WO2021078135A1 - 吡咯酰胺类化合物及其用途 - Google Patents

吡咯酰胺类化合物及其用途 Download PDF

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WO2021078135A1
WO2021078135A1 PCT/CN2020/122388 CN2020122388W WO2021078135A1 WO 2021078135 A1 WO2021078135 A1 WO 2021078135A1 CN 2020122388 W CN2020122388 W CN 2020122388W WO 2021078135 A1 WO2021078135 A1 WO 2021078135A1
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group
atoms
alkyl
methyl
butyl
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PCT/CN2020/122388
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English (en)
French (fr)
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王建成
王晓军
左应林
张英勋
张英俊
池波
韩伟
丁小洪
曾君南
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广东东阳光药业有限公司
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Priority to EP20878312.6A priority Critical patent/EP3950674A4/en
Priority to JP2021562143A priority patent/JP2022553474A/ja
Priority to CA3136989A priority patent/CA3136989A1/en
Priority to AU2020371836A priority patent/AU2020371836A1/en
Priority to KR1020217038554A priority patent/KR20220088375A/ko
Priority to US17/605,934 priority patent/US20220211665A1/en
Publication of WO2021078135A1 publication Critical patent/WO2021078135A1/zh

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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

  • the present invention belongs to the technical field of medicine, and specifically relates to pyrrolamide compounds and uses thereof, and further relates to a pharmaceutical composition containing the compound.
  • the compound or the pharmaceutical composition can be used as a mineralocorticoid receptor antagonist.
  • MR Mineralocorticoid Receptor
  • aldosterone is a nuclear hormone receptor activated by aldosterone, which regulates the expression of many genes involved in electrolyte homeostasis and cardiovascular diseases.
  • the increase in circulating aldosterone increases blood pressure through its effect on urinary sodium excretion, while potentially affecting the brain, heart, and vascular system.
  • hyperaldosteronism is related to many physiological processes that lead to kidney and cardiovascular diseases.
  • hyperaldosteronism is usually caused by aldosterone-producing adenomas, patients with refractory hypertension often have elevated aldosterone levels, commonly referred to as "aldosterone escape", which is due to serum potassium Due to increased content or residual AT1R activity. Hyperaldosteronism and aldosterone escape typically lead to increased MR activity. It has been shown that MR antagonists can be effective antihypertensive agents, and can also be effective in the treatment of heart failure and primary aldostero
  • Aldosterone is a steroid hormone formed in the adrenal cortex. Its production greatly depends on renal blood flow and is indirectly regulated. Any reduction in renal blood flow causes the enzyme renin in the kidney to be released and enter the circulating blood. This in turn activates the formation of angiotensin II, which on the one hand has a constrictive effect on arterial blood vessels, but on the other hand also stimulates the formation of aldosterone in the adrenal cortex. Therefore, the kidney is used as a blood pressure sensor in the blood circulation, and thus indirectly as a volume sensor, and the serious loss of volume is offset by the renin-angiotensin-aldosterone system. This aspect is through increasing blood pressure (vascular Tension II effect), on the other hand, it is achieved by increasing the reabsorption of sodium and water in the kidney to rebalance the filling state of the vascular system (aldosterone effect).
  • the control system can be damaged in various ways. For example, a chronic decrease in renal blood flow (e.g., due to heart failure and consequent blood blockage in the venous system) results in chronic excess release of aldosterone. This is followed by the expansion of blood volume and thereby increasing the weakness of the heart by increasing the supply of blood volume to the heart. Obstruction of blood in the lungs, along with shortness of breath and formation of limb edema, and ascites and pleural effusion may result from this; renal blood flow decreases further. In addition, the effect of excessive aldosterone leads to a decrease in the potassium concentration in the blood and extracellular fluid. In myocardium that has been damaged in other ways before, if there is a deviation below the critical minimum level, it may induce fatal cardiac arrhythmia. This is likely to be one of the main causes of sudden cardiac death that often occurs in patients with heart failure.
  • aldosterone determines many of the myocardial remodeling processes that are typically observed in heart failure.
  • hyperaldosteronism is a decisive component of the pathogenesis and prognosis of heart failure (which can be initially induced by various types of injury such as myocardial infarction, myocardial inflammation, or hypertension).
  • This hypothesis is supported by the fact that in an extensive clinical study of patients with chronic heart failure and post-acute myocardial infarction through the use of aldosterone antagonists, overall mortality was significantly reduced (B. Pitt, F. Zannad, WJ Remme, et al., N. Engl. J. Med. ML 709-717 (1999); B. Pitt, W. Remme, F. Zannad, et al., N. Engl. J. Med, 1309-1321 (2003)).
  • MR MR regulates sodium retention, potassium excretion, and water balance in response to aldosterone.
  • the expression of MR in the brain also seems to play a role in controlling neuronal excitability, negative feedback regulation of the hypothalamic-pituitary adrenal axis, and cognitive aspects of behavioral performance (Castren et al., J. of Neuroendocrinology, 3,461-66 (1993) )).
  • Increased levels of aldosterone or excessive stimulation of mineralocorticoid receptors are related to some physiological disorders or pathological conditions, including Conen’s syndrome, primary and secondary hyperaldosteronism, and sodium retention Increased excretion of magnesium and potassium (polyuria), increased water retention, hypertension (isolated systolic hypertension and combined systolic/diastolic hypertension), arrhythmia, myocardial fibrosis, myocardial infarction , Bart’s syndrome and disorders related to excessive levels of catecholamines (Hadley, ME, ENDOCRINOLOGY, 2nd Ed., pp366-81, (1988); and Brilla et al., Journal of Molecular and Cellular Cardiology, 25(5), pp563-75 (1993)).
  • Compounds and/or pharmaceutical compositions with MR antagonism have therapeutic value for any of the above-mentioned conditions.
  • Patent application WO 2006012642 A2 discloses a pyrrole derivative, a racemate compound of Esaxerenone (Esaxerenone, CS-3150, whose chemical structure is shown below) for regulating the activity of one or more steroid nuclear receptors
  • Patent application WO 2008126831 A1 discloses a three-dimensional escillinone compound, which can be used to treat diseases such as hypertension. According to the "Examination Report" (January 8, 2019) published by PMDA, Japan's Pharmaceuticals and Medical Devices Agency, the compound has phototoxicity. For example, in vitro Balb/c 3T3 fibroblast neutral red uptake test results show The compound is phototoxic (light stimulating factor PIF>17).
  • the present invention addresses those needs by providing compounds and compositions that can be used to treat or prevent hypertension, heart failure, other cardiovascular disorders, and other aldosterone disorders.
  • the present invention provides a pyrrolamide compound with mineralocorticoid receptor (MR) antagonism and a pharmaceutical composition thereof, and the use of the compound or the pharmaceutical composition in the preparation of a medicine, and the medicine is used for treatment , Prevent or alleviate patients with hyperaldosteronism, hypertension, chronic heart failure, sequelae of myocardial infarction, liver cirrhosis, non-alcoholic steatohepatitis, chronic kidney disease, diabetic nephropathy, renal failure, fibrosis and/or stroke, etc. disease.
  • MR mineralocorticoid receptor
  • the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, or atropisomer of a compound represented by formula (I) , Nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
  • R 1 is a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 6-10 aryl group, a heterocyclic group composed of 3-6 atoms, or a heteroaryl group composed of 5-10 atoms, wherein , The C 1-6 alkyl group, C 3-6 cycloalkyl group, C 6-10 aryl group, heterocyclic group composed of 3-6 atoms and heteroaryl group composed of 5-10 atoms independently optionally 2, 3 or 4 substituted with R a;
  • Each R a is independently D, F, Cl, Br, OH, NH 2, SH, CN, NO 2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group composed of 3-6 atoms or heteroaryl group composed of 5-10 atoms; ,
  • the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 6- 10 aryl groups, heterocyclic groups composed of 3-6 atoms and heteroaryl groups composed of 5-10 atoms are independently unsubstituted or are selected from D, F, Cl, Br, Substituents of OH, NH 2 , SH, CN, NO 2 , C 1-6 alkyl, C
  • R 2 and R 3 are each independently H, D, F, Cl, Br, OH, NH 2 , SH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Group or C 1-6 haloalkyl;
  • R 8 , R b and R c is independently H, D, C 1-6 alkyl or C 1-6 haloalkyl.
  • R 2 and R 3 are each independently H, D, F, Cl, Br, OH, NH 2 , SH, CN, NO 2 , methyl, ethyl, n-propyl, isopropyl , Trifluoromethyl or difluoromethyl;
  • R 5 , R 6 and their connected carbon atoms together form cyclobutene, cyclopentene, cyclohexene, benzene ring, dihydrofuran, dihydrothiazole, dihydroimidazole, dihydropyrazole, dihydrooxazole , Dihydropyrrole, tetrahydropyridine, dihydro-1,4-oxazine, pyrrole, pyridine, pyrimidine or quinoline, wherein the cyclobutene, cyclopentene, cyclohexene, benzene ring, dihydrofuran , Dihydrothiazole, dihydroimidazole, dihydropyrazole, dihydrooxazole, dihydropyrrole, tetrahydropyridine, dihydro-1,4-oxazine, pyrrole, pyridine, pyrimidine and quinoline are each independently Substitution or 1, 2, 3, 4 or 5 selected
  • Each R 8 , R b and R c is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, monofluoro Methyl or 2,2-difluoroethyl.
  • the compound represented by formula (I) of the present invention is preferably a compound represented by formula (Ia) or a stereoisomer, geometric isomer, or tautomer of a compound represented by formula (Ia) Isomers, atropisomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
  • R 1 , R 2a , R 2b , R 2c , R 2d and R 2e have the meanings described in the present invention.
  • the compound represented by formula (I) of the present invention is preferably a compound represented by formula (IIa) or a stereoisomer, geometric isomer, or tautomer of a compound represented by formula (IIa) Isomers, atropisomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
  • R 1 has the meaning described in the present invention.
  • R 1 is a C 1-4 alkyl group, a C 3-6 cycloalkyl group, a phenyl group, a 3-6 atom heterocyclic group, or a 5-6 atom heteroaryl group, wherein ,
  • the C 1-4 alkyl group, C 3-6 cycloalkyl group, phenyl group, heterocyclic group composed of 3-6 atoms and heteroaryl group composed of 5-6 atoms are independently optionally selected by 1, 2 , 3 or 4 substituted with R a;
  • Each R a is independently D, F, Cl, Br, OH, NH 2, SH, CN, NO 2, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, vinyl , Ethynyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, Pyrrolyl, pyridyl, pyrimidinyl or quinolinyl; wherein the methyl, ethyl,
  • R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, cyclic Oxyethyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, pyridyl or pyrimidinyl, wherein the methyl, ethyl , N-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxirane, azetidinyl, oxygen heterocycle butyl, tetra
  • Each R a is independently D, F, Cl, Br, OH, NH 2, SH, CN, NO 2, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, vinyl , Ethynyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, Pyrrolyl, pyridyl, pyrimidinyl or quinolinyl; wherein the methyl, ethyl,
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention; optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and At least one kind of vehicle.
  • the pharmaceutical composition of the present invention further comprises one or more other active ingredients, and the other active ingredients are ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists, beta -Receptor blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis derivatives, calcium sensitizers, nitrates or antithrombotic agents.
  • the other active ingredients are ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists, beta -Receptor blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis derivatives, calcium sensitizers, nitrates or antithrombotic agents.
  • the present invention relates to the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicine, wherein the medicine is used to treat, prevent or alleviate the following diseases in patients: hyperaldosteronism , Hypertension, chronic heart failure, sequelae of myocardial infarction, liver cirrhosis, non-alcoholic steatohepatitis, chronic kidney disease, diabetic nephropathy, renal failure, fibrosis and/or stroke.
  • the present invention relates to the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicine, wherein the medicine is used as a mineralocorticoid receptor antagonist.
  • the articles “a”, “an” and “said” used herein are intended to include “at least one” or “one or more.” Therefore, the articles used herein refer to articles of one or more than one (ie at least one) object.
  • a component refers to one or more components, that is, more than one component may be considered to be adopted or used in the embodiment of the described embodiment.
  • patient used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, “patient” refers to a human.
  • Stereoisomers refer to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • Enantiomers refer to two isomers of a compound that cannot overlap but are mirror images of each other.
  • Diastereoisomers refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.
  • “Atropisomers” refer to structural isomers based on axial or planar chirality due to restricted intramolecular rotation.
  • the compound of the present invention has two atropisomers.
  • the compound represented by formula (II) of the present invention has two atropisomers, which are derived from the phenyl substituted by trifluoromethyl at the ortho position of the connection and the substitution The axial chirality of the bond between pyrrole rings due to steric hindrance leads to restricted rotation.
  • the "atropisomer" of the present invention is any one of the two atropisomers of the compound of the present invention.
  • an atropisomer that has more excellent pharmacological activity, stability, in vivo kinetic properties, safety, etc., and thus has advantageous properties as a drug is preferred.
  • the separation of atropisomers can be accomplished by chiral resolution techniques, such as selective crystallization or high performance liquid chromatography.
  • any asymmetric atom (for example, carbon, etc.) of the compound disclosed in the present invention may exist in a racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration form exist.
  • 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.
  • Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physical and chemical properties of the components, for example, by chromatography Method and/or fractional crystallization method.
  • tautomer or "tautomeric form” refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversion through the recombination of some bond-forming electrons.
  • keto-enol tautomerism are the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • the compounds of the present invention can be optionally substituted by one or more substituents, such as the compounds of the general formula above, or the special examples, subclasses, and subclasses included in the examples.
  • substituents such as the compounds of the general formula above, or the special examples, subclasses, and subclasses included in the examples.
  • a class of compounds such as the compounds of the general formula above, or the special examples, subclasses, and subclasses included in the examples.
  • C 1 -C 6 alkyl or “C 1-6 alkyl” specifically refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • C 1-4 alkyl specifically refers to independently disclosed methyl, ethyl, C 3 alkyl (ie propyl, including n-propyl and isopropyl) and C 4 alkyl (ie butyl, including N-butyl, isobutyl, sec-butyl and tert-butyl).
  • linking substituents are described.
  • the Markush variables listed for the group should be understood as the linking group.
  • the Markush group definition of the variable lists “alkyl” or “aryl” it should be understood that the “alkyl” or “aryl” respectively represents the attached Alkylene group or arylene group.
  • alkyl or “alkyl group” used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group can be any Optionally substituted by one or more substituents described in this invention.
  • the alkyl group contains 1-12 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms, ie, C 1-6 alkyl; in still other embodiments
  • the alkyl group contains 1-4 carbon atoms, that is, C 1-4 alkyl; in some embodiments, the alkyl group contains 1-3 carbon atoms, that is, C 1-3 alkyl.
  • the C 1-6 alkyl group described in the present invention includes a C 1-4 alkyl group; in other embodiments, the C 1-6 alkyl group described in the present invention includes a C 1-3 alkyl group. alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, tert-butyl) Base), n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl Base-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3- Methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl Kei and so on.
  • alkoxy means that the alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group has the meaning as described in the present invention.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including 1-propoxy or 2-propoxy), butoxy (including n-butoxy, Isobutoxy, sec-butoxy, tert-butoxy) and so on.
  • haloalkyl or “haloalkoxy” means that an alkyl or alkoxy group is substituted with one or more halogen atoms. Examples of this include, but are not limited to, trifluoromethyl, difluoromethyl, Monofluoromethyl, trifluoromethoxy, chloroethyl (for example, 2-chloroethyl), trifluoroethyl (including but not limited to 2,2,2-trifluoroethyl), 2,2- Difluoroethyl, 2-chloro-1-methylethyl, etc.
  • amino denotes the group -NH 2.
  • carboxy refers to the group -COOH.
  • hydroxyl refers to the group -COOH.
  • hydroxyl refers to the group -COOH.
  • cyano refers to the group -COOH.
  • nitro refers to the groups -OH, -CN, -NO 2 and -SH.
  • alkylamino or “alkylamino” denotes the group -NH 2 is substituted with one or two alkyl groups, wherein the alkyl group is as defined as the present invention.
  • alkylamino groups include, but are not limited to, methylamino, ethylamino, methylethylamino, dimethylamino, and the like.
  • carbocyclyl refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-14 ring carbon atoms with one or more points of attachment connected to the rest of the molecule, wherein The carbocyclic ring is optionally substituted with the substituents described in the present invention.
  • carbocyclic group can be used interchangeably with the term “carbocyclic ring”. Examples of carbocyclic groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, and the like.
  • cycloalkyl refers to a saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 ring carbon atoms.
  • the cycloalkyl group contains 3-10 ring carbon atoms, such as C 3-10 cycloalkyl; in other embodiments, the cycloalkyl group contains 3-8 ring carbon atoms, such as C 3- 8 Cycloalkyl; In still other embodiments, cycloalkyl contains 3-6 ring carbon atoms, such as C 3-6 cycloalkyl.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • C 3-8 cycloalkyl includes C 3-6 cycloalkyl; said C 3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl .
  • the cycloalkyl group may be optionally substituted with one or more substituents described in this invention.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms; wherein, the The heterocyclic group is non-aromatic and does not contain any aromatic ring.
  • the sulfur atom of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atom of the ring can optionally be oxidized to an N-oxide.
  • heterocyclyl can be used interchangeably with the term “heterocyclic”.
  • heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, Oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl, etc.
  • the heterocyclic group can be composed of 3-8 atoms or 3-6 atoms, the atoms are optionally selected from C, N, O or S and at least one atom is N, O or S; wherein the heterocyclic group composed of 3-8 atoms includes a heterocyclic group composed of 3-6 atoms; the heterocyclic group composed of 3-6 atoms includes a heterocyclic group composed of 3-5 atoms Heterocyclic group.
  • the heterocyclic group composed of 3-6 atoms includes, but is not limited to, oxirane Aziridine Azetidinyl Oxetanyl Pyrrolidinyl Tetrahydrofuranyl Tetrahydrothienyl Thiazolidine Dihydrothiazole (for example, ), pyrazolidine Pyrazolinyl Oxazolidinyl Imidazolidine Dihydrooxazole (e.g. ), dihydroimidazole Piperidinyl Piperazinyl Dihydro-1,4-oxazine Morpholinyl Wait.
  • the heterocyclyl group may be optionally substituted with one or more substituents described in the present invention.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • aryl means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, 6-12 ring atoms or 6-10 ring atoms, wherein at least one ring is aromatic, And there are one or more attachment points connected to the rest of the molecule.
  • aryl can be used interchangeably with the terms “aromatic ring” or “aromatic ring”. Examples of aryl groups may include phenyl, 2,3-dihydro-1H-indenyl, naphthyl, and anthracenyl.
  • the aryl group may be optionally substituted with one or more substituents described in the present invention.
  • the group "C 6-10 aryl” means an aryl group containing 6-10 ring carbon atoms.
  • heteroaryl group can be connected to the rest of the molecule (such as the main structure in the general formula) through any reasonable position (which can be C in CH or N in NH).
  • heteroaryl can be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic compound”.
  • heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl and the like.
  • the heteroaryl group may be optionally substituted with one or more substituents described in the present invention.
  • the heteroaryl group is a heteroaryl group consisting of 5-10 atoms, which means that the heteroaryl group contains 1-9 ring carbon atoms and 1, 2, 3, or 4 selected from O, S, and N. Ring heteroatoms; in other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-6 atoms, meaning that the heteroaryl group contains 1-5 ring carbon atoms and 1, 2, 3, or 4 are selected from O , S and N ring heteroatoms, and examples of heteroaryl groups composed 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 "consisting of jk atoms” is generally used to describe a cyclic group, meaning that the cyclic group is composed of jk ring atoms, and the ring atoms include carbon atoms and/or O, N, S, P And other heteroatoms; the j and k are each independently any non-zero natural number, and k>j; the "jk” includes j, k and any natural number in between.
  • “consisting of 3-8 atoms” means that the cyclic group is composed of 3-8, 5-10 or 5-6. It is composed of three ring atoms, and the ring atoms include carbon atoms and/or O, N, S, P and other heteroatoms.
  • pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergies or similar inappropriate reactions, such as gastrointestinal discomfort, dizziness, and the like.
  • pharmaceutically acceptable refers to those approved by a federal regulatory agency or a national government or listed in the US Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, especially in humans.
  • carrier refers to a diluent, adjuvant, excipient or base with which the compound is administered.
  • These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • Water and aqueous solutions e.g., saline solution, dextrose solution, glycerol solution
  • Suitable drug carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin.
  • prodrug used in the present invention represents the conversion of a compound into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the maternal structure in the blood or tissues.
  • the prodrug compounds of the present invention can be esters.
  • esters can be used as prodrugs including phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, that is, it can be acylated to obtain a compound in the form of a prodrug.
  • prodrug forms include phosphate esters.
  • these phosphate ester compounds are obtained by phosphorylation of the parent hydroxyl group.
  • prodrugs please refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.
  • Metal refers to the product obtained by the metabolism of a specific compound or its salt in the body.
  • the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by oxidizing, reducing, hydrolyzing, amidating, deamidating, esterifying, degreasing, enzymatic cleavage and the like of the administered compound.
  • the present invention includes the metabolites of the compound, including the metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.
  • the "pharmaceutically acceptable salt” used in the present invention refers to the organic and inorganic salts of the compound of the present invention.
  • Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts, such as hydrochloride, hydrobromide, phosphate, sulfate, and perchlorate; organic acid salts, such as ethyl acetate.
  • Other pharmaceutically acceptable salts include those obtained by reacting with an appropriate base, including alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also intends to contemplate any quaternary ammonium salt formed by compounds containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali metals or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 Sulfonates and aromatic sulfonates.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 Sulfonates and aromatic sulfonates.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to the association formed by the solvent molecule being water.
  • esters in the present invention refers to a hydrolyzable ester formed by a compound containing a hydroxyl group or a carboxyl group.
  • esters are, for example, pharmaceutically acceptable esters that are hydrolyzed in humans or animals to produce parent alcohols or acids.
  • the compound of formula (I) of the present invention contains a carboxyl group, which can form a hydrolyzable ester in vivo with an appropriate group.
  • Such groups include, but are not limited to, alkyl, arylalkyl and the like.
  • the "nitrogen oxide” in the present invention means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms.
  • the corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or peracid (e.g. peroxycarboxylic acid) to form the N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • N-oxides can be prepared by the method of LWDeady (Syn.Comm.1977, 7,509-514), in which, for example, in an inert solvent such as dichloromethane, the amine compound is combined with m-chloroperoxybenzoic acid (MCPBA) reaction.
  • LWDeady Syn.Comm.1977, 7,509-514
  • MCPBA m-chloroperoxybenzoic acid
  • the "compounds of the present invention”, “compounds described in the present invention”, “compounds described in the present invention” or similar expressions used in the present invention refer to compounds represented by any general structure described in the present invention .
  • the compound of the present invention may refer to a compound represented by formula (I) or formula (Ia) or formula (II) or formula (IIa) in the present invention.
  • the compound of the present invention also includes the specific compound in any one of the examples.
  • treating any disease or condition as used in the present invention, in some embodiments refers to ameliorating the disease or condition (ie slowing down or preventing or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, “treatment” refers to the regulation of the disease or condition physically (e.g., stabilizing the perceptible symptoms) or physiologically (e.g., stabilizing the parameters of the body) or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.
  • any structural formula given in the present invention is also intended to represent the non-isotopically enriched form and the isotopically enriched form of these compounds.
  • the isotope-enriched compound has the structure described by the general formula given in the present invention, except that one or more atoms are replaced by atoms having the selected atomic weight or mass number.
  • Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the compounds of the present invention include isotopically enriched compounds as defined in the present invention, for example, those compounds in which radioactive isotopes such as 3 H, 14 C and 18 F are present, or non-radioactive isotopes such as 2 H and 13 C.
  • isotopically enriched compounds can be used for metabolism 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 including drugs or Single-photon emission computed tomography (SPECT), which measures the distribution of substrate tissue, may be used in radiotherapy of patients.
  • 18 F-enriched compounds are particularly ideal for PET or SPECT research.
  • the isotope-enriched compound represented by formula (I) can be prepared by conventional techniques familiar to those skilled in the art or as described in the examples and preparation process of the present invention, using a suitable isotope-labeled reagent instead of the previously used unlabeled reagent.
  • isotopes particularly deuterium (ie, 2 H or D)
  • deuterium in the present invention is regarded as a substituent of the compound of formula (I).
  • the isotope enrichment factor can be used to define the concentration of such heavier isotopes, especially deuterium.
  • isotopic enrichment factor used in the present invention refers to the ratio between the isotopic abundance and the natural abundance of the specified isotope.
  • the compound has at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), for each designated deuterium atom, At least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping) Deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) isotope enrichment factor.
  • the pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, such as D 2 O, acetone-d 6 , DMSO-d 6 .
  • the present invention provides a pyrrolamide compound that can competitively antagonize the mineralocorticoid receptor (MR) and its use, as well as a pharmaceutical composition containing the compound and the compound or the pharmaceutical composition in the preparation of medicines
  • the medicine is used to treat, prevent or alleviate patients with hyperaldosteronism, hypertension, chronic heart failure, sequelae of myocardial infarction, liver cirrhosis, non-alcoholic steatohepatitis, chronic kidney disease, diabetic nephropathy, kidney Diseases such as exhaustion, fibrosis and/or stroke.
  • the change of the substitution position of F on the benzene ring connected to the amide has a greater impact on the properties of the compound; for example, when F is in the meta position of the acyl group, the compound (ie, the compound of the present invention) has the highest activity.
  • the compound of the present invention has excellent mineralocorticoid receptor antagonistic activity and excellent pharmacokinetic properties; even more excellent, the compound of the present invention has substantially no phototoxicity.
  • the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, or atropisomer of a compound represented by formula (I) , Nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
  • R 1 , R 2 , R 2a , R 2b , R 2c , R 2d , R 2e , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 have the meanings described in the present invention.
  • R 2 and R 3 are each independently H, D, F, Cl, Br, OH, NH 2 , SH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl or C 1-6 haloalkyl.
  • R 2 and R 3 are each independently H, D, F, Cl, Br, OH, NH 2 , SH, CN, NO 2 , C 1-4 alkyl, C 2-4 alkenyl , C 2-4 alkynyl or C 1-4 haloalkyl.
  • R 2 and R 3 are each independently H, D, F, Cl, Br, OH, NH 2 , SH, CN, NO 2 , methyl, ethyl, n-propyl, isopropyl , Trifluoromethyl or difluoromethyl.
  • R 5 , R 6 and the carbon atoms to which they are connected together form a C 3-6 carbocyclic ring, a benzene ring, a heterocyclic ring composed of 3-6 atoms or a heteroaromatic ring composed of 5-6 atoms, wherein the C 3-6 carbon ring, benzene ring, heterocyclic ring composed of 3-6 atoms and heteroaromatic ring composed of 5-6 atoms are each independently unsubstituted or selected from 1, 2, 3, 4 or 5 O, D, F, Cl, Br, OH, NH 2 , SH, CN, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy , C 1-4 haloalkyl, C 1-4 haloalkoxy and C 1-4 alkylamino substituents.
  • R 5 , R 6 and their connected carbon atoms together form cyclobutene, cyclopentene, cyclohexene, benzene ring, dihydrofuran, dihydrothiazole, dihydroimidazole, dihydropyrazole, dihydrooxazole , Dihydropyrrole, tetrahydropyridine, dihydro-1,4-oxazine, pyrrole, pyridine, pyrimidine or quinoline, wherein the cyclobutene, cyclopentene, cyclohexene, benzene ring, dihydrofuran , Dihydrothiazole, dihydroimidazole, dihydropyrazole, dihydrooxazole, dihydropyrrole, tetrahydropyridine, dihydro-1,4-oxazine, pyrrole, pyridine, pyrimidine and quinoline are each independently Substitution or 1, 2, 3, 4 or 5 selected
  • each R 8 , R b and R c is independently H, D, C 1-6 alkyl, or C 1-6 haloalkyl. In some embodiments, each of R 8 , R b and R c is independently H, D, C 1-4 alkyl, or C 1-4 haloalkyl.
  • each R 8 , R b and R c is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, di Fluoromethyl, monofluoromethyl or 2,2-difluoroethyl.
  • the compound represented by formula (I) of the present invention is preferably a compound represented by formula (Ia) or a stereoisomer, geometric isomer, or tautomer of a compound represented by formula (Ia) Isomers, atropisomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
  • R 1 , R 2a , R 2b , R 2c , R 2d and R 2e have the meanings described in the present invention.
  • the compound represented by formula (I) of the present invention is preferably a compound represented by formula (II) or a stereoisomer, geometric isomer, or tautomer of a compound represented by formula (II) Isomers, atropisomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
  • R 1 has the meaning described in the present invention.
  • the compound represented by formula (I) of the present invention is preferably a compound represented by formula (IIa) or a stereoisomer, geometric isomer, or tautomer of a compound represented by formula (IIa) Isomers, atropisomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
  • R 1 has the meaning described in the present invention.
  • R 1 is a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 6-10 aryl group, a heterocyclic group consisting of 3-6 atoms, or a heterocyclic group consisting of 5-10 atoms.
  • Aryl groups, wherein the C 1-6 alkyl group, C 3-6 cycloalkyl group, C 6-10 aryl group, heterocyclic group composed of 3-6 atoms and heteroaryl group composed of 5-10 atoms is independently optionally substituted with three or four R a; wherein, R a has the meaning of the present invention.
  • R 1 is a C 1-4 alkyl group, a C 3-6 cycloalkyl group, a phenyl group, a 3-6 atom heterocyclic group, or a 5-6 atom heteroaryl group, wherein ,
  • the C 1-4 alkyl group, C 3-6 cycloalkyl group, phenyl group, heterocyclic group composed of 3-6 atoms and heteroaryl group composed of 5-6 atoms are independently optionally selected by 1, 2 , 3 or 4 R a ; wherein, R a has the meaning described in the present invention.
  • R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, cyclic Oxyethyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, pyridyl or pyrimidinyl, wherein the methyl, ethyl , N-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxirane, azetidinyl, oxygen heterocycle butyl, tetra
  • each R a is independently D, F, Cl, Br, OH, NH 2, SH, CN, NO 2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group composed of 3-6 atoms or composed of 5-10 atoms The heteroaryl group; wherein, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 ring Alkyl groups, C 6-10 aryl groups, heterocyclic groups composed of 3-6 atoms and heteroaryl groups composed of 5-10 atoms are independently unsubstituted or 1, 2, 3 or 4 selected from D, F, Cl, Br, OH, NH 2 , SH, CN, NO 2 , C 1-6 alkyl, C 2-6 alkeny
  • each R a is independently D, F, Cl, Br, OH, NH 2, SH, CN, NO 2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 3-4 cycloalkyl, C 6-10 aryl, heterocyclic group composed of 3-6 atoms or composed of 5-6 atoms The heteroaryl group; wherein, the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 3-6 ring Alkyl group, C 6-10 aryl group, heterocyclic group composed of 3-6 atoms and heteroaryl group composed of 5-6 atoms are independently unsubstituted or 1, 2, 3 or 4 selected from D, F, Cl, Br, OH, NH 2 , SH, CN, NO 2 , C 1-4 alkyl, C 2-4 alkeny
  • each R a is independently D, F, Cl, Br, OH, NH 2, SH, CN, NO 2, methyl, ethyl, n-propyl, isopropyl, n-butyl, Tert-butyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethane Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidine Group, morpholinyl, pyrrolyl, pyridyl, pyrimidinyl or quinolinyl; wherein the methyl, ethyl
  • the compound of the present invention has one of the following structures or stereoisomers, geometric isomers, tautomers, atropisomers, nitrogen oxides, hydration Substances, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs:
  • the present invention relates to a pharmaceutical composition comprising the compound of the present invention.
  • the pharmaceutical composition of the present invention optionally further comprises at least one of pharmaceutically acceptable carriers, excipients, diluents, adjuvants and vehicles.
  • the pharmaceutical composition of the present invention further comprises one or more other active ingredients, and the other active ingredients are ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists Agents, ⁇ -receptor blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis derivatives, calcium sensitizers, nitrates and/or antithrombotic agents.
  • the other active ingredients are ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists Agents, ⁇ -receptor blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis derivatives, calcium sensitizers, nitrates and/or antithrombotic agents.
