Phenyl heterocyclic compound and use thereof

Abstract

Disclosed in the present invention is a compound as shown in formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite and prodrug thereof, or a pharmaceutically acceptable salt or ester thereof. Further disclosed in the present invention is the use of the compound in the preparation of a drug for treating ophthalmic diseases.

Description

PHENYL HETEROCYCLIC COMPOUND AND USE THEREOF TECHNICAL FIELD The present invention relates to a phenyl heterocyclic compound, and a stereoisomer, tautomer, N-oxide, solvate, metabolite, prodrug, pharmaceutically acceptable salt or ester thereof, and the use thereof in the manufacture of a medicament for treating ophthalmic diseases. BACKGROUND Age-related macular degeneration (AMD) is the most common cause of blindness in developed countries, with atrophic (dry) AMD being the more prevalent form. Currently, there are no FDA-approved therapies for dry AMD. Given the lack of treatment and high prevalence, the development of drugs for dry AMD is of great importance. The age-dependent accumulation of lipofuscin-like retinoid dimers (bisretinoids) in the retina may significantly contribute to the pathogenesis of the dry form of AMD. The synthesis of intraocular retinoid dimers depends on the influx of all-trans retinol from serum into the retina, and this influx requires the formation of a tertiary retinol binding protein 4 (RBP4)-transthyretin (TTR)-retinol complex in serum. The use of RBP4 antagonists to reduce the rate of formation of cytotoxic retinoid dimers (the main component of lipofuscin) in the retinal pigment epithelium (RPE) will prevent further geographic atrophy in patients suffering from atrophic (dry) age-related macular degeneration (AMD), thereby improving conditions characterized by excessive accumulation of lipofuscin in the retina. In addition to AMD, significant accumulation of lipofuscin is also characteristic of fundus flavimaculatus (Stargardt) and vitelliform macular degeneration (Best), wherein Stargardt disease is a genetic form of juvenile-onset macular degeneration, and Best disease is an autosomal dominant disorder caused by carrying the vitelliform macular dystrophy gene. WO2015168286 discloses a class of substituted 4-phenylpiperidine compounds, as exemplified by Compound A; WO2014152018 discloses a class of substituted cyclopentane-fused tetrahydropyrrole compounds, as exemplified by Compound B; and WO2014151936 discloses a class of substituted octahydropyrrolopyrrole compounds, as exemplified by Compound C. As RBP4 antagonists, they provide a therapeutic basis for the treatment of dry AMD and other diseases characterized by excessive accumulation of lipofuscin; however, improvements are still needed in terms of inhibitory effect, membrane permeability, pharmacokinetics, druggability, and drug safety. SUMMARY To address the shortcomings of the prior art, the first aspect of the present invention provides a compound having the structure shown in Formula (I), or a stereoisomer, tautomer, N- oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof; Formula (I) wherein, R1 is selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, cyano, nitro, cycloalkyl, heterocyclyl, -NR7R8, -NR9(CO)R6, -NR9(CO)OR10, -NR9(CO)NR7R8, -NR9SOR11, -NR9SO2R11, -OR10, -O(CO)R6, -O(CO)NR7R8, -C(O)R6, -C(O)OR10, -C(O)NR7R8, -C(S)OR10, -C(S)NR7R8, -C(O)SR10, -SR10, -SOR11, -SO2R11, -SO2NR7R8, -S(O)R11NR9, -C(NR9)NR7R8, and -P(O)R12R13; R2, R3, R4, and R5 are each independently selected from hydrogen, deuterium, hydroxy, nitro, amino, alkoxy, carboxy, mercapto, cyano, alkyl, halogen, cycloalkyl, and haloalkyl; or R1, R2, R3, R4, and R5 are joined at any adjacent positions to form cycloalkyl or heterocyclyl; R6 is selected from hydrogen, deuterium, hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R7, R8, and R9 are selected from hydrogen, deuterium, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R10 is selected from hydrogen, deuterium, alkyl, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, and heteroaryl; R11 is selected from hydrogen, deuterium, amino, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R12 and R13 are selected from hydrogen, deuterium, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or R12 and R13 together with the P atom to which they are attached, form a phosphorus-containing heterocycle; the alkyl, alkoxy, haloalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, and heteroaryl of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 are optionally substituted with 0 to 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, carboxy, mercapto, nitro, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, alkoxy, haloalkoxy, heterocyclyl, aryl, and heteroaryl; L is a bridged ring group, spiro ring group, monocyclic group, or fused ring group, which contains 0 to 2 nitrogen atoms; the bridged ring group, spiro ring group, monocyclic group, or fused ring group in L is optionally substituted with 0 to 4 substituents selected from deuterium, alkyl, hydroxy, amino, alkoxy, and haloalkyl; A is -NR14- or a bond; R14 is selected from hydrogen, deuterium and alkyl; ring B is selected from a heterocycle, an aryl ring and a heteroaryl ring; R15 and each R16 are each independently selected from deuterium, alkyl, aminoalkyl, cycloalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanamido, alkanoyl, aminocarbonyl, heterocyclyl, aryl, heteroaryl and heterocyclylcarbonyl; the alkyl, cycloalkyl, aminoalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanamido, alkanoyl, heterocyclyl, aryl, heteroaryl, and heterocyclylcarbonyl of R15and R16 are each independently substituted with 0 to 4 substituents selected from deuterium, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkanoyl, alkoxycarbonyl, alkanamido, aminocarbonyl, carboxy, -O-C(O)-NR17R18, and oxo; R17 and R18 are each independently selected from hydrogen, deuterium, alkyl, and haloalkyl; n is 0, 1, 2, 3, or 4. In some embodiments, in the compound of Formula (I), ring B is selected from C1- 9heterocycle, C6-10aryl ring, and C1-9heteroaryl ring. In some embodiments, in the compound of Formula (I), ring B is selected from a pyrazole N^                      N'N'N NN ring (e.g., n-nh ), an imidazole ring (e.g.,  —nh), a triazole ring (e.g.,      , ^-nh), and a pyrimidine ring (e.g., n ). V In some embodiments, ring B is selected from a pyrazole ring (e.g., n-nh), an imidazole * ), and a pyrimidine ring (e.g., n ), wherein * N N          V ring (e.g., * NH), a triazole ring (e.g., * represents the attachment site of ring B to the carbonyl in the compound of Formula (I). In some embodiments, R15 and each R16 are each independently selected from deuterium, C1-6alkyl, C1-6cycloalkyl, C1-6aminoalkyl, C1-6alkoxyC1-6alkyl, C1-6haloalkyl, C1-9heterocyclylC1-6alkyl, C1-9heteroarylC1-6alkyl, C1-6alkanamido, C1-6alkanoyl, aminocarbonyl, C1-9heterocyclyl, C6-10aryl, C1-9heteroaryl, and C1-9heterocyclylcarbonyl; the C1-6alkyl, C1-6cycloalkyl, C1-6aminoalkyl, C1-6alkoxyC1-6alkyl, C1-6haloalkyl, C1-9heterocyclylC1-6alkyl, C1-9heteroarylC1-6alkyl, C1-6alkanamido, C1-6alkanoyl, C1-9heterocyclyl, C6-10aryl, C1-9heteroaryl, and C1-9heterocyclylcarbonyl of R15 and R16 are each independently substituted with 0 to 4 substituents selected from deuterium, C1-6alkyl, C1-6cycloalkyl, C1-9heterocyclyl, C6-10aryl, C1-9heteroaryl, C1-6alkanoyl, C1-6alkoxycarbonyl, C1-6alkanamido, aminocarbonyl, carboxy, -O-C(O)-NR17R18 and oxo; R17 and R18 are each independently selected from hydrogen, deuterium, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R15 and each R16 are each independently selected from deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, propylamino, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, halomethyl, haloethyl, pyrrolidinyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidinyl, piperidinylmethyl, piperidinylethyl, piperazinyl, piperazinylmethyl, piperazinylethyl, morpholinyl, morpholinylmethyl, morpholinylethyl, morpholinylcarbonyl, pyrrolyl, pyrrolylmethyl, pyrrolylethyl, pyridyl, pyridylmethyl, pyridylethyl, imidazolyl, imidazolylmethyl, imidazolylethyl, pyrazolyl, pyrazolylmethyl, pyrazolylethyl, pyrazinyl, pyrazinylmethyl, pyrazinylethyl, pyridazinyl, pyridazinylmethyl, pyridazinylethyl, pyrimidinyl, pyrimidinylmethyl, pyrimidinylethyl, triazolyl, triazolylmethyl, triazolylethyl, tetrazolyl, tetrazolylmethyl, tetrazolylethyl, thiomorpholinyl, thiomorpholinylmethyl, thiomorpholinylethyl, formamido, acetamido, aminocarbonyl, formyl, and acetyl; R15 and each R16 are each independently optionally substituted with 0 to 4 substituents selected from deuterium, methyl, ethyl, cyclopropyl, cyclobutyl, formyl, acetyl, formamido, acetamido, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, carboxy, -O-C(O)-NHCH3, -O-C(O)-N(CH3)2, -O-C(O)-NHC2H5, -O-C(O)-NHC3H8 and oxo. In some embodiments, in the compound of Formula (I), the alkyl, cycloalkyl, heterocyclyl, alkoxy, and haloalkyl of R1, R2, R3, R4, R5 are C1-6alkyl, C3-8cycloalkyl, C1-9heterocyclyl, C1-6alkoxy, and C1-6haloalkyl; R6 is selected from hydrogen, deuterium, hydroxy, amino, C1-6alkyl, C1-6alkoxy, C3-8cycloalkyl, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl; R7, R8, and R9 are selected from hydrogen, deuterium, cyano, C1-6alkyl, C3-8cycloalkyl, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl; R10 is selected from hydrogen, deuterium, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C2-6haloalkenyl, C3-8cycloalkyl, C3-8halocycloalkyl, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl; R11 is selected from hydrogen, deuterium, amino, C1-6alkyl, C3-8cycloalkyl, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl; R12 and R13 are selected from hydrogen, deuterium, C1-6alkyl, C3-8cycloalkyl, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl, or R12 and R13 together with the P atom to which they are attached, form a phosphorus-containing C1-9heterocycle; the C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C2-6alkenyl, C2-6haloalkenyl, C2-6alkynyl, C3-8cycloalkyl, C3-8halocycloalkyl, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 are optionally substituted with 0 to 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, carboxy, mercapto, nitro, C1-6alkyl, C3-8cycloalkyl, C3-8halocycloalkyl, C1-6haloalkyl, C2-6alkenyl, C2-6haloalkenyl, C2-6alkynyl, C1-6alkoxy, C1-6haloalkoxy, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl. In some embodiments, in the compound of Formula (I), the cycloalkyl of R1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; the heterocyclyl of R1 is selected from oxetanyl, oxolanyl, azetidinyl, pyrrolidinyl, thietanyl, and thiolanyl; R2, R3, R4, and R5are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropyl, cyclobutyl, halocyclopropyl, and halocyclobutyl; or R1, R2, R3, R4, and R5 are joined at any adjacent positions to form cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, or oxanyl; R6 is selected from hydrogen, deuterium, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, pyrrolidinyl, and tetrahydrofuryl; R7, R8, and R9 are selected from hydrogen, deuterium, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, and tetrahydrofuryl; R10 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tertbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halomethyl, haloethyl, halogenated n-propyl, halogenated isopropyl, halogenated n-butyl, halocyclopropyl, halocyclobutyl, halocyclopentyl, halocyclohexyl, ethenyl, propenyl, ethynyl, propynyl, haloethenyl, halopropenyl, pyrrolidinyl, and tetrahydrofuryl; R11 is selected from hydrogen, deuterium, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, and tetrahydrofuryl; R12 and R13 are selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, and tetrahydrofuryl. In some embodiments, in the compound of Formula (I), L is selected from C6-12 bridged ring group, C5-12 spiro ring group, which contains 0 to 2 nitrogen atoms, C2-6 monocyclic group containing 0 to 2 nitrogen atoms, and C4-12 fused ring group containing 0 to 2 nitrogen atoms; the C6-12 bridged ring group, C5-12 spiro ring group, C2-6 monocyclic group, or C4-12 fused ring group in L are optionally substituted with 0 to 4 substituents selected from deuterium, C1-6alkyl, hydroxy, amino, C1-6alkoxy, and C1-6haloalkyl; the alkyl of R14 is C1-6alkyl. In some embodiments, in the compound of Formula (I), L has one of the following structures: , and In some embodiments, the compound has the structure as shown in Formula (II) or (III), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof; Formula (II), Formula (III) wherein, X1, X2, and X3 are N or CR16; l is 0 or 1, n is 0, 1, 2, 3, or 4; R15 and each R16 are each independently selected from deuterium, alkyl, aminoalkyl, cycloalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanamido, alkanoyl, aminocarbonyl, heterocyclyl, aryl, and heteroaryl; the alkyl, cycloalkyl, aminoalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanamido, alkanoyl, heterocyclyl, aryl, heteroaryl, and heterocyclylcarbonyl of R15 and R16 are each independently substituted with 0 to 4 substituents selected from deuterium, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkanoyl, alkoxycarbonyl, alkanamido, aminocarbonyl, carboxy, -O-C(O)-NR17R18 and oxo; R17 and R18 are each independently selected from hydrogen, deuterium, alkyl, and haloalkyl. In other embodiments, in the compound, ring B is selected from C1-9heterocycle, C6-10aryl ring, and C1-9heteroaryl ring. In some embodiments, in the compound of Formula (III), ring B is selected from a pyrazole . z a....... n.....nA NA. , ring (e.g., n-nh ), an imidazole ring (e.g., ^-nh), a triazole ring (e.g.,       , ^--nh), and a pyrimidine ring (e.g., n ). In some embodiments, in the compound of Formula (III), ring B is selected from a pyrazole ring (e.g., n-nh), an imidazole ring (e.g., N^ L z * nh), a triazole ring (e.g., ), and a pyrimidine ring * J (e.g., n ), wherein * represents the attachment site of ring B to the carbonyl in the compound of Formula (III). In some embodiments, R15 and each R16 are each independently selected from deuterium, C1-6alkyl, C1-6cycloalkyl, C1-6aminoalkyl, C1-6alkoxyC1-6alkyl, C1-6haloalkyl, C1-9heterocyclylC1-6alkyl, C1-9heteroarylC1-6alkyl, C1-6alkanamido, C1-6alkanoyl, aminocarbonyl, C1-9heterocyclyl, C6-10aryl, C1-9heteroaryl, and C1-9heterocyclylcarbonyl; the C1-6alkyl, C1-6cycloalkyl, C1-6aminoalkyl, C1-6alkoxyC1-6alkyl, C1-6haloalkyl, C1-9heterocyclylC1-6alkyl, C1-9heteroarylC1-6alkyl, C1-6alkanamido, C1-6alkanoyl, C1-9heterocyclyl, C6-10aryl, C1-9heteroaryl, and C1-9heterocyclylcarbonyl of R15 and R16 are each independently substituted with 0 to 4 substituents selected from deuterium, C1-6alkyl, C1-6cycloalkyl, C1-9heterocyclyl, C6-10aryl, C1-9heteroaryl, C1-6alkanoyl, C1-6alkoxycarbonyl, C1-6alkanamido, aminocarbonyl, carboxy, -O-C(O)-NR17R18 and oxo; R17 and R18 are each independently selected from hydrogen, deuterium, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R15 and each R16 are each independently selected from deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, propylamino, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, halomethyl, haloethyl, pyrrolidinyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidinyl, piperidinylmethyl, piperidinylethyl, piperazinyl, piperazinylmethyl, piperazinylethyl, morpholinyl, morpholinylmethyl, morpholinylethyl, morpholinylcarbonyl, pyrrolyl, pyrrolylmethyl, pyrrolylethyl, pyridyl, pyridylmethyl, pyridylethyl, imidazolyl, imidazolylmethyl, imidazolylethyl, pyrazolyl, pyrazolylmethyl, pyrazolylethyl, pyrazinyl, pyrazinylmethyl, pyrazinylethyl, pyridazinyl, pyridazinylmethyl, pyridazinylethyl, pyrimidinyl, pyrimidinylmethyl, pyrimidinylethyl, triazolyl, triazolylmethyl, triazolylethyl, tetrazolyl, tetrazolylmethyl, tetrazolylethyl, thiomorpholinyl, thiomorpholinylmethyl, thiomorpholinylethyl, formamido, acetamido, aminocarbonyl, formyl, and acetyl; R15 and each R16 are each independently optionally substituted with 0 to 4 substituents selected from deuterium, methyl, ethyl, cyclopropyl, cyclobutyl, formyl, acetyl, formamido, acetamido, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, carboxy, -O-C(O)-NHCH3, -O-C(O)-N(CH3)2, -O-C(O)-NHC2H5, -O-C(O)-NHC3H8 and oxo. In the second aspect, the present invention further provides a pharmaceutical composition, comprising (a) the compound as described above, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, prodrug, pharmaceutically acceptable salt or ester thereof, and (b) a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof. In the third aspect, the present invention provides use of the compound, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, prodrug, pharmaceutically acceptable salt or ester thereof, or the pharmaceutical composition as described in the present invention, in the manufacture of a medicament, wherein the medicament is used for the prevention, management, treatment, or amelioration of a retinol binding protein 4-related disease. In some embodiments, the retinol binding protein 4-related disease is age-related macular degeneration, Stargardt disease, or Best disease. In the fourth aspect, the present invention provides a method of inhibiting RBP4-TTR complex formation in a cell, comprising contacting the cell with an effective amount of the compound of the first aspect or the pharmaceutical composition of the second aspect. In the fifth aspect, the present invention provides a method of inhibiting excessive accumulation of lipofuscin in a cell, comprising contacting the cell with an effective amount of the compound of the first aspect or the pharmaceutical composition of the second aspect. In the sixth aspect, the present invention provides a method of inhibiting RBP4-TTR complex formation in serum of a subject, comprising administering to the subject an effective amount of the compound of the first aspect or the pharmaceutical composition of the second aspect. In the seventh aspect, the present invention provides a method of inhibiting excessive accumulation of lipofuscin in the retina of a subject, comprising administering to the subject an effective amount of the compound of the first aspect or the pharmaceutical composition of the second aspect. The foregoing summary merely outlines certain aspects of the present invention but is not limited thereto. The content of these and other aspects will be described in more specific and complete detail below. BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings are provided for a further understanding of the present application and constitute a part of the specification. Together with the detailed embodiments set forth below, they serve to explain the present application, but do not constitute a limitation on the present application. Figure 1 shows representative BAF photographs of rats in each group after administration. DETAILED DESCRIPTION Definitions and General Terminology Unless otherwise specified, the terms used in the specification and claims of the present invention have the following definitions. Certain embodiments of the present invention are now described in detail, with examples being illustrated by the accompanying structural and chemical formulas. The present invention is intended to cover all alternatives, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined by the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein may be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated references, patents, and similar documents differ from or contradict the present application (including but not limited to defined terms, term usage, described techniques, etc.), the present application shall prevail. It should be further recognized that certain features of the present invention, for the sake of clarity, are described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the present invention, for the sake of brevity, are described in a single embodiment, but may also be provided separately or in any suitable sub-combination. Unless otherwise specified, all scientific and technical terms used in the present invention have the same meanings as commonly understood by those skilled in the art to which the present invention pertains. All patents and publications referred to in the present invention are incorporated herein by reference in their entirety. Unless otherwise specified, the following definitions as used herein shall apply. For the purposes of the present invention, chemical elements are consistent with the CAS version of the Periodic Table of Elements, and the Handbook of Chemistry and Physics, 75th Edition, 1994. Furthermore, general principles of organic chemistry may be referred to in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference. Unless otherwise specified or where clearly contradictory in context, the articles "a", "an", and "the" as used herein are intended to include "at least one" or "one or more". Therefore, these articles as used herein refer to one or more than one (i.e., at least one) of the objects to which they refer. For example, "a component" refers to one or more components, i.e., more than one component may be contemplated for adoption or use in the embodiments described. The term "subject" as used in the present invention refers to an animal. Typically, the animal is a mammal. The subject also refers to, for example, primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human. The term "patient" as used in the present invention refers to a human (including adults and children) or other animals. In some embodiments, the "patient" refers to a human. The term "comprise" is an open-ended expression, i.e., includes the content specified by the present invention, but does not exclude other content. "Stereoisomers" refer to compounds having the same chemical constitution but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, etc. "Diastereomers" refer to stereoisomers having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Diastereomeric mixtures may be separated by high-resolution analytical operations such as electrophoresis and chromatography, e.g., HPLC. The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to one or more chiral centers. The prefixes d and l or (+) and (-) are used to designate the sign of rotation of plane-polarized light by the compound, where (-) or l indicates that the compound is levorotatory, and (+) or d indicates that the compound is dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed in the present invention may exist in racemic or enantiomerically enriched form, for example in (R)-, (S)-, or (R,S)-configuration form. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. Depending on the choice of starting materials and methods, the compounds of the present invention may exist as one of the possible isomers or mixtures thereof, such as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If a compound contains a double bond, the substituents may be in E or Z configuration; if a compound contains a disubstituted cycloalkyl, the substituents of the cycloalkyl may be in cis or trans configuration. Any mixture of stereoisomers obtained may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers based on differences in the physicochemical properties of the components, e.g., by chromatography and / or fractional crystallization. Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers), diastereomers, and geometric isomers (or conformational isomers): for example, R and S configurations for asymmetric centers, (Z) and (E) isomers for double bonds, and (Z) and (E) conformational isomers. Therefore, individual stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers) are all within the scope of the present invention. The term "prodrug" as used in the present invention represents a compound that is converted in vivo into a compound of Formula (I). Such conversion is affected by hydrolysis of the prodrug in blood or enzymatic conversion in blood or tissue to the parent structure. The prodrug compounds of the present invention may be esters. In the existing invention, esters that may serve as prodrugs include phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, if a compound of the present invention contains a hydroxy group, it may be acylated to obtain a compound in prodrug form. Other prodrug forms include phosphates, for example, those phosphate compounds are obtained by phosphorylation of hydroxy groups on the parent compound. For a complete discussion of prodrugs, reference may be made to the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and S. J. Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345. Any racemate of the resulting final product or intermediate may be resolved into optical enantiomers by methods known to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. Racemic products can also be separated by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers may be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007). The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that may be interconverted via a low energy barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of the tautomers may be reached. For example, proton tautomers (also called prototropic tautomers) include interconversion via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversion via rearrangement of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomeric forms. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion between pyridin-4-ol and pyridin-4(1H)-one tautomeric forms. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention. The salts mentioned in the present invention are pharmaceutically acceptable salts, where "pharmaceutically acceptable salts" are well known in the art, as described in the literature: Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19. Non-limiting examples of pharmaceutically acceptable salts include inorganic acid salts formed by reaction with amino groups, such as hydrochloride, hydrobromide, phosphate, metaphosphate, sulfate, sulfite, nitrate, perchlorate; and organic acid salts, such as carboxylates, sulfonates, sulfinates, thiocarboxylates, etc., specifically for example, but not limited to, mesylate, esylate, formate, acetate, butanedioate, benzoate, succinate, pamoate, salicylate, galactarate, glucoheptonate, mandelate, 1,2-ethyldisulfonate, 2-naphthalenesulfonate, carbonate, trifluoroacetate, glycolate, isethionate, oxalate, maleate, tartrate, citrate, butanedioate, malonate, benzenesulfonate, p-toluenesulfonate, malate, fumarate, lactate, lactobionate or oxalate, or those salts obtained by other methods described in the literature such as ion exchange methods. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, laurate, lauryl sulfate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate, etc. In addition, pharmaceutically acceptable salts also include salts obtained from appropriate bases, such as alkali metals, alkaline earth metals, ammonium and N+(C1-4 alkyl)4 salts. The present invention also contemplates quaternary ammonium salts formed by any compound containing an N group. Water-soluble or oil-soluble or dispersible products may be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed with counterions, such as halides, carboxylates, sulfates, phosphates, nitrates, C1-8 sulfonates and aromatic sulfonates. Pharmaceutically acceptable salts may be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorotheophylline salt, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydriodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate. Inorganic acids from which salts may be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts may be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. The "solvate" of the present invention refers to an associate formed from one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an associate where the solvent molecule is water. The term "protecting group" or "PG" refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with other functional groups. For example, an "amino-protecting group" refers to a substituent attached to an amino group to block or protect the amino functionality of the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group used to block or protect the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxyl-protecting group" refers to a substituent of a carboxyl group used to block or protect the carboxyl functionality. Common carboxyl-protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2- (diphenylphosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, reference may be made to: T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and P.J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005. "Pharmaceutical composition" means a mixture of the salts of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compound to an organism. The term "treating" any disease or disorder as used in the present invention refers, in some embodiments, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In still other embodiments, "treating" refers to physically (e.g., stabilizing a discernible symptom) or physiologically (e.g., stabilizing a physical parameter) or both modulating the disease or disorder. In yet other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of the disease or disorder. Any structural formulae given in the present invention are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures depicted by the general formulae given in the present invention, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Exemplary isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 17O, 18O, 18F, 31P, 32P, 35S, 36Cl, and 125I. On the other hand, the compounds described in the present invention include isotopically enriched compounds as defined in the present invention, for example, those compounds in which radioactive isotopes are present, such as 3H, 14C, and 18F, or those compounds in which nonradioactive isotopes are present, such as 2H and 13C. Such isotopically enriched compounds may be used for metabolic studies (using 14C), reaction kinetics studies (using, for example, 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including determination of drug or substrate tissue distribution, or may be used for radiotherapy in patients. 18F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of Formula (I) may be prepared by conventional techniques well known to those skilled in the art or by using suitable isotopically labeled reagents in place of the previously used unlabeled reagents as described in the examples and preparation processes of the present invention. Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D), can provide certain therapeutic advantages arising from greater metabolic stability. For example, in vivo half-life is increased or dosage requirements are reduced or therapeutic index is improved. It should be understood that deuterium in the present invention is regarded as a substituent of the compounds of Formula (I). The concentration of such heavier isotopes, particularly deuterium, may be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used in the present invention means the ratio between the isotopic abundance of the specified isotope and its natural abundance. If a substituent of a compound of the present invention is designated as deuterium, the compound has an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each designated deuterium atom. Pharmaceutically acceptable solvates of the present invention include those solvates in which the crystallization solvent may be isotopically substituted, such as D2O, acetone-d6, DMSO-d6. As described in the present invention, the compounds of the present invention may optionally be substituted by one or more substituents, such as the general formulae compounds set forth above, or as exemplified in particular examples, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the term "optionally substituted" is interchangeable with the term "substituted or unsubstituted." In general, the term "optionally," whether or not it precedes the term "substituted," refers to the substitution of one or more hydrogen atoms in a given structure with a specific substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure may be substituted by one or more substituents selected from a specified group, the substituents may be the same or different at each position. The substituents may be, but are not limited to, deuterium, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo (=O), carboxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy, and the like. The term "alkyl" as used in the present invention represents a saturated linear or branched monovalent hydrocarbon group having 1-20 carbon atoms, or 1-10 carbon atoms, or 1-8 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, wherein the alkyl group may be independently and optionally substituted by one or more substituents as described in the present invention. Examples of alkyl include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tertbutyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2),   2-methyl-2-butyl   (-C(CH3)2CH2CH3), 3-methyl-2-butyl (- CH(CH3)CH(CH3)2),    3-methyl-1-butyl    (-CH2CH2CH(CH3)2),    2-methyl-1-butyl (- CH2CH(CH3)CH2CH3),     n-hexyl     (-CH2CH2CH2CH2CH2CH3),     2-hexyl     (- CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2, 3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3, 3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alk" as used herein both encompass saturated linear and branched carbon chains. The term "alkylene" as used herein refers to a saturated divalent hydrocarbon group derived from the removal of two hydrogen atoms from a linear or branched saturated hydrocarbon, and examples thereof include, but are not limited to, methylene, ethylene, isopropylene, and the like. The term "alkoxy" as used in the present invention involves an alkyl, as defined in the present invention, attached to the main carbon chain through an oxygen atom. Examples thereof include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. Moreover, the alkoxy may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, hydroxy, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, mercapto, nitro, and the like. The term "alkenyl" represents a linear or branched monovalent hydrocarbon group having 212 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is in an unsaturated state, i.e., a C-C sp2 double bond, wherein the alkenyl may be independently and optionally substituted by one or more substituents as described in the present invention, including groups having "trans," "cis," or "E," "Z" configurations. Specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like. The term "alkynyl" represents a linear or branched monovalent hydrocarbon group having 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is in an unsaturated state, i.e., a C-C sp triple bond, wherein the alkynyl group may be independently and optionally substituted by one or more substituents as described in the present invention. Specific examples of alkynyl include, but are not limited to, ethynyl (-C=CH), propargyl (-CH2C=CH), and the like. The term "cycloalkyl" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring that does not contain heteroatoms, including monocyclic rings of 3-12 carbon atoms or bicyclic rings of 7-12 carbon atoms. Bicyclic carbocycles having 7-12 atoms may be bicyclo[4.5], [5.5], [5.6], or [6.6] systems, while bicyclic carbocycles having 9 or 10 atoms may be bicyclo[5.6] or [6.6] systems. