Heteroaromatic ring derivative containing amide and application thereof in medicine

Abstract

The invention relates to an amide-containing heteroaromatic ring derivative and an application thereof in medicine, in particular to a compound shown in a general formula (I) or a stereoisomer, a racemate and pharmaceutically acceptable salt thereof, an intermediate and a preparation method thereof, and an application in preparation of a medicine for treating pain.

Description

Technical Field

[0001] This invention relates to a compound of general formula (I) or its stereoisomers, racemates, pharmaceutically acceptable salts, intermediates thereof, and methods of preparation thereof, as well as its use in the preparation of medicaments for treating or relieving pain. Background Technology

[0002] Pain originates from nociceptors in the peripheral nervous system. These receptors convert perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials), which are then transmitted via afferent nerve fibers to the cell body of the dorsal root ganglion (DRG), ultimately reaching higher nerve centers and causing pain sensation. The generation and conduction of action potentials in neurons depend on voltage-gated sodium channels (VGSCS) on the cell membrane. When the cell membrane depolarizes, sodium channels are activated, opening and causing an influx of sodium ions, further depolarizing the cell membrane and leading to the generation of action potentials.

[0003] VGSCS consists of a porous α-subunit (approximately 260 kDa) and an associated smaller β-subunit (30–40 kDa). The associated α-subunit family comprises 10 members, nine of which (Nav1.1–1.9) are voltage-gated. Nav1.8 is encoded by the gene SCN10A and is preferentially expressed in peripheral sensory neurons. It has been shown to shape action potentials in these neurons. Nav1.8 transcripts and proteins have been found in dorsal root ganglion (DRG) neurons. Nav1.8 has not been detected in non-neuronal tissues (e.g., heart and skeletal muscle) or the central nervous system (including the brain and spinal cord).

[0004] The crucial role of Nav1.8 in pain signal transduction has been supported by multiple pieces of evidence. Based on a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a novel analgesic therapy. Currently, drugs targeting this target have entered clinical trials. Summary of the Invention

[0005] The purpose of this invention is to provide a class of sulfur-containing heterocyclic derivatives that have inhibitory activity against Nav1.8. These compounds selectively inhibit Nav1.8, which can effectively reduce side effects and have good analgesic activity and oral bioavailability.

[0006] This invention provides a compound of general formula (I) or its stereoisomers, racemates, or pharmaceutically acceptable salts.

[0007]

[0008] In some embodiments, the compound represented by formula (I) is selected from formula (Ia):

[0009] In some implementations, X is selected from -S-, -S(=O)-, or -S(=O)2;

[0010] In some implementations, A is selected from C. 3-12 Carbocyclic rings, 5-12 membered heterocyclic rings, 5-10 membered heteroaryl rings, C 6-10 aryl or

[0011] In some embodiments, A is selected from phenyl, 5-6-membered heteroaryl, benzo[a]C 4-7 Benzyl 5-7-membered heterocyclic group, benzo5-6-membered heteroaryl group, 5-membered 5-membered heterocyclic group, 5-membered 6-membered heterocyclic group, 6-membered 6-membered heterocyclic group or

[0012] In some embodiments, A is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinoneyl, pyridinoneyl, pyrroleyl, pyrazolyl, imidazoleyl, thiazolyl, quinolinyl, isoquinolinyl, benzopyridinyl, quinoxalinyl, quinazolinyl, indoleyl, isoindoleyl, benzimidazolyl, benzopyrazolyl, benzothiophenyl, benzothiazolyl, pyridopyridinyl, pyridopyrazinyl Pyridopyrrole, pyridopyrazolyl, pyridotriazolyl, pyrimidopyrrole, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrimidotriazolyl, pyrazinoimidazolyl, pyrazinopyrrole, pyrazinopyrazolyl, triazinopyrazolyl, benzocyclobutenyl, benzocyclopentenyl, benzooxacyclopentenyl, benzodioxacyclopentenyl, indolone, quinolinone, isoindolone, isoquinolinone.

[0013] In some implementation schemes, A is selected from

[0014] Its left end is connected to -CO-NH-;

[0015] In some implementation schemes, Selected from

[0016] In some implementation schemes, Selected from

[0017] In some implementation schemes, B1, B2, B3, and B4 are each independently selected from N or CR. BB1, B2, B3, and B4 are not all selected from N; in some implementations, two of B1, B2, B3, and B4 are selected from CR. B The other two are selected from N or CR. B In some implementation schemes, B1, B2, B3, and B4 are all selected from CR. B In some implementation schemes, three of B1, B2, B3, and B4 are selected from CR. B The other option is selected from N;

[0018] In some implementation schemes, Selected from B1 and B2 are each independently selected from N or CR. B In some implementations, B1 and B2 are each independently selected from CH or CD; in some implementations, Selected from

[0019] In some implementation schemes, Selected from

[0020] In some implementation schemes, Selected from

[0021] In some implementation schemes, R 1 R 2 R 3 R 4 Each element is independently selected from H, deuterium, halogens, CN, OH, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 Carbocyclic, 3- to 7-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic is optionally surrounded by 1 to 4 R... k replace;

[0022] In some implementation schemes, R 1 R 2 R 3 R 4 Each element is independently selected from H, deuterium, halogens, CN, OH, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 3-6 Carbocyclic, 3- to 7-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic is optionally surrounded by 1 to 4 R...k replace;

[0023] In some implementation schemes, R 1 R 2 R 3 R 4 Each of the following groups is independently selected from H, deuterium, F, Cl, Br, CN, OH, methyl, ethyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, vinyl, and ethynyl, wherein the methyl, ethyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, vinyl, and ethynyl groups are optionally prefixed with 1 to 4 R groups. k replace;

[0024] In some implementation schemes, R 1 R 2 R 3 R 4 Each is independently selected from H, deuterium, methyl, ethyl, CD3, CH2F, CHF2, CF3;

[0025] In some implementation schemes, R 1 R 4 Direct connection forms C 3-6 Carbon rings or 4- to 7-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 6 R... k replace;

[0026] In some implementation schemes, R 1 R 4 Direct connection forms a ring C, where ring C is selected from C. 3-10 Carbon rings or 4- to 10-membered heterocyclic rings, wherein the ring C is optionally divided by 1 to 6 R... k Replacement; in some implementations, ring C is selected from C 3-6 Carbon rings or 4- to 7-membered heterocycles, wherein the ring C is optionally divided by 1 to 6 R... k replace;

[0027] In some implementation schemes, Selected from The ring C is selected from 1 to 4 Rs. k The following groups are substituted: cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, piperidinyl, oxecyclopentyl, oxecyclopentyl, dioxocyclopentyl;

[0028] In some implementation schemes, Selected from The ring C is arbitrarily divided by 1 to 4 Rs. k replace;

[0029] In some implementation schemes, Selected from In some implementation schemes, Selected from

[0030] In some implementation schemes, R 6 Each element is independently selected from H, deuterium, halogens, CN, OH, =O, -C(=O)OH, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbon rings, 3- to 7-membered heterocycles, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -NH-C 3-6 Carbon ring, -C(=O)NR a1 R a2 -S(=O)2NR a1 R a2 -C(=O)R a1 -C(=O)OR a1 -NH-C(=O)R a1 -S(=O)2R a1 -S(=O)(=NR) a1 )R a2 -P(=O)R a3 R a4 -NH-S(=O)2R a1 -NH-S(=O)2NR a1 R a2 -C(=O)NH-C(=NR) a3 )NR a1 R a2 -C(=NR) a3 )NR a1 R a2 The alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0031] In some implementation schemes, R 6 Each element is independently selected from H, deuterium, halogens, CN, OH, =O, -C(=O)OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6Carbon rings, 3- to 7-membered heterocycles, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -NH-C 3-6 Carbon ring, -C(=O)NR a1 R a2 -S(=O)2NR a1 R a2 -C(=O)R a1 -C(=O)OR a1 -NH-C(=O)R a1 -S(=O)2R a1 -S(=O)(=NR) a1 )R a2 -P(=O)R a3 R a4 -NH-S(=O)2R a1 -NH-S(=O)2NR a1 R a2 -C(=O)NH-C(=NR) a3 )NR a1 R a2 -C(=NR) a3 )NR a1 R a2 The alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0032] In some implementation schemes, R 6 Each is independently selected from H, deuterium, F, Cl, Br, CN, OH, =O, -C(=O)OH, -C(=O)NH2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, vinyl, ethynyl, propynyl, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl) -O-cyclopropyl, -O-cyclobutyl, -C(=O)methyl, -C(=O)O-methyl, -C(=O)ethyl, -C(=O)O-ethyl, -S(=O)2-methyl, -S(=O)2NH2, -NH-S(=O)2NH2, -C(=N)(OH)NH2, -C(=N)(O-methyl)NH2, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, vinyl, ethynyl, propynyl are optionally prefixed with 1 to 3 R. k replace;

[0033] In some implementation schemes, R 6Each is independently selected from H;

[0034] In some implementation schemes, R a1 R a2 Each independently selected from H and C 1-6 Alkyl, C 3-6 Carbocyclic, 4- to 7-membered heterocyclic, wherein the alkyl, carbocyclic or heterocyclic is optionally surrounded by 1 to 4 R... k replace;

[0035] In some implementation schemes, R a1 R a2 Each independently selected from H and C 1-4 Alkyl, C 3-6 Carbocyclic, 4- to 7-membered heterocyclic, wherein the alkyl, carbocyclic or heterocyclic is optionally surrounded by 1 to 4 R... k replace;

[0036] In some implementation schemes, R a1 R a2 Each is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0037] In some implementation schemes, R a1 R a2 Direct connection forms a 4- to 7-membered heterocycle, wherein the heterocycle is optionally bounded by 1 to 4 R... k replace;

[0038] In some implementation schemes, R a1 R a2 Direct connection forms an optional 1 to 4 R k The following groups are substituted: aziridine, pyrrolidinyl, piperidinyl;

[0039] In some implementation schemes, R 5 Selected from -YC 1-4 Alkylene-R 5a -YR 5b The alkylene group is optionally surrounded by 1 to 4 R groups. k replace;

[0040] In some implementation schemes, R 5 Selected from -γ-methylene-R 5a γ-Ethylene-R 5a γ-Propylene-R 5a -YR 5b The methylene, ethylene, and propylene groups are optionally coated with 1 to 4 R groups. k replace;

[0041] In some implementation schemes, R 5 Selected from -O-methylene-R 5a -S-methylene-R 5a -O-ethylene-R 5a -OR 5b -SR 5b The methylene and ethylene groups are optionally substituted with 1 to 4 substituents selected from H, deuterium, F, Cl, methyl, ethyl, CD3, CH2F, CHF2, and CF3;

[0042] In some implementation schemes, R 5 Selected from

[0043] In some implementations, Y is selected from -O-, -NH-, and -S-;

[0044] In some implementations, Y is selected from -O-;

[0045] In some implementation schemes, R 5a Selected from C 3-8 Carbocyclic rings, 3- to 8-membered heterocyclic rings, 5- to 6-membered heteroaryl groups, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -C (=NR) a3 )NR a1 R a2 -C(=NR) a3 )R a2 -S(=O)(=NR) a3 )R a4 -P(=O)R a3 R q4 -OP(=O)R a3 R a4 The alkyl, heteroaryl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0046] In some implementation schemes, R 5a Selected from phenyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclic, 5- to 6-membered heteroaryl, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -C (=NR) a3 )NR a1 R a2 -C(=NR) a3 )R a2 -S(=O)(=NR) a3 )R a4 -P(=O)R a3 R q4-OP(=O)R a3 R a4 The alkyl, phenyl, cycloalkyl, heteroaryl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0047] In some implementation schemes, R 5a Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, azacyclobutyl, oxacyclohexyl, pyrrolyl, piperidinyl, pyrazolyl, pyrroleyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, thiophene, -O-cyclopropyl, -O-cyclobutyl, -C(=NR) a3 )NR a1 R a2 -C(=NR) a3 )R a2 -S(=O)(=NH)methyl, -P(=O)(OH)2, -OP(=O)(OH)2, -P(=O)(NH2)2, -OP(=O)(NH2)2, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -OP(=O)(methyl)2, -OP(=O)(ethyl)2, -P(=O)(CH3)(cyclopropyl), wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aziridine, pyrrolyl, piperidinyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, thiophene group is optionally surrounded by 1 to 3 R groups. k replace;

[0048] In some implementation schemes, R 5aSelected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, azacyclobutyl, oxacyclohexyl, pyrrolyl, piperidinyl, pyrazolyl, pyrroloyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, thiophene, -O-cyclopropyl, -O-cyclobutyl, -C(=N-OH)NH2, -C(=N-OH)NH-methyl, -C(=N-OH)NH-(methyl)2, -C(=N-OH)methyl, -C(=N-OH)cyclopropyl, -C(=NO-methyl)-methyl, -S(=O)(=NH)methyl, -P(=O)(OH)2, -OP(=O)(OH)2, -P(=O)(NH2)2, -OP(=O)(NH2)2, -P( =O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl), wherein the methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aziridine, pyrrolyl, piperidinyl, pyrazolyl, pyrroleyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, thiophene group is optionally substituted with 1 to 3 substituents of deuterium, F, Cl, Br, CN, OH, -C(=O)OH, -C(=O)NH2, -CH2OH, -C(=O)CH3, -C(=O)cyclopropyl, methyl, ethyl, CD3, OCD3, CH2F, CHF2, CF3, -C(=O)CH3, -C(=O)cyclopropyl;

