CN114516843A

CN114516843A - Pyrimidinedione derivatives, preparation method and medical application thereof

Info

Publication number: CN114516843A
Application number: CN202111366841.0A
Authority: CN
Inventors: 张晓敏; 胡伟民; 马殿强; 舒春风; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2020-11-19
Filing date: 2021-11-18
Publication date: 2022-05-20

Abstract

The disclosure relates to pyrimidinedione derivatives, processes for their preparation and their use in medicine. In particular to a pyrimidinedione derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and application of the derivative as a therapeutic agent, especially application of the derivative as a Myosin (Myosin) inhibitor and application of the derivative as a medicineUse in a medicament for treating Hypertrophic Cardiomyopathy (HCM) or a heart disease having pathophysiological features associated with HCM.

Description

Pyrimidinedione derivatives, preparation method and medical application thereof

Technical Field

The disclosure belongs to the field of medicines, and relates to a pyrimidinedione derivative, a preparation method thereof and application thereof in medicines. In particular, the disclosure relates to pyrimidinedione derivatives of formula (I), methods of their preparation, pharmaceutical compositions containing them, 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 hereditary myocardial disease associated with genetic mutations. The global incidence is about 0.2%, which is the most important cause of sudden death in young people under 35 years old (C. Vaughan Tuohy, et al, European Journal of Heart Failure,22,2020, 228-. Clinically, it is characterized by the asymmetrical hypertrophy of left ventricular wall, frequent invasion and ventricular septum, small ventricular cavity, obstruction of left ventricular blood filling, and decreased ventricular diastolic compliance. The disease is classified into obstructive and non-obstructive hypertrophic cardiomyopathy according to the presence or absence of obstruction in the left ventricular outflow tract. At present, beta-blockers and calcium channel blockers are mostly adopted for clinically treating hypertrophic cardiomyopathy to reduce cardiac contraction and relieve symptoms. However, these treatments are all palliative and not root-cause. HCM progression to late stages is only amenable to heart transplantation (R adhakrishnan Ramaraj, Cardiology in Review,16(4),2008, 172-. Therefore, it is very urgent to find a treatment method aiming at the pathogenesis source of HCM.

The present study found that 70% of HCM patients are caused by mutations in the sarcomere gene. Multiple site mutations are found in 5-7% of patients. More than about 70 pathogenic mutations have been identified, but most of these have family specificity, with only a few hot spots identified, such as the MYH 7R 403Q and R453C mutations (Norbert Frey, et al, Nature Reviews biology, 9,2011, 91-100; m.sabater-Molina, et al, Clinical Genetics,93,2018, 3-14). Research aiming at the pathogenic probability of gene mutation finds that MYH7 gene mutation 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 the thick myofilaments of myofibrils and plays an important role in muscle movement. The molecular shape is like bean sprout, and is composed of two heavy chains and a plurality of light chains. The myosin head combines with actin to form a transverse bridge, so that the ATPase activity of myosin is greatly improved, ATP hydrolysis reaction is catalyzed, energy is generated to promote the transverse bridge to slide, and muscle contraction is carried out. The results of the studies show that mutation of the MYH7 gene leads to increased myosin ATPase activity, decreased proportion of the hyper-relaxed State (SRX) of myosin, and increased cross-bridging between myosin and actin, leading to abnormal systolic function (Eric M.Green, et al, Science,351(6273),2016, 617-. Myosin is therefore an important target for the treatment of hypertrophic cardiomyopathy.

Patent applications for myosin inhibitors have been disclosed including, inter alia, WO2014205223A1, WO2014205234A1, WO2019028360A1, WO2020092208A1 and CN 110698415A.

Disclosure of Invention

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

wherein:

is selected from

W¹、W²X, Y and Z are the same or different and are each independently selected from a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom, and W¹、W²At most only one of, X, Y and Z is selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; provided that W is¹And X cannot be both carbon atoms;

U¹、U²、U³and U⁴Are the same or different and are each independently a carbon atom or a nitrogen atom;

R¹selected from hydrogen atoms, halogens and alkyl groups;

each R is²Are the same or different and are 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、NR⁹R¹⁰And

L₂is selected from the group consisting of a bond, (CH)₂)_r、C(O)、NR^aOxygen atom and sulfur atom;

R^aselected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

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

each R is⁵The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

each R is³The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl;

R⁰is alkyl or

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

L₁is a bond or (CH)₂)_r；

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

each R is⁴Is the same or different and is each independently selected from the group consisting of a hydrogen atom, 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)NR⁹R¹⁰Cycloalkyl, - (CH)₂)_r-cycloalkyl, heterocyclyl, - (CH)₂)_r-heterocyclyl, aryl, - (CH)₂)_r-aryl, heteroaryl and- (CH)₂)_r-a heteroaryl group;

R⁶selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one member selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkylSubstituted by one or more substituents;

R⁷selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R⁸selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, hydroxyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R⁹and R¹⁰Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, - (CH)₂)_r-cycloalkyl, heterocyclyl, - (CH)₂)_r-heterocyclyl, aryl, - (CH)₂)_r-aryl, heteroaryl and- (CH)₂)_r-a heteroaryl group; or R⁹And R¹⁰Together with the nitrogen atom to which they are attached form a heterocyclyl group, which heterocyclyl group is optionally substituted by 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 is

t is 0, 1 or 2;

provided that

Is composed of

When R is⁰Is not methyl.

