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

A phenyl heterocyclic compound and its application Technical Field

[0001] The present invention relates to a phenyl heterocyclic compound, stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or esters, and applications thereof in preparing drugs for treating ophthalmic diseases. Background Art

[0002] 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 its high prevalence, the development of drugs for dry AMD is crucial.

[0003] Age-dependent accumulation of cytotoxic lipofuscin retinoid dimers (bisretinoids) in the retina may significantly contribute to the pathogenesis of the dry form of AMD. The synthesis of retinoid dimers in the eye depends on the influx of all-trans retinol from the serum into the retina, which requires the formation of the tertiary retinol binding protein 4 (RBP4)-transthyretin (TTR)-retinol complex in the serum.

[0004] Reducing the rate of formation of cytotoxic retinoid dimers (the main component of lipofuscin) in the retinal pigment epithelium (RPE) by selective RBP4 antagonists will prevent further geographic atrophy in patients with atrophic (dry) age-related macular degeneration (AMD), thereby improving the condition characterized by excessive accumulation of lipofuscin in the retina.

[0005] In addition to AMD, significant accumulation of lipofuscin is also a characteristic of fundus macular degeneration (STARGARDT) and Best disease. Stargardt disease is a hereditary form of juvenile-onset macular degeneration, while Best disease is caused by autosomal dominant inheritance of the vitelliform macular dystrophy gene.

[0006] WO2015168286 discloses a class of substituted 4-phenylpiperidine compounds, such as Compound A, WO2014152018 discloses a class of substituted cyclopentazopyrrole compounds, such as Compound B, and WO2014151936 discloses a class of substituted octahydropyrrolopyrrole compounds, such as Compound C. As RBP4 antagonists, these compounds provide therapeutic potential for the treatment of dry AMD and other diseases characterized by excessive lipofuscin accumulation. However, improvements are needed in terms of inhibitory efficacy, membrane permeability, pharmacokinetics, drugability, and safety. Summary of the Invention

[0007] In view of the deficiencies of the prior art, the present invention provides, in a first aspect, a compound having a structure as shown in formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in formula (I);

[0008] Among them, R 1 Selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, cyano, nitro, cycloalkyl, heterocyclyl, -NR 7 R 8 、-NR 9 (CO)R 6 、-NR 9 (CO)OR 10 、-NR 9 (CO)NR 7 R 8 、-NR 9 SOR 11 、-NR 9 SO2R 11 、-OR 10 、-O(CO)R 6 、-O(CO)NR 7 R 8 、-C(O)R 6 、-C(O)OR 10 、-C(O)NR 7 R 8 、-C(S)OR 10 、-C(S)NR 7 R 8 、-C(O)SR 10 、-SR 10 、-SOR 11 、-SO2R 11 、-SO2NR 7 R 8 、-S(O)R 11 NR 9 、-C(NR 9 )NR 7 R 8 or-P(O)R 12 R 13 ;

[0009] R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, deuterium, hydroxy, nitro, amino, alkoxy, carboxyl, mercapto, cyano, alkyl, halogen, cycloalkyl or haloalkyl;

[0010] Or, R1 、R 2 、R 3 、R 4 、R 5 Connect at any ortho position to form a cycloalkyl or heterocyclic group;

[0011] R 6 is selected from hydrogen, deuterium, hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0012] R 7 、R 8 、R 9 is selected from hydrogen, deuterium, cyano, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0013] R 10 is selected from hydrogen, deuterium, alkyl, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0014] R 11 is selected from hydrogen, deuterium, amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0015] R 12 、R 13 is selected from hydrogen, deuterium, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or R 12 、R 13 It forms a phosphorus-containing heterocycle with the P atom connected to it;

[0016] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 wherein the alkyl, alkoxy, haloalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with 0 to 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, carboxyl, thiol, nitro, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, alkoxy, haloalkoxy, heterocyclyl, aryl and heteroaryl groups;

[0017] L is a bridged ring group, spiro ring group, monocyclic group or cyclic group containing 0 to 2 nitrogen atoms;

[0018] The bridged ring group, spiro ring group, monocyclic group or cyclic group in L is optionally substituted by 0 to 4 substituents selected from deuterium, alkyl, hydroxy, amino, alkoxy or haloalkyl;

[0019] A is -NR 14 - or key;

[0020] R 14 is selected from hydrogen, deuterium or alkyl;

[0021] Ring B is selected from a heterocyclic ring, an aromatic ring or a heteroaromatic ring;

[0022] R 15 And every R 16 each independently selected from deuterium, alkyl, aminoalkyl, cycloalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanoyl, alkanoyl, aminocarbonyl, heterocyclyl, aryl, heteroaryl or heterocyclylacyl;

[0023] R 15 and R 16 The alkyl, cycloalkyl, aminoalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanoyl, alkanoyl, heterocyclyl, aryl, heteroaryl and heterocyclylacyl groups are each independently substituted by 0 to 4 groups selected from deuterium, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkanoyl, alkoxyacyl, alkanoyl, aminocarbonyl, carboxyl, -OC(O)-NR 17 R 18 and substituted by a substituent in an oxo group;

[0024] R 17 and R 18 are each independently selected from hydrogen, deuterium, alkyl and haloalkyl;

[0025] n is 0, 1, 2, 3 or 4.

[0026] In some embodiments, in the compound of formula (I), ring B is selected from C 1-9 Heterocyclic, C 6-10 Aromatic ring or C 1-9 Heteroaromatic ring.

[0027] In some embodiments, in the compound of formula (I), Ring B is selected from a pyrazole ring (eg, ), imidazole ring (eg, ), triazole ring (eg, ) or pyrimidine ring (eg, ).

[0028] In some embodiments, Ring B is selected from a pyrazole ring (eg, ), imidazole ring (eg, ), triazole ring (eg, ) or pyrimidine ring (eg, ), wherein * represents the site of attachment of ring B to the carbonyl group in the compound of formula (I).

[0029] In some embodiments, R 15 And every R 16 are each independently selected from deuterium, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-6 aminoalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-9 Heterocyclyl C 1-6 Alkyl, C 1-9 Heteroaryl C 1-6 Alkyl, C 1-6 Alkylamide, C 1-6 Alkanoyl, aminocarbonyl, C 1-9 Heterocyclic group, C 6-10 Aryl, C 1-9 Heteroaryl or C 1-9 heterocyclyl acyl;

[0030] R 15 and R 16 C in 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-6 aminoalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-9 Heterocyclyl C 1-6 Alkyl, C 1-9 Heteroaryl C 1-6 Alkyl, C 1-6 Alkylamide, C 1-6 Alkanoyl, C 1-9 Heterocyclic group, C 6-10 Aryl, C 1-9 Heteroaryl and C 1-9 Heterocyclyl acyl groups are each independently substituted by 0 to 4 atoms selected from deuterium, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl, C 1-9 Heteroaryl, C 1-6 Alkanoyl, C 1-6 Alkoxyacyl, C 1-6 Alkylamide, aminocarbonyl, carboxyl, -OC(O)-NR 17 R 18 and substituted by a substituent in an oxo group;

[0031] R17 and R 18 are each independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0032] In some embodiments, R 15 And every R 16 each independently selected from the group consisting of deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, propylamino, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, halomethyl, haloethyl, tetrahydropyrrolyl, tetrahydropyrrolylmethyl, tetrahydropyrrolylethyl, piperidinyl, piperidinylmethyl, piperidinylethyl, piperazinyl, piperazinylmethyl, piperazinylethyl, morpholinyl, morpholinylmethyl, morpholinylethyl, morpholinoyl, pyrrolyl, pyrrolylmethyl, pyrrolylethyl, pyrrolyl 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 or acetyl;

[0033] R 15 And every R 16 Each is independently optionally substituted by 0 to 4 substituents selected from deuterium, methyl, ethyl, cyclopropyl, cyclobutane, formyl, acetyl, formamido, acetamido, aminocarbonyl, methoxyacyl, ethoxyacyl, carboxyl, -OC(O)-NHCH3, -OC(O)-N(CH3)2, -OC(O)-NHC2H5, -OC(O)-NHC3H8 and oxo.

[0034] In some embodiments, in the compound of formula (I), R 1 、R 2 、R 3 、R 4 、R 5 The alkyl, cycloalkyl, heterocyclic, alkoxy and haloalkyl groups are C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 1-6 Alkoxy and C 1-6 alkyl halide;

[0035] R 6 Selected from hydrogen, deuterium, hydroxyl, amino, C 1-6 Alkyl, C1-6 Alkoxy, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 heteroaryl;

[0036] R 7 、R 8 、R 9 Selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 heteroaryl;

[0037] R 10 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Halogenated alkenyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 heteroaryl;

[0038] R 11 Selected from hydrogen, deuterium, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 heteroaryl;

[0039] R 12 、R 13 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Heteroaryl, or R 12 、R 13 and the P atoms connected to it to form phosphorus-containing C 1-9 heterocyclic ring;

[0040] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10、R 11 、R 12 、R 13 C in 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by 0 to 4 groups selected from deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-9 Heterocyclic group, C 6-10 Aryl and C 1-9 The heteroaryl group is substituted by a substituent.

[0041] In some embodiments, in the compound of formula (I), R 1 The cycloalkyl group in is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, R 1 The heterocyclic group in is selected from oxetanyl, oxolanyl, azetidinyl, azetidine, thietanyl or thiolanyl;

[0042] R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropane, cyclobutane, halocyclopropane or halocyclobutane;

[0043] Or, R 1 、R 2 、R 3 、R 4 、R 5 at any ortho position to form a cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxacyclopentyl or oxacyclohexyl group;

[0044] R 6is selected from hydrogen, deuterium, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, tetrahydropyrrolyl or tetrahydrofuranyl;

[0045] R 7 、R 8 、R 9 is selected from hydrogen, deuterium, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl;

[0046] R 10 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halomethyl, haloethyl, halo-n-propyl, haloisopropyl, halo-n-butyl, halocyclopropyl, halocyclobutyl, halocyclopentyl, halocyclohexyl, vinyl, propenyl, ethynyl, propynyl, halovinyl, halopropenyl, tetrahydropyrrolyl or tetrahydrofuranyl;

[0047] R 11 is selected from hydrogen, deuterium, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl;

[0048] R 12 、R 13 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl.

[0049] In some embodiments, in the compound of formula (I), L is selected from C 6-12 Bridged ring group, C containing 0 to 2 nitrogen atoms 5-12 Spirocyclic group, C containing 0 to 2 nitrogen atoms 2-6 Monocyclic or C containing 0 to 2 nitrogen atoms 4-12 and cyclized groups;

[0050] C in L 6-12 Bridged ring group, C 5-12 Spirocyclyl, C 2-6 Monocyclic or C 4-12 The cyclized group is optionally substituted by 0 to 4 atoms selected from deuterium, C 1-6 Alkyl, hydroxyl, amino, C 1-6 Alkoxy or C 1-6 substituted by a haloalkyl substituent;

[0051] R 14 The alkyl group is C 1-6 alkyl.

[0052] In some embodiments, in the compound of formula (I), L has one of the following structures:

[0053] In some embodiments, the compound has a structure as shown in Formula (II) or Formula (III), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof;

[0054] Among them, X 1 、X 2 、X 3 N or CR 16 ;

[0055] l is 0 or 1, n is 0, 1, 2, 3 or 4;

[0056] R 15 And every R 16 each independently selected from deuterium, alkyl, aminoalkyl, cycloalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanoyl, alkanoyl, aminocarbonyl, heterocyclyl, aryl or heteroaryl;

[0057] R 15 and R 16 The alkyl, cycloalkyl, aminoalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanoyl, alkanoyl, heterocyclyl, aryl, heteroaryl and heterocyclylacyl groups are each independently substituted by 0 to 4 groups selected from deuterium, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkanoyl, alkoxyacyl, alkanoyl, aminocarbonyl, carboxyl, -OC(O)-NR 17 R 18 and substituted by a substituent in an oxo group;

[0058] R 17 and R 18 are each independently selected from hydrogen, deuterium, alkyl and haloalkyl.

[0059] In other embodiments, the compound, Ring B is selected from C 1-9 Heterocyclic, C 6-10 Aromatic ring or C 1-9 Heteroaromatic ring.

[0060] In some embodiments, in the compound of formula (III), ring B is selected from a pyrazole ring (eg, ), imidazole ring (eg, ), triazole ring (eg, ) or pyrimidine ring (eg, ).

[0061] In some embodiments, in the compound of formula (III), ring B is selected from a pyrazole ring (eg, ), imidazole ring (eg, ), triazole ring (eg, ) or pyrimidine ring (eg, ), wherein * represents the site where ring B is connected to the carbonyl group in the compound of formula (III).

[0062] In some embodiments, R 15 And every R 16 are each independently selected from deuterium, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-6 aminoalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-9 Heterocyclyl C 1-6 Alkyl, C 1-9 Heteroaryl C 1-6 Alkyl, C 1-6 Alkylamide, C 1-6 Alkanoyl, aminocarbonyl, C 1-9 Heterocyclic group, C 6-10 Aryl, C 1-9 Heteroaryl or C 1-9 heterocyclyl acyl;

[0063] R 15 and R 16 C in 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-6 aminoalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-9 Heterocyclyl C 1-6 Alkyl, C 1-9 Heteroaryl C 1-6 Alkyl, C 1-6 Alkylamide, C 1-6 Alkanoyl, C 1-9 Heterocyclic group, C 6-10 Aryl, C 1-9 Heteroaryl and C 1-9 Heterocyclyl acyl groups are each independently substituted by 0 to 4 atoms selected from deuterium, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl, C 1-9 Heteroaryl, C 1-6 Alkanoyl, C 1-6 Alkoxyacyl, C 1-6Alkylamide, aminocarbonyl, carboxyl, -OC(O)-NR 17 R 18 and substituted by a substituent in an oxo group;

[0064] R 17 and R 18 are each independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0065] In some embodiments, R 15 And every R 16 each independently selected from the group consisting of deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, propylamino, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, halomethyl, haloethyl, tetrahydropyrrolyl, tetrahydropyrrolylmethyl, tetrahydropyrrolylethyl, piperidinyl, piperidinylmethyl, piperidinylethyl, piperazinyl, piperazinylmethyl, piperazinylethyl, morpholinyl, morpholinylmethyl, morpholinylethyl, morpholinoyl, pyrrolyl, pyrrolylmethyl, pyrrolylethyl, pyrrolyl 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 or acetyl;

[0066] R 15 And every R 16 Each is independently optionally substituted by 0 to 4 substituents selected from deuterium, methyl, ethyl, cyclopropyl, cyclobutane, formyl, acetyl, formamido, acetamido, aminocarbonyl, methoxyacyl, ethoxyacyl, carboxyl, -OC(O)-NHCH3, -OC(O)-N(CH3)2, -OC(O)-NHC2H5, -OC(O)-NHC3H8 and oxo.

[0067] In a second aspect, the present invention also provides a pharmaceutical composition comprising (a) the above-mentioned compound or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or esters, and (b) a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0068] In a third aspect, the present invention provides a use of the compound of the present invention or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or esters or pharmaceutical compositions in the preparation of a drug, wherein the drug is used to prevent, treat, cure or alleviate retinol binding protein 4-related diseases.

[0069] In some embodiments, the retinol binding protein 4-related disease is age-related macular degeneration, Stargardt disease, or Best disease.

[0070] In a fourth aspect, the present invention provides a method for inhibiting the formation of an RBP4-TTR complex 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.

[0071] In a fifth aspect, the present invention provides a method for inhibiting excessive accumulation of lipofuscin in cells, comprising contacting the cells with an effective amount of the compound of the first aspect or the pharmaceutical composition of the second aspect.

[0072] In a sixth aspect, the present invention provides a method for inhibiting the formation of an RBP4-TTR complex in the 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.

[0073] In a seventh aspect, the present invention provides a method for 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.

[0074] The foregoing description only summarizes certain aspects of the present invention, but is not intended to limit the present invention to these aspects. These and other aspects will be described in more detail and fully below. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] The accompanying drawings are used to provide further understanding of the present application and constitute a part of the specification. Together with the following specific embodiments, they are used to explain the present application, but do not constitute a limitation to the present application.

[0076] FIG1 shows representative photographs of BAF in rats of each group after drug administration. DETAILED DESCRIPTION

[0077] Definitions and General Terms

[0078] Unless otherwise stated, the terms used in the specification and claims of the present invention have the following definitions.

[0079] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can 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 combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0080] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0081] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0082] Unless otherwise indicated, the following definitions shall apply as used herein. For purposes of the present invention, the chemical elements are as per the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry may be found 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.

[0083] Unless otherwise specified or clearly contradicted by context, the articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more." Thus, as used herein, these articles refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., more than one component may be contemplated for use or use in implementing the described embodiments.

[0084] As used herein, the term "subject" refers to an animal. Typically, the animal is a mammal. A subject also refers, for example, to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0085] The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0086] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0087] "Stereoisomers" are compounds that have identical chemical constitutions but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis / trans) isomers, atropisomers, and the like.

[0088] "Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0089] Stereochemical definitions and conventions used herein generally follow SP 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.

[0090] Many organic compounds exist in optically active forms, meaning they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are the symbols used to designate the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is left-handed. A compound prefixed with (+) or d is right-handed. 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 can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0091] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[0092] Depending on the choice of starting materials and process, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, such as a racemate or a mixture of diastereoisomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0093] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0094] Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., enantiomers), diastereomers, and geometric isomers (or conformers): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are within the scope of the present invention.

[0095] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds that are obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, see T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0096] Any racemate of the resulting final product or intermediate can be resolved into its optical antipodes by methods familiar to those skilled in the art using known methods, such as by separation of its diastereomeric salts obtained. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can 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 Aubé, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL 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).

[0097] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0098] The salts mentioned in the present invention are pharmaceutically acceptable salts, wherein "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 an amino group, such as hydrochlorides, hydrobromides, phosphates, metaphosphates, sulfates, sulfites, nitrates, and perchlorates, and organic acid salts, such as carboxylates, sulfonates, sulfinates, and thiocarboxylates, specifically, but not limited to, methanesulfonates, ethanesulfonates, formates, acetates, succinates, benzoates, succinates, pamoates, salicylates, galactarates, glucoheptanoates, mandelates, 1,2-ethanedisulfonates, 2-naphthalenesulfonates, carbonates, trifluoroacetates, glycolates, isethionates, oxalates, maleates, tartrates, citrates, succinates, malonates, benzenesulfonates, p-toluenesulfonates, malates, fumarates, lactates, lactobionates, or oxalates, or such salts may be obtained by other methods described in the literature, such as ion exchange. 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, and the like. In addition, pharmaceutically acceptable salts also include salts obtained with appropriate bases, such as alkali metals, alkaline earth metals, ammonium and N+(C 1-4 The present invention also contemplates quaternary ammonium salts formed by any compound containing a N group. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0099] Pharmaceutically acceptable salts can be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalactonate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluenesulfonate, and trifluoroacetate.

[0100] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0101] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.

[0102] As used herein, a "solvate" refers to an association formed between one or more solvent molecules and 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 association formed when the solvent molecule is water.

[0103] The term "protecting group" or "PG" refers to a substituent that blocks or protects a specific functionality when reacting with another functional group. For example, an "amino-protecting group" refers to a substituent attached to an amino group that blocks or protects the amino functionality in a compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent attached to a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxyl-protecting group" refers to a substituent attached to a carboxyl group that blocks or protects the carboxyl functionality. Typical carboxyl-protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, reference may be made to: TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0104] A "pharmaceutical composition" refers to a mixture of one or more salts of the compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0105] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a physical parameter), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0106] Any structural formula given herein is also intended to represent non-isotopically enriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have structures depicted by the general formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0107] In another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, for example, wherein a radioactive isotope is present, such as 3 H, 14 C and 18 Those compounds of F, or in which non-radioactive isotopes are present, such as 2 H and 13 C. This type of isotope-enriched compound can be used for metabolic studies (using 14 C), reaction kinetics studies (using e.g. 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution determination, or may be used in the context of radiotherapy of patients. 18 F-enriched compounds are particularly ideal for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by replacing the previously used unlabeled reagent with an appropriate isotopically labeled reagent as described in the examples and preparations herein.

[0108] In addition, heavier isotopes, particularly deuterium (i.e. 2Substitution with H or D) can provide certain therapeutic advantages resulting from increased metabolic stability. For example, this can result in an increased in vivo half-life, a reduced dosage requirement, or an improved therapeutic index. It should be understood that deuterium in the present invention is considered a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. Where a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, eg D2O, acetone-d6, DMSO-d6.

[0109] As described herein, the compounds of the present invention may optionally be substituted with one or more substituents, such as the compounds of the general formula above, or as specifically exemplified in the Examples, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." In general, the term "optionally," whether or not preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are replaced with the specified 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 formula can be substituted with one or more substituents selected from the specified group, the substituents may be the same or different at each position. The substituents can be, but are not limited to, deuterium, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclic, thiol, nitro, aryloxy, heteroaryloxy, oxo (= O), carboxyl, 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, carboxylalkoxy and the like.

[0110] As used herein, the term "alkyl" refers to a saturated, linear or branched, monovalent hydrocarbon radical of 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, wherein the alkyl radical may be independently and optionally substituted with one or more substituents described herein. Examples of alkyl radicals 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), tert-butyl (t-Bu, -CH(CH3)CH2CH3), ... -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 "alkane" as used herein include both straight and branched saturated carbon chains. The term "alkylene" as used herein refers to a saturated divalent hydrocarbon radical derived from a straight or branched saturated hydrocarbon by eliminating two hydrogen atoms, examples of which include, but are not limited to, methylene, ethylene, isopropylidene, and the like.

[0111] The term "alkoxy" as used herein refers to an alkyl group, as defined herein, connected to the main carbon chain via an oxygen atom, such examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, etc., and the alkoxy group 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, etc.