[0049] In some implementation schemes, R 5b Selected from C 4-10 Carbocyclic rings, 4- to 10-membered heterocyclic rings, 5- to 6-membered heteroaryl groups, wherein R 5b Choose from 1 to 4 Rs k replace;

[0050] In some implementation schemes, R 5b Selected from C 4-6 Monocycloalkyl, C 4-10 cycloalkyl, C 5-10 Spirocycloalkyl, C 5-10 Bridged cycloalkyl, 4- to 8-membered monoheterocyclic, 4- to 10-membered fused heterocyclic, 5- to 10-membered spiroheterocyclic, 5- to 10-membered bridged heterocyclic, 5- to 6-membered heteroaryl, wherein R 5b Choose from 1 to 4 Rs k replace;

[0051] In some implementation schemes, R 5b Selected from bicyclic [1.1.1]pentyl, cyclobutyl, cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, aziroxybutyl, pyrrolyl, piperidinyl, pyrazolyl, pyrroleyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, thiophenyl, wherein R 5b Choose from 1 to 4 Rsk Replace; in some implementations, R a3 R a4 Each element is independently selected from H, OH, NH2, and C. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Carbocyclic, 4- to 7-membered heterocyclic, wherein the alkyl, carbocyclic or heterocyclic is optionally surrounded by 1 to 4 R... k replace;

[0052] In some implementation schemes, R a3 R a4 Each element is independently selected from H, OH, NH2, and C. 1-4 Alkyl, -OC 1-4 Alkyl, C 3-6 Carbocyclic, 4- to 7-membered heterocyclic, wherein the alkyl, carbocyclic or heterocyclic is optionally surrounded by 1 to 4 R... k replace;

[0053] In some implementation schemes, R a3 R a4 Each is independently selected from H, OH, NH2, or optionally influenced by 1 to 4 Rs. k The following groups may be substituted: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, or cyclopentyl;

[0054] In some implementation schemes, R B Each element is independently selected from H, deuterium, halogens, CN, OH, -C(=O)OH, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-7 Carbon ring, -OC 3-7 Carbon rings, 3- to 7-membered heterocycles, or -P(=O)R q1 R q2 The alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0055] In some implementation schemes, R B Each element is independently selected from H, deuterium, halogens, CN, OH, -C(=O)OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4Alkyl, -SC 1-4 Alkyl, C 3-7 Carbon ring, -OC 3-7 Carbon rings, 3- to 7-membered heterocycles, or -P(=O)R q1 R q2 The alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0056] In some implementation schemes, R B Each of the following groups is independently selected from H, deuterium, F, Cl, Br, cyano, OH, -C(=O)OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, -O-cyclopropyl, cyclobutyl, vinyl, ethynyl, propynyl, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl), wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, vinyl, ethynyl, and propynyl groups are optionally prefixed with 1 to 4 R groups. k replace;

[0057] In some implementation schemes, R B Each of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, CH2F, CHF2, CF3, -OCH2F, -OCHF2, -OCF3, -OCD3, methyl, -S-methyl, -S-CF3, ethyl, isopropyl, ethynyl, propynyl, methoxy, ethoxy, isopropyloxy, propyloxy, cyclopropyl, -O-cyclopropyl, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl), wherein the methyl, ethyl, isopropyl, ethynyl, propynyl, methoxy, ethoxy, isopropyloxy, propyloxy, and cyclopropyl groups are optionally prefixed with 1 to 3 R groups. k replace;

[0058] In some implementation schemes, R k Each element is independently selected from deuterium, =O, halogens, CN, OH, -C(=O)OH, -C(=O)NH2, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -C(=O)-C3-6 Carbon ring, -C(=O)-C 1-6 Alkyl, -NH-C 3-6 Carbon rings, -NH-3 to 7-membered heterocycles, -C 1-4 Alkylene-C 3-6 Carbon ring, -C 1-4 Alkylene-3 to 7-membered heterocycles, C 3-6 Carbocyclic rings, 3 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic rings are optionally selected from 1 to 4 deuterium, halogens, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0059] In some implementation schemes, R k Each element is independently selected from deuterium, =O, halogens, CN, OH, -C(=O)OH, -C(=O)NH2, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -C(=O)-C 3-6 Carbon ring, -C(=O)-C 1-4 Alkyl, -NH-C 3-6 Carbon rings, -NH-3 to 7-membered heterocycles, -C 1-2 Alkylene-C 3-6 Carbon ring, -C 1-2 Alkylene-3 to 7-membered heterocycles, C 3-6 Carbocyclic rings, 3 to 7-membered heterocycles, wherein the alkylene group, alkyl group, alkenyl group, alkynyl group, carbocyclic ring or heterocycle is optionally selected from 1 to 4 elements selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0060] In some implementation schemes, R kEach of the following groups is independently selected from deuterium, F, Cl, Br, I, CN, OH, -C(=O)OH, -C(=O)NH2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, -C(=O)methyl, -C(=O)CH(CH3)2, -C(=O)cyclopropyl, -C(=O)cyclobutyl, methyl, ethyl, vinyl, ethynyl, methoxy The methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally selected from one to four elements selected from deuterium, halogens, CN, OH, NH2, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0061] In some implementation schemes, R k Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, -C(=O)OH, -C(=O)NH2, -CH2OH, -C(=O)CH3, -C(=O)CH(CH3)2, -C(=O)cyclopropyl, methyl, ethyl, CD3, OCD3, CH2F, CHF2, CF3, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0062] In some implementation schemes, R k Each is independently selected from deuterium, F, Cl, Br, CN, OH, -CH2OH, methyl, ethyl, CD3, OCD3, CH2F, CHF2, CF3;

[0063] In some implementations, m is selected from 0, 1, 2, 3, 4, 5, or 6;

[0064] In some implementations, m is selected from 0, 1, 2, 3, and 4.

[0065] As a first embodiment of the present invention, the compound represented by the above general formula (I) or (Ia), or its stereoisomer, racemate, or pharmaceutically acceptable salt, is used.

[0066] X is selected from -S-, -S(=O)-, or -S(=O)2;

[0067] A is selected from C 3-12 Carbocyclic rings, 5-12 membered heterocyclic rings, 5-10 membered heteroaryl rings, C 6-10 aryl or

[0068] R 6 Each element is independently selected from H, deuterium, halogens, CN, OH, =O, -C(=O)OH, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbon rings, 3- to 7-membered heterocycles, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -NH-C 3-6 Carbon ring, -C(=O)NR a1 R a2 -S(=O)2NR a1 R a2 -C(=O)R a1 -C(=O)OR a1 -NH-C(=O)R a1 -S(=O)2R a1 -S(=O)(=NR) a1 )R a2 -P(=O)R a3 R a4 -NH-S(=O)2R a1 -NH-S(=O)2NR a1 R a2 -C(=O)NH-C(=NR) a3 )NR a1 R a2 -C(=NR) a3 )NR a1 R a2 The alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0069] R a1 R a2 Each independently selected from H and C 1-6 Alkyl, C 3-6 Carbocyclic, 4- to 7-membered heterocyclic, wherein the alkyl, carbocyclic or heterocyclic is optionally surrounded by 1 to 4 R... k replace;

[0070] As an option, R a1 R a2 Direct connection forms a 4- to 7-membered heterocycle, wherein the heterocycle is optionally bounded by 1 to 4 R... k replace;

[0071] R 5 Selected from -YC 1-4 Alkylene-R 5a -YR 5b The alkylene group is optionally surrounded by 1 to 4 R groups. k replace;

[0072] Y is selected from -O-, -NH-, and -S-.

[0073] R 5a Selected from C 3-8 Carbocyclic rings, 3- to 8-membered heterocyclic rings, 5- to 6-membered heteroaryl groups, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -C (=NR) a3 )NR a1 R a2 -C(=NR) a3 )R a2 -S(=O)(=NR) a3 )R a4 -P(=O)R a3 R q4 -OP(=O)R a3 R a4 The alkyl, heteroaryl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0074] R 5b Selected from C 4-10 Carbocyclic rings, 4- to 10-membered heterocyclic rings, 5- to 6-membered heteroaryl groups, wherein R 5b Choose from 1 to 4 Rs k replace;

[0075] R a3 R a4 Each element is independently selected from H, OH, NH2, and C. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Carbocyclic, 4- to 7-membered heterocyclic, wherein the alkyl, carbocyclic or heterocyclic is optionally surrounded by 1 to 4 R... k replace;

[0076] B1, B2, B3, and B4 are each independently selected from N or CR. B B1, B2, B3, and B4 are not all selected from N simultaneously;

[0077] R B Each element is independently selected from H, deuterium, halogens, CN, OH, -C(=O)OH, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-7 Carbon ring, -OC 3-7 Carbon rings, 3- to 7-membered heterocycles, or -P(=O)R q1 R q2 The alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0078] m is selected from 0, 1, 2, 3, 4, 5 or 6;

[0079] R 1 R 2 R 3 R 4 Each element is independently selected from H, deuterium, halogens, CN, OH, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 Carbocyclic, 3- to 7-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic is optionally surrounded by 1 to 4 R... k replace;

[0080] As an option, R 1 R 4 Direct connection forms C 3-6 Carbon rings or 4- to 7-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 6 R... k replace;

[0081] R k Each element is independently selected from deuterium, =O, halogens, CN, OH, -C(=O)OH, -C(=O)NH2, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -C(=O)-C 3-6 Carbon ring, -C(=O)-C 1-6 Alkyl, -NH-C 3-6 Carbon rings, -NH-3 to 7-membered heterocycles, -C 1-4 Alkylene-C 3-6 Carbon ring, -C 1-4 Alkylene-3 to 7-membered heterocycles, C 3-6Carbocyclic rings, 3 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic rings are optionally selected from 1 to 4 deuterium, halogens, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 The alkoxy group is replaced by a substituent.

[0082] As a second embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomers, racemates, or pharmaceutically acceptable salts are used.

[0083] A is selected from phenyl, 5-6-membered heteroaryl, benzo[C] 4-7 Benzyl 5-7-membered heterocyclic group, benzo5-6-membered heteroaryl group, 5-membered 5-membered heterocyclic group, 5-membered 6-membered heterocyclic group, 6-membered 6-membered heterocyclic group or

[0084] R 6 Each element is independently selected from H, deuterium, halogens, CN, OH, =O, -C(=O)OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Carbon rings, 3- to 7-membered heterocycles, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -NH-C 3-6 Carbon ring, -C(=O)NR a1 R a2 -S(=O)2NR a1 R a2 -C(=O)R a1 -C(=O)OR a1 -NH-C(=O)R a1 -S(=O)2R a1 -S(=O)(=NR) a1 )R a2 -P(=O)R a3 R a4 -NH-S(=O)2R a1 -NH-S(=O)2NR a1 R a2 -C(=O)NH-C(=NR) a3 )NR a1 R a2 -C(=NR) a3 )NR a1 R a2The alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0085] R a1 R a2 Each independently selected from H and C 1-4 Alkyl, C 3-6 Carbocyclic, 4- to 7-membered heterocyclic, wherein the alkyl, carbocyclic or heterocyclic is optionally surrounded by 1 to 4 R... k replace;

[0086] As an option, R a1 R a2 Direct connection forms a 4- to 7-membered heterocycle, wherein the heterocycle is optionally bounded by 1 to 4 R... k replace;

[0087] R 5a Selected from phenyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclic, 5- to 6-membered heteroaryl, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -C (=NR) a3 )NR a1 R a2 -C(=NR) a3 )R a2 -S(=O)(=NR) a3 )R a4 -P(=O)R a3 R q4 -OP(=O)R a3 R a4 The alkyl, phenyl, cycloalkyl, heteroaryl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0088] R 5b Selected from C 4-6 Monocycloalkyl, C 4-10 cycloalkyl, C 5-10 Spirocycloalkyl, C 5-10 Bridged cycloalkyl, 4- to 8-membered monoheterocyclic, 4- to 10-membered fused heterocyclic, 5- to 10-membered spiroheterocyclic, 5- to 10-membered bridged heterocyclic, 5- to 6-membered heteroaryl, wherein R 5b Choose from 1 to 4 Rs k replace;

[0089] R a3 R a4 Each element is independently selected from H, OH, NH2, and C. 1-4 Alkyl, -OC 1-4 Alkyl, C 3-6 Carbocyclic, 4- to 7-membered heterocyclic, wherein the alkyl, carbocyclic or heterocyclic is optionally surrounded by 1 to 4 R... k replace;

[0090] R 1 R 2 R 3 R 4 Each element is independently selected from H, deuterium, halogens, CN, OH, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 3-6 Carbocyclic, 3- to 7-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic is optionally surrounded by 1 to 4 R... k replace;

[0091] As an option, R 1 R 4 Direct connection forms C 3-6 Carbon rings or 4- to 7-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace;

[0092] R B Each element is independently selected from H, deuterium, halogens, CN, OH, -C(=O)OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 3-7 Carbon ring, -OC 3-7 Carbon rings, 3- to 7-membered heterocycles, or -P(=O)R q1 R q2 The alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0093] R k Each element is independently selected from deuterium, =O, halogens, CN, OH, -C(=O)OH, -C(=O)NH2, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -C(=O)-C 3-6 Carbon ring, -C(=O)-C 1-4 Alkyl, -NH-C3-6 Carbon rings, -NH-3 to 7-membered heterocycles, -C 1-2 Alkylene-C 3-6 Carbon ring, -C 1-2 Alkylene-3 to 7-membered heterocycles, C 3-6 Carbocyclic rings, 3 to 7-membered heterocycles, wherein the alkylene group, alkyl group, alkenyl group, alkynyl group, carbocyclic ring or heterocycle is optionally selected from 1 to 4 elements selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0094] The definitions of the remaining functional groups are the same as those in the first embodiment of the present invention.