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

wherein:

is selected from

Provided that

Is composed of

When R is⁰Is not methyl;

W¹、W²、X、Y、Z、R⁰、R¹～R³m 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

Is composed of

When W is¹And X are different and one is a carbon atom and the other is selected from a nitrogen atom, an oxygen atom and a sulfur atom; when in use

Is composed of

When W is²Y 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 W²Y and Z are selected from nitrogen atom and oxygen atomA sulfur atom and a proton; when in use

Is composed of

When W is²X, Y and Z are the same or different and are each independently selected from a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom, and W²At most only one of, X, Y and Z is selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; u shape¹～U⁴、R²、R³M and n are as defined in formula (I).

Is selected from

R²、R³M and n are as defined in formula (I);

preferably selected from

Is selected from

R²、R³M 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

Is composed of

When W is¹And X are different and one is a carbon atom and the other is selected from a nitrogen atom, an oxygen atom and a sulfur atom; when the temperature is higher than the set temperature

Is composed of

When W is²Y 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 W²At most only one of Y and Z is selected from a nitrogen atom, an oxygen atom and a sulfur atom; when in use

Is composed of

When W is²X, Y and Z are the same or different and are each independently selected from a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom, and W²X, Y and Z toMore than one selected from nitrogen atoms, oxygen atoms and sulfur atoms; r²、R³M and n are as defined in formula (II).

Is selected from

R²、R³M and n are as defined in formula (II);

preferably selected from

Is selected from

R²、R³M 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 W¹And W²Are 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 represented by the general formula (I), the general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III-1):

wherein:

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

R⁰、R¹～R³m and n are as defined in formula (I).

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

wherein:

y and Z are the same or different and are each independently selected from 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 a nitrogen atom, an oxygen atom and a sulfur atom;

R⁰、R¹～R³m 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 is⁰Is C_1-6Alkyl or

Wherein, said C_1-6Alkyl is optionally selected from halogen, C_1-6Alkoxy radical, C_1-6Substituted with one or more substituents selected from haloalkoxy, cyano, amino and hydroxyl; l is₁Is a bond or (CH)₂)_r(ii) a 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 is⁴Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, oxo, cyano, hydroxy and C_1-6A hydroxyalkyl group; 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 is⁰Is C_1-6Alkyl or

Wherein, said C_1-6Alkyl is optionally selected from halogen, C_1-6Alkoxy radical, C_1-6Substituted with one or more substituents selected from haloalkoxy, cyano, amino and hydroxyl; l is₁Is 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 is⁴Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6A haloalkoxy group; s is 0, 1 or 2; preferably, R⁰Is C_1-6An alkyl group; more preferably, R⁰Is 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 is¹Is 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 is²Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, cyano, amino, nitro, hydroxy, C_1-6Hydroxyalkyl and

L₂is selected from the group consisting of a bond, (CH)₂)_r、C(O)、NR^aAnd an oxygen atom; r^aIs a hydrogen atom or C_1-6An alkyl group; ring C 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 is⁵Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, cyano, amino, hydroxy and C_1-6A hydroxyalkyl group; r is 0, 1,2,3, 4,5 or 6; 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 is²Selected from hydrogen atoms, halogens, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6A haloalkoxy group; preferably, R²Selected from hydrogen atom, halogen and C_1-6An alkyl group; more preferably, R²Is 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 is³Selected from hydrogen atoms, halogens and C_1-6An alkyl group; preferably, R³Is 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 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 represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof, wherein Y and Z are the same or different and each is independently selected from 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 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 represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof, wherein Y and Z are the same or different and each is independently selected from 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 a nitrogen atom, an oxygen atom and a sulfur atom; r⁰Is C_1-6An alkyl group; r¹Is a hydrogen atom or a halogen; r²Selected from hydrogen atoms, halogens and C_1-6An alkyl group; r³Selected from hydrogen atom, halogen and C_1-6An alkyl group; m is 0, 1 or 2; and n is 0, 1 or 2.

