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JP-2026514388-A - Quinolinone amide compounds and their uses

JP2026514388AJP 2026514388 AJP2026514388 AJP 2026514388AJP-2026514388-A

Abstract

This disclosure generally relates to substituted quinolinone amide compounds or salts of formula (I), (II-A), (IV), or (III), and their pharmaceutically acceptable compositions. The substituted quinolinone amide compounds or salts of formula (I), (II-A), (IV), or (III) disclosed herein may be used to treat or prevent heart disease in individuals where such treatment is necessary. Diseases treated by the methods described herein include, but are not limited to, heart disease. Cardiac diseases treated by the methods described herein include, but are not limited to, myocardial disease (cardiomyopathy), hypertrophic cardiomyopathy (HCM), abnormal heart rhythms, aortic disease, Marfan syndrome, coronary artery disease, heart attack, heart failure, rheumatic heart disease, peripheral vascular disease, stroke, deep vein thrombosis, and pulmonary embolism.

Inventors

  • ホウリラク， ナタリー アン
  • シュラクター， スティーブン トーマス
  • コック， ケビン
  • ルジオ， マイケル ジョゼフ
  • ラッセル， アラン ジェイムズ
  • エバンチク， マーク ジャスティン
  • デル リオ， カルロス ルイス
  • ハント， ケビン

Assignees

  • エッジワイズ セラピューティクス， インコーポレイテッド

Dates

Publication Date
20260511
Application Date
20240326
Priority Date
20230327

Claims (20)

