Biphenyl tetrahydropyrrole compounds, processes for their preparation and uses thereof

Abstract

This invention discloses a biphenyltetrahydropyrrole compound of Formula I, its preparation method, and its use as a monoamine oxidase B inhibitor. The compound according to this invention exhibits selective activity against MAO-B and almost no activity against MAO-A, effectively reducing side effects caused by its action on monoamine oxidase A.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry, specifically relating to a biphenyl tetrahydropyrrole compound or its isotopically labeled compound, or its optical isomers, geometric isomers, tautomers, or mixtures of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, and pharmaceutical compositions thereof. The compound or pharmaceutical composition represented by Formula I can be used as a monoamine oxidase B inhibitor for the treatment or prevention of diseases or conditions associated with monoamine oxidase B. Background Technology

[0002] Monoamine oxidase (MAO) is located in the outer mitochondrial membrane and primarily catalyzes oxidative deamination reactions. MAO exists in two subtypes, MAO-A and MAO-B, composed of 527 and 520 amino acid residues respectively, sharing 72.6% of their amino acid sequences. Due to their different three-dimensional structures, MAO-A and MAO-B exhibit some substrate selectivity. MAO-A mainly metabolizes serotonin (5-HT) and norepinephrine (NE), while MAO-B shows 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 more abundant in noradrenergic neurons projecting from the locus coeruleus, while MAO-B is more abundant in serotonergic and histaminergic neurons in the raphe nuclei and the posterior hypothalamus. In dopaminergic neurons of the substantia nigra, MAO-A is mainly expressed, while MAO-B is mainly expressed in glial cells of the substantia nigra. Quantitative analysis revealed that MAO-B is three times more abundant than MAO-A in the substantia nigra. Due to the tissue-specific distribution of the two MAO subtypes, MAO also exhibits substrate specificity. In the human brain, MAO-B activity accounts for more than 80%, therefore it can be assumed that striatal dopaminergic activity (DA) is primarily inactivated by MAO-B deamination. Non-selective MAO inhibitors have been used clinically for the treatment of depression since the 1950s, but their use was discontinued due to their severe "cheese effect." Non-selective MAO inhibitors not only increase the levels of central nervous system catecholamine neurotransmitters but also indirectly enhance the sympathomimetic excitatory effects of peripheral monoamine neurotransmitters, such as hypertensive crises induced by tyramine (a MAO-A substrate). Further research on MAO has revealed that MAO-B activity is significantly elevated in the brains of the elderly and patients with neurodegenerative diseases, possibly due to aging and neuronal damage leading to an increase in microglia, which in turn increases MAO-B activity. Therefore, selective MAO-B inhibitors are increasingly used to treat neurodegenerative diseases such as Parkinson's disease (PD), such as selegiline, rasagiline, and safinamide. Selegiline and rasagiline are two marketed selective, irreversible MAO-B inhibitors; when used in combination with levodopa, they can significantly increase striatal dopamine (DA) levels. The UKPDRG trial found that patients taking selegiline 10 mg / day experienced increased mortality, possibly due to poor drug selectivity or the weakened cardiovascular regulatory capacity caused by its metabolite, amphetamine. Rasagiline has high selectivity for MAO-B, but due to the irreversibility of the inhibition and the fact that MAO regeneration in the human body takes nearly 30 days, there are still risks associated with its use.

[0003] Safinamide, developed by the Italian company Newron, is a third-generation monoamine oxidase inhibitor. Compared to its predecessors (Selegiline and Rasagiline), it exhibits high selectivity and reversibility. Safinamide's selectivity for MAO-B is significantly greater than that of Selegiline and Rasagiline, thus avoiding the side effects caused by the poor selectivity of these two drugs. Furthermore, this inhibition is reversible, with normal physiological function returning to normal 8 hours after discontinuation. Safinamide not only inhibits MAO-B activity but also increases striatal dopamine levels by inhibiting dopamine reuptake; it also has neuroprotective effects by blocking sodium ion channels and regulating calcium ion channels, thereby inhibiting excessive glutamate release. However, due to its poor pharmacokinetics, its effective dose is relatively high. Therefore, developing highly effective, selective, and reversible MAO-B inhibitors remains an important task in the field of psychotropic disorders (PD).

[0004] In conclusion, MAO-B, as an important enzyme, plays a crucial role in neurotransmitter metabolism, disease development, and treatment. Further research is still necessary for a better understanding and application of MAO-B's functions, which will contribute to a better understanding and treatment of MAO-B-related diseases. Summary of the Invention

[0005] This invention provides a novel, previously unreported biphenyl tetrahydropyrrole compound, or its isotopically labeled compound, or its optical isomers, geometric isomers, tautomers, or mixtures of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite. This type of compound can act as a monoamine oxidase B (MAO-B) inhibitor, exhibiting selective activity against MAO-B and almost no activity against MAO-A.

[0006] According to one aspect of the invention, an object of the invention is to provide a biphenyl tetrahydropyrrole compound of formula I or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof:

[0007]

[0008] in,

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

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

[0017] Preferably, R1 is 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, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy.

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

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

[0020] Preferably, R2 is 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, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy.

[0021] Preferably, R2 is selected from hydrogen, deuterium, halogen, cyano, and 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, 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, cyclopropoxy, cyclobutoxy, cyclopentoxy, 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)Omethyl, -C(=O)Oethyl, -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;

[0024] 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)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;

[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, and C3-C6 cycloalkoxy.

[0026] 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, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy.

[0027] Preferably, R4 and R5 are each independently selected from hydrogen, deuterium, halogen, cyano, and 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 isotopically labeled compound, or its optical isomer, geometric isomer, tautomer, or mixture of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, is represented by the following Formula II:

[0032]

[0033] The definition of R3 is the same as in Equation I.

[0034] The compound represented by Formula I or Formula II, or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer, or mixture of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, is selected from the following compounds:

[0035]

[0036]

[0037] According to another aspect of the invention, another object of the invention is to provide a method for preparing the compound represented by Formula I or Formula II, or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer, or mixture of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein the preparation method is carried out as follows:

[0038]

[0039]

[0040] 1) Methyl pyroglutamic acid containing 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 substituent R1, which is used as intermediate 1.

