Biphenyl tetrahydropyrrole compound, preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a biphenyl tetrahydropyrrole compound as shown in formula I, a preparation method therefor, and a use thereof as a monoamine oxidase B inhibitor. The compound of the present invention has selective activity against MAO-B and almost no activity against MAO-A, and can effectively reduce side effects caused by acting on monoamine oxidase A.

Description

A biphenyl tetrahydropyrrole compound and its preparation method and use Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and, more specifically, relates to a biphenyl tetrahydropyrrole compound or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutical composition thereof. The compound or pharmaceutical composition represented by Formula I can be used as a monoamine oxidase B inhibitor for treating or preventing diseases or conditions associated with monoamine oxidase B. Background Art

[0002] [Corrected 29.10.2024 according to Regulation 91] Monoamine oxidase (MAO) is located in the outer mitochondrial membrane and primarily catalyzes oxidative deamination reactions. MAO is divided into two isoforms, MAO-A and MAO-B, consisting of 527 and 520 amino acid residues, respectively, sharing 72.6% amino acid sequence identity. Due to their different three-dimensional structures, MAO-A and MAO-B exhibit a certain degree of selectivity in their substrates. MAO-A primarily metabolizes serotonin (5-HT) and norepinephrine (NE), while MAO-B has a higher affinity for benzylamine and β-phenylethylamine. Dopamine (DA) can serve as a substrate for both MAO-A and MAO-B. MAO is widely distributed in the central and peripheral nervous systems. MAO-A is found in high concentrations in noradrenergic neurons projecting from the locus coeruleus, while MAO-B is found in high concentrations in serotonergic and histaminergic neurons in the raphe nuclei and posterior hypothalamus. MAO-A is primarily expressed in dopaminergic neurons in the substantia nigra, while MAO-B is primarily expressed in glial cells within the substantia nigra. Quantification revealed that MAO-B is three times more abundant in the substantia nigra than MAO-A. The tissue-specific distribution of the two MAO isoforms dictates that MAO also exhibits substrate specificity. MAO-B activity accounts for over 80% of the human brain, suggesting that striatal DA is primarily inactivated by deamination by MAO-B. Non-selective MAO inhibitors have been used clinically to treat depression since the 1950s, but their use was discontinued due to the severe "cheese effect." Non-selective MAO inhibitors not only increase central nervous system catecholamine neurotransmitter levels but also indirectly enhance the sympathomimetic effects of peripheral monoamine neurotransmitters, such as the hypertensive crisis induced by tyramine (MAO-A substrate). In-depth research on MAO has revealed that MAO-B activity is significantly elevated in the brains of the elderly and patients with neurodegenerative diseases. This may be due to aging and neuronal damage leading to an increase in microglial cells, which in turn leads to increased MAO-B activity. Consequently, selective MAO-B inhibitors, such as selegiline, rasagiline, and safinamide, are increasingly being used to treat neurodegenerative diseases such as Parkinson's disease (PD). Selegiline and rasagiline are two currently marketed selective, irreversible MAO-B inhibitors. When used in combination with levodopa, they significantly increase striatal DA levels. The UKPDRG trial found that patients taking selegiline 10 mg / day were associated with increased mortality, possibly due to the drug's poor selectivity or the reduced cardiovascular regulatory capacity of its metabolite, amphetamine. Rasagiline has high selectivity for MAO-B, but due to the irreversibility of inhibition and the fact that it takes nearly 30 days for MAO to regenerate in the human body, there are still risks associated with its use.

[0003] Safinamide is a third-generation monoamine oxidase inhibitor developed by the Italian company Newron. Compared with the previous two generations (Selegiline and Rasagiline), it has the characteristics of high selectivity and reversibility. Safinamide's selectivity for MAO-B is much greater than that of Selegiline and Rasagiline. Therefore, during use, it can avoid the side effects caused by the poor selectivity of Selegiline and Rasagiline. In addition, this inhibition is reversible, and normal physiological function can be restored 8 hours after discontinuation of the drug. Safinamide can not only inhibit the activity of MAO-B, but also increase the content of striatal dopamine by inhibiting the reuptake of dopamine; it also inhibits excessive glutamate release by blocking sodium ion channels and regulating calcium ion channels, and has a neuroprotective effect. However, due to its poor pharmacokinetics and other characteristics, its onset dose is relatively large. Therefore, the development of high-efficiency, highly selective, and reversible MAO-B inhibitors remains an important task in the field of PD.

[0004] In summary, MAO-B, as an important enzyme, plays a key role in neurotransmitter metabolism, disease development, and treatment. Further research is necessary to better understand and apply the role of MAO-B, which will help us better understand and treat MAO-B-related diseases.

[0005] Summary of the Invention

[0006] The present invention provides a novel, previously unreported biphenyl tetrahydropyrrole compound or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof. These compounds can be used as monoamine oxidase B (MAO-B) inhibitors, exhibiting selective activity against MAO-B and little activity against MAO-A.

[0007] According to one aspect of the present invention, an object of the present invention is to provide a biphenyl tetrahydropyrrole compound or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof as shown in Formula I:

[0008] in,

[0009] R1 is selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, amide, sulfonyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy;

[0010] R2 is selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, amide, sulfonyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy;

[0011] R3 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, carboxyl, amino, amide, sulfonyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyloxy, -C(=O)OC1-C6 alkyl, -C(=O)ONH2;

[0012] R4 and R5 are each independently selected from hydrogen, halogen, cyano, amide, sulfonyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy;

[0013] n1 is an integer selected from 0 to 2.

[0014] n2 is an integer selected from 0 to 4.

[0015] n3 is an integer selected from 0 to 5.

[0016] Preferably, R1 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, amide, sulfonyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkoxy;

[0017] Preferably, R1 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, amido, sulfonyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy;

[0018] Preferably, R1 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl;

[0019] Preferably, R2 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, amide, sulfonyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkoxy;

[0020] Preferably, R2 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, amido, sulfonyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy;

[0021] Preferably, R2 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl;

[0022] R3 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, carboxyl, amino, amide, sulfonyl, C1-C4 alkyl, halogenated C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, C3-C6 cycloalkoxy, -C(=O)OC1-C4 alkyl, -C(=O)ONH2;

[0023] Preferably, R3 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, carboxyl, amino, amido, sulfonyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, monofluoromethyl, difluoromethyl, trifluoromethyl, dichloromethyl, trichloromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, dichloroethyl, trichloroethyl, tetrachloroethyl, pentachloroethyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, pentafluoropropyl, hexafluoropropyl, perfluoropropyl, monochloropropyl, dichloropropyl, trichloropropyl, tetrachloropropyl, pentachloropropyl, hexachloropropyl, perchloropropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, dichloromethoxy, trichloromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, dichloroethoxy, trichloroethoxy, tetrachloroethoxy, pentachloroethoxy, difluoropropoxy, trifluoropropoxy, tetrafluoropropoxy, pentachloropropoxy, hexafluoropropoxy, perfluoropropoxy, monochloropropoxy, dichloropropoxy, trichloropropoxy, tetrachloropropoxy, pentachloropropoxy, hexachloropropoxy, perchloropropoxy, —C(═O)Omethyl, —C(═O)Oethyl, —C(═O)On-propyl, —C(═O)Oisopropyl, —C(═O)On-butyl, —C(═O)Osec-butyl, —C(═O)Otert-butyl, —C(═O)OONH2;

[0024] Preferably, R3 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, carboxyl, amino, amido, sulfonyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, trifluoromethyl, -C(=O)Omethyl, -C(=O)Oethyl, -C(=O)On-propyl, -C(=O)Oisopropyl, -C(=O)On-butyl, -C(=O)Osec-butyl, -C(=O)Otert-butyl, -C(=O)ONH2;

[0025] Preferably, R4 and R5 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, amide, sulfonyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkoxy;

[0026] Preferably, R4 and R5 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, amido, sulfonyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy;

[0027] Preferably, R4 and R5 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl;

[0028] Preferably, n1 is an integer selected from 0, 1 or 2.

[0029] Preferably, n2 is an integer selected from 0, 1, 2 or 3.

[0030] Preferably, n3 is an integer selected from 0, 1, 2 or 3.

[0031] Preferably, the compound represented by Formula I or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite is represented by the following Formula II:

[0032] wherein R3 is defined the same as in formula I.

[0033] [Corrected 29.10.2024 according to Rule 26] The compound represented by Formula I or Formula II or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite is selected from the following compounds:

[0034] According to another aspect of the present invention, another object of the present invention is to provide a method for preparing the compound represented by Formula I or Formula II or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein the preparation method is carried out as follows:

[0035] 1) Methyl pyroglutamate containing a substituent R1 is added to an organic solvent (dichloromethane, chloroform, tetrahydrofuran, etc.), and di-tert-butyl dicarbonate (Boc2O) and N,N-dimethylaminopyridine (DMAP) are added at room temperature to generate tert-butyloxycarbonylated L-methyl pyroglutamate containing a substituent R1 as intermediate 1.

