Tetrazole compound, preparation method therefor and use thereof

Abstract

The present disclosure relates to a tetrazole compound, a preparation method therefor and a use thereof. In particular, the present disclosure relates to a compound represented by formula (I-1), a composition thereof, a preparation method therefor, an intermediate, and a use of the tetrazole compound or a pharmaceutical composition thereof as a CYP51 inhibitor in the preparation of drugs for preventing and / or treating fungal infections.

Description

Tetraazole compounds, their preparation methods and uses

[0001] This disclosure is based on and claims priority to Chinese patent applications No. 202411194903.8, filed August 28, 2024; No. 202510571460.8, filed April 30, 2025; No. 202510629530.0, filed May 15, 2025; and No. 202510957743.6, filed July 11, 2025, the disclosures of which are incorporated herein by reference in their entirety. Technical Field

[0002] This disclosure belongs to the field of medicinal chemistry, and specifically relates to a tetrazolium compound, its preparation method, and its uses. Background Technology

[0003] Invasive fungal disease (IFD) refers to infectious diseases caused by fungi that invade the human body, grow and multiply in tissues, organs, or blood, leading to inflammatory responses and tissue damage. In recent years, due to factors such as increased use of chemotherapy and radiotherapy for cancer, the widespread use of bone marrow and solid organ transplants, the increase in AIDS patients and other patients with primary immunodeficiency, and the long-term and widespread use of broad-spectrum antibiotics, the incidence and mortality rates of clinical invasive fungal infections caused by Candida, Aspergillus, and Cryptococcus neoformans have been rising year by year. Globally, tens of millions of people suffer from fungal infections each year, and at least 1.5 million die from deep fungal invasion.

[0004] Currently, FDA-approved drugs for treating invasive fungal infections include polyenes, flucytosines, azoles, and echinocandins. Generally, echinocandins are the primary treatment for Candida, while triazoles are the primary preventative treatment; triazoles are the primary preventative and treatment for Aspergillus; and polyenes, flucytosines, and azoles are the primary treatments for Cryptococcus. However, current drugs suffer from one or more drawbacks, such as poor safety profile, narrow antifungal spectrum, high resistance rates, complex drug interactions, and insufficient exposure to infected tissues. For example, amphotericin B, a polyene antibiotic, can only be administered intravenously and has significant nephrotoxicity; triazoles have a broad antifungal spectrum but resistance is common, and drug interactions are complex; while resistance to echinocandins is relatively rare, their antifungal spectrum is narrow, oral bioavailability is low, requiring intravenous administration, and the drugs are not easily exposed to the central nervous system and ocular tissues. Currently, drug options for many invasive fungal infections are limited, and there is an urgent clinical need for safe, effective, and broad-spectrum new antifungal drugs.

[0005] Triazole drugs are a class of antifungal drugs with great development potential and advantages. They act on the lanosterol 14α-demethylase (Cyp51) in fungi, inhibiting the conversion of lanosterol to ergosterol, thereby disrupting the stability of the fungal cell membrane and killing the fungus. Several triazole drugs, including fluconazole (1988), itraconazole (1988), voriconazole (2002), posaconazole (2005), and isaconazole (2015), have been marketed and have become first-line drugs for treating fungal infections in clinical practice. However, due to long-term treatment and repeated administration of triazole antifungal drugs, triazole resistance is common. Furthermore, the unintended inhibition of the drug-metabolizing enzyme CYP by triazole drugs leads to complex drug interactions and adverse reactions in clinical practice. Therefore, it is necessary to develop new antifungal drugs to overcome the limitations and defects of existing azole drugs in clinical practice and reduce the mortality rate of invasive fungal infections. Summary of the Invention

[0006] This disclosure provides a tetrazolium CYP51 enzyme inhibitor that can be used to treat fungal infections.

[0007] On the one hand, this disclosure provides compounds of formula (I-1) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs thereof:

[0008] in,

[0009] Ring A is C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic;

[0010] Ring B is C 3-8 Monocyclic cycloalkane rings or 4-14 membered nitrogen-containing heterocycles;

[0011] Ring C does not exist, or it is C. 6-10 aryl, 5-10 heteroaryl, 4-10 heterocyclic, or C 6-10 Aryl benzo[C] 3-8 cycloalkyl;

[0012] X does not exist, or is a key, -C 0-6 Alkylene-OC 0-6 alkylene-, -C 0-6 Alkylene-SC 0-6 alkylene-, -C 0-6 Alkylene-NR A -C 0- 6-alkylene-, -C 0-6 Alkylene-Se-C 0-6 alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, C2-12 imidene group, C 2-12 Ethyne group, C 1- 12 Alkylene, wherein the alkylene, alkenylene, or alkyneyl group is optionally selected independently from one or more of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substituents of cycloalkyl groups;

[0013] R1 and R2 are each independently hydrogen, deuterium, halogen, cyano, nitro, or C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 0-6 Alkylene-R C or -SC 0-6 Alkylene-R C Alternatively, R1 and R2, together with the carbon atoms they are attached to, form C. 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0014] R3 is -C 0-6 Alkylene-NR A R B or -C 0-6 Alkylene-OR C Alternatively, one of R1 and R2 and R3 together with the carbon atom to which they are attached form a 3-8 membered heterocyclic group;

[0015] R4, R5, and R6 are each independently hydrogen, deuterium, halogen, cyano, nitro, oxo, carboxyl, -SF5, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 1-12 Halogenated alkyl groups, -OC 0-12 Alkylene-R C -SC 0-12 Alkylene-R C -S(O)2R C -C(O)NR A R B -P(O)R A RB -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10 heteroaryl, -C 0-6 Alkylene-C 3-8 cycloalkyl, -C 0-6 alkylene-4-10-membered heterocyclic groups, or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected independently by one or more groups selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Hydroxyalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 cycloalkyl, -CONR A R B -P(O)R A R B -COR C -S(O)2R C Substituents are substituted; p is 0, 1, 2, 3, 4 or 5;

[0016] R7 and R8 are independently hydrogen, deuterium, halogen, cyano, nitro, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 0-6 Alkylene-R C or -SC 0-6 Alkylene-R C Alternatively, R7 and R8, together with the carbon atoms they are bonded to, form C. 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0017] m, n, and o are each independently 0, 1, 2, 3, 4, or 5;

[0018] R A and R B Each independently is hydrogen, C 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C6-10 Aryl or 5-10 heteroaryl groups;

[0019] R C Each is independently hydrogen, deuterium, and C. 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0020] On the other hand, this disclosure provides a pharmaceutical composition comprising a preventive and / or therapeutically effective amount of the compound of this disclosure or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

[0021] On the other hand, this disclosure provides a kit containing a compound of the disclosure or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, or a pharmaceutical composition comprising the disclosure.

[0022] On the other hand, this disclosure provides the use of the compounds of this disclosure or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites or prodrugs, or pharmaceutical compositions of this disclosure, or medicaments of this disclosure in the preparation of medicaments for the prevention and / or treatment of diseases, particularly CYP51-mediated diseases.

[0023] On the other hand, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites or prodrugs thereof, or pharmaceutical compositions of the disclosure, or kits of the disclosure, for the prevention and / or treatment of diseases, particularly CYP51-mediated diseases.

[0024] On the other hand, this disclosure provides a method for preventing and / or treating diseases, particularly CYP51-mediated diseases, comprising administering to an individual in need a preventive or therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug of this disclosure, or a pharmaceutical composition of this disclosure, or a cassette of this disclosure.

[0025] On the other hand, this disclosure provides a method for preparing the compounds disclosed herein.

[0026] On the other hand, this disclosure provides intermediates for preparing the compounds of this disclosure. Detailed Implementation

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In case of any conflict, the definitions provided herein shall prevail. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0028] definition

[0029] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group, preferably having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms, i.e., "C". 1-20 Alkyl group. The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 8 carbon atoms (i.e., C14-C ... 1-8 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkyl groups, most preferably alkyl groups having 1 to 3 carbon atoms (i.e., C14-C ... 1-3 Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc.

[0030] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, preferably has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C2). 1-20 Alkylene). "C 0-12 "Alkylene" refers to an alkylene group having 0-12 carbon atoms (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 carbon atoms), such as C 1-12 Alkylene, C 0-6 Alkylene, C 1-6 Alkylene, C 0-3 Alkylene, C 1-2 Alkylenes, etc. Among them, C0 alkylenes with 0 carbon atoms refer to chemical bonds. 0-12 Non-limiting examples of alkylene groups include: bond, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -(CH2)8-, -(CH2) 11 -wait.

[0031] The term "alkenyl" refers to a hydrocarbon group in a molecule that contains at least one carbon-carbon double bond, preferably having 2 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl group). In some embodiments, the alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C10). 2-6 (Alkenyl). Non-limiting examples include: vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc.

[0032] The term "alkenyl" refers to a divalent alkenyl group, where the alkenyl group is as defined above.

[0033] The term "alkynyl" refers to a hydrocarbon group in a molecule that contains at least one carbon-carbon triple bond, preferably having 2 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 (Alkyne group). In some embodiments, the alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C12). 2-6 Alynyl group). Non-limiting examples include: ethynyl, propynyl, butynyl, penynyl, hexynyl, etc.

[0034] The term "ethynyl" refers to a divalent ethynyl group, where the ethynyl group is as defined above.

[0035] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group (i.e., monocyclic cycloalkyl) or a polycyclic cyclic hydrocarbon group (i.e., polycyclic cycloalkyl), preferably having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms, i.e., C64. 3-20 Cycloalkyl group. The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 carbon atoms (i.e., C12). 3-12 cycloalkyl groups, more preferably cycloalkyl groups having 3 to 8 carbon atoms (i.e., C14-C ... 3-8 Cycloalkyl groups, more preferably cycloalkyl groups having 3 to 6 carbon atoms (i.e., C164-C ... 3- 6. Cycloalkyl groups. Non-limiting examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl. Non-limiting examples of polycyclic cycloalkyl groups include: spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0036] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic hydrocarbon group (i.e., monocyclic heterocyclic group) or polycyclic hydrocarbon group (i.e., polycyclic heterocyclic group) containing cyclic heteroatoms, preferably having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3-20 membered heterocyclic group), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, and P(O). m and S(O) nThe heterocyclic group (where m and n are integers from 0 to 2) contains heteroatoms, but excludes the ring portions of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. The heterocyclic group preferably has 3 to 14 ring atoms (i.e., 3-14 membered heterocyclic groups), including 1 to 4 heteroatoms selected from N, O, and S atoms; more preferably, it has 3 to 8 ring atoms (i.e., 3-8 membered heterocyclic groups) or 4 to 10 ring atoms (i.e., 4-10 membered heterocyclic groups), including 1 to 4, 1 to 3, or 1 to 2 heteroatoms selected from N, O, and S atoms; even more preferably, it has 4 to 6 ring atoms (i.e., 4-6 membered heterocyclic groups), including 1 to 4, 1 to 3, or 1 to 2 heteroatoms selected from N, O, and S atoms; and most preferably, it has 5 to 6 ring atoms (i.e., 5-6 membered heterocyclic groups), including 1 to 4, 1 to 3, or 1 to 2 heteroatoms selected from N, O, and S atoms. Non-limiting examples of the heterocyclic groups include: azirrobutyl, oxoheterobutyl, thioheterobutyl, pyrrolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxocyclopentyl, 2,2-difluoro-1,3-dioxocyclopentyl, cyclopentanone, 2,2-difluorocyclopentanone, azirroheptanyl, oxocyclopentyl, azirroheptanyl, benzodihydropyranyl, etc. Non-limiting examples of the polycyclic heterocyclic groups include: spiroheterocyclic, fused heterocyclic, and bridged heterocyclic groups. Heterocyclic groups include nitrogen-containing heterocyclic groups, oxygen-containing heterocyclic groups, and sulfur-containing heterocyclic groups, etc. In addition to containing nitrogen, oxygen, and sulfur, the nitrogen-containing / oxygen / sulfur heterocyclic group may optionally contain 1-3 heteroatoms selected from N, O, and S atoms. Non-limiting examples of nitrogen-containing monocyclic heterocyclic groups include: azirrobutyl, pyrrolidinyl, imidazoalkyl, dihydroimidazolyl, dihydropyrazolyl, dihydropyridyl, piperidinyl, piperazinyl, azirrohepyl, 1,4-diazahepyl, etc.

[0037] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group that shares a single atom (called a spiro atom) between monocyclic rings, preferably having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5-20 membered spiroheterocyclic group), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, and P(O). m and S(O) nThe heteroatoms (where m and n are integers from 0 to 2) are carbon atoms, excluding the ring portions of -OO-, -OS-, or -SS-. It may contain one or more double bonds. The spiroheterocyclic group is preferably a spiroheterocyclic group with 6 to 14 ring atoms (i.e., a 6-14 member spiroheterocyclic group). Based on the number of shared spiro atoms between rings, the spiroheterocyclic group is classified into monospirocyclic, bispirocyclic, or multispirocyclic groups, preferably monospirocyclic or bispirocyclic, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5, or 7 / 6 monospirocyclic groups. Non-limiting examples of nitrogen-containing spiroheterocyclic groups include: Where n1, n2, n3, and n4 are each independently 0, 1, 2, or 3, and n1 and n2 are not both 0 at the same time, nor are n3 and n4 both 0 at the same time. For example, Other non-limiting examples of spiroheterocyclic groups include wait.

[0038] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in a system shares an adjacent pair of atoms with other rings in the system. It preferably has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5-20 membered fused heterocyclic group), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, and P(O). m and S(O) n The heteroatoms (where m and n are integers from 0 to 2) are excluding the ring portions of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. It may contain one or more double bonds. The fused heterocyclic group is preferably a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6-14 member fused heterocyclic group). Based on the number of constituent rings, they are classified into bicyclic, tricyclic, tetracyclic, or more fused heterocyclic groups, with bicyclic or tricyclic groups being preferred. More preferably, they are 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic groups, or 6-membered / 5-membered / 6-membered tricyclic fused heterocyclic groups. Non-limiting examples of nitrogen-containing fused heterocyclic groups include: (For example ),

[0039] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two non-directly connected atoms, preferably having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5-20 membered bridged heterocyclic group), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, and P(O). m and S(O) n The bridged heterocyclic group (where m and n are integers from 0 to 2) contains heteroatoms, but excludes the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. It may contain one or more double bonds. The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a 6-14 membered bridged heterocyclic group), more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., a 7-10 membered bridged heterocyclic group). It is classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups according to the number of constituent rings, with bicyclic or tricyclic bridged heterocyclic groups being preferred. Non-limiting examples of nitrogen-containing bridged heterocyclic groups include: Where n1 is independently 1, 2, or 3, for example, (For example ),

[0040] The term "aryl" refers to a monocyclic group with a conjugated π-electron system (i.e., monocyclic aryl) or a fused polycyclic group (i.e., polycyclic aryl), preferably having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms (i.e., C atoms). 6-14 Aryl group). The aryl group is preferably an aryl group having 6 to 12 carbon atoms (i.e., C64). 6-12 Aryl), more preferably aryl having 6 to 10 carbon atoms (i.e., C10). 6-10 Aryl), further preferably phenyl or naphthyl, most preferably phenyl. The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aryl group include naphthyl, anthraceneyl, phenanthryl, etc.

[0041] The term "heteroaryl" refers to a monocyclic heteroaryl group (i.e., monocyclic heteroaryl) or a fused polycyclic heteroaryl group (i.e., polycyclic heteroaryl) having a conjugated π-electron system, preferably having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., 5-14 membered heteroaryl), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, and P(O). m and S(O) nThe heteroatom (where m and n are integers from 0 to 2) is preferably selected from nitrogen, oxygen, or sulfur, but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5-10 membered heteroaryl group). The monocyclic heteroaryl group is preferably a heteroaryl group having 5 to 6 ring atoms (i.e., a 5-6 membered heteroaryl group), and non-limiting examples include: furanyl, pyranyl, thiophene, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl), thiazolyl (e.g., 1,2,4-thiazolyl or 1,3,4-thiazolyl), imidazole, pyrazolyl, triazolyl, tetrazolyl, pyrrole, pyridinyl, pyrimidinyl, pyridoneyl, pyrazinyl, pyridazinyl, etc. The polycyclic heteroaryl group is preferably a 5-6 member heteroaryl-5-6 member heteroaryl or a 5-10 member heteroaryl-C 6-10 Aryl or C 6-10 The aryl group comprises 5-10 heteroaryl groups, with 5-6 heteroaryl groups, 5-6 heteroaryl groups, or phenyl groups comprising 5-6 heteroaryl groups. Non-limiting examples include: indolyl, inzolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, thiophene, quinazolinyl, benzothiazolyl, carbazolyl, thiophene-pyridyl, pyridinothiophenyl, pyridinopyrroleyl, imidazopyridazinyl, imidazopyrazinyl, triazolylpyrimidinyl, benzoxazolyl, benzopyrazolyl, pyrazolylpyridinyl, imidazopyridinyl, etc.

[0042] The term "alkoxy" refers to -O- (alkyl) or -O- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as described above, and preferably have 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms (i.e., C). 1-12 Alkoxy group). The alkoxy group is preferably an alkoxy group having 1 to 8 carbon atoms (i.e., C14). 1-8 Alkoxy groups, more preferably alkoxy groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1- 6-alkoxy group, preferably alkoxy group with 1 to 3 carbon atoms (i.e., C6-alkoxy group). 1-3 Alkoxy groups. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc.

[0043] The term "alkathioyl" refers to -S- (alkyl) or -S- (unsubstituted cycloalkyl), wherein the definitions of alkyl and cycloalkyl are as described above, and they preferably have 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C). 1-12 Alkylthio group). The alkylthio group is preferably an alkylthio group having 1 to 8 carbon atoms (i.e., C12).1-8 Alkylthioyl), more preferably alkylthioyl groups having 1 to 6 carbon atoms (i.e., C14-C ... 1- 6-alkylthio group), preferably alkylthio group with 1 to 3 carbon atoms (i.e., C64-C ... 1-3 Alkylthioyl). Non-limiting examples include: methylthioyl, ethylthioyl, propylthioyl, butylthioyl, cyclopropylthioyl, cyclobutylthioyl, cyclopentylthioyl, cyclohexylthioyl, etc.

[0044] The terms “halogen” or “halogenated” should be understood to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms, preferably fluorine, chlorine or bromine atoms.

[0045] The term "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2-dichloro-2-fluoroethyl, 2, 2,2-Trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, etc., preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl.

[0046] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above. Non-limiting examples include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, etc.; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2 2-Dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2-chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy.

[0047] The term "thiol" refers to -SH.

[0048] The term "hydroxyl group" refers to -OH.

[0049] The term "nitro" refers to -NO2.

[0050] The term "amino" refers to -NH2.

[0051] The term "cyano" refers to -CN.

[0052] The term "carboxyl group" refers to -C(O)OH.

[0053] The term "oxo" or "oxo group" refers to =O.

[0054] The term "carbonyl" refers to C=O.

[0055] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0056] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0057] The term "one or more species" or similar expression "at least one species" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0058] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood as representing each numerical value and range encompassed within a wider range.

[0059] In this article, "Z" and "-Z-" both refer to the same specific group and can be used interchangeably.

[0060] The expression "mn" used in this paper refers to the range from m to n, the subrange consisting of the individual point values ​​within it, and the individual point values ​​themselves. For example, the expression "C2-C6" or "C 2-6 "Covering a range of 2-6 carbon atoms, and should be understood to also include any subranges within this range and each point value, such as C2-C3, C2-C4, C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, etc., and C2, C3, C4, C5, C6, etc. For example, the expression "C5-C..." 10 "or "C 5-10 "It should also be understood in a similar way, for example, it can cover any subrange and point value contained therein, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C..." 10 C7-C9, C7-C8, C8-C9, etc., as well as C3, C4, C5, C6, C7, C8, C9, C 10 For example, stating "C1-C6" or "C..." 1-6 "The range encompasses 1-6 carbon atoms, and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, and C1, C2, C3, C4, C5, C6, etc. Similarly, the expression "4-14 elements" should be understood to include any subrange within this range and each point value, such as 4-8 elements, 6-14 elements, 5-6 elements, and 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, etc. Other similar expressions in this document should also be understood in a similar manner."

[0061] The different expressions used in this article, such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", and "X is A, B and C", all express the same meaning, that is, X can be any one or more of A, B, and C.

[0062] The terms “optional” or “optionally” mean that an event or condition described below may or may not occur, including both the occurrence and non-occurrence of the event or condition. For example, “optionally (al) alkyl-substituted cycloalkyl” means that an alkyl group may but is not required to be present, and this description includes cases where the cycloalkyl group is substituted with an alkyl group and cases where the cycloalkyl group is not substituted with an alkyl group.

[0063] The terms "substitution" and "substituted" refer to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a chosen substituent from the indicated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound. When describing the absence of a substituent, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. When describing the optional substitution of each carbon atom in a group with a heteroatom, the condition is that the substitution does not exceed the normal valence of all atoms in the group in the present case and that a stable compound is formed.

[0064] If a substituent is described as "optionally...substituted," the substituent may be unsubstituted or substituted. If an atom or group is described as being optionally substituted by one or more of the substituents in the list, one or more hydrogen atoms on that atom or group may be replaced by independently selected, optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted. When the substituent is hydrogen, this may also indicate that the corresponding group is "unsubstituted" or "unsubstituted." Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable position of the substituent.

[0065] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0066] When any variable (e.g., R), and labeled variables (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) appear more than once in the composition or structure of a compound, their definition is independent for each occurrence in each case. For example, if a group is substituted by 0, 1, 2, 3, or 4 R substituents, the group may optionally be substituted by up to four R substituents, and the options for each R substituent in each case are independent of each other.

[0067] This disclosure also includes all pharmaceutically acceptable isotopically labeled compounds identical to those of this disclosure, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this disclosure include, but are not limited to, isotopes of hydrogen (e.g., 2 H, 3 H, deuterium (D), tritium (T); carbon isotopes (e.g., H, deuterium (D), tritium (T)); 11 C 13 C and 14 C); isotopes of chlorine (e.g. 37 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes ... 32 P); and isotopes of sulfur (e.g. 35 S). Certain isotope-labeled compounds of this disclosure (e.g., those doped with radioisotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioisotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13 Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds of this disclosure can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by replacing previously used unlabeled reagents with appropriate isotopically labeled reagents. Pharmaceutically acceptable solvates of this disclosure include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0068] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules may also exist as geometric isomers (cis / trans). Similarly, the compounds of this disclosure can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0069] This disclosure covers all possible crystalline forms or polymorphs of the compounds disclosed herein, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0070] It should also be understood that certain compounds of this disclosure may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In this disclosure, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites, or prodrugs that, upon administration to a patient in need, can directly or indirectly provide the compounds of this disclosure or their metabolites or residues. Therefore, when referring herein to “compounds of this disclosure,” it is also intended to encompass the various derivative forms of the compounds described above.

[0071] Pharmaceutically acceptable salts of the compounds disclosed herein include their acid addition salts and base addition salts. Suitable acid addition salts are formed by acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed by bases that form pharmaceutically acceptable salts. A review of suitable salts can be found in Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds disclosed herein are known to those skilled in the art.