[0112] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group of 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 unsaturated, i.e., one CC is an sp2 double bond, wherein the alkenyl group can be independently and optionally substituted with one or more substituents described in the present invention, including groups with "trans", "cis" or "E", "Z" orientation, wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0113] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is unsaturated, i.e., one C—C is an sp triple bond, wherein the alkynyl group may be independently and optionally substituted with one or more substituents described herein, wherein specific examples of alkynyl include, but are not limited to, ethynyl (—C≡CH), propargyl (—CH2C≡CH), and the like.

[0114] The term "cycloalkyl" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring containing no heteroatoms, including a monocyclic ring of 3-12 carbon atoms or a bicyclic ring of 7-12 carbon atoms. Bicyclic carbocycles having 7-12 atoms may be bicyclic [4,5], [5,5], [5,6], or [6,6] systems, while bicyclic carbocycles having 9 or 10 atoms may be bicyclic [5,6] or [6,6] systems. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of cyclic aliphatic groups include, but are in no way 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. And the "cyclic aliphatic group" or "carbocycle", "carbocyclic group", "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, heterocyclic group, 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.

[0115] The terms "heterocycle," "heterocyclyl," "heteroalicyclic," or "heterocyclic" are used interchangeably herein and refer to a monocyclic, bicyclic, or tricyclic ring system in which one or more carbon atoms in the ring(s) are independently and optionally replaced by heteroatoms, wherein the heteroatoms have the meanings herein, the ring(s) may be fully saturated or contain one or more degrees of unsaturation, but are never aromatic, and have only one point of attachment to another molecule. One or more hydrogen atoms in the ring(s) are independently and optionally replaced by one or more substituents as described herein. In some embodiments, the "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" group is a 3-7 membered monocyclic ring (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally replaced by one or more oxygen atoms to give groups such as SO, SO2, PO, PO2, and when the ring is a three-membered ring, there is only one heteroatom therein), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally replaced by one or more oxygen atoms to give groups such as SO, SO2, PO, PO2).

[0116] Heterocyclic groups can be carbon groups or heteroatom groups. "Heterocyclic group" also includes groups formed by the combination of a heterocyclic group with a saturated or partially unsaturated ring or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, glycidyl, azepanyl, oxetanyl, thiepanyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazepine Base, diazepine Base, thiazolin yl, pyrrolin-1-yl, 2-pyrrolin-1-yl, 3-pyrrolin-1-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinylimidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazinane 1,1-dioxol-2-yl, 4-hydroxy-1,4-azaphosphane 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-4 H-1,2,4-oxadiazin-4-yl, 2-hydroxy-1-(5,6-dihydropyridin-1(2H)-yl)ethan-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 heterocyclic groups also include 1,1-dioxothiomorpholinyl, and pyrimidinedione in which two carbon atoms in the ring are replaced by oxygen atoms. The heterocyclic group may be substituted or unsubstituted, and the substituents may be, but are not limited to, oxo (=O), hydroxy, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic group, 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.

[0117] The term "aryl" can be used alone or as part of "aralkyl," "aralkoxy," or "aryloxyalkyl" to refer to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing a total of 6-14 ring members, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 ring members, and has only one point of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring," and aromatic rings can include, for example, phenyl, naphthyl, and anthracenyl. And the aryl group 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, thiol, 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.

[0118] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems containing 5-14 ring members, at least one of which is aromatic and at least one of which contains one or more heteroatoms, wherein the heteroatoms have the meanings herein, and each ring system contains 3-7 ring members and has only one point of attachment to the rest of the molecule. The term "heteroaryl" is used interchangeably with the terms "heteroaromatic" or "heteroaromatic compound." Furthermore, the heteroaryl group may be substituted or unsubstituted, wherein the substituents may include, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, 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.

[0119] In other embodiments, heteroaryl includes, but is not limited to, the following 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-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl; also includes the following dioxadiazolyl ring, but is in no way limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), benzo[d]thiazol-2-yl, imidazo[1,5-a]pyridin-6-yl.

[0120] The term "heteroatom" means one or more O, S, N, P and Si atoms, including N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring in which the hydrogen 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).

[0121] The term "halogen" refers to F, Cl, Br or I.

[0122] The term "halogenated" used in the present invention means that the group following it is substituted with halogen, and the number of the substituted groups may be one or more.

[0123] The term "hydroxy substituted" used in the present invention means that the group following it is substituted with a hydroxy group, and the number of substitutions may be one or more.

[0124] When "substituted" in the present invention is used between two groups, it is preceded by a substituent, such as "aryl-substituted alkyl" means that the alkyl group has an aryl substituent, and "alkoxycarbonyl-substituted alkyl" means that the alkyl group has an alkoxycarbonyl substituent.

[0125] When multiple groups of the present invention are used in combination, they are in a substitution relationship from left to right, such as "arylalkyl" represents an alkyl substituted by an aryl group, and "alkoxyalkoxy" represents an alkoxy substituted by an alkoxy group.

[0126] As used herein, the term "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0127] Description of the compounds of the present invention

[0128] The present invention provides a compound having a structure as shown in formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in formula (I);

[0129] Among them, R 1 Selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, cyano, nitro, cycloalkyl, heterocyclyl, -NR 7 R 8 、-NR 9 (CO)R 6 、-NR 9 (CO)OR 10 、-NR 9 (CO)NR 7 R 8 、-NR 9 SOR 11 、-NR 9 SO2R 11 、-OR 10 、-O(CO)R 6 、-O(CO)NR 7 R 8 、-C(O)R 6 、-C(O)OR 10 、-C(O)NR 7 R 8 、-C(S)OR 10 、-C(S)NR 7 R 8 、-C(O)SR 10 、-SR 10 、-SOR 11 、-SO2R 11 、-SO2NR 7 R 8 、-S(O)R 11 NR 9 、-C(NR 9 )NR 7 R 8 or-P(O)R 12 R 13;

[0130] R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, deuterium, hydroxy, nitro, amino, alkoxy, carboxyl, mercapto, cyano, alkyl, halogen, cycloalkyl or haloalkyl;

[0131] Or, R 1 、R 2 、R 3 、R 4 、R 5 Connect at any ortho position to form a cycloalkyl or heterocyclic group;

[0132] R 6 is selected from hydrogen, deuterium, hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0133] R 7 、R 8 、R 9 is selected from hydrogen, deuterium, cyano, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0134] R 10 is selected from hydrogen, deuterium, alkyl, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0135] R 11 is selected from hydrogen, deuterium, amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0136] R 12 、R 13 is selected from hydrogen, deuterium, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or R 12 、R 13 It forms a phosphorus-containing heterocycle with the P atom connected to it;

[0137] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13wherein the alkyl, alkoxy, haloalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with 0 to 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, carboxyl, thiol, nitro, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, alkoxy, haloalkoxy, heterocyclyl, aryl and heteroaryl groups;

[0138] L is a bridged ring group, spiro ring group, monocyclic group or cyclic group containing 0 to 2 nitrogen atoms;

[0139] The bridged ring group, spiro ring group, monocyclic group or cyclic group in L is optionally substituted by 0 to 4 substituents selected from deuterium, alkyl, hydroxy, amino, alkoxy or haloalkyl;

[0140] A is -NR 14 - or key;

[0141] R 14 is selected from hydrogen, deuterium or alkyl;

[0142] Ring B is selected from a heterocyclic ring, an aromatic ring or a heteroaromatic ring;

[0143] R 15 And every R 16 each independently selected from deuterium, alkyl, aminoalkyl, cycloalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanoyl, alkanoyl, aminocarbonyl, heterocyclyl, aryl, heteroaryl or heterocyclylacyl;

[0144] R 15 and R 16 wherein the alkyl, cycloalkyl, aminoalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanoyl, alkanoyl, heterocyclyl, aryl, heteroaryl and heterocyclylacyl groups are each independently substituted with 0 to 4 substituents selected from the group consisting of deuterium, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkanoyl, alkoxyacyl, alkanoylamide, aminocarbonyl and oxo;

[0145] n is 0, 1, 2, 3 or 4.

[0146] In some embodiments, in the compound of formula (I), ring B is selected from C 1-9 Heterocyclic, C 6-10 Aromatic ring or C 1-9 Heteroaromatic ring.

[0147] In some embodiments, in the compound of formula (I), ring B is selected from C 4-7 Heteroaromatic ring.

[0148] In some embodiments, in the compound of formula (I), Ring B is selected from a pyrazole ring, an imidazole ring, a triazole ring, or a pyrimidine ring.

[0149] In some embodiments, in the compound of formula (I), Ring B is selected from a pyrazole ring and a triazole ring.

[0150] In some embodiments, R 15 And every R 16 are each independently selected from deuterium, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-6 aminoalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-9 Heterocyclyl C 1-6 Alkyl, C 1-9 Heteroaryl C 1-6 Alkyl, C 1-6 Alkylamide, C 1-6 Alkanoyl, aminocarbonyl, C 1-9 Heterocyclic group, C 6-10 Aryl, C 1-9 Heteroaryl or C 1-9 Heterocyclyl acyl.

[0151] In some embodiments, R 15 and R 16 C in 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-6 aminoalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-9 Heterocyclyl C 1-6 Alkyl, C 1-9 Heteroaryl C 1-6 Alkyl, C 1-6 Alkylamide, C 1-6 Alkanoyl, C 1-9 Heterocyclic group, C 6-10 Aryl, C 1-9 Heteroaryl and C 1-9 Heterocyclyl acyl groups are each independently substituted by 0 to 4 atoms selected from deuterium, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl, C 1-9 Heteroaryl, C 1-6 Alkanoyl, C 1-6 Alkoxyacyl, C 1-6 Alkylamide, aminocarbonyl, carboxyl, -OC(O)-NR 17 R 18 and substituted by a substituent in the oxo group, R 17 and R18 are each independently selected from hydrogen, deuterium, C 1-4 Alkyl and C 1-4 Halogenated alkyl.

[0152] In some embodiments, R 15 And every R 16 are each independently selected from deuterium, C 1-4 Alkyl, C 1-4 aminoalkyl, C 1-6 Heterocyclyl C 1-4 Alkyl, C 1-6 Heteroaryl C 1-4 Alkyl, aminocarbonyl, C 1-6 Heterocyclic group, C 1-6 Heteroaryl or C 1-6 Heterocyclyl acyl.

[0153] In some embodiments, R 15 And every R 16 and each is independently selected from deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, propylamino, methoxymethyl, ethoxymethyl, halomethyl, haloethyl, tetrahydropyrrolyl, tetrahydropyrrolylmethyl, piperidinyl, piperidinylmethyl, piperazinyl, piperazinylmethyl, morpholinyl, morpholinylmethyl, morpholinylethyl, morpholinoyl, pyrrolyl, pyrrolylmethyl, pyridinyl, pyridinylmethyl, imidazolyl, imidazolylmethyl, pyrazolyl, pyrazolylmethyl, pyrazinyl, pyrazinylmethyl, pyridazinyl, pyridazinylmethyl, pyrimidinyl, pyrimidinylmethyl, triazolyl, triazolylmethyl, tetrazolyl, tetrazolylmethyl, thiomorpholinylmethyl, formamido, acetamido, aminocarbonyl, formyl or acetyl.

[0154] In some embodiments, R 15 And every R 16 Each is independently selected from deuterium, methyl, ethyl, methylamino, ethylamino, tetrahydropyrrolylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinyl, morpholinylmethyl, morpholinylethyl, morpholinoyl, imidazolylmethyl, triazolylmethyl, tetrazolylmethyl, thiomorpholinylmethyl and formamido.

[0155] In some embodiments, R 15 is selected from methyl and ethyl, and each R 16 Each R is independently selected from amino, ethylamino, tetrahydropyrrolylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinyl, morpholinylmethyl, morpholinylethyl, morpholinylacyl, imidazolylmethyl, triazolylmethyl, tetrazolylmethyl, thiomorpholinylmethyl and formamido; or each R 16 are each independently selected from methyl and ethyl, and R 15is selected from amino, ethylamino, tetrahydropyrrolylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinyl, morpholinylmethyl, morpholinylethyl, morpholinoyl, imidazolylmethyl, triazolylmethyl, tetrazolylmethyl, thiomorpholinylmethyl and formamido, or R 15 And every R 16 are each independently selected from methyl and ethyl.

[0156] In some embodiments, R 15 And every R 16 Each is independently optionally substituted by 0 to 4 substituents selected from deuterium, methyl, ethyl, cyclopropyl, cyclobutane, formyl, acetyl, formamido, acetamido, aminocarbonyl, methoxyacyl, ethoxyacyl, carboxyl, -OC(O)-NHCH3, -OC(O)-N(CH3)2, -OC(O)-NHC2H5, -OC(O)-NHC3H8 and oxo.

[0157] In some embodiments, R 15 And every R 16 Each is independently optionally substituted with 0 to 2 substituents selected from deuterium, methyl, ethyl, formyl, methoxyacyl, carboxyl, -OC(O)-NHCH3 and oxo.

[0158] In some embodiments, in the compound of formula (I), R 1 、R 2 、R 3 、R 4 、R 5 The alkyl, cycloalkyl, heterocyclic, alkoxy and haloalkyl groups are C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 1-6 Alkoxy and C 1-6 alkyl halide;

[0159] R 6 Selected from hydrogen, deuterium, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 heteroaryl;

[0160] R 7 、R 8 、R 9 Selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10Aryl or C 1-9 heteroaryl;

[0161] R 10 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Halogenated alkenyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 heteroaryl;

[0162] R 11 Selected from hydrogen, deuterium, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 heteroaryl;

[0163] R 12 、R 13 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Heteroaryl, or R 12 、R 13 and the P atoms connected to it to form phosphorus-containing C 1-9 heterocyclic ring;

[0164] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 C in 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl and C1-9 Heteroaryl is optionally substituted by 0 to 4 groups selected from deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-9 Heterocyclic group, C 6-10 Aryl and C 1-9 The heteroaryl group is substituted by a substituent.

[0165] In some embodiments, in the compound of formula (I), R 1 The cycloalkyl group in is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, R 1 The heterocyclic group in is selected from oxetanyl, oxolanyl, azetidinyl, azetidine, thietanyl or thiolanyl;

[0166] R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropane, cyclobutane, halocyclopropane or halocyclobutane;

[0167] Or, R 1 、R 2 、R 3 、R 4 、R 5 at any ortho position to form a cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxacyclopentyl or oxacyclohexyl group;

[0168] R 6 is selected from hydrogen, deuterium, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, tetrahydropyrrolyl or tetrahydrofuranyl;

[0169] R 7 、R 8 、R 9 is selected from hydrogen, deuterium, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl;

[0170] R 10is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halomethyl, haloethyl, halo-n-propyl, haloisopropyl, halo-n-butyl, halocyclopropyl, halocyclobutyl, halocyclopentyl, halocyclohexyl, vinyl, propenyl, ethynyl, propynyl, halovinyl, halopropenyl, tetrahydropyrrolyl or tetrahydrofuranyl;

[0171] R 11 is selected from hydrogen, deuterium, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl;

[0172] R 12 、R 13 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl.

[0173] In some embodiments, R 1 Selected from alkyl, haloalkyl, -OR 10 and-SR 10 , where R 10 is selected from the group consisting of alkyl, alkenyl, haloalkyl and haloalkenyl.

[0174] In some embodiments, R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and-SR 10 , where R 10 Selected from C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Haloalkyl and C 1-4 Halogenated alkenyl.

[0175] In some embodiments, R 1Selected from methyl, ethyl, perhalomethyl, monohalomethyl, dihalomethyl, -O-methyl, -O-ethyl, -O-perhalomethyl, -O-monohalomethyl, -O-dihalomethyl, -O-perhaloethyl, -O-partial halogenated ethyl (the partial halogenated ethyl 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-perhalovinyl, -O-halovinylidene, -O-halovinyl, -S-methyl, -S-ethyl, -S-perhalomethyl, -S-dihalomethyl, -S-perhaloethyl, -S-tetrahaloethyl, -S-perhalovinyl, -S-halovinylidene and -S-monovinyl.

[0176] In some embodiments, R 1 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.

[0177] In some embodiments, R 2 、R 3 、R 4 、R 5 Each is independently selected from hydrogen, deuterium, halogen, alkyl and haloalkyl.

[0178] In some embodiments, R 2 、R 3 、R 4 、R 5 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, perhalogenated methyl and partially halomethyl.

[0179] In some embodiments, R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, deuterium, and fluorine.

[0180] In some embodiments, R 2 and R 3 is fluorine, and R 4 and R 5 Selected from hydrogen and deuterium.

[0181] In some embodiments, in the compound of formula (I), L is selected from C6-12 Bridged ring group, C containing 0 to 2 nitrogen atoms 5-12 Spirocyclic group, C containing 0 to 2 nitrogen atoms 2-6 Monocyclic or C containing 0 to 2 nitrogen atoms 4-12 and cyclized groups;

[0182] C in L 6-12 Bridged ring group, C 5-12 Spirocyclyl, C 2-6 Monocyclic or C 4-12 The cyclized group is optionally substituted by 0 to 4 atoms selected from deuterium, C 1-6 Alkyl, hydroxyl, amino, C 1-6 Alkoxy or C 1-6 substituted by a haloalkyl substituent;

[0183] R 14 The alkyl group is C 1-6 alkyl.

[0184] In some embodiments, in the compound of formula (I), L has one of the following structures:

[0185] In some embodiments, in the compound of formula (I), L is

[0186] In some embodiments, in the compound of Formula (I), A is a bond.

[0187] In some embodiments, the compound has a structure as shown in Formula (II) or Formula (III);

[0188] Among them, X 1 、X 2 、X 3 N or CR 16 ;

[0189] l is 0 or 1, n is 0, 1, 2, 3 or 4;

[0190] R 1 、R 2 、R 3 、R 4 、R 5 、R 15 、R 16 , L, A and Ring B are as defined above for Formula (I), respectively.

[0191] In some embodiments, the compound has a structure as shown in formula (IV),

[0192] where X 4 N or CR 16, and R 1 、R 2 、R 3 、R 15 and R 16 As defined above for formula (I), formula (II) or formula (III).

[0193] 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:

[0194] Compositions, formulations and administration of the compounds of the present invention

[0195] The pharmaceutical composition comprises one or more compounds of the present invention or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or esters of the compounds. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0196] Examples of pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer 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 silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. sodium cellulose, ethylcellulose 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; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol, phosphate buffered solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants.

[0197] When used for treatment, a therapeutically effective amount of a compound of the present invention can be administered as a raw chemical or as an active ingredient in a pharmaceutical composition. Therefore, the present invention also provides a pharmaceutical composition 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 refers to the total amount of each active ingredient sufficient to show a significant patient benefit (e.g., a reduction in viral load). When a separate active ingredient is administered alone, the term refers only to that ingredient. When used in combination, the term refers to the combined amount of active ingredients that causes a therapeutic effect, whether in combination, sequentially, or simultaneously. The carrier, diluent, or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and harmless to the recipient. According to another aspect of the present invention, a method for preparing a pharmaceutical formulation is also provided, comprising mixing the 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 refers to the compounds, raw materials, compositions and / or dosage forms of the present invention, which are suitable for contact with patient tissues without excessive toxicity, irritation, allergic response or other problems and complications commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment, and are effectively used for the intended purpose.

[0198] It should be understood that in addition to the ingredients particularly mentioned above the formulations may include other ingredients conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0199] Uses of the compounds and compositions of the present invention

[0200] The pharmaceutical composition can be used to prevent, treat, cure or alleviate diseases related to retinol binding protein 4. The diseases related to retinol binding protein 4 are age-related macular degeneration, Stargardt disease or Best disease.

[0201] 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, or pharmaceutically acceptable composition thereof, is an amount effective to treat or lessen the severity of one or more of the conditions described herein. According to the methods of the present invention, the compounds and compositions thereof may be administered in any amount and by any route of administration effective to treat or lessen the severity of the condition. The exact amount required will vary depending on the patient's condition, including race, age, general condition of the patient, severity of the infection, special factors, 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 herein.

[0202] The present invention also provides a method for inhibiting the formation of an RBP4-TTR complex in a cell, comprising contacting the cell with an effective amount of the compound or pharmaceutical composition of the present invention.

[0203] The present invention also provides a method for inhibiting excessive accumulation of lipofuscin in cells, comprising contacting the cells with an effective amount of the compound or pharmaceutical composition of the present invention.

[0204] The present invention also provides a method for inhibiting the formation of an RBP4-TTR complex in the serum of a subject, comprising administering to the subject an effective amount of the compound or pharmaceutical composition of the present invention.

[0205] The present invention also provides a method for inhibiting excessive accumulation of lipofuscin in the retina of a subject, comprising administering to the subject an effective amount of the compound or pharmaceutical composition of the present invention.

[0206] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0207] General synthesis process

[0208] Generally, the compounds of the present invention can be prepared by the methods described herein. The following reaction schemes and examples are provided to further illustrate the present invention.

[0209] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modifications, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.

[0210] In the examples described below, all temperatures are set forth in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company, and Alfa Chemical Company and used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.

[0211] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether were dried over sodium reflux. Anhydrous dichloromethane and chloroform were dried over calcium hydride reflux. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

[0212] The following reactions were generally carried out under a positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction flasks were plugged with suitable rubber stoppers, and substrates were introduced via syringe. All glassware was dried.

[0213] Silica gel columns were used for chromatography. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. Nuclear magnetic resonance spectra were performed using CDC13, d6-DMSO, CD3OD, or d6-acetone as solvents (reported in ppm), with TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), and dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).