[0036] 2) Phenylboronic acid containing a substituent R3 and p-bromoiodobenzene containing a substituent R2 with different groups were reacted at 25°C with the addition of sodium carbonate (Na2CO3) and triphenylphosphine palladium chloride [Pd(PPh3)2Cl2], and stirred at 90°C for 2 hours to obtain a brominated biphenyl compound as intermediate 2.

[0037] 3) Under nitrogen, intermediate 2 was dissolved in tetrahydrofuran, and n-butyl lithium was added dropwise at -78°C. The temperature was maintained and the reaction was stirred for 1-2 hours. A dry tetrahydrofuran solution of intermediate 1 was added dropwise at -78°C. The temperature was maintained for 40 minutes. The temperature was then raised to -40°C and the reaction was continued for 2-3 hours to obtain intermediate 3.

[0038] 4) Intermediate 3 was dissolved in dichloromethane at room temperature, and trifluoroacetic acid was added to react overnight to obtain Intermediate 4.

[0039] 5) Intermediate 4 was dissolved in methanol at room temperature under nitrogen protection, and platinum dioxide was added and reacted overnight to obtain intermediate 5.

[0040] 6) Intermediate 5 was dissolved in dichloromethane at room temperature, and di-tert-butyl dicarbonate was added to obtain intermediate 6 protected by secondary amine.

[0041] 7) Intermediate 6 was dissolved in tetrahydrofuran and water at room temperature, lithium hydroxide was added, the temperature was raised to 50°C, and the mixture was stirred for 3-4 hours to obtain carboxyl compound intermediate 7.

[0042] 8) Intermediate 7 is dissolved in N,N-dimethylformamide at room temperature. An ammonia reagent containing R4 and R5 groups, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and N,N-diisopropylethylamine are added. The reaction is allowed to proceed at room temperature for 3-5 hours to obtain the amide compound intermediate 8.

[0043] 9) Intermediate 8 was dissolved in dichloromethane at room temperature, and hydrogen chloride ethyl acetate solution was added, stirred for 2 to 4 hours, concentrated, and the residue was added with water, and the pH was adjusted to 7-8 with 5% sodium bicarbonate aqueous solution to obtain the compound of formula 1.

[0044] The dotted line in the intermediate 3 indicates that the substituent R1 may be present or absent.

[0045] According to another aspect of the present invention, another object of the present invention is to provide a pharmaceutical composition, which comprises a therapeutically effective amount of a compound represented by Formula I or Formula II according to the present invention or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier.

[0046] According to another aspect of the present invention, another object of the present invention is to provide a compound represented by Formula I or Formula II according to the present invention or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof in the preparation of a drug for a monoamine oxidase B inhibitor, wherein the drug is used to treat or prevent a disease or condition associated with monoamine oxidase B in a subject in need thereof.

[0047] Preferably, the disease or disorder associated with monoamine oxidase B is a neuropsychiatric disease or disorder.

[0048] More preferably, the neuropsychiatric disease or disorder is selected from depression, Alzheimer's disease, Parkinson's disease, senile dementia, and narcolepsy.

[0049] According to another aspect of the present invention, another object of the present invention is to provide a kit, which comprises a compound represented by Formula I or Formula II or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or the pharmaceutical composition according to the present invention, as well as a container and instructions for use.

[0050] According to another aspect of the present invention, another object of the present invention is to provide a method for treating diseases or conditions related to monoamine oxidase B, which comprises administering to a subject in need thereof an effective amount of a compound represented by Formula I or Formula II according to the present invention or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or the pharmaceutical composition according to the present invention. Beneficial effects

[0051] The present invention is a novel monoamine oxidase B inhibitor that has not been reported before. This series of compounds has high selectivity between monoamine oxidase B and A. When developed as a drug, it can effectively reduce the side effects caused by acting on monoamine oxidase A. DETAILED DESCRIPTION

[0052] The present invention will be described in detail below. Before describing, it should be understood that the terms used in this specification and the appended claims should not be interpreted as limited to the general meaning and dictionary meaning, but should be interpreted according to the meaning and concept corresponding to the technical aspects of the present invention on the basis of the principle that allows the inventor to appropriately define the terms for the best interpretation. Therefore, the descriptions presented here are merely preferred examples for illustrative purposes and are not intended to limit the scope of the present invention. It should be understood that other equivalents or improvements can be obtained therefrom without departing from the spirit and scope of the present invention.

[0053] The following examples are merely examples of embodiments of the present invention and do not constitute any limitation thereto. Those skilled in the art will appreciate that modifications without departing from the spirit and scope of the present invention fall within the scope of protection of the present invention. Unless otherwise specified, the reagents and instruments used in the following examples are commercially available products.

[0054] As used herein, the terms "comprise," "include," "have," "contain," or any similar terms are open-ended transitional phrases that are intended to encompass non-exclusive inclusions. For example, a composition or article containing multiple elements is not limited to the elements listed herein, but may also include other elements not expressly listed but generally inherent to the composition or article. In addition, unless expressly stated to the contrary, the term "or" refers to an inclusive "or" rather than an exclusive "or." For example, any of the following situations satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist). In addition, as used herein, the terms "comprise," "include," "have," and "contain" should be interpreted as specifically disclosing and encompassing closed or semi-closed transitional phrases such as "consisting of" and "consisting essentially of."

[0055] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for simplicity and convenience only. Accordingly, the description of numerical ranges or percentage ranges should be deemed to have covered and specifically disclosed all possible sub-ranges and individual values ​​within the range, especially integer values. For example, the range description of "1 to 8" should be deemed to have specifically disclosed all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., especially sub-ranges defined by all integer values, and should be deemed to have specifically disclosed individual values ​​within the range such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise indicated, the above interpretation method applies to all contents of the entire invention, regardless of whether the range is broad or not. When a series of values ​​is listed, it is intended to cover every value and sub-range within the range. For example, "C 1-6 "Aims to cover C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 .

[0056] If a quantity or other value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that all ranges consisting of any upper limit or preferred value of the range and any lower limit or preferred value of the range have been specifically disclosed herein, regardless of whether these ranges are disclosed separately. In addition, when a numerical range is mentioned herein, unless otherwise specified, the range should include its endpoints and all integers and fractions within the range.

[0057] In this document, numerical values ​​should be understood to have the accuracy of the number of significant digits of the numerical value, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

[0058] In this document, where Markush groups or optional terms are used to describe features or embodiments of the present invention, those skilled in the art will appreciate that any combination of all subgroups or individual elements within the Markush group or optional list can also be used to describe the present invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," this fully describes the claim that X is X1 and the claim that X is X1 and / or X2. Furthermore, where Markush groups or optional terms are used to describe features or embodiments of the present invention, those skilled in the art will appreciate that any combination of all subgroups or individual elements within the Markush group or optional list can also be used to describe the present invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," this fully describes the claim that X is X1, X2, or X3, and Y is Y1, Y2, or Y3.

[0059] definition

[0060] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th ed., inside cover, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry as well as specific functional moieties and reactivities are described in the following books: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th ed., John Wiley & Sons, New York, 2001. th Edition, John Wiley & Sons, Inc., New York, 2001); Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd ed., Cambridge University Press, Cambridge, 1987.rd Edition, Cambridge University Press, Cambridge, 1987). It is not intended that the present invention be limited in any manner by the exemplary lists of substituents described herein.

[0061] The compounds described herein may contain one or more asymmetric centers and may therefore exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferably, isomers may be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, ed., University of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers, or as mixtures of various isomers.

[0062] The term "alkyl" refers to a group of straight or branched saturated hydrocarbon groups having 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C 2-6 C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl) and hexyl (C6) (e.g., n-hexyl). Unless otherwise specified, each instance of alkyl is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., halogen, such as F). In certain embodiments, alkyl is unsubstituted C 1-6 Alkyl (e.g. unsubstituted C 1-6 In certain embodiments, the alkyl group is a substituted C 1-6 Alkyl (e.g. substituted C 1-6 Alkyl, such as -CF3).

[0063] "Cycloalkyl" or "carbocyclic" refers to a non-aromatic ring system having 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 Carbocyclyl"). Exemplary C 3-6 Carbocyclyl includes but is not limited to cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6) etc. As shown in the above examples, in certain embodiments, cycloalkyl is a monocyclic ring ("monocyclic cycloalkyl") or contains a fused ring, a bridged ring or a spirocyclic ring system, such as a bicyclic ring system ("bicyclic cycloalkyl") and can be saturated or can be partially unsaturated. "Cycloalkyl" also includes a ring system in which the point of attachment of the carbocyclic ring as defined above to one or more aryl or heteroaryl groups is fused to the carbocyclic ring, and in this case, the carbon number continues to refer to the carbon number in the carbocyclic ring system. Unless otherwise stated, each example of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") by one or more substituents. In certain embodiments, a carbocyclyl is an unsubstituted C 3-6 In certain embodiments, a carbocyclyl group is a substituted C 3-6 Cycloalkyl.

