Triazinedione derivatives, methods for preparing the same, and their pharmaceutical applications

Abstract

This invention provides triazinedione derivatives, methods for preparing them, and their pharmaceutical applications. [Solution] The present invention provides a triazinedione derivative represented by general formula (I), a method for preparing the same, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, in particular its use in the preparation of myosin inhibitors and in the preparation of agents for treating hypertrophic cardiomyopathy (HCM) or heart disease having HCM-related pathophysiological characteristics. JPEG2026097848000157.jpg44147 [In the formula, rings A, R 1 , R 2 , R 3a , R 3b , and R 0 [where represents a specific substituent, and m represents 0, 1, 2, 3, or 4]

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 Eventually, Ring A is selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R １ is a halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, C(O)R ６ , C(O)OR ７ , S(O) ｔ R ８ , S(O) ｔ NR ９ R １０ , C(O)NR ９ R １０ , NR ９ R １０ and 【Chemistry 2】 Selected from, Each R ２ These are homologous or different, and each is independently a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, C(O)R ６ , C(O)OR ７ , S(O) ｔ R ８ , S(O) ｔ NR ９ R １０ C(O)NR ９ R １０ and NR ９ R １０ Selected from, Or, R １ and one adjacent R ２ , or two adjacent R ２ It condenses with ring A to form a cycloalkyl group or heterocyclyl group, and the cycloalkyl group or heterocyclyl group is optionally substituted with one or more substituents selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, and hydroxyl groups. L ２ is a covalent bond, (CH ２ ) ｒ , C(O), NR ａ , selected from oxygen atoms and sulfur atoms, R ａ This is selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. Ring C is selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. Each R ５ These are homologous or different and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R ３ａ The alkyl group is selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, of which the alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are each independently and optionally substituted with one or more substituents selected from halogens, alkoxy groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, and hydroxy groups. R ３ｂ It is a hydrogen atom, R ０ is an alkyl group or 【Transformation 3】 The alkyl group is optionally substituted with one or more substituents selected from halogens, alkoxy groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, and hydroxyl groups. L １ is a covalent bond or (CH ２ ) ｒ And, Ring B is selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. Each R ４ These are homologous or different, and each is independently a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, oxo, cyano group, nitro group, hydroxy group, hydroxyalkyl group, C(O)R ６ , C(O)OR ７ , S(O) ｔ R ８ , S(O) ｔ NR ９ R １０ C(O)NR ９ R １０ , cycloalkyl group, -(CH ２ ) ｒ -Cycloalkyl group, heterocyclyl group, -(CH ２ ) ｒ - Heterocyclyl group, aryl group, - (CH ２ ) ｒ -aryl group, heteroaryl group and -(CH ２ ) ｒ - Selected from heteroaryl groups, R ６ Each of these groups is homologous or different in appearance, and each is independently selected from a hydrogen atom, alkyl group, haloalkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group, of which the alkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are independently and optionally substituted with one or more substituents selected from halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, and hydroxyalkyl group. R ７ Each occurrence is homologous or different, and each is independently selected from a hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group. R ８ Each occurrence is homologous or different, and each is independently selected from a hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, hydroxyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group. R ９ and R １０ Each instance is homologous or different, and each is independently a hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, -(CH ２ ) ｒ -Cycloalkyl group, heterocyclyl group, -(CH ２ ) ｒ - Heterocyclyl group, aryl group, - (CH ２ ) ｒ -aryl group, heteroaryl group and -(CH ２ ) ｒ - Selected from heteroaryl groups, or R ９ and R １０ The carbon atom forms a heterocyclyl group with the linked nitrogen atom, and the heterocyclyl group is optionally substituted with one or more substituents selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups. p is 0, 1, 2, 3, 4, 5, or 6. r is 0, 1, 2, 3, 4, 5, or 6. m is 0, 1, 2, 3, or 4. s is 0, 1, 2, 3, 4, 5 or 6, and t is 0, 1, or 2. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.

2. A compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, 【Chemistry 4】 Eventually, Ring A, R ０ , R １ , R ２ , R ３ａ , R ３ｂ and m are as defined in claim 1, A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

3. The compound represented by general formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from a 3- to 8-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, and preferably ring A is a phenyl group.