[0095] As a third embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomers, racemates, or pharmaceutically acceptable salts are used.

[0096] R a1 R a2 Each is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0097] As an option, R a1 R a2 Direct connection forms an optional 1 to 4 R k The following groups are substituted: aziridine, pyrrolidinyl, piperidinyl;

[0098] R a3 R a4 Each is independently selected from H, OH, NH2, or optionally influenced by 1 to 4 Rs. k The following groups may be substituted: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, or cyclopentyl;

[0099] R 1 R 2 R 3 R 4 Each of the following groups is independently selected from H, deuterium, F, Cl, Br, CN, OH, methyl, ethyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, vinyl, and ethynyl, wherein the methyl, ethyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, vinyl, and ethynyl groups are optionally prefixed with 1 to 4 R groups. k replace;

[0100] or, Selected from The ring C is selected from 1 to 4 Rs. kThe following groups are substituted: cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, piperidinyl, oxecyclopentyl, oxecyclopentyl, dioxocyclopentyl;

[0101] A is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridinoneyl, pyridazinoneyl, pyrroleyl, pyrazolyl, imidazoleyl, and thiazolyl. Quinolinyl, isoquinolinyl, benzopyridinyl, quinoxalinyl, quinazolinyl, indole, isoindole, benzimidazolyl, benzopyrazolyl, benzothiophenyl, benzothiazolyl, pyridinopyridinyl, pyridinopyrroleyl, pyridinopyrazolyl, pyridinotriazolyl, pyrimidinopyrroleyl, pyrimidinopyrazolyl, pyrimidinoimidazolyl, pyrimidinotriazolyl, pyrazinoimidazolyl, pyrazinopyrroleyl, pyrazinopyrazolyl, triazinopyrazolyl, benzocyclobutenyl, benzocyclopentenyl, benzooxacyclopentenyl, benzodioxacyclopentenyl, indoleketone, quinolinone, isoindoleketone, isoquinolinone

[0102] R 5 Selected from -γ-methylene-R 5a γ-Ethylene-R 5a γ-Propylene-R 5a -YR 5b The methylene, ethylene, and propylene groups are optionally coated with 1 to 4 R groups. k replace;

[0103] R B Each of the following groups is independently selected from H, deuterium, F, Cl, Br, cyano, OH, -C(=O)OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, -O-cyclopropyl, cyclobutyl, vinyl, ethynyl, propynyl, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl), wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, vinyl, ethynyl, and propynyl groups are optionally prefixed with 1 to 4 R groups. k replace;

[0104] R kEach of the following groups is independently selected from deuterium, F, Cl, Br, I, CN, OH, -C(=O)OH, -C(=O)NH2, NH2, -C(=O)methyl, -C(=O)CH(CH3)2, -C(=O)cyclopropyl, -C(=O)cyclobutyl, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy The methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally selected from one to four elements selected from deuterium, halogens, CN, OH, NH2, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0105] The definitions of the remaining functional groups are the same as those in the first or second embodiment of the present invention.

[0106] As a fourth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomers, racemates, or pharmaceutically acceptable salts are used.

[0107] A is selected from Its left end is connected to -CO-NH-;

[0108] R 6 Each is independently selected from H, deuterium, F, Cl, Br, CN, OH, =O, -C(=O)OH, -C(=O)NH2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, vinyl, ethynyl, propynyl, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl) -O-cyclopropyl, -O-cyclobutyl, -C(=O)methyl, -C(=O)O-methyl, -C(=O)ethyl, -C(=O)O-ethyl, -S(=O)2-methyl, -S(=O)2NH2, -NH-S(=O)2NH2, -C(=N)(OH)NH2, -C(=N)(O-methyl)NH2, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, vinyl, ethynyl, propynyl are optionally prefixed with 1 to 3 R. k replace;

[0109] R 5a Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, azacyclobutyl, oxacyclohexyl, pyrrolyl, piperidinyl, pyrazolyl, pyrroleyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, thiophene, -O-cyclopropyl, -O-cyclobutyl, -C(=NR) a3 )NR a1 R a2 -C(=NR) a3 )R a2 -S(=O)(=NH)methyl, -P(=O)(OH)2, -OP(=O)(OH)2, -P(=O)(NH2)2, -OP(=O)(NH2)2, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -OP(=O)(methyl)2, -OP(=O)(ethyl)2, -P(=O)(CH3)(cyclopropyl), wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aziridine, pyrrolyl, piperidinyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, thiophene group is optionally surrounded by 1 to 3 R groups. k replace;

[0110] R 5b Selected from bicyclic [1.1.1]pentyl, cyclobutyl, cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, aziroxybutyl, pyrrolyl, piperidinyl, pyrazolyl, pyrroleyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, thiophenyl, wherein R 5b Choose from 1 to 4 Rs k replace;

[0111] Selected from B1 and B2 are each independently selected from N or CR. B ;

[0112] R B Each of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, CH2F, CHF2, CF3, -OCH2F, -OCHF2, -OCF3, -OCD3, methyl, -S-methyl, -S-CF3, ethyl, isopropyl, ethynyl, propynyl, methoxy, ethoxy, isopropyloxy, propyloxy, cyclopropyl, -O-cyclopropyl, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl), wherein the methyl, ethyl, isopropyl, ethynyl, propynyl, methoxy, ethoxy, isopropyloxy, propyloxy, and cyclopropyl groups are optionally prefixed with 1 to 3 R groups. k replace;

[0113] R k Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, -C(=O)OH, -C(=O)NH2, -C(=O)CH3, -C(=O)CH(CH3)2, -C(=O)cyclopropyl, -CH2OH, methyl, ethyl, CD3, OCD3, CH2F, CHF2, CF3, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0114] The definitions of the remaining functional groups are the same as those in the first, second, or third embodiments of the present invention.

[0115] As a fifth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomers, racemates, or pharmaceutically acceptable salts are used.

[0116] R 1 R 2 R 3 R 4 Each is independently selected from H, deuterium, methyl, ethyl, CD3, CH2F, CHF2, CF3;

[0117] or, Selected from The ring C is arbitrarily divided by 1 to 4 Rs. k replace;

[0118] Selected from

[0119] Selected from

[0120] R 5 Selected from -O-methylene-R 5a -S-methylene-R 5a -O-ethylene-R 5a -OR 5b -SR 5b The methylene and ethylene groups are optionally substituted with 1 to 4 substituents selected from H, deuterium, F, Cl, methyl, ethyl, CD3, CH2F, CHF2, and CF3;

[0121] R 5aSelected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrroleyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, thiophene, -O-cyclopropyl, -O-cyclobutyl, -C(=N-OH)NH2, -C(=N-OH)NH-methyl, -C(=N-OH)NH-(methyl)2, -C(=N-OH)methyl, -C(=N-OH)cyclopropyl, -C(=NO-methyl)-methyl, -S(=O)(=NH)methyl, -P(=O)(OH)2, -OP(=O)(OH)2, -P(=O)(NH2)2, -OP(=O) (NH2)2, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl), wherein the methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aziridine, pyrrolyl, piperidinyl, pyrazolyl, pyrroloyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, thiophene group is optionally substituted with 1 to 3 substituents of deuterium, F, Cl, Br, CN, OH, -C(=O)OH, -C(=O)NH2, -C(=O)CH3, -C(=O)cyclopropyl, -CH2OH, methyl, ethyl, CD3, OCD3, CH2F, CHF2, CF3;

[0122] The definitions of the remaining functional groups are the same as those in the first, second, third, or fourth embodiments of the present invention.

[0123] As a sixth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomers, racemates, or pharmaceutically acceptable salts are used.

[0124] Selected from Preferred from

[0125] R k Each is independently selected from deuterium, F, Cl, Br, CN, OH, -CH2OH, methyl, ethyl, CD3, OCD3, CH2F, CHF2, CF3;

[0126] Selected from

[0127] Selected from

[0128] R 5 Selected from

[0129] The definitions of the remaining functional groups are the same as those in the first, second, third, fourth, or fifth embodiments of the present invention.

[0130] This invention relates to compounds or their stereoisomers, racemates, or pharmaceutically acceptable salts as shown below, wherein the compound is selected from one of the structures shown in Table E.

[0131] This invention relates to a pharmaceutical composition comprising any of the above-described compounds or their stereoisomers, racemates, pharmaceutically acceptable salts, and pharmaceutically acceptable carriers.

[0132] This invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the above-described compound of the invention or its stereoisomers, racemates, pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier.

[0133] This invention relates to a method for treating or alleviating a disease in mammals, the method comprising administering to a subject a therapeutically effective amount of the aforementioned compound or its stereoisomers, racemates, or pharmaceutically acceptable salts, preferably 1-1500 mg, wherein the disease is preferably pain.

[0134] In some embodiments, the pharmaceutical composition of the present invention may be in unit dosage form (the amount of the active pharmaceutical ingredient in a unit dosage form is also referred to as a "dosage strength").

[0135] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition being treated (e.g., treatment and / or pain relief). In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-800 mg, 1-700 mg, 1-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 0-500 mg, 25-500 mg, 30-500 mg, 40-500 mg, 150-500 mg, 200-500 mg, 250-500 mg, 300-500 mg, 400-500 mg, 5-400 mg, 7 5-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 2 0-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg.

[0136] In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 1 The compounds of the present invention or their stereoisomers, or pharmaceutically acceptable salts thereof, in doses of 10 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, and 840 mg.

[0137] A method for treating a disease in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its stereoisomers, racemates, or pharmaceutically acceptable salts, preferably 1-1500 mg, wherein the disease is preferably a treatment or relief of pain.

[0138] A method for treating or alleviating a disease in a mammal. The method comprises administering a medicament, a compound of the present invention or its stereoisomers, or a pharmaceutically acceptable salt thereof, to a subject at a daily dose of 1-1000 mg / day. The daily dose may be a single dose or multiple doses. In some embodiments, the daily dose includes, but is not limited to, 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, and 25-400 mg / day. / day, 50-400mg / day, 100-400mg / day, 200-400mg / day, and in some embodiments, the daily dose includes, but is not limited to, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 80mg / day, 100mg / day, 125mg / day, 150mg / day, 160mg / day, 200mg / day, 300mg / day, 320mg / day, 400mg / day, 480mg / day, 600mg / day, 640mg / day, 800mg / day, and 1000mg / day.

[0139] This invention relates to a kit that may include a single-dose or multi-dose composition comprising a compound of the present invention or its stereoisomers, racemates, or pharmaceutically acceptable salts, wherein the amount of the compound of the present invention or its stereoisomers, racemates, or pharmaceutically acceptable salts is the same as the amount in the aforementioned pharmaceutical composition.

[0140] This invention relates to the use of any of the above-described compounds or their stereoisomers, racemates, or pharmaceutically acceptable salts in the preparation of medicaments for treating and / or relieving pain.

[0141] This invention relates to the use of the above-described pharmaceutical composition in the preparation of a medicine for treating and / or relieving pain.

[0142] The amounts of the compounds of the present invention, or their stereoisomers, racemates, or pharmaceutically acceptable salts, are converted in each case to the form of free base.

[0143] Synthesis Method 1:

[0144]

[0145] General formula (Z1) and general formula (Z2) are reacted by the Wittig reaction to obtain the corresponding general formula (Z3). General formula (Z3) is reacted by the addition reaction with ethyl mercaptoacetate to obtain the corresponding general formula (Z4). General formula (Z4) is condensed into an intramolecular ester to obtain the corresponding general formula (Z5). General formula (Z5) is protected by a protecting group to obtain the corresponding general formula (Z6). General formula (Z6) and general formula (Z6-1) are coupled to obtain the corresponding general formula (Z7). General formula (Z7) is reduced to obtain the corresponding general formula (Z8). General formula (Z8) is hydrolyzed under alkaline conditions to obtain the corresponding general formula (Z9). General formula (Z9) and general formula (Z10) are condensed to obtain the corresponding general formula (Ia).

[0146] X is a halogen, boric acid, or boron ester.

[0147] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0148] The compounds of this invention also include their racemic, stereoisomer, tautomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal.

[0149] The carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention include their isotopic forms. That is, the carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention may be optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 11 C 12 C 13 C and14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 15 O、 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S, 35 S and 36 S, nitrogen isotopes include 13 N、 14 N and 15 N, isotopes of fluorine include 17 F, 18 F and 19 F, isotopes of chlorine include 35 Cl、 36 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br, an isotope of iodine, includes 123 I, 125 I, phosphorus isotopes include 31 P, 32 P.

[0150] “CN” refers to cyano.

[0151] "Halogen" refers to F, Cl, Br or I.

[0152] "Halogen-substituted" refers to substitution with F, Cl, Br, or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br, or I, 1 to 6 substituents selected from F, Cl, Br, or I, and 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen-substituted" is abbreviated as "halogenated".