[0064] In some embodiments, "cycloalkyl" is a monocyclic saturated carbocyclic group ("C 3-6 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 Cycloalkyl”). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C6). 3-6 Examples of the cycloalkyl group include the aforementioned C 5-6 Cycloalkyl and cyclopropyl (C3) and cyclobutyl (C4). Unless otherwise specified, each instance of cycloalkyl is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, cycloalkyl is an unsubstituted C 3-6 In certain embodiments, the cycloalkyl group is a substituted C 3-6 Cycloalkyl.

[0065] Unless otherwise expressly provided, group is optionally substituted.Term " optionally substituted " refers to be substituted or unsubstituted.In certain embodiments, alkyl, alkoxy, cycloalkyl and cycloalkoxy are optionally substituted (such as " substituted " or " unsubstituted " alkyl, " substituted " or " unsubstituted " alkoxy, " substituted " or " unsubstituted " cycloalkyl, or " substituted " or " unsubstituted " cycloalkoxy). Usually, term " substituted ", no matter whether there is term " optionally " before, means that at least one hydrogen present on group (such as, carbon or nitrogen atom) is replaced by permissible substituent, such as substituent can form stable compound after replacement, for example, can not (such as by rearrangement, cyclization, elimination or other reaction) spontaneously transform compound.Unless otherwise indicated, otherwise " substituted " group has substituent on one or more substitutable positions of the group, and when more than one position in any given structure is substituted, substituent is identical or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any substituent described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations to obtain a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatoms and result in the formation of a stable moiety. In certain embodiments, the substituents are carbon atom substituents. In certain embodiments, the substituents are nitrogen atom substituents. In certain embodiments, the substituents are oxygen atom substituents. In certain embodiments, the substituents are sulfur atom substituents.

[0066] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0067] The term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and that are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods known in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydrogen iodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 Alkyl)4 - Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, as appropriate.

[0068] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, etc. Their preparation is well known to those skilled in the field of cosmetics or topical medicine. For additional information on carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0069] The term "solvate" refers to a compound form that is typically bound to a solvent by a solvolysis reaction. This physical binding can include hydrogen bonds. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates, and also include stoichiometric solvates and non-stoichiometric solvates. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be able to separate. "Solvate" includes solution phase and separable solvates. Representative solvates include hydrates, ethanolates, and methoxides.

[0070] The term "hydrate" refers to a compound that is combined with water. Typically, the number of water molecules contained in a hydrate of a compound is proportional to the number of molecules of the compound in the hydrate. Thus, a hydrate of a compound can, for example, be represented by the general formula R·x H2O, where R is a compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, a monohydrate (x is 1), lower hydrates (x is a number greater than 0 and less than 1, such as hemihydrate (R·0.5H2O)) and polyhydrates (x is a number greater than 1, such as dihydrate (R·2H2O) and hexahydrate (R·6H2O)).

[0071] The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., a single bond becomes a double bond, a triple bond becomes a single bond, and vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization reactions (i.e., reactions that provide tautomeric pairs) can be catalyzed by acids or bases. Exemplary tautomerization reactions include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different enamine) tautomerization reactions.

[0072] It is also understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0073] Stereoisomers that are not mirror images of each other are termed "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by Cahn and Prelog's rules of R- and S-sequencing or by the way the molecule rotates the plane of polarized light, and are denoted as right- or left-handed (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is termed a "racemic mixture."

[0074] The term "prodrug" refers to a compound having a cleavable group and being converted into a compound described herein by solvolysis or under physiological conditions, which has pharmaceutical activity in vivo. Such examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, etc. Other derivatives of the compounds described herein, both their acid and acid derivative forms are active, but the acid-sensitive forms generally provide advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgard, H., "Design of Prodrugs," pp. 7-9, pp. 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, for example, esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine, or anhydrides or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from side acidic groups of the compounds described herein are specific prodrugs. In some cases, it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Preferred may be C1-C8 alkyl esters, C2-C8 alkenyl esters, C2-C8 alkynyl esters, aryl esters, C7-C8 alkynyl esters, C1-C8 alkyl esters, C2-C8 alkynyl ...1-C8 alkyl esters, C2-C8 alkynyl esters, C1-C8 alkyl esters, C2-C8 alkynyl esters, C2-C8 alkynyl esters, C2-C8 alkynyl esters, C2-C8 alkynyl esters, C2- 12 Substituted aryl esters and C7-C 12 Aryl alkyl esters.

[0075] The term "abnormal activity" refers to an activity that deviates from normal activity. The term "increased activity" refers to an activity that is higher than normal activity.

[0076] The terms "composition" and "formulation" are used interchangeably.

[0077] A "subject" intended for administration is a human (i.e., male or female of any age group, such as a pediatric subject (e.g., infant, child, or adolescent) or an adult subject (e.g., young adult, middle-aged, or elderly)). A "patient" is a human subject in need of treatment for a disease.

[0078] The term "biological sample" refers to any sample including tissue samples (e.g., tissue sections and needle biopsies of tissue); cell samples (e.g., cytological smears (e.g., Pap smears or blood smears) or cell samples obtained by microdissection); samples of whole organisms (e.g., yeast or bacterial samples); or cell parts, fragments, or organelles (e.g., obtained by lysing cells and separating their components by centrifugation or other means). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical biopsy or needle biopsy), nipple aspirate, milk, vaginal fluid, saliva, swabs (e.g., buccal swabs), or any material containing biomolecules derived from a first biological sample.

[0079] The term "administering" refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, into or onto a subject.

[0080] The term "treat" refers to reversing, alleviating, delaying the onset of a disease described herein, or inhibiting the development of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., based on a history of symptoms and / or based on exposure to a pathogen) to delay or prevent the onset of the disease. Treatment may also be continued after symptoms subside, for example, to delay or prevent recurrence.

[0081] A "therapeutically effective amount" of a compound described herein is an amount sufficient to elicit the desired biological response (i.e., to treat a condition). As will be appreciated by one of ordinary skill in the art, the effective amount of a compound described herein can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactic treatment. In certain embodiments, the effective amount is the amount of a compound described herein in a single dose. In certain embodiments, the effective amount is the combined amount of the compounds described herein in multiple doses.

[0082] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. Generally, such preparation methods include combining the active ingredient, such as a salt of the present invention, with a carrier or excipient and / or one or more other auxiliary ingredients, if necessary and / or desired, and then forming and / or packaging the product into the desired single or multiple dose units.

[0083] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk as a single unit dose and / or as a plurality of single unit doses. A "unit dose" is a discrete amount of a pharmaceutical composition containing a predetermined amount of an active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient that would be administered to a subject and / or a convenient fraction of that dose, such as one-half or one-third of that dose.

[0084] The relative amounts of the active ingredient, pharmaceutically acceptable excipients, and / or any other ingredients in the pharmaceutical compositions described herein may vary, depending on the identity, size, and / or condition of the subject being treated, and further on the route by which the composition is to be administered. The composition may contain from 0.1% to 100% (w / w) active ingredient.

[0085] Pharmaceutically acceptable excipients that can be used to make the pharmaceutical compositions herein include, for example, inert diluents, dispersants and / or granulating agents, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils. Excipients such as cocoa butter and suppository waxes, colorants, coating agents, sweeteners, flavorings, and perfuming agents may also be present in the compositions.

[0086] The pharmaceutical composition can be formulated for any route of administration, such as oral administration. Typically, the pharmaceutical composition is a solid dosage form. However, in some embodiments, other dosage forms, such as liquids, suspensions, or semisolid dosage forms, can also be used.

[0087] Solid dosage forms for oral administration include, for example, capsules, tablets, pills, powders and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier (e.g., sodium citrate or dicalcium phosphate) and / or (a) fillers or extenders (e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid), (b) binders (e.g., carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia), (c) humectants (e.g., glycerol), (d) disintegrants (e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate), (e) retardants (e.g., paraffin), (f) absorption accelerators (e.g., quaternary ammonium compounds), (g) wetting agents (e.g., cetyl alcohol and glyceryl monostearate), (h) absorbents (e.g., kaolin and bentonite), and (i) lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate), and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may comprise buffering agents.

[0088] Solid compositions of similar types can be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the field of pharmacology. They can optionally contain opacifiers and can have a composition that releases the active ingredient only or preferably in some parts of the intestinal tract, optionally in a delayed manner. Examples of operable encapsulated compositions include polymeric substances and waxes. Solid compositions of similar types can be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol.

[0089] Active ingredient (for example, compound of the present invention) can be in the form of microcapsules with one or more excipients as described above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells well-known in the field of pharmaceutical preparations, such as enteric coatings, controlled-release coatings and other coatings. In such solid dosage forms, the active ingredient can be mixed with at least one inert diluent (for example, sucrose, lactose or starch). Such dosage forms can contain other substances other than inert diluents according to conventional practice, for example, tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form can include a buffer. They can optionally include an opacifier and can have a composition that releases the active ingredient only or preferably in certain parts of the intestinal tract, optionally in a delayed manner. Examples of encapsulating agents that can be used include polymeric substances and waxes.

