CN114671878B - Substituted nitrogen-containing bicyclic compounds and uses thereof - Google Patents

Substituted nitrogen-containing bicyclic compounds and uses thereof Download PDF

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CN114671878B
CN114671878B CN202111589877.5A CN202111589877A CN114671878B CN 114671878 B CN114671878 B CN 114671878B CN 202111589877 A CN202111589877 A CN 202111589877A CN 114671878 B CN114671878 B CN 114671878B
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CN114671878A (en
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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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Guangdong HEC Pharmaceutical
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Sunshine Lake Pharma Co Ltd
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms
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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
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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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
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
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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

Abstract

The invention discloses a substituted nitrogenous bicyclic compound and application thereof. In particular, the present invention relates to a novel class of substituted nitrogen-containing bicyclic compounds and pharmaceutical compositions comprising such compounds, which are useful as chymase inhibitors. The invention also relates to a method for preparing the compound and the pharmaceutical composition, and the application of the compound and the pharmaceutical composition in preparing medicaments for treating heart failure, myocardial infarction and other vascular diseases.

Description

Substituted nitrogen-containing bicyclic compounds and uses thereof
Technical Field
The invention belongs to the technical field of medicines, in particular relates to substituted nitrogenous bicyclic compounds and application thereof, and further relates to a pharmaceutical composition containing the compounds, and a use method and application thereof. In particular, the substituted nitrogen-containing bicyclic compounds and/or pharmaceutical compositions thereof of the present invention are useful as chymase inhibitors for the prevention, treatment or alleviation of vascular diseases of interest, such as heart failure or myocardial infarction.
Background
Cardiovascular disease (Cardiovascular diseases, CVD) is one of the leading causes of death worldwide. CVD refers to ischemic or hemorrhagic diseases of heart, brain and systemic tissues caused by hyperlipidemia, blood viscosity, atherosclerosis, hypertension, etc., such as hypertension, coronary artery disease, cardiomyopathy, vascular disease, congenital heart disease, arrhythmia, pericardial disease, heart attack, stroke, etc. Hypertension, high cholesterol, smoking, obesity and diabetes are major risk factors for developing cardiovascular disease. Health conditions such as lifestyle, age and family history also increase the risk of heart disease. While age, gender, genetic and family history are unalterable risks of susceptibility to cardiovascular disease, the burden of cardiovascular disease can be reduced by performing low fat and low sodium diets, maintaining physical activity and avoiding weight gain, among other methods. Several recent preclinical and several clinical studies point to a relatively unrecognized fact that chymase inhibitors may have significant therapeutic advantages over other treatments in preventing the progression of heart and vascular disease.
Chymase (Chymase) is a chymotrypsin-like serine protease whose macromolecular complex with heparin proteoglycans is stored in secretory vesicles of mast cells. After mast cells are activated, chymase is released into the extracellular matrix to cope with inflammatory signals, tissue damage and cellular stress. There is growing evidence that chymase of mast cells 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 elimination, such as fibrosis, angiogenesis and myocardial remodeling of the wound (Miyazaki et al, pharmacol. Ther,112 (2006), 668-676; shiota et al, J. Hypertens,21 (2003), 1823-1825). An increase in the number of mast cells was observed in the case of heart failure, myocardial infarction and ischemia, in the case of human atherosclerotic plaques and abdominal aortic aneurysms (Kovanen et al Circulation,92 (1995), 1084-1088; libby and Shi et al Circulation,115 (2007), 2555-2558; bacani and Frishman et al, cardiol. Rev,14 (4) (2006), 187-193). Chymase-positive mast cells play an important role in airway vascular remodeling in asthma and chronic obstructive pulmonary disease. It has been found that an increase in the number of mast cells is found in the intrabronchial biopsy of asthmatic patients (Zanini et al, J. Allergy Clin Immunol 120 (2007), 329-333). In addition, chymase is also suspected to be one of the causes of a variety of kidney diseases 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).
Chymase is mainly involved in the production of angiotensin II in the heart, arterial wall and lungs. Early studies by the cleveland clinic researchers demonstrated for the first time the role of chymase as an Ang II (angiotensin II) forming enzyme (uarta H et al, j. Biol. Chem,1990,265 (36): 22348-57). Over the past several decades, several studies have demonstrated and expanded the importance of chymase as a synthase for the Ang II production pathway (Chandrasekharan UM et al Science 1996,271 (5248):502-5). Subsequent studies of human and rodent heart Ang- (1-12) treatment showed that either Ang I or Ang- (1-12) directly formed Ang-II enzymes were chymase-based (Ahmad S et al, J.Am.Soc. Hypertens,2013 (2): 128-36). Ang II (angiotensin II) is an effector molecule that effects blood pressure regulation and water and electrolyte balance control mainly by acting on the cell surface nuclear membrane of the vessel wall, the renal tubule, glomerulus, and multiple target receptors of the adrenal gland. When angiotensin II binds to angiotensin receptor, corresponding physiological effects are caused, including systemic arteriole and venous constriction, blood pressure rise and blood return quantity increase; stimulating adrenal synthesis and release of aldosterone. Thus inhibiting chymase activation can reduce angiotensin production, and can control vasoconstriction and blood pressure elevation to a certain extent.
The possibility of treating various cardiovascular diseases with chymase inhibitors has been demonstrated in many animal experimental studies. Chymase inhibitors, for example, are very useful for treating myocardial infarction (Jin et al, pharmacol. Exp. Ther,309 (2004), 409-417), experiments have shown that when a coronary artery ligation in a dog causes ventricular arrhythmias, the production of angiotensin II in the heart is promoted, enhancing chymase activity. In recent years, bayer corporation is developing an oral small molecule chymase inhibitor BAY-1142524 for the treatment of heart failure and diabetic nephropathy, and preclinical results indicate that the compound can improve cardiac function after myocardial infarction in hamsters. Whereas clinical primary results also showed good safety, tolerability and pharmacokinetic properties of BAY-1142524 in healthy subjects. Currently, bayer company has developed a second-stage clinical experiment of BAY-1142524 for treating diabetic nephropathy, and further verifies the curative effect and safety of the novel chymase inhibitor.
Chymase inhibition thus constitutes an effective method of treating cardiovascular disorders, inflammatory, allergic and various fibrotic disorders.
Disclosure of Invention
The present invention provides a novel class of substituted nitrogen-containing bicyclic compounds as chymase inhibitors for the prevention, treatment or alleviation of vascular diseases of interest such as heart failure or myocardial infarction. Experiments show that the substituted nitrogenous bicyclic compound provided by the invention has stable property, good safety, good pharmacodynamics and pharmacokinetics, such as good chymase inhibition activity, good bioavailability, good metabolic stability and the like. Therefore, the compound has good clinical application prospect.
The invention also provides a method for preparing the compounds, a pharmaceutical composition containing the compounds and application of the compounds and/or the pharmaceutical composition of the compounds in preparing medicines.
In one aspect, the present invention relates to a compound which is a compound of formula (I), or a stereoisomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound of formula (I),
wherein: each A, R 0 、t、E、R 1 And R is 2 Has the meaning as described in the present invention.
In some embodiments, R 2 Is thatWherein R is 5 And m has the meaning described in the present invention.
In some embodiments, m is 0, 1, 2, 3, or 4.
In some embodiments, R 2 Is thatWherein R is 5 Having the meaning described in the present invention.
In some embodiments, the compounds of the present invention may be compounds of formula (IIa) or formula (IIb) or formula (IIc), or stereoisomers, tautomers, nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof of compounds of formula (IIa) or formula (IIb) or formula (IIc),
wherein: each A, R 0 、t、E、R 1 And R is 5 Has the meaning as described in the present invention.
In some embodiments, E is a bond, -CH 2 -or-C (=o) -. Preferably, E is-C (=o) -.
In some embodiments, ring a is a 5-6 membered heteroaryl ring or a benzene ring.
In some embodiments, ring a is pyrrole, pyrazole, imidazole, triazole, tetrazole, furan, thiophene, thiazole, oxazole, pyridine, pyrimidine, pyrazine, pyridazine, or benzene. Preferably, ring a is pyrazole, pyridine or benzene.
In some embodiments, 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 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 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 3-8 Cycloalkyl, heterocyclyl of 3-8 atoms, C 6-10 Aryl and heteroaryl consisting of 5-12 atoms are independently unsubstituted or substituted with 1, 2, 3, 4 or 5R m Substituted; r is R a 、R a1 、R a2 、R a3 、R b And R is m Each independently having the meaning described herein.
In some embodiments, t is 0, 1, 2, 3, or 4.
In some embodiments, R a 、R a1 、R a2 、R a3 And R is b Each independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, heterocyclyl of 3-8 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 12 atoms.
In some embodiments, 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 An alkoxy group.
In some embodiments, R 1 Is thatWherein R is 3 And R is 4 Having the meaning described in the present invention.
In some embodiments, R 3 is-NR n -, -O-, -S-or-CR c R d -; wherein R is n 、R c And R is d Each independently having the meaning described herein.
In some embodiments, R n H, D, C of a shape of H, D, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, heterocyclyl of 3-8 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 12 atoms.
In some embodiments, R c And R is d Each independently H, D, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, heterocyclyl of 3-8 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 12 atoms.
In some embodiments, R 4 H, D, C of a shape of H, D, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, heterocyclyl of 3-8 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 12 atoms.
In some embodiments, each R 5 H, D, halogen, NO independently 2 、CN、OH、NH 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 3-8 Cycloalkyl, heterocyclyl of 3-8 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 12 atoms.
In some embodiments, each R 0 H, D, F, cl, br, C independently 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, C 3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C 6-10 Aryl, heteroaryl consisting 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 said C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, C 3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C 6-10 Aryl and heteroaryl consisting of 5-10 atoms are independently unsubstituted or substituted with 1, 2, 3 or 4R m Substituted, wherein R is a 、R a1 、R a2 、R a3 、R b And R is m Each independently having the meaning described herein.
In some embodiments, R a 、R a 、R a1 、R a2 、R a3 And R is b Each independently H, D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 10 atoms.
In some embodiments, each R m Is independently D, halogen, CN, NO 2 、OH、NH 2 、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or halo C 1-4 An alkoxy group.
