

34 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (III):

or a salt thereof, wherein:

X 1 , X 2 , X 3 , and X 4 are each independently selected from C(R) and N, wherein no more than two of X 1 , X 2 , X 3 , and X 4 are N;

each R is independently selected from:

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28 , —SR 28 , —N(R 28 ) 2 , —C(O)R 28 , —C(O)N(R 28 ) 2 , —N(R 28 )C(O)R 28 , —C(O)OR 28 , —OC(O)R 28 , —N(R 28 )C(O)N(R 28 ) 2 , —OC(O)N(R 28 ) 2 , —N(R 28 )C(O)OR 28 , —S(O)R 28 , —S(O) 2 R 28 , —NO 2 , ═O, ═S, ═N(R 28 ), —CN, C 3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C 3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 27 ; and

R 21 is selected from:

hydrogen;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 28a , —SR 28a , —N(R 28a ) 2 , —C(O)R 28a , —C(O)N(R 28a ) 2 , —N(R 28a )C(O)R 28a , —C(O)OR 28a , —OC(O)R 28a , —N(R 28a )C(O)N(R 28a ) 2 , —OC(O)N(R 28a ) 2 , —N(R 28a )C(O)OR 28a , —S(O)R 28a , —S(O) 2 R 28a , —NO 2 , ═O, ═S, ═N(R 28a ), —CN, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein the C 3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from R 27a ; and

R 22 is selected from:

hydrogen;

R 23 is selected from:

hydrogen, halogen, —OR 28c , —SR 28c , —N(R 28c ) 2 , —NO 2 , and —CN; and

C 1-6 alkyl optionally substituted with one or more substituents independently selected from R 27c ; or

R 24 is selected from:

hydrogen, halogen, —OR 28d , —SR 28d , —N(R 28d ) 2 , —NO 2 , and —CN; and

R 24′ is selected from:

hydrogen, halogen, —OR 28d , —SR 28d , —N(R 28d ) 2 , —NO 2 , and —CN; and

R 24 and R 24 ′ together form a C 3-10 carbocycle, or 3- to 10-membered heterocycle, wherein the C 3-10 carbocycle, or 3- to 10-membered heterocycle, is optionally substituted with one or more substituents independently selected from R 27d ;

R 25 is selected from:

R 26 is selected from:

hydrogen, halogen, —OR 28f , —SR 28f , —N(R 28f ) 2 , —NO 2 , and —CN; and

C 1-6 alkyl optionally substituted with one or more substituents independently selected from R 27f ;

each R 27 , R 27a , R 27b , R 27c , R 27d , R 27e , and R 27f is independently selected from:

each R 28 , R 28a , R 28b , R 28c , R 28d , R 28e , R 28f , and R 28g is independently selected from:

hydrogen and halogen;

provided the compound of Formula (III) is not

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 13, 2025

From: HAWRYLUK, NATALIE ANNE; SCHLACHTER, STEPHEN THOMAS; KOCH, KEVIN; LUZZIO, MICHAEL JOSEPH; RUSSELL, ALAN JAMES; EVANCHIK, MARC JUSTIN; DEL RIO, CARLOS LUIS; HUNT, KEVIN

To: EDGEWISE THERAPEUTICS, INC.

Reel/Frame 072546/0699 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 30, 2025

From: WOOD, TREVOR HOWARD; MALLINA, RAMAKRISHNA VENKATA; JOTHIPRASAD, GIRIDHAR; RAMAKRISHNAN, KISHORE; MALKUS, THOMAS

To: GENERAL ELECTRIC COMPANY

Reel/Frame 072414/0615 →