In some embodiments of the disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein

Is selected from

R⁰Is C_1-6An alkyl group; and R is¹Is a hydrogen atom or a 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 of preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising:

nucleophilic substitution reaction of the compound of general formula (IA) or its salt (preferably hydrochloride) with the compound of general formula (V) to obtain the compound of general formula (I) or its pharmaceutically acceptable salt;

wherein:

is selected from

Provided that

Is composed of

When R is⁰Is not methyl;

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

U¹～U⁴、W¹、W²、X、Y、Z、R⁰、R¹～R³m and n are as defined in formula (I).

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

nucleophilic substitution reaction of the compound of general formula (IIA) or its salt (preferably hydrochloride) with the compound of general formula (V) to obtain the compound of general formula (II) or its pharmaceutically acceptable salt;

wherein:

is selected from

Provided that

Is composed of

When R is⁰Is not methyl;

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

W¹、W²、X、Y、Z、R⁰、R¹～R³m and n are as defined in formula (II).

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

carrying out nucleophilic substitution reaction on the compound of the general formula (IIIA-1) or a salt (preferably hydrochloride) thereof and the compound of the general formula (V) to obtain the compound of the general formula (III-1) or a pharmaceutically acceptable salt thereof;

wherein:

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

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

R⁰、R¹～R³m 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 the general formula (III-2) or a pharmaceutically acceptable salt thereof, which comprises:

carrying out nucleophilic substitution reaction on the compound of the general formula (IIIA-2) or a salt (preferably hydrochloride) thereof and the compound of the general formula (V) to obtain the compound of the general formula (III-2) or a pharmaceutically acceptable salt thereof;

wherein:

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

R⁰、R¹～R³m 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 the present disclosure represented by general formula (I), general formula (II), general formula (III-1), general formula (III-2), and table a, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The disclosure further relates to the use of compounds of formula (I), formula (II), formula (III-1), formula (III-2) and shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of a medicament for the manufacture of a Myosin (Myosin) inhibitor.

The 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 preserved ejection fraction diastolic heart failure, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, Hypertrophic Cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), intermediate ejection fraction heart failure (HFmREF), valve disease, aortic valve stenosis, inflammatory cardiomyopathy, lux endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry disease, glycogen storage disease, congenital heart disease, or a pharmaceutical composition comprising the same, Fadrou tetrad, left ventricular hypertrophy, refractory angina pectoris and chagas disease; preferably selected from ischemic heart disease, restrictive 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), and table a, 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, particularly a disease or disorder mediated by 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) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, selected from the group consisting of preserved ejection fraction diastolic heart failure, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, Hypertrophic Cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), intermediate ejection fraction heart failure (HFmREF), valve disease, aortic stenosis, inflammatory cardiomyopathy, leffer endocarditis, myocardial endocarditis, invasive cardiomyopathy, hemochromatosis, fabry's disease, heart attack, and the like, Glycogen storage disease, congenital heart disease, Fallo tetrad, left ventricular hypertrophy, refractory angina pectoris, and Chagas disease; preferably selected from ischemic heart disease, restrictive 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 disclosure further relates to compounds of formula (I), formula (II), formula (III-1), formula (III-2) and shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament.

The present disclosure further relates to 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, which are useful as Myosin (Myosin) inhibitors.

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 preserved ejection fraction diastolic heart failure, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, Hypertrophic Cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), intermediate ejection fraction 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, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, Fadrou tetrad, left ventricular hypertrophy, refractory angina pectoris and chagas disease; preferably selected from ischemic heart disease, restrictive 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 the general formula (I), general formula (II), general formula (III-1), general formula (III-2), and shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure can alter the natural history of HCM and other diseases, not just the alleviation of symptoms. The mechanisms that confer clinical benefit to HCM patients may be extended to patients with other forms of heart disease that share similar pathophysiology and may or may not have significant genetic influence. For example, effective treatment of HCM by improving ventricular relaxation during diastole may also be effective for a wider range of populations characterized by diastolic dysfunction.

The compounds represented by the general formula (I), the general formula (II), the general formula (III-1), the general formula (III-2) and the table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, which are disclosed by the invention, can specifically target the root cause of diseases or act on other downstream pathways. Accordingly, the compounds of the general formula (I), general formula (II), general formula (III-1), general formula (III-2), and Table A of the present disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, may confer benefits to patients suffering from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, or restrictive cardiomyopathy.

The compounds of the general formula (I), general formula (II), general formula (III-1), general formula (III-2), and table a of the present disclosure or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, may also promote beneficial ventricular remodeling of left ventricular hypertrophy due to 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 reducing the main causes of volume or pressure overload (valve repair/replacement, effective antihypertensive therapy). By reducing 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 persistent 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 obstructions may reduce the likelihood of the need for interval ablation therapy (surgical or percutaneous) and the attendant risks of its short-term and long-term complications.

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

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

The compounds shown in the general formula (I), the general formula (II), the general formula (III-1), the general formula (III-2) and the table A or the pharmaceutically acceptable salts thereof or the pharmaceutical composition containing the compounds can reduce interstitial myocardial fibrosis and/or slow down the progress of left ventricular hypertrophy and prevent or reverse left ventricular hypertrophy.