[0041] 2) Phenyboric acid containing substituent R3 and p-bromoiodobenzene containing substituent R2 with different functional groups were reacted at 25°C with sodium carbonate (Na2CO3) and palladium triphenylphosphine chloride [Pd(PPh3)2Cl2], and stirred at 90°C for 2 hours to obtain a bromobiphenyl compound, which was used as intermediate 2.

[0042] 3) Under nitrogen protection, intermediate 2 was dissolved in tetrahydrofuran, and n-butyllithium 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 then added dropwise at -78°C. The temperature was maintained for 40 minutes, and the temperature was raised to -40°C. The reaction was continued for 2–3 hours to obtain intermediate 3.

[0043] 4) Intermediate 3 was dissolved in dichloromethane at room temperature, and trifluoroacetic acid was added and reacted overnight to obtain intermediate 4.

[0044] 5) Intermediate 4 was dissolved in methanol at room temperature under nitrogen protection, and platinum dioxide was added. The reaction was carried out overnight to obtain intermediate 5.

[0045] 6) Intermediate 5 is dissolved in dichloromethane at room temperature, and di-tert-butyl dicarbonate is added to obtain intermediate 6 protected by secondary amine.

[0046] 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 reaction was stirred for 3-4 hours to obtain carboxyl compound intermediate 7.

[0047] 8) Intermediate 7 was dissolved in N,N-dimethylformamide at room temperature. An ammonia reagent containing R4 and R5 groups, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine were added. The reaction was carried out at room temperature for 3-5 hours to give amide intermediate 8.

[0048] 9) Intermediate 8 was dissolved in dichloromethane at room temperature, and ethyl hydrogen chloride solution was added. The mixture was stirred for 2-4 hours and concentrated. The residue was then mixed with water, and the pH was adjusted to 7-8 with 5% sodium bicarbonate aqueous solution to obtain compound of formula 1.

[0049] In intermediate 3, the dashed line indicates that the substituent R1 may or may not be present.

[0050] According to another aspect of the invention, another object of the invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by Formula I or Formula II according to the invention, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier thereof.

[0051] According to another aspect of the invention, another object of the invention is to provide the use of a compound represented by Formula I or Formula II according to the invention, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, in the preparation of a medicament for use in treating or preventing diseases or conditions associated with monoamine oxidase B in subjects of need.

[0052] Preferably, the disease or condition associated with monoamine oxidase B is a neuropsychiatric disease or condition.

[0053] More preferably, the neuropsychiatric disease or condition is selected from depression, Alzheimer's disease, Parkinson's disease, dementia, and narcolepsy.

[0054] According to another aspect of the invention, another object of the invention is to provide a kit comprising a compound represented by Formula I or Formula II or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition according to the invention, as well as a container and instructions for use.

[0055] According to another aspect of the invention, another object of the invention is to provide a method for treating a disease or condition related to monoamine oxidase B, the method comprising administering to a subject in need an effective amount of a compound represented by Formula I or Formula II according to the invention, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition according to the invention.

[0056] Beneficial effects

[0057] This invention relates to a novel, previously unreported monoamine oxidase B inhibitor. This series of compounds exhibits high selectivity between monoamine oxidase B and A and can be developed as a drug to effectively reduce side effects caused by action on monoamine oxidase A. Detailed Implementation

[0058] The present invention will now be described in detail. Before proceeding with the description, it should be understood that the terminology used in this specification and the appended claims should not be construed as limited to its general or dictionary meaning, but rather should be interpreted according to the meaning and concept corresponding to the technical aspects of the invention, based on the principle that the inventors are allowed to appropriately define the terms for the best interpretation. Therefore, the description presented herein is merely a preferred example for illustrative purposes and is not intended to limit the scope of the invention. It should be understood that other equivalents or modifications can be obtained from it without departing from the spirit and scope of the invention.

[0059] The following embodiments are merely examples illustrating implementations of the present invention and do not constitute any limitation on the present invention. Those skilled in the art will understand that modifications made without departing from the spirit and concept of the present invention fall within the protection scope of the present invention. Unless otherwise specified, the reagents and instruments used in the following embodiments are commercially available products.

[0060] In this document, the terms “comprising,” “including,” “having,” “containing,” or any similar terms are open-ended transitional phrases intended to encompass non-exclusive inclusions. For example, a composition or article containing a plural element is not limited to the elements listed herein, but may also include other elements not explicitly listed but typically inherent to the composition or article. Furthermore, unless explicitly stated otherwise, the term “or” is inclusive, not exclusive. For example, the condition “A or B” is satisfied in any of the following cases: 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); A and B are both true (or exist). Moreover, in this document, the terms “comprising,” “including,” “having,” and “containing” should be interpreted as specifically disclosed and simultaneously encompassing closed or semi-closed transitional phrases such as “composed of” and “substantially composed of.”

[0061] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible sub-ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "1 to 8" should be considered as specifically disclosing all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly sub-ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its breadth. When listing a series of values, it is intended to cover every value and sub-range within that 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 .

[0062] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, regardless of whether such ranges are separately disclosed. Furthermore, when a range of numerical values ​​is mentioned herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

[0063] In this document, numerical values ​​are to be understood as having a precision with significant digits, 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.

[0064] In this document, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that subgroups of all elements within a Markush group or option list, or any individual element, can also be used to describe the invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it also indicates that the claim that X is X1 and the claim that X is X1 and / or X2 have been fully described. Furthermore, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that any combination of subgroups of all elements within a Markush group or option list, or any combination of individual elements, can also be used to describe the 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," it indicates that the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

[0065] definition

[0066] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are determined according to the periodic table on the inner cover of the CAS edition of the *Handbook of Chemistry and Physics*, 75th edition, and specific functional groups are generally defined as described therein. Furthermore, the general principles of organic chemistry, as well as specific functional groups and reactivity, are described in the following books: Thomas Sorrell, *Organic Chemistry*, University Science Books, Sausalito, 1999; and Smith and March, *March's Advanced Organic Chemistry*, 5th edition, 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. This invention is not intended to be limited in any way by the exemplary list of substituents described herein.