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of cyclic aliphatic groups include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. The "cyclic aliphatic group" or "carbocycle," "carbocyclyl," or "cycloalkyl" may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy, and the like. The terms "heterocycle," "heterocyclyl," "heteroalicyclic," or "heterocyclic" are used interchangeably herein and all refer to monocyclic, bicyclic, or tricyclic systems in which one or more carbon atoms in the ring are independently and optionally replaced by heteroatoms having the meanings as described in the present invention. The ring may be fully saturated or contain one or more degrees of unsaturation, but is by no means aromatics, with only one point of attachment to the rest of the molecule. One or more hydrogen atoms on the ring are independently and optionally substituted by one or more substituents as described in the present invention. In some embodiments, the "heterocycle," "heterocyclyl," "heteroalicyclic," or "heterocyclic" groups are 3-7 membered monocyclic rings (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally substituted by one or more oxygen atoms to give groups such as SO, SO2, PO, PO2, when the ring is a three-membered ring, there is only one heteroatom), or 7-10 membered bicyclic rings (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally substituted by one or more oxygen atoms to give groups such as SO, SO2, PO, PO2). Heterocyclyl may be carbon-based or heteroatom-based. "Heterocyclyl" also includes groups formed by fusion of a heterocyclyl group with a saturated or partially unsaturated ring or heterocycle. Examples of heterocyclyl include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, glycidyl, azepanyl, oxepanyl, thiepanyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazepinyl, diazepinyl, thiazepinyl, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazinan-1,1-dioxo-2-yl, 4-hydroxy-1,4-azaphosphinan-4-oxide-1-yl, 2-hydroxy-1-(piperazin-1-yl)ethanone-4-yl, 2-hydroxy-1-(5,6-dihydro-1,2,4-triazin-1(4H)-yl)ethanone-4-yl, 5,6-dihydro-4H-1,2,4-oxadiazin-4-yl, 2-hydroxy-1-(5,6-dihydropyridin-1(2H)-yl)ethanone-4-yl,           3-azabicyclo[3.1.0]hexyl,           3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-c]pyrimidin-6-yl, 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridin-5-yl, 3H-indolyl, 2-oxo-5-azabicyclo[2.2.1]heptan-5-yl, 2-oxo-5-azabicyclo[2.2.2]octan-5-yl, quinolizinyl, and N-pyridylurea. Examples of heterocyclyl groups also include 1,1-dioxothiomorpholinyl, and those in which two carbon atoms in the ring are substituted by oxygen atoms such as pyrimidinedionyl. The heterocyclyl may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, oxo (=O), hydroxy, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy, and the like. The term "aryl" may be used alone or as part of "aralkyl", "aralkoxy", or "aryloxyalkyl", and represents a monocyclic, bicyclic, and tricyclic carbocyclic ring system containing a total of 6-14 ring atoms, wherein at least one ring system is aromatic, each ring system contains a 3-7 membered ring, and there is only one point of attachment to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring," for example, aromatic rings may include phenyl, naphthyl, and anthracenyl. The aryl may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy, and the like. The term "heteroaryl" represents a monocyclic, bicyclic, and tricyclic system containing a total of 5-14 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein the heteroatoms have the meanings as described in the present invention, each ring system contains a 3-7 membered ring, and there is only one point of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound." The heteroaryl may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyalkoxy, and the like. In other embodiments, heteroaryl includes the following monocyclic rings, but is not limited to these monocyclic rings: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5- triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl; and also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), benzo[d]thiazol-2-yl, imidazo[1,5-a]pyridin-6-yl. The term "heteroatom" means one or more O, S, N, P, and Si atoms, including any oxidized forms of N, S, and P; forms of primary, secondary, and tertiary amines and quaternary ammonium salts; or forms where a hydrogen on a nitrogen atom of a heterocycle is substituted, for example, N (e.g., N in 3,4-dihydro-2H-pyrrolyl), NH (e.g., NH in pyrrolidinyl), or NR (e.g., NR in N-substituted pyrrolidinyl). The term "halogen" refers to F, Cl, Br, or I. The term “halo-” means substitution of the group that follows it with a halogen atom, and the number of substitutions may be one or more. The term "hydroxy-substituted" as described in the present invention means substitution of the group that follows it with a hydroxy group, and the number of substitutions may be one or more. The term "substituted" as described in the present invention, when used between two groups, means that the preceding group is the substituent, for example, "aryl-substituted alkyl" means the alkyl having an aryl substituent, and "alkoxycarbonyl-substituted alkyl" means an alkyl group having an alkoxycarbonyl substituent. When multiple groups of the present invention are used in combination, the substituent relationship is in order from left to right, for example, "arylalkyl" means an aryl-substituted alkyl, and "alkoxyalkoxy" means an alkoxy-substituted alkoxy. The term "unsaturated" as used in the present invention means that the structural moiety contains one or more degrees of unsaturation. The description of the compounds of the present application The present application provides a compound having the structure as shown in Formula (I), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure as shown in Formula (I); R3 RtJ^R2 1 X R5^^ L A T R15 0 JR16) 1 Formula (I) wherein, R1 is selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, cyano, nitro, cycloalkyl, heterocyclyl, -NR7R8, -NR9(CO)R6, -NR9(CO)OR10, -NR9(CO)NR7R8, -NR9SOR11, -NR9SO2R11, -OR10, -O(CO)R6, -O(CO)NR7R8, -C(O)R6, -C(O)OR10, -C(O)NR7R8, -C(S)OR10, -C(S)NR7R8, -C(O)SR10, -SR10, -SOR11, -SO2R11, -SO2NR7R8, -S(O)R11NR9, -C(NR9)NR7R8, and -P(O)R12R13; R2, R3, R4, and R5 are each independently selected from hydrogen, deuterium, hydroxy, nitro, amino, alkoxy, carboxy, mercapto, cyano, alkyl, halogen, cycloalkyl, and haloalkyl; or, R1, R2, R3, R4, and R5 are joined at any adjacent positions to form cycloalkyl or heterocyclyl; R6 is selected from hydrogen, deuterium, hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R7, R8, and R9 are selected from hydrogen, deuterium, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R10 is selected from hydrogen, deuterium, alkyl, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, and heteroaryl; R11 is selected from hydrogen, deuterium, amino, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R12 and R13 are selected from hydrogen, deuterium, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or R12 and R13 together with the P atom to which they are attached, form a phosphorus-containing heterocycle; the alkyl, alkoxy, haloalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, and heteroaryl of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 are optionally substituted with 0 to 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, carboxy, mercapto, nitro, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, alkoxy, haloalkoxy, heterocyclyl, aryl, and heteroaryl; L is a bridged ring group, spiro ring group, monocyclic group, or fused ring group, which contains 0 to 2 nitrogen atoms; the bridged ring group, spiro ring group, monocyclic group, or fused ring group in L is optionally substituted with 0 to 4 substituents selected from deuterium, alkyl, hydroxy, amino, alkoxy, and haloalkyl; A is -NR14- or a bond; R14 is selected from hydrogen, deuterium, and alkyl; ring B is selected from a heterocycle, an aryl ring, and a heteroaryl ring; R15 and each R16 are each independently selected from deuterium, alkyl, aminoalkyl, cycloalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanamido, alkanoyl, aminocarbonyl, heterocyclyl, aryl, heteroaryl, and heterocyclylcarbonyl; the alkyl, cycloalkyl, aminoalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanamido, alkanoyl, heterocyclyl, aryl, heteroaryl, and heterocyclylcarbonyl of R15 and R16 are each independently substituted with 0 to 4 substituents selected from deuterium, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkanoyl, alkoxycarbonyl, alkanamido, aminocarbonyl, and oxo; n is 0, 1, 2, 3, or 4. In some embodiments, in the compound of Formula (I), ring B is selected from C1- 9heterocycle, C6-10aryl ring, and C1-9heteroaryl ring. In some embodiments, in the compound of Formula (I), ring B is selected from C4- 7heteroaryl ring. In some embodiments, in the compound of Formula (I), ring B is selected from a pyrazole ring, an imidazole ring, a triazole ring, and a pyrimidine ring. In some embodiments, in the compound of Formula (I), ring B is selected from a pyrazole ring and a triazole ring. In some embodiments, R15 and each R16 are each independently selected from deuterium, C1-6alkyl, C1-6cycloalkyl, C1-6aminoalkyl, C1-6alkoxyC1-6alkyl, C1-6haloalkyl, C1-9heterocyclylC1-6alkyl, C1-9heteroarylC1-6alkyl, C1-6alkanamido, C1-6alkanoyl, aminocarbonyl, C1-9heterocyclyl, C6-10aryl, C1-9heteroaryl, and C1-9heterocyclylcarbonyl. In some embodiments, the C1-6alkyl, C1-6cycloalkyl, C1-6aminoalkyl, C1-6alkoxyC1-6alkyl, C1-6haloalkyl, C1-9heterocyclylC1-6alkyl, C1-9heteroarylC1-6alkyl, C1-6alkanamido, C1-6alkanoyl, C1-9heterocyclyl, C6-10aryl, C1-9heteroaryl, and C1-9heterocyclylcarbonyl of R15 and R16 are each independently substituted with 0 to 4 substituents selected from deuterium, C1-6alkyl, C1-6cycloalkyl, C1-9heterocyclyl, C6-10aryl, C1-9heteroaryl, C1-6alkanoyl, C1-6alkoxycarbonyl, C1-6alkanamido, aminocarbonyl, carboxy, -O-C(O)-NR17R18 and oxo; R17and R18 are each independently selected from hydrogen, deuterium, C1-4alkyl, and C1-4haloalkyl. In some embodiments, R15 and each R16 are each independently selected from deuterium, C1-4alkyl, C1-4aminoalkyl, C1-6heterocyclylC1-4alkyl, C1-6heteroarylC1-4alkyl, aminocarbonyl, C1-6heterocyclyl, C1-6heteroaryl, and C1-6heterocyclylcarbonyl. In some embodiments, R15 and each R16 are each independently selected from deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, propylamino, methoxymethyl, ethoxymethyl, halomethyl, haloethyl, pyrrolidinyl, pyrrolidinylmethyl, piperidinyl , piperidinyl methyl, piperazinyl, piperazinylmethyl, morpholinyl, morpholinylmethyl, morpholinylethyl, morpholinylcarbonyl, pyrrolyl, pyrrolylmethyl, pyridyl, pyridylmethyl, imidazolyl, imidazolylmethyl, pyrazolyl, pyrazolylmethyl, pyrazinyl, pyrazinylmethyl, pyridazinyl, pyridazinylmethyl, pyrimidinyl, pyrimidinylmethyl, triazolyl, triazolylmethyl, tetrazolyl, tetrazolylmethyl, thiomorpholinylmethyl, formamido, acetamido, aminocarbonyl, formyl, and acetyl. In some embodiments, R15 and each R16 are each independently selected from deuterium, methyl, ethyl, methylamino, ethylamino, pyrrolidinylmethyl, piperidinyl methyl, piperazinylmethyl, morpholinyl, morpholinylmethyl, morpholinylethyl, morpholinylcarbonyl, imidazolylmethyl, triazolylmethyl, tetrazolylmethyl, thiomorpholinylmethyl, and formamido. In some embodiments, R15 is selected from methyl and ethyl, and each R16 is each independently selected from amino, ethylamino, pyrrolidinylmethyl, piperidinyl methyl, piperazinylmethyl, morpholinyl, morpholinylmethyl, morpholinylethyl, morpholinylcarbonyl, imidazolylmethyl, triazolylmethyl, tetrazolylmethyl, thiomorpholinylmethyl, and formamido; or each R16 is each independently selected from methyl and ethyl, and R15 is selected from amino, ethylamino, pyrrolidinylmethyl, piperidinyl methyl, piperazinylmethyl, morpholinyl, morpholinylmethyl, morpholinylethyl, morpholinylcarbonyl, imidazolylmethyl, triazolylmethyl, tetrazolylmethyl, thiomorpholinylmethyl, and formamido, or R15 and each R16 are each independently selected from methyl and ethyl. In some embodiments, R15 and each R16 are each independently optionally substituted with 0 to 4 substituents selected from deuterium, methyl, ethyl, cyclopropyl, cyclobutyl, formyl, acetyl, formamido, acetamido, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, carboxy, -O-C(O)-NHCH3, -O-C(O)-N(CH3)2, -O-C(O)-NHC2H5, -O-C(O)-NHC3H8, and oxo. In some embodiments, R15 and each R16each independently optionally substituted with 0 to 2 substituents selected from deuterium, methyl, ethyl, formyl, methoxycarbonyl, carboxy, -O-C(O)-NHCH3 and oxo. In some embodiments, in the compound of Formula (I), the alkyl, cycloalkyl, heterocyclyl, alkoxy, and haloalkyl of R1, R2, R3, R4, and R5 are C1-6alkyl, C3-8cycloalkyl, C1-9heterocyclyl, C1-6alkoxy and C1-6haloalkyl; R6 is selected from hydrogen, deuterium, hydroxy, amino, C1-6alkyl, C1-6alkoxy, C3-8cycloalkyl, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl; R7, R8, and R9 are selected from hydrogen, deuterium, cyano, C1-6alkyl, C3-8cycloalkyl, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl; R10 is selected from hydrogen, deuterium, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C2-6haloalkenyl, C3-8cycloalkyl, C3-8halocycloalkyl, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl; R11 is selected from hydrogen, deuterium, amino, C1-6alkyl, C3-8cycloalkyl, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl; R12 and R13 are selected from hydrogen, deuterium, C1-6alkyl, C3-8cycloalkyl, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl, or R12 and R13 together with the P atom to which they are attached, form a phosphorus-containing C1-9heterocycle; the C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C2-6alkenyl, C2-6haloalkenyl, C2-6alkynyl, C3-8cycloalkyl, C3-8halocycloalkyl, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 are optionally substituted with 0 to 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, carboxy, mercapto, nitro, C1-6alkyl, C3-8cycloalkyl, C3-8halocycloalkyl, C1-6haloalkyl, C2-6alkenyl, C2-6haloalkenyl, C2-6alkynyl, C1-6alkoxy, C1-6haloalkoxy, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl. In some embodiments, in the compound of Formula (I), the cycloalkyl of R1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; the heterocyclyl of R1 is selected from oxetanyl, oxolanyl, azetidinyl, pyrrolidinyl, thietanyl, and thiolanyl; R2, R3, R4, and R5 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropyl, cyclobutyl, halocyclopropyl, and halocyclobutyl; or R1, R2, R3, R4, and R5 are joined at any adjacent positions to form cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, and oxanyl; R6 is selected from hydrogen, deuterium, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, pyrrolidinyl, and tetrahydrofuryl; R7, R8, and R9 are selected from hydrogen, deuterium, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, and tetrahydrofuryl; R10 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tertbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halomethyl, haloethyl, halogenated n-propyl, halogenated isopropyl, halogenated n-butyl, halocyclopropyl, halocyclobutyl, halocyclopentyl, halocyclohexyl, ethenyl, propenyl, ethynyl, propynyl, haloethenyl, halopropenyl, pyrrolidinyl, and tetrahydrofuryl; R11 is selected from hydrogen, deuterium, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, and tetrahydrofuryl; R12 and R13 are selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, and tetrahydrofuryl. In some embodiments, R1 is selected from alkyl, haloalkyl, -OR10, and -SR10, wherein R10 is selected from alkyl, alkenyl, haloalkyl, and haloalkenyl. In some embodiments, R1 is selected from C1-6alkyl, C1-6haloalkyl, -OR10, and -SR10, wherein R10 is selected from C1-4alkyl, C1-4alkenyl, C1-4haloalkyl, and C1-4haloalkenyl. In some embodiments, R1 is selected from methyl, ethyl, perhalomethyl, monohalomethyl, dihalomethyl, -O-methyl, -O-ethyl, -O-perhalomethyl, -O-monohalomethyl, -O-dihalomethyl, -O-perhaloethyl, -O-partially haloethyl (the partially haloethyl includes 1-haloethyl, 2-haloethyl, 1,1-dihaloethyl, 1,2-dihaloethyl, 2,2-dihaloethyl, 1,1,1-trihaloethyl, 1,1,2-trihaloethyl, 1,2,2-trihaloethyl, 1,1,1,2-tetrahaloethyl, 1,1,2,2-tetrahaloethyl), -O-perhaloethenyl, -O-gemhaloethenyl, -O-monohaloethenyl, -S-methyl, -S-ethyl, -S-perhalomethyl, -S-dihalomethyl, -S-perhaloethyl, -S-tetrahaloethyl, -S-perhaloethenyl, -S-gemhaloethenyl, and -S-monohaloethenyl. In some embodiments, R1 is selected from methyl, ethyl, -CF3, -CF2H, -O-methyl, -O-ethyl, -O-CF3, -O-CF2H, -O-CF2CF3, -O-CF2CF2H, -O-CF=CF2, -S-methyl, -S-ethyl, -S-CF3, -S-CF2H, -S-CF2CF3, -S-CF2CF2H, and -S-CF=CF2. In some embodiments, R2, R3, R4, and R5 are each independently selected from hydrogen, deuterium, halogen, alkyl, and haloalkyl. In some embodiments, R2, R3, R4, and R5 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, perhalomethyl, and partially halomethyl. In some embodiments, R2, R3, R4, and R5 are each independently selected from hydrogen, deuterium, and fluorine. In some embodiments, R2 and R3 are fluorine, and R4 and R5 are selected from hydrogen and deuterium. In some embodiments, in the compound of Formula (I), L is selected from C6-12 bridged ring group, C5-12 spiro ring group containing 0 to 2 nitrogen atoms, C2-6 monocyclic group containing 0 to 2 nitrogen atoms, and C4-12 fused ring group, which contains 0 to 2 nitrogen atoms; the C6-12 bridged ring group, C5-12 spiro ring group, C2-6 monocyclic group, or C4-12 fused ring group in L are optionally substituted with 0 to 4 substituents selected from deuterium, C1- 6alkyl, hydroxy, amino, C1-6alkoxy, and C1-6haloalkyl; the alkyl of R14 is C1-6alkyl. In some embodiments, in the compound of Formula (I), L has one of the following structures: N , and In some embodiments, in the compound of Formula (I), L is      . In some embodiments, in the compound of Formula (I), A is a bond. In some embodiments, the compound has the structure as shown in Formula (II) or Formula (III); Formula (II), Formula (III) wherein, X1, X2, and X3 are N or CR16; l is 0 or 1, n is 0, 1, 2, 3, or 4; R1, R2, R3, R4, R5, R15, R16, L, A and ring B are each as defined for Formula (I). In some embodiments, the compound has the structure as shown in Formula (IV), wherein X4 is N or CR16, and R1, R2, R3, R15 and R16 are as defined for Formula (I), Formula (II) or Formula (III). In some embodiments, the compound has one of the following structures, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof: CF3 OH CF3 CF3 O N'N o— O N NH N'NH Compositions, Formulations, and Administration of the Compounds of the Present Invention The pharmaceutical composition comprises one or more compounds of the present invention or a stereoisomer, tautomer, N-oxide, solvate, metabolite, prodrug, pharmaceutically acceptable salt or ester thereof. The pharmaceutical composition can further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof. Materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum protein, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol, phosphate buffer solutions, and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coating materials, sweeteners, flavoring agents and fragrances, preservatives and antioxidants. When available for therapeutic use, a therapeutically effective amount of a compound of the present invention may be administered as the raw chemical alone, or may be provided as the active ingredient of a pharmaceutical composition. Accordingly, the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention and one or more pharmaceutically acceptable carriers, diluents, or excipients. The term "therapeutically effective amount" as used herein means the total amount of each active component that is sufficient to show a meaningful patient benefit (e.g., reduction in viral load). When a single active ingredient is administered alone, the term refers to that ingredient alone. When combination is employed, the term refers to the combined amount of active ingredients that gives a therapeutic effect, regardless of whether they are combined, administered sequentially, or administered simultaneously. The carrier, diluent, or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient. According to another aspect of the present invention, there is also provided a method for preparing a pharmaceutical formulation, which comprises mixing a compound of the present invention with one or more pharmaceutically acceptable carriers, diluents, or excipients. The term "pharmaceutically acceptable" as used in the present invention means that the compounds, raw materials, compositions, and / or dosage forms are, within the scope of reasonable medical judgment, suitable for contact with patient tissue without excessive toxicity, irritation, allergic reaction, or other problems or complications commensurate with a reasonable benefit / risk ratio, and are effective for the intended use. It should be understood that, in addition to the ingredients specifically mentioned above, the formulation can include other ingredients conventional in the art for the type of formulation in question, for example, formulations suitable for oral administration can include flavoring agents. Uses of the Compounds and Compositions of the Present Invention The pharmaceutical compositions may be used for the prevention, management, treatment, or alleviation of retinol binding protein 4-related diseases. The retinol binding protein 4-related diseases are age-related macular degeneration, Stargardt disease, or Best disease. An "effective amount" or "effective dose" of a compound of the present invention or a stereoisomer, tautomer, N-oxide, solvate, metabolite, prodrug, pharmaceutically acceptable salt or ester thereof, or a pharmaceutically acceptable composition thereof, means an amount effective for treating or alleviating the severity of one or more of the conditions mentioned in the present invention. According to the methods of the present invention, the compounds and compositions thereof may be used in any amount and by any route of administration effective for treating or alleviating the severity of the disease. The exact amount required will vary depending on the condition of the patient, depending on race, age, the general condition of the patient, the severity of the infection, particular factors, the mode of administration, and the like. The compounds or compositions of the present invention may be administered in combination with one or more other therapeutic agents, as discussed in the present invention. The present invention also provides a method for inhibiting RBP4-TTR complex formation in a cell, comprising contacting said cell with an effective amount of a compound as described in the present invention or a pharmaceutical composition as described in the present invention. The present invention also provides a method for inhibiting excessive accumulation of lipofuscin in a cell, comprising contacting said cell with an effective amount of a compound as described in the present invention or a pharmaceutical composition as described in the present invention. The present invention also provides a method for inhibiting RBP4-TTR complex formation in the serum of a subject, comprising administering to said subject an effective amount of a compound as described in the present invention or a pharmaceutical composition as described in the present invention. The present invention also provides a method for inhibiting excessive accumulation of lipofuscin in the retina of a subject, comprising administering to said subject an effective amount of a compound as described in the present invention or a pharmaceutical composition as described in the present invention. In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below for further detailed description of the present invention. General Synthetic Procedures In general, the compounds of the present invention may be prepared by the methods described in the present invention. The following reaction schemes and examples are provided to further illustrate the content of the present invention. Those skilled in the art will recognize that the chemical reactions described in the present invention may be suitably used to prepare many other compounds of the present invention, and that other methods for preparing the compounds of the present invention are all considered to be within the scope of the present invention. For example, the synthesis of those non-exemplified compounds according to the present invention may be successfully completed by those skilled in the art by modifying the methods, such as by appropriately protecting interfering groups, by using other known reagents in addition to those described in the present invention, or by making routine modifications to reaction conditions. In addition, the reactions disclosed in the present invention or known reaction conditions are also recognized as applicable to the preparation of other compounds of the present invention. In the examples described below, unless otherwise indicated, all temperatures are given in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company, and Alfa Chemical Company, and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Marine Chemical Factory. Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether were dried by reflux over sodium metal. Anhydrous dichloromethane and chloroform were dried by reflux over calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate prior to use. The following reactions were generally carried out under a positive pressure of nitrogen or argon or with a drying tube attached to anhydrous solvents (unless otherwise indicated), reaction flasks were fitted with appropriate rubber stoppers, and substrates were introduced by syringe. Glassware was dried. Chromatography columns were silica gel columns. Silica gel (300-400 mesh) was purchased from Qingdao Marine Chemical Factory. Nuclear magnetic resonance spectra were recorded using CDCl3, d6-DMSO, CD3OD, or d6-acetone as solvent (reported in ppm unit), using TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When multiplets appeared, the following abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are given in Hertz (Hz). Abbreviations Used Throughout the Present Invention: AcOH: Acetic acid Boc2O, BOC anhydride: di-tert-Butyl dicarbonate Boc: tert-Butyloxycarbonyl Bu4NHSO4: Tetrabutylammonium hydrogen sulfate CH3CN: Acetonitrile DCM: Dichloromethane DIPEA: N,N-Diisopropylethylamine EA: Ethyl acetate HCl: Hydrogen chloride HCl / EA: Hydrogen chloride in ethyl acetate H2O: Water NaOH: Sodium hydroxide NaI: Sodium iodide K2CO3: Potassium carbonate rt, r.t.: Room temperature TABF: Tetrabutylammonium fluoride Example Intermediate Preparation of Intermediate 1 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine hydrochloride (Intermediate 1) Step 1:   Synthesis of tert-butyl 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)-3,6- dihydropyridine- 1(2H)-carboxylate (1b) Compound 1a (1.01 g, 3.88 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (2.40 g, 7.76 mmol) and tetrakis(triphenylphosphine)palladium (0.45 g, 0.39 mmol) were sequentially added to a 25 mL three-necked flask. After replacing air with N2 three times, ethylene glycol dimethyl ether (10 mL) and 2M sodium hydroxide solution (3 mL) were sequentially added. After replacing air with nitrogen three times, the mixture was stirred at 90 °C for 5 hours. The reaction was quenched with water and extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was distillated under reduced pressure to afford a crude product, the crude product was purified by silica gel column chromatography to afford Compound 1b as a yellow oil (1.33 g, yield: 47%). LCMS: 364.3 [M+H]+. Step 2: Synthesis of tert-butyl 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidme-1-carboxylate (1c) In a 100 mL round-bottom flask, Compound 1b (610 mg, 1.68 mmol) was dissolved in ethanol (50 mL), 10% Pd / C (600 mg) was added, and the mixture was stirred at room temperature for 48 hours after replacing air with hydrogen five times. The resultant was filtered through Celite, and the filtrate was concentrated under reduced pressure to afford Compound 1c as a white solid (510 mg, yield: 58%). LCMS: 366.3 [M+H]+. Step 3: Synthesis of 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine hydrochloride (Intermediate 1) In a 100 mL round-bottom flask, Compound 1c (500 mg, 1.37 mmol) was dissolved in dioxane (3 mL), HCl in 1,4-dioxane (0.6 mL, 4 mol / L) was added, and the reaction was carried out at room temperature for 1.5 hours. The organic solvent was removed by concentration under reduced pressure to afford Intermediate 1 as a yellow oil (497 mg). LCMS: 266.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 5 9.52 (s, 1H), 9.24 (s, 1H), 7.88-7.83 (m, 1H), 7.40-7.38 (m, 1H), 3.35-3.32 (m, 2H), 3.18 (t, 1H), 3.07-2.99 (m, 2H), 2.16-2.08 (m, 2H), 1.81-1.79 (m, 2H) ppm. Preparation of Intermediate 2 1-(3-(4-(3,4-Difluoro-2-(methylthio)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (Intermediate 2) 2c                         Intermediate 2 Step 1:   Synthesis of tert-butyl 4-(3,4-difluoro-2-(methylthio)phenyl)piperidine-1- carboxylate (2c) Under nitrogen protection, in a 100 mL three-necked flask, Compound 2a (478 mg, 2.0 mmol), Compound 2b (792 mg, 3.0 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (22 mg, 0.1 mmol), 4,4'-di-tert-butyl-bipyridine (27 mg, 0.1 mmol), 2,6-dimethylpyridine      (1.07      g,      10.0      mmol),      bis[2-(2,4-difluorophenyl)-5- trifluoromethylpyridine][2,2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) (112 mg, 0.1 mmol) and ethylene glycol dimethyl ether (30 mL) were sequentially added, and the mixture was irradiated with 420 nm LED light at room temperature for 2 hours. The reaction was quenched by adding water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to afford Compound 2c as a yellow oil (295 mg, yield: 43%). LCMS: 344.4 [M+H]+. Step 2: Synthesis of 4-(3,4-difluoro-2-(methylthio)phenyl)piperidine hydrochloride (Intermediate 2) In a 100 mL round-bottom flask, Compound 2c (100 mg, 0.29 mmol) was dissolved in dichloromethane (10 mL), 1 mL HCl in 1,4-dioxane (4 mol / L) was added, and the reaction was carried out at room temperature for 2 hours. The organic solvent was removed directly by concentration under reduced pressure to afford Intermediate 2 as a white solid (80 mg). LCMS: 234.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 5 9.21-9.14 (m, 2H), 7.50-7.44 (m, 1H), 7.13-7.10 (m, 1H), 3.53-3.49 (m, 1H), 3.09-2.92 (m, 4H), 2.42 (s, 3H), 1.99-1.87 (m, 2H), 1.83-1.80 (m, 2H) ppm. Preparation of Intermediate 3 4-(2-(ethylthio)-3,4-difluorophenyl)piperidine hydrochloride (Intermediate 3) 2e                            3f                           Intermediate 3 Step 1: Synthesis of tert-butyl 4-(2-amino-3,4-difluorophenyl)piperidine-1-carboxylate (3b) In a 100 mL three-necked flask, Compound 3a (200 mg, 0.96 mmol), tert-butyl 4-bromopiperidine-1-carboxylate (760 mg, 2.88 mmol), sodium iodide (720 mg, 4.81 mmol), potassium carbonate (600 mg, 4.33 mmol), bis(pinacolato)diboron (1.1 g, 4.33 mmol), (SP-4-2)-[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-KN1,KN1‘]dibromonickel (117 mg, 0.24 mmol) were dissolved in anhydrous N,N-dimethylacetamide (10 mL). The reaction solution was then purged with nitrogen three times and heated to 60 °C, and the reaction was maintained at this temperature for 6 hours. The reaction solution was poured directly into water, then was extracted with ethyl acetate. The combined organic phases were sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford a crude product. The crude product was dissolved in petroleum ether (10 mL), stirred at room temperature for 30 minutes, and a large amount of solid precipitated. The solid precipitated was filtered, collected, and dried under vacuum to afford Compound 3b as an off-white solid (600 mg, yield: 80%). LCMS: 213.2 [M-100]-. Step 2: Synthesis of tert-butyl 4-(3,4-difluoro-2-iodophenyl)piperidine-1-carboxylate (3c) In a 50 mL round-bottom flask, copper(I) iodide (731 mg, 3.84 mmol) and tert-butyl nitrite (400 mg, 3.84 mmol) were dissolved in anhydrous acetonitrile (10 mL) and stirred at room temperature for 5 minutes. Then the reaction solution was directly heated to 60 °C and at this temperature, Compound 3b (600 mg, 1.92 mmol) in acetonitrile (1 mL) was added dropwise, and the reaction was maintained at this temperature for 30 minutes. The reaction solution was directly cooled to room temperature, then poured into water, and extracted with ethyl acetate. The combined organic phases were sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 3c as an off-white solid (500 mg, yield: 49.2%). LCMS: 424.2 [M+H]+. Step 3:  Synthesis of tert-butyl  4-(2-((3-((2-ethylhexyl)oxy)-3-oxopropyl)thio)-3,4- difluorophenyl)piperidine-1-carboxylate (3d) In a 100 mL round-bottom flask, Compound 3c (3 g, 7.09 mmol), 2-ethylhexyl 3-mercaptopropionate (4.87 g, 22.30 mmol), potassium carbonate (2.94 g, 21.27 mmol) and 1,4-dioxane (45 mL) were sequentially added. Finally, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.82 g, 1.42 mmol) and tris(dibenzylideneacetone)dipalladium (0.65 g, 0.71 mmol) were sequentially added. After replacing air with nitrogen three times, the reaction was carried out at 100 °C for 6 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure, then ethyl acetate was added to dilute the filtrate, quenched with water, extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotatory evaporated under reduced pressure to dryness to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 3d as a yellow oil (4.58 g). LCMS: 514.2 [M+H]+. Step 4: Synthesis of tert-butyl 4-(3,4-difluoro-2-mercaptophenyl)piperidine-1-carboxylate (3e) In a 100 mL round-bottom flask, Compound 3d (4.58 g, 8.92 mmol) and anhydrous tetrahydrofuran (50 mL) were sequentially added. Sodium ethoxide (0.61 g, 8.92 mmol) was added in portions at 0 °C, and the reaction was carried out at 0 °C for 30 minutes. At 0 °C, potassium bisulfate solution was added to adjust the pH to 5 to quench the reaction. The reaction solution was extracted with ethyl acetate and separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was distillated under reduced pressure to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 3e as a yellow oil (2.2 g, yield: 68%). LCMS: 330.1 [M+H]+. Step 5: Synthesis of tert-butyl 4-(2-(ethylthio)-3,4-difluorophenyl)piperidine-1-carboxylate (3f) In a 25 mL round-bottom flask, Compound 3e (500 mg, 1.52 mmol) and anhydrous tetrahydrofuran (5 mL) were sequentially added. After stirring at 0 °C for 30 minutes, iodoethane (237 mg, 1.52 mmol) was added, and the mixture was stirred at 0 °C for 15 minutes. The reaction was quenched by water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was distillated under reduced pressure to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 3f as a colorless oil (465 mg, yield: 84%). LCMS: 358.2 [M+H]+. Step 6:   Synthesis of  4-(2-(ethylthio)-3,4-difluorophenyl)piperidine  hydrochloride (Intermediate 3) In a 50 mL round-bottom flask, Compound 3f (465 mg, 1.30 mmol) was dissolved in ethyl acetate (1 mL), HCl in ethyl acetate (5 mL, 4 M) was added dropwise at 0 °C, and the reaction solution was stirred at 0 °C for 2 hours. The reaction solution was concentrated under reduced pressure to afford Intermediate 3 as an off-white solid (343 mg, yield: 90%). LCMS: 258.3 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 8 9.23 (s, 2H), 7.53-7.46 (m, 1H), 7.15-7.13 (m, 1H), 3.58-3.55 (m, 1H), 3.36-3.33 (m, 2H), 3.05-3.00 (m, 2H), 2.89-2.85 (m, 2H), 2.01-1.86 (m, 2H), 1.80-1.78 (m, 2H), 1.13 (t, 3H) ppm. Preparation of Intermediate 4 4-(3,4-difluoro-2-((trifluoromethyl)thio)phenyl)piperidine hydrochloride (Intermediate 4) Step 1: Synthesis of tert-butyl 4-(3,4-difluoro-2-((trifluoromethyl)thio)phenyl)piperidine-1-carboxylate (4a) In a 30 mL microwave tube, Compound 3c (500 mg, 1.18 mmol), silver trifluoromethane thiolate (700 mg, 3.54 mmol), copper(I) iodide (450 mg, 2.36 mmol), bipyridine (370 mg, 2.36 mmol) and N-methylpyrrolidone (10 mL) were sequentially added. Under nitrogen protection, the reaction was carried out in a microwave at 150 °C for 1 hour. The reaction solution was directly poured into water, and extracted with ethyl acetate. The combined organic phases were then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 4a as a colorless oil (189 mg, yield: 40%). LCMS: 398.4 [M+H]+. Step 2:    Synthesis of 4-(3,4-difluoro-2-((trifluoromethyl)thio)phenyl)piperidine (Intermediate 4) In a 50 mL round-bottom flask, Compound 4a (180 mg, 0.45 mmol) was dissolved in ethyl acetate (2 mL), HCl in ethyl acetate (4 M, 10 mL) was slowly added dropwise at 0 °C, and the reaction was maintained at this temperature for 2 hours. The reaction solution was then directly concentrated to dryness to afford Intermediate 4 as an off-white solid (136 mg). LCMS: 298.3 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 8 9.37 (s, 1H), 9.15 (s, 1H), 7.85-7.80 (m, 1H), 7.35-7.32 (m, 1H), 3.61-3.56 (m, 1H), 3.39-3.32 (m, 2H), 3.09-3.02 (m, 2H), 2.08-1.99 (m, 2H), 1.811.78 (m, 2H) ppm. Preparation of Intermediate 5 4-(2-((difluoromethyl)thio)-3,4-difluorophenyl)piperidine hydrochloride (Intermediate 5) Step 1: Synthesis of tert-butyl 4-(2-((difluoromethyl)thio)-3,4-difluorophenyl)piperidine-1-carboxylate (5a) In a 100 mL round-bottom flask, Compound 3e (500 mg, 1.52 mmol), potassium hydroxide (425.84 mg, 7.59 mmol), acetonitrile (5 mL) and water (5 mL) were sequentially added. At -20 °C, diethyl bromofluoromethylphosphonate (2.03 g, 7.60 mmol) in acetonitrile (5 mL) was added dropwise, and the reaction was carried out at -20 °C for 1 hour. The reaction was quenched with water and extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 5a as a yellow oil (454 mg, yield: 72%). LCMS: 380.1 [M+H]+. Step 2:    Synthesis of    4-(2-((difluoromethyl)thio)-3,4-difluorophenyl)piperidine hydrochloride (Intermediate 5) In a 50 mL round-bottom flask, Compound 5a (454 mg, 1.20 mmol) was dissolved in ethyl acetate (2 mL), HCl in ethyl acetate (10 mL, 4 M) was added dropwise at 0 °C, and the reaction solution was stirred at 0 °C for 1 hour. The reaction solution was concentrated under reduced pressure to afford Intermediate 5 as an off-white solid (378 mg). LCMS: 280.