  • the present invention relates to the use of the compound or pharmaceutical composition of the present invention in the preparation of a medicine, wherein the medicine is used to treat, prevent or alleviate the following diseases in patients: hyperaldosteronism, hypertension, chronic Heart failure, sequelae of myocardial infarction, liver cirrhosis, non-alcoholic steatohepatitis, chronic kidney disease, diabetic nephropathy, renal failure, fibrosis or stroke.
  • the present invention also relates to the use of the compound or pharmaceutical composition of the present invention in the preparation of a medicine, wherein the medicine is used as a mineralocorticoid receptor antagonist.
  • the compound or pharmaceutical composition of the present invention is used to treat, prevent or alleviate the following diseases in patients: hyperaldosteronism, hypertension, chronic heart failure, sequelae of myocardial infarction, liver cirrhosis, non-alcoholic fat Hepatitis, chronic kidney disease, diabetic nephropathy, renal failure, fibrosis or stroke.
  • the compound or pharmaceutical composition of the present invention can be used to antagonize the mineralocorticoid receptor.
  • the present invention relates to a method for using the compound or pharmaceutical composition of the present invention to treat, prevent or alleviate the following diseases in patients: hyperaldosteronism, hypertension, chronic heart failure, sequelae of myocardial infarction, liver For cirrhosis, non-alcoholic steatohepatitis, chronic kidney disease, diabetic nephropathy, renal failure, fibrosis, or stroke, the method includes treating the patient with a therapeutically effective dose of the compound or pharmaceutical composition of the present invention.
  • the present invention also relates to a method for using the compound or pharmaceutical composition of the present invention to antagonize the mineralocorticoid receptor.
  • the method includes using the compound or pharmaceutical composition of the present invention in an effective dose and biological activity. Body (including in vivo or in vitro) contact.
  • the compounds or pharmaceutical compositions of the present invention competitively antagonize the aldosterone receptor (MR), and therefore they can be useful agents for the treatment and prevention of conditions associated with increased aldosterone levels.
  • MR aldosterone receptor
  • the compound or pharmaceutical composition of the present invention can be used to treat or prevent aldosterone receptor-mediated diseases.
  • the present invention also includes methods for treating or alleviating aldosterone receptor-mediated diseases or susceptibility to these conditions in a patient, which method comprises treating the patient with a therapeutically effective amount of the compound or pharmaceutical composition of the present invention.
  • the present invention includes the use of the compounds of the present invention and pharmaceutically acceptable salts thereof for the production of pharmaceutical products for the treatment of patients with mineralocorticoid receptor or aldosterone-related diseases, including those described in the present invention.
  • the present invention includes a pharmaceutical composition that includes the effective treatment required for the combination of a compound represented by formula (I) and at least one pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle the amount.
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable includes that the substance or composition must be chemically or toxicologically suitable and related to the other components of the formulation and the mammal used for treatment.
  • the salts of the compounds of the present invention also include intermediates used in the preparation or purification of the compound represented by formula (I) or the salts of the separated enantiomers of the compound represented by formula (I), but not necessarily pharmaceutically acceptable. salt.
  • the salt of the compound of the present invention can be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Or use organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranonic acid such as glucuronic acid and galactose Alkyl acid; ⁇ -hydroxy acid, such as citric acid and tartaric acid; amino acid, such as aspartic acid and glutamic acid; aromatic acid, such as benzoic acid and cinnamic acid; sulfonic acid, such as p-toluenesulfonic acid, ethanesulfonic acid, and many more.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid
  • the biological activity of the compounds of the present invention can be assessed by using any conventionally known methods. Appropriate detection methods are well known in the art. For example, the MR antagonistic activity, pharmacokinetic activity, and/or liver microsomal stability of the compounds of the present invention can be tested by appropriate conventional methods.
  • the detection method provided by the present invention is presented only as an example and does not limit the present invention.
  • the compound of the present invention has activity in at least one of the detection methods provided by the present invention.
  • the compound of the present invention has good antagonistic activity against aldosterone receptors, and has good in vivo pharmacokinetic properties, such as better absorption and exposure, and higher bioavailability; another example, the compound of the present invention Has low side effects.
  • the characteristics of the pharmaceutical composition of the present invention include the pyrrolamide compounds represented by formula (I) or formula (Ia) or formula (II) or formula (IIa), the compounds listed in the present invention, or The compounds of Examples 1-8, and pharmaceutically acceptable carriers, adjuvants, or excipients.
  • the amount of the compound in the composition of the present invention can effectively treat or alleviate the mineralocorticoid receptor or aldosterone-related diseases of the patient.
  • the pharmaceutically acceptable composition of the present invention further comprises pharmaceutically acceptable carriers, adjuvants, or excipients, which, like those used in the present invention, include any solvents, diluents, or other Liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for specific target dosage forms.
  • pharmaceutically acceptable carriers, adjuvants, or excipients which, like those used in the present invention, include any solvents, diluents, or other Liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc.
  • Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins, such as human serum proteins, and buffer substances such as phosphate, glycine, sorbic acid, and sorbic acid.
  • Potassium acid a mixture of partial glycerides of saturated plant fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium base cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl ole
  • the pharmaceutical composition of the present invention can be administered directly or in the form of a pharmaceutical composition or drug with a suitable carrier or excipient, which is well known in the art.
  • the treatment method of the present invention may comprise administering an effective compound of the present invention to an individual in need.
  • the individual is a mammalian individual, and in some preferred embodiments, the individual is a human individual.
  • the effective amount of the compound, pharmaceutical composition or drug of the present invention can be easily determined by routine experimentation, and the most effective and convenient route of administration and the most appropriate formulation can also be determined by routine experimentation.
  • the pharmaceutical dosage form of the compound of the present invention can be provided in the form of an immediate release, controlled release, sustained release or target drug release system.
  • commonly used dosage forms include solutions and suspensions, (micro)emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous Or crystalline powder, aerosol and freeze-dried formulations.
  • special devices may be required to administer or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks.
  • Pharmaceutical dosage forms often consist of drugs, excipients, and container/sealing systems.
  • One or more excipients also known as inactive ingredients
  • Pharmaceutical excipients exist in this field and include those listed in various pharmacopoeias.
  • the pharmaceutical dosage form of the compound of the present invention can be manufactured by any method well known in the art, for example, by conventional mixing, sieving, dissolving, melting, granulating, making sugar-coated pills, tableting, suspending, squeezing, spray drying, Grinding, emulsification, (nano/micron) encapsulation, encapsulation or freeze-drying process.
  • the composition of the present invention may include one or more physiologically acceptable inactive ingredients, which can facilitate the processing of active molecules into preparations for medical use.
  • the composition can be formulated in an aqueous solution, if necessary, using physiologically compatible buffers, including, for example, phosphate, histidine or citrate used to adjust the pH of the formulation, and such as chlorine Tonicity agent for sodium or dextrose.
  • physiologically compatible buffers including, for example, phosphate, histidine or citrate used to adjust the pH of the formulation, and such as chlorine Tonicity agent for sodium or dextrose.
  • semi-solid, liquid formulations or patches may be preferred, and may contain penetration enhancers; such penetration agents are generally known in the art.
  • the compounds can be formulated into liquid or solid dosage forms and used as immediate release or controlled release/sustained release formulations.
  • Suitable dosage forms for oral ingestion by individuals include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, ointments, suspensions and emulsions.
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, for example containing conventional suppository bases such as cocoa butter or other glycerides.
  • Solid oral dosage forms can be obtained using excipients, which include fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, anti-adherents, and cation exchange Resins, humectants, antioxidants, preservatives, coloring agents and flavoring agents.
  • excipients include fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, anti-adherents, and cation exchange Resins, humectants, antioxidants, preservatives, coloring agents and flavoring agents.
  • excipients can be of synthetic or natural origin.
  • excipients examples include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium lauryl sulfate/sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicic acid Salt, silicon dioxide, sodium benzoate, sorbitol, starch, stearic acid or its salt, sugar (i.e. dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, vegetable oil (hydrogenated ) And wax. Ethanol and water can be used as granulation aids.
  • the tablet it is necessary to coat the tablet with, for example, a taste-masking film, a gastric acid resistant film, or a delayed release film.
  • a taste-masking film e.g., a gastric acid resistant film, or a delayed release film.
  • natural and synthetic polymers are combined with colorants, sugar and organic solvents or water to coat tablets to produce dragees.
  • the capsule is superior to the tablet, the drug powder, suspension or solution can be delivered in a compatible hard-shell or soft-shell capsule form.
  • compositions formulated for parenteral administration by injection are generally sterile and can be provided in unit dosage forms, such as ampoules, syringes, injection pens, or multi-dose containers, the latter usually containing a preservative.
  • the composition can take the form of a suspension, solution or emulsion in an oily or aqueous carrier, and can contain formulation reagents, such as buffers, tonicity agents, viscosity enhancers, surfactants, suspending and dispersing agents, and antioxidants. , Biocompatible polymers, chelating agents and preservatives.
  • the carrier may contain water, synthetic or vegetable oils, and/or organic co-solvents.
  • parenteral preparations will be reconstituted or diluted before administration.
  • Depot formulations that provide controlled or sustained release of the compounds of the present invention may include injectable suspensions of nano/micro-sized particles or nano/micro-sized or non-micronized crystals.
  • Other well-known matrices in the art, polymers such as poly(lactic acid), poly(glycolic acid) or copolymers thereof, can be used as a controlled release/sustained release matrix.
  • Other depot-type drug delivery systems can be provided in the form of implants and pumps that require incisions.
  • Suitable carriers for the compounds of the present invention for intravenous injection are well known in the art and include water-based solutions containing alkalis (such as sodium hydroxide) for the formation of ionic compounds; sucrose or sodium chloride as tonicity agents; for example Buffer containing phosphate or histidine. Co-solvents such as polyethylene glycol can be added. These water-based systems can effectively dissolve the compounds of the present invention and produce low toxicity after systemic administration. Without destroying the solubility and toxicity characteristics, the ratio of the components of the solution system can be greatly changed. In addition, the characteristics of the components can be changed.
  • alkalis such as sodium hydroxide
  • sucrose or sodium chloride as tonicity agents
  • Buffer containing phosphate or histidine Buffer containing phosphate or histidine.
  • Co-solvents such as polyethylene glycol can be added.
  • low-toxicity surfactants such as polysorbate or poloxamer
  • polyethylene glycol or other co-solvents can also be used
  • biocompatible polymerization such as polyvinylpyrrolidone can be added.
  • other sugars and polyols can be used to replace dextrose.
  • the compounds of the invention can act systemically and/or locally. They can be administered in a suitable manner, for example, by oral administration, gastrointestinal administration, pulmonary administration, nasal administration, sublingual administration, translingual administration, buccal administration, rectal administration, dermal administration. Medicine, transdermal administration, conjunctival administration, ear canal administration, or as a graft or stent.
  • the compounds of the present invention are preferably administered orally or parenterally.
  • Suitable administration modes for oral administration are as follows: according to the work of the prior art, rapid release and/or an improved method of release of the compound of the present invention, they include crystalline and/or amorphous and/or soluble
  • the compound of the present invention in the form of, for example, a tablet (uncoated tablet or, for example, a tablet coated with a gastric juice tolerable or delayed dissolution or insoluble coating that controls the release of the compound of the present invention), in the oral cavity Rapidly disintegrating tablets or films/flakes, films/lyophilized bodies, capsules (such as hard or soft capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can bypass the absorption step (e.g., intravenous, intraarterial, intracardia, intraspinal, or lumbar) or include absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal) absorb).
  • Administration forms suitable for parenteral administration include preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilized bodies or sterile powders.
  • suitable examples are inhaled drug forms (including powder inhalers, sprays), nasal drops, solutions or sprays, tablets for tongue, sublingual or buccal administration, films/ Flakes or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shock mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), emulsions (Milch ), paste, foam, spray powder, implant or stent.
  • inhaled drug forms including powder inhalers, sprays), nasal drops, solutions or sprays, tablets for tongue, sublingual or buccal administration, films/ Flakes or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shock mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), emulsions (Milch ), paste, foam, spray powder, implant or
  • the therapeutically effective amount of the compound of the present invention should be present in the above-mentioned pharmaceutical preparation at a concentration of about 0.1 to 99.5%, preferably about 0.5 to 95% by weight of the entire mixture.
  • the above-mentioned pharmaceutical preparations may also contain other pharmaceutical active ingredients.
  • the therapeutically effective dose can be estimated first using various methods well known in the art.
  • the initial dose for animal studies can be based on the effective concentration established in the cell culture assay.
  • the dosage range suitable for a human individual can be determined, for example, using data obtained from animal studies and cell culture assays.
  • the compound of the present invention can be prepared as a medicament for oral administration.
  • An exemplary dose of the compound of the present invention in a medicament for oral administration is from about 0.01 to about 100 mg/kg (where kg represents the body weight of the subject).
  • the dosage regimen of agents commonly used for oral administration is three times a week, twice a week, once a week, three times a day, twice a day, or once a day.
  • the compound of the present invention is administered as an active ingredient in a total amount of about 0.001 to about 50 mg/kg body weight every 24 hours. In order to obtain the desired result, it may optionally be in the form of multiple single doses. Administer the drug.
  • the effective amount or therapeutically effective amount or dose of an agent refers to the amount of an agent or compound that causes improvement in symptoms or prolonged survival of an individual.
  • Toxicity and therapeutic efficacy of the molecule can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by measuring LD 50 (lethal to 50% of the dose groups) and the ED 50 (50% of the population a therapeutically effective The dosage).
  • the dose ratio of toxicity and therapeutic effects is the therapeutic index and can be expressed as LD 50 / ED 50.
  • a drug showing a high therapeutic index is preferred.
  • the effective amount or therapeutically effective amount is the amount of a compound or pharmaceutical composition that will trigger a biological or medical response in a tissue, system, animal, or human being explored by researchers, veterinarians, doctors, or other clinicians. Dosages preferably fall within a range of circulating concentrations that include the ED 50 of minimal toxicity or no toxicity. The dosage can vary within this range, depending on the dosage form used and/or the route of administration used. The correct formulation, route of administration, dosage, and interval between administrations should be selected according to methods known in the art, taking into account the particularity of individual conditions.
  • the dose and interval can be adjusted individually to provide a plasma level of the active part sufficient to obtain the desired effect; that is, the minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC of each compound will be different, but it can be estimated, for example, from in vitro data and animal experiments.
  • the dose necessary to obtain MEC will depend on individual characteristics and route of administration. In the case of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
  • the amount of the medicament or composition administered can be determined by various factors, including the sex, age and weight of the individual to be treated, the severity of the pain, the method of administration, and the judgment of the prescribing physician.
  • the composition of the present invention can be provided by a packaging or dispensing device containing one or more unit dosage forms (containing the active ingredient).
  • the packaging or device may include metal or plastic foil (such as foam packaging) or glass and rubber stoppers.
  • the packaging or dispensing device may be accompanied by instructions for medicines. It is also possible to prepare a composition containing the compound of the present invention formulated in a compatible pharmaceutical carrier, place it in an appropriate container, and label it for the treatment of a specified condition.
  • the compound of the present invention can be used alone or, if necessary, in combination with other active compounds.
  • the present invention also provides the combined use of at least one compound of the present invention and one or more further active substances, especially drugs for treating and/or preventing the diseases of the present invention.
  • the compounds of the present invention act as mineralocorticoid receptor antagonists and show an unexpected and valuable range of pharmacological effects. They are therefore suitable for use as drugs for the treatment and/or prevention of human and animal diseases.
  • the compounds of the present invention are suitable for the prevention and/or treatment of various diseases and conditions related to diseases, especially those characterized by increased plasma aldosterone concentration or changes in plasma aldosterone concentration relative to plasma renin concentration, or related to these changes.
  • Related illnesses Examples that may be mentioned are: spontaneous primary aldosteronism, hyperaldosteronism associated with adrenal hyperplasia, adrenal adenoma and/or adrenal cancer, hyperaldosteronism associated with cirrhosis, Hyperaldosteronism associated with heart failure, and (relative) hyperaldosteronism associated with essential hypertension, etc.
  • the compounds of the present invention are also suitable for preventing sudden cardiac death in patients with an increased risk of death from sudden cardiac death.
  • patients are especially those suffering from one of the following conditions: primary and secondary hypertension, hypertensive heart disease with or without congestive heart failure, refractory hypertension, acute and chronic heart failure Failure, coronary heart disease, stable and unstable angina pectoris, myocardial ischemia, myocardial infarction, dilated cardiomyopathy, congenital primary cardiomyopathy (such as Bmgada syndrome), cardiomyopathy caused by Chagas disease, shock, Arteriosclerosis, atrial and ventricular arrhythmias, transient and ischemic attacks, stroke, inflammatory cardiovascular disorders, peripheral and cardiovascular disorders, peripheral blood flow disorders, arterial occlusive diseases such as intermittent claudication, asymptomatic left ventricle Dysfunction, myocarditis, hypertrophic changes in the heart, pulmonary hypertension, coronary and peripheral arterial spasm, thrombosis, thromboe
  • the compounds of the present invention can additionally be used to prevent and/or treat the formation of edema, such as pulmonary edema, nephrogenic edema or swelling lungs associated with heart failure, and for example in thrombolytic therapy, percutaneous transluminal angioplasty (PTA) and Restenosis after coronary angioplasty (PTCA), heart transplantation, and bypass surgery.
  • edema such as pulmonary edema, nephrogenic edema or swelling lungs associated with heart failure
  • thrombolytic therapy percutaneous transluminal angioplasty (PTA) and Restenosis after coronary angioplasty (PTCA), heart transplantation, and bypass surgery.
  • PTA percutaneous transluminal angioplasty
  • PTCA Restenosis after coronary angioplasty
  • the compounds of the present invention are also suitable for use as potassium-sparing diuretics and for the treatment of electrolyte disorders such as hypercalcemia, hypernatremia or hypokalemia.
  • the compounds of the present invention are also suitable for the treatment of nephropathy such as acute and chronic renal failure, hypertensive nephropathy, arteriosclerotic nephritis (chronic and interstitial), nephrosclerosis, chronic renal failure and cystic nephropathy, for the prevention of kidney damage (For example, kidney damage caused by immunosuppressive agents related to organ transplantation (for example, cyclosporin A)) and for kidney cancer.
  • nephropathy such as acute and chronic renal failure, hypertensive nephropathy, arteriosclerotic nephritis (chronic and interstitial), nephrosclerosis, chronic renal failure and cystic nephropathy
  • kidney damage for example, kidney damage caused by immunosuppressive agents related to organ transplantation (for example, cyclosporin A)
  • kidney cancer for example, kidney damage caused by immunosuppressive agents related to organ transplantation (for example, cyclosporin A)
  • the compounds of the present invention can additionally be used to prevent and/or treat diabetes and diabetic sequelae, such as neuropathy and diabetic nephropathy.
  • the compound of the present invention can be further used to prevent and/or treat microalbuminuria and proteinuria caused by diabetes or hypertension.
  • the compounds of the present invention can be further used to prevent and/or treat fibrotic diseases, for example, renal fibrosis, pulmonary fibrosis (including idiopathic pulmonary fibrosis), liver fibrosis and the like.
  • fibrotic diseases for example, renal fibrosis, pulmonary fibrosis (including idiopathic pulmonary fibrosis), liver fibrosis and the like.
  • the compounds of the present invention are also suitable for the prevention and/or treatment of conditions associated with an increase in plasma glucocorticoid concentration or with a local increase in glucocorticoid concentration in tissues (such as the heart).
  • Examples that can be mentioned are: adrenal dysfunction (Cushing's syndrome) that leads to excessive production of glucocorticoids, adrenal cortex tumors that lead to excessive production of glucocorticoids, and pituitary tumors, which autonomously produce ACTH (Cushing's syndrome) Adrenal cortex hormones) leading to adrenal hyperplasia and Cushing’s disease.
  • the compounds of the present invention can additionally be used to prevent and/or treat obesity, metabolic syndrome and obstructive sleep apnea.
  • the compounds of the present invention can be further used to prevent and/or treat inflammatory disorders caused by viruses, spirochetes, fungi, bacteria or mycobacteria, and inflammatory disorders of unknown etiology, such as polyarthritis, lupus erythematosus, joints Peripheral inflammation or polyarteritis, dermatomyositis, scleroderma and sarcoidosis.
  • inflammatory disorders caused by viruses, spirochetes, fungi, bacteria or mycobacteria
  • inflammatory disorders of unknown etiology such as polyarthritis, lupus erythematosus, joints Peripheral inflammation or polyarteritis, dermatomyositis, scleroderma and sarcoidosis.
  • the compounds of the present invention can be further used to treat central nervous system disorders, such as depression, anxiety and chronic pain, especially migraine, and neurodegenerative disorders, such as Alzheimer's disease and Parkinson's syndrome.
  • central nervous system disorders such as depression, anxiety and chronic pain, especially migraine
  • neurodegenerative disorders such as Alzheimer's disease and Parkinson's syndrome.
  • the compounds of the present invention are also suitable for the prevention and/or treatment of vascular injury, such as in percutaneous transluminal coronary angioplasty (PTCA), stent implantation, coronary angioscopy, reocclusion or restenosis after bypass surgery Later vascular injury, and endothelial dysfunction, Raynaud's disease, thromboangiitis obliterans (Buerger's syndrome) and tinnitus syndrome.
  • vascular injury such as in percutaneous transluminal coronary angioplasty (PTCA), stent implantation, coronary angioscopy, reocclusion or restenosis after bypass surgery Later vascular injury, and endothelial dysfunction, Raynaud's disease, thromboangiitis obliterans (Buerger's syndrome) and tinnitus syndrome.
  • the compound of the present invention can be used alone, or if necessary, can be used in combination with other active ingredients.
  • the present invention further relates to a medicament comprising at least one compound of the present invention and one or more other active ingredients (especially for the treatment and/or prevention of the aforementioned conditions).
  • Suitable active ingredients for combination include, but are not limited to: active ingredients that lower blood pressure, such as and preferably selected from calcium antagonists, angiotensin II receptor antagonists, ACE inhibitors, endothelin antagonists, renin Inhibitors, ⁇ -receptor blockers, ⁇ -receptor blockers and Rho kinase inhibitors; diuretics, especially loop diuretics, and thiazides and thiazide diuretics; have antithrombotic effects
  • the agent such as and preferably selected from platelet aggregation inhibitors, anticoagulants or fibrinolytic substances; active ingredients that alter lipid metabolism, such as and preferably selected from thyroid receptor agonists, cholesterol synthesis inhibitors such as And preferably HMG-Coenzyme A reductase inhibitor or squalene synthesis inhibitor, ACAT inhibitor, CETP inhibitor, MTP inhibitor, PPAR- ⁇ , PPAR- ⁇ and/or PPAR- ⁇ agonist, cholesterol absorption inhibitor Agents, lipase inhibitors
  • the compound of the present invention can also be administered in combination with other active ingredients other than the above-mentioned active ingredients.
  • the compound of the present invention is combined with a diuretic such as bumetane, bumetanide, torsemide, benzfluthiazine, ketone, hydrochlorothiazide, hydrofluoromethiazine, and diuretics.
  • the compounds of the present invention can be prepared by the methods described in the present invention.
  • the following reaction schemes and examples are used to further illustrate the content of the present invention.
  • Anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained by refluxing and drying with sodium metal.
  • Anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide are dried with anhydrous sodium sulfate beforehand.
  • reaction flask is plugged with a suitable rubber stopper, and the substrate is injected through a syringe.
  • the glassware is dried.
  • the chromatographic column is a silica gel column.
  • Silica gel 300-400 mesh
  • Silica gel 300-400 mesh
  • NMR spectroscopy data are measured by Bruker Avance 400 NMR spectrometer or Bruker Avance III HD 600 NMR spectrometer, with CDC1 3 , DMSO-d 6 , CD 3 OD or Acetone-d 6 as the solvent (reported in ppm as the unit ), using TMS (0ppm) or chloroform (7.26ppm) as the reference standard.
  • MS data is measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C).
  • the G1329A automatic sampler and G1315B DAD detector are used For analysis, the ESI source is applied to the LC-MS spectrometer.
  • MS mass spectrometry
  • the above two spectrometers are equipped with Agilent Zorbax SB-C18 column, the specification is 2.1 ⁇ 30mm, 5 ⁇ m.
  • the injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; the HPLC peak is recorded and read by UV-Vis wavelengths at 210 nm and 254 nm.
  • the mobile phases are 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure aqueous solution (phase B).
  • the gradient elution conditions are shown in Table 1:
  • the HPLC method for testing the atropisomer excess (%ee) of the present invention is as follows: Chromatographic column: CHIRALPAK AS-H 4.6 ⁇ 250mm5 ⁇ m; Flow rate: 1.0mL/min; Column temperature: 30°C; Detection wavelength: 290nm; Dilution Agent: ethanol; mobile phase A: 0.1% TFA: ETOH; mobile phase B: n-hexane; running time: 30 min.
  • the gradient elution conditions are shown in Table 2:
  • %Ee of S configuration (peak area ratio of S configuration-peak area ratio of R configuration) ⁇ (peak area ratio of S configuration + peak area ratio of R configuration) ⁇ 100; or
  • %Ee of R configuration (peak area ratio of R configuration ⁇ peak area ratio of S configuration) ⁇ (peak area ratio of R configuration+peak area ratio of S configuration) ⁇ 100.
  • DMSO-d 6 deuterated dimethyl sulfoxide; g grams; mg milligrams; mol moles; mmol millimoles; mL milliliters; ⁇ L microliters
  • reaction scheme describes the synthetic steps to prepare the compounds of this invention.
  • R 1 , R 2a , R 2b , R 2c , R 2d and R 2e all have the meaning as described in the present invention
  • L 1 is Cl, Br, I, methylsulfonyl or p-toluenesulfonyl Wait for the leaving group.
  • the reaction steps in each reaction scheme of the present invention are all reacted in a solvent inert to the reaction.
  • the solvent inert to the reaction includes, but is not limited to, the solvents involved in the embodiments of the present invention or their substitutes. Things.
  • the intermediate compound S5 can be prepared according to the following method: compound S1 is substituted with bromine to obtain compound S2; compound S2 is substituted with ethyl cyanoacetate to obtain compound S3; compound S3 is reacted under acidic conditions to obtain compound S4, and finally , Compound S4 undergoes dechlorination reaction under the action of a suitable hydrogen transfer reagent to obtain intermediate compound S5.
  • the intermediate compound S5 can also be prepared according to the following method: compound S6 is substituted with N-bromosuccinimide (NBS) to obtain compound S7; compound S7 is coupled with phenylboronic acid compound Sa to obtain intermediate compound S5 .
  • NBS N-bromosuccinimide
  • the intermediate compound S11 can be prepared according to one of the following methods:
  • Compound S15 can be prepared according to the method described in Reaction Scheme 1. The reaction process is as follows: Compound S11 is reacted with a suitable acylating reagent (such as oxalyl chloride) to obtain compound S14; S14 reacts with 3-fluoro-4-methylsulfonyl aniline Acylation reaction yields compound S15.
  • a suitable acylating reagent such as oxalyl chloride
  • Compound S15 can also be prepared according to the method described in Reaction Scheme 2.
  • the reaction process is as follows: Compound S11 and 3-fluoro-4-methylsulfonylaniline undergo condensation reaction under the action of a suitable reagent (such as a condensation reagent) to obtain compound S15 .
  • a suitable reagent such as a condensation reagent
  • Compound S16 can be prepared according to the method described in Reaction Scheme 3. The reaction process is as follows: Compound S14 is acylated with the corresponding aromatic amine substrate to obtain compound S16.
  • reaction solution was extracted with ethyl acetate (200mL ⁇ 3), the organic phases were combined and washed with saturated brine (200mL ⁇ 3), dried with anhydrous sodium sulfate, filtered, and spin-dried.
  • Step 2) 4-Methyl-1-(oxetan-2-ylmethyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid
  • Step 2) 4-Methyl-1-(oxetan-3-yl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid
  • the ethyl ester (20mL/2mL) was slurried for 1h, filtered with suction, and the filter cake was collected and dried at 50°C to obtain a white solid (100mg, 39.42%).
  • the plasmid containing the Gal4 DNA binding domain (DBD) of the mineralocorticoid receptor (MR) ligand binding domain (LBD) and Gal4 UAS (upstream) The firefly luciferase reporter gene plasmid under the control of activation sequence was transfected into human embryonic kidney cells (HEK293). The changes of mineralocorticoid receptor activity before and after stimulation or the influence of different stimuli on mineralocorticoid receptor activity are judged by the level of firefly luciferase activity.
  • the plasmid with Renilla luciferase gene was used as a control plasmid to transfect cells to provide an internal control for transcriptional activity, so that the test results are not interfered by changes in experimental conditions. .
  • test compound solution the test compound is prepared into a solution with 5% dimethyl sulfoxide, 60% PEG400 and 35% physiological saline, which is used for oral or intravenous administration.
  • Beagle dogs 8-10kg were randomly divided into two groups, and the test compound was administered orally at a dose of 5.0 mg/kg; after administration, the time points were 0.0833, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, Blood was collected at 24.0, 32.0 and 48.0 hours.
  • the WinNonLin 6.3 software non-compartmental model method was used to calculate the pharmacokinetic parameters.
  • Three female cynomolgus monkeys of 3.0-3.5 kg were taken orally administered with the test compound at a dose of 3 mg/kg; after the administration, the time points were 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24, 32 and Blood was collected for 48 hours.
  • the WinNnonlin 6.3 software non-compartmental model method was used to calculate the pharmacokinetic parameters.
  • the compound of the present invention has good pharmacokinetic properties in cynomolgus monkeys. Specifically, compared to the control compound CS-3150, the compound of Example 2 of the present invention has more excellent pharmacokinetic properties, for example, higher exposure, blood concentration and bioavailability.
  • test compound solution the test compound is dissolved in dimethyl sulfoxide and prepared as a 10 mg/mL solution, and then diluted with dimethyl sulfoxide in multiples of 2.15 times into solutions of different concentrations.
  • Balb/c 3T3 cells were seeded on 96-well culture plates. After 24 hours of culture, the culture medium was discarded, and the test compound containing different concentrations or the positive control substance (chlorpromazine hydrochloride, CPZ) and the balanced salt of the solvent control substance (HBSS) solution. There are two culture plates for each concentration of the test compound and the positive control substance, respectively, a light (+UV) plate and a non-light (-UV) plate. After incubating for 1 hour, place the illuminated plate under UVA conditions with a light intensity of about 1.7 mw/cm 2 to irradiate the light dose to 5.0 J/cm 2 , and place the non-illuminated plate at room temperature for the same time under dark conditions.
  • the test compound containing different concentrations or the positive control substance (chlorpromazine hydrochloride, CPZ) and the balanced salt of the solvent control substance (HBSS) solution.
  • There are two culture plates for each concentration of the test compound and the positive control substance respectively,
  • the phototoxicity of the compound is determined according to the following criteria: PIF>5 is judged as positive for phototoxicity; 5>PIF>2 is judged as possible phototoxicity; 2>PIF is judged as non-phototoxicity.

