CN110698415B

CN110698415B - Myosin inhibitor and preparation method and application thereof

Info

Publication number: CN110698415B
Application number: CN201911001762.2A
Authority: CN
Inventors: 胡立宏; 王均伟
Original assignee: Shanghai Xianxing Pharmaceutical Co ltd
Current assignee: Shanghai Xianxing Pharmaceutical Co ltd
Priority date: 2019-10-21
Filing date: 2019-10-21
Publication date: 2023-05-09
Anticipated expiration: 2039-10-21
Also published as: CN110698415A

Abstract

The invention relates to the field of pharmaceutical chemistry, in particular to a myosin inhibitor, a preparation method and application thereof. The invention provides a compound or pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, wherein the chemical structural formula of the compound is shown in a formula I. The compounds provided by the invention or pharmaceutically acceptable salts, isomers, prodrugs, polymorphs or solvates thereof have superior activity and more desirable pharmacokinetic properties than other similar drugs in the prior art.

Description

Myosin inhibitor and preparation method and application thereof

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a myosin inhibitor, a preparation method and application thereof.

Background

Hypertrophic cardiomyopathy (hypertrophic cardiomyopathy, HCM) is a cardiomyopathy characterized by cardiac hypertrophy, which is mainly manifested by thickening of the left ventricular wall, left ventricular filling and blocked blood outflow, and reduced diastolic compliance. The left ventricular outflow tract is classified into an obstructive hypertrophic cardiomyopathy and a non-obstructive hypertrophic cardiomyopathy according to the presence or absence of obstruction. HCM has a prevalence of about 1/500 in the population and is characterized by a variety of clinical manifestations, including effort-induced dyspnea, chest distress, palpitations, syncope, etc. There may be no obvious symptoms, but once symptoms appear, the disease may be gradually worsened, and the disease is a progressive disease with significant accumulation of the disease load. The main threats are serious complications such as arrhythmia, sudden cardiac death, arterial embolism, infectious endocarditis, heart failure and the like, which endanger lives. The annual mortality rate of HCM is 1-2%, which is one of the main causes of sudden death in teenagers and athletes. In addition, hypertrophic cardiomyopathy is also one of the most common heart diseases in cats, and can be found in multiple breeds such as american short-haired cats (89.1%), bos cats (6.5%), american long-haired cats (2.2%), and pachinko cat (2.2%), which can lead to sudden death of the cat.

The etiology of HCM is not yet clear, with a clear familial genetic predisposition, most HCM is autosomally dominant inherited, and clear pathogenic gene mutations are detectable in about 60% of adult HCM patients. Current studies show that about 1400 mutations in 11 genes encoding sarcomere or regional thick, thin muscle silk contractile proteins between adjacent Z discs are associated with HCM pathogenesis. The most common mutations among these are the genes MYH7 and MYBPC3 encoding the β -myosin heavy chain and myosin binding protein C, accounting for over 70%. Other genes including TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, etc. each account for a small fraction (1-5%). ( Carolyn y.ho et al cardioview res.2015;105 (4):397-408 )

The HCM related gene mutation can cause myocardial remodeling by changing myocardial contractility, influencing the sensibility of myocardial cells to calcium ions, influencing the energy metabolism of myocardial cells and the like, and has the advantages of myocardial fiber arrangement disorder, abnormal morphology, myocardial cell compensatory hyperplasia and hypertrophy.

Myosin and actin are the material basis for myocardial contraction, and the myosin transverse bridge is periodically combined and dissociated with actin to drive myofilament to slide, so that myocardial contraction is caused. Myosin has atpase activity and provides the motive force for myocardial contraction by hydrolyzing ATP. Myoglobin mutation causes prolonged binding time of myoglobin and actin, excessive contraction and relaxation of left ventricular myocardium are damaged, left ventricular myocardial hypertrophy and fibrosis are caused, and HCM is triggered. Inhibition of myosin ATPase can produce negative myogenic effects, and relieve pathological changes such as myocardial hypertrophy caused by excessive contraction of left ventricular myocardium.

At present, HCM is mainly treated by medicaments and non-medicaments, and can reduce the stenosis of an outflow tract and improve the diastole function by reducing the myocardial contractility. The non-drug treatment mainly comprises ventricular septum ablation treatment, ventricular septum hypertrophic excision operation and the like. Drug therapies include beta blockers, calcium channel blockers, propidium, and the like. The medicine mainly improves symptoms, can not aim at etiology, delays the development of myocardial hypertrophy, does not change prognosis, and has limited treatment effect. The clinic still lacks ideal therapeutic approaches for HCM.

MYK-461 is a pyrimidine diketone myosin allosteric inhibitor in development, and can inhibit excessive myocardial contraction caused by HCM, and relieve left ventricular outflow obstruction. But the elimination in vivo is slow, the residence time of the drug in vivo is too long (the half-life of the human body is presumed to be 9 days), and rapid dose adjustment is inconvenient (Mark p. Grillo et al xenobiotic, 2019;49 (6): 718-733). Therefore, the development of myosin inhibitors with better activity and more desirable pharmacokinetic properties is of great clinical value and significance.

Furthermore, left ventricular hypertrophy and/or diastolic dysfunction can also be seen in the pathological course of a variety of cardiovascular diseases, such as diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina and restrictive cardiomyopathy, chronic mitral regurgitation, chronic aortic stenosis, chronic systemic hypertension, etc., and myosin atpase inhibitors can also exert potential therapeutic effects in alleviating the pathological course of the above diseases by inhibiting myocardial contraction.

Disclosure of Invention

In view of the above-mentioned drawbacks of the prior art, an object of the present invention is to provide an myosin inhibitor, and a preparation method and use thereof, for solving the problems of the prior art.

To achieve the above and other related objects, in one aspect, the present invention provides a compound or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, wherein the chemical structural formula of the compound is shown in formula I:

wherein X is selected from H, F, cl, br or I;

R ¹ selected from optionally at least singulationSubstituted C ₁ -C ₈ Alkyl, optionally at least monosubstituted C ₃ -C ₈ Cycloalkyl, optionally at least monosubstituted C ₃ -C ₈ cycloalkyl-C ₁ -C ₄ Alkyl, optionally at least monosubstituted 4-to 7-membered heterocycloalkyl, optionally at least monosubstituted phenyl-C ₁ -C ₄ Alkyl, optionally at least monosubstituted 5-to 6-membered heteroaryl-C ₁ -C ₄ Alkyl, said R ¹ In C ₁ -C ₈ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₃ -C ₈ cycloalkyl-C ₁ -C ₄ Alkyl, 4-to 7-membered heterocycloalkyl, phenyl-C ₁ -C ₄ Alkyl, 5-to 6-membered heteroaryl-C ₁ -C ₄ The substituents of the alkyl groups are each independently selected from halogen, CN, hydroxy, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, phenyl-C ₁ -C ₄ Alkyl, phenyl-C ₁ -C ₄ Alkoxy, phenoxy, -COR ^a1 、-CO ₂ R ^a1 、SO ₂ R ^a1 、SO ₂ NR ^a1 and-CONR ^a1 R ^a2 Wherein R is ^a1 And R is ^a2 Each independently selected from H, C ₁ -C ₄ Alkyl and phenyl, or R ^a1 And R is ^a2 Forming a 4-to 6-membered heterocycloalkyl group with the bridged nitrogen atom;

R ² selected from H, halogen, CN, hydroxy, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, phenyl-C ₁ -C ₄ Alkyl, phenyl-C ₁ -C ₄ Alkoxy, phenoxy, -COR ^a3 ，-CO ₂ R ^a3 ，SO ₂ R ^a3 ，SO ₂ NR ^a3 R ^a4 ，-CONR ^a3 R ^a4 ，NR ^a3 R ^a4 A 5-to 6-membered heteroaryl, a 5-to 6-membered heterocycloalkyl, wherein R ^a3 And R is ^a4 Each independently selected from H, C ₁ -C ₄ Alkyl, phenyl, or R ^a3 And R is ^a4 Forming a heterocycloalkyl group with the bridged nitrogen atom.

In some embodiments of the invention, X is selected from H and F.

In some embodiments of the invention, R ¹ Selected from optionally at least monosubstituted C ₁ -C ₈ Alkyl, optionally at least monosubstituted C ₃ -C ₈ Cycloalkyl, optionally at least monosubstituted C ₃ -C ₈ cycloalkyl-C ₁ -C ₄ Alkyl, optionally at least monosubstituted 4-to 7-membered heterocycloalkyl, optionally at least monosubstituted phenyl, optionally at least monosubstituted 5-to 6-membered heteroaryl, said R ¹ In C ₁ -C ₈ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₃ -C ₈ cycloalkyl-C ₁ -C ₄ Substituents for alkyl, 4-to 7-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl are each independently selected from halogen.

In some embodiments of the invention, R ¹ A group selected from one of:

in some embodiments of the invention, R ² Selected from H, halogen, C ₁ -C ₄ An alkoxy group.

In some embodiments of the invention, the isomer is selected from the group consisting of enantiomers, diastereomers, cis-trans isomers, or stereoisomers.

In some embodiments of the invention, the compound is selected from:

(S) -3-isopropyl-6- ((1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1 h,3 h) -dione;

(R) -3-isopropyl-6- ((1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1 h,3 h) -dione;

(S) -3-isopentyl-6- ((1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1 h,3 h) -dione;

(S) -3-cyclobutyl-6- ((1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1 h,3 h) -dione;

6- (((S) - (1, 2,3, 4-tetrahydronaphthyl)) amino) -3- (4, 4-trifluoro-2-butyl) pyrimidine-2, 4 (1 h,3 h) -dione;

(S) -3- (tetrahydro-2H-4-pyranyl) -6- (((1- (1, 2,3, 4-tetrahydronaphtyl)) amino) pyrimidine-2, 4 (1H, 3H) -dione;

(S) -3- (4- (piperidine-1-carboxylic acid tert-butyl ester group)) -6- (((1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1 h,3 h) -dione;

(S) -3- (4-piperidinyl) -6- (((1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1 h,3 h) -dione;

(S) -3-phenyl-6- (((1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1 h,3 h) -dione;

(S) -3- (2-pyridinyl) -6- (((1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1 h,3 h) -dione;

(S) -3- (3, 5-difluorophenyl) -6- (((1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1 h,3 h) -dione;

(S) -5-fluoro-3-isopropyl-6- (((1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1 h,3 h) -dione;

(S) -5-chloro-3-isopropyl-6- (((1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1 h,3 h) -dione;

(S) -5-bromo-3-isopropyl-6- (((1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1 h,3 h) -dione;

(S) -3-isopropyl-6- ((5-methoxy-1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1 h,3 h) -dione;

(S) -3-isopropyl-6- ((6-methoxy-1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1 h,3 h) -dione;

