WO2022135502A1

WO2022135502A1 - Multi-substituted uracil derivative and use thereof

Info

Publication number: WO2022135502A1
Application number: PCT/CN2021/140697
Authority: WO
Inventors: 张铮; 池波; 韩伟; 马发城; 刘楚怡; 李明; 左应林; 王晓军
Original assignee: 广东东阳光药业有限公司
Priority date: 2020-12-25
Filing date: 2021-12-23
Publication date: 2022-06-30
Also published as: CN114671856A; CN114671856B

Abstract

Provided are a multi-substituted uracil derivative represented by formula (I) and the use thereof. Specifically, the present invention relates to a class of novel multi-substituted uracil derivatives and a pharmaceutical composition containing such compounds, which can be used as chymase inhibitors. The present invention further relates to a method for preparing such compounds and the pharmaceutical composition, and the use thereof in the preparation of a drug for treating related cardiovascular diseases such as heart failure or myocardial infarction.

Description

Polysubstituted uracil derivatives and uses thereof

technical field

The present invention belongs to the technical field of medicine, specifically relates to novel polysubstituted uracil derivatives and uses thereof, further relates to pharmaceutical compositions comprising these compounds, and methods and uses thereof. In particular, the novel polysubstituted uracil derivatives and/or their pharmaceutical compositions described in the present invention can be used as chymotrypsin-like inhibitors to prevent, treat or alleviate related cardiovascular diseases such as heart failure or myocardial infarction.

Background technique

Cardiovascular diseases (CVD) are one of the leading causes of death worldwide. CVD refers to ischemic or hemorrhagic diseases of the heart, brain and systemic tissues caused by hyperlipidemia, blood viscosity, atherosclerosis, hypertension, etc., such as hypertension, coronary artery disease, myocardial disease, Vascular disease, congenital heart disease, arrhythmia, pericardial disease, heart attack and stroke, etc. Hypertension, high cholesterol, smoking, obesity and diabetes are major risk factors for the development of cardiovascular disease. Health conditions such as lifestyle, age, and family history can also increase the risk of heart disease. Although age, gender, genetics, and family medical history are unmodifiable risks for susceptibility to cardiovascular disease, the burden of cardiovascular disease can be reduced by implementing a low-fat and low-sodium diet, maintaining physical activity, and avoiding weight gain. Several recent preclinical and some clinical studies point to the relatively unrecognized fact that chymase inhibitors may have significant therapeutic advantages over other treatments in halting the progression of cardiac and vascular disease.

Chymase is a chymotrypsin-like serine protease whose macromolecular complex with heparin is stored in secretory vesicles of mast cells. After mast cells are activated, chymase is released into the extracellular matrix in response to inflammatory signals, tissue damage and cellular stress. Growing evidence suggests that mast cell chymase is one of the key factors contributing to tissue remodeling and CVD progression. Activated mast cells play an important role in wound healing and inflammation resolution, such as wound fibrosis, angiogenesis and myocardial remodeling (Miyazaki et al., Pharmacol. Ther, 112 (2006), 668-676; Shiota et al, J. Hypertens, 21 (2003), 1823-1825). Increased numbers of mast cells have been observed in the setting of heart failure, myocardial infarction and ischemia, human atherosclerotic plaque and abdominal aortic aneurysm (Kovanen et al., Circulation, 92 (1995), 1084-1088 ; Libby and Shi et al, Circulation, 115 (2007), 2555-2558; Bacani and Frishman et al, Cardiol. Rev, 14(4) (2006), 187-193). Chymotrypsin-like-positive mast cells play an important role in airway vascular remodeling in asthma and chronic obstructive pulmonary disease. Increased numbers of mast cells have now been found in endobronchial biopsies of asthmatic patients (Zanini et al., J. Allergy Clin Immunol, 120 (2007), 329-333). In addition, chymotrypsin-like enzymes are also suspected to be one of the causes of various nephropathy such as diabetic nephropathy and polycystic kidney disease (Huang et al., J.Am.Soc.Nephrol, 14(7), (2003), 1738-1747 ; McPherson et al., J. Am. Soc. Nephrol, 15(2), (2004), 493-500).

Chymotrypsin-like enzymes are mainly involved in the production of angiotensin II in the heart, arterial walls and lungs. An earlier study by Cleveland Clinic investigators was the first to demonstrate the role of chymase as an Ang II (angiotensin II)-forming enzyme (Urata H et al., J. Biol. Chem, 1990, 265(36):22348-57). Over the past few decades, several studies have confirmed and expanded the importance of chymase as a synthetase in the Ang II production pathway (Chandrasekharan UM et al., Science, 1996, 271(5248):502-5). Then, studies on the treatment of Ang-(1-12) in human and rodent hearts showed that both Ang I and Ang-(1-12) directly form Ang-II enzymes, mainly chymase (Ahmad S et al. Human, J.Am.Soc.Hypertens, 2013 7(2):128-36). Ang II (angiotensin II) is an effector molecule that mainly acts on various target receptors on the surface of vascular wall cells, nuclear membranes, renal tubules, glomeruli, and adrenal glands to achieve blood pressure regulation and water and electrolyte balance. control. When angiotensin II binds to angiotensin receptors, it causes corresponding physiological effects, including constricting arterioles and veins throughout the body, increasing blood pressure, and increasing blood return to the heart; stimulating the adrenal gland to synthesize and release aldosterone. Therefore, inhibiting the activation of chymotrypsin can reduce the production of angiotensin, which can control the contraction of blood vessels and the increase of blood pressure to a certain extent.

The possibility of treating various cardiovascular diseases with chymotrypsin inhibitors has been demonstrated in many animal studies. For example, chymotrypsin-like inhibitors are very useful for the treatment of myocardial infarction (Jin et al., Pharmacol. Exp. Ther, 309 (2004), 409-417), experiments have shown that when coronary artery ligation in dogs causes ventricular arrhythmias, Promotes the production of angiotensin II in the heart and enhances chymotrypsin-like activity. In recent years, Bayer is developing an oral small-molecule chymotrypsin-like inhibitor BAY-1142524 for the treatment of heart failure and diabetic nephropathy. Preclinical results show that the compound can improve cardiac function in hamsters after myocardial infarction. The Phase I clinical results also showed good safety, tolerability and pharmacokinetic properties of BAY-1142524 in healthy subjects. At present, Bayer has launched a phase II clinical trial for diabetic nephropathy to further verify the efficacy and safety of the new chymotrypsin-like inhibitor.

Thus, chymotrypsin-like inhibition constitutes an effective method of treating cardiovascular disorders, inflammation, allergic disorders and various fibrotic disorders.

SUMMARY OF THE INVENTION

The present invention provides a class of novel multi-substituted uracil derivatives as chymotrypsin-like inhibitors for preventing, treating or alleviating related cardiovascular diseases such as heart failure or myocardial infarction. And experiments show that the multi-substituted uracil derivatives of the present invention have stable properties, good safety, good pharmacodynamics and pharmacokinetic properties, such as good chymotrypsin-like inhibitory activity, good bioavailability and / or good metabolic stability, etc. Therefore, the compounds of the present invention have good clinical application prospects.

The present invention also provides methods for preparing such compounds, pharmaceutical compositions containing such compounds, and the use of such compounds and/or pharmaceutical compositions of such compounds in the preparation of medicaments.

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of the compound represented by formula (I). , a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,

Wherein: each of m, A, R ¹ , R ² , R ³ and R ⁴ has the meaning as described in the present invention.

In one embodiment, the compound of the present invention can be a compound represented by formula (IIa) or formula (IIb), or a stereoisomer, mutual isomer of a compound represented by formula (IIa) or formula (IIb). Variants, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,

In one embodiment, A is a saturated or partially unsaturated C _3-10 carbocyclic ring, a heterocyclyl group of 3-8 atoms, a C _6-10 aryl group, or a heteroaryl group of 5-12 atoms, wherein the saturated or partially unsaturated C _3-10 carbocyclic ring, the heterocyclic group consisting of 3-8 atoms, the C _6-10 aryl group and the heteroaryl group consisting of 5-12 atoms are independently unsubstituted or by 1, 2, 3, 4 or 5 selected from D, F, Cl, Br, I, NO ₂ , CN, OH, NH ₂ , C _1-3 alkyl, C _1-3, alkyl, C _1-3 alkoxy and C _1-3 haloalkoxy substituents.

In one embodiment, A is a C _3-8 cycloalkyl group, a C _6-10 aryl group, a heterocyclic group consisting of 3-8 atoms, or a heteroaryl group consisting of 5-12 atoms, wherein the C _3-8 cycloalkyl, C _6-10 aryl, heterocyclyl of 3-8 atoms and heteroaryl of 5-12 atoms are independently unsubstituted or substituted by 1, 2, 3, 4 or 5 selected from D, F, Cl, Br, I, NO ₂ , CN, OH, NH ₂ , C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _1-3 Substituents of haloalkoxy.

In one embodiment, each R ¹ is independently H, D, halogen, NO ₂ , CN, OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-8 cycloalkyl, heterocyclic group consisting of 3-8 atoms, C _6-10 aryl group or heteroaryl group consisting of 5-12 atoms.

In one embodiment, m is 0, 1, 2, 3 or 4.

In one embodiment, R ² is

wherein R ⁵ and R ⁶ have the meanings described in the present invention.

In one embodiment, R5 is ^-NRn- , -O-, -S- or ^-CRcRd- ^{; wherein Rn, Rc and Rd} ^have ^the ^meanings described herein ^.

In one embodiment, R ⁿ is H, D, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, 3 -Heterocyclic group consisting of 8 atoms, C _3-8 cycloalkyl-C _1-6 alkylene group, Heterocyclic group consisting of 3-8 atoms-C _1-6 alkylene group, C _6-10 aryl group, C _6-10 aryl-C _1-6 alkylene group, heteroaryl-C _1-6 alkylene group consisting of 5-12 atoms or heteroaryl group consisting of 5-12 atoms.

In one embodiment, R ^c and R ^d are each independently H, D, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _{1- 6} alkoxy group, C _3-8 cycloalkyl group, heterocyclic group consisting of 3-8 atoms, C _6-10 aryl group or heteroaryl group consisting of 5-12 atoms.

In one embodiment, R ⁶ is H, D, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-C _1-6 alkylene, heterocyclyl composed of 3-8 atoms, heterocyclyl composed of 3-8 atoms-C _1-6 alkylene, C _6-10 aryl group, C _6-10 aryl-C _1-6 alkylene group, heteroaryl-C _1-6 alkylene group consisting of 5-12 atoms or heteroaryl group consisting of 5-12 atoms.

In one embodiment, R ³ is H, D, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy , C _1-6 haloalkoxy, C _3-8 cycloalkyl, heterocyclic group composed of 3-8 atoms, C _6-10 aryl group, heteroaryl group composed of 5-12 atoms, -NR ^a1 R ^b or -OR ^a , wherein the C _3-8 cycloalkyl group, the 3-8 atom heterocyclic group, the C _6-10 aryl group and the 5-12 atom heteroaryl group are independently not substituted or by 1, 2, 3, 4 or 5 selected from D, F, Cl, Br, I, NO ₂ , CN, OH, NH ₂ , C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _1-3 haloalkoxy substituents; wherein R ^a1 , R ^a and R ^b have the meanings described in the present invention.

In one embodiment, R ^a1 , R ^a and R ^b are each independently H, D, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _6-10 aryl , a heterocyclic group consisting of 3-8 atoms or a heteroaryl group consisting of 5-12 atoms.

In one embodiment, R ⁴ is H, D, halogen or C _1-6 alkyl.

In some embodiments, A is C _3-6 cycloalkyl, C _6-10 aryl, 3-6 atoms heterocyclyl or 5-10 atoms heteroaryl, wherein the C _3-6 cycloalkyl, C _6-10 aryl, heterocyclyl of 3-6 atoms or heteroaryl of 5-10 atoms are independently unsubstituted or substituted by 1, 2, 3, 4 or 5 selected from D, F, Cl, Br, I, NO ₂ , CN, OH, NH ₂ , C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _1-3 Substituents of haloalkoxy.

In some embodiments, each R ¹ is independently selected from H, D, halogen, NO ₂ , CN, OH, NH ₂ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy , C _1-4 haloalkoxy, C _3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C _6-10 aryl group or heteroaryl group consisting of 5-10 atoms.