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 9.37 (s, 1H), 9.18 (s, 1H), 7.76-7.69 (m, 1H), 7.62-7.35 (m, 1H), 7.30-7.27 (m, 1H), 3.58-3.51 (m, 1H), 3.38-3.35 (m, 2H), 3.06-2.97 (m, 2H), 2.071.96 (m, 2H), 1.82-1.78 (m, 2H) ppm. Preparation of Intermediate 6 4-(3,4-difluoro-2-((1,1,2,2-tetrafluoroethyl)thio)phenyl)piperidine            hydrochloride (Intermediate 6) Boc                        Boc                                Boc                             HCI 6a                                    gb                          Intermedidate 6 Step 1:   Synthesis of tert-butyl   4-(2-((2-bromo-1,1,2,2-tetrafluoroethyl)thio)-3,4- difluorophenyl)piperidine-1-carboxylate (6a) In a 100 mL three-necked flask, Compound 3e (5.0 g, 15.18 mmol) was dissolved in anhydrous N,N-dimethylformamide (50 mL), then the reaction solution was cooled to 0 °C. Sodium hydride (910 mg, 22.77 mmol, 60% content) was added, and the reaction solution was allowed to warm to room temperature and reacted for 15 minutes, then the reaction solution was cooled to 0 °C again. 1,2-dibromo-1,1,2,2-tetrafluoroethane (11.83 g, 45.54 mmol) was added dropwise, and the reaction was maintained at this temperature for 2 hours. The reaction solution was directly poured into water, then was extracted with ethyl acetate. The combined organic phases were sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 6a as a colorless oil (6.0 g, yield: 78%). LC-MS: 509.3, 511.3 [M+H]+. Step        2:        Synthesis        of       tert-butyl        4-(3,4-difluoro-2-((1,1,2,2- tetrafluoroethyl)thio)phenyl)piperidine-1-carboxylate (6b) In a 100 mL round-bottom flask, Compound 6a (3.0 g, 5.9 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), then the reaction solution was cooled to 0 °C under nitrogen protection, and ethylmagnesium bromide (5.9 mL, 5.9 mmol) was added dropwise, and the reaction was maintained at this temperature for 15 minutes. The reaction solution was poured into ice water, and extracted with ethyl acetate. The combined organic phases were sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 6b as a colorless oil (0.6 g, yield: 24%). LCMS: 430.4 [M+H]+. Step 3: Synthesis of 4-(3,4-difluoro-2-((1,1,2,2-tetrafluoroethyl)thio)phenyl)piperidine (Intermediate 6) In a 100 mL round-bottom flask, Compound 6b (600 mg, 1.4 mmol) was dissolved in anhydrous dioxane (2 mL), then HCl in dioxane (10 mL, 4 mol / L) was added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was directly concentrated to dryness under vacuum to afford a crude Intermediate 6 as an off-white solid (460 mg). LCMS: 330.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 9.36 (s, 1H), 9.21 (s, 1H), 7.83-7.77 (m, 1H), 7.34-7.31 (m, 1H), 7.03-6.75 (m, 1H), 3.58-3.52 (m, 1H), 3.39-3.37 (m, 2H), 3.03-3.01(m, 2H), 2.08-1.98 (m, 2H), 1.81-1.78 (m, 2H) ppm. Preparation of Intermediate 7 4-(3,4-difluoro-2-((1,2,2-trifluoroethenyl)thio)phenyl)piperidine              hydrochloride (Intermediate 7) of        tert-butyl        4-(3,4-difluoro-2-((1,2,2- i Boc Step 1 6a Step        1:        Synthesis trifluorovinyl)thio)phenyl)piperidine-1-carboxylate (7a) In a 100 mL round-bottom flask, ethylmagnesium bromide (18 mL, 17.71 mmol) was added dropwise to anhydrous tetrahydrofuran (40 mL), then the reaction solution was cooled to 0 °C under nitrogen protection. Compound 6a (3.0 g, 5.9 mmol) in tetrahydrofuran (10 mL) was quickly added dropwise, and the reaction was maintained at this temperature for 15 minutes. The reaction solution was poured into ice water, and extracted with ethyl acetate. The combined organic phases were sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to afford Compound 7a as a colorless oil (1.5 g, yield 62%). LCMS: 410.4 [M+H]+. Step 2:   Synthesis of 4-(3,4-difluoro-2-((1,2,2-trifluorovinyl)thio)phenyl)piperidine (Intermediate 7) In a 100 mL round-bottom flask, Compound 7a (1.5 g, 3.66 mmol) was dissolved in anhydrous dioxane (5 mL), then HCl in dioxane (20 mL, 4 M) was added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was directly concentrated to dryness to afford a crude Intermediate 7 as an off-white solid (1.1 g). LCMS: 310.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8 9.39 (s, 1H), 9.24 (s, 1H), 7.71-7.64 (m, 1H), 7.27-7.24 (m, 1H), 3.59-3.53 (m, 1H), 3.40-3.32 (m, 2H), 3.05-2.97 (m, 2H), 2.08-1.98 (m, 2H), 1.851.82 (m, 2H) ppm. Preparation of Intermediate 8 4-(3,4-difluoro-2-(trifluoromethoxy)phenyl)piperidine (Intermediate 8) 8a                              gb                          8c                           8d                       8e                        Intermediate 8 Step 1: Synthesis of tert-butyl 4-(3,4-difluoro-2-methoxyphenyl)piperidine-1-carboxylate (8b) Compound 8a (2.00 g, 8.97 mmol), tert-butyl 4-bromopiperidine-1-carboxylate (2.84 g, 10.76 mmol), bis(pinacolato)diboron (4.10 g, 16.14 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)dibromonickel (0.44 g, 0.89 mmol), sodium iodide (2.69 g, 17.94 mmol) and potassium carbonate (2.48 g, 17.94 mmol) were sequentially added to a solution of N,N-dimethylacetamide (20 mL). The mixture was stirred at 60 °C under nitrogen protection for 8 hours. The reaction was then quenched by adding water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotatory evaporated under reduced pressure to dryness to afford a crude product. The crude product was purified by silica gel column chromatography to give Compound 8b (1.40 g, yield: 48%). LCMS: 328.1 [M+H]+. Step 2: Synthesis of 2,3-difluoro-6-(piperidin-4-yl)phenol (8c) In a 100 mL three-necked flask, Compound 8b (1.40 g, 4.28 mmol) was dissolved in anhydrous dichloromethane (10 mL), cooled to 0 °C, and boron tribromide (21.4 mL, 21.38 mmol, 1 mol / L in dichloromethane) was slowly added dropwise. After the addition was complete, the solution was stirred at 25 °C for 1 hour. After the reaction was complete, the solution was slowly added dropwise to methanol (20 mL) to quench the reaction, and then directly concentrated to dryness under reduced pressure to obtain Compound 8c (1.00 g). LCMS: 214.1 [M+H]+. Step 3: Synthesis of tert-butyl 4-(3,4-difluoro-2-hydroxyphenyl)piperidine-1-carboxylate (8d) Compound 8c (900 mg, 4.22 mmol), triethylamine (2.14 g, 21.10 mmol) and di-tert-butyl dicarbonate (1.38 g, 6.33 mmol) were sequentially added to a solution of dichloroethane (10 mL). The reaction solution was stirred at 25 °C for 8 hours. After the reaction was complete, the reaction was quenched by adding water, extracted with dichloromethane, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography to give Compound 8d (850.00 mg, yield: 64%). LCMS: 314.0 [M+H]+. Step 4: Synthesis of tert-butyl 4-(2-(bromodifluoromethoxy)-3,4-difluorophenyl)piperidine-1-carboxylate (8e) In a 50 mL pressure-resistant flask, Compound 8d (1.00 g, 3.191 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), cooled to 0 °C, sodium hydride (255 mg, 6.38 mmol, purity: 60%) was added, and the mixture was stirred for 30 minutes after the addition. Then dibromodifluoromethane (3.35 g, 15.957 mmol) was added, and the mixture was stirred at 25 °C for 8 hours. After the reaction was complete, the reaction was quenched by adding water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotatory evaporated under reduced pressure to dryness to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 8e (800.00 mg, yield: 57%). LCMS: 442.0, 444.0 [M+H]+. Step 5: Synthesis of 4-(3,4-difluoro-2-(trifluoromethoxy)phenyl)piperidine (Intermediate 8) Compound 8e (800.00 mg, 1.81 mmol) and silver tetrafluoroborate (1.76 g, 9.05 mmol) were sequentially added to a solution of 1,2-dichloroethane (15 mL). After the addition, the reaction solution was stirred at 60 °C under nitrogen protection for 1 hour. After the reaction was complete, the reaction was quenched by adding water, filtered, and the filtrate was rotatory evaporated to dryness to afford a crude product. The crude product was purified by silica gel column chromatography to afford Intermediate 8 (400.00 mg, yield: 79%). LCMS: 282.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 8.82 (s, 1H), 8.67 (s, 1H), 7.65-7.59 (m, 1H), 7.30-7.25 (m, 1H), 3.41-3.39 (m, 2H), 3.23-3.15 (m, 1H), 3.11-3.06 (m, 2H), 1.97-1.86 (m, 2H), 1.831.80 (m, 2H) ppm. Preparation of Intermediate 9 4-(2-(difluoromethoxy)-3,4-difluorophenyl)piperidine hydrochloride (Intermediate 9) Step 1: Synthesis of tert-butyl 4-(2-(difluoromethoxy)-3,4-difluorophenyl)piperidine-1-carboxylate (9b) Compound 8d (5.00 g, 15.96 mmol), Compound 9a (6.39 g, 23.94 mmol) and potassium carbonate (11.03 g, 79.79 mmol) were sequentially added to a mixed solution of acetonitrile (25 mL) and water (25 mL). After the addition, the reaction solution was stirred at 25 °C for 8 hours. After the reaction was complete, the reaction was quenched by adding water, extracted by ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotatory evaporated under reduced pressure to dryness to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 9b (3.00 g, yield: 52%). LCMS: 364.1 [M+H]+. Step 2: Synthesis of 4-(2-(difluoromethoxy)-3,4-difluorophenyl)piperidine hydrochloride (Intermediate 9) Compound 9b (600 mg, 1.65 mmol) was added to HCl in 1,4-dioxane (10 mL, 4 mol / L). After the addition, the reaction solution was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was rotatory evaporated under reduced pressure to dryness to afford Intermediate 9 (450.00 mg). LCMS: 264.2 [M+H]+. 1H NMR (500 MHz, DMSO d) 5 9.22 (s, 2H), 7.50-7.45 (m, 1H), 7.39 (s, 0.25H), 7.24 (s, 0.5H), 7.19-7.15 (m, 1H), 7.10 (s, 0.25H), 3.35-3.33 (m, 2H), 3.19-3.14 (m, 1H), 3.02-2.98 (m, 2H), 2.02-1.93 (m, 2H), 1.81-1.78 (m, 2H) ppm. Preparation of Intermediate 10 4-(3,4-difluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)piperidine hydrochloride (Intermediate 10) Step 1:    Synthesis of tert-butyl    4-(2-(2-bromo-1,1,2,2-tetrafluoroethoxy)-3,4- difluorophenyl)piperidine-1-carboxylate (10b) In a 100 mL pressure-resistant flask, Compound 8d (1.60 g, 5.11 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 mL), cooled to 0 °C, sodium hydride (410 mg, 10.21 mmol, purity: 60%) was added, and the reaction solution was stirred for 30 minutes after the addition. Then Compound 10a (3.35 g, 12.89 mmol) was added, and stirred at 25 °C for 8 hours. After the reaction was complete, the reaction was quenched by adding water, extracted by ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotatory evaporated under reduced pressure to dryness to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 10b (1.80 g, yield: 72%). LCMS: 442.0, 444.0 [M+H]+. Step        2:        Synthesis        of        tert-butyl        4-(3,4-difluoro-2-(1,1,2,2- tetrafluoroethoxy)phenyl)piperidine-1-carboxylate (10c) Compound 10b (250 mg, 0.51 mmol) and cesium fluoride (231.43 mg, 1.52 mmol) were sequentially added to a solution of dimethyl sulfoxide (5 mL). The reaction solution was stirred at 120 °C for 8 hours. After the reaction was complete, the reaction was quenched by adding water, extracted by ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotatory evaporated under reduced pressure to dryness to afford Compound 10c (200 mg, yield: 95%). LCMS: 414.04 [M+H]+. Step 3:   Synthesis of 4-(3,4-difluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)piperidine hydrochloride (Intermediate 10) Compound 10c (200 mg, 0.48 mmol) was added to HCl in 1,4-dioxane (5 mL, 4 mol / L). After the addition, the reaction solution was stirred at 25 °C for 1 hour. After the reaction was complete, the mixture was rotatory evaporated under reduced pressure to dryness to afford Intermediate 10 (169.00 mg). LCMS: 314.2 [M+H]+. 1H NMR (500 MHz, DMSOd) 8 9.28 (s, 2H), 7.60-7.55(m, 1H), 7.25-7.22 (m, 1H), 7.196.98 (m, 1H), 3.37-3.34 (m,2H), 3.14-3.09 (m, 1H), 3.01-2.99 (m ,2H), 2.03-1.95(m, 2H), 1.791.76 (m, 2H) ppm. Preparation of Intermediate 11 4-(3,4-difluoro-2-((1,2,2-trifluoroethenyl)oxy)phenyl)piperidine              hydrochloride (Intermediate 11) 10b                                   11a Step        1:        Synthesis        of        tert-butyl        4-(3,4-difluoro-2-((1,2,2- trifluoroethenyl)oxy)phenyl)piperidine-1-carboxylate (11a) Compound 10b (600 mg, 1.22 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL). Under nitrogen protection, the reaction solution was cooled to 0 °C, ethylmagnesium bromide (3.7 mL, 3.66 mmol, 1 mol / L in tetrahydrofuran) was added, and the reaction solution was stirred at 25 °C for 8 hours. After the reaction was complete, the reaction was quenched by adding water, extracted by ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotatory evaporated under reduced pressure to dryness to afford a crude product. The crude product was purified by silica gel thin-layer chromatography to afford Compound 11a (250 mg, yield: 52%). LCMS: 394.1 [M+H]+. Step 2:  Synthesis of 4-(3,4-difluoro-2-((1,2,2-trifluoroethenyl)oxy)phenyl)piperidine hydrochloride (Intermediate 11) Compound 11a (250 mg, 0.64 mmol) was added to HCl in 1,4-dioxane (5 mL, 4 mol / L). After the addition, the reaction solution was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was rotatory evaporated under reduced pressure to dryness to afford Intermediate 11 (209 mg). LCMS: 294.2 [M+H]+. 1H NMR (500 MHz, DMSOd) 8 9.26-9.20 (m, 2H), 7.51-7.46 (m, 1H), 7.22-7.18 (m, 1H), 3.36-3.34 (m, 2H), 3.26-3.21 (m, 1H), 3.09-2.94 (m, 2H), 2.04-1.95 (m, 2H), 1.84-1.81 (m, 2H) ppm. Example 1 Preparation of N-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4- methyl-1H-pyrazol-5-yl)methyl)acetamide (Compound 1) Step 1: Synthesis of ethyl 5-bromo-4-methyl-1H-pyrazole-3-carboxylate (1b) In a 250 mL round-bottom flask, Compound 1a (5.0 g, 32.32 mmol) was dissolved in dichloromethane (50 mL), and the reaction solution was cooled to 0 °C, then pyridinium tribromide (11.37 g, 35.55 mmol) was added, and the reaction was carried out at room temperature for 24 hours. The reaction was quenched by adding pure water, extracted with dichloromethane, and the organic phase was collected and concentrated to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 1b as an off-white solid (3.0 g, yield: 40%). LC-MS: 232.2 [M+H]+. Step 2: Synthesis of 1-(tert-butyl) 3-ethyl 5-bromo-4-methyl-1H-pyrazole-1,3-dicarboxylate (1c) In a 100 mL round-bottom flask, Compound 1b (2.0 g, 8.58 mmol) was dissolved in dichloromethane (20 mL), 4-dimethylaminopyridine (1.0 g, 8.18 mmol) was added. The reaction solution was cooled to 0 °C, di-tert-butyl dicarbonate (1.8 mL, 8.58 mmol) was slowly added, and the reaction was carried out at room temperature for 3 hours. The reaction was quenched by adding pure water, extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 1c as an off-white solid (2.3 g, yield: 80%). LC-MS: 333.2 [M+H]+. Step 3: Synthesis of 1-(tert-butyl) 3-ethyl 5-(((tert-butoxycarbonyl)amino)methyl)-4-methyl-1H-pyrazole-1,3-dicarboxylate (1d) In a 100 mL round-bottom flask, Compound 1c (2.3 g, 6.9 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (20 mL / 5 mL). Potassium (N-aminomethyl)trifluoroborate (4.9 g, 20.7 mmol), palladium acetate (0.7 g, 3.452 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.5 g, 1.05 mmol), and cesium carbonate (6.7 g, 20.7 mmol) were added. Air was evacuated and nitrogen was introduced, and the reaction was carried out at 110 °C for 8 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, and the organic phase was collected and concentrated. The crude product was purified by silica gel column chromatography to afford Compound 1d as an off-white solid (700 mg, yield: 27%). LC-MS: 384.2 [M+H]+. Step 4: Synthesis of ethyl 5-(aminomethyl)-4-methyl-1H-pyrazole-3-carboxylate (1e) In a 50 mL round-bottom flask, Compound 1d (700 mg, 1.83 mmol) was dissolved in ethyl acetate (2 mL), then HCl in ethyl acetate (10 mL, 4 mol / L) was added, and the reaction was carried out at room temperature for 4 hours. The reaction solution was directly concentrated to dryness to afford Compound 1e as an off-white solid (500 mg). LC-MS: 185.2 [M+H]+. Step 5: Synthesis of ethyl 5-(acetamidomethyl)-4-methyl-1H-pyrazole-3-carboxylate (1f) In a 50 mL round-bottom flask, Compound 1e (400 mg, 2.18 mmol) was dissolved in 2-methyltetrahydrofuran / dichloromethane (8 mL / 4 mL), then triethylamine (1.5 mL, 10.92 mmol) was added. The reaction solution was cooled to 0 °C, acetyl chloride (0.2 mL, 2.62 mmol) dissolved in dichloromethane (4 mL) was slowly added to the reaction system, and the reaction was carried out at 0 °C for 2 hours. The reaction was quenched by adding pure water, extracted with dichloromethane, and the organic phase was collected and concentrated to afford Compound 1f as an off-white solid (350 mg, yield: 71%). LC-MS: 226.2 [M+H]+. Step 6: Synthesis of 5-(acetamidomethyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1g) In a 50 mL round-bottom flask, Compound 1f (350 mg, 1.55 mmol) was dissolved in tetrahydrofuran / methanol / water (4 mL / 4 mL / 2 mL), then lithium hydroxide (112 mg, 4.66 mmol) was added, and the reaction solution was heated to 40 °C for 12 hours. The reaction solution was concentrated to afford a crude product. The crude product was purified by C18 reversed-phase column chromatography to afford Compound 1g as an off-white solid (200 mg, yield: 65%). LC-MS: 198.2 [M+H]+. Step 7:   Synthesis of N-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1- carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)acetamide (Compound 1) In a 50 mL round-bottom flask, Compound 1g (178 mg, 0.9 mmol) was dissolved in N,N-dimethylformamide (2 mL), then triethylamine (0.45 mL, 2.26 mmol) was added, and the reaction solution was cooled to 0 °C. 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (372 mg, 0.98 mmol) was added, stirred at 0 °C for 10 minutes, then Intermediate 1 (200 mg, 0.75 mmol) was added, and the reaction was carried out at room temperature for 3 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, and the organic phase was collected and concentrated to afford a crude product. The crude product was purified by medium-pressure preparative chromatography to afford Compound 1 as an off-white solid (12 mg, yield: 4%). LC-MS: 445.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8 12.81 (s, 1H), 8.24 (s, 1H), 7.79-7.42 (m, 1H), 7.54-7.47 (m, 1H), 4.70-4.68 (m, 1H), 4.42-4.39 (m,1H), 4.24 (d, J = 4.8 Hz,2H), 3.15 (s, 2H), 2.84-2.78 (m, 1H), 2.02 (s, 3H), 1.85 (s, 3H), 1.78-1.67 (m, 3H), 1.25 (s, 1H) ppm. Example 2 Preparation of N-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-ethyl-1H-pyrazol-5-yl)methyl)acetamide (Compound 2) 2a                          2b 2c Step 3 Step 4 2d Step 1: Synthesis of ethyl 4-ethenyl-1H-pyrazole-3-carboxylate (2b) In a 500 mL round-bottom flask, methyltriphenylphosphonium bromide (21.24 g, 59.50 mmol) was dissolved in tetrahydrofuran (350 mL). After replacing air with nitrogen three times, the reaction solution was stirred at 0 °C for 10 minutes, potassium tert-butoxide (6.67 g, 59.50 mmol) was added in portions. After replacing air with nitrogen three times, the reaction solution was stirred at 0 °C for 40 minutes. Ethyl 4-formyl-1H-pyrazole-3-carboxylate (5 g, 29.70 mmol) was added in portions. After replacing air with nitrogen three times, the reaction solution was stirred at 0 °C for 4.5 hours. The reaction was quenched by adding water, extracted by ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was distillated under reduced pressure to afford a crude product, and the crude product was purified by silica gel column chromatography to afford Compound 2b as an off-white solid (2.62 g, yield: 53%). LCMS: 167.2 [M+H]+. Step 2: Synthesis of ethyl 4-ethyl-1H-pyrazole-3-carboxylate (2c) In a 250 mL round-bottom flask, Compound 2b (2.62 g, 15.80 mmol) was dissolved in methanol (80 mL). Platinum dioxide (1.07 g, 4.70 mmol) and glacial acetic acid (90 mg, 1.50 mmol) were sequentially added. After replacing air with hydrogen five times, the reaction solution was stirred at room temperature for 48 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to afford Compound 2c as an off-white solid (2.14 g, yield: 81%). Step 3: Synthesis of ethyl 5-bromo-4-ethyl-1H-pyrazole-3-carboxylate (2d) In a 250 mL round-bottom flask, Compound 2c (1.69 g, 10.00 mmol) was dissolved in acetonitrile (80 mL), and N-bromosuccinimide (1.97 g, 11.1 mmol) was added in portions at 0 °C, and the reaction solution was stirred at 0 °C for 4 hours. The reaction was quenched by adding water, extracted by ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was distillated under reduced pressure to afford a crude product and the crude product was purified by silica gel column chromatography to afford Compound 2d as an off-white solid (725.8 mg, yield: 29%). LCMS: 248.2 [M+H]+. Step 4: Synthesis of ethyl 1-benzyl-5-bromo-4-ethyl-1H-pyrazole-3-carboxylate (2e) In a 100 mL round-bottom flask, Compound 2d (592 mg, 2.40 mmol) and cesium carbonate (1.56 g, 4.79 mmol) were sequentially added to N,N-dimethylformamide (8 mL). Benzyl chloride (303.3 mg, 2.40 mmol) was added dropwise at 0 °C, and the reaction solution was stirred at 0 °C for 1 hour, then stirred at room temperature for 12 hours. The reaction was quenched by adding water, extracted by ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was distillated under reduced pressure to afford a crude product and the crude product was purified by silica gel column chromatography to afford Compound 2e as a yellow oil (800 mg, yield: 99%). LCMS: 338.1 [M+H]+. Step 5: Synthesis of ethyl 1-benzyl-5-(((tert-butoxycarbonyl)amino)methyl)-4-ethyl-1H-pyrazole-3-carboxylate (2f) In a 30 mL reaction tube, Compound 2e (800 mg, 2.40 mmol), potassium (N-aminomethyl)trifluoroborate (2.84 g, 12.00 mmol), cesium carbonate (3.91 g, 12.00 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.14 g, 2.40 mmol) and palladium acetate (269 mg, 1.20 mmol) were sequentially added to 1,4-dioxane (16 mL) and water (4 mL). After replacing air with nitrogen three times, the reaction solution was stirred in a microwave reactor at 100 °C for 2 hours. The reaction was quenched by adding water, extracted by ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was distillated under reduced pressure to afford a crude product. and the crude product was purified by silica gel column chromatography to afford Compound 2f as a yellow oil (107 mg, yield: 12%). LCMS: 388.2 [M+H]+. Step 6: Synthesis of 1-benzyl-5-(((tert-butoxycarbonyl)amino)methyl)-4-ethyl-1H-pyrazole-3-carboxylic acid (2g) In a 100 mL round-bottom flask, Compound 2f (107 mg, 0.28 mmol) and lithium hydroxide (18.8 mg, 0.78 mmol) were sequentially added to a mixed solution of methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL), and the reaction solution was stirred at 40 °C for 10 hours. The reaction solution was distillated under reduced pressure to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 2g as an off-white solid (62 mg, yield: 62%). LCMS: 360.2 [M+H]+. Step      7:      Synthesis      of      tert-butyl      ((1-benzyl-3-(4-(3,4-difluoro-2- (trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-ethyl-1H-pyrazol-5-yl)methyl)carbamate (2h) In a 50 mL round-bottom flask, Compound 2g (60 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (150 pL, 0.83 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (64 mg, 0.17 mmol) were sequentially added at 0 °C, and the reaction solution was stirred at 0 °C for 10 minutes. Finally, Intermediate 1 (100 mg, 0.33 mmol) was added, and the reaction solution was stirred at 0 °C for 1 hour, then reacted at room temperature for 12 hours. The reaction was quenched by adding water, extracted by ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was distillated under reduced pressure to afford a crude product, and the crude product was purified by silica gel column chromatography to afford Compound 2h as a yellow oil (100 mg, yield: 99%). LCMS: 607.2 [M+H]+. Step 8: Synthesis of (5-(aminomethyl)-1-benzyl-4-ethyl-1H-pyrazol-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (2i) In a 50 mL round-bottom flask, Compound 2h (100 mg, 0.16 mmol) was dissolved in ethyl acetate (2 mL). HCl in ethyl acetate (20 mL, 4 mol / L) was added dropwise at 0 °C, and the reaction solution was stirred at 0 °C for 40 minutes. The reaction solution was concentrated under reduced pressure to afford Compound 2i as a yellow oil (90 mg). LCMS: 507.2 [M+H]+. Step 9: Synthesis of N-((1-benzyl-3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-ethyl-1H-pyrazol-5-yl)methyl)acetamide (2j) In a 50 mL round-bottom flask, Compound 2i (90 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), triethylamine (0.14 mL, 1.01 mmol) was added. At 0 °C, acetyl chloride (19 mg, 0.24 mmol) in dichloromethane (1 mL) was added dropwise to the above reaction solution, and the reaction solution was stirred at 0 °C for 30 minutes. The reaction was quenched by adding methanol and water, the reaction solution was concentrated under reduced pressure, extracted by ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was distillated under reduced pressure to afford a crude product and the crude product was purified by silica gel column chromatography to afford Compound 2j as an off-white solid (81 mg, yield: 87%). LCMS: 549.1 [M+H]+. Step 10:  Synthesis of  N-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1- carbonyl)-4-ethyl-1H-pyrazol-5-yl)methyl)acetamide (Compound 2) In a 50 mL round-bottom flask, Compound 2j (80 mg, 0.15 mmol) was added to methanol (20 mL). Palladium hydroxide containing 20% water (80 mg, 0.57 mmol) and palladium on carbon containing 10% water (80 mg) were sequentially added. After replacing air with nitrogen three times, hydrogen was used to replace nitrogen five times, and the reaction solution was stirred at 50 °C for 48 hours. Water and ethyl acetate were added and the layers were separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was distillated under reduced pressure to afford a crude product, and the crude product was purified by silica gel column chromatography to afford Compound 2 as an off-white solid (55 mg, yield: 82%). LCMS: 459.4 [M+H]+. 1H NMR (500 MHz, CDCI3) 5 11.34 (s, 1H), 7.39-7.29 (m, 1H), 7.18-7.06 (m, 1H), 6.33 (s, 1H), 5.05-4.69 (m, 1H), 4.37-4.23 (m, 2H), 3.26-3.15 (m, 1H), 3.15-2.98 (m, 1H), 2.97-2.75 (m, 1H), 2.69-2.47 (m, 2H), 2.05-1.98 (m, 3H), 1.91-1.81 (m, 2H), 1.27-1.24 (m, 3H), 1.15-1.12 (m, 3H) ppm. Example 3 Preparation of N-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)-N-methylacetamide (Compound 3) Step 1: Synthesis of ethyl 1-benzyl-5-bromo-4-methyl-1H-pyrazole-3-carboxylate (3a) In a 50 mL round-bottom flask, Compound 1b (1.0 g, 4.29 mmol) was dissolved in N,N-dimethylformamide (10 mL), cesium carbonate (2.8 g, 8.58 mmol) was added, and the reaction solution was cooled to 0 °C, then benzyl chloride (0.5 mL, 4.29 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was quenched by adding pure water, extracted with ethyl acetate, and the organic phase was collected and concentrated to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 3a as an off-white solid (0.8 g, yield: 58%). LCMS: 323.2 [M+H]+. Step 2: Synthesis of ethyl 1-benzyl-5-(((tert-butoxycarbonyl)amino)methyl)-4-methyl-1H-pyrazole-3-carboxylate (3b) In a 100 mL round-bottom flask, Compound 3a (800 mg, 2.48 mmol) was dissolved in a mixed solution of 1,4-dioxane / water (8 mL / 2 mL). Potassium (N-aminomethyl)trifluoroborate (2.35 g, 9.90 mmol), palladium acetate (270 mg, 1.24 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.18 g, 2.48 mmol), and cesium carbonate (2.42 g, 7.43 mmol) were added. Air was evacuated and nitrogen was introduced, and the reaction was carried out at 110 °C for 8 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, and the organic phase was collected and concentrated. The crude product was purified by silica gel column chromatography to afford Compound 3b as an off-white solid (630 mg, yield: 68%). LCMS: 374.2 [M+H]+. Step 3: Synthesis of ethyl 1-benzyl-5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-4-methyl-1H-pyrazole-3-carboxylate (3c) In a 50 mL round-bottom flask, Compound 3b (530 mg, 1.42 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (68 mg, 2.84 mmol) was added, and the reaction solution was cooled to 0 °C, iodomethane (302 mg, 2.13 mmol) was added, and the reaction was carried out at room temperature for 4 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, and the organic phase was collected and concentrated. The crude product was purified by silica gel column chromatography to afford Compound 3c as an off-white solid (400 mg, yield: 72%). LCMS: 388.2 [M+H]+. Step 4: Synthesis of 1-benzyl-5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-4-methyl-1H-pyrazole-3-carboxylic acid (3d) In a 50 mL round-bottom flask, Compound 3c (400 mg, 1.03 mmol) was dissolved in tetrahydrofuran / methanol / water (4 mL / 4 mL / 2 mL). Lithium hydroxide (74 mg, 3.10 mmol) was added, and the reaction solution was heated to 40 °C for 6 hours. The reaction solution was concentrated to afford a crude product, followed by addition of pure water, and adjustment of pH to weakly acidic, and extraction by ethyl acetate (3 x 50 mL). The organic phase was collected and concentrated, followed by purification by silica gel column chromatography to afford Compound 3d as an off-white solid (300 mg, yield: 80%). LCMS: 360.1 [M+H]+. Step      5:      Synthesis      of      tert-butyl      ((1-benzyl-3-(4-(3,4-difluoro-2- (trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)(methyl)carbamate (3e) In a 50 mL round-bottom flask, Compound 3d (300 mg, 0.80 mmol) was dissolved in N,N-dimethylformamide (4 mL), triethylamine (1 mL, 5.00 mmol) was then added. The reaction solution was cooled to 0 °C, and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (380 mg, 1.00 mmol) was added. After stirring at 0 °C for 10 minutes, Intermediate 1 (332 mg, 1.25 mmol) was added, and the reaction was carried out at room temperature for 3 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, and the organic phase was collected and concentrated to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 3e as an off-white solid (500 mg, yield: 98%). LCMS: 607.2 [M+H]+. Step 6: Synthesis of (1-benzyl-4-methyl-5-((methylamino)methyl)-1H-pyrazol-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (3f) In a 50 mL round-bottom flask, Compound 3e (500 mg, 0.80 mmol) was dissolved in ethyl acetate (2 mL), followed by addition of HCl in ethyl acetate (10 mL, 4 mol / L), and the reaction was carried out at room temperature for 4 hours. The organic solvent was removed directly by concentration under reduced pressure to afford Compound 3f as a white solid (400 mg, yield: 95%). LCMS: 507.2 [M+H]+. Step 7: Synthesis of N-((1-benzyl-3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)-N-methylacetamide (3g) In a 50 mL round-bottom flask, Compound 3f (400 mg, 0.78 mmol) was dissolved in 2-methyltetrahydrofuran / dichloromethane (4 mL / 2 mL). Triethylamine (0.5 mL, 3.95 mmol) was added, and the reaction solution was cooled to 0 °C. Acetyl chloride (70 pL, 0.90 mmol) dissolved in dichloromethane (2 mL) was slowly added to the reaction system, and the reaction was carried out at 0 °C for 2 hours. The reaction was quenched by adding pure water, extracted with dichloromethane, and the organic phase was collected and concentrated to afford Compound 3g as an off-white solid (400 mg, yield: 92%). LCMS: 549.2 [M+H]+. Step 8:   Synthesis of  N-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1- carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)-N-methylacetamide (Compound 3) In a 100 mL round-bottom flask, Compound 3g (400 mg, 0.80 mmol) was dissolved in methanol (30 mL). Palladium hydroxide (400 mg, 2.85 mmol) and palladium on carbon (400 mg, 10%) were added. Air was evacuated and hydrogen was introduced, and the reaction solution was heated to 60 °C for 24 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated to afford a crude product. The crude product was purified by medium-pressure preparative chromatography to afford Compound 3 as an off-white solid (14 mg, yield 4%). LCMS: 459.