WO2022135534A1 - 取代的含氮双环化合物及其用途 - Google Patents

取代的含氮双环化合物及其用途 Download PDF

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WO2022135534A1
WO2022135534A1 PCT/CN2021/140889 CN2021140889W WO2022135534A1 WO 2022135534 A1 WO2022135534 A1 WO 2022135534A1 CN 2021140889 W CN2021140889 W CN 2021140889W WO 2022135534 A1 WO2022135534 A1 WO 2022135534A1
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butyl
methyl
propoxy
group
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French (fr)
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池波
张铮
韩伟
马发城
刘楚怡
王慧
詹志柱
贺艳
左应林
王晓军
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广东东阳光药业有限公司
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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    • C07D239/72—Quinazolines; Hydrogenated quinazolines
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    • C07D239/72—Quinazolines; Hydrogenated quinazolines
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms

Definitions

  • the present invention belongs to the technical field of medicine, and specifically relates to substituted nitrogen-containing bicyclic compounds and uses thereof, and further relates to pharmaceutical compositions comprising these compounds, and methods and uses thereof.
  • the substituted nitrogen-containing bicyclic compounds and/or their pharmaceutical compositions of the present invention can be used as chymotrypsin-like inhibitors for preventing, treating or alleviating cardiovascular diseases such as heart failure or myocardial infarction.
  • CVD Cardiovascular diseases
  • 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.
  • 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).
  • 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).
  • Ang II angiotensin II
  • Ang II angiotensin II
  • Ang 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.
  • angiotensin II 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.
  • 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.
  • Bayer is developing an oral small-molecule chymotrypsin-like inhibitor BAY-1142524 for the treatment of heart failure and diabetic nephropathy.
  • Phase I clinical 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.
  • Bayer has carried out a phase II clinical trial of BAY-1142524 for the treatment of diabetic nephropathy, to further verify the efficacy and safety of this novel chymotrypsin-like inhibitor.
  • chymotrypsin-like inhibition constitutes an effective method of treating cardiovascular disorders, inflammation, allergic disorders and various fibrotic disorders.
  • the present invention provides a class of novel substituted nitrogen-containing bicyclic compounds as chymotrypsin-like inhibitors for preventing, treating or alleviating related cardiovascular diseases such as heart failure or myocardial infarction.
  • the substituted nitrogen-containing bicyclic compound of the present invention has stable properties, good safety, and good pharmacodynamic 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.
  • 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,
  • each of A, R 0 , t, E, R 1 and R 2 has the meaning as described in the present invention.
  • R 2 is wherein R 5 and m have the meanings described in the present invention.
  • m is 0, 1, 2, 3, or 4.
  • R 2 is wherein R 5 has the meaning described in the present invention.
  • the compound of the present invention can be a compound represented by formula (IIa) or formula (IIb) or formula (IIc), or formula (IIa) or formula (IIb) or formula (IIc) Stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof of the indicated compounds,
  • each of A, R 0 , t, E, R 1 and R 5 has the meaning as described in the present invention.
  • Ring A is a 5-6 membered heteroaromatic ring or a benzene ring.
  • Ring A is pyrrole, pyrazole, imidazole, triazole, tetrazolium, furan, thiophene, thiazole, oxazole, pyridine, pyrimidine, pyrazine, pyridazine, or benzene.
  • Ring A is pyrazole, pyridine or benzene.
  • each R 0 is independently H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl consisting of 3-8 atoms, C 6-10 aryl, heteroaryl consisting of 5-12 atoms, CN, NO 2 , -OR a , -C(O )R a1 , -C(O)NR a2 R b , -C(O)OR a , -NR a2 R b , -NR a3 C(O)R a1 , -NR a3 C(O)OR a , -NR a3 C(O)NR a2 R b , -SO 2 R a1 , -SO 2 NR a2 R b or -NR a3 SO 2 NR a2 R b , wherein said C
  • t is 0, 1, 2, 3, or 4.
  • R a , R a1 , R a2 , R a3 , and R b are each independently H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, A heterocyclic group consisting of 3-8 atoms, a C 6-10 aryl group or a heteroaryl group consisting of 5-12 atoms.
  • each R m is independently D, halogen, CN, NO 2 , OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or halo C 1-6 alkoxy.
  • R 1 is wherein R 3 and R 4 have the meanings described in the present invention.
  • R 3 is -NR n -, -O-, -S- or -CR c R d -; wherein R n , R c and R d each independently have the meaning described herein.
  • 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 - a heterocyclic group consisting of 8 atoms, a C 6-10 aryl group or a 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 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.
  • R 4 is H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3 - a heterocyclic group consisting of 8 atoms, a C 6-10 aryl group or a heteroaryl group consisting of 5-12 atoms.
  • each R 5 is independently H, D, halogen, NO 2 , CN, OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated 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.
  • each R 0 is independently H, D, F, Cl, Br, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, halo C 1-4 Alkoxy, C 3-6 cycloalkyl, heterocyclic group composed of 3-6 atoms, C 6-10 aryl group, heteroaryl group composed of 5-10 atoms, CN, NO 2 , -OR a , -C(O)R a1 , -C(O)NR a2 R b , -C(O)OR a , -NR a2 R b , -NR a3 C(O)R a1 , -NR a3 C(O)OR a , -NR a3 C(O)NR a2 R b , -SO 2 R a1 , -SO 2 NR a2 R b or -NR a3 SO 2 NR a2 R b , wherein the C
  • R a , R a , R a1 , R a2 , R a3 , and R b are each independently H, D, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 ring An alkyl group, a heterocyclic group consisting of 3-6 atoms, a C 6-10 aryl group or a heteroaryl group consisting of 5-10 atoms.
  • each Rm is independently D, halogen, CN, NO2, OH, NH2 , C1-4alkyl , C1-4haloalkyl , C1-4alkoxy , or halo C 1-4 alkoxy.
  • 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 - a heterocyclic group consisting of 6 atoms, a C 6-10 aryl group or a heteroaryl group 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 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.
  • R 4 is H, D, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3 - a heterocyclic group consisting of 6 atoms, a C 6-10 aryl group or a heteroaryl group consisting of 5-10 atoms.
  • each R 5 is independently H, D, halogen, NO 2 , CN, OH, NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, Halogenated C 1-4 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.
  • each R0 is independently H, D, F, Cl, Br, NO2, CN, OH, NH2 , methyl, ethyl, n - propyl, isopropyl, n-butyl, Isobutyl, sec - butyl, tert - butyl, -CH2F , -CH2Cl , -CHF2 , -CHCl2 , -CF3 , -CH2CH2F , -CH2CH2Cl , -CH 2CHF2 , -CH2CHCl2 , -CHFCH2F , -CHClCH2Cl , -CH2CF3 , -CH ( CF3 ) 2 , -CF2CH2CH3 , -CH2CH2CH2F , -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , methoxy, ethoxy, 1-propoxy
  • R a , R a1 , R a2 , R a3 , and R b are each independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Butyl, tert - butyl, -CH2F , -CHF2 , -CF3 , -CH2CH2F , -CH2CHF2 , -CHFCH2F , -CH2CF3 , -CH ( CF3 ) 2 , -CF 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Azacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidin
  • each Rm is independently D, F, Cl, Br, NO2, CN, OH, NH2 , methyl, ethyl, n - propyl, isopropyl, n-butyl, isobutyl base, sec - butyl, tert - butyl, -CH2F , -CH2Cl , -CHF2 , -CHCl2 , -CF3 , -CH2CH2F , -CH2CH2Cl , -CH2CHF 2 , -CH2CHCl2 , -CHFCH2F , -CHClCH2Cl , -CH2CF3 , -CH ( CF3 ) 2 , -CF2CH2CH3 , -CH2CH2CH2F , - CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , methoxy, ethoxy, 1-propoxy, 2-
  • Rn is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F , -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-ynylbutynyl base, 3-alkynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
  • Rc and Rd are each independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, - CH2F , -CHF2 , -CH2CH2F , -CH2CHF2 , -CHFCH2F , -CH2CF3 , -CH ( CF3 ) 2 , -CF2CH2CH3 , -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-ynylbutynyl base, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl
  • R4 is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F , -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-ynylbutynyl base, 3-alkynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
  • each R5 is independently H, D, F, Cl, Br, NO2, CN, OH, NH2 , methyl, ethyl, n - propyl, isopropyl, n-butyl, Isobutyl, sec - butyl, tert - butyl, -CH2F , -CH2Cl , -CHF2 , -CHCl2 , -CF3 , -CH2CH2F , -CH2CH2Cl , -CH 2CHF2 , -CH2CHCl2 , -CHFCH2F , -CHClCH2Cl , -CH2CF3 , -CH ( CF3 ) 2 , -CF2CH2CH3 , -CH2CH2CH2F , -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , methoxy, ethoxy, 1-propoxy
  • the compounds described herein have one of the following structures or are stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites of compounds having one of the following structures Product, pharmaceutically acceptable salt or prodrug thereof:
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention; optionally, it further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.
  • 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.
  • 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,
  • 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.
  • the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I) or formula (IIa) or formula (IIb) or formula (IIc).
  • 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 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.
  • any technical feature may be applicable to that technical feature in other embodiments, as long as they do not contradict.
  • 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.
  • these articles refer to articles of one or more than one (ie, at least one) object.
  • 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.
  • 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. .
  • 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.
  • enantiomer refers to two nonsuperimposable, but mirror-image isomers of a compound.
  • racemate or “racemic mixture” refers to an equimolar mixture of two enantiomers lacking optical activity.
  • 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.
  • optically active compounds Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • protontautomers also known as prototropic tautomers
  • 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.
  • 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.
  • subject refers to an animal. Typically the animal is a mammal.
  • a subject also refers to primates (eg, humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like.
  • the subject is a primate. In other embodiments, the subject is a human.
  • patient refers to humans (including adults and children) or other animals. In some embodiments, “patient” refers to a human.
  • C1 - C6 alkyl specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl groups.
  • D represents a single deuterium atom.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • alkyl refers to a saturated straight or branched chain monovalent hydrocarbon group containing 1 to 20 carbon atoms.
  • the alkyl group contains 1-6 carbon atoms, ie, C1-6 alkyl; in another embodiment, the alkyl group contains 1-4 carbon atoms, ie, C1 -4 alkyl; in yet another embodiment, the alkyl group contains 1-3 carbon atoms, ie, C1-3 alkyl.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, -OCH2CH2CH2CH2CH2
  • haloalkoxy means that an alkoxy group is substituted with one or more halogen atoms, wherein alkoxy has the meaning set forth herein.
  • alkoxy has the meaning set forth herein.
  • Such examples include, but are not limited to, difluoromethoxy (-OCHF2 ) , trifluoromethoxy ( -OCF3 ), difluoroethoxy ( eg, -OCH2CHF2 , etc.), trifluoroethyl oxy (eg -OCH 2 CF 3 etc.), etc.
  • haloalkyl denotes an alkyl group substituted with one or more halogen atoms, wherein alkyl has the meaning set forth herein.
  • 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.
  • cycloalkyl denotes a saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring carbon atoms.
  • the cycloalkyl group contains 3-10 ring carbon atoms, such as C 3-10 cycloalkyl; in other embodiments, the cycloalkyl group contains 3-8 ring carbon atoms, such as C 3- 8 cycloalkyl; in yet other embodiments, cycloalkyl contains 3-6 ring carbon atoms, eg, C3-6 cycloalkyl.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • C 3-8 cycloalkyl includes C 3-6 cycloalkyl; the C 3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl .
  • 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.
  • 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.
  • 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.
  • 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 heterocyclic group consisting of 3-6 atoms includes, but is not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl , tetrahydrothienyl, thiazolidinyl, pyrazolidine, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl and the like.
  • s typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is s.
  • piperidinyl is a 6-atom heterocycloalkyl group
  • 1,2,3,4-tetrahydronaphthyl is a 10-atom carbocyclyl group.
  • 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).
  • 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.
  • aryl is used interchangeably with the term “aromatic ring”. Examples of aryl groups may include phenyl, naphthyl, and anthracenyl. Unless otherwise specified, the group “ C6-10 aryl” refers to an aryl group containing 6-10 ring carbon atoms.
  • 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.
  • 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).
  • heteroaryl may be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic”.
  • heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, and the like.
  • 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, examples of heteroaryl groups consisting of 5-6 atoms include, but are not limited to, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, Pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl and the like.
  • protecting group refers to a substituent group that is commonly used to block or protect specific functionality when it reacts with other functional groups.
  • 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).
  • 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.
  • 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.
  • prodrug represents the conversion of a compound into a compound of formula (I) or formula (IIa) or formula (IIb) or formula (IIc) 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.
  • esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonate esters , carbamates and amino acid esters.
  • 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.
  • Metal 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.
  • 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.
  • 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,
  • 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.
  • counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -C 8 sulfonates and aromatic sulfonates.
  • N-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.
  • 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).
  • 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).
  • 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
  • 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.
  • hydrate refers to an association in which the solvent molecule is water.
  • the term "hydrate" may be used.
  • 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.
  • 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.
  • prevent refers to the reduction of the risk of acquiring a disease or disorder (ie: stopping the development of at least one clinical symptom of the disease in a subject who may be facing or predisposed to facing the disease, but also not experience or exhibit symptoms of disease).
  • 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.
  • ischemic attack 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, micro
  • the present invention relates to compounds having the structure of general formula (I), wherein the variables are as defined above.
  • the compound represented by formula (I) of the present invention may be a compound represented by formula (IIa), formula (IIb) or formula (IIc), wherein the definitions of each variable are as described above.
  • stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates of compounds of formula (I) or formula (IIa) or formula (IIb) or formula (IIc) , solvates, metabolites, 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) or formula (IIc), including but not limited to diastereomers, enantiomers Atropisomers, atropisomers and geometric (or conformational) isomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
  • stereochemistry of any particular chiral atom 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 .
  • 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.
  • the compound of formula (I) or formula (IIa) or formula (IIb) or formula (IIc) may exist in the form of a salt.
  • the salt refers to a pharmaceutically acceptable salt.
  • 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.
  • the salt is not necessarily a pharmaceutically acceptable salt, but can be used in the preparation and/or purification of formula (I) or formula (IIa) or formula (IIb) or formula (IIc) Compounds and/or intermediates used to separate enantiomers of compounds represented by formula (I) or formula (IIa) or formula (IIb) or formula (IIc).
  • Pharmaceutically acceptable acid addition salts can be formed by reacting a compound of formula (I) or formula (IIa) or formula (IIb) or formula (IIc) with inorganic or organic acids, such as acetate, aspartate , Benzoate, Benzenesulfonate, Bromide/Hydrobromide, Bicarbonate/Carbonate, Bisulfate/Sulfate, Camphorsulfonate, Chloride/HCl, Chlorophylline , citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydriodate/iodide, isethionate acid salt, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthoate, Naphthalene sulfonate, nicotinate
  • 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.
  • 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.
  • 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.
  • a suitable base eg, hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K
  • Such reactions are usually carried out in water or an organic solvent or a mixture of the two.
  • non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile is required.
  • non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • 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.
  • a solvent eg, ethanol, DMSO, etc.
  • 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.
  • 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.
  • the compounds of the present invention include isotopically enriched compounds as defined herein, eg, 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.
  • 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) or formula (IIc) can be used by conventional techniques familiar to those skilled in the art or as described in the examples and preparation procedures of the present invention.
  • the isotopically-labeled reagents are prepared in place of the previously used unlabeled reagents.
  • substitution of heavier isotopes 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.
  • deuterium in the present invention is regarded as a substituent of the compound represented by formula (I) or formula (IIa) or formula (IIb) or formula (IIc).
  • concentration of such heavier isotopes, especially deuterium can be defined by an isotopic enrichment factor.
  • isotopic enrichment factor refers to the ratio between the isotopic abundance and the natural abundance of a given isotope.
  • 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.
  • the present invention relates to intermediates for the preparation of compounds of formula (I) or formula (IIa) or formula (IIb) or formula (IIc).
  • the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I) or formula (IIa) or formula (IIb) or formula (IIc).