In some embodiments, R n H, D, C of a shape of H, D, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 10 atoms.
In some embodiments, R c And R is d Each independently H, D, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 10 atoms.
In some embodiments, R 4 H, D, C of a shape of H, D, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 10 atoms.
In some embodiments, each R 5 H, D, halogen, NO independently 2 、CN、OH、NH 2 、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, C 3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 10 atoms.
In some embodiments, each R 0 H, D, F, cl, br, NO independently 2 、CN、OH、NH 2 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 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 Methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, -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 methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 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 Methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, difluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl being unsubstituted or substituted with 1, 2, 3, 4 or 5R m Is substituted by a substituent of (2), wherein R a 、R a1 、R a2 、R a3 、R b And R is m Each independently having the meaning described herein.
In some embodiments, R a 、R a1 、R a2 、R a3 And R is b Each independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 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, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.
In some embodiments, each R m D, F, cl, br, NO independently 2 、CN、OH、NH 2 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 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 Methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy.
In some embodiments, R n H, D is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CHF 2 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-propargyl, 2-propargyl, 3-propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.
In some embodiments, R c And R is d Each independently is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CHF 2 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-propargyl, 2-propargyl, 3-propargyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.
In some embodiments, R 4 H, D is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CHF 2 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-propargyl, 2-propargyl, 3-propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl A group, a pyrazinyl group or a pyridazinyl group.
In some embodiments, each R 5 H, D, F, cl, br, NO independently 2 、CN、OH、NH 2 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 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 Methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.
In some embodiments, a compound of the invention has a stereoisomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures:
in another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention; optionally, it further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
In some embodiments, the pharmaceutical compositions of the present invention further comprise one or more additional active ingredients selected from the group consisting of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vascular peptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors, diuretics, kinase inhibitors, matrix metalloproteinase inhibitors, soluble guanylate cyclase stimulators and activators, and phosphodiesterase inhibitors.
In one aspect, the invention relates to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the preparation of a medicament for the treatment or prevention of heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, renal failure, kidney disease, fibrotic disorders of internal organs or skin fibrosis.
In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I) or (IIa) or (IIb) or (IIc).
Biological test results show that the compound has good chymase inhibition activity and can be used as a good chymase inhibitor, thereby having the potential effect of preventing occurrence and progress of diseases.
Any of the embodiments of any of the aspects of the invention may be combined with other embodiments, provided that they do not contradict. Furthermore, in any of the embodiments of any of the aspects of the present invention, any technical feature may be applied to the technical feature in other embodiments as long as they do not contradict.
The foregoing merely outlines certain aspects of the invention and is not limited in this regard. These and other aspects are described more fully below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification is different from that of the cited document, the disclosure of the present specification controls.
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.
It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be referenced to the descriptions in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato:1999, and "March's Advanced Organic Chemistry" by Michael b.smith and Jerry March, john Wiley & Sons, new york:2007, the entire contents of which are incorporated herein by reference.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
The articles "a," "an," and "the" are intended to include "at least one" or "one or more" unless the context clearly dictates otherwise or otherwise. Thus, as used herein, the articles refer to articles of manufacture that include one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., more than one component is contemplated as being employed or used in embodiments of the described embodiments.
The term "stereoisomer" refers to a compound having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like.
The term "chiral molecule" is a molecule that has the property of not overlapping its mirror image; and "achiral molecule" refers to a molecule that may overlap with its mirror image.
The term "enantiomer" refers to two isomers of a compound that do not overlap but are in mirror image relationship to each other.
The term "racemate" or "racemic mixture" refers to an equimolar mixture of two enantiomers lacking optical activity.
The term "diastereoisomer" 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. The diastereomeric mixture may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, ed., mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, new York; and Eliel, E.and Wilen, S, "Stereochemistry of Organic Compounds", john Wiley & Sons, inc., new York,1994.
Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to represent the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light by a compound, where (-) or l indicates that the compound is left-handed. The compound prefixed with (+) or d is dextrorotatory. One particular stereoisomer is an enantiomer, and a mixture of such isomers is referred to as an enantiomeric mixture. A50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
Any asymmetric atom (e.g., carbon, etc.) of the disclosed compounds may exist in racemic or enantiomerically enriched form, such as in the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and methods, the compounds of the invention may be present in the form of one of the possible isomers or mixtures thereof, for example racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. 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 group, the substituents of the cycloalkyl group may have cis or trans configuration.
The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.
Any of the resulting racemates of the end products or intermediates can be resolved into the optical enantiomers by methods familiar to those skilled in the art, e.g., by separation of the diastereoisomeric salts thereof obtained, using known methods. The racemic product can also be separated by chiral chromatography, e.g., high Performance Liquid Chromatography (HPLC) using chiral adsorbents. In particular, enantiomers may be prepared by asymmetric synthesis, for example, reference may be made to Jacques, et al, encomers, 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:APractical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers (prototropic tautomer)) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation.
By "pharmaceutically acceptable" is meant those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
The term "optionally substituted with … …" may be used interchangeably with the term "unsubstituted or substituted with … …," i.e., the structure is unsubstituted or substituted with one or more substituents described herein.
In general, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced with a particular substituent. Unless otherwise indicated, a substituent may be substituted at a reasonable position at which each of the groups may be substituted. When more than one position in a given formula can be substituted with one or more specific substituents selected from, then the substituents may be the same or different at each reasonable position in the formula.
The term "unsubstituted" means that the specified group does not carry a substituent.
In addition, unless explicitly indicated otherwise, the descriptions used in this disclosure of the manner in which each … is independently "and" … is independently "and" … is independently "are to be construed broadly as meaning that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. The subject, for example, also refers to a primate (e.g., human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically intended that the present invention includes such groups of the species and scopeEach of the individual members of (a) are independently sub-combinations. For example, the term "C 1 -C 6 Alkyl "means in particular methyl, ethyl, C independently disclosed 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 An alkyl group.
The term "D" represents a single deuterium atom.
The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
The term "alkyl" or "alkyl group" as used herein means a saturated straight or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms. In one embodiment, the alkyl group contains 1 to 6 carbon atoms, i.e., C 1-6 An alkyl group; in another embodiment, the alkyl group contains 1 to 4 carbon atoms, i.e., C 1-4 An alkyl group; in one embodiment, the alkyl group contains 1 to 3 carbon atoms, i.e., C 1-3 An alkyl group. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ) Ethyl (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) 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) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 2, 2-dimethylbutyl (neopentyl, -CH) 2 CH(CH 3 ) 2 CH 3 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) N-heptyl, n-octyl, and the like.
The term "alkenyl" denotes a straight-chain or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms, in which there is at least one site of unsaturation, i.e. one carbon-carbon sp 2 Double bonds, which include the positioning of "cis" and "trans", or the positioning of "E" and "Z". Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl (propenyl, -ch=ch-CH 3 ) 2-propenyl (allyl, -CH) 2 -CH＝CH 2 ) And so on.
The term "alkynyl" denotes a straight or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms, in which there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond. In some embodiments, alkynyl groups contain 2 to 8 carbon atoms; in other embodiments, alkynyl groups contain 2 to 6 carbon atoms; in still other embodiments, alkynyl groups contain 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH) 2 C.ident.CH), 1-propynyl (-C.ident.C-CH) 3 ) 1-propargyl (-CH) 2 CH 2 C.ident.CH), 2-alkynylbutyl (-CH) 2 C≡CCH 3 ) 3-propargyl (-C.ident.CCH) 2 CH 3 ) Etc.
The term "alkoxy" means that the 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 to 12 carbon atoms. In some embodiments, the alkoxy group contains 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in still other embodiments, the alkoxy group contains 1 to 3 carbon atoms.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) 3 ) Ethoxy (EtO, -OCH) 2 CH 3 ) 1-propoxy (n-PrO, n-propoxy, -OCH) 2 CH 2 CH 3 ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) 3 ) 2 ) 1-butoxy (n-BuO, n-butoxy, -OCH) 2 CH 2 CH 2 CH 3 ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) 2 CH(CH 3 ) 2 ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ) 1-pentoxy (n-pentoxy, -OCH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentoxy (-OCH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentoxy (-OCH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butoxy (-OC (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butoxy (-OCH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-l-butoxy (-OCH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-l-butoxy (-OCH) 2 CH(CH 3 )CH 2 CH 3 ) And so on.
The term "haloalkoxy" means that the alkoxy group is substituted with one or more halogen atoms, wherein alkoxy has the meaning described herein. Examples include, but are not limited to, difluoromethoxy (-OCHF) 2 ) Trifluoromethoxy (-OCF) 3 ) Difluoroethoxy (e.g. -OCH) 2 CHF 2 Etc.), trifluoroethoxy groups (e.g. -OCH 2 CF 3 Etc.), and so on.
The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms, wherein alkyl has the meaning described herein. Some of these embodiments are those wherein the haloalkyl group contains from 1 to 12 carbon atoms; still other embodiments are haloalkyl groups containing 1 to 10 carbon atoms; still other embodiments are haloalkyl groups containing 1 to 8 carbon atoms; still other embodiments are haloalkyl groups containing 1 to 6 carbon atoms; still other embodiments are haloalkyl groups containing 1 to 4 carbon atoms, and still other embodiments are haloalkyl groups containing 1 to 3 carbon atoms. Examples include, but are not limited to, difluoromethyl, trifluoromethyl, trifluoroethyl (e.g. -CH 2 CF 3 Etc.), etc.
The term "cycloalkyl" means a saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring carbon atoms. In some embodiments, cycloalkyl groups contain 3 to 10 ring carbon atoms, e.g., C 3-10 Cycloalkyl; in other embodiments, cycloalkyl groups contain 3 to 8 ring carbon atoms, e.g., C 3-8 Cycloalkyl; in still other embodiments, cycloalkyl groups contain 3 to 6 ring carbon atoms, e.g., C 3-6 Cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Wherein, as described in the invention, C 3-8 Cycloalkyl includes C 3-6 Cycloalkyl; the C is 3-6 Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein to refer to a monovalent or multivalent, saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise indicated, a heterocyclic group may be a carbon or nitrogen group, and-CH 2 The group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. Heterocyclic groups include saturated heterocyclic groups (i.e., heterocycloalkyl groups) and partially unsaturated heterocyclic groups. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, or morpholinyl, and the like. The heterocyclic group, according to the present invention, may consist of 3-8 atoms or 3-6 atoms, optionally selected from C, N, O or S and at least one atom being N, O or S; wherein the heterocyclic group consisting of 3 to 8 atoms comprises a heterocyclic group consisting of 3 to 6 atoms; the heterocyclic group consisting of 3 to 6 atoms includes heterocyclic groups consisting of 3 to 5 atoms. Specifically, the heterocyclic group consisting of 3 to 6 atoms includes, but is not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like.