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 5 12.85 (s, 1H), 7.63-7.53 (m, 1H), 7.08-6.82 (m, 1H), 4.72-4.38 (m, 2H), 3.35 (s, 3H),3.34-3.30 (m, 2H),3.20-3.10 (m, 2H), 2.91 (s, 3H), 2.73 (s, 1H), 2.03 (s, 3H), 1.78-1.66 (m, 4H) ppm. Example 4 Preparation of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-(morpholinomethyl)-1H-pyrazol-3-yl)methanone (Compound 4) F Compound 4 Step 1: Synthesis of ethyl 4-methyl-5-(morpholinomethyl)-1H-pyrazole-3-carboxylate (4a) In a 100 mL round-bottom flask, Compound 1b (500 mg, 2.15 mmol) was dissolved in a mixed solution of 1,4-dioxane / water (12 mL / 3 mL). Potassium (morpholino-4-yl)methyltrifluoroborate (2.2 g, 10.72 mmol), palladium acetate (240 mg, 1.07 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.02 g, 2.15 mmol), and cesium carbonate (3.5 g, 10.72 mmol) were added. Air was evacuated and nitrogen was introduced, and the reaction was carried out at 110 °C for 8 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate. The organic phase was collected and concentrated, followed by purification by silica gel column chromatography to afford Compound 4a as an off-white solid (500 mg, yield: 92%). LCMS: 254.2 [M+H]+. Step 2: Synthesis of 4-methyl-5-morpholinomethyl-1H-pyrazole-3-carboxylic acid (4b) In a 50 mL round-bottom flask, Compound 4a (500 mg, 1.97 mmol) was dissolved in tetrahydrofuran / methanol / water (5 mL / 5 mL / 2 mL). Lithium hydroxide (236 mg, 9.87 mmol) was added, and the reaction solution was heated to 40 °C for 12 hours. The reaction solution was concentrated to afford a crude product. The crude product was purified by medium-pressure preparative chromatography to afford Compound 4b as an off-white solid (200 mg, yield: 45%). LCMS: 226.2 [M+H]+. Step 3: Synthesis of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-(morpholinomethyl)-1H-pyrazol-3-yl)methanone (Compound 4) In a 50 mL round-bottom flask, Compound 4b (101 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (2 mL). Triethylamine (220 pL, 1.13 mmol) was added, and the reaction solution was cooled to 0  °C.  2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (186 mg, 0.49 mmol) was added, stirred at 0 °C for 10 minutes, then Intermediate 1 (100 mg, 0.37 mmol) was added, and the reaction was carried out at room temperature for 3 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, and the organic phase was collected and concentrated to afford a crude product. The crude product was purified by medium-pressure preparative chromatography to afford Compound 4 as an off-white solid (19 mg, yield: 11%). LCMS: 473.4 [M+H]+. HNMR: 1H NMR (500 MHz, CDCI3) 57.30-7.25(m, 1H), 7.08-7.04 (m, 1H), 6.14 (s, 1H), 3.93-3.57 (m, 9H), 2.75-2.72 (m, 1H), 2.32-2.16 (m, 4H), 2.05 (s, 3H), 1.90-1.60 (m, 4H) ppm. Example 5 Preparation of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-ethyl-5-(morpholinomethyl)-1H-pyrazol-3-yl)methanone (Compound 5) Step 1: Synthesis of ethyl 5-bromo-4-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (5a) In a 100 mL round-bottom flask, Compound 2d (1.50 g, 6.07 mmol) was dissolved in N,N-dimethylformamide (15 mL). Cesium carbonate (2.97 g, 9.11 mmol) was added, and the reaction solution was cooled to 0 °C, then 2-(trimethylsilyl)ethoxymethyl chloride (1.4 mL, 7.89 mmol) was added, and the reaction was carried out at 25 °C for 2 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, and the organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 5a as an off-white solid (2.50 g). LCMS: 377.1 [M+H]+. Step      2:      Synthesis      of      ethyl      4-ethyl-5-(morpholinomethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (5b) In a 100 mL round-bottom flask, Compound 5a (2.50 g, 6.63 mmol) was dissolved in a mixed solution of 1,4-dioxane / water (40  mL / 10 mL). Potassium (morpholino-4- yl)methyltrifluoroborate (6.86 g, 33.13 mmol), palladium acetate (743 mg, 3.31 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (3.05 g, 6.63 mmol), and cesium carbonate (6.5 g, 19.88 mmol) were added. Air was evacuated and nitrogen was introduced, and the reaction was carried out at 110 °C for 8 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, and the organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 5b as an off-white solid (1.60 g, yield: 61%). LCMS: 398.2 [M+H]+. Step 3: Synthesis of ethyl 5-(aminomethyl)-4-methyl-1H-pyrazole-3-carboxylate (5c) In a 50 mL round-bottom flask, Compound 5b (1.60 g, 4.02 mmol) was dissolved in ethyl acetate (2 mL), followed by addition of HCl in ethyl acetate (10 mL, 4 mol / L), and the reaction was carried out at room temperature for 4 hours. The reaction solution was directly concentrated to dryness to afford Compound 5c as an off-white solid (900 mg). LCMS: 269.1 [M+H]+. Step 4: Synthesis of 4-ethyl-5-(morpholinomethyl)-1H-pyrazole-3-carboxylic acid (5d) In a 50 mL round-bottom flask, Compound 5c (900 mg, 3.37 mmol) was dissolved in methanol / water (15 mL / 2 mL). Sodium hydroxide (321 mg, 8.05 mmol) was added, and the reaction solution was heated to 60 °C for 12 hours. The reaction solution was concentrated to remove the organic solvent. Pure water was added, 2 M hydrochloric acid was added to adjust pH to 4, and the solution was extracted with ethyl acetate, the layers were separated, and the organic phase was collected and concentrated to afford Compound 5d as an off-white solid (800 mg). LCMS: 240.1 [M+H]+. Step 5: Synthesis of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-ethyl-5-(morpholinomethyl)-1H-pyrazol-3-yl)methanone (Compound 5) In a 50 mL round-bottom flask, Compound 5d (350 mg, 1.46 mmol) was dissolved in N,N-dimethylformamide (8 mL). Intermediate 1 (581 mg, 2.19 mmol) and triethylamine (1.20 mL, 8.78 mmol) were added, and the reaction solution was cooled to 0 °C, then 1-butylphosphonic anhydride (1.58 g, 2.19 mmol, 50% in ethyl acetate) was added, and the reaction was carried out for 4 hours. The reaction was quenched by adding pure water, extracted with ethyl acetate, the layers were separated, and the organic phase was collected and concentrated to afford a crude product. The crude product was purified by medium-pressure preparative chromatography to afford Compound 5 as an off-white solid (170 mg, yield: 24%). LCMS: 487.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 5 12.79 (s, 1H), 7.77-7.72 (m, 1H), 7.49-7.36 (m, 1H), 4.69 (d, J = 9.9 Hz, 1H), 4.28 (d, J = 4.1 Hz, 1H), 3.57 (s, 4H), 3.47 (s, 2H), 3.36 (s, 2H), 3.13 (d, J = 14.0 Hz,2H), 2.88-2.73 (m, 1H), 2.34 (s, 4H), 1.81-1.58 (m, 4H), 1.08-1.05 (m, 3H) ppm. Example 6 Preparation of methyl ((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1- carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)prolinate (Compound 6) Step 1 3d Step 2 Step 3 THP 1b                              6a                                         6b                                   6c Step 4 6d Step 5 Compound 6 Step 1: Synthesis of ethyl 5-bromo-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (6a) In a 500 mL round-bottom flask, Compound 1b (20 g, 85.82 mmol) was dissolved in dichloromethane (200 mL). p-Toluenesulfonic acid (1.48 g, 8.58 mmol) and 3,4-dihydro-2H-pyran (10.83 g, 128.72 mmol) were sequentially added. Under nitrogen protection, the reaction was carried out at room temperature for 3 hours. Water was added, extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to afford Compound 6a, as a white solid (13.13 g, yield 48%). LCMS: 318.2 [M+H]+. Step 2: Synthesis of ethyl 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-ethenyl-1H-pyrazole-3-carboxylate (6b) In a 500 mL round-bottom flask, Compound 6a (13.10 g, 41.30 mmol), 1,4-dioxane (120 mL), water (30 mL), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.97 g, 4.13 mmol), cesium carbonate (40.37 g, 123.90 mmol), palladium acetate (0.93 g, 4.13 mmol) and potassium ethenyltrifluoroborate (8.3 g, 61.95 mmol) were sequentially added. The reaction was carried out at 100 °C for 2 hours. The reaction solution was cooled to room temperature, filtered through Celite. The filter cake was washed with ethyl acetate, and the filtrate was collected. The filtrate was extracted and separated using a separatory funnel, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to afford Compound 6b as a light yellow solid (8.68 g, yield 80%). LCMS: 265.04 [M+H]+. Step 3: Synthesis of ethyl 5-formyl-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (6c) In a 500 mL round-bottom flask, Compound 6b (8.00 g, 30.27 mmol), 1,4-dioxane (100 mL), water (100 mL), potassium osmate dihydrate (2.23 g, 6.05 mmol), and sodium periodate (25.89 g, 121.07 mmol) were added, and the reaction was carried out at room temperature for 4 hours. Saturated sodium metabisulfite solution was added to the reaction solution, filtered through Celite, the filter cake was washed with ethyl acetate, and the filtrate was collected. The filtrate was extracted and separated using a separatory funnel, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to afford Compound 6c as a yellow-black solid (4.64 g, yield 58%). LCMS: 267.1 [M+H]+. Step 4: Synthesis of 5-formyl-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid (6d) In a 100 mL round-bottom flask, Compound 6c (1.00 g, 3.76 mmol), ethanol (15 mL), water (15 mL), and anhydrous lithium hydroxide (0.79 g, 18.78 mmol) were sequentially added, and the reaction was carried out at room temperature for 4 hours. The organic solvent was removed by concentration under reduced pressure, water and ethyl acetate were added for extraction, and the aqueous phase was collected. The pH of the aqueous phase was adjusted to 5 by adding 2 M hydrochloric acid, then ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to afford Compound 6d as a black oil (840 mg, yield 94%). LCMS: 238.73 [M+H]+. Step 5: Synthesis of 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carbaldehyde (6e) In a 100 mL round-bottom flask, Compound 6d (740 mg, 3.106 mmol), N,N-dimethylformamide (30 mL), water (100 mL), Intermediate 1 (824 mg, 3.11 mmol), and 1-butylphosphonic anhydride (3.4 g, 9.32 mmol) were sequentially added. Under nitrogen protection, the reaction was carried out at room temperature for 2 hours. Water and ethyl acetate were added to the reaction solution for extraction and liquid separation, the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to afford Compound 6e as a colorless oily liquid (678 mg, yield 45%). LCMS: 486.10 [M+H]+. Step 6: Synthesis of methyl (3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)prolinate (6g) In a 100 mL three-necked flask, Compound 6e (300 mg, 0.62 mmol), methanol (30 mL), Compound 6f (123 mg, 0.74 mmol), and acetic acid (4 mg, 0.06 mmol) were sequentially added. Under nitrogen protection, the reaction was carried out at room temperature for 0.5 hours; then sodium cyanoborohydride (78 mg, 1.24 mmol) was added, and the reaction was carried out at room temperature for additional 4 hours. The reaction was quenched by adding water, extracted by ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to afford Compound 6g as a colorless oil (188 mg, yield 51%). LCMS: 598.88 [M+H]+. Step 7: Synthesis of methyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)prolinate (Compound 6) In a 100 mL round-bottom flask, Compound 6g (160 mg, 0.27 mmol), dichloromethane (60 mL) and p-toluenesulfonic acid (92 mg, 0.53 mmol) were sequentially added, and the reaction was carried out at room temperature for 3 hours. The organic solvent was removed under reduced pressure, and the residue was purified by preparative chromatography to afford Compound 6 as an off-white solid (43 mg, yield 31%). LCMS: 514.63 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 5 12.81 (s, 1H), 7.75 (m, J = 8.9 Hz, 1H), 7.52-7.46 (m, 1H), 3.58 (s, 3H), 3.38 (m, 6H), 3.16-3.12 (m, 1H), 2.81 (m, 1H), 2.45-2.06 (m, 2H), 2.02 (s, 3H), 1.94-1.56 (m, 8H) ppm. Example 7 Preparation of  1-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4- methyl-1H-pyrazol-5-yl)methyl)pyrrolidin-2-one (Compound 7) 6c                                           7a 7d                                    Compound 7 Step 1: Synthesis of ethyl 5-formyl-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (7a) In a 250 mL single-necked flask, Compound 6c (8 g, 30.04 mmol), methanol (150 mL), 4-aminobutyric acid (4.65 g, 45.06 mmol), and acetic acid (0.18 g, 3.00 mmol) were sequentially added. Under nitrogen protection, the reaction was carried out at room temperature for 30 minutes, then sodium cyanoborohydride (3.78 g, 60.08 mmol) was added, and the reaction was carried out at room temperature for additional 2 hours. The reaction was quenched by adding water, extracted by ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to afford Compound 7a as a colorless oil (3.85 g, yield: 36%). LCMS: 353.6 [M+H]+. Step 2: Synthesis of ethyl 4-methyl-5-((2-oxopyrrolidin-1-yl)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (7b) In a 1 L single-necked flask, Compound 7a (3.8 g, 10.75 mmol), N,N-dimethylformamide (380 mL), N,N-diisopropylethylamine (6.95 g, 53.76 mmol), and 1-butylphosphonic anhydride (23.24 g, 32.256 mmol, 50% in ethyl acetate) were sequentially added. Under nitrogen protection, the reaction was carried out at room temperature for 3 hours. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic phase was washed with saturated brine, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to afford Compound 7b as a colorless oil (2.66 g, yield: 74%). LCMS: 335.7 [M+H]+. Step 3: Synthesis of 4-methyl-5-((2-oxopyrrolidin-1-yl)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid (7c) In a 250 mL single-necked flask, Compound 7b (2.3 g, 6.86 mmol), methanol (30 mL), water (30 mL), and sodium hydroxide (0.55 g, 13.72 mmol) were sequentially added, and the reaction was carried out at room temperature for 2 hours. The organic solvent was removed under reduced pressure, 2 M hydrochloric acid was added to adjust the pH to 5, then ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to afford Compound 7c as a colorless oil (2.05 g, yield: 97%). LCMS: 308.1 [M+H]+. Step 4: Synthesis of 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)pyrrolidin-2-one (7d) In a 100 mL single-necked flask, Compound 7c (160 mg, 0.52 mmol), N,N-dimethylformamide (15 mL), N,N-diisopropylethylamine (336.42 mg, 2.60 mmol), 1-butylphosphonic anhydride (1.10 g, 1.562 mmol, 50% in ethyl acetate), and Intermediate 1 (138.07 mg, 0.521 mmol) were sequentially added. Under nitrogen protection, the reaction was carried out at room temperature for 3 hours. Water and ethyl acetate were added to the reaction solution for extraction and liquid separation, the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to afford Compound 7d as a colorless oil (80 mg, yield: 28%). LCMS: 554.6 [M+H]+. Step 5: Synthesis of 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)pyrrolidin-2-one (Compound 7) In a 50 mL single-necked flask, Compound 7d (90 mg, 0.16 mmol), dichloromethane (9 mL), and HCl in dioxane (0.3 mL) were sequentially added, and the reaction was carried out at room temperature for 1 hour. The residue was purified by preparative chromatography to afford Compound 7 as an off-white solid (40 mg, yield: 52%). LCMS: 471.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 5 12.92 (s, 1H), 7.74 (m, J = 10.6 Hz, 1H), 7.54-7.43 (m, 1H), 4.38 (s, 2H), 3.35 (m, 2H), 3.22 (m, J = 7.0 Hz, 2H), 3.19-3.07 (m, 2H), 2.80 (m, 1H), 2.25 (m, J = 8.1 Hz, 2H), 2.01 (s, 3H), 1.90 (m, J = 7.4 Hz, 2H), 1.83-1.61 (m, 4H) ppm. Example 8 Preparation of  3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-N,4- dimethyl-1H-pyrazole-5-carboxamide (Compound 8) 8a                                 8b                                     8c 8d Compound 8 Step 1: Synthesis of 5-(ethoxycarbonyl)-4-methyl-1H-pyrazole-3-carboxylic acid (8b) In a 100 mL round-bottom flask, Compound 8a (1.02 g, 4.00 mmol) was dissolved in DCM (10 mL). 5 mL HCl (4 M in 1,4-dioxane) was added, and the reaction was carried out at room temperature for 2 hours. The organic solvent was removed directly by concentration under reduced pressure and dispersed with petroleum ether, filtered and dried to afford Compound 8b as a yellow solid (750 mg, yield: 93%). LCMS: 199.1 [M+H]+. Step 2:   Synthesis of   1-(3-(4-(2-(cyclopropylthio)-3,4-difluorophenyl)piperidine-1- carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (8c) In a 50 mL round-bottom flask, Compound 8b (300 mg, 1.5 mmol) was dissolved in N,N-dimethylformamide (10 mL). Triethylamine (227 mg, 2.25 mmol) was added, and the reaction solution was reacted in an ice bath for 2 minutes, then O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (760 mg, 2.00 mmol) was added. After 2 minutes, Intermediate 1 (532 mg, 2.00 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was quenched by adding pure water, ethyl acetate was added for extraction, and the organic phase was collected and concentrated to afford a crude product. The crude product was purified by C18 reversed-phase preparative chromatography to afford Compound 8c as an off-white solid (420 mg, yield 63%). LCMS: 446.2 [M+H]+. Step 3: Synthesis of 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1H-pyrazole-5-carboxylic acid (8d) In a 50 mL round-bottom flask, Compound 8c (420 mg, 0.94 mmol) was dissolved in methanol / water (3:2, 10 mL). Lithium hydroxide (115 mg, 5.00 mmol) was added, and the reaction was carried out at 60 °C for 1 hour. Dilute hydrochloric acid was added for acidification, and 20 mL of pure water was added. A white solid precipitated, which was filtered and dried to afford Compound 8d as an off-white solid (350 mg, yield 89%). LCMS: 446.2 [M+H]+. Step 4: Synthesis of 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-N-(2,4-dimethoxybenzyl)-N,4-dimethyl-1H-pyrazole-5-carboxamide (8e) In a 50 mL round-bottom flask, Compound 8d (208 mg, 0.50 mmol) was dissolved in N,N-dimethylformamide (10 mL). Triethylamine (202 mg, 2.00 mmol) was added, and the the reaction solution was reacted in an ice bath for 2 minutes, then O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (760 mg, 2.00 mmol) was added. After reacting for 2 minutes, 1-(2,4-dimethoxyphenyl)-N-methylmethanamine (181 mg, 1.00 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was quenched by adding pure water, ethyl acetate was added for extraction, and the organic phase was collected and concentrated to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 8e as a yellow solid (200 mg, yield 69%). LCMS: 581.2 [M+H]+. Step 5: Synthesis of 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-N,4-dimethyl-1H-pyrazole-5-carboxamide (Compound 8) In a 100 mL round-bottom flask, Compound 8e (200 mg, 0.34 mmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction was carried out at room temperature for 12 hours. A crude product was obtained directly by concentration under reduced pressure, which was purified by C18 reversed-phase preparative chromatography to afford Compound 8 as a white solid (138 mg, yield: 94%). LCMS: 431.1 [M+H]+. 1H NMR (400 MHz, CDCI3) 5 7.37 (s, 1H), 7.25-7.11 (m, 1H), 7.03-6.77 (m, 1H), 5.064.62 (m, 1H), 4.52-3.99 (m, 3H), 3.41-3.11 (m, 2H), 3.01 (s, 3H), 2.41 (s, 3H), 2.00-1.86 (m, 2H), 1.85-1.59 (m, 2H) ppm. Example 9 Preparation of  (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-(2- morpholinoethyl)-1H-pyrazol-3-yl)methanone (Compound 9) 9a Step 1: Synthesis of ethyl 5-bromo-1-(4-methoxybenzyl)-4-methyl-1H-pyrazole-3-carboxylate (9a) In a 100 mL round-bottom flask, Compound 1b (3.00 g, 12.87 mmol) was dissolved in N,N-dimethylformamide (30 mL). Cesium carbonate (6.30 g, 19.00 mmol) was added, then 4-methoxybenzyl chloride (2.42 g, 15.45 mmol) was slowly added, and the reaction was carried out at 25 °C for 3 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, the organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 9a as an off-white solid (3.80 g, yield: 84%). LCMS: 353.0 [M+H]+. Step 2: Synthesis of ethyl (E)-5-(2-ethoxyethenyl)-1-(4-methoxybenzyl)-4-methyl-1H-pyrazole-3-carboxylate (9b) In a 100 mL round-bottom flask, Compound 9a (3.8 g, 10.76 mmol) was dissolved in 1,4-dioxane / pure water (40 mL / 10 mL). [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium (3.15 g, 4.30 mmol), (E)-2-(2-ethoxyethenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.39 g, 32.27 mmol), and potassium phosphate (4.57 g, 21.52 mmol) were added, and the reaction was carried out at 110 °C for 4 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, the organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 9b as an off-white solid (2.3 g, yield: 62%). LCMS: 345.1 [M+H]+. Step 3: Synthesis of ethyl 1-(4-methoxybenzyl)-4-methyl-5-(2-oxoethyl)-1H-pyrazole-3-carboxylate (9c) In a 50 mL round-bottom flask, Compound 9b (1.1 g, 3.19 mmol) was dissolved in ethanol (5 mL). 4 M hydrochloric acid aqueous solution (5 mL, 20 mmol) was added, and the reaction solution was heated to 60 °C and reacted for 4 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, the organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 9c as an off-white solid (800 mg, yield: 79%). LCMS: 317.1 [M+H]+. Step 4: Synthesis of ethyl  1-(4-methoxybenzyl)-4-methyl-5-(2-morpholinoethyl)-1H- pyrazole-3-carboxylate (9d) In a 50 mL round-bottom flask, Compound 9c (800 mg, 2.53 mmol) was dissolved in tetrahydrofuran (10 mL). Morpholine (1 mL, 11.43 mmol) and acetic acid (0.1 mL, 2.53 mmol) were added, and the reaction solution was stirred at 25 °C for 1 hour. Then sodium cyanoborohydride (794 mg, 12.64 mmol) was added, and the reaction was carried out at room temperature for 6 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, the organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 9d as an off-white solid (500 mg, yield: 51%). LCMS: 388.2 [M+H]+. Step 5: Synthesis of 1-(4-methoxybenzyl)-4-methyl-5-(morpholinomethyl)-1H-pyrazole-3-carboxylic acid (9e) In a 50 mL round-bottom flask, Compound 9d (500 mg, 1.29 mmol) was dissolved in methanol / pure water (4 mL / 1 mL). Sodium hydroxide (103 mg, 2.58 mmol) was added, and the reaction was carried out at 60 °C for 4 hours. The organic solvent was concentrated, pure water and ethyl acetate were added for extraction, and the organic phase was collected and concentrated to afford a crude product. The crude product was dissolved in DCM:MeOH = 10:1 solution, filtered, and the filtrate was collected and concentrated to afford Compound 9e as an off-white solid (400 mg, yield: 86%). LCMS: 360.1 [M+H]+. Step 6: Synthesis of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-(2-morpholinoethyl)-1H-pyrazol-3-yl)methanone (9f) In a 50 mL round-bottom flask, Compound 9e (180 mg, 0.50 mmol) was dissolved in N,N-dimethylformamide (4 mL). Triethylamine (0.42 mL, 3.00 mmol) was added, and the reaction solution was cooled to 0 °C. O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (228 mg, 0.60 mmol) was added, stirred at 0 °C for 10 minutes, then Intermediate 1 (199 mg, 0.75 mmol) was added, and the reaction was carried out at room temperature for 3 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, the organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 9f as an off-white solid (100 mg, yield: 41%). LCMS: 607.2 [M+H]+. Step 7: Synthesis of N-(2-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-methyl-1H-pyrazol-4-yl)ethyl)acetamide (Compound 9) In a 50 mL round-bottom flask, Compound 9f (100 mg, 0.16 mmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction solution was stirred at 90 °C for 4 hours. The reaction solution was concentrated, the reaction was quenched by adding pure water, extracted by ethyl acetate, and the organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 9 as an off-white solid (70 mg, yield: 80%). LCMS: 487.2 [M+H]+. 1H NMR (400 MHz, DMSOd) 5 12.70 (s, 1H), 7.77 (s, 1H), 7.50 (s, 1H), 4.68 (d, J = 11.4 Hz, 1H), 4.42 (s, 1H), 3.66 (s, 4H), 3.18-3.16 (m,2H), 2.87-2.68 (m, 5H), 2.35 (s,2H), 2.02 (s, 3H), 1.78-1.67 (m, 4 H), 1.325-1.25 (m,2H) ppm. Example 10 Preparation of N-(2-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-methyl-1H-pyrazol-4-yl)ethyl)acetamide (Compound 10) Step 1: Synthesis of ethyl 4-(2-((tert-butoxycarbonyl)amino)ethyl)-5-methyl-1H-pyrazole-3-carboxylate (10b) In a 100 mL round-bottom flask, Compound 10a (1.50 g, 6.40 mmol) was dissolved in a mixed solution of 1,4-dioxane / water (20 mL / 5 mL). Potassium (2-(tert-butoxycarbonylamino)ethyl)trifluoroborate (8.10 g, 32.18 mmol), palladium acetate (0.70 g, 3.22 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (3.07 g, 6.50 mmol), and cesium carbonate (6.30 g, 19.00 mmol) were added. Air was evacuated and nitrogen was introduced, and the reaction was carried out at 110 °C for 8 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, and the organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 10b as an off-white solid (1.50 g, yield: 78%). LCMS: 298.1 [M+H]+. Step 2: Synthesis of ethyl 5-(aminomethyl)-4-methyl-1H-pyrazole-3-carboxylate (10c) In a 50 mL round-bottom flask, Compound 10b (1.50 g, 5.04 mmol) was dissolved in N,N-dimethylformamide (20 mL). Cesium carbonate (2.47 g, 7.57 mmol) was added, and the reaction solution was cooled to 0 °C, then 2-(trimethylsilyl)ethoxymethyl chloride (1.01 g, 6.05 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, and the organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 10c as an off-white solid (300 mg, yield: 20%). LCMS: 428.2 [M+H]+. Step 3:    Synthesis of    4-(2-((tert-butoxycarbonyl)amino)ethyl)-5-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylic acid (10d) In a 50 mL round-bottom flask, Compound 10c (300 mg, 0.70 mmol) was dissolved in tetrahydrofuran / methanol / water (2 mL / 2 mL / 1 mL). Lithium hydroxide (67 mg, 2.81 mmol) was added, and the reaction solution was heated to 60 °C and reacted for 12 hours. The reaction solution was concentrated to remove the organic solvent, the reaction was quenched by adding pure water, extracted by ethyl acetate, and the organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 10d as an off-white solid (120 mg, yield: 43%). LCMS: 400.2 [M+H]+. Step 4: Synthesis of tert-butyl (2-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)ethyl)carbamate (10e) In a 50 mL round-bottom flask, Compound 10d (120 mg, 0.30 mmol) was dissolved in N,N-dimethylformamide (2 mL). Triethylamine (0.2 mL, 1.20 mmol) was added, and the reaction solution was cooled to 0 °C. O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (138 mg, 0.38 mmol) was added, stirred at 0 °C for 10 minutes, then Intermediate 1 (120 mg, 0.45 mmol) was added, and the reaction was carried out at room temperature for 3 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, the organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 10e as an off-white solid (120 mg, yield: 62%). LCMS: 647.3 [M+H]+. Step 5: Synthesis of  (4-(2-aminoethyl)-5-methyl-1H-pyrazol-3-yl)(4-(3,4-difluoro-2- (trifluoromethyl)phenyl)piperidin-1-yl)methanone (10f) In a 50 mL round-bottom flask, Compound 10e (100 mg, 0.15 mmol) was dissolved in ethyl acetate (1 mL). HCl in ethyl acetate (3 mL, 4 mol / L) was added, and the reaction was carried out at room temperature for 3 hours. The reaction solution was concentrated to afford Compound 10f as an off-white solid (50 mg, yield: 78%). LCMS: 417.2 [M+H]+. Step 6: Synthesis of N-(2-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1- carbonyl)-5-methyl-1H-pyrazol-4-yl)ethyl)acetamide (Compound 10) In a 50 mL round-bottom flask, Compound 10f (50 mg, 0.12 mmol) was dissolved in 2-methyltetrahydrofuran / dichloromethane (2 mL / 1 mL). Triethylamine (80 gL, 0.60 mmol) was added, and the reaction solution was cooled to 0 °C, acetyl chloride (10 gL, 0.15 mmol) dissolved in dichloromethane (1 mL) was slowly added to the reaction system, and the reaction was carried out at 0 °C for 2 hours. The reaction was quenched by adding pure water, extracted with dichloromethane, and the organic phase was collected and concentrated to afford a crude product. The crude product was purified by C18 reversed-phase column chromatography to afford Compound 10 as an off-white solid (10 mg, yield: 18%). LCMS: 459.1 [M+H]+. 1H NMR (500 MHz, DMSO d) 5 12.68 (s, 1H), 8.03 (s, 1H), 7.77-7.71 (m, 1H), 7.53-7.51 (m, 1H), 4.69 (d, J = 12.8 Hz, 1H), 4.39 (d, J = 13.0 Hz, 1H), 3.13 (d, J = 12.3 Hz, 4H), 2.84-2.79(m, 1H), 2.58-2.55(m, 2H), 2.18 (s, 3H), 1.78 (s, 3H), 1.68 (d, J = 0.7 Hz, 2H), 1.24 (s, 2H) ppm. Example 11 Preparation of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5- (piperazin-1-ylmethyl)-1H-pyrazol-3-yl)methanone (Compound 11) 6e                                    11b                            Compound 11 Step 1: Synthesis of tert-butyl 4-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)piperazine-1-carboxylate (11b) In a 100 mL round-bottom flask, Compound 6e (270 mg, 0.56 mmol), 1,2-dichloroethane (20 mL), Compound 11a (124.30 mg, 0.67 mmol), and sodium triacetoxyborohydride (235 mg, 1.11 mmol) were sequentially added. Under nitrogen protection, the reaction was carried out at room temperature for 2 hours. Water and dichloromethane were added to the reaction solution for extraction and liquid separation, and the organic phase was dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure, and the residue was purified by column chromatography to afford Compound 11b as a colorless oily liquid (126 mg, yield 35%). LCMS: 656.77 [M+H]+. Step 2: Synthesis of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-(piperazin-1-ylmethyl)-1H-pyrazol-3-yl)methanone (Compound 11) In a 50 mL round-bottom flask, Compound 11b (100 mg, 0.15 mmol), dichloromethane (10 mL), and HCl in dioxane (1 mL) were sequentially added, and the reaction was carried out at room temperature for 2 hours. The organic solvent was removed under reduced pressure, and the residue was purified by preparative chromatography to afford Compound 11 as an off-white solid (5 mg, yield 7%). LCMS: 472.66 [M+H]+. 1H NMR (500 MHz, DMSOd) 5 12.79 (s, 1H), 7.75 (m, J = 8.9 Hz, 1H), 7.49 (m, J = 9.3, 4.7 Hz, 1H), 3.42 (s, 2H), 3.28-3.01 (m, 4H), 2.80 (s, 1H), 2.67 (m, J = 4.9 Hz, 4H), 2.27 (m, 4H), 2.03 (s, 3H), 1.81-1.61 (m, 4H), 1.25 (m, J = 4.1 Hz, 1H) ppm. Example 12 Preparation of 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-((4- methylpiperazin-1-yl)methyl)-1H-pyrazol-3-yl)methanone (Compound 12) Compound 12 Step 1: Synthesis of ethyl 4-methyl-5-((4-methylpiperazin-1-yl)methyl)-1H-pyrazole-3-carboxylate (12b) At room temperature, in a 30 mL microwave reaction tube, Compound 1b (500 mg, 2.15 mmol) was dissolved in 1,4-dioxane (20 mL). Water (5 mL), palladium acetate (240 mg, 1.07 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.02 g, 2.15 mmol), cesium carbonate (2.09 g, 6.44 mmol), and Compound 12a (1.42 g, 6.44 mmol) were added respectively. The reaction solution was stirred in a microwave reactor at 100 °C for 2 hours. The reaction was cooled to room temperature, the organic solvent in the reaction solution was removed by concentration under reduced pressure, water was added, ethyl acetate was added for extraction, and the resultant was dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure, and the residue was purified by column chromatography to afford Compound 12b as a light yellow solid (440 mg). LCMS: 267.5 [M+H]+. Step 2: Synthesis of 4-methyl-5-((4-methylpiperazin-1-yl)methyl)-1H-pyrazole-3-carboxylic acid (12c) In a 100 mL round-bottom flask, Compound 12b (440 mg, 1.65 mmol) was dissolved in ethanol (10 mL). Tetrahydrofuran (10 mL), water (5 mL), and anhydrous lithium hydroxide (693 mg, 16.52 mmol) were added, and the reaction was carried out at 50 °C for 2 hours. The reaction was cooled to room temperature, and the organic solvent in the reaction solution was removed by concentration under reduced pressure. 2 M dilute hydrochloric acid was added to adjust the pH of the reaction solution to 6, the organic solvent was removed under reduced pressure, and the residue was purified by column chromatography to afford Compound 12c as a brown oil (150 mg). LCMS: 239.5 [M+H]+. Step 3: Synthesis of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-((4-methylpiperazin-1-yl)methyl)-1H-pyrazol-3-yl)methanone (Compound 12) In a 50 mL round-bottom flask, Compound 12c (80 mg, 0.34 mmol), Intermediate 1 (101.3 mg, 0.34 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (128 mg, 0.67 mmol), 4-dimethylaminopyridine (82 mg, 0.67 mmol) and dichloromethane (20 mL) were sequentially added. Under nitrogen protection, the reaction was carried out at room temperature for 12 hours. The reaction was quenched by adding water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparative chromatography to afford Compound 12 as a white solid (10 mg, yield 6%). LCMS: 486.7 [M+H]+. 1H NMR (400 MHz, DMSO-d6) § 12.83 (s, 1H), 7.76 (m, J = 8.9 Hz, 1H), 7.51 (m, J = 9.2, 4.8 Hz, 1H), 3.46 (s, 2H), 3.15 (m, 4H), 2.80 (m, J = 13.9 Hz, 1H), 2.47-2.23 (m, 8H), 2.16 (s, 3H), 2.04 (s, 3H), 1.68 (m, J = 12.3, 11.7, 7.8 Hz, 4H) ppm. Example 13 Preparation of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-(piperidin-4-ylmethyl)-1H-pyrazol-3-yl)methanone (Compound 13) Step 1: Synthesis of tert-butyl 4-((3-(ethoxycarbonyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)piperidine-1-carboxylate (13b) Compound 6a (2.00 g, 6.31 mmol), Compound 13a  (2.10 g, 7.57 mmol), bis(pinacolato)diboron (2.88 g, 11.35 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)dibromonickel (0.15 g, 0.32 mmol), sodium iodide (1.89 g, 12.61 mmol) and potassium carbonate (1.74 g, 12.61 mmol) were sequentially added to a solution of N,N-dimethylacetamide (20 mL). The reaction solution was stirred at 60 °C under nitrogen protection for 8 hours. The reaction was quenched by adding water, extracted by ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotatory evaporated under reduced pressure to dryness to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 13b (1.70 g, yield: 62%). LCMS: 436.2 [M+H]+. Step 2:   Synthesis of 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-4-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid (13c) Compound 13b (1.00 g, 2.30 mmol) and lithium hydroxide hydrate (0.96 g, 22.96 mmol) were sequentially added to a mixed solution of methanol (5 mL) and water (5 mL). After the addition, the reaction solution was stirred at 25 °C for 8 hours. Methanol was removed by concentration under reduced pressure, the pH was adjusted to 5-6, and a large amount of solid precipitated. The precipitation was filtered, and the filter cake was dried under reduced pressure to afford Compound 13c (450 mg, yield: 48%). LCMS: 408.2 [M+H]+. Step 3: Synthesis of tert-butyl 4-((3-(4-(3,4-difluoro-2-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)piperidine-1-carboxylate (13d) Compound 13c (380 mg, 0.93 mmol), Intermediate 1 (281 mg, 0.93 mmol), N,N-diisopropylethylamine (603 mg, 4.66 mmol) and n-butylphosphonic anhydride (1.34 g, 1.87 mmol, 50% ethyl acetate solution) were sequentially added to a solution of anhydrous N,N-dimethylformamide (5 mL). After the addition, the reaction solution was stirred at 25 °C under nitrogen protection for 8 hours. The reaction was quenched by adding water, extracted by ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 13d (250 mg, yield: 41%). LCMS: 655.3 [M+H]+. Step 4: Synthesis of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-(piperidin-4-ylmethyl)-1H-pyrazol-3-yl)methanone (Compound 13) Compound 13d (100 mg, 0.15 mmol) was added to HCl in 1,4-dioxane (5 mL, 4 mol / L). After the addition, the reaction solution was stirred at 25 °C for 8 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to afford a crude product. The crude product was then directly purified by preparative liquid chromatography to afford Compound 13 (40 mg, yield: 55%). LCMS: 471.2[M+H]+. 1H NMR (500 MHz, DMSO-d6) 5 7.85-7.65 (m, 1H), 7.57-7.37 (m, 1H), 4.86-4.52 (m, 2H),4.50-4.19 (m, 2H), 3.20-3.02 (m, 4H),2.91-2.63 (m, 3H), 2.01(s, 3H),1.90-1.50 (m, 7H), 1.43-1.13 (m, 2H) ppm. Example 14 Preparation of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-3-yl)methanone (Compound 14) Compound 13 (77 mg, 0.15 mmol) and formaldehyde aqueous solution (123 mg, 1.52 mmol, purity: 37%) were sequentially added to a methanol solution (1 mL). The reaction solution was cooled to 0 °C, then sodium cyanoborohydride (19 mg, 0.30 mmol) was added. After the addition, the reaction solution was stirred at 25 °C for 1 hour. The reaction was quenched by adding water, extracted by ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford a crude product. The crude product was then directly purified by preparative liquid chromatography to afford Compound 14 (30 mg, yield: 40%). LCMS: 485.2[M+H]+. 1H NMR (500 MHz, DMSO-d6) 8 7.80-7.70 (m, 1H), 7.52-7.42 (m, 1H), 4.76-4.50 (m, 2H),4.47-4.18 (m, 2H),3.20-3.05 (m, 2H), 3.04-2.91 (m, 2H), 2.89-2.57 (m, 1H), 2.39(s, 3H), 2.33-2.17 (m, 2H), 1.99(s, 3H), 1.88-1.49 (m, 7H), 1.38-1.11 (m, 2H) ppm. Example 15 Preparation of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5- ((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-3-yl)methanone (Compound 15) 15d Compound 15 Step 1: Synthesis of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-3-yl)methanone (15b) In a 100 mL round-bottom flask, Compound 6a (2.5 g, 7.89 mmol), Compound 15a (1.69 g, 9.46 mmol), bis(pinacolato)diboron (3.60 g, 14.20 mmol), sodium iodide (2.36 g, 15.78 mmol), potassium carbonate (2.18 g, 15.77 mmol), 4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-KN1,KN1‘]dibromonickel (384 mg, 0.79 mmol) and N,N-dimethylacetamide (30 mL) were sequentially added. Under nitrogen protection, the reaction was carried out at 60 °C for 8 hours. The reaction solution was filtered through Celite, ethyl acetate was used to wash the filter cake, and the filtrate was collected. Water was added to the filtrate for extraction and liquid separation; the aqueous phase was extracted again with ethyl acetate, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to afford Compound 15b as a colorless oil (550 mg, yield: 17.23%). LCMS: 337.1 [M+H]+. Step 2: Synthesis of 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-((tetrahydro-2,H-pyran-4-yl)methyl)-1H-pyrazole-3-carboxylic acid (15c) In a 100 mL round-bottom flask, Compound 15b (550 mg, 1.63 mmol), methanol (15 mL), water (15 mL), and sodium hydroxide (196 mg, 4.90 mmol) were sequentially added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to afford a crude Compound 15c, which was directly used in the next step. LCMS: 308.8 [M+H]+. Step 3: Synthesis of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-((tetrahydro-2,H-pyran-4-yl)methyl)-1H-pyrazol-3-yl)methanone (15d) In a 100 mL single-necked flask, Compound 15c (410 mg, 1.33 mmol), Intermediate 1 (401 mg, 1.33 mmol), N,N-diisopropylethylamine (859 mg, 6.65 mmol), N,N-dimethylformamide (30 mL) and 1-butylphosphonic anhydride (2.87 g, 3.99 mmol) were sequentially added, and the reaction was carried out at room temperature for 2 hours. Water and ethyl acetate were added and the layers were separated, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparative chromatography to afford Compound 15d as a colorless oil (160 mg, yield: 22%). LCMS: 556.2 [M+H]+. Step 4: Synthesis of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-3-yl)methanone (Compound 15) In a 50 mL round-bottom flask, Compound 15d (160 mg, 0.29 mmol) was dissolved in dichloromethane (15 mL). HCl in dioxane (0.5 mL, 4 mol / L) was added, and the reaction was carried out at room temperature for 2 hours. The organic solvent was removed under reduced pressure, and the residue was purified by preparative chromatography to afford Compound 15 as an off-white solid (107 mg, yield: 79%). LCMS: 472.1 [M+H]+. 