  • the present invention provides a pharmaceutical composition, comprising a compound represented by formula (I) or formula (IIa) or formula (IIb) or formula (IIc) or its individual stereoisomers, racemic or non-isomeric isomers A racemic mixture or a pharmaceutically acceptable salt or solvate thereof.
  • 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.
  • 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, kinas
  • “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.
  • 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.
  • 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
  • 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.
  • 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).
  • the present invention relates to a process for preparing a pharmaceutical composition
  • 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.
  • 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.
  • routes of administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, Solutions, emulsions, sachets, and cachets
  • parenteral administration such as sterile solutions, suspensions, and reconstituted powders
  • transdermal administration such as
  • compositions of the present invention may exist in free form for use in therapy or, if appropriate, in the form of their pharmaceutically acceptable derivatives.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical compositions disclosed herein may be formulated in a dosage form suitable for inhalation administration to a patient as a dry powder.
  • 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.
  • 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.
  • 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.
  • the active ingredient can be delivered from the patch by iontophoresis, as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • ointments, creams and gels can be formulated with an aqueous or oily base, and a suitable thickening and/or gelling agent and/or solvent.
  • 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.
  • soluble polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyoxyethylene polylysine substituted with palmitoyl residues.
  • 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.
  • 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.
  • 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).
  • 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.
  • aqueous carriers water-miscible carriers
  • non-aqueous 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
  • 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.
  • a suitable non-irritating excipient such as cocoa butter, glycerides synthesized from polyethylene glycol
  • 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.
  • 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.
  • a compound of the invention 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.
  • the amount of active compound in a unit dose of the formulation can be varied or adjusted according to the particular application.
  • a typical recommended daily dosing regimen may range from about 1 mg/day to about 500 mg/day in two to four divided doses.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention may be administered orally.
  • a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention may be administered by inhalation.
  • a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention may be administered intranasally.
  • 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 can 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.
  • 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 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.
  • 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).
  • 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.
  • the compounds of the present invention may be administered in prodrug form.
  • 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.
  • 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.
  • 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 organs fibrotic disorders and skin fibrotic diseases.
  • 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
  • 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.
  • myocardial inflammation myocarditis
  • chronic myocarditis chronic myocarditis
  • acute myocarditis acute myocarditis
  • viral myocarditis
  • 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, nephropathy, fibrotic disorders of internal organs, and skin fibrosis.
  • 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.
  • the compounds of the present invention include pharmaceutically acceptable derivatives thereof.
  • the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are as defined in formula (I) or (IIa) or (IIb) or (IIc) Show.
  • the following reaction schemes and examples serve to further illustrate the content of the present invention.
  • the measurement conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 ⁇ 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.
  • ESI electrospray ionization
  • the compound represented by the formula (M11) can be prepared by the synthetic scheme 1, wherein het is a 5-6 membered heteroaromatic ring: the compound represented by the formula (M1) undergoes an esterification reaction to obtain the compound represented by the formula (M2); The compound represented by the formula (M2) reacts with 4-methoxybenzyl chloride to obtain the compound represented by the formula (M3); the compound represented by the formula (M3) is hydrogenated and reduced to obtain the compound represented by the formula (M4); the formula ( The compound shown in M4) reacts with phenyl chloroformate to obtain the compound shown in formula (M5); the compound shown in formula (M5) reacts with the compound shown in formula (M6) to obtain the compound shown in formula (M7); The compound represented by the formula (M7) is closed to obtain the compound represented by the formula (M8); the compound represented by the formula (M8) reacts with the compound represented by the formula (M9) to obtain the compound represented by the formula (M10); The compound represented by M10) is deprotected
  • the compound represented by the formula (M18) can be prepared by this synthetic scheme 2, wherein X, Y, W and Z are each independently CH or N: the compound represented by the formula (M12) and the compound represented by the formula (M13)
  • the compound is subjected to nucleophilic substitution reaction to obtain the compound represented by formula (M14); the compound represented by formula (M14) undergoes condensation reaction to obtain the compound represented by formula (M15); the compound represented by formula (M15) undergoes ring closure with CDI
  • the compound represented by the formula (M16) is obtained by the reaction; the compound represented by the formula (M16) is coupled with the compound represented by the formula (M17) to obtain the compound represented by the formula (M18).
  • the compound represented by the formula (M26) can be prepared through the synthesis scheme 3: the compound represented by the formula (M19) undergoes a nucleophilic substitution reaction with the compound represented by the formula (M20) to obtain the compound represented by the formula (M21); The compound represented by (M21) is hydrogenated and reduced to obtain the compound represented by the formula (M22); the compound represented by the formula (M22) is subjected to ring closure reaction with CDI to obtain the compound represented by the formula (M23); the compound represented by the formula (M23) The compound represented by the formula (M24) undergoes coupling reaction to obtain the compound represented by the formula (M25); the compound represented by the formula (M25) undergoes a carbonyl intercalation reaction to obtain the compound represented by the formula (M26).
  • the reaction mixture was quenched by adding saturated aqueous ammonium chloride solution (300 mL), stirred for 20 minutes, filtered and dried to obtain a small amount of solid product; the filtrate was separated, the aqueous phase was extracted with dichloromethane (400 mL ⁇ 2), the organic phases were combined and anhydrous Dry over sodium sulfate. After filtration, the filtrate was evaporated to remove the solvent under reduced pressure and combined with the previously obtained small amount of solid product to obtain the title compound as a yellow solid (58.4 g, 99.9%).
  • Step 5 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzo[d]oxazole-2(3H )-ketone synthesis
  • Step 9 Synthesis of 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester
  • Step 10 Synthesis of 1-(4-methoxybenzyl)-4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester
  • Step eleven Synthesis of 4-amino-1-(4-methoxybenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester
  • Step 12 Synthesis of 1-(4-methoxybenzyl)-4-((phenoxycarbonyl)amino)-1H-pyrazole-3-carboxylic acid ethyl ester
  • reaction mixture was evaporated under reduced pressure to remove part of the solvent, added water (80 mL), stirred overnight, filtered, added water (40 mL) to wash the filter cake, and dried under reduced pressure to obtain a pale yellow solid (1.33 g, 88.2%).
  • reaction mixture was evaporated to remove the solvent under reduced pressure, adjusted to pH 8 by adding saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (50 mL), the organic phase was collected, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, reduced
  • Step 2 Synthesis of 6-bromo-3-((3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)amino)picolinic acid