[0214] The following abbreviations are used throughout this invention:

[0215] AcOH: acetic acid

[0216] Boc2O, BOC anhydride: di-tert-butyl dicarbonate

[0217] Boc: tert-butyloxycarbonyl

[0218] Bu4NHSO4: Tetrabutylammonium hydrogen sulfate

[0219] CH3CN: acetonitrile

[0220] DCM: dichloromethane

[0221] DIPEA: N,N-diisopropylethylamine

[0222] EA: ethyl acetate

[0223] HCl: hydrogen chloride

[0224] HCl / EA: Hydrogen chloride in ethyl acetate

[0225] H2O: water

[0226] NaOH: sodium hydroxide

[0227] NaI: sodium iodide

[0228] K2CO3: Potassium carbonate

[0229] rt, rt: room temperature

[0230] TABF: Tetrabutylammonium fluoride

[0231] Example

[0232] intermediates

[0233] Preparation of intermediate 1

[0234] 4-(3,4-Difluoro-2-(trifluoromethyl)phenyl)piperidine hydrochloride (Intermediate 1)

[0235] Step 1: Synthesis of tert-butyl 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1b)

[0236] 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 tetrakistriphenylphosphine palladium (0.45 g, 0.39 mmol) were added sequentially to a 25 mL three-necked flask. After displacing the atmosphere with nitrogen three times, ethylene glycol dimethyl ether (10 mL) and 2M sodium hydroxide solution (3 mL) were added sequentially. After displacing the atmosphere 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. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product. This was then separated and purified by silica gel column chromatography to obtain compound 1b as a yellow oil (1.33 g, yield: 47%). LCMS: 364.3 [M+H] + .

[0237] Step 2: Synthesis of tert-butyl 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate (1c)

[0238] In a 100 mL round-bottom flask, 1b (610 mg, 1.68 mmol) was dissolved in ethanol (50 mL). 10% Pd / C (600 mg) was added. The air was replaced with hydrogen five times and the mixture was stirred at room temperature for 48 hours. Filtered through Celite, the filtrate was concentrated under reduced pressure to afford compound 1c as a white solid (510 mg, yield: 58%). LCMS: 366.3 [M+H] + .

[0239] Step 3: Synthesis of 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine hydrochloride (Intermediate 1)

[0240] In a 100 mL round-bottom flask, compound 1c (500 mg, 1.37 mmol) was dissolved in dioxane (3 mL). Hydrochloric acid / 1,4-dioxane (0.6 mL, 4 mol / L) was added and the mixture was allowed to react at room temperature for 1.5 hours. The organic solvent was removed by concentration under reduced pressure to obtain intermediate 1 as a yellow oil (497 mg). LCMS: 266.2 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ9.52(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.

[0241] Preparation of intermediate 2

[0242] 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)

[0243] Step 1: Synthesis of tert-butyl 4-(3,4-difluoro-2-(methylthio)phenyl)piperidine-1-carboxylate (2c)

[0244] Under nitrogen, in a 100 mL three-necked flask, 2a (478 mg, 2.0 mmol), 2b (792 mg, 3.0 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (22 mg, 0.1 mmol), 4-4'-di-tert-butylbipyridyl (27 mg, 0.1 mmol), 2-6-lutidine (1.07 g, 10.0 mmol), bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridinium][2-2'-bi(4-tert-butylpyridinium)]iridium bis(hexafluorophosphate) (112 mg, 0.1 mmol) and ethylene glycol dimethyl ether (30 mL) were added in sequence and the mixture was illuminated with 420 nm LED at room temperature for 2 h. The mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 2c as a yellow oil (295 mg, yield 43%). LCMS: 344.4 [M+H] + .

[0245] Step 2: Synthesis of 4-(3,4-difluoro-2-(methylthio)phenyl)piperidine hydrochloride (Intermediate 2)

[0246] In a 100 mL round-bottom flask, 2c (100 mg, 0.29 mmol) was dissolved in dichloromethane (10 mL). 1 mL of hydrochloric acid / 1,4-dioxane solution (4 mol / L) was added and the mixture was allowed to react at room temperature for 2 hours. The organic solvent was removed by direct concentration under reduced pressure to obtain intermediate 2 (80 mg) as a white solid. LCMS: 234.1 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ9.21–9.14(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.

[0247] Preparation of intermediate 3

[0248] 4-(2-(Ethylthio)-3,4-difluorophenyl)piperidine hydrochloride (Intermediate 3)

[0249] Step 1: Synthesis of tert-butyl 4-(2-amino-3,4-difluorophenyl)piperidine-1-carboxylate (3b)

[0250] In a 100 mL three-necked flask, 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(boronic acid)-pinacol ester (1.1 g, 4.33 mmol), and (SP-4-2)-[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridyl-κN1,κN1′]nickel dibromide (117 mg, 0.24 mmol) were dissolved in anhydrous N,N-dimethylacetamide (10 mL). The reaction mixture was then nitrogen-purged three times and heated to 60°C for 6 hours. The reaction mixture was poured directly into water and extracted with ethyl acetate. The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was dissolved in petroleum ether (10 mL) and stirred at room temperature for 30 minutes. A large amount of solid precipitated, which was collected by filtration and dried in vacuo to obtain an off-white solid compound 3b (600 mg, yield: 80%). LCMS: 213.2 [M-100] - .

[0251] Step 2: Synthesis of tert-butyl 4-(3,4-difluoro-2-iodophenyl)piperidine-1-carboxylate (3c)

[0252] In a 50 mL round-bottom flask, cuprous 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. The reaction solution was then heated directly to 60°C. At this temperature, a solution of 3b (600 mg, 1.92 mmol) in acetonitrile (1 mL) was added dropwise, and the temperature was maintained for 30 minutes. The reaction solution was cooled directly to room temperature, poured into water, and extracted with ethyl acetate. The organic phases were combined and washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. After separation and purification by silica gel column chromatography, compound 3c (500 mg, 49.2% yield) was obtained as an off-white solid. LCMS: 424.2 [M+H] + .

[0253] Step 3: Synthesis of tert-butyl 4-(2-((3-((2-ethylhexyl)oxy)-3-oxopropyl)thio)-3,4-difluorophenyl)piperidine-1-carboxylate (3d)

[0254] To a 100 mL round-bottom flask, 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 added sequentially. 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 added sequentially. The air was replaced with nitrogen three times and the mixture was reacted at 100°C for 6 hours. The mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the filtrate was diluted with ethyl acetate, quenched with water, and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography to obtain compound 3d as a yellow oil (4.58 g). LCMS: 514.2 [M+H] + .

[0255] Step 4: Synthesis of tert-butyl 4-(3,4-difluoro-2-mercaptophenyl)piperidine-1-carboxylate (3e)

[0256] To a 100 mL round-bottom flask, 3d (4.58 g, 8.92 mmol) and anhydrous tetrahydrofuran (50 mL) were added sequentially. Sodium ethoxide (0.61 g, 8.92 mmol) was added portionwise at 0°C and allowed to react for 30 minutes. Potassium bisulfate solution was added at 0°C to adjust the pH to 5 to quench the reaction. The mixture was extracted with ethyl acetate and separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product. Compound 3e was purified by silica gel column chromatography as a yellow oil (2.2 g, yield: 68%). LCMS: 330.1 [M+H]. + .

[0257] Step 5: Synthesis of tert-butyl 4-(2-(ethylthio)-3,4-difluorophenyl)piperidine-1-carboxylate (3f)

[0258] To a 25 mL round-bottom flask, 3e (500 mg, 1.52 mmol) and anhydrous tetrahydrofuran (5 mL) were added sequentially. After stirring at 0°C for 30 minutes, iodoethane (237 mg, 1.52 mmol) was added and stirred at 0°C for 15 minutes. The reaction was quenched by adding water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 3f as a colorless oil (465 mg, yield: 84%). LCMS: 358.2 [M+H] + .

[0259] Step 6: Synthesis of 4-(2-(ethylthio)-3,4-difluorophenyl)piperidine hydrochloride (Intermediate 3)

[0260] In a 50 mL round-bottom flask, 3f (465 mg, 1.30 mmol) was dissolved in ethyl acetate (1 mL). Ethyl acetate hydrochloride (5 mL, 4 M) was added dropwise at 0°C and stirred at 0°C for 2 hours. The reaction mixture was concentrated under reduced pressure to afford intermediate 3 as an off-white solid (343 mg, yield: 90%). LCMS: 258.3 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ9.23(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.

[0261] Preparation of intermediate 4

[0262] 4-(3,4-Difluoro-2-((trifluoromethyl)thio)phenyl)piperidine hydrochloride (Intermediate 4)

[0263] Step 1: Synthesis of tert-butyl 4-(3,4-difluoro-2-((trifluoromethyl)thio)phenyl)piperidine-1-carboxylate (4a)

[0264] In a 30 mL microwave tube, compound 3c (500 mg, 1.18 mmol), silver trifluoromethylthioate (700 mg, 3.54 mmol), cuprous iodide (450 mg, 2.36 mmol), bipyridine (370 mg, 2.36 mmol), and N-methylpyrrolidone (10 mL) were added sequentially. Under nitrogen protection, the mixture was microwaved at 150°C for 1 hour. The reaction solution was poured directly into water and extracted with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Compound 4a was separated and purified by silica gel column chromatography to obtain a colorless oil (189 mg, yield: 40%). LCMS: 398.4 [M+H] + .

[0265] Step 2: Synthesis of 4-(3,4-difluoro-2-((trifluoromethyl)thio)phenyl)piperidine (Intermediate 4)

[0266] In a 50 mL round-bottom flask, compound 4a (180 mg, 0.45 mmol) was dissolved in ethyl acetate (2 mL). Hydrochloric acid / ethyl acetate solution (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 concentrated to dryness to obtain intermediate 4 as an off-white solid (136 mg). LCMS: 298.3 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ9.37(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),1.81–1.78(m,2H)ppm.

[0267] Preparation of intermediate 5

[0268] 4-(2-((difluoromethyl)thio)-3,4-difluorophenyl)piperidine hydrochloride (Intermediate 5)

[0269] Step 1: Synthesis of tert-butyl 4-(2-((difluoromethyl)thio)-3,4-difluorophenyl)piperidine-1-carboxylate (5a)

[0270] To a 100 mL round-bottom flask, 3e (500 mg, 1.52 mmol), potassium hydroxide (425.84 mg, 7.59 mmol), acetonitrile (5 mL), and water (5 mL) were added sequentially. A solution of diethyl bromofluoromethylphosphonate (2.03 g, 7.60 mmol) in acetonitrile (5 mL) was added dropwise at -20°C and allowed to react for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography to obtain compound 5a as a yellow oil (454 mg, yield: 72%). LCMS: 380.1 [M+H]. + .

[0271] Step 2: Synthesis of 4-(2-((difluoromethyl)thio)-3,4-difluorophenyl)piperidine hydrochloride (Intermediate 5)

[0272] In a 50 mL round-bottom flask, 5a (454 mg, 1.20 mmol) was dissolved in ethyl acetate (2 mL). Ethyl acetate hydrochloride (10 mL, 4 M) was added dropwise at 0°C and stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure to afford intermediate 5 as an off-white solid (378 mg). LCMS: 280.3 [M+H] + .1 H NMR(400MHz,DMSO-d6)δ9.37(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),2.07–1.96(m,2H),1.82–1.78(m,2H)ppm.

[0273] Preparation of intermediate 6

[0274] 4-(3,4-Difluoro-2-((1,1,2,2-tetrafluoroethyl)thio)phenyl)piperidine hydrochloride (Intermediate 6)

[0275] Step 1: Synthesis of tert-butyl 4-(2-((2-bromo-1,1,2,2-tetrafluoroethyl)thio)-3,4-difluorophenyl)piperidine-1-carboxylate (6a)

[0276] In a 100mL three-necked flask, 3e (5.0g, 15.18mmol) was dissolved in anhydrous N,N-dimethylformamide (50mL). The reaction solution was then cooled to 0°C and sodium hydride (910mg, 22.77mmol, 60% content) was added. The reaction was allowed to return to room temperature for 15 minutes. The reaction solution was then cooled to 0°C again and 1,2-dibromo-1,1,2,2-tetrafluoroethane (11.83g, 45.54mmol) was added dropwise. The temperature was maintained for 2 hours. The reaction solution was poured directly into water and extracted with ethyl acetate. The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Compound 6a was isolated by silica gel column chromatography as a colorless oil (6.0g, yield: 78%). LC-MS: 509.3, 511.3 [M+H] + .

[0277] Step 2: Synthesis of tert-butyl 4-(3,4-difluoro-2-((1,1,2,2-tetrafluoroethyl)thio)phenyl)piperidine-1-carboxylate (6b)

[0278] In a 100 mL round-bottom flask, compound 6a (3.0 g, 5.9 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL). The reaction mixture was then cooled to 0°C under nitrogen and ethylmagnesium bromide (5.9 mL, 5.9 mmol) was added dropwise. The temperature was maintained for 15 minutes. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phases were combined and washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude compound. Compound 6b was purified by silica gel column chromatography to obtain a colorless oil (0.6 g, yield: 24%). LCMS: 430.4 [M+H] + .

[0279] Step 3: Synthesis of 4-(3,4-difluoro-2-((1,1,2,2-tetrafluoroethyl)thio)phenyl)piperidine (Intermediate 6)

[0280] In a 100 mL round-bottom flask, compound 6b (600 mg, 1.4 mmol) was dissolved in anhydrous dioxane (2 mL). A hydrochloric acid / dioxane solution (10 mL, 4 mol / L) was then added and allowed to react at room temperature for 2 hours. The reaction solution was directly concentrated to dryness under reduced pressure to obtain crude intermediate 6 as an off-white solid (460 mg). LCMS: 330.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.36(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.

[0281] Preparation of intermediate 7

[0282] 4-(3,4-Difluoro-2-((1,2,2-trifluorovinyl)thio)phenyl)piperidine hydrochloride (Intermediate 7)

[0283] Step 1: Synthesis of tert-butyl 4-(3,4-difluoro-2-((1,2,2-trifluorovinyl)thio)phenyl)piperidine-1-carboxylate (7a)

[0284] In a 100 mL round-bottom flask, ethylmagnesium bromide (18 mL, 17.71 mmol) was added dropwise to anhydrous tetrahydrofuran (40 mL). The reaction mixture was then cooled to 0°C under nitrogen. A solution of 6a (3.0 g, 5.9 mmol) in tetrahydrofuran (10 mL) was quickly added dropwise and the temperature maintained for 15 minutes. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phases were combined and washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude compound. Compound 7a was purified by silica gel column chromatography as a colorless oil (1.5 g, 62% yield). LCMS: 410.4 [M+H] + .

[0285] Step 2: Synthesis of 4-(3,4-difluoro-2-((1,2,2-trifluorovinyl)thio)phenyl)piperidine (Intermediate 7)

[0286] In a 100 mL round-bottom flask, compound 7a (1.5 g, 3.66 mmol) was dissolved in anhydrous dioxane (5 mL). A hydrochloric acid / dioxane solution (20 mL, 4 M) was then added and allowed to react at room temperature for 2 hours. The reaction solution was concentrated to dryness to obtain crude intermediate 7 as an off-white solid (1.1 g). LCMS: 310.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.39(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),1.85–1.82(m,2H)ppm.

[0287] Preparation of intermediate 8

[0288] 4-(3,4-Difluoro-2-(trifluoromethoxy)phenyl)piperidine (Intermediate 8)

[0289] Step 1: Synthesis of tert-butyl 4-(3,4-difluoro-2-methoxyphenyl)piperidine-1-carboxylate (8b)

[0290] 8a (2.00 g, 8.97 mmol), tert-butyl 4-bromopiperidine-1-carboxylate (2.84 g, 10.76 mmol), bispinacolatoboron (4.10 g, 16.14 mmol), (4,4'-di-tert-butyl-2,2'-bipyridyl)nickel dibromide (0.44 g, 0.89 mmol), sodium iodide (2.69 g, 17.94 mmol), and potassium carbonate (2.48 g, 17.94 mmol) were added sequentially to a solution of N,N-dimethylacetamide (20 mL). The mixture was stirred at 60°C under nitrogen for 8 hours, then quenched with water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain the crude product, which was then separated and purified by silica gel column chromatography to obtain compound 8b (1.40 g, yield: 48%). LCMS: 328.1 [M+H] + .

[0291] Step 2: Synthesis of 2,3-difluoro-6-(piperidin-4-yl)phenol (8c)

[0292] In a 100 mL three-necked flask, 8b (1.40 g, 4.28 mmol) was dissolved in anhydrous dichloromethane (10 mL). The temperature was lowered to 0°C, and boron tribromide (21.4 mL, 21.38 mmol, 1 mol / L dichloromethane solution) was slowly added dropwise. After the addition, the mixture was stirred at 25°C for 1 hour. After the reaction was complete, the mixture was slowly added dropwise to methanol (20 mL) to quench the reaction. After quenching, the mixture was directly concentrated to dryness under reduced pressure to obtain compound 8c (1.00 g). LCMS: 214.1 [M+H] + .

[0293] Step 3: Synthesis of tert-butyl 4-(3,4-difluoro-2-hydroxyphenyl)piperidine-1-carboxylate (8d)

[0294] 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 added sequentially to a solution of dichloroethane (10 mL) and stirred at 25°C for 8 hours. After completion, water was added to quench the reaction, followed by extraction with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography to obtain compound 8d (850.00 mg, yield: 64%). LCMS: 314.0 [M+H] + .

[0295] Step 4: Synthesis of tert-butyl 4-(2-(bromodifluoromethoxy)-3,4-difluorophenyl)piperidine-1-carboxylate (8e)

[0296] In a 50 mL pressure bottle, 8d (1.00 g, 3.191 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). The temperature was lowered to 0°C, and sodium hydroxide (255 mg, 6.38 mmol, purity: 60%) was added. After the addition, the mixture was stirred for 30 minutes. Dibromodifluoromethane (3.35 g, 15.957 mmol) was then added and stirred at 25°C for 8 hours. After completion, the reaction was quenched with water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography to obtain compound 8e (800.00 mg, yield: 57%). LCMS: 442.0, 444.0 [M+H] + .

[0297] Step 5: Synthesis of 4-(3,4-difluoro-2-(trifluoromethoxy)phenyl)piperidine (Intermediate 8)

[0298] 8e (800.00 mg, 1.81 mmol) and silver tetrafluoroborate (1.76 g, 9.05 mmol) were added sequentially to a solution of 1,2-dichloroethane (15 mL). The mixture was stirred at 60°C under nitrogen for 1 hour. After completion, water was added to quench the reaction, and the mixture was filtered. The filtrate was then dried to give the crude product, which was then separated and purified by silica gel column chromatography to give intermediate 8 (400.00 mg, yield: 79%). LCMS: 282.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.82(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),1.83–1.80(m,2H)ppm.

[0299] Preparation of intermediate 9

[0300] 4-(2-(Difluoromethoxy)-3,4-difluorophenyl)piperidine hydrochloride (Intermediate 9)

[0301] Step 1: Synthesis of tert-butyl 4-(2-(difluoromethoxy)-3,4-difluorophenyl)piperidine-1-carboxylate (9b)

[0302] 8d (5.00 g, 15.96 mmol), 9a (6.39 g, 23.94 mmol), and potassium carbonate (11.03 g, 79.79 mmol) were added sequentially to a mixture of acetonitrile (25 mL) and water (25 mL). The mixture was stirred at 25°C for 8 hours. After completion, water was added to quench the reaction, followed by extraction with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to afford a crude product. The crude product was then separated and purified by silica gel column chromatography to afford compound 9b (3.00 g, yield: 52%). LCMS: 364.1 [M+H] + .

[0303] Step 2: Synthesis of 4-(2-(difluoromethoxy)-3,4-difluorophenyl)piperidine hydrochloride (Intermediate 9)

[0304] 9b (600 mg, 1.65 mmol) was added to a solution of hydrochloric acid / 1,4-dioxane (10 mL, 4 mol / L). The mixture was stirred at 25°C for 1 hour. After the reaction was complete, the mixture was dried under reduced pressure to obtain intermediate 9 (450.00 mg). LCMS: 264.2 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ9.22(s,2H),7.50–7.45(m,1H),7.39(s,0.25H),7.24(s,0.5H),7.19–7.15(m,1H),7.1 0(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.

[0305] Preparation of intermediate 10

[0306] 4-(3,4-Difluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)piperidine hydrochloride (Intermediate 10)

[0307] Step 1: Synthesis of tert-butyl 4-(2-(2-bromo-1,1,2,2-tetrafluoroethoxy)-3,4-difluorophenyl)piperidine-1-carboxylate (10b)

[0308] In a 100 mL pressure bottle, 8d (1.60 g, 5.11 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 mL). The temperature was lowered to 0°C, and sodium hydroxide (410 mg, 10.21 mmol, purity: 60%) was added. After stirring for 30 minutes, 10a (3.35 g, 12.89 mmol) was added and stirred at 25°C for 8 hours. After completion, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography to obtain compound 10b (1.80 g, yield: 72%). LCMS: 442.0, 444.0 [M+H] + .

[0309] Step 2: Synthesis of tert-butyl 4-(3,4-difluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)piperidine-1-carboxylate (10c)

[0310] Compound 10b (250 mg, 0.51 mmol) and cesium fluoride (231.43 mg, 1.52 mmol) were added sequentially to a solution of dimethyl sulfoxide (5 mL) and stirred at 120°C for 8 hours. After completion, water was added to quench the reaction, followed by extraction with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to afford compound 10c (200 mg, yield: 95%). LCMS: 414.04 [M+H] + .

[0311] Step 3: Synthesis of 4-(3,4-difluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)piperidine hydrochloride (Intermediate 10)

[0312] 10c (200 mg, 0.48 mmol) was added to a solution of hydrochloric acid / 1,4-dioxane (5 mL, 4 mol / L). The mixture was stirred at 25°C for 1 hour. After the reaction was complete, the mixture was dried under reduced pressure to give intermediate 10 (169.00 mg). LCMS: 314.2 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ9.28(s,2H),7.60–7.55(m,1H),7.25–7.22(m,1H),7.19–6.98(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),1.79–1.76(m,2H)ppm.