[0067] The compounds described herein may contain one or more asymmetric centers and therefore may exist in a variety of 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 rich in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferably, the isomers can be prepared by asymmetric synthesis. For example, see 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., Notre Dame University Press, Notre Dame, IN 1972). This disclosure further covers the compounds described herein as single isomers substantially free of other isomers, or mixtures of various isomers.

[0068] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). 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 stated, each example of an alkyl group is independently unsubstituted (“unsubstituted alkyl”) or substituted by one or more substituents (e.g., halogens, such as F) (“substituted alkyl”). In some embodiments, the alkyl group is an unsubstituted C1 group. 1-6 Alkyl (e.g., unsubstituted C) 1-6 Alkyl group, such as -CH3). In some embodiments, the alkyl group is a substituted C. 1-6 Alkyl (e.g., substituted C) 1-6 Alkyl groups, such as -CF3).

[0069] "Cycloalkyl" or "carbocyclic" refers to a non-aromatic ring system having 3 to 6 ring carbon atoms ("C"). 3-6 A group consisting of a carbocyclic group (“C”) and a non-aromatic cyclic hydrocarbon group with zero heteroatoms. In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms (“C”). 3-6 (Carbocyclic group). In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms (“C”). 5-10 (Carbocyclic group"). An example C 3-6 Carbocyclic groups include, but are 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 foregoing examples, in some embodiments, the cycloalkyl group is a monocyclic (“monocyclic cycloalkyl”) or contains a fused ring, bridged ring, or spirocyclic system, such as a bicyclic system (“bicyclic cycloalkyl”), and may be saturated or may be partially unsaturated. “Cycloalkyl” also includes ring systems in which the carbon ring as defined above is fused with one or more aryl or heteroaryl groups at the junction point on the carbon ring, and in this case, the carbon number continues to refer to the number of carbons in the carbon ring system. Unless otherwise stated, each instance of a carbocyclic group is optionally substituted independently, i.e., unsubstituted (“unsubstituted cycloalkyl”) or substituted by one or more substituents (“substituted cycloalkyl”). In some embodiments, the carbocyclic group is an unsubstituted C 3-6 Cycloalkyl. In some embodiments, the carbocyclic group is a substituted C. 3-6 Cycloalkyl.

[0070] In some embodiments, "cycloalkyl" is a monocyclic saturated carbocyclic group having 3 to 6 ring carbon atoms ("C..."). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms (“C”). 5-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5-10 cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C6). 3-6 Examples of cycloalkyl groups include the aforementioned C14 groups. 5-6 Cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4) groups. Unless otherwise stated, each instance of a cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C4 group. 3-6 Cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C-shaped group. 3-6 Cycloalkyl.

[0071] Unless otherwise expressly specified, the group may optionally be substituted. The term “optionally substituted” means substituted or unsubstituted. In some embodiments, alkyl, alkoxy, cycloalkyl, and cycloalkoxy groups may optionally be substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkoxy, “substituted” or “unsubstituted” cycloalkyl, or “substituted” or “unsubstituted” cycloalkoxy). Generally, the term “substituted,” regardless of whether it is preceded by the term “optionally,” means that at least one hydrogen atom present on the group (e.g., carbon or nitrogen atom) is substituted with a permissible substituent, such that the substituent, upon substitution, forms a stable compound, for example, a compound that does not spontaneously transform (e.g., through rearrangement, cyclization, elimination, or other reactions). Unless otherwise specified, a “substituted” group has substituents at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituents may be the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of an organic compound, any substituent described herein that results in the formation of a stable compound. This disclosure contemplates any and all such combinations to obtain a stable compound. For the purposes of this disclosure, a heteroatom, such as nitrogen, may have a hydrogen substituent and / or any suitable substituent as described herein that satisfies the valence of the heteroatom and results in the formation of a stable moiety. In some embodiments, the substituent is a carbon atom substituent. In some embodiments, the substituent is a nitrogen atom substituent. In some embodiments, the substituent is an oxygen atom substituent. In some embodiments, the substituent is a sulfur atom substituent.

[0072] "Halogen" or "halogen" refers to fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), or iodine (iodinated, -I).

[0073] The term "pharmaceutically acceptable salt" refers to those salts that, within reasonable medical judgment, are suitable for contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. described 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 acids 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, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentylpropionate, diglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucohepanoate, glyceryl phosphate, glucuronate, hemisulfate, heptahydrate, hexanoate, hydrogen iodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, dodecyl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 - Salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using balancing ions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0074] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of this invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, transdermal penetration enhancers, etc. Their formulations are well known to those skilled in the art of cosmetics or topical pharmaceuticals. For further information on carriers, see Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0075] The term "solvent" refers to a compound form that is typically bound to a solvent via a solvent decomposition reaction. This physical binding can include hydrogen bonds. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. 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 and non-stoichiometric solvates. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. "Solvent" includes both solution phases and separable solvates. Representative solvates include hydrates, ethoxides, and methoxides.

[0076] The term "hydrate" refers to a compound that is bound to water. Typically, the number of water molecules contained in a hydrate of a compound is proportional to the number of compound molecules in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. The given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, such as hemihydrates (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, such as dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

[0077] The term "tautomer" or "tautomerizing" refers to a compound in which two or more interconvertions result 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, or vice versa). The exact proportions of tautomers depend on several factors, including temperature, solvent, and pH. Tautomerization reactions (i.e., reactions that provide tautomer pairs) can be catalyzed by acids or bases. Exemplary tautomerization reactions include keto-enol, amide-imide, lactam-lactamimide, enamine-imide, and enamine-(different enamines) tautomerization reactions.

[0078] It should also be understood that compounds with the same molecular formula but different properties, different atomic bonding sequences, or different spatial arrangements of atoms are called "isomers". Isomers with different atomic spatial arrangements are called "stereoisomers".