  • Step 3 Synthesis of 6-bromo-3-((3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)amino)picolinamide
  • reaction mixture was concentrated under reduced pressure to obtain a yellow solid, tetrahydrofuran (40 mL) was added, an aqueous solution of ammonium hydroxide (28 mass%) (40 mL) was added dropwise to the above tetrahydrofuran solution, and the mixture was stirred at room temperature overnight.
  • the reaction mixture was filtered, water (50 mL) was added to the filtrate, extracted with ethyl acetate (50 mL ⁇ 2), the organic phase was collected, washed with saturated sodium chloride solution (50 mL), then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure
  • the title compound was obtained as a yellow solid (1.55 g, 80%)
  • Step 4 6-Bromo-1-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)pyrido[3,2-d]pyrimidine-2 Synthesis of ,4(1H,3H)-dione
  • reaction mixture was added with water (50 mL), extracted with ethyl acetate (50 mL ⁇ 2), the pH of the aqueous phase was adjusted to 1-2, a large amount of precipitate was precipitated, filtered and dried to obtain the title compound as a yellow solid (0.862 g, 51.9%) .
  • Step 5 6-Bromo-1-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-(4-(trifluoromethyl) Synthesis of -2,3-dihydro-1H-inden-1-yl)pyrido[3,2-d]pyrimidine-2,4(1H,3H)-dione
  • Step 6 1-(3-Methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-2,4-dioxo-3-(4-(tri Synthesis of Fluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidine-6-carboxylic acid
  • Step 4 (R)-6-(6-Bromo-2-oxo-3-(4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-2,3 - Synthesis of -dihydro-1H-benzo[d]imidazol-1-yl)-3-methylbenzo[d]oxazol-2(3H)-one
  • Step 5 (R)-3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-2-oxo-1-(4-( Synthesis of trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid
  • Step 1 Synthesis of N-(5-bromo-2-nitrophenyl)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-amine
  • 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, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtrate was reduced The solvent was evaporated under pressure to give the title compound as a yellow solid (911.0 mg, 99.91%).
  • Step 2 Synthesis of 5-bromo-N 1 -(4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)benzene-1,2-diamine
  • Step 4 6-(5-Bromo-2-oxo-3-(4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-2,3-dihydro- Synthesis of 1H-benzo[d]imidazol-1-yl)-3-methylbenzo[d]oxazol-2(3H)-one
  • Step 5 1-(3-Methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-2-oxo-3-(4-(trifluoromethyl) Synthesis of )-2,3-dihydro-1H-inden-1-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid
  • Example A Enzymatic assay of chymotrypsin-like
  • 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.
  • test substance is diluted with DMSO, 20 nL of the test substance (1000X) and 10 ⁇ L of enzyme solution (2X) are mixed in a 384-well plate and incubated for 15 minutes at room temperature, followed by the addition of the substrate solution (2X), with Synergy 2. Perform dynamic reading of the fluorescence signal excited at 370nm and then emitted at 460nm.
  • Example number IC50 (nM) Example number IC50 (nM) 1 17.0 2 5.5 3 7.7 4 5.7 5 9.2 6 5.9 6a 2.1 7 7.8 8 6.4 9 5.4

Abstract

一类新颖的取代的含氮双环化合物以及包含该类化合物的药物组合物，它们可作为类糜蛋白酶抑制剂。还涉及制备这类化合物和药物组合物的方法，以及它们在制备治疗心力衰竭或心肌梗塞等有关心血管疾病的药物中的用途。

Description

取代的含氮双环化合物及其用途 技术领域
本发明属于药物技术领域，具体涉及取代的含氮双环化合物及其用途，进一步涉及包含这些化合物的药物组合物，及其使用方法和用途。特别地，本发明所述的取代的含氮双环化合物和/或其药物组合物可作为类糜蛋白酶抑制剂，用于预防、治疗或减轻心力衰竭或心肌梗塞等有关心血管疾病。
背景技术
心血管疾病(Cardiovascular diseases，CVD)是全球死亡的主要原因之一。CVD是指由于高脂血症、血液黏稠、动脉粥样硬化、高血压等所导致的心脏、大脑及全身组织发生的缺血性或出血性疾病，如高血压、冠状动脉疾病、心肌疾病、血管疾病、先天性心脏病、心律失常、心包疾病、心脏病发作和中风等。高血压、高胆固醇、吸烟、肥胖和糖尿病是引起心血管疾病发展的主要危险因素。生活方式、年龄和家族史等健康状况也会增加患心脏病的风险。虽然年龄、性别、遗传和家族病史是心血管疾病易感的不可改变的风险，但可以通过实施低脂肪和低钠饮食、保持体育活动和避免体重增加等方法来减轻心血管疾病的负担。最近的几项临床前和一些临床研究指出了一个相对未被认识的事实，即在阻止心脏和血管疾病进展方面，糜酶抑制剂可能比其他治疗方法具有显著的治疗优势。
类糜蛋白酶(Chymase)是一种糜蛋白酶样丝氨酸蛋白酶，其与肝素蛋白聚糖的大分子复合物储存在肥大细胞的分泌小泡中。肥大细胞被活化后，当糜酶被释放到细胞外基质，以应对炎症信号，组织损伤和细胞应激。越来越多的证据表明，肥大细胞的糜酶是促成组织重构和CVD进展的关键因素之一。活化的肥大细胞在伤口的愈合和炎症消除的过程中，如伤口的纤维化、血管生成和心肌重塑起着重要作用(Miyazaki等人，Pharmacol.Ther,112(2006),668-676；Shiota等人，J.Hypertens,21(2003),1823-1825)。在心力衰竭、心肌梗塞和缺血的情况下、人动脉粥样硬化斑块和腹主动脉瘤的情况下观察到肥大细胞数量的增加(Kovanen等人，Circulation,92(1995),1084-1088；Libby和Shi等人，Circulation,115(2007),2555-2558；Bacani和Frishman等人，Cardiol.Rev,14(4)(2006),187-193)。在哮喘和慢性阻塞性肺病中，类糜蛋白酶-阳性肥大细胞在呼吸道血管重构中起重要作用。现已发现在哮喘病人的支气管内活组织检查中发现了肥大细胞数量增加(Zanini等人，J.Allergy Clin Immunol,120(2007),329-333)。此外，类糜蛋白酶也被怀疑是多种肾病变例如糖尿病肾病和多囊性肾病的原因之一(Huang等人，J.Am.Soc.Nephrol,14(7),(2003),1738-1747；McPherson等人，J.Am.Soc.Nephrol,15(2),(2004),493-500)。
类糜蛋白酶主要参与心脏、动脉壁和肺中血管紧张素II的产生。克利夫兰诊所研究者的早期研究首次证实了糜酶作为Ang II(血管紧张素II)形成酶的作用(Urata H等人，J.Biol.Chem,1990,265(36):22348-57)。在过去的几十年里，多项研究证实并扩大了糜酶作为Ang II生产途径的合成酶的重要性(Chandrasekharan UM等人，Science,1996,271(5248):502-5)。而后对人和啮齿类动物心脏Ang-(1-12)处理的研究显示，无论是Ang I还是Ang-(1-12)直接形成Ang-II的酶，均以糜酶为主(Ahmad S等人，J.Am.Soc.Hypertens,2013 7(2):128-36)。Ang II(血管紧张素II)是一种效应分子，主要通过作用于血管壁细胞表面核膜，肾小管、肾小球，肾上腺的多种靶受体，来实现血压调节和水与电解质的平衡控制。当血管紧张素Ⅱ与血管紧张素受体结合，引起相应的生理效应，包括使全身微动脉、静脉收缩，血压升高，回心血量增多；刺激肾上腺合成和释放醛固酮。因此抑制类糜蛋白酶的活化，可以减少血管紧张素的生产，进而在一定程度上能够控制血管的收缩和血压升高。
在许多动物实验的研究中证明了用类糜蛋白酶抑制剂治疗各种心血管疾病的可能性。例如类糜蛋白酶抑制剂对于治疗心肌梗塞是非常有用的(Jin等人，Pharmacol.Exp.Ther,309(2004),409-417)，实验表明当 对狗的冠状动脉结扎引起室性心律失常，促进心脏中血管紧张素II的产生，增强类糜蛋白酶活性。近几年，拜耳公司正在开发一款用于治疗心力衰竭和糖尿病肾病的口服小分子类糜蛋白酶抑制剂BAY-1142524，临床前的结果表明该化合物能够改善仓鼠发生心肌梗塞后的心脏功能。而临床一期结果也显示了BAY-1142524在健康受试者体内良好的安全性、耐受性和药代动力学性质。目前拜耳公司已经开展了BAY-1142524用于治疗糖尿病肾病的二期临床实验，进一步来验证该新型类糜蛋白酶抑制剂的疗效和安全性。
因此，类糜蛋白酶抑制构成了治疗心血管病症、炎症、过敏病症和各种纤维化病症的有效方法。
发明内容
本发明提供了一类作为类糜蛋白酶抑制剂的新颖的取代的含氮双环化合物，用于预防、治疗或减轻心力衰竭或心肌梗塞等有关心血管疾病。并且通过实验表明，本发明的取代的含氮双环化合物的性质稳定，安全性良好，具有良好的药效学和药代动力学性质，例如良好的类糜蛋白酶抑制活性、良好的生物利用度和/或良好的代谢稳定性等。因此，本发明化合物具备良好的临床应用前景。
本发明还提供了制备这类化合物的方法、含有这类化合物的药物组合物以及这类化合物和/或这类化合物的药物组合物在制备药物中的用途。
一方面，本发明涉及一种化合物，其为式(I)所示的化合物，或者式(I)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
Figure PCTCN2021140889-appb-000001
其中：各A、R 0、t、E、R 1和R 2具有如本发明所述的含义。
在一些实施方案中，R 2为
Figure PCTCN2021140889-appb-000002
其中R 5和m具有本发明所述的含义。
在一些实施方案中，m为0、1、2、3或4。
在一些实施方案中，R 2为
Figure PCTCN2021140889-appb-000003
其中R 5具有本发明所述的含义。
在一些实施方案中，本发明所述的化合物，其可为式(IIa)或式(IIb)或式(IIc)所示的化合物，或者式(IIa)或式(IIb)或式(IIc)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
Figure PCTCN2021140889-appb-000004
Figure PCTCN2021140889-appb-000005
其中：各A、R 0、t、E、R 1和R 5具有如本发明所述的含义。
在一些实施方案中，E为键、-CH 2-或-C(＝O)-。优选地，E为-C(＝O)-。
在一些实施方案中，环A为5-6元杂芳环或苯环。
在一些实施方案中，环A为吡咯、吡唑、咪唑、三氮唑、四氮唑、呋喃、噻吩、噻唑、噁唑、吡啶、嘧啶、吡嗪、哒嗪或苯。优选地，环A为吡唑、吡啶或苯。
在一些实施方案中，各R 0独立地为H、D、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-8环烷基、3-8个原子组成的杂环基、C 6-10芳基、5-12个原子组成的杂芳基、CN、NO 2、-OR a、-C(O)R a1、-C(O)NR a2R b、-C(O)OR a、-NR a2R b、-NR a3C(O)R a1、-NR a3C(O)OR a、-NR a3C(O)NR a2R b、-SO 2R a1、-SO 2NR a2R b或-NR a3SO 2NR a2R b，其中所述的C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-8环烷基、3-8个原子组成的杂环基、C 6-10芳基和5-12个原子组成的杂芳基独立地未被取代或被1、2、3、4或5个R m所取代；R a、R a1、R a2、R a3、R b和R m各自独立地具有本发明所述的含义。
在一些实施方案中，t为0、1、2、3或4。
在一些实施方案中，R a、R a1、R a2、R a3和R b各自独立地为H、D、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-12个原子组成的杂芳基。
在一些实施方案中，各R m独立地为D、卤素、CN、NO 2、OH、NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或卤代C 1-6烷氧基。
在一些实施方案中，R 1为
Figure PCTCN2021140889-appb-000006
其中R 3和R 4具有本发明所述的含义。
在一些实施方案中，R 3为-NR n-、-O-、-S-或-CR cR d-；其中，R n、R c和R d各自独立地具有本发明所述的含义。
在一些实施方案中，R n为H、D、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 3-8环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-12个原子组成的杂芳基。
在一些实施方案中，R c和R d各自独立地为H、D、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-12个原子组成的杂芳基。
在一些实施方案中，R 4为H、D、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 3-8环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-12个原子组成的杂芳基。
在一些实施方案中，各R 5独立地为H、D、卤素、NO 2、CN、OH、NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-8环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-12个原子组成的杂芳基。
在一些实施方案中，各R 0独立地为H、D、F、Cl、Br、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、卤代C 1-4烷氧基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基、5-10个原子组成的杂芳基、CN、NO 2、-OR a、-C(O)R a1、-C(O)NR a2R b、-C(O)OR a、-NR a2R b、-NR a3C(O)R a1、-NR a3C(O)OR a、-NR a3C(O)NR a2R b、-SO 2R a1、-SO 2NR a2R b或-NR a3SO 2NR a2R b，其中所述的C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、卤代C 1-4烷氧基、C 3-6 环烷基、3-6个原子组成的杂环基、C 6-10芳基和5-10个原子组成的杂芳基独立地未被取代或被1、2、3或4个R m所取代，其中，R a、R a1、R a2、R a3、R b和R m各自独立地具有本发明所述的含义。
在一些实施方案中，R a、R a、R a1、R a2、R a3和R b各自独立地为H、D、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基。
在一些实施方案中，各R m独立地为D、卤素、CN、NO 2、OH、NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基或卤代C 1-4烷氧基。
在一些实施方案中，R n为H、D、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基。
在一些实施方案中，R c和R d各自独立地为H、D、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4烷氧基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基。
在一些实施方案中，R 4为H、D、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基。
在一些实施方案中，各R 5独立地为H、D、卤素、NO 2、CN、OH、NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、卤代C 1-4烷氧基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基。
在一些实施方案中，各R 0独立地为H、D、F、Cl、Br、NO 2、CN、OH、NH 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、-CH 2F、-CH 2Cl、-CHF 2、-CHCl 2、-CF 3、-CH 2CH 2F、-CH 2CH 2Cl、-CH 2CHF 2、-CH 2CHCl 2、-CHFCH 2F、-CHClCH 2Cl、-CH 2CF 3、-CH(CF 3) 2、-CF 2CH 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-1-丙氧基、2-丁氧基、2-甲基-2-丙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基、三氟乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、-OR a、-C(O)R a1、-C(O)NR a2R b、-C(O)OR a、-NR a2R b、-NR a3C(O)R a1、-NR a3C(O)OR a、-NR a3C(O)NR a2R b、-SO 2R a1、-SO 2NR a2R b或-NR a3SO 2NR a2R b，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、-CH 2F、-CH 2Cl、-CHF 2、-CHCl 2、-CH 2CH 2F、-CH 2CH 2Cl、-CH 2CHF 2、-CH 2CHCl 2、-CHFCH 2F、-CHClCH 2Cl、-CH 2CF 3、-CH(CF 3) 2、-CF 2CH 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-1-丙氧基、2-丁氧基、2-甲基-2-丙氧基、二氟甲氧基、二氟乙氧基、三氟乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基和哒嗪基未被取代或被1、2、3、4或5个R m的取代基所取代，其中，R a、R a1、R a2、R a3、R b和R m各自独立地具有本发明所述的含义。
