4-amino-2, 6-dihydroxypyrimidine derivative and application thereof

Abstract

The invention provides a 4-amino-2, 6-dihydroxypyrimidine derivative and application thereof.The 4-amino-2, 6-dihydroxypyrimidine derivative has the structure shown in the formula I. The 4-amino-2, 6-dihydroxypyrimidine derivative can be used as a small-molecule inhibitor for inhibiting the function of myosin ATPase, and the application of the 4-amino-2, 6-dihydroxypyrimidine derivative can be used for preparing a myosin ATPase inhibitor. The method can be used as an effective means for treating and preventing hypertrophic cardiomyopathy.

Description

[0001] This application claims priority to patent application number 202411172912.7 (filed on August 26, 2024, entitled "A 4-amino-2,6-dihydroxypyrimidine Derivative and Its Application") and to patent application number 202411557923.7 (filed on November 4, 2024, entitled "A 4-amino-2,6-dihydroxypyrimidine Derivative and Its Application"). Technical Field

[0002] This invention belongs to the field of chemical medicine, specifically relating to a 4-amino-2,6-dihydroxypyrimidine derivative and its applications. Background Technology

[0003] The rhythmic contraction of the myocardium is fundamental to the heart's pumping function. The molecular mechanism by which cardiomyocytes contract involves the periodic binding, sliding, and dissociation of actin and myosin, which induces the contraction of the myocardial ganglion. During this process, myosin provides energy for its conformational changes by binding to and hydrolyzing ATP, and completes the conformational change cycle by releasing ADP obtained from ATP hydrolysis. When specific amino acids in myosin mutate, affecting the strength or conformation of its protein-ATP binding, the affinity between myosin and actin changes, leading to abnormalities in myocardial function or cardiac physiology. Studies have found (Norbert Frey, et al., Mechanisms of disease: hypertrophic cardiomyopathy. Nature Reviews Cardiology, 9, 2011, 91-100; M. Sabater-Molina, et al., Genetics of hypertrophic cardiomyopathy: A review of current state. Clinical Genetics, 93, 2018, 3-14) that several point mutations in cardiac myosin, such as MYH7 R403Q and MYH R453, can significantly increase the activity of myosin ATP hydrolases. This leads to an increase in cross-bridges between myosin and actin, and a decrease in the proportion of myosin in a super-relaxed state. Mutations in myosin result in an increased binding time between myosin and actin, leading to left ventricular hypertrophy, narrowing of the ventricular space, and subsequently hypertrophic cardiomyopathy (HCM). Epidemiological studies have also shown that individuals carrying the MYH7 gene mutation have a significantly increased likelihood of developing hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy is a heart disease characterized by thickened myocardium and is the leading cause of sudden cardiac death (C. Vaughan Tuohy et al., Hypertrophic cardiomyopathy: the future of treatment. European Journal of Heart Failure, 22, 2020, 228-240).Previous studies (Eric M. Green et al., A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in the heart. Science, 351, 2016, 617-621; Iacopo Olivotto et al., Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): arandomised, double-blind, placebo-controlled, phase 3 trial Lancet, 396, 2020, 759-769.) have found that small-molecule myosin allosteric inhibitors can reduce the binding time of myosin to actin by inhibiting its activity in binding to ATP or catalyzing ATP hydrolysis, thereby reducing the number of cross-bridges between myosin and actin. Without affecting the heart rhythm, this reduces myocardial systolic pressure and improves the physiological state of left ventricular hypertrophy, thus achieving the goal of treating hypertrophic cardiomyopathy.

[0004] Therefore, developing small molecule inhibitors that can inhibit the function of myosin ATPase as an effective means of treating and preventing hypertrophic cardiomyopathy is a key research focus in this field. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a 4-amino-2,6-dihydroxypyrimidine derivative and its applications.

[0006] To achieve this objective, the present invention adopts the following technical solution:

[0007] On one hand, the present invention provides a 4-amino-2,6-dihydroxypyrimidine derivative or its tautomers, meso compounds, racemates, enantiomers, diastereomers or pharmaceutically acceptable salts thereof, wherein the 4-amino-2,6-dihydroxypyrimidine derivative has the structure shown in Formula I:

[0008]

[0009] Where L is selected from

[0010] Ring A is selected from 5- to 6-membered aryl or heteroaryl groups containing 0 to 3 heteroatoms;

[0011] R1 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -R a OR b -OC(O)R a -OC(O)OR a -OC(O)NR a R b -NR a R b -SR a -S(O)R a -S(O)2R a Or a 3-10 saturated or unsaturated ring containing 0-3 heteroatoms, wherein the 3-10 saturated or unsaturated ring containing 0-3 heteroatoms may optionally be surrounded by 1-3 R... a replace;

[0012] R2 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -R a OR b -OC(O)R a -OC(O)OR a -OC(O)NR a R b -NR a R b -NS(R) a )2O、-SR a -S(O)R a -S(O)2R a Or a 3-10 saturated or unsaturated ring containing 0-3 heteroatoms, wherein the 3-10 saturated or unsaturated ring containing 0-3 heteroatoms may optionally be surrounded by 1-3 R... a replace;

[0013] Each R a R bEach is independently selected from hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, halogen, cyano, nitro, amino, carboxyl, carbonyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, alkoxy-substituted C3-C6 cycloalkyl, C3-C6 heterocyclic, halo-C3-C6 heterocyclic, and C1-C6 alkyl-substituted C5-C 10 heteroaryl, -S(O)2R c -OR c OR d -R c OR d -C(O)R c or -OC(O)R c Each R c R d Each is independently selected from hydrogen or C1-C6 alkyl groups;

[0014] n = 0, 1, 2 or 3.

[0015] In some implementations, ring A is selected from...

[0016] In some embodiments, the 4-amino-2,6-dihydroxypyrimidine derivative has the structure shown in formula (Ia):

[0017]

[0018] R2 is selected from hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogen, -SCF3, Or -N=S(CH3)2=O;

[0019] R1, L, and n are defined as in Equation I.

[0020] In other embodiments, the 4-amino-2,6-dihydroxypyrimidine derivative has the structure shown in formula (Ib):

[0021]

[0022] R2 is selected from hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogen, -SCF3, Or -N=S(CH3)2=O;

[0023] R1, L, and n are defined as in Equation I.

[0024] In other embodiments, the 4-amino-2,6-dihydroxypyrimidine derivative has the structure shown in formula (Ic):

[0025]

[0026] R2 is selected from hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogen, -SCF3, Or -N=S(CH3)2=O;

[0027] R1, L, and n are defined as in Equation I.

[0028] In other embodiments, the 4-amino-2,6-dihydroxypyrimidine derivative has the structure shown in formula (Id):

[0029]

[0030] R2 is selected from hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogen, -SCF3, Or -N=S(CH3)2=O;

[0031] R1, L, and n are defined as in Equation I.

[0032] In other embodiments, the 4-amino-2,6-dihydroxypyrimidine derivative has the structure shown in formula (Ie):

[0033]

[0034] R2 is selected from hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogen, -SCF3, Or -N=S(CH3)2=O;

[0035] R1, L, and n are defined as in Equation I.

[0036] In other embodiments, the 4-amino-2,6-dihydroxypyrimidine derivative has the structure shown in formula (If):

[0037]

[0038] R2 is selected from hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogen, -SCF3, Or -N=S(CH3)2=O;

[0039] R1, L, and n are defined as in Equation I.

[0040] In other embodiments, the 4-amino-2,6-dihydroxypyrimidine derivative has the structure shown in formula (Ig):

[0041]

[0042] R2 is selected from hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogen, -SCF3, Or -N=S(CH3)2=O;

[0043] R1, L, and n are defined as in Equation I.

[0044] In some implementations, R1 is selected from

[0045] In some embodiments, R2 is selected from methyl, cyclopropyl, chlorine, In some embodiments, the 4-amino-2,6-dihydroxypyrimidine derivative is selected from any one of the following compounds:

[0046]

[0047]

[0048] On the other hand, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the 4-amino-2,6-dihydroxypyrimidine derivative, tautomer, meso compound, racemic compound, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof as described above; and a pharmaceutically acceptable carrier or excipient.