In some embodiments, R ⁿ is H, D, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, 3 -Heterocyclyl consisting of 6 atoms, C _3-6 cycloalkyl-C _1-4 alkylene, Heterocyclyl consisting of 3-6 atoms-C _1-4 alkylene, C _6-10 aryl group, C _6-10 aryl-C _1-4 alkylene group, heteroaryl-C _1-4 alkylene group consisting of 5-10 atoms or heteroaryl group consisting of 5-10 atoms.

In some embodiments, R ^c and R ^d are each independently H, D, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _{1-4 4} -alkoxy group, C _3-6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, C _6-10 aryl group or heteroaryl group consisting of 5-10 atoms.

In some embodiments, R ⁶ is H, D, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, 3 -Heterocyclyl consisting of 6 atoms, C _3-6 cycloalkyl-C _1-4 alkylene, Heterocyclyl consisting of 3-6 atoms-C _1-4 alkylene, C _6-10 aryl group, C _6-10 aryl-C _1-4 alkylene group, heteroaryl-C _1-4 alkylene group consisting of 5-10 atoms or heteroaryl group consisting of 5-10 atoms.

In some embodiments, R ³ is H, D, halogen, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 alkoxy , C _1-4 haloalkoxy, C _3-6 cycloalkyl, heterocyclic group composed of 3-6 atoms, C _6-10 aryl group, heteroaryl group composed of 5-10 atoms, -NR ^a1 R ^b or -OR ^a ; wherein said C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 Haloalkoxy, C _3-6 cycloalkyl, 3-6 atoms heterocyclyl, C _6-10 aryl and 5-10 atoms heteroaryl are independently unsubstituted or substituted by 1, 2 , 3, 4 or 5 selected from D, F, Cl, Br, I, NO ₂ , CN, OH, NH ₂ , C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _1-3 haloalkoxy substituents; wherein, R ^a1 , R ^a and R ^b have the meanings described in the present invention.

In some embodiments, R ^a1 , R ^a and R ^b are each independently H, D, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, consisting of 3-6 atoms , a C _6-10 aryl group or a heteroaryl group consisting of 5-10 atoms.

In some embodiments, R ⁴ is H, D, halo, or C _1-4 alkyl.

In some embodiments, A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl , naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazine or pyridazinyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, Phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, Pyrazinyl and pyridazinyl are independently unsubstituted or 1, ₂ , 3, 4 or 5 selected from D, F, Cl, Br, I, NO2, CN, OH, _NH2 , methyl, ethyl radical, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, difluoro Substituents of methoxy, trifluoromethoxy, difluoroethoxy and trifluoroethoxy.

In ^one embodiment, each R1 is independently H, D, F, Cl, Br, I, NO2, CN, OH, _NH2 , methyl, ethyl, n _- propyl, isopropyl, n-butyl base, isobutyl, sec _- butyl, tert _- butyl, _-CH2F , _-CH2Cl , _-CHF2 , _-CHCl2 , _-CF3 , _-CH2CH2F , _-CH2CH2Cl , _-CH2CHF2 , _-CH2CHCl2 , _-CHFCH2F , _-CHClCH2Cl , _-CH2CF3 _, _-CH ₍ _CF3 ₎ ₂ _, _-CF2CH2CH3 _, _-CH2CH2CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl- 1-Propoxy, 2-butoxy, 2-methyl-2-propoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl , pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.

In one embodiment, R ⁿ is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, _-CF3 , _-CH2 F, _-CHF2 , _-CH2CH2F , _-CH2CHF2 , _-CHFCH2F , _-CH2CF3 _, _-CH ₍ _CF3 ₎ ₂ , _-CF2CH2CH3 _, _-CH2CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholine base, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidine pyrazinyl, pyrazinyl or pyridazinyl.

In one embodiment, ^Rc and ^Rd are each independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, - _CF3 , _-CH2F , _-CHF2 , _-CH2CH2F , _-CH2CHF2 , _-CHFCH2F , _-CH2CF3 , _-CH ₍ _CF3 ₎ ₂ _, _-CF2CH2CH ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-alkynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1 -Propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazole oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.

^In one embodiment, R6 is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, _-CF3 , _-CH2 F, _-CHF2 , _-CH2CH2F , _-CH2CHF2 , _-CHFCH2F , _-CH2CF3 _, _-CH ₍ _CF3 ₎ ₂ , _-CF2CH2CH3 _, _-CH2CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholine base, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidine pyrazinyl, pyrazinyl or pyridazinyl.

In one embodiment, ^R is H, D, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, - _CF3 , _-CH2F , _-CHF2 , _-CH2CH2F , _-CH2CHF2 , _-CHFCH2F , _-CH2CF3 , _-CH ₍ _CF3 ₎ ₂ _, _-CF2CH2CH ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-alkynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, difluoromethyl, trifluoromethyl, difluoro Ethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacycle Butyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolium azolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, -NR ^a1 R ^b or -OR ^a ; base, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazole base, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl independently unsubstituted or by 1, 2, 3, 4 or 5 selected from D, F, Cl, Br, I, NO ₂ , CN, OH, NH ₂ , C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy wherein, R _a1 , R ^a and R ^b have the meanings ^described in the present invention.

In one embodiment, R ^a1 , R ^a and R ^b are each independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl base, -CF ₃ , -CH ₂ F, -CHF ₂ , -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CHFCH ₂ F, -CH ₂ CF ₃ , -CH(CF ₃ ) ₂ , -CF ₂ _CH2CH3 , _-CH2CH2CH2F , _-CH2CH2CHF2 _, _-CH2CH2CF3 _, _cyclopropyl , _cyclobutyl , _cyclopentyl , _cyclohexyl , _azetidinyl , pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl , furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.

^In one embodiment, R4 is H, D, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

In one embodiment, it is a compound having one of the following structures or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically Acceptable salt or its prodrug:

In another aspect, the present invention relates to a pharmaceutical composition comprising the compound of the present invention; optionally, it further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

In some embodiments, the pharmaceutical composition of the present invention further comprises one or more other active ingredients selected from calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-blockers, beta-blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors, diuretics, kinase inhibitors, Matrix metalloproteinase inhibitors, soluble guanylate cyclase stimulators and activators, and phosphodiesterase inhibitors.

In one aspect, the present invention relates to the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament, wherein the medicament is used for the treatment or prevention of heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, Asthma, kidney failure, kidney disease, fibrotic conditions of internal organs, or skin fibrosis.

In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds represented by formula (I).

The biological test results show that the compound of the present invention has a good activity of inhibiting chymotrypsin, and can be used as a good chymotrypsin inhibitor, thereby having the potential effect of preventing the occurrence and progression of related diseases.

Any embodiment of any aspect of the invention may be combined with other embodiments so long as they do not appear to be inconsistent. Furthermore, in any embodiment of any aspect of the present invention, any technical feature may be applicable to that technical feature in other embodiments, as long as they do not contradict.

The foregoing has outlined only certain aspects of the invention, but is not limited to these aspects. These and other aspects are described in more detail below. All references in this specification are hereby incorporated by reference in their entirety. When there is a discrepancy between the disclosure content of this specification and the cited documents, the disclosure content of this specification shall prevail.

Definitions and General Terms

Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalents, which are included within the scope of the present invention as defined by the claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, terms defined, uses of terms, techniques described, etc.), this Application shall prevail.

It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of multiple separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

Unless otherwise stated, the following definitions used herein shall apply. For the purposes of the present invention, chemical elements are in accordance with the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007 , the entire contents of which are incorporated herein by reference.

In the description of this specification, description with reference to the terms "one embodiment," "some embodiments," "example," "specific example," or "some examples", etc., mean specific features described in connection with the embodiment or example , structure, material or feature is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine and combine the different embodiments or examples described in this specification, as well as the features of the different embodiments or examples, without conflicting each other.

As used herein, the articles "a", "an" and "the" are intended to include "at least one" or "one or more" unless stated otherwise or otherwise clearly contradicted by context. Thus, as used herein, these articles refer to articles of one or more than one (ie, at least one) object. For example, "a component" refers to one or more components, ie, there may be more than one component contemplated for use or use in the implementation of the described embodiments.

The term "stereoisomers" refers to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, etc. .

The term "chiral molecule" is a molecule that has the property of being non-superimposable with its mirror image; whereas an "achiral molecule" refers to a molecule that is superimposable with its mirror image.

The term "enantiomer" refers to two nonsuperimposable, but mirror-image isomers of a compound.

The term "racemate" or "racemic mixture" refers to an equimolar mixture of two enantiomers lacking optical activity.

The term "diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.

Stereochemistry definitions and rules used in the present invention generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994.

Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about one or more of its chiral centers. The prefixes d and 1 or (+) and (-) are symbols used to designate the rotation of plane polarized light by the compound, where (-) or 1 indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

Any asymmetric atom (eg, carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched forms, such as (R)-, (S)- or (R,S)-configurations exist. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 70% enantiomeric excess in the (R)- or (S)-configuration 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

Depending on the choice of starting materials and methods, the compounds of the present invention may be present as one of the possible isomers or as mixtures thereof, such as racemates and diastereoisomeric mixtures (depending on the number of asymmetric carbon atoms) ) in the form of. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have the cis or trans configuration.

The resulting mixtures of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

Any resulting racemate of the final product or intermediate can be resolved into the optical enantiomers by known methods by methods familiar to those skilled in the art, eg, by performing diastereomeric salts thereof obtained. separation. Racemic products can also be separated by chiral chromatography, eg, high performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 ^nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconvertible through a low energy barrier. A chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution). For example, protontautomers (also known as prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization.

"Pharmaceutically acceptable" means compounds, materials, compositions, and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergy, or compatibility with reasonable The benefit/risk ratio is symmetric with other problems and complications and is effective for the intended use.

The term "optionally substituted by" is used interchangeably with the term "unsubstituted or substituted by", ie the structure is unsubstituted or substituted by one or more of the present invention base substitution.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure or group have been replaced with a specified substituent. Unless otherwise indicated, a substituent may be substituted at each reasonable position in the group that is substitutable. When more than one position in a given formula can be substituted by one or more specific substituents selected from the group, the substituents may be substituted identically or differently at each reasonable position in the formula.

The term "unsubstituted" means that the specified group bears no substituents.

In addition, it should be noted that, unless clearly stated otherwise, the description modes "each independently" and "...independently" and "...independently" used in the present invention can be interchanged, and both are interchangeable. It should be understood in a broad sense. It can either mean that in different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that in the same group, the specific options expressed between the same symbols do not affect each other.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. A subject, for example, also refers to primates (eg, humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is an open-ended expression, that is, it includes the contents specified in the present invention, but does not exclude other aspects.

In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed in terms of group type or scope. Specifically, the present invention includes each and every independent subcombination of each member of these group species and ranges. For example, the term " _C1 _- _C6 alkyl" or " _C1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, _C4 alkyl, _C5 alkyl and _C6 _alkanes base.

The term "D" represents a single deuterium atom.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

As used herein, the term "alkyl" or "alkyl group" refers to a saturated straight or branched chain monovalent hydrocarbon group containing 1 to 20 carbon atoms. In some embodiments, the alkyl group contains 1-12 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms, ie, _C1-6 alkyl; in yet other implementations In schemes, alkyl groups contain 1-4 carbon atoms, ie, _C1-4 alkyl; in still some embodiments, alkyl groups contain 1-3 carbon atoms, ie, _C1-3 alkyl. In some embodiments, the C _1-6 alkyl described in the present invention includes C _1-4 alkyl; in other embodiments, the C _1-6 alkyl described in the present invention includes C _1-3 alkyl.