Abstract

一种吡咯酰胺类化合物、其药物组合物及其用途。所述化合物或所述药物组合物可以用作盐皮质激素受体拮抗剂。

Description

吡咯酰胺类化合物及其用途 技术领域
本发明属于医药技术领域，具体涉及吡咯酰胺类化合物及其用途，进一步涉及包含所述化合物的药物组合物。所述化合物或所述药物组合物可以用作盐皮质激素受体拮抗剂。
背景技术
盐皮质激素受体(Mineralocorticoid Receptor，MR)是醛甾酮活化的核激素受体，其调节许多涉及电解质体内平衡和心血管疾病的基因的表达。循环醛甾酮的增加，通过其对尿钠排泄的影响而提高血压，同时潜在地对脑、心脏和血管系统造成影响。另外，醛甾酮过多症与许多导致肾和心血管疾病的疾病生理过程有关。尽管醛甾酮过多症通常由产生醛甾酮的腺瘤所引起，但顽固性高血压的患者的醛甾酮水平常常升高，通常称为“醛甾酮逃逸”，这是由于血清钾含量提高或残留的AT1R活性所致。醛甾酮过多症和醛甾酮逃逸典型地导致MR活性提高，已经证明，MR拮抗剂可作为有效的抗高血压剂，并且还可以有效的治疗心力衰竭和原发性醛甾酮增多症。
醛甾酮是形成于肾上腺皮质中的甾类激素。它的产生极大地取决于肾血流量而被间接地调节。肾血流量的任何减少都导致肾中的酶肾素释放并进入循环血液。这进而激活血管紧张素II的形成，其一方面对动脉血管具有收缩作用，但是另一方面也刺激肾上腺皮质中醛甾酮的形成。由此，肾用作血液循环中血压传感器，和由此间接用作体积传感器，且经肾素-血管紧张素-醛甾酮体系抵消体积的严重损失，这一方面是通过增加血液压力(血管紧张素II效果)，另一方面通过增加肾中钠和水的再吸收来重新平衡血管系统的填充状态(醛甾酮效果)来实现。
该控制系统可能以各种方式发病而受损。例如，肾血流量的慢性减少(例如，由于心力衰竭和由此引起的静脉系中血液阻塞)导致慢性地过量地释放醛甾酮。继之以血容量的膨胀和由此通过增多地供应血容量至心脏而增加了心脏的虛弱。肺中血液的阻塞连同呼吸急促和形成肢体浮肿，并且腹水和胸膜腔积液可能由此产生；肾血流量进一步下降。另外，过量的醛甾酮效果导致血液和细胞外液中钾浓度减少。在以前已经以其它方式受损的心肌中，如果存在低于临界最小值水平的偏差则可能诱发致命的心脏心律不齐。这很可能是患有心力衰竭的患者中经常出现的心源性猝死的主要起因之一。
另外，也有报道认为醛甾酮决定着典型地要在心力衰竭中观察的许多心肌重塑过程。由此，醛甾酮过多症是心力衰竭(其可以最初是由各种类型的损伤例如心肌梗死、心肌炎症或高血压而诱发)的发病机理和预后的决定性组分。该假设得到如下事实的支持：在对患有慢性心力衰竭和后急性心肌梗塞的患者群进行的通过使用醛甾酮拮抗剂的广泛临床研究中，整体死亡率显著减少(B.Pitt,F.Zannad,W.J.Remme等，N.Engl.J.Med.ML 709-717(1999)；B.Pitt,W.Remme,F.Zannad等，N.Engl.J.Med 1309-1321(2003))。
另外，在内脏组织中，例如肾和肠管，MR在对醛甾酮响应过程中调节钠潴留、钾排出和水平衡。MR在脑中的表达也似乎起到控制神经元兴奋性、下丘脑-垂体肾上腺轴的负反馈调控和行为表现的认知方面的作用(Castren等人，J.of Neuroendocrinology,3,461-66(1993))。
醛甾酮水平提高或过度刺激盐皮质激素受体与一些生理失调或病理性的疾病状态有关，包括康恩(氏) 综合征、原发性和继发性醛甾酮过多症、钠潴留增加、镁和钾排出增加(多尿)、水滞留增加、高血压症(孤立的收缩期高血压症和组合形式的收缩期/舒张期高血压症)、心律失常、心肌纤维化、心肌梗塞、巴特氏综合征和与过量的儿茶酚胺水平相关的病症(Hadley,M.E.,ENDOCRINOLOGY,2nd Ed.,pp366-81,(1988)；以及Brilla等人，Journal of Molecular and Cellular Cardiology,25(5),pp563-75(1993))。具有MR拮抗作用的化合物和/或药物组合物对于任何上述病症具有治疗价值。
国际申请WO 2006012642 A2公开了用于调节一种或多种类固醇核受体的活性的吡咯衍生物——埃沙西林酮(Esaxerenone，CS-3150，其化学结构如下所示)的消旋体化合物，专利申请WO 2008126831 A1公开立体构型的埃沙西林酮化合物，所述化合物可以用于治疗高血压等疾病。根据日本医药品医疗机器综合机构PMDA公开的《审查报告书》(2019年1月8日)显示，该化合物具有光毒性，例如，在体外Balb/c 3T3成纤维细胞中性红摄取试验结果显示该化合物具有光毒性(光刺激因子PIF>17)。
Figure PCTCN2020122388-appb-000001
尽管盐皮质激素受体拮抗剂在治疗高血压症和心力衰竭方面的进展很显著，但护理的现行标准只是接近最佳，并且对于其它治疗/药理干预还存在明显未满足的医学需要。本发明通过提供可以用于治疗或预防高血压症、心力衰竭、其它心血管病症及其它醛甾酮病症的化合物和组合物而解决了那些需要。
发明摘要
本发明提供一种具有盐皮质激素受体(MR)拮抗作用的吡咯酰胺类化合物及其药物组合物，以及所述化合物或所述药物组合物在制备药物中的用途，所述药物用于治疗、预防或减轻患者醛甾酮过多症、高血压、慢性心力衰竭、心肌梗死的后遗症、肝硬化、非酒精性脂肪性肝炎、慢性肾病、糖尿病肾病、肾衰竭、纤维化和/或中风等疾病。
一方面，本发明涉及一种化合物，其为式(I)所示的化合物或式(I)所示化合物的立体异构体、几何异构体、互变异构体、阻转异构体、氮氧化物、水合物、溶剂化物、代谢产物、酯、药学上可接受的盐或前药，
Figure PCTCN2020122388-appb-000002
其中，R 1为C 1-6烷基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基或5-10个原子组成的杂芳基，其中，所述C 1-6烷基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基和5-10个原子组成的杂芳基独立任选地被1、2、3或4个R a所取代；
各R a独立地为D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷 氧基、C 1-6卤代烷基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基或5-10个原子组成的杂芳基；其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基和5-10个原子组成的杂芳基独立地未被取代或被1、2、3或4个选自D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基和C 1-6卤代烷基的取代基所取代；
R 2a、R 2b、R 2c、R 2d和R 2e各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、-C(＝O)C 1-6烷基、-C(＝O)OC 1-6烷基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氨基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基或5-10个原子组成的杂芳基；
R 2和R 3各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基或C 1-6卤代烷基；
R 4、R 5、R 6和R 7各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、-C(＝O)C 1-6烷基、-C(＝O)OC 1-6烷基、-S-C 1-6烷基、-S(＝O)C 1-6烷基、-S(＝O) 2C 1-6烷基、-S(＝O) 2NR bR c、-S(＝O) 2OC 1-6烷基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氨基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基或5-10个原子组成的杂芳基；或者
R 5、R 6和与它们相连的碳原子一起形成C 3-6碳环、C 6-10芳环、3-6个原子组成的杂环或5-10个原子组成的杂芳环，其中，所述C 3-6碳环、C 6-10芳环、3-6个原子组成的杂环和5-10个原子组成的杂芳环各自独立地未被取代或被1、2、3、4或5个选自＝O、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6烷氨基的取代基所取代；
各R 8、R b和R c独立地为H、D、C 1-6烷基或C 1-6卤代烷基。
在一些实施方案中，R 2和R 3各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、甲基、乙基、正丙基、异丙基、三氟甲基或二氟甲基；
R 4、R 5、R 6和R 7各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、-C(＝O)CH 3、-C(＝O)OCH 3、-S-CH 3、-S(＝O)CH 3、-S(＝O) 2CH 3、-S(＝O) 2CH 2CH 3、-S(＝O) 2NR bR c、-S(＝O) 2OCH 3、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、异丙氧基、叔丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、三氟甲氧基、甲氨基、二甲氨基、环丙基、环丁基、环戊基、环己基、苯基、萘基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基、嘧啶基或喹啉基；或者
R 5、R 6和与它们相连的碳原子一起形成环丁烯、环戊烯、环己烯、苯环、二氢呋喃、二氢噻唑、二氢咪唑、二氢吡唑、二氢恶唑、二氢吡咯、四氢吡啶、二氢-1,4-恶嗪、吡咯、吡啶、嘧啶或喹啉，其中，所述环丁烯、环戊烯、环己烯、苯环、二氢呋喃、二氢噻唑、二氢咪唑、二氢吡唑、二氢恶唑、二氢吡咯、四氢吡啶、二氢-1,4-恶嗪、吡咯、吡啶、嘧啶和喹啉各自独立地未被取代或被1、2、3、4或5个选自＝O、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、异丙氧基、叔丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、三氟甲氧基、甲氨基和二甲氨基的取代基所取代；
各R 8、R b和R c独立地为H、D、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、三氟甲基、二氟甲基、一氟甲基或2,2-二氟乙基。
在一些实施方案中，本发明所述的式(I)所示化合物优选地为式(Ia)所示的化合物或式(Ia)所示化 合物的立体异构体、几何异构体、互变异构体、阻转异构体、氮氧化物、水合物、溶剂化物、代谢产物、酯、药学上可接受的盐或前药，
Figure PCTCN2020122388-appb-000003
其中，R 1、R 2a、R 2b、R 2c、R 2d和R 2e具有本发明所描述的含义。
在一些实施方案中，R 2a、R 2b、R 2c、R 2d和R 2e各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、-C(＝O)CH 3、-C(＝O)OCH 3、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、异丙氧基、叔丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、三氟甲氧基、甲氨基、二甲氨基、环丙基、环丁基、环戊基、环己基、苯基、萘基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基、嘧啶基或喹啉基。
在一些实施方案中，本发明所述的式(I)所示化合物优选地为式(IIa)所示的化合物或式(IIa)所示化合物的立体异构体、几何异构体、互变异构体、阻转异构体、氮氧化物、水合物、溶剂化物、代谢产物、酯、药学上可接受的盐或前药，
Figure PCTCN2020122388-appb-000004
其中，R 1具有本发明所描述的含义。
在一些实施方案中，R 1为C 1-4烷基、C 3-6环烷基、苯基、3-6个原子组成的杂环基或5-6个原子组成的杂芳基，其中，所述C 1-4烷基、C 3-6环烷基、苯基、3-6个原子组成的杂环基和5-6个原子组成的杂芳基独立任选地被1、2、3或4个R a所取代；
各R a独立地为D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、异丙氧基、叔丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、环丙基、环丁基、环戊基、环己基、苯基、萘基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基、嘧啶基或喹啉基；其中，所述甲基、乙基、正丙基、异丙基、正丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、异丙氧基、叔丁氧基、二氟甲基、一氟甲基、2,2-二氟乙基、环丙基、环丁基、环戊基、环己基、苯基、萘基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基、嘧啶基和喹啉基独立地未被取代或被1、2、3或4个选自D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、C 1-4烷基、C 2-4烯基、C 2-4炔基、 C 1-4烷氧基和C 1-4卤代烷基的取代基所取代。
在一些实施方案中，R 1为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环丙基、环丁基、环戊基、环己基、苯基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基或嘧啶基，其中，所述甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环丙基、环丁基、环戊基、环己基、苯基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基和嘧啶基独立任选地被1、2、3或4个R a所取代；
各R a独立地为D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、异丙氧基、叔丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、环丙基、环丁基、环戊基、环己基、苯基、萘基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基、嘧啶基或喹啉基；其中，所述甲基、乙基、正丙基、异丙基、正丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、异丙氧基、叔丁氧基、二氟甲基、一氟甲基、2,2-二氟乙基、环丙基、环丁基、环戊基、环己基、苯基、萘基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基、嘧啶基和喹啉基独立地未被取代或被1、2、3或4个选自D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、甲基、乙基、正丙基、异丙基、C 2-4烯基、C 2-4炔基、甲氧基、乙氧基、异丙氧基、三氟甲基、二氟甲基、一氟甲基和2,2-二氟乙基的取代基所取代。
另一方面，本发明涉及一种药物组合物，其包含本发明所述的化合物；任选地，所述药物组合物进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂和媒介物的至少一种。
在一些实施方案中，本发明所述的药物组合物进一步包含一种或多种其他活性成分，所述其他活性成分为ACE抑制剂、肾素抑制剂、血管紧张素II受体拮抗剂、β-受体阻断剂、乙酰水杨酸、利尿剂、钙拮抗剂、他汀类、洋地黄衍生物、钙敏化剂、硝酸盐或抗血栓形成剂。
一方面，本发明涉及本发明所述的化合物或本发明所述的药物组合物在制备药物中的用途，其中，所述药物用于治疗、预防或减轻患者如下疾病：醛甾酮过多症、高血压、慢性心力衰竭、心肌梗死的后遗症、肝硬化、非酒精性脂肪性肝炎、慢性肾病、糖尿病肾病、肾衰竭、纤维化和/或中风。
另一方面，本发明涉及本发明所述的化合物或本发明所述的药物组合物在制备药物中的用途，其中，所述药物用作用作盐皮质激素受体拮抗剂。
本发明详细说明书
定义和一般术语
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以 在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley & Sons,New York:2007中的描述，其全部内容通过引用并入本文。
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
本发明所使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中，“患者”是指人。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。
“阻转异构体”是指基于因分子内旋转受限制而产生的轴向(axial)或平面手性(planar chirality)的结构异构体。本发明的化合物有两种阻转异构体，例如本发明式(II)所示化合物具有两种阻转异构体，这是源于连接邻位被三氟甲基取代的苯基和取代吡咯环之间的键由于空间位阻导致旋转受限制而产生的轴向手性。本发明的“阻转异构体”是本发明化合物的两个阻转异构体中的任何一个。但是，优选具有更优异的药理活性、稳定性、体内动力学性质、安全性等从而具有作为药物的有利性质的阻转异构体。阻转异构体的分离可以通过手性拆分技术，如选择性结晶或者高效液相色谱法来完成。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley & Sons，Inc.，New York，1994。
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。同样的，对于描述方式“…独立任选地”中的“独立”，也应做上述广义理解。
术语“任选”或“任选地”是指随后描述的事件或情形可以但不一定出现，即，该描述包括其中所述事件或情形出现的情况以及不出现的情况。例如，“独立任选地被一个或多个……取代基所取代”是指所述基团是未被取代的或者是被一个或多个相同或不同的取代基所取代的。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1-C 6烷基”或“C 1-6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基；“C 1-4烷基”特指独立公开的甲基、乙基、C 3烷基(即丙基，包括正丙基和异丙基)和C 4烷基(即丁基，包括正丁基、异丁基、仲丁基和叔丁基)。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
本发明使用的术语“烷基”或“烷基基团”，表示含有1至20个碳原子，饱和的直链或支链的一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。在一些实施方案中，烷基基团含有1-12个碳原子；在另一些实施方案中，烷基基团含有1-6个碳原子，即，C 1-6烷基；在又一些实施方案中，烷基基团含有1-4个碳原子，即C 1-4烷基；还在一些实施方案中，烷基基团含有1-3个碳原子，即C 1-3烷基。在一些实施例中，本发明中所述的C 1-6烷基包括C 1-4烷基；在另一些实施例中，本发明中所述的C 1-6烷基包括C 1-3烷基。
烷基基团的实例包含，但并不限于，甲基、乙基、丙基(包括正丙基和异丙基)、丁基(包括正丁基、异丁基、仲丁基、叔丁基)、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、正己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、 2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、正庚基、正辛基等等。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。烷氧基基团的实例包括，但并不限于，甲氧基、乙氧基、丙氧基(包括1-丙氧基或2-丙氧基)、丁氧基(包括正丁氧基、异丁氧基、仲丁氧基、叔丁氧基)等等。
术语“卤代烷基”或“卤代烷氧基”表示烷基或烷氧基基团被一个或多个卤素原子所取代，这样的实例包含，但并不限于，三氟甲基、二氟甲基、一氟甲基、三氟甲氧基、氯乙基(例如，2-氯乙基)、三氟乙基(包括但不限于，2,2,2-三氟乙基)、2,2-二氟乙基、2-氯-1-甲基乙基等。
术语“氨基”表示基团-NH 2。术语“羧基”表示基团-COOH。术语“羟基”、“氰基”、“硝基”、“巯基”分别表示基团-OH、-CN、-NO 2、-SH。术语“氧代”代表基团＝O。
术语“烷氨基”或“烷基氨基”表示基团-NH 2被一个或两个烷基所取代，其中所述烷基具有如本发明所述的含义。烷氨基基团的实例包括，但并不限于，甲氨基、乙氨基、甲基乙基氨基、二甲氨基等。
术语“碳环基”是指有一个或多个连接点连接到分子的其余部分、饱和或部分不饱和的、含有3-14个环碳原子的单环、双环或三环体系，其中，所述碳环任选地被本发明所描述的取代基所取代。术语“碳环基”可以与术语“碳环”交换使用。碳环基团的实例包含，但并不限于，环丙烷、环丁烷、环戊烷、环己烷、环戊烯、环己烯、环戊二烯等等。
术语“环烷基”表示含有3-12个环碳原子的饱和单环、双环或三环体系。在一些实施方案中，环烷基包含3-10个环碳原子，例如C 3-10环烷基；在另一些实施方案中，环烷基包含3-8个环碳原子，例如C 3-8环烷基；在又一些实施方案中，环烷基包含3-6个环碳原子，例如C 3-6环烷基。环烷基基团的实例包括，但并不限于，环丙基、环丁基、环戊基、环己基、环庚基、环辛基，等等。其中，如本发明所述的，C 3-8环烷基包括C 3-6环烷基；所述的C 3-6环烷基包括环丙基、环丁基、环戊基和环己基。所述环烷基基团可以任选地被一个或多个本发明描述的取代基所取代。
术语“杂环基”是指包含3-12个环原子的，饱和或部分不饱和的单环、双环或三环体系，其中至少一个环原子选自氮、硫和氧原子；其中，所述杂环基是非芳香性的，且不包含任何芳香环。除非另外说明，杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化物。术语“杂环基”可以与术语“杂环”交换使用。杂环基的实例包括，但不限于，环氧乙烷基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、四氢噻吩基、噻唑烷基、吡唑烷基、恶唑烷基、咪唑烷基、异恶唑烷基、哌啶基、哌嗪基或吗啉基，等等。如本发明所述的，所述杂环基可以由3-8个原子或3-6个原子组成，所述原子任选地选自C、N、O或S且至少有一个原子为N、O或S；其中，所述3-8个原子组成的杂环基包括3-6个原子组成的杂环基；所述3-6个原子组成的杂环基包括3-5个原子组成的杂环基。具体地，所述3-6个原子组成的杂环基包括但不限于，环氧乙烷基
Figure PCTCN2020122388-appb-000005
氮杂环丙烷基
Figure PCTCN2020122388-appb-000006
氮杂环丁基
Figure PCTCN2020122388-appb-000007
氧杂环丁基
Figure PCTCN2020122388-appb-000008
吡咯烷基
Figure PCTCN2020122388-appb-000009
四氢呋喃基
Figure PCTCN2020122388-appb-000010
四氢噻吩基
Figure PCTCN2020122388-appb-000011
噻唑烷基
Figure PCTCN2020122388-appb-000012
二氢噻唑(例如，
Figure PCTCN2020122388-appb-000013
)、吡唑烷 基
Figure PCTCN2020122388-appb-000014
吡唑啉基
Figure PCTCN2020122388-appb-000015
恶唑烷基
Figure PCTCN2020122388-appb-000016
咪唑烷基
Figure PCTCN2020122388-appb-000017
二氢恶唑(例如
Figure PCTCN2020122388-appb-000018
)、二氢咪唑
Figure PCTCN2020122388-appb-000019
哌啶基
Figure PCTCN2020122388-appb-000020
哌嗪基
Figure PCTCN2020122388-appb-000021
二氢-1,4-恶嗪
Figure PCTCN2020122388-appb-000022
或吗啉基
Figure PCTCN2020122388-appb-000023
等。所述杂环基基团可以任选地被一个或多个本发明描述的取代基所取代。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“芳基”表示含有6-14个环原子、6-12个环原子或6-10个环原子的单环、双环和三环的碳环体系，其中，至少一个环是芳香族的，且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”或“芳环”交换使用。芳基基团的实例可以包括苯基、2,3-二氢-1H-茚基、萘基和蒽基。所述芳基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外说明，基团“C 6-10芳基”表示含有6-10个环碳原子的芳基基团。
术语“杂芳基”表示含有5-12个环原子、5-10个环原子或5-6个环原子的单环、双环和三环体系，其中至少一个环是芳香族的，且至少一个环包含1、2、3或4个选自氮、氧、硫的环杂原子，同时，所述杂芳基有一个或多个附着点与分子其余部分相连。当杂芳基基团中存在-CH 2-基团时，所述的-CH 2-基团可以任选地被-C(＝O)-替代。除非另外说明，所述的杂芳基基团可以通过任何合理的位点(可以为CH中的C，或者NH中N)连接到分子其余部分(例如通式中的主体结构)上。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。杂芳基的实例包括，但并不限于，呋喃基、咪唑基、吡咯基、吡唑基、吡啶基、嘧啶基、吡嗪基等。所述杂芳基基团可以任选地被一个或多个本发明描述的取代基所取代。在一些实施方案中，杂芳基为5-10个原子组成的杂芳基，表示杂芳基含有1-9个环碳原子和1、2、3或4个选自O、S和N的环杂原子；在另一些实施方案中，杂芳基为5-6个原子组成的杂芳基，表示杂芳基含有1-5个环碳原子和1、2、3或4个选自O、S和N的环杂原子，5-6个原子组成的杂芳基的实例包括，但并不限于，呋喃基、咪唑基、异噁唑基、噁唑基、吡咯基、吡唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻吩基、噻唑基等。
术语“j-k个原子组成的”一般用于描述环状基团，表示所述环状基团由j-k个环原子所组成，所述的环原子包括碳原子和/或O、N、S、P等杂原子；所述j和k各自独立地为任意非零的自然数，且k>j；所述“j-k”包括j、k和两者之间的任意自然数。例如，“3-8个原子组成的”、“5-10个原子组成的”或“5-6个原子组成的”表示所述环状基团由3-8、5-10或5-6个环原子所组成，所述的环原子包括碳原子和/或O、N、S、P等杂原子。
术语“药学上可接受的”是指当给人施用时生理上可耐受的并且一般不产生过敏或类似的不适当的反应，例如肠胃不适、眩晕等的分子实体和组合物。优选地，本文所用的术语“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可的药典上列举的在动物中、特别是在人体中使用的。
术语“载体”指与所述化合物一同施用的稀释剂、辅剂、赋形剂或基质。这些药物载体可以是无菌液体，例如水和油类，包括石油、动物、植物或合成来源的，例如花生油、大豆油、矿物油、芝麻油等。水和水 性溶液(例如，盐水溶液、葡萄糖水溶液、甘油水溶液)优选用作载体、特别是可注射溶液。适宜的药物载体描述于E.W.Martin的“Remington′s Pharmaceutical Sciences”中。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.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.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰胺化，脱酰胺作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明所使用的“药学上可接受的盐”是指本发明化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，无机酸盐，如盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐；有机酸盐，如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐等；或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括与适当的碱反应得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。本发明也拟构思了任何包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。可以形成盐的碱金属或碱土金属包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
本发明的“酯”是指含有羟基或羧基的化合物形成的体内可水解的酯。这样的酯是，例如在人或动物体内水解产生母体醇或酸的药学上可接受的酯。本发明式(I)化合物含有羧基，可以与适当的基团形成体内可水解的酯，这样的基团包括，但不限于，烷基、芳基烷基等。
本发明的“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或 过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是，N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514)，其中例如在惰性溶剂例如二氯甲烷中，使胺化合物与间-氯过氧苯甲酸(MCPBA)反应。
本发明中所使用的“本发明的化合物”、“本发明所描述的化合物”、“本发明所述化合物”或类似的表述，指代本发明所述的任意一个通式结构所代表的化合物。例如，本发明的化合物可以指代本发明中式(I)或式(Ia)或式(II)或式(IIa)所代表的化合物。本发明的化合物还包含任意一个实施例中的具体化合物。
如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构，除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如 2H， 3H， 11C， 13C， 14C， 15N， 17O， 18O， 18F， 31P， 32P， 35S， 36Cl和 125I。