在一些实施方案中，R a、R a1、R a2、R a3和R b各自独立为H、D、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CHFCH 2F、-CH 2CF 3、-CH(CF 3) 2、-CF 2CH 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基。
在一些实施方案中，各R m独立地为D、F、Cl、Br、NO 2、CN、OH、NH 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、-CH 2F、-CH 2Cl、-CHF 2、-CHCl 2、-CF 3、-CH 2CH 2F、-CH 2CH 2Cl、 -CH 2CHF 2、-CH 2CHCl 2、-CHFCH 2F、-CHClCH 2Cl、-CH 2CF 3、-CH(CF 3) 2、-CF 2CH 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-1-丙氧基、2-丁氧基、2-甲基-2-丙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基。
在一些实施方案中，R n为H、D、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、-CH 2F、-CHF 2、-CH 2CH 2F、-CH 2CHF 2、-CHFCH 2F、-CH 2CF 3、-CH(CF 3) 2、-CF 2CH 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、乙烯基、丙烯基、烯丙基、乙炔基、炔丙基、1-丙炔基、1-炔丁基、2-炔丁基、3-炔丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基。
在一些实施方案中，R c和R d各自独立地为H、D、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、-CH 2F、-CHF 2、-CH 2CH 2F、-CH 2CHF 2、-CHFCH 2F、-CH 2CF 3、-CH(CF 3) 2、-CF 2CH 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、乙烯基、丙烯基、烯丙基、乙炔基、炔丙基、1-丙炔基、1-炔丁基、2-炔丁基、3-炔丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-1-丙氧基、2-丁氧基、2-甲基-2-丙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基。
在一些实施方案中，R 4为H、D、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、-CH 2F、-CHF 2、-CH 2CH 2F、-CH 2CHF 2、-CHFCH 2F、-CH 2CF 3、-CH(CF 3) 2、-CF 2CH 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、乙烯基、丙烯基、烯丙基、乙炔基、炔丙基、1-丙炔基、1-炔丁基、2-炔丁基、3-炔丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基。
在一些实施方案中，各R 5独立地为H、D、F、Cl、Br、NO 2、CN、OH、NH 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、-CH 2F、-CH 2Cl、-CHF 2、-CHCl 2、-CF 3、-CH 2CH 2F、-CH 2CH 2Cl、-CH 2CHF 2、-CH 2CHCl 2、-CHFCH 2F、-CHClCH 2Cl、-CH 2CF 3、-CH(CF 3) 2、-CF 2CH 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-1-丙氧基、2-丁氧基、2-甲基-2-丙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基、三氟乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基。
在一些实施方案中，本发明所述的化合物具有下列之一结构的化合物或具有下列之一结构的化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药：
Figure PCTCN2021140889-appb-000007
另一方面，本发明涉及一种药物组合物，其包含本发明所述的化合物；任选地，其进一步包含药学上可接受的赋形剂、载体、佐剂或它们的任意组合。
在一些实施方案中，本发明所述的药物组合物进一步包含一种或多种其他活性成分，所述其他活性成 分选自钙拮抗剂、血管紧张素AII拮抗剂、ACE抑制剂、血管肽酶抑制剂、内皮素拮抗剂、肾素抑制剂、α-受体阻断剂、β-受体阻断剂、盐皮质激素受体拮抗剂、ρ-激酶抑制剂、利尿剂、激酶抑制剂、基质金属蛋白酶抑制剂、可溶性乌苷酸环化酶刺激物和激活物以及磷酸二酯酶抑制剂。
一方面，本发明涉及本发明所述的化合物或本发明所述的药物组合物在制备药物中的用途，其中，所述药物用于治疗或预防心力衰竭、肺动脉高血压、慢性阻塞性肺病、哮喘、肾衰竭、肾病、内部器官的纤维化病症或皮肤纤维化。
另一方面，本发明涉及式(I)或式(IIa)或式(IIb)或式(IIc)所示化合物的制备、分离和纯化的方法。
生物试验结果表明，本发明化合物具有良好的抑制类糜蛋白酶的活性，可作为较好的类糜蛋白酶抑制剂，从而具有阻止疾病的发生与进展的潜在功效。
本发明的任一方面的任一实施方案，可以与其它实施方案进行组合，只要它们不会出现矛盾。此外，在本发明任一方面的任一实施方案中，任一技术特征可以适用于其它实施方案中的该技术特征，只要它们不会出现矛盾。
前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他方面的内容将在下面作更加具体完整的描述。本说明书中的所有参考文献通过整体引用于此。当本说明书的公开内容与引用文献有差异时，以本说明书的公开内容为准。
定义和一般术语
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本发明所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本发明所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，应当应用本发明所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,和“March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本发明。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
除非另有说明或者上下文中有明显的冲突，本发明所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本发明所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
术语“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构 体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反异构体)、阻转异构体，等等。
术语“手性分子”是具有与其镜像不能重叠性质的分子；而“非手性分子”是指与其镜像可以重叠的分子。
术语“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
术语“外消旋物”或“外消旋混合物”是指缺少光学活性的两个对映异构体的等摩尔混合物。
术语“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。
本发明所使用的立体化学定义和规则一般遵循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。
许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考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,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,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)。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的 互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。
“药学上可接受的”是指这样一些化合物、原料、组合物和/或剂型，它们在合理医学判断的范围内，适用于与患者组织接触而无过度毒性、刺激性、变态反应或与合理的利益/风险比相对称的其他问题和并发症，并有效用于既定用途。
术语“任选地被…….所取代”，可以与术语“未取代或被…..所取代”交换使用，即所述结构是未取代的或者被一个或多个本发明所述的取代基取代。
一般而言，术语“取代的”表示所给结构或基团中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个取代基可以在基团各个可取代的合理的位置进行取代。当所给出的结构式中不止一个位置能被选自的一个或多个具体取代基所取代，那么取代基可以相同或不同地在结构式中各个合理的位置进行取代。
术语“未取代的”，表示指定基团不带有取代基。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
本发明所使用的术语“受试对象”是指动物。典型地所述动物是哺乳动物。受试对象，例如也指灵长类动物(例如人类，男性或女性)、牛、绵羊、山羊、马、犬、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中，所述受试对象是灵长类动物。在其他实施方案中，所述受试对象是人。
本发明所使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中，“患者”是指人。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1-C 6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。
术语“D”表示单个氘原子。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
本发明使用的术语“烷基”或“烷基基团”，表示含有1-20个碳原子，饱和的直链或支链一价烃基基团。在一实施方案中，烷基基团含有1-6个碳原子，即，C 1- 6烷基；在另一实施方案中，烷基基团含有1-4个碳原子，即，C 1- 4烷基；还在一实施方案中，烷基基团含有1-3个碳原子，即，C 1- 3烷基。烷基基团的实例包含，但并不限于，甲基(Me、-CH 3)，乙基(Et、-CH 2CH 3)，正丙基(n-Pr、-CH 2CH 2CH 3)，异丙基(i-Pr、-CH(CH 3) 2)，正丁基(n-Bu、-CH 2CH 2CH 2CH 3)，异丁基(i-Bu、-CH 2CH(CH 3) 2)，仲丁基(s-Bu、-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu、-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，2,2-二甲基丁基(新戊基,-CH 2CH(CH 3) 2CH 3)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)，2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)，正庚基，正辛基，等等。
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp 2双键，其包括“cis”和“trans”的定位，或者“E”和“Z”的定位。烯基基团的实例包含，但并不限于，乙烯基，1-丙烯基(丙烯基，-CH＝CH-CH 3)，2-丙烯基(烯丙基，-CH 2-CH＝CH 2)，等等。
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键。在一些实施方案中，炔基基团包含2-8个碳原子；在另一些实施方案中，炔基基团包含2-6个碳原子；在又一些实施方案中，炔基基团包含2-4个碳原子。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH 2C≡CH)、1-丙炔基(-C≡C-CH 3)、1-炔丁基(-CH 2CH 2C≡CH)、2-炔丁基(-CH 2C≡CCH 3)、3-炔丁基(-C≡CCH 2CH 3)等等。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一些实施方案中，烷氧基基团含有1-6个碳原子；在另一些实施方案中，烷氧基基团含有1-4个碳原子；在又一些实施方案中，烷氧基基团含有1-3个碳原子。
烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH 3)，乙氧基(EtO、-OCH 2CH 3)，1-丙氧基(n-PrO、n-丙氧基、-OCH 2CH 2CH 3)，2-丙氧基(i-PrO、i-丙氧基、-OCH(CH 3) 2)，1-丁氧基(n-BuO、n-丁氧基、-OCH 2CH 2CH 2CH 3)，2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH 2CH(CH 3) 2)，2-丁氧基(s-BuO、s-丁氧基、-OCH(CH 3)CH 2CH 3)，2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH 3) 3)，1-戊氧基(n-戊氧基、-OCH 2CH 2CH 2CH 2CH 3)，2-戊氧基(-OCH(CH 3)CH 2CH 2CH 3)，3-戊氧基(-OCH(CH 2CH 3) 2)，2-甲基-2-丁氧基(-OC(CH 3) 2CH 2CH 3)，3-甲基-2-丁氧基(-OCH(CH 3)CH(CH 3) 2)，3-甲基-l-丁氧基(-OCH 2CH 2CH(CH 3) 2)，2-甲基-l-丁氧基(-OCH 2CH(CH 3)CH 2CH 3)，等等。
术语“卤代烷氧基”表示烷氧基基团被一个或多个卤素原子所取代，其中烷氧基具有本发明所述的含义。这样的实例包含，但并不限于，二氟甲氧基(-OCHF 2)，三氟甲氧基(-OCF 3)，二氟乙氧基(如-OCH 2CHF 2等)，三氟乙氧基(如-OCH 2CF 3等)，等等。
术语“卤代烷基”表示烷基基团被一个或多个卤素原子所取代，其中烷基具有本发明所述的含义。其中一些实施例是，卤代烷基基团含有1-12个碳原子；另外一些实施例是，卤代烷基基团含有1-10个碳原子；另外一些实施例是，卤代烷基基团含有1-8个碳原子；另外一些实施例是，卤代烷基基团含有1-6个碳原子；另外一些实施例是，卤代烷基基团含有1-4个碳原子，另外一些实施例是，卤代烷基基团含有1-3个碳原子。这样的实例包含，但并不限于，二氟甲基、三氟甲基、三氟乙基(如-CH 2CF 3等)等。
术语“环烷基”表示含有3-12个环碳原子的饱和单环、双环或三环体系。在一些实施方案中，环烷基包含3-10个环碳原子，例如C 3-10环烷基；在另一些实施方案中，环烷基包含3-8个环碳原子，例如C 3-8环烷基；在又一些实施方案中，环烷基包含3-6个环碳原子，例如C 3-6环烷基。环烷基基团的实例包括，但并不限于，环丙基、环丁基、环戊基、环己基、环庚基、环辛基，等等。其中，如本发明所述的，C 3-8环烷基包括C 3-6环烷基；所述的C 3-6环烷基包括环丙基、环丁基、环戊基和环己基。
术语“杂环基”和“杂环”在此处可交换使用，是指包含3-12个环原子的、单价或多价的、饱和或部分不饱和的、非芳香性的单环、双环或三环体系，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。杂环基包括饱和的杂环基(即：杂环烷基)和部分不饱和的杂环基。杂环基的实例包括，但不限于，环氧乙烷基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、四氢噻吩基、噻唑烷基、吡唑烷基、恶唑烷基、咪唑烷基、异恶唑烷基、哌啶基、哌嗪基或吗啉基，等等。如本发明所述的，所述杂环基可以由3-8个原子或3-6个原子组成，所述原子任选地选自C、N、O或S且至少有一个原子为N、O或S；其中，所述3-8个原子组成的杂环基包括3-6个原子组成的杂环基；所述3-6个原子组成的杂环基包括3-5个原子组成的杂环基。具体地，所述3-6个原子组成的杂环基包括但不限于，环氧乙烷基、氮杂环丙烷基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、四氢噻吩基、噻唑烷基、吡唑烷基、吡唑啉基、恶唑烷基、咪唑烷基、哌啶基、哌嗪基或吗啉基等。
术语“s个原子组成的”，其中s是整数，典型地描述分子中成环原子的数目，在所述分子中成环原子的数目是s。例如，哌啶基是6个原子组成的杂环烷基，而1,2,3,4-四氢萘基是10个原子组成的碳环基基团。
在本发明中所使用的术语“不饱和的”表示基团中含有一个或多个不饱和度。
术语“杂原子”是指O、S、N、P和Si，包括N、S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR，其中R为任意合适的取代基)。
术语“芳基”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的环，且有一个或多个连接点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用。芳基基团的实例可以包括苯基、萘基和蒽基。除非另外说明，基团“C 6-10芳基”表示含有6-10个环碳原子的芳基基团。
术语“杂芳基”表示含有5-12个环原子，或5-10个环原子，或5-6个环原子的单环、双环和三环体系，其中至少一个环是芳香族的，且至少一个环包含1、2、3或4个选自氮、氧、硫的环杂原子，同时，所述杂芳基有一个或多个附着点与分子其余部分相连。当杂芳基基团中存在-CH 2-基团时，所述的-CH 2-基团可以任选地被-C(＝O)-替代。除非另外说明，所述的杂芳基基团可以通过任何合理的位点(可以为CH中的C，或者NH中N)连接到分子其余部分(例如通式中的主体结构)上。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。杂芳基的实例包括，但并不限于，呋喃基、咪唑基、吡咯基、吡唑基、吡啶基、嘧啶基、吡嗪基等。在一些实施方案中，杂芳基为5-10个原子组成的杂芳基，表示杂芳基含有1-9个环碳原子和1、2、3或4个选自O、S和N的环杂原子；在另一些实施方案中，杂芳基为5-6个原子组成的杂芳基，表示杂芳基含有1-5个环碳原子和1、2、3或4个选自O、S和N的环杂原子，5-6个原子组成的杂芳基的实例包括，但并不限于，呋喃基、咪唑基、异噁唑基、噁唑基、吡咯基、吡唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻吩基、噻唑基等。
术语“保护基团”或“PG”是指一个取代基与其他官能团起反应的时候，通常用来阻断或保护特殊的功能性。例如，“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性，合适的氨基保护基团包括乙酰基，三氟乙酰基，叔丁氧羰基(BOC,Boc)，苄氧羰基(CBZ,Cbz)和9-芴甲氧羰基(Fmoc)。相似地，“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性，合适的保护基团包括三烷基甲硅烷基，乙酰基，苯甲酰基和苄基。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括-CH 2CH 2SO 2Ph，氰基乙基，2-(三甲基硅烷基)乙基，2-(三甲基硅烷基)乙氧基甲基，2-(对甲苯磺酰基)乙基，2-(对硝基苯磺酰基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。对于保护基团一般的描述可参考文献：Greene et al.,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991and Kocienski et al.,Protecting Groups,Thieme,Stuttgart,2005。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)或式(IIa)或式(IIb)或式(IIc)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium 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 S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.，describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences，1977，66：1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-C 8磺酸化物和芳香磺酸化物。