Examples of alkyl groups include, but are not limited to, methyl (Me, _-CH3 ), ethyl (Et, -CH2CH3), n _- _propyl (n _- Pr, _-CH2CH2CH3 ₎ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH ) (CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH 2CH2CH2CH2CH3), ₂ -pentyl (-CH( _CH3 ₎ _CH2CH2CH3 ₎ , ₃ _- pentyl (-CH( _CH2CH3 ₎ ₂ ₎ , ₂ -methyl -2-butyl(-C( _CH3 )2CH2CH3), 3-methyl- _{2-butyl(-CH(CH3)CH(CH3)2} ₎ _, _2,2 _- _dimethyl Butyl (neopentyl, -CH ₂ CH(CH ₃ ) ₂ CH ₃ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1- Butyl (-CH2CH( _CH3 ) _CH2CH3 ), n _- hexyl ₍ _{-CH2CH2CH2CH2CH2CH3} ₎ , ₂ _- hexyl ₍ -CH ₍ _CH3 ₎ _CH2CH2CH _2CH3 ), ₃ -hexyl (-CH( _CH2CH3 )( _CH2CH2CH3 )), ₂ _- methyl- ₂ _- pentyl ( _-C ( _CH3 ₎ _2CH2CH2CH3 ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH( CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH ( _CH3 )C( _CH3 ) ₃ ), n-heptyl, n-octyl, and the like.

The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one site of unsaturation, i.e. a carbon-carbon sp ^double bond, which includes "cis" and "trans" positioning, or "E" and "Z" positioning. Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl (propenyl, -CH=CH-CH ₃ ), 2-propenyl (allyl, -CH ₂ -CH=CH _{2 )} ),and many more.

The term "alkynyl" refers to a straight or branched chain monovalent hydrocarbon group containing 2 to 12 carbon atoms in which there is at least one site of unsaturation, ie, a carbon-carbon sp triple bond. In some embodiments, the alkynyl group contains 2-8 carbon atoms; in other embodiments, the alkynyl group contains 2-6 carbon atoms; in still other embodiments, the alkynyl group contains 2 -4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), ₁ -propynyl (-C≡C- _CH3 ), 1 -alkynylbutyl ( _{-CH2CH2C≡CH} ), ₂ -alkynylbutyl ₍ -CH2C≡CCH3), ₃ -alkynylbutyl ( _-C≡CCH2CH3 ₎ , and the like.

The term "alkoxy" means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; in still other embodiments, the alkoxy group The group contains 1-3 carbon atoms.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH ₂ CH ₃ ), 1-propoxy (n-PrO, n- Propoxy, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO, n- Butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-butanyl Oxy (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH ₃ ) ₃ ), ₁ -pentyloxy (n _- pentyloxy, -OCH2CH2CH2CH2CH3), ₂ _- pentyloxy (-OCH ₍ _CH3 ₎ _CH2CH2CH3 ₎ , 3-pentyloxy (-OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (-OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butoxy group (-OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butoxy (-OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butoxy (-OCH ₂ CH(CH ₃ )CH ₂ CH ₃ ), etc.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms, wherein alkoxy has the meaning described herein; such examples include, but are not limited to, difluoromethoxy ( -OCHF ₂ ), trifluoromethoxy (-OCF ₃ ), difluoroethoxy (eg, -OCH ₂ CHF ₂ , etc.), trifluoroethoxy (eg, -OCH ₂ CF ₃ , etc.), and the like.

The term "haloalkyl" denotes an alkyl group substituted with one or more halogen atoms, wherein alkyl has the meaning set forth herein. In some embodiments, the haloalkyl group contains 1-12 carbon atoms; in other embodiments, the haloalkyl group contains 1-10 carbon atoms; in other embodiments, the haloalkyl group contains 1-8 carbon atoms carbon atoms; in other embodiments, the haloalkyl group contains 1-6 carbon atoms; in other embodiments, the haloalkyl group contains 1-4 carbon atoms, and in still other embodiments, the haloalkyl group contains Contains 1-3 carbon atoms. Such examples include, but are not limited to, difluoromethyl, trifluoromethyl, trifluoroethyl (eg _-CH2CF3 , etc. ₎ , and the like.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. In some embodiments, the cycloalkyl group contains 3-12 carbon atoms; in other embodiments, the cycloalkyl group contains 3-8 carbon atoms; in other embodiments, the cycloalkyl group contains 4-7 carbon atoms carbon atoms; in other embodiments, the cycloalkyl group contains 3-6 carbon atoms. In some embodiments, the cycloalkyl group is a C _7-12 cycloalkyl group comprising 7-12 carbon atoms, which further comprises C _7-12 spirobicycloalkyl, C _7-12 fused bicycloalkyl, and C _{7-12 -12} bridged bicycloalkyl; in other embodiments, the cycloalkyl is a C8-11 cycloalkyl comprising _8-11 carbon atoms, which further comprises a _C8-11 spirobicycloalkyl, _C8-11 Fused bicycloalkyl and C _8-11 bridged bicycloalkyl. In some embodiments, _{C3-6cycloalkyl} specifically refers to rings containing 3-6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein to refer to a monovalent or polyvalent, saturated or partially unsaturated, non-aromatic monocyclic, bicyclic ring containing 3 to 12 ring atoms. or a tricyclic ring system wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, heterocyclyl can be carbon or nitrogen, and _-CH2- groups can be optionally replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. The nitrogen atoms of the rings can be optionally oxidized to N-oxygen compounds. Heterocyclyl groups include saturated heterocyclyl groups (ie, heterocycloalkyl groups) and partially unsaturated heterocyclyl groups. In some embodiments, the heterocyclyl group is a heterocyclyl group of 3-8 atoms; in other embodiments, the heterocyclyl group is a heterocyclyl group of 3-6 atoms. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl, and the like. According to the present invention, the heterocyclyl group can be composed of 3-8 atoms or 3-6 atoms, the atoms are optionally selected from C, N, O or S and at least one atom is N, O or S; wherein, the heterocyclic group composed of 3-8 atoms includes a heterocyclic group composed of 3-6 atoms; the heterocyclic group composed of 3-6 atoms includes a heterocyclic group composed of 3-5 atoms Heterocyclyl.

The term "consisting of s atoms", where s is an integer, typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is s. For example, piperidinyl is a 6-atom heterocycloalkyl group, while 1,2,3,4-tetrahydronaphthyl is a 10-atom carbocyclyl group.

The term "unsaturated" as used herein means that the group contains one or more degrees of unsaturation.

The term "heteroatom" refers to O, S, N, P, and Si, including N, S, and P in any oxidation state; in the form of primary, secondary, tertiary amines, and quaternary ammonium salts; or on a nitrogen atom in a heterocyclic ring. Hydrogen substituted form, for example, N (like N in 3,4-dihydro-2H-pyrrolidinyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR, where R is any suitable substituent).

The term "aryl" refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic A family of rings in which each ring system contains a ring of 3 to 7 atoms with one or more points of attachment to the rest of the molecule. The term "aryl" is used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl, and anthracenyl.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring is aromatic, and At least one ring contains 1, 2, 3 or 4 ring heteroatoms selected from nitrogen, oxygen, sulfur, and the heteroaryl group has one or more points of attachment to the rest of the molecule. When a _-CH2- group is present in a heteroaryl group, the _-CH2- group can optionally be replaced by -C(=O)-. Unless otherwise specified, the heteroaryl group can be attached to the remainder of the molecule (eg, the host structure in the formula) through any reasonable site (which can be C in CH, or N in NH). The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic". Examples of heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, and the like. The heteroaryl group may be optionally substituted with one or more substituents described herein. In some embodiments, the heteroaryl group is a heteroaryl group of 5-10 atoms, meaning that the heteroaryl group contains 1-9 ring carbon atoms and 1, 2, 3, or 4 atoms selected from O, S, and N Ring heteroatom; in other embodiments, heteroaryl is a heteroaryl group consisting of 5-6 atoms, meaning that the heteroaryl group contains 1-5 ring carbon atoms and 1, 2, 3, or 4 selected from O , S and N ring heteroatoms.

The term "protecting group" or "PG" refers to a substituent group that is commonly used to block or protect specific functionality when it reacts with other functional groups. For example, "amino protecting group" refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenemethoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group, suitable protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl. "Carboxyl protecting group" means that the substituent of the carboxyl group is used to block or protect the functionality of the carboxyl group. General carboxyl protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilane) yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) phosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, reference is made to: Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 and Kocienski et al., Protecting Groups, Thieme, Stuttgart, 2005.

The term "prodrug" as used in the present invention refers to the conversion of a compound into a compound of formula (I) or formula (IIa) or formula (IIb) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue. The prodrug compounds of the present invention can be esters. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, carbonate esters , carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to give the compound in prodrug form. Other prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent. A complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry , 2008, 51, 2328-2345.

"Metabolite" refers to a product obtained by metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized using assays as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups including hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods such as ion exchange method described in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lacturonate, Lactate, Laurate, Lauryl Sulfate, Malonate, Malonate, Mesylate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Oleate, Palmitate, Pamoate, Pectate, Persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates quaternary ammonium salts formed from any compound containing an N-group. Water- or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist the formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, _C1 -C ₈ sulfonates and aromatic sulfonates.

"Nitrogen oxide" in the present invention means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Particular examples of N-oxides are N-oxides of tertiary amines or N-oxides containing nitrogen heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (eg, peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514) in which, for example, in an inert solvent such as dichloromethane, an amine compound is combined with m-chloroperoxybenzoic acid (MCPBA) reaction.

A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association in which the solvent molecule is water.

When the solvent is water, the term "hydrate" may be used. In one embodiment, one molecule of the compound of the present invention may be associated with one molecule of water, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate In yet another embodiment, one molecule of a compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the non-hydrated form of the compounds.

The term "treating" any disease or disorder, in some of these embodiments, refers to ameliorating the disease or disorder (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including a physical parameter that may not be perceived by a patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (eg, stabilizing an observable symptom) or physiologically (eg, stabilizing a physical parameter), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.

The terms "prevent" or "prevent" refer to a reduction in the risk of acquiring a disease or disorder (ie: stopping the development of at least one clinical symptom of a disease in a subject who may be facing or predisposed to facing the disease, but also not experience or exhibit symptoms of disease).

The term "cardiovascular disease" refers to the general term for cardiovascular and cerebrovascular diseases, describing the ischemic disease of the heart, brain and systemic tissues caused by hyperlipidemia, blood viscosity, atherosclerosis, hypertension, etc. or bleeding disorders. such as acute and chronic heart failure, arterial hypertension, coronary heart disease, stable and unstable angina, myocardial ischemia, myocardial infarction, shock, atherosclerosis, cardiac hypertrophy, cardiac fibrosis, atrial and ventricular arrhythmias , transient and ischemic attack, stroke, pre-eclampsia, inflammatory cardiovascular disease, peripheral and cardiovascular disease, peripheral perfusion disorders, pulmonary hypertension, coronary and peripheral arterial spasm, thrombosis, thromboembolic disease, edema development (eg, pulmonary edema, cerebral edema, renal edema, or heart failure-related edema) and restenosis (eg, in thrombolysis, percutaneous transluminal angioplasty (PTA), percutaneous coronary angioplasty (PTCA), heart transplantation and restenosis after bypass surgery), as well as microvascular and macrovascular injury (vasculitis), reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, peripheral and cardiovascular disease, peripheral Perfusion disorders, heart failure-related edema, elevated levels of fibrinogen and low-density LDL, and elevated concentrations of plasminogen activator/inhibitor 1 (PAI-1).

Compounds of the present invention

In one aspect, the present invention relates to compounds having the structure of general formula (I), wherein the variables are as defined above.

In some embodiments, the compound of the present invention may be a compound represented by formula (IIa) or formula (IIb), wherein the definitions of each variable are as described above.

Unless otherwise specified, stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites of compounds of formula (I) or formula (IIa) or formula (IIb) The products, pharmaceutically acceptable salts or prodrugs thereof are included within the scope of the present invention.

Compounds of the present disclosure may contain asymmetric or chiral centers and, therefore, may exist in different stereoisomeric forms. The present invention is intended to make all stereoisomeric forms of compounds represented by formula (I) or formula (IIa) or formula (IIb), including but not limited to diastereomers, enantiomers, atropisomers Conformational and geometric (or conformational) isomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.

In a structure disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated within the present invention and are included in the present invention as compounds disclosed herein . When stereochemistry is indicated by a solid wedge or a dashed line representing a particular configuration, then the stereoisomers of that structure are well defined and defined.

Compounds of formula (I) or formula (IIa) or formula (IIb) may exist in different tautomeric forms, and all these tautomers, such as the tautomers described in the present invention, All are included in the scope of the present invention.