  1. Equation (I): A compound or salt thereof represented by formula (I): X1 , X2 , and X3 are independently selected from C(R) and N, where at least one of X1 , X2 , and X3 is N, and two or fewer of X1 , X2 , and X3 are N; X 4 is selected from C(R); Each R is independent: Hydrogen, halogen, -NO₂ , -CN, -N₃ , -OR₂ , -SR₂ , -N( R₂ ) ₂ , -C(O) R₂ , -C(O)N( R₂ ) ₂ , -N( R₂ )C(O) R₂ , -N( R₂ )C(O)N( R₂ ) ₂ , -OC(O)N( R₂ ) ₂ , -N( R₂ )C(O) OR₂ , -C(O) OR₂ , -OC(O) R₂ , -S(O) R₂ , and -S(O) ₂R₂ ; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is a halogen, -OR8 , -SR8, -N(R8)2, -C(O) R8 , -C(O)N( R8 ) 2 , -N( R8 )C( O ) R8 , -C(O) OR8, -OC(O)R8 , -N ( R8 )C(O)N( R8 ) 2 , -OC(O)N( R8 ) 2 , -N( R8 )C ( O) OR8 , -S(O) R8 , -S(O) 2R8 , -NO2 , = O , =S, =N( R8 ), -CN,C 3-10 carbon rings and 3-10 membered heterocycles are optionally substituted with one or more substituents independently selected from each of the C3-10 carbon rings and 3-10 membered heterocycles, each optionally substituted with one or more substituents independently selected from R7 ; and C3-10 carbon rings and 3-10 membered heterocycles, each of which is a halogen, -OR8, -SR8, -N(R8)2, -C(O )R8 , -C(O)N( R8 ) 2 , -N(R8)C(O) R8 , -N( R8 ) C(O)N( R8 ) 2 , -OC(O)N( R8 ) 2 , -N ( R8 )C( O ) OR8 , -C ( O) OR8 , -OC(O) R8 , -S(O) R8 , -S(O) 2R8 , -NO2 , =O-, =S, =N( R8 ), -CN, optionally substituted with one or more substituents independently selected from C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, where C1-6 alkyl , C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or more substituents independently selected from R7 ; R 1 is: hydrogen; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is a halogen, -OR 8a , -SR 8a , -N(R 8a )2, -C(O)R 8a , -C(O)N(R 8a ) 2 , -N(R 8a ) C (O)R 8a , -C(O)OR 8a , -OC(O)R 8a , -N(R 8a )C(O)N(R 8a ) 2 , -OC(O)N(R 8a ) 2 , -N(R 8a )C(O)OR 8a , -S(O)R 8a , -S(O) 2R 8a , -NO2 , =O, =S, =N(R 8a) ), -CN, C3-10 carbon rings, and 3- to 10 -membered heterocycles, each of which is optionally substituted with one or more substituents independently selected from R7a; and C3-10 carbon rings and 3- to 10-membered heterocycles, each of which is optionally substituted with one or more substituents independently selected from R7a ; and C3-10 carbon rings and 3- to 10-membered heterocycles, each of which is halogen, -OR8a , -SR8a, -N(R8a)2, -C(O) R8a , -C(O)N( R8a ) 2 , -N(R8a)C(O) R8a , -N( R8a ) C (O)N (R8a ) 2 , -OC (O)N( R8a ) 2 , -N ( R8a )C(O)OR 8a , -C(O)OR 8a , -OC(O)R 8a , -S(O)R 8a , -S(O) 2R 8a , -NO2 , =O-, =S, =N(R 8a ), -CN, optionally substituted with one or more substituents independently selected from C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, where C1-6 alkyl, C2-6 alkenyl , and C2-6 alkynyl are each optionally substituted with one or more substituents independently selected from R 7a ; or R 1 together with R 2 to form a C3-10 carbon ring, or a 3- to 10-membered heterocycle, each of which is a halogen, -OR 8a , -SR 8a , -N(R 8a ) 2 , -C(O)R 8a , -C(O)N(R 8a ) 2 , -N(R 8a )C(O)R 8a , -N(R 8a )C(O)N(R 8a ) 2 , -OC(O)N(R 8a ) 2 , -N( R 8a)C(O)OR 8a , -C (O)OR 8a , -OC(O)R 8a , -S(O) R 8a , -S(O) 2R 8a, -NO 2 , =O-, =S, =N(R 8a ), -CN, optionally substituted with one or more substituents independently selected from C1-6 alkyl, C2-6 alkenyl , and C2-6 alkynyl, where C1-6 alkyl, C Each of the 2-6 alkenyls and C2-6 alkynyls is optionally substituted with one or more substituents independently selected from R7b ; R 2 is: hydrogen; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is a halogen, -OR 8b , -SR 8b , -N(R 8b ) 2 , -C(O)R 8b , -C(O)N(R 8b) 2 , -N(R 8b )C(O)R 8b , -C(O)OR 8b , -OC (O)R 8b , -N(R 8b )C(O)N(R 8b ) 2 , -OC(O)N(R 8b ) 2 , -N(R 8b )C(O)OR 8b , -S(O)R 8b , -S(O) 2R 8b , -NO2 , =O, =S, =N(R 8b ), -CN, C3-10 carbon rings, and 3- to 10- membered heterocycles, each optionally substituted with one or more substituents independently selected from R7b ; and C3-10 carbon rings and 3- to 10-membered heterocycles, each optionally substituted with one or more substituents independently selected from R7b; and C3-10 carbon rings and 3- to 10-membered heterocycles, each of which is halogen, -OR8b, -SR8b , -N(R8b)2, -C(O) R8b , -C(O)N( R8b ) 2 , -N(R8b)C(O) R8b , -N( R8b ) C (O)N (R8b ) 2 , -OC (O)N( R8b ) 2 , -N ( R8b )C(O)OR 8b , -C(O)OR 8b , -OC(O)R 8b , -S(O)R 8b , -S(O) 2R 8b , -NO2 , =O-, =S, =N(R 8b ), -CN, -N3 , optionally substituted with one or more substituents independently selected from C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, where C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or more substituents independently selected from R 7b ; or R1 together with R2 to form a C3-10 carbon ring or a 3- to 10-membered heterocycle, each of which is a halogen, -OR 8a , -SR 8a , -N(R 8a ) 2 , -C(O)R 8a , -C(O)N(R 8a ) 2 , -N(R 8a )C(O)R 8a , -N(R 8a )C(O)N(R 8a ) 2 , -OC(O)N(R 8a ) 2 , -N( R 8a ) C(O)OR 8a , -C(O)OR 8a , -OC(O)R 8a , -S( O )R 8a , -S(O) 2R 8a , -NO 2 , =O-, = S, =N(R 8a ), -CN, optionally substituted with one or more substituents independently selected from C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, where C1-6 alkyl, C Each of the 2-6 alkenyls and C2-6 alkynyls is optionally substituted with one or more substituents independently selected from R7b ; R 3 is: Selected from C1-6 alkyl groups, which are optionally substituted with one or more substituents independently selected from hydrogen, halogens, -OR8c , -SR8c , -N( R8c ) 2 , -NO2 , and -CN; and R7c; R 4 is: Hydrogen, halogens, -OR 8d , -SR 8d , -N(R 8d ) 2 , -NO2 , and -CN; and C1-6 alkyl groups optionally substituted with one or more substituents independently selected from halogens, -OR 8d , -SR 8d , -N(R 8d ) 2 , -NO2 , and -CN, C3-10 carbon rings, and 3- to 10-membered heterocycles, where each C3-10 carbon ring and 3- to 10 -membered heterocycle is optionally substituted with one or more substituents independently selected from R 7d ; R 4 ' is: Hydrogen, halogens, -OR 8d , -SR 8d , -N(R 8d ) 2 , -NO2 , and -CN; and C1-6 alkyl groups optionally substituted with one or more substituents independently selected from halogens, -OR 8d , -SR 8d , -N(R 8d ) 2 , -NO2 , and -CN, C3-10 carbon rings, and 3- to 10-membered heterocycles, where each C3-10 carbon ring and 3- to 10 -membered heterocycle is optionally substituted with one or more substituents independently selected from R 7d ; Alternatively, R 4 and R 4 ' combine to form a C3-10 carbon ring or a 3-10 membered heterocycle, where the C3-10 carbon ring or 3-10 membered heterocycle is optionally substituted with one or more substituents independently selected from R 7d ; R 5 is: Hydrogen, halogens, -OR 8e , -SR 8e , -N(R 8e ) 2 , -NO 2 , -CN, C1-6 alkyl, C3-10 carbon rings, and 3- to 10-membered heterocycles, where each C1-6 alkyl, C3-10 carbon ring, and 3- to 10-membered heterocycle is selected from those each optionally substituted with one or more substituents independently selected from R 7e ; R 6 is: Selected from C1-6 alkyl groups, optionally substituted with one or more substituents independently selected from hydrogen, halogens, -OR 8f , -SR 8f , -N(R 8f ) 2 , -NO2 , and -CN; as well as R 7f ; Each of R7 , R7a , R7b , R7c , R7d , R7e , and R7f is independent of: Halogens, -OR 8g , -SR 8g , -N(R 8g ) ² , -C(O)R 8g , -C(O)N(R 8g ) ² , -N(R 8g )C(O)R 8g , -N(R 8g )C(O)N(R 8g ) ² , -OC(O)N(R 8g ) ² , -N(R 8g )C(O)OR 8g , -C(O)OR 8g , -OC(O)R 8g , -S(O)R 8g , -S(O) ²R 8g , -NO² , =O, =S, =N(R 8g ), and -CN; as well as C1-3 alkyl, C2-3 alkenyl, and C 2-3 alkynyls, each of which is a halogen, -OR 8g , -SR 8g , -N(R 8g ) 2 , -C(O)R 8g , -C(O)N(R 8g ) 2 , -N(R 8g )C(O)R 8g , -N(R 8g )C(O)N(R 8g ) 2 , -OC(O)N(R 8g ) 2 , -N(R 8g )C(O)OR 8g , -C(O)OR 8g , -OC(O)R 8g , -S(O)R 8g , -S(O) 2R 8g , -NO 2 , =O, =S, =N(R 8g) ), and selected from those which are optionally substituted with one or more substituents independently selected from -CN; Each of R8 , R8a , R8b , R8c , R8d , R8e , R8f , and R8g is independent of: Hydrogen and halogens; as well as C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 carbon rings, each of which is optionally substituted with one or more substituents independently selected from halogens, -CN , -OH, -SH, -NO₂, -NH₂, = O , =S, -O- C1-6 alkyl, -S- C1-6 alkyl, -N( C1-6 alkyl) ₂ , -NH( C1-6 alkyl), C3-10 carbon rings, and 3- to 10 -membered heterocycles; as well as C3-10 carbon rings and 3- to 10-membered heterocycles, each of which is halogen, -CN, -OH, -SH, -NO₂ , -NH₂ , =O, =S, -O- C1-6 alkyl, -S- C1-6 alkyl, -SO₂ -C Compounds or salts thereof selected from those independently substituted with one or more substituents selected from 1-6 alkyl, -N( C1-6 alkyl) 2 , -NH( C1-6 alkyl), C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbon rings, 3- to 10-membered heterocycles, and C1-6 haloalkyl, as required.