The term "consisting of s atoms", where s is an integer, typically describes the number of ring-forming atoms in a molecule where the number of ring-forming atoms is s. For example, piperidinyl is a heterocycloalkyl of 6 atoms, while 1,2,3, 4-tetrahydronaphthyl is a carbocyclyl of 10 atoms.
The term "unsaturated" as used in the present invention means that the group contains one or more unsaturations.
The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state forms of P; primary, secondary, tertiary and quaternary ammonium salt forms; or a form in which the hydrogen on the nitrogen atom of the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl where R is any suitable substituent).
The term "aryl" means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains rings of 3 to 7 atoms, and has one or more points of attachment to the remainder of the moleculeAre connected. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl and anthracenyl. Unless otherwise indicated, the group "C 6-10 Aryl "means an aryl group containing 6 to 10 ring carbon atoms.
The term "heteroaryl" means monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 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 wherein said heteroaryl has one or more attachment points attached to the remainder of the molecule. When the-CH is present in the heteroaryl group 2 -said-CH, when a group is 2 The group may optionally be replaced by-C (=o) -. Unless otherwise indicated, the heteroaryl group may be attached to the remainder of the molecule (e.g., the host structure in the formula) at any reasonable point (which may be C in CH, or N in NH). The term "heteroaryl" may be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". Examples of heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, and the like. In some embodiments, heteroaryl is a heteroaryl consisting of 5 to 10 atoms, meaning that the heteroaryl contains 1 to 9 ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms selected from O, S and N; in other embodiments, heteroaryl is a heteroaryl consisting of 5-6 atoms, meaning that the heteroaryl contains 1-5 ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms selected from O, S and N, examples of heteroaryl 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.
The term "protecting group" or "PG" refers to a substituent that is commonly used to block or protect a particular functionality when reacted with other functional groups. For example, an "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of an amino group in a compound, suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxy Carbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality that a substituent of a hydroxy group serves to block or protect the hydroxy group, and suitable protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl. "carboxyl protecting group" refers to the functionality of a substituent of a carboxyl group to block or protect the carboxyl group, and typically the carboxyl protecting group includes-CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General description of protecting groups can be found in the literature: greene et al Protective Groups in Organic Synthesis, john Wiley&Sons,New York,1991and Kocienski et al.,Protecting Groups,Thieme,Stuttgart,2005。
The term "prodrug" as used herein means a compound that is converted in vivo to a compound of formula (I) or (IIa) or (IIb) or (IIc). Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be ester, and in the prior invention, the ester can be phenyl ester, aliphatic (C 1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following documents: higuchi and V.stilla, pro-drugs as Novel Delivery Systems, vol.14of 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, prodrug: 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。
"metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.
As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as in the literature: m. berge et al describe pharmaceutically acceptable salts in detail in j. Pharmaceutical Sciences,1977, 66:1-19. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or by other methods described in the literature such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartate, benzenesulfonates, benzoates, bisulfate, borates, butyrates, camphorinates, camphorsulfonates, cyclopentylpropionates, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodinates, 2-hydroxy-ethanesulfonate, lactobionic aldehyde, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenyl sulfonate Propionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained by suitable bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 Alkyl group 4 Is a salt of (a). The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. The water-soluble or oil-soluble or dispersible product may be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. The pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and counter-ion forming amine cations, such as halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C 1 -C 8 Sulfonate and aromatic sulfonate.
"nitroxide" in the present invention means that when a compound contains several amine functions, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocycles. The corresponding amine may be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, wiley Interscience, 4 th edition, jerry March, pages). In particular, the N-oxides can be prepared by the method L.W.Deady (Syn.Comm.1977, 7, 509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent such as methylene chloride.
"solvate" according to the present invention refers to an association of one or more solvent molecules with a compound according to the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association of solvent molecules that are water.
When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of a compound of the invention may be associated with a water molecule, such as a monohydrate; in another embodiment, one molecule of the compounds of the present invention may be combined with more than one water molecule, such as dihydrate; in yet another embodiment, one molecule of the compounds of the present invention may be associated with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates described in the present invention retain the biological effectiveness of the compounds in a non-hydrated form.
The term "treating" any disease or disorder, in some embodiments refers to ameliorating the disease or disorder (i.e., slowing or preventing or alleviating the progression of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, or exacerbation of a disease or disorder.
The term "preventing" or "prevention" refers to a reduction in the risk of acquiring a disease or disorder (i.e., stopping the progression of at least one clinical symptom of a disease in a subject who may or may not have been predisposed to facing such a disease, but who has not yet experienced or exhibited symptoms of the disease).
The term "cardiovascular disease" refers to a collective term for cardiovascular and cerebrovascular diseases, describing ischemic or hemorrhagic diseases of the heart, brain and systemic tissues of a patient due to hyperlipidemia, blood viscosity, atherosclerosis, hypertension, etc. 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 attacks, stroke, preeclampsia, inflammatory cardiovascular diseases, peripheral and cardiovascular diseases, peripheral perfusion disorders, pulmonary hypertension, coronary and peripheral arterial spasms, thrombosis, thromboembolic diseases, edema development (e.g. pulmonary edema, cerebral edema, renal edema or heart failure-related edema), and restenosis (e.g. restenosis after thrombolytic therapy, percutaneous Transluminal Angioplasty (PTA), percutaneous Transluminal Coronary Angioplasty (PTCA), cardiac grafting and bypass surgery), and microvascular and macrovascular injuries (vasculitis), reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, peripheral and cardiovascular diseases, peripheral perfusion disorders, heart failure-related edema, elevated levels of fibrinogen and low density LDL, and elevated levels of activator of fibrinolytic agent (I-1) inhibitors.
Compounds of the invention
In one aspect, the present invention relates to compounds having the structure of formula (I), wherein the variables are as defined above.
In some embodiments, the compounds of formula (I) of the present invention may be compounds of formula (IIa), formula (IIb) or formula (IIc), wherein the variables are as defined above.
Unless otherwise indicated, stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof of the compounds of formula (I) or formula (IIa) or formula (IIb) or formula (IIc) are included within the scope of the invention.
The disclosed compounds may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention is intended to make all stereoisomeric forms of the compounds of formula (I) or (IIa) or (IIb) or (IIc), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, as well as mixtures thereof, such as racemic mixtures, a part of the present invention.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of that structure are contemplated as being within the present invention and are included as presently disclosed compounds. When stereochemistry is indicated by the solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of that structure are so defined and defined.
The compounds of formula (I) or (IIa) or (IIb) or (IIc) may exist in different tautomeric forms and all such tautomers, such as those described herein, are included within the scope of the invention.
The compounds of the formula (I) or (IIa) or (IIb) or (IIc) may be present in salt form. In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. In other embodiments, the salt is not necessarily a pharmaceutically acceptable salt, and may be an intermediate for preparing and/or purifying a compound of formula (I) or (IIa) or (IIb) or (IIc) and/or for isolating an enantiomer of a compound of formula (I) or (IIa) or (IIb) or (IIc).
Pharmaceutically acceptable acid addition salts may be formed from the reaction of a compound of formula (I) or (IIa) or (IIb) or (IIc) with an inorganic or organic acid, for example acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, clenchine salt, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodite/iodide, isethionate, lactate, lactobionic aldehyde, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalactoate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.
Inorganic acids from which salts may be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
Organic acids from which salts may 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 and the like.
Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
Inorganic bases from which salts may be derived include, for example, ammonium salts and metals of groups I to XII of the periodic Table. In certain embodiments, the salt is 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 may be derived include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (choline), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine and tromethamine.
Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound, basic or acidic moiety using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., na, ca, mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixture of both. Generally, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and "manual of pharmaceutically acceptable salts: a list of further suitable salts can be found in Properties, selection and application (Handbook of Pharmaceutical Salts: properties, selection, and Use) ", stahl and Wermuth (Wiley-VCH, weinheim, germany, 2002).
In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) containing them, for their crystallization. The disclosed compounds may form solvates inherently or by design with pharmaceutically acceptable solvents (including water); accordingly, the present invention is intended to include solvated and unsolvated forms.
Any formulae given herein are also intended to represent non-isotopically enriched forms as well as isotopically enriched forms of such compounds. Isotopically enriched compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic or mass number. Exemplary isotopes that can be incorporated into compounds of the 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 Cl 125 I。
In another aspect, the compounds of the invention include isotopically enriched compounds defined in the invention, e.g., wherein a radioisotope, such as 3 H、 14 C and C 18 F, or in which non-radioactive isotopes are present, e.g 2 H and 13 C. such isotopically enriched compounds are useful in metabolic studies (using 14 C) Reaction kinetics studies (using, for example 2 H or 3 H) Detection or imaging techniques, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution assays, or may be used in radiation therapy of a patient. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) or (IIa) or (IIb) or (IIc) can be prepared by conventional techniques familiar to those skilled in the art or by describing the examples and processes of preparation of the present invention using a suitable isotopically labelled reagent in place of the originally used unlabelled reagent.
In addition, heavier isotopes are in particular deuterium (i.e., 2 substitution of H or D) may provide certain therapeutic advantages, which are brought about by a higher metabolic stability.For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is to be understood that deuterium in the context of the present invention is to be regarded as a substituent of a compound of formula (I) or (IIa) or (IIb) or (IIc). The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopically enriched factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), 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 invention include those wherein the crystallization solvent may be isotopically substituted, e.g. D 2 O, acetone-d 6 、DMSO-d 6 Those solvates of (a).
In another aspect, the present invention relates to intermediates for preparing compounds of formula (I) or (IIa) or (IIb) or (IIc).
In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I) or (IIa) or (IIb) or (IIc).