[0049] On the other hand, the present invention also provides the use of the 4-amino-2,6-dihydroxypyrimidine derivatives thereof, or their tautomers, meso compounds, racemates, enantiomers, diastereomers, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, as described above, in the preparation of a medicament for treating heart disease.

[0050] In some implementations, the heart disease refers to a human or companion animal heart disease.

[0051] In some implementations, the heart disease is a human or cat heart lesion.

[0052] In some implementations, the heart disease is hypertrophic cardiomyopathy in humans or cats.

[0053] In other embodiments, the hypertrophic cardiomyopathy is obstructive or non-obstructive or associated with sarcomere and / or non-sarcomere mutations.

[0054] In some implementations, the heart disease is preservative ejection fraction heart failure.

[0055] In some implementations, the heart disease is diastolic dysfunction, primary or secondary restrictive cardiomyopathy, myocardial infarction and angina, left ventricular outflow tract obstruction, hypertensive heart disease, congenital heart disease, myocardial ischemia, coronary heart disease, diabetic heart disease, congestive heart failure, right heart failure, cardiorenal syndrome, and infiltrative cardiomyopathy.

[0056] In some implementations, the heart disease is cardiac aging, diastolic dysfunction due to aging, left ventricular hypertrophy, and left ventricular concentric remodeling.

[0057] the term:

[0058] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0059] The term "isomer" includes enantiomers, diastereomers, and geometric (or conformational) isomers of a given structure. For example, this application includes R and S configurations for each asymmetry center, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers and mixtures of enantiomers, diastereomers, and geometric (or conformational) isomers.

[0060] The term "pharmaceutically acceptable salt" refers to salts such as their acid addition salts and / or base salts. Suitable acid addition salts are formed from acids, which form non-toxic salts, such as hydrochlorides / chlorides. Suitable base salts are formed from bases, which form non-toxic salts, such as calcium and sodium salts. Hemisalts of acids and bases can also be formed, such as hemisulfates and hemicalcium salts.

[0061] The term “therapeutic effective amount” means the following amounts of the compound of this application, which (i) treat a specific disease, symptom or disorder; (ii) reduce, alleviate or eliminate one or more symptoms of a specific disease, symptom or disorder; or (iii) prevent or delay the onset of one or more symptoms of the specific disease, symptom or disorder described in this application.

[0062] The term "pharmaceutically acceptable carrier or excipient" refers to a non-toxic carrier, excipient, or medium that does not impair the pharmacological activity of the compound formulated with it.

[0063] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples of lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.

[0064] The term "alkenyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight-chain and branched chains having at least one carbon-carbon double bond. In some embodiments, the alkenyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 2 to 4 carbon atoms. For example, the term "C 2-6 "Alkenyl" includes straight-chain or branched unsaturated groups with 2 to 6 carbon atoms (having at least one carbon-carbon double bond), including but not limited to vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc.

[0065] The term "alkynyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, including straight-chain and branched chains having at least one carbon-carbon triple bond. In some embodiments, the alkynyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 3 to 6 carbon atoms. For example, "C 2-6 "Alkyne" includes straight-chain or branched unsaturated groups with 2 to 6 carbon atoms (having at least one carbon-carbon triple bond).

[0066] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein the alkyl group is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[0067] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms (e.g., 3, 4, 5, or 6 carbon atoms), and most preferably 5 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0068] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintile rings sharing a single carbon atom (called a spiro atom). It may contain one or more double bonds, but each ring does not have a fully conjugated π-electron system. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles (e.g., 7, 8, 9, or 10 quintiles). Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between rings. Monospirocycloalkyl and bispirocycloalkyl groups are preferred, more preferably 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocycloalkyl groups.

[0069] The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic aromatic hydrocarbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more rings may contain one or more double bonds, but each ring does not have a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl.

[0070] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but each ring does not have a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic.

[0071] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 ring atoms, wherein 1 to 4 are heteroatoms; more preferably, it comprises 3 to 8 ring atoms, wherein 1 to 3 are heteroatoms; most preferably, it comprises 5 to 6 ring atoms, wherein 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, or pyrrolidinyl. Polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0072] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but each ring does not have a fully conjugated π-electron system. Preferably, it is 6 to 14 rings, more preferably 7 to 10 rings. Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups based on the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred, and 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic groups being more preferred.

[0073] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but each ring does not have a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups.

[0074] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. It may contain one or more double bonds, but each ring does not have a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic.

[0075] The heterocyclic group includes heterocyclic groups (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic groups) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0076]

[0077] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl.

[0078] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, containing 1 to 3 heteroatoms; more preferably 5- or 6-membered, containing 1 to 2 heteroatoms; preferred examples include imidazolyl, furanyl, thiophenel, thiazolyl, pyrazolyl, oxazolyl, pyrrolel, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, and pyridazinyl.

[0079] The heteroaryl group includes, as described above, a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0080]

[0081] The term “saturated or unsaturated ring” includes the aforementioned aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.

[0082] The term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group, wherein the alkyl group is as defined above.

[0083] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0084] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0085] The term “deuterated alkyl” refers to an alkyl group that is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0086] The term “deuterated alkoxy” refers to an alkoxy group that is replaced by one or more deuterium atoms, where the alkoxy group is as defined above.

[0087] The term "cycloalkylalkyl" refers to an alkyl group that is substituted by one or more cycloalkyl groups, wherein the cycloalkyl and alkyl groups are as defined above.

[0088] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0089] The term "heterocyclic alkyl" refers to an alkyl group that is substituted with one or more heterocyclic groups, wherein the heterocyclic group and the alkyl group are as defined above.

[0090] The term "arylalkyl" refers to an alkyl group that is substituted with one or more aryl groups, wherein the aryl and alkyl groups are as defined above.

[0091] The term "hydroxyl group" refers to the -OH group.

[0092] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0093] The term "amino" refers to -NH2.

[0094] The term "cyano" refers to -CN.

[0095] The term "nitro" refers to -NO2.

[0096] The term "carboxyl group" refers to -C(O)OH.

[0097] The term "companion animal" refers to any domesticated animal that is owned or intended to be owned by people in a certain type of place, particularly in the home, for personal entertainment or companionship purposes, including cats, dogs, birds, horses, etc.

[0098] Compared with the prior art, the present invention has the following beneficial effects:

[0099] The 4-amino-2,6-dihydroxypyrimidine derivative of the present invention is a small molecule inhibitor that can inhibit the function of myosin ATPase, and can be used as an effective means of treating and preventing hypertrophic cardiomyopathy. Detailed Implementation

[0100] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0101] Example 001 Synthesis of (S)-6-((1-(pyridin-2-yl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione (1)

[0102]

[0103] Step 1: Tetrahydropyran-4-amine (20.50 g, 177.943 mmol, 9.999 e) was added at 0 °C. -1 eq.) was added to a solution of OCNTMS (18.00 g, 177.960 mmol, 1 eq.) in dichloromethane (200 mL), and the reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC until complete. Methanol (400 mL) was added to the reaction mixture and stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure. The residue was added to methyl tert-butyl ether (80 mL), filtered, and the filter cake was collected and evaporated to dryness. A white solid (tetrahydropyran-4-yl)-urea (23.00 g, 159.533 mmol, 89.645%) was given.

[0104] Step 2: Dissolve (tetrahydropyran-4-yl)-urea (10.00 g, 69.362 mmol, 1 eq.) in methanol (100 mL), add dimethyl malonate (9.16 g, 69.334 mmol, 9.996 e-1 eq.) and sodium methoxide (9.36 g, 173.258 mmol, 2.498 eq.), and stir at 65 °C for 12 hours under argon protection. The reaction was complete by TLC. Cool the reaction solution to 0 °C and adjust the pH to 5 with concentrated hydrochloric acid. Concentrate under reduced pressure. Dissolve the residue in anhydrous EtOH (100 mL) and stir at room temperature for 0.5 hours. Filter and concentrate the filtrate. A white solid, 1-(tetrahydropyran-4-yl)-pyrimidine-2,4,6-trione (13.00 g, 61.262 mmol, 88.323%), is obtained.