[0072] The compounds disclosed herein may exist as solvates (preferably hydrates), wherein the compounds contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the compound's crystal lattice. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0073] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires available lone pairs of electrons to be oxidized into oxides; those skilled in the art will identify nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see, for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp. 748-750; A.R. Katritzky and A.J. Boulton, Eds., Academic Press; and G.W. H. Heeseman and E.S. G. Wierstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp. 390-392, A.R. Katritzky and A.J. Boulton, Eds., Academic Press.

[0074] The scope of this disclosure also includes metabolites of the compounds of this disclosure, i.e., substances formed in the body upon administration of the compounds of this disclosure. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Therefore, this disclosure includes metabolites of the compounds of this disclosure, including compounds prepared by methods that expose the compounds of this disclosure to mammals for a time sufficient to produce their metabolites.

[0075] This disclosure further includes, within its scope, prodrugs of the compounds of this disclosure, which are certain derivatives of the compounds of this disclosure that may themselves have little or no pharmacological activity, and which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of this disclosure having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that are readily converted in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987 (EB Roche, editor, American Pharmaceutical Association). Prodrugs of this disclosure can be prepared, for example, by replacing suitable functional groups present in the compounds of this disclosure with certain portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0076] This disclosure also covers compounds of this disclosure containing protecting groups. In any process of preparing the compounds of this disclosure, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of this disclosure. This can be achieved by conventional protecting groups, for example, those described in *Protective Groups in Organic Chemistry*, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P. ​​G.W. M. Uts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0077] Unless otherwise specified, all numerical values ​​in this application are modified by the term "about". The term "about" means within ±20%, preferably within ±10%, more preferably within ±5%, and even more preferably within ±2%.

[0078] The term "pharmaceutical composition" refers to a composition containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertment of its biological activity.

[0079] In this disclosure, "pharmaceuticalally acceptable carrier" means a diluent, excipient, vehicle, or mediator that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio. "Pharmaceuticalally acceptable carrier" includes, but is not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0080] The terms "administration" or "giving" refer to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral or parenteral administration (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, and intravascular injection or infusion), local administration, and rectal administration. In particular, injection or oral administration.

[0081] As used in this article, the term "prevention" includes suppressing and delaying the onset of disease, and includes not only prevention before the development of disease, but also prevention of recurrence of disease after treatment.

[0082] As used in this article, the term “treatment” means to reverse, alleviate or eliminate the progression of one or more symptoms of a condition or illness to which such term is applied.

[0083] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat or prevent a target disorder, disease, or symptom.

[0084] For the purposes of pharmaceuticals, pharmaceutical units, or active ingredients, the terms "effective amount," "therapeutic effective amount," or "preventive effective amount" refer to a sufficient quantity of a drug or agent that provides acceptable side effects while achieving the desired therapeutic effect. The determination of the effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0085] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this disclosure, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0086] The term "room temperature" refers to a temperature ranging from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature ranging from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature ranging from 18°C ​​to 25°C.

[0087] "Equivalent" or its abbreviation "eq" is the equivalent amount of other raw materials required based on the equivalence relationship of a chemical reaction, using the basic raw materials used in each step as a reference (1 equivalent).

[0088] The abbreviations "Int" or "int" mentioned in this article refer to intermediates. "NaH" refers to sodium hydride. "DMF" refers to N,N-dimethylformamide. "THF" refers to tetrahydrofuran. "TFA" refers to trifluoroacetic acid. "DCM" refers to dichloromethane. "DMSO-I" refers to trimethyl sulfoxide. "NaOH" refers to sodium hydroxide. "K2CO3" refers to potassium carbonate. "TEA" refers to triethylamine. "NaOtBu" refers to sodium tert-butoxide. "TTZ" refers to tetrazolium. "MSA" is mesylate. "(Ms)2O" is mesylate anhydride. "MTBE" refers to methyl tert-butyl ether. "Pd(dppf)Cl2" refers to [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride. "Pd / C" refers to palladium on carbon. "Pd2(dba)3" refers to tris(dibenzylacetone)dipalladium. “BINAP” refers to S-(-)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine). “Tol” refers to toluene. “Na(OAc)3BH” refers to sodium triacetylborohydride. “AcOH” refers to acetic acid. “(PPh3)2PdCl2” refers to palladium dichloride bis(triphenylphosphine). “Na2CO3” refers to sodium carbonate. “MeCN” refers to acetonitrile. “PPh3” refers to triphenylphosphine. “DIAD” refers to diisopropyl azodicarbonate. “NMP” refers to N-methylpyrrolidone. “EtOH” refers to ethanol. “Boc” refers to tert-butyloxycarbonyl.

[0089] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other skilled in the art to more fully understand the technical solutions, principles, and practical applications of this disclosure, so that other skilled in the art can modify and implement this disclosure in many forms to best suit the requirements of a particular application.

[0090] compound

[0091] This disclosure provides compounds of formula (I-1) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs thereof:

[0092] in,

[0093] Ring A is C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic;

[0094] Ring B is C 3-8 Monocyclic cycloalkane rings or 4-14 membered nitrogen-containing heterocycles;

[0095] Ring C does not exist, or it is C. 6-10 aryl, 5-10 heteroaryl, 4-10 heterocyclic, or C 6-10 Aryl benzo[C] 3-8 cycloalkyl;

[0096] X does not exist, or is a key, -C 0-6 Alkylene-OC 0-6 alkylene-, -C 0-6 Alkylene-SC 0-6 alkylene-, -C 0-6 Alkylene-NR A -C 0- 6-alkylene-, -C 0-6 Alkylene-Se-C 0-6 alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, C 2-12 imidene group, C 2-12 Ethyne group, C 1- 12 Alkylene, wherein the alkylene, alkenylene, or alkyneyl group is optionally selected independently from one or more of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substituents of cycloalkyl groups;

[0097] R1 and R2 are each independently hydrogen, deuterium, halogen, cyano, nitro, or C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A RB -OC 0-6 Alkylene-R C or -SC 0-6 Alkylene-R C Alternatively, R1 and R2, together with the carbon atoms they are attached to, form C. 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0098] R3 is -C 0-6 Alkylene-NR A R B or -C 0-6 Alkylene-OR C Alternatively, one of R1 and R2 and R3 together with the carbon atom to which they are attached form a 3-8 membered heterocyclic group;

[0099] R4, R5, and R6 are each independently hydrogen, deuterium, halogen, cyano, nitro, oxo, carboxyl, -SF5, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 1-12 Halogenated alkyl groups, -OC 0-12 Alkylene-R C -SC 0-12 Alkylene-R C -S(O)2R C -C(O)NR A R B -P(O)R A R B -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10 heteroaryl, -C 0-6 Alkylene-C 3-8 cycloalkyl, -C 0-6 alkylene-4-10-membered heterocyclic groups, or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected independently by one or more groups selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Hydroxyalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12Alkylthio, C 1-12 alkylamine group, C 3-8 cycloalkyl, -CONR A R B -P(O)R A R B -COR C -S(O)2R C Substituents are substituted; p is 0, 1, 2, 3, 4 or 5;

[0100] R7 and R8 are independently hydrogen, deuterium, halogen, cyano, nitro, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 0-6 Alkylene-R C or -SC 0-6 Alkylene-R C Alternatively, R7 and R8, together with the carbon atoms they are bonded to, form C. 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0101] m, n, and o are each independently 0, 1, 2, 3, 4, or 5;

[0102] R A and R B Each independently is hydrogen, C 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0103] R C Each is independently hydrogen, deuterium, and C. 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0104] In some implementations, in equation (I-1),

[0105] Ring A is C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic;

[0106] Ring B is C 3-8 Monocyclic cycloalkane rings or 4-14 membered nitrogen-containing heterocycles;

[0107] Ring C does not exist, or it is C. 6-10aryl, 5-10 heteroaryl, 4-10 heterocyclic, or C 6-10 Aryl benzo[C] 3-8 cycloalkyl;

[0108] X does not exist, or is a key, -C 0-6 Alkylene-OC 0-6 alkylene-, -C 0-6 Alkylene-SC 0-6 alkylene-, -C 0-6 Alkylene-NR A -C 0- 6-alkylene-, -C 0-6 Alkylene-Se-C 0-6 alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, C 2-12 imidene group, C 2-12 Ethyne group, C 1- 12 Alkylene, wherein the alkylene, alkenylene, or alkyneyl group is optionally selected independently from one or more of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substituents of cycloalkyl groups;

[0109] R1 and R2 are each independently hydrogen, deuterium, halogen, cyano, nitro, or C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 0-6 Alkylene-R C or -SC 0-6 Alkylene-R C Alternatively, R1 and R2, together with the carbon atoms they are attached to, form C. 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0110] R3 is -C 0-6 Alkylene-NR A R B or -C 0-6 Alkylene-OR C Alternatively, one of R1 and R2 and R3 together with the carbon atom to which they are attached form a 3-8 membered heterocyclic group;

[0111] R4, R5, and R6 are each independently hydrogen, deuterium, halogen, cyano, nitro, oxo, -SF5, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2- 12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 1-12 Halogenated alkyl groups, -OC 0-12 Alkylene-R C -SC 0-12 Alkylene-R C -S(O)2R C -C(O)NR A R B -P(O)R A R B -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10 heteroaryl, -C 0-6 Alkylene-C 3-8 cycloalkyl, -C 0-6 alkylene-4-10-membered heterocyclic groups, or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected independently by one or more groups selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Hydroxyalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 cycloalkyl, -CONR A R B -P(O)R A R B -COR C -S(O)2R C Substituents are substituted; p is 0, 1, 2, 3, 4 or 5;

[0112] R7 and R8 are independently hydrogen, deuterium, halogen, cyano, nitro, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NRA R B -OC 0-6 Alkylene-R C or -SC 0-6 Alkylene-R C Alternatively, R7 and R8, together with the carbon atoms they are bonded to, form C. 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0113] m, n, and o are each independently 0, 1, 2, 3, 4, or 5;

[0114] R A and R B Each independently is hydrogen, C 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0115] R C Each is independently hydrogen, deuterium, and C. 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0116] In some implementations, ring B is a 4-14 member nitrogen-containing heterocycle.

[0117] In some embodiments, ring B is a 4-14 member nitrogen-containing heterocycle with the following structure: The left end of ring B is connected to X in the general formula, and the right end is connected to -C(R1)(R2)-.

[0118] In some implementations, in equation (I-1),

[0119] Ring A is C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic;

[0120] Ring B is C 3-8 Monocyclic cycloalkane rings or 4-14 membered nitrogen-containing heterocycles;

[0121] Ring C does not exist, or it is C. 6-10 aryl, 5-10 heteroaryl, 4-10 heterocyclic, or C 6-10 Aryl benzo[C] 3-8 cycloalkyl;

[0122] X does not exist, or is a key, -C 0-6 Alkylene-OC 0-6 alkylene-, -C 0-6 Alkylene-SC0-6 alkylene-, -C 0-6 Alkylene-NR A -C 0- 6-alkylene-, -C 0-6 Alkylene-Se-C 0-6 alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, C 2-12 imidene group, C 2-12 Ethyne group, C 1- 12 Alkylene, wherein the alkylene, alkenylene, or alkyneyl group is optionally selected independently from one or more of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substituents of cycloalkyl groups;

[0123] R1 and R2 are each independently hydrogen, deuterium, halogen, cyano, nitro, or C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 0-6 Alkylene-R C or -SC 0-6 Alkylene-R C Alternatively, R1 and R2, together with the carbon atoms they are attached to, form C. 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0124] R3 is -C 0-6 Alkylene-NR A R B or -C 0-6 Alkylene-OR C Alternatively, one of R1 and R2 and R3 together with the carbon atom to which they are attached form a 3-8 membered heterocyclic group;

[0125] R4, R5, and R6 are each independently hydrogen, deuterium, halogen, cyano, nitro, oxo, -SF5, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2- 12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC1-12 Halogenated alkyl groups, -OC 0-12 Alkylene-R C -SC 0-12 Alkylene-R C -S(O)2R C -C(O)NR A R B -P(O)R A R B -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10 heteroaryl, -C 0-6 Alkylene-C 3-8 cycloalkyl, -C 0-6 alkylene-4-10-membered heterocyclic groups, or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected independently by one or more groups selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Hydroxyalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 cycloalkyl, -CONR A R B -P(O)R A R B Substituents are substituted; p is 0, 1, 2, 3, 4 or 5;

[0126] R7 and R8 are independently hydrogen, deuterium, halogen, cyano, nitro, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 0-6 Alkylene-R C or -SC 0-6 Alkylene-R C Alternatively, R7 and R8, together with the carbon atoms they are bonded to, form C. 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0127] m, n, and o are each independently 0, 1, 2, 3, 4, or 5;

[0128] R A and R B Each independently is hydrogen, C 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0129] R C Each is independently hydrogen, deuterium, and C. 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0130] In some embodiments, this application provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof:

[0131] in,

[0132] Ring A is C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic;

[0133] Ring B is a 4-14 member nitrogen-containing heterocycle;

[0134] Ring C does not exist, or it is C. 6-10 aryl, 5-10 heteroaryl, 4-10 heterocyclic, or C 6-10 Aryl benzo[C] 3-8 cycloalkyl;

[0135] X does not exist, or is a key, -C 0-6 Alkylene-OC 0-6 alkylene-, -C 0-6 Alkylene-SC 0-6 alkylene-, -C 0-6 Alkylene-NR A -C 0- 6-alkylene-, -C 0-6 Alkylene-Se-C 0-6 alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, C 2-12 imidene group, C 2-12 Ethyne group, C 1- 12Alkylene, wherein the alkylene, alkenylene, or alkyneyl group is optionally selected independently from one or more of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substituents of cycloalkyl groups;

[0136] R1 and R2 are each independently hydrogen, deuterium, halogen, cyano, nitro, or C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 0-6 Alkylene-R C or -SC 0-6 Alkylene-R C Alternatively, R1 and R2, together with the carbon atoms they are attached to, form C. 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0137] R3 is -C 0-6 Alkylene-NR A R B or -C 0-6 Alkylene-OR C Alternatively, one of R1 and R2 and R3 together with the carbon atom to which they are attached form a 3-8 membered heterocyclic group;

[0138] R4, R5, and R6 are each independently hydrogen, deuterium, halogen, cyano, nitro, oxo, -SF5, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2- 12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 1-12 Halogenated alkyl groups, -OC 0-12 Alkylene-R C -SC 0-12 Alkylene-R C -S(O)2R C -C(O)NR A R B -P(O)R A R B -C 0-6 Alkylene-C 6-10 Aryl, -C0-6 alkylene-5-10 heteroaryl, -C 0-6 alkylene-4-10-membered heterocyclic groups, or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, and heteroaryl groups are optionally selected independently by one or more groups selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substituents of cycloalkyl groups; p is 0, 1, 2, 3, 4 or 5;

[0139] R7 and R8 are independently hydrogen, deuterium, halogen, cyano, nitro, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 0-6 Alkylene-R C or -SC 0-6 Alkylene-R C Alternatively, R7 and R8, together with the carbon atoms they are bonded to, form C. 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0140] m, n, and o are each independently 0, 1, 2, 3, 4, or 5;

[0141] R A and R B Each independently is hydrogen, C 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0142] R C Each is independently hydrogen, deuterium, and C. 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0143] In some implementations, ring C does not exist, and X does not exist.

[0144] In some implementations, ring C is C 6-10 aryl, 5-10 heteroaryl, 4-10 heterocyclic, or C 6-10 Aryl benzo[C] 3-8 cycloalkyl; X is a bond, -C 0-6 Alkylene-OC 0-6 alkylene-, -C 0-6 Alkylene-SC 0-6 alkylene-, -C 0-6 Alkylene-NR A -C 0-6 alkylene-, -C 0-6 Alkylene-Se-C 0-6 alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, C 2-12 imidene group, C 2-12 Ethyne group, C 1-12 Alkylene, wherein the alkylene, alkenylene, or alkyneyl group is optionally selected independently from one or more of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substitution of cycloalkyl groups.

[0145] In some implementations, ring A is C 6-10 Aryl or 5-10 heteroaryl compounds.

[0146] In some embodiments, ring A is phenyl, naphthyl, pyridyl, quinolinyl, imidazopyridyl, indolyl, or thiophenyl.

[0147] In some embodiments, ring A is a phenyl group.

[0148] In some embodiments, ring A is a phenyl group.

[0149] In some implementations, ring B is C. 3-8 Monocyclic cycloalkane rings, 4-8 member nitrogen-containing monocyclic heterocycles, 6-14 member nitrogen-containing spirocyclic heterocycles, 6-14 member nitrogen-containing fused heterocycles, or 6-14 member nitrogen-containing bridged heterocycles.

[0150] In some implementations, ring B is C 3-8 Monocyclic cycloalkane rings, such as cyclohexane.

[0151] In some embodiments, ring B is a 4-8 member nitrogen-containing monocyclic heterocycle, a 6-14 member nitrogen-containing spirocyclic heterocycle, a 6-14 member nitrogen-containing fused heterocycle, or a 6-14 member nitrogen-containing bridged heterocycle.

[0152] In some embodiments, ring B is a nitrogen-containing heterocyclic ring, and at least the rings bonded to the carbon atoms connected to R1 / R2 are not aromatic. In further embodiments, none of the rings in ring B are aromatic.

[0153] In some embodiments, the ring in ring B that is immediately adjacent to the carbon atom connected to R1 / R2 is not an aromatic ring.

[0154] In some implementations, ring B is a 4-14 member saturated nitrogen-containing heterocycle.

[0155] In some implementations, ring B is (For example ),

[0156] In some implementations, ring B is (For example ), Or for The wavy lines represent the connection sites between the nitrogen atom in ring B and the carbon atoms connected to R1 and R2, and the connection sites with X (if present) in the general formula are not shown.

[0157] In some implementations... for (For example ), The wavy lines represent the connection sites between the nitrogen atom in ring B and the carbon atoms connected to R1 and R2, and the connection sites with X (if present) in the general formula are not shown.

[0158] In some implementations, ring B is (For example ), The wavy lines represent the connection points between the nitrogen atom in ring B and the carbon atoms connected to R1 and R2, and the connection sites with X (if present) in the general formula are not shown.

[0159] In some implementations, ring C does not exist, X does not exist, and ring B is...

[0160] In some implementations, ring C does not exist, X does not exist, and ring B is...

[0161] In some implementations, ring C exists, X exists, and ring B is... (For example ), (For example ), Unless otherwise defined, the ring B listed herein can be connected to the rest of the general formula in any direction. In some embodiments, the left end of the ring B listed herein is connected to X in the general formula, and the right end is connected to -C(R1)(R2)-.

[0162] In some implementations, ring C exists, X exists, and ring B is... (For example ), (For example ),

[0163] In some implementations, ring B is

[0164] In some implementations, ring B is

[0165] In some implementations, ring C exists, X exists, and ring B is... Where n1, n2, n3, and n4 are each independently 1, 2, or 3. This indicates a single or double bond. In a further embodiment, when n1, n2, n3, or n4 is 2 or 3, two repeating -CH2- units can form a carbon-carbon double bond.

[0166] In some implementations, ring C exists, X exists, and ring B is... Where n1 and n2 are each independently 1, 2 or 3.

[0167] In some implementations, ring C exists, X exists, and ring B is...

[0168] In some implementations, ring C is C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclic, or benzo[a]C 3-6 Cycloalkyl.

[0169] In some implementations, ring C is C 6-10 Aryl, 5-10 heteroaryl or 5-10 heterocyclic.

[0170] In some embodiments, the ring C is a phenyl, a 5-10 membered heteroaryl, or a 6-membered heterocyclic group.

[0171] In some implementations, ring C is C 6-10 Aryl or 5-10 heteroaryl compounds.

[0172] In some embodiments, the ring C is a phenyl or a 5-6 membered heteroaryl group.

[0173] In some embodiments, the ring C is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolopyridinyl, imidazopyridinyl, benzoxazolyl, benzopyrazolyl, pyrazolyl, pyridinoneyl, pyridazinyl, benzocyclopentyl, tetrahydropyranyl, piperidinyl, naphthyl, benzodihydropyranyl, triazolopyrimidinyl, imidazopyridazinyl, thiadiazoyl, imidazopyrazinyl, or oxadiazolyl.

[0174] In some embodiments, the ring C is phenyl, pyridinyl, pyrimidinyl, benzoxazolyl, benzopyrazolyl, pyrazolyl, pyridoneyl, pyridazinyl, benzocyclopentyl, tetrahydropyranyl, piperidinyl, naphthyl, benzodihydropyranyl, triazolopyrimidinyl, imidazopyridazinyl, thiadiazoyl, imidazopyrazinyl, or oxadiazolyl.

[0175] In some embodiments, the ring C is phenyl, pyridinyl, pyrimidinyl, benzoxazolyl, benzopyrazolyl, pyrazolyl, pyridoneyl, pyridazinyl, benzocyclopentyl, tetrahydropyranyl, piperidinyl, naphthyl, benzodihydropyranyl, or triazolylpyrimidinyl.

[0176] In some embodiments, the ring C is phenyl, pyridinyl, pyrimidinyl, benzoxazolyl, benzopyrazolyl, pyrazolyl, pyridoneyl, pyridazinyl, benzocyclopentyl, tetrahydropyranyl, piperidinyl, naphthyl, or benzodihydropyranyl.

[0177] In some embodiments, the ring C is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzopyrazolyl, pyrazolyl, pyridoneyl, pyridazinyl, piperidinyl, triazolopyrimidinyl, imidazopyrazinyl, thiadiazolyl, imidazopyrazinyl, or oxadiazolyl.

[0178] In some embodiments, the ring C is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, or imidazopyridazinyl.

[0179] In some embodiments, the ring C is phenyl,

[0180] In some embodiments, the ring C is phenyl,

[0181] In some embodiments, the ring C is phenyl,

[0182] In some embodiments, the ring C is phenyl.

[0183] When describing the structure of ring A, ring B, or ring C, the connection sites indicated are the connection sites between each ring and other parts of the general skeleton, and the connection sites between each ring and substituents on the ring (such as R4, R5, or R6) are not indicated.

[0184] In some implementations, X is a key, -C 0-6 Alkylene-OC 0-6 alkylene-, -C 0-6 Alkylene-SC 0-6 alkylene-, -C 0-6 Alkylene-NR A -C 0-6 alkylene-, -C 0-6 Alkylene-Se-C 0-6 alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, C 2-12 imidene group, C 2-12 etyne group, or C 1-12Alkylene, wherein the alkylene, alkenylene, or alkyneyl group is optionally selected independently from one or more of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substitution of cycloalkyl groups.

[0185] In some implementations, X is a key, -C 0-3 Alkylene-OC 0-3 alkylene-, -C 0-3 Alkylene-SC 0-3 alkylene-, -C 0-3 Alkylene-NR A -C 0-3 alkylene-, -C 0-3 Alkylene-Se-C 0-3 alkylene-, -C 0-3 Alkylene-C(O)-C 0-3 Alkylene-, C 2-4 imidene group, C 2-4 etyne group, or C 1-4 Alkylene, wherein the alkylene, alkenylene, or alkyneyl group is optionally selected independently from one or more of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substitution of cycloalkyl groups.