The active compounds may be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers to formulate compositions of the disclosure by conventional methods. Thus, 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), 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, lozenges, or syrups.

As a general guide, the active compound is preferably administered in a unit dose or in a manner such that the patient can self-administer it in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.

The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following: 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 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 which 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 an 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. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

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. Sweetening agents such as those set forth above, 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 oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed 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, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump of the model Deltec CADD-PLUS. TM. 5400.

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 suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into 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 therefore will melt in the rectum to release the drug.

Dispersible powders and granules of the compounds of the present disclosure can be administered by the addition of water to prepare an aqueous suspension. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular 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, and the like; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of compound or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

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

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group having 1 to 20 carbon atoms, preferably an alkyl (i.e., C) group having 1 to 12 (e.g., 1,2,3, 4,5, 6,7,8,9, 10, 11, and 12) carbon atoms_1-12Alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C)_1-6Alkyl). 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-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl group, n-decyl group, 3-diethylhexyl group, 2-diethylhexyl group,and various branched chain isomers thereof, and the like. Most preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which 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. Alkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, 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 aliphatic hydrocarbon group, which is a residue derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, and is a straight or branched chain group having from 1 to 20 carbon atoms, preferably an alkylene (i.e., C) group having from 1 to 12 (e.g., 1,2,3, 4,5, 6,7,8,9, 10, 11, and 12) carbon atoms_1-12Alkylene), more preferably alkylene having 1 to 6 carbon atoms (i.e., C)_1-6Alkylene). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH)₂-), 1-ethylidene (-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 (-CH₂CH₂CH₂CH₂-) and the like. The alkylene group may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, the substituent preferably being selected from alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylOne or more of thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Having alkenyl groups (i.e., C) of 2 to 12 (e.g., 2,3, 4,5, 6,7,8,9, 10, 11, and 12) carbon atoms_2-12Alkenyl), preferably having 2 to 6 carbon atoms (i.e., C)_2-6Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is 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 containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Having alkynyl (i.e. C) groups of 2 to 12 (e.g. 2,3, 4,5, 6,7,8,9, 10, 11 and 12) carbon atoms_2-12Alkynyl), preferably alkynyl having 2 to 6 carbon atoms (i.e., C)_2-6Alkynyl). 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 from 3 to 20 carbon atoms, preferably having from 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 groups), more preferably having from 3 to 8 carbon atoms (i.e., 3 to 8 membered cycloalkyl groups), and most preferably having from 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl groups). 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 a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between single rings, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8,9 or 10). Spirocycloalkyl groups are classified as mono-or polyspirocycloalkyl (e.g., a bispyridyl cycloalkyl group), preferably mono-or bispyridyl, depending on the number of spiro atoms shared between rings. 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 spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which the rings share an adjacent pair of carbon atoms between them, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8,9 or 10). They may be classified into polycyclic fused alkyl groups such as bicyclic, tricyclic, tetracyclic, etc., according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 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/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 bicycloalkyl groups. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8,9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic, etc. polycyclic bridged cycloalkyl groups according to the number of constituent rings, and preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

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

Etc.; preference is given to

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available 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. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from D atoms, 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 mono-or polycyclic cyclic substituent having from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), but which does not include the ring portion 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 1-4 (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), with 1-3 being heteroatoms (e.g., 1,2 and 3) (i.e., 3-to 8-membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms (i.e. 3 to 6 membered heterocyclyl); most preferably having 5 or 6 ring atoms of which 1-3 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 heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

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

the term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members sharing an adjacent pair of atoms between the rings, one or more of the rings may contain one or more double bonds in which 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), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8,9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituting rings, preferably bicyclic or tricyclic, more preferably 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/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 groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, 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., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8,9 or 10). They may be divided into polycyclic bridged heterocyclic groups such as bicyclic, tricyclic, tetracyclic, etc., depending on the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

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

and the like.

The heterocyclyl group may be substituted or unsubstituted and when substituted may be substituted at any available 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 "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (fused polycyclic is 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. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, 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, may be substituted at any available 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 "heteroaryl" refers to a heteroaromatic system comprising 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, e.g., furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be substituted or unsubstituted, and when substituted, 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 above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include those derived from the parent ring atom by removal of one hydrogen atom, or those derived from the parent ring atom by removal of two hydrogen atoms from the same ring atom or from two different ring atoms, i.e., "cycloalkylene", "heterocyclylene", "arylene", "heteroarylene".

The term "amino protecting group" refers to a group that is easily removed by introduction onto an amino group in order to keep the amino group unchanged during the reaction at other sites of the molecule. Non-limiting examples include, but are not limited to, (trimethylsilanyl) ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, and 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 suitable group known in the art for hydroxy protection, non-limiting examples include: trimethylsilyl (TMS), Triethylsilyl (TES), Triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl and the like.