[0105] Step 3: 1-(tetrahydropyran-4-yl)-pyrimidine-2,4,6-trione (10.00 g, 47.125 mmol, 1 eq.) and TEBAC (15.00 g, 65.855 mmol, 1.397 eq.) were dissolved in phosphorus oxychloride (100 mL). The mixture was stirred at 50 °C for 12 hours under argon protection. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (400 mL). Water (500 mL) was slowly added, and the mixture was extracted and washed. The organic layer was separated and washed once each with water (200 mL) and saturated sodium chloride (200 mL). The mixture was dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated. The solution was purified by column chromatography (CH2Cl2:CH3OH = 100:1 as eluent) to give a white solid 6-chloro-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (10.00 g, 43.356 mmol, 92.003%).

[0106] Step 4: 6-Chloro-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (50 mg, 216.781 μmol, 1 eq.) and 1-pyridin-2-ylethylamine (106 mg, 867.663 μmol, 4.002 eq.) were dissolved in dioxane (1 mL), and the reaction mixture was stirred at 90 °C for 12 hours. New spots were observed during TLC. The reaction mixture was concentrated under reduced pressure. Purification was performed by column chromatography using ethyl acetate:methanol = 5:1 as the eluent. The product (S)-6-((1-(pyridin-2-yl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidin-2,4(1H,3H)-dione (43.8 mg, 138.452 μmol, 63.867%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ10.10 (s, 1H), 8.57 (d, J = 4.4Hz, 1H), 7.85–7.77 (m, 1H), 7.43(d,J=7.8Hz,1H),7.36–7.29(m,1H),6.73(d,J=7.1Hz,1H),4.84–4.72(m,1 H),4.69–4.58(m,1H),4.52(s,1H),3.88(dd,J=11.0,3.7Hz,2H),3.33–3.23(m, 2H),2.60–2.52(m,2H),1.40(d,J=6.6Hz,3H),1.33(d,J=10.8Hz,2H).LCMS[M+H] + =317.20.

[0107] Example 002 Synthesis of (S)-6-((1-(pyridin-4-yl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione (2)

[0108]

[0109] Step 1: 6-Chloro-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (100 mg, 433.561 μmol, 1 eq.) and 1-pyridin-4-ethylamine (210 mg, 1.719 mmol, 3.965 eq.) were dissolved in dioxane (2 mL), and the reaction mixture was stirred at 90 °C for 48 hours. The reaction was confirmed by TLC. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:methanol = 5:1). The product (S)-6-((1-(pyridin-4-yl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidin-2,4(1H,3H)-dione (6.4 mg, 20.230 μmol, 4.666%) was obtained. 1 H NMR (400MHz, DMSO-d6) 1 H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.55-8.500(m,2H),7.36–7.32(m,2H),4.96-4.95(m,1H),4.756-4.69(m,1H),4.56–4.5 4(m,1H),4.33(s,1H),3.88-3.85(m,2H),3.53-3.51(m,2H),3.31-3.25(m,2H),1.41-1.38(d,J=6.6Hz,3H),1.29-1.35(m,2H). LCMS[M+H]+=317.20.

[0110] Example 003 Synthesis of (S)-3-(tetrahydro-2H-pyran-4-yl)-6-((1-(thiophen-2-yl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (3)

[0111]

[0112] Step 1: 6-Chloro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrimidin-2,4-dione (50 mg, 216.781 μmol, 1 eq.) and 1-thiophene-2-ethylamine (110 mg, 864.732 μmol, 3.989 eq.) were dissolved in dioxane (1 mL), and the reaction mixture was stirred at 90 °C for 12 hours. New spots were observed during TLC. The reaction mixture was concentrated under reduced pressure. The eluent was purified by column chromatography (ethyl acetate:methanol = 5:1). A white solid (S)-3-(tetrahydro-2H-pyran-4-yl)-6-((1-(thiophene-2-yl)ethyl)amino)pyrimidin-2,4(1H,3H)-dione (5.2 mg, 16.180 μmol, 7.464%) was obtained. 1 H NMR(400MHz,CHLOROFORM-d)δ9.95(s,1H),7.26(d,J=5.1Hz,1H),7.06–6.94(m,2H),5.19–4.92(m,3H),4.85– 4.76(m,1H),4.08–3.96(m,2H),3.47(t,J=10.6Hz,2H),2.76–2.60(m,2H),1.68(d,J=6.6Hz,3H),1.54(s,2H). LCMS[M+H]+=322.10.

[0113] Example 004 Synthesis of (S)-3-(tetrahydro-2H-pyran-4-yl)-6-((1-(thiophen-3-yl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (4)

[0114]

[0115] Step 1: 6-Chloro-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (50 mg, 216.781 μmol, 1 eq.) and 1-thiophene-3-ethylamine (110 mg, 864.732 μmol, 3.989 eq.) were dissolved in dioxane (1 mL), and the reaction mixture was stirred at 90 °C for 12 hours. New spots were observed during TLC. The reaction mixture was concentrated under reduced pressure. The eluent was purified by column chromatography (ethyl acetate:methanol = 5:1). A white solid (S)-3-(tetrahydro-2H-pyran-4-yl)-6-((1-(thiophene-3-yl)ethyl)amino)pyrimidin-2,4(1H,3H)-dione (39.1 mg, 121.658 μmol, 56.120%) was obtained. 1H NMR(400MHz, DMSO-d6)δ9.88(s,1H),7.55–7.50(m,1H),7.42–7.39(m,1H),7.10(dd,J=5.1,1.2Hz,1H),6.46(d,J=6.6Hz,1H),4.86–4.72(m,1H),4. 69–4.59(m,1H),4.56(s,1H),3.88(dd,J=11.4,4.0Hz,2H),3.33–3.23(m, 2H),2.63–2.52(m,2H),1.42(d,J=6.8Hz,3H),1.33(d,J=11.7Hz,2H).LCMS

[0116] [M+H]+=322.10.

[0117] Example 005 Synthesis of (S)-6-((1-(1-methyl-1H-pyrazol-4-yl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione (5)

[0118]

[0119] Step 1: 1-(1-methyl-1H-pyrazol-4-yl)-acetone (4.00 g, 32.222 mmol, 1 eq.) and (R)-(+)-tert-butylsulfinamide (5.19 g, 42.821 mmol, 1.329 eq.) were dissolved in THF (40 mL). Ti(OEt)4 (8.60 g, 37.701 mmol, 1.17 eq.) was added dropwise to the reaction solution. The reaction solution was stirred at 60 °C for 12 hours. The reaction was confirmed by LCMS. 80 mL of saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was filtered. The filtrate was extracted with ethyl acetate (3 x 80 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by column chromatography using n-heptane:ethyl acetate = 3:1 as the eluent. A white solid, 2-methyl-propane-2-sulfinic acid [1-(1-methyl-1H-pyrazol-4-yl)-ethylene]-amide (3.50 g, 15.396 mmol, 47.783%), was obtained.

[0120] Step 2: Dissolve 2-methyl-propane-2-sulfinic acid [1-(1-methyl-1H-pyrazol-4-yl)-ethylidene]-amide (3.50 g, 15.396 mmol, 1 eq.) in THF (40 mL). Under a nitrogen atmosphere, slowly add L-selectride (4.36 g, 22.935 mmol, 1 M, 22.935 mL, 1.490 eq.) dropwise to the reaction solution at -78 °C. After the addition is complete, raise the temperature to 0 °C and stir at 0 °C for 2 hours. The reaction is confirmed by LCMS. Add 80 mL of saturated ammonium chloride aqueous solution to the reaction solution. Extract the aqueous phase with dichloromethane (3 x 60 mL). Dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify by reverse-phase extraction using water:acetonitrile = 30% as the eluent. A colorless oily 2-methyl-propane-2-sulfinic acid [1-(1-methyl-1H-pyrazol-4-yl)-ethyl]-amide (1.20 g, 5.232 mmol, 33.984%) was obtained.

[0121] Step 3: Dissolve 2-methyl-propane-2-sulfinic acid [1-(1-methyl-1H-pyrazole-4-yl)-ethyl]-amide (1.20 g, 5.232 mmol, 1 eq.) in MeOH (20 mL), add HCl / dioxane (10 mL), and stir the reaction solution at 25 °C for 2 hours. The reaction was complete as detected by TLC. The reaction solution was concentrated under reduced pressure. The mixture was then prepared by reverse phase reaction. A yellow oily compound, 1-(1-methyl-1H-pyrazole-4-yl)ethylamine (300 mg, 1.856 mmol, 35.473%), was obtained.