[0186] In some implementations, X represents bond, O, S, NH, N (C) 1-6 Alkyl), Se, C 2-4 Ethyne group, C 1-4 alkylene, carbonyl, or -C 0-3 Alkylene-OC 0-3 Alkylene-.

[0187] In some embodiments, X is a bond, O, S, NH, ethynyl, methylene, carbonyl, -CH2-O-, -O-CH2-, Se, -N(CH3)-, or -CH(CH3)-.

[0188] In some embodiments, X is a bond, O, S, methylene, -O-CH2-, or NH.

[0189] In some implementations, X is a bond, O, or NH.

[0190] In some embodiments, R1 and R2 are each independently hydrogen, deuterium, halogen, or C. 1-12 Alkyl (e.g., C) 1-6 Alkyl or C 1-3 Alkyl group). In some embodiments, both R1 and R2 are hydrogen; or one is hydrogen and the other is methyl.

[0191] In some embodiments, R1 and R2 together with the carbon atoms they are attached to form C 3-6 Cycloalkyl.

[0192] In some implementations, R3 is -C 0-3 Alkylene-NR A R B or -C 0-3 Alkylene-OR C .

[0193] In some implementations, R3 is -C 0-3 Alkylene-OR C .

[0194] In some implementations, R3 is -C 0-3 Alkylene-OH.

[0195] In some embodiments, R3 is a hydroxyl group or a hydroxymethyl group.

[0196] In some implementations, one of R1 and R2 and R3 together with the carbon atom to which they are attached form a 4-6 membered heterocyclic group.

[0197] In some embodiments, one of R1 and R2 and R3 together with the carbon atom to which they are attached form a 4-6 member oxygen-containing heterocyclic group, such as a tetrahydrofuran group.

[0198] In some embodiments, one of R1 and R2 is hydrogen, and the other is C. 1-12 Alkyl (e.g., methyl, ethyl).

[0199] In some embodiments, R4 is independently hydrogen, deuterium, halogen, cyano, or C. 1-12 Alkyl, -C(O)NR A R B (For example, -CONH2, -CONH(C) 1-6 alkyl) and -CON(C) 1-6 Alkyl)2), C 1-12Alkyl group, or -SF5.

[0200] In some implementations, m is 2, and R4 is each independently a halogen, such as fluorine or chlorine, for example, fluorine.

[0201] In some implementation schemes, It is 2,4-difluorophenyl.

[0202] In some embodiments, R5 is independently hydrogen, deuterium, halogen, oxo group, or C. 1-12 Alkyl, -OC 0-12 Alkylene-R C 、or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl group or alkylene group is optionally selected independently from one or more groups selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substitution of cycloalkyl groups.

[0203] In some embodiments, R5 is independently hydrogen, deuterium, halogen, oxo group, or C. 1-12 Alkyl, -OC 0-12 Alkylene-R C 、or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl group or alkylene group is optionally selected independently from one or more groups selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substituents of cycloalkyl groups;

[0204] R C Selected from hydrogen, C 1-12 Alkyl, C 1-12 Halogenated alkyl groups;

[0205] p is 0, 1, or 2.

[0206] In some embodiments, R5 is independently hydrogen, deuterium, halogen, oxo group, methyl, hydroxyl, or -OC. 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkylene group is optionally replaced by one or more halogens;

[0207] R C Selected from hydrogen, C 1-12 Alkyl, C 1-12 Halogenated alkyl groups;

[0208] p is 0, 1, or 2.

[0209] In some embodiments, R5 is independently hydrogen, deuterium, halogen, oxo group, or C. 1-12 Alkyl, or C 1-12 Alkyl group.

[0210] In some implementations, R5 is independently hydrogen, deuterium, hydroxyl, halogen such as fluorine, or chlorine.

[0211] In some implementations, R5 is either hydrogen or fluorine.

[0212] In some embodiments, R6 is independently hydrogen, deuterium, halogen, cyano, oxo, hydroxyl, carboxyl, or C. 1-12 Alkyl, -OC 1-12 Alkyl, -OC 1-12 Halogenated alkyl groups, -OC 0-6 Alkylene-C 6-10 Aryl, -OC 0-6 alkylene-5-10 heteroaryl, -OC 0-6 Alkylene-C 3-8 cycloalkyl, -OC 0-6 Alkyl-4-6-membered heterocyclic group, -C 0-6 Alkylene-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 heterocyclic group, -C 0- 6-alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10-membered heteroaryl, -S(O)2R C -P(O)R A R B 、or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR CThe alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected independently by one or more halogens, hydroxyl groups, cyano groups, nitro groups, oxo groups, and C6 groups. 1-12 Alkyl, C 1-12 Hydroxyalkyl, C 1-12 Alkoxy, C 1-12 Haloalkyl, C 1-12 Halogenated alkoxy groups, -CONR A R B -P(O)R A R B -COR C -S(O)2R C Substituents of R; preferably, wherein R C Each independently is hydrogen, C 1-12 Alkyl or C 1-12 Halogenated alkyl groups.

[0213] In some embodiments, R6 is independently hydrogen, deuterium, halogen, cyano, oxo, hydroxyl, C 1-12 Alkyl, -OC 1-12 Alkyl, -OC 1-12 Halogenated alkyl groups, -OC 0-6 Alkylene-C 6-10 Aryl, -OC 0-6 alkylene-5-10 heteroaryl, -OC 0-6 Alkylene-C 3-8 cycloalkyl, -OC 0-6 Alkyl-4-6-membered heterocyclic group, -C 0-6 Alkylene-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 heterocyclic group, -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10-membered heteroaryl, -S(O)2R C -P(O)R A R B 、or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected independently by one or more halogens, hydroxyl groups, cyano groups, nitro groups, oxo groups, and C6 groups. 1-12 Alkyl, C 1-12 Hydroxyalkyl, C 1-12 Alkoxy, C 1-12 Haloalkyl, C 1-12 Halogenated alkoxy groups, -CONR AR B -P(O)R A R B -COR C -S(O)2R C Substituents of R; preferably, wherein R C Each independently is hydrogen, C 1-12 Alkyl or C 1-12 Halogenated alkyl groups.

[0214] In some embodiments, R6 is independently hydrogen, deuterium, halogen, cyano, oxo, hydroxyl, carboxyl, or C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, -OC 1-12 Alkyl, -OC 1-12 Halogenated alkyl groups, -OC 0-6 Alkylene-C 6-10 Aryl, -OC 0-6 alkylene-5-10 heteroaryl, -OC 0-6 Alkylene-C 3-8 cycloalkyl, -OC 0-6 Alkyl-4-6-membered heterocyclic group, -C 0-6 Alkylene-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 heterocyclic group, -C 0-6 Alkylene-C 6-10 Aryl, 5-10 heteroaryl, -S(O)2R C -P(O)R A R B 、or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected independently by one or more halogens, hydroxyl groups, cyano groups, nitro groups, oxo groups, and C6 groups. 1-12 Alkyl, C 1-12 Hydroxyalkyl, C 1-12 Alkoxy, C 1-12 Haloalkyl, C 1-12 Halogenated alkoxy groups, -CONR A R B -P(O)R A R B -COR C -S(O)2R C Substituents of the substituents;

[0215] Each R A and R B Independently hydrogen or methyl;

[0216] Each R C It can be hydrogen, methyl, ethyl, or trifluoromethyl independently;

[0217] p is 0, 1, or 2.

[0218] In some embodiments, R6 is independently hydrogen, deuterium, halogen, cyano, oxo, hydroxyl, C 1-12 Alkyl, -OC 1-12 Alkyl, -OC 1-12 Halogenated alkyl groups, -OC 0-6 Alkylene-C 6-10 Aryl, -OC 0-6 alkylene-5-10 heteroaryl, -OC 0-6 Alkyl-4-6-membered heterocyclic group, -C 0-6 Alkylene-C 3-8 cycloalkyl, -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10-membered heteroaryl, -S(O)2R C -P(O)R A R B 、or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected independently by one or more halogens, hydroxyl groups, cyano groups, nitro groups, oxo groups, and C6 groups. 1-12 Alkyl, C 1-12 Hydroxyalkyl, C 1- 12 Alkoxy, C 1-12 Haloalkyl, C 1-12 Halogenated alkoxy groups, -CONR A R B -P(O)R A R B Substituents of R; preferably, wherein R C Each independently is hydrogen, C 1-12 Alkyl or C 1-12 Halogenated alkyl groups.

[0219] In some embodiments, R6 is independently hydrogen, deuterium, halogen, cyano, oxo, hydroxyl, C 1-12 Alkyl, -OC 1-12 Alkyl, -OC 1-12 Halogenated alkyl groups, -OC 0-6 Alkylene-C 6-10 Aryl, -OC0-6 alkylene-5-10 heteroaryl, -OC 0-6 Alkyl-4-6-membered heterocyclic group, -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10-membered heteroaryl, -P(O)R A R B 、or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, and heteroaryl groups are optionally selected independently by one or more halogens, hydroxyl groups, cyano groups, nitro groups, oxo groups, and C6 groups. 1-12 Hydroxyalkyl, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Haloalkyl, C 1-12 Halogenated alkoxy groups, -CONR A R B Substituents are substituted.

[0220] In some embodiments, R6 is independently hydrogen, deuterium, halogen, cyano, oxo, hydroxyl, C 1-12 Alkyl, -OC 1-12 Alkyl, -OC 1-12 Halogenated alkyl groups, -OC 0-6 Alkylene-C 6-10 Aryl, -OC 0-6 alkylene-5-10 heteroaryl, -OC 0-6 Alkyl-4-6-membered heterocyclic group, -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10-membered heteroaryl, -P(O)R A R B 、or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, and heteroaryl groups are optionally selected independently by one or more halogens, hydroxyl groups, cyano groups, nitro groups, oxo groups, and C6 groups. 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Haloalkyl, C 1-12 Halogenated alkoxy groups, -CONR A R B Substituents are substituted.

[0221] In some implementations, R A and RB Each is independently hydrogen or C 1-12 alkyl.

[0222] In some implementations, R C Each independently is hydrogen, C 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 cycloalkyl, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0223] In some implementations, p is 0, 1, 2, or 3.

[0224] In some implementations, m, n, and o are each independently 0, 1, 2, 3, or 4.

[0225] In some implementations, R7 and R8 are each independently hydrogen, deuterium, or C. 1-12 alkyl.

[0226] In some implementations, R7 and R8 together with the carbon atoms they are attached to form C 3-6 Cycloalkyl.

[0227] In some implementations, both R7 and R8 are hydrogen.

[0228] In some embodiments, the compounds of this disclosure contain one or more asymmetric centers, thereby enabling them to exist in the form of racemic derivatives, racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers.

[0229] In some embodiments, the compounds disclosed herein are compounds of formula (IA) or formula (IB), or mixtures thereof:

[0230] Among them, rings A, B, C, X, R1, R2, R3, R4, R5, R6, R7, R8, m, n and o are as defined in the preceding term.

[0231] In some embodiments, the compounds disclosed herein are compounds of formula (IA).

[0232] In some embodiments, the compounds disclosed herein are further compounds as shown in formula (II), preferably compounds of formula (IIA):

[0233] Among them, rings A, B, C, X, R4, R5, R6, R7, R8, m, n and o are as defined in the preceding term.

[0234] In some embodiments, the compounds disclosed herein are further compounds as shown in formula (III), preferably compounds of formula (IIIA):

[0235] Among them, rings A, B, C, X, R4, R5, R6, R7, R8, m, n and o are as defined in the preceding term.

[0236] In some embodiments, the compounds disclosed herein are further compounds as shown in formula (IV), preferably compounds of formula (IVA):

[0237] Among them, rings B, C, X, R4, R5, R6, R7, R8, m, n, and o are as defined in the preceding term.

[0238] In some embodiments, the compounds disclosed herein are further compounds as shown in formula (V), preferably compounds of formula (VA):

[0239] Among them, rings B, C, X, R4, R5, R6, R7, R8, m, n, and o are as defined in the preceding term.

[0240] In some embodiments, the compounds disclosed herein are further compounds as shown in formula (VI), preferably compounds of formula (VIA):

[0241] Among them, rings B, C, X, R4, R5, R6, m, n, and o are as defined in the preceding term.

[0242] In some embodiments, the compounds disclosed herein are further compounds as shown in formula (VII), preferably compounds of formula (VIIA):

[0243] Among them, rings B, C, X, R4, R5, R6, m, n, and o are as defined in the preceding term.

[0244] In some embodiments of formulas (I-1), (I), (IA), (IB), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI), (VIA), (VII), and (VIIA) of this disclosure, ring A is C. 6-10 Aryl or 5-10 membered heteroaryl, ring B is a 4-14 membered saturated nitrogen-containing heterocycle, and ring C is C 6-10 Aryl or 5-10 heteroaryl, where X is a bond, O or NH.

[0245] In some embodiments, the compounds disclosed herein are further compounds as shown in formula (VIII):

[0246] Among them, ring A, ring B, R1, R2, R3, R4, R5, R7, R8, m, and n are as defined in the previous term.

[0247] In some embodiments, the compounds disclosed herein are further compounds as shown in formula (I-B1) or formula (I-B2):

[0248] Among them, rings A, C, X, R1, R2, R3, R4, R5, R6, R7, R8, m, n, o, n1, n2, n3 and n4 are as defined in the preceding term.

[0249] In some embodiments of formulas (I-B1) and (I-B2) of this disclosure, ring A is C. 6-10 Aryl or 5-10 heteroaryl, with ring C being C 6-10 Aryl or 5-10 heteroaryl, where X is a bond, O or NH.

[0250] In some embodiments, the compounds disclosed herein are selected from:

[0251] This disclosure covers compounds obtained by any combination of various embodiments. Embodiments obtained by combining technical features or preferred technical features from one embodiment with technical features or preferred technical features from another embodiment are also included within the scope of this disclosure.

[0252] Preparation method

[0253] In some embodiments, a method for preparing the compound of formula (IV) is provided, comprising one or more of the following steps:

[0254] Among them, rings B, C, X, R4, R5, R6, R7, R8, m, n, and o are as defined in the preceding term.

[0255] In some embodiments, a method for preparing the compound of disclosure (VIIA) is provided, comprising one or more of the following steps:

[0256] Among them, rings B, C, X, R4, R5, R6, m, n, and o are as defined in the preceding term.

[0257] The preparation method described herein can use commercially available raw materials and synthesize them using known methods. The reaction conditions for each step can be those conventional for such reactions in the art.

[0258] intermediate

[0259] In some embodiments, compounds of formulas (IV-2), (IV-3), (IV-4), (VIIA-2), (VIIA-3), (VIIA-4), and (VIIA-5) or their salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, and isotopically labeled compounds are provided, wherein ring B, ring C, X, R4, R5, R6, R7, R8, m, n, and o are as defined in any of the preceding claims.

[0260] The compounds shown in formulas (IV-2), (IV-3), (IV-4), (VIIA-2), (VIIA-3), (VIIA-4), and (VIIA-5) above, or their salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, or isotopically labeled compounds, can be used to prepare the compounds shown in the general formulas herein, or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs.

[0261] Pharmaceutical Compositions and Kits

[0262] Another aspect of this disclosure provides a pharmaceutical composition comprising a preventive and / or therapeutically effective amount of the compound of this disclosure or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

[0263] Another aspect of this disclosure provides a kit comprising a compound of the disclosure or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, or a pharmaceutical composition of the disclosure.

[0264] In some embodiments, the kit may further comprise instructions for administering the compound of the present disclosure or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, or a pharmaceutical composition of the present disclosure.

[0265] In some embodiments, the pharmaceutical composition may be a pharmaceutical formulation, such as a solid dosage form, a semi-solid dosage form, a liquid dosage form, or a gaseous dosage form. The solid dosage form may be, for example, a tablet, capsule, powder, granule, or suppository, while the liquid dosage form may be, for example, a solution, suspension, or injection. The composition may also be a dosage form such as liposomes or microspheres.

[0266] In some embodiments, the content or amount of the aforementioned compound in the pharmaceutical composition or pharmaceutical preparation may be from about 0.01 mg to about 1000 mg.

[0267] The pharmaceutical compositions disclosed herein can act systemically and / or locally. For this purpose, they can be administered via suitable routes, such as by injection (e.g., intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including infusion) or transdermal administration; or by oral, sublingual, nasal, transmucosal, topical, ophthalmic formulations or by inhalation.

[0268] In some embodiments, this disclosure provides a method for preparing a pharmaceutical composition of the present disclosure, the method comprising combining a compound of the present disclosure or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof with one or more pharmaceutically acceptable carriers.

[0269] Treatment methods and uses

[0270] Another aspect of this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites or prodrugs thereof, or pharmaceutical compositions of the disclosure, for the prevention and / or treatment of diseases, particularly CYP51-mediated diseases.

[0271] Another aspect of this disclosure provides the use of the compounds of this disclosure or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs, or pharmaceutical compositions of this disclosure, in the preparation of medicaments for the prevention and / or treatment of CYP51-mediated diseases.

[0272] Another aspect of this disclosure provides a method for preventing and / or treating CYP51-mediated diseases, comprising administering to an individual in need a preventive or therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, or a pharmaceutical composition of this disclosure.

[0273] In some embodiments, the CYP51-mediated disease is a fungal infection. In some embodiments, the fungal infection is an invasive fungal infection.

[0274] In some embodiments, the CYP51-mediated disease is associated with one or more of the following pathogenic fungal genera, including those genera and species herein: *Absidia corymbifera*, *Ajellomyces capsulatus*, *Ajellomyces dermatitidis*, *Arthroderma benhamiae*, *Arthroderma fulvum*, *Arthroderma gypseum*, *Arthroderma incurvatum*, *Arthroderma otae*, *Arthroderma vanbreuseghemii*, *Aspergillus flavus*, *Aspergillus fumigatus*, *Aspergillus niger*, *Blastomyces dermatitidis*, and *Candida albicans*. Candida albicans, Candida glabrata, Candida guilliermondii, Candida krusei, Candida parapsilosis, Candida tropicalis, Candida pelliculosa, Cladophialophora carrionii, Coccidioides immitis, Cryptococcus neoformans, Cunninghamella sp., Epidermophyton floccosum, Exophiala dermatitidis, Filobasidiella neoformans, Fonsecaea pedrosoi, Fusarium solani, Geotrichum *Candida candidum*, *Histoplasma capsulatum*, *Hortaea werneckii*, *Issatschenkia**Malassezia orientalis*, *Madurella grisae*, *Malassezia fur fur*, *Malassezia globosa*, *Malassezia obtusa*, *Malassezia pachydermatis*, *Malassezia restricta*, *Malassezia slooffiae*, *Malassezia sympodialis*, *Microsporum canis*, *Microsporum fulvum*, *Microsporum gypseum*, *Mucor circinelloides*, *Nectria haematococca*, *Paecilomyces variotii*, *Paracoccidioides* * *P. brasiliensis*, *Penicillium marneffei*, *Pichia anomala*, *Pichia guilliermondii*, *Pneumocystis carinii*, *Pseudallescheria boydii*, *Rhizopus oryzae*, *Rhodotorula rubra*, *Scedosporium apiospernium*, *Schizophyllum commune*, *Sporothrix schenckii*, *Trichophyton mentagrophytes*, *Trichophyton rubrum*, *Trichophyton verrucosum*, *Trichophyton violaceum*, *Trichosporon asahii*, *Trichosporon dermatophyte* Trichosporum cutaneum, Trichosporon inkin, and Trichosporon mucoides.

[0275] In some embodiments, the fungal infection is Candida albicans infection and / or Aspergillus fumigatus infection. Beneficial effects

[0276] The compounds disclosed herein have one or more of the following beneficial effects:

[0277] (1) It has a good inhibitory effect on the target enzyme human sterol-14-demethylase (CYP51);

[0278] (2) It has a suitable half-life;

[0279] (3) It has a low risk of inhibiting enzymes outside the target (such as major subtypes of human CYP enzymes), and therefore has a low risk of drug-drug interactions;

[0280] (4) It has high security;

[0281] (5) It has improved antifungal activity, for example, it has good antifungal activity against a wide range of fungi, including Candida albicans and Aspergillus fumigatus.

[0282] This application includes the following implementation scheme:

[0283] Implementation Scheme 1. The compound represented by formula (I-1) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof:

[0284] in,

[0285] Ring A is C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic;

[0286] Ring B is C 3-8 Monocyclic cycloalkane rings or 4-14 membered nitrogen-containing heterocycles;

[0287] Ring C does not exist, or it is C. 6-10 aryl, 5-10 heteroaryl, 4-10 heterocyclic, or C 6-10 Aryl benzo[C] 3-8 cycloalkyl;

[0288] X does not exist, or is a key, -C 0-6 Alkylene-OC 0-6 alkylene-, -C 0-6 Alkylene-SC 0-6 alkylene-, -C 0-6 Alkylene-NR A -C 0- 6-alkylene-, -C 0-6 Alkylene-Se-C 0-6alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, C 2-12 imidene group, C 2-12 Ethyne group, C 1- 12 Alkylene, wherein the alkylene, alkenylene, or alkyneyl group is optionally selected independently from one or more of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substituents of cycloalkyl groups;

[0289] R1 and R2 are each independently hydrogen, deuterium, halogen, cyano, nitro, or C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 0-6 Alkylene-R C or -SC 0-6 Alkylene-R C Alternatively, R1 and R2, together with the carbon atoms they are attached to, form C. 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0290] R3 is -C 0-6 Alkylene-NR A R B or -C 0-6 Alkylene-OR C Alternatively, one of R1 and R2 and R3 together with the carbon atom to which they are attached form a 3-8 membered heterocyclic group;

[0291] R4, R5, and R6 are each independently hydrogen, deuterium, halogen, cyano, nitro, oxo, carboxyl, -SF5, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 1-12 Halogenated alkyl groups, -OC 0-12 Alkylene-R C -SC 0-12 Alkylene-R C -S(O)2R C -C(O)NRA R B -P(O)R A R B -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10 heteroaryl, -C 0-6 Alkylene-C 3-8 cycloalkyl, -C 0-6 alkylene-4-10-membered heterocyclic groups, or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C Examples include hydrogen, deuterium, halogen, cyano, nitro, oxo, -SF5, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 1-12 Halogenated alkyl groups, -OC 0-12 Alkylene-R C -SC 0-12 Alkylene-R C -S(O)2R C -C(O)NR A R B -P(O)R A R B -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10 heteroaryl, -C 0-6 Alkylene-C 3-8 cycloalkyl, -C 0-6 alkylene-4-10-membered heterocyclic groups, or -OC 1- 12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected independently by one or more groups selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1- 12 Hydroxyalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C3-8 cycloalkyl, -CONR A R B -P(O)R A R B -COR C -S(O)2R C Substituents are substituted; p is 0, 1, 2, 3, 4 or 5;

[0292] R7 and R8 are independently hydrogen, deuterium, halogen, cyano, nitro, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 0-6 Alkylene-R C or -SC 0-6 Alkylene-R C Alternatively, R7 and R8, together with the carbon atoms they are bonded to, form C. 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0293] m, n, and o are each independently 0, 1, 2, 3, 4, or 5;

[0294] R A and R B Each independently is hydrogen, C 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0295] R C Each is independently hydrogen, deuterium, and C. 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0296] Implementation Scheme 2. The compound according to Implementation Scheme 1 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, wherein the compound is a compound represented by formula (I):

[0297] in,

[0298] Ring A is C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic;

[0299] Ring B is a 4-14 member nitrogen-containing heterocycle;

[0300] Ring C does not exist, or it is C. 6-10 aryl, 5-10 heteroaryl, 4-10 heterocyclic, or C 6-10 Aryl benzo[C] 3-8 cycloalkyl;

[0301] X does not exist, or is a key, -C 0-6 Alkylene-OC 0-6 alkylene-, -C 0-6 Alkylene-SC 0-6 alkylene-, -C 0-6 Alkylene-NR A -C 0- 6-alkylene-, -C 0-6 Alkylene-Se-C 0-6 alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, C 2-12 imidene group, C 2-12 Ethyne group, C 1- 12 Alkylene, wherein the alkylene, alkenylene, or alkyneyl group is optionally selected independently from one or more of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substituents of cycloalkyl groups;

[0302] R1 and R2 are each independently hydrogen, deuterium, halogen, cyano, nitro, or C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 0-6 Alkylene-R C or -SC 0-6 Alkylene-R C Alternatively, R1 and R2, together with the carbon atoms they are attached to, form C. 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0303] R3 is -C 0-6 Alkylene-NR A R B or -C 0-6 Alkylene-OR CAlternatively, one of R1 and R2 and R3 together with the carbon atom to which they are attached form a 3-8 membered heterocyclic group;

[0304] R4, R5, and R6 are each independently hydrogen, deuterium, halogen, cyano, nitro, oxo, -SF5, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2- 12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 1-12 Halogenated alkyl groups, -OC 0-12 Alkylene-R C -SC 0-12 Alkylene-R C -S(O)2R C -C(O)NR A R B -P(O)R A R B -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10 heteroaryl, -C 0-6 alkylene-4-10-membered heterocyclic groups, or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, and heteroaryl groups are optionally selected independently by one or more groups selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substituents of cycloalkyl groups; p is 0, 1, 2, 3, 4 or 5;

[0305] R7 and R8 are independently hydrogen, deuterium, halogen, cyano, nitro, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 0-6 Alkylene-R C or -SC 0-6 Alkylene-R C Alternatively, R7 and R8, together with the carbon atoms they are bonded to, form C.3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0306] m, n, and o are each independently 0, 1, 2, 3, 4, or 5;

[0307] R A and R B Each independently is hydrogen, C 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0308] R C Each is independently hydrogen, deuterium, and C. 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0309] Implementation Scheme 3. The compound according to Implementation Scheme 1 or 2 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, wherein ring C is absent and X is absent.