[0090] Although the description of the pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, such compositions are generally suitable for administration to various animals. Modifications of pharmaceutical compositions suitable for administration to humans are well known in order to make the compositions suitable for administration to various animals, and veterinary pharmacists of ordinary skill can design and / or perform such modifications through ordinary experimentation. For veterinary use, the compounds of the present disclosure can be administered as appropriate, acceptable formulations according to normal veterinary practice. Veterinarians can readily determine the dosage regimen and route of administration that is most suitable for a particular animal.

[0091] The compounds disclosed herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. However, it will be understood that the total daily dosage of the compositions described herein will be determined by a physician within the scope of sound medical judgment. For any particular subject or organism, the specific therapeutically effective dosage level will depend on a variety of factors, including the disease being treated and the severity of the disease; the activity of the specific active ingredient being used; the specific composition being used; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and excretion rate of the specific active ingredient being used; the duration of treatment; drugs used in combination with or concomitantly with the specific active ingredient being used; and factors well known in the medical field.

[0092] The present invention also includes isotopically-labeled compounds of the present invention which are identical to those described herein except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 18 F and 36 Cl.

[0093] Certain isotopically labeled compounds of the present invention (e.g., 3 H and 14 C-labeled compounds) can be used to identify the distribution of compounds and / or substrate tissues. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred because of their ease of preparation and detection. 2Heavier isotope substitution with H) may afford certain therapeutic benefits resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and, therefore, may be preferred in certain situations. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0094] The present invention also includes kits (e.g., pharmaceutical packaging). The kit provided may include a pharmaceutical composition or salt as described herein and a container (e.g., a vial, an ampoule, a bottle, a syringe and / or a dispenser package, or other suitable container). In some embodiments, the kit provided may optionally further include a second container comprising a pharmaceutically acceptable carrier for diluting or suspending the pharmaceutical composition or salt of the present disclosure herein. In some embodiments, the pharmaceutical composition or salt of the present invention provided in the first container and the second container are combined to form a unit dosage form.

[0095] In certain embodiments, the kits described herein further include instructions for using the compounds or pharmaceutical compositions contained in the kit. The kits described herein may also include information required by regulatory agencies such as the China Food and Drug Administration (SFDA). In certain embodiments, the information included in the kit is prescription information. In certain embodiments, the kits and instructions provide methods for treating a disease or condition associated with monoamine oxidase B (e.g., a neuropsychiatric disease or condition) in a subject in need thereof and / or preventing a disease or condition associated with monoamine oxidase B (e.g., a neuropsychiatric disease or condition) in a subject in need thereof. The kits described herein may include one or more additional agents described herein as separate compositions.

[0096] In addition, unless otherwise stated, the reagents and solvents disclosed below were purchased from Beijing Yinuokai Technology Co., Ltd., and 1 H NMR was performed using a Quantum-I plus AS 400 nuclear magnetic resonance instrument. LCMS was performed using a Shimadzu LCMS-IT-TOF liquid chromatography-mass spectrometer. HPLC was performed using an Agilent Technologies 1200 series; purity was calculated as HPLC area %.

[0097] Example 1 Synthesis of (2S,5R)-5-{4-[4-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide hydrochloride

[0098] Step 1

[0099] Compound L-pyroglutamic acid methyl ester A1 (20.0 g, 139.7 mmol) was dissolved in dichloromethane (200 mL). Boc2O (45.7 g, 209.6 mmol) and DMAP (1.0 g, 8.4 mmol) were added at room temperature. The mixture was stirred for 4 hours. The reaction solution was concentrated and the residue was separated by silica gel column (eluent: petroleum ether / ethyl acetate = 5:1 to obtain a white solid, compound A2 (23.0 g, 67.7%).

[0100] 1 H NMR (400MHz, CDCl3): δppm 4.61(dd,J=9.6,3.2Hz,1H),3.78(s,3H),2.72-2.57(m,1H),2.57-2.44(m,1 H),2.41-2.23(m,1H),2.10-1.97(m,1H),1.49(s,9H).LCMS:509.2([2M+Na] + ).

[0101] Step 2

[0102] Under nitrogen, compound 1 (5.0 g, 26.4 mmol) was dissolved in 1,4-dioxane (75 mL) and water (25 mL). SM (8.2 g, 28.9 mmol), Na2CO3 (8.4 g, 78.9 mmol), and Pd(PPh3)2Cl2 (924 mg, 1.3 mmol) were added at 25°C. The mixture was stirred at 90°C for 2 hours. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (150 mL × 2). The mixture was washed with water (50 mL × 2) and saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and spin-dried. The crude product was separated on a silica gel column (eluent: petroleum ether) to obtain compound 2 (8.2 g) as a white solid.

[0103] 1 H NMR (400MHz, CDCl3): δppm 7.78-7.57(m,6H),7.52-7.43(m,2H).

[0104] Step 3

[0105] Under nitrogen, compound 2 (1.5 g, 5.0 mmol) was dissolved in tetrahydrofuran (8.0 mL). n-Butyl lithium (2.5 M in hexane, 1.8 mL, 4.5 mmol) was added dropwise at -78°C. The mixture was stirred and reacted for 1 hour while maintaining the temperature. This was Solution 1.

[0106] Compound A2 (1.0 g, 4.1 mmol, 1.0 eq) was dissolved in dry tetrahydrofuran (8.0 mL) to form solution 2.

[0107] Solution 1 was added dropwise to Solution 2 at -78°C, and the reaction was maintained at this temperature for 40 minutes. The temperature was then raised to -40°C and the reaction continued for 2 hours. Saturated aqueous ammonium chloride (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with saturated brine (15 mL), and dried over anhydrous sodium sulfate to obtain Compound 3 (2.2 g, crude) as a pale yellow oil.

[0108] LCMS: 366.1 ([M-100+H] + ).

[0109] Step 4

[0110] Compound 3 (2.2 g, 4.7 mmol) was dissolved in dichloromethane (20 mL) at room temperature, and trifluoroacetic acid (10.8 g, 94.5 mmol) was added. The mixture was allowed to react overnight and then dried. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to give compound 4 (1.2 g, 71.7%) as a white solid.

[0111] LCMS: 348.1 ([M+H] + ).

[0112] Step 5

[0113] At room temperature, under nitrogen protection, compound 4 (500 mg, 1.44 mmol) was dissolved in methanol (10 mL), and platinum dioxide (16 mg, 0.07 mmol) was added. The mixture was reacted overnight, filtered, and the filtrate was concentrated to obtain compound 5 (500 mg, crude product) as a white solid.

[0114] LCMS: 350.1 ([M+H] + ).

[0115] Step 6

[0116] Compound 5 (500 mg, 1.4 mmol) was dissolved in dichloromethane (5 mL) at room temperature, and di-tert-butyl dicarbonate (3.1 g, 14.3 mmol) was added. The mixture was stirred and reacted overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain compound 6 (480 mg, 74.2%) as a white solid.

[0117] LCMS: 350.1 ([M-100+H] + ).

[0118] Step 7

[0119] At room temperature, compound 6 (440 mg, 0.98 mmol) was dissolved in tetrahydrofuran (7 mL) and water (3.5 mL). Lithium hydroxide (117 mg, 4.89 mmol) was added, and the temperature was raised to 50°C. The mixture was stirred for 3 hours. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, and water (5 mL) was added. The pH value was adjusted to 4 with 1 equivalent of aqueous hydrochloric acid. The aqueous solution was extracted with methyl tert-butyl ether (10 mL x 3). The organic layers were combined, washed with water (10 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 7 (410 mg, 96.2%) as a white solid.

[0120] LCMS: 434.1 ([MH] - ).

[0121] Step 8

[0122] Compound 7 (380 mg, 0.87 mmol) was dissolved in N,N-dimethylformamide (4 mL) at room temperature. Ammonium chloride (117 mg, 2.6 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (497 mg, 1.3 mmol), and N,N-diisopropylethylamine (563 mg, 4.4 mmol) were added. The mixture was reacted at room temperature for 3 hours. Water (10 mL) was then added, and the mixture was extracted with ethyl acetate (15 mL x 2). The mixture was washed with saturated brine (20 mL x 2), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to obtain compound 8 (400 mg, crude) as a white oil.

[0123] LCMS: 457.1 ([M+Na] + ).

[0124] Step 9

[0125] At room temperature, compound 8 (400 mg, 0.92 mmol) was dissolved in dichloromethane (4 mL), and a solution of hydrogen chloride in ethyl acetate (3.0 M, 4 mL, 12.00 mmol) was added. The mixture was stirred for 2 hours and concentrated. Water (5 mL) was added to the residue, and the pH was adjusted to 7-8 with 5% aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by thin layer plate (dichloromethane / methanol = 10:1). The resulting compound was added to a solution of hydrogen chloride in ethyl acetate (3.0 M, 5 mL), stirred for 2 hours, concentrated, added with water (5 mL), and freeze-dried to give compound HYD-P-001 (50 mg, 15.5%) as a white solid.