[0122] Step 4: 6-Chloro-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (100 mg, 433.561 μmol, 1 eq.) and 1-(1-methyl-1H-pyrazol-4-yl)ethylamine (313 mg, 1.936 mmol, 4.466 eq.) were dissolved in dioxane (2 mL). Nitrogen gas was purged three times, and the reaction mixture was stirred at 120 °C for 12 hours. The reaction was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure. The mixture was then prepared by reverse phase reaction. A white solid (S)-6-((1-(1-methyl-1H-pyrazol-4-yl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidin-2,4(1H,3H)-dione (39 mg, 122.120 μmol, 28.167%) was obtained. 1H NMR(400MHz,DMSO-d6)δ9.82(br s,1H),7.64(s,1H),7.38(s,1H),6.28(br d,J=6.8Hz,1H),4.86–4.74(m,1H),4.59(s,1H),4.56–4.46(m,1H),3.96–3.83(m,2H),3 .79(s,3H),3.31–3.26(m,2H),2.53(brs,2H),1.38(d,J=6.6Hz,3H),1.37–1.30(m,2H). LCMS[M+1]+=320.20.

[0123] Example 006 Synthesis of (S)-6-(1-(3-(6-methylpyridin-3-yl)oxy)phenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione (6)

[0124]

[0125] Step 1: 1-(3-bromophenyl)ethylamine (2.00 g, 18.328 mmol, 1 eq.), 6-methylpyridin-3-ol (4.40 g, 21.992 mmol, 1.2 eq.), and N,N-dimethylglycine hydrochloride (278 mg, 1.992 mmol, 1.087 e) were added. -1 eq.), CuI (380mg, 1.995mmol, 1.089e -1 eq.) was dissolved in dioxane (20 mL). The mixture was stirred at 105 °C for 12 hours. The reaction was monitored by TLC until complete. Water (200 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (3 x 100 mL). The organic phase was washed with saturated brine (3 x 200 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The eluent was purified by column chromatography (ethyl acetate:methanol = 5:1). The compound 1-[3-(6-methylpyridin-3-yloxy)-phenyl]ethylamine (900 mg, 3.942 mmol, 21.511%) was obtained.

[0126] Step 2: 1-[3-(6-methylpyridin-3-yloxy)-phenyl]ethylamine (800 mg, 3.504 mmol, 4.041 eq.) and 6-chloro-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (200 mg, 867.123 μmol, 1 eq.) were dissolved in dioxane (2 mL), and the reaction mixture was stirred at 90 °C for 12 hours. New spots were observed on TLC. The reaction mixture was concentrated under reduced pressure. Column chromatography was used for purification, with ethyl acetate:methanol = 10:1 as the eluent. The product (S)-6-(1-(3-(6-methylpyridin-3-yl)oxy)phenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidin-2,4(1H,3H)-dione (41.2 mg, 97.520 μmol, 11.246%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ9.94 (s, 1H), 8.25 (d, J = 2.9Hz, 1H), 7.41–7.33 (m, 2H), 7.31–7.25 (m, 1H), 7.13(d,J=7.8Hz,1H),7.07–7.02(m,1H),6.87(dd,J=8.1,2.0Hz,1H),6.66(d,J=1.0Hz,1H),4.84 –4.70(m,1H),4.59–4.48(m,1H),4.39(s,1H),3.88(dd,J=11.1,4.0Hz,2H),3.30–3.24(m,2H),2. 60–2.52(m,2H),2.46(s,3H),1.39(d,J=6.6Hz,3H),1.33(d,J=14.4Hz,2H), LCMS[M+H]+=423.20.

[0127] Example 007 Synthesis of (S)-3-(tetrahydro-2H-pyran-4-yl)-6-(1-(3-(trifluoromethyl)thio)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (7)

[0128]

[0129] Step 1: Add 3-trifluoromethylthiobenzaldehyde (4.00 g, 19.400 mmol, 1 eq.), (R)-(+)-tert-butylsulfinamide (2.82 g, 23.267 mmol, 1.199 eq.), and PPTS (244 mg, 970.947 μmol, 5.005 e) to the solution. -2MgSO4 (11.68 g, 97.036 mmol, 5.002 eq.) was dissolved in DCM (40 mL), and the reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC until completion. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by column chromatography using a polar eluent (n-heptane:ethyl acetate = 10:1). The result was (R, E)-2-methyl-N-(3-(trifluoromethyl)thio)benzyl)propane-2-sulfinamide (3.00 g, 9.697 mmol, 49.985%).

[0130] Step 2: Dissolve (R,E)-2-methyl-N-(3-(trifluoromethyl)thio)benzyl)propane-2-sulfinamide (3.00 g, 9.697 mmol, 1 eq.) in DCM (30 mL). Replace with nitrogen, and under nitrogen protection, slowly add MeMgBr (2.30 g, 19.288 mmol, 3 M, 6.429 mL, 1.989 eq.) dropwise at -40 °C. After the addition is complete, raise the temperature of the reaction system to room temperature and stir for 12 hours at room temperature. The reaction is confirmed by TLC. Quench the reaction system with water (100 mL) in an ice bath, separate the layers, extract the aqueous phase with dichloromethane (3 x 80 mL), dry with anhydrous magnesium sulfate, filter, and concentrate the organic phase under reduced pressure. Purify the eluent by column chromatography (n-heptane:ethyl acetate = 5:3). A white solid (R)-2-methyl-N-((S)-1-(3-(trifluoromethyl)thio)phenyl)ethyl)propane-2-sulfonamide (1.50 g, 4.610 mmol, 47.535%) was obtained.

[0131] Step 3: (R)-2-methyl-N-((S)-1-(3-(trifluoromethyl)thio)phenyl)ethyl)propane-2-sulfonamide (1.50 g, 4.610 mmol, 1 eq.) was dissolved in MeOH (15 mL), and HCl / dioxane (8 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction was confirmed by TLC. The reaction mixture was then concentrated under reduced pressure to obtain a colorless oily compound (S)-1-(3-(trifluoromethyl)thio)phenyl)ethyl-1-amine (800 mg, 3.104 mmol, 67.346%).

[0132] Step 4: 6-Chloro-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (200 mg, 867.123 μmol, 1 eq.) and (S)-1-(3-(trifluoromethyl)thio)phenyl)ethyl-1-amine (732 mg, 3.499 mmol, 4.035 eq.) were dissolved in dioxane (1 mL). The reaction mixture was stirred at 90 °C for 12 hours. New spots were observed during TLC. The reaction mixture was concentrated under reduced pressure. Column chromatography was performed for purification, using ethyl acetate:methanol = 10:1 as eluent. The fraction was concentrated under reduced pressure, and the residue was slurried in ethyl acetate (5 mL) and filtered. A white solid (S)-3-(tetrahydro-2H-pyran-4-yl)-6-(1-(3-(trifluoromethyl)thio)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (72.8 mg, 180.458 μmol, 20.811%) was obtained. 1 H NMR(400MHz,DMSO-d6)δ7.72(s,1H),7.65–7.51(m,3H),6.70(s,1H),4.85–4.70(m,1H),4.68–4.55(m,1H),4.37(s, 1H),3.87(dd,J=11.4,3.8Hz,2H)),3.32–3.22(m,3H),2.57-2.51(m,2H),1.41(d,J=6.8Hz,3H),1.35–1.26(m,2H). LCMS[M+H] + =416.20.

[0133] Example 008 Synthesis of 6-(1-phenylcyclopropylamino)-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (8)

[0134]

[0135] Step 1: 6-Chloro-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (300 mg, 1.301 mmol, 1 eq.) and 1-phenylcyclopropylamine (1.00 g, 7.508 mmol, 5.772 eq.) were added, purged with nitrogen three times, and the reaction mixture was stirred at 120 °C for 12 hours. LC-MS analysis showed product formation. Ethyl acetate (5 mL) was added to the reaction mixture, resulting in solid precipitation. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Column chromatography was performed for purification, using ethyl acetate:methanol = 100:2 as the eluent. The result was a white solid 6-(1-phenylcyclopropylamino)-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (23.7 mg, 72.394 μmol, 5.566%). 1H NMR (400MHz, DMSO-d6) δ10.10(s,1H),7.37–7.28(m,2H),7.24–7.13(m,3H),6.99(s,1H),4.85–4.70(m,1H),4.41(d,J=2.2Hz,1H),3.88(br dd,J=10.8,4.2Hz,2H),3.30–3.22(m,2H),2.60–2.53(m,2H),1.38–1.21(m,6H), LCMS[M+H]+=328.20.