[0153] "alkyl" refers to a substituted or unsubstituted straight-chain or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups with 1 to 20 carbon atoms, alkyl groups with 1 to 8 carbon atoms, alkyl groups with 1 to 6 carbon atoms, and alkyl groups with 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and their various branched isomers; the alkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0154] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2). v - (v is an integer from 1 to 10), alkylene examples include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0155] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirobutyl, adamantane, etc. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0156] "Heterocyclic alkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms or 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, S, or Se. The C, N, and S atoms on the ring of the heterocyclic alkyl group can be oxidized to various oxidation states. Heterocyclic alkyl groups can be monocyclic, fused, bridged, or spirocyclic. Heterocyclic alkyl groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, aziridinepropyl, oxacyclobutyl, aziridinebutyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxopentyl, dioxohexyl, pyrrolylalkyl, piperidinyl, imidazoalkyl, oxazolidinyl, oxazinylalkyl, morpholinyl, hexahydropyrimidinyl, piperazineyl, etc. Heterocyclic alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0157] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon double bonds. The main chain has, but is not limited to, 2 to 10, 2 to 6, or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2... -Methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent, or tetravalent.

[0158] "Alynyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon triple bonds. The main chain comprises 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms on the main chain, or 2 to 4 carbon atoms on the main chain. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, and 4-pentynyl. The alkynyl group can be monovalent, divalent, trivalent, or tetravalent.

[0159] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

[0160] "Carbocyclic group" or "carbocyclic ring" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system. The carbocyclic group can be attached to an aromatic or non-aromatic ring, and the ring can be optionally a monocyclic, fused, bridged, or spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, etc. "Carbocyclic group" or "carbon ring" can be monovalent, divalent, trivalent or tetravalent.

[0161] "Heterocyclic group" or "heterocyclic" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se selectively substituted in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused, or spirocyclic ring. Non-limiting examples include epoxyethyl, aziridinepropyl, oxacyclobutyl, aziridinebutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexane, aziridineheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithioyl, dihydrofuranyl, dihydropyranyl, dithiapentylcycloyl. Tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophene, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl, "Heterocyclic group" or "heterocyclic" can be monovalent, divalent, trivalent or tetravalent.

[0162] A "spirocyclic" or "spirocyclic group" refers to a polycyclic group in which substituted or unsubstituted rings share a single atom (called a spiro atom). The number of ring atoms in a spirocyclic system includes, but is not limited to, 5 to 20, 6 to 14, 6 to 12, or 6 to 10. One or more rings may contain zero or more (including but not limited to 1, 2, 3, or 4) double bonds, and optionally, may contain 0 to 5 double bonds selected from N, O, or S (=O). n Heteroatoms (n is 0, 1, or 2). Non-limiting embodiments include:

[0163]

[0164] "Spirocyclic" or "spirocyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0165] "Circular fused" or "circular fused group" refers to a polycyclic group in which each ring in a system shares a pair of adjacent atoms with other rings in the system. One or more rings may contain zero or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted. Each ring in a circular fused system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to those selected from N, S (=O)). n Or O, where n is 0, 1, or 2). The number of ring atoms in a cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include:

[0166]

[0167] "Cyclone" or "cyclone base" can be monovalent, divalent, trivalent, or tetravalent.

[0168] A “bridged ring” or “bridged ring group” refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in a bridged ring system may contain 0 to 5 groups selected from heteroatoms or containing heteroatoms (including but not limited to N, S(=O)n, or O, where n is 0, 1, or 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include:

[0169] Cubicane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0170] "Carbon spirocyclic", "spirocyclic carbon cyclic", "spirocarbon cyclic", or "carbon spirocyclic" refers to a spirocyclic system composed only of carbon atoms.

[0171] "Carbon fused ring", "fused cyclic carbon cyclic group", "fused carbon cyclic group" or "carbon fused cyclic group" refers to a ring system composed only of carbon atoms.

[0172] "Carbon bridged ring", "bridged ring carbon cyclo group", "bridged carbon cyclo group" or "carbon bridged ring group" refers to a ring system composed only of carbon atoms.

[0173] "Hybrid monocyclic", "monocyclic heterocyclic group" or "hybrid monocyclic group" refers to the "heterocyclic group" or "heterocyclic" in a monocyclic system.

[0174] "Hydrocyclic ring", "hydrocyclic cyclic group", "fused cyclic heterocyclic group" or "fused heterocyclic group" refers to a "fused ring" containing heteroatoms.

[0175] "Heterospirocyclic", "heterospirocyclic group", "spirocyclic heterocyclic group" or "spiroheterocyclic group" refers to a "spirocycle" containing heteroatoms.

[0176] "Hybrid-bridged ring", "hybrid-bridged ring group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing heteroatoms.

[0177] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring. Non-limiting embodiments include benzene rings, naphthalene rings, etc. The "aryl" or "aryl ring" can be monovalent, divalent, trivalent, or tetravalent. When it is divalent, trivalent, or tetravalent, the linking site is located on the aryl ring.

[0178] "Heteroaryl" or "heteroary ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or a group containing heteroatoms (including but not limited to N, O, S(=O)n or Se(=O)n, where n is 0, 1, or 2). The number of ring atoms in the heteroaryl ring includes, but is not limited to, 5 to 15, 5 to 10, or 5 to 6. The atoms C, N, and S on the ring may be optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1 or 2). Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furanyl, thiophenyl, selenyl, pyridyl, pyranyl, N-alkylpyrrolithyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazoleyl, benzopyrazolyl, benzimidazoleyl, benzopyridyl, pyrrolopyridyl, pyridinoneyl, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbon ring or heterocycle, wherein the ring connected to the parent structure is an aryl ring. Non-limiting embodiments include: The heteroaryl groups mentioned in this article are defined in accordance with this definition. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the linkage site is located on an aromatic ring.

[0179] "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4, or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged cyclic, spirocyclic, fused cyclic, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, and -(CH2). m -C(=O)-R a -O-(CH2) m -C(=O)-R a -(CH2) m -C(=O)-NR b R c -(CH2) mS(=O) n R a -(CH2) m -Alkenyl-R a OR d Or -(CH2) m -alkynyl-R a (where m and n are 0, 1, or 2), arylthio, thiocarbonyl, silyl, or -NR b R c Groups, wherein R b With R c Independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, R b With R c It can form five- or six-membered cycloalkyl or heterocyclic groups, R a With R d Each group is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic, carbonyl, ester, bridged cyclic, spirocyclic, or fused cyclic groups.

[0180] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from..., where X is any integer between 1 and 10. For example, "1 to 4 R..." k "Replace" refers to being replaced by 1, 2, 3, or 4 Rs. k Substitution. For example, "1 to 5 substituents selected from ..." means that the ring is substituted by 1, 2, 3, 4 or 5 substituents selected from .... For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

[0181] XY-membered rings (where X and Y are integers, and 3 ≤ X < Y, X < Y ≤ 20, selected from any integer between 4 and 20) include rings of the X, X+1, X+2, X+3, X+4…Y-membered types. These rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterofused rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7-membered heteromonocyclic rings" refers to heteromonocyclic rings of 4, 5, 6, or 7 members, and "5-10-membered heterofused rings" refers to heterofused rings of 5, 6, 7, 8, 9, or 10 members.

[0182] C x-y Carbocyclic rings (including aryl, cycloalkyl, monocyclic, spirocyclic, fused, or bridged carbocyclic rings) include C x C x+1 C x+2 C x+3 C x+4 …C yA ring of elements (x is an integer, and 3 ≤ x < y, where y is any integer between 4 and 20), for example, C. 3-6 "Cycloalkyl" refers to C3, C4, C5, or C6 cycloalkyl groups.

[0183] When a functional group has one or more connectable sites, any one or more of these sites can be linked to other functional groups via chemical bonds. When the chemical bond connection is non-directional and a hydrogen atom is present at the connectable site, the number of hydrogen atoms at that site decreases accordingly with the number of bonds being formed, resulting in a functional group with a corresponding valence. For example... This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... These four connection methods, even if an H atom is drawn on -N-, This also includes For example This indicates that the R group on the piperidinyl group can be located on C or N, and at least includes [missing information]. For example, the general formula segment is: When X is selected from CH2 or NH, it means that the R group on the general formula fragment can be located on C or X. When X is selected from CH2, the general formula fragment can be... When X is selected from NH, the general formula fragment can be:

[0184] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key Represents the relative configuration of the center of a solid.

[0185] When the listed linking groups do not specify their linking direction, the linking direction includes the direction of the reading order from left to right and from right to left. For example, when ALB is selected from -MW-, it includes AMWB and AWMB.

[0186] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or possibility that the event or environment may or may not occur. For example, "optionally substituted F alkyl" means that the alkyl group may but does not have to be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

[0187] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, and that the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0188] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this invention, or stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0189] "Carrier" refers to a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the compound given.

[0190] "Prodrug" refers to a compound of the present invention that can be metabolized in vivo and converted into a biologically active compound. The prodrug of the present invention is prepared by modifying the amino or carboxyl groups in the compound of the present invention. This modification can be performed through conventional procedures or removed in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free amino or carboxyl groups.

[0191] "Co-crystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a co-crystal form (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids at room temperature in their pure states, and a fixed stoichiometric ratio exists between the components. Co-crystal is a multi-component crystal, encompassing both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0192] "Stereoisomers" refer to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0193] "Tautomers" refer to functional group isomers that are produced by the rapid movement of an atom in two positions within a molecule, such as keto-enol isomers and amide-imine alcohol isomers.

[0194] "Animals" refers to mammals, such as humans, companion animals, zoo animals, and livestock, with humans, horses, or dogs being preferred.

[0195] IC 50 "It refers to the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of that process, such as an enzyme, receptor, or cell) by half." Detailed Implementation

[0196] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0197] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0198] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0199] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0200] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) are 0.15mm-0.20mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4mm-0.5mm in diameter.

[0201] Column chromatography typically uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0202] To accomplish the objectives of this invention, compounds used in the reactions described herein are prepared from commercially available chemicals and / or compounds described in chemical literature, according to organic synthesis techniques known to those skilled in the art. "Commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai Maclean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Esa (China) Chemical Co., Ltd., THIAI (Shanghai) Chemical Industry Development Co., Ltd., Energie Chemicals, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.

[0203] Example 1: Preparation of Compound 1

[0204]

[0205]

[0206] Step 1: Preparation of compound 1b

[0207] Under ice bath conditions, 1a-1 (30.96 g, 129.95 mmol) was dissolved in tetrahydrofuran (130 mL), and sodium hydride (5.20 g, 130 mmol) was added in portions. The reaction was carried out under nitrogen atmosphere and ice bath conditions for 30 minutes. 1a (11.20 g, 100 mmol) was dissolved in tetrahydrofuran (20 mL) and added dropwise to the reaction system. The reaction was carried out under nitrogen atmosphere and allowed to naturally warm to room temperature for 18 hours. Under ice bath conditions, 1M hydrochloric acid was slowly added dropwise to the reaction system until the pH reached 7-8. The mixture was extracted with diethyl ether (150 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated (at room temperature) to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 1b (14.1 g, yield 71.88%, E / Z configuration mixture).

[0208] Step 2: Preparation of compound 1c

[0209] Under ice bath conditions, 1b-1 (8.63 g, 71.88 mmol) was added to a round-bottom flask, followed by piperidine (1.22 g, 14.38 mmol) and then 1b (6.0 g, 71.88 mmol). The reaction was carried out at 50 °C for 24 h under nitrogen protection. The reaction was quenched with 0.1 M hydrochloric acid (100 mL) under ice bath conditions, and the mixture was extracted with diethyl ether (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated (at 25 °C) to obtain crude 1c. The crude product was purified by silica gel column chromatography to obtain 1c (6.3 g, yield 27.96%).

[0210] LC-MSm / z = 317.1 [M+H] +

[0211] Step 3: Preparation of compound 1d

[0212] Under ice bath conditions, 1c (6.3 g, 19.92 mmol) was dissolved in ether (120 mL). Under nitrogen protection, potassium tert-butoxide (2.91 g, 25.90 mmol) was slowly added dropwise to the system, and the reaction was carried out in an ice bath for 2 h. Under ice bath conditions, glacial acetic acid (1.56 mL) and water (100 mL) were added to the reaction system to quench the reaction, and the mixture was extracted with ether (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1d.

[0213] Step 4: Preparation of compound 1e

[0214] 1d (4.05 g, 15 mmol) was dissolved in dichloromethane (40 mL), pre-cooled at -78 °C for 15 min, and N,N-diisopropylethylamine (2.32 g, 17.99 mmol) was added dropwise under a nitrogen atmosphere. Trifluoromethanesulfonic anhydride (4.23 g, 15 mmol) was dissolved in dichloromethane (10 mL) and slowly added dropwise to the system. After the addition was complete, the reaction was continued at -78 °C for 2 h. The reaction was quenched by slowly adding saturated sodium bicarbonate aqueous solution (50 mL) to the reaction system under ice bath conditions. The mixture was extracted with dichloromethane (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 1e (5.2 g, yield 86.16%).

[0215] Step 5: Preparation of compound 1f

[0216] 1e (5.2 g, 12.92 mmol) was dissolved in toluene (50 mL), followed by the addition of 1e-1 (2.67 g, 14.21 mmol) and Pd(PPh3)4 (0.75 g, 0.65 mmol). A 2 M aqueous solution of potassium phosphate (8.23 g, 38.71 mmol) was added to the system. The reaction was carried out at 100 °C for 6 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (10 mL × 2). The filtrate was separated into layers, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 1f (5.1 g, 99.59% yield).

