CN114516843B - Pyrimidine diketone derivative, preparation method and medical application thereof - Google Patents

Abstract

The present disclosure relates to pyrimidinedione derivatives, methods of preparing the same, and their use in medicine. In particular, the present disclosure relates to pyrimidinedione derivatives of general formula (I), methods for their preparation and pharmaceutical compositions containing them, and their use as therapeutic agents, particularly as Myosin (Myosin) inhibitors and as medicaments for the treatment of Hypertrophic Cardiomyopathy (HCM) or heart diseases with pathophysiological characteristics associated with HCM.

Description

Pyrimidine diketone derivative, preparation method and medical application thereof

Technical Field

The present disclosure belongs to the field of medicine, and relates to a pyrimidinedione derivative, a preparation method thereof and an application thereof in medicine. In particular, the present disclosure relates to pyrimidinedione derivatives of general formula (I), methods for their preparation and pharmaceutical compositions containing them, as well as their use as Myosin (Myosin) inhibitors and as medicaments for the treatment of Hypertrophic Cardiomyopathy (HCM) or heart diseases with pathophysiological features associated with HCM.

Background

Hypertrophic Cardiomyopathy (HCM) is a dominant inherited cardiomyopathy associated with gene mutations. Global morbidity is about 0.2% and is the most important cause of sudden death in young people under 35 years of age (c.vaughan Tuohy et al European Journal of Heart Failure,22,2020,228-240). Clinically, the characteristics are that the left ventricle wall is asymmetrically hypertrophic, is frequently invaded and is frequently separated, the inner cavity of the ventricle is reduced, the left ventricle blood filling is blocked, and the compliance of the ventricular diastole is reduced. The left ventricular outflow tract is classified into obstructive and non-obstructive hypertrophic cardiomyopathy according to the presence or absence of obstruction. Currently, beta-blockers and calcium channel blockers are mostly used clinically for treating hypertrophic cardiomyopathy to reduce heart contraction and relieve symptoms. However, these treatments are both palliative and not palliative. HCM progresses to advanced stages where only heart transplants can be performed (R ADHAKRISHNAN Ramaraj, cardiology in Review,16 (4), 2008, 172-180). Thus, it is urgent to find a therapeutic method for the root cause of HCM.

The existing study found that 70% of HCM patients are caused by the mutation of sarcomere protein gene. Wherein a plurality of site mutations are found in 5-7% of patients. More than about 70 pathogenic mutations have been identified, but most of these mutations are family specific and only a few hot spots have been identified, e.g., MYH 7R 403Q and R453C mutations (Norbert Frey,et al.,Nature Reviews Cardiology,9,2011,91-100;M.Sabater-Molina,et al.,Clinical Genetics,93,2018,3-14). have been studied for the probability of pathogenic gene mutation to find that MYH7 gene mutant patients account for about 30%. MYH7 causes early onset of disease and more severe myocardial hypertrophy compared to other sarcomere genes. Myosin is a constituent unit of myofibrillar crude muscle filaments and plays an important role in muscle movement. The molecular shape of the light chain is like bean sprout, and the light chain consists of two heavy chains and a plurality of light chains. The head of myosin is combined with actin to form transverse bridge, so that the ATPase activity of myosin is greatly raised, and the ATP hydrolysis reaction is catalyzed to produce energy to promote the transverse bridge to slide and to contract muscle. The research result shows that the MYH7 gene mutation can cause the increase of the ATPase activity of the myosin, the proportion of super-relaxed State (SRX) of the myosin is reduced, and the transverse bridge between the myosin and actin is increased, so that the abnormal (Eric M.Green,et al.,Science,351(6273),2016,617-621;Ruth F.Sommese,et al.,Proceedings of the National Academy Sciences,110(31),2013,12607-12612). of the heart contraction function is caused, and the myosin is an important target point for treating hypertrophic cardiomyopathy.

Patent applications for which myosin inhibitors have been disclosed include WO2014205223A1, WO2014205234A1, WO2019028360A1, WO2020092208A1, and CN110698415A, among others.

Disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by general formula (I):

Wherein:

Selected from the group consisting of

W ¹、W², X, Y and Z are the same or different and are each independently selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom, and only at most one of W ¹、W², X, Y and Z is selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; provided that W ¹ and X cannot be both carbon atoms;

U ¹、U²、U³ and U ⁴ are the same or different and are each independently a carbon atom or a nitrogen atom;

R ¹ is selected from the group consisting of a hydrogen atom halogen and alkyl;

Each R ² is the same or different and is each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl 、C(O)R⁶、C(O)OR⁷、S(O)_tR⁸、S(O)_tNR⁹R¹⁰、C(O)NR⁹R¹⁰、NR⁹R¹⁰, and

L ₂ is selected from the group consisting of a bond, (CH ₂)_r、C(O)、NR^a, an oxygen atom, and a sulfur atom;

R ^a is selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

Each R ⁵ is the same or different and is each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

Each R ³ is the same or different and is each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl;

r ⁰ is alkyl or Wherein the alkyl group is optionally substituted with one or more substituents selected from halogen, alkoxy, haloalkoxy, cyano, amino, nitro and hydroxy;

L ₁ is a bond or (CH ₂)_r;

ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

Each R ⁴ is the same or different and is each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, nitro, hydroxy, hydroxyalkyl 、C(O)R⁶、C(O)OR⁷、S(O)_tR⁸、S(O)_tNR⁹R¹⁰、C(O)NR⁹R¹⁰、 cycloalkyl, - (CH ₂)_r -cycloalkyl, heterocyclyl, - (CH ₂)_r -heterocyclyl, aryl, - (CH ₂)_r -aryl, heteroaryl, and- (CH ₂)_r -heteroaryl);

R ⁶ is selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl;

R ⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ⁹ and R ¹⁰ are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, - (CH ₂)_r -cycloalkyl, heterocyclyl, - (CH ₂)_r -heterocyclyl, aryl, - (CH ₂)_r -aryl, heteroaryl and- (CH ₂)_r -heteroaryl), or R ⁹ and R ¹⁰ together with the attached nitrogen atom form a heterocyclyl, said heterocyclyl optionally being substituted with one or more substituents selected from the group consisting of halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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;

n is 0,1, 2, 3, 4, 5 or 6;

s is 0,1,2, 3, 4,5 or 6; and

T is 0,1 or 2; provided that whenIs thatWhen R ⁰ is not methyl.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II):

Wherein:

Selected from the group consisting of

Provided that whenIs thatWhen R ⁰ is not methyl;

W ¹、W²、X、Y、Z、R⁰、R¹～R³, m and n are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein whenIs thatWhen W ¹ and X are different, one of them is a carbon atom, and the other is selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; when (when)Is thatWhen W ², Y, and Z are the same or different and are each independently selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom, and only at most one of W ², Y, and Z is selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom; when (when)Is thatWhen W ², X, Y and Z are the same or different and are each independently selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom, and only at most one of W ², X, Y and Z is selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; u ¹～U⁴、R²、R³, m and n are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting of R ²、R³, m and n are as defined in formula (I);

Preferably selected from

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting of R ²、R³, m and n are as defined in formula (I);

Preferably selected from

In some preferred embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein whenIs thatWhen W ¹ and X are different, one of them is a carbon atom, and the other is selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; when (when)Is thatWhen W ², Y, and Z are the same or different and are each independently selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom, and only at most one of W ², Y, and Z is selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom; when (when)Is thatWhen W ², X, Y and Z are the same or different and are each independently selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom, and only at most one of W ², X, Y and Z is selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; r ²、R³, m and n are as defined in the general formula (II).