The compound of formula (I) or formula (IIa) or formula (IIb) may exist in the form of a salt. In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that a substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated with it. In other embodiments, the salt is not necessarily a pharmaceutically acceptable salt, but can be used for preparing and/or purifying the compound represented by formula (I) or formula (IIa) or formula (IIb) and/or using Intermediates for separating enantiomers of compounds represented by formula (I) or formula (IIa) or formula (IIb).

Pharmaceutically acceptable acid addition salts can be formed by reacting compounds of formula (I) or formula (IIa) or (IIb) with inorganic or organic acids, such as acetate, aspartate, benzoate , benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulphate/sulfate, camphor sulphonate, chloride/hydrochloride, chlorophylline, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodate/iodide, isethionate, lactic acid salt, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthoate, naphthylsulfonate, Niacinate, Nitrate, Octateate, Oleate, Oxalate, Palmitate, Pamoate, Phosphate/Hydrogen Phosphate/Dihydrogen Phosphate, Polygalactonate, Propionate, Stearates, succinates, sulfosalicylates, tartrates, tosylate and trifluoroacetates.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid , ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the Periodic Table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include primary, secondary, and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include, for example, isopropylamine, benzathine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine .

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moieties, using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (eg, hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K), or by The preparations are carried out by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, where appropriate, the use of non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile is required. In, for example, "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Additional lists of suitable salts can be found in Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

In addition, the compounds disclosed herein, including their salts, can also be obtained in their hydrate form or in a form containing a solvent (eg, ethanol, DMSO, etc.) for their crystallization. Compounds of the present disclosure may form solvates, inherently or by design, with pharmaceutically acceptable solvents, including water; thus, the present invention is intended to include both solvated and unsolvated forms.

Any structural formula given herein is also intended to represent both isotopically unenriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures depicted by the general formulae given herein, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O , ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.

In another aspect, the compounds of the present invention include isotopically enriched compounds as defined in the present invention, for example, those compounds in which radioactive isotopes, such as ³ H, ¹⁴ C and ¹⁸ F are present, or in which non-radioactive isotopes, such as ² H and ¹³ C. Such isotopically enriched compounds can be used in metabolic studies (using ¹⁴ C), reaction kinetic studies (using eg ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single photon emission computed tomography (SPECT) for substrate tissue distribution measurements, or may be used in radiation therapy of patients. ¹⁸ F-enriched compounds are particularly ideal for PET or SPECT studies. Isotopically enriched compounds of formula (I) or formula (IIa) or formula (IIb) can be replaced by suitable isotopically labeled reagents by conventional techniques familiar to those skilled in the art or as described in the examples and preparation procedures of the present invention Prepared with unlabeled reagents originally used.

In addition, substitution of heavier isotopes, particularly deuterium (ie, ² H or D), may provide certain therapeutic advantages that result from greater metabolic stability. For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It should be understood that deuterium in the present invention is regarded as a substituent of the compound represented by formula (I) or formula (IIa) or formula (IIb). The concentration of such heavier isotopes, especially deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a given isotope. If a substituent of a compound of the present invention is designated as deuterium, the compound has for each designated deuterium atom at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), At least 4500 (67.5% deuterium incorporated), at least 5000 (75% deuterium incorporated), at least 5500 (82.5% deuterium incorporated), at least 6000 (90% deuterium incorporated), at least 6333.3 (95% deuterium incorporated) deuterium incorporation), an isotopic enrichment factor of at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, eg, _D2O , acetone _- d6, _DMSO -d6.

In another aspect, the present invention relates to intermediates for the preparation of compounds of formula (I) or formula (IIa) or formula (IIb).

In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I) or formula (IIa) or formula (IIb).

PHARMACEUTICAL COMPOSITIONS, FORMULATIONS AND ADMINISTRATION OF THE COMPOUNDS OF THE INVENTION

The present invention provides a pharmaceutical composition comprising a compound represented by formula (I) or formula (IIa) or formula (IIb) or its individual stereoisomers, racemic or non-racemic mixtures of isomers or A pharmaceutically acceptable salt or solvate thereof. In one embodiment of the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally, other therapeutic and/or prophylactic ingredients.

Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel H.C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro A.R. et al ., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

A method of treatment comprising the administration of a compound or pharmaceutical composition of the present invention, further comprising additional therapeutic agents, wherein said other active ingredients: calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin Antagonists, renin inhibitors, alpha-blockers, beta-blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors, diuretics, kinase inhibitors, matrix metalloproteinase inhibitors , soluble guanylate cyclase stimulators and activators, and phosphodiesterase inhibitors.

"Pharmaceutically acceptable excipient" as used in the present invention means a pharmaceutically acceptable material, admixture or vehicle that is relevant to the consistency of the administered dosage form or pharmaceutical composition. Each excipient must, when mixed, be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would greatly reduce the efficacy of the disclosed compounds when administered to a patient and would result in a pharmaceutical composition that is not pharmaceutically acceptable Interaction. In addition, each excipient must be pharmaceutically acceptable, eg, of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form chosen. Furthermore, pharmaceutically acceptable excipients can be selected based on their particular function in the composition. For example, certain pharmaceutically acceptable excipients can be selected to aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected which aid in carrying or transporting the compounds of the present invention from one organ or part of the body to another organ or part of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected to enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , solvent, co-solvent, suspending agent, emulsifier, sweetener, flavoring agent, taste masking agent, coloring agent, anti-caking agent, humectant, chelating agent, plasticizer, tackifier, antioxidant, Preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may serve more than one function, and provide alternative functions, depending on how much of that excipient is present in the formulation and what other excipients are present in the formulation. agent.

The skilled artisan possesses the knowledge and skills in the art to enable them to select appropriate amounts of suitable pharmaceutically acceptable excipients for use in the present invention. In addition, there are numerous resources available to the skilled artisan describing pharmaceutically acceptable excipients and for use in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

For preparing pharmaceutical compositions using the compounds described in this invention, pharmaceutically acceptable carriers can be solid or liquid carriers. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may contain from about 5 to about 95% of the active ingredient. Suitable solid carriers are known in the art, for example, magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods for preparing various compositions can be found in: A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th ^ed ., 1990, Mack Publishing Company Co., Easton, Pennsylvania.

In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York Various carriers for formulating pharmaceutically acceptable compositions, and well-known techniques for their preparation, are disclosed, and the contents of each of these documents are incorporated herein by reference. Except for any commonly used carriers that are incompatible with the compounds of the present invention, such as by producing any undesired biological effects, or interacting in a deleterious manner with any other ingredient of the pharmaceutically acceptable composition, concerns for their use are within the scope of the present invention. scope of invention.

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. A description of some commonly used methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

Accordingly, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, the process comprising Mix various ingredients. Pharmaceutical compositions containing compounds of the present disclosure can be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by the desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, Solutions, emulsions, sachets, and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes , sprays, foams and gels.

It will also be recognized that certain compounds of the present invention may exist in free form for use in therapy or, if appropriate, in the form of their pharmaceutically acceptable derivatives. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of these esters, or can provide, directly or indirectly, the invention described herein when administered to a patient in need thereof. Any additional adducts or derivatives of the compound or its metabolites or residues.

In one embodiment, the compounds disclosed herein can be formulated into oral dosage forms. In another embodiment, the compounds disclosed herein may be formulated in an inhalation dosage form. In another embodiment, the compounds disclosed herein may be formulated for nasal administration. In yet another embodiment, the compounds disclosed herein may be formulated for transdermal administration. In yet another embodiment, the compounds disclosed herein may be formulated for topical administration.

The pharmaceutical compositions provided by the present invention can be provided as compressed tablets, triturated tablets, chewable lozenges, fast-dissolving tablets, recompressed tablets, enteric-coated tablets, sugar-coated or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of gastric acid but dissolves or disintegrates in the intestine, thus preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can help mask unpleasant taste or odor and prevent tablet oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Multiplexed tablets are compressed tablets prepared by more than one compression cycle, including multi-layer, compression-coated, or dry-coated tablets.

Tablet dosage forms may be prepared from the active ingredient in powdered, crystalline or granular form, alone or in combination with one or more of the carriers or excipients described herein, including binders, disintegrating disintegrants, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are especially useful in forming chewable tablets and lozenges.

The pharmaceutical compositions provided by the present invention can be provided in soft capsules or hard capsules, which can be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules, also known as dry-filled capsules (DFC), consist of two segments, one inserted into the other, thus completely encapsulating the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention can be encapsulated in capsules. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in US Patents U.S. Pat. Nos. 4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain active ingredient dissolution.

The pharmaceutical compositions provided herein can be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems in which one liquid is completely dispersed in the other liquid in the form of pellets, which can be either oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers and preservatives. Suspensions may include pharmaceutically acceptable suspending agents and preservatives. The aqueous alcoholic solution may include pharmaceutically acceptable acetals, such as di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as Propylene Glycol and Ethanol. Elixirs are clear, sweetened hydroalcoholic solutions. A syrup is an aqueous solution of a concentrated sugar such as sucrose, and may also contain a preservative. For liquid dosage forms, for example, solutions in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for precise and convenient administration.

The pharmaceutical compositions provided by the present invention can be formulated into any dosage form suitable for inhalation administration to patients, such as dry powder, aerosol, suspension or solution compositions. In one embodiment, the pharmaceutical compositions disclosed herein may be formulated in a dosage form suitable for inhalation administration to a patient as a dry powder. In yet another embodiment, the pharmaceutical compositions disclosed herein may be formulated in a dosage form suitable for inhalation administration to a patient via a nebulizer. Dry powder compositions for delivery to the lungs by inhalation typically comprise a finely powdered compound of the present disclosure and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that are particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di- and polysaccharides. Fine powders can be prepared, for example, by micronization and grinding. In general, size-reduced (eg, micronized) compounds can be defined by _D50 values (eg, as measured by laser diffraction) of about 1 to 10 microns.

Pharmaceutical compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of a patient for an extended period of time. For example, the active ingredient can be delivered from the patch by iontophoresis, as generally described in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams and gels can be formulated with an aqueous or oily base, and a suitable thickening and/or gelling agent and/or solvent. Such bases may include, water, and/or oils such as liquid paraffin and vegetable oils (eg, peanut oil or castor oil), or solvents such as polyethylene glycols. Thickening and gelling agents used depending on the nature of the base include soft paraffin, aluminium stearate, cetearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or mono Glyceryl stearate and/or nonionic emulsifiers.

The compounds of the present invention can also be combined with soluble polymers as targetable drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the compounds disclosed herein can be combined with a class of biodegradable polymers used in achieving controlled release of drugs, eg, polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters , crosslinked or amphiphilic block copolymers of polyacetal, polydihydropyran, polycyanoacrylate and hydrogel.

The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and in liquid prior to injection Solid forms are prepared as solutions or suspensions. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical sciences (see Remington: The Science and Practice of Pharmacy, supra).

Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients including, but not limited to, aqueous carriers, water-miscible carriers, non-aqueous carriers, anti- Microbial or anti-microbial growth preservatives, stabilizers, dissolution enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, polyvalent Chelating or sequestering agents, antifreeze agents, cryoprotectants, thickeners, pH adjusters and inert gases.

The pharmaceutical composition provided by the present invention can be administered by rectal suppository, by mixing the medicine with a suitable non-irritating excipient (such as cocoa butter, glycerides synthesized from polyethylene glycol), it is solid at room temperature, and then It liquefies or dissolves in the rectal cavity to release the drug. The severity of symptoms can vary widely due to individual differences, and each drug has unique therapeutic properties, so the precise mode of administration, dosage form, and treatment regimen for each individual should be determined by a licensed physician determination.

The pharmaceutical compositions provided by the present invention can be formulated into immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release forms.

As used herein, the term "therapeutically effective amount" refers to the total amount of each active ingredient sufficient to exhibit a beneficial therapeutic effect. For example, an amount sufficient to treat, cure or reduce symptoms of a disease is administered or brought into balance in the body. The effective amount required for a particular treatment regimen will depend on a variety of factors, including the disease being treated, the severity of the disease, the activity of the particular drug used, the mode of administration, the clearance of the particular drug, the duration of treatment, the combination of medications, age , weight, gender, diet and patient health, etc. Additional considerations in the art regarding a "therapeutically effective amount" can be found in Gilman et al., eds., Goodman And Gilman's: The Pharmacological Bases of Therapeutics, 8th ^ed ., Pergamon Press, 1990; Remington's Pharmaceutical Sciences, 17 ^th ed., Mack Publishing Company, Easton, Pa., 1990.