(S) -3-isopropyl-6- ((7-methoxy-1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1 h,3 h) -dione;

(S) -3-isopropyl-6- ((5-amino-1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1 h,3 h) -dione;

(S) -3-isopropyl-6- ((6-amino-1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1 h,3 h) -dione;

(S) -3-isopropyl-6- ((7-amino-1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1 h,3 h) -dione;

(S) -6- ((5-fluoro- (1, 2,3, 4-tetrahydronaphthyl)) amino) -3-isopropylpyrimidine-2, 4 (1 h,3 h) -dione;

(S) -6- ((6-fluoro- (1, 2,3, 4-tetrahydronaphthyl)) amino) -3-isopropylpyrimidine-2, 4 (1 h,3 h) -dione;

(S) -6- ((7-fluoro- (1, 2,3, 4-tetrahydronaphthyl)) amino) -3-isopropylpyrimidine-2, 4 (1 h,3 h) -dione;

(S) -6- ((5-chloro- (1, 2,3, 4-tetrahydronaphthyl)) amino) -3-isopropylpyrimidine-2, 4 (1 h,3 h) -dione;

(S) -6- ((6-chloro- (1, 2,3, 4-tetrahydronaphthyl)) amino) -3-isopropylpyrimidine-2, 4 (1 h,3 h) -dione;

(S) -6- ((7-chloro- (1, 2,3, 4-tetrahydronaphthyl)) amino) -3-isopropylpyrimidine-2, 4 (1 h,3 h) -dione;

(S) -6- ((5-bromo- (1, 2,3, 4-tetrahydronaphthyl)) amino) -3-isopropylpyrimidine-2, 4 (1 h,3 h) -dione;

(S) -6- ((6-bromo- (1, 2,3, 4-tetrahydronaphthyl)) amino) -3-isopropylpyrimidine-2, 4 (1 h,3 h) -dione;

(S) -6- ((7-bromo- (1, 2,3, 4-tetrahydronaphthyl)) amino) -3-isopropylpyrimidine-2, 4 (1 h,3 h) -dione;

(S) -3-isopropyl-6- ((4-methyl-1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1 h,3 h) -dione.

In another aspect the invention provides the use of the compound or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof in the manufacture of a medicament.

In some embodiments of the invention, the drug is selected from myosin inhibitors;

in some embodiments of the invention, the medicament is selected from the group consisting of medicaments for treating heart diseases, preferably from the group consisting of medicaments for treating diastolic and/or systolic dysfunction, more preferably from the group consisting of medicaments for treating heart diseases associated with left ventricular hypertrophy and/or diastolic dysfunction, further preferably from the group consisting of medicaments for treating hypertrophic cardiomyopathy, diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris and restrictive cardiomyopathy, chronic mitral regurgitation, chronic aortic valve stenosis, chronic systemic hypertension.

In another aspect, the invention provides a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, and at least one pharmaceutically acceptable carrier, additive, adjuvant or excipient.

Drawings

FIG. 1 is a graph showing the effect of example 7 of the present invention on the systolic blood pressure of the left ventricle of the isolated heart of a rat.

FIG. 2 shows a schematic representation of the effect of example 7 of the invention on rat isolated heart left chamber +dP/dt.

FIG. 3 shows a schematic representation of the effect of example 7 of the invention on rat left ventricle-dP/dt in vitro.

FIG. 4 is a graph showing the intravenous and oral administration of I-1 drug to rats in example 7 of the present invention.

Detailed Description

In order to make the objects, technical solutions and advantageous technical effects of the present invention more apparent, the present invention will be further described in detail with reference to the following examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the disclosure of the present specification.

The present inventors have made extensive practical studies to provide a novel compound which is a myosin inhibitor and has superior activity and more desirable pharmacokinetic properties than MYK-461 commonly used in the prior art, and have completed the present invention on the basis of this.

The first aspect of the present invention provides a compound or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, wherein the chemical structural formula of the compound is shown in formula I:

wherein X is selected from H, F, cl, br or I;

R ¹ selected from optionally at least monosubstituted C ₁ -C ₈ Alkyl, optionally at least monosubstituted C ₃ -C ₈ Cycloalkyl, optionally at least monosubstituted C ₃ -C ₈ cycloalkyl-C ₁ -C ₄ Alkyl, optionally at least monosubstituted 4-to 7-membered heterocycloalkyl, optionally at least monosubstituted phenyl-C ₁ -C ₄ Alkyl, optionally at least monosubstituted 5-to 6-membered heteroaryl-C ₁ -C ₄ Alkyl, said R ¹ In C ₁ -C ₈ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₃ -C ₈ cycloalkyl-C ₁ -C ₄ Alkyl, 4-to 7-membered heterocycloalkyl, phenyl-C ₁ -C ₄ Alkyl, 5-to 6-membered heteroaryl-C ₁ -C ₄ The substituents of the alkyl groups are each independently selected from halogen, CN, hydroxy, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, phenyl-C ₁ -C ₄ Alkyl, phenyl-C ₁ -C ₄ Alkoxy, phenoxy, -COR ^a1 、-CO ₂ R ^a1 、SO ₂ R ^a1 、SO ₂ NR ^a1 and-CONR ^a1 R ^a2 Wherein R is ^a1 And R is ^a2 Each independently selected from H, C ₁ -C ₄ Alkyl and phenyl, or R ^a1 And R is ^a2 Forming a 4-to 6-membered heterocycloalkyl group with the bridged nitrogen atom;

Isotopically-labeled forms of the compounds of the present invention are also encompassed within the scope of the present invention unless otherwise indicated. For example, in the compounds having the structures of the invention given above, at least one hydrogen atom is replaced by deuterium or tritium, or at least one carbon is replaced by ¹³ C-or ¹⁴ C-enriched carbon substitution, or at least one nitrogen is replaced ¹⁵ N-enriched nitrogen substitution.

In the present invention, the term "salt" shall be understood as any form of active compound used by the present invention, wherein the compound may be in ionic form or charged or coupled to a counter ion (cation or anion) or in solution. This definition may also include quaternary ammonium salts and complexes of active molecules with other molecules and ions, particularly complexes through ionic interactions. This definition includes, inter alia, physiologically acceptable salts, which term is to be understood as being equivalent to "pharmacologically acceptable salts".

In the present invention, the term "pharmaceutically acceptable salt" generally refers to any salt that is physiologically tolerable (generally, meaning that it is non-toxic, in particular as a result of counter ions) when used in a suitable manner for treatment, in particular for application or use in humans and/or mammals. These physiologically acceptable salts may be formed with cations or bases and in the context of the present invention, in particular when administered in humans and/or mammals, they are understood to be salts formed from at least one compound provided according to the present invention, typically an acid (deprotonated), such as an anion and at least one physiologically tolerated cation, preferably an inorganic cation. In the context of the present invention, it is possible in particular to include salts with alkali metals and alkaline earth metals, and salts with ammonium cations (NH) ₄ ⁺ ) The salts formed may specifically be salts including, but not limited to, salts with (mono) or (di) sodium, (mono) or (di) potassium, magnesium or calcium. These physiologically acceptable salts can also be formed with anions or acids and are of interest in the present inventionIn the following, in particular when administered in humans and/or mammals, they are understood to be salts formed from at least one compound provided according to the present invention, typically protonated (e.g. on nitrogen), such as a cation and at least one physiologically tolerable anion. In the context of the present invention, salts formed with physiologically tolerable acids, i.e. salts of the specific active compounds with physiologically tolerable organic or inorganic acids, may be included in particular, including but not limited to, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.

The compounds of the invention represented by formula I above may include enantiomers depending on the chiral center present or isomers depending on the double bond present (e.g. Z, E). Single isomers, enantiomers, diastereomers or cis-trans isomers and mixtures thereof are all within the scope of the present invention.

The term "prodrug" is used in its broadest sense in the present invention and includes those derivatives which can be converted in vivo to the compounds of the present invention. Methods for preparing prodrugs of the indicated active compounds should be known to those skilled in the art, for example, see, e.g., krogsgaard-Larsen et al, "pharmaceutical design and discovery textbook" (Textbook of Drug design and Discovery) Taylor & Francis, U.S. Purpurease, 2002.

In the present invention, the term "solvate" generally refers to any form of active compound according to the present invention, which is bound to another molecule (usually a polar solvent) by a non-covalent bond, and the substances obtained may in particular include, but are not limited to, hydrates and alcoholates, such as methanolate.

In the present invention, the "halogen" or "halo" generally refers to fluorine, chlorine, bromine or iodine.

In the present invention, the "alkyl" groups generally refer to saturated aliphatic groups, which may be straight or branched. For example, C _1-8 Alkyl is generally meant to include 1, 2, 3Alkyl groups of 4, 5, 6, 7, 8 carbon atoms, which may specifically be, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and the like.

In the present invention, "cycloalkyl" generally refers to a saturated or unsaturated (but not aromatic) cyclic hydrocarbon having a carbon atom. For example, C _3-8 Cycloalkyl generally refers to saturated or unsaturated (but not aromatic) cyclic hydrocarbons having 3, 4, 5, 6, 7, 8 carbon atoms, which may specifically be, but is not limited to, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, noradamantyl, and the like.

In the present invention, "haloalkyl" generally refers to halogenated saturated aliphatic groups which may be straight or branched chain and which may optionally be mono-or polysubstituted independently selected from fluorine, chlorine, bromine or iodine. For example, C _1-4 Haloalkyl generally refers to haloalkyl groups comprising 1, 2, 3, 4 carbon atoms, which can be specifically, including but not limited to, halomethyl, haloethyl, halopropyl, halobutyl, and the like.

In the present invention, "heterocycloalkyl" generally refers to a saturated or unsaturated (but not aromatic) cyclic hydrocarbon and has at least one heteroatom in its structure selected from N, O or S. The heterocycloalkyl group may specifically be, but is not limited to, pyrroline, pyrrolidine, pyrazoline, aziridine, azetidine, tetrahydropyrrole, oxirane, oxetane, dioxetane, tetrahydropyran, tetrahydrofuran, dioxane, dioxolane, oxazolidine, piperidine, piperazine, morpholine, azepane, or diazepane, and the like. Heterocycloalkyl groups in the present invention are typically 4, 5, 6 or 7 membered ring systems.

In the present invention, "heteroaryl" generally refers to a heterocyclic ring system having at least one aromatic ring and which may optionally contain one or more heteroatoms selected from N, O. The heteroaryl group may specifically be, but is not limited to, furan, benzofuran, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, phthalazine, triazole, pyrazole, isoxazole, indole, benzotriazole, benzodioxole, benzodioxan, benzimidazole, carbazole, quinazoline, and the like. Heteroaryl groups in the present invention may be 5 or 6 membered ring systems.

In some preferred embodiments of the invention, X is selected from H and F.