[0126] 1 H NMR (400MHz, CDCl3): δppm 10.59(brs,1H),8.36(brs,1H),8.06(s,1H),7.98-7.89(m,2H),7.89-7.80(m,4H),7.75(s,1H),7.72-7.43 (m,2H),4.86-4.60(m,1H),4.48-4.31(m,1H),2.48-2.31(m,2H),2.30-1.90(m,2H).LCMS:335.1([M-HCl+H] + ).

[0127] Example 2 Synthesis of (2S,5R)-5-[4-(4-fluorophenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0128] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 4-fluorophenylboric acid (5.0 g, 35.7 mmol, 1.0 eq) to obtain a white solid (2S, 5R)-5-[4-(4-fluorophenyl)phenyl]-1H-pyrrole-2-carboxamide (40 mg, 24.0%). 1 H NMR (400MHz, DMSO-d6): δppm 10.63(brs,1H),8.30(brs,1H),8.06(s,1H),7.85-7.70(m,5H),7.68-7.57(m,2H),7.32(t ,J=8.8Hz,2H),4.80-4.62(m,1H),4.44-4.27(m,1H),2.47-2.30(m,2H),2.28-1.97(m,2H). 19 F NMR(376MHz,DMSO-d6,ppm):δ-115.06(1F).LCMS:285.1([M-HCl+H]+ ).

[0129] Example 3 Synthesis of (2S,5R)-5-{4-[4-(trifluoromethoxy)phenyl]-phenyl}-1H-pyrrole-2-carboxamide hydrochloride

[0130] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 4-trifluoromethoxyphenylboronic acid (5.0 g, 24.2 mmol, 1.0 eq) to obtain a white solid (2S,5R)-5-{4-[4-(trifluoromethoxy)phenyl]-phenyl}-1H-pyrrole-2-carboxamide (74 mg, 24.6%). 1 H NMR (300MHz, CDCl3): δppm 10.60(brs,1H),8.32(brs,1H),8.06(s,1H),7.90-7.70(m,5H),7.70-7.58(m,2H),7.48(d ,J=8.4Hz,2H),4.82-4.62(m,1H),4.48-4.28(m,1H),2.47-2.30(m,2H),2.30-1.98(m,2H). 19 FNMR(400MHz,DMSO-d6,ppm):δ-56.73(3F).LCMS:351.1([M-HCl+H] + ).

[0131] Example 4 Synthesis of (2S,5R)-5-{4-[3-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide hydrochloride

[0132] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 3-trifluoromethylphenylboronic acid (5.0 g, 26.3 mmol, 1.0 eq) to obtain a white solid (2S, 5R)-5-{4-[3-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide (49 mg, 11.8%). 1 H NMR (300MHz, DMSO-d6): δppm 10.66(brs,1H),8.37(brs,1H),8.17-7.93(m,3H),7.90-7.80(m,2H),7.80-7.55( m,5H),4.85-4.65(m,1H),4.47-4.30(m,1H),2.47-2.30(m,2H),2.30-1.93(m,2H). 19F NMR(300MHz,DMSO-d6,ppm):δ-60.98(3F).LCMS:335.1([M-HCl+H] + ).

[0133] Example 5 Synthesis of (2S,5R)-5-[4-(3-fluorophenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0134] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 3-fluorophenylboric acid (5.0 g, 35.7 mmol, 1.0 eq) to obtain a white solid (2S, 5R)-5-[4-(3-fluorophenyl)phenyl]-1H-pyrrole-2-carboxamide (55 mg, 23.2%). 1 H NMR (300MHz, DMSO-d6): δppm 10.60(brs,1H),8.32(brs,1H),8.05(s,1H),7.90-7.70(m,3H),7.70-7.60(m,2H),7.60-7.43(m,3 H),7.32-7.13(m,1H),4.83-4.62(m,1H),4.48-4.26(m,1H),2.47-2.32(m,2H),2.31-1.90(m,2H). 19 FNMR(282MHz,DMSO-d6,ppm):δ-112.69(1F).LCMS:285.1([M-HCl+H] + ).

[0135] Example 6 Synthesis of (2S,5S)-5-{4-[4-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide hydrochloride

[0136] The corresponding compound was prepared in a manner similar to that of Preparation Example 1, except for the choice of chirality of the product, to give (2S,5S)-5-{4-[4-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide (42 mg, 70.5%) as a white solid. 1 HNMR (400MHz, DMSO-d6): δppm 9.36(brs,2H),7.99-7.93(m,3H),7.85-7.82(m,4H),7.72-7.70(m,3H),4.79-4.75 (m,1H),4.43-4.39(m,1H),2.59-2.55(m,1H),2.44-2.43(m,1H),2.20-1.98(m,2H). 19F NMR(376MHz,DMSO-d6,ppm):δ-60.92(3F).LCMS:335.1([M-HCl+H] + ).

[0137] Example 7 Synthesis of (2R,5R)-5-{4-[4-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide hydrochloride

[0138] The corresponding compound was prepared in a manner similar to that of Preparation Example 1, except for the choice of chirality of the product, to give (2R,5R)-5-{4-[4-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide (28 mg, 32.9%) as a white solid. 1 HNMR (400MHz, DMSO-d6): δppm 9.36(brs,2H),8.00(brs,1H),7.95-7.93(m,2H),7.85-7.82(m,4H),7.72-7.68(m,3H),4.7 9-4.75(m,1H),4.38-4.34(m,1H),2.58-2.55(m,1H),2.50-2.43(m,1H),2.31-1.99(m,2H). 19 F NMR(376MHz,DMSO-d6,ppm):δ-60.92(3F).LCMS:335.1([M-HCl+H] + ).

[0139] Example 8 Synthesis of (2R,5S)-5-{4-[4-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide hydrochloride

[0140] The corresponding compound was prepared in a manner similar to that of Preparation Example 1, except for the choice of chirality of the product, to give (2R,5S)-5-{4-[4-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide (50.1 mg, 58.6%) as a white solid. 1 HNMR (400MHz, DMSO-d6): δppm 10.58(brs,1H),8.40(brs,1H),8.06(brs,1H),7.94-7.92(m,2H),7.85-7.83(m,5H),7 .69-7.67(m,2H),4.73-4.72(m,1H),4.36(m,1H),2.50-2.39(m,2H),2.19-1.08(m,2H). 19F NMR(376MHz,DMSO-d6,ppm):δ-60.92(3F).LCMS:335.1([M-HCl+H] + ).

[0141] Example 9 Synthesis of (2S,5R)-5-{4-[2-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide hydrochloride

[0142] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 2-trifluoromethylphenylboronic acid (5.0 g, 26.3 mmol, 1.0 eq) to obtain a yellow solid (2S,5R)-5-{4-[2-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide (23.2 mg, 38.5%). 1 H NMR (400MHz, DMSO-d6): δppm10.97(brs,1H),8.36(brs,1H),8.12(brs,1H),7.97-7.57(m,6H),7.53- 7.30(m,3H),4.73(s,1H),4.37(s,1H),2.48-2.30(m,2H),2.30-1.92(m,2H).LCMS:335.1([M-HCl+H] + ).

[0143] Example 10 Synthesis of (2S,5R)-5-[4-(4-chlorophenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0144] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 4-chlorophenylboronic acid (5.0 g, 32.0 mmol, 1.0 eq) to obtain a white solid (2S, 5R)-5-[4-(4-chlorophenyl)phenyl]-1H-pyrrole-2-carboxamide (42 mg, 49.9%). 1 H NMR (400MHz, DMSO-d6): δppm 10.32(brs,1H),8.32(brs,1H),8.02(s,1H),7.88-7.70(m,5H),7.68-7.60(m,2H),7.60-7.50(m,2H) ,4.80-4.64(m,1H),4.40-4.30(m,1H),2.46-2.30(m,2H),2.28-2.00(m,2H).LCMS:301.1([M-HCl+H] + ).

[0145] Example 11 Synthesis of (2S,5R)-5-[4-(4-cyanophenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0146] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 4-cyanophenylboronic acid (5.0 g, 34.0 mmol, 1.0 eq) to obtain a white solid (2S, 5R)-5-[4-(4-cyanophenyl)phenyl]-1H-pyrrole-2-carboxamide (35.2 mg, 41.8%). 1 H NMR (400MHz, DMSO-d6): δppm 10.69(brs,1H),8.36(brs,1H),8.07(s,1H),8.01-7.90(m,4H),7.85(d,J=8.4Hz,2H),7.76(s,1H),7.69 (d,J=8.4Hz,2H),4.73(s,1H),4.37(s,1H),2.47-2.30(m,2H),2.27-2.00(m,2H).LCMS:292.1([M-HCl+H] + ).