[0310] Implementation Scheme 4. The compound according to Implementation Scheme 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein,

[0311] Ring C is C 6-10 aryl, 5-10 heteroaryl, 4-10 heterocyclic, or C 6-10 Aryl benzo[C] 3-8 cycloalkyl;

[0312] X is the key, -C 0-6 Alkylene-OC 0-6 alkylene-, -C 0-6 Alkylene-SC 0-6 alkylene-, -C 0-6 Alkylene-NR A -C 0-6 alkylene-, -C 0-6 Alkylene-Se-C 0-6 alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, C 2-12 imidene group, C 2-12 Ethyne group, C 1-12Alkylene, wherein the alkylene, alkenylene, or alkyneyl group is optionally selected independently from one or more of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substitution of cycloalkyl groups.

[0313] Implementation Scheme 5. The compound according to any one of Implementation Schemes 1-4, or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, which satisfies one or more of the following conditions:

[0314] (1) Ring A is C 6-10 Aryl or 5-10 heteroaryl; preferably phenyl, naphthyl, pyridyl, quinolinyl, imidazopyridyl, indole, or thiophene; for example, phenyl, Phenyl is preferred;

[0315] (2) Ring B is C 3-8 Monocyclic cycloalkane rings, 4-8 member nitrogen-containing monocyclic heterocycles, 6-14 member nitrogen-containing spirocyclic heterocycles, 6-14 member nitrogen-containing fused heterocycles, or 6-14 member nitrogen-containing bridged heterocycles;

[0316] Preferably, ring B is a 4-8 member nitrogen-containing monocyclic heterocycle, a 6-14 member nitrogen-containing spirocyclic heterocycle, a 6-14 member nitrogen-containing fused heterocycle, or a 6-14 member nitrogen-containing bridged heterocycle;

[0317] Preferably, ring B is (For example ),

[0318] More preferably, ring B is Or for Preferably, the wavy line represents the connection point between the nitrogen atom of ring B and the carbon atoms connected to R1 and R2, and the connection site with X (if present) in the general formula is not shown;

[0319] (3) Ring C is C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclic, or benzo[a]C 3-6Cycloalkyl; preferably phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolopyridinyl, imidazopyridinyl, benzoxazolyl, benzopyrazolyl, pyrazolyl, pyridinoneyl, pyridazinyl, benzocyclopentyl, tetrahydropyranyl, piperidinyl, naphthyl, benzodihydropyranyl, triazolopyrimidinyl, imidazopyridazinyl, thiadiazoyl, imidazopyrazinyl, or oxadiazolyl; for example, phenyl, pyridinyl, pyrimidinyl, benzoxazolyl, benzopyrazolyl, or pyrazolyl. Pyridone, pyridazinyl, benzocyclopentyl, tetrahydropyranyl, piperidinyl, naphthyl, benzodihydropyranyl, triazolopyrimidinyl, imidazopyridazinyl, thiadiazolyl, imidazopyrazinyl, or oxadiazolyl; for example, phenyl, pyridinyl, pyrimidinyl, benzoxazolyl, benzopyrazolyl, pyrazolyl, pyridone, pyridazinyl, benzocyclopentyl, tetrahydropyranyl, piperidinyl, naphthyl, benzodihydropyranyl, or triazolopyrimidinyl; for example, phenyl,

[0320] (4) X is a bond, -C 0-6 Alkylene-OC 0-6 alkylene-, -C 0-6 Alkylene-SC 0-6 alkylene-, -C 0-6 Alkylene-NR A -C 0-6 alkylene-, -C 0-6 Alkylene-Se-C 0-6 alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, C 2-12 imidene group, C 2-12 etyne group, or C 1- 12 Alkylene, wherein the alkylene, alkenylene, or alkyneyl group is optionally selected independently from one or more of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substituents of cycloalkyl groups;

[0321] Preferably, X is a bond, -C 0-3 Alkylene-OC 0-3 alkylene-, -C 0-3 Alkylene-SC 0-3 alkylene-, -C 0-3 Alkylene-NR A -C 0-3 alkylene-, -C0-3 Alkylene-Se-C 0-3 alkylene-, -C 0-3 Alkylene-C(O)-C 0-3 Alkylene-, C 2-4 imidene group, C 2-4 etyne group, or C 1- 4. Alkylene, wherein the alkylene, alkenylene, or alkyne group is optionally selected independently by one or more groups selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substituents of cycloalkyl groups;

[0322] More preferably, X is a bond, O, S, NH, N (C 1-6 Alkyl), Se, C 2-4 Ethyne group, C 1-4 alkylene, carbonyl, or -C 0-3 Alkylene-OC 0-3 Alkylene; for example, a bond, O, or NH;

[0323] (5) R1 and R2 are each independently hydrogen, deuterium, halogen, or C. 1-12 Alkyl groups; or R1 and R2 together with the carbon atoms they are attached to form C2 groups. 3-6 Cycloalkyl; preferably, both R1 and R2 are hydrogen; or one is hydrogen and the other is methyl;

[0324] (6) R3 is -C 0-3 Alkylene-NR A R B or -C 0-3 Alkylene-OR C More preferably -C 0-3 alkylene-OH, such as hydroxyl groups;

[0325] (7) One of R1 and R2 and R3 together with the carbon atom to which they are attached form a 4-6 membered heterocyclic group;

[0326] (8) R4 can be hydrogen, deuterium, halogen, cyano, or C independently. 1-12 Alkyl, -C(O)NR A R B C 1-12 Alkoxy or -SF5; preferably, R4 is fluorine and m is 2;

[0327] (9) R5 can be hydrogen, deuterium, halogen, oxo group, or C independently.1-12 Alkyl, -OC 0-12 Alkylene-R C 、or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl group or alkylene group is optionally selected independently from one or more groups selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substituents of cycloalkyl groups;

[0328] For example, R5 can be hydrogen, deuterium, halogen, oxo group, or C. 1-12 Alkyl, or C 1-12 Alkoxy groups, such as hydrogen, deuterium, or fluorine;

[0329] (10) R6 is independently hydrogen, deuterium, halogen, cyano, oxo, hydroxyl, C 1-12 Alkyl, -OC 1-12 Alkyl, -OC 1-12 Halogenated alkyl groups, -OC 0-6 Alkylene-C 6-10 Aryl, -OC 0-6 alkylene-5-10 heteroaryl, -OC 0-6 Alkylene-C 3-8 cycloalkyl, -OC 0-6 Alkyl-4-6-membered heterocyclic group, -C 0-6 Alkylene-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 heterocyclic group, -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10-membered heteroaryl, -S(O)2R C -P(O)R A R B 、or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected independently by one or more halogens, hydroxyl groups, cyano groups, nitro groups, oxo groups, and C6 groups. 1-12 Alkyl, C 1-12 Hydroxyalkyl, C 1-12Alkoxy, C 1-12 Haloalkyl, C 1-12 Halogenated alkoxy groups, -CONR A R B -P(O)R A R B -COR C -S(O)2R C Substituents of the substituents;

[0330] Preferably, each of R6 is independently hydrogen, deuterium, halogen, cyano, oxo, hydroxyl, or C. 1-12 Alkyl, -OC 1-12 Alkyl, -OC 1- 12 Halogenated alkyl groups, -OC 0-6 Alkylene-C 6-10 Aryl, -OC 0-6 alkylene-5-10 heteroaryl, -OC 0-6 Alkyl-4-6-membered heterocyclic group, -C 0-6 Alkylene-C 3-8 cycloalkyl, -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10-membered heteroaryl, -S(O)2R C -P(O)R A R B 、or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected independently by one or more halogens, hydroxyl groups, cyano groups, nitro groups, oxo groups, and C6 groups. 1-12 Alkyl, C 1-12 Hydroxyalkyl, C 1-12 Alkoxy, C 1-12 Haloalkyl, C 1-12 Halogenated alkoxy groups, -CONR A R B -P(O)R A R B Substituents of R; preferably, wherein R C Each independently is hydrogen, C 1-12 Alkyl or C 1-12 Halogenated alkyl groups;

[0331] Preferably, each of R6 is independently hydrogen, deuterium, halogen, cyano, oxo, hydroxyl, or C. 1-12 Alkyl, -OC 1-12 Alkyl, -OC 1-12 Halogenated alkyl groups, -OC 0-6 Alkylene-C 6-10 Aryl, -OC 0-6 alkylene-5-10 heteroaryl, -OC 0-6 Alkyl-4-6-membered heterocyclic group, -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10-membered heteroaryl, -P(O)R A R B 、or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, and heteroaryl groups are optionally selected independently by one or more halogens, hydroxyl groups, cyano groups, nitro groups, oxo groups, and C6 groups. 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Haloalkyl, C 1-12 Halogenated alkoxy groups, -CONR A R B Substituents of the substituents;

[0332] (11) R7 and R8 are each independently hydrogen, deuterium, or C. 1-12 Alkyl groups; or R7 and R8 together with the carbon atoms they are attached to form C24. 3-6 Cycloalkyl; preferably, R7 and R8 are both hydrogen;

[0333] (12)R A and R B Each is independently hydrogen or C 1-12 alkyl;

[0334] (13)R C Each independently is hydrogen, C 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 cycloalkyl, C 6-10 Aryl or 5-10 heteroaryl groups;

[0335] (14) m, n and o are each independently 0, 1, 2, 3 or 4;

[0336] (15) p is 0, 1, 2 or 3;

[0337] (16) The compound is a compound of formula (IA) or a compound of formula (IB) or a mixture thereof, preferably a compound of formula (IA):

[0338] Implementation Scheme 6. The compound according to any one of Implementation Schemes 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein,

[0339] Ring C exists, X exists, and ring B is... Where n1, n2, n3, and n4 are each independently 1, 2, or 3. Indicates a single bond or a double bond;

[0340] Optionally, when n1, n2, n3 or n4 are 2 or 3, two repeating -CH2- units can form a carbon-carbon double bond.

[0341] Implementation Scheme 7. The compound according to any one of Implementation Schemes 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein the compound is further a compound of formula (II) or (III), preferably a compound of formula (IIA) or (IIIA):

[0342] Alternatively, it may be a compound of formula (IV) or formula (V), preferably a compound of formula (IVA) or formula (VA):

[0343] Alternatively, it may be a compound of formula (VI) or formula (VII), preferably a compound of formula (VIA) or formula (VIIA):

[0344] Or further, compounds of formula (VIII), formula (I-B1), or formula (I-B2):

[0345] Wherein, rings A, B, C, X, R1, R2, R3, R4, R5, R6, R7, R8, m, n, and o are as defined in any of the aforementioned implementation schemes 1-7.

[0346] n1, n2, n3, and n4 are each independently 1, 2, or 3.

[0347] Implementation Scheme 8. The compound according to Implementation Scheme 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, wherein the compound is selected from compound 1 to compound 502, compound 16A, compound 19A to compound 502A, and compound 104B.

[0348] Implementation Scheme 9. A pharmaceutical composition comprising a preventive and / or therapeutically effective amount of any one of the compounds of Implementation Schemes 1-8 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

[0349] Implementation Scheme 10. A medicine box comprising any one of the compounds of embodiments 1-8 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, or the pharmaceutical composition of embodiment 9.

[0350] Implementation Scheme 11. The use of any compound of any one of Implementation Schemes 1-8 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug of the same, or the pharmaceutical composition of Implementation Scheme 9, or the kit of Implementation Scheme 10 in the preparation of a medicament for the prevention and / or treatment of diseases, particularly CYP51-mediated diseases;

[0351] Preferably, the disease is a fungal infection, such as an invasive fungal infection;

[0352] Preferably, the fungi include: *Absidia corymbifera*, *Ajellomyces capsulatus*, *Ajellomyces dermatitidis*, *Arthroderma benhamiae*, *Arthroderma fulvum*, *Arthroderma gypseum*, *Arthroderma incurvatum*, *Arthroderma otae*, *Arthroderma vanbreuseghemii*, *Aspergillus flavus*, *Aspergillus fumigatus*, *Aspergillus niger*, *Blastomyces dermatitidis*, *Candida albicans*, and *Candida glabrata*. Candida glabrata, Candida guilliermondii, Candida krusei, Candida parapsilosis, Candida tropicalis, Candida pelliculosa, Cladophialophora carrionii, Coccidioides immitis, Cryptococcus neoformans, Cunninghamella sp., Epidermophyton floccosum, Exophiala dermatitidis, Filobasidiella neoformans, Fonsecaea pedrosoi, Fusarium solani, Geotrichum candidum, Histoplasma capsulatum *Capsulatum*, *Hortaea werneckii*, *Issatschenkia orientalis*, *Madurella grisae*, *Malassezia*Malassezia fur, Malassezia globosa, Malassezia obtusa, Malassezia pachydermatis, Malassezia restricta, Malassezia slooffiae, Malassezia sympodialis, Microsporum canis, Microsporum fulvum, Microsporum gypseum, Mucor circinelloides, Nectria haematococca, Paecilomyces variotii, Paracoccidioides brasiliensis, Penicillium marneffei, Pichia aberrant anomala, Pichia guilliermondii, Pneumocystis carinii, Pseudallescheria boydii, Rhizopus oryzae, Rhodotorula rubra, Scedosporium apiospernium, Schizophyllum commune, Sporothrix schenckii, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton verrucosum, Trichophyton violaceum, Trichosporon asahii, Trichosporon cutaneum, Trichosporon Candida albicans and / or Aspergillus fumigatus are preferred.

[0353] Implementation Scheme 12. The compound of any one of Implementation Schemes 1-8 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, or the pharmaceutical composition of Implementation Scheme 9, or the kit of Implementation Scheme 10, for the prevention and / or treatment of diseases, particularly CYP51-mediated diseases;

[0354] Preferably, the disease is a fungal infection, such as an invasive fungal infection;

[0355] Preferably, the fungi include: *Absidia corymbifera*, *Ajellomyces capsulatus*, *Ajellomyces dermatitidis*, *Arthroderma benhamiae*, *Arthroderma fulvum*, *Arthroderma gypseum*, *Arthroderma incurvatum*, *Arthroderma otae*, *Arthroderma vanbreuseghemii*, *Aspergillus flavus*, *Aspergillus fumigatus*, *Aspergillus niger*, *Blastomyces dermatitidis*, *Candida albicans*, and *Candida glabrata*. Candida glabrata, Candida guilliermondii, Candida krusei, Candida parapsilosis, Candida tropicalis, Candida pelliculosa, Cladophialophora carrionii, Coccidioides immitis, Cryptococcus neoformans, Cunninghamella sp., Epidermophyton floccosum, Exophiala dermatitidis, Filobasidiella neoformans, Fonsecaea pedrosoi, Fusarium solani, Geotrichum candidum, Histoplasma capsulatum *Capsulatum*, *Hortaea werneckii*, *Issatschenkia orientalis*, *Madurella grisae*, *Malassezia*Malassezia fur, Malassezia globosa, Malassezia obtusa, Malassezia pachydermatis, Malassezia restricta, Malassezia slooffiae, Malassezia sympodialis, Microsporum canis, Microsporum fulvum, Microsporum gypseum, Mucor circinelloides, Nectria haematococca, Paecilomyces variotii, Paracoccidioides brasiliensis, Penicillium marneffei, Pichia aberrant anomala, Pichia guilliermondii, Pneumocystis carinii, Pseudallescheria boydii, Rhizopus oryzae, Rhodotorula rubra, Scedosporium apiospernium, Schizophyllum commune, Sporothrix schenckii, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton verrucosum, Trichophyton violaceum, Trichosporon asahii, Trichosporon cutaneum, Trichosporon Candida albicans and / or Aspergillus fumigatus are preferred.

[0356] Implementation Scheme 13. A method for preventing and / or treating CYP51-mediated diseases, comprising administering to an individual in need a preventive or therapeutically effective amount of any one of Implementation Schemes 1-8 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, or the pharmaceutical composition of Implementation Scheme 9, or the kit of Implementation Scheme 10;

[0357] Preferably, the disease is a fungal infection, such as an invasive fungal infection;

[0358] Preferably, the fungi include: *Absidia corymbifera*, *Ajellomyces capsulatus*, *Ajellomyces dermatitidis*, *Arthroderma benhamiae*, *Arthroderma fulvum*, *Arthroderma gypseum*, *Arthroderma incurvatum*, *Arthroderma otae*, *Arthroderma vanbreuseghemii*, *Aspergillus flavus*, *Aspergillus fumigatus*, *Aspergillus niger*, *Blastomyces dermatitidis*, *Candida albicans*, and *Candida glabrata*. Candida glabrata, Candida guilliermondii, Candida krusei, Candida parapsilosis, Candida tropicalis, Candida pelliculosa, Cladophialophora carrionii, Coccidioides immitis, Cryptococcus neoformans, Cunninghamella sp., Epidermophyton floccosum, Exophiala dermatitidis, Filobasidiella neoformans, Fonsecaea pedrosoi, Fusarium solani, Geotrichum candidum, Histoplasma capsulatum *Capsulatum*, *Hortaea werneckii*, *Issatschenkia orientalis*, *Madurella grisae*, *Malassezia*Malassezia fur, Malassezia globosa, Malassezia obtusa, Malassezia pachydermatis, Malassezia restricta, Malassezia slooffiae, Malassezia sympodialis, Microsporum canis, Microsporum fulvum, Microsporum gypseum, Mucor circinelloides, Nectria haematococca, Paecilomyces variotii, Paracoccidioides brasiliensis, Penicillium marneffei, Pichia aberrant anomala, Pichia guilliermondii, Pneumocystis carinii, Pseudallescheria boydii, Rhizopus oryzae, Rhodotorula rubra, Scedosporium apiospernium, Schizophyllum commune, Sporothrix schenckii, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton verrucosum, Trichophyton violaceum, Trichosporon asahii, Trichosporon cutaneum, Trichosporon Candida albicans and / or Aspergillus fumigatus are preferred.

[0359] Implementation Scheme 14. A method for preparing a compound of formula (IV), comprising one or more of the following steps: Step 1 to Step 3:

[0360] Among them, rings B, C, X, R4, R5, R6, R7, R8, m, n and o are as defined in any of embodiments 1-8.

[0361] Implementation Scheme 15. A method for preparing a compound of formula (VIIA), comprising one or more of the following steps: Step 1 to Step 5

[0362] Among them, rings B, C, X, R4, R5, R6, m, n and o are as defined in any of embodiments 1-8.

[0363] Implementation Scheme 16. The following compounds or their salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, and isotope-labeled compounds:

[0364] Among them, rings B, C, X, R4, R5, R6, R7, R8, m, n and o are as defined in any of embodiments 1-8.

[0365] Example

[0366] The embodiments of this disclosure will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are only for further illustration of this disclosure and should not be regarded as limiting the scope of this disclosure. Unless otherwise specified, specific conditions in the examples are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used without specified manufacturers are all commercially available conventional products. Unless otherwise specified, proportions or percentages used herein are by weight.

[0367] Intermediate 1: Synthesis of 1-((2-(2,4-difluorophenyl)epoxy-2-yl)methyl)-1H-tetrazole (int-1).

[0368] Step 1: Synthesis of 1-(2,4-difluorophenyl)-2-(1H-tetrazol-1-yl)ethyl-1-one (int-1-1).

[0369] In a 250 mL single-necked flask equipped with a magnetic stirrer, tetrazolium (1.63 g, 23.23 mmol) and dried DMF (15 mL) were added sequentially. The flask was cooled in an ice bath, and sodium hydride (1.0 g, 25.02 mmol, 60% in oil) was added at a controlled temperature of 5 °C. After the addition was complete, the mixture was reacted at low temperature for 1 hour, and then 2-bromo-1-(2,4-difluorophenyl)ethyl ketone (4.2 g, 17.87 mmol, dissolved in 5 mL) was added. Add DMF and react at room temperature for 2 hours. After the reaction is complete, pour the reaction solution into 100 mL of ice water. Filter the precipitated solid, extract the filtrate with ethyl acetate (30 mL x 3), then dissolve the filtered solid in the organic extract. Wash the organic phase with saturated sodium bicarbonate (25 mL x 2), dry, filter, concentrate to dryness, and silica gel column chromatography to obtain 1.4 g of 1-(2,4-difluorophenyl)-2-(1H-tetrazol-1-yl)ethyl-1-one, yield: 34.95%, MS [ESI]: m / z = 225.7, [M+H] + .