另一方面，本发明所述化合物包括同位素富集的本发明所定义的化合物，例如，其中存在放射性同位素，如 3H， 14C和 18F的那些化合物，或者其中存在非放射性同位素，如 2H和 13C。该类同位素富集的化合物可用于代谢研究(使用 14C)、反应动力学研究(使用例如 2H或 3H)、检测或成像技术，如正电子发射断层扫描术(PET)或包括药物或底物组织分布测定的单光子发射计算机断层成像术(SPECT)，或可用于患者的放疗中。 18F富集的化合物对PET或SPECT研究而言是特别理想的。同位素富集的式(I)所示化合物可以通过本领域技术人员熟悉的常规技术或本发明中的实施例和制备过程所描述使用合适的同位素标记试剂替代原来使用过的未标记试剂来制备。
此外，较重同位素特别是氘(即， 2H或D)的取代可提供某些治疗优点，这些优点是由代谢稳定性更高带来的。例如，体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。应当理解，本发明中的氘被看作式(I)化合物的取代基。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。本发明所使用的术语“同位素富集因子”是指所指定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物的取代基被指定为氘，该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5％的氘掺入)、至少4000(60％的氘掺入)、至少4500(67.5％的氘掺入)，至少5000(75％的氘掺入)，至少5500(82.5％的氘掺入)、至少6000(90％的氘掺入)、至少6333.3(95％的氘掺入)、至少6466.7(97％的氘掺入)、至少6600(99％的氘掺入)或至少6633.3(99.5％的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D 2O、丙酮-d 6、DMSO-d 6的那些溶剂化物。
除非其他方面表明，本发明的化合物的所有互变异构形式都包含在本发明的范围之内。另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。
本发明所使用的任何保护基团、氨基酸和其它化合物的缩写，除非另有说明，都以它们通常使用的、公认的缩写为准，或参照IUPAC-IUBCommission on Biochemical Nomenclature(参见Biochem.1972，11： 942-944)。
本发明化合物的描述
本发明提供一种可以竞争性地拮抗盐皮质激素受体(MR)的吡咯酰胺类化合物及其用途，以及包含所述化合物的药物组合物和所述化合物或所述药物组合物在制备药物中的用途，所述药物用于治疗、预防或减轻患者醛甾酮过多症、高血压、慢性心力衰竭、心肌梗死的后遗症、肝硬化、非酒精性脂肪性肝炎、慢性肾病、糖尿病肾病、肾衰竭、纤维化和/或中风等疾病。经研究意外的发现，与酰胺相连的苯环上的F的取代位置改变对化合物的性质影响较大；如当F处于酰基的间位时，化合物(即本发明化合物)的活性最高。总体而言，本发明化合物具有优异的盐皮质激素受体拮抗活性和优异的药代动力学性质；更优异的是，本发明化合物基本无光毒性。
一方面，本发明涉及一种化合物，其为式(I)所示的化合物或式(I)所示化合物的立体异构体、几何异构体、互变异构体、阻转异构体、氮氧化物、水合物、溶剂化物、代谢产物、酯、药学上可接受的盐或前药，
Figure PCTCN2020122388-appb-000024
其中，R 1、R 2、R 2a、R 2b、R 2c、R 2d、R 2e、R 3、R 4、R 5、R 6、R 7和R 8具有本发明所描述的含义。
在一些实施方案中，R 2和R 3各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基或C 1-6卤代烷基。
在一些实施方案中，R 2和R 3各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、C 1-4烷基、C 2-4烯基、C 2-4炔基或C 1-4卤代烷基。
在一些实施方案中，R 2和R 3各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、甲基、乙基、正丙基、异丙基、三氟甲基或二氟甲基。
在一些实施方案中，R 4、R 5、R 6和R 7各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、-C(＝O)C 1-6烷基、-C(＝O)OC 1-6烷基、-S-C 1-6烷基、-S(＝O)C 1-6烷基、-S(＝O) 2C 1-6烷基、-S(＝O) 2NR bR c、-S(＝O) 2OC 1-6烷基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氨基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基或5-10个原子组成的杂芳基，其中，R b和R c具有本发明所描述的含义；或者
R 5、R 6和与它们相连的碳原子一起形成C 3-6碳环、C 6-10芳环、3-6个原子组成的杂环或5-10个原子组成的杂芳环，其中，所述C 3-6碳环、C 6-10芳环、3-6个原子组成的杂环和5-10个原子组成的杂芳环各自独立地未被取代或被1、2、3、4或5个选自＝O、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6烷氨基的取代基所取代。
在一些实施方案中，R 4、R 5、R 6和R 7各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、-C(＝O)C 1-4烷基、-C(＝O)OC 1-4烷基、-S-C 1-4烷基、-S(＝O)C 1-4烷基、-S(＝O) 2C 1-4烷基、-S(＝O) 2NR bR c、-S(＝O) 2OC 1-4烷基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4烷氨基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基或5-6个原子组成的杂芳基，其中，R b和R c具有本发明所描述的含义；或者
R 5、R 6和与它们相连的碳原子一起形成C 3-6碳环、苯环、3-6个原子组成的杂环或5-6个原子组成的杂芳环，其中，所述C 3-6碳环、苯环、3-6个原子组成的杂环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2、3、4或5个选自＝O、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基和C 1-4烷氨基的取代基所取代。
在一些实施方案中，R 4、R 5、R 6和R 7各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、-C(＝O)CH 3、-C(＝O)OCH 3、-S-CH 3、-S(＝O)CH 3、-S(＝O) 2CH 3、-S(＝O) 2CH 2CH 3、-S(＝O) 2NR bR c、-S(＝O) 2OCH 3、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、异丙氧基、叔丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、三氟甲氧基、甲氨基、二甲氨基、环丙基、环丁基、环戊基、环己基、苯基、萘基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基、嘧啶基或喹啉基，其中，R b和R c具有本发明所描述的含义；或者
R 5、R 6和与它们相连的碳原子一起形成环丁烯、环戊烯、环己烯、苯环、二氢呋喃、二氢噻唑、二氢咪唑、二氢吡唑、二氢恶唑、二氢吡咯、四氢吡啶、二氢-1,4-恶嗪、吡咯、吡啶、嘧啶或喹啉，其中，所述环丁烯、环戊烯、环己烯、苯环、二氢呋喃、二氢噻唑、二氢咪唑、二氢吡唑、二氢恶唑、二氢吡咯、四氢吡啶、二氢-1,4-恶嗪、吡咯、吡啶、嘧啶和喹啉各自独立地未被取代或被1、2、3、4或5个选自＝O、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、异丙氧基、叔丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、三氟甲氧基、甲氨基和二甲氨基的取代基所取代。
优选地，R 4、R 5和R 7各自独立地为H或D，R 6为-S(＝O) 2CH 3或-S(＝O) 2CH 2CH 3。
在一些实施方案中，各R 8、R b和R c独立地为H、D、C 1-6烷基或C 1-6卤代烷基。在一些实施方案中，各R 8、R b和R c独立地为H、D、C 1-4烷基或C 1-4卤代烷基。
在一些实施方案中，各R 8、R b和R c独立地为H、D、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、三氟甲基、二氟甲基、一氟甲基或2,2-二氟乙基。
在一些实施方案中，本发明所述的式(I)所示化合物优选地为式(Ia)所示的化合物或式(Ia)所示化合物的立体异构体、几何异构体、互变异构体、阻转异构体、氮氧化物、水合物、溶剂化物、代谢产物、酯、药学上可接受的盐或前药，
Figure PCTCN2020122388-appb-000025
其中，R 1、R 2a、R 2b、R 2c、R 2d和R 2e具有本发明所描述的含义。
在一些实施方案中，R 2a、R 2b、R 2c、R 2d和R 2e各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、-C(＝O)C 1-6烷基、-C(＝O)OC 1-6烷基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氨基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基或5-10个原子组成的杂芳基。
在一些实施方案中，R 2a、R 2b、R 2c、R 2d和R 2e各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、-C(＝O)C 1-4烷基、-C(＝O)OC 1-4烷基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4烷氨基、C 3-4环烷基、C 6-10芳基、3-6个原子组成的杂环基或5-6个原子组成的杂芳基。
在一些实施方案中，R 2a、R 2b、R 2c、R 2d和R 2e各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、-C(＝O)CH 3、-C(＝O)OCH 3、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、异丙氧基、叔丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、三氟甲氧基、甲氨基、二甲氨基、环丙基、环丁基、环戊基、环己基、苯基、萘基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基、嘧啶基或喹啉基。
在一些实施方案中，本发明所述的式(I)所示化合物优选地为式(II)所示的化合物或式(II)所示化合物的立体异构体、几何异构体、互变异构体、阻转异构体、氮氧化物、水合物、溶剂化物、代谢产物、酯、药学上可接受的盐或前药，
Figure PCTCN2020122388-appb-000026
其中，R 1具有本发明所描述的含义。
在一些实施方案中，本发明所述的式(I)所示化合物优选地为式(IIa)所示的化合物或式(IIa)所示化合物的立体异构体、几何异构体、互变异构体、阻转异构体、氮氧化物、水合物、溶剂化物、代谢产物、酯、药学上可接受的盐或前药，
Figure PCTCN2020122388-appb-000027
其中，R 1具有本发明所描述的含义。
在一些实施方案中，R 1为C 1-6烷基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基或5-10个原子组成的杂芳基，其中，所述C 1-6烷基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基和5-10个原子组成的杂芳基独立任选地被1、2、3或4个R a所取代；其中，R a具有本发明所述的含义。
在一些实施方案中，R 1为C 1-4烷基、C 3-6环烷基、苯基、3-6个原子组成的杂环基或5-6个原子组成的杂芳基，其中，所述C 1-4烷基、C 3-6环烷基、苯基、3-6个原子组成的杂环基和5-6个原子组成的杂芳基独立任选地被1、2、3或4个R a所取代；其中，R a具有本发明所述的含义。
在一些实施方案中，R 1为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环丙基、环丁基、环戊基、环己基、苯基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基或嘧啶基，其中，所述甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环丙基、环丁基、环戊基、环己基、苯基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基和嘧啶基独立任选地被1、2、3或4个R a所取代；其中，R a具有本发明所述的含义。
在一些实施方案中，各R a独立地为D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基或5-10个原子组成的杂芳基；其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基和5-10个原子组成的杂芳基独立地未被取代或被1、2、3或4个选自D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基和5-10个原子组成的杂芳基的取代基所取代。
在一些实施方案中，各R a独立地为D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4卤代烷基、C 3-4环烷基、C 6-10芳基、3-6个原子组成的杂环基或5-6个原子组成的杂芳基；其中，所述C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4卤代烷基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基和5-6个原子组成的杂芳基独立地未被取代或被1、2、3或4个选自D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基和5-6个原子组成的杂芳基的取代基所取代。
在一些实施方案中，各R a独立地为D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、异丙氧基、叔丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、环丙基、环丁基、环戊基、环己基、苯基、萘基、环氧乙烷基、氮杂 环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基、嘧啶基或喹啉基；其中，所述甲基、乙基、正丙基、异丙基、正丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、异丙氧基、叔丁氧基、二氟甲基、一氟甲基、2,2-二氟乙基、环丙基、环丁基、环戊基、环己基、苯基、萘基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基、嘧啶基和喹啉基独立地未被取代或被1、2、3或4个选自D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、甲基、乙基、正丙基、异丙基C 2-4烯基、C 2-4炔基、甲氧基、乙氧基、异丙氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、C 3-6环烷基、苯基、3-6个原子组成的杂环基和5-6个原子组成的杂芳基的取代基所取代。
在一些实施方案中，本发明所述化合物具有以下其中之一的结构或所述结构的立体异构体、几何异构体、互变异构体、阻转异构体、氮氧化物、水合物、溶剂化物、代谢产物、酯、药学上可接受的盐或前药：
Figure PCTCN2020122388-appb-000028
另一方面，本发明涉及一种药物组合物，其包含本发明所述的化合物。
在一些实施方案中，本发明所述的药物组合物任选地进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂和媒介物的至少一种。
在另一些实施方案中，本发明所述的药物组合物，其进一步包含一种或多种其他活性成分，所述其他活性成分为ACE抑制剂、肾素抑制剂、血管紧张素II受体拮抗剂、β-受体阻断剂、乙酰水杨酸、利尿剂、钙拮抗剂、他汀类、洋地黄衍生物、钙敏化剂、硝酸盐和/或抗血栓形成剂。
一方面，本发明涉及本发明所述的化合物或药物组合物在制备药物中的用途，其中，所述药物用于治疗、预防或减轻患者如下疾病：醛甾酮过多症、高血压、慢性心力衰竭、心肌梗死的后遗症、肝硬化、非酒精性脂肪性肝炎、慢性肾病、糖尿病肾病、肾衰竭、纤维化或中风。
另一方面，本发明还涉及本发明所述的化合物或药物组合物在制备药物中的用途，其中，所述药物用作盐皮质激素受体拮抗剂。
一方面，本发明所述的化合物或药物组合物用于治疗、预防或减轻患者如下疾病：醛甾酮过多症、高血压、慢性心力衰竭、心肌梗死的后遗症、肝硬化、非酒精性脂肪性肝炎、慢性肾病、糖尿病肾病、肾衰竭、纤维化或中风。
另一方面，本发明所述的化合物或药物组合物可用于拮抗盐皮质激素受体。
一方面，本发明涉及一种使用本发明所述的化合物或药物组合物治疗、预防或减轻患者如下疾病的方法：醛甾酮过多症、高血压、慢性心力衰竭、心肌梗死的后遗症、肝硬化、非酒精性脂肪性肝炎、慢性肾病、糖尿病肾病、肾衰竭、纤维化或中风，所述方法包括使用本发明所述的化合物或药物组合物的治疗有效剂量对患者进行治疗。
另一方面，本发明还涉及一种使用本发明所述的化合物或药物组合物拮抗盐皮质激素受体的方法，所述方法包括使用本发明所述的化合物或药物组合物的有效剂量与生物体(包括体内或体外)接触。
本发明所述化合物或药物组合物竞争性地拮抗醛甾酮受体(MR)，并因此它们可以是治疗和预防与醛甾酮水平提高相关的病症的有用药剂。
本发明所述化合物或药物组合物可用于治疗或预防醛甾酮受体介导的疾病。本发明同样包含治疗或减轻患者的醛甾酮受体介导的疾病，或对这些病症敏感的方法，该方法包含使用本发明化合物或药物组合物的治疗有效量对患者进行治疗。
本发明包含本发明化合物及其药学上可接受的盐的应用，用于生产医药产品治疗患者与盐皮质激素受体或醛甾酮相关的疾病，包括那些本发明所描述的疾病。本发明包含药物组合物，该药物组合物包括式(I)所代表的化合物与至少一种药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物的结合所需的有效治疗量。
除非其他方面表明，本发明的化合物所有的水合物、溶剂化物和药学上可接受的盐都属于本发明的范围。
具体地说，盐是药学上可接受的盐。术语“药学上可接受的”包括物质或组合物必须是适合化学或毒理学的，与组成制剂的其他组分和用于治疗的哺乳动物有关。
本发明的化合物的盐还包括用于制备或纯化式(I)所示化合物的中间体或式(I)所示化合物分离的对映异构体的盐，但不一定是药学上可接受的盐。
本发明的化合物的盐可以通过文献上提供的任何合适的方法制备得到，例如，使用无机酸，如盐酸，氢溴酸，硫酸，硝酸和磷酸等等。或者使用有机酸，如乙酸，马来酸，琥珀酸，扁桃酸，富马酸，丙二酸，丙酮酸，草酸，羟乙酸和水杨酸；吡喃糖酸，如葡萄糖醛酸和半乳糖醛酸；α-羟酸，如柠檬酸和酒石酸；氨基酸，如天门冬氨酸和谷氨酸；芳香族酸，如苯甲酸和肉桂酸；磺酸，如对甲苯磺酸，乙磺酸，等等。
本发明化合物的生物活性可通过使用任何常规已知方法评定。适当的检测方法是本领域众所周知的。例如，可以通过适当的常规方法检测本发明化合物的MR拮抗活性、药代动力学活性和/或肝微粒体稳定性等。本发明提供的检测方法仅作为实例呈现且不限制本发明。本发明化合物在至少一种本发明提供的检测方法中具有活性。例如，本发明化合物对醛甾酮受体具有良好的拮抗活性，具有较好的体内药代动力学性质，比如有较好的吸收和暴露量，生物利用度较高；又如，本发明化合物具有较低的毒副作用。
本发明化合物的药物组合物、制剂、给药和用途
另一方面，本发明的药物组合物的特点包括式(I)或式(Ia)或式(II)或式(IIa)所示的吡咯酰胺类化合物，本发明所列出的化合物，或实施例1-8的化合物，和药学上可接受的载体，辅剂，或赋形剂。本发明的组合物中化合物的量能有效地治疗或减轻患者的与盐皮质激素受体或醛甾酮相关的疾病。
像本发明所描述的，本发明药学上可接受的组合物进一步包含药学上可接受的载体，辅剂，或赋形剂，这些像本发明所应用的，包括任何溶剂，稀释剂，或其他液体赋形剂，分散剂或悬浮剂，表面活性剂，等渗剂，增稠剂，乳化剂，防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：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,综合此处文献的内容，表明不同的载体可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的载体媒介与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。
可作为药学上可接受载体的物质包括，但并不限于，离子交换剂，铝，硬脂酸铝，卵磷脂，血清蛋白，如人血清蛋白，缓冲物质如磷酸盐，甘氨酸，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶体硅，三硅酸镁，聚乙烯吡咯烷酮，聚丙烯酸脂，蜡，聚乙烯-聚氧丙烯-阻断聚合体，羊毛脂，糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇，磷酸缓冲溶液，和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁，着色剂，释放剂，包衣衣料，甜味剂，调味剂和香料，防腐剂和抗氧化剂。
本发明的药物组合物可直接给药或随同合适的载体或赋形剂以医药组合物或药物形式给药，这是本领域所熟知的。本发明的治疗方法可包含向有需要的个体施以有效的本发明化合物。在一些实施方案中，所述个体是哺乳动物个体，并且在一些优选实施方案中，所述个体是人类个体。
本发明所述化合物、药物组合物或药物的有效量可通过常规实验容易的测定，最有效和方便的给药途径以及最适当的制剂也可通过常规实验测定。
本发明的化合物的医药剂型可以以速释、控释、缓释或靶药物释放系统形式提供。例如，常用剂型包括溶液和悬浮液、(微)乳液、软膏、凝胶和贴片、脂质体、片剂、糖衣药丸、软壳或硬壳胶囊、栓剂、胚珠、植入物、非晶形或结晶粉末、气溶胶和冻干制剂。视所用的给药途径而定，可能需要特殊装置来施用或给予药物，例如注射器和针、吸入器、泵、注射笔、涂药器或专用瓶(Special flask)。药物剂型常常由药物、赋形剂和容器/密封系统组成。可将一种或多种赋形剂(又称为非活性成分)添加到本发明的化合物中来改善或促进药物的制造、稳定性、给药和安全性，并且可提供获得所需药物释放曲线的方法。因此，添加到药物中的赋形剂类型可视各种因素而定，例如药物的物理和化学特性、给药途径和制备步骤。在该领域中存在药用赋形剂并且包括各种药典中所列的那些。(参见美国药典(U.S.Pharmacopeia,USP)、日本药典(Japanese Pharmacopoeia,JP)、欧洲药典(European Pharmacopoeia,EP)和英国药典(British pharmacopoeia,BP)；美国食品与药品管理局(the U.S.Food and Drug Administration,www.fda.gov)药物评价与研究中心(Center for Drug Evaluation and Research,CEDR)出版物，例如《非活性组分指南》(Inactive Ingredient Guide,1996)；Ash和Ash编写的《药物添加剂手册》(Handbook of Pharmaceutical Additives,2002,联合信息资源公司(Synapse Information Resources,Inc.,Endicott NY；etc.)。
本发明化合物的药物剂型可通过本领域中熟知的任一种方法来制造，例如通过常规混合、筛分、溶解、熔化、造粒、制造糖衣药丸、压片、悬浮、挤压、喷雾干燥、研磨、乳化、(纳米/微米级)囊封、包理或冻干工艺。如上文所述，本发明的组合物可包括一种或一种以上生理学上可接受的非活性成分，这些非活性成分会促进活性分子被加工成用于医药用途的制剂。
适当的制剂视所需的给药途径而定。例如，对于静脉注射来说，组合物可配制于水溶液中，必要时使用生理上相容的缓冲剂，包括例如用于调整制剂pH值的磷酸盐、组氨酸或柠檬酸盐，以及诸如氯化钠或右旋糖的张度剂。对于经粘膜或鼻给药来说，可首选半固体、液体制剂或者贴片、可能含有渗透增强剂；所述渗透剂通常为本领域所已知。对于口服给药来说，化合物可配制成液体或固体剂型并作为速释或控释/缓释制剂。用于个体口服摄取的合适剂型包括片剂、药丸、糖衣药丸、硬壳和软壳胶囊、液体、凝胶、糖浆、膏剂、悬浮液和乳液。化合物也可以被配制在直肠组合物中，诸如栓剂或保留灌肠剂，例如含有常规的栓剂基质如可可脂或其它甘油酯。
固体口服剂型可使用赋形剂获得，所述赋形剂包括填充剂、崩解剂、粘合剂(干和湿)、溶解延缓剂、润滑剂、助流剂、抗粘剂、阳离子性交换树脂、湿润剂、抗氧化剂、防腐剂、着色剂和调味剂。这些赋形剂可为合成或天然来源。所述赋形剂的实例包括纤维素衍生物、柠檬酸、磷酸二钙、明胶、碳酸镁、月桂基硫酸镁/月桂基硫酸钠、甘露糖醇、聚乙二醇、聚乙烯吡咯烷酮、硅酸盐、二氧化硅、苯甲酸钠、山梨糖醇、淀粉、硬脂酸或其盐、糖(即右旋糖、蔗糖、乳糖等)、滑石、西黄蓍胶浆(tragacanth mucilage)、植物油(氢化)和蜡。乙醇和水可用作造粒助剂。在某些情况下，需要用例如掩味膜、抗胃酸膜或延缓释放膜来涂覆片剂。常常将天然和合成的聚合物与着色剂、糖和有机溶剂或水组合用于涂覆片剂，从而产生糖衣药丸。当胶囊优于片剂时，可以用兼容的硬壳或软壳胶囊形式递送其药物粉末、悬浮液或溶液。
用于通过注射非经肠给药而配制的组合物通常是无菌的并且可以用单位剂型提供，例如安瓿瓶、注射 器、注射笔、或多剂量容器，后者通常含有防腐剂。组合物可采用在油性或水性载体中的悬浮液、溶液或乳液等形式，并且可含有配制试剂，例如缓冲剂、张度剂、粘度增强剂、表面活性剂、悬浮剂和分散剂、抗氧化剂、生物相容性聚合物、鳌合剂和防腐剂。视注射部位而定，所述载体可含有水、合成或植物油和/或有机共溶剂。在某些情况下，例如对于冻干产物或浓缩物，会在给药之前将非经肠制剂重组或加以稀释。提供本发明的化合物的控释或缓释的贮库制剂(depot formulation)可包括纳米/微米级微粒或者纳米/微米级或非微细化晶体的可注射悬浮液。本领域其它熟知的基质，聚(乳酸)、聚(乙醇酸)或其共聚物等聚合物可被用作控释/缓释基质。可以以需要切口的植入物和泵的形式提供其它的贮库型(depot)给药系统。
用于静脉注射的本发明化合物的合适的载体为本领域所熟知并且包括含有碱(如氢氧化钠)的水基溶液，用于形成离子化合物；作为张度剂的蔗糖或氯化钠；例如含有磷酸盐或组氨酸的缓冲剂。可添加如聚乙二醇的共溶剂。这些水基体系能有效溶解本发明的化合物并且在全身性给药后产生低毒性。在不破坏溶解性和毒性特征的情况下，可大大改变溶液体系的组分的比例。此外，可改变组分的特性。举例来说，可使用诸如聚山梨醇酯或泊洛沙姆(poloxamer)的低毒性表面活性剂，也可使用聚乙二醇或其它共溶剂，可添加诸如聚乙烯吡咯烷酮的生物相容性聚合物，并且可用其它糖和多元醇来替代右旋糖。
本发明化合物可全身和/或局部作用。它们可以以适合的方式给药，例如，通过口服给药、经肠胃给药、经肺给药、经鼻给药、舌下给药、经舌给药、含服、直肠给药、真皮给药、经皮给药、结膜给药、耳道给药或作为移植片或支架给药。本发明化合物优选地经口服给药或非经肠给药。
口服给药的适合给药方式如下：根据现有技术工作的方式，迅速释放和/或以改良的方法释放本发明的化合物的给药方式，它们包含结晶和/或无定形和/或溶解的形式的本发明的化合物，例如片剂(未包衣片剂或例如用控制本发明的化合物释放的胃液耐受的或延迟溶解的或不溶性的包衣进行包衣的片剂)、在口腔中迅速碎裂的片剂或薄膜/薄片、薄膜/冻干体、胶囊(例如硬胶囊或软胶囊)、糖衣片剂、颗粒剂、丸剂、粉剂、乳剂、混悬剂、气溶胶或溶液。
非经肠给药可以绕过吸收步骤(例如静脉内、动脉内、贲门内、脊柱内或腰内)或包括吸收(例如：肌内吸收、皮下吸收、皮内吸收、经皮吸收或腹膜内吸收)。适合于非经肠给药的给药形式包括溶液、混悬液、乳液、冻干体或无菌粉体形式的用于注射和输注的制剂。
对于其它给药途径，适合的例子是吸入的药物形式(包括粉体吸入器、喷雾器)、滴鼻剂、溶液或喷雾剂、用于舌、舌下或含服给药的片剂、薄膜/薄片或胶囊、栓剂、耳或眼制剂、阴道胶囊、水混悬液(洗剂、震荡合剂)、亲脂性混悬剂、软膏、霜剂、经皮治疗体系(例如贴片)、乳剂(Milch)、糊剂、泡沫、喷洒粉剂、植入物或支架。
本发明化合物的治疗有效量应当是以整个混合物约0.1至99.5％，优选约0.5至95％重量的浓度存在于上述药物制剂中。
除本发明化合物外，上述药物制剂还可以包含其它药物活性成分。
治疗有效剂量可首先使用本领域中熟知的各种方法来估算。用于动物研究的初始剂量可基于细胞培养测定中所确立的有效浓度。适合于人个体的剂量范围例如可使用从动物研究和细胞培养测定所获得的数据来确定。在某些实施方案中，可以将本发明的化合物制备为用于口服的药剂。本发明的化合物在用于口服 的药剂中的示例性的剂量是从约0.01至约100mg/kg(其中kg表示受试者的体重)。
通常用于口服施用的药剂的给药方案是每周三次、每周两次、每周一次、每日三次、每日两次或者每日一次。在某些实施例中，本发明化合物作为活性成分以每24小时约0.001至约50mg/kg体重的总量进行给药，为了获得所需的结果，任选可以采用多个单剂量的形式来进行给药。
药剂(例如本发明的化合物)的有效量或治疗有效量或剂量指的是引起个体症状改善或存活延长的药剂或化合物的量。所述分子的毒性和治疗功效可在细胞培养物或实验动物中通过标准医药程序来测定，例如通过测定LD 50(使群体的50％致死的剂量)和ED 50(对群体的50％治疗有效的剂量)。毒性作用与治疗作用的剂量比是治疗指数，可表示为LD 50/ED 50。优选显示高治疗指数的药剂。
有效量或治疗有效量是将会引发研究人员、兽医、医生或其它临床医生所探求的组织、系统、动物或人类的生物或医学反应的化合物或医药组合物的量。剂量优选在包括极小毒性或无毒性的ED 50的循环浓度的范围内。剂量可在这个范围内变化，视所用的剂型和/或所用的给药途径而定。应根据本领域中已知的方法，考虑个体状况的特殊性来选择正确的制剂、给药途径、剂量和给药间隔时间。
剂量和间隔时间可个别地加以调整以提供足以获得所需效果的活性部分的血浆水平；即最小有效浓度(minimal effective concentration,MEC)。各化合物的MEC将有所不同，但可以例如从体外(in vitro)数据和动物实验估算。获得MEC所必需的剂量将视个体特征和给药途径而定。在局部给药或选择性摄取的情况下，药物的有效局部浓度可能与血浆浓度无关。
所施予的药剂或组合物的量可视各种因素而定，包括所治疗个体的性别、年龄和体重、病痛的严重性、给药方式和处方医师的判断。
在需要时，本发明的组合物可以用含有一个或一个以上单位剂型(含有活性成分)的包装或分配装置提供。举例来说，所述包装或装置可包含金属或塑料箔(如发泡包装)或玻璃和橡皮塞。所述包装或分配装置可附有用药说明书。也可以制备包含在相容性医药载体中配制的本发明化合物的组合物，将其置于适当容器中，并且加上用于治疗指定病状的标签。
本发明的化合物可以单独或者，如需要，与其它的活性化合物结合使用。本发明还提供了包括至少一种本发明的化合物和一种或多种进一步的活性物质，特别是用于治疗和/或预防本发明所述的疾病的药物的联合使用。