In some preferred embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting of

R ²、R³, m and n are as defined in formula (II);

Preferably selected from

In some preferred embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting of R ²、R³, m and n are as defined in formula (II);

Preferably selected from

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), or a pharmaceutically acceptable salt thereof, wherein W ¹ and W ² are the same or different and are each independently a carbon atom or an oxygen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), or a pharmaceutically acceptable salt thereof is a compound of formula (III-1):

Wherein:

X is selected from nitrogen atom, oxygen atom and sulfur atom;

r ⁰、R¹～R³, m and n are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), or a pharmaceutically acceptable salt thereof is a compound of formula (III-2):

Wherein:

Y and Z are the same or different and are each independently selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom, and at most only one of Y and Z is selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom;

R ⁰、R¹～R³, m and n are as defined in formula (I). In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III-1), formula (III-2), or a pharmaceutically acceptable salt thereof, wherein R ⁰ is C _1-6 alkyl or Wherein said C _1-6 alkyl is optionally substituted with one or more substituents selected from halogen, C _1-6 alkoxy, C _1-6 haloalkoxy, cyano, amino and hydroxy; l ₁ is a bond or (CH ₂)_r; ring B is selected from 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl, each R ⁴ is the same or different and is each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, oxo, cyano, hydroxy and C _1-6 hydroxyalkyl, and R is 0,1,2, 3, 4,5 or 6;s is 0,1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III-1), formula (III-2), or a pharmaceutically acceptable salt thereof, wherein R ⁰ is C _1-6 alkyl orWherein said C _1-6 alkyl is optionally substituted with one or more substituents selected from halogen, C _1-6 alkoxy, C _1-6 haloalkoxy, cyano, amino and hydroxy; l ₁ is a bond; ring B is selected from 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; each R ⁴ is the same or different and is each independently selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkyl, and C _1-6 haloalkoxy; s is 0, 1 or 2; preferably, R ⁰ is C _1-6 alkyl; more preferably, R ⁰ is isopropyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III-1), formula (III-2), or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom or a halogen.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III-1), formula (III-2), or a pharmaceutically acceptable salt thereof, wherein each R ² is the same or different and is each independently selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, amino, nitro, hydroxy, C _1-6 hydroxyalkyl, andL ₂ is selected from the group consisting of a bond, (CH ₂)_r、C(O)、NR^a and an oxygen atom; R ^a is a hydrogen atom or a C _1-6 alkyl group; ring C is selected from the group consisting of 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; each R ⁵ is the same or different and is each independently selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, amino, hydroxy and C _1-6 hydroxyalkyl group; R is 0, 1, 2,3, 4, 5 or 6; and p is 0, 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III-1), formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R ² is selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkyl, and C _1-6 haloalkoxy; preferably, R ² is selected from the group consisting of a hydrogen atom, halogen, and C _1-6 alkyl; more preferably, R ² is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III-1), formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from the group consisting of a hydrogen atom, a halogen, and a C _1-6 alkyl group; preferably, R ³ is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III-1), formula (III-2) or a pharmaceutically acceptable salt thereof, wherein m is 0,1 or 2; preferably, m is 0.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III-1), formula (III-2) or a pharmaceutically acceptable salt thereof, wherein n is 0,1 or 2; preferably, n is 0.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; preferably, X is a nitrogen atom or an oxygen atom; more preferably, X is an oxygen atom.

In some preferred embodiments of the present disclosure, the compound of formula (III-2) or a pharmaceutically acceptable salt thereof, wherein Y and Z are the same or different and are each independently selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom, and at most one of Y and Z is selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom; preferably, Y and Z are both carbon atoms, or Y is an oxygen atom and Z is a carbon atom, or Y is a carbon atom and Z is an oxygen atom.

In some preferred embodiments of the present disclosure, the compound of formula (III-2) or a pharmaceutically acceptable salt thereof, wherein Y and Z are the same or different and are each independently selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom, and at most one of Y and Z is selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom; r ⁰ is C _1-6 alkyl; r ¹ is a hydrogen atom or halogen; r ² is selected from the group consisting of a hydrogen atom, a halogen, and a C _1-6 alkyl group; r ³ is selected from the group consisting of a hydrogen atom, a halogen, and a C _1-6 alkyl group; m is 0, 1 or 2; and n is 0, 1 or 2.

In some embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting of R ⁰ is C _1-6 alkyl; and R ¹ is a hydrogen atom or halogen.

Table a typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

Nucleophilic substitution reaction of the compound of formula (IA) or a salt thereof (preferably hydrochloride) with the compound of formula (V) to give the compound of formula (I) or a pharmaceutically acceptable salt thereof;

Wherein:

Selected from the group consisting of

Provided that whenIs thatWhen R ⁰ is not methyl;

R ^w is a leaving group, preferably halogen, more preferably a chlorine atom;

U ¹～U⁴、W¹、W²、X、Y、Z、R⁰、R¹～R³, m and n are as defined in formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

Nucleophilic substitution reaction of the compound of formula (IIA) or a salt thereof (preferably hydrochloride) with the compound of formula (V) to give a compound of formula (II) or a pharmaceutically acceptable salt thereof;

Wherein:

Selected from the group consisting of

Provided that whenIs thatWhen R ⁰ is not methyl;

R ^w is a leaving group, preferably halogen, more preferably a chlorine atom;

w ¹、W²、X、Y、Z、R⁰、R¹～R³, m and n are as defined in formula (II).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

Nucleophilic substitution reaction of the compound of formula (IIIA-1) or a salt thereof (preferably hydrochloride) with the compound of formula (V) to give the compound of formula (III-1) or a pharmaceutically acceptable salt thereof;

Wherein:

R ^w is a leaving group, preferably halogen, more preferably a chlorine atom;

X is selected from nitrogen atom, oxygen atom and sulfur atom;

R ⁰、R¹～R³, m and n are as defined in the general formula (III-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

nucleophilic substitution reaction of the compound of formula (IIIA-2) or a salt thereof (preferably hydrochloride) with the compound of formula (V) to give the compound of formula (III-2) or a pharmaceutically acceptable salt thereof;

Wherein:

R ^w is a leaving group, preferably halogen, more preferably a chlorine atom;

Y and Z are the same or different and are each independently selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom, and at most only one of Y and Z is selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom;

R ⁰、R¹～R³, m and n are as defined in the general formula (III-2).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III-1), formula (III-2), and table a of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The disclosure further relates to the use of a compound of formula (I), formula (II), formula (III-1), formula (III-2) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for Myosin (Myosin) inhibitor.