The term "cycloalkyloxy" refers to cycloalkyl-O-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 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 the group-NH₂。

The term "cyano" refers to — CN.

The term "nitro" means-NO₂。

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 disclosed compounds may exist in specific 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, as well as racemic and other mixtures thereof, such as 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, as well as mixtures thereof, are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.

In the chemical structure of the compounds described in this disclosure, a bond "

"denotes an unspecified configuration, i.e. if chiral isomers, bonds, are present in the chemical structure"

Can be "

'or'

", or both"

"and"

"two configurations. In the chemical structure of the compounds described in this disclosure, a bond "

"configuration not specified, i.e.can be Z configuration or E configurationOr both configurations. For all carbon-carbon double bonds, both Z-and E-forms 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 present 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 referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine, lactam-lactam isomerizations. Examples of lactam-lactam equilibria.

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

The disclosure also includes some isotopically-labeled compounds of the present disclosure that are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as respectively²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、¹²³I、¹²⁵I and³⁶cl, and the like. Such compounds are useful as analytical tools or probes in, for example, biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.

The disclosure also includes various deuterated forms of the compounds. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane in tetrahydrofuran, deuterated lithium aluminum hydrides, deuterated iodoethanes, and deuterated iodomethanes, among others. Unless otherwise stated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). The compound of examples can have a natural abundance of deuterium greater than that of deuterium of at least 1000 times the abundance of deuterium, deuterium of at least 2000 times the abundance of deuterium, deuterium of at least 3000 times the abundance of deuterium, deuterium of at least 4000 times the abundance of deuterium, deuterium of at least 5000 times the abundance of deuterium, deuterium of at least 6000 times the abundance of deuterium, or deuterium of greater abundance.

"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 optionally substituted by halogen or cyano_1-6Alkyl "means that halogen or cyano may, 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, preferably 1 to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure, which may be selected from inorganic or organic salts. The salt has safety and effectiveness when used in a mammal body, and has due biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group 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 acids as well as 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 desired effect. The 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, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

The term "solvate" as used herein refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. The physical bonding includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated into the crystal lattice of a crystalline solid, 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.

By "prodrug" is meant a compound that can be converted in vivo under physiological conditions, for example, by hydrolysis in blood, to yield the active parent compound.

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 effective for the intended use.

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

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

Synthesis of the Compounds of the disclosure

In order to achieve the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

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 is carried out on the compound of the general formula (IA) or salt (preferably hydrochloride) thereof and the compound of the general formula (V) in the presence of alkali under microwave condition to obtain the compound of the general formula (I) or pharmaceutically acceptable salt thereof;

wherein:

is selected from

Provided that

Is composed of

When R is⁰Is not methyl;

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

Scheme two

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

nucleophilic substitution reaction is carried out on the compound of the general formula (IIA) or salt (preferably hydrochloride) thereof and the compound of the general formula (V) in the presence of alkali under the microwave condition to obtain the compound of the general formula (II) or pharmaceutically acceptable salt thereof;

wherein:

is selected from

Provided that

Is composed of

When R is⁰Is not methyl;

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

W¹、W²、X、Y、Z、R⁰、R¹～R³m and n are as defined in formula (II).

Scheme three

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 is carried out on the compound of the general formula (IIIA-1) or salt (preferably hydrochloride) thereof and the compound of the general formula (V) in the presence of alkali under the microwave condition to obtain the compound of the general formula (III-1) or pharmaceutically acceptable salt thereof;

wherein:

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

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

R⁰、R¹～R³m and n are as defined in the general formula (III-1).

Scheme four

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 is carried out on the compound of the general formula (IIIA-2) or salt (preferably hydrochloride) thereof and the compound of the general formula (V) in the presence of alkali under the microwave condition to obtain the compound of the general formula (III-2) or pharmaceutically acceptable salt thereof;

wherein:

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

y and Z are the same or different and are each independently selected from 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 a nitrogen atom, an oxygen atom and a sulfur atom; (ii) a

R⁰、R¹～R³M and n are as defined in the general formula (III-2).

The base comprises organic base and inorganic base, the organic base comprises but is not limited to triethylamine, N-diisopropylethylamine, N-butyl lithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and N, N-diisopropylethylamine is preferred; 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 microwave reaction is 100-160 ℃, and preferably 130 ℃.

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

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not 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). NMR shift (. delta.) of 10^-6The units in (ppm) are given. NMR was measured using Bruker AVANCE-400 NMR spectrometer or Bruker AVANCE NEO 500M in deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS).

MS was measured using an Agilent 1200/1290DAD-6110/6120Quadrupole MS LC MS (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultratate 3000-Q active (manufacturer: THERMO, MS model: THERMO Q active).