  2. The compound or salt according to claim 1, wherein X1 is N.
  3. The compound or salt according to claim 1, wherein X1 is C(R).
  4. A compound or salt according to any one of claims 1 to 3, wherein X2 is N.
  5. A compound or salt according to any one of claims 1 to 3, wherein X2 is C(R).
  6. Each R independently: Hydrogen, halogen, -CN, -N3 , -OR8 , -SR8 , -N( R8 ) 2 ; C1-6 alkyl and C2-6 alkynyl compounds, each of which is optionally substituted with one or more substituents independently selected from halogens; and compounds or salts according to any one of claims 1-5, selected from C3-10 carbon rings and 3- to 10-membered heterocycles.
  7. Each R independently: hydrogen, -F, -Cl, -Br, -I, -CN, -N3 , -OH, -OMe, -OEt, -O(n-Pr), -O(iPr), -O(i-Bu), A compound or salt according to any one of claims 1 to 5, selected from -CF3 , -methyl, -ethyl, cyclopropyl, -CH2N ( CH3 ) 2 , -CCMe, -CCH, phenyl, N-morpholinyl, and N-pyrrolidinyl.
  8. The compound or salt according to any one of claims 1 to 7, wherein each R 8 is independently selected from hydrogen, methyl , ethyl, propyl, isopropyl, cyclopropyl, isobutyl , -CF3 , -CH2CF3 , -CH2CHF2 , -CH2C (F)(Me) 2 , and -CH2 -phenyl.
  9. R1 is hydrogen, methyl, -CH2OH , -CH2CH2OH , C(Me) 2OH , -CH2OMe , or R1 together with R2 to form a C3-10 carbon ring or a 3-10 membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from -F, -COMe, -CN, and methyl. The compound or salt according to any one of claims 1 to 8.
  10. The compound or salt according to any one of claims 1 to 9, wherein R1 is methyl, -CH₂OH , -CH₂CH₂OH , C(Me) ₂OH , or -CH₂OMe .
  11. A compound or salt according to any one of claims 1 to 10, wherein R1 is methyl.
  12. R 2 : A selection of C3-10 carbon rings and 3- to 10-membered heterocycles, each of which is optionally substituted with one or more substituents independently selected from halogens, -OR 8b , -C(O)R 8b , -S(O) 2R 8b , -CN, and C1-6 alkyl groups, where the C1-6 alkyl groups are optionally substituted with one or more R 7b groups ; or R 1 together with R 2 to form a C3-10 carbon ring or a 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogens, -C(O)R 8a , -CN, N 3 , and C1-6 alkyl groups, where the C1-6 alkyl groups are optionally substituted with one or more R 7b groups . The compound or salt according to any one of claims 1 to 11.
  13. The compound or salt according to any one of claims 1 to 12, wherein R2 is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, each of which is optionally substituted with one or more substituents independently selected from -F, -OH, -OMe, -COMe, -SO2Me , -CN, and methyl.
  14. R2 is, A compound or salt according to any one of claims 1 to 12, selected from the above.
  15. R1 and R2 come together, A compound or salt according to any one of claims 1 to 8 or 12, comprising a C3-10 carbon ring or a 3-10 membered heterocycle selected from the above.
  16. but: A compound or salt according to any one of claims 1 to 8, selected from the above.
  17. A compound or salt according to any one of claims 1 to 16, wherein R3 is hydrogen.
  18. R 4 is independent: Hydrogen, halogen, -OR 8d , and -CN; and C1-6 alkyl groups optionally substituted with one or more substituents independently selected from halogen, -OR 8d , and -CN, C3-10 carbon rings, and 3- to 10 -membered heterocycles, where the C3- to 10 carbon rings and 3- to 10-membered heterocycles are selected from those each optionally substituted with one or more R 7d ; and R 4 ' is: A compound or salt according to any one of claims 1 to 17, wherein hydrogen, halogens, -OR 8d , and -CN; and a C1-6 alkyl group optionally substituted with one or more substituents independently selected from halogens, -OR 8d , and -CN, C3-10 carbon rings, and 3- to 10-membered heterocycles, wherein the C3-10 carbon rings and 3- to 10-membered heterocycles are each optionally substituted with one or more R 7d .
  19. The compound or salt according to any one of claims 1 to 18, wherein each R4 is selected from hydrogen and R4 ' is selected from hydrogen.
  20. A compound or salt according to any one of claims 1 to 18, wherein R4 is -F and R4 ' is -F.