[0313] Preparation of intermediate 11

[0314] 4-(3,4-Difluoro-2-((1,2,2-trifluorovinyl)oxy)phenyl)piperidine hydrochloride (Intermediate 11)

[0315] Step 1: Synthesis of tert-butyl 4-(3,4-difluoro-2-((1,2,2-trifluorovinyl)oxy)phenyl)piperidine-1-carboxylate (11a)

[0316] 10b (600 mg, 1.22 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL), cooled to 0°C under nitrogen, and ethylmagnesium bromide (3.7 mL, 3.66 mmol, 1 mol / L tetrahydrofuran solution) was added. The mixture was stirred at 25°C for 8 hours. After completion, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to afford the crude product. The crude product was isolated and purified by silica gel thin-layer chromatography to afford 11a (250 mg, yield: 52%). LCMS: 394.1 [M+H] + .

[0317] Step 2: Synthesis of 4-(3,4-difluoro-2-((1,2,2-trifluorovinyl)oxy)phenyl)piperidine hydrochloride (Intermediate 11)

[0318] 11a (250 mg, 0.64 mmol) was added to a solution of hydrochloric acid / 1,4-dioxane (5 mL, 4 mol / L). After the addition, the mixture was stirred at 25°C for 1 hour. After the reaction was complete, the mixture was dried under reduced pressure to obtain intermediate 11 (209 mg). LCMS: 294.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ9.26–9.20(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.

[0319] Example 1

[0320] Preparation of N-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)acetamide (Compound 1)

[0321] Step 1: Synthesis of ethyl 5-bromo-4-methyl-1H-pyrazole-3-carboxylate (1b)

[0322] In a 250 mL round-bottom flask, 1a (5.0 g, 32.32 mmol) was dissolved in dichloromethane (50 mL). The temperature was cooled to 0°C, and pyridinium tribromide (11.37 g, 35.55 mmol) was added. The mixture was allowed to react at room temperature for 24 hours. The reaction was quenched with pure water and extracted with dichloromethane. The organic phase was collected and concentrated to obtain the crude product. Compound 1b was purified by silica gel column chromatography as an off-white solid (3.0 g, yield: 40%). LC-MS: 232.2 [M+H] + .

[0323] Step 2: Synthesis of 1-(tert-butyl) 3-ethyl 5-bromo-4-methyl-1H-pyrazole-1,3-dicarboxylate (1c)

[0324] In a 100 mL round-bottom flask, 1b (2.0 g, 8.58 mmol) was dissolved in dichloromethane (20 mL). 4-Dimethylaminopyridine (1.0 g, 8.18 mmol) was added, and the temperature was lowered to 0°C. Di-tert-butyl dicarbonate (1.8 mL, 8.58 mmol) was slowly added. The mixture was allowed to react at room temperature for 3 hours. The reaction was quenched by adding purified water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound. Compound 1c was purified by silica gel column chromatography to obtain an off-white solid (2.3 g, yield: 80%). LC-MS: 333.2 [M+H] + .

[0325] Step 3: Synthesis of 1-(tert-butyl)3-ethyl 5-(((tert-butoxycarbonyl)amino)methyl)-4-methyl-1H-pyrazole-1,3-dicarboxylate (1d)

[0326] In a 100 mL round-bottom flask, 1c (2.3 g, 6.9 mmol) was dissolved in a mixture of 1,4-dioxane and water (20 mL / 5 mL). Potassium N-aminomethyltrifluoroborate (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 then added. The air was purged and nitrogen was introduced. The reaction was allowed to proceed at 110°C for 8 hours. The reaction was quenched by the addition of pure water and extracted with ethyl acetate. The organic phase was collected and concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 1d as an off-white solid (700 mg, yield: 27%). LC-MS: 384.2 [M+H] + .

[0327] Step 4: Synthesis of ethyl 5-(aminomethyl)-4-methyl-1H-pyrazole-3-carboxylate (1e)

[0328] In a 50 mL round-bottom flask, dissolve 1d (700 mg, 1.83 mmol) in ethyl acetate (2 mL). Add hydrochloric acid-ethyl acetate solution (10 mL, 4 mol / L) and allow to react at room temperature for 4 hours. Concentrate the reaction mixture to dryness to obtain compound 1e as an off-white solid (500 mg). LC-MS: 185.2 [M+H] + .

[0329] Step 5: Synthesis of ethyl 5-(acetylaminomethyl)-4-methyl-1H-pyrazole-3-carboxylate (1f)

[0330] In a 50 mL round-bottom flask, 1e (400 mg, 2.18 mmol) was dissolved in 2-methyltetrahydrofuran / dichloromethane (8 mL / 4 mL). Triethylamine (1.5 mL, 10.92 mmol) was then added. The temperature was lowered to 0°C. Acetyl chloride (0.2 mL, 2.62 mmol) was dissolved in dichloromethane (4 mL) and slowly added to the reaction system. The mixture was allowed to react at 0°C for 2 hours. The reaction was quenched with pure water and extracted with dichloromethane. The organic phase was collected and concentrated to yield compound 1f as an off-white solid (350 mg, yield: 71%). LC-MS: 226.2 [M+H] + .

[0331] Step 6: Synthesis of 5-acetylaminomethyl-4-methyl-1H-pyrazole-3-carboxylic acid (1 g)

[0332] In a 50 mL round-bottom flask, 1f (350 mg, 1.55 mmol) was dissolved in tetrahydrofuran / methanol / water (4 mL / 4 mL / 2 mL). Lithium hydroxide (112 mg, 4.66 mmol) was then added and heated to 40°C for 12 hours. The reaction mixture was concentrated to obtain a crude product, which was then purified using a C18 reverse-phase column to afford compound 1g as an off-white solid (200 mg, yield: 65%). LC-MS: 198.2 [M+H] + .

[0333] 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)

[0334] In a 50 mL round-bottom flask, 1 g (178 mg, 0.9 mmol) was dissolved in N,N-dimethylformamide (2 mL). Triethylamine (0.45 mL, 2.26 mmol) was then added. The mixture was cooled to 0°C and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (372 mg, 0.98 mmol) was added. Stirring was continued at 0°C for 10 minutes. Intermediate 1 (200 mg, 0.75 mmol) was then added and allowed to react at room temperature for 3 hours. The reaction was quenched with pure water and extracted with ethyl acetate. The organic phase was concentrated to obtain the crude product, which was then purified by medium pressure preparative separation to yield compound 1 as an off-white solid (12 mg, 4% yield). LC-MS: 445.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.81(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=4.8Hz,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.

[0335] Example 2

[0336] Preparation of N-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-ethyl-1H-pyrazol-5-yl)methyl)acetamide (Compound 2)

[0337] Step 1: Synthesis of ethyl 4-vinyl-1H-pyrazole-3-carboxylate (2b)

[0338] In a 500 mL round-bottom flask, methyltriphenylphosphonium bromide (21.24 g, 59.50 mmol) was dissolved in tetrahydrofuran (350 mL). After displacing the air with nitrogen three times, the mixture was stirred at 0°C for 10 minutes. Potassium tert-butoxide (6.67 g, 59.50 mmol) was added portionwise. After displacing the air with nitrogen three times, the mixture was stirred at 0°C for 40 minutes. Ethyl 4-formyl-1H-pyrazole-3-carboxylate (5 g, 29.70 mmol) was added portionwise. After displacing the air with nitrogen three times, the mixture was stirred at 0°C for 4.5 hours. Water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography to obtain compound 2b as an off-white solid (2.62 g, yield: 53%). LCMS: 167.2 [M+H]. +.

[0339] Step 2: Synthesis of ethyl 4-ethyl-1H-pyrazole-3-carboxylate (2c)

[0340] In a 250 mL round-bottom flask, 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 added sequentially. The atmosphere was replaced with hydrogen five times and the mixture was stirred at room temperature for 48 hours. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure to afford compound 2c as an off-white solid (2.14 g, 81% yield).

[0341] Step 3: Synthesis of ethyl 5-bromo-4-ethyl-1H-pyrazole-3-carboxylate (2d)

[0342] In a 250 mL round-bottom flask, 2c (1.69 g, 10.00 mmol) was dissolved in acetonitrile (80 mL). N-bromosuccinimide (1.97 g, 11.1 mmol) was added portionwise at 0°C and stirred at 0°C for 4 hours. Water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product. Compound 2d was purified by silica gel column chromatography to obtain an off-white solid (725.8 mg, yield: 29%). LCMS: 248.2 [M+H] + .

[0343] Step 4: Synthesis of 1-benzyl-5-bromo-4-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester (2e)

[0344] In a 100 mL round-bottom flask, 2d (592 mg, 2.40 mmol) and cesium carbonate (1.56 g, 4.79 mmol) were added sequentially to N,N-dimethylformamide (8 mL). Benzyl chloride (303.3 mg, 2.40 mmol) was added dropwise at 0°C. The mixture was stirred at 0°C for 1 hour and then at room temperature for 12 hours. Water was added to quench the mixture, followed by extraction with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to afford the crude product. Compound 2e was purified by silica gel column chromatography to afford a yellow oil (800 mg, 99% yield). LCMS: 338.1 [M+H]. + .

[0345] Step 5: Synthesis of ethyl 1-benzyl-5-(((tert-butoxycarbonyl)amino)methyl)-4-ethyl-1H-pyrazole-3-carboxylate (2f)

[0346] In a 30 mL reaction tube, 2e (800 mg, 2.40 mmol), potassium N-aminomethyltrifluoroborate (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 added sequentially to 1,4-dioxane (16 mL) and water (4 mL). The atmosphere was replaced with nitrogen three times, and the mixture was stirred at 100°C in a microwave reactor for 2 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product. Compound 2f was purified by silica gel column chromatography to obtain a yellow oil (107 mg, yield: 12%). LCMS: 388.2 [M+H]. + .

[0347] Step 6: Synthesis of 1-benzyl-5-(((tert-butoxycarbonyl)amino)methyl)-4-ethyl-1H-pyrazole-3-carboxylic acid (2 g)

[0348] In a 100 mL round-bottom flask, 2f (107 mg, 0.28 mmol) and lithium hydroxide (18.8 mg, 0.78 mmol) were sequentially added to a mixture of methanol (2 mL), tetrahydrofuran (2 mL), and water (1 mL). The mixture was stirred at 40°C for 10 hours. The reaction mixture was distilled under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography to obtain compound 2g as an off-white solid (62 mg, yield: 62%). LCMS: 360.2 [M+H] + .

[0349] 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)

[0350] In a 50 mL round-bottom flask, 2 g (60 mg, 0.17 mmol) of the compound was dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (150 μL, 0.83 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (64 mg, 0.17 mmol) were added sequentially at 0°C. The mixture was stirred at 0°C for 10 minutes. Finally, Intermediate 1 (100 mg, 0.33 mmol) was added and stirred at 0°C for 1 hour. The reaction was allowed to proceed at room temperature for 12 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product. This was then purified by silica gel column chromatography to obtain Compound 2h as a yellow oil (100 mg, yield: 99%). LCMS: 607.2 [M+H]. + .

[0351] 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)

[0352] In a 50 mL round-bottom flask, 2h (100 mg, 0.16 mmol) was dissolved in ethyl acetate (2 mL). Ethyl acetate hydrochloride (20 mL, 4 mol / L) was added dropwise at 0°C and stirred at 0°C for 40 minutes. The reaction solution was concentrated under reduced pressure to obtain compound 2i as a yellow oil (90 mg). LCMS: 507.2 [M+H] + .

[0353] 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)

[0354] In a 50 mL round-bottom flask, 2i (90 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (0.14 mL, 1.01 mmol) was added, and a solution of acetyl chloride (19 mg, 0.24 mmol) in dichloromethane (1 mL) was added dropwise to the reaction mixture at 0°C. The mixture was stirred at 0°C for 30 minutes. Methanol and water were added to quench the reaction. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product. Compound 2j was purified by silica gel column chromatography to obtain an off-white solid (81 mg, yield: 87%). LCMS: 549.1 [M+H]. + .

[0355] 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)

[0356] In a 50 mL round-bottom flask, 2j (80 mg, 0.15 mmol) was added to methanol (20 mL), followed by 20% aqueous palladium hydroxide (80 mg, 0.57 mmol) and 10% aqueous palladium on carbon (80 mg). The air was replaced with nitrogen three times, then with hydrogen five times, and stirred at 50°C for 48 hours. Water and ethyl acetate were added for separation. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain the crude product. Compound 2 was purified by column chromatography on a silica gel column to obtain an off-white solid (55 mg, yield: 82%). LCMS: 459.4 [M+H] + . 1 H NMR (500MHz, CDCl3) δ11.34(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,1 H),3.15–2.98(m,1H),2.97–2.75(m,1H),2.69–2.47(m,2H),2.05–1.9 8(m,3H),1.91–1.81(m,2H),1.27–1.24(m,3H),1.15–1.12(m,3H)ppm.

[0357] Example 3

[0358] 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)

[0359] Step 1: Synthesis of ethyl 1-benzyl-5-bromo-4-methyl-1H-pyrazole-3-carboxylate (3a)

[0360] In a 50 mL round-bottom flask, 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 mixture was cooled to 0°C. Benzyl chloride (0.5 mL, 4.29 mmol) was then added and allowed to react at room temperature for 2 hours. The reaction was quenched with pure water and extracted with ethyl acetate. The organic phase was collected and concentrated to obtain the crude product, which was then purified by silica gel column chromatography to obtain compound 3a as an off-white solid (0.8 g, yield: 58%). LCMS: 323.2 [M+H]+ .

[0361] Step 2: Synthesis of ethyl 1-benzyl-5-(((tert-butoxycarbonyl)amino)methyl)-4-methyl-1H-pyrazole-3-carboxylate (3b)

[0362] In a 100 mL round-bottom flask, 3a (800 mg, 2.48 mmol) was dissolved in a mixture of 1,4-dioxane and water (8 mL / 2 mL). Potassium N-aminomethyltrifluoroborate (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 then added. The air was purged and nitrogen was introduced. The reaction was allowed to proceed at 110°C for 8 hours. The reaction was quenched with pure water and extracted with ethyl acetate. The organic phase was collected and concentrated, and purified by silica gel column chromatography to obtain compound 3b as an off-white solid (630 mg, yield: 68%). LCMS: 374.2 [M+H] + .

[0363] Step 3: Synthesis of ethyl 1-benzyl-5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-4-methyl-1H-pyrazole-3-carboxylate (3c)

[0364] In a 50 mL round-bottom flask, 3b (530 mg, 1.42 mmol) was dissolved in a mixed solution of N,N-dimethylformamide (10 mL). Sodium hydroxide (68 mg, 2.84 mmol) was then added, the temperature was lowered to 0°C, and iodomethane (302 mg, 2.13 mmol) was added. The reaction was allowed to react at room temperature for 4 hours. The reaction was quenched by the addition of pure water, extracted with ethyl acetate, and the organic phase was collected and concentrated. The crude product was purified by silica gel column chromatography to obtain compound 3c as an off-white solid (400 mg, yield: 72%). LCMS: 388.2 [M+H] + .

[0365] Step 4: Synthesis of 1-benzyl-5-(((tert-butyloxycarbonyl)(methyl)amino)methyl)-4-methyl-1H-pyrazole-3-carboxylic acid (3d)

[0366] In a 50 mL round-bottom flask, 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 then added and heated to 40°C for 6 hours. The reaction mixture was concentrated to obtain a crude product. Purified water was added, and the pH was adjusted to a weakly acidic state. Extraction was performed with ethyl acetate (3 x 50 mL). The organic phase was collected and concentrated. The crude product was purified by silica gel column chromatography to obtain compound 3d as an off-white solid (300 mg, yield: 80%). LCMS: 360.1 [M+H] + .

[0367] 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)

[0368] In a 50 mL round-bottom flask, 3d (300 mg, 0.80 mmol) was dissolved in N,N-dimethylformamide (4 mL). Triethylamine (1 mL, 5.00 mmol) was then added. The mixture 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. The mixture was stirred at 0°C for 10 minutes, followed by the addition of intermediate 1 (332 mg, 1.25 mmol). The reaction was allowed to react at room temperature for 3 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was concentrated to obtain the crude product, which 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]. + .

[0369] 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)

[0370] In a 50 mL round-bottom flask, 3e (500 mg, 0.80 mmol) was dissolved in ethyl acetate (2 mL). A hydrochloric acid / ethyl acetate solution (10 mL, 4 mol / L) was added and the mixture was allowed to react at room temperature for 4 hours. The organic solvent was removed by direct concentration under reduced pressure to afford compound 3f as a white solid (400 mg, yield: 95%). LCMS: 507.2 [M+H] + .

[0371] 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 (3 g)

[0372] In a 50 mL round-bottom flask, 3f (400 mg, 0.78 mmol) was dissolved in 2-methyltetrahydrofuran / dichloromethane (4 mL / 2 mL). Triethylamine (0.5 mL, 3.95 mmol) was then added. The temperature was lowered to 0°C. Acetyl chloride (70 μL, 0.90 mmol) was dissolved in dichloromethane (2 mL) and slowly added to the reaction system. The mixture was allowed to react at 0°C for 2 hours. The reaction was quenched with pure water and extracted with dichloromethane. The organic phase was collected and concentrated to yield 3 g of compound 1 as an off-white solid (400 mg, yield: 92%). LCMS: 549.2 [M+H]. + .

[0373] 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)

[0374] In a 100 mL round-bottom flask, 3 g (400 mg, 0.80 mmol) of the compound was dissolved in methanol (30 mL). Palladium hydroxide (400 mg, 2.85 mmol) and palladium on carbon (400 mg, 10%) were then added. The air was expelled, hydrogen was introduced, and the mixture was heated to 60°C for 24 hours. Filtered through celite, the filtrate was concentrated, and the crude product was obtained. This crude product was then purified by medium-pressure preparative separation to obtain compound 3 as an off-white solid (14 mg, 4% yield). LCMS: 459.1 [M+H]. + . 1 H NMR(500MHz,DMSO-d6)δ12.85(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.

[0375] Example 4

[0376] Preparation of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-(morpholinomethyl)-1H-pyrazol-3-yl)methanone (Compound 4)

[0377] Step 1: Synthesis of ethyl 4-methyl-5-(morpholinomethyl)-1H-pyrazole-3-carboxylate (4a)

[0378] In a 100 mL round-bottom flask, 1b (500 mg, 2.15 mmol) was dissolved in a mixture of 1,4-dioxane and water (12 mL / 3 mL). Potassium (morpholin-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 then added. The air was purged and nitrogen was introduced. The reaction was allowed to proceed at 110°C for 8 hours. The reaction was quenched by the addition of pure water and extracted with ethyl acetate. The organic phase was collected and concentrated, and purified by silica gel column chromatography to obtain compound 4a as an off-white solid (500 mg, yield: 92%). LCMS: 254.2 [M+H] + .

[0379] Step 2: Synthesis of 4-methyl-5-morpholinomethyl-1H-pyrazole-3-carboxylic acid (4b)

[0380] In a 50 mL round-bottom flask, 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 then added and heated to 40°C for 12 hours. The reaction mixture was concentrated to obtain the crude product, which was then purified by medium-pressure preparative separation to afford compound 4b as an off-white solid (200 mg, 45% yield). LCMS: 226.2 [M+H] + .

[0381] 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)

[0382] In a 50 mL round-bottom flask, 4b (101 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (2 mL). Triethylamine (220 μL, 1.13 mmol) was then added. The mixture was cooled to 0°C and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (186 mg, 0.49 mmol) was added. The mixture was stirred at 0°C for 10 minutes, followed by the addition of intermediate 1 (100 mg, 0.37 mmol). The reaction was allowed to react at room temperature for 3 hours. The reaction was quenched with pure water and extracted with ethyl acetate. The organic phase was concentrated to obtain the crude product, which was purified by medium-pressure preparative separation to afford compound 4 as an off-white solid (19 mg, yield: 11%). LCMS: 473.4 [M+H]. + .HNMR: 1H NMR(500MHz, CDCl3)δ7.30–7.25(m,1H),7.08–7.04(m,1H),6.14(s,1H),3.93–3.5 7(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.

[0383] Example 5

[0384] Preparation of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-ethyl-5-(morpholinomethyl)-1H-pyrazol-3-yl)methanone (Compound 5)

[0385] Step 1: Synthesis of ethyl 5-bromo-4-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (5a)

[0386] In a 100 mL round-bottom flask, 2d (1.50 g, 6.07 mmol) was dissolved in N,N-dimethylformamide (15 mL). Cesium carbonate (2.97 g, 9.11 mmol) was then added. The temperature was lowered to 0°C, followed by 2-(trimethylsilyl)ethoxymethyl chloride (1.4 mL, 7.89 mmol). The mixture was allowed to react at 25°C for 2 h. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was collected and concentrated, and purified by column chromatography to afford compound 5a as an off-white solid (2.50 g). LCMS: 377.1 [M+H]. + .

[0387] Step 2: Synthesis of ethyl 4-ethyl-5-(morpholinomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (5b)

[0388] In a 100 mL round-bottom flask, 5a (2.50 g, 6.63 mmol) was dissolved in a mixture of 1,4-dioxane and water (40 mL / 10 mL). Potassium (morpholin-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 then added. The air was purged and nitrogen was introduced. The reaction was allowed to proceed at 110°C for 8 hours. The reaction was quenched by the addition of pure water and extracted with ethyl acetate. The organic phase was collected and concentrated, and purified by column chromatography to afford compound 5b as an off-white solid (1.60 g, yield: 61%). LCMS: 398.2 [M+H] + .

[0389] Step 3: Synthesis of ethyl 5-(aminomethyl)-4-methyl-1H-pyrazole-3-carboxylate (5c)

[0390] In a 50 mL round-bottom flask, 5b (1.60 g, 4.02 mmol) was dissolved in ethyl acetate (2 mL). Hydrochloric acid-ethyl acetate solution (10 mL, 4 mol / L) was then added and the mixture was allowed to react at room temperature for 4 hours. The reaction mixture was directly concentrated to dryness to obtain compound 5c as an off-white solid (900 mg). LCMS: 269.1 [M+H] + .