In some preferred embodiments of the invention, R ¹ In C ₁ -C ₈ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₃ -C ₈ cycloalkyl-C ₁ -C ₄ Alkyl, 4-to 7-membered heterocycloalkyl, phenyl-C ₁ -C ₄ Alkyl, 5-to 6-membered heteroaryl-C ₁ -C ₄ The alkyl groups may each independently be optionally monosubstituted or polysubstituted, i.e. each independently may be unsubstituted, monosubstituted or polysubstituted, in particular optionally may be substituted by 1, 2, 3 substituents.

In some preferred embodiments of the invention, R ¹ Selected from optionally at least monosubstituted C ₁ -C ₈ Alkyl, optionally at least monosubstituted C ₃ -C ₈ Cycloalkyl, optionally at least monosubstituted C ₃ -C ₈ cycloalkyl-C ₁ -C ₄ Alkyl, optionally at least monosubstituted 4-to 7-membered heterocycloalkyl, optionally at least monosubstituted phenyl, optionally at least monosubstituted 5-to 6-membered heteroaryl, said R ¹ In C ₁ -C ₈ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₃ -C ₈ cycloalkyl-C ₁ -C ₄ Substituents for alkyl, 4-to 7-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl are each independently selected from halogen.

In some preferred embodiments of the invention, R ¹ Selected from optionally at least monosubstituted C ₁ -C ₈ Alkyl, C ₃ -C ₈ Cycloalkyl, 4-to 7-membered heterocycloalkyl, optionally at least monosubstituted phenyl, 5-to 6-membered heteroaryl, said R ¹ In C ₁ -C ₈ Substituents of the alkyl and phenyl are each independently selected from F.

In some further preferred embodiments of the invention, R ¹ Selected from the followingA group shown in:

in some preferred embodiments of the invention, R ² Selected from H, halogen, C ₁ -C ₄ An alkoxy group.

In some further preferred embodiments of the invention, the compound may be a compound as shown in table 1:

TABLE 1

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In a second aspect, the present invention provides a process for the preparation of a compound as provided in the first aspect of the present invention, comprising: reacting a compound of formula 4 with a compound of formula 5 to produce a compound of formula I.

In the preparation method provided by the invention, the reaction can be carried out in the presence of the acid-binding agent, and a person skilled in the art can select an appropriate type and amount of the acid-binding agent to be used for the condensation reaction. For example, the acid-binding agent may be an organic base and/or an inorganic base, and specifically may be a combination of one or more of N, N-diisopropylethylamine, triethylamine, DBU, pyridine, sodium carbonate, potassium carbonate, cesium carbonate, or the like, including but not limited to. In a preferred embodiment of the present invention, the acid binding agent may be N, N-diisopropylethylamine and/or triethylamine. For another example, the acid-binding agent may be used in an amount of 2 to 4 times, 2 to 2.5 times, 2.5 to 3 times, 3 to 3.5 times, or 3.5 to 4 times the amount of the compound of formula 4.

In the preparation methods provided by the present invention, the compound of formula 5 is generally used in an amount substantially equal to or in excess of the compound of formula 4, e.g., the molar ratio of the compound of formula 5 to the compound of formula 4 may be 1-4:1, 1-1.2:1, 1.2-1.4:1, 1.4-1.6:1, 1.6-1.8:1, 1.8-2:1, 2-2.5:1, 2.5-3:1, 3-3.5:1, or 3.5-4:1. In general, when the compound of formula 5 is in a large excess, the reaction may be carried out without adding an acid-binding agent, for example, when the molar ratio of the compound of formula 5 to the compound of formula 4 exceeds 3:1, the reaction may be carried out without adding an acid-binding agent.

In the preparation method provided by the invention, the reaction can be generally carried out under the condition of room temperature to the boiling point of the reaction solvent, preferably under the condition of heating, for example, the reaction temperature can be 80-100 ℃, preferably can be 90-100 ℃. The reaction time of the condensation reaction can be appropriately adjusted by those skilled in the art according to the reaction progress, and the method of monitoring the reaction progress should be known to those skilled in the art, and may be, for example, an analytical method such as chromatography, nuclear magnetic resonance, etc., and the specific reaction time may be, for example, 12 to 24 hours, 12 to 16 hours, 16 to 20 hours, or 20 to 24 hours.

In the preparation method provided by the invention, the reaction is usually carried out in the presence of a solvent, and the solvent can be a good solvent of the reaction raw materials, so that the reaction raw materials can be fully dispersed to ensure the smooth progress of the reaction. The type and amount of suitable reaction solvent should be known to those skilled in the art, and for example, the reaction solvent may be one or more combinations of dioxane, ethylene glycol dimethyl ether, toluene, xylene, DMF, DMSO, or the like.

In the preparation method provided by the present invention, the reaction may be generally carried out under a gas-shielded condition, and a suitable method for providing a gas-shielded condition should be known to those skilled in the art, for example, the gas-shielded condition may be provided by nitrogen and/or a rare gas, and may specifically be one or more combinations including, but not limited to, nitrogen, helium, neon, argon, krypton, and the like.

In the preparation method provided by the invention, a person skilled in the art can select a proper method to post-treat the reaction product, and for example, the method can include: extracting, desolventizing and purifying the organic phase.

Among the preparation methods provided by the present invention, the preparation methods of the compounds of formula 4 are known to those skilled in the art, and for example, reference may be made to CN105473576, WO2019028360, or the like.

In a third aspect, the present invention provides the use of a compound provided in the first aspect of the invention, or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, in the manufacture of a medicament. As described above, the compound provided by the present invention or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof can be used as a myosin inhibitor to inhibit myocardial contraction, and thus can be used as a medicament for treating diseases such as diastole and/or systolic dysfunction (excessive or insufficient), preferably for improving ventricular diastole in diastole, and for treating cardiac diseases associated with left ventricular hypertrophy and/or diastolic dysfunction, more preferably for treating hypertrophic cardiomyopathy. The compounds of the invention, or pharmaceutically acceptable salts, isomers, prodrugs, polymorphs, or solvates thereof, may specifically target the cause of the disease or act on other downstream pathways. The compounds provided herein, or pharmaceutically acceptable salts, isomers, prodrugs, polymorphs, or solvates thereof, may also provide benefit to patients suffering from diastolic heart failure, ischemic heart disease, angina, or restrictive cardiomyopathy with a retained ejection fraction. The compounds provided herein, or pharmaceutically acceptable salts, isomers, prodrugs, polymorphs, or solvates thereof, may also promote beneficial ventricular remodeling of left ventricular hypertrophy due to excessive volume or pressure complexation, e.g., chronic mitral regurgitation, chronic aortic stenosis, or chronic systemic hypertension, etc. These drugs are combined with therapies aimed at correcting or alleviating the primary cause of volume or pressure overload (including valve repair/replacement or effective antihypertensive therapies, etc.). By lowering left ventricular filling pressure, the compounds may reduce the risk of pulmonary edema and respiratory failure. Reducing or eliminating functional mitral regurgitation and/or reducing left atrial pressure may reduce the risk of sudden or permanent atrial fibrillation, and it reduces the concomitant risk of arterial thromboembolic complications including, but not limited to, cerebral arterial embolic stroke. Reducing or eliminating dynamic and/or static left ventricular outflow tract obstruction may reduce the likelihood of requiring intermittent ablative treatment (surgical or percutaneous) and the attendant risks of short-term and long-term complications thereof. The compounds or pharmaceutically acceptable salts, isomers, prodrugs, polymorphs, or solvates thereof may reduce the severity of the chronic ischemic state associated with HCM and thereby reduce the risk of sudden cardiac death or equivalent disease thereof in patients with implantable cardioverter-defibrillators and/or reduce the need for potentially toxic antiarrhythmic drugs. The compound or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof is effective in reducing or eliminating the need for concomitant medications, and also in reducing interstitial myocardial fibrosis and/or slowing the progression of left ventricular hypertrophy, preventing or reversing left ventricular hypertrophy.

In a fourth aspect, the present invention provides a pharmaceutical composition comprising a compound provided in the first aspect of the present invention or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, which may further comprise at least one pharmaceutically acceptable carrier.

In the present invention, the composition may include one or more pharmaceutically acceptable carriers, which generally refer to carriers for administration of therapeutic agents that do not themselves induce the production of antibodies harmful to the individual receiving the composition, and which are not overly toxic after administration. Such carriers are well known to those skilled in the art, and related content is disclosed, for example, in Remington's Pharmaceutical Sciences (Mack Pub.Co., N.J.1991) for pharmaceutically acceptable carriers. In particular, the carrier may be a combination including, but not limited to, one or more of saline, buffer, glucose, water, glycerol, ethanol, adjuvants, and the like.

In the pharmaceutical composition provided by the invention, the compound can be a single active ingredient or can be combined with other active components to form a combined preparation. The other active components can be other various medicines which can be used for heart diseases and hypertrophic cardiomyopathy. The amount of active ingredient in the composition will generally be a safe and effective amount which should be adjustable to the skilled person, e.g. the amount of active ingredient of the compound and pharmaceutical composition to be administered will generally depend on the patient's body weight, the type of application, the condition and severity of the disease, e.g. the amount of the compound to be administered as active ingredient may generally be 0.1 to 1000mg/kg/day, 20 to 200mg/kg/day, 0.1 to 0.3mg/kg/day, 0.3 to 0.5mg/kg/day, 0.5 to 1mg/kg/day, 1 to 3mg/kg/day, 3 to 5mg/kg/day, 5 to 10mg/kg/day, 10 to 20mg/kg/day, 20 to 30mg/kg/day, 30 to 40mg/kg/day, 40 to 60mg/kg/day, 60 to 80mg/kg/day, 80 to 100 mg/day, 100mg to 1 mg/day, 150mg to 300 mg/day, 500 mg/day.

The compounds provided herein may be adapted for any form of administration, be it oral or parenteral, for example, be it pulmonary, nasal, rectal and/or intravenous, more particularly intradermal, subcutaneous, intramuscular, intra-articular, intraperitoneal, pulmonary, buccal, sublingual, nasal, transdermal, vaginal, oral or parenteral. The skilled artisan can select a suitable formulation depending on the mode of administration, for example, a formulation suitable for oral administration may be a formulation including, but not limited to, a pill, tablet, chew, capsule, granule, drop, or syrup, etc., and for further example, a formulation suitable for parenteral administration may be a formulation including, but not limited to, a solution, suspension, reconstitutable dry preparation, spray, etc., and for further example, a suppository may be generally suitable for rectal administration.

In a fifth aspect, the invention provides a method of treatment comprising: administering to the individual a therapeutically effective amount of a compound provided in the first aspect of the invention, or a pharmaceutical composition provided in the fourth aspect of the invention.

In the present invention, "individual" generally includes human, non-human primates, such as mammals, dogs, cats, horses, sheep, pigs, cattle, etc., which may benefit from treatment with the formulation, kit or combination.