One skilled in the art (eg, attending physician, pharmacist, or other skilled person) can readily determine the appropriate dose of a compound of the invention to administer to a patient, and may vary depending on the patient's health, age, weight, frequency of administration, other active ingredients use and/or indications for the compound to be administered. Dosages of the compounds of the present invention may range from about 0.001 to 500 mg/kg body weight/day. In some embodiments, the amount of active compound in a unit dose of the formulation can be varied or adjusted according to the particular application. In other embodiments, for oral administration, a typical recommended daily dosing regimen may range from about 1 mg/day to about 500 mg/day in two to four divided doses.

The term "administration" refers to the provision of a therapeutically effective amount of a drug to an individual by means of oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, epidural, intraocular, intracranial, Inhalation, rectal, vaginal, etc. Dosage forms include ointments, lotions, tablets, capsules, pills, dispersible powders, granules, suppositories, pills, lozenges, injections, sterile solutions or non-aqueous solutions, suspensions, emulsions, patches agent, etc. The active ingredient is combined with a non-toxic pharmaceutically acceptable carrier (such as glucose, lactose, acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, silica gel, potato starch, urea , dextran, etc.) complex.

The preferred route of administration will vary with clinical characteristics, dosage changes must depend on the condition of the patient being treated, and the appropriate dosage will be determined by the physician on a case-by-case basis. The therapeutically effective amount per unit dose depends on body weight, physiology and the chosen vaccination regimen. Compound per unit dose refers to the weight of the compound per administration, excluding the weight of the carrier (which is contained in the drug).

The pharmaceutical compositions provided by the present invention can be formulated for single-dose or multiple-dose administration. The single-dose formulation is packaged in ampoules, vials or syringes. The multiple-dose parenteral formulation must contain a bacteriostatic or fungistatic concentration of the antimicrobial agent. All parenteral formulations must be sterile, as known and practiced in the art.

The pharmaceutical compositions provided by the present invention can be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.

In one embodiment, the methods of treatment of the present invention comprise administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. Various embodiments of the present invention encompass the treatment of diseases referred to herein by administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention.

In one embodiment, a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention may be administered by any suitable route of administration, including systemic and topical administration. Systemic administration includes oral, parenteral, transdermal, and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular and subcutaneous injection or infusion. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, inhalation and intranasal administration. In one embodiment, a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention may be administered orally. In another embodiment, a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention may be administered by inhalation. In yet another embodiment, a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention may be administered intranasally.

In one embodiment, a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention may be administered once, or several times at different time intervals over a specified period of time, depending on the dosing regimen. For example, it is administered once, twice, three times or four times a day. In one embodiment, the administration is once a day. In yet another embodiment, the administration is twice daily. Administration may be performed until the desired therapeutic effect is achieved or maintained indefinitely. A suitable dosing regimen for a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention depends on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by the skilled artisan. In addition, a suitable dosing regimen for a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention, including the duration for which the regimen is carried out, depends on the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated , the medical history of the patient being treated, the nature of concomitant therapy, the desired therapeutic effect, etc., factors within the knowledge and experience of the technician. Such skilled artisans will also appreciate that adjustments to appropriate dosing regimens may be required as individual patient responses to dosing regimens or as individual patient needs change over time.

The compounds of the present invention may be administered concurrently with, before or after one or more other therapeutic agents. The compounds of the present invention can be administered separately with other therapeutic agents by the same or different route of administration, or in the same pharmaceutical composition. This is selected by those skilled in the art according to the actual conditions of the patient's health, age, weight and other physical conditions. If formulated as a fixed dose, such combination products employ the compounds of the invention (within the dosage ranges described herein) and the other pharmaceutically active agents (within their dosage ranges).

Accordingly, in one aspect, the present invention includes combinations comprising an amount of at least one compound of the present invention, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more of the foregoing Additional therapeutic agents.

In addition, the compounds of the present invention may be administered in prodrug form. In the present invention, the "prodrug" of the compound of the present invention is a functional derivative that can finally release the compound of the present invention in vivo when administered to a patient. When administering the compounds of the present invention in prodrug form, those skilled in the art can implement one or more of the following methods: (a) altering the in vivo onset time of the compound; (b) altering the in vivo duration of action of the compound; (c) altering in vivo delivery or distribution of the compound; (d) altering the in vivo solubility of the compound; and (e) overcoming side effects or other difficulties faced by the compound. Typical functional derivatives used to prepare prodrugs include variants of compounds that are chemically or enzymatically cleaved in vivo. These variants, including the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.

Use of the Compounds and Pharmaceutical Compositions of the Invention

The compounds and pharmaceutical compositions provided by the present invention can be used to prepare medicines for inhibiting chymotrypsin, and can also be used to prepare medicines for the treatment or prevention of heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, renal failure, renal disease, internal organ fibrotic disorders or skin fibrotic diseases.

In the context of the present invention, diseases of the cardiovascular system or cardiovascular diseases are understood to mean diseases such as the following: acute and chronic heart failure, arterial hypertension, coronary heart disease, stable and unstable angina, myocardial ischemia , myocardial infarction, shock, atherosclerosis, cardiac hypertrophy, cardiac fibrosis, atrial and ventricular arrhythmias, transient and ischemic attacks, stroke, pre-eclampsia, inflammatory cardiovascular disease, peripheral and cardiovascular disease, Peripheral perfusion disturbance, pulmonary hypertension, coronary and peripheral arterial spasm, thrombosis, thromboembolic disease, development of edema (eg, pulmonary edema, cerebral edema, renal edema, or edema associated with heart failure), and restenosis (eg, during thrombolytic therapy , percutaneous transluminal angioplasty (PTA), percutaneous coronary angioplasty (PTCA), restenosis after heart transplantation and bypass surgery), as well as microvascular and macrovascular injury (vasculitis), reperfusion injury, arterial and Venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, peripheral and cardiovascular disease, peripheral perfusion disturbance, edema associated with heart failure, elevated levels of fibrinogen and low-density LDL, and plasminogen activation The concentration of agent/inhibitor 1 (PAI-1) was increased.

In the context of the present invention, the term "heart failure" also includes more specific or related types of disease, such as acute decompensated heart failure, right heart failure, left heart failure, global failure, ischemic cardiomyopathy, dilated heart failure Cardiomyopathy, congenital heart defects, heart valve defects, heart failure associated with heart valve defects, mitral valve stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation, tricuspid stenosis, tricuspid Valve insufficiency, pulmonary stenosis, pulmonary insufficiency, combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, and diastolic and Systolic heart failure.

The compounds of the present invention may be applied, but in no way limited to, the use of an effective amount of the compounds or pharmaceutical compositions of the present invention to be administered to a patient to prevent, treat or alleviate chymotrypsin-related diseases. The chymotrypsin-related diseases further include, but are not limited to, heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, renal failure, renal disease, fibrotic disorders of internal organs or skin fibrosis.

In addition to their therapeutic benefits in humans, the compounds and pharmaceutical compositions of the present invention may also be used in veterinary treatment of mammals in pets, introduced species and farm animals. Examples of other animals include horses, dogs and cats. Here, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.

General synthetic steps

To illustrate the invention, the following examples are set forth. It is to be understood, however, that the invention is not limited to these examples, but merely provides methods of practicing the invention.

In general, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the substituents are as defined in formula (I) or formula (IIa) or formula (IIb). The following reaction schemes and examples serve to further illustrate the content of the present invention.

Those skilled in the art will recognize that the chemical reactions described in this invention can be used to suitably prepare many other compounds of this invention, and that other methods for preparing compounds of this invention are considered to be within the scope of this invention. Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modifying methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described herein, or by combining The reaction conditions were modified routinely. In addition, the reactions disclosed herein or known reaction conditions are also acknowledged to be applicable to the preparation of other compounds of the present invention.

In the examples described below, all temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers and were used without further purification unless otherwise indicated.

¹ H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. ^1H NMR spectra were performed with CDC13, _DMSO _- d6, _CD3OD or acetone _- d6 as solvent (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are present, the following abbreviations are used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), brs (broadened singlet, broad singlet), dd (doublet of doublets, double doublet), ddd (doublet of doublet of doublets, double double doublet), dt (doublet of triplets, double triplet), td (triplet of doublets, triple doublet), tt (triplet of triplets, triple triplet). The coupling constant, J, is expressed in Hertz (Hz).

The measurement conditions for low-resolution mass spectrometry (MS) data were: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 microns, 6 min, flow rate 0.6 mL/min. Mobile phase: 5 %-95% ( _CH3CN with 0.1% formic acid) in ( _H2O with 0.1% formic acid) using electrospray ionization (ESI) at 210 nm/254 nm with UV detection.

The following abbreviations are used throughout this disclosure:

CDC1 ₃ deuterated chloroform μg μg

DMSO dimethyl sulfoxide mg mg mg mg

DMSO-d ₆ -deuterated dimethyl sulfoxide g g

mL, ml, ml, μL, μl, μL

mol mol mol mmol mmol mmol mmol

The following synthetic schemes describe steps for the preparation of the ^compounds disclosed herein, where R2 has the definition described herein unless otherwise indicated.

Synthesis Scheme 1

The compound represented by the formula (M9) can be prepared through the synthesis scheme 1: the compound represented by the formula (M1) is reacted under the action of NBS to obtain the compound represented by the formula (M2). The compound represented by the formula (M2) is reacted under the action of triethylamine to obtain the compound represented by the formula (M3). The compound represented by the formula (M3) is reacted under the action of trimethylsilylated diazomethane to obtain the compound represented by the formula (M4). The compound represented by the formula (M4) can obtain the compound represented by the formula (M5) after removing the trimethylsilyl group. The compound represented by the formula (M5) is subjected to chiral catalytic reduction with triethylamine and formic acid to obtain the compound represented by the formula (M6). The compound represented by the formula (M6) and the compound represented by the formula (M7) are coupled to obtain the compound represented by the formula (M8). The compound represented by formula (M8) is hydrolyzed under strong acid conditions to obtain the compound represented by formula (M9).

Synthesis Scheme 2

The compound represented by the formula (M12) can be prepared by the synthesis scheme 2: the compound represented by the formula (M5) is reduced by sodium borohydride to obtain the compound represented by the formula (M10). The compound represented by the formula (M10) and the compound represented by the formula (M7) are coupled to obtain the compound represented by the formula (M11). The compound represented by formula (M11) is hydrolyzed under strong acid conditions to obtain the compound represented by formula (M12).

The compounds, pharmaceutical compositions and applications provided by the present invention will be further described below with reference to the examples.

Example

Example 1:

Compound 1a:

Compound 1b:

Step 1: Synthesis of 3-bromo-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one

4-(Trifluoromethyl)-2,3-dihydro-1H-inden-1-one (10.00 g, 49.96 mmol) was dissolved in chlorobenzene (100 mL), and N-bromosuccinimide (10.67 g) was added. g, 59.95 mmol) and azobisisobutyronitrile (253 mg, 1.49 mmol), the temperature was raised to 70° C. to react for 1 h. The reaction mixture was filtered to remove insolubles and the filter cake was washed with chlorobenzene (20 mL×2). The filtrate was collected and concentrated under reduced pressure to give the title compound as a reddish-brown oil (15.10 g, 100%).

Step 2: Synthesis of 4-(trifluoromethyl)-1H-inden-1-one

3-Bromo-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one (13.90 g, 49.8 mmol) was dissolved in tetrahydrofuran (100 mL), and triethyl was added dropwise under ice bath Amine (20.8 mL, 150 mmol) was added dropwise and then moved to room temperature for 0.5 h. The reaction mixture was filtered under reduced pressure to remove insolubles, and the filter cake was washed with tetrahydrofuran (20 mL×2). The filtrate was collected and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether) to obtain the title compound as a yellow oil ( 7.80g, 79%).

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm) 7.95(d,J=5.9Hz,1H),7.70(d,J=8.0Hz,1H),7.63(d,J=7.1Hz,1H) ,7.51(t,J=7.6Hz,1H),6.25(d,J=6.1Hz,1H).