[0391] Step 4: Synthesis of 4-ethyl-5-(morpholinomethyl)-1H-pyrazole-3-carboxylic acid (5d)

[0392] In a 50 mL round-bottom flask, 5c (900 mg, 3.37 mmol) was dissolved in methanol / water (15 mL / 2 mL). Sodium hydroxide (321 mg, 8.05 mmol) was then added and heated to 60°C for 12 hours. The reaction mixture was concentrated to remove the organic solvent, and purified water was added. 2 M hydrochloric acid was added to adjust the pH to 4, and ethyl acetate was added for extraction. The layers were separated, and the organic phase was collected and concentrated to obtain compound 5d as an off-white solid (800 mg). LCMS: 240.1 [M+H] + .

[0393] 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)

[0394] In a 50 mL round-bottom flask, 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 then added. The temperature was lowered to 0°C, and 1-butylphosphonic anhydride (1.58 g, 2.19 mmol, in a 50% ethyl acetate solution) was added. The reaction was allowed to react for 4 hours. The reaction was quenched by adding pure water, and ethyl acetate was added for extraction. The layers were separated, and the organic phase was collected and concentrated to obtain the crude product. Compound 5 was isolated and purified by medium-pressure preparative separation to obtain compound 5 as an off-white solid (170 mg, yield: 24%). LCMS: 487.2 [M+H]. + . 1H NMR (500MHz, DMSO-d6) δ12.79(s,1H),7.77–7.72(m,1H),7.49–7.36(m,1H),4.69(d,J=9.9Hz,1H),4.28(d,J=4.1Hz,1H),3.57(s ,4H),3.47(s,2H),3.36(s,2H),3.13(d,J=14.0Hz,2H),2.88–2.73(m,1H),2.34(s,4H),1.81–1.58(m,4H),1.08–1.05(m,3H)ppm.

[0395] Example 6

[0396] Preparation of (3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)proline methyl ester (Compound 6)

[0397] Step 1: Synthesis of ethyl 5-bromo-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (6a)

[0398] In a 500 mL round-bottom flask, 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 added sequentially. The mixture was reacted at room temperature under nitrogen for 3 hours. Water was added, and the mixture was extracted with dichloromethane. 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 silica gel column chromatography to obtain 6a as a white solid (13.13 g, 48% yield). LCMS: 318.2 [M+H] + .

[0399] Step 2: Synthesis of ethyl 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-vinyl-1H-pyrazole-3-carboxylate (6b)

[0400] To a 500 mL round-bottom flask, 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 ethylene trifluoroborate (8.3 g, 61.95 mmol) were added sequentially. The mixture was reacted at 100°C for 2 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with ethyl acetate and the filtrate was collected. The filtrate was separated by 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 obtain compound 6b as a pale yellow solid (8.68 g, 80% yield). LCMS: 265.04 [M+H] + .

[0401] Step 3: Synthesis of ethyl 5-formyl-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (6c)

[0402] In a 500 mL round-bottom flask, 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 in sequence and allowed to react at room temperature for 4 hours. A saturated sodium imide sulfate solution was added to the reaction solution, which was filtered through celite. The filter cake was washed with ethyl acetate, and the filtrate was collected. The filtrate was extracted with a separatory funnel, and 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 obtain compound 6c as a yellow-black solid (4.64 g, 58% yield). LCMS: 267.1 [M+H] + .

[0403] Step 4: Synthesis of 5-formyl-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid (6d)

[0404] In a 100 mL round-bottom flask, 6c (1.00 g, 3.76 mmol), ethanol (15 mL), water (15 mL), and anhydrous lithium hydroxide (0.79 g, 18.78 mmol) were added in sequence and reacted at room temperature for 4 hours. The organic solvent was removed by concentration under reduced pressure, and 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 2M hydrochloric acid, and then ethyl acetate was added for extraction. 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 obtain compound 6d as a black oil (840 mg, yield 94%). LCMS: 238.73 [M+H] + .

[0405] 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)

[0406] To a 100 mL round-bottom flask, 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 added sequentially. The mixture was reacted at room temperature under nitrogen for 2 hours. Water and ethyl acetate were added to the reaction solution for extraction. 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 obtain compound 6e as a colorless oil (678 mg, 45% yield). LCMS: 486.10 [M+H] + .

[0407] Step 6: Synthesis of (3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)proline methyl ester (6 g)

[0408] In a 100 mL three-necked flask, 6e (300 mg, 0.62 mmol), methanol (30 mL), 6f (123 mg, 0.74 mmol), and acetic acid (4 mg, 0.06 mmol) were added sequentially. Under nitrogen, the reaction was allowed to proceed at room temperature for 0.5 h. Sodium cyanoborohydride (78 mg, 1.24 mmol) was then added and the reaction continued at room temperature for 4 h. The mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to yield compound 6g as a colorless oil (188 mg, 51% yield). LCMS: 598.88 [M+H] + .

[0409] Step 7: Synthesis of 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)proline methyl ester (Compound 6)

[0410] In a 100 mL round-bottom flask, 6 g (160 mg, 0.27 mmol), dichloromethane (60 mL), and p-toluenesulfonic acid (92 mg, 0.53 mmol) were added sequentially and allowed to react at room temperature for 3 hours. The organic solvent was removed under reduced pressure, and the residue was purified by preparative purification to obtain compound 6 as an off-white solid (43 mg, 31% yield). LCMS: 514.63 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ12.81(s,1H),7.75(m,J=8.9Hz,1H),7.52–7.46(m,1H),3.58(s,3H),3.3 8(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.

[0411] Example 7

[0412] 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)

[0413] Step 1: Synthesis of ethyl 5-formyl-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (7a)

[0414] To a 250 mL single-necked flask, 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 added sequentially. Under nitrogen, the mixture was allowed to react at room temperature for 30 minutes. Sodium cyanoborohydride (3.78 g, 60.08 mmol) was then added and the reaction continued at room temperature for 2 hours. The mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to afford compound 7a as a colorless oil (3.85 g, yield: 36%).

[0415] LCMS: 353.6 [M+H] + .

[0416] Step 2: Synthesis of ethyl 4-methyl-5-((2-oxopyrrolidin-1-yl)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (7b)

[0417] In a 1L single-necked flask, 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% ethyl acetate solution) were added in sequence. Under nitrogen, the reaction mixture was allowed to react at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was separated with ethyl acetate. The organic phase was washed with saturated brine, collected, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to obtain compound 7b as a colorless oil (2.66 g, yield: 74%). LCMS: 335.7 [M+H] + .

[0418] Step 3: Synthesis of 4-methyl-5-((2-oxopyrrolidin-1-yl)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid (7c)

[0419] In a 250 mL single-necked flask, 7b (2.3 g, 6.86 mmol), methanol (30 mL), water (30 mL), and sodium hydroxide (0.55 g, 13.72 mmol) were added sequentially and allowed to react at room temperature for 2 hours. The organic solvent was removed under reduced pressure, and the pH was adjusted to 5 by adding 2 M hydrochloric acid. The product was then extracted with ethyl acetate. 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 obtain compound 7c as a colorless oil (2.05 g, yield: 97%). LCMS: 308.1 [M+H] + .

[0420] 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)

[0421] To a 100 mL single-necked flask, 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% ethyl acetate solution), and intermediate 1 (138.07 mg, 0.521 mmol) were added sequentially. Under nitrogen, the mixture was allowed to react at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to obtain compound 7d as a colorless oil (80 mg, yield: 28%). LCMS: 554.6 [M+H] + .

[0422] 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)

[0423] In a 50 mL single-necked flask, 7d (90 mg, 0.16 mmol), dichloromethane (9 mL), and dioxane hydrochloride solution (0.3 mL) were added sequentially and allowed to react at room temperature for 1 hour. The residue was purified by preparative purification to afford compound 7 as an off-white solid (40 mg, yield: 52%). LCMS: 471.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.92(s,1H),7.74(m,J=10.6Hz,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=8.1Hz,2H),2.01(s,3H),1.90(m,J=7.4Hz,2H),1.83–1.61(m,4H)ppm.

[0424] Example 8

[0425] Preparation of 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carboxamide)-N,4-dimethyl-1H-pyrazole-5-carboxamide (Compound 8)

[0426] Step 1: Synthesis of 5-(ethoxycarbonyl)-4-methyl-1H-pyrazole-3-carboxylic acid (8b)

[0427] In a 100 mL round-bottom flask, 8a (1.02 g, 4.00 mmol) was dissolved in DCM (10 mL). 5 mL of HCl (4 M in 1,4-dioxane) was added and the mixture was allowed to react at room temperature for 2 hours. The organic solvent was removed by direct concentration under reduced pressure, and the mixture was dispersed in petroleum ether, filtered, and dried to afford compound 8b as a yellow solid (750 mg, yield: 93%). LCMS: 199.1 [M+H] + .

[0428] Step 2: Synthesis of 1-(3-(4-(2-(cyclopropylthio)-3,4-difluorophenyl)piperidin-1-carboxyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (8c)

[0429] In a 50 mL round-bottom flask, 8b (300 mg, 1.5 mmol) was dissolved in N,N-dimethylformamide (10 mL), and triethylamine (227 mg, 2.25 mmol) was added. The mixture was reacted in an ice bath for 2 minutes. O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (760 mg, 2.00 mmol) was then added. After 2 minutes, intermediate 1 (532 mg, 2.00 mmol) was added and the mixture was reacted at room temperature for 2 hours. The reaction was quenched by adding pure water, extracted with ethyl acetate, and the organic phase was concentrated to obtain a crude product. The crude product was purified by C 18 Compound 8c was obtained by reverse phase column preparative separation and purification as an off-white solid (420 mg, yield 63%). LCMS: 446.2 [M+H] + .

[0430] Step 3: Synthesis of 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1H-pyrazole-5-carboxylic acid (8d)

[0431] In a 50 mL round-bottom flask, 8c (420 mg, 0.94 mmol) was dissolved in methanol / water (3:2, 10 mL). Lithium hydroxide (115 mg, 5.00 mmol) was then added and the mixture was allowed to react at 60°C for 1 hour. Dilute hydrochloric acid was added to the mixture, and 20 mL of pure water was added to precipitate a white solid. Filter and dry to obtain compound 8d as an off-white solid (350 mg, 89% yield). LCMS: 446.2 [M+H] + .

[0432] 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)

[0433] In a 50 mL round-bottom flask, 8d (208 mg, 0.50 mmol) was dissolved in N,N-dimethylformamide (10 mL). Triethylamine (202 mg, 2.00 mmol) was then added and the mixture was allowed to react in an ice bath for 2 minutes. O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (760 mg, 2.00 mmol) was then added. After 2 minutes, 1-(2,4-dimethoxyphenyl)-N-methylmethanamine (181 mg, 1.00 mmol) was added and the mixture was allowed to react at room temperature for 2 hours. The reaction was quenched with pure water and extracted with ethyl acetate. The organic phase was concentrated to obtain the crude product, which was then separated and purified by silica gel column chromatography to obtain compound 8e as a yellow solid (200 mg, 69% yield). LCMS: 581.2 [M+H] + .

[0434] Step 5: Synthesis of 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carboxamide)-N,4-dimethyl-1H-pyrazole-5-carboxamide (Compound 8)

[0435] In a 100 mL round-bottom flask, 8e (200 mg, 0.34 mmol) was dissolved in trifluoroacetic acid (5 mL) and reacted at room temperature for 12 hours. The crude product was directly concentrated under reduced pressure and then treated with C 18 Reverse phase column preparative separation and purification gave compound 8 as a white solid (138 mg, yield: 94%). LCMS: 431.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.37(s,1H),7.25–7.11(m,1H),7.03–6.77(m,1H),5.06–4.62(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.

[0436] Example 9

[0437] Preparation of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-(2-morpholinoethyl)-1H-pyrazol-3-yl)methanone (Compound 9)

[0438] Step 1: Synthesis of ethyl 5-bromo-1-(4-methoxybenzyl)-4-methyl-1H-pyrazole-3-carboxylate (9a)

[0439] In a 100 mL round-bottom flask, 1b (3.00 g, 12.87 mmol) was dissolved in N,N-dimethylformamide (30 mL). Cesium carbonate (6.30 g, 19.00 mmol) was then added, followed by the slow addition of 4-methoxybenzyl chloride (2.42 g, 15.45 mmol). The mixture was allowed to react at 25°C for 3 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was collected and concentrated, and purified by column chromatography to afford compound 9a as an off-white solid (3.80 g, yield: 84%). LCMS: 353.0 [M+H] + .

[0440] Step 2: Synthesis of ethyl (E)-5-(2-ethoxyvinyl)-1-(4-methoxybenzyl)-4-methyl-1H-pyrazole-3-carboxylate (9b)

[0441] In a 100 mL round-bottom flask, 9a (3.8 g, 10.76 mmol) was dissolved in 1,4-dioxane / pure water (40 mL / 10 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (3.15 g, 4.30 mmol), (E)-2-(2-ethoxyvinyl)-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 reacted at 110°C for 4 hours. The reaction was quenched by adding pure water and extracted with ethyl acetate. The organic phase was collected and concentrated, and purified by column chromatography to afford compound 9b as an off-white solid (2.3 g, yield: 62%). LCMS: 345.1 [M+H] + .

[0442] Step 3: Synthesis of ethyl 1-(4-methoxybenzyl)-4-methyl-5-(2-oxoethyl)-1H-pyrazole-3-carboxylate (9c)

[0443] In a 50 mL round-bottom flask, 9b (1.1 g, 3.19 mmol) was dissolved in ethanol (5 mL). 4 M aqueous hydrochloric acid (5 mL, 20 mmol) was then added and heated to 60°C for 4 hours. The reaction was quenched by adding pure water and extracted with ethyl acetate. The organic phase was collected and concentrated, and purified by column chromatography to afford compound 9c as an off-white solid (800 mg, yield: 79%). LCMS: 317.1 [M+H] + .

[0444] Step 4: Synthesis of ethyl 1-(4-methoxybenzyl)-4-methyl-5-(2-morpholinoethyl)-1H-pyrazole-3-carboxylate (9d)

[0445] In a 50 mL round-bottom flask, 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 then added. The mixture was stirred at 25°C for 1 hour, followed by the addition of sodium cyanoborocyanide (794 mg, 12.64 mmol). The reaction was allowed to react at room temperature for 6 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was collected, concentrated, and purified by column chromatography to afford compound 9d as an off-white solid (500 mg, yield: 51%). LCMS: 388.2 [M+H] + .

[0446] Step 5: Synthesis of 1-(4-methoxybenzyl)-4-methyl-5-(morpholinomethyl)-1H-pyrazole-3-carboxylic acid (9e)

[0447] In a 50 mL round-bottom flask, 9d (500 mg, 1.29 mmol) was dissolved in methanol / purified water (4 mL / 1 mL). Sodium hydroxide (103 mg, 2.58 mmol) was then added and the mixture was allowed to react at 60°C for 4 hours. The organic solvent was concentrated, and the mixture was extracted with purified water and ethyl acetate. The organic phase was collected and concentrated to obtain the crude product. The crude product was dissolved in a 10:1 solution of DCM:MeOH, filtered, and the filtrate was collected and concentrated to obtain compound 9e as an off-white solid (400 mg, yield: 86%). LCMS: 360.1 [M+H] + .

[0448] 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)

[0449] In a 50 mL round-bottom flask, 9e (180 mg, 0.50 mmol) was dissolved in N,N-dimethylformamide (4 mL). Triethylamine (0.42 mL, 3.00 mmol) was then added. The mixture was cooled to 0°C and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (228 mg, 0.60 mmol) was added. The mixture was stirred at 0°C for 10 minutes, followed by the addition of intermediate 1 (199 mg, 0.75 mmol). The reaction was allowed to react at room temperature for 3 hours. The reaction was quenched with pure water and extracted with ethyl acetate. The concentrated organic phase was collected and purified by column chromatography to afford compound 9f as an off-white solid (100 mg, yield: 41%). LCMS: 607.2 [M+H] + .

[0450] 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)

[0451] In a 50 mL round-bottom flask, 9f (100 mg, 0.16 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred at 90°C for 4 hours. The reaction mixture was concentrated and quenched with water. The mixture was extracted with ethyl acetate. The concentrated organic phase was collected and purified by column chromatography to afford compound 9 as an off-white solid (70 mg, yield: 80%). LCMS: 487.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.70(s,1H),7.77(s,1H),7.50(s,1H),4.68(d,J=11.4Hz,1H),4.42(s,1H),3.66(s,4 H),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,4H),1.325–1.25(m,2H)ppm.

[0452] Example 10

[0453] 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)

[0454] Step 1: Synthesis of ethyl 4-(2-((tert-Butoxycarbonyl)amino)ethyl)-5-methyl-1H-pyrazole-3-carboxylate (10b)

[0455] In a 100 mL round-bottom flask, 10a (1.50 g, 6.40 mmol) was dissolved in a mixture of 1,4-dioxane and water (20 mL / 5 mL). Potassium 2-tert-butyloxycarbonyl-aminoethyl 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 then added. The air was purged and nitrogen was introduced. The reaction was allowed to proceed at 110°C for 8 hours. The reaction was quenched with pure water and extracted with ethyl acetate. The organic phase was collected and concentrated, and purified by column chromatography to afford compound 10b as an off-white solid (1.50 g, yield: 78%). LCMS: 298.1 [M+H] + .

[0456] Step 2: Synthesis of ethyl 5-(aminomethyl)-4-methyl-1H-pyrazole-3-carboxylate (10c)

[0457] In a 50 mL round-bottom flask, 10b (1.50 g, 5.04 mmol) was dissolved in N,N-dimethylformamide (20 mL). Cesium carbonate (2.47 g, 7.57 mmol) was then added. The temperature was cooled to 0°C, and 2-(trimethylsilyl)ethoxymethyl chloride (1.01 g, 6.05 mmol) was added. The mixture was allowed to react at room temperature for 2 hours. The reaction was quenched by adding pure water and extracted with ethyl acetate. The organic phase was collected and concentrated, and purified by column chromatography to afford compound 10c as an off-white solid (300 mg, yield: 20%). LCMS: 428.2 [M+H] + .

[0458] Step 3: Synthesis of 4-(2-((tert-Butoxycarbonyl)amino)ethyl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylic acid (10d)

[0459] In a 50 mL round-bottom flask, 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 then added and heated to 60°C for 12 hours. The reaction mixture was concentrated to remove the organic solvent and quenched with pure water. The mixture was extracted with ethyl acetate, and the organic phase was collected and concentrated. Purification by column chromatography afforded compound 10d as an off-white solid (120 mg, yield: 43%). LCMS: 400.2 [M+H] + .

[0460] 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)

[0461] In a 50 mL round-bottom flask, 10d (120 mg, 0.30 mmol) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of triethylamine (0.2 mL, 1.20 mmol). The mixture was cooled to 0°C and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (138 mg, 0.38 mmol) was added. The mixture was stirred at 0°C for 10 minutes, followed by the addition of intermediate 1 (120 mg, 0.45 mmol). The reaction was allowed to react at room temperature for 3 hours. The reaction was quenched with pure water, extracted with ethyl acetate, and the concentrated organic phase was collected and purified by column chromatography to afford compound 10e as an off-white solid (120 mg, yield: 62%). LCMS: 647.3 [M+H]. + .

[0462] 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)

[0463] In a 50 mL round-bottom flask, 10e (100 mg, 0.15 mmol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate solution (3 mL, 4 mol / L) was then added and allowed to react at room temperature for 3 hours. The reaction mixture was concentrated to afford compound 10f as an off-white solid (50 mg, yield: 78%). LCMS: 417.2 [M+H] + .

[0464] 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)

[0465] In a 50 mL round-bottom flask, 10f (50 mg, 0.12 mmol) was dissolved in 2-methyltetrahydrofuran / dichloromethane (2 mL / 1 mL), and then triethylamine (80 μL, 0.60 mmol) was added. The temperature was lowered to 0°C, and acetyl chloride (10 μL, 0.15 mmol) was dissolved in dichloromethane (1 mL) and slowly added to the reaction system. The reaction was allowed to proceed at 0°C for 2 hours. Pure water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was collected and concentrated to obtain the crude product, which was then purified by C 18 Compound 10 was separated by reverse phase column as an off-white solid (10 mg, yield: 18%). LCMS: 459.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.68(s,1H),8.03(s,1H),7.77–7.71(m,1H),7.53–7.51(m,1H),4.69(d,J=12.8Hz,1H),4.39(d,J=13.0Hz, 1H), 3.13(d,J=12.3Hz,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=0.7Hz,2H),1.24(s,2H)ppm.

[0466] Example 11

[0467] 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)

[0468] 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)

[0469] To a 100 mL round-bottom flask, 6e (270 mg, 0.56 mmol), 1,2-dichloroethane (20 mL), 11a (124.30 mg, 0.67 mmol), and sodium triacetoxyborohydride (235 mg, 1.11 mmol) were added sequentially. The mixture was reacted at room temperature under nitrogen for 2 hours. Water and dichloromethane were added to the reaction solution for extraction. 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 obtain compound 11b as a colorless oil (126 mg, 35% yield). LCMS: 656.77 [M+H] + .

[0470] 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)

[0471] In a 50 mL round-bottom flask, 11b (100 mg, 0.15 mmol), dichloromethane (10 mL), and dioxane hydrochloride solution (1 mL) were added sequentially and allowed to react at room temperature for 2 hours. The organic solvent was removed under reduced pressure, and the residue was purified by preparative purification to obtain compound 11 as an off-white solid (5 mg, 7% yield). LCMS: 472.66 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.79(s,1H),7.75(m,J=8.9Hz,1H),7.49(m,J=9.3,4.7Hz,1H),3.42(s,2H),3.28–3.01( m,4H),2.80(s,1H),2.67(m,J=4.9Hz,4H),2.27(m,4H),2.03(s,3H),1.81–1.61(m,4H),1.25(m,J=4.1Hz,1H)ppm.