In the present invention, a "therapeutically effective amount" generally means an amount that, after a suitable period of administration, achieves the effect of treating the diseases as set forth above.

Compared with other similar medicines in the prior art, the compound provided by the invention or pharmaceutically acceptable salts, isomers, prodrugs, polymorphs or solvates thereof have better activity and more ideal pharmacokinetic properties, and have good industrialization prospect.

The invention of the present application is further illustrated by the following examples, which are not intended to limit the scope of the present application.

Example 1

Preparation of (S) -3-isopropyl-6- ((1- (1, 2,3, 4-tetrahydro-1-naphtyl)) amino) pyrimidine-2, 4 (1H, 3H) -dione (I-1)

Synthesis of iprodione 2 a: isopropylamine (5.13 g,86.80 mmol) was dissolved in anhydrous CH ₂ Cl ₂ (25 mL), cooled to 0℃and trimethylsilyl isocyanate (10.01 g,86.80 mmol) was added dropwise to the reaction solution under argon. After the completion of the dropwise addition, the reaction was stirred at room temperature overnight. After the completion of the reaction by LC/MS detection, the reaction mixture was cooled to 0℃and 8mL of anhydrous methanol was added dropwise, followed by stirring at room temperature for 3 hours. Concentrating under reduced pressure, adding diethyl ether into the residue, washing and filtering, and drying the filter cake at 50 ℃ to obtain 6.12g of white solid with the yield of 69.1%. LC/MS (ESI) ⁺ ):m/z 103[M+H] ⁺ .

Synthesis of 1-isopropyl barbituric acid 3 a: 2a (6.12 g,59.95 mmol) was dissolved in CH ₃ OH (20 mL), dimethyl malonate (8.31 g,62.95 mmol) and sodium methoxide (16.19 g,299.76 mmol) were added thereto, and the mixture was stirred under argon at 65℃overnight. After the completion of the reaction, the reaction mixture was cooled to 0℃and pH 3 was adjusted with concentrated hydrochloric acid. Concentrated under reduced pressure, the residue was dissolved in anhydrous EtOH (65 mL) and stirred at room temperature for 2.5h. Suction filtration, concentration of the filtrate, column chromatography purification (CH ₂ Cl ₂ :CH ₃ Oh=100:1 as eluent) to yield 7g of white solid in 68.6%. ¹ H NMR(500MHz,DMSO-d ₆ )δ(ppm):11.20(s,1H),4.82(m,1H),3.57(s,2H),1.32(d,J＝6.9Hz,6H).LC/MS(ES+):m/z 171[M+H] ⁺ .

Synthesis of 6-chloro-3-isopropylpyrimidine-2, 4 (1H, 3H) -dione 4 a: 3a (7 g,41.16 mmol) and triethylbenzyl ammonium chloride (18.75 g,82.32 mmol) were dissolved in POCl ₃ (45 mL) was stirred at 50deg.C overnight under argon. TLC (CH) ₂ Cl ₂ :CH ₃ Oh=20:1) and the reaction of the starting materials was detected, the reaction was stopped, and cooled to room temperature. Concentrating under reduced pressure, dissolving the residue in CH ₂ Cl ₂ (70 mL), water (70 mL) was slowly added thereto, the mixture was washed by extraction, and the organic layer was separated, followed by H ₂ O (250 mL) and saturated sodium chloride (250 mL) were each washed once and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate and column chromatography purification (petroleum ether: ethyl acetate=1:4 as eluent) gave 1.15g of yellow solid in 14.9% yield. ¹ H NMR(500MHz,CDCl ₃ -d ₆ )δ(ppm):10.07(s,1H),5.84(s,1H),5.14(m,1H),1.48(d,J＝7Hz,6H).

Synthesis of I-1: 4a (400 mg,2.13 mmol) and (S)1,2,3, 4-tetrahydro-1-naphthylamine 5a (627 mg,4.26 mmol) was dissolved in 1, 4-dioxane (10 mL), DIPEA (284 mg,6.38 mmol) was added, and the mixture was stirred under nitrogen at 95℃for 20h. TLC (CH) ₂ Cl ₂ :CH ₃ Oh=20:1) detecting that the raw materials were reacted completely, stopping the reaction, cooling to room temperature, concentrating under reduced pressure, and adding CH ₂ Cl ₂ (50 mL) was dissolved, 0.16mmol/mL diluted hydrochloric acid (40 mL) was extracted and washed, the organic layer was further washed with saturated sodium chloride (150 mL. Times.2), dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated, and purified by column chromatography (CH ₂ Cl ₂ :CH ₃ Oh=150:1 as eluent) and slurried with a mixed solvent (ethyl acetate: n-hexane=1:1) to give 145mg of a white solid in 22.8% yield. ¹ H NMR(500MHz,DMSO-d ₆ )δ(ppm):9.67(s,1H),7.27-7.17(m,3H),7.14(d,J＝7.4Hz,1H),6.39(s,1H),4.99(m,1H),4.77(s,1H),4.64-4.57(m,1H),2.74(m,2H),1.95-1.85(m,1H),1.82-1.72(m,3H),1.33(d,J＝6.9Hz,6H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ(ppm):163.87,151.96,150.95,137.67,136.54,129.43,129.06,127.82,126.55,73.61,49.51,42.81,29.02,28.92,19.91,19.52.HRMS(ESI):m/z[M+H] ⁺ calcd for C ₁₇ H ₂₂ N ₃ O ₂ 300.1712；found 300.1697

Example 2

Preparation of (R) -3-isopropyl-6- ((1- (1, 2,3, 4-tetrahydro-1-naphtyl)) amino) pyrimidine-2, 4 (1H, 3H) -dione (I-2)

Synthesis of I-2: using compound 4a (500 mg,2.65 mmol) and (R) -1,2,3, 4-tetrahydro-1-naphthylamine 5b (781 mg,5.30 mmol) as starting materials, the same procedure as for I-1 gave 96mg of a yellow solid with a yield of 12.1%. ¹ H NMR(500MHz,DMSO-d ₆ )δ(ppm):9.67(s,1H),7.27-7.17(m,3H),7.14(d,J＝7.4Hz,1H),6.39(s,1H),4.99(m,1H),4.78(s,1H),4.65-4.57(m,1H),2.83-2.66(m,2H),1.89(m,1H),1.82-1.70(m,3H),1.33(d,J＝6.9Hz,6H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ(ppm):163.86,151.95,150.94,137.67,136.53,129.44,129.08,127.83,126.56,73.59,49.48,42.78,29.00,28.92,19.91,19.51.HRMS(ESI):m/z[M+H] ⁺ calcd for C ₁₇ H ₂₂ N ₃ O ₂ 300.1712；found 300.1694

Example 3

Preparation of (S) -3- (3-pentyl) -6- ((1, 2,3, 4-tetrahydro-1-naphtyl) amino) pyrimidine-2, 4 (1H, 3H) -dione (I-3)

Synthesis of 1- (3-pentyl) urea 2 b: 3-aminopentane (3 g,34.42 mmol) was dissolved in anhydrous CH ₂ Cl ₂ (20 mL), cooled to 0℃and trimethylsilyl isocyanate (3.97 g,34.42 mmol) was added dropwise to the reaction solution under argon. After the completion of the dropwise addition, the reaction was stirred at room temperature overnight. After completion of the LC/MS detection reaction, the reaction mixture was cooled to 0℃and 10mL of anhydrous methanol was added dropwise, followed by stirring at room temperature for 2 hours. Concentrating under reduced pressure, adding diethyl ether into the residue, washing and filtering, and drying the filter cake at 50 ℃ to obtain 3.69g of white solid with the yield of 82.4%. LC/MS (ES+): m/z 131[ M+H ]] ⁺ . ¹ H NMR(500MHz,CDCl ₃ )δ(ppm):4.31(s,2H),4.24(s,1H),3.54-3.43(m,1H),1.61-1.53(m,2H),1.45-1.35(m,2H),0.94(t,J＝7.4Hz,6H).

Synthesis of 1- (3-pentyl) barbituric acid 3 b: 2b (2.7 g,20.74 mmol) in CH ₃ OH (12 mL), dimethyl malonate (2.88 g,21.78 mmol) and sodium methoxide (5.6 g,103.70 mmol) were added and the reaction was stirred overnight at 65℃under argon. After the completion of the reaction, the reaction mixture was cooled to 0℃and pH 3 was adjusted with concentrated hydrochloric acid. Concentrated under reduced pressure, the residue was dissolved in anhydrous EtOH (50 mL) and stirred at room temperature for 1.5h. Suction filtration, concentration of the filtrate, column chromatography purification (CH ₂ Cl ₂ :CH ₃ Oh=100:1 as eluent) to give 1.4g of white solid in 36.6% yield. ¹ H NMR(500MHz,CDCl ₃ )δ(ppm):7.94(s,1H),4.60(s,1H),3.67(s,2H),2.07-1.96(m,2H),1.84-1.74(m,2H),0.88(t,J＝7.5Hz,6H).LC/MS(ES+):m/z 199[M+H] ⁺ .

Synthesis of 6-chloro-3- (3-pentyl) pyrimidine-2, 4 (1H, 3H) -dione 4 b: 3b (1.4 g,6.48 mmol) and triethylbenzyl ammonium chloride (2.95 g,12.96 mmol) were dissolved in POCl ₃ (20 mL) was stirred at 50deg.C overnight under argon. TLC (CH) ₂ Cl ₂ :CH ₃ Oh=20:1) and the reaction of the starting materials was detected, the reaction was stopped, and cooled to room temperature. Concentrating under reduced pressure, dissolving the residue in CH ₂ Cl ₂ (40 mL), slowly adding water (50 mL), extracting and washing, separating organic layers, and using H respectively ₂ O (150 mL) and saturated sodium chloride (150 mL) were each washed once and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, column chromatography purification (CH ₂ Cl ₂ :CH ₃ Oh=150:1 as eluent) to afford 671mg as a white solid in 43.8% yield. ¹ H NMR(500MHz,CDCl ₃ )δ(ppm):10.71(s,1H),5.86(s,1H),4.77(s,1H),2.08(d,J＝14.8Hz,2H),1.83-1.74(m,2H),0.88(t,J＝7.5Hz,6H).