[0217] LC-MSm / z = 397.1 [M+H] +

[0218] Step 6: Preparation of compounds 1f-2a and 1f-2b

[0219] 1f (3.7 g, 9.33 mmol) was dissolved in methanol (50 mL), and palladium on carbon (1.99 g, 18.56 mmol) was added. After the addition was complete, the mixture was pressurized to 2 MPa under a hydrogen atmosphere and reacted at room temperature for 24 h. The reaction was filtered and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a mixture of 1g-1a and 1g-1b (1.02 g, yield 27.44%), and a mixture of unreacted configurational starting materials 1f-2a and 1f-2b (0.148 g, yield 4.00%) was recovered.

[0220] Step 7: Preparation of compounds 1g-2a and 1g-2b

[0221] A mixture of 1f-2a and 1f-2b (0.148 g, 0.38 mmol) was dissolved in methanol (10 mL), and palladium on carbon (0.15 g, 1.41 mmol) was added. After the addition was complete, the pressure was increased to 2.5 MPa under a hydrogen atmosphere, and the reaction was carried out at 90 °C for 24 h. The reaction was filtered and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a mixture of 1g-2a and 1g-2b (0.052 g, yield 34.35%).

[0222] Step 8: Preparation of compounds 1h-2a and 1h-2b

[0223] Under a nitrogen atmosphere and in an ice bath, a mixture of 1 g⁻²a and 1 g⁻²b (0.052 g, 0.13 mmol) was dissolved in tetrahydrofuran (5 mL), pre-cooled for 15 minutes, and potassium tert-butoxide (0.048 g, 0.43 mmol) was slowly added dropwise to the system (internal temperature < 13 °C). After the addition was complete, the reaction was carried out in an ice bath for 2 h. Under an ice bath, 1 N hydrochloric acid was slowly added dropwise to the system (internal temperature < 13 °C) until pH = 1, water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture of 1 h⁻²a and 1 h⁻²b.

[0224] LC-MSm / z = 369.0 [MH] -

[0225] Step 9: Preparation of compound 1h-2a

[0226] A mixture of 3.0 g of compounds 1h-2a and 1h-2b was prepared by SFC (Self-Fluorescence Method), and after lyophilization, compound 1h-2a (1.28 g, SFC retention time: 0.760 min) and compound 1h-2b (1.11 g, SFC retention time: 0.966 min) were obtained. SFC assay method: (Instrument: SHIMADZU LC-30AD, Chiralcel IG column. Preparation method: The crude product was dissolved in acetonitrile to prepare the sample solution. Mobile phase: Carbon dioxide / 0.05% DEA in ethanol. Elution gradient: 5%-40%; elution time: 3 min).

[0227] SFC preparation conditions: Instrument: Waters 150Prep-SFC A; Preparative column: Chiralcel IG column. Preparation method: The crude product was dissolved in acetonitrile to prepare a sample solution with a concentration of 2 mg / mL. Mobile phase system: carbon dioxide / ethanol, ethanol content 10%; flow rate: 100 mL / min; elution time: 2 min.

[0228] Compound 1h-2a:

[0229] 1 HNMR (400MHz, CDCl3): δ6.91–6.78(m,2H),4.53(d,1H),4.46–4.34(m,1H),4.02(d,3H),2.68-2.54(m,1H),1.93(s,3H),0.88–0.75(m,3H).

[0230] Step 10: Preparation of Compound 1i

[0231] Substrate 1h-2a (150 mg, 0.41 mmol) was dissolved in a 2 M, 2 mL solution of oxalyl chloride in dichloromethane. DMF (0.002 g, 0.028 mmol) was added dropwise under ice bath conditions, and the reaction was allowed to proceed to room temperature for 2 hours. After concentration, the crude product was added to ethanol (2 mL) and reacted overnight at room temperature. The crude product was then concentrated and purified by silica gel column chromatography to give 1i (140 mg, 86.76% yield).

[0232] LCMSm / z = 399.1 [M+H] +

[0233] Step 11: Preparation of Compound 1j

[0234] Substrate 1i (140 mg, 0.35 mmol) was dissolved in dichloromethane (2 mL), and boron tribromide (1 mL) was added dropwise. The reaction was carried out overnight at room temperature. The crude product was concentrated and purified by silica gel column chromatography to give 1j (90 mg, yield 66.63%).

[0235] LCMSm / z = 385.0 [M+H] +

[0236] Step 12: Preparation of compound 1k

[0237] 1J (70 mg, 0.18 mmol) was dissolved in acetonitrile (5 mL), and bromomethylcyclopropane (36 mg, 0.27 mmol) and potassium carbonate (75 mg, 0.54 mmol) were added. The mixture was heated to 75 °C and reacted for 2 hours. The reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain 1K (70 mg, yield 87.66%).

[0238] LCMSm / z = 439.1 [M+H] +

[0239] Step 13: Preparation of Compound 1l

[0240] 1kJ (20mg, 0.05mmol) was dissolved in ethanol (2mL), and cesium carbonate (60mg, 0.18mmol) was added. The mixture was heated to 50°C and reacted for 2 hours. The reaction system was concentrated to obtain a crude product, which was dissolved in water (5mL), the pH was adjusted to 1-2 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate (5mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1L of crude product.

[0241] LCMSm / z = 409.2 [MH] -

[0242] Step 14: Preparation of Compound 1

[0243] 1 L (15 mg, 0.04 mmol) was dissolved in DMF (2 mL), and HATU (21 mg, 0.06 mmol), 5-amino-2-fluorobenzamide (6.84 mg, 0.04 mmol), and triethylamine (14 mg, 0.11 mmol) were added sequentially. The reaction was carried out under nitrogen atmosphere at room temperature for 18 hours. Sodium bicarbonate aqueous solution (5 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 1 (8.6 mg, yield 43.05%).

[0244] LCMSm / z = 545.2 [MH] -

[0245] 1 H NMR(400MHz,DMSO-d6)δ10.51(s,1H),7.84-7.80(m,1H),7.66-7.58(m,3 H),7.24-7.10(m,2H),7.09-7.03(m,1H),4.83(d,1H),4.63-4.56(m,1H), 4.12-4.05(m,1H),3.99-3.92(m,1H),2.76-2.68(m,1H),1.88(s,3H),1. 36-1.25(m,1H),0.81-0.73(m,3H),0.66-0.56(m,2H),0.43-0.32(m,2H).

[0246] Example 2: Preparation of Compound 2

[0247]

[0248] Step 1: Preparation of Compound 2

[0249] Compound 1 (129 mg, 0.24 mmol) was dissolved in dichloromethane (2 mL), and m-CPBA (207 mg, 1.2 mmol) was added. The mixture was reacted at room temperature for 18 hours. The crude product was concentrated and purified by silica gel column chromatography to obtain compound 2 (10 mg, yield 7.32%).

[0250] LCMSm / z = 579.2 [M+H] +

[0251] Example 3: Preparation of Compound 3

[0252]

[0253] Step 1: Preparation of compound 3a

[0254] 1 L (80 mg, 0.19 mmol) of substrate was dissolved in a 2 M, 5 mL solution of oxalyl chloride in dichloromethane. DMF (0.002 g, 0.028 mmol) was added dropwise under ice bath conditions, and the reaction was allowed to proceed to room temperature for 2 hours. After concentration, the crude product was added to methyl 4-aminopyridine-2-carboxylate (34.7 mg, 0.23 mmol), and the reaction was allowed to proceed overnight at room temperature. The crude product was concentrated and purified by silica gel column chromatography to give 3a (57 mg, 53.7% yield).

[0255] LCMSm / z = 545.2 [M+H] +

[0256] Step 2: Preparation of Compound 3

[0257] Substrate 3a (57 mg, 0.10 mmol) was dissolved in a methanol solution of ammonia (7 M, 2 mL) and reacted overnight at room temperature. The crude product was concentrated and purified by silica gel column chromatography to give compound 3 (28.8 mg, yield 51.96%).

[0258] LCMSm / z = 530.2 [M+H] +

[0259] 1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),7.86-7.80(m,1H),7.67-7.57(m,3 H),7.24-7.11(m,2H),7.10-7.03(m,1H),4.83(d,1H),4.54-4.46(m,1H), 4.25-4.18(m,1H),4.16-4.08(m,1H),2.84-2.72(m,1H),2.68-2.58(m,1 H),2.18-2.06(m,2H),2.01-1.87(m,4H),1.84(s,3H),0.79-0.70(m,3H).

[0260] Example 4: Preparation of Compound 4

[0261]

[0262] Step 1: Preparation of compound 4a

[0263] 1j (50 mg, 0.13 mmol) was dissolved in acetonitrile (5 mL), and bromomethylcyclobutane (29 mg, 0.20 mmol) and potassium carbonate (54 mg, 0.39 mmol) were added. The mixture was heated to 75 °C and reacted for 2 hours. The reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain 4a (58 mg, yield 98.54%).

[0264] Step 2: Preparation of compound 4b

[0265] Dissolve 4a (58 mg, 0.13 mmol) in ethanol (2 mL), add cesium carbonate (170 mg, 0.52 mmol), and react at 50 °C for 2 hours. Concentrate the reaction system to obtain the crude product, dissolve the crude product in water (5 mL), adjust the pH to 1-2 with 1 N hydrochloric acid, extract with ethyl acetate (5 mL x 3), combine the organic phases, dry to anhydrous sodium sulfate, filter and concentrate to obtain crude product 4b.

[0266] LCMSm / z = 423.2 [MH] -

[0267] Step 3: Preparation of Compound 4

[0268] 4b (50 mg, 0.12 mmol) was dissolved in DMF (2 mL), and HATU (68 mg, 0.18 mmol), 5-amino-2-fluorobenzamide (22.2 mg, 0.14 mmol), and DIPEA (47 mg, 0.36 mmol) were added sequentially. The reaction was carried out under nitrogen atmosphere at room temperature for 18 hours. Sodium bicarbonate aqueous solution (5 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 4 (35 mg, yield 53%).

[0269] LCMSm / z = 561.2 [MH] -

[0270] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.47(d,1H),8.16(d,1H),8.04(s,1H) ,7.70-7.65(m,1H),7.61(s,1H),7.19-7.02(m,2H),4.87(d,1H),4.65-4.57( m,1H),4.14-4.07(m,1H),4.01-3.94(m,1H),2.79-2.70(m,1H),1.89(s,3H) ,1.36-1.26(m,1H),0.83-0.73(m,3H),0.66-0.59(m,2H),0.44-0.33(m,2H).

[0271] Example 5: Preparation of Compound 5

[0272]

[0273] Step 1: Preparation of compound 5a

[0274] 1 L (100 mg, 0.24 mmol) was dissolved in dichloromethane (3 mL), and m-CPBA (207 mg, 1.2 mmol) was added. The mixture was reacted at room temperature for 48 hours. The crude product was concentrated and purified by silica gel column chromatography to give 5a (76 mg, yield 70.5%).

[0275] LCMSm / z = 443.1 [M+H] +

[0276] Step 2: Preparation of compound 5b

[0277] 5a (76 mg, 0.17 mmol) was dissolved in tetrahydrofuran (3 mL), and triethylamine (103.2 mg, 1.02 mmol) and T3P (432.7 mg, 0.68 mmol) were added sequentially. The mixture was stirred at room temperature for 15 minutes, and then methyl 4-aminopyridine-2-carboxylate (38.8 mg, 0.26 mmol) was added. The mixture was reacted at room temperature under a nitrogen atmosphere for 18 hours. Saturated sodium bicarbonate aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 5b (37 mg, yield 37.36%).

[0278] LCMSm / z = 577.3 [M+H] +

[0279] Step 3: Preparation of Compound 5

[0280] Substrate 5b (37 mg, 0.064 mmol) was dissolved in ammonia in methanol (7 M, 2 mL) and reacted overnight at room temperature. The crude product was concentrated and purified by silica gel column chromatography to give compound 5 (21 mg, yield 58.27%).

[0281] LCMSm / z = 562.1 [M+H] +

[0282] Example 6: Preparation of Compound 6

[0283]

[0284] Compound 6 (25 mg, 44.3%) was obtained by referring to step fourteen of Example 1 using 1 L (40 mg, 0.10 mmol) and 6a (22 mg, 0.12 mmol) as raw materials.

[0285] LCMSm / z = 583.1 [M+H] +

[0286] 1H NMR(400MHz, CDCl3)δ8.16(s,1H),8.00-7.91(m,1H),7.80-7.74(m,1H),7. 21-7.13(m,1H),7.05-6.98(m,1H),6.90-6.82(m,1H),5.07(s,2H),4.59(s, 2H),4.12-4.05(m,1H),4.01-3.94(m,1H),2.80-2.71(m,1H),1.95(s,3H), 1.28-1.24(m,1H),0.90-0.83(m,3H),0.66-0.58(m,2H),0.38-0.28(m,2H).

[0287] Example 7: Preparation of Compound 7

[0288]

[0289] Compound 6 (90.0 mg, 0.15 mmol) was dissolved in dichloromethane (1 mL), and then m-chloroperoxybenzoic acid (76.0 mg, 0.38 mmol, Purity 85%) was added to the system. The reaction was continued at room temperature for 18 hours. The crude product was concentrated under reduced pressure and dissolved in saturated sodium bicarbonate solution (10 mL). The crude product was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The organic phase was backwashed with saturated sodium chloride aqueous solution (30 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was prepared by prep-HPLC and lyophilized to obtain compound 6-2a (20.0 mg, yield 21.07%).