[0079] Stereoisomers that are not mirror images of each other are called "diastereomers," while stereoisomers that are not mirror images of each other are called "enantiomers." When a compound has an asymmetry center, for example, if it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetry center and are described by the R- and S-sequence rules of Cahn and Prelog or by rotating the molecular plane of polarization, and are represented as dextrorotatory or levorotatory (i.e., (+) or (-)- isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0080] The term "prodrug" refers to a compound having a cleavable group and being converted into the compound described herein by solvent decomposition or under physiological conditions, and which possesses pharmaceutical activity in vivo. Examples of such compounds include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, etc. Other derivatives of the compounds described herein, in both their acid and acid derivative forms, are active, but the acid-sensitive forms often offer advantages in mammalian organisms such as solubility, tissue compatibility, or delayed release (see Bundgard, H., Design of Prodrugs, pp. 7–9, 21–24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives known to those skilled in the art, such as esters prepared by reacting a parent acid with a suitable alcohol, or amides prepared by reacting a parent acid compound with a substituted or unsubstituted amine, or acid anhydrides or mixed acid anhydrides. Simple aliphatic or aromatic esters, amides, and acid anhydrides derived from the acidic side groups of the compounds described herein are specific prodrugs. In some cases, it is necessary to prepare diester-type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. C1-C8 alkyl esters, C2-C8 alkenyl esters, C2-C8 alkynyl esters, aryl esters, and C7-C... of the compounds described herein are likely preferred. 12 Substituted aryl esters and C7-C 12 Arylalkyl esters.

[0081] The term "abnormal activity" refers to activity that deviates from normal activity. The term "increased activity" refers to activity that is higher than normal activity.

[0082] The terms “composition” and “formulation” are used interchangeably.

[0083] The term "subject" to be administered refers to a person (i.e., a male or female of any age group, such as a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, middle-aged, or elderly person)). "Patient" refers to a human subject who requires treatment for a disease.

[0084] The term "biological sample" refers to any sample that includes tissue samples (e.g., tissue sections and needle biopsies); cell samples (e.g., cytological smears such as Pap smears or blood smears or cell samples obtained by microdissection); samples of whole organisms (e.g., yeast or bacterial samples); or any sample containing cellular parts, fragments, or organelles (e.g., obtained by lysing cells and separating their components by centrifugation or other methods). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspirate, milk, vaginal fluid, saliva, swabs (e.g., oral swabs), or any material containing biomolecules derived from the first biological sample.

[0085] The term “administration” means the implantation, absorption, ingestion, injection, inhalation or other introduction of the compound or a combination thereof described herein into or onto a subject.

[0086] The term "treatment" refers to reversing, alleviating, delaying the onset of the disease described herein, or inhibiting its development. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or 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 susceptible subjects before 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 occurrence of the disease. Treatment may also continue after symptoms have subsided, for example, to delay or prevent recurrence.

[0087] The "therapeutic effective amount" of the compounds described herein refers to an amount sufficient to elicit the desired biological response (i.e., to treat the condition). As will be understood by those skilled in the art, the effective amount of the compounds described herein can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the route of administration, and the age and health status of the subject. In some embodiments, the effective amount is a therapeutic effective amount. In some embodiments, the effective amount is a prophylactic treatment. In some embodiments, the effective amount is the amount of the compound described herein in a single dose. In some embodiments, the effective amount is a combined amount of the compound described herein in multiple doses.

[0088] The pharmaceutical compositions described herein can be prepared by any method known in the field of pharmacology. Typically, such preparation methods involve combining the active ingredient, such as the 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 shaping and / or packaging the product into the desired single-dose or multi-dose units.

[0089] Pharmaceutical compositions may be prepared, packaged, and / or sold as a single unit dose and / or as multiple single unit doses in bulk. A “unit dose” is a discrete amount of a pharmaceutical composition containing a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient to be administered to a subject and / or a simplified dose of that dose, such as half or one-third of that dose.

[0090] The relative amounts of the active ingredient, pharmaceutically acceptable excipients, and / or any other components 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 will be administered. The composition may contain from 0.1% to 100% (w / w) of the active ingredient.

[0091] Pharmaceutically acceptable excipients that can be used to manufacture the pharmaceutical compositions described herein include, for example, inert diluents, dispersants and / or granulators, 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 flavorings may also be present in the compositions.

[0092] Pharmaceutical compositions can be formulated for any route of administration, such as oral administration. Typically, pharmaceutical compositions are in solid dosage form. However, in some embodiments, other dosage forms, such as liquids, suspensions, or semi-solid dosage forms, may also be used.

[0093] Solid dosage forms for oral administration include, for example, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is combined with at least one inert, pharmaceutically acceptable excipient or carrier (e.g., sodium citrate or dicalcium phosphate) and / or (a) filler or extender (e.g., starch, lactose, sucrose, glucose, mannitol, and silica), (b) binder (e.g., carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic), (c) humectant (e.g., glycerin), (d) disintegrant (e.g., agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate), (e) inhibitor (e.g., paraffin), (f) absorption enhancer (e.g., quaternary ammonium compounds), (g) wetting agent (e.g., cetyl alcohol and glyceryl monostearate), (h) absorbent (e.g., kaolin and bentonite), and (i) lubricant (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate), and mixtures thereof. For capsules, tablets, and pills, the dosage form may contain a buffer.

[0094] Similar types of solid compositions 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, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells such as enteric coatings and other coatings well known in the field of pharmacology. They may optionally contain light-blocking agents and may have a composition that optionally releases the active ingredient in a delayed manner only or preferably in certain portions of the intestine. Examples of encapsulation compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose and high molecular weight polyethylene glycol.

[0095] The active ingredient (e.g., the compound of the present invention) may be in microencapsulated form having one or more excipients as described above. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells well known in the pharmaceutical formulation field, such as enteric coatings, controlled-release coatings, and other coatings. In such solid dosage forms, the active ingredient may be mixed with at least one inert diluent (e.g., sucrose, lactose, or starch). Such dosage forms may, according to conventional practice, contain substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pellets, the dosage form may contain a buffer. They may optionally contain a light-blocking agent and may have a composition that releases the active ingredient only or preferably in a delayed manner in certain portions of the intestine. Examples of encapsulating agents that can be used include polymers and waxes.

[0096] Although the description of the pharmaceutical compositions provided herein is primarily directed toward pharmaceutical compositions suitable for human administration, such compositions are generally suitable for administration to a wide variety of animals. Modifications to pharmaceutical compositions suitable for human administration are well known to make them suitable for administration to a wide variety of animals, and such modifications can be designed and / or performed by a veterinary pharmacist of ordinary skill through routine experiments. For veterinary use, the compounds disclosed herein can be administered as appropriately acceptable formulations according to normal veterinary practice. Veterinarians can readily determine the dosing regimen and route of administration best suited for a particular animal.