Synthesis of I-3: 4b (600 mg,2.77 mmol) and (S) -1,2,3, 4-tetrahydro-1-naphthylamine 5a (815 mg,5.54 mmol) were dissolved in 1, 4-dioxane (13 mL), DIPEA (1.789 g,13.85 mmol) was added and stirred under nitrogen at 90℃for 24h. TLC (CH) ₂ Cl ₂ :CH ₃ Oh=20:1) detecting that the raw materials were reacted completely, stopping the reaction, cooling to room temperature, concentrating under reduced pressure, and adding CH ₂ Cl ₂ (50 mL) was dissolved, 0.16mmol/mL diluted hydrochloric acid (50 mL) was extracted and washed, the organic layer was further washed with saturated sodium chloride (150 mL. Times.2), dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated, and purified by column chromatography (CH ₂ Cl ₂ :CH ₃ Oh=150:1 as eluent) and pulping with a mixed solvent (ethyl acetate: n-hexane=1:1) to give white279mg of coloured solid was obtained in 30.8% yield. ¹ H NMR(500MHz,DMSO-d ₆ )δ(ppm):9.62(s,1H),7.28-7.17(m,3H),7.14(d,J＝7.0Hz,1H),6.39(s,1H),4.82-4.72(s,1H),4.62(s,1H),4.51-4.33(m,1H),2.75(m,2H),12.04-1.93(m,2H),1.92-1.87(m,1H),1.83-1.72(m,3H),1.67-1.57(m,2H),0.76(t,J＝7.3Hz,6H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ(ppm):164.83,152.09,137.69,136.53,129.44,129.11,127.84,126.54,114.76,72.96,53.88,49.52,28.98,28.92,24.72,19.49,11.57.HRMS(ESI):m/z[M+H] ⁺ calcd for C ₁₉ H ₂₆ N ₃ O ₂ 328.2025；found 328.2005

Example 4

Preparation of (S) -3-cyclobutyl-6- ((1, 2,3, 4-tetrahydro-1-naphtyl) amino) pyrimidine-2, 4 (1H, 3H) -dione (I-4)

Synthesis of 1-cyclobutylurea 2 b: 3-aminopentane (1.85 g,26.04 mmol) was dissolved in anhydrous CH ₂ Cl ₂ (15 mL), cooled to 0℃and trimethylsilyl isocyanate (3.0 g,26.04 mmol) was added dropwise to the reaction solution under argon. After the completion of the dropwise addition, the reaction was stirred at room temperature overnight. After the completion of the LC/MS detection reaction, the reaction mixture was cooled to 0℃and 8mL of anhydrous methanol was added dropwise, followed by stirring at room temperature for 1.5 hours. Concentrating under reduced pressure, adding diethyl ether into the residue, washing and filtering, and drying the filter cake at 50 ℃ to obtain 2.77g of white solid with the yield of 93.3%. LC/MS (ES+): m/z 115[ M+H ]] ⁺ .1H NMR(500MHz,CDCl ₃ )δ(ppm):4.78(s,1H),4.40(s,2H),4.11(d,J＝7.0Hz,1H),2.42-2.32(m,2H),1.86(m,2H),1.73(m,2H).

Synthesis of 1-cyclobutylbarbituric acid 3 c: 2c (1.5 g,13.14 mmol) was dissolved in CH ₃ OH (10 mL), dimethyl malonate (2.60 g,19.71 mmol) and sodium methoxide (3.55 g,65.71 mmol) were added, under argon,the reaction was stirred at 65℃overnight. After the completion of the reaction, the reaction mixture was cooled to 0℃and pH 3 was adjusted with concentrated hydrochloric acid. Concentrated under reduced pressure, the residue was dissolved in anhydrous EtOH (40 mL) and stirred at room temperature for 1h. Suction filtration, concentration of the filtrate, column chromatography purification (CH ₂ Cl ₂ :CH ₃ Oh=100:1 as eluent) to give 1.1g of white solid in 44.6% yield. ¹ H NMR(500MHz,CDCl ₃ )δ(ppm):8.12(s,1H),5.06(p,J＝9.0Hz,1H),3.64(s,2H),2.85-2.73(m,2H),2.29(dd,J＝17.2,8.7Hz,2H),1.92(dd,J＝20.8,10.1Hz,1H),1.76(dd,J＝19.0,8.9Hz,1H).LC/MS(ES+):m/z 199[M+H] ⁺ .

Synthesis of 6-chloro-3-cyclobutylpyrimidine-2, 4 (1H, 3H) -dione 4 c: 3c (1.07 g,5.86 mmol) and triethylbenzyl ammonium chloride (1.87 g,8.20 mmol) were dissolved in POCl ₃ (20 mL) was stirred at 50deg.C overnight under argon. TLC (CH) ₂ Cl ₂ :CH ₃ Oh=20:1) and the reaction of the starting materials was detected, the reaction was stopped, and cooled to room temperature. Concentrating under reduced pressure, dissolving the residue in CH ₂ Cl ₂ (40 mL), water (50 mL) was slowly added, the mixture was washed by extraction, and the organic layer was separated and then purified with H ₂ O (150 mL) and saturated sodium chloride (150 mL) were each washed once and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, column chromatography purification (CH ₂ Cl ₂ :CH ₃ Oh=150:1 as eluent) to give 450mg of white solid in 38.3% yield. ¹ H NMR(500MHz,CDCl ₃ )δ(ppm):9.34(s,1H),5.83(s,1H),5.27-5.18(m,1H),2.99-2.87(m,2H),2.25(dd,J＝17.3,8.6Hz,2H),1.92(dd,J＝20.2,10.1Hz,1H),1.82-1.71(m,1H).

Synthesis of I-4: 4c (400 mg,1.99 mmol) and (S) -1,2,3, 4-tetrahydro-1-naphthylamine 5a (587 mg,3.99 mmol) were dissolved in 1, 4-dioxane (10 mL), DIPEA (773 mg,5.98 mmol) was added under nitrogenStirring is carried out at 90℃for 24h. TLC (CH) ₂ Cl ₂ :CH ₃ Oh=20:1) detecting that the raw materials were reacted completely, stopping the reaction, cooling to room temperature, concentrating under reduced pressure, and adding CH ₂ Cl ₂ (50 mL) was dissolved, 0.16mmol/mL diluted hydrochloric acid (40 mL) was extracted and washed, the organic layer was further washed with saturated sodium chloride (50 mL. Times.2), dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated, and purified by column chromatography (CH ₂ Cl ₂ :CH ₃ Oh=100:1 as eluent) and slurried with a mixed solvent (ethyl acetate: n-hexane=1:1) to give 150mg of a white solid in 24.2% yield. ¹ H NMR(500MHz,DMSO-d ₆ )δ(ppm):9.75(s,1H),7.25-7.16(m,3H),7.14(d,J＝7.6Hz,1H),6.42(s,1H),5.26-5.14(m,1H),4.78(s,1H),4.66-4.57(m,1H),2.95-2.85(m,2H),2.83-2.66(m,2H),2.05-1.98(m,2H),1.93-1.84(m,1H),1.81-1.74(m,3H),1.70-1.60(m,1H),1.27-1.22(m,2H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ(ppm):163.98,152.05,151.37,137.66,136.54,129.43,128.97,127.81,126.55,73.48,49.53,45.10,29.08,28.91,27.23,19.56,14.74.HRMS(ESI):m/z[M+H]+calcd for C18H22N3O2 312.1712；found 312.1694

Example 5

Preparation of (S) -3- (4-tetrahydropyranyl) -6- ((1, 2,3, 4-tetrahydro-1-naphtyl) amino) pyrimidine-2, 4 (1H, 3H) -dione (I-6)

Synthesis of 1- (4-tetrahydropyranyl) urea 2 d: 4-Aminotetrahydropyran (878 mg,8.68 mmol) was dissolved in anhydrous CH ₂ Cl ₂ (10 mL), cooled to 0℃and trimethylsilyl isocyanate (1.0 g,8.68 mmol) was added dropwise to the reaction solution under argon. After the completion of the dropwise addition, the reaction was stirred at room temperature overnight. After the completion of the reaction by LC/MS detection, the reaction mixture was cooled to 0℃and 8mL of anhydrous methanol was added dropwise, followed by stirring at room temperature for 1 hour. Concentrating under reduced pressure, adding diethyl ether into the residue, washing and filtering, and drying the filter cake at 50 ℃ to obtain 427mg of white solid with the yield of 34.1%. ¹ H NMR(500MHz,CH ₃ OD)δ(ppm):3.95-3.89(m,2H),3.71-3.63(m,1H),3.49(m,J＝11.6,2.1Hz,2H),1.86(m,J＝12.6,2.1Hz,2H),1.51-1.40(m,2H).LC/MS(ES+):m/z 145[M+H] ⁺ .

Synthesis of 1- (4-tetrahydropyranyl) barbituric acid 3 d: 2d (452 mg,3.14 mmol) was dissolved in CH ₃ OH (10 mL), dimethyl malonate (435 mg,3.29 mmol) and sodium methoxide (423 mg,7.84 mmol) were added thereto, and the mixture was stirred overnight at 65℃under argon. After the completion of the reaction, the reaction mixture was cooled to 0℃and pH was adjusted to 5 with concentrated hydrochloric acid. Concentrated under reduced pressure, the residue was dissolved in anhydrous EtOH (40 mL) and stirred at room temperature for 0.5h. Suction filtration and concentration of the filtrate gave 550mg of a white solid in 89.0% yield. ¹ H NMR(500MHz,CDCl ₃ )δ(ppm):8.29(s,1H),4.82-4.90(m,J＝12.3,4.0Hz,1H),4.10(dd,J＝11.5,4.5Hz,2H),3.66(d,J＝12.6Hz,2H),3.48-3.43(m,2H),2.62-2.70(m,2H),1.62-1.53(m,2H).LC/MS(ES+):m/z 213[M+H] ⁺ .

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Synthesis of 6-chloro-3- (4-tetrahydropyranyl) pyrimidine-2, 4 (1H, 3H) -dione 4 d: 3d (500 mg,2.36 mmol) and triethylbenzyl ammonium chloride (751 mg,3.30 mmol) were dissolved in POCl ₃ (6 mL) was stirred at 50deg.C overnight under argon. TLC (CH) ₂ Cl ₂ :CH ₃ Oh=20:1) and the reaction of the starting materials was detected, the reaction was stopped, and cooled to room temperature. Concentrating under reduced pressure, dissolving the residue in CH ₂ Cl ₂ (40 mL), water (50 mL) was slowly added, the mixture was washed by extraction, and the organic layer was separated and then purified with H ₂ O (100 mL) and saturated sodium chloride (100 mL) were each washed once and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, column chromatography purification (CH ₂ Cl ₂ :CH ₃ Oh=150:1 as eluent) to give 357mg of white solid in 65.7% yield. ¹ H NMR(500MHz,CDCl ₃ )δ(ppm):9.52(s,1H),5.86(s,1H),4.94-5.04(m,1H),4.09(dd,J＝11.4,4.3Hz,2H),3.50(t,J＝11.4Hz,2H),2.70-2.80(m,2H),1.55(d,J＝9.9Hz,2H).