[0147] Example 12 Synthesis of (2S,5R)-5-[4-(4-nitrophenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0148] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 4-nitrophenylboronic acid (5.0 g, 29.8 mmol, 1.0 eq) to obtain a white solid (2S, 5R)-5-[4-(4-nitrophenyl)phenyl]-1H-pyrrole-2-carboxamide (25.6 mg, 59.2%). 1 H NMR (400MHz, DMSO-d6): δppm 10.85(brs,1H),8.32(d,J=8.4Hz,2H),8.09(s,1H),8.01(d,J=8.8Hz,2H),7.88(d,J=8.0Hz,2H),7.80-7.62 (m,3H),4.83-4.67(m,1H),4.44-4.30(m,1H),2.47-2.30(m,2H),2.28-1.93(m,2H).LCMS:312.1([M-HCl+H] + ).

[0149] Example 13 Synthesis of (2S,5R)-5-[4-(4-carboxyphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0150] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 4-carboxyphenylboronic acid (5.0 g, 29.6 mmol, 1.0 eq) to obtain a white solid (2S, 5R)-5-[4-(4-carboxyphenyl)phenyl]-1H-pyrrole-2-carboxamide (46.3 mg, 53.8%). 1 H NMR (300MHz, DMSO-d6): δppm 13.01(brs,1H),10.38(brs,1H),8.32(brs,1H),8.10-7.93(m,3H),7.90-7.80(m,4H),7.76(s,1H),7.66(d,J= 8.1Hz,2H),4.82-4.62(m,1H),4.43-4.27(m,1H),2.48-2.30(m,2H),2.30-1.90(m,2H).LCMS:311.1([M-HCl+H] + ).

[0151] Example 14 Synthesis of (2S,5R)-5-[4-(4-benzamido)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0152] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 4-amidophenylboronic acid (5.0 g, 29.6 mmol, 1.0 eq) to finally obtain a white solid (2S, 5R)-5-[4-(4-benzamido)phenyl]-1H-pyrrole-2-carboxamide (23.5 mg, 54.5%). 1 H NMR (400MHz, DMSO-d6): δppm 10.45(brs,1H)8.35(brs,1H),8.12-7.92(m,4H),7.90-7.70(m,5H),7.65(d,J=8.0Hz,2H),7.41(s,1H ),4.80-4.64(m,1H),4.40-4.30(m,1H),2.46-2.30(m,2H),2.27-1.93(m,2H).LCMS:310.1([M-HCl+H] + ).

[0153] Example 15 Synthesis of (2S,5R)-5-[4-(4-benzoylmethyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0154] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 4-chlorophenylboronic acid (5.0 g, 27.8 mmol, 1.0 eq) to obtain a white solid (2S, 5R)-5-[4-(4-benzoic acid methyl ester) phenyl]-1H-pyrrole-2-carboxamide (50.1 mg, 58.8%). 1 H NMR (400MHz, DMSO-d6): δppm 10.60(brs,1H),8.37(brs,1H),8.12-7.98(m,3H),7.93-7.80(m,4H),7.75(s,1H),7.68(d,J=8.4Hz,2H),4.8 0-4.65(m,1H),4.43-4.30(m,1H),3.88(s,3H),2.47-2.30(m,2H),2.28-2.20(m,2H).LCMS:325.2([M-HCl+H] + ).

[0155] Example 16 Synthesis of (2S,5R)-5-[4-biphenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0156] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: phenylboronic acid (5.0 g, 41.0 mmol, 1.0 eq), and finally a white solid (2S, 5R)-5-[4-biphenyl]-1H-pyrrole-2-carboxamide (25.0 mg, 50.4%) was obtained. 1 H NMR (400MHz, DMSO-d6): δppm 10.48(brs,1H),8.30(brs,1H),8.05(s,1H),7.85-7.60(m,7H),7.49(t,J=7.2Hz,2H),7.45-7.35(m,1 H),4.80-4.63(m,1H),4.43-4.30(m,1H),2.47-2.30(m,2H),2.28-2.00(m,2H).LCMS:267.1([M-HCl+H] + ).

[0157] Example 17 Synthesis of (2S,5R)-5-[4-(4-methylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0158] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 4-methylphenylboronic acid (5.0 g, 36.8 mmol, 1.0 eq) to obtain a white solid (2S, 5R)-5-[4-(4-methylphenyl)phenyl]-1H-pyrrole-2-carboxamide (26.2 mg, 44.6%). 1 H NMR (400MHz, DMSO-d6): δppm 10.48(brs,1H),8.29(brs,1H),8.04(s,1H),7.85-7.68(m,3H),7.67-7.50(m,4H),7.29(d,J=7.6Hz,2 H),4.78-4.62(m,1H),4.42-4.28(m,1H),2.45-2.30(m,5H),2.27-2.00(m,2H).LCMS:281.2([M-HCl+H] + ).

[0159] Example 18 Synthesis of (2S,5R)-5-[4-(4-methoxyphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0160] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 4-methoxyphenylboronic acid (5.0 g, 32.9 mmol, 1.0 eq) to obtain a white solid (2S, 5R)-5-[4-(4-methoxyphenyl)phenyl]-1H-pyrrole-2-carboxamide (25.4 mg, 33.1%). 1 H NMR (400MHz, DMSO-d6): δppm 10.19(brs,1H),8.29(brs,1H),8.00(s,1H),7.76(s,1H),7.70(d,J=8.4Hz,2H),7.68-7.62(m,2H),7.58(d,J=8.4Hz,2H),7.10 -7.00(m,2H),4.73-4.62(m,1H),4.38-4.28(m,1H),3.80(s,3H),2.46-2.30(m,2H),2.25-2.00(m,2H).LCMS:297.2([M-HCl+H] + ).

[0161] Example 19 Synthesis of (2S,5R)-5-[2-methyl-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0162] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 2-iodo-5-bromotoluene (8.6 g, 28.9 mmol, 1.1 eq) to finally obtain a white solid (2S, 5R)-5-[2-methyl-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride (29 mg, 34.3%). 1 H NMR (400MHz, DMSO-d6): δppm10.19(brs,1H),8.27(brs,1H),8.01(s,1H),7.77(s,1H),7.71(d,J=8.4Hz,2H),7.56(d,J=8.4Hz,2H), 7.10-7.00(m,2H),4.70-4.61(m,1H),4.39-4.21(m,1H),3.10(s,3H),2.39-2.20(m,2H),2.13-1.96(m,2H).LCMS:348.6([M-HCl+H] + ).

[0163] Example 20 Synthesis of (2S,5R)-5-[2-methoxy-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0164] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 1-iodo-2-methoxy-4-bromotoluene (9.0 g, 28.9 mmol, 1.1 eq) to finally obtain a white solid (2S, 5R)-5-[2-methoxy-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride (30.0 mg, 39.1%). 1 H NMR (400MHz, DMSO-d6): δppm 10.17(brs,1H),8.29(brs,1H),8.00(s,1H),7.76(s,1H),7.70(d,J=8.4Hz,2H),7.58(d,J=8.4Hz,2H),7.10-7.00(m, 2H),4.73-4.62(m,1H),4.38-4.28(m,1H),3.80(s,3H),2.46-2.30(m,2H),2.25-2.00(m,2H).LCMS:365.1([M-HCl+H] + ).

[0165] Example 21 Synthesis of (2S,5R)-5-[2-cyano-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0166] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 5-bromo-2-iodobenzonitrile (8.9 g, 28.9 mmol, 1.1 eq) to obtain (2S,5R)-5-[2-cyano-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride (30.1 mg, 41.9%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δppm 10.19(brs,1H),8.29(brs,1H),8.00(s,1H),7.78(s,1H),7.72(d,J=8.4Hz,2H),7.59(d,J=8.4Hz,2H),7.10-7 .02(m,2H),4.73-4.62(m,1H),4.38-4.28(m,1H),2.46-2.30(m,2H),2.25-2.00(m,2H).LCMS:360.3([M-HCl+H] + ).

[0167] Example 22 Synthesis of (2S,5R)-5-[3,5-difluoro-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloric acid

[0168] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 2-bromo-1,3-difluoro-5-iodobenzene (9.2 g, 28.9 mmol, 1.1 eq) to obtain (2S,5R)-5-[3,5-difluoro-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloric acid (36.1 mg, 40.2%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δppm 10.19(brs,1H),8.29(brs,1H),8.01(s,1H),7.70(d,J=8.2Hz,2H),7.58(d,J=8.2Hz,2H),7.21(s,2H ),4.73-4.62(m,1H),4.38-4.28(m,1H),2.46-2.35(m,2H),2.22-2.01(m,2H).LCMS:371.3([M-HCl+H] + ).

[0169] Example 23 Synthesis of (2S,5R)-5-[3-cyano-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0170] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 2-bromo-5-iodobenzonitrile (8.9 g, 28.9 mmol, 1.1 eq) to obtain (2S, 5R)-5-[3-cyano-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride (30.3 mg, 40.2%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δppm 10.19(brs,1H),8.29(brs,1H),8.00(s,1H),7.76(s,1H),7.70(d,J=8.4Hz,2H),7.68-7.62(m,2H),7.58(d,J=8.4Hz,2H),7.10 -7.00(m,2H),4.73-4.62(m,1H),4.38-4.28(m,1H),3.80(s,3H),2.46-2.30(m,2H),2.25-2.00(m,2H).LCMS:360.3([M-HCl+H] + ).