The present disclosure further relates to the use of a compound of formula (I), formula (II), formula (III-1), formula (III-2) and table a or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same in the manufacture of a medicament for the treatment of a disease or disorder selected from the group consisting of ejection fraction preserved diastolic heart failure, ischemic heart disease, angina, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic Cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), ejection fraction intermediate heart failure (HFmREF), valve disease, aortic valve stenosis, inflammatory cardiomyopathy, taylor endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, fabry-perot, left ventricular hypertrophy, refractory angina pectoris and chagas disease; preferably selected from ischemic heart disease, limited cardiomyopathy, hypertrophic Cardiomyopathy (HCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM); the Hypertrophic Cardiomyopathy (HCM) is preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

The present disclosure further relates to a method of inhibiting Myosin (Myosin) comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III-1), formula (III-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of treating a disease or disorder (especially a disease or disorder mediated by myosin) selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, limited cardiomyopathy, diastolic dysfunction, hypertrophic Cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), ejection fraction intermediate heart failure (HFmREF), valve disease, aortic valve stenosis, inflammatory cardiomyopathy, lux endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, fabry-perot, left ventricular hypertrophy, refractory angina and chagas disease, or a pharmaceutical composition comprising the same; preferably selected from ischemic heart disease, limited cardiomyopathy, hypertrophic Cardiomyopathy (HCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM); the hypertrophic cardiomyopathy is preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

The present disclosure further relates to a compound of formula (I), formula (II), formula (III-1), formula (III-2) and formula (III-2) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The present disclosure further relates to a compound of formula (I), formula (II), formula (III-1), formula (III-2) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a Myosin (Myosin) inhibitor.

The present disclosure further relates to a compound of formula (I), formula (II), formula (III-1), formula (III-2) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for treating a disease or disorder selected from the group consisting of ejection fraction preserved diastolic heart failure, ischemic heart disease, angina, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic Cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), ejection fraction intermediate heart failure (HFmREF), valve disease, aortic valve stenosis, inflammatory cardiomyopathy, lux endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, farfour-linkage disease, left ventricular hypertrophy, refractory angina and chagas disease; preferably selected from ischemic heart disease, limited cardiomyopathy, hypertrophic Cardiomyopathy (HCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM); the hypertrophic cardiomyopathy is preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

The compounds of formula (I), formula (II), formula (III-1), formula (III-2) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may alter the natural history of HCM and other diseases, rather than merely ameliorate symptoms. The mechanism by which clinical benefit is imparted to HCM patients can be extended to patients with other forms of heart disease that together have similar pathophysiology, with or without the influence of significant genetic factors. For example, effective treatment of HCM by improving ventricular diastole during diastole may also be effective for a broader population characterized by diastolic dysfunction.

The compounds of formula (I), formula (II), formula (III-1), formula (III-2), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may specifically target the root cause of the disorder or act on other downstream pathways. Thus, the compounds of formula (I), formula (II), formula (III-1), formula (III-2), and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may confer a benefit to patients suffering from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina, or restrictive cardiomyopathy.

The compounds of formula (I), formula (II), formula (III-1), formula (III-2), and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may also promote beneficial ventricular remodeling due to left ventricular hypertrophy resulting from volume or pressure overload; such as chronic mitral regurgitation, chronic aortic stenosis, or chronic systemic hypertension; the compounds or pharmaceutically acceptable salts thereof are combined with therapies aimed at correcting or alleviating the main cause of volume or pressure overload (valve repair/replacement, effective antihypertensive therapies). By lowering left ventricular filling pressure, the compounds may reduce the risk of pulmonary edema and respiratory failure. Reducing or eliminating functional mitral regurgitation and/or reducing left atrial pressure may reduce the risk of sudden or permanent atrial fibrillation, and it reduces the concomitant risk of arterial thromboembolic complications including, but not limited to, cerebral arterial embolic stroke. Reducing or eliminating dynamic and/or static left ventricular outflow tract obstruction may reduce the likelihood of requiring intermittent ablative treatment (surgical or percutaneous) and the attendant risks of short-term and long-term complications thereof.

The compounds of general formula (I), general formula (II), general formula (III-1), general formula (III-2), and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may reduce the severity of chronic ischemic conditions associated with HCM, and thereby reduce the risk of Sudden Cardiac Death (SCD) or equivalent diseases thereof and/or reduce the need for potentially toxic antiarrhythmic drugs in patients with implantable cardioverter-defibrillators (frequent and/or repeated ICD discharges).

The compounds of formula (I), formula (II), formula (III-1), formula (III-2), and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may be valuable in reducing or eliminating the need for concomitant drugs (with their attendant potential toxicity, drug-drug interactions, and/or side effects).

The compounds of formula (I), formula (II), formula (III-1), formula (III-2), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may reduce interstitial myocardial fibrosis and/or slow the progression of left ventricular hypertrophy, prevent or reverse left ventricular hypertrophy.

The active compounds can be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers by conventional methods to formulate the compositions of the present disclosure. Accordingly, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation. The compounds of the present disclosure may also be formulated in sustained release dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, troches or syrups.

As a general guideline, the active compounds are preferably administered in unit doses, or in a manner whereby the patient can self-administer a single dose. The unit dosage of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled lotion, powder, granule, lozenge, suppository, reconstituted powder or liquid formulation. Suitable unit doses may be in the range 0.1 to 1000mg.

The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of the active compound.

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.

The oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, which is prepared by injecting a liquid or microemulsion into the blood stream of a patient by topical mass injection. Or preferably the solution and microemulsion are administered in a manner that maintains a constant circulating concentration of the compound of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump of the DELTEC CADD-PLUS. TM.5400 type.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, nontoxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used. In addition, fatty acids can also be used to prepare injections.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

The compounds of the present disclosure may be administered by adding water to prepare water-suspended dispersible powders and granules. These pharmaceutical compositions may be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

As is well known to those skilled in the art, the amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

Unless stated to the contrary, the terms used in the specification have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group having from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., a C _1-12 alkyl group), more preferably an alkyl group having from 1 to 6 carbon atoms (i.e., a C _1-6 alkyl group). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof, and the like. Most preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any useful point of attachment, preferably selected from one or more of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group, which is a residue derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, which is a straight or branched chain group having from 1 to 20 carbon atoms, preferably an alkylene group having from 1 to 12 (e.g., 1,2,3, 4,5, 6,7, 8, 9, 10, 11, and 12) carbon atoms (i.e., a C _1-12 alkylene group), more preferably an alkylene group having from 1 to 6 carbon atoms (i.e., a C _1-6 alkylene group). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH ₂ -), 1-ethylene (-CH (CH ₃) -), 1, 2-ethylene (-CH ₂CH₂) -, 1-propylene (-CH (CH ₂CH₃) -), 1, 2-propylene (-CH ₂CH(CH₃) -), 1, 3-propylene (-CH ₂CH₂CH₂ -), 1, 4-butylene (-CH ₂CH₂CH₂CH₂ -), and the like. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably selected from one or more of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