Step 3: Synthesis of 2-(trifluoromethyl)-1-(trimethylsilyl)-1a,6a-dihydrocyclopropano[a]inden-6(1H)-one

To a toluene solution (80 mL) of 4-(trifluoromethyl)-1H-inden-1-one (7.80 g, 39.00 mmol) was added palladium acetate (900 mg, 3.93 mmol), under nitrogen protection, the system was cooled to 0 °C , trimethylsilylated diazomethane (39 mL, 78 mmol, 2.0 mol/L n-hexane solution) was added dropwise, and after the dropping was completed, the reaction was raised to room temperature for 12 h. The reaction mixture was added with water (50 mL), extracted with ethyl acetate (50 mL×2), the organic phases were combined, washed with saturated brine (30 mL×2), the organic phases were collected, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether) to give the title compound as a yellow semisolid (2.48 g, 22%).

MS (ESI, pos.ion) m/z: 285.1 [M+H] ⁺ .

Step 4: Synthesis of 2-(trifluoromethyl)-1a,6a-dihydrocyclopropano[a]inden-6(1H)-one

To 2-(trifluoromethyl)-1-(trimethylsilyl)-1a,6a-dihydrocyclopropano[a]inden-6(1H)-one (2.48 g, 8.73 g) under ice bath mmol) in tetrahydrofuran (25 mL) was slowly added tetrabutylammonium fluoride solution in tetrahydrofuran (26.2 mL, 26.2 mmol, 1 mol/L), and after the addition was completed, the temperature was raised to 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added, extracted with ethyl acetate (20 mL×2), the organic phases were combined, washed with saturated brine (15 mL×2), the organic phases were collected, and the solvent was evaporated under reduced pressure to obtain the residue. Purification by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=96/4) gave the title compound as a yellow oil (1.03 g, 55.6%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.81 (d, J=7.6 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.42 (t, J=7.7 Hz, 1H), 3.22 (s, 1H), 2.66–2.53 (m, 1H), 1.75–1.68 (m, 1H), 1.44–1.33 (m, 1H).

Step 5: Synthesis of (6S)-2-(trifluoromethyl)-1,1a,6,6a-tetrahydrocyclopropano[a]inden-6-ol

To a solution of 2-(trifluoromethyl)-1a,6a-dihydrocyclopropano[a]inden-6(1H)-one (507 mg, 2.39 mmol) in dichloromethane (3 mL) was added under nitrogen protection Triethylamine (1.67 mL, 11.9 mmol) and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine(p-cumene)ruthenium(II) chloride ( 16 mg, 0.0244 mmol), the temperature was raised to 35 °C, formic acid (0.51 mL, 12 mmol) was added dropwise, and the reaction was incubated for 2 h. Additional (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-cumene) ruthenium(II) chloride (16mg, 0.0244mmol), triethylamine (1.67 mL, 11.9 mmol) and formic acid (0.51 mL, 12 mmol), and the reaction was continued for 2 h. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a white solid (431 mg, 84.21%).

Step 6: Synthesis of N ¹ -methyl-4-nitrobenzene-1,2-diamine

To a solution of 2-fluoro-5-nitroaniline (20.00 g, 128.1 mmol) in N,N-dimethylformamide (150 mL) was added methylamine aqueous solution (35.00 g, 450.8 mmol), and the reaction was carried out at 90 °C for 8 h . The reaction mixture was added with water (500 mL), extracted with ethyl acetate (300 mL×2), the organic phases were combined, washed with water (400 mL×2), the organic phases were collected, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether). /ethyl acetate (v/v)=3/7) to give the title compound as a red solid (10.20 g, 47.63%).

MS(ESI,pos.ion)m/z:168.1[M+H] ⁺ .

Step 7: Synthesis of 1-methyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

To a solution of N ¹ -methyl-4-nitrobenzene-1,2-diamine (1.67 g, 9.99 mmol) in dry tetrahydrofuran (30 mL) was added N,N'-carbonyldiimidazole (1.94 g, 12.0 mmol) ), heated to 65°C and stirred overnight. The reaction mixture was filtered under reduced pressure, and the filter cake was collected and dried in vacuo to give the title compound as a yellow solid (1.79 g, 92.8%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 11.41 (s, 1H), 7.99 (dd, J=8.7, 2.1 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 7.26 ( d, J=8.7Hz, 1H), 3.34(s, 3H).

Step 8: Synthesis of 3-ethyl-1-methyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

To 1-methyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (500 mg, 2.58 mmol) in N,N-dimethylmethane under ice bath Potassium carbonate (723 mg, 5.18 mmol) was added to the amide (6 mL) solution, and then iodoethane (0.25 mL, 3.1 mmol) was added dropwise. After the dropwise addition, the solution was moved to room temperature and reacted for 9 h. The reaction mixture was slowly poured into ice water (100 mL), and stirred for 0.5 h. Filtration under reduced pressure, the filter cake was washed with water (20 mL×2), the filter cake was collected, and dried in vacuo to obtain the title compound as a yellow solid (515 mg, 89.94%).

MS(ESI,pos.ion)m/z:222.1[M+H] ⁺ .

Step 9: Synthesis of 5-amino-3-ethyl-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

To a solution of 3-ethyl-1-methyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (515 mg, 2.32 mmol) in ethanol (30 mL) was added palladium Carbon (52 mg) was replaced with hydrogen twice, and the reaction was carried out at room temperature for 12 h under a hydrogen gas bag. The reaction mixture was filtered under reduced pressure to remove palladium carbon, the filtrate was collected, and concentrated under reduced pressure to obtain the title compound as a pale pink solid (434 mg, 97.48%).

MS(ESI,pos.ion)m/z:192.1[M+H] ⁺ .

Step Ten: 1-(3-Ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2,4-dioxo- Synthesis of 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester

To a solution of 5-amino-3-ethyl-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (434 mg, 2.27 mmol) in ethanol (20 mL) was added (Z )-ethyl 3-ethoxy-2-((ethoxycarbonyl)carbamoyl)acrylate (647 mg, 2.49 mmol) and warmed to reflux for 4 h. Then, the reaction mixture was cooled to 60° C., potassium tert-butoxide (280 mg, 2.49 mmol) was added, and the temperature was raised to reflux for 2 h. The reaction mixture was cooled to 60°C, slowly poured into iced 1N hydrochloric acid (100 mL), and stirring was continued for 1 h. Suction filtration under reduced pressure, the filter cake was washed with ice water (10 mL×2), the filter cake was collected, and concentrated under reduced pressure to obtain the title compound as a white solid (320 mg, 39.34%).

MS(ESI,pos.ion)m/z:359.2[M+H] ⁺ .

Step Eleven: 1-(3-Ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2,4-dioxo -3-((6R)-2-(trifluoromethyl)-1,1a,6,6a-tetrahydrocyclopropano[a]inden-6-yl)-1,2,3,4-tetrahydro Synthesis of Pyrimidine-5-Carboxylic Acid Ethyl Ester

To 1-(3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2,4-dioxo-1, Ethyl 2,3,4-tetrahydropyrimidine-5-carboxylate (300 mg, 0.83 mmol) and (6S)-2-(trifluoromethyl)-1,1a,6,6a-tetrahydrocyclopropano[ a] Triphenylphosphine (441 mg, 1.67 mmol) was added to a mixed solution of inden-6-ol (180 mg, 0.84 mmol) in tetrahydrofuran (4 mL) and N,N-dimethylformamide (8 mL), and under nitrogen protection Cool to 0°C, slowly add diisopropyl azodicarboxylate (0.35 mL, 1.7 mmol) dropwise, and continue to react at 0°C overnight after the dropwise addition is complete. The reaction mixture was added with water (50 mL), extracted with ethyl acetate (50 mL×2), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, the organic phases were collected, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (Petroleum ether/ethyl acetate (v/v)=56/44) to give the title compound as a yellow oil (464 mg, 99.97%).

MS(ESI,pos.ion)m/z:555.2[M+H] ⁺ .

Step 12: Synthesis of Compounds 1a and 1b

1-(3-Ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2,4-dioxo-3- ((6R)-2-(trifluoromethyl)-1,1a,6,6a-tetrahydrocyclopropano[a]inden-6-yl)-1,2,3,4-tetrahydropyrimidine-5 - Ethyl carboxylate (464 mg, 0.83 mmol) was dissolved in a mixed solvent of glacial acetic acid (6 mL) and concentrated hydrochloric acid (3 mL, 12 mol/L), and the temperature was raised to 70 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain crude products, which were isolated and purified by chiral preparation to obtain compound 1a (50 mg) and compound 1b (60 mg), both as white solids.

Compound 1a: HPLC: 99.87%; MS (ESI, pos.ion) m/z: 527.0 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm) 8.60 (s, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.26 (d, J= 7.7Hz, 1H), 7.08(d, J=39.8Hz, 3H), 6.43(s, 1H), 3.96(s, 2H), 3.47(s, 3H), 2.99(s, 1H), 2.20(s, 1H), 1.35(s, 2H), 1.29(d, J=10.4Hz, 3H).

Compound 1b: HPLC: 99.10%; MS (ESI, pos.ion) m/z: 527.0 [M+H] ⁺ .

Example 2:

Compound 2a:

Compound 2b:

Step 1: Synthesis of 3-cyclopropyl-1-methyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

To the free solution of 1-methyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1.00 g, 5.18 mmol) and cyclopropylboronic acid (889 mg, 10.35 mmol) Copper acetate (2.82 g, 15.5 mmol), triethylamine (3.63 mL, 25.9 mmol) and 4A molecular sieve (1.00 g) were added to the aqueous dichloromethane (15 mL) solution, and the reaction was stirred at room temperature for 8 h under oxygen protection. Molecular sieves were removed by filtration, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a yellow solid (521 mg, 43.2%).

MS(ESI,pos.ion)m/z:234.1[M+H] ⁺ .

Step 2: Synthesis of 5-amino-3-cyclopropyl-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

To a solution of 3-cyclopropyl-1-methyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (521 mg, 2.23 mmol) in ethanol (30 mL) was added Pd/C (52 mg), replaced by hydrogen for 2 times, and reacted at room temperature for 14 h under a hydrogen gas bag. The palladium carbon was removed from the reaction mixture by suction filtration under reduced pressure, and the filtrate was collected and concentrated under reduced pressure to obtain the title compound as a pale pink solid (434 mg, 95.58%).

Step 3: 1-(3-Cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2,4-dioxo -Synthesis of ethyl 1,2,3,4-tetrahydropyrimidine-5-carboxylate

To a solution of 5-amino-3-cyclopropyl-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (434 mg, 2.13 mmol) in ethanol (30 mL) was added ( Z)-ethyl 3-ethoxy-2-((ethoxycarbonyl)carbamoyl)acrylate (608 mg, 2.34 mmol), heated to reflux for 1 h. Then it was cooled to 60° C., potassium tert-butoxide (263 mg, 2.34 mmol) was added, the temperature was raised to reflux, and stirring was continued for 2 h. The reaction mixture was cooled to 60°C, slowly poured into iced 1N hydrochloric acid (200 mL), stirred for 30 minutes, filtered under reduced pressure, the filter cake was washed with ice water (20 mL×2), the filter cake was collected, and dried in vacuo to obtain the title compound as a white solid (544 mg, 68.78%).

MS(ESI,pos.ion)m/z:371.1[M+H] ⁺ .

Step 4: 1-(3-Cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2,4-dioxo -3-((6R)-2-(trifluoromethyl)-1,1a,6,6a-tetrahydrocyclopropane[a]inden-6-yl)-1,2,3,4-tetrahydropyrimidine Synthesis of -5-carboxylate ethyl ester

To 1-(3-cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2,4-dioxo-1 (6S)- 2-(Trifluoromethyl)-1,1a,6,6a-tetrahydrocyclopropano[a]inden-6-ol (173 mg, 0.81 mmol) and triphenylphosphine (427 mg, 1.62 mmol), under nitrogen It was cooled to -10°C, and diisopropyl azodicarboxylate (0.35 mL, 1.7 mmol) was slowly added dropwise. After the dropwise addition, the reaction was continued at -10°C for 1 h. The reaction mixture was added with water (50 mL), extracted with ethyl acetate (50 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, the organic phases were collected, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=52/48) to give the title compound as a yellow oil (459 mg, 100.0%).