[0097] The compounds disclosed herein are generally formulated in dosage units for ease of administration and uniform dosage. However, it should be understood that the total daily dosage of the compositions described herein will be determined by a physician within the bounds of reasonable medical judgment. For any given subject or organism, the specific therapeutically effective dose level will depend on a variety of factors, including the disease being treated and its severity; the activity of the specific active ingredient used; the specific composition used; the subject's age, weight, general health condition, sex, and diet; the timing of administration, route of administration, and excretion rate of the specific active ingredient used; the duration of treatment; drugs used in combination with or concurrently with the specific active ingredient used; and factors well-known in the medical field.

[0098] This invention also includes isotopically labeled compounds of this invention, which are identical to those described herein unless one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this 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.

[0099] Certain isotopically labeled compounds of the present invention (e.g., those labeled with...) 3 H and 14 C-labeled compounds can be used to identify the distribution of compounds and / or matrix tissues. Tritiumization (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detection. Furthermore, isotopes such as deuterium (i.e., 2The heavier isotope substitution of H) can provide certain therapeutic benefits due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and is therefore preferred for use in certain conditions. The isotopically labeled compounds of the present invention can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents through a procedure similar to that disclosed in the processes and / or examples below.

[0100] The present invention also includes kits (e.g., pharmaceutical packaging). The provided kits may contain the pharmaceutical compositions or salts described herein and containers (e.g., vials, ampoules, bottles, syringes and / or dispenser packages, or other suitable containers). In some embodiments, the provided kits may optionally further include a second container containing a pharmaceutically acceptable carrier for diluting or suspending the pharmaceutical compositions or salts of the present disclosure herein. In some embodiments, the pharmaceutical compositions or salts of the present invention provided in the first and second containers are combined to form a unit dosage form.

[0101] In some embodiments, the kits described herein further include instructions for use of the compounds or pharmaceutical compositions contained in the kit. The kits described herein may also include information required by regulatory agencies such as the National Medical Products Administration (NMPA). In some embodiments, the information included in the kit is prescribing information. In some embodiments, the kit and instructions provide a method for treating and / or preventing monoamine oxidase B-related diseases or conditions (e.g., neuropsychiatric diseases or conditions) in subjects in need. The kits described herein may include one or more of the additional pharmaceutical agents described herein as a separate composition.

[0102] Furthermore, unless otherwise stated, the reagents and solvents disclosed below were purchased from Beijing Innocare Technology Co., Ltd., and 1 ¹H NMR was performed using a Quantum-I plus AS 400 NMR spectrometer. LCMS was performed using a Shimadzu LCMS-IT-TOF LC-MS / MS system. HPLC was performed using an Agilent Technologies 1200 series system; purity was calculated as area % by HPLC.

[0103] Example 1: Synthesis of (2S,5R)-5-{4-[4-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide hydrochloride

[0104]

[0105] Step 1

[0106]

[0107] 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 chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to give a white solid, compound A2 (23.0 g, 67.7%).

[0108] 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] + ).

[0109] Step 2

[0110]

[0111] Under nitrogen protection, compound 1 (5.0 g, 26.4 mmol) was dissolved in 1,4-dioxane (75 mL) and water (25 mL). At 25 °C, 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. 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), washed with water (50 mL × 2) and saturated brine (50 mL × 2), respectively. The extract was dried over anhydrous sodium sulfate, evaporated to dryness, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether) to give compound 2 (8.2 g) as a white solid.

[0112] 1 H NMR (400MHz, CDCl3): δppm 7.78-7.57(m,6H),7.52-7.43(m,2H).

[0113] Step 3

[0114]

[0115] Under nitrogen protection, compound 2 (1.5 g, 5.0 mmol) was dissolved in tetrahydrofuran (8.0 mL), and n-butyllithium (2.5 M hexane solution, 1.8 mL, 4.5 mmol) was added dropwise at -78 °C. The temperature was maintained, and the reaction was stirred for 1 hour. This is solution one.

[0116] Compound A2 (1.0 g, 4.1 mmol, 1.0 eq) was dissolved in dry tetrahydrofuran (8.0 mL), which is solution two.

[0117] 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 was continued for 2 hours. Saturated ammonium chloride aqueous solution (10 mL) was added, and ethyl acetate (30 mL x 3) was used for extraction. The organic layers were combined, washed with saturated brine (15 mL), and dried over anhydrous sodium sulfate to give a pale yellow oily compound 3 (2.2 g, crude product).

[0118] LCMS: 366.1 ([M-100+H]) + ).

[0119] Step 4

[0120]

[0121] At room temperature, compound 3 (2.2 g, 4.7 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (10.8 g, 94.5 mmol) was added. The mixture was reacted overnight, evaporated to dryness, and 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.

[0122] LCMS:348.1([M+H] + ).

[0123] Step 5

[0124]

[0125] Compound 4 (500 mg, 1.44 mmol) was dissolved in methanol (10 mL) at room temperature under nitrogen protection, and platinum dioxide (16 mg, 0.07 mmol) was added. The reaction was allowed to proceed overnight. The mixture was filtered, and the filtrate was concentrated to give compound 5 (500 mg, crude product), a white solid.

[0126] LCMS:350.1([M+H] + ).

[0127] Step 6

[0128]

[0129] 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 overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to give compound 6 (480 mg, 74.2%) as a white solid.

[0130] LCMS: 350.1([M-100+H]) + ).

[0131] Step 7

[0132]

[0133] Compound 6 (440 mg, 0.98 mmol) was dissolved in tetrahydrofuran (7 mL) and water (3.5 mL) at room temperature. Lithium hydroxide (117 mg, 4.89 mmol) was added, and the mixture was heated to 50 °C and stirred for 3 hours. The mixture was concentrated under reduced pressure to remove the tetrahydrofuran. Water (5 mL) was added, and the pH was adjusted to 4 with 1 equivalent of hydrochloric acid aqueous solution. 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 give compound 7 (410 mg, 96.2%) as a white solid.

[0134] LCMS: 434.1 ([MH]) - ).