The term "alkenyl" refers to an alkyl group having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C _2-12 alkenyl), preferably alkenyl having 2 to 6 carbon atoms (i.e., C _2-6 alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl group having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Which has an alkynyl group of 2 to 12 (e.g., 2,3,4,5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., a C _2-12 alkynyl group), preferably an alkynyl group of 2 to 6 carbon atoms (i.e., a C _2-6 alkynyl group). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted and when substituted, the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring having 3 to 20 carbon atoms, preferably having 3 to 12 (e.g., 3,4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., 3 to 12 membered cycloalkyl), more preferably having 3 to 8 carbon atoms (i.e., 3 to 8 membered cycloalkyl), and most preferably having 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a5 to 20 membered, monocyclic, polycyclic group sharing one carbon atom (referred to as the spiro atom) between the monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The spirocycloalkyl groups are classified into single spirocycloalkyl groups or multiple spirocycloalkyl groups (e.g., double spirocycloalkyl groups) according to the number of common spiro atoms between rings, and preferably single spirocycloalkyl groups and double spirocycloalkyl groups. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/4-membered or 6-membered/5-membered monocyclocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "fused ring alkyl" refers to an all-carbon polycyclic group having 5 to 20 members with rings sharing an adjacent pair of carbon atoms, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The polycyclic condensed ring alkyl group may be classified into a bicyclic ring, a tricyclic ring, a tetracyclic ring and the like according to the number of constituent rings, and is preferably a bicyclic ring or a tricyclic ring, and more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic alkyl group. Non-limiting examples of fused ring alkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms that are not directly attached, which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). Polycyclic bridged cycloalkyl groups, which may be classified as bicyclic, tricyclic, tetracyclic, etc., are preferred, bicyclic, tricyclic, or tetracyclic, more preferred, bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring includes cycloalkyl (including monocyclic, spiro, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the ring attached to the parent structure is cycloalkyl, non-limiting examples include Etc.; preferably

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any useful point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent having 3 to 20 ring atoms in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form sulfoxides or sulfones), but excluding the ring portions of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably 3 to 12 (e.g., 3,4,5,6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (e.g., 1,2,3, and 4) are heteroatoms (i.e., 3 to 12 membered heterocyclyl); more preferably 3 to 8 ring atoms (e.g., 3,4,5,6, 7, and 8), wherein 1-3 is a heteroatom (e.g., 1,2, and 3) (i.e., 3 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms, 1-3 of which are heteroatoms (i.e., 3 to 6 membered heterocyclyl); most preferably having 5 or 6 ring atoms, 1-3 of which are heteroatoms (i.e., 5 or 6 membered heterocyclyl). Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group having a single ring sharing one atom (referred to as the spiro atom) therebetween, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form a sulfoxide or sulfone), the remaining ring atoms being carbon. Which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The spiroheterocyclyl groups are classified into single spiroheterocyclyl groups or multiple spiroheterocyclyl groups (e.g., double spiroheterocyclyl groups) according to the number of common spiro atoms between rings, and are preferably single spiroheterocyclyl groups and double spiroheterocyclyl groups. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered single spiro heterocyclyl. Non-limiting examples of spiroheterocyclyl groups include:

The term "fused heterocyclyl" refers to a5 to 20 membered polycyclic heterocyclic group having a ring sharing an adjacent pair of atoms, one or more of which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form sulfoxides or sulfones), the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7,8,9 or 10 membered). The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:

The term "bridged heterocyclyl" refers to a5 to 14 membered, polycyclic heterocyclic group in which any two rings share two atoms which are not directly connected, which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form sulfoxides or sulfones), the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). Polycyclic bridged heterocyclic groups which can be classified into bicyclic, tricyclic, tetracyclic and the like according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

The heterocyclyl ring includes heterocyclyl (including monocyclic, spiro, fused and bridged heterocyclic rings) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:

The heterocyclic group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (fused polycyclic being a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. The aryl ring includes aryl rings fused to heteroaryl, heterocyclyl, or cycloalkyl rings as described above, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

Aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any useful point of attachment, preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heteroaryl" refers to heteroaromatic systems containing 1 to 4 heteroatoms (e.g., 1,2, 3, and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g., 5, 6, 7, 8, 9, or 10 membered), more preferably 5 or 6 membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryl condensed onto an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any useful point of attachment, preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The cycloalkyl, heterocyclyl, aryl and heteroaryl groups mentioned above include residues derived from the removal of one hydrogen atom from the parent ring atom, or residues derived from the removal of two hydrogen atoms from the same or two different ring atoms of the parent, i.e. "cycloalkylene", "heterocyclylene", "arylene", "heteroarylene".

The term "amino protecting group" refers to an easily removable group introduced on an amino group in order to keep the amino group unchanged when the reaction is performed at other positions of the molecule. Non-limiting examples include, but are not limited to, (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy and nitro.

The term "hydroxy protecting group" is a group known in the art to be suitable for hydroxy protection, non-limiting examples of which include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl, methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like.

The term "cycloalkyloxy" refers to a cycloalkyl-O-group, wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.

The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

The term "alkylthio" refers to an alkyl-S-, wherein alkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

The term "amino" refers to-NH ₂.

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂.

The term "oxo" refers to "=o".

The term "carbonyl" refers to c=o.

The term "carboxy" refers to-C (O) OH.

The term "carboxylate" refers to-C (O) O (alkyl), -C (O) O (cycloalkyl), (alkyl) C (O) O-or (cycloalkyl) C (O) O-, wherein alkyl and cycloalkyl are as defined above.

The compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. All such compounds of the present disclosure, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, e.g., enantiomerically or diastereomerically enriched mixtures, are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present disclosure. The asymmetric carbon atom containing compounds of the present disclosure may be isolated in optically active pure or racemic forms. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

In the chemical structure of the compounds of the present disclosure, the bondIndicating unspecified configuration, i.e. bonds if chiral isomers are present in the chemical structureMay beOr (b)Or at the same time containAndTwo configurations. In the chemical structure of the compounds of the present disclosure, the bondThe configuration is not specified, i.e., either the Z configuration or the E configuration, or both configurations are included. For all carbon-carbon double bonds, Z and E are included even if only one configuration is named.

The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include tautomers via proton transfer, such as keto-enol and imine-enamine, lactam-lactam isomerization. Lactam-lactam balance examples.

All compounds in the present disclosure may be drawn as form a or form B. All tautomeric forms are within the scope of the disclosure. The naming of the compounds does not exclude any tautomers.

The present disclosure also includes some isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the replacement of one or more atoms by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、¹²³I、¹²⁵I and ³⁶ Cl, respectively, and the like. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as diagnostic imaging tracers in vivo for diseases, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.

The present disclosure also includes various deuterated forms of the compounds. Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art are able to refer to the relevant literature for the synthesis of deuterated forms of the compounds. Commercially available deuterated starting materials may be used in preparing the deuterated form of the compound or they may be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, tridentate borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like. Unless otherwise indicated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium (i.e., at least 10% deuterium incorporation) having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). The natural abundance of a compound in an example can be at least 1000 times greater than the abundance of deuterium, at least 2000 times greater than the abundance of deuterium, at least 3000 times greater than the abundance of deuterium, at least 4000 times greater than the abundance of deuterium, at least 5000 times greater than the abundance of deuterium, at least 6000 times greater than the abundance of deuterium, or higher than the abundance of deuterium.

"Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "C _1-6 alkyl optionally substituted with halogen or cyano" means that halogen or cyano may be, but need not be, present, and the description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.

"Substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3, in the group are independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

"Pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure, which may be selected from inorganic salts or organic salts. Such salts are safe and effective when used in mammals and have desirable biological activity. Salts may be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate groups with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic and organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the intended effect. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

The term "solvate" as used herein refers to a physical combination of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. The physical bond includes a hydrogen bond. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated into the crystalline solid lattice, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates and isopropanolates. Solvation methods are well known in the art.

"Prodrug" means a compound that can be converted in vivo under physiological conditions, for example by hydrolysis in the blood, to yield an active prodrug.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and are effective for the intended use.

As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is shown that the parameter may vary by + -10%, and sometimes more preferably within + -5%. As will be appreciated by those skilled in the art, where parameters are not critical, numerals are generally given for illustration purposes only and are not limiting.

Methods of synthesizing compounds of the present disclosure

In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical scheme:

Scheme one

The preparation method of the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof comprises the following steps:

nucleophilic substitution reaction of a compound of formula (IA) or a salt thereof (preferably a hydrochloride) with a compound of formula (V) in the presence of a base under microwave conditions to give a compound of formula (I) or a pharmaceutically acceptable salt thereof;

Wherein:

Selected from the group consisting of

Provided that whenIs thatWhen R ⁰ is not methyl;

R ^w is a leaving group, preferably halogen, more preferably a chlorine atom;

U ¹～U⁴、W¹、W²、X、Y、Z、R⁰、R¹～R³, m and n are as defined in formula (I).

Scheme II

A process for the preparation of a compound of formula (II) of the present disclosure, or a pharmaceutically acceptable salt thereof, comprising the steps of:

Nucleophilic substitution reaction of a compound of formula (IIA) or a salt thereof (preferably a hydrochloride) with a compound of formula (V) in the presence of a base under microwave conditions to give a compound of formula (II) or a pharmaceutically acceptable salt thereof;

Wherein:

Selected from the group consisting of

Provided that whenIs thatWhen R ⁰ is not methyl;

R ^w is a leaving group, preferably halogen, more preferably a chlorine atom;

w ¹、W²、X、Y、Z、R⁰、R¹～R³, m and n are as defined in formula (II).

Scheme III

The preparation method of the compound shown in the general formula (III-1) or the pharmaceutically acceptable salt thereof comprises the following steps:

Nucleophilic substitution reaction of a compound of formula (IIIA-1) or a salt thereof (preferably a hydrochloride) with a compound of formula (V) in the presence of a base under microwave conditions to give a compound of formula (III-1) or a pharmaceutically acceptable salt thereof;

Wherein:

R ^w is a leaving group, preferably halogen, more preferably a chlorine atom;

X is selected from nitrogen atom, oxygen atom and sulfur atom;

R ⁰、R¹～R³, m and n are as defined in the general formula (III-1).

Scheme IV

The preparation method of the compound shown in the general formula (III-2) or the pharmaceutically acceptable salt thereof comprises the following steps:

nucleophilic substitution reaction of a compound of formula (IIIA-2) or a salt thereof (preferably a hydrochloride) with a compound of formula (V) in the presence of a base under microwave conditions to give a compound of formula (III-2) or a pharmaceutically acceptable salt thereof;

Wherein:

R ^w is a leaving group, preferably halogen, more preferably a chlorine atom;

y and Z are the same or different and are each independently selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom, and at most only one of Y and Z is selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; ;

R ⁰、R¹～R³, m and n are as defined in the general formula (III-2).

The base includes organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, preferably N, N-diisopropylethylamine; the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide, and potassium hydroxide.

The above reaction is preferably carried out in a solvent, including but not limited to: n-methylpyrrolidone, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, 1, 2-dibromoethane, and mixtures thereof.

The reaction temperature of the above-mentioned microwave reaction is 100 to 160℃and preferably 130 ℃.

The reaction time of the microwave reaction is 0.5-4 hours; preferably 1-2 hours.

Detailed Description

The present disclosure is further described below in conjunction with the examples, which are not intended to limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). The NMR shift (. Delta.) is given in units of 10 ^-6 (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO M with deuterated dimethyl sulfoxide (DMSO-d ₆), deuterated chloroform (CDCl ₃), deuterated methanol (CD ₃ OD) and Tetramethylsilane (TMS) as internal standard.

MS was determined using an Agilent 1200/1290DAD-6110/6120 Quadrapol MS liquid chromatography-mass spectrometry (manufacturer: agilent, MS model: 6110/6120 Quadrapol MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

High Performance Liquid Chromatography (HPLC) analysis used AGILENT HPLC DAD, AGILENT HPLC VWD, and WATERS HPLC E2695-2489 high performance liquid chromatographs.

Chiral HPLC analysis was determined using an Agilent 1260DAD high performance liquid chromatograph.

High performance liquid phase preparation was performed using Waters 2767, waters 2767-SQ Detecor2, shimadzu LC-20AP and Gilson-281 preparative chromatographs.

Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash rapid preparation instrument used CombiFlash Rf200 (TELEDYNE ISCO).

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea of the tobacco stand as a carrier.

The average inhibition rate of kinase and IC ₅₀ were measured by NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or following methods known in the art, or may be purchased from ABCR GmbH & co.kg, acros Organics, ALDRICH CHEMICAL Company, shao Yuan chemical technology (Accela ChemBio Inc), dary chemicals, and the like.

The reaction can be carried out under argon atmosphere or nitrogen atmosphere without any particular explanation in examples.

An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

The pressure hydrogenation reaction uses Parr 3916EKX type hydrogenometer and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.

The microwave reaction used was a CEM Discover-S908860 type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: n-hexane/ethyl acetate system, B: the volume ratio of the methylene dichloride to the methanol is adjusted according to the polarity of the compound, and small amounts of alkaline or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

3-Isopropyl-6- ((6, 7,8, 9-tetrahydro-5H-benzo [7] rota-n-5-yl) amino) pyrimidine-2, 4 (1H, 3H) -dione 1

First step

3-Isopropyl-6- ((6, 7,8, 9-tetrahydro-5H-benzo [7] rota-n-5-yl) amino) pyrimidine-2, 4 (1H, 3H) -dione 1

6-Chloro-3-isopropylpyrimidine-2, 4 (1H, 3H) -dione 1a (100 mg,0.53mmol, prepared by the method disclosed in patent application "WO2014205223A1, page 23, example 1.3") and 6,7,8, 9-tetrahydro-5H-benzo [7] rotaen-5-amine 1b (100 mg,0.62mmol, jiedav (Shanghai) pharmaceutical technology development Co., ltd.) were dissolved in anhydrous dioxane (2.0 mL) and N, N-diisopropylethylamine (340 mg,2.63 mmol) was added. The reaction was carried out for 1 hour at 130℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex C, 5 μm,30 mM. Times.150 mM, elution system: H ₂ O (10 mM ammonium bicarbonate), acetonitrile up to 95% (v/v) from 35% (v/v) over 20 min, detection wavelength 214&254 nm) to give the title product 1 (30 mg, 18.1%). MS m/z (ESI) 314.0[ M+1].