[0290] Prep-HPLC preparation conditions:

[0291] Instrumentation: Waters AutoP; Preparative column: Sunfire C18 (30mm × 150mm). Preparation method: The crude product was dissolved in methanol and filtered through a 0.45μm filter to prepare the sample solution. Mobile phase system: Acetonitrile / water (0.1% TFA); gradient elution, acetonitrile content 10%-60%, flow rate: 30mL / min, elution time: 25min.

[0292] LCMSm / z = 615.1 [M+H] + ;

[0293] Example 8: Preparation of Compound 8

[0294]

[0295] Step 1: Preparation of compound 8a

[0296] 100 mg (0.26 mmol), N-Boc-4-piperidinemethanol (112.0 mg, 0.52 mmol), and triphenylphosphine (136.4 mg, 0.52 mmol) were dissolved in THF (1 mL). DIAD (105.2 mg, 0.52 mmol) was slowly added dropwise under a nitrogen atmosphere at 0 °C. After the addition was complete, the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was extracted with water (5 mL) and ethyl acetate (5 mL × 3). The organic phases were combined, backwashed with saturated sodium chloride aqueous solution (30 mL), and collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to give compound 8a (125 mg, yield 82.6%).

[0297] Step 2: Preparation of compound 8b

[0298] 8a (125 mg, 0.21 mmol) was dissolved in hydrochloric acid / 1,4-dioxane solution (2 mL, 1 mol / L) and reacted at room temperature for 2 hours. The reaction system was concentrated to give crude compound 8b (110 mg, 99.0% yield), which was used directly in the next step of the reaction.

[0299] Step 3: Preparation of compound 8c

[0300] Compound 8b (110 mg, 0.21 mmol) was dissolved in dichloromethane (1 mL). Triethylamine (63.8 mg, 0.63 mmol) and cyclopropylformyl chloride (33.0 mg, 0.32 mmol) were added to the system at room temperature. After the addition was complete, the reaction was allowed to proceed at room temperature for 16 hours. The reaction system was concentrated to obtain a crude product, which was purified by column chromatography to give compound 8c (89 mg, yield 76.1%).

[0301] Step 4: Preparation of compound 8d

[0302] Using compound 8c (89 mg, 0.16 mmol) as a starting material, compound 8d (82 mg, 97.1% yield) was obtained by referring to step 13 of Example 1.

[0303] Step 4: Preparation of Compound 8

[0304] Compound 8 (17 mg, yield 22.47%) was obtained from compound 8d (60 mg, 0.12 mmol) as a starting material, following step fourteen of Example 1.

[0305] LCMSm / z = 658.4 [M+H] +

[0306] Example 9: Preparation of Compound 9

[0307]

[0308] Compound 9 (9 mg, 85.82% yield) was obtained from compound 8 (10 mg, 0.015 mmol) as a starting material, referring to Example 7.

[0309] LCMSm / z = 690.2[M+H] +

[0310] Example 10: Preparation of Compound 10

[0311]

[0312] Step 1: Preparation of compound 10a

[0313] 1 L (100 mg, 0.24 mmol) was dissolved in tetrahydrofuran (5 mL), and triethylamine (145.7 mg, 1.44 mmol) and T3P (305.5 mg, 0.96 mmol) were added sequentially. The mixture was stirred at room temperature for 15 minutes, and 10a-1 (60.5 mg, 0.36 mmol) was added. The reaction was carried out at room temperature under a nitrogen atmosphere for 18 hours. Saturated sodium bicarbonate aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 10a (90 mg, yield 65.89%).

[0314] LCMSm / z = 561.2 [M+H] +

[0315] Step 2: Preparation of compound 10b

[0316] Substrate 10a (90 mg, 0.10 mmol) was dissolved in ammonia in methanol (7 M, 2 mL) and reacted overnight at room temperature. The crude product was concentrated and purified by silica gel column chromatography to give 10b (41 mg, yield 46.81%).

[0317] LCMSm / z = 546.2 [M+H] +

[0318] Step 3: Preparation of Compound 10

[0319] 10b (51 mg, 0.075 mmol) was dissolved in dichloromethane (2 mL), and m-CPBA (64.7 mg, 0.38 mmol) was added. The mixture was reacted at room temperature for 48 hours. The crude product was concentrated and purified by silica gel column chromatography to give compound 10 (9.36 mg, yield 21.56%).

[0320] LCMSm / z = 578.0 [M+H] +

[0321] Example 11: Preparation of Compound 11

[0322]

[0323] Step 1: Preparation of compound 11a

[0324] Compound 11a (1.1 g, yield 89.12%) was obtained from 1j (1000 mg, 2.60 mmol) and 2,2-difluorocyclopropylmethanol (560 mg, 5.18 mmol) in step 1 of Example 8.

[0325] Step 2: Preparation of compound 11b

[0326] Using 11a (1.0 g, 2.32 mmol) as the starting material, compound 11b (1000 mg, yield 96.62%) was obtained by referring to step 13 of Example 1.

[0327] LCMSm / z = 445.0 [MH] -

[0328] Step 3: Preparation of Compound 11

[0329] Compound 11 (30 mg, yield 23.0%) was obtained from 11b (100 mg, 0.22 mmol) as a starting material, following step fourteen of Example 1.

[0330] LCMSm / z = 583.1 [M+H] +

[0331] Example 12: Preparation of Compound 12

[0332]

[0333] 11b (100 mg, 0.22 mmol) was dissolved in DMF (2 mL), and TCFH (126 mg, 0.45 mmol), 6a (64 mg, 0.34 mmol), and N-methylimidazole (37 mg, 0.45 mmol) were added sequentially. The reaction was carried out under nitrogen atmosphere at room temperature for 18 hours. Sodium bicarbonate aqueous solution (5 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 12 (45 mg, yield 32.47%).

[0334] LCMSm / z = 619.3 [M+H] +

[0335] Example 13: Preparation of Compound 13

[0336]

[0337] Step 1: Preparation of compound 13a

[0338] 11b (200 mg, 0.45 mmol) was dissolved in tetrahydrofuran (4 mL), followed by the addition of triethylamine (0.2 mL, 1.44 mmol) and methyl 4-aminopyridine-2-carboxylate (103 mg, 0.68 mmol). The mixture was stirred at room temperature for 15 minutes, and T3P (428 mg, 0.67 mmol) was added under ice bath. The reaction was carried out at room temperature for 18 hours under a nitrogen atmosphere. The mixture was then extracted with saturated sodium bicarbonate aqueous solution (4 mL) and ethyl acetate (3 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 13a (123 mg, yield 47.29%).

[0339] Step 2: Preparation of Compound 13

[0340] 13a (123 mg, 0.21 mmol) was dissolved in 7 M ammonia-methanol solution (4 mL) and reacted at room temperature for 18 h. The reaction system was concentrated to obtain a crude product, which was then subjected to silica gel column chromatography to give compound 13 (50 mg, yield 42.77%).

[0341] LCMSm / z = 566.0 [M+H] +

[0342] Example 14: Preparation of Compound 14

[0343]

[0344] Step 1: Preparation of compound 14a

[0345] 1j (0.76 g, 1.97 mmol), 1-bromomethyl-1'-trifluoromethylcyclopropane (0.52 g, 2.56 mmol), cesium carbonate (1.28 g, 3.94 mmol), and sodium iodide (0.15 g, 1.00 mmol) were dissolved in DMF (10 mL) and reacted at 50 °C under a nitrogen atmosphere for 16 hours. The reaction mixture was extracted with water (15 mL) and ethyl acetate (10 mL × 3). The organic phases were combined, backwashed with saturated sodium chloride aqueous solution (10 mL × 3), collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to give compound 14a (0.93 g, 93.24% yield).

[0346] LCMSm / z = 507.1 [M+H] +

[0347] Step 2: Preparation of compound 14b

[0348] 14a (930 mg, 1.83 mmol) was dissolved in ethanol (20 mL), and cesium carbonate (1.79 g, 5.51 mmol) was added. The mixture was heated to 50 °C and reacted for 2 hours. The reaction mixture was concentrated to obtain a crude product, which was dissolved in water (10 mL), and the pH was adjusted to 1–2 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 14b (800 mg, yield 91.07%).

[0349] LCMSm / z = 477.1 [MH] -

[0350] Step 3: Preparation of Compound 14

[0351] Compound 14 (70 mg, yield 51.47%) was obtained from 14b (100 mg, 0.21 mmol) as a starting material, according to Example 6.

[0352] LCMSm / z = 651.1 [M+H] +

[0353] Example 15: Preparation of Compound 15

[0354]

[0355] Compound 15 (70 mg, yield 54.49%) was obtained from compound 14b (100 mg, 0.21 mmol) as a starting material, following step fourteen of Example 1.

[0356] LCMSm / z = 615.1 [M+H] +

[0357] Example 16: Preparation of Compound 16

[0358]

[0359] Step 1: Preparation of compound 16a

[0360] Compound 16a (1.02 g, yield 83.7%) was obtained by referring to the first step of Example 8, using 1j (1000 mg, 2.60 mmol) and (1-fluorocyclopropyl)methanol (265.5 mg, 2.60 mmol) as raw materials.

[0361] Step 2: Preparation of compound 16b

[0362] Using 16a (1.0 g, 2.19 mmol) as the starting material, compound 16b (921 mg, 98.1% yield) was obtained by referring to step 13 of Example 1.

[0363] Step 3: Preparation of Compound 16

[0364] 16b (100 mg, 0.23 mmol) was dissolved in oxalyl chloride / dichloromethane solution (2 mL), and one drop of DMF was added to activate the reaction. The reaction was allowed to proceed at room temperature for 1 hour. The reaction mixture was then concentrated, dissolved in dichloromethane (2 mL), and triethylamine (67 mg, 0.66 mmol) and 16c (62 mg, 0.33 mmol) were added. The mixture was allowed to proceed at room temperature for 16 hours. The reaction mixture was then concentrated to obtain a crude product, which was purified by column chromatography to give compound 16 (18 mg, yield 13.4%).

[0365] LCMSm / z = 599.1 [M+H] +

[0366] 1 H NMR(400MHz,DMSO-d6)δ10.74(s,1H),8.13-8.06(m,1H),7.82-7.75(m,1H),7.36(t,1H),7.22-7.13(m,1H),7.12-7.06(m,1H),4.87(d,1H), 4.65-4.53(m,2H),4.48-4.36(m,1H),3.14(s,3H),2.84-2.75(m,1H), 1.84(s,3H),1.28-1.10(m,2H),0.95-0.90(m,2H),0.80-0.74(m,3H).

[0367] Example 17: Preparation of Compound 17

[0368]

[0369] Compound 17 (14 mg, 10.5% yield) was obtained by referring to the third step of Example 16 using 16b (100 mg, 0.23 mmol) and 17a (62 mg, 0.33 mmol) as starting materials.

[0370] LCMSm / z = 599.1 [M+H] +

[0371] Example 18: Preparation of Compound 18

[0372]

[0373] Compound 18 (64 mg, 48.6%) was obtained from 16b (100 mg, 0.23 mmol) in step fourteen of Example 1.

[0374] LCMSm / z = 565.1 [M+H] +

[0375] 1 H NMR(400MHz, CDCl3)δ9.53(s,1H),8.34-8.25(m,1H),8.02-7.96(m,1H),7.08-6.99(m,1H),6.93-6.83(m,2H),6.83-6.73(m,1H),6.47(s,1H) ,4.77(d,1H),4.69-4.60(m,1H),4.53-4.40(m,1H),4.36-4.22(m,1H) ,2.83-2.72(m,1H),1.87(s,3H),1.22-1.08(m,2H),0.83-0.75(m,5H).

[0376] Example 19: Preparation of Compound 19

[0377]

[0378] Compound 19 (47 mg, 33.5% yield) was obtained from 16b (100 mg, 0.23 mmol) as a starting material, according to Example 6.

[0379] LCMSm / z = 601.1[M+H] +

[0380] Example 20: Preparation of Compound 20

[0381]

[0382] Step 1: Preparation of compound 20a

[0383] 1j (0.77 g, 2.00 mmol), 4-bromomethyltetrahydropyran (0.72 g, 4.02 mmol), cesium carbonate (1.30 g, 3.99 mmol), and sodium iodide (0.15 g, 1.00 mmol) were dissolved in DMF (10 mL) and reacted at 50 °C under a nitrogen atmosphere for 16 hours. The reaction mixture was extracted with water (15 mL) and ethyl acetate (10 mL × 3). The organic phases were combined, backwashed with saturated sodium chloride aqueous solution (10 mL × 3), collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to give compound 20a (0.95 g, 98.28% yield).

[0384] LCMSm / z = 483.2[M+H] +

[0385] Step 2: Preparation of compound 20b

[0386] Dissolve 20a (950 mg, 1.97 mmol) in ethanol (15 mL), add cesium carbonate (2.0 g, 6.14 mmol), and react at 50 °C for 2 hours. Concentrate the reaction mixture to obtain the crude product, dissolve the crude product in water (10 mL), adjust the pH to 1-2 with 1 N hydrochloric acid, extract with ethyl acetate (10 mL x 3), combine the organic phases, dry to anhydrous sodium sulfate, filter and concentrate to obtain crude product 20b (890 mg, yield 99.47%).