Synthesis of I-6: 4d (120 mg,0.52 mmol) and (S) -1,2,3, 4-tetrahydro-1-naphthylamine 5a (305 mg,2.08 mmol) are dissolved in 1, 4-dioxane (5 mL) and stirred under nitrogen at 90℃for 24h. TLC (CH) ₂ Cl ₂ :CH ₃ Oh=20:1) detecting that the raw materials were reacted completely, stopping the reaction, cooling to room temperature, concentrating under reduced pressure, and adding CH ₂ Cl ₂ (50 mL) dissolution, H ₂ O (60 mL) and the organic layer was washed with saturated sodium chloride (60 mL. Times.2), dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated, and purified by column chromatography (CH ₂ Cl ₂ :CH ₃ Oh=100:1 as eluent) and slurried with a mixed solvent (ethyl acetate: n-hexane=1:1) to give 64mg of a white solid in 36% yield. ¹ H NMR(500MHz,CDCl ₃ )δ(ppm):9.69(s,1H),7.28-7.11(m,4H),5.03(s,1H),4.99(s,1H),4.97-4.92(m,1H),4.56-4.52(m,1H),3.99(dd,J＝11.3,4.1Hz,1H),3.91(dd,J＝12.0,3.8Hz,1H),3.42(td,J＝11.5,5.2Hz,2H),2.90-2.75(m,2H),2.69-2.52(m,2H),2.08-2.00(m,2H),1.82-1.98(m,3H),1.46-1.52(m,2H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ(ppm):163.78,152.08,151.10,137.68,136.51,129.43,129.03,127.82,126.55,73.54,67.66,49.55,48.44,29.19,29.06,28.92,19.53.

Example 6

Preparation of (S) -3- (4- (tert-butyl-piperidine-1-carboxylate)) -6- (((1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1H, 3H) -dione (I-7)

Synthesis of 1- (N-Boc-4-piperidinyl) urea 2 e: N-Boc-4-aminopiperidine (2.61 g,13.04 mmol) was dissolved in dry CH ₂ Cl ₂ (18 mL), cooled to 0℃and trimethylsilyl isocyanate (1.5 g,13.04 mmol) was added dropwise to the reaction solution under argon. After the dripping is finishedThe reaction was stirred overnight at room temperature. After completion of the LC/MS detection reaction, the reaction mixture was cooled to 0℃and 10mL of anhydrous methanol was added dropwise, followed by stirring at room temperature for 2 hours. Concentrating under reduced pressure, adding diethyl ether into the residue, washing and filtering, and drying the filter cake at 50 ℃ to obtain 2.28g of white solid with the yield of 71.9%. ¹ H NMR(500MHz,CDCl ₃ )δ(ppm):4.48(d,J＝7.6Hz,1H),4.36(s,2H),4.05(s,2H),3.78-3.69(m,1H),2.87(s,2H),1.96(d,J＝11.0Hz,2H),1.47(s,9H),1.29(d,J＝11.3Hz,2H).LC/MS(ES+):m/z 244[M+H] ⁺ .

Synthesis of 1- (N-Boc-piperidinyl) barbituric acid 3 e: 2e (2.28 g,9.38 mmol) was dissolved in CH ₃ OH (12 mL), dimethyl malonate (1.30 g,9.85 mmol) and sodium ethoxide (1.56 g,23.45 mmol) were added and the reaction stirred overnight at 65℃under argon. After the completion of the reaction, the reaction mixture was cooled to 0℃and pH was adjusted to 4 with concentrated hydrochloric acid. Concentrating under reduced pressure, dissolving the residue in CH ₂ Cl ₂ (60 mL), slowly adding water (60 mL), extracting and washing, separating out an organic layer, and then using H respectively ₂ O (150 mL) and saturated sodium chloride (150 mL) were each washed once and dried over anhydrous sodium sulfate. . Suction filtration, concentration of the filtrate, use of n-hexane: ethyl acetate=1:3 was slurried to give 2.20g of a white solid in 75.4% yield. ¹ H NMR(500MHz,CDCl ₃ )δ(ppm):11.26(s,1H),5.36(s,2H),4.63(s,1H),3.79(d,J＝12.4Hz,2H),2.82(s,3H),2.22(d,J＝9.7Hz,2H),1.53(d,J＝10.8Hz,2H),1.41(s,9H).LC/MS(ES+):m/z 312[M+H] ⁺ .

Synthesis of 6-chloro-3- (4-piperidinyl) pyrimidine-2, 4 (1H, 3H) -dione hydrochloride 4 e: 3e (1.0 g,3.21 mmol) was dissolved in POCl ₃ (12 mL) was slowly dropped in 0.35mL of pure water under an ice bath, and the mixture was stirred at 80℃under argon atmosphere for 4 hours. TLC (CH) ₂ Cl ₂ :CH ₃ Oh=20:1) detectionStopping the reaction after the reaction of the raw materials is finished, and cooling to room temperature. Concentrating under reduced pressure, pulping with ethanol to obtain 737mg of white solid with 86.3% yield. ¹ H NMR(500MHz,DMSO)δ(ppm):12.38(s,1H),9.12(s,1H),8.43(s,1H),5.93(s,1H),4.93-4.80(m,1H),3.32(d,J＝12.0Hz,2H),2.98(dd,J＝23.1,11.4Hz,2H),2.73-2.62(m,2H),1.72(d,J＝12.6Hz,2H).

Synthesis of 6-chloro-3- (N-Boc-4-piperidinyl) pyrimidine-2, 4 (1H, 3H) -dione 6 e: 4e (737 mg,2.77 mmol) was dissolved in tetrahydrofuran (10 mL), 0.45mL of triethylamine was added, and the mixture was added dropwise at room temperature (Boc) ₂ A tetrahydrofuran solution (10 mL) of O was reacted at 70℃under reflux for 13h. TLC (CH) ₂ Cl ₂ :CH ₃ Oh=20:1) after the reaction of the starting materials was detected, the reaction was stopped, cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (CH ₂ Cl ₂ :CH ₃ Oh=100:1 as eluent) to give 808mg of white solid in 88.5% yield. ¹ H NMR(500MHz,DMSO)δ(ppm):12.30(s,1H),5.87(s,1H),4.75(t,J＝12.0Hz,1H),4.02(s,2H),2.73(s,2H),2.38-2.30(m,2H),1.50(d,J＝9.9Hz,2H),1.41(s,9H).

Synthesis of I-4: 5e (200 mg,0.61 mmol) and (S) -1,2,3, 4-tetrahydro-1-naphthylamine 5a (356 mg,2.43 mmol) are dissolved in 1, 4-dioxane (10 mL) and stirred under nitrogen at 120deg.C for 24h. TLC (CH) ₂ Cl ₂ :CH ₃ Oh=20:1) detecting that the raw materials were reacted completely, stopping the reaction, cooling to room temperature, concentrating under reduced pressure, and adding CH ₂ Cl ₂ Dissolving (50 mL), extracting with 1mol/L dilute hydrochloric acid (20 mL), washing the organic layer with saturated sodium chloride (50 mL. Times.2), drying over anhydrous sodium sulfate, suction filtering, concentrating the filtrate, and purifying by column Chromatography (CH) ₂ Cl ₂ :CH ₃ Oh=100:1 as eluent) and pulping with a mixed solvent (ethyl acetate: n-hexane=1:1) to give a white solid 86mg, yield 32.2%. ¹ H NMR(500MHz,DMSO-d ₆ )δ(ppm):9.75(s,1H),7.25-7.18(m,3H),7.14(d,J＝7.6Hz,1H),6.44(s,1H),4.81(s,1H),4.80-4.74(m,1H),4.65-4.60(m,1H),4.07-3.98(m,2H),2.82-2.66(m,4H),2.42-2.34(m,2H),1.94-1.85(m,1H),1.81-1.72(m,3H),1.46-1.42(m,2H),1.41(s,9H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ(ppm):189.41,163.77,154.23,152.12,151.11,137.68,136.47,129.44,129.02,127.83,126.55,79.09,73.53,60.21,49.56,49.06,29.04,28.91,28.57,28.13,19.51,14.55.

Example 7

Preparation of (S) -5-chloro-3-isopropyl-6- ((1, 2,3, 4-tetrahydro-1-naphtyl) amino) pyrimidine-2, 4 (1H, 3H) -dione (I-13)

Synthesis of I-13: i-1 (80 mg,0.27 mmol) was dissolved in acetic acid (1.5 mL), N-chlorosuccinimide NCS (36 mg,0.27 mmol) was added thereto, and the reaction was stirred at room temperature for 1h. TLC (Petroleum ether: ethyl acetate=2:1) detects that the reaction of the raw materials is finished, the reaction is stopped, the reaction is concentrated under reduced pressure, water (30 mL) and ethyl acetate (30 mL) are added into the residue to be stirred and dissolved, an organic layer is separated, then the organic layer is washed with water (30 mL×2), saturated sodium chloride (30 mL×2) is washed, anhydrous sodium sulfate is dried, suction filtration is carried out, filtrate is concentrated, column chromatography purification (petroleum ether: ethyl acetate=10:1 is used as eluent), and then a white solid 43mg is obtained by pulping through a mixed solvent (ethyl acetate: n-hexane=1:4), and the yield is 48.2%. ¹ H NMR(500MHz,DMSO-d ₆ )δ(ppm):10.99(s,1H),7.22-7.15(m,3H),7.13-7.09(m,1H),6.84(d,J＝9.8Hz,1H),5.18-5.08(m,1H),5.07-4.98(m,1H),2.83-2.67(m,2H),1.95-1.81(m,1H),1.95-1.82(m,2H),1.78-1.67(m,1H),1.38(d,J＝6.9Hz,6H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ(ppm):159.15,150.17,149.35,137.79,137.54,129.22,127.73,127.37,126.41,81.52,50.55,44.62,30.54,29.07,20.79,19.80.