¹H NMR(500MHz,DMSO-d₆)δ9.74(s,1H),7.18-7.13(m,4H),6.56(s,1H),4.94(m,1H),4.60(m,1H),4.39(s,1H),2.93(m 1H),2.83(m 1H),1.90-1.80(m 3H),1.75-1.68(m 2H),1.43(m 1H),1.29(d,6H).

Examples 1 to 1,1 to 2

(S) -3-isopropyl-6- ((6, 7,8, 9-tetrahydro-5H-benzo [7] rota-en-5-yl) amino) pyrimidine-2, 4 (1H, 3H) -dione 1-1

(R) -3-isopropyl-6- ((6, 7,8, 9-tetrahydro-5H-benzo [7] rota-en-5-yl) amino) pyrimidine-2, 4 (1H, 3H) -dione 1-2

Chiral preparation of compound 1 (20 mg,0.0638 mmol) (separation conditions: CHIRALPAK IF chiral preparation column, 2.0cm i.f.×25cml,5 μm; mobile phase: n-hexane/ethanol (containing 0.1% diethylamine) =95/5 (V/V), flow rate: 20 mL/min), collection of its corresponding components, concentration under reduced pressure gave the title product (5.0 mg,10 mg).

Single configuration compound (shorter retention time, 5.0mg, yield: 25%):

chiral HPLC analysis: retention time 13.889 min, chiral purity: 100% (column: CHIRALPAK IF 0.46.46 cm I.D.×15cm L,5 μm; mobile phase: n-hexane/ethanol (containing 0.1% diethylamine) =95/5 (V/V). MS m/z (ESI): 314.0[ M+1].

¹H NMR(500MHz,DMSO-d₆)δ9.74(s,1H),7.18-7.13(m,4H),6.56(s,1H),4.94(m,1H),4.60(m,1H),4.39(s,1H),2.93(m 1H),2.83(m 1H),1.90-1.80(m 3H),1.75-1.68(m 2H),1.43(m 1H),1.29(d,6H).

Single configuration compound (longer retention time, 10mg, yield: 50%):

Chiral HPLC analysis: retention time 16.562 min, chiral purity: 91.9% (column: CHIRALPAK IF 0.46.46 cm I.F.×15cmL,5 μm; mobile phase: n-hexane/ethanol (0.1% diethylamine) =95/5 (V/V). MS m/z (ESI): 314.0[ M+1].

¹H NMR(500MHz,DMSO-d₆)δ9.74(s,1H),7.18-7.13(m,4H),6.56(s,1H),4.94(m,1H),4.60(m,1H),4.39(s,1H),2.93(m 1H),2.83(m 1H),1.90-1.80(m 3H),1.75-1.68(m 2H),1.43(m 1H),1.29(d,6H).

Example 2

(S) -6- (chroman-4-ylamino) -3-isopropylpyrimidine-2, 4 (1H, 3H) -dione 2

First step

(S) -6- (chroman-4-ylamino) -3-isopropylpyrimidine-2, 4 (1H, 3H) -dione 2

Compound (S) -chroman-4-amine 2a (150.0 mg,1.0mmol, jiangsu Aikang Biometrics Co., ltd.) compound 1a (208.6 mg,1.1 mmol) and N, N-diisopropylethylamine (648.5 mg,5.0 mmol) were dissolved in anhydrous dioxane (3 mL). The reaction was carried out for 1 hour at 130℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Welch Ultimate XB-C18,5 μm,30mm x 150mm, elution system: H ₂O(10mM NH₄HCO₃), acetonitrile rising from 25% (v/v) to 95% (v/v) over 15 minutes, detection wavelength 214&254 nm) to give the title product 2 (30.0 mg, yield: 9.9%).

MS m/z(ESI):302.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ9.67(s,1H),7.23-7.18(m,2H),6.91(t,1H),6.81(d,1H),6.52(d,1H),4.97(m,1H),4.79(s,1H),4.65(s,1H),4.23(m,1H),4.11(m,1H),2.09-1.91(m,2H),1.31(d,6H).

Example 3

(R) -6- (chroman-4-ylamino) -3-isopropylpyrimidine-2, 4 (1H, 3H) -dione 3

First step

(R) -6- (chroman-4-ylamino) -3-isopropylpyrimidine-2, 4 (1H, 3H) -dione 3

Compound (R) -chroman-4-amine 3a (50.0 mg,0.3mmol, shanghai taitant technologies Co., ltd.) compound 1a (69.6 mg,0.4 mmol) and N, N-diisopropylethylamine (216.2 mg,1.7 mmol) were dissolved in anhydrous dioxane (1 mL). The reaction was carried out for 1 hour at 130℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Welch Ultimate XB-C18,5 μm,30mm x 150mm, elution system: H ₂O(10mM NH₄HCO₃), acetonitrile rising from 25% (v/v) to 95% (v/v) over 15 minutes, detection wavelength 214&254 nm) to give the title product 3 (6.0 mg, yield: 6.0%).

MS m/z(ESI):302.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ9.67(s,1H),7.24-7.18(m,2H),6.91(t,1H),6.81(d,1H),6.52(d,1H),4.98(m,1H),4.81(s,1H),4.67(m,1H),4.23(m,1H),4.10(m,1H),2.10-1.91(m,2H),1.31(d,6H).

Example 4

(R) -3-isopropyl-6- ((1, 2,4, 5-tetrahydrobenzo [ d ] oxahept-1-yl) amino) pyrimidine-2, 4 (1H, 3H) -dione 4

First step

1-Methylene-1, 2,4, 5-tetrahydrobenzo [ d ] oxepin 4b

To a solution of 1- (2- (allyloxy) ethyl) -2-bromobenzene 4a (3.3 g,13.7mmol, prepared by the method of literature "Journal of Organic Chemistry,2020, vol.85,5, p.3728-3741") in acetonitrile (60 mL) was added silver carbonate (4.5 g,16.4mmol, national pharmaceutical chemicals Co., ltd.) and palladium tetraphenylphosphine (1.6 g,1.4mmol, shanghai taitant technologies Co., ltd.). And carrying out microwave reaction for 2 hours at 120 ℃ under the protection of nitrogen. The residue was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title product 4b (500.0 mg, yield: 22.8%).

MS m/z(ESI):161.1[M+1]。

Second step

4, 5-Dihydrobenzo [ d ] oxaheptan-1 (2H) -one 4c

To a solution of compound 4b (450.0 mg,2.8 mmol) in dichloromethane (30 mL) at-70℃was added ozone for about 30min until the reaction was saturated with ozone. Then, nitrogen was introduced for about 30 minutes until the reaction solution was saturated with nitrogen. Triphenylphosphine (883.1 mg,3.4mmol, national pharmaceutical chemicals Co., ltd.) was added thereto, and the reaction was stirred at room temperature for 30 minutes. The residue was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title product 4c (320.0 mg, yield: 70.2%).