4. A compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, 【Transformation 5】 Eventually, R ０ , R １ , R ２ , R ３ａ , R ３ｂ and m are as defined in claim 1, A compound represented by general formula (I) as described in claim 1 or 3, or a pharmaceutically acceptable salt thereof.

5. A compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, 【Transformation 6】 Eventually, R ０ , R １ , R ２ , R ３ａ , R ３ｂ and m are as defined in claim 1, A compound represented by general formula (I) as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. R ０ is selected from a C １－６ alkyl group, a 3- to 8-membered cycloalkyl group, and a 3- to 12-membered heterocyclyl group, and preferably, R ０ is selected from a C １－６ alkyl group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclyl group, and more preferably, R ０ is selected from an isopropyl group, a tetrahydropyranyl group, and a cyclohexyl group, and still more preferably, R ０ is an isopropyl group or a tetrahydropyranyl group, and most preferably, R ０ is a tetrahydropyranyl group, the compound represented by the general formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

7. R １ is a halogen, C １－６ alkyl group, C １－６ alkoxy group, C １－６ haloalkyl group, C １－６ haloalkoxy group and 【Transformation 7】 Selected from, L ２ The R is a covalent bond or an oxygen atom, and the ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, and each R ５ These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. １－６ alkyl group, C １－６ Alkoxy group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group and C １－６ Selected from hydroxyalkyl groups, p is 0, 1, 2, 3, 4, 5 or 6, R ２ is a hydrogen atom, halogen, C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Haloalkyl and C １－６ Selected from haloalkoxy groups, or R １ and one adjacent R ２ , or two adjacent R ２ A compound represented by general formula (I) according to any one of claims 1 to 3, 6, or a pharmaceutically acceptable salt thereof, wherein the compound condenses with ring A to form a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclyl group.

8. R １ C １－６ alkyl group, C １－６ Haloalkoxy group and 【Transformation 8】 Selected from, L ２ The C is a covalent bond or an oxygen atom, and the ring C is selected from a cyclopropyl group, a tetrahydrofuranyl group, and a pyridyl group, and each R ５ These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. １－６ Selected from alkyl groups, p is 0, 1, or 2, and each R ２ are homologous or different, and each is independently a hydrogen atom or a halogen, or R １ and one adjacent R ２ A compound represented by general formula (I) according to any one of claims 1 to 3, 6 to 7, or a pharmaceutically acceptable salt thereof, wherein the compound condenses with ring A to form a cyclobutyl group, a tetrahydrofuranyl group, a cyclopentyl group, and a cyclohexyl group.

9. R ３ａ is halogen, C １－６ alkyl group, C １－６ Alkoxy group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group and C １－６ Selected from hydroxyalkyl groups, preferably R ３ａ C １－６ It is an alkyl group, more preferably R ３ａ The compound represented by general formula (I) as described in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein is a methyl group. 【Request Item 10】 【Chemistry 9】 A compound represented by general formula (I) according to any one of claims 1 to 9, which is any one compound selected from the above, or a pharmaceutically acceptable salt thereof.

11. A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 10】 This method involves a nucleophilic substitution reaction between a compound represented by general formula (IA) or a salt thereof (preferably a hydrochloride salt) and a compound represented by general formula (V) to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. Eventually, R ｗ is a leaving group, preferably a pyrazolyl group, Ring A, R ０ , R １ , R ２ , R ３ａ , R ３ｂ and m are as defined in claim 1, A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound represented by general formula (I) as described in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable vectors, diluents, or excipients.

13. Use of a compound represented by general formula (I) as described in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 12, in the preparation of a myosin inhibitor.

14. Use of a compound represented by general formula (I) as described in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 12, in the preparation of a drug for treating a disease or condition, wherein the disease or condition is preserved ejection fraction diastolic heart failure, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), moderate ejection fraction heart failure (HFmREF), valvular heart disease, aortic stenosis, inflammatory cardiomyopathy, etc. Use of a drug selected from Frel's endocarditis, cardiomyopathy and endocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry disease, glycogen storage disease, congenital heart disease, Tetralogy of Fallot, left ventricular hypertrophy, refractory angina, and Chagas disease, preferably selected from ischemic heart disease, restrictive cardiomyopathy, hypertrophic cardiomyopathy (HCM), inflammatory cardiomyopathy, infiltrative cardiomyopathy, congenital heart disease, and left ventricular hypertrophy, more preferably hypertrophic cardiomyopathy (HCM), and most preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

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