本发明的“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是，N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514)，其中例如在惰性溶剂例如二氯甲烷中，使胺化合物与间-氯过氧苯甲酸(MCPBA)反应。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸、乙醇胺或其混合物。术语“水合物”是指溶剂分子是水所形成的缔合物。
当所述溶剂为水时，可以使用术语“水合物”。在一实施方案中，一个本发明化合物分子可以与一个水分子相结合，比如一水合物；在另一实施方案中，一个本发明化合物分子可以与多于一个的水分子相结合，比如二水合物；在又一实施方案中，一个本发明化合物分子可以与少于一个的水分子相结合，比如半水合物。应注意，本发明所述的水合物保留有非水合形式的所述化合物的生物有效性。
术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
术语“防止”或“预防”指获病或障碍的风险的减少(即：使疾病的至少一种临床症状在主体内停止发展， 该主体可能面对或预先倾向面对这种疾病，但还没有经历或表现出疾病的症状)。
术语“心血管疾病”是指心脏血管和脑血管疾病的统称，描述患者由于高脂血症、血液黏稠、动脉粥样硬化、高血压等所导致的心脏、大脑及全身组织发生的缺血性或出血性疾病。例如急性和慢性心力衰竭、动脉性高血压、冠心病、稳定型和不稳定型心绞痛、心肌缺血、心肌梗死、休克、动脉粥样硬化、心脏肥大、心脏纤维化、房性和室性心律失常、暂时和缺血性发作、中风、先兆子痫、炎性心血管疾病、外周和心血管疾病、外周灌注障碍、肺动脉高压、冠状动脉和外周动脉痉挛、血栓症、血栓栓塞性疾病、水肿发展(例如肺水肿、脑水肿、肾水肿或心力衰竭相关的水肿)和再狭窄(例如在溶栓治疗、经皮腔内血管成形术(PTA)、经皮冠状动脉成形术(PTCA)、心脏移植和搭桥手术后的再狭窄)，以及微血管和大血管损伤(血管炎)、再灌注损伤、动脉和静脉血栓症、微量白蛋白尿、心肌机能不全、内皮功能障碍、外周和心脏血管疾病、外围灌注障碍、心力衰竭相关的水肿、纤维蛋白原和低密度LDL的水平升高以及纤溶酶原激活剂/抑制剂1(PAI-1)的浓度升高。
本发明的化合物
一方面，本发明涉及具有通式(I)所示的结构的化合物，其中，各变量的定义如前所述。
在一些实施方案中，本发明所述式(I)所示化合物可为式(IIa)、式(IIb)或式(IIc)所示化合物，其中，各变量的定义如前所述。
除非另作说明，式(I)或式(IIa)或式(IIb)或式(IIc)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药都包含在本发明范围内。
本发明公开化合物可含有不对称或手性中心，因此可以不同的立体异构体形式存在。本发明旨在使式(I)或式(IIa)或式(IIb)或式(IIc)所示化合物的所有立体异构体形式，包括但不限于非对映异构体、对映异构体、阻转异构体和几何(或构象)异构体，以及它们的混合物如外消旋混合物，成为本发明的组成部分。
在本发明公开的结构中，当任意特定的手性原子的立体化学未指明时，则该结构的所有立体异构体都考虑在本发明之内，并且作为本发明公开化合物包括在本发明中。当立体化学被表示特定构型的实楔形线(solid wedge)或虚线指明时，则该结构的立体异构体就此明确和定义。
式(I)或式(IIa)或式(IIb)或式(IIc)所示化合物可以以不同的互变异构体形式存在，并且所有这些互变异构体，如本发明所述的互变异构体，都包括在本发明范围内。
式(I)或式(IIa)或式(IIb)或式(IIc)所示化合物可以以盐的形式存在。在一些实施方案中，所述盐是指药学上可接受的盐。术语“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。在另一些实施方案中，所述盐不一定是药学上可接受的盐，可以是用于制备和/或提纯式(I)或式(IIa)或式(IIb)或式(IIc)所示化合物和/或用于分离本式(I)或式(IIa)或式(IIb)或式(IIc)所示化合物的对映体的中间体。
可药用的酸加成盐可由式(I)或式(IIa)或式(IIb)或式(IIc)所示化合物与无机酸或有机酸反应形成，例如乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、氯茶碱盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。
可以由其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以由其衍生得到盐的有机酸包括例如乙酸、丙酸、羟基乙酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、磺基水杨酸等。
可药用碱加成盐可与无机碱和有机碱形成。
可以由其衍生得到盐的无机碱包括，例如铵盐和周期表的I族至XII族的金属。在某些实施方案中，该盐衍生自钠、钾、铵、钙、镁、铁、银、锌和铜；特别适合的盐包括铵、钾、钠、钙和镁盐。
可以由其衍生得到盐的有机碱包括伯胺、仲胺和叔胺，取代的胺包括天然存在的取代的胺、环状胺、碱性离子交换树脂等。某些有机胺包括，例如，异丙胺、苄星青霉素(benzathine)、胆碱盐(cholinate)、二乙醇胺、二乙胺、赖氨酸、葡甲胺(meglumine)、哌嗪和氨丁三醇。
本发明的可药用盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言，该类盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应，或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。一般地，在适当的情况中，需要使用非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。在例如“Remington′s Pharmaceutical Sciences”，第20版，Mack Publishing Company，Easton，Pa.，(1985)；和“药用盐手册：性质、选择和应用(Handbook of Pharmaceutical Salts：Properties，Selection，and Use)”，Stahl and Wermuth(Wiley-VCH，Weinheim，Germany，2002)中可找到另外一些适宜盐的列表。
另外，本发明公开的化合物、包括它们的盐，也可以以它们的水合物形式或包含其溶剂(例如乙醇、DMSO，等等)的形式得到，用于它们的结晶。本发明公开化合物可以与药学上可接受的溶剂(包括水)固有地或通过设计形成溶剂化物；因此，本发明旨在包括溶剂化的和未溶剂化的形式。
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构，除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如 2H、 3H、 11C、 13C、 14C、 15N、 17O、 18O、 18F、 31P、 32P、 35S、 36Cl和 125I。
另一方面，本发明所述化合物包括同位素富集的本发明所定义的化合物，例如，其中存在放射性同位素，如 3H、 14C和 18F的那些化合物，或者其中存在非放射性同位素，如 2H和 13C。该类同位素富集的化合物可用于代谢研究(使用 14C)、反应动力学研究(使用例如 2H或 3H)、检测或成像技术，如正电子发射断层扫描术(PET)或包括药物或底物组织分布测定的单光子发射计算机断层成像术(SPECT)，或可用于患者的放疗中。 18F富集的化合物对PET或SPECT研究而言是特别理想的。同位素富集的式(I)或式(IIa)或式(IIb)或式(IIc)所示化合物可以通过本领域技术人员熟悉的常规技术或本发明中的实施例和制备过程所描述使用合适的同位素标记试剂替代原来使用过的未标记试剂来制备。
此外，较重同位素特别是氘(即， 2H或D)的取代可提供某些治疗优点，这些优点是由代谢稳定性更高带来的。例如，体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。应当理解，本发明中的氘被看作式(I)或式(IIa)或式(IIb)或式(IIc)所示化合物的取代基。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。本发明所使用的术语“同位素富集因子”是指所指定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物的取代基被指定为氘，该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5％的氘掺入)、至少4000(60％的氘掺入)、至少4500(67.5％的氘掺入)，至少5000(75％的氘掺入)，至少5500(82.5％的氘掺入)、至少6000(90％的氘掺入)、至少6333.3(95％的氘掺入)、至少6466.7(97％的氘掺入)、至少6600(99％的氘掺入)或至少6633.3(99.5％的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D 2O、丙酮-d 6、DMSO-d 6的那些溶剂化物。
另一方面，本发明涉及制备式(I)或式(IIa)或式(IIb)或式(IIc)所示化合物的中间体。
另一方面，本发明涉及式(I)或式(IIa)或式(IIb)或式(IIc)所示化合物的制备、分离和纯化的方法。
本发明化合物的药物组合物、制剂和给药
本发明提供一种药物组合物，包括式(I)或式(IIa)或式(IIb)或式(IIc)所示化合物或其单独的立体异构体，异构体的外消旋或非外消旋混合物或其药学上可接受的盐或溶剂化物。在本发明的一个实施方式中，所述药物组合物进一步包含至少一种药学上可接受的载体、辅剂或赋形剂，以及任选地，其它的治疗 和/或预防成分。
合适的载体、辅剂和赋形剂对于本领域技术人员是熟知的并且详细描述于例如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；和Rowe R.C.,Handbook of Pharmaceutical Excipients(2005)Pharmaceutical Press,Chicago中。
包含本发明化合物或药物组合物给药的治疗方法，进一步包含附加治疗剂，其中所述其他活性成分：钙拮抗剂、血管紧张素AII拮抗剂、ACE抑制剂、血管肽酶抑制剂、内皮素拮抗剂、肾素抑制剂、α-受体阻断剂、β-受体阻断剂、盐皮质激素受体拮抗剂、ρ-激酶抑制剂、利尿剂、激酶抑制剂、基质金属蛋白酶抑制剂、可溶性乌苷酸环化酶刺激物和激活物以及磷酸二酯酶抑制剂。
本发明所用“药学上可接受的赋形剂”意指与给药剂型或药物组合物一致性相关的药学上可接受的材料，混合物或溶媒。每种赋形剂在混合时必须与药物组合物的其它成分相容，以避免对患者给药时会大大降低本发明公开化合物的功效的相互作用和会导致不是药学上可接受的药物组合物的相互作用。此外，每种赋形剂必须是药学上可接受的，例如，具有足够高的纯度。
合适的药学上可接受的赋形剂会依所选具体剂型而不同。此外，可根据它们在组合物中的特定功能来选择药学上可接受的赋形剂。例如，可选择能有助于生产均一剂型的某些药学上可接受的赋形剂。可选择能有助于生产稳定剂型的某些药学上可接受的赋形剂。可选择对患者给药时有助于携带或运输本发明化合物从身体的一个器官或部分到身体的另一个器官或部分的某些药学上可接受的赋形剂。可选择增强患者依从性的某些药学上可接受的赋形剂。
合适的药学上可接受的赋形剂包括以下类型的赋形剂：稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、造粒剂、包衣剂、润湿剂、溶剂、共溶剂、助悬剂、乳化剂、甜味剂、矫味剂、掩味剂、着色剂、防结块剂、保湿剂、螯合剂、塑化剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂。技术人员可认识到，某些药学上可接受的赋形剂可提供不止一种功能，并提供可供选择的功能，这取决于制剂中存在多少该赋形剂和制剂中存在哪些其他赋形剂。
技术人员掌握本领域的知识和技能，以使他们能选择用于本发明的适当量的合适的药学上可接受的赋形剂。此外，存在大量技术人员可获得的资源，他们描述药学上可接受的赋形剂，并用于选择合适的药学上可接受的赋形剂。实例包括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)。
为了用本发明所描述的化合物来制备药物组合物，药学上可接受的载体可以是固体或液体载体。固体形式制剂包括粉剂，片剂，可分散的颗粒剂，胶囊剂，扁囊剂和栓剂。粉剂和片剂可以包含大约5％至大约95％的活性组分。合适的固体载体在本领域是已知的，例如，碳酸镁，硬脂酸镁，滑石粉，糖或乳糖。片剂、粉剂、扁囊剂和胶囊剂可以用作适合与口服的固体剂型。制备各种组合物的可药用载体和方法的例子可以在下列中得到：A.Gennaro(ed.),Remington's Pharmaceutical Sciences,18 th ed.,1990,Mack Publishing Company Co.,Easton,Pennsylvania。
在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中披露了用于配制药学上可接受的组合物的各种载体，和用于其制备的公知技术，这些文献各自的内容通过引用并入本发明。除任何诸如因产生任何不期望的生物作用，或以 有害方式与药学上可接受组合物中的任何其它成分发生相互作用而与本发明化合物不相容的任何常用载体外，关注其应用属于本发明的范围。
本发明公开的药物组合物使用本领域技术人员已知的技术和方法来制备。本领域一些常用方法的描述可参见Remington's Pharmaceutical Sciences(Mack Publishing Company)。
因此，另一方面，本发明涉及制备药物组合物的工艺，所述药物组合物包含本发明公开化合物和药学上可接受的赋形剂，载体，辅剂，溶媒或它们的组合，该工艺包括混合各种成分。包含本发明公开化合物的药物组合物，可以在例如环境温度和大气压下混合来制备。
本发明公开的化合物通常被配制成适合于通过所需途径对患者给药的剂型。例如，剂型包括那些适合于以下给药途径的剂型：(1)口服给药，例如片剂、胶囊剂、囊片剂、丸剂、含片剂、粉剂、糖浆剂、酏剂、混悬剂、溶液剂、乳剂、香包剂和扁囊剂；(2)胃肠外给药，例如无菌溶液剂、混悬剂和复溶粉末；(3)透皮给药，例如透皮贴片剂；(4)直肠给药，例如栓剂；(5)吸入，例如气雾剂、溶液剂和干粉剂；和(6)局部给药，例如乳膏剂、油膏剂、洗剂、溶液剂、糊剂、喷雾剂、泡沫剂和凝胶剂。
也应认识到，本发明的某些化合物可以以游离形式存在用于治疗，或者如果适当可以以其药学上可接受的衍生物的形式存在。药学上可接受衍生物的一些非限制性的实施方案包括药学上可接受的前药，盐，酯，这些酯的盐，或者对有需要的患者给药时能直接或间接提供本发明所述化合物或其代谢产物或残留物的任何另外的加合物或衍生物。
在一实施方案中，本发明公开的化合物可以配制成口服剂型。在另一实施方案中，本发明公开的化合物可以配制成吸入剂型。在另一实施方案中，本发明公开的化合物可以配制成经鼻给药剂型。在又一实施方案中，本发明公开的化合物可以配制成透皮给药剂型。还在一实施方案中，本发明公开的化合物可以配制成局部给药剂型。
本发明提供的药物组合物可以以压制片、研制片、可咀嚼锭剂、速溶片、复压片、肠溶片、糖衣或薄膜衣片来提供。肠溶片是用能抗胃酸作用但在肠中溶解或崩解的物质包衣的压制片，从而防止了活性成分接触胃的酸性环境。肠包衣包括，但不限于，脂肪酸、脂肪、水杨酸苯酯、蜡、紫胶、氨化紫胶和邻苯二甲酸乙酸纤维素酯。糖衣片为糖衣包围的压制片，其可利于掩盖令人不愉快的味道或气味并且能防止片剂氧化。薄膜包衣片为用水溶性物质的薄层或薄膜覆盖的压制片。薄膜包衣包括，但不限于，羟乙基纤维素、羧甲基纤维素钠、聚乙二醇4000和邻苯二甲酸乙酸纤维素酯。薄膜包衣赋有和糖包衣相同的一般特性。复压片为经过超过一个压缩周期制备的压制片，包括多层片、压制包衣或干包衣片。
片剂剂型可以由呈粉末、结晶或颗粒状的活性成分单独的或与本发明描述的一种或多种载体或赋形剂组合来制备，所述载体和赋形剂包括粘合剂、崩解剂、控释聚合物、润滑剂、稀释剂和/或着色剂。增香剂和甜味剂在形成咀嚼片和锭剂时特别有用。
本发明提供的药物组合物可以以软胶囊或硬胶囊来提供，其可以由明胶、甲基纤维素、淀粉或海藻酸钙来制备。所述硬明胶胶囊也称为干填充胶囊(DFC)，由两段组成，一段塞入另一段中，因此完全包封了活性成分。软弹性胶囊(SEC)是软的、球形壳，比如明胶壳，其通过加入甘油、山梨醇或类似的多元醇塑化。软明胶壳可以包含防腐剂来预防微生物生长。合适的防腐剂为如本发明所述的那些，包括尼泊金甲酯和尼泊金丙酯，以及山梨酸。本发明提供的液体、半固体和固体剂型可以包囊在胶囊中。合适的液体和半固体剂型包括在碳酸丙烯酯、植物油或甘油三酯中的溶液和混悬剂。包含这样的溶液的胶囊可以如在美国专利U.S.Pat.Nos.4,328,245；4,409,239和4,410,545中描述的来制备。所述胶囊也可以采用如本领域技术人员已知的涂层，从而改善或维持活性成分的溶出。
本发明提供的药物组合物可以以液体和半固体剂型来提供，包括乳剂、溶液、混悬剂、酏剂和糖浆剂。乳剂为二相系统，其中一种液体以小球形式完全分散在另一种液体中，其可以是水包油型或油包水型。乳剂可以包括药学上可接受的非水液体和溶剂、乳化剂和防腐剂。混悬剂可以包括药学上可接受的助悬剂和防腐剂。含水醇溶液可以包括药学上可接受的缩醛，比如低级烷基醛的二(低级烷基)缩醛，例如乙醛二乙基缩醛；和具有一个或多个羟基的水溶性溶剂，比如丙二醇和乙醇。酏剂是透明的、甜味的水醇溶液。糖浆剂是浓的糖例如蔗糖的水溶液，并且还可以包含防腐剂。对于液体剂型，例如，在聚乙二醇中的溶液可以用足量的药学上可接受的液体载体例如水稀释，以精确方便地给药。
本发明提供的药物组合物可以配制成适于对患者吸入给药的任何剂型，例如干粉剂、气雾剂、混悬剂或溶液组合物。在一实施方案中，本发明所公开的药物组合物可以配制成适于用干粉剂对患者吸入给药的剂型。在又一实施方案中，本发明所公开的药物组合物可以配制成适于通过喷雾器对患者吸入给药的剂型。通过吸入递送至肺的干粉组合物通常包含精细粉末状的本发明所公开的化合物和一种或多种精细粉末状的药学上可接受的赋形剂。特别适合用作干粉剂的药学上可接受的赋形剂为本领域技术人员所知晓，其包括乳糖、淀粉、甘露醇、和单-、二-和多糖。精细粉末可通过例如微粉化和研磨制备得到。一般来说，尺寸减小的(如微粉化的)化合物可以通过约1至10微米的D 50值(例如，用激光衍射法测量的)来定义。
适合于透皮给药的药物组合物可制备成不连续的贴片剂，意在与患者的表皮保持紧密接触一段延长的时间。例如，可通过离子渗透从贴片剂中递送活性成分，如Pharmaceutical Research,3(6),318(1986)中的一般描述。
适合于局部给药的药物组合物可以被配制成油膏剂、乳膏剂、混悬剂、洗剂、粉剂、溶液剂、糊剂、凝胶剂、喷雾剂、气雾剂或油剂。例如，油膏剂、乳膏剂和凝胶剂可以用水或油基质，和适合的增稠剂和/或凝胶剂和/或溶剂来配制。这样的基质可以包括，水，和/或油例如液体石蜡和植物油(例如花生油或蓖麻油)，或溶剂例如聚乙二醇。根据基质性质使用的增稠剂和凝胶剂包括软石蜡、硬脂酸铝、鲸蜡硬脂醇、聚乙二醇、羊毛脂、蜂蜡、聚羧乙烯和纤维素衍生物，和/或单硬脂酸甘油脂和/或非离子型乳化剂。
本发明化合物也可以与作为靶向药物载体的可溶性聚合物结合。这样的聚合物包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺-苯酚、聚羟乙基天冬酰胺苯酚或棕榈酰残基取代的聚氧乙烯聚赖氨酸。此外，本发明所公开的化合物可以与在实现药物的控制释放中使用的一类生物可降解的聚合物结合，例如，聚乳酸、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯和水凝胶的交联或两亲嵌段共聚物。
本发明提供的药物组合物可以配制成适于肠胃外给药的任何剂型，包括溶液、混悬剂、乳剂、胶束、脂质体、微球、纳米体系和适于在注射前在液体中制成溶液或混悬液的固体形式。这样的剂型可以根据药物科学领域的技术人员已知的常规方法来制备(参见Remington:The Science和Practice of Pharmacy,同上)。
预期用于肠胃外给药的药物组合物可以包括一种或多种药学上可接受的载体和赋形剂，包括，但不限于，含水运载体、水混溶性运载体、非水运载体、抗微生物剂或抗微生物生长的防腐剂、稳定剂、溶解增强剂、等渗剂、缓冲剂、抗氧剂、局部麻醉剂、助悬剂和分散剂、湿润剂或乳化剂、络合剂、多价螯合剂或螯合剂、防冻剂、冷冻保护剂、增稠剂、pH调节剂和惰性气体。
本发明提供的药物组合物可以通过直肠栓剂给药，通过将药物与合适的无刺激性的赋形剂(如可可油，聚乙烯乙二醇合成的甘油酯)混合，常温下为固体，然后在直肠腔内液化或溶解释放药物。由于个体差异，症状的严重程度会呈现比较大的变化，而且每种药都有其独特的治疗特性，因此，对于每个个体的精确的给药方式，剂型和治疗方案都应该由执业医生来判定。
本发明提供的药物组合物可以配制成立即或改性释放剂型，包括延迟-、缓释-、脉冲-、控制-、靶向-和程序化释放形式。