Description

Cross-reference This application claims the benefit of U.S. Provisional Patent Application No. 63/492,441, filed on 27 March 2023, which is incorporated herein by reference in its entirety. Background of the Invention More than 80 million people suffer from one or more forms of heart disease, which is a leading cause of death in the population, with nearly 18 million deaths each year. The onset of heart disease can be due to either genetic characteristics or lifestyle. The cardiomyocyte is involuntary striated muscle that has electrical impulses in the form of cardiac action potentials. Cardiac action potentials induce the release of calcium from the sarcoplasmic reticulum. Cardiomyopathy is a disease of the cardiomyocyte that can result in symptoms including but not limited to heart failure, irregular heartbeat, short respiration, fatigue, and weakness, and those affected are at increased risk of sudden cardiac death. Many medical treatments for heart disease are limited to treating symptoms rather than addressing the underlying causes. Furthermore, some treatments become less effective as the duration of the disease increases. Therefore, there remains a need to develop novel compounds for improved treatment of heart disease. Hypertrophic cardiomyopathy (HCM) is a chronic, progressive disease of the cardiac sarcomere. The etiology of HCM is multifactorial; a significant proportion of affected individuals have at least one mutation in a gene encoding cardiac sarcomeric proteins. Regardless of the cause of HCM, in many cases, excessive myosin-actin cross-bridge formation during systole and diastole leads to hyperkinetic contraction and relaxation disorders. Over time, this excessive stress leads to tissue remodeling, histologically characterized by myocyte hypertrophy, myofilamentous disorder, microvascular remodeling, and fibrosis. HCM can be hereditary (e.g., genetic) or non-hereditary. HCM includes hyperosmotic, monogenic, autosomal dominant cardiomyopathy. Such HCM can be caused by one or more of the more than 1,000 known point mutations in any one of the proteins contributing to the sarcomere, the functional unit of the cardiomyocyte. It is known that approximately 1 in 500 individuals in the general population have left ventricular hypertrophy that cannot be explained by other known causes (e.g., hypertension or valvular heart disease). For example, once other hereditary causes (e.g., lysosomal storage disorders), metabolic, or invasive causes are ruled out, many of these individuals may be found to have HCM. Pharmacological treatments for HCM are limited, and the symptoms of many patients are empirically managed with beta-blockers, non-dihydropyridine calcium channel blockers, and/or disopyramides. None of these agents are labeled for the treatment of HCM, and essentially, rigorous clinical trial evidence to guide their use is unavailable. In approximately 60% of patients with HCM, left ventricular outflow tract obstruction impairs blood flow and creates a pressure gradient between the LV lumen and the aorta. Surgical myocardial resection or alcohol septal ablation may be used to alleviate hemodynamic obstruction in patients with hemodynamically significant outflow tract obstruction (gradient > 50 mmHg), although clinical morbidity and mortality are significant. Novel therapeutic agents and methods addressing the long-standing need for improved treatment of HCM and related cardiac disorders are provided herein. Detailed Description of the Invention Preferred embodiments of the present invention are shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided only as examples. Many variations, modifications, and substitutions can now be conceived by those skilled in the art without departing from the present invention. It should be understood that various modifications to the embodiments of the present invention described herein may be used in carrying out the present invention. The following claims define the scope of the present invention, and methods and structures within the scope of these claims, as well as their equivalents, are intended to be covered by the claims. In a specific context, this disclosure provides a method for treating cardiac disease in an individual requiring treatment of cardiac disease, the method comprising the step of administering an effective amount of a compound of formula (I), (II-A), (IV), or (III). Diseases treated by the methods described herein include, but are not limited to, cardiomyopathy, hypertrophic cardiomyopathy (HCM), abnormal heart rhythms, aortic disease, Marfan syndrome, coronary artery disease, heart attack, heart failure, rheumatic heart disease, peripheral vascular disease, stroke, deep vein thrombosis, and pulmonary embolism. Cardiomyopathy is a heart disease in which the heart may become abnormally enlarged, thickened, and/or stiffened, and may have few or no symptoms in its early stages. As the d