[0370] Int-1-1 NMR: 1 H NMR (400MHz, CDCl3) δ8.80 (s, 1H), 8.09 (td, J = 8.4, 6.4Hz, 1H), 7.15-6.97 (m, 2H), 5.87 (d, J = 3.2Hz, 2H).

[0371] Step 2: Synthesis of 1-((2-(2,4-difluorophenyl)epoxy-2-yl)methyl)-1H-tetrazole (int-1)

[0372] In a 10 mL microwave tube equipped with a magnetic stirrer, 1-(2,4-difluorophenyl)-2-(1H-tetrazol-1-yl)ethyl-1-one (300 mg, 1.338 mmol), DCM (4 mL), trimethyl sulfoxide (618 mg, 2.82 mmol), and sodium hydroxide (1.6 mL, 2 M) were added sequentially. After purging with nitrogen, the mixture was microwaved at 50 W and 42 °C for 6 hours. After the reaction was completed, the reaction solution was poured into 10 mL of ice water and extracted with dichloromethane (15 mL * 4). The organic phase was washed with saturated brine (15 mL * 2), dried, filtered, and concentrated to obtain 270 mg of crude 1-((2-(2,4-difluorophenyl)epoxy-2-yl)methyl)-1H-tetrazolium. This crude product was used directly in the next reaction without further purification. MS [ESI]: m / z = 239.1, [M+H]+.

[0373] Intermediate 2: Synthesis of 4-((4-(piperidin-4-ylethynyl)phenoxy)methyl)benzonitrile (int-2)

[0374] Step 1: Synthesis of 4-((4-iodophenoxy)methyl)benzonitrile (int-2-1)

[0375] 4-Iodophenol (1 g, 4.55 mmol), 4-bromomethylbenzonitrile (891.08 mg, 4.55 mmol), anhydrous potassium carbonate (1.88 g, 13.64 mmol), and N,N-dimethylformamide (10 mL) were added to a dry round-bottom flask and stirred at 90 °C for 3 hours. The reaction was confirmed to be complete by LCMS, and the title compound (1.42 g, 4.24 mmol, yield 93.22%) was purified by normal-phase column chromatography (DCM / MeOH: 100 / 0).

[0376] 1 H NMR (400MHz, DMSO-d6) δ7.87(d,J=8.4Hz,2H),7.62(dd,J=8.4,5.6Hz,4H),6.87(d,J=8.8Hz,2H),5.22(s,2H).

[0377] Step 2: Synthesis of 4-((4-((4-cyanobenzyl)oxy)phenyl)ethynyl)piperidine-1-carboxylic acid tert-butyl ester (int-2-2)

[0378] To a dry round-bottom flask, add 4-((4-iodophenoxy)methyl)benzonitrile (1 g, 2.98 mmol), 4-ethynylpiperidin-1-carboxylic acid tert-butyl ester (686.92 mg, 3.28 mmol), bis(triphenylphosphine)palladium dichloride (209.43 mg, 298.38 μmol), cuprous iodide (113.65 mg, 596.77 μmol), triethylamine (5 mL), and tetrahydrofuran (5 mL). Stir at 60 °C for five hours under nitrogen protection. The reaction was confirmed to be complete by LC-MS. The title compound (1.22 g, 2.93 mmol, 98.17% yield) was separated by normal-phase column chromatography (PE / EA: 70 / 30 to 65 / 35). MS [ESI]: m / z = 317.3, [M-100+H]+.

[0379] Step 3: Synthesis of 4-((4-(piperidin-4-ylethynyl)phenoxy)methyl)benzonitrile (int-2)

[0380] Compound 4-((4-((4-cyanobenzyl)oxy)phenyl)ethynyl)piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 2.88 mmol) and dioxane hydrochloride solution (10 mL) were added to a dry round-bottom flask and stirred for one hour. The reaction was confirmed to be complete by LC-MS. After adjusting the pH to 7-8 with saturated sodium bicarbonate solution, the mixture was extracted, dried over the organic phase (15 mL x 3) in dichloromethane, filtered, and concentrated to dryness to give the title compound (820 mg, 2.59 mmol, yield 89.69%). MS [ESI]: m / z = 317.2, [M+H]+.

[0381] Intermediate 3: Synthesis of 1-(((2R,3S)-2-(2,4-difluorophenyl)-3-methylepoxyethylene-2-yl)methyl)-1H-tetrazole compound (int-3)

[0382] Step 1 / 2: Synthesis of (2R,3R)-2-(2,4-difluorophenyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)-1-(1H-tetrazazole-1-yl)but-2-ol (int-3-2)

[0383] In a 500 mL three-necked flask equipped with a reflux condenser and a magnetic stirrer, DMF (25 mL) and trimethyl sulfoxide (22.87 g, 103.9 mmol) were added sequentially. Sodium tert-butoxide (9.99 g, 103.90 mmol) was added at 0 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 h. Then, the mixture was cooled to 0 °C and (2R)-1-(2,4-difluorophenyl)-2-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-one (26.05 g, 94.46 mmol) was added. The mixture was stirred further at room temperature for 1 h. After the epoxidation reaction was completed as monitored by LCMS, tetrazolium (13.23 g, 188.89 mmol) and potassium carbonate (2... 6.11 g (188.89 mmol) was added, and the reaction was carried out at 90 °C for 14 hours. After the reaction was monitored by LCMS, the reaction solution was poured into 150 mL of ice water and extracted with MTBE (150 mL * 3). The organic phases were combined and washed with saturated ammonium chloride water (60 mL * 2), dried, filtered and concentrated, and subjected to silica gel column chromatography (n-heptane: methyl tert-ether = 100:0 ~ 60:40) to give 20 g of oily (2R,3R)-2-(2,4-difluorophenyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)-1-(1H-tetrazazole-1-yl)but-2-ol, yield: 59.76%, MS [ESI]: m / z = 271.2, [M-THP]+.

[0384] 1H NMR(400MHz,DMSO-d6)δ9.13(d,J=33.6Hz,1H),7.90-6.77(m,3H),5.84(d,J=16.0Hz,1H),5.04(s,1H ),4.36(dd,J=10.4,5.2Hz,1H),3.44(dd,J=7.2,5.2Hz,2H),1.50(d,J=4.0Hz,6H),1.09-0.82(m,4H).

[0385] Step 3: Synthesis of (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-tetrazol-1-yl)butyl-2,3-diol (int-3-3)

[0386] In a 500 mL three-necked flask equipped with a magnetic stirrer, add 20.0 g of (2R,3R)-2-(2,4-difluorophenyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)-1-(1H-tetrazol-1-yl)but-2-ol sequentially. 56.44 mmol) and ethyl acetate (80 mL) were added, and methanesulfonic acid (5.42 g, 56.44 mmol) was added at 0 °C. After the addition was complete, the reaction was carried out at room temperature for 6 h. After the reaction was completed by LCMS, the reaction solution was poured into 150 mL of water and extracted with ethyl acetate (150 mL * 3). The organic phases were combined and washed with saturated ammonium chloride water (60 mL * 2), dried, filtered and concentrated, and subjected to silica gel column chromatography (n-heptane:ethyl acetate = 100:0 ~ 0:100) to give 9.6 g of crude (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-tetrazol-1-yl)butyl-2,3-diol compound. The crude product was recrystallized from ethyl acetate at 80 °C to give 2.55 g of the target compound, yield: 16.72%, MS [ESI]: m / z = 288.2, [M+NH4]+.

[0387] 1 H NMR (400MHz, DMSO-d6) δ9.08 (s, 1H), 7.24-7.11 (m, 2H), 6.88 (d, J = 2.4Hz, 1H), 5.61 (s, 1H), 5.4 3(d,J=5.2Hz,1H), 4.96(dd,J=34.0,14.4Hz,2H), 4.24(d,J=2.8Hz,1H), 0.82(d,J=6.4Hz,3H).

[0388] Step 4: Synthesis of 1-(((2R,3S)-2-(2,4-difluorophenyl)-3-methylepoxyethylene-2-yl)methyl)-1H-tetrazazole compound (int-3)

[0389] In a 100 mL three-necked flask equipped with a magnetic stirrer, (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-tetrazol-1-yl)butyl-2,3-diol (2.5 g, 9.25 mmol), MTBE / THF (15.00 mL / 15.00 mL), and triethylamine (2.81 g, 27.75 mmol) were added sequentially. Methanesulfonic anhydride (3.22 g, 18.50 mmol) was added at 0 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 hours. After the reaction was completed, sodium hydroxide (11.56 mL, 2 M) was added at 0 °C. The reaction was carried out for 12 hours. After the reaction was completed, the mixture was extracted with MTBE (25 mL * 3) by LCMS. The organic phases were combined and washed with saturated ammonium chloride water (60 mL * 2), dried, filtered and concentrated, and then subjected to silica gel column chromatography (n-heptane:MTBE = 100:0 ~ 0:100) to give crude 1-(((2R,3S)-2-(2,4-difluorophenyl)-3-methylepoxyethylene-2-yl)methyl)-1H-tetrazole. The crude product was recrystallized twice with ethyl acetate-petroleum ether to give 1.22 g of the target compound, yield: 52.29%, MS [ESI]: m / z = 253.7, [M+H]+.

[0390] 1 H NMR(400MHz,DMSO-d6)δ9.25(s,1H),7.28-7.21(m,1H),7.12-6.92(m,2H),5.11(d ,J=14.8Hz,1H),4.93(d,J=14.8Hz,1H),3.31-3.26(m,2H),1.61(d,J=5.6Hz,3H).

[0391] Intermediate 4: Synthesis of 4-(4-(2,2,2-trifluoroethoxy)phenyl)piperidine (int-4)

[0392] Step 1: Synthesis of tert-butyl 4-[4-(2,2,2-trifluoroethoxy)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid ester (int-4-1)

[0393] In a 100 mL single-necked flask equipped with a magnetic stirrer, borate ester 01 (8.73 g, 28.23 mmol), 1-bromo-4-(2,2,2-trifluoroethoxy)benzene (6.0 g, 23.53 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (859.89 mg, 1.18 mmol), dioxane, water (30 mL / 8 mL), and potassium carbonate (9.75 g, 70.58 mmol) were added sequentially. After purging with nitrogen, the reaction was carried out at 95 °C for 4 hours, and the reaction was monitored. After the reaction was complete, the reaction solution was filtered to remove insoluble matter. The filter cake was washed with ethyl acetate and then extracted with an ethyl acetate / water system (50 mL * 3). The organic phase was washed with saturated brine (50 mL), dried, filtered, concentrated, and purified by silica gel column chromatography (n-heptane:ethyl acetate = 100:0 ~ 40:60) to give 7.5 g of tert-butyl 4-[4-(2,2,2-trifluoroethoxy)phenyl]-3,6-dihydro-2H-piperidine-1-carboxylic acid ester, yield: 89.12%, MS [ESI]: m / z = 353.2, [M+H]+.

[0394] Step 2: Synthesis of tert-butyl 4-[4-(2,2,2-trifluoroethoxy)phenyl]piperidine-1-carboxylic acid ester (int-4-2)

[0395] In a 25 mL single-necked flask equipped with a magnetic stirrer, tert-butyl 4-[4-(2,2,2-trifluoroethoxy)phenyl]-3,6-dihydro-2H-piperidine-1-carboxylic acid ester (0.612 g, 0.99 mmol), methanol (10 mL), and Pd / C (10%, 178.67 mg) were added sequentially. After the addition was complete, the mixture was pressurized with hydrogen at 0.5 MPa and reacted at 25 °C for 12 hours. After the reaction was completed, the palladium on carbon was removed by filtration, the solvent was concentrated, and silica gel column chromatography (dichloromethane:methanol = 100:0 to 40:60) was performed to give tert-butyl 4-[4-(2,2,2-trifluoroethoxy)phenyl]piperidine-1-carboxylic acid ester (compound int-4-2) 0.5 g, yield: 82.87%, MS [ESI]: m / z = 360.7, [M+H]+.

[0396] Step 3: Synthesis of 4-(4-(2,2,2-trifluoroethoxy)phenyl)piperidine (int-4)

[0397] In a 25 mL single-port container equipped with a magnetic stirrer, tert-butyl 4-[4-(2,2,2-trifluoroethoxy)phenyl]piperidine-1-carboxylic acid ester (0.5 g, 2.84 mmol), DCM (12 mL), and TFA (4 mL) were added sequentially. After addition, the reaction was carried out at 25 °C for 3 hours. After the reaction was completed, all solvent was removed by rotary evaporation. Dichloromethane (20 mL) was added, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. Extraction was then performed, followed by dichloromethane (15 mL * 3). The organic phase was dried, filtered, and concentrated to obtain crude 4-(4-(2,2,2-trifluoroethoxy)phenyl)piperidine (int-4) 0.35 g. This crude product did not require further purification and proceeded directly to the next step. Yield: 97.12%, MS [ESI]: m / z = 260.7, [M+H]+.

[0398] Intermediate 5: Synthesis of 1-(4-(2,2,2-trifluoroethoxy)phenyl)piperazine (int-5)

[0399] Step 1: Synthesis of tert-butyl 4-(4-(2,2,2-trifluoroethoxy)phenyl)piperazine-1-carboxylic acid ester (int-5-1)

[0400] In a 100 mL single-necked flask equipped with a magnetic stirrer, 1-bromo-4-(2,2,2-trifluoroethoxy)benzene (1.0 g, 3.92 mmol), tert-butylpiperazine-1-carboxylate (949.40 mg, 5.10 mmol), dried toluene (25 mL), sodium tert-butoxide (753.66 mg, 7.84 mmol), Pd2(dba)3 (359.06 mg, 392.11 μmol), and S-(-)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (488.31 mg, 392.11 μmol) were added sequentially. l), after purging with nitrogen, the reaction was carried out at 100℃ for 12 hours. After the reaction was completed, the reaction solution was filtered to remove insoluble matter. The filter cake was washed with ethyl acetate and then extracted with an ethyl acetate / water system (20 mL * 3). The organic phase was washed with saturated brine (15 mL), dried, filtered, concentrated, and purified by silica gel column chromatography (n-heptane:ethyl acetate = 100:0 ~ 40:60) to give 0.8 g of tert-butyl 4-(4-(2,2,2-trifluoroethoxy)benzene)piperazine-1-carboxylic acid ester, yield: 56.62%, MS [ESI]: m / z = 304.7, [M-1 / 2Boc]+.

[0401] Step 2: Synthesis of 1-(4-(2,2,2-trifluoroethoxy)phenyl)piperazine (int-5)

[0402] In a 25 mL single-port container equipped with a magnetic stirrer, tert-butyl 4-(4-(2,2,2-trifluoroethoxy)phenyl)piperazine-1-carboxylic acid ester (0.5 g, 1.39 mmol), DCM (6 mL), and TFA (2 mL) were added sequentially. After addition, the reaction mixture was reacted at 25 °C for 3 hours. After the reaction was completed, the reaction solution was transferred to 10 mL of ice water, and dichloromethane (20 mL) was added. The pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted. Dichloromethane (15 mL * 3) was added, the organic phase was dried, filtered, and the solvent was concentrated to obtain 0.298 g of crude 4-(4-(2,2,2-trifluoroethoxy)phenyl)piperidine (int-6). This crude product did not require further purification and proceeded directly to the next step. Yield: 82.53%, MS [ESI]: m / z = 261.2, [M+H]+.

[0403] Intermediate 6: Synthesis of 4'-(piperidin-4-ylamino)-[1,1'-diphenyl]-4-carboxynitrile (int-6)

[0404] Step 1: Synthesis of tert-butyl-4-((4-bromophenyl)amino)piperidine-1-carboxylic acid ester (int-6-1)

[0405] In a 250 mL single-necked flask equipped with a magnetic stirrer, tert-butyl 4-oxopiridine-1-carboxylic acid ester (7.91 g, 39.72 mmol), 4-bromoaniline (8.2 g, 47.67 mmol), DCM (100 mL), and glacial acetic acid (10 mL) were added sequentially. After the addition was complete, sodium triacetylborohydride (12.63 g, 59.59 mmol) was added at 25 °C and the reaction was carried out for 6 hours. After the reaction was completed, sodium hydroxide aqueous solution (100 mL, 2 M) was added, and the mixture was extracted with dichloromethane (40 mL * 2). The organic phases were combined, dried, filtered, concentrated, and subjected to silica gel column chromatography (n-heptane: ethyl acetate = 100:0 ~ 50:50) to give 5.4 g of tert-butyl 4-((4-bromophenyl)amino)piperidine-1-carboxylic acid ester, yield: 38.26%, MS [ESI]: m / z = 355.2, [M+H]+.

[0406] Step 2: Synthesis of tert-butyl 4-((4'-cyano-[1,1'-diphenyl]-4-yl)amino)piperidine-1-carboxylic acid ester (int-6-2)

[0407] In a 250 mL single-necked flask equipped with a magnetic stirrer, (4-cyanobenzene)boric acid (4.47 g, 30.40 mmol), tert-butyl-4-((4-bromophenyl)amino)piperidine-1-carboxylic acid ester (5.4 g, 15.20 mmol), sodium carbonate (4.83 g, 45.60 mmol), bis(triphenylphosphine)palladium dichloride (1.07 g, 1.52 mmol), acetonitrile (45 mL), toluene (15 mL), dioxane, and water (4 mL / 1 mL) were added sequentially. After purging with nitrogen, the mixture was reacted at 80 °C. After 12 hours of monitoring, the reaction solution was filtered to remove insoluble matter. The filter cake was washed with ethyl acetate and then extracted with an ethyl acetate / water system (50 mL * 3). The organic phase was washed with saturated brine (50 mL), dried, filtered, concentrated, and purified by silica gel column chromatography (n-heptane:ethyl acetate = 100:0 ~ 40:60) to give 2.1 g of tert-butyl 4-((4'-cyano-[1,1'-diphenyl]-4-yl)amino)piperidine-1-carboxylic acid ester, yield: 36.60%, MS [ESI]: m / z = 378.7, [M+H]+.

[0408] Step 3: Synthesis of 4'-(piperidin-4-ylamino)-[1,1'-diphenyl]-4-carboxynitrile (int-6)

[0409] In a 25 mL single-port container equipped with a magnetic stirrer, tert-butyl-4-((4'-cyano-[1,1'-diphenyl]-4-yl)amino)piperidin-1-carboxylic acid ester (2.1 g, 5.56 mmol), DCM (12 mL), and TFA (4 mL) were added sequentially. After the addition was complete, the reaction mixture was reacted at 25 °C for 2 hours. After the reaction was completed, the reaction solution was transferred to 30 mL of ice water, and dichloromethane (20 mL) was added. The pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted. Dichloromethane (15 mL * 3) was added, the organic phase was dried, filtered, and the solvent was concentrated to obtain 0.67 g of crude 4'-(piperidin-4-ylamino)-[1,1'-diphenyl]-4-carboxylonitrile (int-6). This crude product did not require further purification and proceeded directly to the next step. Yield: 43.42%, MS [ESI]: m / z = 278.7, [M+H]+.

[0410] Intermediate 7: Synthesis of 4-(6-(piperidin-4-yloxy)pyridin-3-yl)benzyl nitrile (Int-7)

[0411] Step 1: Synthesis of 4-(6-fluoropyridin-3-yl)benzyl nitrile (Int-7-1)

[0412] To a mixture of (4-cyanophenyl)boronic acid (2 g, 13.6 mmol) dissolved in 1,4-dioxane (20 mL) and water (2 mL), 5-bromo-2-fluoropyridine (2.36 g, 13.6 mmol), potassium carbonate (3.48 g, 27.2 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (798 mg, 1.36 mmol) were added. The mixture was heated to 90 °C and stirred overnight under nitrogen protection, then cooled to room temperature. The solution was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound Int-7-1 (1.6 g, 8.08 mmol, yield 59%), MS [ESI]: m / z = 199, [M+H] + .

[0413] Step 2: Synthesis of tert-butyl 4-((5-(4-cyanophenyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (Int-7-2)

[0414] At 0 °C, 406 mg (2.02 mmol) of tert-butyl 4-hydroxypiperidin-1-carboxylate was dissolved in 6 mL of tetrahydrofuran. Sodium hydride (80 mg, 2.02 mmol) was added to the solution, and the mixture was stirred at 0 °C for 10 minutes. Then, 200 mg (1.01 mmol) of 4-(6-fluoropyridin-3-yl)benzyl nitrile (Int-7-1) was added. Under nitrogen protection, the mixture was heated to 70 °C and stirred overnight, then cooled to room temperature. The solution was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound Int-7-2 (80 mg, 0.21 mmol, yield 19%). MS [ESI]: m / z = 380, [M+H] + .

[0415] Step 3: Synthesis of 4-(6-(piperidin-4-yloxy)pyridin-3-yl)benzyl nitrile (Int-7)

[0416] At 0 °C, tert-butyl 4-((5-(4-cyanophenyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (Int-7-2) (80 mg, 0.41 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added to the solution. The mixture was stirred at room temperature for half an hour, and an aqueous sodium bicarbonate solution was added to adjust the pH to >7. The solution was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound Int-7 (60 mg, 0.21 mmol, 99% yield). MS [ESI]: m / z = 280, [M+H] + .

[0417] Intermediate 8: Synthesis of 4'-(piperidin-4-yloxy)-[1,1'-biphenyl]-4-carboxynitrile (Int-8)

[0418] Step 1: Synthesis of tert-butyl 4-(4-bromophenoxy)piperidine-1-carboxylate (Int-8-1)

[0419] At 0 °C, tert-butyl 4-hydroxypiperidin-1-carboxylate (5 g, 24.8 mmol) and 4-bromophenol (4.3 g, 24.8 mmol) were dissolved in tetrahydrofuran (60 mL). Triphenylphosphine (10.4 g, 49.6 mmol) and diisopropyl azodicarbonate (10.1 g, 49.6 mmol) were added to the solution. Under nitrogen protection, the mixture was heated to 60 °C and stirred overnight, then cooled to room temperature. The solution was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound Int-8-1 (6.8 g, 19.1 mmol, yield 77%), MS [ESI]: m / z = 356, [M+H] + .

[0420] Step 2: Synthesis of tert-butyl 4-((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)piperidine-1-carboxylate (Int-8-2)

[0421] 4-(4-bromophenoxy)piperidine-1-carboxylic acid tert-butyl ester (6.8 g, 19.1 mmol) was dissolved in a mixture of 1,4-dioxane (120 mL) and water (12 mL). (4-cyanophenyl)boronic acid (2.8 g, 19.1 mmol), potassium carbonate (4.8 g, 38.2 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.1 g, 1.9 mmol) were added to the solution. The mixture was heated to 90 °C and stirred overnight under nitrogen protection, then cooled to room temperature. The solution was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound Int-8-2 (4 g, 10.5 mmol, yield 55%), MS [ESI]: m / z = 379, [M+H] + .

[0422] Step 3: Synthesis of 4'-(piperidin-4-yloxy)-[1,1'-biphenyl]-4-carboxynitrile (Int-8)

[0423] At 0 °C, 4 g (10.5 mmol) of 4-((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester was dissolved in 30 mL of dichloromethane, and 6 mL of trifluoroacetic acid was added to the solution. The mixture was stirred at room temperature for half an hour, and an aqueous sodium bicarbonate solution was added to adjust the pH to >7. The solution was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound Int-8 (2.3 g, 8.2 mmol, yield 78%), MS [ESI]: m / z = 279, [M+H] + .