MS m/z(ESI):163.1[M+1]。

Third step

(R) -N- (4, 5-Dihydrobenzo [ d ] oxaheptyl-1 (2H) -subunit)) -2-methylpropane-2-sulfinamide 4d

To anhydrous tetrahydrofuran (10 mL) of compound 4c (320.0 mg,2.0 mmol) and (R) -2-methylpropane-2-sulfinamide (478.3 mg,4.0mmol, shanghai taitan technologies Co., ltd.) was added titanium tetraethoxide (1.5 g,2.2mmol, shanghai taitan technologies Co., ltd.). The reaction was refluxed for 8 hours. Saturated aqueous sodium hydrogencarbonate (30 mL) was added, and extraction was performed with ethyl acetate (50 mL. Times.2). The organic phases were combined and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography with eluent system A, followed by filtration, concentration under reduced pressure, to give the title product 4d (190.0 mg, yield: 36.3%).

MS m/z(ESI):266.1[M+1]。

Fourth step

(R) -2-methyl-N- ((R) -1,2,4, 5-tetrahydrobenzo [ d ] oxahept-1-yl) propane-2-sulfinamide 4e

To a solution of compound 4d (190.0 mg,0.7 mmol) in anhydrous tetrahydrofuran (3 mL) was added dropwise 1M solution of lithium tri-sec-butylborohydride in tetrahydrofuran (1.2 mL,1.2mmol, shanghai-Tech Co., ltd.) at-78deg.C. The reaction was carried out at 0℃for 1 hour. Saturated aqueous ammonium chloride (20 mL) was added and extracted with ethyl acetate (30 mL. Times.2). The organic phases were combined and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography with eluent system A, followed by filtration, concentration under reduced pressure, to give the title product 4e (180.0 mg, yield: 95.0%). MS m/z (ESI): 268.1[ M+1].

Fifth step

(R) -1,2,4, 5-tetrahydrobenzo [ d ] oxaheptyl-1-amine hydrochloride 4f

Compound 4e (180.0 mg,0.7 mmol) was dissolved in methanol (1.5 mL), and a solution of 4M hydrogen chloride in 1, 4-dioxane (3 mL) was added dropwise. The reaction was carried out at room temperature for 1 hour. Concentration under reduced pressure afforded crude title product 4f (144.0 mg) which was used in the next step without purification.

MS m/z(ESI):147.1[M-16]。

Sixth step

(R) -3-isopropyl-6- ((1, 2,4, 5-tetrahydrobenzo [ d ] oxahept-1-yl) amino) pyrimidine-2, 4 (1H, 3H) -dione 4

Crude compound 4f (144.0 mg,0.7 mmol), compound 1a (135.8 mg,0.7 mmol) and N, N-diisopropylethylamine (465.4 mg,3.6 mmol) were dissolved in anhydrous 1, 4-dioxane (2 mL). The reaction was carried out for 2 hours at 130 ℃. Concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex Prep C, 5 μm,30 mM. Times.150 mM, elution system: water (10 mM ammonium bicarbonate), acetonitrile rising from 25% (v/v) to 45% (v/v) over 15 minutes, detection wavelength 214&254 nm) to give the title product 4 (49.1 mg, yield: 21.6%). MS m/z (ESI) 316.1[ M+1].

¹H NMR(500MHz,DMSO-d₆)δ7.78-7.37(m,1H),7.20-7.14(m,3H),6.91(s,1H),6.03(brs,1H),4.94-4.88(m,1H),4.68(s,1H),4.46-4.43(m,1H),4.10-4.07(m,1H),4.01(dd,1H),3.61(d,1H),3.49(t,1H),3.40-3.35(m,1H),3.75(dd,1H),1.26(dd,6H).

Example 5

(S) -3-isopropyl-6- ((1, 3,4, 5-tetrahydrobenzo [ c ] oxahept-5-yl) amino) pyrimidine-2, 4 (1H, 3H) -dione 5

First step

1-Bromo-2- ((but-3-en-1-yloxy) methyl) benzene 5c

To anhydrous tetrahydrofuran (40 mL) of but-3-en-1-ol 5b (1.5 g,20.8mmol, an Naiji chemical) was added sodium hydrogen (749.1 mg,18.7mmol,60% content, national pharmaceutical products chemical Co.) at 0deg.C. The reaction was carried out at room temperature for 30 minutes under nitrogen protection. 1-bromo-2- (bromomethyl) benzene 5a (3.9 g,15.6mmol, shao Yuan technology Co., ltd.) was added and reacted at room temperature for 16 hours. Saturated aqueous ammonium chloride (40 mL) was added and extracted with ethyl acetate (50 mL. Times.2). The organic phases were combined and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography with eluent system A, filtered, concentrated under reduced pressure to give the title product 5c (3.7 g, yield: 87.7%). MS m/z (ESI): 241.1[ M+1].

Second step

5-Methylene-1, 3,4, 5-tetrahydrobenzo [ d ] oxepin 5d

To acetonitrile (100 mL) of compound 5c (2.8 g,11.7 mmol) was added silver carbonate (3.9 g,14.2mmol, national medicine group chemical Co., ltd.) and palladium tetraphenylphosphine (1.4 g,1.2 mmol). The reaction was carried out at 100℃for 20 hours under nitrogen protection. The residue obtained was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title product 5d (1.6 g, yield: 83.3%).

MS m/z(ESI):161.1[M+1]。

Third step

3, 4-Dihydrobenzo [ c ] oxaheptan-5 (1H) -one 5e

To a solution of compound 5d (1.6 g,10.0 mmol) in dichloromethane (50 mL) at-70℃was added ozone for about 30 minutes until the reaction solution was saturated with ozone. Then, nitrogen was introduced for about 30 minutes until the reaction solution was saturated with nitrogen. Triphenylphosphine (3.2 g,12.2 mmol) was added and the reaction stirred at room temperature for 30 min. The residue was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title product 5e (530.0 mg, yield: 32.7%).

MS m/z(ESI):163.1[M+1]。

Fourth step

(R) -N- (3, 4-Dihydrobenzo [ c ] oxaheptyl-5 (1H) -subunit)) -2-methylpropane-2-sulfinamide 5f

To compound 5e (530.0 mg,3.3 mmol) and (R) -2-methylpropane-2-sulfinamide (792.2 mg,6.5 mmol) in anhydrous tetrahydrofuran (10 mL) was added titanium tetraethoxide (1.5 g,6.5 mmol). The reaction was refluxed for 16 hours. Saturated aqueous sodium hydrogencarbonate (30 mL) was added, and extraction was performed with ethyl acetate (50 mL. Times.2). The organic phases were combined and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography with eluent system A, followed by filtration, concentration under reduced pressure, to give the title product 5f (600.0 mg, yield: 69.2%).

MS m/z(ESI):266.1[M+1]。

Fifth step

(R) -2-methyl-N- ((S) -1,3,4, 5-tetrahydrobenzo [ c ] oxahept-5-yl) propane-2-sulfinamide 5g

To compound 5f (600.0 mg,2.3 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise a 1M solution of lithium tri-sec-butylborohydride in tetrahydrofuran (3.7 mL,3.7 mmol) at-78deg.C. The reaction was carried out at 0℃for 1 hour. Saturated aqueous ammonium chloride (20 mL) was added and extracted with ethyl acetate (30 mL. Times.2). The organic phases were combined and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography with eluent system A, filtered, concentrated under reduced pressure, to give the title product 5g (570.0 mg, yield: 95.0%).