本发明的化合物作为盐皮质激素受体的拮抗剂且显示出不可预料的有价值的药理学作用范围。它们因此适于用作用于治疗和/或预防人类和动物疾病的药物。
本发明的化合物适于预防和/或治疗各种病症和疾病的相关状况，特别是特征在于血浆醛甾酮浓度上升或者血浆醛甾酮浓度相对于血浆肾素浓度变化的病症、或与这些变化相关的病症。可被提及的实例是：自发原发性醛甾酮增多症，与肾上腺增生相关的醛甾酮过多症，肾上腺腺瘤和/或肾上腺癌，肝硬化相关的醛甾酮过多症，与心力衰竭相关的醛甾酮过多症，和与原发性高血压相关的(相对的)醛甾酮过多症等。
由于其作用机理，本发明的化合物也适用于预防心源性猝死死亡风险增加的患者的心源性猝死。这些患者尤其是患有如下病症之一的患者：原发性和继发性高血压，伴有或者不伴有充血性心力衰竭的高血压性心脏病，难治性高血压，急性和慢性心力衰竭，冠心病，稳定性和不稳定性心绞痛，心肌缺血，心肌梗 死，扩张型心肌病，先天性原发性心肌病(比如Bmgada综合征)，查加斯病引起的心肌病，休克，动脉硬化，心房和心室心律失常，短暂性和缺血性发作，中风，炎性心血管病症，外周和心脏血管病症，外周血流紊乱，动脉闭塞性疾病比如间歇性跛行，无症状的左心室功能障碍，心肌炎，心脏肥大性改变，肺动脉高血压，冠状动脉和外周动脉痉挛，血栓形成，血栓栓塞性病症和血管炎。
本发明的化合物另外可以用于预防和/或治疗水肿形成，例如肺水肿、肾原性水肿或心力衰竭相关的浮肺，和比如在溶栓疗法、经皮腔内血管成形术(PTA)和冠状动脉成形术(PTCA)、心脏移植和旁路手术之后的再狭窄。
本发明的化合物还适合用作保钾利尿剂和用于治疗电解质紊乱比如高钙血症，高钠血症或低钾血症。
本发明的化合物同样适用于治疗肾病比如急性和慢性肾衰竭，高血压肾病，动脉硬化性肾炎(慢性的和间质性的)，肾硬化，慢性肾衰竭和囊性肾病，用于预防肾损伤(例如由与器官移植有关的免疫抑制剂(例如，环孢菌素A)引起的肾损伤)和用于肾癌。
本发明的化合物可以另外用于预防和/或治疗糖尿病和糖尿病后遗症，比如神经病变和糖尿病肾病。
本发明的化合物可以进一步用于预防和/或治疗由糖尿病或高血压所引起的微白蛋白尿，和蛋白尿。
本发明的化合物可以进一步用于预防和/或治疗纤维化疾病，例如，肾脏纤维化、肺纤维化(包括特发性肺纤维化)、肝纤维化等。
本发明的化合物也适合预防和/或治疗与血浆糖皮质激素浓度增加相关或与组织(例如心脏)中糖皮质激素浓度局部增加相关的病症。可被提及的实例是：导致糖皮质激素过度产生的肾上腺功能紊乱(库兴氏综合征，Cushing's syndrome)，导致糖皮质激素过度产生的肾上腺皮质肿瘤，和垂体瘤，其自主产生ACTH(促肾上腺皮质激素)从而导致肾上腺增生和库兴氏病。
本发明的化合物可以另外用于预防和/或治疗肥胖症，代谢综合征和阻塞性睡眠呼吸暂停。
本发明的化合物可以进一步用于预防和/或治疗例如由病毒，螺旋体，真菌，细菌或分枝杆菌引起的炎性病症，和病因不明的炎性病症，比如多发性关节炎，红斑狼疮，关节周围炎或多动脉炎，皮肌炎，硬皮病和结节病。
本发明的化合物可以进一步用于治疗中枢神经障碍，比如抑郁症，焦虑症和慢性疼痛，特别是偏头痛，和神经退行性病症，比如阿尔茨海默病和帕金森综合征。
本发明的化合物也适用于预防和/或治疗血管损伤，例如在比如经皮腔内冠状动脉成形术(PTCA)，支架植入，冠状动脉血管镜检查，旁路手术后的再闭塞或再狭窄后的血管损伤，和内皮功能障碍，雷诺氏病，血栓闭塞性脉管炎(Buerger's综合征)和耳鸣综合征。
本发明的化合物可以单独使用，或如果需要，可以与其它活性成分组合使用。本发明进一步涉及包括至少一种本发明的化合物和一种或多种其他活性成分(特别是用于治疗和/或预防上述病症)的药物。用于组合的合适的活性成分包括但并不限于：降低血压的活性成分，例如和优选地选自钙拮抗剂，血管紧张素II受体拮抗剂，ACE抑制剂，内皮素拮抗剂，肾素抑制剂，α-受体阻断剂，β-受体阻断剂和Rho激酶抑制剂；利尿剂，特别是袢利尿药，以及噻嗪类和噻嗪类的利尿剂；具有抗血栓形成作用的试剂，例如和优选地选自血小板聚集抑制剂、抗凝剂或或促纤维蛋白溶解物质；改变脂类代谢的活性成分，例如和优选地选 自甲状腺受体激动剂，胆固醇合成抑制剂例如且优选地HMG-辅酶A还原酶抑制剂或角鲨烯合成抑制剂，ACAT抑制剂，CETP抑制剂，MTP抑制剂，PPAR-α、PPAR-γ和/或PPAR-δ激动剂，胆固醇吸收抑制剂，脂肪酶抑制剂，高分子胆汁吸附剂(polymeric bile adsorbents)，胆汁酸重吸收抑制剂和脂蛋白(a)拮抗剂；有机硝酸盐和NO供体，比如硝普钠，硝酸甘油，单硝酸异山梨酯，二硝酸异山梨酯，吗多明或SIN-1，和吸入的NO；具有正性肌力作用的化合物，例如强心苷(地高辛)，β-肾上腺素能和多巴胺能的激动剂比如异丙肾上腺素，肾上腺素，去甲肾上腺素，多巴胺和多巴酚丁胺；抑制环-磷酸鸟苷(cGMP)和/或环-磷酸腺苷(cAMP)分解的化合物，例如磷酸二酯酶(PDE)1、2、3、4和/或5抑制剂，特别是PDE5抑制剂比如昔多芬，伐地那非和他达那非，和PDE3抑制剂比如氨力农(aminone)和米力农(milrinone)；利尿钠肽，比如心房利钠肽(ANP，阿那立肽、anaritide)，B型利钠肽或脑利钠肽(BNP，奈西立肽、nesiritide)，C型利钠肽(CNP)和尿扩张素；钙敏化剂，例如且优选左西孟旦；NO-非依赖性但血红素-依赖性鸟苷酸环化酶刺激剂，特別是WO 00/06568、WO00/06569、WO02/42301和WO03/095451(例如，Riociguat)中描述的化合物；NO-和血红素-非依赖性的鸟苷酸环化酶活化剂，特别是WO 01/19355、WO 01/19776、WO 01/19778、WO 02/070462和WO 02/070510描述的化合物；人嗜中性粒细胞弹性蛋白酶(HNE)抑制剂，例如西维来司酮或DX-890(Reltran)；抑制信号转导级联的化合物，例如酪氨酸激酶抑制剂，特別是索拉非尼，伊马替尼，吉非替尼(Gefitinib)和厄洛替尼(Erlotinib)；和/或影响心脏能量代谢的化合物，比如乙莫克舍，二氯乙酸盐，雷诺嗪或曲美他嗪。
本发明化合物还可以与上述活性成分以外的其他活性成分组合给药。例如，在本发明的优选实施方案中，本发明的化合物与利尿剂比如腹安酸，布美他尼，托塞米，苄氟噻嗪，克尿塞，双氢氯噻嗪，氢氟甲噻，甲氯噻嗪，泊利噻嗪，三氯噻嗪，氯噻酮，吲达帕胺，美托拉宗，喹乙宗，乙酰唑胺，二氯苯磺胺，醋甲唑胺，甘油，异山梨醇，甘露醇，阿米洛利或氨苯蝶啶组合给药。
一般合成过程
在本说明书中，如果在化学名称和化学结构间存在任何差异，结构是占优的。
一般地，本发明的化合物可以通过本发明所描述的方法制备得到。下面的反应方案和实施例用于进一步举例说明本发明的内容。
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
下面所描述的实施例，除非其他方面表明，所有的温度定为摄氏度。除非其他方面表明，试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，使用时都没有经过进一步纯化；一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。
无水四氢呋喃，二氧六环，甲苯，乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，石油醚，正己烷，N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事 先干燥使用。
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿均是经过干燥的。
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。核磁共振光谱数据通过Bruker Avance 400核磁共振谱仪或Bruker Avance III HD 600核磁共振谱仪来测定，以CDC1 3,DMSO-d 6,CD 3OD或Acetone-d 6为溶剂(报导以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰),d(doublet，双峰),t(triplet，三重峰),m(multiplet，多重峰),q(quartet，四重峰),br(broadened，宽峰),dd(doublet of doublets，双二重峰),dt(doublet of triplets，双三重峰),dq(doublet of quartets，双四重峰),ddd(doublet of doublet of doublets，双双二重峰),ddt(doublet of doublet of triplets，双双三重峰),dddd(doublet of doublet of doublet of doublets，双双双二重峰)。偶合常数，用赫兹(Hz)表示。
低分辨率质谱(MS)数据通过配备G1312A二元泵和a G1316A TCC(柱温保持在30℃)的Agilent 6320系列LC-MS的光谱仪来测定的，G1329A自动采样器和G1315B DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。
低分辨率质谱(MS)数据通过配备G1311A四元泵和G1316A TCC(柱温保持在30℃)的Agilent 6120系列LC-MS的光谱仪来测定的，G1329A自动采样器和G1315D DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。
以上两种光谱仪都配备了Agilent Zorbax SB-C18柱，规格为2.1×30mm，5μm。注射体积是通过样品浓度来确定；流速为0.6mL/min；HPLC的峰值是通过在210nm和254nm处的UV-Vis波长来记录读取的。流动相为0.1％的甲酸乙腈溶液(相A)和0.1％的甲酸超纯水溶液(相B)。梯度洗脱条件如表1所示：
表1 低分辨率质谱流动相的梯度洗脱条件
时间(min) A(CH 3CN，0.1％HCOOH) B(H 2O,0.1％HCOOH)
0-3 5-100 95-0
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
测试本发明所述阻转异构体过量(％ee)的HPLC方法如下：色谱柱：CHIRALPAK AS-H 4.6×250mm5μm；流速：1.0mL/min；柱温：30℃；检测波长：290nm；稀释剂：乙醇；流动相A：0.1％TFA:ETOH；流动相B：正己烷；运行时间：30min。梯度洗脱条件如表2所示：
表2
时间(min) A％ B％
0 20 80
30 20 80
使用S构型和R构型的峰面积比来计算相应对映异构体过量(％ee)。计算公式如下：
S构型的％ee＝(S构型的峰面积比–R构型的峰面积比)÷(S构型的峰面积比+R构型的峰面积比)×100；或者
R构型的％ee＝(R构型的峰面积比–S构型的峰面积比)÷(R构型的峰面积比+S构型的峰面积比)×100。
下面简写词的使用贯穿本发明：
DMSO-d 6氘代二甲基亚砜；g克；mg毫克；mol摩尔；mmol毫摩尔；mL毫升；μL微升
下列反应方案描述了制备本发明化合物的合成步骤。其中，除非另外说明，R 1、R 2a、R 2b、R 2c、R 2d和R 2e均具有如本发明所述的含义；L 1为Cl、Br、I、甲磺酰基或对甲苯磺酰基等离去基团。除非另外说明，本发明所述各反应方案中的各反应步骤均在对该反应惰性的溶剂中反应，所述对反应惰性的溶剂包括但不限于本发明实施例中所涉及的溶剂或其替代物。
反应方案
中间体化合物S5的合成
Figure PCTCN2020122388-appb-000029
中间体化合物S5可以按照以下方法制备得到：化合物S1与溴素发生取代反应得到化合物S2；化合物S2与氰乙酸乙酯发生取代反应得到化合物S3；化合物S3在酸性条件下发生反应得到化合物S4，最后，化合物S4在合适的氢转移试剂的作用下发生脱氯反应得到中间体化合物S5。
中间体化合物S5还可以按照以下方法制备得到：化合物S6与N-溴代丁二酰亚胺(NBS)发生取代反应得到化合物S7；化合物S7与苯硼酸化合物S-a发生偶联反应得到中间体化合物S5。
中间体化合物S11的合成
Figure PCTCN2020122388-appb-000030
中间体化合物S11可以按照以下其中之一的方法制备得到：
(1)化合物S5发生皂化反应得到化合物S8；化合物S8与苄溴在碱性条件下发生取代反应得到中间体化合物S9；化合物S9与合适的试剂L 1-R 1反应得到化合物S12；化合物S12发生皂化反应得到化合物S11。或者
(2)化合物S5与合适的试剂L 1-R 1反应得到化合物S10；化合物S10发生皂化反应得到化合物S11。
反应方案1
Figure PCTCN2020122388-appb-000031
化合物S15可以按照反应方案1所描述的方法制备得到，其反应过程如下：化合物S11与合适的酰化试剂(例如草酰氯)反应得到化合物S14；S14与3-氟-4-甲砜基苯胺发生酰基化反应得到化合物S15。
反应方案2
Figure PCTCN2020122388-appb-000032
化合物S15还可以按照反应方案2所描述的方法制备得到，其反应过程如下：化合物S11与3-氟-4-甲砜基苯胺在合适试剂(例如缩合试剂)的作用下发生缩合反应得到化合物S15。
反应方案3
Figure PCTCN2020122388-appb-000033
化合物S16可以按照反应方案3所描述的方法制备得到，其反应过程如下：化合物S14与相应的芳胺底物发生酰基化反应得到化合物S16。
下面的实施例可以对本发明做进一步的描述，然而，这些实施例不应作为对本发明的范围的限制。
实施例
中间体1 4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸乙酯的合成
Figure PCTCN2020122388-appb-000034
方法一：
步骤1)2-溴-1-(2-(三氟甲基)苯基)丙烷-1-酮
称取2'-(三氟甲基)苯丙酮(139g,687.5mmol)于2000毫升四口瓶中，向其中加入二氯甲烷(800mL)，向反应瓶中加入1滴(含量48％)氢溴酸和1滴液溴，搅拌下发现溴素颜色褪去，然后慢慢滴加液溴(121.5g,760.3mmol)，滴加完毕后室温搅拌0.5h。向反应瓶中加入饱和亚硫酸钠溶液(300mL)，减压旋蒸除去二氯甲烷，残留物中加入水(600mL)和乙酸乙酯(1000mL)，分出有机相并用饱和食盐水洗涤(500mL)，无水硫酸钠干燥，过滤，直接旋干得淡黄色固体(193g,99.9％)。
步骤2)2-氰基-3-甲基-4-氧代-4-(2-(三氟甲基)苯基)丁酸乙酯
称取碳酸钾(166.6g,1205mmol)于2000毫升烧瓶中，向其中加入氰乙酸乙酯(128mL,1203mmol)，升温至50℃加热搅拌2h。将反应瓶移出并冷至室温，滴加2-溴-1-(2-(三氟甲基)苯基)丙烷-1-酮(188g,668.9mmol)的丙酮(1000mL)溶液，完毕后室温搅拌过夜。反应液经硅藻土抽滤，滤饼用丙酮洗涤(50mL×3)，滤液浓缩，乙酸乙酯萃取(200mL×4)，无水硫酸钠干燥，过滤，旋干，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝5/1)，得米黄色固体(180.4g,86.09％)。
MS(ESI,pos.ion)m/z:314.2(M+1).
步骤3)2-氯-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸乙酯
称取2-氰基-3-甲基-4-氧代-4-(2-(三氟甲基)苯基)丁酸乙酯(30g,95.8mmol)于200毫升封管中，向其中加入氯化氢的乙酸乙酯溶液(120mL,480mmol,4mol/L)，完毕后加热至65℃反应48h。减压旋蒸除去溶剂，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝10/1)，得米黄色固体(31.7g,99.8％)。
MS(ESI,pos.ion)m/z:332.0(M+1).
步骤4)4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸乙酯
称取2-氯-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸乙酯(93.1g,281mmol)于2000毫升烧瓶中，向其中加入乙醇(635mL)、四氢呋喃(115mL)、水(47mL)、甲酸钠(25.17g,370.1mmol)和钯碳(9.79g,10mass％)，完毕后加热至65℃搅拌4.5h。反应液冷至室温，反应液中加入四氢呋喃(93mL)，抽滤，滤饼用乙醇洗涤(93mL×4)，滤液浓缩。向其中加入水(750mL)，室温搅拌过夜。抽滤，滤饼用乙醇/水(280mL,v/v＝7/8)的混合溶液洗涤，收集滤饼并在40℃下减压干燥，得类白色固体(71.3g,85.4％)。
MS(ESI,pos.ion)m/z:298.3(M+1).
方法二：
步骤1)5-溴-4-甲基-1H-吡咯-3-甲酸乙酯
称取4-甲基吡咯-3-甲酸乙酯(6.0g,39mmol)于100毫升烧瓶中，向其中加入四氢呋喃(50mL)，冷至-78℃，加入N-溴代丁二酰亚胺(6.99g,39.3mmol)，-78℃下搅拌15min后加入6滴吡啶，然后缓慢升至5℃，继续搅拌过夜。反应液乙酸乙酯萃取(100mL×3)，无水硫酸钠干燥，过滤，旋干，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝10/1)，得白色固体(7.41g,82％)。
MS(ESI,pos.ion)m/z:232.1(M+1).
1H NMR(400MHz,DMSO-d 6)δ(ppm)11.97(s,1H),7.40(s,1H),4.15(q,J＝7.1Hz,2H),2.11(s,3H),1.24(t,J＝7.1Hz,3H).
步骤2)4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸乙酯
称取5-溴-4-甲基-1H-吡咯-3-甲酸乙酯(15.8g,68.1mmol)于500毫升烧瓶中，向其中加入2-(三氟甲基)苯硼酸(20.9g,110mmol)、氯化锂(289.3mg,6.83mmol)、碳酸钠溶液(68mL,136mmol,2mol/L)、1,4-二氧六环(200mL)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(3.49g,4.19mmol)，完毕后加热至90℃反应22h。减压旋蒸除去溶剂，乙酸乙酯萃取(80mL×4)，无水硫酸钠干燥，过滤，旋干，残留物经硅胶柱层析分离(石油醚/二氯甲烷(v/v)＝5/1)，得白色固体(6.9g,34％)。
MS(ESI,pos.ion)m/z:298.2(M+1).
实施例1 N-(3-氟-4-(甲磺酰基)苯基)-1-(2-羟乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺
Figure PCTCN2020122388-appb-000035
步骤1)1-(2-(苄氧基)乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸乙酯
称取4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸乙酯(25g,84.1mmol)于500毫升烧瓶中，向其中加入N,N-二甲基甲酰胺(160mL)、碳酸铯(41.7g,128mmol)和苄基2-溴乙基醚(16mL,101mmol)，完毕后升温至70℃搅拌12h。反应液乙酸乙酯萃取(150mL×3)，合并有机相并用饱和食盐水洗涤(150mL×3)，无水硫酸钠干燥，过滤，旋干，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝10/1)，得棕黄色固体(36.2g,99.8％)。
MS(ESI,pos.ion)m/z:432.4(M+1).
步骤2)1-(2-(苄氧基)乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸
称取1-(2-(苄氧基)乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸乙酯(36.2g,83.9mmol)于1000毫升烧瓶中，向其中加入氢氧化钠溶液(60mL,960mmol,16mol/L)和乙醇(200mL)。完毕后加热至70℃搅拌过夜。减压旋蒸除去乙醇，残留物中加入水(1000mL)并在室温下搅拌30min，甲基叔丁基醚洗涤(200mL×3)，水相用6M HCl溶液调节pH＝2，乙酸乙酯萃取(200mL×3)，无水硫酸钠干燥，过滤，旋干得棕黄色固体(33.4g,98.7％)。
MS(ESI,pos.ion)m/z:404.2(M+1).
步骤3)1-(2-(苄氧基)乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰氯
称取1-(2-(苄氧基)乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸(401mg,0.994mmol)于100毫升烧瓶中，向其中加入二氯甲烷(15mL)和2滴N,N-二甲基甲酰胺，冰浴条件下滴加草酰氯(0.40mL,4.7mmol)。完毕后移至室温反应2.5h。减压旋蒸除去溶剂，得棕黄色固体(400mg,95.40％)。
步骤4)1-(2-(苄氧基)乙基)-N-(3-氟-4-(甲磺酰基)苯基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺
称取1-(2-(苄氧基)乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰氯(400mg,0.948mmol)于50毫升封管中，向其中加入四氢呋喃(10mL)、吡啶(0.14mL,1.7mmol)、3-氟-4-甲砜基苯胺(160mg,0.846mmol)和4-二甲氨基吡啶(10.7mg,0.0876mmol)，完毕后加热至80℃搅拌过夜。减压旋蒸除去溶剂，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝2/1)，得淡黄色固体(337mg,69.36％)。
MS(ESI,pos.ion)m/z:575.2(M+1).
步骤5)N-(3-氟-4-(甲磺酰基)苯基)-1-(2-羟乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺
称取1-(2-(苄氧基)乙基)-N-(3-氟-4-(甲磺酰基)苯基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺(337mg,0.587mmol)于100毫升烧瓶中，向其中加入甲醇(10mL)和钯碳(66.7mg,10mass％)，完毕后置于氢气气氛下室温搅拌1.5h。反应液经硅藻土抽滤，滤饼用甲醇洗涤(10mL×3)，滤液浓缩，残留物 经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝1/2)，得白色固体(220.5mg,77.60％)。
MS(ESI,pos.ion)m/z:485.3(M+1)；
1H NMR(400MHz,DMSO-d 6)δ(ppm):10.15(s,1H),7.99(dd,J＝13.4,1.1Hz,1H),7.90(d,J＝7.7Hz,1H),7.83–7.76(m,3H),7.74–7.69(m,2H),7.47(d,J＝7.4Hz,1H),4.94(t,J＝4.8Hz,1H),3.73–3.64(m,1H),3.55–3.44(m,3H),3.28(s,3H),1.93(s,3H).
实施例2(S)-1-(2-羟乙基)-4-甲基-N-(3-氟-4-(甲磺酰基)苯基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺
Figure PCTCN2020122388-appb-000036
称取N-(3-氟-4-(甲磺酰基)苯基)-1-(2-羟乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺(3.4g,7.02mmol)于25毫升烧瓶中，向其中加入无水乙腈(8mL)使样品全部溶解，采用高效液相色谱法(仪器：Waters SFC；色谱柱：大赛璐AS-H 10mm×250mm 5μm；条件：等梯度20％MeOH+80％CO 2；流速：8mL/min；柱温：35℃；背压：100bar；每次进样10μL)进行手性拆分，减压旋蒸，除去溶剂，得标题目标物为白色固体(1.43g,42.1％；HPLC保留时间8.627min；纯度99.85％；ee值99.80％)。
MS(ESI,pos.ion)m/z:485.1(M+1)；
1H NMR(400MHz,DMSO-d 6)δ(ppm):10.15(s,1H),7.98(dd,J＝13.5,1.3Hz,1H),7.90(d,J＝7.8Hz,1H),7.82–7.76(m,3H),7.75–7.68(m,2H),7.47(d,J＝7.4Hz,1H),4.94(t,J＝4.9Hz,1H),3.73–3.64(m,1H),3.56–3.45(m,3H),3.28(s,3H),1.92(s,3H).
实施例3 N-(3-氟-4-(甲磺酰基)苯基)-1-((1-羟基环丙基)甲基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺
Figure PCTCN2020122388-appb-000037
步骤1)1-(苄氧基)环丙烷羧酸甲酯
称取1-羟基-1-环丙羧酸甲酯(1.02g,8.78mmol)于100毫升烧瓶中，向其中加入N,N-二甲基甲酰胺(30mL)，冷至0℃，加入氢化钠(521.6mg,13.04mmol,60mass％)，0℃下搅拌20min后加入苄溴(1.1mL,9.3mmol)，完毕后移至室温反应3h。反应液用乙酸乙酯萃取(80mL×3)，合并有机相并用饱和食盐水洗涤(50mL×2)，无水硫酸钠干燥，过滤，旋干，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝5/1)， 得棕黄色液体(1.465g,80.9％)。
MS(ESI,pos.ion)m/z:207.2(M+1).
步骤2)(1-(苄氧基)环丙基)甲醇
称取四氢铝锂(233.1mg,6.14mmol)于100毫升烧瓶中，向其中加入四氢呋喃(15mL)，逐滴滴加1-(苄氧基)环丙烷羧酸甲酯(1.40g,6.79mmol)的四氢呋喃(15mL)溶液，完毕后室温搅拌1.5h。向反应瓶中加入十水硫酸钠至溶液澄清，硅藻土抽滤，滤饼用乙酸乙酯洗涤(20mL×3)，滤液浓缩，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝5/1)，得黄色液体(871.9mg,72.1％)。
MS(ESI,pos.ion)m/z:196.2(M+NH 4).
步骤3)(1-(苄氧基)环丙基)甲基甲磺酸酯
称取(1-(苄氧基)环丙基)甲醇(511mg,2.87mmol)于50毫升烧瓶中，向其中加入二氯甲烷(15mL)，冷至0℃，加入三乙胺(0.80mL,5.8mmol)，滴加甲磺酰氯(0.29mL,3.7mmol)，完毕后移至室温反应2h。反应液二氯甲烷萃取(40mL×3)，无水硫酸钠干燥，过滤，旋干得黄色液体(730mg,99.34％)。
MS(ESI,pos.ion)m/z:279.0(M+Na).
步骤4)1-((1-(苄氧基)环丙基)甲基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸乙酯
称取4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸乙酯(450mg,1.51mmol)于50毫升烧瓶中，向其中加入N,N-二甲基甲酰胺(15mL)和氢化钠(186.3mg,4.66mmol,60mass％)，室温搅拌10min后滴加(1-(苄氧基)环丙基)甲基甲磺酸酯(730mg,2.85mmol)的N,N-二甲基甲酰胺(5mL)溶液，完毕后室温搅拌过夜。反应液乙酸乙酯萃取(80mL×3)，合并有机相并用饱和食盐水洗涤(50mL×2)，无水硫酸钠干燥，过滤，旋干，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝10/1)，得淡黄色油状液体(617mg,89.10％)。
MS(ESI,pos.ion)m/z:458.1(M+1).
步骤5)1-((1-(苄氧基)环丙基)甲基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸
称取1-((1-(苄氧基)环丙基)甲基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸乙酯(617mg,1.35mmol)于50毫升烧瓶中，向其中加入乙醇(10mL)、氢氧化钠溶液(2.0mL,12mmol,6mol/L)，完毕后加热至70℃搅拌8h。减压旋蒸除去溶剂，残留物中加入水(50mL)，甲基叔丁基醚洗涤(30mL×2)，水相用1M HCl溶液调节pH＝2，乙酸乙酯萃取(60mL×4)，无水硫酸钠干燥，过滤，直接旋干得淡黄色固体(523.1mg,90.33％)。
MS(ESI,pos.ion)m/z:430.3(M+1).
步骤6)1-((1-(苄氧基)环丙基)甲基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰氯
向反应瓶中加入1-((1-(苄氧基)环丙基)甲基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸(300mg,0.699mmol)和二氯甲烷(20mL)，滴加草酰氯(0.30mL,3.5mmol)和N,N-二甲基甲酰胺(5mg,0.0684mmol)，反应体系室温搅拌22h。减压蒸去溶剂，得黄色固体(312mg,99.70％)。
步骤7)1-((1-(苄氧基)环丙基)甲基)-N-(3-氟-4-(甲磺酰基)苯基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲 酰胺
在封管中加入3-氟-4-甲砜基苯胺(110mg,0.581mmol)、1-((1-(苄氧基)环丙基)甲基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰氯(312mg,0.697mmol)和吡啶(10mL)，反应体系100℃加热搅拌29h。冷却到室温，加1M HCl溶液调pH＝3，乙酸乙酯萃取(80mL)，有机相用饱和碳酸氢钠水溶液调pH＝8，饱和食盐水(60mL)洗涤，无水硫酸钠干燥。过滤，减压蒸去溶剂，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝10/1-4/1)，得淡黄色固体(140mg,40.10％)。
MS(ESI,pos.ion)m/z:601.0(M+1).
步骤8)N-(3-氟-4-(甲磺酰基)苯基)-1-((1-羟基环丙基)甲基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺
向反应瓶中加入1-((1-(苄氧基)环丙基)甲基)-N-(3-氟-4-(甲磺酰基)苯基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺(140mg,0.233mmol)、甲醇(10mL)和钯碳(30mg,10mass％)，反应体系置于氢气气氛下室温搅拌3h。反应液过滤，滤液减压浓缩，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝10/1-4/1)，再经石油醚/乙酸乙酯(10mL/1mL)打浆1h，过滤，干燥，得白色固体(80mg,67.23％)。
MS(ESI,pos.ion)m/z:511.1(M+1).