本文所使用的术语“治疗有效量”是指足以显示出有益的治疗效果的各活性组分的总量。例如，给药或使体内达到平衡的足以治疗、治愈或减轻疾病的症状的量。特殊的治疗方案所需的有效量依赖于多种因素，包括治疗的疾病，疾病的严重程度，使用的特定药物的活性，给药方式，特定药物的清除率，治疗持续时间，联合用药，年龄，体重，性别，饮食和病人的健康等。本领域关于“治疗有效量”需要考虑的其他因素的描述可参见Gilman et al.,eds.,Goodman And Gilman’s:The Pharmacological Bases of Therapeutics,8 th ed.,Pergamon Press,1990；Remington's Pharmaceutical Sciences,17 th ed.,Mack Publishing Company,Easton,Pa.,1990。
本领域技术人员(例如，主治医师、药剂师或其他技术人员)可以容易地确定给予患者的本发明化合物的合适剂量，并且可以根据患者健康情况、年龄、体重、给药频率、其他活性组分的使用和/或所给予化合物的适应症来改变。本发明化合物的剂量可以在大约0.001-500mg/kg体重/天的范围。在一些实施方案中，根据具体应用，可以改变或调节制剂的单位剂量中的活性化合物的数量。在另一些实施方案中，对于口服给药，建议的典型日给药方案可以在大约1mg/天至大约500mg/天的范围，给予两个至四个分开剂量。
术语“给药”指给个体提供治疗有效量的药物，给药方式包括口服，舌下，静脉，皮下，经皮，肌内，皮内，鞘内，硬膜上，眼内，颅内，吸入，直肠，阴道等。给药剂型包括膏剂，洗剂，片剂，胶囊剂，丸剂，飞散性粉末剂，颗粒剂，栓剂，丹剂，锭剂，注射剂，无菌溶液或非水溶液剂，悬浮剂，乳剂，贴片剂等。活性组分与无毒的药学上可接受的载体(如葡萄糖，乳糖，阿拉伯树胶，明胶，甘露醇，淀粉糊，三硅酸镁，滑石粉，玉米淀粉，角蛋白，硅胶，土豆淀粉，尿素，右旋糖酐等)复合。
优选的给药途径会随着临床特征而变化，剂量的变化必须依赖于正在治疗的病人的情况，医生会根据个体患者来确定合适的剂量。每单位剂量的治疗有效量取决于体重，生理机能和选择的接种方案。每单位剂量的化合物是指每次给药时化合物的重量，不包括载体的重量(药物里含有载体)。
本发明提供的药物组合物可以配制成单剂量或多剂量给药。所述单剂量制剂被包装在安瓿剂、小瓶或注射器中。所述多剂量肠胃外制剂必须包含抑菌或抑真菌浓度的抗微生物剂。所有的肠胃外制剂都必须是无菌的，如本领域已知和实践的。
本发明提供的药物组合物可以与不会损害预期的治疗作用的其它活性成分共同配制，或者与补充预期的作用的物质共同配制。
在一实施方案中，本发明的治疗方法包括对有需要的患者给予安全有效量的本发明化合物或包含本发明化合物的药物组合物。本发明各实施方案包括通过对有需要的患者给予安全有效量的本发明化合物或包含本发明化合物的药物组合物，来治疗本发明提及的疾病。
在一实施方案中，本发明化合物或包含本发明化合物的药物组合物可以通过任何适合的给药途径来给药，包括全身给药和局部给药。全身给药包括口服给药、胃肠外给药、透皮给药和直肠给药。典型的胃肠外给药是指通过注射或输注给药，包括静脉内、肌内和皮下注射或输注给药。局部给药包括施用于皮肤以及眼内、耳、阴道内、吸入和鼻内给药。在一个实施方案中，本发明化合物或包含本发明化合物的药物组合物可以是口服给药。在另一实施方案中，本发明化合物或包含本发明化合物的药物组合物可以是吸入给药。还在一实施方案中，本发明化合物或包含本发明化合物的药物组合物可以是经鼻内给药。
在一实施方案中，本发明化合物或包含本发明化合物的药物组合物可以一次性给药，或者根据给药方案，在指定时间段内，在不同的时间间隔给药若干次。例如，每天给药一次、两次、三次或四次。在一实施方案中，每天给药一次。在又一实施方案中，每天给药两次。可以给药直至达到想要的治疗效果或无限 期地维持想要的治疗效果。本发明化合物或包含本发明化合物的药物组合物的合适给药方案取决于该化合物的药代动力学性质，例如吸收、分布和半衰期，这些可以由技术人员测定。此外，本发明化合物或包含本发明化合物的药物组合物的合适给药方案，包括实施该方案的持续时间，取决于被治疗的疾病，被治疗疾病的严重程度、被治疗患者的年龄和身体状况、被治疗患者的医疗史、同时疗法的性质、想要的治疗效果等在技术人员知识和经验范围内的因素。这样的技术人员还应该理解，对于个体患者对给药方案的反应，或随着时间推移个体患者需要变化时，可要求调整适宜的给药方案。
本发明化合物可以与一种或多种其它治疗剂同时，或在其之前或之后给药。本发明化合物可以与其他治疗剂通过相同或不同给药途径分别给药，或与之以同一药物组合物形式给药。这由本领域技术人员根据患者的健康、年龄、体重等身体的实际情况选择。如果配制为固定剂量，这种联用产品使用本发明的化合物(在本文所描述的剂量范围之内)和其他药学活性剂(在其剂量范围之内)。
相应地，在一个方面，本发明包括联合用药，其包括一定数量的至少一种本发明的化合物或其可药用盐、溶剂化物、酯或前体药物和有效量的一种或多种上述附加治疗剂。
此外，本发明化合物可以以前药形式给药。在本发明中，本发明化合物的“前药”是对患者给药时，最终能在体内释放出本发明化合物的功能性衍生物。以前药形式给予本发明化合物时，本领域技术人员可实施下列方式中的一种及以上：(a)变更化合物的体内起效时间；(b)变更化合物的体内作用持续时间；(c)变更化合物的体内输送或分布；(d)变更化合物的体内溶解度；及(e)克服化合物所面临的副作用或其他难点。用于制备前药的典型的功能性衍生物，包含在体内以化学方式或酶的方式裂解的化合物的变体。包含制备磷酸盐、酰胺、酯、硫代酯、碳酸盐及氨基甲酸盐的这些变体对本领域技术人员来讲是众所周知的。
本发明化合物和药物组合物的用途
本发明提供的化合物和药物组合物可用于制备抑制类糜蛋白酶的药品，也可以用于制备用于治疗或预防心力衰竭、肺动脉高血压、慢性阻塞性肺病、哮喘、肾衰竭、肾病、内部器官的纤维化病症和皮肤纤维化的疾病。
在本发明的上下文中，心血管系统的疾病或心血管疾病理解为意指例如以下的疾病：急性和慢性心力衰竭、动脉性高血压、冠心病、稳定型和不稳定型心绞痛、心肌缺血、心肌梗死、休克、动脉粥样硬化、心脏肥大、心脏纤维化、房性和室性心律失常、暂时和缺血性发作、中风、先兆子痫、炎性心血管疾病、外周和心血管疾病、外周灌注障碍、肺动脉高压、冠状动脉和外周动脉痉挛、血栓症、血栓栓塞性疾病、水肿发展(例如肺水肿、脑水肿、肾水肿或心力衰竭相关的水肿)和再狭窄(例如在溶栓治疗、经皮腔内血管成形术(PTA)、经皮冠状动脉成形术(PTCA)、心脏移植和搭桥手术后的再狭窄)，以及微血管和大血管损伤(血管炎)、再灌注损伤、动脉和静脉血栓症、微量白蛋白尿、心肌机能不全、内皮功能障碍、外周和心脏血管疾病、外围灌注障碍、心力衰竭相关的水肿、纤维蛋白原和低密度LDL的水平升高以及纤溶酶原激活剂/抑制剂1(PAI-1)的浓度升高。
在本发明的上下文中，术语“心力衰竭”还包括更特定或相关类型的疾病，例如急性失代偿性心力衰竭、右心衰竭、左心衰竭、整体衰竭、缺血性心肌病、扩张型心肌病、先天性心脏缺损、心脏瓣膜缺陷、与心脏瓣膜缺陷相关的心力衰竭、二尖瓣狭窄、二尖瓣关闭不全、主动脉瓣狭窄、主动脉瓣关闭不全、三尖瓣狭窄、三尖瓣关闭不全、肺动脉瓣狭窄、肺动脉瓣关闭不全、合并心脏瓣膜缺陷、心肌炎症(心肌炎)、慢性心肌炎、急性心肌炎、病毒性心肌炎、糖尿病心脏衰竭、酒精性心肌病、心脏储存障碍以及舒张性和收缩性心力衰竭。
本发明的化合物可以应用于，但绝不限于，使用本发明的化合物或药物组合物的有效量对患者给药来预防、治疗或减轻与类糜蛋白酶有关的疾病。所述与类糜蛋白酶有关的疾病，进一步包括但并不限于，心 力衰竭、肺动脉高血压、慢性阻塞性肺病、哮喘、肾衰竭、肾病、内部器官的纤维化病症和皮肤纤维化。
本发明的化合物及药物组合物除了对人类治疗有益以外，还可应用于兽医治疗宠物、引进品种的动物和农场的动物中的哺乳动物。另外一些动物的实例包括马、狗和猫。在此，本发明的化合物包括其药学上可接受的衍生物。
一般合成步骤
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)或式(IIa)或式(IIb)或式(IIc)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。
所属领域的专业人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商，使用时都没有经过进一步纯化，除非其他方面表明。
1H NMR谱使用Bruker 400MHz或600MHz核磁共振谱仪记录。 1H NMR谱以CDC1 3、DMSO-d 6、CD 3OD或丙酮-d 6为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)，d(doublet，双峰)，t(triplet，三重峰)，q(quartet，四重峰)，m(multiplet，多重峰)，br(broadened，宽峰)，brs(broadened singlet，宽的单峰)，dd(doublet of doublets，双二重峰)，ddd(doublet of doublet of doublets，双双二重峰)，dt(doublet of triplets，双三重峰)，td(triplet of doublets，三双重峰)，tt(triplet of triplets，三三重峰)。偶合常数J，用赫兹(Hz)表示。
低分辨率质谱(MS)数据的测定条件是：Agilent 6120四级杆HPLC-M(柱子型号：Zorbax SB-C18,2.1×30mm,3.5微米,6min,流速为0.6mL/min。流动相：5％-95％(含0.1％甲酸的CH 3CN)在(含0.1％甲酸的H 2O)中的比例，采用电喷雾电离(ESI)，在210nm/254nm下，用UV检测。
下面简写词的使用贯穿本发明：
CDC1 3  氘代氯仿    CDI      N,N'-羰基二咪唑
DMSO   二甲基亚砜  DMSO-d 6  氘代二甲基亚砜
下列合成方案描述了制备本发明公开化合物的步骤，除非另外说明，其中R 1和R 2具有本发明所述的定义。
合成方案1
Figure PCTCN2021140889-appb-000008
其中，PMB是指对甲氧基苄基，即
Figure PCTCN2021140889-appb-000009
式(M11)所示的化合物可以通过该合成方案1制备得到，其中het为5-6元杂芳环：式(M1)所示的化合物发生酯化反应得到式(M2)所示的化合物；式(M2)所示的化合物与4-甲氧基苄氯反应得到式(M3)所示的化合物；式(M3)所示的化合物加氢还原得到式(M4)所示的化合物；式(M4)所示的化合物与氯甲酸苯酯反应得到式(M5)所示的化合物；式(M5)所示的化合物与式(M6)所示的化合物反应得到式(M7)所示的化合物；式(M7)所示的化合物关环得到式(M8)所示的化合物；式(M8)所示的化合物与式(M9)所示的化合物反应得到式(M10)所示的化合物；式(M10)所示的化合物在酸性的条件下脱去保护基得到式(M11)所示的化合物。
合成方案2
Figure PCTCN2021140889-appb-000010
式(M18)所示的化合物可以通过该合成方案2制备得到，其中，X、Y、W和Z各自独立地为CH或N：式(M12)所示的化合物与式(M13)所示的化合物发生亲核取代反应得到式(M14)所示的化合物；式 (M14)所示的化合物发生缩合反应得到式(M15)所示的化合物；式(M15)所示的化合物与CDI进行关环反应得到式(M16)所示的化合物；式(M16)所示的化合物与式(M17)所示的化合物发生偶联反应，得到式(M18)所示的化合物。
合成方案3
Figure PCTCN2021140889-appb-000011
式(M26)所示的化合物可以通过该合成方案3制备得到：式(M19)所示的化合物与式(M20)所示的化合物发生亲核取代反应得到式(M21)所示的化合物；式(M21)所示的化合物加氢还原得到式(M22)所示的化合物；式(M22)所示的化合物与CDI进行关环反应得到式(M23)所示的化合物；式(M23)所示的化合物与式(M24)所示的化合物发生偶联反应，得到式(M25)所示的化合物；式(M25)所示的化合物发生插羰反应，得到式(M26)所示的化合物。
以下结合实施例对本发明提供的化合物、药物组合物及其应用进行进一步说明。
实施例
实施例2
4-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)-6-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-2,4-二氢-5H-吡唑并[4,3-d]嘧啶-5,7(6H)-二酮的合成
Figure PCTCN2021140889-appb-000012
步骤一：6-硝基苯并[d]恶唑-2(3H)-酮的合成
在冰浴下，向三光气(58.9g,198mmol)的二氯甲烷(300mL)溶液缓慢滴加2-氨基-5-硝基苯酚(50.0g,324mmol)和三乙胺(119mL,856mmol)的二氯甲烷(300mL)混合溶液，反应体系室温搅拌1小时。反应混合物加入饱和氯化铵水溶液(300mL)淬灭，搅拌20分钟，过滤，干燥，得到少量固体产物；滤液分液，水相用二氯甲烷(400mL×2)萃取，合并有机相，无水硫酸钠干燥。过滤，滤液减压蒸去溶剂，与之前得到的少量固体产物合并，得到标题化合物为黄色固体(58.4g,99.9％)。
1H NMR(400MHz,CDCl 3)δ(ppm)8.25(dd,J＝8.6,2.0Hz,1H),8.12(d,J＝1.9Hz,1H),7.10(d,J＝8.6Hz,1H).
步骤二：3-甲基-6-硝基苯并[d]恶唑-2(3H)-酮的合成
向6-硝基苯并[d]恶唑-2(3H)-酮(58.4g,324mmol)的N,N-二甲基甲酰胺(300mL)溶液中加入碳酸钾(134g,971.01mmol)，冰浴下滴加碘甲烷(30.3mL,487mmol)，室温搅拌16小时。反应混合物加水(1500mL)淬灭，过滤，滤饼干燥，得到标题化合物为黄色固体(62.9g,99.9％)。
步骤三：6-氨基-3-甲基苯并[d]恶唑-2(3H)-酮的合成
在高压釜中加入3-甲基-6-硝基苯并[d]恶唑-2(3H)-酮(62.9g,324mmol)、四氢呋喃(400mL)、甲醇(400mL)和钯碳(12.6g,3.87mmol)，氢气置换3次，通入氢气，反应体系升温至80℃搅拌24小时。反应混合物过滤，滤液减压蒸去溶剂，所得残留物加入石油醚/乙酸乙酯(500mL/50mL)，加热打浆，抽滤后得到标题化合物为淡黄色固体(46.0g,86.5％)。
1H NMR(400MHz,CDCl 3)δ(ppm)6.75(d,J＝8.2Hz,1H),6.63(d,J＝2.0Hz,1H),6.53(dd,J＝8.2,2.1Hz,1H),3.66(s,2H),3.36(s,3H).
步骤四：6-溴-3-甲基苯并[d]恶唑-2(3H)-酮的合成
在50℃下，向溴化亚铜(17.4g,91.4mmol)的乙腈(100mL)溶液缓慢滴加亚硝酸叔丁酯(13.3mL,110mmol)，搅拌0.5h，滴加6-氨基-3-甲基苯并[d]恶唑-2(3H)-酮(10.0g,60.9mmol)的乙腈(100mL)溶液，加热至80℃反应6小时。反应混合物减压蒸去溶剂，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝20/1-10/1)分离纯化，得到标题化合物为黄色固体(11.81g,85％)。
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.40–7.34(m,2H),6.86(d,J＝8.2Hz,1H),3.41(s,3H).
步骤五：3-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯并[d]恶唑-2(3H)-酮的合成
向6-溴-3-甲基苯并[d]恶唑-2(3H)-酮(5.10g,22.4mmol)的N,N-二甲基甲酰胺(100mL)溶液中加入双联频哪醇硼酸酯(6.95g,26.8mmol)、醋酸钾(8.78g,89.5mmol)、[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)二氯甲烷络合物(1.82g,2.23mmol)，氮气保护下在80℃反应3.5h。反应混合物减压蒸去部分溶剂，加水(80mL)，用乙酸乙酯(100mL×2)萃取，有机相用饱和食盐水(80mL×2)洗涤，无水硫酸钠干燥，过滤，减压蒸去溶剂，得到标题化合物为棕色固体(6.15g,100％)。
1H NMR(400MHz,CDCl 3)δ(ppm)7.61(d,J＝7.7Hz,1H),7.55(s,1H),6.93(d,J＝7.7Hz,1H),3.37(s,3H),1.30(s,12H).
步骤六：(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)硼酸的合成
向3-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯并[d]恶唑-2(3H)-酮(6.15g,22.4mmol)的丙酮(120mL)和水(120mL)的溶液中加入高碘酸钠(28.7g,134mmol)和醋酸铵(6.89g,89.4mmol)，室温搅拌11小时。反应混合物减压蒸去大部分溶剂，加入水(200mL)搅拌过夜，过滤，用水(50mL)洗涤滤饼，真空干燥，粗产品经硅胶柱层析(二氯甲烷/乙酸乙酯(v/v)＝10/1-4/1)分离纯化，得到标题化合物为棕色固体(3.10g,71.9％)。
MS(ESI,pos.ion)m/z:194.1[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.07(s,2H),7.67(d,J＝7.7Hz,1H),7.63(s,1H),7.21(d,J＝7.7Hz,1H),3.33(s,3H).
步骤七：N-苄基-4-(三氟甲基)-2,3-二氢-1H-茚-1-胺的合成
向4-(三氟甲基)-2,3-二氢-1H-茚-1-酮(10.0g,50.0mmol)的二氯甲烷(200mL)溶液中加入苯甲胺(6.42g,59.9mmol)和钛酸乙酯(20.4mL,74.9mmol)，室温搅拌1h。在0℃下，分批加入硼氢化钠(3.78g,99.9mmol)，室温搅拌18h。反应混合物倒入冰水中，用硅藻土过滤，静置分层，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥。过滤，滤液减压蒸去溶剂，所得残留物经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝10/1-4/1)，得到标题化合物为淡黄色液体(12.0g,82.5％)。
步骤八：4-(三氟甲基)-2,3-二氢-1H-茚-1-胺的合成
向N-苄基-4-(三氟甲基)-2,3-二氢-1H-茚-1-胺(12.0g,41.2mmol)的四氢呋喃(120mL)溶液中加入钯碳(1.20g)，通入氢气，室温搅拌24h。反应混合物过滤，滤液减压蒸去溶剂，所得残留物经硅胶柱层析纯化(二氯甲烷/甲醇(v/v)＝20/1-10/1)，得到标题化合物为淡黄色液体(6.17g,74.4％)。
1H NMR(400MHz,CDCl 3)δ(ppm)7.53(d,J＝7.5Hz,1H),7.49(d,J＝7.7Hz,1H),7.34(t,J＝7.6Hz,1H),4.39(t,J＝7.5Hz,1H),3.19(dd,J＝16.1,8.2Hz,1H),2.95(dt,J＝16.8,8.4Hz,1H),2.57(dtd,J＝11.1,7.8,3.3Hz,1H),1.79(d,J＝8.6Hz,1H).
步骤九：4-硝基-1H-吡唑-3-羧酸乙酯的合成
向4-硝基-1H-吡唑-3-羧酸(10.0g,63.7mmol)的乙醇(200mL)溶液中滴加二氯亚砜(5.08mL,70.0mmol)，室温搅拌21h。反应混合物减压蒸去溶剂，加水(200mL)，用乙酸乙酯(200mL×2)萃取，有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，滤液减压蒸去溶剂，得到标题化合物为白色固体(11.5g,97.6％)。
步骤十：1-(4-甲氧基苄基)-4-硝基-1H-吡唑-3-羧酸乙酯的合成
在0℃下向4-硝基-1H-吡唑-3-羧酸乙酯(11.5g,62.1mmol)的N,N-二甲基甲酰胺(200mL)的溶液中加入NaH(2.48g,62.0mmol)，搅拌0.5h后滴加4-甲氧基苄氯(10.1mL,74.5mmol)，室温搅拌18.5h。反应混合物缓慢加水(100mL)淬灭，用乙酸乙酯(200mL×2)萃取，有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，减压蒸去溶剂，所得残留物经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝10/1-4/1)，得到标题化合物为无色液体(14.0g,73.8％)。
1H NMR(400MHz,CDCl 3)δ(ppm)8.01(s,1H),7.27(d,J＝8.4Hz,2H),6.94(d,J＝8.6Hz,2H),5.27(s,2H),4.46(q,J＝7.1Hz,2H),3.83(s,3H),1.41(t,J＝7.1Hz,3H).
步骤十一：4-氨基-1-(4-甲氧基苄基)-1H-吡唑-3-羧酸乙酯的合成
向1-(4-甲氧基苄基)-4-硝基-1H-吡唑-3-羧酸乙酯(14.0g,45.9mmol)的甲醇(200mL)溶液中加入钯碳(1.40g,21.4mmol)，通入氢气，室温搅拌20小时。反应混合物过滤，滤液减压蒸去溶剂，粗产品经硅胶柱层析纯化(二氯甲烷/乙酸乙酯(v/v)＝10/1-4/1)，得到标题化合物为淡黄色液体(11.4g,90.3％)。
MS(ESI,pos.ion)m/z:276.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ(ppm)7.18(d,J＝8.1Hz,2H),6.85(m,3H),5.17(s,2H),4.41(qd,J＝7.1,0.8Hz,2H),3.78(d,J＝0.9Hz,3H),1.41(td,J＝7.1,0.8Hz,3H).