1H NMR (500 MHz, DMSOd) 5 12.62 (s, 1H), 7.72 (m, J = 8.9 Hz, 1H), 7.47 (m, J = 9.6, 4.3 Hz, 1H), 4.53 (m, J = 140.3, 13.3 Hz, 2H), 3.86-3.75 (m, 2H), 3.48-3.41 (m, 2H), 3.23 (m, J = 11.7, 2.1 Hz, 2H), 3.11 (m, J = 13.6 Hz, 2H), 2.77 (m, J = 12.9 Hz, 1H), 1.98 (s, 3H), 1.801.63 (m, 5H), 1.45 (m, J = 13.1 Hz, 2H), 1.25-1.13 (m, 2H) ppm. Example 16 Preparation of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5- (piperidin-1-ylmethyl)-1H-pyrazol-3-yl)methanone (Compound 16) Step 1: Synthesis of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-(piperidin-1-ylmethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methanone (16b) In a 100 mL three-necked flask, Compound 6e (350 mg, 0.72 mmol), methanol (30 mL), Compound 16a (123 mg, 1.44 mmol), and acetic acid (4 mg, 0.07 mmol) were sequentially added. Under nitrogen protection, the reaction was carried out at room temperature for 0.5 hours, then sodium cyanoborohydride (136 mg, 2.16 mmol) was added, and the reaction was carried out at room temperature for additional 3 hours. The reaction was quenched by adding water, extracted by ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to afford Compound 16b as a colorless oil (79 mg, yield: 20%). LCMS: 554.88 [M+H]+. Step 2: Synthesis of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-3-yl)methanone (Compound 16) In a 50 mL round-bottom flask, Compound 16b (70 mg, 0.13 mmol) was dissolved in dichloromethane (15 mL). HCl in dioxane (0.3 mL, 4 mmol / L) was added, and the reaction was carried out at room temperature for 1 hour. The residue was purified by preparative chromatography to afford Compound 16 as an off-white solid (7 mg, yield: 12%). LCMS: 471.03 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 5 12.78 (s, 1H), 7.73 (m, J = 8.9 Hz, 1H), 7.48 (m, J = 9.3, 4.7 Hz, 1H), 4.68 (m, J = 13.1 Hz, 1H), 4.40 (m, J = 13.4 Hz, 1H), 3.42 (m, J = 7.6 Hz, 4H), 2.79 (m, J = 12.4 Hz, 1H), 2.45-2.10 (m, 4H), 2.02 (s, 3H), 1.81-1.62 (m, 4H), 1.49 (m, J = 5.6 Hz, 4H), 1.42-1.32 (m, 2H) ppm. Example 17 Preparation of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5- morpholino-1H-pyrazol-3-yl)methanone (Compound 17) 17c Compound 17 Step 1: Synthesis of ethyl 4-methyl-5-morpholino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (17a) In a 100 mL round-bottom flask, Compound 6a (2.00 g, 5.50 mmol) was dissolved in 1,4-dioxane (20 mL). Morpholine (0.96 g, 11.00 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.46 g, 0.50 mmol), and cesium carbonate (3.59 g, 11.00 mmol) were added. Air was evacuated and nitrogen was introduced, and the reaction was carried out at 110 °C for 3 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, the organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 17a as an off-white solid (450 mg, yield: 23%). LCMS: 370.2 [M+H]+. Step 2: Synthesis of 4-methyl-5-morpholino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylic acid (17b) In a 50 mL round-bottom flask, Compound 17a (450 mg, 1.22 mmol) was dissolved in methanol / pure water (4 mL / 1 mL). Sodium hydroxide (97 mg, 2.44 mmol) was added, and the reaction solution was reacted at 60 °C for 4 hours. The organic solvent was removed by concentration, 2 M hydrochloric acid aqueous solution was added to adjust the pH to 4, and ethyl acetate was added for extraction. The layers were separated, the organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 17b as an off-white solid (400 mg, yield: 96%). LCMS: 342.1 [M+H]+. Step 3: Synthesis of 4-methyl-5-morpholino-1H-pyrazole-3-carboxylic acid (17c) In a 50 mL round-bottom flask, Compound 17b (300 mg, 0.88 mmol) was dissolved in ethyl acetate (2 mL). HCl in ethyl acetate (5 mL, 4 mmol / L) was added, and the reaction was carried out at 25 °C for 4 hours. The reaction solution was concentrated to afford Compound 17c as an off-white solid (200 mg, yield: 80%). LCMS: 212.1 [M+H]+. Step 4: Synthesis of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-morpholino-1H-pyrazol-3-yl)methanone (Compound 17) In a 50 mL round-bottom flask, Compound 17c (200 mg, 0.95 mmol) was dissolved in N,N-dimethylformamide (4 mL). Triethylamine (0.8 mL, 5.68 mmol) and Intermediate 1 (376 mg, 1.42 mmol) were added, and the reaction solution was cooled to 0 °C, 1-butylphosphonic anhydride (1.02 g, 1.42 mmol, 50% in ethyl acetate) was added, and the reaction was carried out at room temperature for 3 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, the organic phase was collected and concentrated to afford a crude product. The crude product was purified by C18 reversed-phase column preparative chromatography to afford Compound 17 as an off-white solid (85 mg, yield: 20%). LCMS: 459.1[M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 12.50 (s, 1H), 7.84-7.71 (m, 1H), 7.50 (d, J = 4.0 Hz, 1H), 4.86-4.26 (m, 1H), 3.71 (s, 4H), 3.15 (s, 2H), 3.01 (s,4H), 2.52 (s, 3H),1.97 (s, 2H), 1.83-1.63 (m, 4H) ppm. Example 18 Preparation of N-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-carbonyl)-1H-pyrazol-5-yl)methyl)acetamide (Compound 18) Step 1: Synthesis of ethyl 5-formyl-1H-pyrazole-3-carboxylate (18b) In a 100 mL round-bottom flask, Compound 18a (1.50 g, 8.81 mmol) was dissolved in dichloromethane (15 mL). Manganese dioxide (3.83 g, 44.07 mmol) was added, and the reaction was carried out at 25 °C for 12 hours. The reaction solution was filtered through Celite, and the filter cake was washed with dichloromethane. The organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 18b as an off-white solid (1.40 g, yield: 94%). LCMS: 169.0 [M+H]+. Step 2: Synthesis of ethyl 5-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (18c) In a 100 mL round-bottom flask, Compound 18b (1.40 g, 8.33 mmol) was dissolved in N,N-dimethylformamide (14 mL). Cesium carbonate (5.43 g, 16.65 mmol) was then added, and the reaction solution was cooled to 0 °C, then 2-(trimethylsilyl)ethoxymethyl chloride (2.08 g, 12.49 mmol) was added, and the reaction was carried out at 25 °C for 3 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, the layers were separated, and the organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 18c as an off-white solid (600 mg, yield: 25%). LCMS: 299.1 [M+H]+. Step 3: Synthesis of ethyl 5-(acetamidomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (18d) In a 50 mL round-bottom flask, Compound 18c (600 mg, 2.01 mmol) was dissolved in toluene (10 mL). Triethylsilane (1 mL, 6.03 mmol), trifluoroacetic acid (0.77 mL, 10.05 mmol), and acetamide (593 mg, 10.05 mmol) were added, and the reaction was carried out at 120 °C for 8 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, the layers were separated, and the organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 18d as off-white solid (600 mg, yield: 87%). LCMS: 342.1 [M+H]+. Step 4: Synthesis of ethyl 5-(acetamidomethyl)-1H-pyrazole-3-carboxylate (18e) In a 50 mL round-bottom flask, Compound 18d (600 mg, 1.76 mmol) was dissolved in 1,4-dioxane (2 mL). HCl in 1,4-dioxane (6 mL, 4 mol / L) was added, and the reaction was carried out at room temperature for 4 hours. The organic phase was collected and concentrated to afford Compound 18e as an off-white solid (300 mg, yield: 81%). LCMS: 212.1 [M+H]+. Step 5: Synthesis of 5-(acetamidomethyl)-1H-pyrazole-3-carboxylic acid (18f) In a 50 mL round-bottom flask, Compound 18e (200 mg, 0.95 mmol) was dissolved in methanol / pure water (4 mL / 1 mL). Sodium hydroxide (76 mg, 1.89 mmol) was added, and the reaction was carried out at 60 °C for 4 hours. The organic solvent was concentrated, 2 M hydrochloric acid aqueous solution was added to adjust the pH to 4, ethyl acetate was added for extraction, the layers were separated, and the organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 18f as an off-white solid (150 mg, yield: 86%). LCMS: 184.0 [M+H]+. Step 6:   Synthesis of  N-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1- carbonyl)-1H-pyrazol-5-yl)methyl)acetamide (Compound 18) In a 50 mL round-bottom flask, Compound 18f (150 mg, 0.82 mmol) was dissolved in N,N-dimethylformamide (4 mL). Triethylamine (0.7 mL, 4.91 mmol) and Intermediate 1 (217 mg, 0.82 mmol) were added, and the reaction solution was cooled to 0 °C, 1-butylphosphonic anhydride (886 mg, 1.23 mmol, 50% in ethyl acetate) was added, and the reaction was carried out at room temperature for 3 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, the organic phase was collected and concentrated to afford a crude product. The crude product was purified by C18 reversed-phase column preparative chromatography to afford Compound 18 as an off-white solid (40 mg, yield: 11%). LCMS: 431.1[M+H]+. 1H NMR (500 MHz, DMSO-d6) 5 13.15 (d, J = 19.1 Hz,1H), 8.40 (d, J = 20.4 Hz, 1H), 7.74-7.71 (m, 1H), 7.52-7.50 (m,1H), 6.42 (s, 1H), 4.27 (d, J = 5.3 Hz, 2H), 3.20 (s, 2H), 3.16 (s, 2H), 2.81 (d, J = 4.9 Hz,1H), 1.86 (s, 3H), 1.76-1.72 (m, 4H) ppm. Example 19 Preparation of N-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-carbonyl)-1,4- dimethyl-1H-pyrazol-5-yl)methyl)acetamide (Compound 19) \ Compound 19 Step 1: Synthesis of ethyl 5-(acetamidomethyl)-4-methyl-1H-pyrazole-3-carboxylate (1f) In a 100 mL round-bottom flask, Compound 6c (1.6 g, 6.01 mmol) was dissolved in toluene (20 mL). Triethylsilane (2.10 g, 18.02 mmol), trifluoroacetic acid (3.43 g, 30.04 mmol), and acetamide (1.77 g, 30.04 mmol) were added, and the reaction was carried out at 120 °C for 4 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, the layers were separated, and the organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 1f as an off-white solid (1.00 g, yield: 74%). LCMS: 226.1 [M+H]+. Step 2: Synthesis of ethyl 5-(acetamidomethyl)-1,4-dimethyl-1H-pyrazole-3-carboxylate (19a) In a 100 mL round-bottom flask, Compound 1f (300 mg, 1.33 mmol) was dissolved in N,N-dimethylformamide (6 mL). Cesium carbonate (867 mg, 2.66 mmol) was added, then iodomethane (100 pL, 1.60 mmol) was added, and the reaction was carried out at 25 °C for 3 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, the layers were separated, and the organic phase was collected and concentrated, followed by purification by column chromatography to afford Compound 19a as an off-white solid (200 mg, yield: 63%). LCMS: 240.1 [M+H]+. Step 3: Synthesis of 5-(acetamidomethyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid (19b) In a 50 mL round-bottom flask, Compound 19a (140 mg, 0.56 mmol) was dissolved in methanol / pure water (4 mL / 1 mL). Sodium hydroxide (47 mg, 1.17 mmol) was added, and the reaction was carried out at 60 °C for 4 hours. The reaction solution was concentrated to dryness to afford Compound 19b as an off-white solid (100 mg, yield: 81%). LCMS: 212.1 [M+H]+. Step 4:   Synthesis of N-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1- carbonyl)-1,4-dimethyl-1H-pyrazol-5-yl)methyl)acetamide (Compound 19) In a 50 mL round-bottom flask, Compound 19b (100 mg, 0.48 mmol) was dissolved in N,N-dimethylformamide (4 mL). Triethylamine (300 pL, 2.37 mmol) and Intermediate 1 (150 mg, 0.57 mmol) were added, and the reaction solution was cooled to 0 °C, 1-butylphosphonic anhydride (511 mg, 0.72 mmol, 50% in ethyl acetate) was added, and the reaction was carried out at room temperature for 3 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, and the organic phase was collected and concentrated to afford a crude product. The crude product was purified by C18 reversed-phase column preparative chromatography to afford Compound 19 as an off-white solid (10 mg, yield: 5%). LCMS: 459.1[M+H]+. 1H NMR (500 MHz, DMSO-d6) § 8.11 (s,1H), 7.77 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 30.2 Hz, 1H), 4.17 (s, 2H), 3.79 (s, 3H), 3.65 (d, J = 19.1 Hz, 2H), 3.14 (d, J = 9.1 Hz,2H), 2.91 (s, 1H), 2.04 (s, 3H), 1.95-1.83 (m, 2H), 1.82 (s, 3H), 1.73-1.59(m, 2H) ppm. Example 20 Preparation of 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-N,N,4-trimethyl-1H-pyrazole-5-carboxamide (Compound 20) 8d                     Compound 20 In a 50 mL round-bottom flask, Compound 8d (70.0 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (4 mL). Triethylamine (101 mg, 1.0 mmol) was added, then O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (190 mg, 0.50 mmol) was added. After reacting in an ice bath for 2 minutes, dimethylamine hydrochloride (81 mg, 1.00 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, and the organic phase was collected and concentrated to afford a crude product. The crude product was purified by C18 reversed-phase column preparative chromatography to afford Compound 20 as an off-white solid (38 mg, yield 51%). LCMS: 445.2 [M+H]+. 1H NMR (400 MHz, CDCI3) 5 7.41-7.31 (m, 1H), 7.26-7.14 (m, 1H), 5.15-4.17 (m, 4H), 3.33-3.20 (m, 1H), 3.15 (s, 6H), 3.04-2.80 (m, 1H), 2.25 (s, 3H), 2.00-1.83 (m, 2H), 1.82-1.63 (m, 2H) ppm. Example 21 Preparation of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5- (morpholine-4-carbonyl)-1H-pyrazol-3-yl)methanone (Compound 21) 8d Compound 21 In a 50 mL round-bottom flask, Compound 8d (180 mg, 0.40 mmol) was dissolved in N,N-dimethylformamide (5 mL). Triethylamine (155 mg, 1.5 mmol) was added, then O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (228 mg, 0.60 mmol) was added. After reacting in an ice bath for 2 minutes, morpholine (87 mg, 1.0 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, the organic phase was collected and concentrated to afford a crude product. The crude product was purified by C18 reversed-phase column preparative chromatography to afford Compound 21 as an off-white solid (145 mg, yield 75%). LCMS: 487.2 [M+H]+. 1H NMR (500 MHz, CDCI3) 8 11.62 (s, 1H), 7.41-7.30 (m, 1H), 7.19-7.09 (m, 1H), 5.114.62 (m, 1H), 4.44-3.99 (m, 1H), 3.93-3.55 (m, 8H), 3.34-3.07 (m, 2H), 3.07-2.78 (m, 1H), 2.25 (s, 3H), 1.99-1.83 (m, 2H), 1.82-1.73 (m, 2H) ppm. Example 22 Preparation of 1-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4- methyl-1H-pyrazol-5-yl)methyl)piperidin-2-one (Compound 22) 22a                         22b                                                                    Compound 22 6c Step 1: Synthesis of ethyl 5-(hydroxymethyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (22a) At room temperature, in a 100 mL round-bottom flask, Compound 6c (3 g, 11.26 mmol), tetrahydrofuran (30 mL), and sodium borohydride (0.43 g, 11.26 mmol) were sequentially added at 0 °C. Under nitrogen protection, the reaction was carried out at room temperature for 2 hours. Water and ethyl acetate were added and the layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography to afford Compound 22a as a white solid (1.68 g, yield 56%). LCMS: 269.2 [M+H]+. Step 2: Synthesis of ethyl 5-(bromomethyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (22b) In a 100 mL round-bottom flask, Compound 22a (540 mg, 2.0 mmol) was dissolved in tetrahydrofuran (20 mL). Triphenylphosphine (655 mg, 2.5 mmol) was added, and carbon tetrabromide (835 mg, 2.5 mmol) was added in an ice bath. The reaction was carried out at room temperature for 2 hours. The reaction was quenched by adding pure water, extracted by ethyl acetate, the organic phase was collected and concentrated to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 22b as an off-white solid (180 mg, yield 27%). LCMS: 331.2 [M+H]+. Step 3: Synthesis of 4-methyl-5-((2-oxopiperidin-1-yl)methyl)-1H-pyrazole-3-carboxylic acid (22d) In a 100 mL round-bottom flask, Compound 22c (150 mg, 1.5 mmol) was dissolved in 1,4-dioxane (5 mL). NaH (120 mg, 3.0 mmol, 60% content) was added in an ice bath, and the reaction was carried out at room temperature for 0.5 hours. Compound 22b (200 mg, 0.62 mmol) was dissolved in tetrahydrofuran (2 mL) and added dropwise to the reaction. The reaction was quenched by adding water, methanol was added, and the reaction was carried out at 60 °C for 2 hours. HCl (2 mol / L) solution was added for acidification, and the reaction solution was concentrated under reduced pressure to afford a crude product. The crude product was purified by C18 reversed-phase column chromatography to afford Compound 22d as an off-white solid (120 mg, yield 80%). LCMS: 238.1 [M+H]+. Step 4: Synthesis of 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)piperidin-2-one (Compound 22) In a 50 mL round-bottom flask, Compound 22d (120 mg, 0.5 mmol) was dissolved in N,N-dimethylformamide (4 mL). Triethylamine (155 mg, 1.5 mmol) was added, then O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (285 mg, 0.75 mmol) was added. After reacting in an ice bath for 2 minutes, Intermediate 1 (160 mg, 0.6 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was quenched by adding water, extracted by ethyl acetate, and the organic phase was collected and concentrated to afford a crude product. The crude product was purified by C18 reversed-phase column chromatography to afford Compound 22 as an off-white solid (80 mg, yield 33%). LCMS: 485.2 [M+H]+. 1H NMR (500 MHz, CDCI3) 8 10.96 (s, 1H), 7.41-7.29 (m, 1H), 7.21-7.10 (m, 1H), 5.004.79 (m, 1H), 4.63-4.29 (m, 3H), 3.42-3.33 (m, 2H), 3.28-3.18 (m, 2H), 3.18-3.04 (m, 1H), 2.95-2.69 (m, 1H), 2.47-2.34 (m, 1H), 2.22 (s, 3H), 1.99-1.71 (m, 8H) ppm. Example 23 Preparation of 4-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4- methyl-1H-pyrazol-5-yl)methyl)morpholin-3-one (Compound 23) Step 1: Synthesis of 4-methyl-5-((3-oxomorpholino)methyl)-1H-pyrazole-3-carboxylic acid (23b) In a 100 mL round-bottom flask, Compound 23a (150 mg, 1.5 mmol) was dissolved in tetrahydrofuran (5 mL). NaH (120 mg, 3.0 mmol, 60% content) was added in an ice bath, and the reaction was carried out at room temperature for 0.5 hours. Compound 22b (165 mg, 0.5 mmol) was dissolved in tetrahydrofuran (2 mL) and added dropwise to the reaction. The reaction was quenched by adding water, methanol was added, and the reaction was carried out at 60 °C for 2 hours. HCl solution (2 mol / L) was added for acidification, and the reaction solution was concentrated under reduced pressure to afford a crude product. The crude product was purified by C18 reversed-phase column chromatography to afford Compound 23b as an off-white solid (100 mg, yield 84%). LCMS: 240.1 [M+H]+. Step 2:   Synthesis of   4-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1- carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)morpholin-3-one (Compound 23) In a 50 mL round-bottom flask, Compound 23b (100 mg, 0.3 mmol) was dissolved in N,N-dimethylformamide (4 mL). Triethylamine (122 mg, 1.2 mmol) was added, then O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (228 mg, 0.6 mmol) was added. After reacting in an ice bath for 2 minutes, Intermediate 1 (160 mg, 0.6 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was quenched by adding water, extracted by ethyl acetate, and the organic phase was collected and concentrated to afford a crude product. The crude product was purified by C18 reversed-phase column chromatography to afford Compound 23 as an off-white solid (80 mg, yield 41%). LCMS: 487.2 [M+H]+. 1H NMR (500 MHz, CDCI3) 6 7.40-7.30 (m, 1H), 7.21-7.13 (m, 1H), 5.03-4.74 (m, 1H), 4.60-4.32 (m, 3H), 4.22 (s, 2H), 3.88 (t, 2H), 3.68 (d, 1H), 3.46 (t, 2H), 3.29-3.10 (m, 2H), 2.942.82 (m, 1H), 2.21 (s, 3H), 1.82-1.70 (m, 4H) ppm. Example 24 Preparation of 4-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4- methyl-1H-pyrazol-5-yl)methyl)thiomorpholin-3-one (Compound 24) Step 1: Synthesis of 4-methyl-5-((3-oxothiomorpholino)methyl)-1H-pyrazole-3-carboxylic acid (24b) In a 100 mL round-bottom flask, Compound 24a (175 mg, 1.5 mmol) was dissolved in 1,4-dioxane (5 mL). NaH (120 mg, 3.0 mmol, 60% content) was added in an ice bath, and the reaction was carried out at room temperature for 0.5 hours. Compound 22b (200 mg, 0.62 mmol) was dissolved in tetrahydrofuran (2 mL) and added dropwise to the reaction. The reaction was quenched by adding water, methanol was added, and the reaction was carried out at 60 °C for 2 hours. HCl solution (2 mol / L) was added for acidification, and the reaction solution was concentrated under reduced pressure to afford a crude product. The crude product was purified by C18 reversed-phase column chromatography to afford Compound 24b as an off-white solid (135 mg, yield 85%). LCMS: 256.1 [M+H]+. Step 2:   Synthesis of   4-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1- carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)thiomorpholin-3-one (Compound 24) In a 50 mL round-bottom flask, Compound 24b (135 mg, 0.40 mmol) was dissolved in N,N-dimethylformamide (4 mL). Triethylamine (155 mg, 1.5 mmol) was added, then O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (285 mg, 0.75 mmol) was added. After reacting in an ice bath for 2 minutes, Intermediate 1 (160 mg, 0.6 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was quenched by adding water, extracted by ethyl acetate, the organic phase was collected and concentrated to afford a crude product. The crude product was purified by C18 reversed-phase column chromatography to afford Compound 24 as an off-white solid (150 mg, yield 56%). LCMS: 502.2 [M+H]+. 1H NMR (500 MHz, CDCI3) 5 7.40-7.30 (m, 1H), 7.22-7.10 (m, 1H), 5.01-4.76 (m, 1H), 4.59-4.34 (m, 3H), 3.75-3.62 (m, 2H), 3.38 (s, 2H), 3.28-3.03 (m, 2H), 2.98-2.74 (m, 3H), 2.23 (s, 3H), 1.96-1.81 (m, 2H), 1.81-1.67 (m, 2H) ppm. Example 25 to Example 94 Preparation of Compound 25 to Compound 94 The synthesis of Compound 25 to Compound 94 employed Intermediate 2 to Intermediate 11, which were condensed with the corresponding pyrazole carboxylic acid derivatives. The structures and characterization of Compounds 25 to 94 are shown in Table 1. Table 1 Compound # Structure Chemical Name HNMR / LCMS Compound 25 F & ,      P n-nh N-((3 -(4-(3,4-difluoro-2- (methylthio)phenyl)piperi dine-1-carbonyl)-4-methyl- 1H-pyrazol-5 -yl)methyl)acetamide 1H NMR (400 MHz, DMSOd) 5 12.86(s, 1H), 8.19(s, 1H), 7.43-7.37 (m, 1H), 7.23-7.11(m,  1H),  4.26-4.23(m,  2H),  3.56- 3.50(m, 1H), 3.19-3.13(m, 1H),2.87-2.81(m, 1H), 2.53 (s, 2H), 2.44(s, 3H), 2.02(s, 3H), 1.86 (s, 3H), 1.82-1.51(m, 4H) ppm; LCMS: 423.1 [M+H]+. Compound 26 F ( T / / P 1    / HN—\ °nrp n~nh N-((3-(4-(2-(ethylthio)-.              3,4-   .     . . difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)acetamide 1H NMR (500 MHz, CDCh) 5 7.15-7.06(m, 1H), 6.99-6.92(m, 1H), 6.62-6.54(m, 1H), 4.84(s, 1H), 4.42-4.13(m, 3H), 3.61(t, J = 12.1 Hz, 1H), 3.28-3.07(m, 1H), 2.93- 2.86(m, 2H), 2.10(s, 3H), 2.01(s, 3H), 1.84-1.75(m, 2H), 1.68-1.59(m, 2H), 1.34-1.24(m, 2H), 1.24-1.19(m, 3H ppm; LCMS: 437.2 [M+H]+. Compound 27 F Il J CF ^N^ ,     9 1    / HN—\ n~NH N-((3-(4-(3,4-difluoro-2-((trifluoromethyl)thio)phe nyl)piperidine-1 -carbonyl)-4-methyl- 1H-pyrazol-5-yl)methyl)acetamide 1H NMR (500 MHz, CDCh) 5 11.06(s, 1H), 7.37-7.32(m, 1H), 7.14-7.10(m, 1H), 6.38(t, J = 5.0 Hz, 1H), 4.97-4.75(m, 1H), 4.44-4.30(m, 3H), 3.67-3.59(m, 1H), 3.21-2.84(m, 2H), 2.12(s, 3H), 2.02(s, 3H), 1.83-1.75(m, 2H), 1.27-1.25(m, 2H) ppm; LCMS: 477.1 [M+H]+ Compound 28 F Yr LAs.CF2H .         p 1 J HN—\ °^TY n~NH N-((3-(4-(2-((difluoromethyl)thio)-.              3,4-   .     . . difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)acetamide 1H NMR (500 MHz, CDCh) 5 7.31-7.28(m, 1H), 7.11-7.07(m, 1H), 6.86(t, J = 57.0 Hz, 1H), 6.13(t, J = 6.0 Hz, 1H), 5.35(t, J = 4.8 Hz, 1H), 4.89-4.82(m, 1H), 4.34(d, J = 5.8 Hz, 2H), 3.63-3.57(m, 1H), 3.09-2.84(m, 3H), 2.14(s, 3H), 2.03(s, 3H), 1.84-1.78(m, 2H), 1.71-1.66(m, 2H) ppm; LCMS: 459.1[M+H]+ Compound 29 F ILXs,cf2cf2h p 1   / HN—\ °YY n~nh N-((3 -(4-(3,4-difluoro-2-((1,1,2,2-tetrafluoroethyl)thio)phen yl)piperidine-1 -carbonyl)-4-methyl- 1H-pyrazol-5-yl)methyl)acetamide 1H NMR (500 MHz, CDCh) 5 11.32(s, 1H), 7.37-7.29(m, 1H), 7.13-7.08(m, 1H), 6.70(t, J = 5.5 Hz, 1H), 5.90(tt, J = 53.8, 2.7 Hz, 1H), 4.86(s, 1H), 4.41-4.18(m, 3H), 3.68-3.61(m, 1H), 3.24-2.79(m, 2H), 2.10(s, 3H), 2.00(s, 3H), 1.84-1.74(m, 2H), 1.70-1.65(m, 2H) ppm; LCMS: 509.1 [M+H]+ Compound # Structure Chemical Name HNMR / LCMS Compound 30 F F 'N''   ,        P 1 J HN—\ ° W x n~NH N-((3 -(4-(3,4-difluoro-2- ((1,2,2-trifluoroethenyl)thio)phen yl)piperidine-1 -carbonyl)-4-methyl- 1H-pyrazol-5-yl)methyl)acetamide 1H NMR (500 MHz, CDCh) 5 7.25-7.19(m, 1H), 7.08-7.02(m, 1H), 6.55(t, J = 5.1 Hz, 1H), 4.85(s, 1H), 4.32(d, J = 5.6 Hz, 2H), 3.67-3.57(m, 1H), 3.29- 2.75(m, 4H), 2.11(s, 3H), 2.01(s, 3H), 1.88-1.78(m, 2H), 1.71-1.63(m, 2H) ppm; LCMS: 489.1 [M+H]+ Compound 31 F U CF N" ,       9 n-nh N-((3 -(4-(3,4-difluoro-2-(trifluoromethoxy)phenyl) piperidine-1-carbonyl)-4-methyl- 1H-pyrazol-5 -yl)methyl)acetamide 1H NMR (400 MHz, DMSOd) 5 12.81(s, 1H), 8.22(s, 1H), 7.61-7.48(m, 1H), 7.45-7.28(m, 1H), 4.83-4.30(m, 2H), 4.29-4.15(m, 2H), 3.24-3.03(m, 2H), 2.97-2.66(m, 1H), 2.02(s, 3H), 1.86(s, 3H), 1.81-1.50(m, 4H) ppm; LCMS: 461.1[M+H]+ Compound 32 F LXo.cf2h J J HN—\ °w n~nh N-((3-(4-(2-(difluoromethoxy)-3,4-difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)acetamide 1H NMR (400 MHz, DMSOd) 5 12.74(s, 1H), 8.23(s, 1H), 7.48-7.04(m, 3H), 4.78-4.05(m,  4H),  3.20-3.00(m,  2H),  2.95- 2.61(m,  1H),  2.11-1.92(m,  3H),  1.86- 1.73(m,  3H),  1.62-1.04(m,  4H)  ppm; LCMS: 443.1[M+H]+ Compound 33 F CAo,cf2cf2h Sr ,     0 1    / HN—\ °w n-nh N-((3 -(4-(3,4-difluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl) piperidine-1-carbonyl)-4-methyl- 1H-pyrazol-5 -yl)methyl)acetamide 1H NMR (400 MHz, DMSO-d6) 5 12.94-12.70(m, 1H), 8.30-8.01(m, 1H), 7.59-7.42(m,  1H),  7.41-7.31(m,  1H),  7.21- 6.85(m,  1H),  4.78-4.60(m,  1H),  4.50- 4.31(m,  1H),  4.29-4.17(m,  2H),  3.16- 2.98(m, 2H), 2.85-2.66(m,  1H), 2.02(s, 3H), 1.86(s, 3H), 1.81-1.50(m, 4H) ppm; LCMS: 493.2[M+H]+ Compound 34 F Ccv 1          / ? J / HN—\ °V V7 x n-nh N-((3 -(4-(3,4-difluoro-2- ((1,2,2-trifluoroethenyl)oxy)phen yl)piperidine-1 -carbonyl)-4-methyl- 1H-pyrazol-5-yl)methyl)acetamide 1H NMR (400 MHz, DMSO-d6) 5 12.96-12.66(m,  1H),  8.30-8.03(m,  1H), 7.52- 7.36(m,  1H),  7.35-7.25(m,  1H),  4.77- 4.58(m,  1H),  4.46-4.31(m,  1H),  4.30- 4.15(m,  2H),  3.26-3.02(m,  2H),  2.93- 2.70(m, 1H), 2.01(s, 3H), 1.85(s, 3H), 1.81-1.50(m, 4h) ppm; LCMS: 473.2[M+H]+ Compound 35 JF vH_rm z=\ — / —\ i Y\ \ Li z z^O N-((3 -(4-(3,4-difluoro-2-(methylthio)phenyl)piperi dine-1 -carbonyl)-4-ethyl-1H-pyrazol-5-yl)methyl)acetamide 1H NMR (400 MHz, CDCh) 5 7.68-7.50(m, 1H), 7.17-7.07(m, 1H), 7.06-6.96(m, 1H), 4.71-4.55(m, 4H), 3.89-3.69(m, 1H), 3.69-3.54(m, 1H), 3.48-3.23(m, 1H), 3.09-2.88(m, 1H), 2.69-2.58(m, 2H), 2.48(s, 3H), 2.13(s, 3H), 2.00-1.65(m, 4H), 1.22(t, J = 7.1 Hz, 3H) ppm; LCMS: 437.2 [M+H]+. Compound # Structure Chemical Name HNMR / LCMS Compound 36 F ,k .F ML J / HN—\ °MrM n-nh N-((4-ethyl-3-(4-(2- (ethylthio)-3,4-difluorophenyl)piperidine -1 -carbonyl)-1H-pyrazol-5 -yl)methyl)acetamide 1H NMR (500 MHz, DMSO-d6) 5 12.74(s, 1H), 8.23(s, 1H), 7.42(d, 1H), 7.20-7.13(m, 1H), 4.67(s, 1H), 4.25(d, 3H), 3.56(t, 1H), 3.13(s,  1H),  2.87(q, 2H), 2.45(d, 2H), 1.84(s, 3H), 1.75(s, 1H), 1.65(s, 1H), 1.54(s, 2H), 1.24(s, 1H), 1.13(t, 3H), 1.04(t, 3H) ppm; LCMS: 451.2 [M+H]+ Compound 37 F ( Y OF \ -T     -''—I 3 S J N          O J / HN—A °nrp x n~nh N-((3 -(4-(3,4-difluoro-2-((trifluoromethyl)thio)phe nyl)piperidine-1 -carbonyl)-4-ethyl- 1H-pyrazol-5-yl)methyl)acetamide 1H NMR (500 MHz, DMSO-d6) 5 12.77(s, 1H), 8.24(s, 1H), 7.74(d, 1H), 7.40(d, 1H), 4.68(s, 1H), 4.25(d, 2H), 3.56(t, 1H), 3.17(s, 1H), 2.84(s, 1H), 2.45(s, 1H), 1.86(d, 3H), 1.76(s,  1H),  1.67(s,  1H),  1.56(d,  2H), 1.23(d, 2H), 1.04(t, 3H) ppm; LCMS: 491.2 [M+H]+ Compound 38 F r^MF MLs,cf2h 0 J / HN—\ x n~NH N-((3-(4-(2-((difluoromethyl)thio)-.           3,4- difluorophenyl)piperidine -1 -carbonyl)-4-ethyl-1H-pyrazol-5-yl)methyl)acetamide 1H NMR (500 MHz, DMSO-d6) 5 12.79(s, 1H), 8.25(s, 1H), 7.62(d, 1H), 7.45(s, 1H), 7.32-7.28(m, 1H), 4.67(s, 1H), 4.25(d, 2H), 3.53(t, 1H), 3.11(s, 1H), 2.80(s, 1H), 2.47-2.41(m, 2H),  1.84(s, 3H),  1.75(s,  1H), 1.67(s, 1H), 1.57(s, 2H), 1.24(s, 1H), 1.04(t, 3H) ppm; LCMS: 473.2 [M+H]+ Compound 39 F LAg.CFjCFsH FT           0 1 J UN—\ Av n'NH N-((3 -(4-(3,4-difluoro-2- ((1,1,2,2-tetrafluoroethyl)thio)phen yl)piperidine-1 -carbonyl)-4-ethyl- 1H-pyrazol-5-yl)methyl)acetamide 1H NMR (500 MHz, DMSO-d6) 5 12.76(s, 1H),  8.21(s,  1H),  7.70(dd,  1H),  7.41- 7.34(m, 1H), 6.84(t, 1H), 4.25(d, 3H), 3.60-3.51(m, 2H),  3.18(s, 2H), 2.81(s,  1H), 1.84(s, 3H), 1.71(s, 2H), 1.59(s, 2H), 1.24(s, 1H), 1.07-1.01(m, 3H) ppm; LCMS: 523.2 [M+H]+. Compound 40 F Yv V, F P 1 / HN—\ wv x n^nh N-((3 -(4-(3,4-difluoro-2- ((1,2,2-trifluoroethenyl)thio)phen yl)piperidine-1 -carbonyl)-4-ethyl- 1H-pyrazol-5-yl)methyl)acetamide 1H NMR (500 MHz, DMSO-d6) 5 12.74(s, 1H), 8.22(s, 1H), 7.59(dd, 1H), 4.68(s, 1H), 4.25(d, 2H),  3.53(d, 2H),  3.15(d, 2H), 2.83(s, 1H), 2.47-2.39(m, 1H), 1.84(s, 3H), 1.75(d, 2H), 1.59(s, 2H), 1.24(s, 1H), 1.04(t, 3H) ppm; LCMS: 503.2 [M+H]+ Compound 41 O^ / z CM p       \ }—(    / —\ v=z \= /  \-- /  Q N-((3-(4-(3,4-difluoro-2-(trifluoromethoxy)phenyl) piperidine-1-carbonyl)-4-ethyl- 1H-pyrazol-5 -yl)methyl)acetamide 1H NMR (400 MHz, DMSO-d6) 5 12.97-12.59(m, 1H), 8.39-8.03(m,  1H), 7.65- 7.45(m,  1H),  7.42-7.28(m,  1H),  4.81- 4.57(m,  1H),  4.39-4.11(m,  3H),  3.24- 3.04(m,  2H),  2.93-2.73(m,  1H),  2.49- 2.37(m, 2H),  1.86(s, 3H),  1.81-1.44(m, 4H), 1.05 (t, J = 8.0 Hz, 3H) ppm; LCMS: 475.2[M+H]+ Compound 42 F / M V MLoXF2H <- p J / HN—\ °TV N-NH N-((3-(4-(2-(difluoromethoxy)-3,4-difluorophenyl)piperidine -1 -carbonyl)-4-ethyl-1H-pyrazol-5-yl)methyl)acetamide 1H NMR (400 MHz, DMSO-d6) 5 12.92-12.67(m, 1H), 8.31-8.03(m, 1H), 7.50- 6.99(m, 3H), 4.76-4.58(m, 1H), 4.37-4.17(m, 3H), 3.23-3.03(m, 2H), 2.91-2.72(m,  1H), 2.49-2.37(m, 2H),  1.86(s, 3H), 1.81-1.44(m, 4H), 1.05(t, J = 8.0 Hz, 3H) ppm; LCMS: 457.2[M+H]+ Compound # Structure Chemical Name HNMR / LCMS Compound 43 F A^cf2cf2h -F 0   2 2 ^hr          0 J     hn-4 oArV n~nh N-((3 -(4-(3,4-difluoro-2- (1,1,2,2-tetrafluoroethoxy)phenyl) piperidine-1-carbonyl)-4-ethyl- 1H-pyrazol-5 -yl)methyl)acetamide 1H NMR (400 MHz, DMSOd) 5 12.97-12.59(m, 1H), 8.36-8.00(m, 1H), 7.61-7.38(m,  1H),  7.37-7.20(m,  1H),  7.18- 6.81(m,  1H),  4.82-4.54(m,  1H),  4.43- 4.03(m,  3H),  3.21-2.90(m,  2H),  2.89- 2.65(m,  1H), 2.49-2.26(m, 2H),  1.86(s, 3H), 1.81-1.38(m, 4H), 1.05(t, J = 8.0 Hz, 3H) ppm; LCMS: 507.2[M+H]+ Compound 44 F COy c" / 9 1 J HN—\ ° n~NH N-((3 -(4-(3,4-difluoro-2- ((1,2,2-trifluoroethenyl)oxy)phen yl)piperidine-1 -carbonyl)-4-ethyl- 1H-pyrazol-5-yl)methyl)acetamide 1H NMR (400 MHz, DMSO-d6) 5 12.92-12.67(m, 1H), 8.35-8.04(m,  1H), 7.52- 7.33(m,  1H),  7.31-7.18(m,  1H),  4.75- 4.56(m,  1H),  4.35-4.15(m,  3H),  3.27- 3.02(m,  2H),  2.91-2.72(m,  1H),  2.49- 2.34(m, 2H),  1.84(s, 3H),  1.80-1.45(m, 4H), 1.03(t, J = 8.0 Hz, 3H) ppm; LCMS: 487.2[M+H]+. Compound 45 & Wh N-((3-(4-(3,4-difluoro-2-(methylthio)phenyl)piperi dine-1-carbonyl)-4-methyl- 1H-pyrazol-5 -yl)methyl)-N-methylacetamide 1H NMR (400 MHz, DMSOd) 5 12.81(s, 1H), 7.46-7.37(m, 1H), 7.22-7.16(m, 1H), 4.50(s, 2H), 3.57-3.48(m, 1H), 3.34-3.06(m, 2H), 2.92(s, 3H), 2.89-2.72(m, 2H), 2.44(s, 3H), 2.04(s, 3H), 2.00(s, 3H), 1.86-1.48(m, 4H) ppm; LCMS: 437.1 [M+H]+ Compound 46 F ( Y A J N~\ “^rV7 x n~nh N-((3-(4-(2-(ethylthio)-.              3,4-   .     . . difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)-N-methylacetamide 1H NMR (500 MHz, CDCh) 5 10.91(s, 1H), 7.12-7.05(m, 1H), 6.98-6.94(m, 1H), 4.95-4.37(m, 4H), 3.65-3.57(m, 1H), 3.26-3.08(m,  1H), 3.03(s, 3H), 2.95-2.78(m, 3H), 2.20-2.16(m, 3H), 2.11(s, 3H), 1.80-1.68(m, 4H), 1.22 (t, J = 7.4 Hz, 3H) ppm; LCMS: 451.2 [M+H]+ Compound 47 F U^F LAs^cf3 oux N~NH N-((3-(4-(3,4-difluoro-2-((trifluoromethyl)thio)phe nyl)piperidine-1 -carbonyl)-4-methyl- 1H-pyrazol-5 -yl)methyl) -N -methylacetamide 1H NMR (500 MHz, CDCh) 5 10.98(s, 1H), 7.37-7.29(m, 1H), 7.15-7.08(m, 1H), 5.13-4.23(m,  4H),  3.68-3.55(m,  1H),  3.24- 3.09(m,  1H),  3.06-2.96(m,  3H),  2.93- 2.78(m,  1H),  2.22-2.16(m,  3H),  2.13- 2.05(m,  3H),  1.86-1.72(m,  2H),  1.71- 1.65(m, 2H) ppm; LCMS: 491.1 [M+H]+. Compound 48 F L^Xj^CFjH i \ / 9 J 7   N—\ ° TlV7 n~nh N-((3-(4-(2-((difluoromethyl)thio)-.              3,4-   .     . . difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)-N-methylacetamide 1H NMR (500 MHz, CDCh) 5 7.30-7.26(m, 1H), 7.11-7.06(m, 1H), 6.86(t, J = 57.0 Hz, 1H), 5.11-4.21(m, 5H), 3.64-3.56(m, 1H), 3.24-3.06(m, 1H), 3.04(s, 3H), 2.91-2.76(m, 1H), 2.19(s, 3H), 2.11(s, 3H), 1.84-1.73(m, 2H), 1.71-1.63(m, 2H) ppm; LCMS: 473.2 [M+H]+ Compound 49 F U^F vAs,cf2cf2h N'NH N-((3-(4-(3,4-difluoro-2-((1,1,2,2-tetrafluoroethyl)thio)phen yl)piperidine-1 -carbonyl)-4-methyl- 1H-pyrazol-5-yl)methyl)-N-methylacetamide 1H NMR (500 MHz, CDCh) 5 10.82(s, 1H), 7.35-7.29(m, 1H), 7.15-7.09(m, 1H), 5.90(t, J = 53.7 Hz, 1H), 4.92-4.40(m, 4H), 3.70-3.59(m, 1H), 3.25-3.08(m, 1H), 3.05(s, 3H), 2.93-2.75(m, 1H), 2.20(s, 3H), 2.11(s, 3H), 1.87-1.72(m, 2H), 1.72-1.67(m, 2H) ppm; LCMS: 523.2 [M+H]+ Compound # Structure Chemical Name HNMR / LCMS Compound 50 MH" n-nh N-((3 -(4-(3,4-difluoro-2-((1,2,2-  . trifluoroethenyl)thio)phen yl)piperidine-1 -carbonyl)-4-methyl- 1H-pyrazol-5-yl)methyl)-N-methylacetamide 1H NMR (500 MHz, CDCh) 5 10.46(s, 1H), 7.25-7.19(m, 1H), 7.08-7.03(m, 1H), 4.98-4.37(m, 4H), 3.66-3.59(m, 1H), 3.22-2.79(m, 5H), 2.20(s, 3H), 2.11(s, 3H), 1.88-1.76(m, 2H), 1.73-1.67(m, 2H) ppm; LCMS: 503.2 [M+H]+ Compound 51 ?" / \ / ? J J N~\ °Mv v n-nh N-((3 -(4-(3,4-difluoro-2-(trifluoromethoxy)phenyl) piperidine-1-carbonyl)-4-methyl- 1H-pyrazol-5 -yl)methyl)-N-methylacetamide 1H NMR (400 MHz, DMSO-d6) 5 13.07-12.72(m, 1H), 7.63-7.46(m,  1H), 7.43- 7.30(m,  1H),  4.74-4.20(m,  4H),  3.24- 3.04(m,  2H),  2.97-2.67(m,  4H),  2.15- 1.88(m,  6H),  1.81-1.53(m,  4H)  ppm; LCMS: 475.2[M+H]+ Compound 52 F MH n-nh N-((3-(4-(2-(difluoromethoxy)-3,4-difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)-N-methylacetamide 1H NMR (400 MHz, DMSO-d6) 5 13.06-12.76(m, 1H), 7.49-7.02(m, 3H), 4.77- 4.25(m, 4H), 3.24-3.04(m, 2H), 2.97-2.70(m, 4H), 2.18-1.92(m, 6H), 1.84-1.52(m, 4H) ppm; LCMS: 457.2[M+H]+ Compound 53 F CX / ^CFjH X J J N-\ n-nh N-((3 -(4-(3,4-difluoro-2- (1,1,2,2-tetrafluoroethoxy)phenyl) piperidine-1-carbonyl)-4-methyl- 1H-pyrazol-5 - yl)methyl)-N-methylacetamide 1H NMR (400 MHz, DMSO-d6) 5 13.08-12.72(m, 1H), 7.59-7.42(m, 1H), 7.41-7.28(m,  1H),  7.22-6.82(m,  1H),  4.82- 4.21(m, 4H), 3.21-3.00(m 2H), 2.98- 2.66(m,  4H),  2.19-1.91(m,  6H),  1.84- 1.50(m, 4H) ppm; LCMS: 507.2[M+H]+ Compound 54 F 60yF MM   F TT . x 9 1   /   N-\ °Mrv x N-NH N-((3 -(4-(3,4-difluoro-2-((1,2,2-trifluoroethenyl)oxy)phen yl)piperidine-1 -carbonyl)-4-methyl- 1H-pyrazol-5-yl)methyl)-N-methylacetamide 1H NMR (400 MHz, DMSO-d6) 5 13.04-12.73(m, 1H), 7.48-7.35(m,  1H), 7.34- 7.23(m,  1H),  4.74-4.23(m,  4H),  3.27- 3.05(m,  2H),  2.95-2.66(m,  4H),  2.15- 1.90(m,  6H),  1.86-1.51(m,  4H)  ppm; LCMS: 487.2[M+H]+ Compound 55 O   y--k - / r”A_       / \ C2x (4-(3,4-difluoro-2-(methylthio)phenyl)piperi din-1 -yl)(4-methyl-5-(morpholinomethyl)-1H-pyrazol-3 -yl)methanone 1H NMR (500 MHz, CDCh) 5 10.65(s, 1H), 7.11-7.05(m, 1H), 6.97-6.92(m, 1H), 5.00-4.79(m,  1H),  4.46-4.25(m,  1H),  3.76- 3.67(m,  4H),  3.59-3.53(m,  1H),  3.53- 3.49(m,  2H),  3.28-3.09(m,  1H),  2.98- 2.80(m,  1H),  2.52-2.45(m,  4H),  2.45- 2.42(m, 3H), 2.12(s, 3H), 1.87-1.65(m, 4H) ppm; LCMS: 451.2 [M+H]+ Compound 56 I LL      ( / }                          / \— /  , .   >Z "=■""   \— /   o (4-(2-(ethylthio)-3,4-difluorophenyl)piperidin-1-yl)(4-methyl-5-(morpholinomethyl)-1H-pyrazol-3 -yl)methanone 1H NMR (500 MHz, CDCh) 5 10.52(s, 1H), 7.13-7.06(m, 1H), 6.99-6.94(m, 1H), 4.89(s, 1H), 4.38(s, 1H), 3.75-3.68(m, 4H), 3.65-3.57(m, 1H), 3.52(s, 2H), 3.19(s, 1H), 2.99-2.80(m, 3H), 2.54-2.42(m, 4H), 2.13(s, 3H), 1.90-1.77(m, 2H), 1.70-1.65(m, 2H), 1.22(t, J = 7.4 Hz, 3H) ppm; LCMS: 465.2 [M+H]+. Compound # Structure Chemical Name HNMR / LCMS Compound 57 F ( T CF / ^O / ( 1    /   n—7 n-nh (4-(3,4-difluoro-2-((trifluoromethyl)thio)phe nyl)piperidin-1 -yl)(4-methyl-5-(morpholinomethyl)-1H-pyrazol-3 -yl)methanone 1H NMR (500 MHz, CDCh) 5 10.38(s, 1H), 7.38-7.29(m, 1H), 7.17-7.07(m, 1H), 5.05-4.73(m, 1H), 4.59-4.23(m, 1H), 3.77-3.60(m, 5H), 3.56-3.47(m, 2H), 3.25-2.81(m, 2H), 2.55-2.43(m, 4H), 2.13(s, 3H), 1.86-1.77(m, 2H), 1.74-1.67(m, 2h) ppm; LCMS: 505.2 [M+H]+ Compound 58 F A^F LAs^cf2h r-O N I Cj J J N-^ ° x V7 n'NH (4-(2- ((difluoromethyl)thio)-.              