1H NMR(400MHz,CDCl 3)δ(ppm):8.00(d,J＝12.1Hz,1H),7.94–7.79(m,3H),7.72–7.56(m,3H),7.41(d,J＝7.6Hz,1H),3.73–3.69(m,2H),3.24(s,3H),2.11(s,3H),0.92–0.87(m,2H),0.54–0.48(m,1H),0.44–0.40(m,1H).
19F NMR(376MHz,CDCl 3)δ(ppm):-60.95,-107.35.
实施例4 1-环丁基-N-(3-氟-4-(甲磺酰基)苯基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺
Figure PCTCN2020122388-appb-000038
步骤1)4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸
称取4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸乙酯(30g,100.9mmol)于1000毫升烧瓶中，向其中加入氢氧化钠溶液(60mL,1020mmol,17mol/L)和乙醇(300mL)，完毕后加热至70℃搅拌12h。减压旋蒸除去溶剂，残留物中加入水(1000mL)并在室温下搅拌30min，甲基叔丁基醚洗涤(100mL×3)，水相用6M HCl溶液调节pH＝2，乙酸乙酯萃取(200mL×3)，无水硫酸钠干燥，过滤，直接旋干得棕黄色固体(27.1g,99.8％)。
MS(ESI,pos.ion)m/z:270.2(M+1).
步骤2)4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸苄酯
称取4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸(27.3g,101mmol)于500毫升烧瓶中，向其中加入N,N-二甲基甲酰胺(250mL)，冷至0℃，加入碳酸铯(33.09g,101.6mmol)和苄溴(12mL,101mmol)，完 毕后在0℃下反应7h。向体系中补加碳酸铯(3.31g,10.16mmol)和苄溴(1.2mL,10.1mmol)，0℃下继续反应过夜。反应液用乙酸乙酯萃取(200mL×3)，合并有机相并用饱和食盐水洗涤(200mL×3)，无水硫酸钠干燥，过滤，旋干，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝10/1)，得棕黄色固体(29.7g,81.5％)。
MS(ESI,pos.ion)m/z:360.1(M+1).
步骤3)1-环丁基-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸苄酯
称取4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸苄酯(1.0g,2.8mmol)于100毫升烧瓶中，向其中加入N,N-二甲基甲酰胺(25mL)和氢化钠(334.6mg,8.37mmol,60mass％)，室温搅拌10min后加入溴代环丁烷(1.0mL,11mmol)。完毕后加热至100℃搅拌15h。反应液冷至室温，乙酸乙酯萃取(60mL×3)，合并有机相并用饱和食盐水洗涤(50mL×2)，无水硫酸钠干燥，过滤，旋干，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝10/1)，得淡黄色油状液体(839mg,73％)。
MS(ESI,pos.ion)m/z:414.3(M+1).
步骤4)1-环丁基-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸
称取1-环丁基-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸苄酯(830mg,2.01mmol)于100毫升烧瓶中，向其中加入甲醇(25mL)和钯碳(216.1mg,10mass％)，完毕后置于氢气气氛下室温搅拌5h。反应液经硅藻土抽滤，滤饼用甲醇洗涤(10mL×3)，滤液浓缩，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝2/1)，得白色固体(183.6mg,28.29％)。
MS(ESI,pos.ion)m/z:324.2(M+1).
步骤5)1-环丁基-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰氯
在反应瓶中加入1-环丁基-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸(210mg,0.65mmol)和二氯甲烷(20mL)，滴加草酰氯(0.27mL,3.2mmol)和N,N-二甲基甲酰胺(5mg,0.0684mmol)，反应体系室温搅拌21h。减压蒸去溶剂，得黄色固体(222mg,99.99％)。
步骤6)1-环丁基-N-(3-氟-4-(甲磺酰基)苯基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺
在封管中加入3-氟-4-甲砜基苯胺(102mg,0.539mmol)、1-环丁基-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰氯(221mg,0.647mmol)和吡啶(10mL)，反应体系加热至90℃搅拌24h。冷却到室温，加1M HCl溶液调pH＝3，乙酸乙酯萃取(80mL)，有机相加饱和碳酸氢钠水溶液调pH＝8，饱和食盐水洗涤(60mL)，无水硫酸钠干燥。过滤，减压蒸去溶剂，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝10/1-4/1)，得黄色固体(116mg,43.51％)。
MS(ESI,pos.ion)m/z:495.1(M+1).
1H NMR(400MHz,CDCl 3)δ(ppm):7.99(d,J＝12.4Hz,1H),7.90(s,1H),7.89–7.76(m,2H),7.72–7.60(m,3H),7.59(s,1H),7.32–7.28(m,2H),4.13–4.00(m,1H),3.23(s,3H),2.45–2.31(m,1H),2.25–2.18(m,2H),2.17–2.08(m,2H),2.07(s,3H),1.80–1.74(m,1H).
19F NMR(376MHz,CDCl 3)δ(ppm):-60.91,-107.38,-107.41,-107.43.
实施例5 N-(3-氟-4-(甲磺酰基)苯基)-4-甲基-1-(氧杂环丁-2-基甲基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺
Figure PCTCN2020122388-appb-000039
步骤1)4-甲基-1-(氧杂环丁-2-基甲基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸苄酯
向反应瓶中加入4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸苄酯(1.09g,3.03mmol)和N,N-二甲基甲酰胺(20mL)，冰浴下加入氢化钠(133mg,3.33mmol,60mass％)，氮气保护下搅拌0.5h，滴加2-溴甲基氧杂环丁烷(687mg,4.55mmol)，反应体系室温搅拌24.5h。向反应瓶中加入饱和氯化铵溶液(40mL)淬灭反应，乙酸乙酯萃取(80mL×2)，合并有机相并用饱和食盐水洗涤(40mL×2)，无水硫酸钠干燥。过滤，减压蒸去溶剂，残留物经硅胶柱层析分离(二氯甲烷/乙酸乙酯(v/v)＝100/1-50/1)，得淡黄色固体(660mg,50.7％)。
MS(ESI,pos.ion)m/z:430.1(M+1).
1H NMR(400MHz,CDCl 3)δ(ppm):7.81(d,J＝7.5Hz,1H),7.67–7.51(m,3H),7.46(d,J＝7.5Hz,2H),7.39(t,J＝7.4Hz,2H),7.33(t,J＝7.2Hz,2H),5.35–5.25(m,2H),4.94–4.74(m,1H),4.67–4.57(m,1H),4.43(ddt,J＝34.0,9.2,5.9Hz,1H),3.96–3.62(m,2H),2.59(qd,J＝14.1,7.0Hz,1H),2.36–2.19(m,1H),2.03(d,J＝4.6Hz,3H).
步骤2)4-甲基-1-(氧杂环丁-2-基甲基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸
向反应瓶中加入4-甲基-1-(氧杂环丁-2-基甲基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸苄酯(650mg,1.51mmol)、甲醇(20mL)和钯碳(130mg,10mass％)，完毕后置于氢气气氛下室温搅拌11h。反应液经硅藻土过滤，滤液减压浓缩，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝4/1-1/1)，得淡黄色固体(480mg,93.46％)。
MS(ESI,pos.ion)m/z:340.2(M+1).
1H NMR(400MHz,CDCl 3)δ(ppm):7.81(d,J＝7.4Hz,1H),7.70–7.54(m,3H),7.37(d,J＝7.3Hz,1H),4.97–4.79(m,1H),4.70–4.57(m,1H),4.45(ddt,J＝31.5,9.2,5.9Hz,1H),3.88(ddd,J＝19.1,14.7,5.6Hz,1H),3.76–3.64(m,1H),2.69–2.55(m,1H),2.40–2.20(m,1H),2.06–2.00(m,3H).
步骤3)N-(3-氟-4-(甲磺酰基)苯基)-4-甲基-1-(氧杂环丁-2-基甲基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺
向反应瓶中加入4-甲基-1-(氧杂环丁-2-基甲基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸(320mg,0.943mmol)、3-氟-4-甲砜基苯胺(178mg,0.941mmol)、吡啶(20mL)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(365mg,1.89mmol)，反应体系在室温下搅拌47h。减压蒸去溶剂，加乙酸乙酯(60mL)溶解，再分别用1M HCl溶液(20mL)、饱和碳酸氢钠水溶液(20mL)和饱和食盐水(20mL)洗涤，无水硫酸钠干燥。过滤，减压蒸去溶剂，残留物经硅胶柱层析分离(二氯甲烷/乙酸乙酯(v/v)＝50/1-20/1)，得淡黄色固 体(90mg,18.69％)。
MS(ESI,pos.ion)m/z:511.2(M+1).
1H NMR(400MHz,CDCl 3)δ(ppm):8.18–8.13(m,1H),7.99–7.94(m,1H),7.86–7.81(m,2H),7.69–7.60(m,2H),7.59–7.51(m,1H),7.37–7.31(m,2H),5.01–4.78(m,1H),4.71–4.59(m,1H),4.57–4.40(m,1H),3.84–3.53(m,2H),3.22(s,3H),2.64–2.58(m,1H),2.37–2.22(m,1H),2.11–2.05(m,3H).
19F NMR(376MHz,CDCl 3)δ(ppm):-60.99,-61.07,-107.65,-107.68.
实施例6 N-(3-氟-4-(甲磺酰基)苯基)-4-甲基-1-(氧杂环丁-3-基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺
Figure PCTCN2020122388-appb-000040
步骤1)4-甲基-1-(氧杂环丁-3-基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸乙酯
称取4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸乙酯(401mg,1.35mmol)于50毫升烧瓶中，冰浴条件下加入N,N-二甲基甲酰胺(12mL)和氢化钠(168.9mg,4.22mmol,60mass％)，完毕后移至室温搅拌10min。然后再加入3-碘氧杂环丁烷(0.36mL,4.2mmol)，完毕后加热至100℃搅拌24h。向体系中补加氢化钠(168.9mg,4.22mmol,60mass％)和3-碘氧杂环丁烷(0.36mL,4.2mmol)，100℃继续加热搅拌24h。反应液用乙酸乙酯萃取(40mL×3)，合并有机相并用饱和食盐水洗涤(50mL×2)，无水硫酸钠干燥，过滤，旋干，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝5/1)，得淡黄色固体(365mg,76.59％)。
MS(ESI,pos.ion)m/z:354.3(M+1).
步骤2)4-甲基-1-(氧杂环丁-3-基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸
称取4-甲基-1-(氧杂环丁-3-基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸乙酯(365mg,1.03mmol)于50毫升烧瓶中，向其中加入乙醇(10mL)和氢氧化钠溶液(3.0mL,12mmol,4mol/L)，完毕后加热至70℃搅拌过夜。减压旋蒸除去溶剂，残留物加入水(60mL)溶解，甲基叔丁基醚洗涤(20mL×2)，水相用1M HCl溶液调节pH＝2，乙酸乙酯萃取(30mL×4)，无水硫酸钠干燥，过滤，旋干得橘黄色固体(319.7mg,95.13％)。
MS(ESI,pos.ion)m/z:326.2(M+1).
步骤3)1-(1-氯-3-羟基丙烷-2-基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰氯
向反应瓶中加入4-甲基-1-(氧杂环丁-3-基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸(400mg,1.23mmol)和二氯甲烷(20mL)，滴加草酰氯(0.52mL,6.1mmol)和N,N-二甲基甲酰胺(9mg,0.123mmol)，反应体系室温搅拌16h。减压蒸去溶剂，得黄色固体(467mg,99.89％)。
步骤4)1-(1-氯-3-羟基丙烷-2-基)-N-(3-氟-4-(甲磺酰基)苯基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺
在封管中加入3-氟-4-甲砜基苯胺(193mg,1.02mmol)、1-(1-氯-3-羟基丙烷-2-基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰氯(465mg,1.286mmol)和吡啶(10mL)，反应体系加热至90℃搅拌29h。冷却到室温，加1M HCl溶液调pH＝3，乙酸乙酯萃取(80mL)，有机相加饱和碳酸氢钠水溶液调pH＝8，饱和食盐水(60mL)洗涤，无水硫酸钠干燥。过滤，减压蒸去溶剂，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝10/1-4/1)，得淡黄色固体(100mg,18.40％)。
MS(ESI,pos.ion)m/z:533.0(M+1).
步骤5)N-(3-氟-4-(甲磺酰基)苯基)-4-甲基-1-(氧杂环丁-3-基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺
向反应中加入1-(1-氯-3-羟基丙烷-2-基)-N-(3-氟-4-(甲磺酰基)苯基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺(100mg,0.188mmol)、氢氧化钠(22mg,0.55mmol)和四氢呋喃(50mL)，反应体系加热至70℃搅拌4h。反应液冷却到室温，加1M HCl溶液调pH＝7，乙酸乙酯萃取(80mL)，有机相用饱和食盐水洗涤(60mL)，无水硫酸钠干燥。过滤，减压蒸去溶剂，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝10/1-4/1)，得淡黄色固体(40mg,42.93％)。
MS(ESI,pos.ion)m/z:497.1(M+1).
1H NMR(400MHz,CDCl 3)δ(ppm):8.25–7.77(m,5H),7.66(s,2H),7.28(s,2H),4.90–4.72(m,5H),3.25(s,3H),2.09(s,3H).
19F NMR(376MHz,CDCl 3)δ(ppm):-61.26,-107.28.
实施例7 N-(3-氟-4-(甲磺酰基)苯基)-4-甲基-1-(吡啶-3-基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺
Figure PCTCN2020122388-appb-000041
步骤1)4-甲基-1-(吡啶-3-基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸苄酯
在封管中加入4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸苄酯(1.00g,2.78mmol)、3-氟吡啶(1.35g,13.9mmol)、碳酸铯(2.72g,8.35mmol)和N,N-二甲基甲酰胺(20mL)，氮气保护下，加热至100℃反应73h。冷却至室温，加水(40mL)淬灭反应，乙酸乙酯萃取(80mL)，有机相用饱和食盐水洗涤(40mL×2)，无水硫酸钠干燥。过滤，减压蒸去溶剂，得黄色固体(1.10g,90.6％)。
步骤2)4-甲基-1-(吡啶-3-基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸
向反应瓶中加入4-甲基-1-(吡啶-3-基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸苄酯(1.10g,2.52mmol)、甲醇(20mL)和钯碳(110mg,10mass％)，反应体系置于氢气气氛下室温搅拌17h。反应液经硅藻土抽滤，滤液减压浓缩，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝4/1-1/1)，得淡黄色固体(340mg,39.0％)。
MS(ESI,pos.ion)m/z:347.1(M+1).
1H NMR(400MHz,CDCl 3)δ(ppm):8.49(d,J＝4.1Hz,1H),8.44(s,1H),7.70(d,J＝7.7Hz,2H),7.54(dd,J＝18.7,7.4Hz,2H),7.41(dd,J＝16.2,7.8Hz,2H),7.22(dd,J＝8.1,4.8Hz,1H),2.15(s,3H).
步骤3)4-甲基-1-(吡啶-3-基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰氯
向反应瓶中加入4-甲基-1-(吡啶-3-基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸(340mg,0.982mmol)和二氯甲烷(20mL)，滴加草酰氯(0.42mL,5.0mmol)和N,N-二甲基甲酰胺(7mg,0.0958mmol)，反应体系室温搅拌14.5h。减压蒸去溶剂，得黄色固体(358mg,99.95％)。
步骤4)N-(3-氟-4-(甲磺酰基)苯基)-4-甲基-1-(吡啶-3-基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺
在封管中加入3-氟-4-甲砜基苯胺(131mg,0.692mmol)、4-甲基-1-(吡啶-3-基)-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰氯(358mg,0.981mmol)、吡啶(0.17mL,2.1mmol)和四氢呋喃(20mL)，反应体系加热至90℃搅拌49h。反应液冷却到室温，加1M HCl溶液调pH＝3，乙酸乙酯萃取(80mL)，有机相加饱和碳酸氢钠水溶液调pH＝8，有机相再用饱和食盐水洗涤(60mL)，无水硫酸钠干燥。过滤，减压蒸去溶剂，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝2/1-1/1)，得淡黄色固体(100mg,27.91％)。
MS(ESI,pos.ion)m/z:518.1(M+1)；
1H NMR(400MHz,CDCl 3)δ(ppm):8.46(d,J＝17.9Hz,2H),8.22(s,1H),7.97(d,J＝12.2Hz,1H),7.85(t,J＝8.1Hz,1H),7.71(d,J＝7.3Hz,1H),7.60(s,1H),7.59–7.48(m,2H),7.47–7.30(m,3H),7.23(d,J＝4.7Hz,1H),3.23(s,3H),2.18(s,3H).
19F NMR(376MHz,CDCl 3)δ(ppm):-60.42,-107.35.
实施例8 N-(4-氟-3-甲基-2-氧代-2,3-二氢苯并[d]噻唑-6-基)-1-(2-羟乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺
Figure PCTCN2020122388-appb-000042
步骤1)4-氟-6-硝基苯并[d]噻唑-2(3H)-酮
-10℃下，在反应瓶中加入2(3H)-4-氟苯并噻唑酮(5.00g,29.6mmol)和浓H 2SO 4(50mL)，缓慢滴加浓HNO 3(2.03mL,29.5mmol)，-10℃下继续搅拌1h。反应液倒入冰水中，搅拌1h，抽滤，滤饼用冰水(20mL×2)洗涤，收集滤饼，60℃真空干燥12h，得淡黄色固体(5.40g,85.3％)。
MS(ESI,pos.ion)m/z:215.0(M+1).
步骤2)4-氟-3-甲基-6-硝基苯并[d]噻唑-2(3H)-酮
在反应瓶中加入4-氟-6-硝基苯并[d]噻唑-2(3H)-酮(1.00g,4.67mmol)、DBU(0.84mL,5.6mmol)和N,N-二甲基甲酰胺(20mL,375.2mmol)，缓慢滴加碘甲烷(0.35mL,5.6mmol)，加热至65℃搅拌16.5h。反应液乙酸乙酯(50mL×3)萃取，合并有机相并分别用1M HCl溶液(50mL)和饱和食盐水(50mL)洗 涤，无水硫酸钠干燥。过滤，减压蒸去溶剂，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝10/1-4/1)，得黄色固体(1.07g,100％)。
MS(ESI,pos.ion)m/z:229.1(M+1).
步骤3)6-氨基-4-氟-3-甲基苯并[d]噻唑-2(3H)-酮
在反应瓶中加入4-氟-3-甲基-6-硝基苯并[d]噻唑-2(3H)-酮(1.07g,4.69mmol)、四氢呋喃(50mL)、甲醇(50mL)和钯碳(107mg,10mass％)，反应体系置于氢气气氛下室温反应9h。向体系中补加钯碳(107mg,10mass％)，反应体系置于氢气气氛下室温继续反应12h。反应液经硅藻土抽滤，滤液减压浓缩，粗产品经乙酸乙酯/甲醇(10mL/2mL)打浆得黄色固体(400mg,43.0％)。
MS(ESI,pos.ion)m/z:199.1(M+1).
1H NMR(400MHz,CDCl 3)δ(ppm):6.53(s,1H),6.41(d,J＝13.7Hz,1H),3.71(s,2H),3.61(d,J＝3.2Hz,3H).
步骤4)1-(2-(苄氧基)乙基)-N-(4-氟-3-甲基-2-氧代-2,3-二氢苯并[d]噻唑-6-基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺
在封管中加入1-(2-(苄氧基)乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰氯(312mg,0.740mmol)、6-氨基-4-氟-3-甲基苯并[d]噻唑-2(3H)-酮(122mg,0.615mmol)和吡啶(10mL)，反应体系加热至90℃反应30h。反应液冷却到室温，加饱和碳酸氢钠水溶液调pH＝8，二氯甲烷(40mL×2)萃取，合并有机相并用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。过滤，减压蒸去溶剂，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝10/1-5/1)，得淡黄色固体(300mg,83.52％)。
MS(ESI,pos.ion)m/z:584.2(M+1).
步骤5)N-(4-氟-3-甲基-2-氧代-2,3-二氢苯并[d]噻唑-6-基)-1-(2-羟乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺
在反应瓶中加入1-(2-(苄氧基)乙基)-N-(4-氟-3-甲基-2-氧代-2,3-二氢苯并[d]噻唑-6-基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺(300mg,0.514mmol)、甲醇(20mL)和钯碳(60mg,10mass％)，反应体系置于氢气气氛下室温反应22h。向体系中补加钯碳(60mg,10mass％)，升温至50℃搅拌24h。反应液经硅藻土抽滤，滤液减压浓缩，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝4/1-1/2)，再经石油醚/乙酸乙酯(20mL/2mL)打浆1h，抽滤，收集滤饼并在50℃下干燥，得白色固体(100mg,39.42％)。
MS(ESI,pos.ion)m/z:494.1(M+1).
1H NMR(400MHz,CDCl 3)δ(ppm):7.84(d,J＝7.5Hz,1H),7.70–7.60(m,2H),7.58(d,J＝15.8Hz,2H),7.47(s,1H),7.403-7.38(m,2H),3.85–3.67(m,4H),3.67(d,J＝2.9Hz,3H),2.09(s,3H).
19F NMR(376MHz,CDCl 3)δ(ppm):-60.97,-131.08.
实施例A 体外活性测试
实验原理：
利用荧光素酶与底物结合发生化学发光反应的特性，将含有盐皮质激素受体(MR)配体结合结构域 (LBD)的Gal4 DNA结合结构域(DBD)融合的质粒及Gal4 UAS(上游激活序列)控制下的萤火虫荧光素酶报告基因质粒转染人胚肾细胞(HEK293)。通过萤火虫荧光素酶活性的高低判断刺激前后盐皮质激素受体活性的变化或不同刺激对盐皮质激素受体活性的影响。同时，为了减少内在的变化因素对实验准确度的影响，将带有海肾荧光素酶基因的质粒作为对照质粒转染细胞，提供转录活力的内对照，使测试结果不受实验条件变化的干扰。
实验方法：
1)胰蛋白酶消化后收集HEK293细胞并将细胞密度调整至500,000个/mL；
2)向细胞悬浮液中加入FuGENE HD转染试剂；
3)将上述细胞悬浮液按照100μL/孔接种至96孔细胞培养板中，37℃、5％CO 2条件下培养24小时；
4)将一系列浓度的待测化合物溶液及EC 80浓度的激动剂醛甾酮加入到各孔中，孵育18小时；
5)通过Promega双重荧光素酶报告基因测试系统检测萤火虫及海肾荧光素酶信号。
结果处理：
1)得到萤火虫荧光素酶信号(F)及海肾荧光素酶信号(R)后，使用海肾荧光素酶信号进行校正，即使用F/R值进行后续抑制率计算；
2)％抑制率＝(Max-X)/(Max-Min)×100％，其中Max为阳性对照孔F/R值，Min为阴性对照孔F/R值，X为不同浓度待测化合物孔F/R值；
3)通过GraphPrism 5.0作图软件进行IC 50计算。
实验结果：
表3 本发明化合物的体外活性数据
实施例编号 MR IC 50(nM)
实施例1 6.93
实施例2 3.4
实施例3 47.6
实施例5 21.5
实施例6 30.3
实施例7 84.5
实施例8 82.2
实验结论：由表3的实验结果可知，本发明实施例化合物具有良好的盐皮质激素受体(MR)拮抗活性，其可作为有效的盐皮质激素受体拮抗剂。
实施例B 本发明化合物的药代动力学实验
待测化合物溶液的配制：待测化合物用5％二甲亚砜、60％PEG400和35％生理盐水配制成溶液，用 于口服或静脉注射给药。
实施例B1 本发明化合物在比格犬体内的药代动力学实验
取8-10kg比格犬，随机分为两组，分别口服给予待测化合物，剂量为5.0mg/kg；给药后按时间点0.0833,0.25,0.5,1.0,2.0,4.0,6.0,8.0,24.0,32.0和48.0小时采血。根据样品浓度建立合适范围的标准曲线，使用AB SCIEX API4000型LC-MS/MS，在MRM模式下测定血浆样品中待测化合物的浓度。根据药物浓度-时间曲线，采用WinNonLin 6.3软件非房室模型法计算药代动力学参数。
实验结果：
表4 本发明化合物在比格犬体内的药代动力学数据
Figure PCTCN2020122388-appb-000043
实验结论：由表4数据可知，本发明化合物具有较好的体内药代动力学性质，例如，相对于对照化合物CS-3150，本发明的实施例2化合物在比格犬体内表现出更高的暴露量、血药浓度和较长的半衰期。
实施例B2 本发明化合物在食蟹猴体内的药代动力学实验
取3.0-3.5kg雌性食蟹猴3只，口服给予待测化合物，剂量为3mg/kg；给药后按时间点0.083,0.25,0.5,1,2,4,6,8,24,32和48小时采血。根据样品浓度建立合适范围的标准曲线，使用AB SCIEX API 5000型LC-MS/MS，在MRM模式下测定血浆样品中待测化合物的浓度。根据药物浓度-时间曲线，采用WinNnonlin 6.3软件非房室模型法计算药代动力学参数。
实验结果：
表5 本发明化合物在食蟹猴体内的药代动力学数据
Figure PCTCN2020122388-appb-000044
结论：本发明化合物在食蟹猴体内具有良好的药代动力学性质。具体地，相对于对照化合物CS-3150，本发明实施例2化合物具有更优异的药代动力学性质，例如，更高的暴露量、血药浓度和生物利用度。
实施例C 本发明化合物的体外光毒性实验
待测化合物溶液的配制：待测化合物用二甲亚砜溶解后配置成10mg/mL溶液，再以二甲亚砜按照2.15倍的倍数依次稀释成不同浓度的溶液。
Balb/c 3T3细胞接种于96孔培养板，培养24小时后，弃去培养液，加入含有不同浓度的待测化合物或阳性对照品(盐酸氯丙嗪，CPZ)、溶媒对照品的平衡盐(HBSS)溶液。待测化合物各浓度和阳性对照 品各2块培养板，分别为光照(+UV)板和无光照(-UV)板。培养1小时后，将光照板置于光强度约为1.7mw/cm 2的UVA条件下照射至光剂量达5.0J/cm 2，无光照板于室温避光条件下放置相同的时间。光照结束后，更换新鲜的培养液继续培养18～22小时。培养结束前约3小时，培养液更换为含中性红无血清的培养液。培养结束后，加入中性红洗脱液，振荡后在540nm下测定各孔的吸光度值(OD540)。计算细胞50％抑制浓度(IC 50)、光刺激因子(PIF)和/或平均光效应(MPE)。按照以下标准确定化合物的光毒性：PIF>5判断为光毒性阳性；5>PIF>2判断为可能有光毒性；2>PIF判断为无光毒性。
表6 本发明化合物的体外3T3细胞中性红摄取光毒性试验结果
Figure PCTCN2020122388-appb-000045
结论：本发明实施例2化合物的体外光毒性测试结果如表6所示。由检测结果可知，本发明实施例2化合物没有体外光毒性。即，本发明实施例2化合物的毒性低，安全性高，成药性更好。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (12)