步骤十二：1-(4-甲氧基苄基)-4-((苯氧羰基)氨基)-1H-吡唑-3-羧酸乙酯的合成
向4-氨基-1-(4-甲氧基苄基)-1H-吡唑-3-羧酸乙酯(1.10g,4.00mmol)的二氯甲烷(20mL)溶液中加入吡啶(0.64mL,8.0mmol)，在氮气保护和0℃下滴加氯甲酸苯酯(0.75mL,6.0mmol)的二氯甲烷(20mL)溶液，升温至室温搅拌6小时。反应混合物加稀盐酸调pH至6，用二氯甲烷(40mL×2)萃取，有机相用无水硫酸钠干燥。过滤，减压蒸去溶剂，所得残留物经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝10/1-2/1)，得到标题化合物为白色固体(1.44g,91.1％)。
1H NMR(400MHz,CDCl 3)δ(ppm)8.68(s,1H),7.85(s,1H),7.39(t,J＝7.9Hz,2H),7.25(t,J＝7.4Hz,3H),7.21–7.14(m,2H),6.88(d,J＝8.6Hz,2H),5.28(s,2H),4.50(q,J＝7.1Hz,2H),3.80(s,3H),1.48(t,J＝7.1Hz,3H).
步骤十三：1-(4-甲氧基苄基)-4-(3-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)脲基)-1H-吡唑-3-羧酸乙酯的合成
向1-(4-甲氧基苄基)-4-((苯氧羰基)氨基)-1H-吡唑-3-羧酸乙酯(1.43g,3.62mmol)的二甲基亚砜(20mL)溶液中加入4-(三氟甲基)-2,3-二氢-1H-茚-1-胺(606mg,3.0121mmol)，氮气保护下升温至90℃搅拌 17.5h。反应混合物冷却至室温，加水(40mL)，用乙酸乙酯(80mL×2)萃取，有机相用无水硫酸钠干燥。过滤，减压蒸去溶剂，所得残留物经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝4/1-1/1)，得到标题化合物为淡黄色固体(1.45g,95.8％)。
步骤十四：2-(4-甲氧基苄基)-6-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-2,4-二氢-5H-吡唑并[4,3-d]嘧啶-5,7(6H)-二酮的合成
在1-(4-甲氧基苄基)-4-(3-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)脲基)-1H-吡唑-3-羧酸乙酯(1.66g,3.30mmol)的DMF(40mL)溶液中加入氢化钠(198mg,4.95mmol)，室温搅拌7h。反应混合物减压蒸去部分溶剂，加水(80mL)搅拌过夜，过滤，加水(40mL)洗涤滤饼，滤饼减压干燥，得到淡黄色固体(1.33g,88.2％)。
MS(ESI,neg.ion)m/z:455.1[M-H] +.
1H NMR(600MHz,CDCl 3)δ(ppm)9.97(s,1H),7.41(d,J＝7.5Hz,1H),7.28(t,J＝4.1Hz,2H),7.23(d,J＝7.5Hz,1H),7.17(t,J＝7.6Hz,1H),6.99(s,1H),6.92(d,J＝8.6Hz,2H),6.71(s,1H),5.33(s,2H),3.83(s,3H),3.50(s,1H),3.20–3.11(m,1H),2.64–2.56(m,1H),2.40(s,1H).
步骤十五:2-(4-甲氧基苄基)-4-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)-6-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-2,4-二氢-5H-吡唑并[4,3-d]嘧啶-5,7(6H)-二酮的合成
向2-(4-甲氧基苄基)-6-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-2,4-二氢-5H-吡唑并[4,3-d]嘧啶-5,7(6H)-二酮(1.33g,2.91mmol)的乙腈(10mL)溶液中加入(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)硼酸(843mg,4.3688mmol)，醋酸铜(794mg,4.3715mmol)、三乙胺(0.88mL,6.3mmol)、二甲基亚砜(0.40mL,8.8mmol)和分子筛(1.0g)，在氮气保护下室温搅拌20h。反应混合物过滤，减压蒸去溶剂，所得残留物经硅胶柱层析(二氯甲烷/乙酸乙酯(v/v)＝50/1-20/1)分离纯化，得到标题化合物为黄色固体(1.70g,96.6％)。
MS(ESI,pos.ion)m/z:604.1[M+H] +.
1H NMR(400MHz,CDCl 3)δ(ppm)7.46(d,J＝7.4Hz,1H),7.30(s,1H),7.23(t,J＝6.9Hz,3H),7.22–7.13(m,2H),7.03(d,J＝8.1Hz,1H),6.87(d,J＝8.6Hz,2H),6.81(s,1H),6.77(s,1H),5.30(s,2H),3.80(s,3H),3.53(s,1H),3.43(s,3H),3.22–3.08(m,1H),2.62(dtd,J＝14.2,9.6,4.7Hz,1H),2.51(ddd,J＝19.6,13.0,6.4Hz,1H).
步骤十六：4-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)-6-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-2,4-二氢-5H-吡唑并[4,3-d]嘧啶-5,7(6H)-二酮的合成
向反应瓶中加入2-(4-甲氧基苄基)-4-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)-6-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-2,4-二氢-5H-吡唑并[4,3-d]嘧啶-5,7(6H)-二酮(800mg,1.325mmol)和三氟乙酸(20mL)，反应体系80℃搅拌2.5h。反应混合物减压蒸去溶剂，加饱和碳酸氢钠水溶液调pH至8，用乙酸乙酯(50mL)萃取，收集有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压蒸去溶剂，所得残留物经硅胶柱层析纯化(二氯甲烷/乙酸乙酯(v/v)＝10/1-4/1)，得到标题化合物为淡黄色固体(0.60g,93.7％)。
MS(ESI,pos.ion)m/z:484.0[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.44(ddd,J＝25.5,14.0,7.5Hz,7H),6.57(s,1H),3.40(s,3H),3.31(s,1H),3.17–3.04(m,1H),2.61–2.54(m,1H),2.48–2.44(m,1H).
实施例1：3-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)-1-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-3,9-二氢-1H-嘌呤-2,6-二酮的合成
Figure PCTCN2021140889-appb-000013
本实施例使用5-氨基-1H-咪唑-4-羧酸作为原料，参照实施例2所描述的方法制备得到标题化合物为褐色固体，产率5％。
MS(ESI,pos.ion)m/z:484.0[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.95(s,1H),7.69–7.20(m,5H),6.59(s,1H),5.33(s,1H),3.49(s,3H),3.32(s,1H),3.10(dd,J＝12.7,6.3Hz,1H),2.05–1.94(m,1H),1.37–1.29(m,1H).
实施例9：1-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)-2,4-二氧代-3-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-6-羧酸
Figure PCTCN2021140889-appb-000014
步骤一：4-(三氟甲基)-2,3-二氢-1H-茚-1-醇的合成
在0℃下向4-(三氟甲基)-2,3-二氢-1H-茚-1-酮(1.00g,5.00mmol)的甲醇(10mL)溶液中缓慢加入硼氢化钠(236mg,5.988mmol)，继续0℃反应。反应混合物减压除去大部分溶剂，加水(50mL)，用乙酸乙酯(50mL×2)萃取，合并有机相，用饱和食盐水(30mL×2)洗涤，收集有机相，减压浓缩得到标题化合物为黄色油状物(1.00g,99.0％)。
步骤二：6-溴-3-((3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)氨基)吡啶甲酸的合成
在-78℃下向6-氨基-3-甲基苯并[d]恶唑-2(3H)-酮(1.492g,9.09mmol)的四氢呋喃(20mL)溶液中滴加入双三甲基硅基胺基锂(23mL,23mmol,1mol/L的THF溶液)，保温搅拌15min后，滴加入6-溴-3-氟吡啶-2-甲酸(2g,9.09mmol)的THF(20mL)溶液，保温搅拌1h，然后升至室温搅拌过夜。反应混合物用1N HCl溶液调节pH值至1-2，用乙酸乙酯(50mL×2)萃取，有机相用饱和氯化钠(50mL)洗涤，然后用无水硫酸钠固体干燥，过滤并减压浓缩，所得残留物经硅胶柱层析纯化(二氯甲烷/甲醇(v/v)＝100/0-85/15)，得到标题化合物为黄褐色固体(1.943g,58.68％)。
MS(ES-API,pos.ion)m/z:364.0[M+H] +。
步骤三：6-溴-3-((3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)氨基)吡啶甲酰胺的合成
向6-溴-3-((3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)氨基)吡啶甲酸(1.943g,5.335mmol)的二氯甲烷(50mL)溶液中滴加草酰氯(0.92mL,10mmol)，然后滴加N,N-二甲基甲酰胺(0.1mL)，在室温下搅拌5h。反应混合物减压浓缩后得到黄色固体，加入四氢呋喃(40mL)，向上述的四氢呋喃溶液中滴加氢氧化铵(28mass％)的水溶液(40mL)，在室温下搅拌过夜。反应混合物过滤，滤液加入水(50mL)，用乙酸乙酯(50mL×2)萃取，收集有机相，用饱和氯化钠溶液(50mL)洗涤，然后用无水硫酸钠干燥，过滤并减压浓缩后得到标题化合物为黄色固体(1.55g，80％)
MS(ES-API,pos.ion)m/z:364.9[M+H] +。
步骤四：6-溴-1-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)吡啶并[3,2-d]嘧啶-2,4(1H,3H)-二酮的合成
向6-溴-3-((3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)氨基)吡啶甲酰胺(1.55g,4.27mmol)的N,N-二甲基甲酰胺(40mL)溶液中加入氢化钠(0.341g,8.53mmol，60mass％)，搅拌5min后加入CDI(1.384g,8.279mmol)，然后在室温下搅拌过夜。反应混合物加入水(50mL)，用乙酸乙酯(50mL×2)萃取，将水相调节pH至1-2，有大量沉淀析出，过滤后干燥得到标题化合物为黄色固体(0.862g,51.9％)。
1H NMR(400MHz,DMSO-d 6)δ(ppm)12.04(s,1H),7.73(d,J＝8.8Hz,1H),7.52(d,J＝1.7Hz,1H),7.47(d,J＝8.3Hz,1H),7.33(dd,J＝8.3,1.8Hz,1H),6.90(d,J＝8.8Hz,1H),3.41(s,3H).
步骤五：6-溴-1-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)-3-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)吡啶并[3,2-d]嘧啶-2,4(1H,3H)-二酮的合成
向6-溴-1-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)吡啶并[3,2-d]嘧啶-2,4(1H,3H)-二酮(0.862g,2.21mmol)的四氢呋喃(7mL)和N,N-二甲基甲酰胺(14mL,180mmol)溶液中加入4-(三氟甲基)-2,3-二氢-1H-茚-1-醇(0.537g,2.66mmol)和三苯基膦(1.162g,4.386mmol)，降温至-15℃。随后滴加入偶氮二甲酸二异丙酯(0.87mL,4.3mmol)，保温搅拌1h后升至室温搅拌过夜。反应混合物加入水(50mL)，用乙酸乙酯(50mL×2)萃取，收集有机相，用饱和氯化钠溶液(50mL)洗涤，然后用无水硫酸钠干燥，过滤并减压浓缩，所得残留物经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v＝9/1)～100％乙酸乙酯)，得到标题化合物淡黄色固体(0.491g,38.7％)。
MS(ES-API,pos.ion)m/z:572.9[M+H] +.
步骤六：1-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)-2,4-二氧代-3-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-6-羧酸的合成
向6-溴-1-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)-3-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)吡啶并[3,2-d]嘧啶-2,4(1H,3H)-二酮(0.491g,0.856mmol)的N,N-二甲基甲酰胺(8mL,100mmol)溶液中加入甲酸钠(0.175g,2.55mmol)、醋酸钯(0.012g,0.051mmol)和1,1'-双(二苯基膦)二茂铁(0.028g,0.050mmol)，通氮气10min后加入N,N-二异丙基乙胺(0.28mL,1.7mmol)和乙酸酐(0.16mL,1.7mmol)。在氮气保护下加热至100℃反应过夜。反应混合物加入水(50mL)，用乙酸乙酯(50mL×2)萃取，收集有机相，用饱和氯化钠溶液(50mL)洗涤，然后用无水硫酸钠干燥，过滤并减压浓缩，所得残留物送制备色谱纯化，得到标题化合物为白色固体(0.007g,2％)。
MS(ES-API,neg.ion)m/z:536.9[M-H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.14(d,J＝8.6Hz,1H),7.63–7.35(m,7H),7.10(d,J＝9.2Hz,1H),6.58(s,1H),3.42(s,3H),3.13(m,2H),2.58(m,2H).
参照实施例9所描述的方法制备，通过不同的起始物料经过多步反应得到如下实施例化合物，其中所得产物结构及其表征数据如下表：
Figure PCTCN2021140889-appb-000015
Figure PCTCN2021140889-appb-000016
Figure PCTCN2021140889-appb-000017
实施例10：(R)-3-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)-2-氧代-1-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-2,3-二氢-1H-苯并[d]咪唑-5-羧酸的合成
Figure PCTCN2021140889-appb-000018
步骤一：6-((5-溴-2-硝基苯基)氨基)-3-甲基苯并[d]恶唑-2(3H)-酮的合成
向4-溴-2-氟-1-硝基苯(1.00g,4.55mmol)和6-氨基-3-甲基苯并[d]恶唑-2(3H)-酮(746.0mg,4.54mmol)的无水N,N-二甲基甲酰胺(20mL)溶液中加入碳酸钾(1.27g,9.10mmol)，升温至90℃反应22h。反应混合物加水(50mL)，用乙酸乙酯(50mL×2)萃取，合并有机相，有机相经饱和食盐水(30mL×2)洗涤，收集有机相，无水硫酸钠干燥，减压抽滤，滤液减压浓缩，所得残留物经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝2/1)，得到标题化合物为橙黄色固体(0.87g,53％)。
MS(ES-API,pos.ion)m/z:364.0[M+H] +.
步骤二：6-((2-氨基-5-溴苯基)氨基)-3-甲基苯并[d]恶唑-2(3H)-酮的合成
向6-((5-溴-2-硝基苯基)氨基)-3-甲基苯并[d]恶唑-2(3H)-酮(0.87g,2.4mmol)溶于甲醇(20mL)中加入氯化铵(1.30g,24.3mmol)，分批缓慢加入锌粉(1.60g,24.4mmol)，室温反应4h。反应混合物经硅藻土过滤，滤液减压浓缩，所得残留物经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物为棕色固体(0.66g,83％)。
步骤三：6-(6-溴-2-氧代-2,3-二氢-1H-苯并[d]咪唑-1-基)-3-甲基苯并[d]恶唑-2(3H)-酮的合成
向6-((2-氨基-5-溴苯基)氨基)-3-甲基苯并[d]恶唑-2(3H)-酮(0.66g,2.0mmol)的四氢呋喃(20mL)溶液中加入CDI(0.64g,3.9mmol)，室温反应16h。反应混合物减压浓缩，所得残留物经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物为浅黄色固体(0.66g,93％)。
步骤四：(R)-6-(6-溴-2-氧代-3-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-2,3-二氢-1H-苯并[d]咪唑-1-基)-3-甲基苯并[d]恶唑-2(3H)-酮的合成
将(S)-4-(三氟甲基)-2,3-二氢-1H-茚-1-醇(230.0mg,1.14mmol)，6-(6-溴-2-氧代-2,3-二氢-1H-苯并[d]咪唑-1-基)-3-甲基苯并[d]恶唑-2(3H)-酮(340.0mg,0.94mmol)和三苯基膦(495.0mg,1.89mmol)混合溶于无水四氢呋喃(5mL)和N,N-二甲基甲酰胺(10mL)中，氮气保护，冷却至0℃，滴加偶氮二羧酸二异丙酯(0.38mL,1.9mmol)，0℃保温反应8h。反应混合物升至室温，加水(50mL)，用乙酸乙酯(50mL×2)萃取，合并有机相，有机相经饱和食盐水(30mL×2)洗涤，收集有机相，无水硫酸钠干燥，减压抽滤，滤液减压浓缩，所得残留物经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝2/1)，得到标题化合物为红棕色固体(418.0mg,81.36％)。
MS(ES-API,pos.ion)m/z:544.0[M+H] +.