[0424] Synthesis of Intermediate 9: (3aR,6aS)-2-(4-(2,2,2-trifluoroethoxy)benzyl)octahydropyrrolo[3,4-c]pyrrole (Int-9)

[0425] Step 1: Synthesis of 4-(2,2,2-trifluoroethoxy)benzaldehyde (Int-9-1)

[0426] Compound 2,2,2-trifluoroethanol (2.1 g, 20.99 mmol), 4-fluorobenzaldehyde (2.61 g, 20.99 mmol), anhydrous potassium carbonate (4.35 g, 31.49 mmol), and N,N-dimethylformamide (20 mL) were added to a dry round-bottom flask. The system was heated to 80 °C and stirred for 12 hours. The reaction was confirmed to be complete by LC-MS. After adding water to the reaction system, extraction was performed, and the extract was evaporated to dryness to give the title compound (3.7 g, 18.12 mmol, yield 86.34%). MS [ESI]: m / z = 205.1, [M+H]+

[0427] Step 2: Synthesis of (3aR,6aS)-5-(4-(2,2,2-trifluoroethoxy)benzyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (Int-9-2)

[0428] Compound 4-(2,2,2-trifluoroethoxy)benzaldehyde (200 mg, 979.69 μmol), (3aR,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylic acid tert-butyl ester (228.77 mg, 1.08 mmol), sodium triacetoxyborohydride (186.87 mg, 881.72 μmol), glacial acetic acid (0.05 mL), and anhydrous dichloromethane (5 mL) were added to a dry round-bottom flask. The mixture was stirred at room temperature for 2 hours. The reaction was confirmed to be complete by LC-MS. The title compound (260 mg, 649.30 μmol, yield 66.28%) was separated by normal-phase column PE / EA: 60 / 40 to 45 / 55. MS [ESI]: m / z = 401.1, [M+H]+.

[0429] Step 3: Synthesis of (3aR,6aS)-2-(4-(2,2,2-trifluoroethoxy)benzyl)octahydropyrrolo[3,4-c]pyrrole (Int-9)

[0430] To a dry round-bottom flask, add compound (3aR,6aS)-5-(4-(2,2,2-trifluoroethoxy)benzyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylic acid tert-butyl ester (260 mg, 649.30 μmol) and a dioxane solution (2 mL) of hydrogen chloride. Stir at room temperature for 2 hours. The reaction was confirmed to be complete by LC-MS. The title compound (180 mg, 599.36 μmol, yield 92.31%) was obtained by free extraction with sodium bicarbonate. MS [ESI]: m / z = 301.2, [M+H]+.

[0431] Intermediate 10: Synthesis of 3-fluoro-5-(4-fluorophenyl)-2-((3R,4S)-3-fluoropiperidin-4-yl)oxy)pyridine (Int-10)

[0432] Step 1: Synthesis of (3R,4S)-4-((5-bromo-3-fluoropyridin-2-yl)oxy)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (int-10-1)

[0433] In a 50 mL two-necked flask equipped with a magnetic stirrer, tert-butyl (3R,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (1.5 g, 6.84 mmol) was added and dissolved in DMF (15 mL). The nitrogen atmosphere was replaced, and sodium hydride (410.4 mg, 10.26 mmol) was added to the solution under an ice-water bath. The mixture was stirred for 30 minutes, and then 5-bromo-2,3-difluoropyridine (1.32 g, 6.84 mmol) was added. The mixture was then refluxed and stirred overnight at 80 °C for 12 hours. After the reaction was monitored by LCMS, water was added to quench the reaction, followed by extraction with an ethyl acetate / water system (40 mL * 3), washing once with saturated ammonium chloride solution (30 mL * 1), drying, filtering, and concentration. Silica gel column chromatography (n-heptane:ethyl acetate = 100:0 ~ 40:60) was performed to give 1.62 g of (3R,4S)-4-((5-bromo-3-fluoropyridin-2-yl)oxy)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (int-10-1), yield: 60.38%, MS [ESI]: m / z = 392.05, [M-(1 / 2)Boc]+.

[0434] Step 2: Synthesis of (3R,4S)-3-fluoro-4-((3-fluoro-5-(4-fluorophenyl)pyridin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (int-10-2)

[0435] Take a 50 mL reaction flask, add (3R,4S)-4-((5-bromo-3-fluoropyridin-2-yl)oxy)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (1.04 g, 2.64 mmol), 4-fluorophenylboronic acid (739.41 mg, 5.28 mmol), and potassium carbonate (912.94 mg, 6.61 mmol), then add 1,4-dioxane (21 mL) and water (3 mL) and stir to dissolve. Then, purge the mixture under a nitrogen atmosphere, and finally add Pd(dppf)Cl2 (2... 90.00 mg (0.39 mmol) was stirred at 95 °C for 12 h. After LCMS monitoring, the sample was filtered through diatomaceous earth, concentrated, mixed, and passed through a column. The ratio of n-heptane to ethyl acetate was 100:0 to 60:40. Finally, 1.05 g of (3R,4S)-3-fluoro-4-((3-fluoro-5-(4-fluorophenyl)pyridin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (int-10-2) was obtained, with a yield of 97.33%. MS [ESI]: m / z = 408.17, [M+H]+.

[0436] Step 3: Synthesis of 3-fluoro-5-(4-fluorophenyl)-2-((3R,4S)-3-fluoropiperidin-4-yl)oxy)pyridine (int-10)

[0437] In a 25 mL reaction flask equipped with a magnetic stirrer, tert-butyl (3R,4S)-3-fluoro-4-((3-fluoro-5-(4-fluorophenyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (int-10-2) (1.05 g, 2.57 mmol) was added, dissolved in dichloromethane (10 mL), and then trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was monitored by LCMS, saturated sodium bicarbonate solution was added to adjust to weak alkalinity, and then extracted with a dichloromethane / water system (30 mL * 3). The extract was dried, filtered, concentrated, and purified by silica gel column chromatography (water:methanol = 100:0 ~ 20:80) to obtain 3-fluoro-5-(4-fluorophenyl)-2-((3R,4S)-3-fluoropiperidin-4-yl)oxy)pyridine (int-10) 716 mg, 90.45%, MS [ESI]: m / z = 308.11, [M+H]+.

[0438] Synthesis of intermediate 11: 6-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzyl nicotinate (Int-11)

[0439] Step 1: Synthesis of 6-chloronicotinic acid benzyl ester (int-11-1)

[0440] In a 250 mL three-necked flask equipped with a magnetic stirrer, benzyl bromide (5.18 g, 30.28 mmol, 3.60 mL) was added and dissolved in DMF (50 mL). The nitrogen atmosphere was then replaced, and 6-chloronicotinic acid (4.0 g, 25.23 mmol) was added under an ice-water bath. Potassium carbonate (6.97 g, 50.46 mmol) was added to the solution, and the mixture was stirred at 80 °C for 12 hours. After the reaction was monitored and completed, water was added to quench the reaction, followed by extraction with an ethyl acetate / water system (40 mL * 3), drying, filtration, and concentration. The solution was then concentrated and purified by silica gel column chromatography (n-heptane: methyl tert-butyl ether = 100:0 to 0:100) to obtain 4.8 g of benzyl 6-chloronicotinic acid, yield: 76.81%, MS [ESI]: m / z = 248.2, [M+H]+.

[0441] 1H NMR (400MHz, CDCl3) δ9.03 (d, J = 2.2Hz, 1H), 8.26 (dd, J = 8.3, 2.4Hz, 1H), 7.46-7.36 (m, 6H), 5.39 (s, 2H).

[0442] Step 2: Synthesis of 6-(((3R,4S)-1-(tert-butoxycarbonyl)-3-fluoropiperidinyl-4-yl)oxy)benzyl nicotinate (int-11-2)

[0443] In a 100 mL three-necked flask equipped with a magnetic stirrer, tert-butyl (3R,4S)-3-fluoro-4-hydroxy-piperidine-1-carboxylic acid (2.97 g, 13.55 mmol) was added sequentially and dissolved in THF (30 mL). The nitrogen atmosphere was then displaced. Under an ice-water bath, NaH (738.80 mg, 18.47 mmol, 60% purity) was added to the solution, and the mixture was stirred for 30 minutes. Then, benzyl 6-chloronicotinate (3.05 g, 12.31 mmol) was added, and the mixture was kept at 25 °C. After stirring for 1 hour and monitoring the reaction by LCMS, the reaction was quenched with ice water, then extracted with ethyl acetate / water (40 mL * 3), dried, filtered, concentrated, and subjected to silica gel column chromatography (n-heptane:ethyl acetate = 100:0 ~ 50:50) to give 6-(((3R,4S)-1-(tert-butoxycarbonyl)-3-fluoropiperidinyl-4-yl)oxy)benzyl nicotinate (1.32 g, 3.07 mmol, 24.90% yield), MS [ESI]: m / z = 375.2, [M-55]+.

[0444] Step 3: Synthesis of 6-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzyl nicotinate (Int-11)

[0445] In a 100 mL single-necked flask equipped with a magnetic stirrer, 1.26 g (2.93 mmol) of 6-(((3R,4S)-1-(tert-butyloxycarbonyl)-3-fluoropiperidinyl-4-yl)oxy)benzyl nicotinate, 12 mL of DCM, and 3 mL of TFA were added sequentially. The reaction was allowed to proceed at room temperature for 1 hour after the addition was complete. After the reaction was completed, the solvent was concentrated to dryness. The residue was added to dichloromethane / methanol (30 ml / 3 ml) and 10 ml of ice water. After adjusting the pH to 7-8 with saturated sodium bicarbonate solution, the mixture was extracted with dichloromethane / methanol at a ratio of 10:1 (30 ml * 4). The organic phase was then subjected to normal-phase column chromatography (dichloromethane:methanol = 100:0 ~ 40:60) to obtain 0.86 g of 6-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)nicotinic acid benzyl ester, yield: 88.94%, MS [ESI]: m / z = 331.2, [M+H]+.

[0446] Synthesis of Intermediate 12: (3R,4S)-3-fluoro-4-(4-(methanesulfonyl)phenoxy)piperidine (Int-12)

[0447] Step 1: Synthesis of (3R,4S)-3-fluoro-4-(4-(methylsulfonyl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester (Int-12-1)

[0448] NaH (228.12 mg, 5.70 mmol, 60% purity) and DMF (5 mL) were added sequentially to a 100 mL three-necked flask equipped with a stir bar. The mixture was purged with N2 three times, and the temperature was lowered to 0 °C. A DMF (3 mL) solution of (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.28 mmol) was added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 30 min. Then, a DMF (3 mL) solution of 1-bromo-4-(methanesulfonyl)benzene (590 mg, 2.51 mmol) was added dropwise again. The reaction was carried out at 60 °C for 2 hours after the addition was complete. The reaction was monitored by LCMS until complete, quenched with saturated ammonium chloride, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated, mixed, and purified by forward purging (n-heptane:ethyl acetate = 1:2) to give (3R,4S)-3-fluoro-4-(4-(methanesulfonyl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester (678 mg, 1.82 mmol, 79.58% yield). MS [ESI]: m / z = 318.2, [M-55]+.

[0449] Step 2: Synthesis of (3R,4S)-3-fluoro-4-(4-(methylsulfonyl)phenoxy)piperidine (Int-12)

[0450] (3R,4S)-3-fluoro-4-(4-(methanesulfonyl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester (670 mg, 1.79 mmol) and dichloromethane (3 mL) were added sequentially to a 50 mL single-necked flask equipped with a stir bar. The mixture was cooled to 0 °C, and HCl / 1,4-dioxane (4.0 M, 17.94 mmol, 4.49 mL) was slowly added dropwise. After the addition was complete, the reaction mixture was kept at 25 °C for 2 hours. The reaction was monitored by LC-MS until complete. The reaction solution was concentrated, and the residue was cooled to 0 °C. The pH was adjusted to 7 with saturated sodium bicarbonate, and the mixture was purified by reverse C18 chromatography to give (3R,4S)-3-fluoro-4-(4-(methanesulfonyl)phenoxy)piperidine (360 mg, 1.32 mmol, 73.41% yield). MS [ESI]: m / z = 274.1, [M+H]+.

[0451] Synthesis of Intermediate 13: 3-Fluoro-6-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)pyridazine (Int-13)

[0452] Step 1: Synthesis of (3R,4S)-3-fluoro-4-((6-fluoropyridazine-3-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (Int-13-1)

[0453] Take 100ml reaction flask No. 1, add (3R,4S)-3-fluoro-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.08g, 4.93mmol) and DMF (15mL), replace with nitrogen gas, add NaH (129.01mg, 5.38mmol) under ice-water bath, and stir for 30 minutes. Then take another 100ml reaction flask No. 2, add 3,6-difluoropyridazine (520mg, 4.48mmol), add DMF (15mL) to dissolve, and slowly add the reaction solution from reaction flask No. 1 to flask No. 2 dropwise under ice-water bath. After the addition is complete, place the mixture at 65℃ for 1 hour. After LCMS monitoring, the organic phase was extracted with ethyl acetate / water (40 ml * 3), followed by washing with saturated ammonium chloride solution, and column chromatography (79:21) to obtain (3R,4S)-3-fluoro-4-((6-fluoropyridazine-3-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (200 mg, 634.29 μmol), yield: 14.16% yield, MS [ESI]: m / z = 260.1, [M-55]+.

[0454] Step 2: Synthesis of 3-fluoro-6-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)pyridazine (Int-13)

[0455] Take a 100ml reaction flask, add (3R,4S)-3-fluoro-4-((6-fluoropyridazine-3-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (200mg, 634.29μmol), dissolve in DCM (6mL), add TFA (1.48g, 12.98mmol, 1mL), react at room temperature for 3 hours, monitor the reaction by LCMS, concentrate all solvent residue to dryness, add dichloromethane / methanol (30ml / 3ml) and 10ml ice water, adjust pH to 7-8 with saturated sodium bicarbonate solution, extract with DCM / MeOH = 10:1 (30ml*4), and then pass the organic phase by normal phase column chromatography (DCM, MeOH = 100:0~40:60) to obtain 105mg of 3-fluoro-6-(((3R,4S)-3-fluoropiperidine-4-yl)oxy)pyridazine. Yield: 76.92%, MS[ESI]: m / z = 216.2, [M+H]+.

[0456] Synthesis of Intermediate 14: 2-(5-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)pyrazin-2-yl)prop-2-ol (Int-14)

[0457] Step 1: Synthesis of 2-(5-chloropyrazin-2-yl)prop-2-ol (Int-14-1)

[0458] Ethyl 5-chloropyrazine-2-carboxylate (2 g, 10.72 mmol) and THF (20 mL) were added sequentially to a 50 mL single-necked flask equipped with a stir bar. The mixture was purged with N2 three times, cooled to 0 °C, and then methyl magnesium bromide (1.0 M, 23.58 mmol, 23.58 mL) was slowly added dropwise. After the addition was complete, the reaction was carried out at 60 °C for 12 hours. The reaction was monitored by LC-MS until completion. The mixture was quenched with water, extracted with dichloromethane:methanol (10:1) (30 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated. The solution was then purified by forward silica gel chromatography (n-heptane:ethyl acetate = 1:1) to give 2-(5-chloropyrazine-2-yl)prop-2-ol (254 mg, 1.47 mmol, 13.73% yield). MS [ESI]: m / z = 173.1, [M+H]+.

[0459] Step 2: Synthesis of (3R,4S)-3-fluoro-4-((5-(2-hydroxypropyl-2-yl)pyrazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (Int-14-2)

[0460] (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (293.30 mg, 1.34 mmol) and DMF (6 mL) were added sequentially to a 100 mL three-necked flask equipped with a stir bar. The mixture was purged with N2 three times, cooled to 0 °C, and then NaH (133.76 mg, 3.34 mmol, 60% purity) was added. After the addition was complete, the mixture was stirred at 0 °C for 30 min. Then, a solution of 2-(5-chloropyrazin-2-yl)prop-2-ol (254 mg, 1.47 mmol) in DMF (6 mL) was added. After the addition was complete, the mixture was reacted at 60 °C for 3 h. The reaction was monitored by LCMS until complete, quenched with saturated ammonium chloride, extracted with ethyl acetate (30 ml * 3), dried over saturated brine (30 ml) and anhydrous sodium sulfate, filtered, and purified by silica gel forward chromatography (heptane:ethyl acetate = 2:1) to give (3R,4S)-3-fluoro-4-((5-(2-hydroxypropyl-2-yl)pyrazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (380 mg, 1.07 mmol, 79.93% yield). MS [ESI]: m / z = 356.2, [M+H]+.

[0461] Step 3: Synthesis of 2-(5-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)pyrazin-2-yl)prop-2-ol (Int-14)

[0462] (3R,4S)-3-fluoro-4-((5-(2-hydroxypropyl-2-yl)pyrazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (382 mg, 1.07 mmol) and dichloromethane (2 mL) were added sequentially to a 25 mL single-necked flask equipped with a stir bar. The temperature was lowered to 0 °C, and HCl / 1,4-dioxane (4.0 M, 10.75 mmol, 2.69 mL) was slowly added. After the addition was complete, the reaction was carried out at 25 °C for 12 hours. The reaction was monitored by LCMS until complete. The organic phase was concentrated, pH adjusted to 7 with saturated sodium bicarbonate, and extracted with DCM:MeOH = 10:1 (30 ml * 3). The extract was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by reverse C18 purification (ammonia:methanol = 30%) to give 2-(5-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)pyrazin-2-yl)prop-2-ol (180 mg, 705.09 μmol, 65.60% yield). MS [ESI]: m / z = 256.1, [M+H]+.

[0463] Synthesis of Intermediate 15: N-((3R,4S)-3-fluoropiperidin-4-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole-2-amine (Int-15)

[0464] Step 1: Synthesis of (3R,4S)-3-fluoro-4-((5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)amine)piperidine-1-carboxylic acid tert-butyl ester (Int-15-1)

[0465] (3R,4S)-4-amine-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (974.20 mg, 4.46 mmol) was added to a 25 mL pressure-resistant tube equipped with a magnetic stir bar and dissolved in dioxane (15 mL). DIEA (1.33 g, 10.30 mmol) and 2-bromo-5-(trifluoromethyl)-1,3,4-thiadiazole (0.8 g, 3.43 mmol) were added, and the mixture was stirred at 120 °C for 2 hours. After the reaction was monitored by LCMS, the solution was diluted with water, extracted with ethyl acetate / water (50 mL * 3), dried, filtered, concentrated, and purified by silica gel column chromatography (n-heptane: methyl tert-butyl ether = 100:0 ~ 0:100) to give (3R,4S)-3-fluoro-4-((5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)amine)piperidine-1-carboxylic acid tert-butyl ester (1.21 g, 3.27 mmol, 95.16% yield), MS [ESI]: m / z = 315.2, [M-55]+.

[0466] Step 2: Synthesis of N-((3R,4S)-3-fluoropiperidin-4-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole-2-amine (Int-15)

[0467] In a 100 mL three-necked flask equipped with a magnetic stirrer, add 0.87 g (2.35 mmol) of (3R,4S)-3-fluoro-4-((5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)amine)piperidine-1-carboxylic acid tert-butyl ester, dissolve it in dichloromethane (10 mL), add trifluoroacetic acid (5 mL), and stir at 20 °C for 2 hours. After the reaction was completed under LCMS monitoring, all solvents were concentrated to dryness. The residue was added to dichloromethane / methanol (30 ml / 3 ml) and 10 ml of ice water. The pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and then extracted with dichloromethane / methanol at a ratio of 10:1 (30 ml * 4). The organic phase was then subjected to normal-phase column chromatography (dichloromethane, methanol = 100:0 ~ 40:60) to obtain 0.47 g of N-((3R,4S)-3-fluoropiperidin-4-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole-2-amine, yield: 74.04%, MS [ESI]: m / z = 271.2, [M+H]+.

[0468] Example 1: Synthesis of 2-(2,4-difluorophenyl)-1-(1H-tetrazol-1-yl)-3-(4-(4-(2,2,2-trifluoroethoxy)phenyl)piperidin-1-yl)propyl-2-ol (Example 1)

[0469] In a 10 mL sealed tube equipped with a magnetic stir bar, 4-(4-(2,2,2-trifluoroethoxy)phenyl)piperidine (int-4, 0.04 g, 0.154 mmol), 1-((2-(2,4-difluorophenyl)epoxy-2-yl)methyl)-1H-tetrazole (int-1, 0.037 g, 0.154 mmol), NMP (1.5 mL), and potassium carbonate (191.2 mg, 0.462 mg) were added sequentially. The solution was added to 2-(2,4-difluorophenyl)-1-(1H-tetrazol-1-yl)-3-(4-(4-(2,2,2-trifluoroethoxy)phenyl)piperidin-1-yl)propyl-2-ol (Example 1, 20 mg, 0.039 mmol, yield 25.9%), and the reaction was carried out at 85°C for 3 hours. LC-MS was used to confirm the completeness of the reaction. The product was purified by reverse-phase preparation to obtain 2-(2,4-difluorophenyl)-1-(1H-tetrazol-1-yl)-3-(4-(4-(2,2,2-trifluoroethoxy)phenyl)piperidin-1-yl)propyl-2-ol (MS [ESI]: m / z = 498.2, [M+H]). + .

[0470] 1H NMR(400MHz, CDCl3)δ8.91(s,1H),7.67-7.472(m,1H),7.20-7.08(m,2H),6.98-6.78(m,4H),5. 14-4.75(m,2H),4.32(q,J=8.0Hz,2H),3.81-3.40(m,2H),3.21-2.92(m,1H),2.78-1.47(m,8H).

[0471] Example 2: Synthesis of 4-((4-((1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-tetrazol-1-yl)but-2-yl)piperidin-4-yl)ethynyl)phenoxy)methyl)benzonitrile (Example 2)

[0472] Compounds 1-(((2R,3S)-2-(2,4-difluorophenyl)-3-methylepoxyethylene-2-yl)methyl)-1H-tetrazole (Int-3, 10 mg, 39.65 μmol), 4-((4-(piperidin-4-ylethynyl)phenoxy)methyl)benzonitrile (Int-2, 25.09 mg, 79.30 μmol), and ethanol / water (0.75 mL / 0.25 mL) were added to a dry round-bottom flask. The system was heated to 90 °C and stirred for 36 hours. The reaction was confirmed to be complete by LC-MS. The product was purified by reverse-phase chromatography to obtain Example 2 (2.0 mg, 3.517 μmol, yield 8.87%). MS [ESI]: m / z = 569.3, [M+H] + .

[0473] 1 H NMR(400MHz,CD3OD)δ9.01(s,1H),7.74(d,J=8.4Hz,2H),7.62(d,J=8.4Hz,2H),7 .35-7.24(m,3H),6.97-6.89(m,3H),6.81(td,J=8.4,2.4Hz,1H),5.23-5.08(m,4 H),3.21(q,J=7.2Hz,1H),3.09-2.99(m,1H),2.81-2.66(m,2H),2.61-2.51(m,1H ),2.33(t,J=9.2Hz,1H),1.99-1.88(m,2H),1.87-1.71(m,2H),0.98-0.86(m,3H).