Pharmaceutical compositions, formulations and administration of the compounds of the invention
The invention provides a pharmaceutical composition, which comprises a compound shown as a formula (I) or a formula (IIa) or a formula (IIb) or a formula (IIc) or individual stereoisomers, racemic or non-racemic mixtures of isomers or pharmaceutically acceptable salts or solvates thereof. In one embodiment of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally, other therapeutic and/or prophylactic ingredients.
Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail in, for example, ansel h.c. et al, ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, williams & Wilkins, philiadelphia; 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 administration of a compound or pharmaceutical composition of the invention, further comprising an additional therapeutic agent, wherein the additional active ingredient: calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vascular peptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors, diuretics, kinase inhibitors, matrix metalloproteinase inhibitors, soluble guanylate cyclase stimulators and activators, and phosphodiesterase inhibitors.
As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle associated with consistency of administration dosage form or pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that would greatly reduce the efficacy of the disclosed compounds and interactions that would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.
Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form selected. Furthermore, pharmaceutically acceptable excipients may be selected according to their particular function in the composition. For example, certain pharmaceutically acceptable excipients may be selected that can aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients that can aid in the production of stable dosage forms can be selected. Certain pharmaceutically acceptable excipients may be selected that facilitate carrying or transporting the compounds of the present invention from one organ or portion of the body to another organ or portion of the body when administered to a patient. Certain pharmaceutically acceptable excipients that enhance patient compliance may be selected.
Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives, stabilizers, surfactants, and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and alternative functions, depending on how much of the excipient is present in the formulation and which other excipients are present in the formulation.
The skilled artisan will know and be familiar with the art to which they will be able to select the appropriate amount of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there are a number of resources available to the skilled person, who describe pharmaceutically acceptable excipients and are used to select the appropriate pharmaceutically acceptable excipient. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), the Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
For preparing pharmaceutical compositions from the compounds described herein, the pharmaceutically acceptable carrier may be a solid or liquid carrier. 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 the various compositions can be found in the following: gennaro (ed.), remington's Pharmaceutical Sciences,18 th ed.,1990,Mack Publishing Company Co.,Easton,Pennsylvania。
Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed in Remington, the Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York, the contents of each of which are incorporated herein by reference. It is within the scope of the present invention to contemplate its use in addition to any common carrier that is incompatible with the compounds of the present invention, such as by producing any undesirable biological effect, or by interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition.
The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
Thus, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof, which process comprises mixing the various ingredients. Pharmaceutical compositions comprising the compounds of the present disclosure may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.
The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by the desired route. For example, dosage forms include those suitable for the following routes of administration: (1) Oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) Parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patch tablets; (4) rectal administration, such as suppositories; (5) inhalations, such as aerosols, solutions and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.
It will also be appreciated that certain compounds of the invention may exist in free form for use in therapy or, if appropriate, in the form of pharmaceutically acceptable derivatives thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adducts or derivatives that provide, directly or indirectly, the compounds of the present invention, or metabolites or residues thereof, when administered to a patient in need thereof.
In one embodiment, the presently disclosed compounds may be formulated into oral dosage forms. In another embodiment, the presently disclosed compounds may be formulated into an inhalation dosage form. In another embodiment, the presently disclosed compounds may be formulated for nasal administration. In yet another embodiment, the presently disclosed compounds may be formulated into transdermal dosage forms. In yet another embodiment, the presently disclosed compounds may be formulated into topical dosage forms.
The pharmaceutical compositions provided by the present invention may be provided in the form of compressed tablets, developed tablets, chewable lozenges, instant tablets, reconstituted tablets, enteric 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, thereby 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, aminated shellac, and cellulose acetate phthalate. Dragees are dragee-enclosed compressed tablets that can facilitate masking of unpleasant tastes or odors and prevent oxidation of the tablet. The film coated tablet is a compressed tablet 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. The film coating imparts the same general characteristics as the sugar coating. The composite tablet is a compressed tablet prepared through more than one compression cycle, and comprises a multi-layer tablet, a compression coating or a dry coating tablet.
Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or particulate form alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.
The pharmaceutical composition provided by the invention can be provided in a soft capsule or a hard capsule, and can be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsule, also known as a Dry Filled Capsule (DFC), consists of two segments, one segment being filled 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. The soft gelatin shell may contain a preservative 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 herein may be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in U.S. patent 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 dissolution of the active ingredient.
The pharmaceutical compositions provided herein may 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 form of pellets in another liquid, which may be oil-in-water or water-in-oil. The emulsion may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers, and preservatives. Suspensions may include pharmaceutically acceptable suspending agents and preservatives. The aqueous alcohol solution may include a pharmaceutically acceptable acetal, such as a di (lower alkyl) acetal of a lower alkyl aldehyde, for example, acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweet aqueous alcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example sucrose, and may also contain a preservative. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for accurate and convenient administration.
The pharmaceutical compositions provided herein may be formulated in any dosage form suitable for administration by inhalation to a patient, such as a dry powder, aerosol, suspension or solution composition. In one embodiment, the disclosed pharmaceutical compositions can be formulated into dosage forms suitable for administration by inhalation to a patient using dry powders. In yet another embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for administration by inhalation to a patient via a nebulizer. Dry powder compositions for delivery to the lungs by inhalation typically comprise a finely powdered compound of the presently disclosed invention and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients 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. The fine powder can be prepared by, for example, micronization and grinding. In general, the size-reduced (e.g., micronized) compound may be produced by a D of about 1 to 10 microns 50 Values (e.g., measured using laser diffraction methods) are defined.
Pharmaceutical compositions suitable for transdermal administration may be formulated as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch by ion permeation, as generally described in Pharmaceutical Research,3 (6), 318 (1986).
Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams and gels may be formulated with water or oil bases, with appropriate thickening and/or gelling agents and/or solvents. Such a base may include water, and/or oils such as liquid paraffin and vegetable oils (e.g., peanut oil or castor oil), or solvents such as polyethylene glycol. Thickening and gelling agents used according to the nature of the matrix include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or glyceryl monostearate and/or nonionic emulsifiers.
The compounds of the present invention may also be conjugated to soluble polymers as carriers for targeted drugs. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl asparaginol or palmitoyl residue substituted polyoxyethylene polylysine. In addition, the disclosed compounds may be combined with a class of biodegradable polymers used in achieving controlled release of drugs, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphiphilic block copolymers of hydrogels.
The pharmaceutical compositions provided herein may be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for making solutions or suspensions in liquids prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical sciences (see Remington: the Science and Practice of Pharmacy, supra).
Pharmaceutical compositions contemplated for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients including, but not limited to, aqueous vehicles, water miscible vehicles, non-aqueous vehicles, antimicrobial or antimicrobial growth preservatives, stabilizers, dissolution enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, freezing point depressants, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.
The pharmaceutical compositions provided by the present invention may be administered via rectal suppositories by mixing the drug with suitable non-irritating excipients such as cocoa butter, polyethylene glycol synthetic glycerides, which are solid at ordinary temperatures, and then liquefying or dissolving the drug in the rectal cavity. Because of individual differences, the severity of symptoms can vary considerably and each drug has its unique therapeutic properties, the dosage form and treatment regimen should be determined by the practitioner for each individual precise mode of administration.
The pharmaceutical compositions provided herein may be formulated in immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.
The term "therapeutically effective amount" as used herein 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 alleviate symptoms of the disease is administered or equilibrated in vivo. The effective amount required for a particular therapeutic regimen will depend upon a variety of factors including the disease being treated, the severity of the disease, the activity of the particular agent being used, the mode of administration, the rate of clearance of the particular agent, the duration of the treatment, the combination, the age, body weight, sex, diet and health of the patient, etc. Other factors considered in the art for "therapeutically effective amounts" are described in 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。
The appropriate dosage of the compounds of the invention to be administered to a patient can be readily determined by one skilled in the art (e.g., an attending physician, pharmacist or other skilled person) and can vary depending on the health of the patient, age, weight, frequency of administration, use of other active ingredients, and/or the indication for which the compounds are being administered. The dosage of the compounds of the present invention may range from about 0.001 to 500mg/kg body weight/day. In some embodiments, the amount of active compound in a unit dose of the formulation may be varied or adjusted depending on the particular application. In other embodiments, for oral administration, a typical daily dosing regimen suggested may be in the range of about 1 mg/day to about 500 mg/day, given two to four separate doses.
The term "administering" refers to providing a therapeutically effective amount of a drug to an individual by means including oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, and the like. The administration form includes paste, lotion, tablet, capsule, pill, powder, granule, suppository, pellet, lozenge, injection, sterile solution or nonaqueous solution, suspension, emulsion, patch, etc. The active ingredient is compounded with a non-toxic pharmaceutically acceptable carrier (e.g., dextrose, lactose, gum 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, and the dosage will vary depending on the condition of the patient being treated, and the physician will determine the appropriate dosage for the individual patient. The therapeutically effective amount per unit dose depends on the body weight, physiology and the chosen vaccination regimen. The weight of the compound per unit dose is the weight of the compound per administration and does not include the weight of the carrier (the carrier is contained in the drug).
The pharmaceutical compositions provided by the invention can be formulated for single or multiple dose administration. The single dose formulation is packaged in ampules, vials or syringes. The multi-dose parenteral formulation must contain antimicrobial agents at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as is known and practiced in the art.
The pharmaceutical compositions provided herein may be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.
In one embodiment, the methods of treatment of the present invention comprise administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. Embodiments of the present invention include treating the diseases mentioned herein by administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention.
In one embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention may be administered by any suitable route of administration, including systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, and rectal administration. Typical parenteral administration refers to administration by injection or infusion and includes intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin, intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention may be administered orally. In another embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention may be administered by inhalation. In yet another embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention may be administered intranasally.
In one embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention may be administered at once, or at several times at different time intervals over a specified period of time, depending on the dosing regimen. For example, once, twice, three times or four times daily. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. The administration may be performed until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for a compound of the invention or a pharmaceutical composition comprising a compound of the invention depend on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by the skilled artisan. Furthermore, suitable dosing regimens for a compound of the invention or a pharmaceutical composition comprising a compound of the invention, including the duration of time for which the regimen is performed, will depend 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 concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that adjustments to the appropriate dosing regimen may be required for the individual patient's response to the dosing regimen, or as the individual patient needs to change over time.