[0135] Step 8

[0136]

[0137] At room temperature, a solution of compound 7 (380 mg, 0.87 mmol) in N,N-dimethylformamide (4 mL) was added with ammonium chloride (117 mg, 2.6 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (497 mg, 1.3 mmol), and N,N-diisopropylethylamine (563 mg, 4.4 mmol). The reaction was allowed to proceed for 3 hours at room temperature. Water (10 mL) was added, followed by extraction with ethyl acetate (15 mL x 2), washing with saturated brine (20 mL x 2), and drying over anhydrous sodium sulfate. The solution was filtered and concentrated to give compound 8 (400 mg, crude) as a white oil.

[0138] LCMS: 457.1 ([M+Na]) + ).

[0139] Step 9

[0140]

[0141]

[0142] At room temperature, a solution of compound 8 (400 mg, 0.92 mmol) was added to dichloromethane (4 mL), followed by ethyl hydrochloride solution (3.0 M, 4 mL, 12.00 mmol). The mixture was stirred for 2 hours, concentrated, and the residue was added to water (5 mL). The pH was adjusted to 7-8 with 5% sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by thin-layer chromatography (dichloromethane / methanol = 10:1). The obtained compound was added to ethyl hydrochloride solution (3.0 M, 5 mL), stirred for 2 hours, concentrated, and then water (5 mL) was added. The mixture was freeze-dried to give a white solid compound HYD-P-001 (50 mg, 15.5%).

[0143] 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] + ).

[0144] Example 2: Synthesis of (2S,5R)-5-[4-(4-fluorophenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0145]

[0146] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 4-fluorophenylboronic acid (5.0 g, 35.7 mmol, 1.0 eq), and finally a white solid (2S,5R)-5-[4-(4-fluorophenyl)phenyl]-1H-pyrrole-2-carboxamide (40 mg, 24.0%) was obtained. 1H 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] + ).

[0147] Example 3: Synthesis of (2S,5R)-5-{4-[4-(trifluoromethoxy)phenyl]-phenyl}-1H-pyrrole-2-carboxamide hydrochloride

[0148]

[0149] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 4-trifluoromethoxyphenylboronic acid (5.0 g, 24.2 mmol, 1.0 eq), finally yielding 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] + ).

[0150] Example 4: Synthesis of (2S,5R)-5-{4-[3-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide hydrochloride

[0151]

[0152] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 3-trifluoromethylphenylboronic acid (5.0 g, 26.3 mmol, 1.0 eq), which eventually yielded 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). 19 F NMR(300MHz,DMSO-d6,ppm):δ-60.98(3F).LCMS:335.1([M-HCl+H] + ).

[0153] Example 5: Synthesis of (2S,5R)-5-[4-(3-fluorophenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0154]

[0155] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 3-fluorophenylboronic acid (5.0 g, 35.7 mmol, 1.0 eq), and finally a white solid (2S,5R)-5-[4-(3-fluorophenyl)phenyl]-1H-pyrrole-2-carboxamide (55 mg, 23.2%) was obtained. 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 F NMR(282MHz,DMSO-d6,ppm):δ-112.69(1F).LCMS:285.1([M-HCl+H] + ).

[0156] Example 6: Synthesis of (2S,5S)-5-{4-[4-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide hydrochloride

[0157]

[0158] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except for the choice of product chirality, and the final product was a white solid (2S,5S)-5-{4-[4-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide (42 mg, 70.5%). 1 H NMR (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). 19 F NMR(376MHz,DMSO-d6,ppm):δ-60.92(3F).LCMS:335.1([M-HCl+H] + ).

[0159] Example 7: Synthesis of (2R,5R)-5-{4-[4-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide hydrochloride

[0160]

[0161] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except for the choice of product chirality, and the final product was a white solid (2R,5R)-5-{4-[4-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide (28 mg, 32.9%). 1 H NMR (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] + ).

[0162] Example 8: Synthesis of (2R,5S)-5-{4-[4-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide hydrochloride

[0163]

[0164] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except for the choice of product chirality, and the final product was a white solid (2R,5S)-5-{4-[4-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide (50.1 mg, 58.6%). 1 H NMR (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). 19 F NMR(376MHz,DMSO-d6,ppm):δ-60.92(3F).LCMS:335.1([M-HCl+H] + ).

[0165] Example 9: Synthesis of (2S,5R)-5-{4-[2-(trifluoromethyl)phenyl]-phenyl}-1H-pyrrole-2-carboxamide hydrochloride

[0166]

[0167] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 2-trifluoromethylphenylboronic acid (5.0 g, 26.3 mmol, 1.0 eq), which eventually yielded 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] + ).

[0168] Example 10 Synthesis of (2S,5R)-5-[4-(4-chlorophenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0169]

[0170] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 4-chlorophenylboronic acid (5.0 g, 32.0 mmol, 1.0 eq), finally yielding 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] + ).

[0171] Example 11 Synthesis of (2S,5R)-5-[4-(4-cyanophenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0172]

[0173] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 4-cyanobenzoic acid (5.0 g, 34.0 mmol, 1.0 eq), which eventually yielded 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] + ).

[0174] Example 12 Synthesis of (2S,5R)-5-[4-(4-nitrophenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0175]

[0176] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 4-nitrophenylboronic acid (5.0 g, 29.8 mmol, 1.0 eq), which eventually yielded 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] + ).

[0177] Example 13 Synthesis of (2S,5R)-5-[4-(4-carboxyphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0178]

[0179] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 4-carboxyphenylboronic acid (5.0 g, 29.6 mmol, 1.0 eq), which eventually yielded 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] + ).

[0180] Example 14 Synthesis of (2S,5R)-5-[4-(4-benzamido)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0181]

[0182] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 4-amidophenylboronic acid (5.0 g, 29.6 mmol, 1.0 eq), which eventually yielded 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] + ).

[0183] Example 15 Synthesis of (2S,5R)-5-[4-(4-methylbenzoate)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0184]

[0185] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 4-chlorophenylboronic acid (5.0 g, 27.8 mmol, 1.0 eq), which eventually yielded a white solid (2S,5R)-5-[4-(4-methylbenzoate)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] + ).