[0474] Example 176: Synthesis of (2R,3R)-2-(2,4-difluorobenzene)-3-((3R,4S)-3-fluoro-4-((3-fluoro-5-(4-fluorophenyl)pyridin-2-yl)oxy)piperidin-1-yl)-1-(1H-tetrazol-1-yl)butyl-2-ol (Example 176)

[0475] In a 25 ml sealed tube equipped with a magnetic stirrer, 3-fluoro-5-(4-fluorophenyl)-2-((3R,4S)-3-fluoropiperidin-4-yl)oxy)pyridine (int-10, 206.4 mg, 0.67 mmol), 1-(((2R,3S)-2-(2,4-difluorophenyl)-3-methylepoxyethylene-2-yl)methyl)-1H-tetrazole (70 mg, 0.27 mmol), ethanol (1.6 mL), and water (0.8 mL) were added sequentially. The mixture was heated to 95 °C and reacted for 48 hours, with the reaction monitored. After the reaction was completed, the crude product was purified and concentrated by pre-HPLC to obtain (2R,3R)-2-(2,4-difluorophenyl)-3-((3R,4S)-3-fluoro-4-((3-fluoro-5-(4-fluorophenyl)pyridin-2-yl)oxy)piperidin-1-yl)-1-(1H-tetrazol-1-yl)butyl-2-ol, 21.1 mg, 0.037 mmol, yield: 13.56%, purity: 96.826%, MS [ESI]: m / z=561.20, [M+H]+.

[0476] 1 H NMR(400MHz,MeOD)δ8.99(s,1H),8.15(d,J=2.0Hz,1H),7.79(dd,J=11.2,2.0Hz,1H),7.68-7.56(m,2H),7.27(t d,J=9.2,6.4Hz,1H),7.23-7.15(m,2H),7.00-6.91(m,1H),6.81(td,J=8.4,2.0Hz,1H),5.37-5.29(m,1H),5.22( s,2H),5.11-5.05(m,0.5H),4.97-4.93(m,0.5H),3.58-3.54(m,1H),3.41(q,J=7.2Hz,1H),2.93(t,J=10.2Hz,1H ),2.88-2.83(m,1H),2.71(dd,J=26.4,11.8Hz,1H),2.32-2.24(m,1H),2.10-1.97(m,1H),0.95(d,J=6.4Hz,3H).

[0477] Example 321: Synthesis of (2R,3R)-2-(2,4-difluorophenyl)-3-((3R,4S)-3-fluoro-4-(4-(methylsulfonyl)phenoxy)piperidin-1-yl)-1-(1H-tetrazol-1-yl)but-2-ol (Example 321)

[0478] (3R,4S)-3-fluoro-4-(4-(methylsulfonyl)phenoxy)piperidine (189 mg, 691.49 μmol), 1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-epoxy-2-yl]methyl]tetrazole (64.79 mg, 276.60 μmol), ethanol (1.6 mL), and water (0.8 mL) were added sequentially to a 25 mL pressure-resistant tube equipped with a stir bar, and the reaction was carried out at 95 °C for 48 hours. After the reaction was monitored by LCMS, pre-HPLC was used to prepare and purify (2R,3R)-2-(2,4-difluorophenyl)-3-((3R,4S)-3-fluoro-4-(4-(methanesulfonyl)phenoxy)piperidin-1-yl)-1-(1H-tetrazol-1-yl)but-2-ol (11 mg, 20.93 μmol, 7.57% yield), purity: 95.244%, MS [ESI]: m / z = 526.1, [M+H]+

[0479] 1H NMR (400MHz, DMSO) δ9.09 (s, 1H), 7.87-7.80 (m, 2H), 7.25 (dd, J = 9.2, 2.4Hz, 2H), 7.20(ddd,J=9.2,7.2,2.4Hz,2H),6.93(td,J=8.4,2.4Hz,1H),5.83(s,1H),5.09 (s,2H),5.05-4.79(m,2H),3.50-3.41(m,1H),3.31-3.25(m,1H),3.17(s,3H),2. 85(t,J=8.4Hz,1H),2.81-2.63(m,2H),2.09-1.87(m,2H),0.81(d,J=6.8Hz,3H).

[0480] Example 324: Synthesis of 6-(((3R,4S)-1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-tetrazol-1-yl)but-2-yl)-3-fluoropiperidin-4-yl)oxy)nicotinic acid (Example 324)

[0481] Step 1: Synthesis of 6-(((3R,4S)-1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-tetrazol-1-yl)butyl-2-ol)-3-fluoropiperidin-4-yl)oxy)benzyl nicotinate (Int-11-3)

[0482] In a 25 ml sealed tube equipped with a magnetic stir bar, 6-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzyl nicotinate (838.26 mg, 2.54 mmol), 1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-epoxy-2-yl]methyl]tetrazole (320 mg, 1.27 mmol), ethanol (4.0 ml), and purified water (2.0 ml) were added sequentially. The mixture was reacted at 95°C for 48 hours. After the reaction was completed, the reaction was monitored. The reaction solution was purified by silica gel normal-phase column chromatography (n-heptane:ethyl acetate = 100:0 to 0:100) to give 6-(((3R,4S)-1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-tetrazol-1-yl)but-2-yl)-3-fluoropiperidin-4-yl)oxy)benzyl nicotinate (198 mg, 339.87 μmol, 26.79% yield), MS [ESI]: m / z = 583.2, [M+H]+

[0483] Step 2: Synthesis of 6-(((3R,4S)-1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-tetrazol-1-yl)but-2-yl)-3-fluoropiperidin-4-yl)oxy)nicotinic acid (Example 324)

[0484] In a 25 ml sealed tube equipped with a magnetic stirrer, 6-(((3R,4S)-1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-tetrazol-1-yl)but-2-yl)-3-fluoropiperidin-4-yl)oxy)benzyl nicotinate (60 mg, 102.99 μmol), methanol (4 ml), and Pd / C (32.75 mg, 10%) were added sequentially. After addition, the hydrogen pressure was controlled at 1.0 MPa, and the reaction was carried out at 25 °C for 12 hours. LC After the reaction was completed under MS monitoring, the filtered reaction solution was purified by pre-HPLC to obtain 6-(((3R,4S)-1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-tetrazol-1-yl)but-2-yl)-3-fluoropiperidin-4-yl)oxy)nicotinic acid (21 mg, 42.64 μmol), yield 41.41%, purity: 99.510%, MS [ESI+]: m / z=493.2, [M+H]+

[0485] 1H NMR (400MHz, DMSO) δ9.13 (s, 1H), 8.62 (d, J = 2.0Hz, 1H), 8.11 (dd, J = 8.4, 2.4Hz, 1H) ,7.29-7.10(m,2H),6.93(d,J=2.4Hz,1H),6.83(d,J=8.4Hz,1H),5.36-5.23(m,1H) ,5.10(s,2H),5.04(s,0.5H),4.92(s,0.5H),3.33-3.25(m,2H),2.86(t,J=10.0Hz, 1H),2.77-2.60(m,2H),2.14-2.07(m,1H),1.98-1.89(s,1H),0.81(d,J=6.8Hz,3H).

[0486] Example 326: Synthesis of (2R,3R)-2-(2,4-difluorophenyl)-3-((3R,4S)-3-fluoro-4-((6-fluoropyridazin-3-yl)oxy)piperidin-1-yl)-1-(1H-tetrazol-1-yl)but-2-ol (Example 326)

[0487] Take a 25 mL pressure-resistant tube, add 3-fluoro-6-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)pyridazine (100 mg, 464.69 μmol), 1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-epoxy-2-yl]methyl]tetrazole (50 mg, 198.24 μmol), water (0.5 mL), and ethanol (1 mL), replace with nitrogen gas, and then react at 95 °C for 24 hours. After the reaction was monitored by LCMS, the reaction solution was purified by pre-HPLC to obtain 30 mg (0.05 mmol) of (2R,3R)-2-(2,4-difluorophenyl)-3-((3R,4S)-3-fluoro-4-((6-fluoropyridazin-3-yl)oxy)piperidin-1-yl)-1-(1H-tetrazol-1-yl)but-2-ol, yield: 18.9%, purity: 81.886%, MS [ESI]: m / z=468.2, [M+H]+.

[0488] 1H NMR(400MHz, Methanol-d4)δ8.97(s,1H),7.46(dd,J=9.6,1.6Hz,1H),7.37(dd,J=9.2,6.0Hz,1H), 7.26(td,J=9.2,6.4Hz,1H),6.95(ddd,J=12.4,8.8,2.8Hz,1H),6.85-6.76(m,1H),5.37-5.26(m,1 H),5.21(s,2H),5.03(d,J=49.2Hz,1H),3.62-3.52(m,1H),3.41(q,J=7.2Hz,1H),2.97-2.79(m,2H ),2.70(dd,J=28.0,12.8Hz,1H),2.33-2.28(m,1H),2.12-2.04(m,1H),0.94(dd,J=7.2,1.2Hz,3H).

[0489] Example 329: Synthesis of (2R,3R)-2-(2,4-difluorophenyl)-3-((3R,4S)-3-fluoro-4-((5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)amine)piperidin-1-yl)-1-(1H-tetrazol-1-yl)butyl-2-ol (Example 329)

[0490] 2-(5-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)pyrazin-2-yl)prop-2-ol (100 mg, 391.71 μmol), 1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-epoxy-2-yl]methyl]tetrazole (36.70 mg, 156.69 μmol), ethanol (1.2 mL) and water (0.6 mL) were added sequentially to a 25 mL pressure-resistant tube equipped with a stir bar, and the reaction was carried out at 95 °C for 48 hours. The reaction was monitored by LCMS until completion. Pre-HPLC purification yielded (2R,3R)-2-(2,4-difluorophenyl)-3-((3R,4S)-3-fluoro-4-((5-(2-hydroxypropyl-2-yl)pyrazin-2-yl)oxy)piperidin-1-yl)-1-(1H-tetrazol-1-yl)but-2-ol (11 mg, 21.67 μmol, 13.83% yield), purity: 97.420%. MS [ESI]: m / z = 508.1, [M+H]+.

[0491] 1H NMR(400MHz,MeOD)δ8.98(s,1H),8.37(d,J=1.2Hz,1H),8.15(d,J=1.2Hz,1H),7.27(td,J= 9.2,6.4Hz,1H),6.99-6.91(m,1H),6.81(td,J=8.0,2.4Hz,1H),5.21(s,3H),5.00(dd,J=2 6.4,24.0Hz,1H),3.58-3.50(m,1H),3.40(q,J=7.2Hz,1H),2.96-2.80(m,2H),2.70(dd,J= 27.2,12.0Hz,1H),2.33-2.17(m,1H),2.07-1.97(m,1H),1.54(s,6H),0.95(d,J=6.4Hz,3H)

[0492] Example 330: Synthesis of (2R,3R)-2-(2,4-difluorophenyl)-3-((3R,4S)-3-fluoro-4-((5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)amine)piperidin-1-yl)-1-(1H-tetrazol-1-yl)butyl-2-ol (Example 330)

[0493] In a 25 mL pressure-resistant tube equipped with a magnetic stirrer, N-((3R,4S)-3-fluoropiperidin-4-yl)-5-(trifluoromethyl)-1,3,4-thiadiazol-2-amine (80 mg, 318.43 μmol), 1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-epoxy-2-yl]methyl]tetrazole (215.14 mg, 796.08 μmol), ethanol (1.6 mL), and pure water (0.8 mL) were added. After the addition was complete, the mixture was reacted at 95 °C for 48 hours, and the reaction was monitored. After completion, the reaction solution was purified and concentrated by pre-HPLC to obtain (2R,3R)-2-(2,4-difluorophenyl)-3-((3R,4S)-3-fluoro-4-((5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)amine)piperidin-1-yl)-1-(1H-tetrazole-1-yl)butyl-2-ol (35 mg, 66.99 μmol), yield: 21.04%, purity: 99.570%, MS [ESI+]: m / z=523.2, [M+H]+.

[0494] 1H NMR (400MHz, MeOD) δ8.96 (s, 1H), 7.26 (d, J = 6.4Hz, 1H), 7.01-6.90 (m, 1H), 6.81 (t d,J=8.0,2.4Hz,1H),5.20(s,2H),4.98(s,0.5H),4.87-4.83(m,0.5H),4.04-3.89( m,1H),3.64(t,J=9.2Hz,1H),3.40(s,1H),3.35-3.32(m,1H),2.88(s,2H),2.59(dd ,J=35.2,13.2Hz,1H),2.17-2.06(m,1H),2.04-1.94(m,1H),0.93(d,J=6.4Hz,3H).

[0495] The following examples were prepared using the procedures described in Examples 1, 2, 176, 321, 324, 326, 329, and 330, with reference to the respective intermediates (partially referring to the synthesis methods of intermediates 1-15) and reagents under conditions deemed suitable by those skilled in the art. Other compounds of this application can be synthesized similarly.

[0496] Biological testing evaluation

[0497] The present disclosure is further described and explained below with reference to test examples, but these examples are merely illustrative of the effects of some compounds and are not intended to limit the scope of the present disclosure.

[0498] Test Example 1: Minimum Inhibitory Concentration (MIC) for Fungal Growth

[0499] experimental strains

[0500] Test culture medium

[0501] RPMI1640 medium

[0502] Experimental Procedure

[0503] The MIC test method was performed in accordance with the guidelines and requirements of CLSI M27 (for yeasts) and M38 (for Aspergillus).

[0504] Preparation of fungal inoculum

[0505] Candida albicans ATCC 90028: Using a sterile inoculation loop, scrape a small amount of frozen Candida albicans onto an SDA plate and streak it. Incubate at 35±2℃ for approximately 24 hours. Pick 3-5 single colonies from the above solid culture dish and resuspend them in sterile physiological saline (0.9% NaCl). Adjust the turbidity to ~0.2 using a turbidimeter. Dilute the above bacteria 2000 times using RPMI 1640 to achieve an inoculum concentration of 5×10⁻⁶. 2 ~2.5×10 3 CFU / ml. This is the inoculation solution.

[0506] Aspergillus fumigatus ATCC MYA-3626: Using a sterile inoculation loop, scrape a small amount of frozen fungus and streak it onto an SDA-containing Petri dish. Incubate at 35±2℃ for 2-4 days. Cover the cultured fungus with 1 ml of sterile physiological saline (0.9% NaCl). Collect spores using an L-spreader, dilute to a certain factor, and count under a microscope using a hemocytometer. Dilute the spores to an inoculation concentration of 0.4-5 × 10⁻⁵ using RPMI 1640. 4 CFU / ml. This is the inoculation solution.

[0507] Compound preparation and processing

[0508] On the day of the experiment, the compound in the bottle was dissolved in 100% DMSO to prepare a compound stock solution for later use. According to the required test concentration, a 100x working solution was prepared on a 96-well plate, and the compound was serially diluted 10 times (2-fold) using DMSO, resulting in 11 concentrations. 100% DMSO was used as a growth control. This is the compound stock plate.

[0509] Transfer 2 μL of 100x working solution from the compound master plate to a 96-well plate, then add 198 μL of bacterial inoculum to each well to obtain the MIC test plate. A final concentration of 1% DMSO was used as a growth control.

[0510] Incubate for the appropriate time according to the testing requirements of different bacterial species and read the MIC results.

[0511] MIC detection and result reading

[0512] Candida albicans ATCC 90028: Incubate the inoculated 96-well plates at 35±2℃ for approximately 24 hours. Visually inspect and record the MIC value for ≥50% growth inhibition (compared to the growth control wells).

[0513] Aspergillus fumigatus ATCC MYA-3626: Incubate the inoculated 96-well plates at 35±2℃ for approximately 48 hours. Visually observe and read the MIC value of 100% growth inhibition (compared to the growth control well).

[0514] Experimental results:

[0515] See Tables 1 and 2, where A: ≤0.010 μg / mL; B: >0.010 μg / mL and ≤0.125 μg / mL; C: >0.125 μg / mL and ≤1.0 μg / mL; D: >1.0 μg / mL and ≤16.0 μg / mL.

[0516] Table 1. Inhibitory activity of the disclosed compounds against Candida albicans.

[0517] Table 2. Inhibitory activity of the compounds disclosed herein against Aspergillus fumigatus.

[0518] Experimental results exemplarily demonstrate that the disclosed compounds have a strong inhibitory effect on Candida albicans and Aspergillus fumigatus.

[0519] Test Example 2: Inhibition of major CYP enzyme isoforms in the human body

[0520] 2.1 Implementation of reagents and consumables

[0521] Information on the control inhibitor compounds: α-naphthylflavonoid (from TRC); sulfamethoxazole (from MCE); clopidogrel sulfate (from aladdin); montelukast sodium (from the National Institutes for Food and Drug Control); (+)-N-3-benzylphenanol (from Sigma-Aldrich); quinidine (from MCE); ketoconazole (from Meilunbio).

[0522] Probe substrate compound information: Phenacetin (from MCE); Bupropion hydrochloride (from aladdin); Amodiaquine hydrochloride (from Sigma-Aldrich); Diclofenac sodium (from Wokai); S-Mexenotoin (from Chengdu Yuannuo Tiancheng Technology); Dextromethorphan hydrobromide (from TRC); Testosterone (from Chengdu Yuannuo Tiancheng Technology); Midazolam (from China National Institutes for Food and Drug Control).

[0523] Reagent information: Phosphate buffer PB (dipotassium hydrogen phosphate + potassium dihydrogen phosphate) (from Chengdu Kelong); β-NADPH (from MYM).

[0524] Liver microsome information: Human liver microsomes (derived from BIOIVT).

[0525] Experimental incubation system: MgCl2-PB solution (final concentration 3mM); liver microsomes (final concentration 0.2mg / mL); substrates (e.g., phenacetin, bupropion, amodiaquine, diclofenac, S-methoxyphentol, dextromethorphan, midazolam, testosterone); test compounds (final concentrations 0, 10.0μM); inhibitors (e.g., α-naphthylflavonoid, clopidogrel, montelukast, sulfamethoxazole, (+)-N-3-benzylnivanol, quinidine, and ketoconazole); β-NADPH (final concentration 1mM).

[0526] 2.2 Test Procedure

[0527] (1) Prepare a 4 mM β-NADPH solution using PB solution;

[0528] (2) Take PB solution into a centrifuge tube, add MgCl2-PB solution and human liver microsomal solution, add the corresponding substrate compound working solution respectively, vortex to mix, and dispense;

[0529] (3) Add the control inhibitor compound or test compound to each tube and pre-incubate in a 37°C water bath for 5 min. At the same time, pre-incubate β-NADPH in a 37°C water bath for 5 min.

[0530] (4) Incubate with β-NADPH working solution;

[0531] (5) Add internal standard working solution, vortex for 5 min to terminate the reaction, and centrifuge at 5500g for 10 min;

[0532] (6) Take the supernatant and analyze it by LC-MS / MS.

[0533] 2.3 Test Results

[0534] The inhibition rates of the test compound and the control inhibitor compound on the metabolic rates of each specific probe substrate were calculated at different concentration levels. See Table 3 for the specific results.

[0535] Table 3. Inhibitory activity of control inhibitor compounds and test compounds against CYP enzymes.

[0536] Furthermore, other compounds disclosed herein, such as those in Examples 42, 75, 122, 123, 130, 131, 132, 149, 154, 156, 168, 169, 174, 176, 181, 185, 195, 196, 198, 204, 211, 216, 218, 244, 257, 271, 274, 275, and 276, also exhibited inhibition rates below 50% at 10.0 μM.

[0537] Exemplary experimental results demonstrate that the compounds disclosed herein have a low risk of inhibiting major CYP enzyme subtypes in humans and exhibit good liver safety.

[0538] Test Example 3: Study on the stability of liver microsomes in humans, rats, and mice

[0539] Liver microsomal information:

[0540] Preparation of test compounds: Dissolve the test compound in DMSO to prepare a stock solution, and dilute it with methanol to prepare a 100 μM working solution of the test compound for later use.

[0541] Experimental incubation system:

[0542] Experimental Procedure: Transfer an appropriate amount of liver microsome solution into a 1 mL 96-well plate. Add the test reagent (or probe substrate solution) and pre-incubate at 37°C for 5 min. Take two aliquots of the mixture from the system, add 1xPBS instead of NADPH to each aliquot, and take the aliquots at 0 and 60 min respectively. Add methanol (containing the selected appropriate internal standard compound) to terminate the reaction. Add NADPH to each well of the remaining mixture to start the reaction. Take the aliquots of the mixture from the system at 0, 5, 15, 30, and 60 min respectively, and add methanol (containing the selected appropriate internal standard compound) to terminate the reaction. After the incubation time is complete, mix the terminated samples and centrifuge at 3800 rpm for 15 min. Take the supernatant for LC-MS / MS analysis.

[0543] Data analysis: Calculate the half-life (t1 / 2) and clearance rate (CL) using the following first-order kinetic formula.

[0544] LC-MS / MS analysis method for analytes:

[0545] Experimental results:

[0546] Table 4. Half-life (min) of the disclosed compounds in liver microsomal stability tests in humans, rats, and mice.

[0547] Test Example 4: Efficacy Study of Drugs for Systemic Candida Infection in Mice

[0548] Experimental animals: female CD-1 mice, 6-8 weeks old, approximately 27g, n=8;

[0549] Microbial pathogen: Candida albicans ATCC MYA-2876;

[0550] Inoculation level and route of administration: Approximately 6.0E+0.5 CFU / mouse, infection via tail vein injection;

[0551] Test substance: 3mpk, Examples 132, 176, and 181, administered orally;

[0552] Treatment: Treatment begins 24 hours after infection, once daily for a total of 13 days, with an oral administration volume of 20 mL / kg;

[0553] Observation indicators: changes in body weight, mortality, and renal fungal load count in mice within 13 days after infection in each group;

[0554] Conclusion: After CD-1 mice were injected intravenously with a certain dose of Candida albicans ATCC MYA-2876, the mortality rate of the untreated model group reached 100% within 7 days, and the mean fungal load in the kidneys of the deceased animals was greater than 6.01g. In this model, oral administration of 3mpk (Examples 132, 176, and 181) completely protected mice infected with Candida albicans ATCC MYA-2876 from death caused by Candida systemic infection, and the mean fungal load in the kidneys of these mice was reduced by more than 1.01g compared to the untreated model group.

[0555] Test Example 5: Efficacy Study of Drugs for Vaginal Candida Infection in Mice

[0556] Experimental animals: female C3H / HeJ mice, 6-8 weeks old, approximately 20g, n=8;

[0557] Microbial pathogen: Candida albicans ATCC MYA-2876;

[0558] Inoculation level and route of administration: Approximately 9.0E+06 CFU / mouse, infection via vaginal instillation;

[0559] Test substance: 25 mpk Example 132, Example 174, Example 176, Example 220, Example 257, Example 275, Example 276, Example 305, orally administered;

[0560] Treatment: Treatment begins 2 hours after infection, once daily for 3 days, with an oral administration volume of 20 mL / kg;

[0561] Observation indicators: 24 hours after the last administration of the drug to each group of mice, vaginal tissue was collected for fungal load counting.