[0136] Example 009 Synthesis of 6-(3-phenyl-oxetane-3-ylamino)-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (9)

[0137]

[0138] Step 1: 6-Chloro-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (100 mg, 433.561 μmol, 1 eq.) and 3-phenyloxetane-3-amine (400 mg, 2.681 mmol, 6.184 eq.). The reaction solution was stirred at 120 °C for 12 hours. The reaction was completed by LCMS. The reaction solution was concentrated under reduced pressure. The reaction was prepared by reverse phase. A white solid 6-(3-phenyloxetane-3-ylamino)-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (10.3 mg, 29.996 μmol, 6.919%, 1 eq.) was obtained. 1 H NMR(400MHz,DMSO-d6)δ8.65(br s,1H),7.47–7.36(m,5H),7.35–7.30(m,1H),5.41(br s,1H),4.89–4.77(m,1H),4.77–4.61(m,2H),4.33(d,J=10.8Hz,1H),3.96–3.82(m,3H),3.67(br d,J=9.0Hz,1H),3.55(br d,J=10.5Hz,1H),2.63–2.53(m,2H),1.35(brt,J=10.9Hz,2H). LCMS[M+1]+=344.20.

[0139] Example 010 Synthesis of 6-(1-(3-chlorophenyl)-cyclopropylamino)-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (10)

[0140]

[0141] Step 1: 1-(3-chlorophenyl)cyclopropylamine (800 mg, 433.561 μmol, 1 eq.) and 6-chloro-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (400 mg, 433.561 μmol, 1 eq.) were stirred at 120 °C for 12 hours. The reaction was detected by LCMS to indicate completion. The reaction solution was concentrated under reduced pressure. The mixture was then prepared by reverse phase reaction. A white solid, 6-(1-(3-chlorophenyl)-cyclopropylamino)-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (88.8 mg, 245.425 μmol, 2.057%), was obtained. 1 H NMR(400MHz,DMSO-d6)δ10.18(s,1H),7.39–7.32(m,1H),7.29–7.23(m,1H),7.21(s,1H),7.15(d ,J=7.6Hz,1H),7.07(s,1H),4.85–4.69(m,1H),4.41(d,J=2.2Hz,1H),3.94–3.84(m,2H),3.29(br t,J=11.5Hz,2H),2.59–2.54(m,1H),1.44–1.29(m,4H),1.29–1.21(m,2H). LCMS[M+1]+=362.20.

[0142] Example 011 Synthesis of 6-(1-(3-cyclopropylphenyl)-cyclopropylamino)-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (11)

[0143]

[0144] Step 1: 1-(3-bromophenyl)cyclopropylamine (2.00 g, 9.430 mmol, 1 eq.) was dissolved in DCM (20 mL), and TEA (1.43 g, 14.132 mmol, 1.499 eq.) and (Boc)₂O (2.47 g, 11.318 mmol, 1.2 eq.) were added sequentially. The reaction was detected by TLC. The reaction solution was concentrated under reduced pressure. Column chromatography was used for purification, with n-heptane:ethyl acetate as the eluent (5:1). A white solid, [1-(3-bromophenyl)-cyclopropyl]-tert-butyl carbamate (2.10 g, 6.726 mmol, 71.329%), was obtained.

[0145] Step 2: Add cyclopropylboronic acid (82 mg, 954.629 μmol, 1.490 eq.), [1-(3-bromophenyl)-cyclopropyl]-tert-butyl carbamate (200 mg, 640.612 μmol, 1 eq.), tricyclohexylphosphine (34 mg, 121.429 μmol, 1.896 e-1 eq.), potassium phosphate (405 mg, 1.910 mmol, 2.982 eq.), and palladium acetate (14 mg, 62.222 μmol, 9.713 e-1 eq.). -2 The ethyl acetate (eq.) was dissolved in H2O (0.1 mL) and toluene (2 mL), and the mixture was purged with nitrogen three times. The mixture was stirred at 100 °C for 12 hours under nitrogen protection. The reaction was confirmed by LCMS. Water (30 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by column chromatography using n-heptane:ethyl acetate = 5:1 as the eluent. A colorless oily compound, [1-(3-cyclopropylphenyl)-cyclopropyl]-tert-butyl carbamate (100 mg, 365.806 μmol, 57.103%), was obtained.

[0146] Step 3: [1-(3-cyclopropylphenyl)-cyclopropyl]-tert-butyl carbamate (200 mg, 731.612 μmol, 1 eq.) was dissolved in DCM (1 mL) and HCl / dioxane (1 mL). The reaction mixture was stirred at 25 °C for 2 hours. The reaction was confirmed by TLC. The reaction mixture was concentrated under reduced pressure, and water (30 mL) was added. The aqueous phase was extracted with ethyl acetate (3 x 30 mL). The pH of the aqueous phase was adjusted to 3 with 1 M HCl and extracted with ethyl acetate (3 x 40 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. A colorless oily compound, 1-(3-cyclopropylphenyl)-cyclopropylamine (100 mg, 577.189 μmol, 78.893%), was obtained.

[0147] Step 4: 1-(3-cyclopropylphenyl)-cyclopropylamine (200 mg, 867.123 μmol, 1 eq.) and 6-chloro-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (800 mg, 4.618 mmol, 5.325 eq.) were dissolved in dioxane (2 mL). The reaction mixture was stirred at 120 °C for 12 hours. The reaction was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure. The mixture was then prepared by reverse phase reaction. A white solid, 6-(1-(3-cyclopropylphenyl)-cyclopropylamino)-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (33.1 mg, 90.083 μmol, 10.389%), was obtained. 1H NMR (400MHz, DMSO-d6) δ7.62(br s,1H),7.33–7.28(m,1H),7.19–7.15(m,1H),6.96(br d,J=7.8Hz,1H),6.89(s,1H),6.84(br d,J=7.6Hz,1H),4.85–4.70(m,1H),4.39(s,1H),3.90–3.85(m,2H),3.72–3.61(m,2H),1.93–1.85(m ,1H),1.36–1.26(m,4H),1.21–1.17(m,2H),1.16–1.07(m,2H),0.96–0.88(m,2H),0.68–0.60(m,2H).

[0148] LCMS[M+1]+=368.20.

[0149] Example 012(S)-6-((1-(3-((dimethyl(oxo)-λ) 6 Synthesis of 3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione (12)

[0150]

[0151] Step 1: 6-Chloro-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (350 mg, 1.517 mmol, 1 eq.) was dissolved in 1,4-dioxane (5 mL), and 1-(3-bromophenyl)-ethylamine (1.10 g, 5.498 mmol, 3.623 eq.) was added. The mixture was reacted at 120 °C for 16 hours. The reaction solution was concentrated and purified by column chromatography (CH2Cl2:CH3OH = 100:1 as eluent) to give a yellow solid product (R)-6-(2-(3-bromophenyl)propyl)-3-(tetrahydro-2H-pyran-4-yl)pyrimidin-2,4(1H,3H)-dione (400 mg, yield 66.8%). MS (m / z) 394.10 (Mw+H) + .