MS(ESI,pos.ion)m/z:567.2[M+H] ⁺ .

Step 5: Synthesis of Compounds 2a and 2b

1-(3-Cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2,4-dioxo-3 -((6R)-2-(trifluoromethyl)-1,1a,6,6a-tetrahydrocyclopropane[a]inden-6-yl)-1,2,3,4-tetrahydropyrimidine-5 - Ethyl carboxylate (350 mg, 0.62 mmol) was dissolved in a mixed solvent of glacial acetic acid (6 mL) and concentrated hydrochloric acid (3 mL, 12 mol/L), and the temperature was raised to 70 °C for 1 h. The reaction solution was cooled to room temperature, and the solvent was removed under reduced pressure. The obtained crude product was isolated and purified by preparation to obtain compound 2a (50 mg) and compound 2b (42 mg), both of which were white solids.

Compound 2a: HPLC: 99.94%; MS (ESI, pos.ion) m/z: 539.0 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm) 8.60 (s, 1H), 7.53 (d, J=7.1 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.27 (d, J= 7.7Hz, 1H), 7.06(d, J=56.5Hz, 3H), 6.43(s, 1H), 3.43(s, 3H), 3.00(s, 1H), 2.91(s, 1H), 2.21(s, 1H), 1.53(dd, J=13.3, 7.9Hz, 1H), 1.32(d, J=7.3Hz, 1H), 1.14(s, 2H), 1.03(s, 2H).

Compound 2b: HPLC: 98.76%; MS (ESI, pos.ion) m/z: 539.0 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 8.65 (s, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.25 (t, J=7.6 Hz, 1H), 7.21-7.15 (m, 2H) ,7.09(d,J＝8.0Hz,1H),7.05(d,J＝8.2Hz,1H),6.63(d,J＝6.4Hz,1H),3.44(s,3H),2.96–2.89(m, 1H), 2.83(s, 1H), 2.28(d, J=5.6Hz, 1H), 1.40(dd, J=8.2, 4.2Hz, 1H), 1.32(dd, J=14.1, 6.9Hz, 1H), 1.16(d, J=5.9Hz, 2H), 1.04(s, 2H).

Example 3

Compounds 3a, 3b, 3c and 3d are each independently one of the following structures:

Step 1: Synthesis of 2-(trifluoromethyl)-1,1a,6,6a-tetrahydrocyclopropano[a]inden-6-ol

To a solution of 2-(trifluoromethyl)-1a,6a-dihydrocyclopropano[a]inden-6(1H)-one (961 mg, 4.53 mmol) in methanol (10 mL) at 0 °C, slowly Sodium borohydride (196 mg, 4.97 mmol) was added, and the reaction was continued at 0°C for 1 h. The reaction mixture was quenched by adding 1M dilute hydrochloric acid (10 mL), concentrated under reduced pressure to remove most of the methanol, added water (10 mL), extracted with ethyl acetate (10 mL×3), combined organic phases, washed with saturated brine (10 mL×2) , the organic phase was collected, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=6/1) to obtain the title compound as a white solid (745mg, 76.80%).

MS (ESI, pos.ion) m/z: 197.1 [MH ₂ O+H] ⁺ .

Step 2: 1-(3-Methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-2,4-dioxo-3-(2-(tri Synthesis of fluoromethyl)-1,1a,6,6a-tetrahydrocyclopropano[a]inden-6-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl ester

To 1-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-2,4-dioxo-1,2,3,4-tetra To a mixed solution of ethyl hydrogen pyrimidine-5-carboxylate (400 mg, 1.21 mmol) in dry tetrahydrofuran (4 mL) and dry N,N-dimethylformamide (8 mL) was added 2-(trifluoromethyl) -1,1a,6,6a-Tetrahydrocyclopropano[a]inden-6-ol (258mg, 1.20mmol) and triphenylphosphine (637mg, 2.42mmol), cooled to -10°C under nitrogen protection, slowly dropped Diisopropyl azodicarboxylate (0.49 mL, 2.4 mmol) was added, and the reaction was continued at -10° C. for 1 h after the dropwise addition. The reaction mixture was added with water (50 mL), extracted with ethyl acetate (50 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, the organic phases were collected, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ Ethyl acetate (v/v)=3/2) to give the title compound as a yellow oil (636 mg, 99.86%).

MS(ESI,pos.ion)m/z:528.2[M+H] ⁺ .

Step 3: Synthesis of Compounds 3a and 3b

1-(3-Methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-2,4-dioxo-3-(2-(trifluoromethane yl)-1,1a,6,6a-tetrahydrocyclopropano[a]inden-6-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate (600 mg, 1.14 mmol) It was dissolved in a mixed solvent of glacial acetic acid (6 mL) and concentrated hydrochloric acid (3 mL, 12 mol/L), and the temperature was raised to 80 °C to react for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was isolated and purified by preparation to obtain a mixture of compounds 3a and 3b (42 mg) and a mixture of compounds 3c and 3d (13 mg), which were white solids with the same molecular weight and non-corresponding to each other. Construct.

Mixture of compounds 3c and 3d: MS (ESI, pos.ion) m/z: 500.0 [M+H] ⁺ ; HPLC: 97.89%;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 13.27-12.12 (m, 1H), 8.42 (s, 1H), 7.43 (dd, J=72.4, 41.9Hz, 6H), 6.45 (s, 1H) ), 2.64(s, 1H), 2.11(d, J=30.8Hz, 1H), 1.23–1.12(m, 1H), 1.04(s, 1H).

Mixture of compounds 3a and 3b: MS (ESI, pos.ion) m/z: 500.0 [M+H] ⁺ ; HPLC: 97.88%;

The mixture of compounds 3a and 3b was isolated by chiral preparation to give compound 3a and compound 3b.

Compound 3a: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 8.38 (s, 1H), 7.39 (d, J=75.1 Hz, 6H), 6.14 (d, J=89.1 Hz, 1H), 2.70 (s, 1H), 2.30(s, 1H), 1.46(s, 1H), 1.22(s, 1H).

Compound 3b: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 8.38 (s, 1H), 7.39 (d, J=75.1 Hz, 6H), 6.14 (d, J=89.1 Hz, 1H), 2.70 (s, 1H), 2.30(s, 1H), 1.46(s, 1H), 1.22(s, 1H).

biological test

Example A: Enzymatic assay of chymotrypsin-like

experimental method:

1) The enzyme source used was recombinant human chymotrypsin (sigma). The chymotrypsin-like substrate used was N-succinyl-Ala-Ala-Pro-Phe-7-amido-4-methylcoumarin.

2) For this assay, the test substance was diluted with DMSO, 20nL test substance (1000X) and 10 μL enzyme solution (2X) were mixed in a 384-well plate and incubated at room temperature for 15 minutes, followed by the addition of substrate solution (2X), with Synergy 2. Perform dynamic reading of the fluorescence signal excited at 370nm and then emitted at 460nm.

3) One test compound was assayed twice on the same microtiter plate at 10 different concentrations ranging from 300 nM to 0.0152 nM. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all assay components without enzyme = 100% inhibition) and IC50 values were calculated using GraphPad Prism 5 software.

Compounds in the context of the invention tested in this assay inhibit chymotrypsin-like activity and the results are shown in Table A.

Table A Test results of in vitro inhibition of chymotrypsin-like compounds by the compounds of the present invention

测试化合物test compound	IC ₅₀(nM) _IC50 (nM)	测试化合物test compound	IC ₅₀(nM) _IC50 (nM)
化合物1aCompound 1a	2.92.9	化合物1bCompound 1b	9.39.3
化合物2aCompound 2a	3.53.5	化合物2bCompound 2b	11.011.0
化合物3bCompound 3b	2.72.7

The experimental results show that the compounds of the present invention have a good inhibitory effect on chymase.

Example B: Pharmacokinetic Experiment

experimental method:

1) Preparation of compound solution: The test compound was prepared into a solution with 10% dimethyl sulfoxide, 10% RH40 and 80% normal saline for oral or intravenous administration.

2) Get 180-220g male SD rats and divide them into 2 groups at random. One group is given the compound to be tested by intravenous injection at a dose of 1.0 mg/kg, and the other group is given the compound to be tested orally at a dose of 5 mg/kg; administration; Blood was collected at time points 0.083, 0.25, 0.5, 1, 2, 5, 7 and 24 hours later.

3) Establish a standard curve with an appropriate range according to the sample concentration, and use AB SCIEX API4000 LC-MS/MS to determine the concentration of the test compound in the plasma sample in MRM mode. According to the drug concentration-time curve, the non-compartmental model method of WinNonLin 6.3 software was used to calculate the pharmacokinetic parameters. The results are shown in Table B.

Table B Pharmacokinetic data of the compounds of the present invention in SD rats

The experimental results showed that the compounds of the present invention exhibited good pharmacokinetic properties in SD rats.

Example C: Liver Microsome Stability Experiment

experimental method:

1) Preparation of compound solution: prepare a stock solution of the test compound and positive control with dimethyl sulfoxide, then dilute it with a diluent (ACN:H ₂ O=1:1) to make a working solution, and then dilute it with potassium phosphate buffer solution to the appropriate concentration of the dosing solution.

2) The compound administration solution was added to the above-mentioned liver microsome buffer, mixed well, and roughly equally divided into 3 duplicate wells. Immediately take an appropriate amount from the mixed solution into a 96 shallow-well plate, add an appropriate amount of internal standard working solution (100ng/ml propranolol in acetonitrile solution) to precipitate, add an appropriate amount of NADPH solution, mix well, and put it at 2 ~ 8 ℃ Refrigerator as initial 0-point sample.

3) Add an appropriate amount of the solution mixed with the above compound and liver microsomes to the designed time point, and place the system at 37°C for pre-incubation for 5-10 minutes. An appropriate amount of potassium phosphate buffer was added to the NCF time point, and an appropriate amount of NADPH was added to the remaining time points to initiate the reaction. In the experimental system, the final concentration of microsomes was 0.5 mg/mL, the compound was 1 μM, and the proportion of organic solvent was less than 1%. After the incubation time, an appropriate amount of internal standard working solution was added to terminate the reaction. After the sample was centrifuged, the supernatant was taken and detected by AB SCIEX API4000 LC-MS/MS in MRM mode. The results are shown in Table C. Table C is the experimental results of the stability of the compounds provided in the examples of the present invention in human, rat and canine liver microparticles.

Table C Experimental results of the stability of the compounds provided in the examples of the present invention in liver microparticles

As can be seen from Table C, the compounds of the present invention exhibit suitable stability in human, rat and canine liver microsomes.

Embodiment D: Oxidative metabolism phenotype identification experiment

experimental method:

1) Preparation of the test compound solution: the test compound and the probe substrate were prepared with dimethyl sulfoxide to prepare a stock solution, and then diluted with a diluent (ACN:H ₂ O=1:1) to be a working solution, and then phosphoric acid was used to prepare a stock solution. The potassium buffer solution is diluted to the appropriate concentration for the administration solution.

2) Add a certain amount of dosing solution and a certain amount of human recombinase to the potassium phosphate buffer solution, and add the mixed solution of the compound to be tested/substrate and human recombinase in the set position of the 96-well plate, every time The point is at least parallel to the double compound hole parallel operation. The compound in the experimental system is 1 μM, and the proportion of organic solvent is less than 1%. After pre-incubating at 37°C for 5 min, NADPH/phosphate buffer solution was added to the corresponding well of each CYP subenzyme to start the reaction. After a certain period of incubation, a certain amount of working solution containing internal standard was used to stop the reaction. Centrifuge, take the supernatant, and use AB SCIEX API4000 LC-MS/MS to detect in MRM mode. The experimental results are shown in Table D, and Table D is the identification data of the oxidative metabolism phenotype of the compounds provided in the examples of the present invention.

Table D Compound oxidative metabolism phenotype identification data provided in the examples of the present invention

As can be seen from Table D, the compounds of the present invention are not significantly metabolized in the recombinase systems of the seven major CYP subtypes, indicating that they may not be metabolized.