3,4-   .     . . difluorophenyl)piperidin-1-yl)(4-methyl-5- (morpholinomethyl)-1H-pyrazol-3 -yl)methanone 1H NMR (500 MHz, CDCh) 5 10.63 (s, 1H), 7.30-7.26(m, 1H), 7.11-7.06(m, 1H), 6.86(1, J = 57.0 Hz, 1H), 4.88(s, 1H), 4.39(s, 1H), 3.74-3.68(m, 4H), 3.65-3.56(m, 1H), 3.52(s, 2H), 3.26-2.71(m, 2H), 2.52-2.42(m, 4H), 2.13(s, 3H),  1.83-1.75(m, 2H), 1.70-1.61(m, 2H) ppm; LCMS: 487.2 [M+H]+ Compound 59 F f; LA,s.CF2CF2H y / o n-nh (4-(3,4-difluoro-2-((1,1,2,2-tetrafluoroethyl)thio)phen yl)piperidin-1 -yl)(4-methyl-5-(morpholinomethyl)-1H-pyrazol-3 -yl)methanone 1H NMR (500 MHz, CDCh) 5 10.62(s, 1H), 7.36-7.29(m, 1H), 7.15-7.08(m, 1H), 5.90(t, J = 53.7 Hz, 1H), 5.03-4.76(m, 1H), 4.53-4.29(m, 1H), 3.73-3.69(m, 4H), 3.68-3.60(m,  1H), 3.52(s, 3H), 3.27-2.78(m, 2H), 2.51-2.44(m, 4H), 2.13(s, 3H), 1.81-1.75(m, 2H), 1.73-1.66(m, 2H) ppm; LCMS: 537.2 [M+H]+ Compound 60 F ¢,0 N'NH (4-(3,4-difluoro-2-(( 1,2,2-trifluoroethenyl)thio)phen yl)piperidin-1 -yl)(4-methyl-5- (morpholinomethyl)-1H-pyrazol-3 -yl)methanone 1H NMR (500 MHz, CDCh) 5 10.56 (s, 1H), 7.25-7.18(m, 1H), 7.07-7.03 (m, 1H), 4.92(s, 1H), 4.41(s, 1H), 3.73-3.68(m, 4H), 3.66-3.58(m, 1H), 3.52(s, 2H), 3.28-2.75(m, 2H), 2.52-2.43(m, 4H), 2.13(s, 3H), 1.87-1.77 (m, 2H), 1.74-1.67(m, 2H) ppm; LCMS: 517.2 [M+H]+ Compound 61 F A^f U>rCF’ z—O । / o J / N—J °0V n-nh (4-(3,4-difluoro-2-(trifluoromethoxy)phenyl) piperidin-1 -yl)(4-methyl-5-(morpholinomethyl)-1H-pyrazol-3-yl)methanone 1H NMR (500 MHz, CDCh) 5 10.49 (s, 1H), 7.18-7.09(m, 1H), 7.04-6.99 (m, 1H), 4.89(s, 1H), 4.42(s, 1H), 3.74-3.67(m, 4H), 3.52(s, 2H), 3.22-3.01(m, 2H), 2.84(s, 1H), 2.48(s, 4H), 2.13(s, 3H), 1.89-1.77(m, 2H), 1.70-1.66(m, 2H) ppm; LCMS: 489.2 [M+H]+ Compound 62 F .,-0,,-F CLo,cf2h r-Q Y . c? J / N—J AV n'NH (4-(3,4-difluoro-2- ((1,1,2,2-tetrafluoroethyl)thio)phen yl)piperidin-1 -yl)(4-ethyl-5-(morpholinomethyl)-1H-pyrazol-3-yl)methanone 1H NMR (500 MHz, CDCh) 5 10.36 (s, 1H), 7.11-7.04(m, 1H), 7.04-6.96 (m, 1H), 6.64(t, 1H), 4.99-4.75(m, 1H), 4.54-4.24(m, 1H), 3.78-3.69(m, 4H), 3.58-3.46(m, 2H), 3.29-3.21(m, 1h), 3.18-3.06(m, 1H), 2.94-2.75(m, 1H), 2.50(s, 4H), 2.15(s, 3H), 1.91-1.78(m, 2H), 1.75-1.67(m, 2H) ppm; LCMS: 471.2 [M+H]+ Compound 63 F .,4,, -F 100o,cf2cf2h £ / 0 °YV n~nh (4-(3,4-difluoro-2- (1,1,2,2-tetrafluoroethoxy)phenyl) piperidin-1 -yl)(4-methyl-5-(morpholinomethyl)-1H-pyrazol-3-yl)methanone 1H NMR (500 MHz, CDCh) 5 10.57 (s, 1H), 7.19-7.09(m, 1H), 7.09-6.97 (m, 1H), 6.07(t ,  1H),  5.01-4.77(m,  1H),  4.59- 4.29(m,  1H), 3.80-3.63(m, 4H), 3.58(s, 2H), 3.22-2.99(m, 2H), 2.93-2.77(m, 1H), 2.63-2.40(m, 4H), 2.15(s, 3H), 1.86-1.63(m, 4H) ppm; LCMS: 521.2 [M+H]+ Compound # Structure Chemical Name HNMR / LCMS Compound 64 F cep J- 1 1    (     / A 1   N-7 N'NH (4-(3,4-difluoro-2-(( 1,2,2-trifluoroethenyl)oxy)phen yl)piperidin-1 -yl)(4-methyl-5-(morpholinomethyl)-1H-pyrazol-3 -yl)methanone 1H NMR (500 MHz, CDCh) 5 10.46 (s, 1H), 7.12-7.02(m, 1H), 7.02-6.93 (m, 1H), 5.04-4.74(m, 1H), 4.59-4.28 (m, 1H), 3.81-3.65(m, 4H), 3.56(s, 2H), 3.28-3.04(m, 2H), 2.97-2.74(m, 1H), 2.52(s, 4H), 2.15(s, 3h), 1.86(s, 2H), 1.76-1.63(m, 2H) ppm; LCMS: 501.2 [M+H]+ Compound 65 F [ T TrO 1    /   N"7 °nrv n~nh (4-(3,4-difluoro-2-(methylthio)phenyl)piperi din-1 -yl)(4-ethyl-5-(morpholinomethyl)-1H-pyrazol-3 -yl)methanone 1H NMR (400 MHz, DMSOd) 5 12.82(s, 1H), 7.65-7.29(m, 1H), 7.28-6.92(m, 1H), 4.71-4.69(m, 1H), 4.27-4.25(m, 1H), 3.62-3.46(m, 6H), 3.16-3.14(m, 1H), 2.81-2.47(m, 6H), 2.44(s,3H), 2.36(s, 2H), 1.851.48 (m, 4H), 1.09-1.06(m, 3H) ppm; LCMS: 465.2 [M+H]+ Compound 66 (4-ethyl-5-(morpholinomethyl)-1H-pyrazol-3-yl)(4-(2-(ethylthio)-3,4-difluorophenyl)piperidin-1-yl)methanone 1H NMR (400 MHz, DMSOd) 5 12.81(s, 1H), 7.43(d, 1H), 7.19(s, 1H), 4.68(s, 1H), 4.25 (s, 1H), 3.58 (s, 8H), 3.15(s, 1H), 2.89(d,  3H),  2.36(s, 4H),  1.72(d,  2H), 1.58(s, 2H), 1.25(s, 1H), 1.15(t, 3H), 1.08(d, 3H) ppm; LCMS: 479.2 [M+H]+ Compound 67 7-0 1    /   N—' ° TV n-nh (4-(3,4-difluoro-2-(trifluoromethyl)thio)pipe ridin-1 -yl)(4-ethyl-5-(morpholinomethyl)-1H-pyrazol-3 -yl)methanone 1H NMR (500 MHz, CDCh) 5 7.43-7.30(m, 1H), 7.21-7.07(m, 1H), 5.03-4.74(m, 1H), 4.57-4.26(m, 1H), 3.96-3.78(m, 5H), 3.70-3.60(m, 1H), 3.31-3.08(m, 1H), 2.98-2.69(m, 5H), 2.68-2.48(m, 3H), 1.93-1.65(m, 4H), 1.17 (t, 3H) ppm; LCMS: 519.2 [M+H]+ Compound 68 F A_f YXs,cf2h r~° y J J ° iV N^NH (4-(2- ((difluoromethyl)thio)-.              3,4-   .     . . difluorophenyl)piperidin-1-yl)(4-ethyl-5- (morpholinomethyl)-1H-pyrazol-3 -yl)methanone 1H NMR (400 MHz, DMSO-d6) 5 10.27(s, 1H), 7.74-7.59(m, 1H), 7.48 (s, 1H), 7.36-7.28(m, 1H), 4.36(s, 2H), 3.96(s, 3H), 3.64-3.53(m, 5H), 3.30(d, 5H), 2.60-2.54(m, 2H), 1.75 (s, 2H), 1.60(dt, 2H), 1.10(t, 3H) ppm; LCMS: 501.2 [M+H]+ Compound 69 F J^^F CYs^cf2cf2h 1        / —o r" \ ) A J n-7 °AV n-nh (4-(3,4-difluoro-2- ((1,1,2,2-tetrafluoroethyl)thio)phen yl)piperidin-1 -yl)(4-ethyl-5-(morpholinomethyl)-1H-pyrazol-3-yl)methanone 1H NMR (500 MHz, CDCh) 5 7.41-7.29(m, 1H), 7.17-7.11(m, 1H), 6.06-5.77(m, 1H), 4.91(s, 1H), 4.44(s, 1H), 3.96(s, 5H), 3.83-3.50(m, 1H), 3.18 (s, 1H), 2.90(s, 4H), 2.74-2.51(m, 2H), 1.88-1.57(m, 4H), 1.37-1.26(m, 2H), 1.22-1.09(m, 3H) ppm; LCMS: 551.2 [M+H]+ Compound 70 O / --\    / =\ JzvHrT z=<   —  )—( z zY “> m ^Z      X (4-(3,4-difluoro-2- ((1,1,2,2-tetrafluoroethyl)thio)phen yl)piperidin-1 -yl)(4-ethyl-5-(morpholinomethyl)-1H-pyrazol-3-yl)methanone 1H NMR (500 MHz, CDCh) 5 7.28-7.21(m, 1H), 7.11-7.03(m, 1H), 4.93 (s, 1H), 4.51-4.17(m, 1H), 3.85-3.73 (m, 4H), 3.73-3.58(m, 3H), 3.19(s, 1H), 2.91(s, 1H), 2.62(s, 5H), 2.09(s, 2H), 1.94-1.77(m, 2H), 1.78-1.63 (m, 2H), 1.16(t, 3H) ppm; LCMS: 531.2 [M+H]+ Compound 71 F LXOzcF3 y <CJ A J n^ 0 Tp n-nh (4-(3,4-difluoro-2-(trifluoromethoxy)phenyl) piperidin-1 -yl)(4-ethyl-5-(morpholinomethyl)-1H-pyrazol-3 -yl)methanone 1H NMR (400 MHz, DMSO-d6) 5 12.81(s, 1H), 7.61-7.49(m, 1H), 7.43-7.29(m, 1H), 4.83-4.51(m, 1H), 4.44-4.11(m, 1H), 3.65-3.42(m, 6H), 3.23-2.98(m, 2H), 2.95-2.74(m, 1H), 2.49-2.42(m, 2H), 2.41-2.27(m, 4H), 1.84-1.50(m, 4H), 1.08(t, J = 8.0 Hz, 3H) ppm; LCMS: 503.2 [M+H]+ Compound # Structure Chemical Name HNMR / LCMS Compound 72 F LJo.cf2h ^hr           / J J N^7 gW7 n-nh (4-(2-(difluoromethoxy)-.              3,4—   .     . . difluorophenyl)piperidin-1-yl)(4-ethyl-5- (morpholinomethyl)-1H-pyrazol-3 -yl)methanone 1H NMR (400 MHz, DMSOd) 5 12.79(s, 1H), 7.47-7.05(m, 3H), 4.74-4.59(m, 1H), 4.33-4.18(m, 1H), 3.62-3.41(m, 6H), 3.20-3.00(m, 2H), 2.87-2.71(m, 1H), 2.49-2.42(m, 2H), 2.40-2.23(m, 4H), 1.84-1.42(m, 4H), 1.06(t, J = 7.3 Hz, 3H) ppm; LCMS: 485.2[M+H]+ Compound 73 F / V / F LA0-cf2cf2h Sr c" \ / 1  1 N—7 “"yV N~NH (4-(3,4-difluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl) piperidin-1 -yl)(4-ethyl-5-(morpholinomethyl)-1H-pyrazol-3 -yl)methanone 1H NMR (400 MHz, DMSOd) 5 12.79(s, 1H), 7.56-7.41(m, 1H), 7.37-7.23(m, 1H), 7.14-6.84(m, 1H), 4.75-4.59(m, 1H), 4.36-4.18(m,  1H),  3.65-3.41(m,  6H),  3.15- 2.97(m,  2H),  2.83-2.66(m,  1H),  2.49- 2.41(m,  2H),  2.40-2.24(m,  4H),  1.83- 1.45(m, 4H), 1.06 (t, J = 7.2 Hz, 3H) ppm; LCMS: 535.2 [M+H]+ Compound 74 F o r" \ / J, J N—7 "^ry-7 n~nh (4-(3,4-difluoro-2-(( 1,2,2-trifluoroethenyl)oxy)phen yl)piperidin-1 -yl)(4-ethyl-5-(morpholinomethyl)-1H-pyrazol-3-yl)methanone 1H NMR (400 MHz, DMSOd) 5 12.79(s, 1H), 7.52-7.35(m, 1H), 7.34-7.16(m, 1H), 4.75-4.58(m, 1H), 4.37-4.15(m, 1H), 3.65-3.41(m, 6H), 3.26-3.02(m, 2H), 2.89-2.74(m, 1H), 2.49-2.41(m, 2H), 2.40-2.22(m, 4H), 1.86-1.44(m, 4H), 1.08(t, J = 7.3 Hz, 3H) ppm; LCMS: 515.2 [M+H]+ Compound 75 F ( Y Y's" ^hr . < / 1 J N-Yx n'NH 1-(3-(4-(3,4-difluoro-2-(methylthio)phenyl)piperi dine-1-carbonyl)-4-methyl- 1H-pyrazol-5 -yl)methyl)pyrrolidin-2- one 1H NMR (400 MHz, DMSOd) 5 12.94(s, 1H), 7.47-7.35(m, 1H), 7.24-7.14(m, 1H), 4.38(s, 2H), 3.62-3.37(m, 4H), 3.29-3.20(m, 2H), 3.17-2.60(m, 1H), 2.45(s, 3H), 2.32-2.22 (m, 2H), 2.01(s, 3H), 1.98-1.88(m, 2H), 1.86-1.67(m, 2H), 1.66-1.50(m, 2H) ppm; LCMS: 449.1 [M+H]+ Compound 76 f Yw-f t J Y's'"^ 1 \l J /  N—Y o^Yyj 0 N~NH 1-(3-(4-(2-(ethylthio)-3,4-difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)pyrrolidin-2- one 1H NMR (400 MHz, DMSOd) 5 12.94(s, 1H), 7.51-7.34(m, 1H), 7.28-7.14(m, 1H), 4.38 (s, 2H), 3.63-3.37(m, 4H), 3.26-3.21(m, 2H), 3.19-3.06(m, 1H), 2.92-2.86(m, 2H), 2.31-2.22(m, 2H), 2.01 (s, 3H), 1.97-1.87 (m, 2H), 1.83-1.66(m, 2H), 1.65-1.51(m, 2H), 1.19-1.11(m, 3H) ppm; LCMS: 463.1 [M+H]+ Compound 77 F LAs>cf3 Sr . <Y a Y 0 N-nh 1-(3-(4-(3,4-difluoro-2-((trifluoromethyl)thio)phe nyl)piperidine-1 -carbonyl)-4-methyl- 1H-pyrazol-5-yl)methyl)pyrrolidin-2-one 1H NMR (400 MHz, DMSOd) 5 12.94(s, 1H), 7.82-7.62(m, 1H), 7.52-7.32(m, 1H), 4.38(s, 2H), 3.63-3.37(m, 4H), 3.26-3.21(m, 2H), 2.92-2.76(m, 1H), 2.30-2.21(m, 2H), 2.01(s, 3H),  1.97-1.87(m, 2H), 1.80-1.57(m, 4H) ppm; LCMS: 503.1 [M+H]+ Compound 78 F A. 'F LY-s^cf2h oYV ° n-nii 1-(3-(4-(2- ((difluoromethyl)thio)-.              3,4-   .     . . difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)pyrrolidin-2-one 1H NMR (400 MHz, DMSOd) 5 12.94(s, 1H), 7.70-7.30(m, 3H), 4.39 (s, 2H), 3.63-3.35(m, 4H), 3.28-3.20 (m, 2H), 2.90- 2.71(m, 1h), 2.32-2.22 (m, 2H), 2.01(s, 3H), 1.96-1.89(m, 2H), 1.82-1.54(m, 4H) ppm.; LCMS: 485.2 [M+H]+ Compound # Structure Chemical Name HNMR / LCMS Compound 79 F C;Xs^F2CF2H Y7 ! ( 1 1   / N-Y oAcV n~nh 1-(3-(4-(3,4-difluoro-2-(1,1,2,2-tetrafluoroethyl)thio)phen yl)piperidine-1 -carbonyl)-4-methyl- 1H-pyrazol-5-yl)methyl)pyrrolidin-2-one 1H NMR (400 MHz, DMSO-d6) 5 12.92(s, 1H), 7.78-7.63(m, 1H), 7.47-7.34(m, 1H), 6.69-6.67(m, 1H), 4.37(s, 2H), 3.32-3.31(m, 4H), 3.25-3.18(m, 2H), 2.86-2.70(m,  1H), 2.28-2.20(m, 2H), 2.00(s, 3H), 1.94-1.86(m, 2H), 1.78-1.55(m, 4H) ppm; LCMS: 535.2 [M+H]+ Compound 80 F >L F । / a n~NH 1-(3-(4-(3,4-difluoro-2-((1,2,2-trifluoroethenyl)thio)phen yl)piperidine-1 -carbonyl)-4-methyl- 1H-pyrazol-5-yl)methyl)pyrrolidin-2-one 1H NMR (400 MHz, DMSO-d6) 5 12.92(s, 1H), 7.70-7.52(m, 1H), 7.43-7.25(m, 1H), 4.37(s, 2H), 3.39-3.36(m, 4H), 3.25-3.19(m, 2H), 2.84-2.75(m, 1H), 2.31-2.20(m, 2H), 2.00(s, 3H),  1.94-1.86(m, 2H) , 1.85-1.70(m, 2H), 1.67-1.55(m, 2H) ppm; LCMS: 515.1 [M+H]+ Compound 81 ( Ay (T CF yVF1 Sr I \l °AV 0 N-NH 1-(3-(4-(3,4-difluoro-2-(trifluoromethoxy)phenyl) piperidine-1-carbonyl)-4-methyl- 1H-pyrazol-5 -yl)methyl)pyrrolidin-2-one 1H NMR (400 MHz, DMSO-d6) 5 11.38(s, 1H), 7.18-7.10(m, 1H), 7.04-6.98(m, 1H), 4.41(s, 2H), 3.45-3.33(m, 2H), 3.22-3.07(m, 2H), 2.98-2.70(m, 1H), 2.45-2.36(m, 2H), 2.16 (s, 3H) , 209-1.97(m, 2H), 1.87-1.76(m, 4H), 1.74-1.61(m, 2H) ppm; LCMS: 487.1 [M+H]+ Compound 82 F Aj IXxf2h । i o o^NA) n'NH 1-(3-(4-(2- (difluoromethoxy)-3,4-difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)pyrrolidin-2-one 1H NMR (400 MHz, DMSO-d6) 5 12.92(s, 1H), 7.44-7.06(m, 3H), 4.38 (s, 2H), 3.33-3.28(m, 2H), 3.25-3.20(m, 2H), 3.19-3.05(m, 2H), 2.86-2.71(m, 1H), 2.29-2.21(m, 2H), 2.00(s, 3H) , 1.95-1.86(m, 2H), 1.81-1.65(m, 2H), 1.64-1.52(m, 2H) ppm; LCMS: 469.1 [M+H]+ Compound 83 F Ay LA Y2CF2H । / o A A N y N-nh 1-(3-(4-(3,4-difluoro-2- (1,1,2,2-tetrafluoroethoxy)phenyl) piperidine-1-carbonyl)-4-methyl- 1H-pyrazol-5 -yl)methyl)pyrrolidin-2-one 1H NMR (400 MHz, DMSO-d6) 5 7.57-7.46(m, 1H), 7.42-7.32(m, 1H), 7.22-6.83(m,  1H), 4.38(s, 2H), 3.39-3.29(m, 2H), 3.27-3.20(m, 2H), 3.18-3.03(m, 2H), 2.93-2.70(m,  1H),  2.32-2.21(m,  2H), 2.01(s, 3H),  1.98-1.87  (m, 2H),  1.83- 1.66(m, 2H),  1.65-1.54 (m, 2H) ppm; LCMS: 519.2 [M+H]+ Compound 84 F Av F J / NYs oAvy ° n-inh 1-(3-(4-(3,4-difluoro-2- ((1,2,2-trifluoroethenyl)oxy)phen yl)piperidine-1 -carbonyl)-4-methyl- 1H-pyrazol-5-yl)methyl)pyrrolidin-2-one 1H NMR (400 MHz, DMSO-d6) 5 7.46-7.38(m,  1H), 7.33-7.27(m,  1H), 4.37(s, 2H), 3.26-3.14(m, 6H), 2.92-2.74(m, 1H), 2.29-2.22(m, 2H), 1.99 (s, 3H), 1.95-1.87(m, 2H), 1.83-1.69 (m, 2H), 1.66-1.56(m, 2H) ppm; LCMS: 499.2 [M+H]+ Compound 85 A Y / —\ / —\ / 2 1 I — / /        /        / \=J \— / XQ 3-(4-(2-(ethylthio)-3,4-difluorophenyl)piperidine -1-carbonyl)-N, 4-dimethyl- 1H-pyrazol-5 -carboxamide 1H NMR (500 MHz, CDCh) 5 11.78 (s, 1H), 7.13-7.06(m, 1H), 6.96-6.91 (m, 1H), 6.89-6.59(m, 1H), 4.82(s, 1H), 4.03(s, 1H), 3.66-3.59(m, 1H), 3.45-2.99(m, 2H), 2.96(d, J = 4.9 Hz, 3H), 2.93-2.86(m, 2H), 2.40(s, 3H), 1.91-1.77(m, 2H), 1.69-1.66(m, 2H), 1.22(t, J = 7.4 Hz, 3H) ppm; LCMS: 423.2 [M+H]+ Compound # Structure Chemical Name HNMR / LCMS Compound 86 F At T^S^F Y / X 1 J NH N-NH 0 3-(4-(3,4-difluoro-2-((trifluoromethyl)thio)phe nyl)piperidine-1 -carbonyl)-N, 4-dimethyl-1H-pyrazol-5-carboxamide 1H NMR (500 MHz, CDCh) 5 11.66 (s, 1H), 7.39-7.31(m, 1H), 7.12-7.07 (m, 1H), 6.82(s, 1H), 4.83(s, 1H), 4.10(s, 1H), 3.69-3.60(m, 1H), 3.45-3.02(m, 2H), 2.97(d, J = 4.7 Hz, 3H), 2.41(s, 3H), 1.88-1.76(m, 2H), 1.73-1.66(m,  2H) ppm; LCMS: 463.1 [M+H]+ Compound 87 J 1 J NH 0 th N~NH 0 3-(4-(3,4-difluoro-2-((1,2,2-trifluoroethenyl)thio)phen yl)piperidine-1 -carbonyl)-N,4-dimethyl-1H-pyrazol-5-carboxamide 1H NMR (500 MHz, CDCh) 5 11.30 (s, 1H), 7.25-7.21(m, 1H), 7.05-7.01 (m, 1H), 6.74(s, 1H), 4.82(s, 1H), 4.10(s, 1H), 3.68-3.61(m, 1H), 3.44-3.03(m, 2H), 3.02-2.89(m, 3H), 2.41 (s, 3H), 1.92-1.80(m, 2H), 1.76-1.63 (m, 2H) ppm. LCMS: 475.1 [M+H]+ Compound 88 F Ar 1 1 nh ° rH N-nh 0 3-(4-(2- ((difluoromethyl)thio)-.              3,4-   .     . . difluorophenyl)piperidine -1 -carbonyl)-N,4-dimethyl- 1H-pyrazol-5 -carboxamide 1H NMR (500 MHz, CDCh) 5 11.64 (s, 1H), 7.32-7.27(m, 1H), 7.08-7.03 (m, 1H), 6.99-6.71(m, 2H), 5.04-4.62 (m, 1H), 4.30-3.85(m, 1H), 3.66-3.57 (m, 1H), 3.36- 2.99(m, 2H), 2.98-2.93 (m, 3H), 2.41(s, 3H), 1.90-1.77(m, 2H), 1.67-1.65(m, 2H) ppm; LCMS: 475.1 [M+H]+ Compound 89 p       \ * I I   / /        /        / \= /  \-- /  XQ 3-(4-(3,4-difluoro-2-((1,1,2,2-tetrafluoroethyl)thio)phen yl)piperidine-1 -carbonyl)-N,4-dimethyl-1H-pyrazol-5-carboxamide 1H NMR (500 MHz, CDCh) 5 11.54(s, 1H), 7.37-7.29(m,   1H),  7.11-7.07(m,  1H), 6.75(s,  1H),  6.03-5.76(m,  1H),  5.07- 4.65(m,  1H),  4.34-3.86(m,  1H),  3.72- 3.61(m,  1H),  3.43-3.01(m,  2H),  2.98- 2.93(m, 3H), 2.41(s, 3H),  1.88-1.77(m, 2H), 1.72-1.65(m, 2H) ppm; LCMS: 495.1 [M+H]+ Compound 90 F ( J Y / x 1    / NH o:nrV< N-NH 0 3-(4-(3,4-difluoro-2-(methylthio)phenyl)piperi dine-1 -carbonyl)-N,4-dimethyl- 1H-pyrazol-5 -carboxamide 1H NMR (500 MHz, CDCh) 5 11.85(s, 1H), 7.12-7.05(m, 1H), 6.94-6.89(m, 1H), 6.88-6.66(m, 1H), 5.00-4.67(m, 1H), 4.25-3.84(m, 1H), 3.61-3.53(m, 1H), 3.50-2.99(m, 2H), 2.99-2.89(m, 3H), 2.44(s, 3H), 2.40(s, 3H), 1.93-1.75(m, 2H), 1.70-1.69(m, 2H) ppm; LCMS: 409.1 [M+H]+ Compound 91 1 At 'y^O F Jj "nh ^H N-nh 0 3-(4-(3,4-difluoro-2-(trifluoromethoxy)phenyl) piperidine-1 -carbonyl)-N,4-dimethyl-1H-pyrazol-5-carboxamide 1H NMR (400 MHz, CDCF) 5 11.40(s, 1H), 7.20-7.09(m, 1H), 7.05-6.95(m, 1H), 6.84-6.62(m, 1H), 4.98-4.49(m, 1H), 4.31-3.91(m,  1H), 3.30-2.87(m, 6H), 2.41(s, 3H), 1.95-1.81(m, 2H), 1.73-1.66(m, 2H) ppm; LCMS: 447.1 [M+H]+ Compound 92 : J / NH 0 ithA n-nh o 3-(4-(2- (difluoromethoxy)-3,4-difluorophenyl)piperidine -1 -carbonyl)-N,4-dimethyl- 1H-pyrazol-5 -carboxamide 1H NMR (500 MHz, CDCF) 5 11.91(s, 1H), 7.10-7.04(m, 1H), 6.98-6.94(m, 1H), 6.87-6.79(m, 1H), 6.77-6.47(m, 1H), 4.99-4.61(m, 1H), 4.23-3.80(m, 1H), 3.37-3.16(m, 2H), 3.04-2.83(m, 4H), 2.40(s, 3H), 1.93-1.83(m, 2H), 1.70-1.62(m, 2H) ppm; LCMS: 429.2 [M+H]+. Compound # Structure Chemical Name HNMR / LCMS Compound 93 fev N I \ 1 / NH 0 VH N-nh 0 3-(4-(3,4-difluoro-2- (1,1,2,2-tetrafluoroethoxy)phenyl) piperidine-1 -carbonyl)-N,4-dimethyl-1H-pyrazol-5-carboxamide 1H NMR (500 MHz, CDCh) 5 11.54(s, 1H), 7.17-7.09(m, 1H), 7.01-6.96(m, 1H), 6.88-6.58(m, 1H), 6.19-5.91(m, 1H), 4.96-4.60(m, 1H), 4.27-3.85(m, 1H), 3.35-3.09(m, 2H), 3.02-2.76(m, 4H), 2.40(s, 3H), 1.90-1.80(m, 2H), 1.65-1.62(m, 2H) ppm; LCMS: 479.1 [M+H]+ Compound 94 F CCv I / \h N-NH O 3-(4-(3,4-difluoro-2- ((1,2,2-trifluoroethenyl)oxy)phen yl)piperidine-1 -carbonyl)-N,4-dimethyl-1H-pyrazol-5-carboxamide 1H NMR (500 MHz, CDCh) 5 11.89(s, 1H), 7.09-7.01(m, 1H), 6.97-6.92(m, 1H), 6.89-6.64(m, 1H), 5.02-4.62(m, 1H), 4.26-3.86(m, 1H), 3.39-3.15(m, 2H), 3.04-2.82(m, 4H), 2.40(s, 3H), 1.94-1.84(m, 2H), 1.71-1.63(m, 2H) ppm; LCMS: 459.1 [M+H]+ Example 95 Preparation of   ((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4- methyl-1H-pyrazol-5-yl)methyl)proline (Compound 95) Compound 6 (100 mg, 0.19 mmol) was dissolved in methanol (5 mL) and water (1 mL). Sodium hydroxide (15 mg, 0.39 mmol) was added, and the reaction solution was reacted at room temperature for 1 hour. The reaction solution was directly purified by C18 reversed-phase preparative chromatography to afford Compound 95 as a white solid (50 mg, yield: 51%). LCMS: 501.2 [M+1]+. 1H NMR (500 MHz, DMSO-d6) 5 7.78-7.72 (m, 1H), 7.50-7.47 (m, 1H), 3.97-3.69 (m, 4H), 3.15-3.11 (m, 2H), 2.87-2.79 (m, 1H), 2.76-2.57 (m, 1H), 2.49-2.27 (m, 2H), 2.03 (s, 3H), 1.90-1.79 (m, 2H), 1.77-1.63 (m, 6H) ppm. Example 96 Preparation of methyl    ((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1- carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)carbamate (Compound 96) Step 1: Synthesis of tert-butyl 5-(hydroxymethyl)-4-methyl-1H-pyrazole-3-carboxylate (96a) In a 100 mL round-bottom flask, Compound 8a (3.2 g, 12.60 mmol) was dissolved in dichloromethane (30 mL) and cooled to -78 °C. Diisobutylaluminum hydride (44 mL, 1.0 M in tetrahydrofuran, 44 mmol) was slowly added, and the reaction was carried out for additional 2 hours. The reaction was quenched by adding saturated potassium sodium tartrate aqueous solution, stirred for 30 minutes, ethyl acetate was added and the layers were separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried and concentrated to afford a crude product. The crude product was directly used in the next step without further purification. Crude Compound 96a was a yellow solid (2.3 g). LCMS: 213.1 [M+H]+. Step 2: Synthesis of tert-butyl 5-formyl-4-methyl-1H-pyrazole-3-carboxylate (96b) In a 100 mL round-bottom flask, Compound 96a (2.3 g, 10.85 mmol) was dissolved in dichloromethane (30 mL). Dess-Martin oxidant (5.52 g, 13.02 mmol) was added. The reaction was carried out for additional 1 hour. The reaction was quenched by adding saturated potassium sodium tartrate aqueous solution, stirred for 30 minutes. Dichloromethane (50 mL x 3) was added for extraction, and the organic phase was collected and concentrated to afford a crude product. The residue was purified by silica gel column chromatography to afford Compound 96b as a yellow solid (1.79 g, yield: 78%). LCMS: 211.1 [M+H]+. Step 3:  Synthesis of 5-(((methoxycarbonyl)amino)methyl)-4-methyl-1H-pyrazole-3- carboxylic acid (96c) In a 100 mL round-bottom flask, Compound 96b (422 mg, 2.0 mmol) was dissolved in toluene (10 mL). Methyl carbamate (750 mg, 10.0 mmol), trifluoroacetic acid (5 mL), and triethylsilane (465 mg, 4.0 mmol) were added, and the reaction was carried out at 100 °C for additional 6 hours. The reaction solution was directly concentrated. The residue was triturated with methyl tert-butyl ether to precipitate a solid, which was filtered and dried to afford Compound 96c as a light yellow solid (300 mg, yield: 70%). LCMS: 214.1 [M+H]+. Step 4: Synthesis of methyl ((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)carbamate (Compound 96) In a 50 mL round-bottom flask, Compound 96c (213 mg, 1.0 mmol) was dissolved in N,N- dimethylformamide (10 mL). Triethylamine (202 mg, 2.0 mmol) was added, then 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (470 mg, 1.5 mmol) was added. After reacting in an ice bath for 2 minutes, Intermediate 1 (200 mg, 0.75 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was quenched by adding pure water, ethyl acetate (20 mL x 3) was added for extraction, and the organic phase was collected and concentrated to afford a crude product. The crude product was purified by C18 reversed-phase column chromatography to afford Compound 96 as an off-white solid (135 mg, yield 29%). LCMS: 461.2[M+H]+. 1H NMR (500 MHz, CDCI3) 8 11.62 (s, 1H), 7.40-7.31 (m, 1H), 7.22-7.00 (m, 1H), 5.83 (s, 1H), 4.89 (s, 1H), 4.44-4.01 (m, 3H), 3.70 (s, 3H), 3.31-3.02 (m, 2H), 2.98-2.65 (m, 1H), 2.13 (s, 3H), 1.97-1.78 (m, 2H), 1.78-1.60 (m, 2H) ppm. Example 97 Preparation of (3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4- methyl-1H-pyrazol-5-yl)methyl methylcarbamate (Compound 97) 97a                               97b                            97c                       Compound 97 Step 1: Synthesis of ethyl  3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1- carbonyl)-4-methyl-1H-pyrazole-3-carboxylate (97b) In a 50 mL round-bottom flask, Compound 97a (500 mg, 2.51 mmol) was dissolved in N,N-dimethylformamide (20 mL). Triethylamine (505 mg, 5.0 mmol) was added, then 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.43 g, 1.5 mmol) was added. After reacting in an ice bath for 2 minutes, Intermediate 1 (665 mg, 2.51 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was quenched by adding pure water, ethyl acetate (30 mL x 3) was added for extraction, and the organic phase was collected and concentrated to afford a crude product. The crude product was purified by C18 reversed-phase column chromatography to afford Compound 97b as an off-white solid (550 mg, yield 49%). LCMS: 446.1 [M+H]+. Step 2:   Synthesis of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5- (hydroxymethyl)-4-methyl-1H-pyrazol-3-yl)methanone (97c) In a 100 mL round-bottom flask, Compound 97b (550 mg, 1.24 mmol) was dissolved in dichloromethane (10 mL) and the reaction solution was cooled to -78 °C. Diisobutylaluminum hydride (2.0 mL, 1.0 M in tetrahydrofuran, 2.0 mmol) was slowly added. The reaction was carried out for additional 2 hours. The reaction was quenched by adding saturated potassium sodium tartrate aqueous solution and stirred for 30 minutes, ethyl acetate (50 mL x 3) was added for extraction, and the organic phase was collected and concentrated to afford a crude product. The residue was purified by silica gel column chromatography to afford Compound 97c as a yellow solid (100 mg, yield: 19.7%). LCMS: 404.1 [M+H]+. Step 3: Synthesis of (3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl methylcarbamate (Compound 97) In a 100 mL round-bottom flask, Compound 97c (100 mg, 0.24 mmol) was dissolved in dichloromethane (10 mL). N,N'-carbonyldiimidazole (50 mg, 0.32 mmol) was added, and the reaction was carried out at room temperature for 2 hours. Methylamine (62 mg, 2.0 mmol) was added, and the reaction was carried out for additional 16 hours. The reaction solution was directly concentrated, and the crude product was purified by C18 reversed-phase column chromatography to afford Compound 97 as an off-white solid (15 mg, yield 13%). LCMS: 461.2 [M+H]+. 1H NMR (400 MHz, CDCI3) 6 7.43-7.31 (m, 1H), 7.24-7.13 (m, 1H), 5.17-5.03 (m, 2H), 5.01-4.82 (m, 1H), 4.77 (s, 1H), 4.60-4.33 (m, 1H), 3.31-3.19 (m, 1H), 3.17-2.94 (m, 1H), 2.92-2.76 (m, 4H), 2.26-2.17 (m, 3H), 1.99-1.83 (m, 2H), 1.82-1.70 (m, 2H) ppm. Example 98 Preparation of (5-((1H-tetrazol-1-yl)methyl)-4-methyl-1H-pyrazol-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (Compound 98-1) and (5-((2H-tetrazol-2-yl)methyl)-4-methyl-1H-pyrazol-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (Compound 98-2) Step 1: Synthesis of ethyl 4-methyl-5-(((methylsulfonyl)oxy)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (98a) In a 25 mL round-bottom flask, Compound 22a (500 mg, 1.86 mmol) and triethylamine (283 mg, 2.80 mmol) were sequentially dissolved in dichloromethane (5 mL). The reaction solution was stirred at 0 °C for 5 min, then methanesulfonic anhydride (390 mg, 2.24 mmol) was added. The reaction was quenched by adding saturated ammonium chloride solution (8 mL) and extracted with dichloromethane, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distillated under reduced pressure to afford Compound 98a as a yellow oil (642 mg), which was directly used in the next step. LCMS: 347.1 [M+H]+. Step 2: Synthesis of ethyl 5-((1H-tetrazol-1-yl)methyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (98b) In a 25 mL round-bottom flask, Compound 98a (642 mg, 1.85 mmol), tetrazole (649 mg, 9.26 mmol) and potassium carbonate (768 mg, 5.56 mmol) were sequentially dissolved in N,N-dimethylformamide (6 mL), and the reaction solution was stirred at 25 °C for 1.5 hours. The reaction was quenched by adding saturated ammonium chloride solution (8 mL), extracted by ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distillated under reduced pressure to afford Compound 98b as a brown oil (590 mg), which was directly used in the next step. LCMS: 321.2 [M+H]+. Step 3: Synthesis of ethyl 5-((1H-tetrazol-1-yl)methyl)-4-methyl-1H-pyrazole-3-carboxylate (98c) In a 25 mL round-bottom flask, Compound 98b (590 mg, 1.84 mmol) was dissolved in 1,4-dioxane (3 mL). 4 M HCl in 1,4-dioxane was added at 0 °C, and the reaction solution was stirred at 0 °C for 3.5 hours. The reaction solution was distillated under reduced pressure to afford Compound 98c as a yellow oil (500 mg), which was directly used in the next step. LCMS: 237.1 [M+H]+. Step 4: Synthesis of 5-((1H-tetrazol-1-yl)methyl)-4-methyl-1H-pyrazole-3-carboxylic acid (98d) In a 25 mL round-bottom flask, Compound 98c (500 mg, 2.12 mmol) and lithium hydroxide (304 mg, 12.70 mmol) were sequentially dissolved in methanol (6 mL) and water (2 mL), and the reaction solution was stirred at 25 °C for 30 minutes. 2 M hydrochloric acid was added to adjust the pH to 3 to quench the reaction, ethyl acetate was added for extraction, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distillated under reduced pressure to afford Compound 98d as an orange solid (360 mg), which was directly used in the next step. LCMS: 209.1 [M+H]+. Step 5: Synthesis of (5-((1H-tetrazol-1-yl)methyl)-4-methyl-1H-pyrazol-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (Compound 98-1) and (5-((2H-tetrazol-2-yl)methyl)-4-methyl-1H-pyrazol-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (Compound 98-2) In a 25 mL round-bottom flask, Intermediate 1 (401 mg, 1.33 mmol) and Compound 98d (360 mg, 1.73 mmol) were dissolved in N,N-dimethylformamide (5 mL). At 0 °C, N,N-diisopropylethylamine (1031 mg, 7.98 mmol) and butylphosphonic anhydride (721 mg, 50% in ethyl acetate, 2.00 mmol) were sequentially added, and the reaction solution was stirred at 0 °C for 2 hours. The reaction was quenched by adding water (5 mL), extracted by ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distillated under reduced pressure to afford a crude product. The crude product was purified by C18 reversed-phase column chromatography to afford Compound 98-1 as an off-white solid (56 mg, yield: 9%) and Compound 98-2 as an off-white solid (31 mg, yield: 5%). Compound 98-1: LCMS: 456.2[M+H]+; 1H NMR (400 MHz, CDCI3) 8 8.70-8.57 (m, 1H), 7.37-7.28 (m, 1H), 7.20-7.11 (m, 1H), 5.80-5.43 (m, 3H), 4.94-4.84 (m, 1H), 4.55-4.43 (m, 1H), 3.29-3.11 (m, 2H), 2.86-2.74 (m, 1H), 2.28-2.21 (m, 3H), 2.11-1.86 (m, 4H) ppm. Compound 98-2: LCMS: 456.2 [M+H]+; 1H NMR (400 MHz, CDCl3) 8 8.51-8.46 (m, 1H), 7.36-7.28 (m, 1H), 7.19-7.10 (m, 1H), 6.01-5.79 (m, 2H), 5.70-5.63 (m, 1H), 4.95-4.84 (m, 1H), 4.56-4.45 (m, 1H), 3.24-3.04 (m, 2H), 2.86-2.74 (m, 1H), 2.31-2.27 (m, 3H), 2.07-1.81 (m, 4H)ppm. Example 99 Preparation of (5-((1H-1,2,4-triazol-1-yl)methyl)-4-methyl-1H-pyrazol-3-yl)(4-(3,4 difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (Compound 99) Compound 99 Step 1: Synthesis of ethyl 5-((1H-1,2,4-triazol-1-yl)methyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (99a) In a 25 mL round-bottom flask, Compound 98a (645 mg, 1.86 mmol), 1,2,4-triazole (643 mg, 9.31 mmol) and potassium carbonate (772 mg, 5.59 mmol) were sequentially dissolved in N,N-dimethylformamide (6 mL), and the reaction solution was stirred at 25 °C for 2 hours. The reaction solution was quenched by adding saturated ammonium chloride solution (8 mL), extracted by ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distillated under reduced pressure to afford a crude Compound 99a as an off-white solid (595 mg), which was directly used in the next step. LCMS: 320.2 [M+H]+. Step 2: Synthesis of 5-((1H-1,2,4-triazol-1-yl)methyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid (99b) In a 25 mL round-bottom flask, Compound 99a (595 mg, 1.86 mmol) and lithium hydroxide (223 mg, 9.32 mmol) were sequentially dissolved in methanol (6 mL) and water (2 mL), and the reaction solution was stirred at 25 °C for 3 hours. 2 M hydrochloric acid was added to adjust the pH to 5 to quench the reaction, ethyl acetate was added for extraction, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distillated under reduced pressure to afford Compound 99b as an off-white solid (420 mg), which was directly used in the next step. LCMS: 292.1 [M+H]+. Step 3: Synthesis of 5-((1H-1,2,4-triazol-1-yl)methyl)-4-methyl-1H-pyrazole-3-carboxylic acid (99c) In a 25 mL round-bottom flask, Compound 99b (420 mg, 1.44 mmol) was dissolved in 1,4-dioxane (5 mL). 4 M hydrochloric acid / 1,4-dioxane was added at 0 °C, and the reaction solution was stirred at 0 °C for 2 hours. The reaction solution was distillated under reduced pressure to afford Compound 99c as a yellow solid (350 mg), which was directly used in the next step. LCMS: 208.1 [M+H]+. Step 4: Synthesis of (5-((1H-1,2,4-triazol-1-yl)methyl)-4-methyl-1H-pyrazol-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (Compound 99) In a 25 mL round-bottom flask, Intermediate 1 (361 mg, 1.20 mmol) and Compound 99c (350 mg, 1.44 mmol) were dissolved in N,N-dimethylformamide (5 mL). At 0 °C, N,N-diisopropylethylamine (928 mg, 7.18 mmol) and butylphosphonic anhydride (648 mg, 50% in ethyl acetate, 1.80 mmol) were sequentially added, and the reaction solution was stirred at 0 °C for 40 minutes. The reaction was quenched by adding water (5 mL), extracted by ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distillated under reduced pressure to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 99 as an off-white solid (60 mg, yield: 11%). LCMS: 455.2 [M+H]+. 1H NMR (400 MHz, CDCI3) S 12.01 (s, 1H), 8.14 (s, 1H), 7.94 (s, 1H), 7.35-7.27 (m, 1H), 7.16-7.07 (m, 1H), 5.36 (s, 2H), 4.97-4.54 (m, 1H), 4.43-3.93 (m, 1H), 3.29-2.77 (m, 3H), 2.14 (s, 3H), 1.91-1.80 (m, 2H), 1.76-1.57 (m, 2H) ppm. Example 100 Preparation of N-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl-d2)acetamide (Compound 100) Compound 100 Step 1: Synthesis of 3-(tert-butyl) 5-ethyl 4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3,5-dicarboxylate (100a) Compound 8a (1.00 g, 3.93 mmol) and cesium carbonate (3.84 g, 11.80 mmol) were dissolved in acetonitrile (40 mL). Chloromethyltrimethylsilylethyl ether (788 mg, 4.72 mmol) was added dropwise at room temperature, and the reaction was maintained at room temperature and carried out for 1 hour. The reaction was quenched by adding water (50 mL), and extracted by ethyl acetate (50 mL x 3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotatory evaporated under reduced pressure to dryness to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 100a as a colorless liquid (1.00 g, yield: 66%). LCMS: 385.2 [M+H]+. Step 2:     Synthesis of tert-butyl     5-(hydroxymethyl-D2)-4-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (100b) Compound 100a (800 mg, 2.08 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). The reaction solution was directly cooled to 0 °C. Lithium aluminum deuteride (130 mg, 3.12 mmol) was added, and the reaction was maintained at this temperature and carried out for 15 minutes. Water (0.8 mL), 15% sodium hydroxide solution (0.8 mL), and water (2.4 mL) were sequentially added. Ethyl acetate (50 mL) was added for dilution, and the reaction solution was stirred for 30 minutes. Anhydrous magnesium sulfate was added for overnight drying. The reaction solution was filtered, and the filtrate was collected, and directly concentrated to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 100b as a colorless liquid (410 mg, yield: 57%). LCMS: 345.2 [M+H]+. Step 3: Synthesis of tert-butyl 4-methyl-5-(((methylsulfonyl)oxy)methyl-D2)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (100c) Compound 100b (410 mg, 1.19 mmol) was dissolved in anhydrous dichloromethane (10 mL). The reaction solution was cooled to 0 °C. Triethylamine (361 mg, 3.57 mmol) and methanesulfonic anhydride (250 mg, 1.43 mmol) were added, and the reaction was maintained at this temperature and carried out for 15 minutes. After the reaction was complete, the obtained solution of Compound 100c was directly used for the next step. LCMS: 423.3 [M+H]+. Step     4:     Synthesis     of     tert-butyl     5-(aminomethyl-D2)-4-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (100d) The reaction solution of Compound 100c (10 mL) obtained in the previous step was directly added dropwise to ammonia solution (7 mL, 7 mol / L in methanol) at 0 °C. The reaction solution was maintained at that temperature and stirred for 30 minutes, then the reaction solution was allowed to warm to room temperature and reacted overnight. After the reaction was complete, the reaction solution was directly concentrated to dryness to afford a crude Compound 100d as a colorless liquid (400 mg), which was directly used for the next step. LCMS: 344.2 [M+H]+. Step 5:    Synthesis of tert-butyl    5-(acetamidomethyl-D2)-4-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (100e) Compound 100d (400 mg, 1.16 mmol) obtained in the previous step was dissolved in tetrahydrofuran (5 mL) and water (5 mL). Sodium carbonate (250 mg, 2.33 mmol) was added, and the reaction solution was stirred for 15 minutes. Acetic acid-N-succinimidyl ester (220 mg, 1.4 mmol) was added, and the reaction solution was allowed to warm to room temperature and stirred for 1 hour. Water and ethyl acetate were added and the layers were separated, the organic phase was collected, and directly concentrated to dryness to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 100e as a colorless liquid (360 mg, yield: 80%). LCMS: 386.2 [M+H]+. Step 6: Synthesis of 5-(acetamidomethyl-d2)-4-methyl-1H-pyrazole-3-carboxylic acid (100f) Compound 100e (360 mg, 0.93 mmol) was dissolved in anhydrous dichloromethane (10 mL). Trifluoroacetic acid (1 mL) was added. The reaction solution was directly heated to 45 °C and reacted for 1 hour. The reaction solution was directly concentrated to dryness to afford Compound 100f as a colorless oil (184 mg). LCMS: 200.1 [M+H]+. Step 7:   Synthesis of  N-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1- carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl-d2)acetamide (Compound 100) In a 25 mL round-bottom flask, Intermediate 1 (540 mg, 1.81 mmol) and Compound 100f (180 mg, 0.90 mmol) were dissolved in N,N-dimethylformamide (5 mL). At 0 °C, N,N-diisopropylethylamine (700 mg, 5.42 mmol) and butylphosphonic anhydride (1.30 g, 50% in ethyl acetate, 1.80 mmol) were sequentially added, and the reaction solution was stirred at 0 °C for 40 minutes. The reaction was quenched by adding water (5 mL), extracted by ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distillated under reduced pressure to afford a crude product. The crude product was purified by C18 reversed-phase preparative chromatography to afford Compound 100 as an off-white solid (45 mg, yield: 11%). LCMS: 447.