The compounds of the invention may be administered simultaneously with, or before or after, one or more other therapeutic agents. The compounds of the present invention may be administered separately from other therapeutic agents by the same or different routes of administration, or in the same pharmaceutical compositions as they are. This is chosen by the person skilled in the art according to the physical conditions of the patient's health, age, weight, etc. If formulated as a fixed dose, such combination products employ the compounds of the invention (within the dosage ranges described herein) and other pharmaceutically active agents (within the dosage ranges thereof).
Accordingly, in one aspect, the invention includes combinations comprising an amount of at least one compound of the invention, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more of the additional therapeutic agents described above.
Furthermore, the compounds of the present invention may be administered in the form of prodrugs. In the present invention, a "prodrug" of a compound of the invention is a functional derivative that, when administered to a patient, ultimately releases the compound of the invention in vivo. When the compounds of the invention are administered in prodrug form, one skilled in the art can practice one or more of the following modes: (a) altering the in vivo onset time of the compound; (b) altering the duration of in vivo 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 compounds. Typical functional derivatives useful for the preparation of prodrugs include variants of compounds that cleave chemically or enzymatically in vivo. These variants, including the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.
Use of the compounds and pharmaceutical compositions of the invention
The compound and the pharmaceutical composition provided by the invention can be used for preparing medicines for inhibiting chymase and also can be used for preparing medicines for treating or preventing heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, renal failure, nephropathy, fibrosis diseases of internal organs and skin fibrosis.
In the context of the present invention, a disease of the cardiovascular system or cardiovascular disease is understood to mean, for example, the following diseases: 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, preeclampsia, inflammatory cardiovascular disease, peripheral and cardiovascular disease, peripheral perfusion disorders, pulmonary hypertension, coronary and peripheral arterial spasms, thrombosis, thromboembolic disease, edema development (e.g., pulmonary edema, cerebral edema, renal edema, or heart failure-related edema), and restenosis (e.g., restenosis following thrombolytic therapy, percutaneous Transluminal Angioplasty (PTA), percutaneous Transluminal Coronary Angioplasty (PTCA), cardiac transplantation, and bypass surgery), and microvascular and macrovascular injuries (vasculitis), reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, peripheral and heart vascular disease, peripheral perfusion disorders, heart failure-related edema, elevated levels of fibrinogen and low density LDL, and elevated concentrations of activator of fibrinolytic activator/1 (PAI-1) inhibitors.
In the context of the present invention, the term "heart failure" also includes more specific or related types of diseases, such as acute decompensated heart failure, right heart failure, left heart failure, overall failure, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, heart valve defects, heart failure associated with heart valve defects, mitral stenosis, mitral insufficiency, aortic stenosis, aortic insufficiency, tricuspid stenosis, pulmonary valve insufficiency, combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, heart storage disorders, and diastolic and systolic heart failure.
The compounds of the invention may be used, but are in no way limited to, the administration to a patient of an effective amount of a compound or pharmaceutical composition of the invention to prevent, treat or ameliorate chymase-related diseases. The chymase-associated diseases further include, but are not limited to, heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, renal failure, kidney disease, fibrotic disorders of internal organs, and skin fibrosis.
The compounds and pharmaceutical compositions of the present invention are useful for veterinary treatment of mammals, in addition to human therapy, in pets, in animals of introduced species and in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.
General synthetic procedure
For the purpose of illustrating the invention, examples are set forth below. It is to be understood that the invention is not limited to these examples but provides a method of practicing the invention.
In general, the compounds of the invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I) or (IIa) or (IIb) or (IIc), unless otherwise indicated. The following reaction schemes and examples are provided to further illustrate the present invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-exemplified compounds according to the invention can be successfully accomplished by modification methods, such as appropriate protection of interfering groups, by use of other known reagents in addition to those described herein, or by some conventional modification of the reaction conditions, by those skilled in the art. In addition, the reactions disclosed herein or known reaction conditions are also well-known to be applicable to the preparation of other compounds of the present invention.
The examples described below are given unless otherwise indicated that all temperatures are given in degrees celsius. Reagents were purchased from commercial suppliers and used without further purification unless otherwise indicated.
1 H NMR spectra were recorded using a Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer. 1 H NMR Spectroscopy with CDC1 3 、DMSO-d 6 、CD 3 OD or acetone-d 6 As solvent (in ppm),TMS (0 ppm) or chloroform (7.26 ppm) was used as a reference standard. When multiple peaks occur, the following abbreviations will be used: s (single, singlet), d (doublet ), t (triplet, quartet), q (quartet), m (multiplet ), br (broadened, broad), brs (broadened singlet, broad singlet), dd (doublet of doublets, doublet), ddd (doublet of doublet of doublets, doublet), dt (doublet of triplets, doublet), td (triplet of doublets, triplet), tt (triplet of triplets, triplet). Coupling constant J, expressed in hertz (Hz).
The measurement conditions for low resolution Mass Spectrometry (MS) data are: agilent 6120 four-stage HPLC-M (column type: zorbax SB-C18, 2.1X130 mm,3.5 μm, 6min, flow rate 0.6mL/min. Mobile phase: 5% -95% (CH containing 0.1% formic acid) 3 CN) in (H containing 0.1% formic acid) 2 O) was detected by UV at 210nm/254nm using electrospray ionization (ESI).
The following abbreviations are used throughout the present invention:
the following synthetic schemes describe the steps for preparing the disclosed compounds of the present invention, wherein R, unless otherwise indicated 1 And R is 2 Having the definition according to the invention.
Synthesis scheme 1
Wherein PMB means p-methoxybenzyl, i.e
A compound of formula (M11) may be prepared by this synthetic scheme 1 wherein het is a 5-6 membered heteroaromatic ring: esterifying the compound shown in the formula (M1) to obtain a compound shown in the formula (M2); reacting the compound shown in the formula (M2) with 4-methoxybenzyl chloride to obtain a compound shown in the formula (M3); the compound shown in the formula (M3) is subjected to hydrogenation reduction to obtain a compound shown in the formula (M4); reacting a compound shown in a formula (M4) with phenyl chloroformate to obtain a compound shown in a formula (M5); reacting a compound represented by the formula (M5) with a compound represented by the formula (M6) to obtain a compound represented by the formula (M7); closing a ring of the compound shown in the formula (M7) to obtain a compound shown in the formula (M8); reacting a compound represented by the formula (M8) with a compound represented by the formula (M9) to obtain a compound represented by the formula (M10); the compound represented by the formula (M10) is deprotected under acidic conditions to give a compound represented by the formula (M11).
Synthesis scheme 2
A compound of formula (M18) may be prepared by this synthetic scheme 2 wherein X, Y, W and Z are each independently CH or N: nucleophilic substitution reaction is carried out on the compound shown in the formula (M12) and the compound shown in the formula (M13) to obtain a compound shown in the formula (M14); the compound shown in the formula (M14) is subjected to condensation reaction to obtain a compound shown in the formula (M15); performing ring-closing reaction on the compound shown in the formula (M15) and CDI to obtain a compound shown in the formula (M16); the compound represented by the formula (M16) and the compound represented by the formula (M17) undergo a coupling reaction to obtain the compound represented by the formula (M18).
Synthesis scheme 3
The compound of formula (M26) can be prepared by this synthesis scheme 3: nucleophilic substitution reaction is carried out on the compound shown in the formula (M19) and the compound shown in the formula (M20) to obtain a compound shown in the formula (M21); the compound shown in the formula (M21) is subjected to hydrogenation reduction to obtain a compound shown in the formula (M22); performing ring-closing reaction on the compound shown in the formula (M22) and CDI to obtain a compound shown in the formula (M23); coupling reaction between the compound shown in the formula (M23) and the compound shown in the formula (M24) to obtain a compound shown in the formula (M25); the compound represented by the formula (M25) undergoes an insertion reaction to give a compound represented by the formula (M26).
The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further described below in conjunction with the examples.
Examples
Example 2
Synthesis of 4- (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) -6- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -2, 4-dihydro-5H-pyrazolo [4,3-d ] pyrimidine-5, 7 (6H) -dione
Step one: synthesis of 6-nitrobenzo [ d ] oxazol-2 (3H) -one
A mixed solution of 2-amino-5-nitrophenol (50.0 g,324 mmol) and triethylamine (119 mL, 850 mmol) in methylene chloride (300 mL) was slowly added dropwise to a solution of triphosgene (58.9 g,198 mmol) in methylene chloride (300 mL) under ice-bath, and the reaction system was stirred at room temperature for 1 hour. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (300 mL), stirred for 20 min, filtered and dried to give a small amount of solid product; the filtrate was separated, the aqueous phase was extracted with dichloromethane (400 mL. Times.2), the organic phases were combined and dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent from the filtrate under reduced pressure combined with a small amount of the solid product obtained previously gave the title compound as a yellow solid (58.4 g, 99.9%).
1 H 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).
Step two: synthesis of 3-methyl-6-nitrobenzo [ d ] oxazol-2 (3H) -one
To a solution of 6-nitrobenzo [ d ] oxazol-2 (3H) -one (58.4 g,324 mmol) in N, N-dimethylformamide (300 mL) was added potassium carbonate (134 g,971.01 mmol), methyl iodide (30.3 mL,487 mmol) was added dropwise under ice-bath, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (1500 mL), filtered and the filter cake dried to give the title compound as a yellow solid (62.9 g, 99.9%).
Step three: synthesis of 6-amino-3-methylbenzo [ d ] oxazol-2 (3H) -one
3-methyl-6-nitrobenzo [ d ] oxazol-2 (3H) -one (62.9 g,324 mmol), tetrahydrofuran (400 mL), methanol (400 mL) and palladium on carbon (12.6 g,3.87 mmol) were added to the autoclave, hydrogen was replaced 3 times, hydrogen was introduced, and the reaction system was warmed to 80℃and stirred for 24 hours. The reaction mixture was filtered, the solvent was distilled off from the filtrate under reduced pressure, and petroleum ether/ethyl acetate (500 mL/50 mL) was added to the obtained residue, which was beaten with heat and filtered with suction to give the title compound as a pale yellow solid (46.0 g, 86.5%).