MS m/z(ESI):268.1[M+1]。

Sixth step

(S) -1,3,4, 5-tetrahydrobenzo [ c ] oxaheptyl-5-amine hydrochloride for 5h

5G (570.0 mg,2.1 mmol) of the compound was dissolved in methanol (4 mL), and a1, 4-dioxane solution (2.2 mL) of 4M hydrogen chloride was added dropwise. The reaction was carried out at room temperature for 1 hour. Concentration under reduced pressure afforded the title product as crude 5h (450.0 mg), which was used in the next step without purification.

MS m/z(ESI):164.2[M+1]。

Seventh step

(S) -3-isopropyl-6- ((1, 2,4, 5-tetrahydrobenzo [ c ] oxahept-5-yl) amino) pyrimidine-2, 4 (1H, 3H) -dione 5

Crude compound 5h (450.0 mg,2.3 mmol), compound 1a (472.4 mg,2.5 mmol) and N, N-diisopropylethylamine (1.6 g,12.5 mmol) were dissolved in anhydrous 1, 4-dioxane (5 mL). The reaction was carried out for 2 hours at 130 ℃. Concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex Prep C, 5 μm,30 mM. Times.150 mM, elution system: water (10 mM ammonium bicarbonate), acetonitrile rising from 25% (v/v) to 50% (v/v) in 15 minutes, detection wavelength 214&254 nm) to give the title product 5 (200.0 mg, yield: 25.3%). MS m/z (ESI) 316.1[ M+1].

¹H NMR(500MHz,DMSO-d₆)δ7.30-7.20(m,4H),6.74(brs,1H),4.98-4.88(m,2H),4.77(d,1H),4.66(d,1H),4.58(s,1H),4.05-3.93(m,2H),1.95-1.92(m,2H),1.30(d,6H).

Biological evaluation

The present disclosure is explained in further detail below in conjunction with test examples, which are not meant to limit the scope of the present disclosure.

Test example 1, the inhibitory effect of the compounds of the present disclosure on myosin atpase activity.

The following methods were used to determine the inhibitory effect of the compounds of the present disclosure on myosin atpase activity, and the experimental methods are briefly described below:

1. Experimental material and instrument

1. Myocardial actin (CARDIAC ACTIN) (Cytoskeleton, AD 99)

2. Myosin motor protein S1 Fragment (Myosin Motor Protein S Fragment) (Cytoskeleton, CS-MYS 03)

3.ATP(Sigma，A7699-1G)

UltraPure ^TM M Tris-HCI buffer, pH 7.5 (Thermo, 15567027)

Cytophos ^TM phosphate detection biological kit (Phosphate Assay Biochem Kit) (Cytopheleton, BK 054)

6. Magnesium chloride solution (Sigma, 68475-100 ML-F)

7. Potassium chloride solution (Sigma, 60142-100 ML-F)

8.EGTA(Sigma，E3889-100G)

9.96 Well plate (Corning, 3697)

U-shaped bottom 96 well plate (Corning 3795)

11. Enzyme label instrument (BMG, PHERAstar)

12. Constant temperature incubator (Shanghai Boxun, SPX-100B-Z)

2. Experimental procedure

Myocardial actin 1.61. Mu.M, myosin motor protein S1 fragment 0.07. Mu.M was mixed with different concentrations of small molecule compound (initial 100. Mu.M, 3-fold gradient 9 concentrations) and incubated at 37℃for 1 hour. ATP 120. Mu.M was added and incubated at 37℃for 2 hours. Finally, cytoPhos ^TM phosphate detection solutions (70. Mu.L/well) in the biological kit were added to each well and incubated at room temperature for 10min. And (3) reading an OD value of 650nM wavelength by using an enzyme-labeled instrument, calculating Pi generation amount according to a standard curve, processing data by using GraphPad software, drawing an inhibition curve according to each concentration of the compound and the corresponding inhibition rate, and calculating the concentration of the compound, namely an IC ₅₀ value when the inhibition rate reaches 50%. The experimental results are detailed in table 1.

TABLE 1 inhibitory Activity of the compounds of the present disclosure against myosin ATPase

Examples numbering	IC50(μM)
		1	1.31
1-1 And 1-2, and the shorter retention time corresponds to the compound	0.45
		1-1 And 1-2, and longer retention times	5.18
4	3.96
		5	4.37

Conclusion: the compound disclosed by the disclosure has a good inhibition effect on myosin ATPase.

Claims (16)

1. A compound of formula (II) or a pharmaceutically acceptable salt thereof:

Wherein:

Selected from the group consisting of

R ¹ is selected from the group consisting of a hydrogen atom, a halogen, and a C _1-6 alkyl group;

r ² is a hydrogen atom;

R ³ is a hydrogen atom;

r ⁰ is C _1-6 alkyl;

m is 0,1, 2,3 or 4;

n is 0,1, 2, 3, 4, 5 or 6.

2. The compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (III-2):

Wherein:

Y and Z are the same or different and are each independently a carbon atom or an oxygen atom, and at most one of Y and Z is an oxygen atom;

r ⁰、R¹～R³, m and n are as defined in claim 1.

3. The compound of formula (II) according to claim 1, wherein R ⁰ is isopropyl, or a pharmaceutically acceptable salt thereof.

4. The compound represented by the general formula (II) according to claim 1, wherein R ¹ is a hydrogen atom or halogen, or a pharmaceutically acceptable salt thereof.

5. The compound represented by the general formula (II) according to claim 1 or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting of

6. A compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from any one of the following:

7. a process for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, which comprises:

Nucleophilic substitution reaction of the compound of the general formula (IIA) or a salt thereof with the compound of the general formula (V) to obtain a compound of the general formula (II) or a pharmaceutically acceptable salt thereof;

Wherein:

Selected from the group consisting of

R ^w is a leaving group;

r ⁰、R¹～R³, m and n are as defined in claim 1.

8. The method of claim 7, wherein R ^w is halogen.

9. The method of claim 6 or 7, wherein R ^w is a chlorine atom.

10. A pharmaceutical composition comprising a compound of general formula (II) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

11. Use of a compound of general formula (II) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 10 for the manufacture of a medicament for Myosin (Myosin) inhibitors.

12. Use of a compound of general formula (II) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 10 in the manufacture of a medicament for the treatment of a disease or condition selected from the group consisting of ejection fraction preserved diastolic heart failure, ischemic heart disease, angina, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic Cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), ejection fraction median heart failure (HFmREF), valve disease, inflammatory cardiomyopathy, taylor endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, fabry quadruple disease, left ventricular hypertrophy, refractory angina and chagas disease.

13. The use according to claim 12, wherein the disease or condition is selected from ischemic heart disease, restrictive cardiomyopathy, hypertrophic Cardiomyopathy (HCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease, and left ventricular hypertrophy.

14. The use according to claim 12, wherein the disease or condition is Hypertrophic Cardiomyopathy (HCM).

15. The use according to any one of claims 12 to 14, wherein the hypertrophic cardiomyopathy is a non-obstructive hypertrophic cardiomyopathy (nHCM) or an obstructive hypertrophic cardiomyopathy (oHCM).

16. The use according to claim 12, wherein the valve disorder is aortic stenosis.