High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 HPLC.

Chiral HPLC assay using Agilent 1260DAD HPLC.

High Performance liquid preparation A preparative chromatograph was used from Waters 2767, Waters 2767-SQ Detector 2, Shimadzu LC-20AP and Gilson-281.

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

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

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by 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.

Silica gel column chromatography generally uses 200-300 mesh silica gel of wakame as a carrier.

Average inhibition rate of kinase and IC₅₀The values were determined with a NovoStar microplate reader (BMG, Germany).

Known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan ChemBiotech (Accela ChemBio Inc), Darril Chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

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

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: n-hexane/ethyl acetate system, B: the volume ratio of the solvent in the dichloromethane/methanol system is adjusted according to the polarity of the compound, and a small amount of basic 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] annulen-5-yl) amino) pyrimidine-2, 4(1H,3H) -dione 1

First step of

6-chloro-3-isopropylpyrimidine-2, 4(1H,3H) -dione 1a (100mg, 0.53mmol, prepared as disclosed in the patent application WO2014205223A1, page 23, example 1.3) and 6,7,8, 9-tetrahydro-5H-benzo [ 7.7]Rotalen-5-amine 1b (100mg, 0.62mmol, Jeldavir (Shanghai) pharmaceutical science and technology development Co., Ltd.) was dissolved in anhydrous dioxane (2.0mL), and N, N-diisopropylethylamine (340mg, 2.63mmol) was added. Microwave reaction at 130 deg.c for 1 hr. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (Boston Phlex C18,5 μm,30 mm. about.150 mm, elution system: H)₂O (10mM ammonium bicarbonate), acetonitrile, from 35% (v/v) to 95% (v/v) in 20 minutes, detection wavelength 214&254nm) to yield the title product 1(30mg, 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 1-1,1-2

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

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

Compound 1(20mg, 0.0638mmol) was subjected to chiral preparation (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: 20mL/min), and the corresponding fractions were collected and concentrated under reduced pressure to give the title product (5.0mg, 10 mg).

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

chiral HPLC analysis: retention time 13.889 minutes, chiral purity: 100% (column: CHIRALPAK IF 0.46cm i.d. × 15cmL,5 μ M; mobile phase: n-hexane/ethanol (containing 0.1% diethylamine) ═ 95/5 (V/V). MS M/z (esi):314.0[ M +1 ].

Compound of single configuration (longer retention time, 10mg, yield: 50%):

chiral HPLC analysis: retention time 16.562 minutes, chiral purity: 91.9% (column: CHIRALPAK IF 0.46cm I.F.. times.15 cm L,5 μ M; mobile phase: n-hexane/ethanol (containing 0.1% diethylamine): 95/5 (V/V). MS M/z (ESI):314.0[ M +1 ].

Example 2

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

First step of

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

Compound (S) -chroman-4-amine 2a (150.0mg, 1.0mmol, Jiangsu Aikang biomedical research and development Co., Ltd.), compound 1a (208.6mg, 1.1mmol) and N, N-diisopropylethylamine (648.5mg, 5.0mmol) were dissolved in anhydrous dioxane (3 mL). Microwave reaction at 130 deg.c for 1 hr. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (Welch Ultimate XB-C18,5 μm,30mm × 150mm, elution system: H₂O(10mM NH₄HCO₃) Acetonitrile, acetonitrile from 25% (v/v) to 95% (v/v) in 15 minutes, detection wavelength 214&254nm) to give the title product 2(30.0mg, 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 of

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

Compound (R) -chroman-4-amine 3a (50.0mg, 0.3mmol, Shanghai Tantake Technique, Co., Ltd.), compound 1a (69.6mg, 0.4mmol) and N, N-diisopropylethylamine (216.2mg, 1.7mmol) were dissolved in anhydrous dioxane (1 mL). Microwave reaction at 130 deg.c for 1 hr. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (Welch Ultimate XB-C18,5 μm,30mm × 150mm, elution system: H₂O(10mM NH₄HCO₃)、Acetonitrile, acetonitrile from 25% (v/v) to 95% (v/v) in 15 minutes, detection wavelength 214&254nm) to give the title product 3(6.0mg, 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 ] oxepin-1-yl) amino) pyrimidine-2, 4(1H,3H) -dione 4

First step of

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

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

MS m/z(ESI):161.1[M+1]。

Second step of

4, 5-dihydrobenzo [ d ] oxepin-1 (2H) -one 4c

To a solution of compound 4b (450.0mg, 2.8mmol) in dichloromethane (30mL) at-70 ℃ was bubbled ozone for about 30 minutes until the reaction solution was saturated with ozone. Nitrogen was then introduced for about 30 minutes until the reaction solution was saturated with nitrogen. Triphenylphosphine (883.1mg, 3.4mmol, Chemicals group, Inc., national pharmaceuticals) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 4c (320.0mg, yield: 70.2%).