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 5 12.81 (s, 1H), 8.20 (s, 1H), 7.79-7.73 (m, 1H), 7.52-7.49 (m, 1H), 4.75-4.60 (m, 1H), 4.45-4.20 (m, 1H), 3.20-3.10 (m, 2H), 2.90-2.75 (m, 1H), 2.02 (s, 3H), 1.85 (s, 3H), 1.77-1.64 (m, 4H) ppm. Example 101 Preparation of (5-((1H-imidazol-1-yl)methyl)-4-methyl-1H-pyrazol-3-yl)(4-(3,4-difluoro-2- (trifluoromethyl)phenyl)piperidin-1-yl)methanone (Compound 101) Compound 101 Step 1: Synthesis of ethyl 4-methyl-5-(((methylsulfonyl)oxy)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (101a) Compound 22a (400 mg, 1.49 mmol) was dissolved in anhydrous dichloromethane (10 mL). The reaction solution was cooled to 0 °C. Triethylamine (453 mg, 4.47 mmol) and methanesulfonic anhydride (312 mg, 1.79 mmol) were added, and the reaction was maintained at this temperature and carried out for 15 minutes. After the reaction was complete, the obtained solution of Compound 101a was directly used for the next step. LCMS: 447.2 [M+H]+. Step 2: Synthesis of ethyl 5-((1H-imidazol-1-yl)methyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (101b) The reaction solution of Compound 101a (10 mL) obtained in the previous step was directly added dropwise to a suspension of potassium carbonate (600 mg, 4.33 mmol) and imidazole (491 mg, 7.22 mmol) in N,N-dimethylformamide (10 mL) at 0 °C. The mixture was maintained at that temperature and stirred for 30 minutes, then the mixture was allowed to warm to room temperature and reacted overnight. Water and ethyl acetate were added and the layers were separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were sequentially washed with water and brine, dried, and concentrated to afford a crude product. The crude product was purified by silica gel column chromatography to afford Compound 101b as a colorless oil (250 mg, yield: 54%). LCMS: 319.2 [M+H]+. Step 3: Synthesis of 5-((1H-imidazol-1-yl)methyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid (101c) Compound 101b (250 mg, 0.79 mmol) was dissolved in methanol (5 mL) and water (5 mL). Anhydrous lithium hydroxide (188 mg, 7.90 mmol) was added, and the reaction was carried out at room temperature for 2 hours. Water was added for dilution, methanol was removed by concentration, the pH was adjusted to 3-4 with 1 M dilute hydrochloric acid, then ethyl acetate was added for extraction, and the organic phase was dried, and concentrated to afford a crude Compound 101c as a colorless oil (180 mg), which was directly used for the next step without further purification. LCMS: 291.2 [M+H]+. Step 4: Synthesis of 5-((1H-imidazol-1-yl)methyl)-4-methyl-1H-pyrazole-3-carboxylic acid (101d) Compound 101c (180 mg, 0.62 mmol) was dissolved in dioxane (2 mL). HCl in dioxane (5 mL, 4 mmol / L) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was directly concentrated to dryness to afford Compound 101d as a white solid (120 mg), which was directly used for the next step without further purification. LCMS: 207.1 [M+H]+. Step 5: Synthesis of (5-((1H-imidazol-1-yl)methyl)-4-methyl-1H-pyrazol-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (Compound 101) In a 25 mL round-bottom flask, Intermediate 1 (175 mg, 0.58 mmol) and Compound 101d (120 mg, 0.58 mmol) were dissolved in N,N-dimethylformamide (5 mL). At 0 °C, N,N-diisopropylethylamine (225 mg, 1.75 mmol) and butylphosphonic anhydride (629 mg, 50% in ethyl acetate, 0.88 mmol) were sequentially added, and the reaction solution was stirred at 0 °C for 40 minutes. The reaction was quenched by adding water (5 mL), extracted by ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distillated under reduced pressure to afford a crude product. The crude product was purified by C18 reversed-phase preparative chromatography to afford Compound 101 as an off-white solid (10 mg, yield: 4%). LCMS: 454.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 5 13.14 (s, 1H), 7.78 (s, 1H), 7.71 (s, 1H), 7.50 (s, 1H), 7.15 (s, 1H), 6.91 (s, 1H), 5.22 (s, 2H), 4.68-4.34 (m, 2H), 3.20-3.10(m, 2H), 2.90-2.75 (m, 1H), 2.06 (s, 3H), 1.86-1.62 (m,4H) ppm. Example 102 to Example 141 Preparation of Compound 102 to Compound 141 The synthesis of Compound 102 to Compound 141 employed Intermediate 2 to Intermediate 11, which were condensed with the corresponding pyrazole carboxylic acid derivatives. The structures and characterization of Compound 102 to Compound 141 are shown in Table 2. Table 2 Compound # Structure Chemical Name HNMR / LCMS Compound 102 F ( JI IT 1  (| 1 J      o °W r \ n~nh Methyl (3-(4-(3,4-difluoro-2-(methylthio)phenyl)piper idine-1 -carbonyl)-4-methyl- 1H-pyrazol-5 -yl)methyl)prolinate 1H NMR (500 MHz, DMSOd) 5 12.79(s, 1H), 7.44-7.36(m, 1H), 7.21-7.14(m, 1H), 3.56(s, 3H), 3.33-3.29(m, 6H), 3.23-3.18(m, 1H), 2.91-2.86(m, 1H), 2.49-2.46(m, 2H), 2.42 (s, 3H), 2.07(s, 3H), 2.00-1.99(m, 2H), 1.80- 1.68(m, 4H), 1.61-1.50 (m, 2H) ppm; LCMS: 493.2 [M+H]+ Compound 103 F CCS^ ^hr . (J A 7 n-X o T \ n~nh Methyl (3-(4-(2-(ethylthio)-3,4-difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)prolinate 1H NMR (500 MHz, DMSO-d6) 5 7.47-7.41(m, 1H), 7.22-7.19(m, 1H), 4.498-4.33(m, 4H), 3.72(s, 3H), 3.29-3.17(m, 4H), 2.90-2.86(m, 2H), 2.45-2.42(m, 2H), 2.09(s, 3H), 2.05-1.97(m, 2H), 1.93-1.74(m, 4H), 1.63-1.55(m, 2H), 1.15-1.12(m, 3H) ppm; LCMS: 507.2 [M+H]+ Compound 104 2=(   '—z   )—< X / - ^Z^X o / 1 Methyl (3-(4-(3,4-difluoro-2-((trifluoromethyl)thio)ph enyl)piperidine-1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)prolinate 1H NMR (400 MHz, DMSOd) 5 12.81(s, 1H), 7.84-7.63(m, 1H), 7.50-7.38(m, 1H), 3.83-3.59(m, 2H), 3.57(s, 3H), 3.35-3.31(m, 4H), 3.24-3.18(m, 1H), 2.93-2.86(m, 1H), 2.51-2.33(m, 2H), 2.02(s, 3H), 1.90-1.54(m, 8H) ppm; LCMS: 547.1 [M+H]+ Compound # Structure Chemical Name HNMR / LCMS Compound 105 F LA^CF.H Sr . < / .A 1 N-k 0 O'TfX— /  « x N-NH     0 Methyl (3-(4-(2-((difluoromethyl)thio)-.              3,4-   .     . . difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)prolinate 1H NMR (400 MHz, DMSOd) 5 7.69-7.63(m, 1H), 7.58-7.44(m, 1H), 7.377.31 (m, 1H), 3.72(s, 3H), 3.40-3.20(m, 6H), 3.15-3.01(m, 1H), 2.97-2.80(m, 1H), 2.49-2.38(m, 2H), 2.09(s, 3H), 2.06-1.96(m, 2H), 1.95-1.78(m, 2H), 1.78-1.65(m, 2H), 164-1.56(m, 2h); LCMS: 529.1 [M+H]+ Compound 106 F F CA^CFzCFzH ST / ¢ / J. 1 N-\n O^rfV- / T < n-nh 0 Methyl (3-(4-(3,4-difluoro-2-(1,1,2,2-tetrafluoroethyl)thio)phen yl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)prolinate 1H NMR (400 MHz, DMSOd) 5 7.79-7.66(m, 1H), 7.47-7.37(m, 1H), 7.13-6.60(m, 1H), 4.53-4.48(m, 2H), 4.45-4.35(m, 2H), 3.74(s, 3H), 3.62-3.52(m, 2H), 3.37-3.27(m, 1H), 3.00-2.78(m, 1H), 2.52-2.40(m, 2H), 2.12 (s, 3H), 2.00-1.57(m, 6H), 1.56-1.24(m, 2H) ppm. LCMS: 579.1 [M+H]+ Compound 107 F ocv ^rr . ( / A J N-< o o^Y\_7 JT x n-nh Methyl (3-(4-(3,4-difluoro-2-((1,2,2-trifluoroethenyl)thio)phe nyl)piperidine-1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)prolinate 1H NMR (500 MHz, CDCh) 5 10.72 (s, 1H), 7.24-7.18(m, 1H), 7.09-7.04 (m, 1H), 5.02-4.80(m, 1H), 4.55-4.38 (m, 1H), 3.92-3.85(m, 1H), 3.74-3.66(m, 4H), 3.65-3.57(m, 1H), 3.34 (t, J = 7.4 Hz, 1H), 3.25-3.07(m, 2H), 2.95-2.78(m, 1H), 2.52-2.44(m, 1H), 2.26-2.15(m, 1H), 2.12(s, 3H), 2.03-1.72(m, 7H) ppm; LCMS: 559.2 [M+H]+ Compound 108 O y--\    / = M ) o " ^Z^X    ’ O^ / o / Methyl (3-(4-(3,4-difluoro-2-(trifluoromethoxy)phenyl )piperidine-1 -carbonyl)-4 -methyl- 1H-pyrazol-5 -yl)methyl)prolinate 1H NMR (400 MHz, DMSO-d6) 5 12.82 (s, 1H), 7.60-7.48 (m, 1H), 7.44 -7.35 (m, 1H), 3.56 (s, 3H), 3.40-3.31 (m, 6H), 3.24-3.19 (m, 1H), 2.93-2.86 (m, 1H), 2.52-2.48 (m, 2h), 2.01 (s, 3H) , 1.92-1.53 (m, 8H) ppm; LCMS: 531.2 [M+H]+ Compound 109 F J^F LXo,CF2H . ( / J. J N—k, o IT n-nh ° Methyl (3-(4-(2-(difluoromethoxy)-3,4-difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)prolinate 1H NMR (500 MHz, DMSOd) 5 12.80(s, 1H), 7.42-7.36(m, 1H), 7.27-7.24(m, 1H), 7.23-7.19(m, 1H), 3.78-3.60(m, 2H), 3.55(s, 3H), 3.22-3.11(m, 4H), 2.92-2.85(m, 1H), 2.84-2.74(m, 1H) , 2.49-2.33(m, 2H) , 2.00 (s, 3H), 1.85-1.64(m, 6H), 1.62-1.52 (m, 2H) ppm; LCMS: 513.1 [M+H]+ Compound 110 F LAo,cf2cf2h Sr . (^ A 1 N—\T) O'W A X N-nh     0 Methyl (3-(4-(3,4-difluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl) piperidine-1 -carbonyl)-4-methyl- 1H-pyrazol-5 -yl)methyl)prolinate 1H NMR (500 MHz, DMSOd) 5 12.81(s, 1H), 7.54-7.43(m, 1H), 7.39-7.31(m, 1H), 7.15-6.87(m, 1H), 3.55(s, 3H), 3.32-3.26(m, 2H), 3.24-3.15(m, 2H), 3.13-3.03(m, 2H), 2.91 -2.85(m, 1H), 2.80-2.68(m, 1H), 2.43-2.34(m, 1H), 2.09-2.02(m,  1H), 2.00(s, 3H), 1.90-1.51(m, 8H) ppm; LCMS: 563.1 [M+H]+ Compound 111 o / Methyl (3-(4-(3,4-difluoro-2-((1,2,2-trifluoroethenyl)oxy)phe nyl)piperidine-1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)prolinate 1H NMR (500 MHz, DMSO-d6) 5 7.45-7.37(m, 1H), 7.33-7.26(m, 1H), 3.56(s, 3H), 3.45-3.39(m, 4H), 3.24-3.18(m, 2H), 3.17-3.07(m, 1H), 2.94-2.86(m, 1H), 2.45-2.35(m, 1H), 2.11-2.03(m, 1H), 2.00(s, 3H), 1.85-1.67(m, 6H), 1.66-1.55(m, 2H) ppm; LCMS: 543.2 [M+H]+ Compound # Structure Chemical Name HNMR / LCMS Compound 112 F F Y 1 J 1 J HN A n-nh Methyl ((3-(4-(3,4-difluoro-2-((1,2,2-trifluoroethenyl)oxy)phe nyl)piperidine-1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)carbamate 1H NMR (500 MHz, CDCh) 5 11.23 (s, 1H), 7.07-7.01(m, 1H), 7.00-6.93 (m, 1H), 5.69-5.55(m, 1H), 4.87 (s, 1H), 4.46-4.09(m, 3H), 3.69(s, 3H), 3.27- 3.18(m, 1H), 3.16-2.69(m, 2H), 2.12 (s, 3H), 1.90-1.75(m, 2H), 1.72-1.57(m, 2H) ppm; LCMS: 489.2 [M+H]+ Compound 113 y. I / HN-X °' n~nh Methyl ((3-(4-(3,4-difluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl) piperidine-1 -carbonyl)-4-methyl- 1H-pyrazol-5 -yl)methyl)carbamate 1H NMR (500 MHz, CDCh) 5 11.54 (s, 1H), 7.17-7.06(m, 1H), 7.03-6.93 (m, 1H), 6.04(t, J = 52.9 Hz, 1H), 5.87-5.72(m, 1H), 4.85(s, 1H), 4.38-4.03(m, 3H), 3.67(s, 3H), 3.29-2.74 (m, 3H), 2.10(s, 3H), 1.87-1.70 (m, 2H), 1.68-1.54(m, 2H) ppm; LCMS: 509.2 [M+H]+ Compound 114 F ,        9 1    / hn-K Av °" N-NH Methyl ((3-(4-(2--difluoromethoxy)-3,4-difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)carbamate 1H NMR (500 MHz, CDCh) 5 11.36 (s, 1H), 7.09-7.02(m, 1H), 7.01-6.95 (m, 1H), 6.61(t, J = 74.2 Hz, 1H), 5.72-5.63(m, 1H), 4.85(s, 1H), 4.42-4.15(m, 3H), 3.68(s, 3H), 3.29-3.20 (m, 1H), 3.18-2.98(m, 1H), 2.94-2.67 (m, 1H), 2.11(s, 3H), 1.83-1.74(m, 2H), 1.69- 1.56(m, 2H) ppm; LCMS: 459.2 [M+H]+ Compound 115 F f ""O F 1 / hA °*w N-NH methyl((3-(4-(3,4-difluoro-2-(trifluoromethoxy)phenyl )piperidine-1 -carbonyl)-4 -methyl- 1H-pyrazol-5 -yl)methyl)carbamate 1H NMR (500 MHz, CDCh) 5 11.17 (s, 1H), 7.18-7.10(m, 1H), 7.05-6.97 (m, 1H), 5.58-5.50(m, 1H), 4.85(s, 1H), 4.48-4.13(m, 3H), 3.69(s, 3H), 3.24- 3.14(m, 1H), 3.13-2.61(m, 2H), 2.12(s, 3H), 1.90-1.76(m, 2H), 1.73-1.68 (m, 2H) ppm; LCMS: 477.2 [M+H]+ Compound 116 F QV A, F /        9 4 J HN A. F          o— n-nh methyl((3-(4-(3,4-difluoro-2-)(1,2,2-trifluoroethenyl)thio)phe nyl)piperidine-1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)carbamate 1H NMR (500 MHz, CDCh) 5 7.25-7.17(m, 1H), 7.07-7.01(m, 1H), 5.71 (s, 1H), 4.86 (s, 1H), 4.40-4.17(m, 3H), 3.76-3.66(m, 3H), 3.65-3.55(m, 1H), 3.32-3.03(m, 1H), 3.02-2.77 (m, 1H), 2.12(s, 3H), 1.91-1.75(m, 2H), 1.73- 1.57(m, 2H) ppm; LCMS: 505.1 [M+H]+ Compound 117 y 1 / J 1   1 HN'A °Arv n'NH Methyl (3-(4-(3,4-difluoro-2-(( 1,1,2,2-tetrafluoroethyl)thio)phen yl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)carbamate 1H NMR (500 MHz, CDCh) 5 11.11 (s, 1H), 7.38-7.28(m, 1H), 7.14-7.06 (m, 1H), 6.05-5.73(m, 1H), 5.51(t, J = 5.7 Hz, 1H), 4.87(s, 1H), 4.61-4.17 (m, 3H), 3.70(s, 3H), 3.66-3.59(m, 1H), 3.31- 3.05(m, 1H), 3.02-2.70(m, 1H), 2.13(s, 3H), 1.86-1.75(m, 2H), 1.69-1.63(m, 2H) ppm; LCMS: 525.1 [M+H]+ Compound 118 F Vf Y^s^f । I J 1  1 hn-A °Vy °' N-NH Methyl ((3-(4-(2-(difluoromethyl)thio)-.              3,4-   .     . . difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)carbamate 1H NMR (500 MHz, CDCh) 5 11.23 (s, 1H), 7.30-7.26(m, 1H), 7.11-7.04 (m, 1H), 6.86(t, J = 56.9 Hz, 1H), 5.58(t, J = 5.0 Hz, 1H), 4.86(s, 1H), 4.48-4.16 (m, 3H), 3.69(s, 3H), 3.63-3.53(m,  1H), 3.30-3.03(m, 1H), 3.01-2.73(m, 1H), 2.12(s, 3H), 1.82-1.75(m, 2H), 1.67- 1.57(m, 2H) ppm; LCMS: 475.1 [M+H]+ Compound # Structure Chemical Name HNMR / LCMS Compound 119 F M , 9 1 1 hn-A o<W 0 n-nh Methyl ((3-(4-(3,4-difluoro-2-((trifluoromethyl)thio)ph enyl)piperidine-1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)carbamate 1H NMR (500 MHz, CDCh) 5 11.08 (s, 1H), 7.38-7.31(m, 1H), 7.15-7.09 (m, 1H), 5.51-5.45(m, 1H), 4.88 (s, 1H), 4.41-4.14(m, 3H), 3.70(s, 3H), 3.66- 3.59(m, 1H), 3.28-3.09(m, 1H), 3.00-2.79(m, 1H), 2.13 (s, 3H), 1.89-1.74(m, 2H), 1.67-1.64(m, 2H) ppm; LCMS: 493.1 [M+H]+ Compound 120 F AjJ [ T Y'U''^'" M . ° 1    / hn-A n~nh Methyl ((3-(4-(2-ethylthio)-3,4-difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)carbamate 1H NMR (500 MHz, CDCh) 5 11.34 (s, 1H), 7.19-7.06(m, 1H), 6.98-6.84 (m, 1H), 5.68(t, J = 5.2 Hz, 1H), 4.85 (s, 1H), 4.48-4.14(m, 3H), 3.68 (s, 3H), 3.64-3.53(m, 1H), 3.18(s, 1H), 3.04- 2.76(m, 3H), 2.11(s, 3H), 1.82-1.75(m, 2H), 1.69-1.54(m, 2H), 1.21 (t, J = 7.4 Hz, 3H) ppm; LCMS: 453.2 [M+H]+ Compound 121 F J^.f ( T y s^ M , z? J J HN^X oAfiV °" n'NH Methyl ((3-(4-(3,4-difluoro-2-(methylthio)phenyl)piper idine-1 -carbonyl)-4-methyl- 1H-pyrazol-5 -yl)methyl)carbamate 1H NMR (500 MHz, CDCh) 5 11.27 (s, 1H), 7.11-7.03(m, 1H), 6.96-6.88 (m, 1h), 5.62(t, J = 5.4 Hz, 1H), 4.86 (s, 1H), 4.46-4.06(m, 3H), 3.69(s, 3H), 3.55 (t, J = 12.1 Hz, 1H), 3.20(s, 1H), 2.91(s, 1H), 2.44(s, 3H), 2.12(s, 3H), 1.85- 1.77(m, 2H), 1.67-1.58(m, 2H) ppm; LCMS: 439.2 [M+H]+ Compound 122 F J^F 00 i / Q o jfy-t o n~nh 1-((3-(4-(3,4-difluoro-2-(methylthio)phenyl)piper idine-1 -carbonyl)-4-methyl- 1H-pyrazol-5 -yl)methyl)piperidin-2- one 1H NMR (500 MHz, CDCh) 5 10.96 (s, 1H), 7.11-7.04(m, 1H), 6.98-6.92 (m, 1H), 4.89(s, 1H), 4.54-4.30 (m, 3H), 3.56(t, J = 12.0 Hz, 1H), 3.39-3.30(m, 2H), 3.25-3.08(m, 1H), 3.00-2.78(m, 1H), 2.46-2.42(m, 3H), 2.42-2.37(m, 2H), 2.18(s, 3H), 1.80-1.75 (m, 4H), 1.72-1.67(m, 4H) ppm; LCMS: 463.2 [M+H]+ Compound 123 F OU ■ i Q A J ,NU 0 n~nh 1-((3-(4-(2-)ethylthio)- .              3,4-   .     . . difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)piperidin-2-one 1H NMR (500 MHz, CDCh) 5 11.14 (s, 1H), 7.12-7.04(m, 1H), 6.99-6.92 (m, 1H), 4.88(s, 1H), 4.42(s, 3H), 3.64- 3.56(m, 1H), 3.37-3.30(m, 2H), 3.24-3.08(m, 1H), 2.94-2.78(m, 3H), 2.45-2.33(m, 2H), 2.17(s, 3H), 1.91-1.77(m, 6H), 1.70-1.61(m, 2H), 1.23-1.18(m, 3H) ppm; LCMS: 477.2 [M+H]+ Compound 124 F 6cO Y^S F , ( / J / N—4 o^yy—^ ° n~nh 1-((3-(4-(3,4-difluoro-2-((trifluoromethyl)thio)ph enyl)piperidine-1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)piperidin-2-one 1H NMR (500 MHz, CDCh) 5 11.20 (s, 1H), 7.38-7.29(m, 1H), 7.18-7.07 (m, 1H), 4.89(s,  1H), 4.60-4.25(m, 3H), 3.66-3.58(m, 1H), 3.38-3.29(m, 2H), 3.24-3.04(m, 1H), 3.00-2.75(m, 1H), 2.45-2.34(m, 2H), 2.18(s, 3H), 1.95- 1.78(m, 6H), 1.72-1.65(m, 2H) ppm; LCMS: 517.2 [M+H]+ Compound # Structure Chemical Name HNMR / LCMS Compound 125 F &A Sr . ( / 1    / N—\ o n~nh 1-((3-(4-(2-(difluoromethyl)thio)-.              3,4-   .     . . difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)piperidin-2-one 1H NMR (500 MHz, CDCh) 5 11.14 (s, 1H), 7.30-7.23(m, 1H), 7.12-7.06 (m, 1H), 6.85(t, J = 56.9 Hz, 1H), 4.88(s, 1H), 4.55-4.31(m, 3H), 3.63-3.54(m, 1H), 3.39-3.30(m, 2H), 3.24-3.04(m, 1H), 2.96-2.75(m, 1H), 2.43-2.36(m, 2H), 2.18(s, 3H), 1.88-1.76 (m, 6H), 1.71-1.61(m, 2H) ppm; LCMS: 499.2 [M+H]+ Compound 126 F Oto y i O A J N-S ozYyj 0 n-nh 1-((3-(4-(3,4-difluoro-2- )((1,1,2,2-tetrafluoroethyl)thio)phen yl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)piperidin-2-one 1H NMR (500 MHz, CDCh) 5 11.14 (s, 1H), 7.37-7.27(m, 1H), 7.16-7.02 (m, 1H), 5.90(t, J = 53.8 Hz, 1H), 4.89(s, 1H), 4.63-4.22(m, 3H), 3.68-3.59(m, 1H), 3.47(s, 2H), 3.37-3.31 (m, 2H), 3.23-3.05(m, 1H), 2.98-2.76 (m, 1H), 2.45-2.34(m, 2H), 2.18(s, 3H), 1.88- 1.79(m, 4H), 1.73-1.66 (m, 2H) ppm; LCMS: 549.2 [M+H]+ Compound 127 O    / --X     / =. 1-((3-(4-(3,4-difluoro-2-.         )((1,2-    . trifluoroethenyl)thio)phe nyl)piperidine-1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)piperidin-2-one 1H NMR (500 MHz, CDCh) 5 10.85 (s, 1H), 7.25-7.19(m, 1H), 7.08-7.04 (m, 1H), 4.91(s,  1H), 4.56-4.35(m, 3H), 3.63(t, J = 11.9 Hz, 1H), 3.40-3.32(m, 2H), 3.24-3.10(m, 1H), 2.95-2.77(m, 1H), 2.43-2.37(m, 2H), 2.19(s, 3H), 1.90-1.76(m, 6H), 1.74-1.67 (m, 2H) ppm; LCMS: 529.2[M+H]+ Compound 128 F to Y^O F j i o A J N-S o n-nh 1-((3-(4-(3-(3-4-difluoro-2- (trifluoromethoxy)phenyl )piperidine-1 -carbonyl)-4 -methyl- 1H-pyrazol-5 -yl)methyl)piperidin-2-one 1H NMR (500 MHz, CDCh) 5 11.00 (s, 1H), 7.18-7.09(m, 1H), 7.05-6.99 (m, 1H), 4.89(s,  1H), 4.61-4.27(m, 3H), 3.39-3.31(m, 2H), 3.23-3.02 (m, 2H), 2.83(s, 1H), 2.44-2.35(m, 2H), 2.19(s, 3H), 1.91-1.74 (m, 6H), 1.73-1.70(m, 2H) ppm; LCMS: 501.2 [M+H]+ Compound 129 F to Y °' F । / Q n'NH 1-((3-(4-(2--difluoromethoxy)-3,4-difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)piperidin-2-one 1H NMR (500 MHz, CDCh) 5 11.13 (s, 1H), 7.09-7.02(m, 1H), 7.01-6.94 (m, 1H), 6.61(t, J = 74.2 Hz, 1H), 4.88(s, 1H), 4.53-4.31(m, 3H), 3.37- 3.30(m, 2H), 3.27-3.19(m, 1H), 3.19-3.03(m, 1H), 2.96-2.76(m, 1H), 2.44 -2.34(m, 2H), 2.17(s, 3H), 1.94-1.78 (m, 6H), 1.71-1.60(m, 2H) ppm; LCMS: 483.2 [M+H]+ Compound 130 Y^ 1 \ / 1 I N—\ o^YYy-J 0 n-nh 1-((3-(4-(3,4-difluoro-2- (1,1,2,2-tetrafluoroethoxy)phenyl) piperidine-1 -carbonyl)-4-methyl- 1H-pyrazol-5 -yl)methyl)piperidin-2-one 1H NMR (500 MHz, CDCh) 5 11.13 (s, 1H), 7.15-7.08(m, 1H), 7.04-6.98 (m, 1H), 6.04(t, J = 52.9 Hz, 1H), 4.89(s, 1H), 4.59-4.27(m, 3H), 3.38- 3.29(m, 2h), 3.18-3.00(m, 2H), 2.92-2.71 (m, 1H), 2.42-2.35 (m, 2H), 2.17 (s, 3H), 1.91-1.78(m, 6H), 1.71-1.60 (m, 2H) ppm; LCMS: 533.2 [M+H]+ Compound # Structure Chemical Name HNMR / LCMS Compound 131 F F , ( / J I   N—4 o'lyJ o n~nh 1-((3-(4-(3,4-difluoro-2-(1,2-trifluoroethenyl)oxy)phe nyl)piperidine-1 -carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)piperidin-2-one 1H NMR (500 MHz, CDCh) 5 7.07-7.00(m, 1H), 7.00-6.95(m, 1H), 4.95-4.81(m, 2H), 4.52-4.29(m, 3H), 3.34 (s, 2H), 3.26-3.18(m, 1H), 3.17-3.04 (m, 1H), 2.94-2.76(m, 1H), 2.45-2.35 (m, 2H), 2.19-2.14(m, 3H), 1.96-1.75(m, 6H), 1.73-1.62(m, 2H) ppm; LCMS: 513.2 [M+H]+ Compound 132 F ( J .     HN— I J 0-4 °nrv 0 n~nh (3-(4-(3,4-difluoro-2-(methylthio)phenyl)piper idine-1 -carbonyl)-4-methyl- 1H-pyrazol-5 -yl)methyl methylcarbamate 1H NMR (500 MHz, CDCh) 5 11.10 (s, 1H), 7.12-7.03(m, 1H), 6.96-6.90 (m, 1H), 5.14-5.02(m, 2H), 4.99-4.70(m, 2H), 4.57-4.19(m, 1H), 3.59-3.50(m, 1H), 3.28-3.07(m, 1H), 3.04-2.83(m, 1H), 2.82-2.73(m, 3H), 2.43 (s, 3H), 2.24-2.14 (m, 3H), 1.91-1.70 (m, 4H) ppm; LCMS: 439.2 [M+H]+ Compound 133 F U^F ( T ,     HN- 1    /   0-4 o-^Yy. / o n-nh (3-(4-(2-)ethylthio)-3,4-difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5 -yl)methyl methylcarbamate 1H NMR (500 MHz, CDCh) 5 11.21 (s, 1H), 7.13-7.04(m, 1H), 6.97-6.91 (m, 1H), 5.14-4.73(m, 4H), 4.48-4.17 (m, 1H), 3.65-3.56(m, 1H), 3.28-3.02 (m, 1H), 2.99-2.69(m, 6H), 2.23-2.13(m, 3H), 1.89-1.77(m, 2H), 1.70-1.58(m, 2H), 1.21(t, J = 7.1 Hz, 3H) ppm; LCMS: 453.2 [M+H]+ Compound 134 F Ay .     HN- .,,1 J    o—\ °yV ° N'NH (3 -(4-(3,4-difluoro-2-((trifluoromethyl)thio)ph enyl)piperidine-1 -carbonyl)-4-methyl-1H-pyrazol-5 -yl)methyl methylcarbamate 1H NMR (500 MHz, CDCh) 5 11.17 (s, 1H), 7.38-7.30(m, 1H), 7.15-7.08 (m, 1H), 5.14-4.77(m, 4H), 4.59- 4.27(m, 1H), 3.67-3.59(m, 1H), 3.26-3.05(m, 1H), 3.04-2.73(m, 4H), 2.24-2.14(m, 3H), 1.88-1.69(m, 4H) ppm; LCMS: 493.1 [M+H]+ Compound 135 F &A ,     HN- j / o Y oyy ° n'NH (3-(4-(2-(difluoromethyl)thio)-.           3,4- difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5 -yl)methyl methylcarbamate 1H NMR (500 MHz, CDCh) 5 11.08 (s, 1H), 7.31-7.26(m, 1H), 7.11-7.04 (m, 1H), 6.86(t, J = 56.9 Hz, 1H), 5.16-4.74 (m, 4H), 4.54-4.22(m, 1H), 3.64-3.55(m, 1H), 3.27-3.05(m, 1H), 3.03-2.72(m, 4H), 2.23-2.14(m, 3H), 1.89-1.69(m, 4H) ppm; LCMS: 475.1 [M+H]+ Compound 136 HN- A J pY 0" V y_ /  0 n-nh (3-(4-(3,4-difluoro-2-)((1,1,2,2-tetrafluoroethyl)thio)phen yl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5 -yl)methyl methylcarbamate 1H NMR (500 MHz, CDCh) 5 11.01 (s, 1H), 7.38-7.28(m, 1H), 7.16-7.06 (m, 1H), 5.90(t, J = 53.7 Hz, 1H), 5.17-4.66(m, 4H), 4.54-4.23(m, 1H), 3.64(t, J = 11.4 Hz, 1H), 3.29-3.06 (m, 1H), 3.05-2.72 (m, 4H), 2.24-2.09(m, 3H), 1.89-1.68(m, 4H);   LCMS:   525.1 [M+H]+ Compound 137 I y w °> AY (3-(4-(3,4-difluoro-2-difluoroethenyl)thio)phen yl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5 -yl)methyl methylcarbamate 1H NMR (500 MHz, CDCh) 5 10.99 (s, 1H), 7.25-7.19(m, 1H), 7.09- 6.98(m, 1H), 5.14-4.67(m, 4H), 4.59-4.28 (m, 1H), 3.62 (t, J = 12.1 Hz, 1H), 3.29-3.02(m, 1H), 3.00-2.70(m, 4H), 2.26-2.11(m, 3H), 1.93-1.69(m, 4H) ppm; LCMS: 505.1 [M+H]+ Compound # Structure Chemical Name HNMR / LCMS Compound 138 UN" J., j o n-nh (3-(4-(3,4-difluoro-2-(trifluoromethoxy)phenyl )piperidine-1 -carbonyl)-4 -methyl- 1H-pyrazol-5 -yl)methyl methylcarbamate 1H NMR (500 MHz, CDCh) 5 11.10 (s, 1H), 7.18-7.10(m, 1H), 7.04-6.98(m, 1H), 5.19-4.73(m, 4H), 4.54-4.25(m, 1H), 3.28-2.69(m, 6H), 2.23-2.10 (m, 3H), 1.91-1.68(m, 4H); LCMS: 477.2 [M+H]+ Compound 139 F Afi F °nrV 0 N-NH (3-(4-(2--difluoromethoxy)-3,4-difluorophenyl)piperidine -1 -carbonyl)-4-methyl-1H-pyrazol-5 -yl)methyl methylcarbamate 1H NMR (500 MHz, CDCh) 5 11.08 (s, 1H), 7.09-7.02 (m, 1H), 7.00-6.94 (m, 1H), 6.76-6.46(m, 1H), 5.17-4.68(m, 4H), 4.52-4.21(m, 1H), 3.31-2.68(m, 6H), 2.24-2.10(m, 3H), 1.91-1.67(m, 4H) ppm; LCMS: 459.2 [M+H]+ Compound 140 \= / '—o (3-(4-(3,4-difluoro-2- (1,1,2,2-tetrafluoroethoxy)phenyl) piperidine-1 -carbonyl)-4-methyl- 1H-pyrazol-5 -yl)methyl methylcarbamate 1H NMR (500 MHz, CDCh) 5 11.18 (s, 1H), 7.15-7.09(m, 1H), 7.02-6.97 (m, 1H), 6.04(t, J = 52.9 Hz, 1H), 5.12-4.66(m, 4H), 4.49-4.18(m, 1H), 3.21-3.05(m, 2H), 2.91-2.71(m, 4H), 2.22-2.13(m, 3H), 1.89-1.77(m, 2H), 1.67-1.57(m, 2H) ppm; LCMS: 509.2 [M+H]+ Compound 141 F .     HN— J / o—\ AV ° n'NH (3 -(4-(3,4-difluoro-2- (1,2-trifluoroethenyl)oxy)phe nyl)piperidine-1 -carbonyl)-4-methyl-1H-pyrazol-5 -yl)methyl methylcarbamate 1H NMR (500 MHz, CDCh) 5 11.17 (s, 1H), 7.08-7.00(m, 1H), 6.99-6.92 (m, 1H), 5.13-4.73(m, 4H), 4.53-4.23(m, 1H), 3.26-3.02(m, 2H), 2.95 -2.71(m, 4H), 2.22-2.13(m, 3H), 1.93-1.79(m, 2H), 1.71-1.59(m, 2H) ppm; LCMS: 489.2 [M+H]+ Biological Activity Tests Test Example 1: Inhibition of RBP4-TTR Complex Formation by Compounds This example evaluated the inhibitory activity of Compounds 1-2 against RBP4-TTR complex formation using the HTRF method. Test compounds were prepared as 10 mM stock solutions in DMSO and subsequently serially diluted in Reaction buffer (50 mM Tris-HCl, pH 7.5, 1 mM DTT, 0.05% NP-40, 0.05% Prionex, 6% glycerol) to various test concentrations (starting at 1 pM, 3-fold dilution, 8 concentrations, 2 replicates). 1 pL of each compound dilution was dispensed into a 384-well plate (PerkinElmer, Proxiplate), followed by addition of 2 pL RBP4-hFc protein (MCE, final concentration 12.5 nM), and incubated at room temperature for 20 min. 1 pL all-trans Retinol (Sigma, final concentration 1 pM) was added to each well and incubated at room temperature for 20 min. 1 pL Human Transthyretin-His (Acro, final concentration 2 nM) was added to each well and incubated at room temperature for 20 min. 2.5 pL of 1x PAb Anti-Human IgG-XL665 (Cisbio) and 2.5 pL of 1x MAb Anti-6His-Tb cryptate (Cisbio) were added to each well and incubated at room temperature for 1 h. Emission intensities at 615 nm and 665 nm were measured using a Varioskan LUX microplate reader (Thermo Fisher), and the 665 / 615 ratio was calculated. Wells without compound (0 nM) served as the 100% control. After background subtraction, data were processed and curve-fitted using GraphPad Prism 8.0 (nonlinear fitting, four-parameter), and IC50 values were calculated. The results are shown in Table 3. Test Example 2: Radioligand Binding Assay This example assessed the inhibitory activity of compounds against RBP4-retinol binding by Radioligand binding assay. Test compounds were prepared as 10 mM stock solutions in DMSO and subsequently serially diluted in binding buffer (0.01 M PBS, pH 7.2, containing 0.1% BSA, 0.5% CHAPS, 1 mM EDTA) to various test concentrations (starting at 1 pM, 3-fold dilution, 8 concentrations, 2 replicates). 1 pL of each compound dilution was dispensed into a 384-well plate (Perkin Elmer, Proxiplate), followed by addition of 2 pL of 50 nM RBP4-biotin protein (MCE), and incubated at room temperature for 30 min. 2 pL of 30 nM 3H retinol was added and incubated at room temperature for 3 h. 5 pL of streptavidin SPA beads was added to each well and incubated at room temperature for 10 min. Counts were measured using a MicroBeta2. Wells containing 1 pM retinol served as the blank control, and wells without compound served as the 100% control. The binding inhibition rate (%) for each well was calculated. Data were processed and curve-fitted using GraphPad Prism 8.0 (nonlinear fitting, four-parameter), and IC50 values were calculated. The results are shown in Table 3. Table 3 Compound # HTRF assay for antagonists of RBP4-TTR interaction: IC50 (nM) SPA binding assay for RBP4: IC50 (nM) Compound # HTRF assay for antagonists of RBP4-TTR interaction: IC50 (nM) SPA binding assay for RBP4: IC50 (nM) Compound 1 5.78 9.49 Compound 18 216 n.d. Compound 2 7.8 7.89 Compound 19 103.5 n.d. Compound 3 22.1 5.53 Compound 20 60.4 n.d. Compound 4 7.36 n.d. Compound 21 86.3 n.d. Compound 5 33.6 n.d. Compound 22 13.5 7.95 Compound 6 12.8 15.76 Compound 23 24.2 11.42 Compound 7 14.4 5.2 Compound 24 26.9 4.09 Compound 8 9.6 8.29 Compound 25 8.8 6.85 Compound 9 51.0 n.d. Compound 26 17.8 10.31 Compound 10 >1000 n.d. Compound 27 23.1 9.64 Compound 11 54.7 n.d. Compound 28 24.5 2.73 Compound 12 84.3 n.d. Compound 29 37.4 6.06 Compound 13 35.4 n.d. Compound 30 19.8 10.73 Compound 14 23.5 30.07 Compound 31 13.8 10.27 Compound 15 22.9 n.d. Compound 32 10.4 7.52 Compound 16 126.8 n.d. Compound 33 19.7 7.77 Compound 17 36.4 n.d. Compound 34 17.3 4.67 Compound 35 11.6 5.8 Compound 70 13.2 16.23 Compound 36 41.5 4.09 Compound 71 12.3 6.38 Compound # HTRF assay for antagonists of RBP4-TTR interaction: IC50 (nM) SPA binding assay for RBP4: IC50 (nM) Compound # HTRF assay for antagonists of RBP4-TTR interaction: IC50 (nM) SPA binding assay for RBP4: IC50 (nM) Compound 37 24.6 n.d. Compound 72 12.5 13.26 Compound 38 24.4 n.d. Compound 73 11.9 10.04 Compound 39 55.9 n.d. Compound 74 18.5 17 Compound 40 24.6 n.d. Compound 75 13.0 8.31 Compound 41 15.3 13.67 Compound 76 7.85 4.28 Compound 42 19.9 5.16 Compound 77 11.2 5.84 Compound 43 17.5 11.12 Compound 78 13.4 5.93 Compound 44 12.9 11.4 Compound 79 11.3 3.88 Compound 45 36.8 7.15 Compound 80 11.5 12.86 Compound 46 21.4 5.11 Compound 81 14.2 15.5 Compound 47 18.5 6.86 Compound 82 72.4 n.d. Compound 48 3.4 3.47 Compound 83 8.1 7.55 Compound 49 17.0 3.93 Compound 84 188.1 n.d. Compound 50 36.4 n.d. Compound 85 8.1 3.55 Compound 51 24.6 7.45 Compound 86 7.5 10.05 Compound 52 11.6 13.45 Compound 87 13.5 5.17 Compound 53 37.3 n.d. Compound 88 11.7 5.31 Compound 54 16.0 7.19 Compound 89 9.1 4.84 Compound 55 13.8 n.d. Compound 90 12.7 10.18 Compound 56 16.3 5.34 Compound 91 11.0 12.71 Compound 57 12.7 6.75 Compound 92 12.1 10.96 Compound 58 20.7 3.92 Compound 93 11.7 2.79 Compound 59 17.9 5.87 Compound 94 11.0 8.02 Compound 60 17.2 9.27 Compound 95 138.2 n.d. Compound 61 17.3 9.29 Compound 96 11.8 13.72 Compound 62 55.0 n.d. Compound 97 11.9 15.31 Compound 63 28.3 7.41 Compound 98-1 >1000 n.d. Compound 64 30.8 6.74 Compound 98-2 >1000 n.d. Compound 65 6.2 13.82 Compound 99 23.9 n.d. Compound 66 23.5 7.91 Compound 100 27.0 n.d. Compound 67 9.3 11.9 Compound 101 31.7 n.d. Compound 68 28.5 5.34 Compound 102 18.2 n.d. Compound 69 15.7 6.37 Compound 103 19.5 n.d. Compound 104 18.3 n.d. Compound 105 24.8 n.d. Compound 106 39.4 n.d. Compound 124 8.5 n.d. Compound 107 18.9 n.d. Compound 125 11.0 n.d. Compound 108 18.1 16.99 Compound 126 17.6 n.d. Compound 109 28.7 n.d. Compound 127 9.4 n.d. Compound 110 45.9 n.d. Compound 128 14.0 n.d. Compound 111 25.1 n.d. Compound 129 27.8 n.d. Compound 112 10.2 n.d. Compound 130 14.2 n.d. Compound 113 24.8 n.d. Compound 131 15.8 n.d. Compound 114 15.3 n.d. Compound 132 10.1 n.d. Compound 115 7.6 n.d. Compound 133 7.7 n.d. Compound # HTRF assay for antagonists of RBP4-TTR interaction: IC50 (nM) SPA binding assay for RBP4: IC50 (nM) Compound # HTRF assay for antagonists of RBP4-TTR interaction: IC50 (nM) SPA binding assay for RBP4: IC50 (nM) Compound 116 18.1 n.d. Compound 134 9.4 n.d. Compound 117 14.2 n.d. Compound 135 6.5 n.d. Compound 118 8.8 n.d. Compound 136 17.8 n.d. Compound 119 11.8 n.d. Compound 137 10.1 n.d. Compound 120 5.0 n.d. Compound 138 9.3 n.d. Compound 121 10.2 n.d. Compound 139 12.1 n.d. Compound 122 18.3 n.d. Compound 140 7.2 n.d. Compound 123 9.1 n.d. Compound 141 10.0 n.d. Note: n.d. indicated Not determined Test Example 3: Mouse Pharmacokinetics (PK) This example evaluated the pharmacokinetic characteristics of compound in vivo by measuring drug concentrations in mice at various time points after dosing. Six C57 / 6j mice (male, 4-6 weeks old, Vital River) were housed in the animal facility for 3 days of acclimatization before use. A specific amount of compound was weighed and dissolved in the appropriate vehicle (oral: 0.5% MC; intravenous: DMSO : 30% HP-P-CD = 5 : 95) to prepare the corresponding compound solution. Three mice were each orally administered 10 mg / kg compound, and blood was micro-sampled at 0 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after dosing. Three mice were each administered 1 mg / kg compound via tail vein injection, and blood was micro-sampled at 0 h, 5 h, 0.25 h, 0.5 h, 1 h, 2 h, 6 h, and 24 h after dosing. Plasma drug concentrations in each sample were determined by LC-MS / MS. Pharmacokinetic parameters and bioavailability were calculated using WinNonlin. The results are shown in Table 4. Table 4 Compound # Mouse PK IV (1mpk)DMSO / HS-15 / saline (5:5:90) PO (10 mpk) 0.5%MC T1 / 2 (h) AUC0-t (ng*h / mL) Cmax (ng / mL) Tmax (h) T1 / 2 (h) AUC0-t (ng*h / mL) F (%) Compound 1 2.27 1839 667 0.67 4.87 3794 20.6 Compound 2 1.55 1554 1049 1 4.43 3304 21.3 Compound 31 1.32 1566 1245 1 2.95 3994 27.5 Compound 96 1.51 n.d. 1327 1 1.48 6024 38.7 Compound 97 0.876 n.d. 1015 2 1.72 3702 31.1 Note: n.d. indicated Not determined Test Example 4: Rat Pharmacokinetics (PK) This example evaluated the pharmacokinetic characteristics of compound in vivo by measuring drug concentrations in rats at various time points after dosing. Six SD rats (male, 4-6 weeks old, Vital River) were housed in the animal facility for 3 days of acclimatization before use. A specific amount of compound was weighed and dissolved in the appropriate vehicle (oral: 0.5% MC; intravenous: DMSO : 30% HP-P-CD = 5:95) to prepare the corresponding compound solution. Three rats were each orally administered 5 mg / kg compound, and blood was microsampled at 0 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after dosing. Three rats were each administered 1 mg / kg compound via tail vein injection, and blood was micro-sampled at 0 h, 5 h, 0.25 h, 0.5 h, 1 h, 2 h, 6 h, and 24 h after dosing. Plasma drug concentrations in each sample were determined by LC-MS / MS. Pharmacokinetic parameters and bioavailability were calculated using WinNonlin. The results are shown in Table 5. Table 5 Compound # Rat PK IV (1 mpk)DMSO / HS-15 / saline (5:5:90) PO (5 mpk) 0.5%MC T1 / 2 (h) AUC0-t (ng*h / mL) Cmax (ng / mL) Tmax (h) T1 / 2 (h) AUC0-t (ng*h / mL) F (%) Compound 1 5.94 2051 564 2 6.04 4477 44.5 Compound 2 5.32 1311 351 4 3.85 2093 31.2 Compound 3 1.3 597 954 0.5 1.17 1775 58.7 Compound 31 4.9 1511 776 2 3.09 4727 61.3 Compound 96 3.99 1911 542 2 3.4 2700 28 Compound 97 2.25 1274 774 2 1.74 3439 53.9 Test Example 5: Mouse PD (Pharmacodynamics) This example evaluated the pharmacodynamic characteristics of compound in vivo by measuring RBP4 levels in mouse blood at various time points after dosing. Twelve C57 / 6j mice (male, 4-6 weeks old, Vital River) were housed in the animal facility for 3 days of acclimatization before use. A specific amount of compound was weighed and dissolved in the appropriate vehicle (oral: 0.5% MC) to prepare the corresponding compound solution. Each mouse was orally administered 20 mg / kg compound via gavage, and 3 mice were sacrificed at 1 h, 3 h, 6 h, and 24 h after dosing, respectively. Plasma was collected, and plasma RBP4 levels were determined (R&D Systems). The plasma RBP4 level in untreated mice was set as 100%, and the maximum inhibition rate (Inhibition max, %) of plasma RBP4 by each compound was calculated. The results are shown in Table 6. Table 6 Compound # Mouse PD (20 mpk) Compound # Mouse PD (20 mpk) Inhibition (max %) Inhibition (AUC, %) Inhibition (max %) Inhibition (AUC, %) Compound 1 89.2 76.2 Compound 24 79.6 48.2 Compound 2 96.0 75.6 Compound 25 76.1 29.1 Compound 3 89.2 64.8 Compound 26 89.0 55.2 Compound 6 85.2 78.1 Compound 27 58.6 34.7 Compound 7 80.3 68.8 Compound 28 77.2 46.6 Compound # Mouse PD (20 mpk) Compound # Mouse PD (20 mpk) Inhibition (max %) Inhibition (AUC, %) Inhibition (max %) Inhibition (AUC, %) Compound 8 84.5 78.4 Compound 29 58.8 30.5 Compound 22 48.5 33.1 Compound 31 92.4 77.8 Compound 23 72.6 41.2 Compound 33 90.0 73.9 Compound 34 65.2 21.1 Compound 78 69.6 41.2 Compound 35 81.9 46.7 Compound 80 24.2 19.2 Compound 36 79.6 48.2 Compound 81 88.0 74.4 Compound 38 80.9 55.8 Compound 83 75.4 45.7 Compound 43 66.3 43.0 Compound 85 79.4 58.5 Compound 46 80.5 53.7 Compound 86 70.5 41.9 Compound 47 80.9 55.8 Compound 87 59.1 40.0 Compound 48 80.7 64.7 Compound 88 92.3 73.6 Compound 49 53.5 33.8 Compound 89 54.9 15.3 Compound 51 86.8 82.0 Compound 90 81.5 37.4 Compound 56 82.3 76.2 Compound 91 87.2 82.4 Compound 57 60.4 51.3 Compound 92 83.7 50.9 Compound 58 65.8 46.6 Compound 93 85.2 79.2 Compound 59 77.7 58.8 Compound 94 85.6 53.9 Compound 60 71.2 50.4 Compound 95 43.0 29.0 Compound 61 72.9 68.7 Compound 96 90.8 83.2 Compound 63 71.5 50.8 Compound 97 86.8 79.2 Compound 64 72.0 47.0 Compound 99 90.8 58.3 Compound 65 79.3 53.6 Compound 100 89.0 72.4 Compound 66 60.4 37.5 Compound 101 87.2 63.0 Compound 67 74.0 54.3 Compound 104 82.4 54.0 Compound 68 87.5 62.3 Compound 105 63.8 43.1 Compound 70 57.6 40.5 Compound 106 45.2 34.4 Compound 71 86.1 79.4 Compound 108 89.0 69.7 Compound 72 77.3 51.6 Compound 109 86.7 57.0 Compound 73 78.6 58.8 Compound 110 85.3 68.3 Compound 74 59.6 37.5 Compound 111 55.7 54.6 Compound 75 72.8 43.3 Compound 119 80.5 51.6 Compound 76 19.5 12.4 Compound 121 91.9 77.1 Compound 77 71.1 44.1 Test Example 6: Intense Light-Induced Retinal Damage Model in Rats This example simulated early clinical symptoms of dAMD by inducing retinal damage with intense light in rats; the effects of compound on rats with retinal damage were evaluated by flash electroretinography (fERG) and fundus autofluorescence (BAF). Male SD rats (4-6 weeks old, Vital River) were randomly divided into 4 groups, with 8 rats per group. They were designated as the control group (no light exposure, vehicle), the model group (light exposure, vehicle), and the test group (light exposure, Compound 1). After 3 days of acclimatization, rats were administered with different compounds (10 mg / kg, QD) or vehicle (0.5% MC) according to their group assignment. After 3 consecutive days of dosing, rats were anesthetized by intraperitoneal injection of ketamine (30-80 mg / kg) and xylazine (1-3 mg / kg), and simultaneously, the pupils were dilated using a mydriatic agent containing tropicamide. The eyes were then exposed to intense light (3000 lux, 6 h) for model induction. After model induction, dosing was continued for additional 6 days. Before dosing (Day 0) and after the completion of dosing (Day 9), rats were subjected to fERG and BAF examination or photography. The fERG data are shown in Table 7, and representative post-dosing BAF images of rats in each group are shown in Figure 1. The fERG amplitude was used to indicate the integrity of the optic nerve, and the BAF area (abnormal autofluorescence region in Figure 1) was used to indicate the extent of retinal damage. The left and right eyes of each rat were treated as independent samples and analyzed separately. fERG results are expressed as mean ± SD. Table 7. Changes in fERG in rats of each group at 10.0 light intensity after dosing Group fERG Implicit time (ms) Amplitude (mV) a wave b wave a wave b wave Control Group 10.49±0.65 51.40±2.76 259.56±70.38 617.94±175.80 Model Group 10.00±0.40 53.84±5.16 120.64±107.83 319.88±254.04 Test Group 10.17±0.21 50.53±1.23 156.35±49.16 418.81±75.51 This Example demonstrates that intense light exposure caused a significant reduction in rat ERG amplitude, and oral administration of Compound 1 improved the amplitude; intense light also induced lipofuscin accumulation and fluorescent granule formation in the rat retina, and oral administration of Compound 1 significantly reduced the accumulation of lipofuscin fluorescent granules. It will be apparent to those skilled in the art that the present invention is not limited to the foregoing illustrative Examples, and may be embodied in other specific forms without departing from its essential characteristics. Accordingly, the Examples are intended to be regarded in all respects as illustrative and non-limiting, and reference should be made to the appended claims rather than to the foregoing Examples. Therefore, all changes coming within the meaning and range of equivalency of the appended claims are intended to be embraced herein.