[0562] Conclusion: A stable vaginal infection model can be established in mice by vaginal instillation of a certain dose of Candida albicans ATCC MYA-2876. The mean fungal load in the vaginal tissue of the untreated model group was greater than 4.01g. In this model, oral administration of 25mpk in Examples 132, 174, 176, 220, 257, 275, 276, and 305 all achieved a mycological cure rate of >50%, and the mean fungal load in the vaginal tissue of these animals was reduced by more than 1.01g compared to the untreated model group.

[0563] The above embodiments do not limit the scope of this disclosure in any way. In addition to those described herein, various modifications to this disclosure will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

1. A compound of formula (I-1) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof: in, Ring A is C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic; Ring B is C 3-8 Monocyclic cycloalkane rings or 4-14 membered nitrogen-containing heterocycles; Ring C does not exist, or it is C. 6-10 aryl, 5-10 heteroaryl, 4-10 heterocyclic, or C 6-10 Aryl benzo[C] 3-8 cycloalkyl; X does not exist, or is a key, -C 0-6 Alkylene-OC 0-6 alkylene-, -C 0-6 Alkylene-SC 0-6 alkylene-, -C 0-6 Alkylene-NR A -C 0-6 alkylene-, -C 0-6 Alkylene-Se-C 0-6 alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, C 2-12 imidene group, C 2-12 Ethyne group, C 1-12 Alkylene, wherein the alkylene, alkenylene, or alkyneyl group is optionally selected independently from one or more of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substituents of cycloalkyl groups; R1 and R2 are each independently hydrogen, deuterium, halogen, cyano, nitro, or C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 0-6 Alkylene-R C or -SC 0-6 Alkylene-R C Alternatively, R1 and R2, together with the carbon atoms they are attached to, form C. 3-8 cycloalkyl or 3-8 membered heterocyclic groups; R3 is -C 0-6 Alkylene-NR A R B or -C 0-6 Alkylene-OR C Alternatively, one of R1 and R2 and R3 together with the carbon atom to which they are attached form a 3-8 membered heterocyclic group; R4, R5, and R6 are each independently hydrogen, deuterium, halogen, cyano, nitro, oxo, carboxyl, -SF5, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 1-12 Halogenated alkyl groups, -OC 0-12 Alkylene-R C -SC 0-12 Alkylene-R C -S(O)2R C -C(O)NR A R B -P(O)R A R B -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10 heteroaryl, -C 0-6 Alkylene-C 3-8 cycloalkyl, -C 0-6 alkylene-4-10-membered heterocyclic groups, or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C Examples include hydrogen, deuterium, halogen, cyano, nitro, oxo, -SF5, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 1-12 Halogenated alkyl groups, -OC 0-12 Alkylene-R C -SC 0-12 Alkylene-R C -S(O)2R C -C(O)NR A R B -P(O)R A R B -C 0- 6-alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10 heteroaryl, -C 0-6 Alkylene-C 3-8 cycloalkyl, -C 0-6 alkylene-4-10-membered heterocyclic groups, or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected independently by one or more groups selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-12 Alkyl, C 1- 12 Haloalkyl, C 1-12 Hydroxyalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 cycloalkyl, -CONR A R B -P(O)R A R B -COR C -S(O)2R C Substituents are substituted; p is 0, 1, 2, 3, 4 or 5; R7 and R8 are independently hydrogen, deuterium, halogen, cyano, nitro, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 0-6 Alkylene-R C or -SC 0-6 Alkylene-R C Alternatively, R7 and R8, together with the carbon atoms they are bonded to, form C. 3-8 cycloalkyl or 3-8 membered heterocyclic groups; m, n, and o are each independently 0, 1, 2, 3, 4, or 5; R A and R B Each independently is hydrogen, C 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups; R C Each is independently hydrogen, deuterium, and C. 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl compounds.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein, The compound is the compound represented by formula (I): in, Ring A is C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic; Ring B is a 4-14 member nitrogen-containing heterocycle; Ring C does not exist, or it is C. 6-10 aryl, 5-10 heteroaryl, 4-10 heterocyclic, or C 6-10 Aryl benzo[C] 3-8 cycloalkyl; X does not exist, or is a key, -C 0-6 Alkylene-OC 0-6 alkylene-, -C 0-6 Alkylene-SC 0-6 alkylene-, -C 0-6 Alkylene-NR A -C 0-6 alkylene-, -C 0-6 Alkylene-Se-C 0-6 alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, C 2-12 imidene group, C 2-12 Ethyne group, C 1-12 Alkylene, wherein the alkylene, alkenylene, or alkyneyl group is optionally selected independently from one or more of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substituents of cycloalkyl groups; R1 and R2 are each independently hydrogen, deuterium, halogen, cyano, nitro, or C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 0-6 Alkylene-R C or -SC 0-6 Alkylene-R C Alternatively, R1 and R2, together with the carbon atoms they are attached to, form C. 3-8 cycloalkyl or 3-8 membered heterocyclic groups; R3 is -C 0-6 Alkylene-NR A R B or -C 0-6 Alkylene-OR C Alternatively, one of R1 and R2 and R3 together with the carbon atom to which they are attached form a 3-8 membered heterocyclic group; R4, R5, and R6 are each independently hydrogen, deuterium, halogen, cyano, nitro, oxo, -SF5, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 1-12 Halogenated alkyl groups, -OC 0-12 Alkylene-R C -SC 0-12 Alkylene-R C -S(O)2R C -C(O)NR A R B -P(O)R A R B -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10 heteroaryl, -C 0-6 alkylene-4-10-membered heterocyclic groups, or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, and heteroaryl groups are optionally selected independently by one or more groups selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substituents of cycloalkyl groups; p is 0, 1, 2, 3, 4 or 5; R7 and R8 are independently hydrogen, deuterium, halogen, cyano, nitro, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Halogenated alkyl groups, -NR A R B -OC 0-6 Alkylene-R C or -SC 0-6 Alkylene-R C Alternatively, R7 and R8, together with the carbon atoms they are bonded to, form C. 3-8 cycloalkyl or 3-8 membered heterocyclic groups; m, n, and o are each independently 0, 1, 2, 3, 4, or 5; R A and R B Each independently is hydrogen, C 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups; R C Each is independently hydrogen, deuterium, and C. 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl compounds.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein, Ring C does not exist, and X does not exist.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein, Ring C is C 6-10 aryl, 5-10 heteroaryl, 4-10 heterocyclic, or C 6-10 Aryl benzo[C] 3-8 cycloalkyl; X is the key, -C 0-6 Alkylene-OC 0-6 alkylene-, -C 0-6 Alkylene-SC 0-6 alkylene-, -C 0-6 Alkylene-NR A -C 0-6 alkylene-, -C 0-6 Alkylene-Se-C 0-6 alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, C 2-12 imidene group, C 2-12 Ethyne group, C 1-12 Alkylene, wherein the alkylene, alkenylene, or alkyneyl group is optionally selected independently from one or more of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substitution of cycloalkyl groups.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, satisfying one or more of the following conditions: (1) Ring A is C 6-10 Aryl or 5-10 heteroaryl; preferably phenyl, naphthyl, pyridyl, quinolinyl, imidazopyridyl, indole, or thiophene; for example, phenyl, Phenyl is preferred; (2) Ring B is C 3-8 Monocyclic cycloalkane rings, 4-8 member nitrogen-containing monocyclic heterocycles, 6-14 member nitrogen-containing spirocyclic heterocycles, 6-14 member nitrogen-containing fused heterocycles, or 6-14 member nitrogen-containing bridged heterocycles; Preferably, ring B is a 4-8 member nitrogen-containing monocyclic heterocycle, a 6-14 member nitrogen-containing spirocyclic heterocycle, a 6-14 member nitrogen-containing fused heterocycle, or a 6-14 member nitrogen-containing bridged heterocycle; Preferably, ring B is (For example )、 More preferably, ring B is Or for Preferably, the wavy line represents the connection point between the nitrogen atom of ring B and the carbon atoms connected to R1 and R2, and the connection site with X (if present) in the general formula is not shown; (3) Ring C is C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclic, or benzo[a]C 3-6 Cycloalkyl; preferably phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolopyridinyl, imidazopyridinyl, benzoxazolyl, benzopyrazolyl, pyrazolyl, pyridinoneyl, pyridazinyl, benzocyclopentyl, tetrahydropyranyl, piperidinyl, naphthyl, benzodihydropyranyl, triazolopyrimidinyl, imidazopyridazinyl, thiadiazoyl, imidazopyrazinyl, or oxadiazolyl; for example, phenyl, pyridinyl, pyrimidinyl, benzoxazolyl, benzopyrazolyl, or pyrazolyl. Pyridone, pyridazinyl, benzocyclopentyl, tetrahydropyranyl, piperidinyl, naphthyl, benzodihydropyranyl, triazolopyrimidinyl, imidazopyridazinyl, thiadiazolyl, imidazopyrazinyl, or oxadiazolyl; for example, phenyl, pyridinyl, pyrimidinyl, benzoxazolyl, benzopyrazolyl, pyrazolyl, pyridone, pyridazinyl, benzocyclopentyl, tetrahydropyranyl, piperidinyl, naphthyl, benzodihydropyranyl, or triazolopyrimidinyl; for example, phenyl, (4) X is a bond, -C 0-6 Alkylene-OC 0-6 alkylene-, -C 0-6 Alkylene-SC 0-6 alkylene-, -C 0-6 Alkylene-NR A -C 0-6 alkylene-, -C 0-6 Alkylene-Se-C 0-6 alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, C 2-12 imidene group, C 2-12 etyne group, or C 1-12 Alkylene, wherein the alkylene, alkenylene, or alkyneyl group is optionally selected independently from one or more of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substituents of cycloalkyl groups; Preferably, X is a bond, -C 0-3 Alkylene-OC 0-3 alkylene-, -C 0-3 Alkylene-SC 0-3 alkylene-, -C 0-3 Alkylene-NR A -C 0- 3-alkylene-, -C 0-3 Alkylene-Se-C 0-3 alkylene-, -C 0-3 Alkylene-C(O)-C 0-3 Alkylene-, C 2-4 imidene group, C 2-4 etyne group, or C 1-4 Alkylene, wherein the alkylene, alkenylene, or alkyneyl group is optionally selected independently from one or more of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 Substituents of cycloalkyl groups; More preferably, X is a bond, O, S, NH, N (C 1-6 Alkyl), Se, C 2-4 Ethyne group, C 1-4 alkylene, carbonyl, or -C 0- 3-alkylene-OC 0-3 Alkylene; for example, a bond, O, or NH; (5) R1 and R2 are each independently hydrogen, deuterium, halogen, or C. 1-12 Alkyl groups; or R1 and R2 together with the carbon atoms they are attached to form C2 groups. 3-6 Cycloalkyl; preferably, both R1 and R2 are hydrogen; or one is hydrogen and the other is methyl; (6) R3 is -C 0-3 Alkylene-NR A R B or -C 0-3 Alkylene-OR C More preferably -C 0-3 alkylene-OH, such as hydroxyl groups; (7) One of R1 and R2 and R3 together with the carbon atom to which they are attached form a 4-6 membered heterocyclic group; (8) R4 can be hydrogen, deuterium, halogen, cyano, or C independently. 1-12 Alkyl, -C(O)NR A R B C 1-12 Alkoxy or -SF5; preferably, R4 is fluorine and m is 2; (9) R5 can be hydrogen, deuterium, halogen, oxo group, or C independently. 1-12 Alkyl, -OC 0-12 Alkylene-R C 、or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl group or alkylene group is optionally selected independently from one or more groups selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkoxy groups, C 1-12 Alkylthio, C 1-12 alkylamine group, C 3-8 The cycloalkyl group is substituted with, for example, hydrogen, deuterium or fluorine; For example, R5 can be hydrogen, deuterium, halogen, oxo group, or C. 1-12 Alkyl, or C 1-12 Alkoxy; (10) R6 is independently hydrogen, deuterium, halogen, cyano, oxo, hydroxyl, C 1-12 Alkyl, -OC 1-12 Alkyl, -OC 1-12 Halogenated alkyl groups, -OC 0-6 Alkylene-C 6-10 Aryl, -OC 0-6 alkylene-5-10 heteroaryl, -OC 0-6 Alkylene-C 3-8 cycloalkyl, -OC 0-6 Alkyl-4-6-membered heterocyclic group, -C 0-6 Alkylene-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 heterocyclic group, -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10-membered heteroaryl, -S(O)2R C -P(O)R A R B 、or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected independently by one or more halogens, hydroxyl groups, cyano groups, nitro groups, oxo groups, and C6 groups. 1-12 Alkyl, C 1-12 Hydroxyalkyl, C 1-12 Alkoxy, C 1-12 Haloalkyl, C 1-12 Halogenated alkoxy groups, -CONR A R B -P(O)R A R B -COR C -S(O)2R C Substituents of the substituents; Preferably, each of R6 is independently hydrogen, deuterium, halogen, cyano, oxo, hydroxyl, or C. 1-12 Alkyl, -OC 1-12 Alkyl, -OC 1- 12 Halogenated alkyl groups, -OC 0-6 Alkylene-C 6-10 Aryl, -OC 0-6 alkylene-5-10 heteroaryl, -OC 0-6 Alkyl-4-6-membered heterocyclic group, -C 0-6 Alkylene-C 3-8 cycloalkyl, -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10-membered heteroaryl, -S(O)2R C -P(O)R A R B 、or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected independently by one or more halogens, hydroxyl groups, cyano groups, nitro groups, oxo groups, and C6 groups. 1-12 Alkyl, C 1-12 Hydroxyalkyl, C 1-12 Alkoxy, C 1-12 Haloalkyl, C 1-12 Halogenated alkoxy groups, -CONR A R B -P(O)R A R B Substituents of R; preferably, wherein R C Each independently is hydrogen, C 1-12 Alkyl or C 1-12 Halogenated alkyl groups; Preferably, each of R6 is independently hydrogen, deuterium, halogen, cyano, oxo, hydroxyl, or C. 1-12 Alkyl, -OC 1-12 Alkyl, -OC 1- 12 Halogenated alkyl groups, -OC 0-6 Alkylene-C 6-10 Aryl, -OC 0-6 alkylene-5-10 heteroaryl, -OC 0-6 Alkyl-4-6-membered heterocyclic group, -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 alkylene-5-10-membered heteroaryl, -P(O)R A R B 、or -OC 1-12 Alkylene-(OC) 1-12 Alkylene) p -OR C The alkyl, alkylene, aryl, and heteroaryl groups are optionally selected independently by one or more halogens, hydroxyl groups, cyano groups, nitro groups, oxo groups, and C6 groups. 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Haloalkyl, C 1-12 Halogenated alkoxy groups, -CONR A R B Substituents of the substituents; (11) R7 and R8 are each independently hydrogen, deuterium, or C. 1-12 Alkyl groups; or R7 and R8 together with the carbon atoms they are attached to form C24. 3- 6-cycloalkyl; preferably, R7 and R8 are both hydrogen; (12)R A and R B Each is independently hydrogen or C 1-12 alkyl; (13)R C Each independently is hydrogen, C 1-12 Alkyl, C 1-12 Haloalkyl, C 3-8 cycloalkyl, C 6-10 Aryl or 5-10 heteroaryl groups; (14) m, n and o are each independently 0, 1, 2, 3 or 4; (15) p is 0, 1, 2 or 3; (16) The compound is a compound of formula (IA) or a compound of formula (IB) or a mixture thereof, preferably a compound of formula (IA):

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein, Ring C exists, X exists, and ring B is... Where n1, n2, n3, and n4 are each independently 1, 2, or 3. Indicates a single bond or a double bond; Optionally, when n1, n2, n3 or n4 are 2 or 3, two repeating -CH2- units can form a carbon-carbon double bond.

7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein the compound is further a compound of formula (II) or (III), preferably a compound of formula (IIA) or (IIIA): Alternatively, it may be a compound of formula (IV) or formula (V), preferably a compound of formula (IVA) or formula (VA): Alternatively, it may be a compound of formula (VI) or formula (VII), preferably a compound of formula (VIA) or formula (VIIA): Or further, compounds of formula (VIII), formula (I-B1), or formula (I-B2): in, Rings A, B, C, X, R1, R2, R3, R4, R5, R6, R7, R8, m, n, and o are as defined in any one of claims 1-7. n1, n2, n3, and n4 are each independently 1, 2, or 3.

8. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein the compound is selected from:

9. A pharmaceutical composition comprising a preventive and / or therapeutically effective amount of the compound of any one of claims 1-8 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

10. A pharmaceutical kit comprising the compound of any one of claims 1-8 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, or the pharmaceutical composition of claim 9.

11. The use of any compound of claims 1-8 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug of claim 9, or the cassette of claim 10 in the preparation of a medicament for the prevention and / or treatment of diseases, particularly CYP51-mediated diseases; Preferably, the disease is a fungal infection, such as an invasive fungal infection; Preferably, the fungus comprises: Absidia corymbifera, Ajellomyces capsulatus, Ajellomyces dermatitidis, Arthroderma benhamiae, Arthroderma fulvum, Arthroderma gypseum, Arthroderma incurvatum, Arthroderma otae, Arthroderma vanbreuseghemii, Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Blastomyces dermatitidis, Candida albicans, Candida glabrata, Candida guinea Candida guilliermondii, Candida krusei, Candida parapsilosis, Candida tropicalis, Candida pelliculosa, Cladophialophora carrionii, Coccidioides immitis, Cryptococcus neoformans, Cunninghamella sp., Epidermophyton floccosum, Exophiala dermatitidis, Filobasidiella neoformans, Fonsecaea pedrosoi, Fusarium solani, Geotrichum candidum, Histoplasma capsulatum, Hortaea *Issatschenkia orientalis*, *Madurella grisae*, *Malassezia furfur*Malassezia fur, Malassezia globosa, Malassezia obtusa, Malassezia pachydermatis, Malassezia restricta, Malassezia slooffiae, Malassezia sympodialis, Microsporum canis, Microsporum fulvum, Microsporum gypseum, Mucor circinelloides, Nectria haematococca, Paecilomyces variotii, Paracoccidioides brasiliensis, Penicillium marneffei, Pichia aberrant anomala, Pichia guilliermondii, Pneumocystis carinii, Pseudallescheria boydii, Rhizopus oryzae, Rhodotorula rubra, Scedosporium apiospernium, Schizophyllum commune, Sporothrix schenckii, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton verrucosum, Trichophyton violaceum, Trichosporon asahii, Trichosporon cutaneum, Trichosporon Candida albicans and / or Aspergillus fumigatus are preferred.

12. The compound of any one of claims 1-8 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug of the same, or the pharmaceutical composition of claim 9, or the kit of claim 10, for the prevention and / or treatment of diseases, particularly CYP51-mediated diseases; Preferably, the disease is a fungal infection, such as an invasive fungal infection; Preferably, the fungus comprises: Absidia corymbifera, Ajellomyces capsulatus, Ajellomyces dermatitidis, Arthroderma benhamiae, Arthroderma fulvum, Arthroderma gypseum, Arthroderma incurvatum, Arthroderma otae, Arthroderma vanbreuseghemii, Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Blastomyces dermatitidis, Candida albicans, Candida glabrata, Candida guinea Candida guilliermondii, Candida krusei, Candida parapsilosis, Candida tropicalis, Candida pelliculosa, Cladophialophora carrionii, Coccidioides immitis, Cryptococcus neoformans, Cunninghamella sp., Epidermophyton floccosum, Exophiala dermatitidis, Filobasidiella neoformans, Fonsecaea pedrosoi, Fusarium solani, Geotrichum candidum, Histoplasma capsulatum, Hortaea *Issatschenkia orientalis*, *Madurella grisae*, *Malassezia furfur*Malassezia fur, Malassezia globosa, Malassezia obtusa, Malassezia pachydermatis, Malassezia restricta, Malassezia slooffiae, Malassezia sympodialis, Microsporum canis, Microsporum fulvum, Microsporum gypseum, Mucor circinelloides, Nectria haematococca, Paecilomyces variotii, Paracoccidioides brasiliensis, Penicillium marneffei, Pichia aberrant anomala, Pichia guilliermondii, Pneumocystis carinii, Pseudallescheria boydii, Rhizopus oryzae, Rhodotorula rubra, Scedosporium apiospernium, Schizophyllum commune, Sporothrix schenckii, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton verrucosum, Trichophyton violaceum, Trichosporon asahii, Trichosporon cutaneum, Trichosporon Candida albicans and / or Aspergillus fumigatus are preferred.

13. A method for preventing and / or treating CYP51-mediated diseases, comprising administering to an individual in need a preventive or therapeutically effective amount of any one of claims 1-8 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, or a pharmaceutical composition of claim 9, or a kit of claim 10; Preferably, the disease is a fungal infection, such as an invasive fungal infection; Preferably, the fungus comprises: Absidia corymbifera, Ajellomyces capsulatus, Ajellomyces dermatitidis, Arthroderma benhamiae, Arthroderma fulvum, Arthroderma gypseum, Arthroderma incurvatum, Arthroderma otae, Arthroderma vanbreuseghemii, Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Blastomyces dermatitidis, Candida albicans, Candida glabrata, Candida guinea Candida guilliermondii, Candida krusei, Candida parapsilosis, Candida tropicalis, Candida pelliculosa, Cladophialophora carrionii, Coccidioides immitis, Cryptococcus neoformans, Cunninghamella sp., Epidermophyton floccosum, Exophiala dermatitidis, Filobasidiella neoformans, Fonsecaea pedrosoi, Fusarium solani, Geotrichum candidum, Histoplasma capsulatum, Hortaea *Issatschenkia orientalis*, *Madurella grisae*, *Malassezia furfur*Malassezia fur, Malassezia globosa, Malassezia obtusa, Malassezia pachydermatis, Malassezia restricta, Malassezia slooffiae, Malassezia sympodialis, Microsporum canis, Microsporum fulvum, Microsporum gypseum, Mucor circinelloides, Nectria haematococca, Paecilomyces variotii, Paracoccidioides brasiliensis, Penicillium marneffei, Pichia aberrant anomala, Pichia guilliermondii, Pneumocystis carinii, Pseudallescheria boydii, Rhizopus oryzae, Rhodotorula rubra, Scedosporium apiospernium, Schizophyllum commune, Sporothrix schenckii, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton verrucosum, Trichophyton violaceum, Trichosporon asahii, Trichosporon cutaneum, Trichosporon Candida albicans and / or Aspergillus fumigatus are preferred.

14. A method for preparing a compound of formula (IV), comprising one or more of the following steps: Step 1 to Step 3: in, Rings B, C, X, R4, R5, R6, R7, R8, m, n, and o are as defined in any one of claims 1-8.

15. A method for preparing a compound of formula (VIIA), comprising one or more of the following steps: in, Rings B, C, X, R4, R5, R6, m, n, and o are as defined in any one of claims 1-8.

16. The following are examples of compounds or their salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, and isotope-labeled compounds: in, Rings B, C, X, R4, R5, R6, R7, R8, m, n, and o are as defined in any one of claims 1-8.

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