[0387] LCMSm / z = 453.1 [MH] -

[0388] Step 3: Preparation of Compound 20

[0389] Using compound 20b (100 mg, 0.22 mmol) as a starting material, compound 20 (90 mg, yield 69.25%) was obtained by referring to step fourteen of Example 1.

[0390] LCMSm / z = 591.3 [M+H] +

[0391] Example 21: Preparation of compound 21

[0392]

[0393] Step 1: Preparation of compound 21a

[0394] Using 1j (750 mg, 1.95 mmol) and 3-iodomethyloxetane (500 mg, 2.53 mmol) as starting materials, compound 21a (658 mg, 74.2% yield) was obtained in step 1 of Example 20.

[0395] LCMSm / z = 455.2[M+H] +

[0396] Step 2: Preparation of compound 21b

[0397] Using 21a (658 mg, 1.45 mmol) as the starting material, compound 21b (560 mg, 90.70% yield) was obtained in step 2 of Example 20.

[0398] LCMSm / z = 425.1 [MH] -

[0399] Step 3: Preparation of Compound 21

[0400] Compound 21 (100 mg, 0.23 mmol) was obtained from compound 21b (100 mg, 75.80%) in step fourteen of Example 1.

[0401] LCMSm / z = 563.3 [M+H] +

[0402] Example 22: Preparation of compound 22

[0403]

[0404] Compound 22 (80 mg, yield 58.02%) was obtained from 20b (100 mg, 0.22 mmol) as a starting material, according to Example 6.

[0405] LCMSm / z = 627.3 [M+H] +

[0406] Example 23: Preparation of compound 23

[0407]

[0408] Step 1: Preparation of compound 23a

[0409] Compound 23a (119 mg, 61.25% yield) was obtained from 20b (150 mg, 0.33 mmol) as a starting material, according to Example 13.

[0410] LCMSm / z = 589.2 [M+H] +

[0411] Step 2: Preparation of Compound 23

[0412] Compound 23 (75 mg, yield 64.67%) was obtained from 23a (119 mg, 0.20 mmol) as a starting material, according to Example 13.

[0413] LCMSm / z = 574.2 [M+H] +

[0414] Example 24: Preparation of compound 24

[0415]

[0416] Step 1: Preparation of compound 24a

[0417] Compound 24a (115 mg, 62.49%) was obtained from 21b (140 mg, 0.33 mmol) as a starting material, according to Example 13.

[0418] LCMSm / z = 561.2 [M+H] +

[0419] Step 2: Preparation of Compound 24

[0420] Compound 24 (60 mg, yield 53.61%) was obtained from 24a (115 mg, 0.21 mmol) as a starting material, according to Example 13.

[0421] LCMSm / z = 546.1 [M+H] +

[0422] Example 25: Preparation of Compound 25

[0423]

[0424] Using 20b (150 mg, 0.33 mmol) and 16c (100 mg, 0.45 mmol) as starting materials, compound 25 (95 mg, 46.08% yield) was obtained by referring to step 3 of Example 16.

[0425] LCMSm / z = 625.2 [M+H] +

[0426] Example 26: Preparation of Compound 26

[0427]

[0428] Compound 26 (110 mg, 53.35%) was obtained by referring to the third step of Example 16 using 20b (150 mg, 0.33 mmol) and 17a (100 mg, 0.45 mmol) as starting materials.

[0429] LCMSm / z = 625.2 [M+H] +

[0430] Example 27: Preparation of Compound 27

[0431]

[0432] Compound 27 (20 mg, 14.25% yield) was obtained from 21b (100 mg, 0.23 mmol) as a starting material, according to Example 6.

[0433] LCMSm / z = 599.2 [M+H] +

[0434] Example 28: Preparation of Compound 28

[0435]

[0436] Using 21b (70 mg, 0.16 mmol) and 16c (55 mg, 0.24 mmol) as starting materials, compound 28 (20 mg, yield 20.42%) was obtained by referring to the first step of Example 23.

[0437] LCMSm / z = 597.3 [M+H] +

[0438] Example 29: Preparation of compound 29

[0439]

[0440] Using 21b (100 mg, 0.23 mmol) and 17a (80 mg, 0.36 mmol) as starting materials, compound 29 (35 mg, yield 25.01%) was obtained by referring to the first step of Example 23.

[0441] LCMSm / z = 597.1 [M+H] +

[0442] Example 30: Preparation of compound 30

[0443]

[0444] Step 1: Preparation of compound 30a

[0445] Using 1j (1.5 g, 3.90 mmol) and toluene-4-sulfonic acid oxetane-3-yl ester (1.35 g, 5.91 mmol) as starting materials, compound 30a (1.20 g, yield 69.82%) was obtained by referring to the first step of Example 20.

[0446] Step 2: Preparation of compound 30b

[0447] Using 30a (1.20 g, 2.72 mmol) as the starting material, compound 30b (900 mg, yield 80.10%) was obtained by referring to step 13 of Example 1.

[0448] LCMSm / z = 411.0 [MH] -

[0449] Step 3: Preparation of Compound 30

[0450] Using 30b (100 mg, 0.24 mmol) and 17a (82 mg, 0.36 mmol) as starting materials, compound 30 (35 mg, yield 24.77%) was obtained in step 1 of Example 23.

[0451] LCMSm / z = 582.9 [M+H] +

[0452] Example 31: Preparation of compound 31

[0453]

[0454] Using 30b (100 mg, 0.24 mmol) and 16c (82 mg, 0.36 mmol) as starting materials, compound 31 (30 mg, yield 21.24%) was obtained in step 1 of Example 23.

[0455] LCMSm / z = 582.9 [M+H] +

[0456] Example 32: Preparation of compound 32

[0457]

[0458] Step 1: Preparation of compound 32a

[0459] Compound 32a (87 mg, 43.76%) was obtained from 30b (150 mg, 0.36 mmol) as a starting material, according to Example 13.

[0460] LCMSm / z = 547.3 [M+H] +

[0461] Step 2: Preparation of Compound 32

[0462] Compound 32 (40 mg, 47.28% yield) was obtained from 32a (87 mg, 0.16 mmol) as a starting material, according to Example 13.

[0463] LCMSm / z = 531.9 [M+H] +

[0464] Examples 33 and 34: Preparation of compounds 33c-P1 and 33c-P2

[0465]

[0466] Step 1: Preparation of compound 33a

[0467] Substrate 1j (859 mg, 2.23 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the sequential addition of 3-hydroxytetrahydrofuran (216.13 mg, 2.45 mmol), triphenylphosphine (1169.81 mg, 4.46 mmol), and diethyl azodicarbonate (776.71 mg, 4.46 mmol). The reaction was carried out at room temperature under a nitrogen atmosphere for 18 hours. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 33a (790 mg, yield 77.78%).

[0468] Step 2: Preparation of compound 33b

[0469] Substrate 33a (790 mg, 1.74 mmol) was dissolved in ethanol (5 mL), followed by the addition of cesium carbonate (850.39 mg, 2.61 mmol). After the addition was complete, the mixture was heated to 60 °C and reacted for 2 hours. The reaction mixture was concentrated to obtain a crude product, which was dissolved in water (10 mL), extracted with ethyl acetate (2 mL), and the aqueous phase was collected. The pH was adjusted to 2–3 with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 33b (740 mg, 99.83% yield). The crude product was used directly in the next reaction step.

[0470] LCMSm / z = 425.1 [MH] -

[0471] Step 3: Preparation of compound 33c

[0472] Substrate 33b (97 mg, 0.23 mmol) was dissolved in THF (5 mL), followed by the sequential addition of 5-amino-2-fluorobenzamide (39.0 mg, 0.25 mmol), HATU (131.18 mg, 0.35 mmol), and DIPEA (45 mg, 0.46 mmol). After the addition was complete, the reaction was carried out at room temperature under a nitrogen atmosphere for 18 hours. The reaction was quenched by adding water (50 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The organic phase was backwashed with saturated sodium chloride aqueous solution (30 mL), collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 33c (120 mg, yield 93.78%).

[0473] LCMSm / z = 562.8 [M+H] +

[0474] Step 4: Preparation of compounds 33c-P1 and 33c-P2

[0475] 120 mg of a mixture of compound 33c was prepared by SFC and lyophilized to obtain compound 33c-P1 (45 mg, SFC retention time: 8.5 min) and compound 33c-P2 (25 mg, SFC retention time: 9.8 min) (compound 33c-P1 and compound 33c-P2, one of which is compound 33 and the other is compound 34).

[0476] SFC preparation conditions: Instrumentation: SFC Prep 150AP; Preparative column: Daicel IC (19mm × 250mm). Preparation method: The sample was dissolved in methanol and filtered through a 0.45μm filter to prepare the sample solution. Mobile phase system: Carbon dioxide / isopropanol (0.05% ammonia), isocratic elution, isopropanol (0.05% ammonia) content 30%, flow rate: 37mL / min.

[0477] Examples 35 and 36: Preparation of compounds 35a-P1 and 35a-P2

[0478]

[0479] Step 1: Preparation of compound 35a

[0480] Under ice bath conditions, substrate 33b (100 mg, 0.23 mmol) was dissolved in DMF (5 mL), followed by the sequential addition of TCFH (0.13 g, 0.46 mmol) and N-methylimidazole (0.038 g, 0.46 mmol). The mixture was stirred under ice bath conditions for 0.5 hours. Finally, substrate 5-amino-2-fluorobenzene-1-sulfonamide (65.62 mg, 0.35 mmol) was added to the system. After the addition was complete, the reaction was carried out at 30 °C for 24 hours under a nitrogen atmosphere. The reaction was quenched by adding water (20 mL), and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 35a (106 mg, yield 75.51%).

[0481] LCMSm / z = 598.8 [M+H] +

[0482] Step 2: Preparation of compounds 35a-P1 and 35a-P2

[0483] 106 mg of a mixture of compounds 35a was prepared by SFC and lyophilized to obtain compounds 35a-P1 (25 mg, SFC retention time: 6.28 min) and compounds 35a-P2 (23 mg, SFC retention time: 7.85 min).

[0484] SFC preparation conditions: Instrumentation: SFC Prep 150AP; Preparative column: Daicel AD (19mm × 250mm). Preparation method: The sample was dissolved in methanol and filtered through a 0.45μm filter to prepare the sample solution. Mobile phase system: Carbon dioxide / isopropanol (0.05% ammonia), isopropanol (0.05% ammonia) concentration 9 mL / min, flow rate: 37 mL / min. (Compounds 35a-P1 and 35a-P2, one being compound 35 and the other compound 36.)

[0485] Examples 37 and 38: Preparation of compounds 37b-P1 and 37b-P2

[0486]

[0487] Step 1: Preparation of compound 37a

[0488] Under ice bath conditions, substrate 33b (150 mg, 0.35 mmol) was dissolved in THF (5 mL), followed by the sequential addition of methyl 4-aminopyridine-2-carboxylate (80 mg, 0.52 mmol) and triethylamine (140 mg, 1.4 mmol). Finally, 1-propylphosphonic anhydride (560.0 mg, 0.88 mmol, 50% wt in EtOAc) was added dropwise under ice bath conditions. After the addition was complete, the reaction was carried out at 30 °C for 24 hours under a nitrogen atmosphere. The reaction was quenched by the addition of saturated sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (15 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 37a (46 mg, yield 23.33%).

[0489] LCMSm / z = 561.2 [M+H] +

[0490] Step 2: Preparation of compound 37b

[0491] Substrate 37a (46 mg, 0.082 mmol) was dissolved in 7 M ammonia-methanol solution (5 mL) and reacted at room temperature for 18 hours. The crude product 37b (44 mg, 98.28% yield) was concentrated under reduced pressure and used directly for SFC preparation without any purification.

[0492] LCMSm / z = 546.2 [M+H] +

[0493] Step 3: Preparation of Compound 37

[0494] A mixture of 44 mg of compound 37b was prepared by SFC and lyophilized to obtain compound 37b-P1 (12 mg, SFC retention time: 7.2 min) and compound 37b-P2 (11 mg, SFC retention time: 8.02 min).

[0495] SFC preparation conditions: Instrument: SFC Prep 150AP; Preparative column: Daicel AD (19mm × 250mm). Preparation method: The sample was dissolved in methanol and filtered through a 0.45μm filter to prepare the sample solution. Mobile phase system: Carbon dioxide / isopropanol (0.05% ammonia), isopropanol (0.05% ammonia) concentration 9 mL / min, flow rate: 39 mL / min. (Compounds 37b-P1 and 37b-P2, one being compound 37 and the other compound 38.)

[0496] Examples 39 and 40: Preparation of compounds 39c-P1 and 39c-P2

[0497]

[0498] Step 1: Preparation of compound 39c

[0499] A mixture of substrate 33b (100 mg, 0.23 mmol) was dissolved in DCM (5 mL) under an ice bath and nitrogen atmosphere. Then, DMF (1.7 mg, 0.023 mmol) and a 2 M oxalyl chloride solution in dichloromethane (0.175 mL, 0.35 mmol) were added dropwise. The mixture was stirred in an ice bath for 1 hour (LCMS analysis showed the reaction was complete). The system was concentrated to obtain crude acyl chloride. Then, 16c (64.94 mg, 0.35 mmol) was dissolved in DCM (3 mL). Triethylamine (120 mg, 1.15 mmol) was added dropwise. Finally, acyl chloride dissolved in DCM (2 mL) was added dropwise to the system. After the addition was complete, the mixture was reacted at room temperature under a nitrogen atmosphere for 18 hours. The reaction was quenched by adding sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product, and purified by silica gel column chromatography to obtain compound 39c (104 mg, yield 74.33%).