1 H 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).
Step four: synthesis of 6-bromo-3-methylbenzo [ d ] oxazol-2 (3H) -one
To a solution of cuprous bromide (17.4 g,91.4 mmol) in acetonitrile (100 mL) was slowly added dropwise tert-butyl nitrite (13.3 mL,110 mmol) at 50deg.C, stirred for 0.5H, 6-amino-3-methylbenzo [ d ] oxazol-2 (3H) -one (10.0 g,60.9 mmol) in acetonitrile (100 mL) was added dropwise and heated to 80deg.C for reaction for 6H. The solvent was removed by evaporation of the reaction mixture under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =20/1-10/1) to give the title compound as a yellow solid (11.81 g, 85%).
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.40–7.34(m,2H),6.86(d,J＝8.2Hz,1H),3.41(s,3H).
Step five: synthesis of 3-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzo [ d ] oxazol-2 (3H) -one
To a solution of 6-bromo-3-methylbenzo [ d ] oxazol-2 (3H) -one (5.10 g,22.4 mmol) in N, N-dimethylformamide (100 mL) was added bis-pinacolato borate (6.95 g,26.8 mmol), potassium acetate (8.78 g,89.5 mmol), and [1,1' -bis (diphenylphosphine) ferrocene ] palladium (II) dichloride dichloromethane complex (1.82 g,2.23 mmol) reacted at 80℃for 3.5H under nitrogen protection. The reaction mixture was evaporated under reduced pressure, water (80 mL) was added, extracted with ethyl acetate (100 mL. Times.2), and the organic phase was washed with saturated brine (80 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title compound as a brown solid (6.15 g, 100%).
1 H 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).
Step six: synthesis of (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) boronic acid
To a solution of 3-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzo [ d ] oxazol-2 (3H) -one (6.15 g,22.4 mmol) in acetone (120 mL) and water (120 mL) was added sodium periodate (28.7 g,134 mmol) and ammonium acetate (6.89 g,89.4 mmol) and stirred at room temperature for 11 hours. The reaction mixture was evaporated under reduced pressure to remove most of the solvent, water (200 mL) was added and stirred overnight, filtered, the filter cake was washed with water (50 mL), dried in vacuo, and the crude product was isolated and purified by silica gel column chromatography (dichloromethane/ethyl acetate (v/v) =10/1-4/1) to give the title compound as a brown solid (3.10 g, 71.9%).
MS(ESI,pos.ion)m/z:194.1[M+H] + .
1 H 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).
Step seven: synthesis of N-benzyl-4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-amine
To a solution of 4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-one (10.0 g,50.0 mmol) in methylene chloride (200 mL) was added benzylamine (6.42 g,59.9 mmol) and ethyl titanate (20.4 mL,74.9 mmol), and the mixture was stirred at room temperature for 1H. Sodium borohydride (3.78 g,99.9 mmol) was added in portions at 0deg.C and stirred at room temperature for 18h. The reaction mixture was poured into ice water, filtered through celite, and the layers were separated by standing, and the organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. Filtration, evaporation of the solvent from the filtrate under reduced pressure, and purification of the resulting residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1-4/1) gave the title compound as a pale yellow liquid (12.0 g, 82.5%).
Step eight: synthesis of 4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-amine
To a solution of N-benzyl-4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-amine (12.0 g,41.2 mmol) in tetrahydrofuran (120 mL) was added palladium on carbon (1.20 g), followed by introducing hydrogen gas and stirring at room temperature for 24H. The reaction mixture was filtered, the solvent was removed by evaporation of the filtrate under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) =20/1-10/1) to give the title compound as a pale yellow liquid (6.17 g, 74.4%).
1 H 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).
Step nine: synthesis of 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester
To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (10.0 g,63.7 mmol) in ethanol (200 mL) was added thionyl chloride (5.08 mL,70.0 mmol) dropwise and stirred at room temperature for 21H. The reaction mixture was evaporated under reduced pressure, water (200 mL) was added, extracted with ethyl acetate (200 mL. Times.2), and the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title compound as a white solid (11.5 g, 97.6%).
Step ten: synthesis of ethyl 1- (4-methoxybenzyl) -4-nitro-1H-pyrazole-3-carboxylate
To a solution of ethyl 4-nitro-1H-pyrazole-3-carboxylate (11.5 g,62.1 mmol) in N, N-dimethylformamide (200 mL) was added NaH (2.48 g,62.0 mmol) at 0deg.C, and after stirring for 0.5H, 4-methoxybenzyl chloride (10.1 mL,74.5 mmol) was added dropwise and stirring was carried out at room temperature for 18.5H. The reaction mixture was quenched with water (100 mL), extracted with ethyl acetate (200 ml×2), the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1-4/1) to give the title compound as a colorless liquid (14.0 g, 73.8%).
1 H 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).
Step eleven: synthesis of 4-amino-1- (4-methoxybenzyl) -1H-pyrazole-3-carboxylic acid ethyl ester
To a solution of 1- (4-methoxybenzyl) -4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester (14.0 g,45.9 mmol) in methanol (200 mL) was added palladium on carbon (1.40 g,21.4 mmol), followed by introducing hydrogen gas and stirring at room temperature for 20 hours. The reaction mixture was filtered, the solvent was distilled off from the filtrate under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/ethyl acetate (v/v) =10/1-4/1) to give the title compound as a pale yellow liquid (11.4 g, 90.3%).
MS(ESI,pos.ion)m/z:276.2[M+H] + .
1 H 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).
Step twelve: synthesis of ethyl 1- (4-methoxybenzyl) -4- ((phenoxycarbonyl) amino) -1H-pyrazole-3-carboxylate
To a solution of ethyl 4-amino-1- (4-methoxybenzyl) -1H-pyrazole-3-carboxylate (1.10 g,4.00 mmol) in dichloromethane (20 mL) was added pyridine (0.64 mL,8.0 mmol), and a solution of phenyl chloroformate (0.75 mL,6.0 mmol) in dichloromethane (20 mL) was added dropwise under nitrogen at 0deg.C and stirred at room temperature for 6 hours. The reaction mixture was adjusted to pH 6 with dilute hydrochloric acid, extracted with dichloromethane (40 mL. Times.2) and the organic phase was dried over anhydrous sodium sulfate. Filtration, evaporation of the solvent under reduced pressure, and purification of the resulting residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1-2/1) gave the title compound as a white solid (1.44 g, 91.1%).
1 H 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).
Step thirteen: synthesis of ethyl 1- (4-methoxybenzyl) -4- (3- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) ureido) -1H-pyrazole-3-carboxylate
To a solution of ethyl 1- (4-methoxybenzyl) -4- ((phenoxycarbonyl) amino) -1H-pyrazole-3-carboxylate (1.43 g,3.62 mmol) in dimethyl sulfoxide (20 mL) was added 4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-amine (606 mg,3.0121 mmol), and the mixture was stirred for 17.5H at 90℃under nitrogen. The reaction mixture was cooled to room temperature, water (40 mL) was added, extraction was performed with ethyl acetate (80 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate. Filtration, evaporation of the solvent under reduced pressure, and purification of the resulting residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =4/1-1/1) gave the title compound as a pale yellow solid (1.45 g, 95.8%).
Step fourteen: synthesis of 2- (4-methoxybenzyl) -6- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -2, 4-dihydro-5H-pyrazolo [4,3-d ] pyrimidine-5, 7 (6H) -dione
To a solution of ethyl 1- (4-methoxybenzyl) -4- (3- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) ureido) -1H-pyrazole-3-carboxylate (1.66 g,3.30 mmol) in DMF (40 mL) was added sodium hydride (198 mg,4.95 mmol) and the mixture was stirred at room temperature for 7H. The reaction mixture was evaporated under reduced pressure to remove part of the solvent, stirred overnight with water (80 mL), filtered, the filter cake was washed with water (40 mL) and the filter cake was dried under reduced pressure to give a pale yellow solid (1.33 g, 88.2%).
MS(ESI,neg.ion)m/z:455.1[M-H] + .
1 H 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).
Step fifteen Synthesis of 2- (4-methoxybenzyl) -4- (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) -6- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -2, 4-dihydro-5H-pyrazolo [4,3-d ] pyrimidine-5, 7 (6H) -dione
To a solution of 2- (4-methoxybenzyl) -6- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -2, 4-dihydro-5H-pyrazolo [4,3-d ] pyrimidine-5, 7 (6H) -dione (1.33 g,2.91 mmol) in acetonitrile (10 mL) was added (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) boronic acid (843 mg,4.3688 mmol), copper acetate (794 mg,4.3715 mmol), triethylamine (0.88 mL,6.3 mmol), dimethyl sulfoxide (0.40 mL,8.8 mmol) and molecular sieve (1.0 g), and the mixture was stirred at room temperature under nitrogen for 20H. The reaction mixture was filtered, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane/ethyl acetate (v/v) =50/1-20/1) to give the title compound as a yellow solid (1.70 g, 96.6%).
MS(ESI,pos.ion)m/z:604.1[M+H] + .
1 H 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).
Step sixteen: synthesis of 4- (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) -6- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -2, 4-dihydro-5H-pyrazolo [4,3-d ] pyrimidine-5, 7 (6H) -dione
2- (4-methoxybenzyl) -4- (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) -6- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -2, 4-dihydro-5H-pyrazolo [4,3-d ] pyrimidine-5, 7 (6H) -dione (800 mg,1.325 mmol) and trifluoroacetic acid (20 mL) were added to the reaction flask, and the reaction system was stirred at 80℃for 2.5H. The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to adjust the pH to 8, extraction was performed with ethyl acetate (50 mL), and the organic phase was collected, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane/ethyl acetate (v/v) =10/1-4/1) to give the title compound as a pale yellow solid (0.60 g, 93.7%).
MS(ESI,pos.ion)m/z:484.0[M+H] + .
1 H 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).
Example 1: synthesis of 3- (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) -1- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -3, 9-dihydro-1H-purine-2, 6-dione
This example prepared the title compound as a brown solid in 5% yield using 5-amino-1H-imidazole-4-carboxylic acid as starting material by the method described in example 2.