[0171] Example 24 Synthesis of (2S,5R)-5-[2,6-difluoro-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0172] The corresponding compound was prepared in a manner similar to that of Preparation Example 1, except that the following corresponding reactants were used: 2,6-difluoro-4-bromo-iodobenzene (9.2 g, 28.9 mmol, 1.1 eq) to finally obtain a white solid (2S,5R)-5-[2,6-difluoro-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride (34.5 mg, 42.4%). 1 H NMR (400MHz, DMSO-d6): δppm 10.19(brs,1H),8.29(brs,1H),8.01(s,1H),7.70(d,J=8.4Hz,2H),7.58(d,J=8.4Hz,2H),7.41(s,2H),4.73 -4.62(m,1H),4.38-4.28(m,1H),3.80(s,3H),2.46-2.30(m,2H),2.25-2.00(m,2H).LCMS:371.3([M-HCl+H] + ).

[0173] Example 25 Synthesis of (2S,5R)-5-[2-methoxy-4-(4-trifluoromethylphenyl)phenyl]-3-methyl-1H-pyrrole-2-carboxamide hydrochloride

[0174] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 4-methyl-L-pyroglutamic acid (21.9 g, 139.7 mmol) to finally obtain a white solid (2S,5R)-5-[4-(4-trifluoromethylphenyl)phenyl]-3-methyl-1H-pyrrole-2-methylformamide hydrochloride (26.5 mg, 38.6%). 1 H NMR (400MHz, CDCl3): δppm 10.59(brs,1H),8.36(brs,1H),8.06(s,1H),7.98-7.89(m,2H),7.89-7.80(m,4H),7.75(s,1H),7.72-7.43(m,2H) ,4.86-4.60(m,1H),4.48-4.31(m,1H),2.48-2.31(m,2H),2.30-1.90(m,1H),0.93(s,3H).LCMS:349.3([M-HCl+H] + ).

[0175] Example 26 Synthesis of (2S,5R)-5-[2-methoxy-4-(4-trifluoromethylphenyl)phenyl]-N-methyl-pyrrole-2-carboxamide

[0176] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: iodomethane (42.6 mg, 0.3 mmol, 1.5 eq) to obtain a white solid (2S, 5R)-5-[2-methoxy-4-(4-trifluoromethylphenyl)phenyl]-N-methyl-pyrrole-2-carboxamide (30.5 mg, 43.8%). 1 H NMR (400MHz, DMSO-d6): δppm 10.19(brs,1H),8.01(s,1H),7.70(d,J=8.4Hz,2H),7.58(d,J=8.4Hz,2H),7.41(s,2H),4.73-4.62( m,1H),4.38-4.28(m,1H),2.76(s,3H),2.46-2.30(m,2H),2.25-2.00(m,2H).LCMS:349.4([M-HCl+H] + ).

[0177] Example 27 Synthesis of (2S,5R)-5-[4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-methylformamide hydrochloride

[0178] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: methylamine (3.1 mL, 33%, 930.0 mg, 30.0 mmol, 1.1 eq) to give (2S,5R)-5-[4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-methylformamide hydrochloride (30.5 mg, 43.8%) as a white solid.

[0179] 1 H NMR (400MHz, CDCl3): δppm 10.56(brs,1H),8.37(brs,1H),8.03(s,1H),7.98-7.88(m,2H),7.89-7.80(m,4H),7.76(s,1H),7.72-7.45(m,2H) ,4.86-4.61(m,1H),4.48-4.31(m,1H),2.80(s,3H),2.46-2.31(m,2H),2.310-1.90(m,2H).LCMS:349.4([M-HCl+H] + ).

[0180] Example 28 Synthesis of (2S,5R)-5-[2-methoxy-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-dimethylformamide hydrochloride

[0181] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: dimethylamine (3.3 mL, 40% in methanol, 1350.0 mg, 30.0 mmol, 1.1 eq) to give (2S, 5R)-5-[2-methoxy-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-dimethylformamide hydrochloride (28.7 mg, 37.8%) as a white solid.

[0182] 1 H NMR (400MHz, CDCl3): δppm 10.56(brs,1H),8.37(brs,1H),8.06(s,1H),7.98-7.89(m,2H),7.89-7.80(m,4H),7.76(s,1H),7.72-7.45(m,2H) ,4.86-4.61(m,1H),4.48-4.31(m,1H),2.80(s,6H),2.46-2.31(m,2H),2.310-1.90(m,2H).LCMS:363.4([M-HCl+H] + ).

[0183] Example 29 Synthesis of (2S,5R)-5-[4-(4-trifluoromethylphenyl)phenyl]-4-methyl-1H-pyrrole-2-methylformamide hydrochloride

[0184] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: 3-methyl-L-pyroglutamic acid (21.9 g, 139.7 mmol) to finally obtain a white solid (2S,5R)-5-[4-(4-trifluoromethylphenyl)phenyl]-4-methyl-1H-pyrrole-2-methylformamide hydrochloride (25.5 mg, 36.6%). 1 H NMR (400MHz, CDCl3): δppm 10.59(brs,1H),8.36(brs,1H),8.06(s,1H),7.98-7.89(m,2H),7.89-7.80(m,4H),7.75(s,1H),7.72-7.43(m,2H) ,4.86-4.60(m,1H),4.48-4.31(m,1H),2.48-2.31(m,1H),2.30-1.90(m,2H),0.93(s,3H).LCMS:349.3([M-HCl+H] + ).

[0185] Example 30 Synthesis of (2S,5R)-5-[4-(4-trifluoromethylphenyl)phenyl]-N-ethyl-pyrrole-2-methylformamide

[0186] The corresponding compound was prepared in a manner similar to that of Example 1, except that the following corresponding reactants were used: iodoethane (46.7 mg, 0.3 mmol, 1.5 eq) to obtain a white solid (2S, 5R)-5-[4-(4-trifluoromethylphenyl)phenyl]-N-ethyl-pyrrole-2-methylformamide (32.6 mg, 43.8%). 1 H NMR (400MHz, DMSO-d6): δppm 10.19(brs,1H),8.01(s,1H),7.70(d,J=8.4Hz,2H),7.58(d,J=8.4Hz,2H),7.41(s,2H),4.73-4.62(m,1H) ,4.38-4.28(m,1H),2.68(m,2H),2.46-2.30(m,2H),2.25-2.00(m,2H),1.02(m,3H)LCMS:363.4([M-HCl+H] + ).

[0187] Example 31 Synthesis of (2S,5R)-5-[4-(4-fluorophenyl)phenyl]-1H-pyrrole-2-carboxylic acid hydrochloride

[0188] The corresponding compound was prepared in a manner similar to that of Preparation Example 1, except that the methyl carboxylate was not aminated but directly hydrolyzed to the carboxyl group to give (2S,5R)-5-[4-(4-fluorophenyl)phenyl]-1H-pyrrole-2-carboxylic acid hydrochloride (35.5 mg, 28.2%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δppm 12.39(brs,1H),10.63(brs,1H),8.30(brs,1H),7.85-7.70(m,5H),7.68-7.57(m,2H),7.32(t,J=8.8Hz,2 H),4.80-4.62(m,1H),4.44-4.27(m,1H),2.47-2.30(m,2H),2.28-1.97(m,2H).LCMS:286.3([M-HCl+H]+).

[0189] Example 32 Synthesis of (2S,5R)-5-[4-(4-fluorophenyl)phenyl]-1H-pyrrole-2-carboxylic acid methyl ester hydrochloride

[0190] The corresponding compound was prepared in a manner similar to that of Preparation Example 1, except that methyl carboxylate was used as the effective group for the reaction and no amination was performed to obtain (2S,5R)-5-[4-(4-fluorophenyl)phenyl]-1H-pyrrole-2-carboxylic acid methyl ester hydrochloride (45.5 mg, 46.2%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δppm 10.68(brs,1H),8.31(brs,1H),7.83-7.70(m,5H),7.64-7.55(m,2H),7.31(t,J=8.4Hz,2H),4.80-4.6 2(m,1H),4.51(s,3H),4.44-4.27(m,1H),2.47-2.30(m,2H),2.28-1.97(m,2H).LCMS:300.3([M-HCl+H] + ).

[0191] Test Example 1

[0192] 1. Human recombinant MAO-A / B inhibitory activity test

[0193] Full-chain recombinant human MAO-A and MAO-B proteins were expressed in Baculovirus-infected Sf9 cells. They contained an N-terminal FLAG tag and had a molecular weight of 59.8 kDa. The recombinant proteins were purified by SDS-PAGE to a purity of >85% at a concentration of 0.3 μg / μL. MAO proteins were incubated with 40 μM substrate at room temperature for 1 hour. The substrate, generated by oxidative deamination of MAO with the substrate, was incubated with a fluorescent luminescent agent for 0.5 hour. MAO activity was then measured using the Promega MAO-Glo™ assay.