  1. 一种化合物，其为式(I)所示的化合物或式(I)所示化合物的立体异构体、几何异构体、互变异构体、阻转异构体、氮氧化物、水合物、溶剂化物、代谢产物、酯、药学上可接受的盐或前药，
    Figure PCTCN2020122388-appb-100001
    其中，R 1为C 1-6烷基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基或5-10个原子组成的杂芳基，其中，所述C 1-6烷基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基和5-10个原子组成的杂芳基独立任选地被1、2、3或4个R a所取代；
    各R a独立地为D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基或5-10个原子组成的杂芳基；其中，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基和5-10个原子组成的杂芳基独立地未被取代或被1、2、3或4个选自D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基和C 1-6卤代烷基的取代基所取代；
    R 2a、R 2b、R 2c、R 2d和R 2e各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、-C(＝O)C 1-6烷基、-C(＝O)OC 1-6烷基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氨基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基或5-10个原子组成的杂芳基；
    R 2和R 3各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基或C 1-6卤代烷基；
    R 4、R 5、R 6和R 7各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、-C(＝O)C 1-6烷基、-C(＝O)OC 1-6烷基、-S-C 1-6烷基、-S(＝O)C 1-6烷基、-S(＝O) 2C 1-6烷基、-S(＝O) 2NR bR c、-S(＝O) 2OC 1-6烷基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氨基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基或5-10个原子组成的杂芳基；或者
    R 5、R 6和与它们相连的碳原子一起形成C 3-6碳环、C 6-10芳环、3-6个原子组成的杂环或5-10个原子组成的杂芳环，其中，所述C 3-6碳环、C 6-10芳环、3-6个原子组成的杂环和5-10个原子组成的杂芳环各自独立地未被取代或被1、2、3、4或5个选自＝O、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6烷氨基的取代基所取代；
    各R 8、R b和R c独立地为H、D、C 1-6烷基或C 1-6卤代烷基。
  2. 根据权利要求1所述的化合物，其中，R 2和R 3各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、甲基、乙基、正丙基、异丙基、三氟甲基或二氟甲基；
    R 4、R 5、R 6和R 7各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、-C(＝O)CH 3、-C(＝O)OCH 3、-S-CH 3、-S(＝O)CH 3、-S(＝O) 2CH 3、-S(＝O) 2CH 2CH 3、-S(＝O) 2NR bR c、-S(＝O) 2OCH 3、甲基、乙基、正丙基、 异丙基、正丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、异丙氧基、叔丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、三氟甲氧基、甲氨基、二甲氨基、环丙基、环丁基、环戊基、环己基、苯基、萘基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基、嘧啶基或喹啉基；或者
    R 5、R 6和与它们相连的碳原子一起形成环丁烯、环戊烯、环己烯、苯环、二氢呋喃、二氢噻唑、二氢咪唑、二氢吡唑、二氢恶唑、二氢吡咯、四氢吡啶、二氢-1,4-恶嗪、吡咯、吡啶、嘧啶或喹啉，其中，所述环丁烯、环戊烯、环己烯、苯环、二氢呋喃、二氢噻唑、二氢咪唑、二氢吡唑、二氢恶唑、二氢吡咯、四氢吡啶、二氢-1,4-恶嗪、吡咯、吡啶、嘧啶和喹啉各自独立地未被取代或被1、2、3、4或5个选自＝O、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、异丙氧基、叔丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、三氟甲氧基、甲氨基和二甲氨基的取代基所取代；
    各R 8、R b和R c独立地为H、D、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、三氟甲基、二氟甲基、一氟甲基或2,2-二氟乙基。
  3. 根据权利要求1或2所述的化合物，其为式(Ia)所示的化合物或式(Ia)所示化合物的立体异构体、几何异构体、互变异构体、阻转异构体、氮氧化物、水合物、溶剂化物、代谢产物、酯、药学上可接受的盐或前药，
    Figure PCTCN2020122388-appb-100002
  4. 根据权利要求1-3任意一项所述的化合物，其中，R 2a、R 2b、R 2c、R 2d和R 2e各自独立地为H、D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、-C(＝O)CH 3、-C(＝O)OCH 3、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、异丙氧基、叔丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、三氟甲氧基、甲氨基、二甲氨基、环丙基、环丁基、环戊基、环己基、苯基、萘基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基、嘧啶基或喹啉基。
  5. 根据权利要求1-4任意一项所述的化合物，其为式(IIa)所示的化合物或式(IIa)所示化合物的立体异构体、几何异构体、互变异构体、阻转异构体、氮氧化物、水合物、溶剂化物、代谢产物、酯、药学上可接受的盐或前药，
    Figure PCTCN2020122388-appb-100003
  6. 根据权利要求1-5任意一项所述的化合物，其中，R 1为C 1-4烷基、C 3-6环烷基、苯基、3-6个原子组成的杂环基或5-6个原子组成的杂芳基，其中，所述C 1-4烷基、C 3-6环烷基、苯基、3-6个原子组成的杂环基和5-6个原子组成的杂芳基独立任选地被1、2、3或4个R a所取代；
    各R a独立地为D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、异丙氧基、叔丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、环丙基、环丁基、环戊基、环己基、苯基、萘基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基、嘧啶基或喹啉基；其中，所述甲基、乙基、正丙基、异丙基、正丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、异丙氧基、叔丁氧基、二氟甲基、一氟甲基、2,2-二氟乙基、环丙基、环丁基、环戊基、环己基、苯基、萘基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基、嘧啶基和喹啉基独立地未被取代或被1、2、3或4个选自D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基和C 1-4卤代烷基的取代基所取代。
  7. 根据权利要求1-6任意一项所述的化合物，其中，R 1为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环丙基、环丁基、环戊基、环己基、苯基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基或嘧啶基，其中，所述甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环丙基、环丁基、环戊基、环己基、苯基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基和嘧啶基独立任选地被1、2、3或4个R a所取代；
    各R a独立地为D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、异丙氧基、叔丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、环丙基、环丁基、环戊基、环己基、苯基、萘基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基、嘧啶基或喹啉基；其中，所述甲基、乙基、正丙基、异丙基、正丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、异丙氧基、叔丁氧基、二氟甲基、一氟甲基、2,2-二氟乙基、环丙基、环丁基、环戊基、环己基、苯基、萘基、环氧乙烷基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、吗啉基、吡咯基、吡啶基、嘧啶基和喹啉基独立地未被取代或被1、2、3或4个选自D、F、Cl、Br、OH、NH 2、SH、CN、NO 2、甲基、乙基、正丙基、异丙基、C 2-4烯基、C 2-4炔基、甲氧基、乙氧基、异丙氧基、三氟甲基、二氟甲基、一氟甲基和2,2-二氟乙基的取代基所取代。
  8. 根据权利要求1-7任意一项所述的化合物，其具有以下其中之一的结构或所述结构的立体异构体、几何异构体、互变异构体、阻转异构体、氮氧化物、水合物、溶剂化物、代谢产物、酯、药学上可接受的 盐或前药：
    Figure PCTCN2020122388-appb-100004
  9. 一种药物组合物，其包含权利要求1-8任意一项所述的化合物；任选地，所述药物组合物进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂和媒介物的至少一种。
  10. 根据权利要求9所述的药物组合物，其进一步包含一种或多种其他活性成分，所述其他活性成分为ACE抑制剂、肾素抑制剂、血管紧张素II受体拮抗剂、β-受体阻断剂、乙酰水杨酸、利尿剂、钙拮抗剂、他汀类、洋地黄衍生物、钙敏化剂、硝酸盐或抗血栓形成剂。
  11. 根据权利要求1-8任意一项所述的化合物或权利要求9-10任意一项所述的药物组合物在制备药物中的用途，其中，所述药物用于治疗、预防或减轻患者如下疾病：醛甾酮过多症、高血压、慢性心力衰竭、心肌梗死的后遗症、肝硬化、非酒精性脂肪性肝炎、慢性肾病、糖尿病肾病、肾衰竭、纤维化或中风。
  12. 根据权利要求1-8任意一项所述的化合物或权利要求9-10任意一项所述的药物组合物在制备药物中的用途，其中，所述药物用作盐皮质激素受体拮抗剂。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115141132A (zh) * 2021-03-30 2022-10-04 年衍药业(珠海)有限公司 吡咯酰胺化合物的晶型及其制备方法和用途
WO2023134677A1 (zh) * 2022-01-14 2023-07-20 广东东阳光药业有限公司 制备吡咯化合物的方法及其中间体