MS(ESI,pos.ion)m/z:484.0[M+H] + ；
1 H 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).
Example 9:1- (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) -2, 4-dioxo-3- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -1,2,3, 4-tetrahydropyrido [3,2-d ] pyrimidine-6-carboxylic acid
Step one: synthesis of 4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-ol
To a solution of 4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-one (1.00 g,5.00 mmol) in methanol (10 mL) at 0deg.C was slowly added sodium borohydride (236 mg,5.988 mmol) and the reaction was continued at 0deg.C. The reaction mixture was freed of most of the solvent under reduced pressure, water (50 mL) was added, extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined, washed with saturated brine (30 mL. Times.2), and the organic phases were collected and concentrated under reduced pressure to give the title compound as a yellow oil (1.00 g, 99.0%).
Step two: synthesis of 6-bromo-3- ((3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) amino) picolinic acid
To a solution of 6-amino-3-methylbenzo [ d ] oxazol-2 (3H) -one (1.492 g,9.09 mmol) in tetrahydrofuran (20 mL) was added dropwise lithium bis trimethylsilylamide (23 mL,23mmol,1mol/L in THF) at-78deg.C, stirred for 15min with heat preservation, and then a solution of 6-bromo-3-fluoropyridine-2-carboxylic acid (2 g,9.09 mmol) in THF (20 mL) was added dropwise with heat preservation and stirring for 1H, then warmed to room temperature and stirred overnight. The reaction mixture was adjusted to pH 1-2 with 1N HCl solution, extracted with ethyl acetate (50 ml×2), the organic phase was washed with saturated sodium chloride (50 mL), then dried over anhydrous sodium sulfate solid, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) =100/0-85/15) to give the title compound as a tan solid (1.943 g, 58.68%).
MS(ES-API,pos.ion)m/z:364.0[M+H] + 。
Step three: synthesis of 6-bromo-3- ((3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) amino) pyridine carboxamide
To a solution of 6-bromo-3- ((3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) amino) picolinic acid (1.943 g,5.335 mmol) in dichloromethane (50 mL) was added dropwise oxalyl chloride (0.92 mL,10 mmol), followed by N, N-dimethylformamide (0.1 mL) and stirring at room temperature for 5h. The reaction mixture was concentrated under reduced pressure to give a yellow solid, tetrahydrofuran (40 mL) was added, an aqueous solution (40 mL) of ammonium hydroxide (28 mass%) 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, extraction was performed with ethyl acetate (50 mL. Times.2), and 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 to give the title compound as a yellow solid (1.55 g, 80%)
MS(ES-API,pos.ion)m/z:364.9[M+H] + 。
Step four: synthesis of 6-bromo-1- (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) pyrido [3,2-d ] pyrimidine-2, 4 (1H, 3H) -dione
To a solution of 6-bromo-3- ((3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) amino) pyridine carboxamide (1.55 g,4.27 mmol) in N, N-dimethylformamide (40 mL) was added sodium hydride (0.3411 g,8.53mmol,60 mass%), CDI (1.284 g,8.279 mmol) after stirring for 5min, and then stirring overnight at room temperature. The reaction mixture was added with water (50 mL), extracted with ethyl acetate (50 mL. Times.2), and the aqueous phase was adjusted to pH 1-2 with a large amount of precipitate precipitated, which was filtered and dried to give the title compound as a yellow solid (0.862 g, 51.9%).
1 H 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).
Step five: synthesis of 6-bromo-1- (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) -3- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) pyrido [3,2-d ] pyrimidine-2, 4 (1H, 3H) -dione
To a solution of 6-bromo-1- (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) pyrido [3,2-d ] pyrimidine-2, 4 (1H, 3H) -dione (0.862 g,2.21 mmol) in tetrahydrofuran (7 mL) and N, N-dimethylformamide (14 mL,180 mmol) was added 4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-ol (0.537 g,2.66 mmol) and triphenylphosphine (1.162 g, 4.3836 mmol), and the mixture was cooled to-15 ℃. Diisopropyl azodicarboxylate (0.87 mL,4.3 mmol) was then added dropwise, stirred for 1h at room temperature and then allowed to stir overnight. The reaction mixture was added with water (50 mL), 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, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v=9/1) to 100% ethyl acetate) to give the title compound as a pale yellow solid (0.491 g, 38.7%).
MS(ES-API,pos.ion)m/z:572.9[M+H] + .
Step six: synthesis of 1- (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) -2, 4-dioxo-3- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -1,2,3, 4-tetrahydropyrido [3,2-d ] pyrimidine-6-carboxylic acid
To a solution of 6-bromo-1- (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) -3- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) pyrido [3,2-d ] pyrimidine-2, 4 (1H, 3H) -dione (0.491 g,0.856 mmol) in N, N-dimethylformamide (8 mL,100 mmol) was added sodium formate (0.175 g,2.55 mmol), palladium acetate (0.0123 g,0.051 mmol) and 1,1' -bis (diphenylphosphine) ferrocene (0.028 g,0.050 mmol), and after 10min nitrogen was added N, N-diisopropylethylamine (0.28 mL,1.7 mmol) and acetic anhydride (0.16 mL,1.7 mmol). The reaction was heated to 100 ℃ under nitrogen overnight. The reaction mixture was added with water (50 mL), 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, and the resulting residue was purified by preparative chromatography to give the title compound as a white solid (0.0070 g, 2%).
MS(ES-API,neg.ion)m/z:536.9[M-H] + ；
1 H 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).
Prepared by the method described in example 9, by reacting the various starting materials in multiple steps, the following example compounds were obtained, wherein the resulting product structures and their characterization data are shown in the following table:
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Example 10: synthesis of (R) -3- (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) -2-oxo-1- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -2, 3-dihydro-1H-benzo [ d ] imidazole-5-carboxylic acid
Step one: synthesis of 6- ((5-bromo-2-nitrophenyl) amino) -3-methylbenzo [ d ] oxazol-2 (3H) -one
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1.00 g,4.55 mmol) and 6-amino-3-methylbenzo [ d ] oxazol-2 (3H) -one (746.0 mg,4.54 mmol) in anhydrous N, N-dimethylformamide (20 mL) was added potassium carbonate (1.27 g,9.10 mmol), and the mixture was warmed to 90℃and reacted for 22H. 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, suction-filtered under reduced pressure, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2/1) to give the title compound as an orange-yellow solid (0.87 g, 53%).
MS(ES-API,pos.ion)m/z:364.0[M+H] + .
Step two: synthesis of 6- ((2-amino-5-bromophenyl) amino) -3-methylbenzo [ d ] oxazol-2 (3H) -one
To 6- ((5-bromo-2-nitrophenyl) amino) -3-methylbenzo [ d ] oxazol-2 (3H) -one (0.87 g,2.4 mmol) was dissolved in methanol (20 mL), ammonium chloride (1.30 g,24.3 mmol) was added, and zinc powder (1.60 g,24.4 mmol) was slowly added in portions and reacted at room temperature for 4H. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =1/1) to give the title compound as a brown solid (0.66 g, 83%).
Step three: synthesis of 6- (6-bromo-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-1-yl) -3-methylbenzo [ d ] oxazol-2 (3H) -one
To a solution of 6- ((2-amino-5-bromophenyl) amino) -3-methylbenzo [ d ] oxazol-2 (3H) -one (0.66 g,2.0 mmol) in tetrahydrofuran (20 mL) was added CDI (0.64 g,3.9 mmol) and reacted at room temperature for 16H. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =1/1) to give the title compound as a pale yellow solid (0.66 g, 93%).
Step four: synthesis of (R) -6- (6-bromo-2-oxo-3- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -2, 3-dihydro-1H-benzo [ d ] imidazol-1-yl) -3-methylbenzo [ d ] oxazol-2 (3H) -one
(S) -4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-ol (230.0 mg,1.14 mmol), 6- (6-bromo-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-1-yl) -3-methylbenzo [ d ] oxazol-2 (3H) -one (340.0 mg,0.94 mmol) and triphenylphosphine (495.0 mg,1.89 mmol) were mixed and dissolved in anhydrous tetrahydrofuran (5 mL) and N, N-dimethylformamide (10 mL), and the mixture was cooled to 0℃under nitrogen protection, diisopropyl azodicarboxylate (0.38 mL,1.9 mmol) was added dropwise, and the mixture was reacted at 0℃for 8 hours. The reaction mixture was warmed to room temperature, water (50 mL) was added, extracted with ethyl acetate (50 ml×2), the organic phases were combined, the organic phases were washed with saturated brine (30 ml×2), the organic phases were collected, dried over anhydrous sodium sulfate, suction-filtered under reduced pressure, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2/1) to give the title compound as a reddish brown solid (418.0 mg, 81.36%).
MS(ES-API,pos.ion)m/z:544.0[M+H] + .
Step five: synthesis of (R) -3- (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) -2-oxo-1- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -2, 3-dihydro-1H-benzo [ d ] imidazole-5-carboxylic acid
To a solution of (R) -6- (6-bromo-2-oxo-3- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -2, 3-dihydro-1H-benzo [ d ] imidazol-1-yl) -3-methylbenzo [ d ] oxazol-2 (3H) -one (418.0 mg,0.77 mmol) in anhydrous N, N-dimethylformamide (4.6 mL) was added sodium formate (157.0 mg,2.31 mmol), palladium acetate (9.0 mg,0.04 mmol), 1' -bis (diphenylphosphino) ferrocene (24.0 mg,0.04 mmol), N-diisopropylethylamine (0.28 mL,1.5 mmol) and acetic anhydride (0.15 mL,1.6 mmol), and after three nitrogen substitutions were heated to 120℃under nitrogen for reaction for 21H. After cooling, the reaction mixture was added with water (40 mL), the pH was adjusted to about 4 with 1N hydrochloric acid, extracted with ethyl acetate (30 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, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =3/1 to 1/9) to give the title compound as a white solid (226.0 mg, 57.77%).
MS(ES-API,pos.ion)m/z:510.0[M+H] + .