Example E: Enzyme Inhibition Experiment

experimental method:

1) Preparation of the solution of the compound to be tested: the compound to be tested, the positive control and the probe substrate are prepared as a stock solution with dimethyl sulfoxide, and then diluted with a diluent (ACN:H ₂ O=1:1) to be a working solution, It is then diluted with 0.1M potassium phosphate buffer solution to the appropriate concentration of the dosing solution.

2) Add the mixed solution of compound and human liver microsomes to the set position of the 96-well plate, and operate at least three replicate wells for each concentration point in parallel. The corresponding substrate solution was added to the corresponding well of each subenzyme, the compound in the system was 10 μM, and the proportion of organic solvent was less than 1%. After preheating at 37°C, NADPH solution was added to start the reaction. After a certain period of incubation (the recommended incubation time is 5 min for 3A4, 10 min for 1A2, 2B6, 2C9, and 2D6, and 20 min for 2C8 and 2C19), the reaction was terminated with the internal standard working solution. After centrifugation, the supernatant was taken and processed, and detected by AB SCIEX API4000 LC-MS/MS in MRM mode. The experimental results are shown in Table E, and Table E is the enzyme inhibition data of the compounds provided in the examples of the present invention.

Table E Enzyme inhibition data for compounds provided in the examples of the present invention.

It can be seen from Table E that the compounds of the present invention have no risk of inhibiting the seven major CYP subtypes except CYP2C8.

Example F: Hepatocyte Enzyme Induction Experiment

experimental method:

1) Preparation of the test compound solution: The test compound, positive control and negative control were prepared with dimethyl sulfoxide to prepare a stock solution, and then the culture medium was used to prepare a corresponding induction incubation solution

2) The cryopreserved primary human hepatocytes were recovered at 37°C, and seeded into 48 wells at a density of about 5-7×105/mL (200 μL per well). Generally, two plates are plated in parallel for the enzyme induction test and the cytotoxicity test, respectively. Inducer incubation: Design the sample location map of the culture plate before the experiment, and each compound has three replicate wells. According to the sample position map of the culture plate, freshly prepared and preheated dosing solution containing positive/negative control or test compound was added to the corresponding wells, and the drug was administered for three consecutive days, and the solution was changed every day. The enzyme induction test plate and the cytotoxicity test plate were administered in parallel.

3) Cytotoxicity test: Add the prepared and preheated substrate solution to the enzyme induction test plate about 24 hours after the last administration, and place it in an incubator for about 2 hours. To the cytotoxicity test plate, 100-200 μL of 10% CCK-8 solution was added and incubated for about 1.5 h. After the incubation time, the cells were passed out of the cell chamber, and the absorbance of each cell well at 450 nm was measured immediately with a microplate reader or a spectrophotometer. Enzyme induction assay: The enzyme induction assay plate is removed from the incubator and 0.5mL of cell lysate (usually RNAiso plus) is added to each well of the plate. cDNA was obtained by RNA extraction and reverse transcription. The expression level of CYP mRNA in the samples was detected by fluorescence quantitative PCR reaction (setting: pre-denaturation, 95°C for 20s; PCR reaction, 95°C for 3s; 60°C for 30s, 40 cycles). The experimental results are shown in Table F, and Table F is the hepatocyte enzyme induction data of the compounds provided in the examples of the present invention.

Table F Hepatocyte Enzyme Induction Data of Compounds Provided in the Examples of the Present Invention

Among them, N/A means not detected.

It can be seen from Table F that the compounds of the present invention have no obvious induction risk for the three main CYP subtypes that have the risk of enzyme induction

In the description of this specification, reference to the terms "one embodiment", "an embodiment", "some embodiments", "example", "specific example" or "some examples", etc. A particular feature, structure, material or characteristic described by an embodiment or example is included in at least one embodiment, implementation or example of the invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment, implementation or example. Furthermore, the particular features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments, implementations or examples. Furthermore, those skilled in the art may combine and combine the different embodiments, implementations or examples described in this specification and the features of the different embodiments, implementations or examples without conflicting each other.

Although the embodiments of the present invention have been shown and described above, it should be understood that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. Embodiments are subject to variations, modifications, substitutions and variations.

Claims

A compound, which is a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable compound represented by formula (I) an acceptable salt or a prodrug thereof,

Wherein: A is a C 3-8 cycloalkyl group, a C 6-10 aryl group, a heterocyclic group consisting of 3-8 atoms or a heteroaryl group consisting of 5-12 atoms, wherein the C 3-8 ring Alkyl, C 6-10 aryl, heterocyclyl of 3-8 atoms, and heteroaryl of 5-12 atoms are independently unsubstituted or 1, 2, 3, 4 or 5 selected from of D, F, Cl, Br, I, NO 2 , CN, OH, NH 2 , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy and C 1-3 haloalkoxy substituted by a substituent;

Each R 1 is independently H, D, halogen, NO 2 , CN, OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy base, C 3-8 cycloalkyl, heterocyclic group consisting of 3-8 atoms, C 6-10 aryl group or heteroaryl group consisting of 5-12 atoms;

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

R2 is

R 5 is -NR n -, -O-, -S- or -CR c R d -;

R n is H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, composed of 3-8 atoms Heterocyclic group, C 6-10 aryl group or heteroaryl group consisting of 5-12 atoms;

R c and R d are each independently H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclic group consisting of 3-8 atoms, C 6-10 aryl group or heteroaryl group consisting of 5-12 atoms;

R 6 is H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, composed of 3-8 atoms Heterocyclyl, C 6-10 aryl or heteroaryl consisting of 5-10 atoms;

R 3 is H, D, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkane Oxy group, C 3-8 cycloalkyl group, heterocyclic group consisting of 3-8 atoms, C 6-10 aryl group, heteroaryl group consisting of 5-12 atoms, -NR a1 R b or -OR a , wherein the C 3-8 cycloalkyl group, the heterocyclic group consisting of 3-6 atoms, the C 6-10 aryl group and the heteroaryl group consisting of 5-10 atoms are independently unsubstituted or by 1, 2 , 3, 4 or 5 selected from D, F, Cl, Br, I, NO 2 , CN, OH, NH 2 , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy and C 1-3 halogenated alkoxy substituents;

R a1 , R a and R b are each independently H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, 3-8 atoms composed of a heterocyclic group or a heteroaryl group composed of 5-12 atoms;

R 4 is H, D, halogen or C 1-6 alkyl.
The compound according to claim 1, wherein A is a C 3-6 cycloalkyl group, a C 6-10 aryl group, a heterocyclic group consisting of 3-6 atoms or a heteroaryl group consisting of 5-10 atoms, wherein said C 3-6 cycloalkyl, C 6-10 aryl, 3-6 atoms heterocyclic group and 5-10 atom heteroaryl group are independently unsubstituted or replaced by 1, 2 , 3, 4 or 5 selected from D, F, Cl, Br, I, NO 2 , CN, OH, NH 2 , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy and C 1-3 haloalkoxy substituents.
The compound of claim 1 or 2, wherein each R 1 is independently H, D, halogen, NO 2 , CN, OH, NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1 -4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3-6 atoms heterocyclyl, C 6-10 aryl or 5-10 atoms heteroaryl ;

R n is H, D, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, composed of 3-6 atoms Heterocyclyl, C 6-10 aryl or heteroaryl consisting of 5-10 atoms;

R c and R d are each independently H, D, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 aryl group or heteroaryl group consisting of 5-10 atoms;

R 6 is H, D, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, composed of 3-6 atoms Heterocyclyl, C 6-10 aryl or heteroaryl consisting of 5-10 atoms;

R 3 is H, D, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkane Oxy group, C 3-6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, C 6-10 aryl group, heteroaryl group consisting of 5-10 atoms, -NR a1 R b or -OR a ; Wherein the C 3-6 cycloalkyl group, the heterocyclic group consisting of 3-6 atoms, the C 6-10 aryl group and the heteroaryl group consisting of 5-10 atoms are independently unsubstituted or by 1, 2 , 3, 4 or 5 selected from D, F, Cl, Br, I, NO 2 , CN, OH, NH 2 , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy and C 1-3 halogenated alkoxy substituents;

R a1 , R a and R b are each independently H, D, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 3-6 atoms composed of a heterocyclic group or a heteroaryl group composed of 5-10 atoms;

R 4 is H, D, halogen or C 1-4 alkyl.
The compound according to any one of claims 1-3, wherein A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, Piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, Pyrazinyl or pyridazinyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholine base, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazine groups are independently unsubstituted or substituted by 1, 2 , 3, 4 or 5 selected from D, F, Cl, Br, I, NO2, CN, OH, NH2 , methyl, ethyl, n-propyl, Isopropyl, trifluoromethyl, difluoromethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, difluoromethoxy, trifluoro Substituents of methoxy, difluoroethoxy and trifluoroethoxy.
The compound of any one of claims 1-4, wherein each R 1 is independently H, D, F, Cl, Br, I, NO 2 , CN, OH, NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec - butyl, tert - butyl, -CH2F , -CH2Cl , -CHF2, -CHCl2 , -CF3 , -CH2CH 2F , -CH2CH2Cl , -CH2CHF2 , -CH2CHCl2 , -CHFCH2F , -CHClCH2Cl , -CH2CF3 , -CH ( CF3 ) 2 , -CF2CH 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , methoxy, ethoxy, 1-propoxy, 2-propoxy, 1 -Butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy , trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;

R n is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF 3 , -CH 2 F, -CHF 2 , -CH2CH2F , -CH2CHF2 , -CHFCH2F , -CH2CF3 , -CH ( CF3 ) 2 , -CF2CH2CH3 , -CH2CH2CH2F , - CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-alkynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrole base, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;

Rc and Rd are each independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF3 , -CH2 F, -CHF2 , -CH2CH2F , -CH2CHF2 , -CHFCH2F , -CH2CF3 , -CH ( CF3 ) 2 , -CF2CH2CH3 , -CH2CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2 -Butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazine base, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazine or pyridazinyl;

R 6 is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF 3 , -CH 2 F, -CHF 2 , -CH2CH2F , -CH2CHF2 , -CHFCH2F , -CH2CF3 , -CH ( CF3 ) 2 , -CF2CH2CH3 , -CH2CH2CH2F , - CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-alkynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrole pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.
The compound according to any one of claims 1-5, wherein R 3 is H, D, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec - butyl, tert - butyl, -CF3 , -CH2F , -CHF2 , -CH2CH2F , -CH2CHF2 , -CHFCH2F , -CH2CF3 , -CH ( CF 3 ) 2 , -CF2CH2CH3 , -CH2CH2CH2F , -CH2CH2CHF2 , -CH2CH2CF3 , vinyl , propenyl , allyl , ethynyl , propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, difluoro Methyl, trifluoromethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, Tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, -NR a1 R b or -OR a ; wherein said cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, tris Azazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl are independently unsubstituted or substituted by 1, 2, 3, 4 or 5 selected from D, F, Cl, Br, I, NO 2 , CN, OH, NH 2 , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy and C 1-3 Substituted by halogenated alkoxy substituents;

R a1 , R a and R b are each independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF 3 , -CH2F , -CHF2 , -CH2CH2F , -CH2CHF2 , -CHFCH2F , -CH2CF3 , -CH ( CF3 ) 2 , -CF2CH2CH3 , - CH2CH2CH2F , -CH2CH2CHF2 , -CH2CH2CF3 , cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl , azetidine , pyrrolidinyl, tetrahydrofuran base, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, Pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;

R4 is H, D, F, Cl, Br, methyl, ethyl, n - propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
The compound according to any one of claims 1-6, which is a compound having one of the following structures or a stereoisomer, tautomer, nitrogen oxide, hydrate, Solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:
A pharmaceutical composition comprising the compound of any one of claims 1-7, and a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.
The pharmaceutical composition according to claim 8, further comprising one or more other active ingredients selected from the group consisting of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists agents, renin inhibitors, alpha-blockers, beta-blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors, diuretics, kinase inhibitors, matrix metalloproteinase inhibitors, Soluble guanylate cyclase stimulator and activator and phosphodiesterase inhibitor.
Use of the compound according to any one of claims 1-7 or the pharmaceutical composition according to any one of claims 8-9 in the preparation of a medicament, wherein the medicament is used for the treatment or prevention of heart failure, pulmonary hypertension, Chronic obstructive pulmonary disease, asthma, kidney failure, kidney disease, fibrotic conditions of internal organs or skin fibrosis.