[0472] Example 12

[0473] 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)

[0474] Step 1: Synthesis of ethyl 4-methyl-5-((4-methylpiperazin-1-yl)methyl)-1H-pyrazole-3-carboxylate (12b)

[0475] At room temperature, 1b (500 mg, 2.15 mmol) was dissolved in 1,4-dioxane (20 mL) in a 30 mL microwave reaction tube. 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 12a (1.42 g, 6.44 mmol) were then added. The mixture was stirred in a microwave reactor at 100°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. Water was added, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to obtain compound 12b as a light yellow solid (440 mg). LCMS: 267.5 [M+H]. + .

[0476] Step 2: Synthesis of 4-methyl-5-((4-methylpiperazin-1-yl)methyl)-1H-pyrazole-3-carboxylic acid (12c)

[0477] In a 100 mL round-bottom flask, 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 reacted at 50°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. 2 M dilute hydrochloric acid was added to adjust the pH to 6. The organic solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain compound 12c as a brown oil (150 mg). LCMS: 239.5 [M+H] + .

[0478] 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)

[0479] To a 50 mL round-bottom flask, 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 added sequentially under nitrogen atmosphere and allowed to react at room temperature for 12 hours. The mixture was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by preparative purification to afford compound 12 as a white solid (10 mg, 6% yield). LCMS: 486.7 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.83(s,1H),7.76(m,J=8.9Hz,1H),7.51(m,J=9.2,4.8Hz,1H),3.46(s,2H),3.15(m,4 H),2.80(m,J=13.9Hz,1H),2.47–2.23(m,8H),2.16(s,3H),2.04(s,3H),1.68(m,J=12.3,11.7,7.8Hz,4H)ppm.

[0480] Example 13

[0481] 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)

[0482] 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)

[0483] 6a (2.00 g, 6.31 mmol), 13a (2.10 g, 7.57 mmol), bispinacolatoboronate (2.88 g, 11.35 mmol), (4,4'-di-tert-butyl-2,2'-bipyridyl)nickel dibromide (0.15 g, 0.32 mmol), sodium iodide (1.89 g, 12.61 mmol), and potassium carbonate (1.74 g, 12.61 mmol) were added sequentially to a solution of N,N-dimethylacetamide (20 mL). The mixture was stirred at 60°C under nitrogen for 8 h. The reaction was quenched by adding water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain compound 13b (1.70 g, yield: 62%). LCMS: 436.2 [M+H]+ .

[0484] Step 2: Synthesis of 5-((1-(tert-Butyloxycarbonyl)piperidin-4-yl)methyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid (13c)

[0485] Compound 13b (1.00 g, 2.30 mmol) and lithium hydroxide hydrate (0.96 g, 22.96 mmol) were added sequentially to a mixture of methanol (5 mL) and water (5 mL). The mixture was stirred at 25°C for 8 hours, then concentrated under reduced pressure to remove methanol. The pH was adjusted to 5-6. A large amount of solid precipitated, which was filtered and the filter cake was dried under reduced pressure to obtain compound 13c (450 mg, yield: 48%). LCMS: 408.2 [M+H] + .

[0486] 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)

[0487] 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 added sequentially to a solution of anhydrous N,N-dimethylformamide (5 mL). After the addition was complete, the mixture was stirred at 25°C under nitrogen for 8 hours. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography to obtain compound 13d (250 mg, yield: 41%). LCMS: 655.3 [M+H] + .

[0488] 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)

[0489] 13d (100 mg, 0.15 mmol) was added to a hydrochloric acid / 1,4-dioxane solution (5 mL, 4 mol / L). The mixture was stirred at 25°C for 8 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product, which was then directly isolated and purified by preparative liquid chromatography to obtain compound 13 (40 mg, yield: 55%). LCMS: 471.2 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ7.85–7.65(m,1H),7.57–7.37(m,1H),4.86–4.52(m,2H),4.50–4.19(m,2 H),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.

[0490] Example 14

[0491] 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)

[0492] Compound 13 (77 mg, 0.15 mmol) and aqueous formaldehyde solution (123 mg, 1.52 mmol, purity: 37%) were added sequentially to a methanol (1 mL) solution, cooled to 0°C, and then sodium cyanoborohydride (19 mg, 0.30 mmol) was added. After the addition, the mixture was stirred at 25°C for 1 hour. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was then directly isolated and purified by preparative liquid chromatography to obtain compound 14 (30 mg, yield: 40%). LCMS: 485.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ7.80–7.70(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.

[0493] Example 15

[0494] 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)

[0495] 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)

[0496] In a 100 mL round-bottom flask, 6a (2.5 g, 7.89 mmol), 15a (1.69 g, 9.46 mmol), pinacol diboronate (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'] nickel dibromide (384 mg, 0.79 mmol) and N,N-dimethylacetamide (30 mL) were added in sequence under nitrogen protection and reacted at 60 °C for 8 h. The reaction mixture was filtered through celite, and the filter cake was washed with ethyl acetate. The filtrate was collected and extracted with water; the aqueous phase was extracted with ethyl acetate again and separated. 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 obtain compound 15b as a colorless oil (550 mg, yield: 17.23%). LCMS: 337.1 [M+H] + .

[0497] 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)

[0498] In a 100 mL round-bottom flask, 15b (550 mg, 1.63 mmol), methanol (15 mL), water (15 mL), and sodium hydroxide (196 mg, 4.90 mmol) were added sequentially and allowed to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain crude compound 15c, which was used directly in the next step. LCMS: 308.8 [M+H] + .

[0499] 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)

[0500] In a 100 mL single-necked flask, 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 added in sequence and allowed to react at room temperature for 2 hours. Water and ethyl acetate were added for separation, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by preparative purification to obtain compound 15d as a colorless oil (160 mg, yield: 22%). LCMS: 556.2 [M+H] + .

[0501] 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)

[0502] In a 50 mL round-bottom flask, 15d (160 mg, 0.29 mmol) was dissolved in dichloromethane (15 mL). Dioxane hydrochloride solution (0.5 mL, 4 mol / L) was added and allowed to react at room temperature for 2 hours. The organic solvent was removed under reduced pressure, and the residue was purified by preparative purification to afford compound 15 as an off-white solid (107 mg, yield: 79%). LCMS: 472.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.62(s,1H),7.72(m,J=8.9Hz,1H),7.47(m,J=9.6,4 .3Hz,1H),4.53(m,J=140.3,13.3Hz,2H),3.86–3.75(m,2H),3.48–3.41(m,2H) ,3.23(m,J=11.7,2.1Hz,2H),3.11(m,J=13.6Hz,2H),2.77(m,J=12.9Hz,1H), 1.98(s,3H),1.80–1.63(m,5H),1.45(m,J=13.1Hz,2H),1.25–1.13(m,2H)ppm.

[0503] Example 16

[0504] 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)

[0505] 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)

[0506] To a 100 mL three-necked flask, 6e (350 mg, 0.72 mmol), methanol (30 mL), 16a (123 mg, 1.44 mmol), and acetic acid (4 mg, 0.07 mmol) were added sequentially. Under nitrogen, the mixture was allowed to react at room temperature for 0.5 hour. Sodium cyanoborohydride (136 mg, 2.16 mmol) was then added and the reaction continued at room temperature for 3 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by column chromatography to yield compound 16b as a colorless oil (79 mg, yield: 20%). LCMS: 554.88 [M+H] + .

[0507] 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)

[0508] In a 50 mL round-bottom flask, 16b (70 mg, 0.13 mmol) was dissolved in dichloromethane (15 mL). Dioxane hydrochloride solution (0.3 mL, 4 mmol / L) was added and the mixture was allowed to react at room temperature for 1 hour. The residue was purified by preparative method to afford compound 16 as an off-white solid (7 mg, yield: 12%). LCMS: 471.03 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.78(s,1H),7.73(m,J=8.9Hz,1H),7.48(m,J=9.3,4.7Hz,1H),4.68(m,J=13.1Hz,1H),4.40(m,J=13.4Hz,1H),3.4 2(m,J=7.6Hz,4H),2.79(m,J=12.4Hz,1H),2.45–2.10(m,4H),2.02(s,3H),1.81–1.62(m,4H),1.49(m,J=5.6Hz,4H),1.42–1.32(m,2H)ppm.

[0509] Example 17

[0510] Preparation of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-morpholinyl-1H-pyrazol-3-yl)methanone (Compound 17)

[0511] Step 1: Synthesis of ethyl 4-methyl-5-morpholinyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (17a)

[0512] In a 100 mL round-bottom flask, 6a (2.00 g, 5.50 mmol) was dissolved in 1,4-dioxane (20 mL). Morpholine (0.96 g, 11.00 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (0.46 g, 0.50 mmol), and cesium carbonate (3.59 g, 11.00 mmol) were then added. The air was purged and nitrogen was introduced. The reaction was allowed to proceed at 110°C for 3 hours. The reaction was quenched by the addition of pure water and extracted with ethyl acetate. The organic phase was collected and concentrated, and purified by column chromatography to afford compound 17a as an off-white solid (450 mg, yield: 23%). LCMS: 370.2 [M+H]. + .

[0513] Step 2: Synthesis of 4-methyl-5-morpholinyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylic acid (17b)

[0514] In a 50 mL round-bottom flask, 17a (450 mg, 1.22 mmol) was dissolved in methanol / purified water (4 mL / 1 mL). Sodium hydroxide (97 mg, 2.44 mmol) was then added and the mixture was allowed to react at 60°C for 4 hours. The organic solvent was removed by concentration, and the pH was adjusted to 4 by adding 2 M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, and the layers were separated. The organic phase was collected and concentrated, and purified by column chromatography to obtain compound 17b as an off-white solid (400 mg, yield: 96%). LCMS: 342.1 [M+H] + .

[0515] Step 3: Synthesis of 4-methyl-5-morpholino-1H-pyrazole-3-carboxylic acid (17c)

[0516] In a 50 mL round-bottom flask, 17b (300 mg, 0.88 mmol) was dissolved in ethyl acetate (2 mL). Hydrochloric acid / ethyl acetate solution (5 mL, 4 mmol / L) was then added and the mixture was allowed to react at 25°C for 4 hours. The reaction mixture was concentrated to afford compound 17c as an off-white solid (200 mg, yield: 80%). LCMS: 212.1 [M+H] + .

[0517] Step 4: Synthesis of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4-methyl-5-morpholinyl-1H-pyrazol-3-yl)methanone (Compound 17)

[0518] In a 50 mL round-bottom flask, 17c (200 mg, 0.95 mmol) was dissolved in N,N-dimethylformamide (4 mL), and triethylamine (0.8 mL, 5.68 mmol) and intermediate 1 (376 mg, 1.42 mmol) were added. The temperature was lowered to 0°C, and 1-butylphosphonic anhydride (1.02 g, 1.42 mmol, 50% ethyl acetate solution) was added. The reaction was allowed to react at room temperature for 3 hours. The reaction was quenched by adding pure water, extracted with ethyl acetate, and the organic phase was concentrated to obtain a crude product. The crude product was then purified by C 18 Reverse phase column preparative separation and purification gave compound 17 as an off-white solid (85 mg, yield: 20%). LCMS: 459.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.50(s,1H),7.84–7.71(m,1H),7.50(d,J=4.0Hz,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.

[0519] Example 18

[0520] Preparation of N-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1H-pyrazol-5-yl)methyl)acetamide (Compound 18)

[0521] Step 1: Synthesis of ethyl 5-formyl-1H-pyrazole-3-carboxylate (18b)

[0522] In a 100 mL round-bottom flask, 18a (1.50 g, 8.81 mmol) was dissolved in dichloromethane (15 mL). Manganese dioxide (3.83 g, 44.07 mmol) was then added and the mixture was allowed to react at 25°C for 12 hours. The mixture was filtered through celite and the filter cake was washed with dichloromethane. The organic phase was collected and concentrated, and purified by column chromatography to afford compound 18b as an off-white solid (1.40 g, yield: 94%). LCMS: 169.0 [M+H] + .

[0523] Step 2: Synthesis of ethyl 5-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (18c)

[0524] In a 100 mL round-bottom flask, 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. The temperature was cooled to 0°C, and 2-(trimethylsilyl)ethoxymethyl chloride (2.08 g, 12.49 mmol) was added. The mixture was allowed to react at 25°C for 3 hours. The reaction was quenched with water and extracted with ethyl acetate. The layers were separated, and the organic phase was collected and concentrated. Compound 18c was purified by column chromatography to obtain an off-white solid (600 mg, 25% yield).

[0525] LCMS: 299.1[M+H] + .

[0526] Step 3: Synthesis of ethyl 5-(acetamidomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (18d)

[0527] In a 50 mL round-bottom flask, 18c (600 mg, 2.01 mmol) was dissolved in toluene (10 mL). Triethylsilyl hydrochloride (1 mL, 6.03 mmol), trifluoroacetic acid (0.77 mL, 10.05 mmol), and acetamide (593 mg, 10.05 mmol) were then added. The mixture was reacted at 120°C for 8 hours. The reaction was quenched by water and extracted with ethyl acetate. The layers were separated, and the organic phase was collected and concentrated. Compound 18d was purified by column chromatography to obtain an off-white solid (600 mg, 87% yield).

[0528] LCMS: 342.1[M+H] + .

[0529] Step 4: Synthesis of ethyl 5-(acetylaminomethyl)-1H-pyrazole-3-carboxylate (18e)

[0530] In a 50 mL round-bottom flask, 18d (600 mg, 1.76 mmol) was dissolved in 1,4-dioxane (2 mL). Hydrochloric acid / 1,4-dioxane (6 mL, 4 mol / L) was then added and allowed to react at room temperature for 4 hours. The organic phase was collected and concentrated to afford compound 18e as an off-white solid (300 mg, 81% yield).

[0531] LCMS: 212.1[M+H] + .

[0532] Step 5: Synthesis of 5-(acetylaminomethyl)-1H-pyrazole-3-carboxylic acid (18f)

[0533] In a 50 mL round-bottom flask, 18e (200 mg, 0.95 mmol) was dissolved in methanol / purified water (4 mL / 1 mL). Sodium hydroxide (76 mg, 1.89 mmol) was then added and the mixture was reacted at 60°C for 4 hours. The organic solvent was concentrated, and the pH was adjusted to 4 with 2 M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, and the layers were separated. The organic phase was collected and concentrated, and purified by column chromatography to afford compound 18f as an off-white solid (150 mg, yield: 86%).

[0534] LCMS: 184.0 [M+H] + .

[0535] Step 6: Synthesis of N-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1H-pyrazol-5-yl)methyl)acetamide (Compound 18)

[0536] In a 50 mL round-bottom flask, 18f (150 mg, 0.82 mmol) was dissolved in N,N-dimethylformamide (4 mL), and then triethylamine (0.7 mL, 4.91 mmol) and intermediate 1 (217 mg, 0.82 mmol) were added. The temperature was lowered to 0°C, and 1-butylphosphonic anhydride (886 mg, 1.23 mmol, 50% ethyl acetate solution) was added. The reaction was allowed to react at room temperature for 3 hours. Pure water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was collected and concentrated to obtain the crude product, which was then purified by C 18 Compound 18 was obtained by reverse phase column preparative separation and purification as an off-white solid (40 mg, yield: 11%). LCMS: 431.1 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ13.15(d,J=19.1Hz,1H),8.40(d,J=20.4Hz,1H),7.74–7.71(m,1H),7.52–7.50(m,1H),6.42 (s,1H),4.27(d,J=5.3Hz,2H),3.20(s,2H),3.16(s,2H),2.81(d,J=4.9Hz,1H),1.86(s,3H),1.76–1.72(m,4H)ppm.

[0537] Example 19

[0538] Preparation of N-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4-dimethyl-1H-pyrazol-5-yl)methyl)acetamide (Compound 19)

[0539] Step 1: Synthesis of ethyl 5-acetamidomethyl-4-methyl-1H-pyrazole-3-carboxylate (1f)

[0540] In a 100 mL round-bottom flask, 6c (1.6 g, 6.01 mmol) was dissolved in toluene (20 mL). Triethylsilyl hydride (2.10 g, 18.02 mmol), trifluoroacetic acid (3.43 g, 30.04 mmol), and acetamide (1.77 g, 30.04 mmol) were then added. The mixture was reacted at 120°C for 4 hours. The reaction was quenched by adding pure water and extracted with ethyl acetate. The layers were separated, and the organic phase was collected and concentrated. Compound 1f was purified by column chromatography to obtain an off-white solid (1.00 g, yield: 74%). LCMS: 226.1 [M+H] + .

[0541] Step 2: Synthesis of ethyl 5-(acetylaminomethyl)-1,4-dimethyl-1H-pyrazole-3-carboxylate (19a)

[0542] In a 100 mL round-bottom flask, 1f (300 mg, 1.33 mmol) was dissolved in N,N-dimethylformamide (6 mL). Cesium carbonate (867 mg, 2.66 mmol) and iodomethane (100 μL, 1.60 mmol) were then added. The mixture was allowed to react at 25°C for 3 hours. The reaction was quenched with pure water and extracted with ethyl acetate. The layers were separated, and the organic phase was collected and concentrated. Compound 19a was purified by column chromatography to obtain an off-white solid (200 mg, yield: 63%). LCMS: 240.1 [M+H] + .

[0543] Step 3: Synthesis of 5-(acetylaminomethyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid (19b)

[0544] In a 50 mL round-bottom flask, 19a (140 mg, 0.56 mmol) was dissolved in methanol / purified water (4 mL / 1 mL). Then, sodium hydroxide (47 mg, 1.17 mmol) was added and the mixture was allowed to react at 60°C for 4 hours. The reaction solution was concentrated to dryness to obtain compound 19b as an off-white solid (100 mg, yield: 81%). LCMS: 212.1 [M+H] + .

[0545] 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)

[0546] In a 50 mL round-bottom flask, 19b (100 mg, 0.48 mmol) was dissolved in N,N-dimethylformamide (4 mL), and triethylamine (300 μL, 2.37 mmol) and intermediate 1 (150 mg, 0.57 mmol) were added. The temperature was lowered to 0°C, and 1-butylphosphonic anhydride (511 mg, 0.72 mmol, 50% ethyl acetate solution) was added. The reaction was allowed to react at room temperature for 3 hours. The reaction was quenched by adding pure water, extracted with ethyl acetate, and the organic phase was concentrated to obtain a crude product. The crude product was purified by C 18 Compound 19 was obtained by preparative separation and purification on a reverse phase column as an off-white solid (10 mg, yield: 5%). LCMS: 459.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ8.11(s,1H),7.77(d,J=8.6Hz,1H),7.51(d,J=30.2Hz,1H),4.17(s,2H),3.79(s,3H),3.65(d, J=19.1Hz,2H),3.14(d,J=9.1Hz,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.

[0547] Example 20

[0548] Preparation of 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carboxamide)-N,N,4-trimethyl-1H-pyrazole-5-carboxamide (Compound 20)

[0549] In a 50 mL round-bottom flask, 8d (70.0 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (4 mL), and triethylamine (101 mg, 1.0 mmol) was added, followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (190 mg, 0.50 mmol). After reacting for 2 minutes under ice bath, dimethylamine hydrochloride (81 mg, 1.00 mmol) was added and the reaction was allowed to proceed 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 obtain a crude product. The crude product was purified by C 18 Compound 20 was obtained by reverse phase column preparative separation and purification as an off-white solid (38 mg, yield 51%). LCMS: 445.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.41–7.31(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.

[0550] Example 21

[0551] 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)

[0552] In a 50 mL round-bottom flask, 8d (180 mg, 0.40 mmol) was dissolved in N,N-dimethylformamide (5 mL), and triethylamine (155 mg, 1.5 mmol) was added, followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (228 mg, 0.60 mmol). The mixture was reacted under ice bath for 2 minutes, and morpholine (87 mg, 1.0 mmol) was added. The reaction was allowed to react at room temperature for 2 hours. Pure water was added to quench the reaction, and ethyl acetate was added for extraction. The organic phase was collected and concentrated to obtain a crude product, which was then purified by C 18 Compound 21 was obtained by reverse phase column preparative separation and purification as an off-white solid (145 mg, yield 75%). LCMS: 487.2 [M+H] + . 1 H NMR(500MHz, CDCl3)δ11.62(s,1H),7.41–7.30(m,1H),7.19–7.09(m,1H),5.11–4.62(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.

[0553] Example 22

[0554] 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)

[0555] Step 1: Synthesis of ethyl 5-(hydroxymethyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (22a)

[0556] At room temperature, a 100 mL round-bottom flask was charged with 6c (3 g, 11.26 mmol) and tetrahydrofuran (30 mL). Sodium borohydride (0.43 g, 11.26 mmol) was then added at 0°C. The mixture was reacted under nitrogen for 2 hours at room temperature. Water and ethyl acetate were added, 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 obtain compound 22a as a white solid (1.68 g, 56% yield). LCMS: 269.2 [M+H] + .

[0557] Step 2: Synthesis of ethyl 5-(bromomethyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (22b)

[0558] In a 100 mL round-bottom flask, 22a (540 mg, 2.0 mmol) was dissolved in tetrahydrofuran (20 mL). Triphenylphosphine (655 mg, 2.5 mmol) was then added. Carbon tetrabromide (835 mg, 2.5 mmol) was then added under an ice bath. The mixture was allowed to react at room temperature for 2 hours. The reaction was quenched with pure water and extracted with ethyl acetate. The organic phase was concentrated to obtain the crude product, which was purified on a silica gel column to afford compound 22b as an off-white solid (180 mg, 27% yield). LCMS: 331.2 [M+H] + .