[0152] Step 2: Dissolve (S)-6-[1-(3-bromo-phenyl)-ethylamino]-3-(tetrahydro-pyran-4-yl)-1H-pyrimidin-2,4-dione in (150 mg, 380.457 μmol, 1 eq.) and dissolve in 1,4-dioxane (5 mL). Add iminodimethylsulfonamide (400 mg, 4.294 mmol, 11.287 eq.), cesium carbonate (250 mg, 767.297 μmol, 2.017 eq.), and XPhos (15 mg, 31.465 μmol, 8.270 eq.). -2 The mixture was reacted at 90°C for 16 hours, evaporated to dryness, diluted with methanol, filtered, and the filtrate was evaporated to dryness again. After purification by reverse-phase flash, water:acetonitrile (30%), a white solid product (S)-6-((1-(3-((dimethyl(oxo)-λ)) was obtained. 6 -Thiodinium)amino)phenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidin-2,4(1H,3H)-dione (110 mg, 270.604 μmol, 71.126%). MS (m / z) 407.20 (Mw+H) + . 1 H NMR(400MHz,DMSO-d6)δ9.95(s,1H),7.19–7.11(m,1H),6.87–6.80(m,3H),6.64(br d,J=6.4Hz,1H),4.83–4.70(m,1H),4.49–4.33(m,2H),3.90–3.85(m,2H),3.28(br s,2H),3.21(d,J=5.4Hz,6H),2.59–2.52(m,2H),1.38(d,J=6.6Hz,3H),1.33(br s,2H), LCMS[M+1]+=407.20.

[0153] Example 013 Synthesis of 3-(tetrahydropyran-4-yl)-6-(1-tolyl-cyclopropylamino)-1H-pyrimidin-2,4-dione (13)

[0154]

[0155] Step 1: 6-Chloro-3-(tetrahydropyran-4-yl)-1H-pyrimidin-2,4-dione (150 mg, 650.342 μmol, 1 eq.) and 1-methylcyclopropylamine (390 mg, 2.649 mmol, 4.073 eq.) were dissolved in 1,4-dioxane (2 mL) and reacted at 120 °C for 16 hours. The solution was evaporated to dryness. The solution was purified by normal-phase flash n-heptane:ethyl acetate (70%), then slurried with EA, filtered, and dried. A pale yellow solid product, 3-(tetrahydropyran-4-yl)-6-(1-tolyl-cyclopropylamino)-1H-pyrimidin-2,4-dione (40 mg, 117.163 μmol, 18.016%), was obtained. 1 H NMR (400MHz, DMSO-d6) δ1.16-1.37(m,6H),2.29(s,3H),2.53-2.60(m,2H),3.16-3.31(m,2H),3.84-3.93(m,2H),4.42(d ,J=2.20Hz,1H),4.68-4.84(m,1H),6.88-7.05(m,4H),7.16-7.23(m,1H),10.07(d,J=1.47Hz,1H), LCMS[M+1]+=342.20.

[0156] Example 014 Synthesis of (R)-6-((2-hydroxy-1-phenylethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione (14)

[0157]

[0158] Step 1: (2R)-2-amino-2-phenylethanol (360 mg, 2.624 mmol, 4.035 eq.) and 6-chloro-3-tetrahydropyran-4-yl-1H-pyrimidin-2,4-dione (150 mg, 650.342 μmol, 1 eq.) were dissolved in 1,4-dioxane (2 mL) and reacted at 120 °C for 12 h. The solution was evaporated to dryness. The solution was purified by flash normal-phase EA:MeOH (10:1), slurried with EA, filtered, and dried. A white solid product (R)-6-((2-hydroxy-1-phenylethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidin-2,4(1H,3H)-dione (90 mg, 271.603 μmol, 41.763%) was obtained. 1H NMR (400MHz, DMSO-d6) δ10.11(br d,J=1.7Hz,1H),7.47–7.22(m,5H),6.68(br d,J=6.4Hz,1H),5.23(br t,J=4.6Hz,1H),4.80–4.71(m,1H),4.40(br d,J=4.4Hz,1H),4.30(s,1H),3.90–3.83(m,2H),3.74–3.64(m,2H),3.57–3.49(m,2H),3.31–3.25(m,2H),1.31(br d,J=10.8Hz,2H). LCMS[M+1]+=332.20.

[0159] Example 015 Synthesis of (R)-6-((2-methoxy-1-phenylethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione (15)

[0160]

[0161] Step 1: 6-Chloro-3-tetrahydropyran-4-yl-1H-pyrimidin-2,4-dione (150 mg, 650.342 μmol, 1 eq.) and (1R)-2-methoxy-1-phenylethanolamine (500 mg, 3.307 mmol, 5.085 eq.) were dissolved in 1,4-dioxane (1 mL) and reacted at 90 °C for 16 hours. The mixture was then evaporated to dryness. The solution was purified using a normal-phase flash, n-heptane:ethyl acetate (70%). The solution was evaporated to dryness, slurried with ethyl acetate, filtered, and dried to obtain a white solid product (R)-6-((2-methoxy-1-phenylethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidin-2,4(1H,3H)-dione (60 mg, 173.716 μmol, 26.711%). 1 H NMR(400MHz,DMSO-d6)δ10.04(br s,1H),7.39–7.33(m,4H),7.32–7.24(m,1H),6.71(br d,J=6.4Hz,1H),4.79–4.70(m,1H),4.67–4.57(m,1H),4.34(s,1H),3.91–3.82(m,2H),3.59–3.51(m,2H),3.29(s,5H),2.54(br s,2H),1.31(br d,J=11.0Hz,2H).LCMS[M+1]+=346.20.

[0162] Example 016 Synthesis of (S)-3-(1,1-dioxide tetrahydro-2H-thiopyran-4-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione (16)

[0163]

[0164] Step 1: Dissolve tetrahydrothiaran-4-amine (10.00 g, 85.315 mmol, 1 eq.) in DCM (100 mL), replace with nitrogen, cool to 0 °C, add isocyanate (trimethyl)silane (10.00 g, 86.801 mmol, 1.017 eq.) dropwise, heat to room temperature, and react at 26 °C for 16 hours. Cool to 0 °C, add 40 mL of methanol dropwise, react at room temperature for 1 hour, and evaporate to dryness. Add methyl tert-butyl ether, slurry, filter, dry, and collect the filter cake. A white solid product, tetrahydrothiaran-4-ylurea (10.00 g, 62.408 mmol, 73.149%), was obtained (LCMS [M+1]). + =161.20.

[0165] Step 2: Tetrahydrothiaran-4-ylurea was dissolved in methanol (150 mL), and dimethyl malonate (23.00 g, 174.092 mmol, 3.100 eq.) and sodium methoxide (23.00 g, 425.737 mmol, 7.580 eq.) were added. Nitrogen was purged, and the mixture was reacted at 65 °C for 16 hours. The mixture was cooled to 0 °C, the pH was adjusted to 5 with concentrated hydrochloric acid, and the solution was evaporated to dryness. The solution was extracted with DCM and water, and the organic phase was evaporated to dryness. The solution was purified by flash normal phase reaction with EA:n-heptane (1:1). A white oily product, 1-tetrahydrothiaran-4-ylhexahydropyrimidine-2,4,6-trione (5.00 g, 21.904 mmol, 38.998%), was obtained.

[0166] Step 3: 1-Tetrahydrothiaran-4-ylhexahydropyrimidine-2,4,6-trione (4.50 g, 19.714 mmol, 1 eq.) was added to a three-necked flask, followed by POCl3 (30 mL). The mixture was cooled to 0 °C, and then TEBAC (9.50 g, 41.708 mmol, 2.116 eq.) was added. The nitrogen atmosphere was replaced, and the mixture was reacted at 50 °C for 16 hours. Most of the POCl3 was removed by rotary evaporation, and the mixture was diluted with DCM. The crude product was slowly added dropwise to ice water and extracted with DCM. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. The product was purified by flash normal phase reaction with n-heptane:EA (1:1). A yellow solid product, 6-chloro-3-tetrahydrothiaran-4-yl-1H-pyrimidine-2,4-dione (1.35 g, 54.72 mmol, 27.757%), was obtained.

[0167] Step 4: Dissolve 6-chloro-3-tetrahydrothiaran-4-yl-1H-pyrimidin-2,4-dione (250 mg, 1.013 mmol, 1 eq.) in DCM (2 mL), cool to 0 °C, add m-CPBA (450 mg, 2.608 mmol, 2.573 eq.), replace with nitrogen, and react at 28 °C for 16 hours. Filter, wash the filter cake with DCM, and dry. A white solid product, 6-chloro-3-(1,1-dioxothiophen-4-yl)-1H-pyrimidin-2,4-dione (250 mg, 896.983 μmol, 88.519%), is obtained.