[0186] Example 16 Synthesis of (2S,5R)-5-[4-biphenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0187]

[0188] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: phenylboronic acid (5.0 g, 41.0 mmol, 1.0 eq), which eventually yielded a white solid (2S,5R)-5-[4-biphenyl]-1H-pyrrole-2-carboxamide (25.0 mg, 50.4%). 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] + ).

[0189] Example 17 Synthesis of (2S,5R)-5-[4-(4-methylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0190]

[0191] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 4-methylphenylboronic acid (5.0 g, 36.8 mmol, 1.0 eq), which eventually yielded 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] + ).

[0192] Example 18 Synthesis of (2S,5R)-5-[4-(4-methoxyphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0193]

[0194] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 4-methoxyphenylboronic acid (5.0 g, 32.9 mmol, 1.0 eq), which eventually yielded 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] + ).

[0195] Example 19 Synthesis of (2S,5R)-5-[2-methyl-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0196]

[0197] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 2-iodo-5-bromotoluene (8.6 g, 28.9 mmol, 1.1 eq), which eventually yielded a white solid (2S,5R)-5-[2-methyl-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride (29 mg, 34.3%). 1H 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] + ).

[0198] Example 20: Synthesis of (2S,5R)-5-[2-methoxy-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0199]

[0200] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 1-iodo-2-methoxy-4-bromotoluene (9.0 g, 28.9 mmol, 1.1 eq), which eventually yielded 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] + ).

[0201] Example 21 Synthesis of (2S,5R)-5-[2-cyano-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0202]

[0203] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 5-bromo-2-iodobenzonitrile (8.9 g, 28.9 mmol, 1.1 eq), which eventually yielded a white solid (2S,5R)-5-[2-cyano-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride (30.1 mg, 41.9%). 1 H NMR (400MHz, DMSO-d6): δppm10.19(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=8.4H z,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] + ).

[0204] Example 22 Synthesis of (2S,5R)-5-[3,5-difluoro-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0205]

[0206] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 2-bromo-1,3-difluoro-5-iodobenzene (9.2 g, 28.9 mmol, 1.1 eq), which eventually yielded a white solid (2S,5R)-5-[3,5-difluoro-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride (36.1 mg, 40.2%). 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] + ).

[0207] Example 23 Synthesis of (2S,5R)-5-[3-cyano-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0208]

[0209] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 2-bromo-5-iodobenzonitrile (8.9 g, 28.9 mmol, 1.1 eq), which eventually yielded a white solid (2S,5R)-5-[3-cyano-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride (30.3 mg, 40.2%). 1 H NMR (400MHz, DMSO-d6): δppm10.19(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] + ).

[0210] Example 24 Synthesis of (2S,5R)-5-[2,6-difluoro-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-carboxamide hydrochloride

[0211]

[0212] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 2,6-difluoro-4-bromo-iodobenzene (9.2 g, 28.9 mmol, 1.1 eq), which eventually yielded 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] + ).

[0213] Example 25 Synthesis of (2S,5R)-5-[2-methoxy-4-(4-trifluoromethylphenyl)phenyl]-3-methyl-1H-pyrrole-2-carboxamide hydrochloride

[0214]

[0215] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 4-methyl-L-pyroglutamic acid (21.9 g, 139.7 mmol), which eventually yielded 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] + ).

[0216] Example 26 Synthesis of (2S,5R)-5-[2-methoxy-4-(4-trifluoromethylphenyl)phenyl]-N-methyl-pyrrole-2-carboxamide

[0217]

[0218] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: iodomethane (42.6 mg, 0.3 mmol, 1.5 eq), which eventually yielded 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): δppm10.19(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] +).

[0219] Example 27 Synthesis of (2S,5R)-5-[4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-methylformamide hydrochloride

[0220]

[0221] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: methylamine (3.1 mL, 33%, 930.0 mg, 30.0 mmol, 1.1 eq), which eventually yielded a white solid (2S,5R)-5-[4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-methylformamide hydrochloride (30.5 mg, 43.8%).

[0222] 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] + ).

[0223] Example 28 Synthesis of (2S,5R)-5-[2-methoxy-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-dimethylformamide hydrochloride

[0224]

[0225] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: dimethylamine (3.3 mL, 40% in methanol, 1350.0 mg, 30.0 mmol, 1.1 eq), finally yielding a white solid (2S,5R)-5-[2-methoxy-4-(4-trifluoromethylphenyl)phenyl]-1H-pyrrole-2-dimethylformamide hydrochloride (28.7 mg, 37.8%).

[0226] 1H 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] + ).

[0227] Example 29 Synthesis of (2S,5R)-5-[4-(4-trifluoromethylphenyl)phenyl]-4-methyl-1H-pyrrole-2-methylformamide hydrochloride

[0228]

[0229] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: 3-methyl-L-pyroglutamic acid (21.9 g, 139.7 mmol), which eventually yielded 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] + ).

[0230] Example 30 Synthesis of (2S,5R)-5-[4-(4-trifluoromethylphenyl)phenyl]-N-ethyl-pyrrole-2-methylformamide

[0231]

[0232] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the following corresponding reactant was used: iodoethane (46.7 mg, 0.3 mmol, 1.5 eq), which eventually yielded 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] + ).

[0233] Example 31: Synthesis of (2S,5R)-5-[4-(4-fluorophenyl)phenyl]-1H-pyrrole-2-carboxylate

[0234]

[0235] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that the methyl carboxylate was not amination-treated but directly hydrolyzed to a carboxyl group, ultimately yielding a white solid (2S,5R)-5-[4-(4-fluorophenyl)phenyl]-1H-pyrrole-2-carboxylate (35.5 mg, 28.2%). 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]+).

[0236] Example 32 Synthesis of (2S,5R)-5-[4-(4-fluorophenyl)phenyl]-1H-pyrrole-2-carboxylic acid methyl ester hydrochloride

[0237]

[0238] The corresponding compound was prepared in a manner similar to that in Preparation Example 1, except that methyl carboxylate was used as the active group in the reaction and no amination was performed, and the final product was a white solid (2S,5R)-5-[4-(4-fluorophenyl)phenyl]-1H-pyrrole-2-carboxylate hydrochloride (45.5 mg, 46.2%). 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] + ).