Example 8

Preparation of (S) -5-bromo-3-isopropyl-6- ((1, 2,3, 4-tetrahydro-1-naphtyl) amino) pyrimidine-2, 4 (1H, 3H) -dione (I-14)

Synthesis of I-14: i-1 (146 mg,0.49 mmol) was dissolved in acetic acid (4 mL), N-bromosuccinimide NBS (87 mg,0.49 mmol) was added, and the reaction was stirred at room temperature for 1h. TLC (CH) ₂ Cl ₂ :CH ₃ Oh=20:1), stopping the reaction, concentrating under reduced pressure, adding water (50 mL) and ethyl acetate (50 mL) into the residue, stirring for dissolution, separating an organic layer, washing with water (50 ml×2), washing with saturated sodium chloride (50 ml×2), drying with anhydrous sodium sulfate, suction filtering, concentrating the filtrate, purifying by column chromatography (petroleum ether: ethyl acetate=10:1 as eluent), and pulping by a mixed solvent (ethyl acetate: n-hexane=1:1) to obtain 69mg of white solid with a yield of 37.4%. ¹ H NMR(500MHz,DMSO-d ₆ )δ(ppm):(s,1H),7.18(m,3H),7.12(d,J＝3.6Hz,1H),6.54(d,J＝9.7Hz,1H),5.12(m,1H),5.03(m,1H),2.74(m,2H),2.02-1.95(m,1H),1.92-1.83(m,2H),1.77-1.68(m,1H),1.37(d,J＝6.8Hz,6H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ(ppm):159.24,150.48,150.04,137.79,137.45,129.28,127.71,127.44,126.48,71.33,50.79,44.90,30.44,29.03,20.77,19.82.HRMS(ESI):m/z[M+H] ⁺ calcd for C ₁₈ H ₂₂ N ₃ O ₂ 378.0817；found 378.0801

Example 9

Preparation of (S) -3-isopropyl-6- ((5-methoxy-1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1H, 3H) -dione (I-15)

Synthesis of I-15: 4a (150 mg,0.80 mmol) and (S) -5-methoxy-1, 2,3, 4-tetrahydro-1-naphthylamine 5c (534 mg,3.03 mmol) are dissolved in 1, 4-dioxane (8 mL) and reacted at 120℃under reflux for 24h. TLC (CH) ₂ Cl ₂ :CH ₃ Oh=20:1) detecting that the raw materials were reacted completely, stopping the reaction, cooling to room temperature, concentrating under reduced pressure, and adding CH ₂ Cl ₂ (50 mL) of the solution was dissolved,H ₂ o (50 mL) and the organic layer was washed with saturated sodium chloride (70 mL. Times.2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography (CH ₂ Cl ₂ :CH ₃ Oh=100:1 as eluent) and slurried with a mixed solvent (ethyl acetate: n-hexane=1:1) to give 120mg of a white solid in 45.5% yield. ¹ H NMR(500MHz,CDCl3)δ(ppm):9.95(s,1H),7.17(t,J＝7.9Hz,1H),6.90(d,J＝7.7Hz,1H),6.77(d,J＝8.0Hz,1H),5.09-5.00(m,1H),4.96(d,J＝2.2Hz,1H),4.92(d,J＝7.8Hz,1H),4.55-4.48(m,1H),3.84(s,3H),2.71-2.80(m,1H),2.66-2.55(m,1H),2.02-1.88(m,2H),1.79-1.88(m,2H),1.31(d,J＝6.9Hz,6H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ(ppm):163.89,158.87,151.82,150.96,139.07,130.42,128.52,113.63,113.11,73.56,55.52,49.04,42.82,29.26,29.08,19.91,19.35.

Example 10

Preparation of (S) -3-isopropyl-6- ((6-methoxy-1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1H, 3H) -dione (I-16)

Synthesis of I-16: 4a (92 mg,0.49 mmol) and (S) -6-methoxy-1, 2,3, 4-tetrahydro-1-naphthylamine 5d (345 mg,1.95 mmol) were dissolved in 1, 4-dioxane (6 mL) and reacted at 120℃under reflux for 24h. TLC (CH) ₂ Cl ₂ :CH ₃ Oh=20:1) detecting that the raw materials were reacted completely, stopping the reaction, cooling to room temperature, concentrating under reduced pressure, and adding CH ₂ Cl ₂ (50 mL) dissolution, H ₂ O (50 mL) and the organic layer was washed with saturated sodium chloride (60 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column Chromatography (CH) ₂ Cl ₂ :CH ₃ Oh=100:1 as eluent) and slurried with a mixed solvent (ethyl acetate: n-hexane=1:1) to give 63mg of a white solid in 39.0% yield. ¹ H NMR(500MHz,DMSO-d ₆ )δ(ppm):9.60(s,1H),7.15(d,J＝8.5Hz,1H),6.78(dd,J＝8.5,2.4Hz,1H),6.69(s,1H),6.28(s,1H),4.94-5.03(m,1H),4.75(s,1H),4.58-4.49(m,1H),3.73(s,3H),2.76-2.66(m,2H),1.91-1.82(m,1H),1.68-1.80(m,3H),1.32(d,J＝6.9Hz,6H). ¹³ C NMR(126MHz,CDCl ₃ -d ₆ )δ(ppm):164.92,159.06,152.32,151.16,138.93,

Example 11

Preparation of (S) -3-isopropyl-6- ((7-methoxy-1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1H, 3H) -dione (I-17)

Synthesis of I-17: 4a (105 mg,0.56 mmol) and (S) -7-methoxy-1, 2,3, 4-tetrahydro-1-naphthylamine 5e (298 mg,1.67 mmol) were dissolved in 1, 4-dioxane (6 mL) and reacted at 120℃under reflux for 24h. TLC (CH) ₂ Cl ₂ :CH ₃ Oh=20:1) detecting that the raw materials were reacted completely, stopping the reaction, cooling to room temperature, concentrating under reduced pressure, and adding CH ₂ Cl ₂ (50 mL) was dissolved, the organic layer was washed with saturated sodium chloride (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to give a filtrate (CH) ₂ Cl ₂ :CH ₃ Oh=100:1 as eluent) and slurried with a mixed solvent (ethyl acetate: n-hexane=1:1) to give 90mg of a white solid in 48.9% yield. ¹ H NMR(500MHz,DMSO-d ₆ )δ(ppm):9.66(s,1H),7.06(d,J＝8.4Hz,1H),6.82(dd,J＝8.4,2.4Hz,1H),6.79(s,1H),6.38(s,1H),4.91-5.03(m,1H),4.76(s,1H),4.60-4.50(m,1H),3.71(s,3H),2.76-2.58(m,2H),1.94-1.81(m,1H),1.80-1.67(m,3H),1.33(d,J＝6.9Hz,6H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ(ppm):163.89,157.96,150.96,137.41,130.45,129.61,114.29,113.60,73.67,55.58,49.77,49.06,42.85,28.88,28.11,19.90,19.68.

Example 12

Preparation of (S) -3-isopropyl-6- ((7-amino-1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1H, 3H) -dione (I-20)

Synthesis of I-20: 4a (120 mg,0.64 mmol) and (S) -7-amino-1, 2,3, 4-tetrahydro-1-)Naphthylamine 5f (367 mg,1.91 mmol) was dissolved in 1, 4-dioxane (12 mL) and reacted at 120℃under reflux for 24h. TLC (CH) ₂ Cl ₂ :CH ₃ Oh=20:1) detecting that the raw materials were reacted completely, stopping the reaction, cooling to room temperature, concentrating under reduced pressure, and adding CH ₂ Cl ₂ (70 mL) was dissolved, the organic layer was washed with saturated sodium chloride (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated, and purified by column Chromatography (CH) ₂ Cl ₂ :CH ₃ Oh=100:1 as eluent) and slurried through a mixed solvent (ethyl acetate: n-hexane=1:1) to give 60mg of yellow solid in 27.3% yield. ¹ H NMR(500MHz,DMSO-d ₆ )δ(ppm):9.64(s,1H),6.79(d,J＝8.3Hz,1H),6.48(d,J＝7.0Hz,1H),6.46(s,1H),6.33(s,1H),5.11(s,2H),5.01-4.95(m,1H),4.74(s,1H),4.48-4.41(m,1H),2.64-2.54(m,2H),1.87-1.81(m,1H),1.73-1.66(m,3H),1.33(d,J＝6.9Hz,6H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ(ppm):

Example 13

Preparation of (S) -3-isopropyl-6- ((7-fluoro-1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1H, 3H) -dione (I-23)

Synthesis of I-23: 4a (142 mg,0.75 mmol) and 5g (498 mg,3.01 mmol) of (S) -7-fluoro-1, 2,3, 4-tetrahydro-1-naphthylamine are dissolved in 1, 4-dioxane (13 mL) and reacted at 120℃under reflux for 24h. TLC (CH) ₂ Cl ₂ :CH ₃ Oh=20:1) detecting that the raw materials were reacted completely, stopping the reaction, cooling to room temperature, concentrating under reduced pressure, and adding CH ₂ Cl ₂ (70 mL) was dissolved, the organic layer was washed with saturated sodium chloride (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated, and purified by column Chromatography (CH) ₂ Cl ₂ :CH ₃ Oh=100:1 as eluent) and slurried with a mixed solvent (ethyl acetate: n-hexane=1:1) to give 91mg of a yellow solid in a yield of 38.2%. ¹ H NMR(500MHz,DMSO-d ₆ )δ(ppm):9.71(s,1H),7.22-7.17(m,1H),7.03-7.11(m,2H),6.40(d,J＝8.4Hz,1H),4.94-5.03(m,1H),4.77(s,1H),4.57-4.66(m,1H),2.80-2.67(m,3H),1.96-1.89(m,1H),1.81-1.68(m,3H),1.33(d,J＝6.9Hz,6H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ(ppm):163.90,152.04,150.96,138.90,138.85,133.75,131.30,131.24,114.85,73.83,49.62,42.86,28.78,28.19,19.89,19.70.

Example 14

Preparation of (S) -3-isopropyl-6- ((7-bromo-1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1H, 3H) -dione (I-29)

Synthesis of I-29: 4a (67 mg,0.36 mmol) and (S) -7-bromo-1, 2,3, 4-tetrahydro-1-naphthylamine (236 mg,1.04 mmol) are dissolved in 1, 4-dioxane (5 mL) and reacted at 120℃under reflux for 24h. TLC (CH) ₂ Cl ₂ :CH ₃ Oh=20:1) detecting that the raw materials were reacted completely, stopping the reaction, cooling to room temperature, concentrating under reduced pressure, and adding CH ₂ Cl ₂ (20 mL) dissolution, H ₂ O (50 mL) and the organic layer was washed with saturated sodium chloride (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography (CH ₂ Cl ₂ :CH ₃ Oh=100:1 as eluent) and slurried with a mixed solvent (ethyl acetate: n-hexane=1:1) to give 40mg of a white solid in 29.8% yield. ¹ H NMR(500MHz,DMSO-d ₆ )δ(ppm):9.68(s,1H),7.25-7.19(m,3H),7.12-7.18(m,1H),6.40(d,J＝7.0Hz,1H),4.94-5.04(m,1H),4.77(s,1H),4.65-4.57(m,1H),2.84-2.65(m,2H),1.95-1.85(m,1H),1.82-1.70(s,3H),1.33(d,J＝6.9Hz,6H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ(ppm):163.92,152.05,150.94,137.65,136.55,129.42,129.00,127.80,126.53,73.55,49.54,42.82,29.05,28.91,19.91,19.54.