[0168] Step 5: Add 6-chloro-3-(1,1-dioxothiophene-4-yl)-1H-pyrimidin-2,4-dione (70 mg, 251.155 μmol, 1 eq.) to a 4 mL reaction flask, then add (1R)-1-phenylethylamine (61 mg, 503.387 μmol, 2.004 eq.), followed by 2 mL of Dioxane, and finally DIEA (163 mg, 1.261 mmol, 5.022 eq.). After the addition is complete, purge with nitrogen four times. React at 95 °C for 18 hours under nitrogen protection. Cool the reaction system to room temperature and evaporate to dryness under reduced pressure. Purify using a preparative agar plate with a developing solvent of DCM:MeOH = 15:1. The target product (S)-3-(1,1-dioxide tetrahydro-2H-thiopyran-4-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione (3 mg, 8.255 μmol, 3.287%) was obtained as a white solid.

[0169] Example 017 Synthesis of (S)-3-morpholino-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione (17)

[0170]

[0171] Step 1: Morpholin-4-amine (7.00 g, 68.537 mmol, 1 eq.) was added to a three-necked flask, followed by 60 mL of ultra-dry DCM. The system was cooled to 0 °C in an ice bath. Trimethyl isocyanate silane (7.90 g, 68.573 mmol, 1.001 eq.) was then added dropwise, maintaining a temperature not exceeding 5 °C. After the addition was complete, the mixture was purged with nitrogen four times. The reaction was then carried out at 20 °C for 16 hours under nitrogen protection, and the reaction was monitored and processed. The reaction system was cooled to 0 °C in an ice bath, and 60 mL of methanol was added dropwise. The mixture was stirred at room temperature for 3 hours, concentrated under reduced pressure, and then slurried with methyl ether and filtered. The resulting filter cake was washed with methyl ether (150 mL * 3). The filter cake was then evaporated under reduced pressure to obtain the white solid product morpholinurine (9.79 g, 67.443 mmol).

[0172] Step 2: Moroxydine (1.00 g, 6.889 mmol, 1 eq.) and diethyl malonate (2.20 g, 13.736 mmol, 1.994 eq.) were added to 20% sodium ethoxide ethanol solution (11.80 g, 34.453 mmol, 20% purity, 5.001 eq.), and the mixture was heated to 90 °C and reacted for 16 hours. The pH was adjusted to 3 at °C, and the mixture was extracted with EA (200 mL), backwashed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The crude product was purified using a flash normal-phase column chromatography with EA:MeOH (10:1). A yellow solid, 1-morpholinohexahydropyrimidine-2,4,6-trione (700 mg, 3.283 mmol, 47.662%, 1 eq.), was obtained. LCMS [M+1]+ = 214.20.

[0173] Step 3: Add 1-morpholinohexahydropyrimidine-2,4,6-trione (700 mg, 3.283 mmol, 1 eq.) to a 4 mL reaction flask, add 2 mL of ACN, and cool the system to 0 °C in an ice bath. Then add POCl3 (800 mg, 5.218 mmol, 1.589 eq.), keeping the temperature below 5 °C. After the addition is complete, purge with nitrogen four times and react at 80 °C for 18 hours under nitrogen protection. Rotate the reaction solution to dryness, dilute with 50 mL of dichloromethane, backwash with saturated brine, dry with anhydrous magnesium sulfate, filter, and rotate to dryness to obtain the crude product. Purify the crude product using a flash normal-phase column chromatography with n-heptane:ethyl acetate (1:3). A yellow solid product, 6-chloro-3-morpholino-1H-pyrimidin-2,4-dione (220 mg, 949.766 μmol, 28.926%), was obtained. LCMS [M+1]+ = 232.30.

[0174] Step 4: Add 6-chloro-3-morpholino-1H-pyrimidin-2,4-dione (200 mg, 863.424 μmol, 1 eq.) to a 4 mL reaction flask, followed by (1R)-1-phenylethylamine (210 mg, 1.733 mmol, 2.007 eq.), then add Dioxane (2 mL), and finally add DIEA (558 mg, 4.318 mmol, 5.001 eq.). After the addition is complete, purge with nitrogen four times. React at 95 °C for 18 hours under nitrogen protection. Cool the reaction system to room temperature and evaporate to dryness under reduced pressure. Purify using a preparative agar plate (developing solvent: DCM:MeOH = 15:1). The target product (S)-3-morpholino-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione (10 mg, 31.610 μmol, 3.661%) was obtained as a white solid. 1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),7.36(m,4H),7.27(m,1H),6.61(d,J=6.9Hz,1H),4 .49(m,1H),4.32(s,1H),3.59(s,4H),3.25(s,2H),3.04(s,2H),1.39(d,J=6.8Hz,3H).

[0175] Example 018 Synthesis of 3-(1-cyclopropyl-2,2,2-trifluoroethyl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione (18)

[0176]

[0177] Step 1: Add 1-cyclopropyl-2,2,2-trifluoroethylamine (3.00 g, 21.564 mmol, 1 eq.) to a three-necked flask, then add ultradry DCM (35 mL), followed by triethylamine (2.19 g, 21.643 mmol, 1.004 eq.). Cool the system to 0°C in an ice bath. Then, add isocyanate (trimethyl)silane (2.49 g, 21.614 mmol, 1.002 eq.) dropwise, keeping the temperature below 5°C. After the addition is complete, purge with nitrogen four times and react at 24°C for 18 hours under nitrogen protection. Cool the reaction system to 0°C in an ice bath, add 10 mL of methanol dropwise, stir at room temperature for 3 hours, concentrate under reduced pressure, add methyl ether to form a slurry, and filter. Wash the filter cake with methyl ether (50 mL * 3), and evaporate the filter cake to dryness under reduced pressure to obtain a white solid product. No further purification was performed. The target product (1-cyclopropyl-2,2,2-trifluoroethyl)urea (3.23 g, 17.733 mmol) was finally obtained as a white solid.

[0178] Step 2: Add (1-cyclopropyl-2,2,2-trifluoroethyl)urea (2.00 g, 10.980 mmol, 1 eq.) to a three-necked flask, then add MeOH (20 mL). Cool the system to 0°C in an ice bath. Next, add dimethyl malonate (1.75 g, 13.246 mmol, 1.206 eq.) and MeONa (2.97 g, 55.000 mmol, 5.009 eq.), maintaining a temperature not exceeding 5°C. After the addition is complete, purge with nitrogen four times and react at 65°C for 18 hours under nitrogen protection. Cool the reaction system to 0°C in an ice bath, add HCl dropwise to adjust the pH to 3, evaporate to dryness under reduced pressure, add 65 mL of anhydrous ethanol, stir for 2.5 hours, filter, and wash the filter cake with anhydrous ethanol (50 mL * 3). Evaporate the filter cake to dryness under reduced pressure to obtain a white solid product. Purify by forward chromatography. The product 1-(1-cyclopropyl-2,2,2-trifluoroethyl)hexahydropyrimidine-2,4,6-trione (1.68 g, 6.715 mmol, 61.158%) was obtained as a white solid.

[0179] Step 3: Add 1-(1-cyclopropyl-2,2,2-trifluoroethyl)hexahydropyrimidine-2,4,6-trione (300 mg, 1.199 mmol, 1 eq.) to a 50 mL reaction flask, then add 5 mL of ACN. Cool the system to 0 °C in an ice bath, then add POCl3 (240 mg, 1.565 mmol, 142 μL, 1.305 eq.). The temperature should not exceed 5 °C. After the addition is complete, purge with nitrogen four times and react at 80 °C for 18 hours under nitrogen protection. Cool the reaction system to room temperature and evaporate to dryness under reduced pressure. Purify using reversed-phase chromatography. Obtain the target product 6-chloro-3-(1-cyclopropyl-2,2,2-trifluoroethyl)-1H-pyrimidine-2,4-dione (278 mg, 1.035 mmol, 86.303%) as a yellow solid.