[0239] Test Example 1

[0240] 1. Human recombinant MAO-A / B inhibitory activity test

[0241] Full-strand human recombinant MAO-A and MAO-B proteins were expressed in Baculovirus-infected Sf 9 cells, containing an N-terminal FLAG marker, with a molecular weight of 59.8 kDa. The recombinant proteins were purified by SDS-PAGE to a purity >85%, and the protein concentration was 0.3 μg / μL for both. MAO protein was incubated with 40 μM substrate at room temperature for 1 hour. The resulting substrate, generated by oxidative deamination of MAO, was then incubated with a fluorescent agent for 0.5 hours. MAO activity was then detected using the Promega MAO-Glo™ assay.

[0242] 2. Test methods

[0243] Human recombinant monoamine oxidase A / B was expressed in Sf9 cells. In the experiment, recombinant monoamine oxidase 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 monoamine oxidase A / B solution was added to each well of a 384-well plate, and 10 concentration gradients of the test compound (DMSO final concentration 1%) were added to each well. The positive control was either clogiline or selegiline hydrochloride. The plates were incubated at room temperature for 15 minutes. Then, 10 μL of substrate solution (40 μM, MAO-A / B substrates were tyramine and benzylamine, respectively) was 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, mix thoroughly, and incubate at room temperature for 20 minutes to generate a stable fluorescence signal. Read the fluorescence signal using a fluorescence microplate reader, and express the value as relative light intensity (RLU). The experiment was designed with duplicate wells, and the average value was used to calculate the enzyme activity inhibition rate. The calculation formula is as follows:

[0244] Inh%=(Max-Signal) / (Max-Min)*100

[0245] Where Max is the value detected at the maximum sample concentration, Min is the value detected at the minimum sample concentration, and Signal is the value detected at the current sample concentration; IC50 is calculated using Graphpad Prism 5 software based on the experimental results. 50 The calculation formula is as follows:

[0246] Y=Bottom+(Top-Bottom) / (1+10^((Log IC 50 -X)*Hill Slope)

[0247] X: Logarithm of compound concentration; Y: Inhibition rate (%); Top and Bottom: Plateau units are the same as Y; Hillslop: Slope coefficient or curve slope.

[0248] Table 1 Activity data IC 50 (nM)

[0249]

[0250]

[0251] 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 variations or substitutions that can be easily conceived by those 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 determined by the scope of the claims.

Claims

1. A biphenyltetrahydropyrrole compound of Formula I or a pharmaceutically acceptable salt thereof: Formula I in, R1 is selected from hydrogen and C1~C6 alkyl groups; R2 is selected from hydrogen, halogen, cyano, C1~C6 alkyl, and C1~C6 alkoxy. R3 is selected from hydrogen, halogen, cyano, carboxyl, C1~C6 alkyl, halogenated C1~C6 alkyl, C1~C6 alkoxy, halogenated C1~C6 alkoxy, -C(=O)OC1~C6 alkyl; R4 and R5 are each independently selected from hydrogen and C1-C6 alkyl groups; 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 shown in Formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R1 is selected from hydrogen and C1~C4 alkyl groups.

3. The biphenyltetrahydropyrrole compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.

4. The biphenyltetrahydropyrrole compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R2 is selected from hydrogen, halogen, cyano, C1~C4 alkyl, and C1~C4 alkoxy.

5. The biphenyltetrahydropyrrole compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R2 is selected from hydrogen, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert-butoxy.

6. The biphenyltetrahydropyrrole compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R3 is selected from hydrogen, halogen, cyano, carboxyl, C1~C4 alkyl, halogenated C1~C4 alkyl, C1~C4 alkoxy, halogenated C1~C4 alkoxy, and -C(=O)OC1~C4 alkyl.

7. The biphenyltetrahydropyrrole compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R3 is selected from hydrogen, halogen, cyano, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, 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, monochloropropyl, dichloropropyl, trichloropropyl, tetrachloropropyl, pentachloropropyl, hexachloropropyl, perchloropropyl, monofluoromethoxy, difluoromethoxy, trifluoro Methoxy, 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.

8. The biphenyltetrahydropyrrole compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R3 is selected from hydrogen, halogen, cyano, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, trifluoromethyl, -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.

9. The biphenyltetrahydropyrrole compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R4 and R5 are each independently selected from hydrogen and C1-C4 alkyl groups.

10. The biphenyltetrahydropyrrole compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R4 and R5 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.

11. The biphenyltetrahydropyrrole compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, n1 is an integer selected from 0, 1, or 2; n2 is an integer selected from 0, 1, 2, or 3; n3 is an integer selected from 0, 1, 2, or 3.

12. The biphenyltetrahydropyrrole compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I or a pharmaceutically acceptable salt thereof is derived from the following formula: express: Mode The definition of R3 is the same as that in claim 1.

13. A biphenyl tetrahydropyrrole compound or a pharmaceutically acceptable salt thereof, characterized in that, It is selected from the following compounds: 。 14. A pharmaceutical composition comprising a therapeutically effective amount of the formula I according to any one of claims 1 to 11 or the formula according to claim 12. The biphenyl tetrahydropyrrole compound shown herein, or a pharmaceutically acceptable salt thereof, or the biphenyl tetrahydropyrrole compound or a pharmaceutically acceptable salt thereof according to claim 13, and a pharmaceutically acceptable carrier.

15. The formula I as described in any one of claims 1 to 11, or the formula as described in claim 12. The use of the biphenyltetrahydropyrrole compound shown herein or a pharmaceutically acceptable salt thereof, or the biphenyltetrahydropyrrole compound or a pharmaceutically acceptable salt thereof according to claim 13, in the preparation of a medicament for the treatment or prevention of a disease or condition associated with monoamine oxidase B in a subject in need, said disease or condition associated with monoamine oxidase B being selected from depression, Alzheimer's disease, Parkinson's disease, and narcolepsy.

16. A kit comprising the formula I according to any one of claims 1 to 11 or the formula according to claim 12. The biphenyl tetrahydropyrrole compound shown, or a pharmaceutically acceptable salt thereof, or the biphenyl tetrahydropyrrole compound or a pharmaceutically acceptable salt thereof according to claim 13, or the pharmaceutical composition according to claim 14, along with the container and instructions for use.

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