MS m/z(ESI):163.1[M+1]。

The third step

(R) -N- (4, 5-dihydrobenzo [ d ] oxepin-1 (2H) -ylidene)) -2-methylpropane-2-sulfinamide 4d

To compound 4c (320.0mg, 2.0mmol) and (R) -2-methylpropane-2-sulfinamide (478.3mg, 4.0mmol, Shanghai Tanta Tech Co., Ltd.) in anhydrous tetrahydrofuran (10mL), tetraethoxytitanium (1.5g, 2.2mmol, Shanghai Tanta Tech Co., Ltd.) was added. The reaction was refluxed for 8 hours. Saturated aqueous sodium bicarbonate (30mL) was added and extracted with ethyl acetate (50 mL. times.2). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 4d (190.0mg, yield: 36.3%).

MS m/z(ESI):266.1[M+1]。

The fourth step

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

To a solution of compound 4d (190.0mg, 0.7mmol) in anhydrous tetrahydrofuran (3mL) at-78 deg.C, a 1M solution of lithium tri-sec-butylborohydride in tetrahydrofuran (1.2mL, 1.2mmol, Shanghai Tantake Techno Co., Ltd.) was added dropwise. The reaction was carried out at 0 ℃ for 1 hour. Saturated aqueous ammonium chloride (20mL) was added and extracted with ethyl acetate (30 mL. times.2). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 4e (180.0mg, yield: 95.0%).

MS m/z(ESI):268.1[M+1]。

The fifth step

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

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

MS m/z(ESI):147.1[M-16]。

The sixth step

The crude compound 4f (144.0mg, 0.7mmol), compound 1a (135.8mg, 0.7mmol) and N, N-diisopropylethylamine (465.4mg, 3.6mmol) were dissolved in anhydrous 1, 4-dioxane (2 mL). Microwave reaction is carried out for 2 hours at 130 ℃. Concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex Prep C18,5 μm,30 mM. times.150 mM, elution: water (10mM ammonium bicarbonate), acetonitrile, which rose from 25% (v/v) to 45% (v/v) over 15 minutes, detection wavelength 214&254nm) to give the title product 4(49.1mg, 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 ] oxepin-5-yl) amino) pyrimidine-2, 4(1H,3H) -dione 5

First step of

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

To but-3-en-1-ol 5b (1.5g, 20.8mmol, Annagi chemical) in anhydrous tetrahydrofuran (40mL) at 0 deg.C was added sodium hydride (749.1mg, 18.7mmol, 60% content, national chemical group, Ltd.). The reaction was carried out at room temperature for 30 minutes under nitrogen. 1-bromo-2- (bromomethyl) benzene 5a (3.9g, 15.6mmol, Shaoshima technologies Co., Ltd.) was added and reacted at room temperature for 16 hours. Saturated aqueous ammonium chloride (40mL) was added and extracted with ethyl acetate (50 mL. times.2). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 5c (3.7g, yield: 87.7%).

MS m/z(ESI):241.1[M+1]。

Second step of

5-Methylidene-1, 3,4, 5-tetrahydrobenzo [ d ] oxepine 5d

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

MS m/z(ESI):161.1[M+1]。

The third step

3, 4-dihydrobenzo [ c ] oxepin-5 (1H) -one 5e

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

MS m/z(ESI):163.1[M+1]。

The fourth step

(R) -N- (3, 4-dihydrobenzo [ c ] oxepin-5 (1H) -ylidene)) -2-methylpropane-2-sulfinamide 5f

To compound 5e (530.0mg, 3.3mmol) and (R) -2-methylpropane-2-sulfinamide (792.2mg, 6.5mmol) in dry tetrahydrofuran (10mL) was added titanium tetraethoxide (1.5g, 6.5 mmol). The reaction was refluxed for 16 hours. Saturated aqueous sodium bicarbonate (30mL) was added and extracted with ethyl acetate (50 mL. times.2). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration, concentration under reduced pressure and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 5f (600.0mg, yield: 69.2%).