[0559] Step 3: Synthesis of (4-methyl-5-((2-oxopiperidin-1-yl)methyl)-1H-pyrazole-3-carboxylic acid (Compound 22d)

[0560] In a 100 mL round-bottom flask, 22c (150 mg, 1.5 mmol) was dissolved in 1,4-dioxane (5 mL). NaH (120 mg, 3.0 mmol, 60% content) was added under ice bath and reacted at room temperature for 0.5 h. 22b (200 mg, 0.62 mmol) was dissolved in tetrahydrofuran (2 mL) and added dropwise to the reaction. Water was added to quench the reaction, and methanol was added. The reaction was allowed to react at 60°C for 2 h. HCl (2 mol / L) solution was added to acidify the reaction and the crude product was concentrated under reduced pressure. The crude product was purified by C 18 Compound 22d was separated and purified by reverse phase column as an off-white solid (120 mg, yield 80%). LCMS: 238.1 [M+H] + .

[0561] 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)

[0562] In a 50 mL round-bottom flask, 22d (120 mg, 0.5 mmol) was dissolved in N,N-dimethylformamide (4 mL), and triethylamine (155 mg, 1.5 mmol) was added, followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (285 mg, 0.75 mmol). The reaction was allowed to proceed in an ice bath for 2 minutes, and intermediate 1 (160 mg, 0.6 mmol) was added. The reaction was allowed to proceed at room temperature for 2 hours. Water was added to quench the reaction, and ethyl acetate was added for extraction. The organic phase was collected and concentrated to obtain a crude product, which was then purified by C 18 Reverse phase column separation and purification gave compound 22 as an off-white solid (80 mg, yield 33%). LCMS: 485.2 [M+H] + . 1 H NMR(500MHz, CDCl3)δ10.96(s,1H),7.41–7.29(m,1H),7.21–7.10(m,1H),5.00–4.79(m,1H),4.63–4.29(m,3H),3.42–3.3 3(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.

[0563] Example 23

[0564] Preparation of 4-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)morpholin-3-one (Compound 23)

[0565] Step 1: Synthesis of 4-methyl-5-((3-oxomorpholino)methyl)-1H-pyrazole-3-carboxylic acid (23b)

[0566] In a 100 mL round-bottom flask, 23a (150 mg, 1.5 mmol) was dissolved in tetrahydrofuran (5 mL). NaH (120 mg, 3.0 mmol, 60% content) was added under ice bath and reacted at room temperature for 0.5 h. 22b (165 mg, 0.5 mmol) was dissolved in tetrahydrofuran (2 mL) and added dropwise to the reaction. Water was added to quench the reaction, and methanol was added. The reaction was allowed to proceed at 60°C for 2 h. HCl solution (2 mol / L) was added to acidify the reaction and the crude product was concentrated under reduced pressure. The crude product was purified by C 18 Reverse phase column separation and purification gave compound 23b as an off-white solid (100 mg, yield 84%). LCMS: 240.1 [M+H] + .

[0567] Step 2: Synthesis of 4-((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)morpholin-3-one (Compound 23)

[0568] In a 50 mL round-bottom flask, 23b (100 mg, 0.3 mmol) was dissolved in N,N-dimethylformamide (4 mL), and triethylamine (122 mg, 1.2 mmol) was added, followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (228 mg, 0.6 mmol). The reaction was carried out in an ice bath for 2 minutes, and intermediate 1 (160 mg, 0.6 mmol) was added. The reaction was allowed to react at room temperature for 2 hours. Water was added to quench the reaction, and ethyl acetate was added for extraction. The organic phase was collected and concentrated to obtain a crude product, which was then purified by C 18 Compound 23 was separated and purified by reverse phase column as an off-white solid (80 mg, yield 41%). LCMS: 487.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.40–7.30(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),2.94–2.82(m,1H),2.21(s,3H),1.82-1.70(m,4H)ppm.

[0569] Example 24

[0570] 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)

[0571] Step 1: Synthesis of (4-methyl-5-((3-oxothiomorpholino)methyl)-1H-pyrazole-3-carboxylic acid (24b)

[0572] In a 100 mL round-bottom flask, 24a (175 mg, 1.5 mmol) was dissolved in 1,4-dioxane (5 mL). NaH (120 mg, 3.0 mmol, 60% content) was added under ice bath and reacted at room temperature for 0.5 hours. 22b (200 mg, 0.62 mmol) was dissolved in tetrahydrofuran (2 mL) and added dropwise to the reaction. Water was added to quench the reaction, and methanol was added. The reaction was incubated at 60°C for 2 hours. HCl solution (2 mol / L) was added to acidify the mixture and the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by C 18 Compound 24b was separated and purified by reverse phase column as an off-white solid (135 mg, yield 85%). LCMS: 256.1 [M+H] + .

[0573] 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)

[0574] In a 50 mL round-bottom flask, 24b (135 mg, 0.40 mmol) was dissolved in N,N-dimethylformamide (4 mL), and triethylamine (155 mg, 1.5 mmol) was added, followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (285 mg, 0.75 mmol). After reacting in an ice bath for 2 minutes, intermediate 1 (160 mg, 0.6 mmol) was added and reacted at room temperature for 2 hours. Water was added to quench the reaction, and ethyl acetate was added for extraction. The organic phase was collected and concentrated to obtain the crude product, which was then purified by C 18 Reverse phase column separation and purification gave compound 24 as an off-white solid (150 mg, yield 56%). LCMS: 502.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.40–7.30(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.

[0575] Example 25 to Example 94

[0576] Preparation of Compounds 25 to 94

[0577] Compounds 25 to 94 were synthesized by condensing intermediates 2 to 11 with the corresponding pyrazolecarboxylic acid derivatives. The structures and characterizations of compounds 25 to 94 are shown in Table 1.

[0578] Table 1

[0579] Example 95

[0580] Preparation of ((3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)proline (Compound 95)

[0581] Compound 6 (100 mg, 0.19 mmol) was dissolved in methanol (5 mL) and water (1 mL), followed by the addition of sodium hydroxide (15 mg, 0.39 mmol). The reaction mixture was allowed to react at room temperature for 1 hour. The reaction mixture was directly subjected to C18 reverse phase preparative separation and purification to obtain compound 95 as a white solid (50 mg, yield: 51%). LCMS: 501.2 [M+1] + . 1 H NMR(500MHz,DMSO-d6)δ7.78–7.72(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.

[0582] Example 96

[0583] Preparation of methyl (3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methyl)carbamate (Compound 96)

[0584] Step 1: Synthesis of tert-butyl 5-(hydroxymethyl)-4-methyl-1H-pyrazole-3-carboxylate (96a)

[0585] In a 100 mL round-bottom flask, 8a (3.2 g, 12.60 mmol) was dissolved in dichloromethane (30 mL) and cooled to -78°C. Diisobutylaluminum hydride (44 mL, 1.0 mol tetrahydrofuran solution, 44 mmol) was then slowly added and the reaction continued for 2 hours. The reaction was quenched by adding saturated aqueous potassium sodium tartrate solution and stirred for 30 minutes. Ethyl acetate was added to separate the layers, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to obtain the crude product, which was directly used in the next step without further purification. The crude product 96a was obtained as a yellow solid (2.3 g). LCMS: 213.1 [M+H] + .

[0586] Step 2: Synthesis of tert-butyl 5-formyl-4-methyl-1H-pyrazole-3-carboxylate (96b)

[0587] In a 100 mL round-bottom flask, 96a (2.3 g, 10.85 mmol) was dissolved in dichloromethane (30 mL), followed by the addition of Dess-Martin periodinane (5.52 g, 13.02 mmol). The reaction was continued for 1 hour. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution, stirred for 30 minutes, and extracted with dichloromethane (50 mL x 3). The organic phase was concentrated to obtain the 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] + .

[0588] Step 3: Synthesis of 5-(((methoxycarbonyl)amino)methyl)-4-methyl-1H-pyrazole-3-carboxylic acid (96c)

[0589] In a 100 mL round-bottom flask, 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 then added. The reaction was continued at 100°C for 6 hours. The reaction solution was directly concentrated, and the residue was slurried with tert-methyl ether to precipitate a solid. The solid was filtered and dried to obtain compound 96c as a light yellow solid (300 mg, yield: 70%). LCMS: 214.1 [M+H] + .

[0590] 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)

[0591] In a 50 mL round-bottom flask, 96c (213 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (10 mL). Triethylamine (202 mg, 2.0 mmol) was then added, followed by 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (470 mg, 1.5 mmol). After reacting in an ice bath for 2 minutes, intermediate 1 (200 mg, 0.75 mmol) was added and the mixture was allowed to react at room temperature for 2 hours. The reaction was quenched by adding pure water and extracted with ethyl acetate (20 mL x 3). The organic phase was concentrated to obtain the crude product, which was separated and purified using a C18 reverse phase column to afford compound 96 as an off-white solid (135 mg, 29% yield). LCMS: 461.2 [M+H]. + . 1 H NMR (500MHz, CDCl3) δ11.62(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.

[0592] Example 97

[0593] Preparation of methyl (3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methylcarbamate (Compound 97)

[0594] Step 1: Synthesis of ethyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1H-pyrazole-5-carboxylate (97b)

[0595] In a 50 mL round-bottom flask, 97a (500 mg, 2.51 mmol) was dissolved in N,N-dimethylformamide (20 mL). Triethylamine (505 mg, 5.0 mmol) was then added, followed by 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.43 g, 1.5 mmol). After reacting in an ice bath for 2 minutes, intermediate 1 (665 mg, 2.51 mmol) was added and allowed to react at room temperature for 2 hours. The reaction was quenched by adding pure water and extracted with ethyl acetate (30 mL x 3). The organic phase was concentrated to obtain the crude product, which was separated and purified using a C18 reverse phase column to afford compound 97b as an off-white solid (550 mg, 49% yield). LCMS: 446.1 [M+H]. + .

[0596] Step 2: Synthesis of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(hydroxymethyl)-4-methyl-1H-pyrazol-3-yl)methanone (97c)

[0597] In a 100 mL round-bottom flask, 97b (550 mg, 1.24 mmol) was dissolved in dichloromethane (10 mL) and cooled to -78°C. Diisobutylaluminum hydride (2.0 mL, 1.0 mol tetrahydrofuran solution, 2.0 mmol) was then slowly added. The reaction was continued for 2 hours. Saturated aqueous potassium sodium tartrate solution was added to quench the reaction, stirred for 30 minutes, and extracted with ethyl acetate (50 mL x 3). The organic phase was concentrated and collected to obtain the crude product. The residue was purified by silica gel column chromatography to obtain compound 97c as a yellow solid (100 mg, yield: 19.7%). LCMS: 404.1 [M+H] + .

[0598] Step 3: Synthesis of methyl (3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4-methyl-1H-pyrazol-5-yl)methylcarbamate (Compound 97)

[0599] In a 100 mL round-bottom flask, 97c (100 mg, 0.24 mmol) was dissolved in dichloromethane (10 mL). N,N'-carbonyldiimidazole (50 mg, 0.32 mmol) was then added. The reaction was allowed to react at room temperature for 2 hours. Methylamine (62 mg, 2.0 mmol) was then added and the reaction continued for 16 hours. The reaction solution was directly concentrated, and the crude product was purified using a C18 reverse phase column to obtain compound 97 as an off-white solid (15 mg, 13% yield). LCMS: 461.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.43–7.31(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.

[0600] Example 98

[0601] 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)

[0602] Step 1: Synthesis of ethyl 4-methyl-5-(((methylsulfonyl)oxy)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (98a)

[0603] In a 25 mL round-bottom flask, compound 22 (500 mg, 1.86 mmol) and triethylamine (283 mg, 2.80 mmol) were sequentially dissolved in dichloromethane (5 mL) and stirred at 0°C for 5 min. Methanesulfonic anhydride (390 mg, 2.24 mmol) was then added. The reaction was quenched by the addition of saturated ammonium chloride solution (8 mL). The mixture was extracted with dichloromethane, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to afford compound 98a as a yellow oil (642 mg), which was used directly in the next reaction. LCMS: 347.1 [M+H]. + .

[0604] Step 2: Synthesis of ethyl 5-((1H-tetrazol-1-yl)methyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (98b)

[0605] 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 stirred at 25°C for 1.5 hours. The reaction was quenched by the addition of saturated ammonium chloride solution (8 mL), extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to afford compound 98b as a brown oil (590 mg), which was used directly in the next reaction. LCMS: 321.2 [M+H] + .

[0606] Step 3: Synthesis of ethyl 5-((1H-tetrazol-1-yl)methyl)-4-methyl-1H-pyrazole-3-carboxylate (98c)

[0607] In a 25 mL round-bottom flask, 98b (590 mg, 1.84 mmol) was dissolved in 1,4-dioxane (3 mL). A 4 mol hydrochloric acid / 1,4-dioxane solution was added at 0°C and stirred at 0°C for 3.5 hours. The reaction solution was distilled under reduced pressure to obtain compound 98c as a yellow oil (500 mg), which was used directly in the next reaction. LCMS: 237.1 [M+H] + .

[0608] Step 4: Synthesis of 5-((1H-tetrazol-1-yl)methyl)-4-methyl-1H-pyrazole-3-carboxylic acid (98d)

[0609] In a 25 mL round-bottom flask, compound 98c (500 mg, 2.12 mmol) and lithium hydroxide (304 mg, 12.70 mmol) were dissolved in methanol (6 mL) and water (2 mL) sequentially and stirred at 25°C for 30 minutes. The reaction was quenched by adding 2 mol / L hydrochloric acid to adjust the pH to 3. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to afford compound 98d as an orange solid (360 mg), which was used directly in the next reaction. LCMS: 209.1 [M+H] + .

[0610] 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)

[0611] In a 25 mL round-bottom flask, Intermediate 1 (401 mg, 1.33 mmol) and 98d (360 mg, 1.73 mmol) were dissolved in N,N-dimethylformamide (5 mL). N,N-diisopropylethylamine (1031 mg, 7.98 mmol) and butylphosphonic anhydride (721 mg, 50% ethyl acetate solution, 2.00 mmol) were added sequentially at 0°C. The mixture was stirred at 0°C for 2 hours. Water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product. The crude product was separated and purified by reverse phase separation on a C18 column to obtain 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, CDCl3) δ 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] + ; 1 H NMR (400MHz, CDCl3) δ8.51–8.46(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.

[0612] Example 99

[0613] 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)

[0614] 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)

[0615] In a 25 mL round-bottom flask, 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 stirred at 25°C for 2 hours. The reaction was quenched by the addition of saturated ammonium chloride solution (8 mL), extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to afford compound 99a as a crude off-white solid (595 mg), which was used directly in the next reaction. LCMS: 320.2 [M+H] + .

[0616] 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)

[0617] In a 25 mL round-bottom flask, 99a (595 mg, 1.86 mmol) and lithium hydroxide (223 mg, 9.32 mmol) were dissolved in methanol (6 mL) and water (2 mL) sequentially and stirred at 25°C for 3 hours. The reaction was quenched by adding 2 M hydrochloric acid to adjust the pH to 5. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to afford compound 99b as an off-white solid (420 mg), which was used directly in the next reaction. LCMS: 292.1 [M+H] + .

[0618] Step 3: Synthesis of 5-((1H-1,2,4-triazol-1-yl)methyl)-4-methyl-1H-pyrazole-3-carboxylic acid (99c)

[0619] In a 25 mL round-bottom flask, 99b (420 mg, 1.44 mmol) was dissolved in 1,4-dioxane (5 mL). 4 mol hydrochloric acid / 1,4-dioxane was added at 0°C and stirred at 0°C for 2 hours. The reaction solution was distilled under reduced pressure to obtain compound 99c as a yellow solid (350 mg), which was used directly in the next reaction. LCMS: 208.1 [M+H] + .

[0620] 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)

[0621] In a 25 mL round-bottom flask, Intermediate 1 (361 mg, 1.20 mmol) and 99c (350 mg, 1.44 mmol) were dissolved in N,N-dimethylformamide (5 mL). N,N-Diisopropylethylamine (928 mg, 7.18 mmol) and butylphosphonic anhydride (648 mg, 50% ethyl acetate solution, 1.80 mmol) were added sequentially at 0°C. The mixture was stirred at 0°C for 40 minutes. Water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product. The crude product was isolated by silica gel column chromatography to obtain compound 99 as an off-white solid (60 mg, yield: 11%). LCMS: 455.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ12.01(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.

[0622] Example 100

[0623] 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)

[0624] Step 1: Synthesis of 3-(tert-butyl)-5-ethyl-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3,5-dicarboxylate (100a)

[0625] 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 then added dropwise at room temperature. The reaction mixture was allowed to react for 1 hour. Water (50 mL) was added to the reaction solution to quench the reaction. The mixture was then extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to afford the crude product. The crude product was isolated and purified by silica gel column chromatography to afford compound 100a as a colorless liquid (1.00 g, yield: 66%). LCMS: 385.2 [M+H] + .

[0626] Step 2: Synthesis of tert-butyl 5-(hydroxymethyl-D2)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (100b)

[0627] 100a (800 mg, 2.08 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). The reaction solution was cooled directly to 0°C, followed by the addition of solid lithium aluminum hydride (130 mg, 3.12 mmol). The temperature was maintained for 15 minutes. Water (0.8 mL), 15% sodium hydroxide solution (0.8 mL), and water (2.4 mL) were added sequentially. Ethyl acetate (50 mL) was added for dilution and stirring continued for 30 minutes. Anhydrous magnesium sulfate was added and dried overnight. The mixture was filtered, the filtrate was collected, and the crude product was directly concentrated. Compound 100b was separated and purified by silica gel column chromatography to obtain a colorless liquid (410 mg, yield: 57%). LCMS: 345.2 [M+H] + .

[0628] Step 3: Synthesis of tert-butyl 4-methyl-5-(((methylsulfonyl)oxy)methyl-D2)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (100c)

[0629] Dissolve 100b (410 mg, 1.19 mmol) in anhydrous dichloromethane (10 mL). Cool the reaction to 0°C, then add triethylamine (361 mg, 3.57 mmol) and methanesulfonic anhydride (250 mg, 1.43 mmol). Maintain the reaction temperature for 15 minutes. After completion of the reaction, the resulting solution of compound 100c was used directly in the next step. LCMS: 423.3 [M+H] + .

[0630] Step 4: Synthesis of tert-butyl 5-(aminomethyl-D2)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (100d)

[0631] The reaction mixture (10 mL) of compound 100c obtained in the previous step was directly added dropwise to a 0°C ammonia solution (7 mL, 7 mol / L methanol solution). Stirring was continued at this temperature for 30 minutes, and then the mixture was returned to room temperature and allowed to react overnight. Upon completion of the reaction, the reaction mixture was directly concentrated to dryness to obtain crude compound 100d as a colorless liquid (400 mg), which was used directly in the next reaction. LCMS: 344.2 [M+H] + .

[0632] Step 5: Synthesis of tert-butyl 5-(acetylaminomethyl-D2)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (100e)

[0633] Dissolve 100d (400 mg, 1.16 mmol) from the previous step in tetrahydrofuran (5 mL) and water (5 mL), followed by the addition of sodium carbonate (250 mg, 2.33 mmol). The reaction mixture was stirred for 15 minutes, and N-succinimidyl acetate (220 mg, 1.4 mmol) was added. The mixture was returned 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 concentrated to dryness to obtain the crude product. This was then purified by silica gel column chromatography to afford compound 100e as a colorless liquid (360 mg, yield: 80%). LCMS: 386.2 [M+H] + .

[0634] Step 6: Synthesis of 5-(acetylaminomethyl-d2)-4-methyl-1H-pyrazole-3-carboxylic acid (100f)

[0635] Dissolve 100e (360 mg, 0.93 mmol) in anhydrous dichloromethane (10 mL), then add trifluoroacetic acid (1 mL). Heat the reaction mixture to 45°C and allow to react for 1 hour. Concentrate the reaction mixture to dryness to obtain compound 100f as a colorless oil (184 mg). LCMS: 200.1 [M+H] + .

[0636] 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)

[0637] In a 25 mL round-bottom flask, Intermediate 1 (540 mg, 1.81 mmol) and 100f (180 mg, 0.90 mmol) were dissolved in N,N-dimethylformamide (5 mL). N,N-Diisopropylethylamine (700 mg, 5.42 mmol) and butylphosphonic anhydride (1.30 g, 50% ethyl acetate solution, 1.80 mmol) were added sequentially at 0°C. The mixture was stirred at 0°C for 40 minutes. Water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product. The crude product was separated using C18 reverse phase preparative separation to obtain compound 100 as an off-white solid (45 mg, yield: 11%). LCMS: 447.2 [M+H]. + ; 1H NMR(500MHz,DMSO-d6)δ12.81(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.

[0638] Example 101

[0639] 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)

[0640] Step 1: Synthesis of ethyl 4-methyl-5-(((methylsulfonyl)oxy)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (101a)

[0641] Dissolve 22a (400 mg, 1.49 mmol) in anhydrous dichloromethane (10 mL). Cool the reaction to 0°C, then add triethylamine (453 mg, 4.47 mmol) and methanesulfonic anhydride (312 mg, 1.79 mmol). Maintain the temperature for 15 minutes. After completion of the reaction, the resulting solution of compound 101a was used directly in the next step. LCMS: 447.2 [M+H] + .

[0642] Step 2: Synthesis of ethyl 5-((1H-imidazol-1-yl)methyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (101b)

[0643] The reaction mixture (10 mL) of compound 101a 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. Stirring was continued at this temperature for 30 minutes, and then the mixture was returned to room temperature for overnight reaction. Water and ethyl acetate were added, the liquids were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed sequentially with water and brine, dried, and concentrated to obtain the crude product. Compound 101b was purified by silica gel column chromatography to obtain a colorless oil (250 mg, yield: 54%). LCMS: 319.2 [M+H] + .