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2022264993A1 (en) * 2021-04-26 2023-11-09 Sunshine Lake Pharma Co., Ltd. Preparation method for pyrrole amide compound
CN115784961A (zh) * 2021-09-10 2023-03-14 上海鼎雅药物化学科技有限公司 埃沙西林酮及其中间体的合成方法

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006568A1 (de) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Substituierte pyrazolderivate
WO2001019778A1 (de) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Neuartige dicarbonsäurederivate mit pharmazeutischen eigenschaften
WO2001019776A2 (de) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Neuartige dicarbonsäurederivate mit pharmazeutischen eigenschaften
WO2001019355A2 (de) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Dicarbonsäurederivate mit neuartigen pharmazeutischen eigenschaften
WO2002042301A1 (de) 2000-11-22 2002-05-30 Bayer Aktiengesellschaft Neue pyridin-substituierte pyrazolopyridinderivate
WO2002070462A1 (de) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Substituierte aminodicarbonsäurederivate
WO2002070510A2 (de) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Aminodicarbonsäurederivate mit pharmazeutischen eigenschaften
WO2006012642A2 (en) 2004-07-30 2006-02-02 Exelixis, Inc. Pyrrole derivatives as pharmaceutical agents
WO2006076202A1 (en) * 2005-01-10 2006-07-20 Exelixis, Inc. Heterocyclic carboxamide compounds as steroid nuclear receptors ligands
CN101006052A (zh) * 2004-07-30 2007-07-25 埃克塞利希斯股份有限公司 作为药用制剂的吡咯衍生物
WO2008126831A1 (ja) 2007-04-09 2008-10-23 Daiichi Sankyo Company, Limited ピロール誘導体のアトロプ異性体
CN102186817A (zh) * 2008-10-08 2011-09-14 埃克塞利希斯股份有限公司 (羟烷基)吡咯衍生物的阻转异构体
WO2012144661A1 (en) * 2011-04-20 2012-10-26 Shionogi & Co., Ltd. Aromatic heterocyclic derivative having trpv4-inhibiting activity

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006568A1 (de) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Substituierte pyrazolderivate
WO2001019778A1 (de) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Neuartige dicarbonsäurederivate mit pharmazeutischen eigenschaften
WO2001019776A2 (de) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Neuartige dicarbonsäurederivate mit pharmazeutischen eigenschaften
WO2001019355A2 (de) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Dicarbonsäurederivate mit neuartigen pharmazeutischen eigenschaften
WO2002042301A1 (de) 2000-11-22 2002-05-30 Bayer Aktiengesellschaft Neue pyridin-substituierte pyrazolopyridinderivate
WO2002070510A2 (de) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Aminodicarbonsäurederivate mit pharmazeutischen eigenschaften
WO2002070462A1 (de) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Substituierte aminodicarbonsäurederivate
WO2006012642A2 (en) 2004-07-30 2006-02-02 Exelixis, Inc. Pyrrole derivatives as pharmaceutical agents
CN101006052A (zh) * 2004-07-30 2007-07-25 埃克塞利希斯股份有限公司 作为药用制剂的吡咯衍生物
WO2006076202A1 (en) * 2005-01-10 2006-07-20 Exelixis, Inc. Heterocyclic carboxamide compounds as steroid nuclear receptors ligands
WO2008126831A1 (ja) 2007-04-09 2008-10-23 Daiichi Sankyo Company, Limited ピロール誘導体のアトロプ異性体
CN101679243A (zh) * 2007-04-09 2010-03-24 第一三共株式会社 吡咯衍生物的阻转异构体
CN102186817A (zh) * 2008-10-08 2011-09-14 埃克塞利希斯股份有限公司 (羟烷基)吡咯衍生物的阻转异构体
WO2012144661A1 (en) * 2011-04-20 2012-10-26 Shionogi & Co., Ltd. Aromatic heterocyclic derivative having trpv4-inhibiting activity

Non-Patent Citations (18)

* Cited by examiner, † Cited by third party
Title
"Bioreversible Carriers in Drug Design", 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS
"McGraw-Hill Dictionary of Chemical Terms", 1984, MCGRAW-HILL BOOK COMPANY
B. PITTF. ZANNADWJ REMME ET AL., N. ENGL. J. MED. ML, 1999, pages 709 - 717
B. PITTW. REMMEF. ZANNAD ET AL., N. ENGL. J. MED, 2003, pages 1309 - 1321
BIOCHEM, vol. 11, 1972, pages 942 - 944
BRILLA ET AL., JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, vol. 25, no. 5, 1993, pages 563 - 75
CASTREN ET AL., J. OF NEUROENDOCRINOLOGY, vol. 3, 1993, pages 461 - 66
ELIEL, E.WILEN, S.: "Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics", 1994, JOHN WILEY & SONS, INC.
HADLEY, ME, ENDOCRINOLOGY, 1988, pages 366 - 81
J. RAUTIO ET AL.: "Prodrugs: Design and Clinical Applications", NATURE REVIEW DRUG DISCOVERY, vol. 7, 2008, pages 255 - 270, XP055227338, DOI: 10.1038/nrd2468
L. W. DEADY, SYN. COMM., vol. 7, 1977, pages 509 - 514
S. J. HECKER ET AL.: "Prodrugs of Phosphates and Phosphonates", JOURNAL OF MEDICINAL CHEMISTRY, vol. 51, 2008, pages 2328 - 2345, XP008148502, DOI: 10.1021/jm701260b
S. M. BERGE ET AL.: "describe pharmaceutically acceptable salts in detail", J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19
SMITH ET AL.: "March's Advanced Organic Chemistry", 2007, JOHN WILEY & SONS
SWARBRICK ET AL.: "Encyclopedia of Pharmaceutical Technology", MARCEL DEKKER
T. HIGUCHIV. STELLA: "A.C.S. Symposium Series", vol. 14, article "Pro-drugs as Novel Delivery Systems"
THOMAS SORRELL: "Organic Chemistry", 1999, UNIVERSITY SCIENCE BOOKS
TROY ET AL.: "Remington: The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115141132A (zh) * 2021-03-30 2022-10-04 年衍药业(珠海)有限公司 吡咯酰胺化合物的晶型及其制备方法和用途
WO2022206666A1 (zh) 2021-03-30 2022-10-06 广东东阳光药业有限公司 吡咯酰胺化合物的晶型及其制备方法和用途
WO2023134677A1 (zh) * 2022-01-14 2023-07-20 广东东阳光药业有限公司 制备吡咯化合物的方法及其中间体

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