1 H 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).
Example 11: synthesis of 1- (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) -2-oxo-3- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -2, 3-dihydro-1H-benzo [ d ] imidazole-5-carboxylic acid
Step one: synthesis of N- (5-bromo-2-nitrophenyl) -4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-amine
4-bromo-2-fluoro-1-nitrobenzene (500.0 mg,2.27 mmol) and 4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-amine (457.0 mg,2.27 mmol) were mixed and dissolved in anhydrous N, N-dimethylformamide (10 mL), potassium carbonate (635.0 mg,4.55 mmol) was added, and the mixture was heated to 90℃for 2 hours. The reaction mixture was added with water (50 mL), extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined, washed with saturated brine (30 mL. Times.2), the organic phases were collected, dried over anhydrous sodium sulfate, suction filtered under reduced pressure, and the filtrate was evaporated under reduced pressure to give the title compound as a yellow solid (911.0 mg, 99.91%).
Step two: 5-bromo-N 1 Synthesis of- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) benzene-1, 2-diamine
To a solution of N- (5-bromo-2-nitrophenyl) -4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-amine (911.0 mg,2.27 mmol) in methanol (15 mL) was added ammonium chloride (1.22 g,22.8 mmol), zinc powder (1.49 g,22.8 mmol) was added slowly in portions, and the mixture was reacted at room temperature for 15H. The reaction mixture was filtered through celite to remove insoluble matters, the filtrate was evaporated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =9/1) to give the title compound as a tan solid (590.0 mg, 70.00%).
MS(ES-API,pos.ion)m/z:371.1[M+H] + .
Step three: synthesis of 6-bromo-1- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -1, 3-dihydro-2H-benzo [ d ] imidazol-2-one
To 5-bromo-N 1 To a solution of- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) benzene-1, 2-diamine (590.0 mg,1.59 mmol) in tetrahydrofuran (20 mL) was added CDI (515.0 mg,3.18 mmol), and the mixture was reacted at room temperature for 22H. The solvent was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2/1) to give the title compound as a pale yellow solid (0.61 g, 97%).
MS(ES-API,pos.ion)m/z:397.0[M+H] + .
Step four: synthesis of 6- (5-bromo-2-oxo-3- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -2, 3-dihydro-1H-benzo [ d ] imidazol-1-yl) -3-methylbenzo [ d ] oxazol-2 (3H) -one
To a solution of 6-bromo-1- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -1, 3-dihydro-2H-benzo [ d ] imidazol-2-one (610 mg, 1.534 mmol) and (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) boronic acid (355 mg,1.84 mmol) in dry dichloromethane (25 mL) were added copper acetate (279.0 mg,1.54 mmol), triethylamine (0.65 mL,4.60 mmol) and 4A molecular sieve (3.00 g), respectively, and the mixture was reacted at room temperature under nitrogen for 4H. The reaction mixture was filtered through celite to remove insoluble matters, the cake was washed with dichloromethane, the filtrate was collected, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =3/1) to give the title compound as a yellow oil (764.0 mg, 91.40%).
MS(ES-API,pos.ion)m/z:544.0[M+H] + .
Step five: synthesis of 1- (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) -2-oxo-3- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -2, 3-dihydro-1H-benzo [ d ] imidazole-5-carboxylic acid
To a solution of 6- (5-bromo-2-oxo-3- (4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -2, 3-dihydro-1H-benzo [ d ] imidazol-1-yl) -3-methylbenzo [ d ] oxazol-2 (3H) -one (418.0 mg,0.77 mmol) in anhydrous N, N-dimethylformamide (4.6 mL) was added sodium formate (157.0 mg,2.31 mmol), palladium acetate (9.0 mg,0.04 mmol), 1' -bis (diphenylphosphine) ferrocene (24.0 mg,0.04 mmol), N-diisopropylethylamine (0.28 mL,1.5 mmol) and acetic anhydride (0.15 mL,1.6 mmol), and after three nitrogen substitutions, the reaction was heated to 120℃under nitrogen protection for 21H. After cooling, the reaction mixture was adjusted to pH 4 with water (40 mL), 1N hydrochloric acid was extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated brine (30 mL. Times.2), the organic phases were collected, dried over anhydrous sodium sulfate, suction filtered under reduced pressure, the filtrate was distilled off under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =3/1 to 1/9) to give the title compound as a white solid (226.0 mg, 57.77%).
MS(ES-API,pos.ion)m/z:510.1[M+H] + .
1 H 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).
Biological assay
Example a: enzymatic assay of chymotrypsin-like enzymes
The experimental method comprises the following steps:
1. the enzyme source used was recombinant human chymotrypsin (sigma). The chymotrypsin-like substrate used was N-succinyl-Ala-Ala-Pro-Phe-7-amido-4-methyloumarin.
2. For this assay, the test article was diluted with DMSO, 20nL of test article (1000X) and 10 μl of enzyme solution (2X) were mixed in 384 well plates and incubated at room temperature for 15 minutes, followed by addition of substrate solution (2X), and dynamic reading of the fluorescent signal emitted at 460nm after excitation at 370nm wavelength was performed with Synergy 2.
3. One test compound was assayed twice on the same microtiter plate at 10 different concentrations ranging from 300nM to 0.0152 nM. The data were normalized (enzyme reaction without inhibitor = 0% inhibition, all assay components without enzyme = 100% inhibition) and IC was calculated using GraphPad Prism 5 software 50 Values.
The compounds of the invention were tested in this experiment for inhibition of chymase activity and the results are shown in table a.
Table A results of in vitro inhibition test of chymase by the inventive Compounds
Example number IC 50 (nM) Example number 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
Experimental results show that the compound has good inhibition effect on chymase.
In the description of the present specification, reference to the terms "one embodiment," "an embodiment," "some embodiments," "examples," "a particular example," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment, or example is included in at least one embodiment, implementation, or example of the present invention. In this specification, the schematic representations of the above terms are not necessarily for the same examples, implementations or illustrations. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments, implementations, or examples. Furthermore, the features of the different embodiments, implementations or examples and the different embodiments, implementations or examples described in this specification may be combined and combined by persons skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims (11)

1. A compound represented by the formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt of the compound represented by the formula (I),
wherein: ring a is pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine or benzene; e is a bond or-C (=O) -;
each R is 0 Is independently H, D, OR-C (O) OR a ；
t is 0, 1, 2, 3 or 4;
R a is H or D;
R 1 is thatR 3 is-O-or-S-;
R 4 h, D or C 1-6 An alkyl group;
R 2 is thatWherein each R is 5 H, D or C independently 1-6 A haloalkyl group;
m is 0, 1, 2, 3 or 4.
2. The compound of claim 1, wherein R 2 Is that
3. The compound according to claim 1, which is a compound represented by the formula (IIb) or (IIc), or a stereoisomer, tautomer, or pharmaceutically acceptable salt of the compound represented by the formula (IIb) or (IIc),
4. a compound according to claim 1 or 3, wherein,
R 4 h, D or C 1-4 An alkyl group;
each R is 5 H, D, or C independently 1-4 A haloalkyl group.
5. A compound according to claim 1 or 3, wherein,
R 4 h, D is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
each R is 5 Is independently H, D, -CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 or-CH 2 CH 2 CF 3 。
6. A compound according to claim 1 or 3 which is a stereoisomer, tautomer, or pharmaceutically acceptable salt of a compound having one of the following structures:
7. a pharmaceutical composition comprising the compound of any one of claims 1-6, and optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
8. The pharmaceutical composition of claim 7, further comprising one or more additional active ingredients selected from the group consisting of: calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vascular peptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, diuretics, kinase inhibitors, matrix metalloproteinase inhibitors, soluble guanylate cyclase stimulators and activators, and phosphodiesterase inhibitors.
9. The pharmaceutical composition of claim 8, wherein the kinase inhibitor is a p-kinase inhibitor.
10. Use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to any one of claims 7 to 9 for the manufacture of a medicament for the treatment or prophylaxis of heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, renal disease, fibrotic disorders of the internal organs or skin fibrosis.
11. The use of claim 10, wherein the kidney disease is renal failure.
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101505752A (en) * 2006-06-23 2009-08-12 史密丝克莱恩比彻姆公司 Prolyl hydroxylase inhibitors
CN104395310A (en) * 2012-05-09 2015-03-04 拜耳药业股份公司 Bicyclically substituted uracils and the use thereof
CN105873919A (en) * 2013-11-08 2016-08-17 拜耳医药股份有限公司 Substituted uracils as chymase inhibitors
CN105899500A (en) * 2013-11-08 2016-08-24 拜耳医药股份有限公司 Substituted 1,2,4-triazine-3,5-diones and the use thereof as chymase inhibitors
CN105980381A (en) * 2013-11-08 2016-09-28 拜耳医药股份有限公司 Substituted uracils and use thereof
CN106414430A (en) * 2014-05-09 2017-02-15 奥赖恩公司 Pharmacologically active quinazolinedione derivatives
CN110072527A (en) * 2016-12-20 2019-07-30 拜耳制药股份公司 Inhibitors of chymase treatment mullerianosis, post-operative fibrosis and by fibrosis formed characterized by disease in purposes
WO2021000933A1 (en) * 2019-07-03 2021-01-07 南京明德新药研发有限公司 Pyrimidinone compounds as chymase inhibitors and application thereof

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101505752A (en) * 2006-06-23 2009-08-12 史密丝克莱恩比彻姆公司 Prolyl hydroxylase inhibitors
CN104395310A (en) * 2012-05-09 2015-03-04 拜耳药业股份公司 Bicyclically substituted uracils and the use thereof
CN105873919A (en) * 2013-11-08 2016-08-17 拜耳医药股份有限公司 Substituted uracils as chymase inhibitors
CN105899500A (en) * 2013-11-08 2016-08-24 拜耳医药股份有限公司 Substituted 1,2,4-triazine-3,5-diones and the use thereof as chymase inhibitors
CN105980381A (en) * 2013-11-08 2016-09-28 拜耳医药股份有限公司 Substituted uracils and use thereof
CN106414430A (en) * 2014-05-09 2017-02-15 奥赖恩公司 Pharmacologically active quinazolinedione derivatives
CN110072527A (en) * 2016-12-20 2019-07-30 拜耳制药股份公司 Inhibitors of chymase treatment mullerianosis, post-operative fibrosis and by fibrosis formed characterized by disease in purposes
WO2021000933A1 (en) * 2019-07-03 2021-01-07 南京明德新药研发有限公司 Pyrimidinone compounds as chymase inhibitors and application thereof

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