[0180] Step 4: Add 6-chloro-3-(1-cyclopropyl-2,2,2-trifluoroethyl)-1H-pyrimidin-2,4-dione (278 mg, 1.035 mmol, 1 eq.) to a 4 mL reaction flask, followed by (1R)-1-phenylethylamine (126 mg, 1.040 mmol, 1.005 eq.). Purge with nitrogen four times and react at 120 °C for 2 hours under nitrogen protection. Cool the reaction system to room temperature and evaporate to dryness under reduced pressure. Purify using reversed-phase chromatography. Obtain the white solid product 3-(1-cyclopropyl-2,2,2-trifluoroethyl)-6-(((S)-1-phenylethyl)amino)pyrimidin-2,4(1H,3H)-dione (17 mg, 48.113 μmol, 4.649%). 1H NMR(400MHz, Methanol-d4)δ7.45–7.34(m,4H),7.30(dt,J=9.3,5.1Hz,2H),4.58(dddd,J=16.8,13.4,7.7,3.0Hz,2H),2.02(q,J=5.8,4.7Hz,1H),1 .53(dd,J=6.8,1.1Hz,3H),1.40(d,J=7.0Hz,1H),0.78(ddd,J=10.7,7.1, 2.7Hz, 1H), 0.68–0.40 (m, 2H), 0.19 (dddd, J = 30.0, 15.0, 9.3, 5.0Hz, 1H).

[0181] Biological testing evaluation

[0182] Experimental Example 1: Cardiac Actin and Myosin Motor S1: Activity Assay

[0183] Relevant reagents:

[0184] Cardiac Actin; Manufacturer: Cytoskeleton; Product Number: AD99.

[0185] Myosin Motor S1; Manufacturer: Cytoskeleton; Part Number: CS-MYS03.

[0186] CytoPhos Phosphate Assay Biochem Kit™; Manufacturer: Cytoskeleton; Catalog Number: BK054

[0187] Analysis buffer: 50mM Tris-HCl, pH 7.5; 5mM CaCl2; 5mM KCl; 1mM MgCl2; 1mM DTT.

[0188] Experimental steps:

[0189] 1. Add 4 μL of inhibitor to a 96-well plate;

[0190] 2. Add 8 μL of cardiac actin and Myosin Motor S1 respectively;

[0191] Incubate at 3.37℃ for 60 minutes;

[0192] 4. Add 4 μL of ATP to start the reaction and incubate at 37°C for 2 hours;

[0193] 5. Add 56 μL of Cytophos Reagent to terminate the reaction;

[0194] 6. After 10 minutes at room temperature, read the plate using an ELISA reader (A650);

[0195] 7. Formula for calculating inhibition rate:

[0196] In the above formula, Ratio cpd The OD value of the corresponding compound at the corresponding concentration; Ratio PC The OD value is the value obtained in step 1 when DMSO solution without the compound was added; RatioVC is the OD value obtained in step 2 when a blank buffer was used instead of the cardiac agonist protein solution. According to the above formula, the inhibition rate of the compound on ATP hydrolysis by the cardiac agonist protein at the corresponding concentration can be obtained. Data were processed using GraphPad software. Inhibition curves were plotted based on the compound concentrations and corresponding inhibition rates, and the concentration of the compound at which the inhibition rate reached 50%, i.e., the IC50 value, was calculated. Experimental results are detailed in Table 1.

[0197] Experimental results:

[0198] IC was obtained after compound calculation. 50 ≤1.0μM is denoted as "A"; 1.0μM <IC 50 ≤10μM is denoted as "B"; 10μM <IC 50 It is denoted as "C".

[0199] Table 1

[0200] Example number <![CDATA[IC 50 ]]> Example number <![CDATA[IC 50 ]]> Example 1 C Example 10 B Example 2 C Example 11 B Example 3 B Example 12 B Example 4 C Example 13 B Example 5 C Example 14 B Example 6 A Example 15 B Example 7 B Example 16 B Example 8 B Example 17 B Example 9 C Example 18 B

[0201] The applicant declares that the present invention illustrates the 4-amino-2,6-dihydroxypyrimidine derivative and its application through the above embodiments, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A compound represented by formula (I): Or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers or their pharmaceutically usable salts; in, L is selected from Ring A is selected from 5- to 6-membered aryl or heteroaryl groups containing 0 to 3 heteroatoms; R1 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -R a OR b -OC(O)R a -OC(O)OR a -OC(O)NR a R b -NR a R b -SR a -S(O)R a -S(O)2R a Or a 3-10 saturated or unsaturated ring containing 0-3 heteroatoms, wherein the 3-10 saturated or unsaturated ring containing 0-3 heteroatoms may optionally be surrounded by 1-3 R... a replace; R2 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -R a OR b -OC(O)R a -OC(O)OR a -OC(O)NR a R b -NR a R b -NS(R) a )2O、-SR a -S(O)R a -S(O)2R a Or a 3-10 saturated or unsaturated ring containing 0-3 heteroatoms, wherein the 3-10 saturated or unsaturated ring containing 0-3 heteroatoms may optionally be surrounded by 1-3 R... a replace; Each R a R b Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, halogen, cyano, nitro, amino, carboxyl, carbonyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, alkoxy-substituted C3-C6 cycloalkyl, C3-C6 heterocyclic, halo-C3-C6 heterocyclic, and C1-C6 alkyl-substituted C5-C 10 heteroaryl, -S(O)2R c -OR c OR d -R c OR d -C(O)R c or -OC(O)R c Each R c R d Each is independently selected from hydrogen or C1-C6 alkyl; and n = 0, 1, 2 or 3.

2. The compound represented by formula (I) according to claim 1, wherein formula (I) is formula (Ia): R2 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogen, -SCF3 or -N = S(CH3)2 = O; R1, L, n are as defined in claim 1.

3. The compound of formula (I) according to claim 1, wherein formula (I) is formula (Ib): R2 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogen, -SCF3 or -N = S(CH3)2 = O; R1, L, n are as defined in claim 1.

4. The compound represented by formula (I) according to claim 1, wherein formula (I) is formula (Ic): R2 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogen, -SCF3 or -N = S(CH3)2 = O; R1, L, n are as defined in claim 1.

5. The compound represented by formula (I) according to claim 1, wherein formula (I) is formula (Id): R2 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogen, -SCF3 or -N = S(CH3)2 = O; R1, L, n are as defined in claim 1.

6. The compound represented by formula (I) according to claim 1, wherein formula (I) is formula (Ie): R2 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogen, -SCF3 or -N = S(CH3)2 = O; R1, L, n are as defined in claim 1.

7. The compound represented by formula (I) according to claim 1, wherein formula (I) is formula (If): R2 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogen, -SCF3 or -N = S(CH3)2 = O; R1, L, n are as defined in claim 1.

8. The compound represented by formula (I) according to claim 1, wherein formula (I) is formula (Ig): R2 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogen, -SCF3 or -N = S(CH3)2 = O; R1, L, n are as defined in claim 1.

9. The compound of formula (I) according to claim 1, wherein ring A is selected from...

10. The compound of formula (I) according to claim 1, wherein R1 is selected from...

11. The compound of formula (I) according to claim 1, wherein R2 is selected from methyl, cyclopropyl, chloro, 12. The compound of formula (I) according to claim 1, wherein the compound is selected from:

13. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-12, an isomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.

14. Use of any compound of claims 1-12, its isomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 13 in the preparation of a medicament for the treatment of heart disease.

15. The use according to claim 14, wherein, The heart disease refers to heart disease in humans or companion animals.

16. The use according to claim 15, wherein, The heart disease mentioned refers to a heart condition in humans or cats.

17. The use according to claim 15, wherein, The heart disease mentioned is hypertrophic cardiomyopathy in humans or cats.

18. The use according to claim 17, wherein, The hypertrophic cardiomyopathy is obstructive or non-obstructive or associated with sarcomere and / or non-sarcomere mutations.

19. The use according to claim 14, wherein, The heart disease described is heart failure with preserved ejection fraction.

20. The use according to claim 14, wherein, The heart diseases mentioned are selected from: diastolic dysfunction, primary or secondary restrictive cardiomyopathy, myocardial infarction and angina pectoris, left ventricular outflow tract obstruction, hypertensive heart disease, congenital heart disease, myocardial ischemia, coronary heart disease, diabetic heart disease, congestive heart failure, right heart failure, cardiorenal syndrome and infiltrative cardiomyopathy.

21. The use according to claim 14, wherein, The heart disease is selected from: cardiac aging, diastolic dysfunction due to aging, left ventricular hypertrophy, and left ventricular concentric remodeling.

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