Example 15

Preparation of (S) -3-isopropyl-6- ((4-methyl-1- (1, 2,3, 4-tetrahydronaphthyl)) amino) pyrimidine-2, 4 (1H, 3H) -dione (I-30)

Synthesis of I-30: 4a (130 mg,0.69 mmol) and (S) -4-methyl-1, 2,3, 4-tetrahydro-1-naphthylamine 5i (442 mg,2.74 mmol) are dissolved in 1, 4-dioxane (8 mL) and reacted at 120℃under reflux for 24h. TLC (CH) ₂ Cl ₂ :CH ₃ Oh=20:1) detecting that the raw materials were reacted completely, stopping the reaction, cooling to room temperature, concentrating under reduced pressure, and adding CH ₂ Cl ₂ (30 mL) dissolution, H ₂ O (50 mL) and the organic layer was washed with saturated sodium chloride (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography (CH ₂ Cl ₂ :CH ₃ Oh=100:1 as eluent) and slurried with a mixed solvent (ethyl acetate: n-hexane=1:1) to give 78mg of a white solid in 36.3% yield. ¹ H NMR(500MHz,DMSO-d ₆ )δ(ppm):9.67(s,1H),7.31-7.18(m,4H),6.41(s,1H),4.89-5.05(m,1H),4.77(s,1H),4.63-4.52(m,1H),2.81-2.88(m,1H),1.78-1.97(m,3H),1.56-1.48(m,1H),1.33(d,J＝6.9Hz,6H),1.29(d,J＝7.0Hz,3H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ(ppm):163.63,152.45,151.70,138.37,133.78,129.07,127.14,127.00,126.57,76.86,52.11,43.02,27.91,21.13,19.84,19.81.

Example 16

Inhibition activity of myosin atpase by compounds:

cardiac myosin atpase provides energy for myocardial contraction by catalyzing the hydrolysis of ATP to ADP. The rat cardiac myosin ATPase activity can be detected using an enzyme-coupled system of pyruvate kinase and lactate dehydrogenase (PK/LDH). PK converts ADP to ATP (adenosine triphosphate) by converting PEP (phosphoenolpyruvate) to pyruvate. LDH then converts pyruvate to lactate by converting NADH (nicotinamide adenine dinucleotide) to NAD (oxidized nicotinamide adenine dinucleotide). The inhibition activity of the drug against myosin ATPase was assessed by detecting the decrease in absorbance of NADH (at 340 nm) as a function of time, reflecting the change in myosin ADP. The source of cardiac myosin is the rat heart in myofibrillar form.

Anesthetized rats (SPF grade, 200-220g, male), heart was harvested, washed with cold 0.9% NaCl, and right heart was excised after removal of fat, connective tissueThe left part is cut into small pieces. Transfer to standard buffer solution (75 mM KCl,10mM imidazole, pH 7.2,2mM MgCl) containing 4 times (buffer volume/left heart tissue weight) 0.3M sucrose ₂ 2mM EGTA,0.3M sucrose) was homogenized for 1min and centrifuged (17300 Xg, 15min,4 ℃ C.) to obtain a precipitate. The pellet was transferred to 4-fold standard buffer (75 mM KCl,10mM imidazole, pH 7.2,2mM MgCl) ₂ After mixing and breaking up, the pellet was removed by centrifugation (750 Xg, 15min,4 ℃), and repeated 4 times. The pellet was transferred to 4-fold standard buffer containing Triton x-100 (75 mM KCl,10mM imidazole, pH 7.2,2mM MgCl) ₂ After homogenization in 2mM EGTA,1% v/v Triton X-100, the pellet was centrifuged (750 Xg, 15min,4 ℃) and repeated 2 times. The pellet was transferred to 8-fold standard buffer, mixed and broken up, centrifuged (750 Xg, 15min,4 ℃) to obtain pellet, which was repeated 4 times. Transfer of the pellet to PM12 buffer solution (12mM PIPES,2mM MgCl) ₂ pH 6.8). BCA method (BCA kit (enhanced) purchased from shanghai bi yun) for determining myofibril concentration in PM12 buffer. The calcium response of rat myofibrils was evaluated prior to testing the drug and 50% of the myofibril system was selected to be achieved (pCa ₅₀ ) The activated calcium concentration serves as the final condition for assessing the activity of the drug. All the above operations were performed on ice. Assay conditions were 1mg/mL rat cardiac myofibril, 0.4mM PK/LDH,0.1mg/mL BSA and 1mM DTT; 50. Mu.M ATP,0.5mM NADH and 1.5mM PEP and calcium concentration are calcium solutions that achieve 50% activation of the myofibril system.

The compounds were diluted 3-fold in DMSO to 11 different concentrations at an initial concentration of 0.1mM. mu.L of the above-mentioned compounds of different concentrations were added to 96-well plates, 100. Mu.L of rat cardiac myofibrils was added, 40. Mu.L of a solution containing PK/LDH, BSA and DTT and 40. Mu.L of a solution containing ATP, NADH and PEP were added, and finally 20. Mu.L of a calcium solution (the free calcium concentration required to achieve 50% activation of the myofibril system) was added to initiate an enzymatic reaction. At 25 ℃ by

M200 PRO-grating type multifunctional microplate detector, read absorbance at 340nm, read once every 30s, read continuously for 15min. The data are recorded as the slope of absorbance response versus time.The slope of absorbance response as a function of time was normalized to the slope on the DMSO-containing plate. The normalized ratio was then plotted as a function of drug concentration, and the data was fitted to a curve using Graph PadPrism. The midpoint of the curve is the IC50, i.e. the drug concentration when 50% of the total response is inhibited. The experimental results are detailed in table 2.

Inhibitory Activity of the compounds of Table 2 against rat myosin ATPase

Example 16

Inhibition of isolated cardiac contractile function in rats by the compounds:

SD rat is injected with 20% of uliose and heparin (500 IU/kg) in the abdominal cavity, the chest cavity is opened rapidly, the heart is removed and placed in precooled K-H liquid rapidly, the aorta is connected with an HSE isolated heart perfusion system in the shortest time, the silk thread is fixed, a constant temperature circulating pump of the isolated heart perfusion device is started, the temperature of the system is kept to 37 ℃, isolated heart perfusion is started, the heart is recovered to normal beating, and the test is carried out after the heart is stabilized for 15-20 min. The test substance is prepared into a series of concentrations by taking K-H liquid as a solvent, and is injected into a perfusion system, and the heart miller catheter is adopted for detecting the heart function of the left ventricle.

Results: i-1 significantly reduced Left Ventricular Systolic Pressure (LVSP) and left ventricular pressure rise rate (+dP/dt) compared to vehicle control, which was concentration dependent, indicating that I-1 inhibited left ventricular myocardial contraction. Moreover, I-1 can reduce the rate of left ventricular pressure drop (-dP/dt), indicating an enhancement in myocardial diastolic function. The inhibitory effect of I-1 was superior to MYK-461 at equivalent molar concentrations, half the inhibitory concentration (IC ₅₀ ) Are all lower than MYK-461. The experimental results are shown in Table 3 and FIGS. 1 to 3.

TABLE 3 inhibition of left ventricular function in rat isolated hearts

Example 17

Pharmacokinetic test of compounds in rats:

the 6 male SD rats were divided into two groups, 3 animals/group, and the test compound I-1 was administered by intravenous injection and by intragastric administration at doses of 0.2mg/kg and 2mg/kg, respectively. The dosing was followed by an overnight fast, and the dosing was resumed for 4 hours after dosing with free water throughout the trial period. 0.2-0.3mL of blood was taken through the orbital venous plexus at time points (pre-dose, 5min, 15min, 30min, 1h, 2h, 4h, 8h and 24h post-dose), placed in an anticoagulation tube containing 2. Mu.L of 20% EDTA-K2 and stored on wet ice. Centrifuging at 6000rpm at low temperature (4-10deg.C) for 8min for 1 hr to obtain supernatant, and storing in ultralow temperature refrigerator (below-60deg.C) for testing. Detecting the concentration of I-1 in plasma sample by LC-MS/MS method and using software

6.3 calculation of pharmacokinetic parameters.

The results show that: intravenous injection administration to rats, rapid elimination of plasma I-1, average T _1/2 For 0.4h, the average Vz was 0.65L/kg and the average CLp was 1.14L/h/kg. By oral administration, I-1 can achieve rapid and good in vivo absorption, and the average Tmax is 0.5 hr, AUC _0-inf The average bioavailability is up to 90.2% for 1553 ng.hr/mL. Compared with MYK-461, the pharmacokinetic properties of I-1 are obviously improved, the apparent distribution volume is reduced, the in vivo clearance is accelerated, the half-life period is shortened, and better oral bioavailability is shown. Is hopeful to overcome the defect that MYK-461 is too slow to eliminate in vivo and is unfavorable for dosage adjustment. ( Mark p.grillo et al xenobiotics, 2019;49 (6):718-733 )

TABLE 3 pharmacokinetic parameters of oral I-1 in rats

In summary, the present invention effectively overcomes the disadvantages of the prior art and has high industrial utility value.

The above embodiments are merely illustrative of the principles of the present invention and its effectiveness, and are not intended to limit the invention. Modifications and variations may be made to the above-described embodiments by those skilled in the art without departing from the spirit and scope of the invention. Accordingly, it is intended that all equivalent modifications and variations of the invention be covered by the claims, which are within the ordinary skill of the art, be within the spirit and scope of the present disclosure.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, which has the chemical structural formula shown in formula I:

wherein X is selected from H, F, cl, br or I;

R ¹ selected from optionally at least monosubstituted C ₁ -C ₆ Alkyl, optionally at least monosubstituted C ₃ -C ₆ Cycloalkyl, optionally at least monosubstituted 4-to 6-membered heterocycloalkyl, optionally at least monosubstituted phenyl, optionally at least monosubstituted 5-to 6-membered heteroaryl, said R ¹ In C ₁ -C ₆ Alkyl, C ₃ -C ₆ The substituents of cycloalkyl, 4-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl are each independently selected from halogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ An alkoxy group;

R ² selected from H, halogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, amino.

2. The compound of claim 1, wherein X is selected from H and F.

3. The compound of claim 1, wherein R ¹ A group selected from one of:

4. the compound of claim 1, wherein R ² Selected from H, halogen, C ₁ -C ₄ An alkoxy group.

5. The compound of claim 1, wherein the compound is selected from the group consisting of:

6. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament selected from myosin inhibitors;

And/or the drug is selected from drugs for treating heart diseases;

and/or the drug is selected from the group consisting of drugs for treating diastolic heart failure, ischemic heart disease, angina and restrictive cardiomyopathy with preserved ejection fraction;

and/or the medicament is selected from medicaments for treating chronic mitral regurgitation, chronic aortic stenosis, chronic systemic hypertension.

7. The use according to claim 6, wherein the medicament is selected from medicaments for the treatment of diastolic and/or systolic dysfunction.

8. Use according to claim 6, wherein the medicament is selected from medicaments for the treatment of heart diseases associated with left ventricular hypertrophy and/or diastolic dysfunction.

9. The use according to claim 6, wherein the medicament is selected from the group consisting of medicaments for the treatment of hypertrophic cardiomyopathy.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.