步骤五：(R)-3-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)-2-氧代-1-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-2,3-二氢-1H-苯并[d]咪唑-5-羧酸的合成
向(R)-6-(6-溴-2-氧代-3-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-2,3-二氢-1H-苯并[d]咪唑-1-基)-3-甲基苯并[d]恶唑-2(3H)-酮(418.0mg,0.77mmol)的无水N,N-二甲基甲酰胺(4.6mL)溶液中加入甲酸钠(157.0mg,2.31mmol)、醋酸钯(9.0mg,0.04mmol)、1,1'-双(二苯基膦)二茂铁(24.0mg,0.04mmol)、N,N-二异丙基乙胺(0.28mL,1.5mmol)和乙酸酐(0.15mL,1.6mmol)，氮气置换三次后于氮气保护下加热至120℃反应21h。冷却后，反应混合物加水(40mL)，用1N盐酸调节pH至4左右，用乙酸乙酯(30mL×2)萃取，合并有机相，有机相经饱和食盐水(30mL×2)洗涤，收集有机相，无水硫酸钠干燥，减压抽滤，滤液减压浓缩，所得残留物经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝3/1～1/9)，得到标题化合物为白色固体(226.0mg,57.77％)。
MS(ES-API,pos.ion)m/z:510.0[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.68(d,J＝5.0Hz,2H),7.62(d,J＝8.2Hz,1H),7.51–7.39(m,4H),6.88(s,1H),6.65(s,1H),6.21(t,J＝8.7Hz,1H),3.42(s,4H),3.21(dd,J＝17.2,8.4Hz,2H),2.67(s,1H).
实施例11：1-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)-2-氧代-3-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-2,3-二氢-1H-苯并[d]咪唑-5-羧酸的合成
Figure PCTCN2021140889-appb-000019
步骤一：N-(5-溴-2-硝基苯基)-4-(三氟甲基)-2,3-二氢-1H-茚-1-胺的合成
将4-溴-2-氟-1-硝基苯(500.0mg,2.27mmol)和4-(三氟甲基)-2,3-二氢-1H-茚-1-胺(457.0mg,2.27mmol)混合溶于无水N,N-二甲基甲酰胺(10mL)中，加入碳酸钾(635.0mg,4.55mmol)，升温至90℃反应2h。反应混合物加水(50mL)，用乙酸乙酯(50mL×2)萃取，合并有机相，用饱和食盐水(30mL×2)洗涤，收集有机相，无水硫酸钠干燥，减压抽滤，滤液减压蒸去溶剂得到标题化合物为黄色固体(911.0mg,99.91％)。
步骤二：5-溴-N 1-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)苯-1,2-二胺的合成
向N-(5-溴-2-硝基苯基)-4-(三氟甲基)-2,3-二氢-1H-茚-1-胺(911.0mg,2.27mmol)的甲醇(15mL)溶液中加入氯化铵(1.22g,22.8mmol)，分批缓慢加入锌粉(1.49g,22.8mmol)，室温反应15h。反应混合物经硅藻土过滤除去不溶物，滤液减压蒸去溶剂，所得残留物经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝9/1)，得到标题化合物为棕黄色固体(590.0mg,70.00％)。
MS(ES-API,pos.ion)m/z:371.1[M+H] +.
步骤三：6-溴-1-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-1,3-二氢-2H-苯并[d]咪唑-2-酮的合成
向5-溴-N 1-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)苯-1,2-二胺(590.0mg,1.59mmol)的四氢呋喃(20mL)溶液中，加入CDI(515.0mg,3.18mmol)，室温反应22h。反应液减压蒸去溶剂，残留物经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝2/1)，得到标题化合物为浅黄色固体(0.61g,97％)。
MS(ES-API,pos.ion)m/z:397.0[M+H] +.
步骤四：6-(5-溴-2-氧代-3-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-2,3-二氢-1H-苯并[d]咪唑-1-基)-3-甲基苯并[d]恶唑-2(3H)-酮的合成
向6-溴-1-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-1,3-二氢-2H-苯并[d]咪唑-2-酮(610mg,1.536mmol)和(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)硼酸(355mg,1.84mmol)的无水二氯甲烷(25mL)溶液中分别加入醋酸铜(279.0mg,1.54mmol)、三乙胺(0.65mL,4.60mmol)和4A分子筛(3.00g)，在氮气保护下室温反应4h。反应混合物经硅藻土过滤除去不溶物，滤饼以二氯甲烷洗涤，收集滤液，减压蒸去溶剂，所得残留物经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝3/1)，得到标题化合物为黄色油状物(764.0mg,91.40％)。
MS(ES-API,pos.ion)m/z:544.0[M+H] +.
步骤五：1-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-6-基)-2-氧代-3-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-2,3-二氢-1H-苯并[d]咪唑-5-羧酸的合成
向6-(5-溴-2-氧代-3-(4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-2,3-二氢-1H-苯并[d]咪唑-1-基)-3-甲基苯并[d]恶唑-2(3H)-酮(418.0mg,0.77mmol)的无水N,N-二甲基甲酰胺(4.6mL)溶液中加入甲酸钠(157.0mg,2.31mmol)、醋酸钯(9.0mg,0.04mmol)、1,1'-双(二苯基膦)二茂铁(24.0mg,0.04mmol)、N,N-二异丙基乙胺(0.28mL,1.5mmol)和乙酸酐(0.15mL,1.6mmol)，氮气置换三次后在氮气保护下加热至120℃反应 21h。冷却后，反应混合物加水(40mL)，1N盐酸调节pH至4左右，用乙酸乙酯(30mL×2)萃取，合并有机相，用饱和食盐水(30mL×2)洗涤，收集有机相，无水硫酸钠干燥，减压抽滤，滤液减压蒸去溶剂，所得残留物经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝3/1～1/9)，得到标题化合物为白色固体(226.0mg,57.77％)。
MS(ES-API,pos.ion)m/z:510.1[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ(ppm)12.66(s,1H),7.77–7.58(m,3H),7.56–7.35(m,4H),7.06(t,J＝11.1Hz,2H),6.23(t,J＝8.4Hz,1H),3.42(s,3H),3.27–3.11(m,2H),2.80–2.58(m,1H),2.45(dd,J＝10.8,6.7Hz,1H).
生物试验
实施例A：类糜蛋白酶的酶法测定
实验方法：
1.使用的酶源是重组人类糜蛋白酶(sigma)。所用的类糜蛋白酶底物为N-succinyl-Ala-Ala-Pro-Phe-7-amido-4-methylcoumarin。
2.对于该测定，测试物用DMSO进行稀释，将20nL测试物(1000X)和10μL酶溶液(2X)于384孔板中进行混合室温孵育15分钟，随后加入底物溶液(2X)，用Synergy 2进行动态读取在370nm波长处激发后再在460nm波长处发射的荧光信号。
3.将一个测试化合物在同一微量滴定板上以从300nM至0.0152nM的10个不同浓度各测定两次。将数据归一化(没有抑制剂的酶反应＝0％抑制作用，没有酶的全部测定组分＝100％抑制作用)，并使用GraphPad Prism 5软件计算IC 50值。
在此实验中测试本发明的化合物抑制类糜蛋白酶活性，结果见表A。
表A本发明化合物对类糜蛋白酶体外抑制作用测试结果
实施例号 IC 50(nM) 实施例号 IC 50(nM)
1 17.0 2 5.5
3 7.7 4 5.7
5 9.2 6 5.9
6a 2.1 7 7.8
8 6.4 9 5.4
实验结果显示，本发明化合物对类糜蛋白酶具有良好的抑制作用。
在本说明书的描述中，参考术语“一个实施例”、“一实施方案”、“一些实施例”、“示例”、“具体示例”或“一些示例”等的描述意指结合该实施例、实施方案或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例、实施方案或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例、实施方案或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例、实施方案或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例、实施方案或示例以及不同实施例、实施方案或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (10)

  1. 一种化合物，其为式(I)所示的化合物，或者式(I)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
    Figure PCTCN2021140889-appb-100001
    其中：环A为5-6元杂芳环或苯环；E为键、-CH 2-或-C(＝O)-；
    各R 0独立地为H、D、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-8环烷基、3-8个原子组成的杂环基、C 6-10芳基、5-12个原子组成的杂芳基、CN、NO 2、-OR a、-C(O)R a1、-C(O)NR a2R b、-C(O)OR a、-NR a2R b、-NR a3C(O)R a1、-NR a3C(O)OR a、-NR a3C(O)NR a2R b、-SO 2R a1、-SO 2NR a2R b或-NR a3SO 2NR a2R b，其中所述的C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-8环烷基、3-8个原子组成的杂环基、C 6-10芳基和5-12个原子组成的杂芳基独立地未被取代或被1、2、3、4或5个R m所取代；
    t为0、1、2、3或4；
    R a、R a1、R a2、R a3和R b各自独立地为H、D、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-12个原子组成的杂芳基；
    各R m独立地为D、卤素、CN、NO 2、OH、NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或卤代C 1-6烷氧基；
    R 1为
    Figure PCTCN2021140889-appb-100002
    R 3为-NR n-、-O-、-S-或-CR cR d-；
    R n为H、D、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 3-8环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-12个原子组成的杂芳基；
    R c和R d各自独立地为H、D、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-12个原子组成的杂芳基；
    R 4为H、D、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 3-8环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-12个原子组成的杂芳基；
    R 2为
    Figure PCTCN2021140889-appb-100003
    其中各R 5独立地为H、D、卤素、NO 2、CN、OH、NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-8环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-12个原子组成的杂芳基；
    m为0、1、2、3或4。
  2. 根据权利要求1所述的化合物，其中，R 2为
    Figure PCTCN2021140889-appb-100004
  3. 根据权利要求1的化合物，其为式(IIb)或式(IIc)所示的化合物，或者式(IIb)或式(IIc)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
    Figure PCTCN2021140889-appb-100005
  4. 根据权利要求1或3所述的化合物，其中，各R 0独立地为H、D、F、Cl、Br、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、卤代C 1-4烷氧基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基、5-10个原子组成的杂芳基、CN、NO 2、-OR a、-C(O)R a1、-C(O)NR a2R b、-C(O)OR a、-NR a2R b、-NR a3C(O)R a1、-NR a3C(O)OR a、-NR a3C(O)NR a2R b、-SO 2R a1、-SO 2NR a2R b或-NR a3SO 2NR a2R b，其中所述的C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、卤代C 1-4烷氧基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基和5-10个原子组成的杂芳基独立地未被取代或被1、2、3、4或5个R m所取代；
    R a、R a1、R a2、R a3和R b各自独立地为H、D、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基；
    各R m独立地为D、卤素、CN、NO 2、OH、NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基或卤代C 1-4烷氧基；
    R n为H、D、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基；
    R c和R d各自独立地为H、D、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4烷氧基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基；
    R 4为H、D、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基；
    各R 5独立地为H、D、卤素、NO 2、CN、OH、NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、卤代C 1-4烷氧基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基。
  5. 根据权利要求1或3所述的化合物，其中，环A为吡咯、吡唑、咪唑、三氮唑、四氮唑、呋喃、噻吩、噻唑、噁唑、吡啶、嘧啶、吡嗪、哒嗪或苯；
    各R 0独立地为H、D、F、Cl、Br、NO 2、CN、OH、NH 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、-CH 2F、-CH 2Cl、-CHF 2、-CHCl 2、-CF 3、-CH 2CH 2F、-CH 2CH 2Cl、-CH 2CHF 2、-CH 2CHCl 2、-CHFCH 2F、-CHClCH 2Cl、-CH 2CF 3、-CH(CF 3) 2、-CF 2CH 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、 -CH 2CH 2CF 3、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-1-丙氧基、2-丁氧基、2-甲基-2-丙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基、三氟乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、-OR a、-C(O)R a1、-C(O)NR a2R b、-C(O)OR a、-NR a2R b、-NR a3C(O)R a1、-NR a3C(O)OR a、-NR a3C(O)NR a2R b、-SO 2R a1、-SO 2NR a2R b或-NR a3SO 2NR a2R b，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、-CH 2F、-CH 2Cl、-CHF 2、-CHCl 2、-CH 2CH 2F、-CH 2CH 2Cl、-CH 2CHF 2、-CH 2CHCl 2、-CHFCH 2F、-CHClCH 2Cl、-CH 2CF 3、-CH(CF 3) 2、-CF 2CH 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-1-丙氧基、2-丁氧基、2-甲基-2-丙氧基、二氟甲氧基、二氟乙氧基、三氟乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基和哒嗪基独立地未被取代或被1、2、3、4或5个R m所取代。
  6. 根据权利要求1或3所述的化合物，其中，R a、R a1、R a2、R a3和R b各自独立为H、D、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CHFCH 2F、-CH 2CF 3、-CH(CF 3) 2、-CF 2CH 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基；
    各R m独立地为D、F、Cl、Br、I、NO 2、CN、OH、NH 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、-CH 2F、-CH 2Cl、-CHF 2、-CHCl 2、-CF 3、-CH 2CH 2F、-CH 2CH 2Cl、-CH 2CHF 2、-CH 2CHCl 2、-CHFCH 2F、-CHClCH 2Cl、-CH 2CF 3、-CH(CF 3) 2、-CF 2CH 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-1-丙氧基、2-丁氧基、2-甲基-2-丙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基；
    R n为H、D、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、-CH 2F、-CHF 2、-CH 2CH 2F、-CH 2CHF 2、-CHFCH 2F、-CH 2CF 3、-CH(CF 3) 2、-CF 2CH 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、乙烯基、丙烯基、烯丙基、乙炔基、炔丙基、1-丙炔基、1-炔丁基、2-炔丁基、3-炔丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基；
    R c和R d各自独立地为H、D、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、-CH 2F、-CHF 2、-CH 2CH 2F、-CH 2CHF 2、-CHFCH 2F、-CH 2CF 3、-CH(CF 3) 2、-CF 2CH 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、乙烯基、丙烯基、烯丙基、乙炔基、炔丙基、1-丙炔基、1-炔丁基、2-炔丁基、3-炔丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-1-丙氧基、2-丁氧基、2-甲基-2-丙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、 苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基；
    R 4为H、D、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、-CH 2F、-CHF 2、-CH 2CH 2F、-CH 2CHF 2、-CHFCH 2F、-CH 2CF 3、-CH(CF 3) 2、-CF 2CH 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、乙烯基、丙烯基、烯丙基、乙炔基、炔丙基、1-丙炔基、1-炔丁基、2-炔丁基、3-炔丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基；
    各R 5独立地为H、D、F、Cl、Br、NO 2、CN、OH、NH 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、-CH 2F、-CH 2Cl、-CHF 2、-CHCl 2、-CF 3、-CH 2CH 2F、-CH 2CH 2Cl、-CH 2CHF 2、-CH 2CHCl 2、-CHFCH 2F、-CHClCH 2Cl、-CH 2CF 3、-CH(CF 3) 2、-CF 2CH 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-1-丙氧基、2-丁氧基、2-甲基-2-丙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基、三氟乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基。
  7. 根据权利要求1或3所述的化合物，其为具有下列之一结构的化合物或具有下列之一结构的化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药：
    Figure PCTCN2021140889-appb-100006
    Figure PCTCN2021140889-appb-100007
  8. 一种药物组合物，其包含权利要求1-7任意一项所述的化合物，和所述药物组合物任选地进一步包含药学上可接受的赋形剂、载体、佐剂或它们的任意组合。
  9. 根据权利要求8所述的药物组合物，进一步包含一种或多种选自以下的其他活性成分：钙拮抗剂、血管紧张素AII拮抗剂、ACE抑制剂、血管肽酶抑制剂、内皮素拮抗剂、肾素抑制剂、α-受体阻断剂、β-受体阻断剂、盐皮质激素受体拮抗剂、ρ-激酶抑制剂、利尿剂、激酶抑制剂、基质金属蛋白酶抑制剂、可溶性乌苷酸环化酶刺激物和激活物以及磷酸二酯酶抑制剂。
  10. 权利要求1-7任意一项所述的化合物或权利要求8-9任意一项所述的药物组合物在制备药物中的用途，所述药物用于治疗或预防心力衰竭、肺动脉高血压、慢性阻塞性肺病、哮喘、肾衰竭、肾病、内部器官的纤维化病症或皮肤纤维化。
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