[0644] Step 3: Synthesis of 5-((1H-imidazol-1-yl)methyl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid (101c)

[0645] Dissolve 101b (250 mg, 0.79 mmol) in methanol (5 mL) and water (5 mL), then add anhydrous lithium hydroxide (188 mg, 7.90 mmol) and react at room temperature for 2 hours. Dilute with water, concentrate to remove methanol, adjust the pH to 3-4 with 1M dilute hydrochloric acid, extract with ethyl acetate, dry, and concentrate to obtain crude compound 101c as a colorless oil (180 mg). Used directly in the next step without further purification. LCMS: 291.2 [M+H] + .

[0646] Step 4: Synthesis of 5-((1H-imidazol-1-yl)methyl)-4-methyl-1H-pyrazole-3-carboxylic acid (101d)

[0647] 101c (180 mg, 0.62 mmol) was dissolved in dioxane (2 mL), followed by the addition of a hydrochloric acid / dioxane solution (5 mL, 4 mmol / L) and stirring at room temperature for 1 hour. The reaction mixture was concentrated to dryness to afford compound 101d as a white solid (120 mg), which was used directly in the next reaction without further purification. LCMS: 207.1 [M+H] + .

[0648] 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)

[0649] In a 25 mL round-bottom flask, Intermediate 1 (175 mg, 0.58 mmol) and 101d (120 mg, 0.58 mmol) were dissolved in N,N-dimethylformamide (5 mL). N,N-Diisopropylethylamine (225 mg, 1.75 mmol) and butylphosphonic anhydride (629 mg, 50% ethyl acetate solution, 0.88 mmol) were added sequentially at 0°C. The mixture was stirred at 0°C for 40 minutes. Water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product. The crude product was separated using C18 reverse phase preparative separation to obtain compound 101 as an off-white solid (10 mg, yield: 4%). LCMS: 454.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ13.14(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.

[0650] Examples 102 to 141

[0651] Preparation of Compounds 102 to 141

[0652] The synthesis of compounds 102 to 141 was carried out by condensing intermediates 2 to 11 with corresponding pyrazolecarboxylic acid derivatives.

[0653] The structures and characterizations of compounds 102 to 141 are shown in Table 2.

[0654] Table 2

[0655] Biological activity test

[0656] Test Example 1: Compounds inhibit RBP4-TTR complex formation

[0657] In this example, the inhibitory ability of compounds 1 and 2 on RBP4-TTR complex formation was tested using the HTRF method. The test compounds were prepared as 10 mM stock solutions in DMSO. The stock solutions were then further diluted to various test concentrations (1 μM starting point, 3-fold dilutions, 8 concentrations, 2 replicates) using reaction buffer (50 mM Tris-HCl pH 7.5, 1 mM DTT, 0.05% NP-40, 0.05% Prionex, 6% glycerol). 1 μL of each compound at various concentrations was added to a 384-well plate (Perkin Elmer, Proxiplate). 2 μL of RBP4-hFc (MCE, final concentration 12.5 nM) protein was added and incubated at room temperature for 20 min. 1 μL of all-trans Retinol (Sigma, final concentration 1 μM) was added to each well and incubated at room temperature for 20 min. 1 μL of Human Transthyretin-His (Acro, final concentration 2 nM) was added to each well and incubated at room temperature for 20 min. 2.5 μL of 1× PAb Anti-Human IgG-XL665 (Cisbio) and 2.5 μL of 1× MAb Anti-6His-Tb cryptate (Cisbio) were added to each well and incubated at room temperature for 1 h. The emission intensity at 615 nM and 665 nM in each well was measured using a Varioskan LUX microplate reader (Thermo Fisher), and the 665 / 615 ratio was calculated. The wells without compound (0 nM) were taken as 100%. After deducting the background value, data processing and curve fitting (non-linear fitting, 4 parameters) were performed using Graphpad Prism 8.0 software, and IC 50 The results are shown in Table 3.

[0658] Test Example 2: Radioligand binding test

[0659] In this example, the ability of the compound to inhibit RBP4-retinol binding was detected by radioligand binding. The test compound was prepared into a 10mM stock solution using DMSO, and then the stock solution was further diluted to different test concentrations (1μM starting, 3-fold dilution, 8 concentrations, 2 repeats) using binding buffer (0.01M PBS, pH 7.2, containing 0.1% BSA, 0.5% CHAPS, 1mM EDTA). 1μL of the above-mentioned different concentrations of compounds were added to a 384-well plate (Perkin Elmer, Proxiplate), 2μL of 50nM RBP4-biotin (MCE) protein was added, and incubated at room temperature for 30min; then 2μL of 30nM3 H Retinol, incubated at room temperature for 3 hours. 5 μL streptomycin SPA beads were added to each well and incubated at room temperature for 10 minutes. The readings were taken with a MicroBeta 2. The addition of 1 μM retinol was used as a blank control, and the absence of compound was taken as 100%. The binding inhibition rate (%) of each well was calculated. Data processing and curve fitting (nonlinear fitting, 4 parameters) were performed using Graphpad Prism 8.0 software, and IC 50 The results are shown in Table 3.

[0660] Table 3 Note: nd means not determined

[0661] Test Example 3: Mouse PK

[0662] In this example, the pharmacokinetic characteristics of the compound in vivo were evaluated by measuring drug levels at different time points after administration to mice. Six C57 / 6j mice (male, 4-6 weeks old, Vitallife) were placed in the animal room for acclimation for 3 days before use. A certain amount of compound was weighed and prepared using the corresponding solvent (oral: 0.5% MC; intravenous: DMSO: 30% HP-β-CD = 5:95). Three mice were orally administered with 10 mg / kg of compound, and micro-blood samples were collected at 0 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. Three mice were injected with 1 mg / kg of compound through the tail vein, and micro-blood samples were collected at 0 h, 5 h, 0.25 h, 0.5 h, 1 h, 2 h, 6 h, and 24 h after administration. The drug content in each sample was determined by LC-MS / MS. Pharmacokinetic parameters and bioavailability were calculated using WinNonlin. The results are shown in Table 4.

[0663] Table 4 Note: nd means not determined

[0664] Test Example 4: Rat PK

[0665] In this example, the pharmacokinetic characteristics of the compound in vivo were evaluated by measuring drug levels at different time points after administration in rats. Six male SD rats (4-6 weeks old, Vital River) were placed in the animal room for acclimation for 3 days before use. A certain amount of compound was weighed and prepared using the corresponding solvent (oral: 0.5% MC; intravenous: DMSO: 30% HP-β-CD = 5:95). Three rats were orally administered with 5 mg / kg of compound, and microblood samples were collected at 0 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. Three rats were injected with 1 mg / kg of compound through the tail vein, and microblood samples were collected at 0 h, 5 h, 0.25 h, 0.5 h, 1 h, 2 h, 6 h, and 24 h after administration. The drug content in each sample was determined by LC-MS / MS. Pharmacokinetic parameters and bioavailability were calculated using WinNonlin. The results are shown in Table 5.

[0666] Table 5

[0667] Test Example 5: Mouse PD

[0668] In this example, the pharmacodynamic characteristics of the compound in vivo were evaluated by detecting the content of RBP4 in the blood of mice at different time points after administration. Twelve C57 / 6j mice (male, 4-6 weeks old, Vital River) were placed in the animal room for 3 days of adaptation and then used. A certain amount of compound was weighed and the corresponding compound solution was prepared using the corresponding solvent (oral: 0.5% MC). Each mouse was gavaged with 20 mg / kg of the compound, and 3 mice were killed at 1h, 3h, 6h, and 24h after administration. Plasma was sampled and collected, and the RBP4 content in the plasma was detected (R&D system). The RBP4 content in the plasma of untreated mice was taken as 100%, and the maximum inhibition rate (Inhibition max, %) of each compound on the RBP4 content in the plasma was calculated. The results are shown in Table 6.

[0669] Table 6

[0670] Test Example 6: Strong light-induced retinal damage model in rats

[0671] In this example, retinal damage in rats was induced by strong light to simulate clinical early dAMD symptoms; the effects of the compound on retinal damage in rats were tested by electrophysiological examination (fERG) and fundus autofluorescence (BAF).

[0672] Male SD rats (4-6 weeks old, Weitonglihua) were randomly divided into 4 groups, 8 in each group. They were respectively set as a control group (no light, given solvent), a model group (light, given solvent), and a test group (light, given compound 1). After the rats adapted for 3 days, different compounds (10 mg / kg, QD) or solvent (0.5% MC) were given according to the situation of each group. After 3 consecutive days of administration, rats were anesthetized by intraperitoneal injection of ketamine (30-80 mg / kg) and xylazine (1-3 mg / kg), and the mydriatic agent containing tropicamide was used to dilate the animals' pupils at the same time, and strong light was used to irradiate the eyes (3000 lux, 6h) to make the model. After the modeling was completed, the drug was continued for 6 days. Before dosing (D 0) and after dosing (D 9), rats underwent ocular electrophysiology (fERG) and fundus autofluorescence (BAF) testing or photographs. The fERG data are shown in Table 7, and representative BAF photographs of rats in each group after dosing are shown in Figure 1. The fERG amplitude represents the degree of optic nerve integrity, and the BAF area (the area of ​​abnormal autofluorescence in Figure 1) represents the extent of retinal damage. The left and right eyes of each rat were treated as independent samples, and the fERG results are expressed as mean ± SD.

[0673] Table 7 Changes of fERG in rats in each group after drug administration at a light intensity of 10.0

[0674] This example shows that strong light can cause a significant decrease in the ERG amplitude of rats, and oral administration of Compound 1 can improve the amplitude; strong light can cause lipofuscin accumulation in the rat retina and form fluorescent particles, and oral administration of Compound 1 can significantly reduce the accumulation of lipofuscin fluorescent particles.

[0675] It will be apparent to those skilled in the art that the present invention is not limited to the foregoing illustrative embodiments but may be embodied in other specific forms without departing from its essential characteristics. It is therefore intended that the embodiments be considered in all respects as illustrative and non-restrictive, and that reference should be made to the appended claims rather than to the foregoing embodiments, and all changes coming within the meaning and range of equivalents of the appended claims are intended to be embraced herein.

Claims

1. A compound having a structure as represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure represented by formula (I); in, R 1 Selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, cyano, nitro, cycloalkyl, heterocyclyl, -NR 7 R 8 、-NR 9 (CO)R 6 、-NR 9 (CO)OR 10 、-NR 9 (CO)NR 7 R 8 、-NR 9 SOR 11 、-NR 9 SO2R 11 、-OR 10 、-O(CO)R 6 、-O(CO)NR 7 R 8 、-C(O)R 6 、-C(O)OR 10 、-C(O)NR 7 R 8 、-C(S)OR 10 、-C(S)NR 7 R 8 、-C(O)SR 10 、-SR 10 、-SOR 11 、-SO2R 11 、-SO2NR 7 R 8 、-S(O)R 11 NR 9 、-C(NR 9 )NR 7 R 8 or-P(O)R 12 R 13 ; R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, deuterium, hydroxy, nitro, amino, alkoxy, carboxyl, mercapto, cyano, alkyl, halogen, cycloalkyl or haloalkyl; Or, R 1 、R 2 、R 3 、R 4 、R 5 Connect at any ortho position to form a cycloalkyl or heterocyclic group; R 6 is selected from hydrogen, deuterium, hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 7 、R 8 、R 9 is selected from hydrogen, deuterium, cyano, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 10 is selected from hydrogen, deuterium, alkyl, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, or heteroaryl; R 11 is selected from hydrogen, deuterium, amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 12 、R 13 is selected from hydrogen, deuterium, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or R 12 、R 13 It forms a phosphorus-containing heterocycle with the P atom connected to it; R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 wherein the alkyl, alkoxy, haloalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with 0 to 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, carboxyl, thiol, nitro, alkyl, cycloalkyl, halocycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, alkoxy, haloalkoxy, heterocyclyl, aryl and heteroaryl groups; L is a bridged ring group, spiro ring group, monocyclic group or cyclic group containing 0 to 2 nitrogen atoms; The bridged ring group, spiro ring group, monocyclic group or cyclic group in L is optionally substituted by 0 to 4 substituents selected from deuterium, alkyl, hydroxy, amino, alkoxy or haloalkyl; A is -NR 14 - or key; R 14 is selected from hydrogen, deuterium or alkyl; Ring B is selected from a heterocyclic ring, an aromatic ring or a heteroaromatic ring; R 15 And every R 16 each independently selected from deuterium, alkyl, aminoalkyl, cycloalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanoyl, alkanoyl, aminocarbonyl, heterocyclyl, aryl, heteroaryl or heterocyclylacyl; R 15 and R 16 The alkyl, cycloalkyl, aminoalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanoyl, alkanoyl, heterocyclyl, aryl, heteroaryl and heterocyclylacyl groups are each independently substituted by 0 to 4 groups selected from deuterium, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkanoyl, alkoxyacyl, alkanoyl, aminocarbonyl, carboxyl, -OC(O)-NR 17 R 18 and substituted by a substituent in an oxo group; R 17 and R 18 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 C 1-9 Heterocyclic, C 6-10 Aromatic ring or C 1-9 heteroaromatic rings; R 15 And every R 16 are each independently selected from deuterium, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-6 aminoalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-9 Heterocyclyl C 1-6 Alkyl, C 1-9 Heteroaryl C 1-6 Alkyl, C 1-6 Alkylamide, C 1-6 Alkanoyl, aminocarbonyl, C 1-9 Heterocyclic group, C 6-10 Aryl, C 1-9 Heteroaryl or C 1-9 heterocyclyl acyl; R 15 and R 16 C in 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-6 aminoalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-9 Heterocyclyl C 1-6 Alkyl, C 1-9 Heteroaryl C 1-6 Alkyl, C 1-6 Alkylamide, C 1-6 Alkanoyl, C 1-9 Heterocyclic group, C 6-10 Aryl, C 1-9 Heteroaryl and C 1-9 Heterocyclyl acyl groups are each independently substituted by 0 to 4 atoms selected from deuterium, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl, C 1-9 Heteroaryl, C 1-6 Alkanoyl, C 1-6 Alkoxyacyl, C 1-6 Alkylamide, aminocarbonyl, carboxyl, -OC(O)-NR 17 R 18 and substituted by a substituent in an oxo group; R 17 and R 18 are each independently selected from hydrogen, deuterium, C 1-4 Alkyl and C 1-4 Halogenated alkyl.

3. The compound according to claim 1, wherein Ring B is selected from a pyrazole ring, an imidazole ring, a triazole ring or a pyrimidine ring; R 15 And every R 16 each independently selected from the group consisting of deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, propylamino, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, halomethyl, haloethyl, tetrahydropyrrolyl, tetrahydropyrrolylmethyl, tetrahydropyrrolylethyl, piperidinyl, piperidinylmethyl, piperidinylethyl, piperazinyl, piperazinylmethyl, piperazinylethyl, morpholinyl, morpholinylmethyl, morpholinylethyl, morpholinoyl, pyrrolyl, pyrrolylmethyl, pyrrolylethyl, pyrrolyl 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 or acetyl; R 15 And every R 16 Each is independently optionally substituted by 0 to 4 substituents selected from deuterium, methyl, ethyl, cyclopropyl, cyclobutane, formyl, acetyl, formamido, acetamido, aminocarbonyl, methoxyacyl, ethoxyacyl, carboxyl, -OC(O)-NHCH3, -OC(O)-N(CH3)2, -OC(O)-NHC2H5, -OC(O)-NHC3H8 and oxo.

4. The compound according to claim 1, wherein R 1 、R 2 、R 3 、R 4 、R 5 The alkyl, cycloalkyl, heterocyclic, alkoxy and haloalkyl groups are C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 1-6 Alkoxy and C 1-6 alkyl halide; R 6 Selected from hydrogen, deuterium, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 heteroaryl; R 7 、R 8 、R 9 Selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 heteroaryl; R 10 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Halogenated alkenyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 heteroaryl; R 11 Selected from hydrogen, deuterium, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 heteroaryl; R 12 、R 13 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Heteroaryl, or R 12 、R 13 and the P atoms connected to it to form phosphorus-containing C 1-9 heterocyclic ring; R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 C in 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by 0 to 4 groups selected from deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-9 Heterocyclic group, C 6-10 Aryl and C 1-9 The heteroaryl group is substituted by a substituent.

5. The compound according to claim 1, wherein R 1 The cycloalkyl group in is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, R 1 The heterocyclic group in is selected from oxetanyl, oxolanyl, azetidinyl, azetidine, thietanyl or thiolanyl; R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, cyclopropane, cyclobutane, halocyclopropane or halocyclobutane; Or, R 1 、R 2 、R 3 、R 4 、R 5 at any ortho position to form a cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxacyclopentyl or oxacyclohexyl group; R 6 is selected from hydrogen, deuterium, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, tetrahydropyrrolyl or tetrahydrofuranyl; R 7 、R 8 、R 9 is selected from hydrogen, deuterium, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl; R 10 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halomethyl, haloethyl, halo-n-propyl, haloisopropyl, halo-n-butyl, halocyclopropyl, halocyclobutyl, halocyclopentyl, halocyclohexyl, vinyl, propenyl, ethynyl, propynyl, halovinyl, halopropenyl, tetrahydropyrrolyl or tetrahydrofuranyl; R 11 is selected from hydrogen, deuterium, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl; R 12 、R 13 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or tetrahydrofuranyl.

6. The compound according to claim 1, wherein L is selected from C 6-12 Bridged ring group, C containing 0 to 2 nitrogen atoms 5-12 Spirocyclic group, C containing 0 to 2 nitrogen atoms 2-6 Monocyclic or C containing 0 to 2 nitrogen atoms 4-12 and cyclized groups; C in L 6-12 Bridged ring group, C 5-12 Spirocyclyl, C 2-6 Monocyclic or C 4-12 The cyclized group is optionally substituted by 0 to 4 atoms selected from deuterium, C 1-6 Alkyl, hydroxyl, amino, C 1-6 Alkoxy or C 1-6 substituted by a haloalkyl substituent; R 14 The alkyl group is C 1-6 alkyl.

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

8. The compound according to claim 1, having a structure as shown in Formula (II) or Formula (III), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof; in, X 1 、X 2 、X 3 N or CR 16 ; l is 0 or 1; n is 0, 1, 2, 3 or 4; R 15 And every R 16 each independently selected from deuterium, alkyl, aminoalkyl, cycloalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanoyl, alkanoyl, aminocarbonyl, heterocyclyl, aryl, heteroaryl or heterocyclylacyl; R 15 and R 16 The alkyl, cycloalkyl, aminoalkyl, alkoxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, alkanoyl, alkanoyl, heterocyclyl, aryl, heteroaryl and heterocyclylacyl groups are each independently substituted by 0 to 4 groups selected from deuterium, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkanoyl, alkoxyacyl, alkanoyl, aminocarbonyl, carboxyl, -OC(O)-NR 17 R 18 and substituted by a substituent in an oxo group; R 17 and R 18 are each independently selected from hydrogen, deuterium, alkyl and haloalkyl.

9. The compound according to claim 8, wherein Ring B is selected from C 1-9 Heterocyclic, C 6-10 Aromatic ring or C 1-9 heteroaromatic rings; R 15 And every R 16 are each independently selected from deuterium, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-6 aminoalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-9 Heterocyclyl C 1-6 Alkyl, C 1-9 Heteroaryl C 1-6 Alkyl, C 1-6 Alkylamide, C 1-6 Alkanoyl, aminocarbonyl, C 1-9 Heterocyclic group, C 6-10 Aryl, C 1-9 Heteroaryl or C 1-9 heterocyclyl acyl; R 15 and R 16 C in 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-6 aminoalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-9 Heterocyclyl C 1-6 Alkyl, C 1-9 Heteroaryl C 1-6 Alkyl, C 1-6 Alkylamide, C 1-6 Alkanoyl, C 1-9 Heterocyclic group, C 6-10 Aryl, C 1-9 Heteroaryl and C 1-9 Heterocyclyl acyl groups are each independently substituted by 0 to 4 atoms selected from deuterium, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Aryl, C 1-9 Heteroaryl, C 1-6 Alkanoyl, C 1-6 Alkoxyacyl, C 1-6 Alkylamide, aminocarbonyl, carboxyl, -OC(O)-NR 17 R 18 and substituted by a substituent in an oxo group; R 17 and R 18 are each independently selected from hydrogen, deuterium, C 1-4 Alkyl and C 1-4 Halogenated alkyl.

10. The compound according to claim 8, wherein Ring B is selected from a pyrazole ring, an imidazole ring, a triazole ring or a pyrimidine ring; R 15 And every R 16 each independently selected from the group consisting of deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, propylamino, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, halomethyl, haloethyl, tetrahydropyrrolyl, tetrahydropyrrolylmethyl, tetrahydropyrrolylethyl, piperidinyl, piperidinylmethyl, piperidinylethyl, piperazinyl, piperazinylmethyl, piperazinylethyl, morpholinyl, morpholinylmethyl, morpholinylethyl, morpholinoyl, pyrrolyl, pyrrolylmethyl, pyrrolylethyl, pyrrolyl 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 or acetyl; R 15 And every R 16 Each is independently optionally substituted by 0 to 4 substituents selected from deuterium, methyl, ethyl, cyclopropyl, cyclobutane, formyl, acetyl, formamido, acetamido, aminocarbonyl, methoxyacyl, ethoxyacyl, carboxyl, -OC(O)-NHCH3, -OC(O)-N(CH3)2, -OC(O)-NHC2H5, -OC(O)-NHC3H8 and oxo.

11. The compound according to any one of claims 1 to 10, which has one of the following structures, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

13. Use of the compound according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 11 in the preparation of a medicament for treating retinol binding protein 4-related diseases. 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 for inhibiting RBP4-TTR complex formation in a cell, comprising contacting the cell with an effective amount of the compound according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12. 16 . A method for inhibiting excessive accumulation of lipofuscin in cells, comprising contacting the cells with an effective amount of the compound according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12.

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

18. A method for 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 to 11 or the pharmaceutical composition of claim 12.

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