[0194] 2. Test methods

[0195] Recombinant human monoamine oxidase A / B was expressed in Sf9 cells. Recombinant MAO-A / B was first dissolved in HEPES buffer (0.8% NaCl, 0.037% KCl, 0.0135% Na2HPO4·2H2O, 0.1% Glucan, 0.5% HEPES, pH 7.0). 10 μL of the MAO-A / B solution was placed in a 384-well plate. Ten concentrations of the test compound (final DMSO concentration of 1%) were added to each well. Clorgyline or selegiline hydrochloride were used as the positive agent, and the plates were incubated at room temperature for 15 minutes. Then, 10 μL of substrate solution (40 μM; tyramine and benzylamine, respectively, are added to each well) and the plates were incubated at room temperature for 60 minutes. Add 20 μL of fluorescein detection reagent to each well again, mix thoroughly, and incubate at room temperature for 20 minutes to generate a stable fluorescent signal. The fluorescent signal is read using a fluorescence microplate reader and the value is expressed as relative light intensity (RLU). The experiment is designed with duplicate wells, and the average value is used to calculate the enzyme activity inhibition rate. The calculation formula is as follows: Inh% = (Max-Signal) / (Max-Min) * 100

[0196] Among them, Max is the value detected at the maximum concentration of the sample, Min is the value detected at the minimum concentration of the sample, and Signal is the value detected at the current concentration of the sample; IC was calculated using the software Graphpad Prism 5 based on the experimental results. 50 , the calculation formula is as follows: Y = Bottom + (Top-Bottom) / (1 + 10^((Log IC 50 -X)*Hill Slope)

[0197] X: Logarithm of compound concentration, Y: Inhibition rate%, Top and Bottom: Platform unit is the same as Y, Hillslop: Slope coefficient or curve slope

[0198] Table 1 Activity data IC50 (nM)

[0199] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any modifications or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. A biphenyl tetrahydropyrrole compound of formula I or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof: in, R1 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, amide, sulfonyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy; R2 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, amide, sulfonyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy; R3 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, carboxyl, amino, amide, sulfonyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyloxy, -C(=O)OC1-C6 alkyl, -C(=O)ONH2; R4 and R5 are each independently selected from hydrogen, halogen, cyano, amide, sulfonyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy; n1 is an integer selected from 0 to 2; n2 is an integer selected from 0 to 4; n3 is an integer selected from 0 to 5.

2. The biphenyl tetrahydropyrrole compound of formula I according to claim 1 or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, characterized in that: Preferably, R1 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, amide, sulfonyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkoxy; Preferably, R1 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, amido, sulfonyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy; Preferably, R1 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl; Preferably, R2 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, amide, sulfonyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkoxy; Preferably, R2 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, amido, sulfonyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy; Preferably, R2 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl; R3 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, carboxyl, amino, amide, sulfonyl, C1-C4 alkyl, halogenated C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, C3-C6 cycloalkyloxy, -C(=O)OC1-C4 alkyl, -C(=O)ONH2; Preferably, R3 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, carboxyl, amino, amide, sulfonyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, monofluoromethyl, difluoromethyl, trifluoromethyl, dichloromethyl, trichloromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, dichloroethyl, trichloroethyl, tetrachloroethyl, pentachloroethyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, pentafluoropropyl, hexafluoropropyl, perfluoropropyl, monochloropropyl, dichloropropyl, trichloropropyl, tetrachloropropyl, pentachloropropyl, hexachloropropyl, perchloropropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, dichloromethoxy, trichloromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, dichloroethoxy, trichloroethoxy, tetrachloroethoxy, pentachloroethoxy, difluoropropoxy, trifluoropropoxy, tetrafluoropropoxy, pentafluoropropoxy, hexafluoropropoxy, perfluoropropoxy, monochloropropoxy, dichloropropoxy, trichloropropoxy, tetrachloropropoxy, pentachloropropoxy, hexachloropropoxy, perchloropropoxy, -C(=O)O methyl, -C(=O)O ethyl, -C(=O)O n-propyl, -C(=O)O isopropyl, -C(=O)O n-butyl, -C(=O)O sec-butyl, -C(=O)O tert-butyl, -C(=O)ONH2; Preferably, R3 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, carboxyl, amino, amide, sulfonyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, trifluoromethyl, -C(=O)Omethyl, -C(=O)Oethyl, -C(=O)On-propyl, -C(=O)Oisopropyl, -C(=O)On-butyl, -C(=O)Osec-butyl, -C(=O)Otert-butyl, -C(=O)ONH2; Preferably, R4 and R5 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, amide, sulfonyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkoxy; Preferably, R4 and R5 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, amide, sulfonyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy; Preferably, R4 and R5 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl; Preferably, n1 is an integer selected from 0, 1 or 2; Preferably, n2 is an integer selected from 0, 1, 2 or 3; Preferably, n3 is an integer selected from 0, 1, 2 or 3.

3. The biphenyl tetrahydropyrrole compound of formula I according to claim 1 or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, characterized in that: Preferably, the compound represented by Formula I or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite is represented by the following Formula II: Wherein, the definition of R3 is the same as that in claim 1.

4. [Corrected 29.10.2024 according to Rule 26] A biphenyl tetrahydropyrrole compound of formula I or II according to any one of claims 1 to 3, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, characterized in that: It is selected from the following compounds:

5. A method for preparing a biphenyl tetrahydropyrrole compound of formula I or formula II according to any one of claims 1 to 4, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, the preparation method being carried out as follows: 1) Pyroglutamic acid methyl ester containing a substituent R1 is added to an organic solvent (dichloromethane, chloroform, tetrahydrofuran, etc.), and di-tert-butyl dicarbonate (Boc2O) and N,N-dimethylaminopyridine (DMAP) are added at room temperature to generate tert-butyloxycarbonylated L-pyroglutamic acid methyl ester containing a substituent R1 as intermediate 1; 2) Phenylboronic acid containing a substituent R3 and p-bromoiodobenzene containing a substituent R2 with different groups are reacted at 25°C, sodium carbonate (Na2CO3) and triphenylphosphine palladium chloride [Pd(PPh3)2Cl2] are added, and the mixture is stirred at 90°C for 2 hours to obtain a brominated biphenyl compound as intermediate 2; 3) Under nitrogen protection, intermediate 2 was dissolved in tetrahydrofuran, n-butyl lithium was added dropwise at -78°C, the temperature was maintained, and the reaction was stirred for 1 to 2 hours, and a dry tetrahydrofuran solution of intermediate 1 was added dropwise at -78°C, the temperature was maintained for 40 minutes, the temperature was raised to -40°C, and the reaction was continued for 2 to 3 hours to obtain intermediate 3; 4) Intermediate 3 was dissolved in dichloromethane at room temperature, trifluoroacetic acid was added and reacted overnight to obtain intermediate 4; 5) Intermediate 4 was dissolved in methanol at room temperature under nitrogen protection, and platinum dioxide was added and reacted overnight to obtain intermediate 5; 6) Intermediate 5 was dissolved in dichloromethane at room temperature, and di-tert-butyl dicarbonate was added to obtain intermediate 6 protected by secondary amine; 7) The intermediate 6 is dissolved in tetrahydrofuran and water at room temperature, lithium hydroxide is added, the temperature is raised to 50° C., and the reaction is stirred for 3 to 4 hours to obtain the carboxyl compound intermediate 7; 8) The intermediate 7 is dissolved in N,N-dimethylformamide at room temperature, and an ammonia reagent containing R4 and R5 groups, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine are added, and the reaction is carried out at room temperature for 3 to 5 hours to obtain an amide compound intermediate 8; 9) The intermediate 8 was dissolved in dichloromethane at room temperature, and a solution of hydrogen chloride in ethyl acetate was added, stirred for 2 to 4 hours, concentrated, and the residue was added with water, and the pH value was adjusted to 7-8 with a 5% aqueous sodium bicarbonate solution to obtain a compound of formula 1; in, The dotted line in Intermediate 3 indicates that the substituent R1 may be present or absent.

6. A pharmaceutical composition comprising a therapeutically effective amount of a biphenyl tetrahydropyrrole compound of formula I or II according to any one of claims 1 to 4 or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier.

7. Use of the biphenyl tetrahydropyrrole compound of formula I or II according to any one of claims 1 to 4, or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite in the preparation of a drug for a monoamine oxidase B inhibitor, wherein the drug is used to treat or prevent a disease or condition associated with monoamine oxidase B in a subject in need thereof; Preferably, the disease or disorder associated with monoamine oxidase B is a neuropsychiatric disease or disorder; More preferably, the neuropsychiatric disease or disorder is selected from depression, Alzheimer's disease, Parkinson's disease, senile dementia, narcolepsy.

8. A kit comprising a biphenyl tetrahydropyrrole compound of formula I or II according to any one of claims 1 to 4 or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition according to claim 6, as well as a container and instructions for use.

9. A method for treating a disease or condition associated with monoamine oxidase B, the method comprising administering to a subject in need thereof an effective amount of a biphenyl tetrahydropyrrole compound of formula I or II according to any one of claims 1 to 4 or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition according to claim 6.

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