MS m/z(ESI):266.1[M+1]。

The fifth step

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

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

MS m/z(ESI):268.1[M+1]。

The sixth step

(S) -1,3,4, 5-Tetrahydrobenzo [ c ] oxepin-5-amine hydrochloride 5h

Compound 5g (570.0mg, 2.1mmol) was dissolved in methanol (4mL) and a 4M solution of hydrogen chloride in 1, 4-dioxane (2.2mL) was added dropwise. The reaction was carried out at room temperature for 1 hour. Concentration under reduced pressure gave the title product as crude 5h (450.0mg) 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 ] oxepin-5-yl) amino) pyrimidine-2, 4(1H,3H) -dione 5

Compound 5h crude (450.0mg, 2.3mmol), compound 1a (472.4mg, 2.5mmol) and N, N-diisopropylethylamine (1.6g, 12.5mmol) were dissolved in anhydrous 1, 4-dioxane (5 mL). Microwave reaction is carried out for 2 hours at 130 ℃. Concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex Prep C18,5 μm,30 mM. times.150 mM, elution: water (10mM ammonium bicarbonate), acetonitrile, which rose from 25% (v/v) to 50% (v/v) within 15 minutes, detection wavelength 214&254nm) to give the title product 5(200.0mg, 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 further described and explained below in conjunction with test examples, but these examples are not meant to limit the scope of the present disclosure.

Test example 1 compounds of the disclosure have an inhibitory effect 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 summarized below:

first, experimental material and instrument

1. Myocardial Actin (Cardiac Actin) (Cytoskeleton, AD99)

2. Myosin Motor Protein S1 Fragment (Myosin Motor Protein S1 Fragment) (Cytoskeleton, CS-MYS03)

3.ATP(Sigma，A7699-1G)

4.UltraPure^TM1M Tris-HCI buffer, pH 7.5(Thermo, 15567027)

5.CytoPhos^TMPhosphate detection biological Kit (Phosphate Assay Biochem Kit) (Cytoskeleton, BK054)

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

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

8.EGTA(Sigma，E3889-100G)

9.96 well plate (Corning 3697)

U type bottom 96-well plate (Corning, 3795)

11. Enzyme mark instrument (BMG, PHERAStar)

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

Second, the experimental procedure

Myocardial actin was mixed at 1.61. mu.M, myosin motor protein S1 fragment 0.07. mu.M with different concentrations of small molecule compounds (first concentration 100. mu.M, 3-fold gradient dilution 9 concentrations) and incubated at 37 ℃ for 1 hour. Further 120. mu.M ATP was added and incubated at 37 ℃ for 2 hours. Finally, Cytophos was added to each well^TMThe detection solution (70. mu.L/well) in the phosphate detection biosafety was incubated at room temperature for 10 min. Reading OD value of 650nM wavelength with microplate reader, calculating Pi production according to standard curve,data were processed using GraphPad software, and inhibition curves were plotted against each concentration of compound and the corresponding inhibition, and the concentration of compound at which the inhibition reached 50%, i.e., IC, was calculated₅₀The value is obtained. The results are detailed in table 1.

TABLE 1 inhibition of myosin ATPase by compounds of this disclosure

Example numbering	IC₅₀(μM)
		1	1.31
Compounds corresponding to shorter retention times in 1-1 and 1-2	0.45
		Compounds corresponding to longer retention times in 1-1 and 1-2	5.18
4	3.96
		5	4.37

And (4) conclusion: the compounds of the present disclosure have good inhibitory effects on myosin ATPase.

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

is selected from

R¹selected from hydrogen atoms, halogens and alkyl groups;

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

each R is⁵Are identical to each otherOr are different and are each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R⁰is alkyl or

L₁is a bond or (CH)₂)_r；

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

R⁶selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each 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;

R⁷is selected fromHydrogen atom, alkyl group, alkenyl group, alkynyl group, halogenated alkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group;

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 is

t is 0, 1 or 2;

provided that

When R is⁰Is not methyl.

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

wherein:

is selected from

Provided that

When R is⁰Is not methyl;

W¹、W²、X、Y、Z、R⁰、R¹～R³m and n are as defined in claim 1.

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or2, wherein W¹And W²Are the same or different and are each independently a carbon atom or an oxygen atom.

4. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, which is a compound represented by the general formula (III-1):

wherein:

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

R⁰、R¹～R³m and n are as defined in claim 1.

5. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, which is a compound represented by the general formula (III-2):

wherein:

R⁰、R¹～R³m and n are as defined in claim 1.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R⁰Is C_1-6An alkyl group; preferably, R⁰Is isopropyl.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R¹Is a hydrogen atom or a halogen.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R²Selected from hydrogen atoms, halogens, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6A haloalkoxy group; preferably, R²Is a hydrogen atom.

9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R³Is a hydrogen atom.

10. A compound of general formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:

11. a process for the preparation of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises:

carrying out nucleophilic substitution reaction on the compound of the general formula (IA) or the salt thereof and the compound of the general formula (V) to obtain the compound of the general formula (I) or the pharmaceutically acceptable salt thereof;

wherein:

is selected from

Provided that

When R is⁰Is not methyl;

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

U¹～U⁴、W¹、W²、X、Y、Z、R⁰、R¹～R³m and n are as defined in claim 1.

12. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, and one or more pharmaceutically acceptable carriers, diluents or excipients.

13. Use of a compound of formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, in the manufacture of a medicament for the preparation of a Myosin (Myosin) inhibitor.

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