Claims

1. A compound having a structure as shown in Formula (I), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure as shown in Formula (I);R3 Rtj. r2R5'"^LIAFormula (I)wherein, R1 is selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, cyano, nitro, cycloalkyl, heterocyclyl, -NR7R8, -NR9(CO)R6, -NR9(CO)OR10, -NR9(CO)NR7R8, -NR9SOR11, -NR9SO2R11, -OR10, -O(CO)R6, -O(CO)NR7R8, -C(O)R6, -C(O)OR10, -C(O)NR7R8, -C(S)OR10, -C(S)NR7R8, -C(O)SR10, -SR10, -SOR11, -SO2R11, -SO2NR7R8, -S(O)R11NR9, -C(NR9)NR7R8, and -P(O)R12R13;R2, R3, R4, and R5 are each independently selected from hydrogen, deuterium, hydroxy, nitro, amino, alkoxy, carboxy, mercapto, cyano, alkyl, halogen, cycloalkyl, and haloalkyl; or R1, R2, R3, R4, and R5 are joined at any adjacent positions to form cycloalkyl or heterocyclyl;R6 is selected from hydrogen, deuterium, hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;R7, R8, and R9 are selected from hydrogen, deuterium, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;R10 is selected from hydrogen, deuterium, alkyl, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, and heteroaryl;R11 is selected from hydrogen, deuterium, amino, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;R12 and R13 are selected from hydrogen, deuterium, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or R12 and R13 together with the P atom to which they are attached, form a phosphorus-containing heterocycle;the alkyl, alkoxy, haloalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, and heteroaryl of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 are optionally substituted with 0 to 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, carboxy, mercapto, nitro, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, alkoxy, haloalkoxy, heterocyclyl, aryl, and heteroaryl;L is a bridged ring group, spiro ring group, monocyclic group, or fused ring group, which contains 0 to 2 nitrogen atoms;the bridged ring group, spiro ring group, monocyclic group, or fused ring group in L is optionally substituted with 0 to 4 substituents selected from deuterium, alkyl, hydroxy, amino, alkoxy, and haloalkyl;A is -NR14- or a bond;R14 is selected from hydrogen, deuterium, and alkyl;ring B is selected from a heterocycle, an aryl ring and a heteroaryl ring;R15 and each R16 are each independently selected from deuterium, alkyl, aminoalkyl, cycloalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanamido, alkanoyl, aminocarbonyl, heterocyclyl, aryl, heteroaryl, and heterocyclylcarbonyl;the alkyl, cycloalkyl, aminoalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanamido, alkanoyl, heterocyclyl, aryl, heteroaryl, and heterocyclylcarbonyl of R15 and R16 are each independently substituted with 0 to 4 substituents selected from deuterium, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkanoyl, alkoxycarbonyl, alkanamido, aminocarbonyl, carboxy, -O-C(O)-NR17R18 and oxo;R17 and R18 are each independently selected from hydrogen, deuterium, alkyl, and haloalkyl; n is 0, 1, 2, 3, or 4.

2. The compound according to claim 1, wherein,ring B is selected from C1-9heterocycle, C6-10aryl ring, and C1-9heteroaryl ring;R15 and each R16 are each independently selected from deuterium, C1-6alkyl, C1-6cycloalkyl, C1-6aminoalkyl, C1-6alkoxyC1-6alkyl, C1-6haloalkyl, C1-9heterocyclylC1-6alkyl, C1-9heteroarylC1-6alkyl, C1-6alkanamido, C1-6alkanoyl, aminocarbonyl, C1-9heterocyclyl, C6-10aryl, C1-9heteroaryl, and C1-9heterocyclylcarbonyl;the C1-6alkyl, C1-6cycloalkyl, C1-6aminoalkyl, C1-6alkoxyC1-6alkyl, C1-6haloalkyl, C1-9heterocyclylC1-6alkyl, C1-9heteroarylC1-6alkyl, C1-6alkanamido, C1-6alkanoyl, C1-9heterocyclyl, C6-10aryl, C1-9heteroaryl, and C1-9heterocyclylcarbonyl of R15 and R16 are each independently substituted with 0 to 4 substituents selected from deuterium, C1-6alkyl, C1-6cycloalkyl, C1-9heterocyclyl, C6-10aryl, C1-9heteroaryl, C1-6alkanoyl, C1-6alkoxycarbonyl, C1-6alkanamido, aminocarbonyl, carboxy, -O-C(O)-NR17R18 and oxo;R17 and R18 are each independently selected from hydrogen, deuterium, C1-4alkyl, and C1-4haloalkyl.

3. The compound according to claim 1, wherein,ring B is selected from a pyrazole ring, an imidazole ring, a triazole ring, and a pyrimidine ring;R15 and each R16 are each independently selected from deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, propylamino, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, halomethyl, haloethyl, pyrrolidinyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidinyl, piperidinylmethyl, piperidinylethyl, piperazinyl, piperazinylmethyl, piperazinylethyl, morpholinyl, morpholinylmethyl, morpholinylethyl, morpholinylcarbonyl, pyrrolyl, pyrrolylmethyl, pyrrolylethyl, pyridyl, pyridylmethyl, pyridylethyl, imidazolyl, imidazolylmethyl, imidazolylethyl, pyrazolyl, pyrazolylmethyl, pyrazolylethyl, pyrazinyl, pyrazinylmethyl, pyrazinylethyl, pyridazinyl, pyridazinylmethyl, pyridazinylethyl, pyrimidinyl, pyrimidinylmethyl, pyrimidinylethyl, triazolyl, triazolylmethyl, triazolylethyl, tetrazolyl, tetrazolylmethyl, tetrazolylethyl, thiomorpholinyl, thiomorpholinylmethyl, thiomorpholinylethyl, formamido, acetamido, aminocarbonyl, formyl, and acetyl;R15 and each R16 are each independently optionally substituted with 0 to 4 substituents selected from deuterium, methyl, ethyl, cyclopropyl, cyclobutyl, formyl, acetyl, formamido, acetamido, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, carboxy, -O-C(O)-NHCH3, -O-C(O)-N(CH3)2, -O-C(O)-NHC2H5, -O-C(O)-NHC3H8 and oxo.

4. The compound according to claim 1, wherein,the alkyl, cycloalkyl, heterocyclyl, alkoxy, and haloalkyl of R1, R2, R3, R4, and R5 are C1-6alkyl, C3-8cycloalkyl, C1-9heterocyclyl, C1-6alkoxy, and C1-6haloalkyl;R6 is selected from hydrogen, deuterium, hydroxy, amino, C1-6alkyl, C1-6alkoxy, C3-8cycloalkyl, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl;R7, R8, and R9 are selected from hydrogen, deuterium, cyano, C1-6alkyl, C3-8cycloalkyl, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl;R10 is selected from hydrogen, deuterium, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C2-6haloalkenyl, C3-8cycloalkyl, C3-8halocycloalkyl, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl;R11 is selected from hydrogen, deuterium, amino, C1-6alkyl, C3-8cycloalkyl, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl;R12 and R13 are selected from hydrogen, deuterium, C1-6alkyl, C3-8cycloalkyl, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl, or R12 and R13 together with the P atom to which they are attached, form a phosphorus-containing C1-9heterocycle;the C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C2-6alkenyl, C2-6haloalkenyl, C2-6alkynyl, C3-8cycloalkyl, C3-8halocycloalkyl, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13are optionally substituted with 0 to 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, carboxy, mercapto, nitro, C1-6alkyl, C3-8cycloalkyl, C3-8halocycloalkyl, C1-6haloalkyl, C2-6alkenyl, C2-6haloalkenyl, C2-6alkynyl, C1-6alkoxy, C1-6haloalkoxy, C1-9heterocyclyl, C6-10aryl, and C1-9heteroaryl.

5. The compound according to claim 1, wherein,the cycloalkyl of R1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; the heterocyclyl of R1 is selected from oxetanyl, oxolanyl, azetidinyl, pyrrolidinyl, thietanyl, and thiolanyl;R2, R3, R4, and R5 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropyl, cyclobutyl, halocyclopropyl, and halocyclobutyl; or R1, R2, R3, R4, and R5 are joined at any adjacent positions to form cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, or oxanyl;R6 is selected from hydrogen, deuterium, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, pyrrolidinyl, and tetrahydrofuryl;R7, R8, and R9 are selected from hydrogen, deuterium, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,pyrrolidinyl, and tetrahydrofuryl;R10 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tertbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halomethyl, haloethyl, halogenated n-propyl, halogenated isopropyl, halogenated n-butyl, halocyclopropyl, halocyclobutyl, halocyclopentyl, halocyclohexyl, ethenyl, propenyl, ethynyl, propynyl, haloethenyl, halopropenyl, pyrrolidinyl, and tetrahydrofuryl;R11 is selected from hydrogen, deuterium, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl,  cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, andtetrahydrofuryl;R12 and R13 are selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, and tetrahydrofuryl.

6. The compound according to claim 1, wherein,L is selected from C6-12 bridged ring group, C5-12 spiro ring group containing 0 to 2 nitrogen atoms, C2-6 monocyclic group containing 0 to 2 nitrogen atoms, and C4-12 fused ring group, which contains 0 to 2 nitrogen atoms;the C6-12 bridged ring group, C5-12 spiro ring group, C2-6 monocyclic group, or C4-12 fused ring group in L are optionally substituted with 0 to 4 substituents selected from deuterium, C1-6alkyl, hydroxy, amino, C1-6alkoxy, and C1-6haloalkyl;the alkyl of R14 is C1-6alkyl.

7. The compound according to claim 1, wherein, L has one of the following structures:, and •'tw .

8. The compound according to claim 1, having the structure as shown in Formula (II) or Formula (III), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof;Formula (II),Formula (III)wherein, X1, X2, and X3 are N or CR16;l is 0 or 1;n is 0, 1, 2, 3, or 4;R15 and each R16 are each independently selected from deuterium, alkyl, aminoalkyl,cycloalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanamido, alkanoyl, aminocarbonyl, heterocyclyl, aryl, heteroaryl, and heterocyclylcarbonyl;the alkyl, cycloalkyl, aminoalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanamido, alkanoyl, heterocyclyl, aryl, heteroaryl, and heterocyclylcarbonyl of R15 and R16 are each independently substituted with 0 to 4 substituents selected from deuterium, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkanoyl, alkoxycarbonyl, alkanamido, aminocarbonyl, carboxy, -O-C(O)-NR17R18, and oxo;R17 and R18 are each independently selected from hydrogen, deuterium, alkyl, and haloalkyl.

9. The compound according to claim 8, wherein,ring B is selected from C1-9heterocycle, C6-10aryl ring, or C1-9heteroaryl ring;R15 and each R16 are each independently selected from deuterium, C1-6alkyl, C1-6cycloalkyl, C1-6aminoalkyl, C1-6alkoxyC1-6alkyl, C1-6haloalkyl, C1-9heterocyclylC1-6alkyl, C1-9heteroarylC1-6alkyl, C1-6alkanamido, C1-6alkanoyl, aminocarbonyl, C1-9heterocyclyl, C6-10aryl, C1-9heteroaryl, and C1-9heterocyclylcarbonyl;the C1-6alkyl, C1-6cycloalkyl, C1-6aminoalkyl, C1-6alkoxyC1-6alkyl, C1-6haloalkyl,  C1-9heterocyclylC1-6alkyl, C1-9heteroarylC1-6alkyl, C1-6alkanamido,  C1-6alkanoyl,  C1-9heterocyclyl, C6-10aryl, C1-9heteroaryl, and C1-9heterocyclylcarbonyl of R15 and R16 are each independently substituted with 0 to 4 substituents selected from deuterium, C1-6alkyl, C1-6cycloalkyl, C1-9heterocyclyl, C6-10aryl, C1-9heteroaryl, C1-6alkanoyl, C1-6alkoxycarbonyl, C1-6alkanamido, aminocarbonyl, carboxy, -O-C(O)-NR17R18 and oxo;R17 and R18 are each independently selected from hydrogen, deuterium, C1-4alkyl, and C1-4haloalkyl.

10. The compound according to claim 8, wherein,ring B is selected from a pyrazole ring, an imidazole ring, a triazole ring, and a pyrimidine ring;R15 and each R16 are each independently selected from deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, propylamino, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, halomethyl, haloethyl, pyrrolidinyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidinyl, piperidinylmethyl, piperidinylethyl, piperazinyl, piperazinylmethyl, piperazinylethyl, morpholinyl, morpholinylmethyl, morpholinylethyl, morpholinylcarbonyl, pyrrolyl, pyrrolylmethyl, pyrrolylethyl, pyridyl, pyridylmethyl, pyridylethyl, imidazolyl, imidazolylmethyl, imidazolylethyl, pyrazolyl, pyrazolylmethyl, pyrazolylethyl, pyrazinyl, pyrazinylmethyl, pyrazinylethyl, pyridazinyl, pyridazinylmethyl, pyridazinylethyl, pyrimidinyl, pyrimidinylmethyl, pyrimidinylethyl, triazolyl, triazolylmethyl, triazolylethyl, tetrazolyl, tetrazolylmethyl, tetrazolylethyl, thiomorpholinyl, thiomorpholinylmethyl, thiomorpholinylethyl, formamido, acetamido, aminocarbonyl, formyl, and acetyl;R15 and each R16 are each independently optionally substituted with 0 to 4 substituents selected from deuterium, methyl, ethyl, cyclopropyl, cyclobutyl, formyl, acetyl, formamido, acetamido, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, carboxy, -O-C(O)-NHCH3, -O-C(O)-N(CH3)2, -O-C(O)-NHC2H5, -O-C(O)-NHC3H8 and oxo.

11. The compound according to any one of claims 1-10, having one of the following structures, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:T1?T, and12. A pharmaceutical composition, comprising the compound of any one of claims 1-10, and apharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combinationthereof.

13. Use of the compound of any one of claims 1-10, or the pharmaceutical composition of claim 11, in the manufacture of a medicament for treatment of a retinol binding protein 4-related disease.

14. The use according to claim 13, wherein the retinol binding protein 4-related disease is age-related macular degeneration, Stargardt disease, or Best disease.

15. A method of inhibiting RBP4-TTR complex formation in a cell, comprising contacting the cell with an effective amount of the compound of any one of claims 1-11 or the pharmaceutical composition of claim 12.

16. A method of inhibiting excessive accumulation of lipofuscin in a cell, comprising contactingthe cell with an effective amount of the compound of any one of claims 1-11 or the pharmaceutical composition of claim 12.

17. A method of inhibiting RBP4-TTR complex formation in serum of a subject, comprising administering to the subject an effective amount of the compound of any one of claims 1-11 or the pharmaceutical composition of claim 12.

18. A method of inhibiting excessive accumulation of lipofuscin in the retina of a subject, comprising administering to the subject an effective amount of the compound of any one of claims 1-11 or the pharmaceutical composition of claim 12.

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