[0500] LCMSm / z = 597.2 [M+H] +

[0501] Step 2: Preparation of compounds 39c-P1 and 39c-P2

[0502] 104 mg of a mixture of compound 39c was prepared by SFC and lyophilized to obtain compound 39c-P1 (43 mg, SFC retention time: 3.68 min) and compound 39c-P2 (36 mg, SFC retention time: 5.02 min).

[0503] SFC preparation conditions: Instrument: SFC Prep 150AP; Preparative column: Daicel IG (19mm × 250mm). Preparation method: The sample was dissolved in methanol and filtered through a 0.45μm filter to prepare the sample solution. Mobile phase system: Carbon dioxide / isopropanol (0.05% ammonia), isopropanol (0.05% ammonia) concentration 10mL / min, flow rate: 40mL / min. (Compounds 39c-P1 and 39c-P2, one being compound 39 and the other compound 40.)

[0504] Examples 41 and 42: Preparation of compounds 41c-P1 and 41c-P2

[0505]

[0506] Step 1: Preparation of compound 41c

[0507] 41c (99 mg, 70.76% yield) was synthesized from substrate 33b (100 mg, 0.23 mmol) in step 1 of Example 39.

[0508] LCMSm / z = 597.2 [M+H] +

[0509] Step 2: Preparation of compounds 41c-P1 and 41c-P2

[0510] A mixture of 99 mg of compound 41c was prepared by SFC and lyophilized to obtain compound 41c-P1 (42 mg, SFC retention time: 8.23 ​​min) and compound 41c-P2 (40 mg, SFC retention time: 10.17 min).

[0511] SFC preparation conditions: Instrument: SFC Prep 150AP; Preparative column: Daicel AD (19mm × 250mm). Preparation method: The sample was dissolved in methanol and filtered through a 0.45μm filter to prepare the sample solution. Mobile phase system: Carbon dioxide / isopropanol (0.05% ammonia), isopropanol (0.05% ammonia) concentration 8 mL / min, flow rate: 37 mL / min. (Compounds 41c-P1 and 41c-P2, one being compound 41 and the other compound 42.)

[0512] Example 43: Preparation of compound 43

[0513]

[0514] Step 1: Preparation of compound 43a

[0515] Compound 43a (694 mg, 94.9%) was obtained by referring to the first step of Example 8, using 1j (600 mg, 1.56 mmol) and tetrahydropyran-4-ol (319 mg, 3.12 mmol) as raw materials.

[0516] Step 2: Preparation of compound 43b

[0517] Using 43a (694 mg, 1.48 mmol) as the starting material, compound 43b (645 mg, 98.86% yield) was obtained by referring to step 13 of Example 1.

[0518] LCMSm / z = 439.1 [MH] -

[0519] Step 3: Preparation of Compound 43

[0520] Compound 43 (50 mg, yield 35.95%) was obtained from 43b (100 mg, 0.23 mmol) as a starting material, according to Example 12.

[0521] LCMSm / z = 613.2[M+H] +

[0522] Example 44: Preparation of compound 44

[0523]

[0524] Compound 44 (30 mg, yield 55.01%) was obtained from 43b (200 mg, 0.45 mmol) as a starting material, according to Example 13.

[0525] LCMSm / z = 560.1 [M+H] +

[0526] Example 45: Preparation of compound 45

[0527]

[0528] Using 11b (118 mg, 0.26 mmol) as a starting material, compound 45 (10 mg, yield 6.14%) was obtained in step 1 of Example 13.

[0529] LCMSm / z = 617.1 [M+H] +

[0530] Example 46: Preparation of Compound 46

[0531]

[0532] Using 11b (200 mg, 0.45 mmol) as a starting material, compound 46 (70 mg, yield 25.34%) was obtained in step 1 of Example 13.

[0533] LCMSm / z = 617.1 [M+H] +

[0534] Example 47: Preparation of Compound 47

[0535]

[0536] Compound 47 (17 mg, yield 6.13%) was obtained from the first step of Example 13 using 43b (200 mg, 0.43 mmol) as the starting material.

[0537] LCMSm / z = 611.2[M+H] +

[0538] Example 48: Preparation of Compound 48

[0539]

[0540] Using 43b (160 mg, 0.36 mmol) as a starting material, compound 48 (55 mg, yield 24.79%) was obtained in step 1 of Example 13.

[0541] LCMSm / z = 611.2[M+H] +

[0542] Example 49: Preparation of Compound 49

[0543]

[0544] Using 43b (300 mg, 0.68 mmol) as the starting material, compound 49 (146 mg, 37.18% yield) was obtained by referring to step fourteen of Example 1.

[0545] LCMSm / z = 577.2 [M+H] +

[0546] Example 50: Preparation of Compound 50

[0547]

[0548] Step 10: Preparation of Compound 50a

[0549] 16b (200 mg, 0.47 mmol) was dissolved in tetrahydrofuran (2 mL), followed by the addition of triethylamine (118.9 mg, 1.17 mmol) and T3P (448.63 mg, 0.70 mmol). The mixture was stirred at room temperature for 15 minutes, and then methyl 4-aminopyridine-2-carboxylate (107.27 mg, 0.70 mmol) was added. The reaction was carried out at room temperature for 18 hours under a nitrogen atmosphere. The mixture was extracted with saturated sodium bicarbonate aqueous solution (4 mL) and ethyl acetate (3 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 50a (96 mg, yield 36.6%).

[0550] Step 11: Preparation of Compound 50

[0551] 50a (96 mg, 0.17 mmol) was dissolved in 7 M ammonia-methanol solution (1 mL) and reacted at room temperature for 18 h. The reaction system was concentrated to obtain a crude product, which was then subjected to silica gel column chromatography to give compound 50 (52 mg, yield 55.7%).

[0552] LCMSm / z = 548.2 [M+H] +

[0553] Examples 51 and 52: Preparation of compounds 51c-P1 and 51c-P2

[0554]

[0555] Step 1: Preparation of compound 51a

[0556] Compound 51a (1.14 g, yield 46.8%) was obtained by referring to the first step of Example 8, using 1j (2000 mg, 5.20 mmol) and 3-tetrahydrofuran methanol (531.1 mg, 5.20 mmol) as raw materials.

[0557] Step 2: Preparation of compound 51b

[0558] Using 20a (1.14 g, 2.43 mmol) as the starting material, compound 51b (1.07 g, 99.8% yield) was obtained by referring to step 13 of Example 1.

[0559] Step 3: Preparation of compound 51c

[0560] Using 20b (200 mg, 0.45 mmol) as the starting material, compound 51c (75 mg, yield 28.2%) was obtained by referring to the third step of Example 16.

[0561] Step 4: Preparation of compounds 51c-P1 and 51c-P2

[0562] Compound 51c (75 mg, 0.13 mmol) was chirally resolved to yield compounds 51c-P1 (22 mg, SFC retention time: 5.317 min) and 51c-P2 (15 mg, SFC retention time: 5.853 min). Purification method: Instrument: CAS-05-Prep-SFC-G; Column: AD column; Mobile phase: A was CO2; B was 0.1% NH3·H2O in ethanol; Flow rate: 110 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm. (Compounds 51c-P1 and 51c-P2, one is compound 51, and the other is compound 52.)

[0563] Compound 51 LCM m / z = 611.2 [M+H] +

[0564] Compound 52 LCM m / z = 611.2 [M+H] +

[0565] Example 53: Preparation of compound 53

[0566]

[0567] Compound 53 (13 mg, 9.28% yield) was obtained by referring to the third step of Example 16 using 14b (100 mg, 0.21 mmol) and 16c (40 mg, 0.21 mmol) as starting materials.

[0568] LCMSm / z = 649.1 [M+H] +

[0569] Example 54: Preparation of compound 54

[0570]

[0571] Step 1: Preparation of compound 54a

[0572] Compound 54a (20 mg, 15.62%) was obtained from 14b (100 mg, 0.21 mmol) as a starting material, according to Example 13.

[0573] LCMSm / z = 613.1 [M+H] +

[0574] Step 2: Preparation of Compound 54

[0575] Compound 54 (15 mg, 76.88%) was obtained from 54a (20 mg, 0.21 mmol) as a starting material, according to Example 13.

[0576] LCMSm / z = 598.2 [M+H] +

[0577] Example 55: Preparation of compound 55

[0578]

[0579] Using 14b (140 mg, 0.29 mmol) and 17a (70 mg, 0.32 mmol) as starting materials, compound 55 (35 mg, 18.44% yield) was obtained by referring to the third step of Example 16.

[0580] LCMSm / z = 649.1 [M+H] +

[0581] 1 HNMR(400MHz, CDCl3)δ9.03(s,1H),8.21-8.13(m,1H),7.92-7.86(m,1H),7.2 2-7.14(m,1H),7.07-7.01(m,1H),6.90-6.80(m,1H),4.77-4.68(m,1H),4.64 -4.56(m,1H),4.46-4.37(m,1H),4.18-4.11(m,1H),3.39(s,3H),2.73-2.63( m,1H),1.91(s,3H),1.28-1.16(m,2H),1.10-0.96(m,2H),0.91-0.79(m,3H).

[0582] Examples 56 and 57: Preparation of compounds 56c-P1 and 56c-P2

[0583]

[0584] Step 1: Preparation of compound 56a

[0585] Using 1j (2000 mg, 5.20 mmol) and 2-hydroxymethyltetrahydrofuran (531.1 mg, 5.20 mmol) as starting materials, compound 56a (2.02 g, yield 82.86%) was obtained by referring to the first step of Example 8.

[0586] Step 2: Preparation of compound 56b

[0587] Using 56a (2.30 g, 4.91 mmol) as the starting material, compound 56b (1.80 g, 83.3% yield) was obtained by referring to step 13 of Example 1.

[0588] Step 3: Preparation of compound 56c

[0589] Compound 56c (175 mg, yield 64.71%) was obtained from compound 56b (200 mg, 0.47 mmol) in step fourteen of Example 1.

[0590] LCMSm / z = 577.2 [M+H] +

[0591] Step 4: Preparation of compounds 56c-P1 and 56c-P2

[0592] Compound 56c (175 mg, 0.30 mmol) was chirally resolved to yield compounds 56c-P1 (80 mg, SFC retention time: 28.9 min) and 56c-P2 (75 mg, SFC retention time: 30.5 min). Purification method: Instrument: SFCPrep 150AP; Column: Daicel AD column; Mobile phase: A was CO2; B was 0.05% NH3·H2O in isopropanol solution; Flow rate: 40 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm. (Compounds 56c-P1 and 56c-P2, one is compound 56, and the other is compound 57.)

[0593] Compound 56c-P1: LCMSm / z = 577.2 [M+H] +

[0594] Compound 56c-P2: LCMSm / z = 577.2 [M+H] +

[0595] Examples 58 and 59: Preparation of compounds 58c-P1 and 58c-P2

[0596]

[0597] Using 56b and 5-amino-2-fluorobenzene-1-sulfonamide as starting materials, compound 58a (31 mg, yield 11.1%) was obtained according to the synthesis methods in Examples 56 and 57. Further separation by SFC yielded 58a-P1 (16 mg, SFC retention time: 15.9 min) and 58a-P2 (13 mg, SFC retention time: 18.6 min). Purification method: Instrument: SFC Prep 150AP; Column: Daicel AD column (19 mm × 250 mm); Mobile phase: A was CO2; B was 0.05% NH3·H2O in isopropanol solution; Flow rate: 40 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm. (Compounds 58a-P1 and 58a-P2, one is compound 58, and the other is compound 59.)

[0598] Compound 58c-P1: LCMSm / z = 613.2 [M+H] +

[0599] Compound 58c-P2: LCMSm / z = 613.2 [M+H] +

[0600] The target compounds (with the same configuration as the substrate) were prepared according to the preparation method in Example 6, as shown in the table below.

[0601]

[0602]

[0603] The target compounds (with consistent substrate configuration) were prepared according to the preparation method in Example 13, as shown in the table below.

[0604]

[0605] Example 70: Preparation of Compound 70

[0606]

[0607] Step 1: Preparation of compound 70b

[0608] Compound 70b (95 mg, yield 44.8%) was obtained from 21b (150 mg, 0.35 mmol) using the method in step 3 of Example 4.

[0609] LCMSm / z = 605.2 [M+H] +

[0610] Step 2: Preparation of Compound 70

[0611] 70b (95 mg, 0.17 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (0.5 mL) was added dropwise. The reaction was carried out at room temperature for 2 hours. The reaction system was concentrated to obtain a crude product, which was then subjected to prep-HPLC to prepare compound 70 (9 mg, yield 9.47%).

[0612] LCMSm / z = 563.2 [M+H] +

[0613] Examples 71 and 72: Preparation of compounds 71c-P1 and 71c-P2

[0614]

[0615] Step 1: Preparation of compound 71b

[0616] Substrate 16b (100 mg, 0.24 mmol) was prepared according to the method in step one of Example 3 to obtain 71b (70 mg, yield 47.74%).

[0617] Step 2: Preparation of compound 71c

[0618] 71b (70 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (0.5 mL) was added dropwise. The reaction was carried out at room temperature for 2 hours. The reaction system was concentrated to obtain a crude product, which was then subjected to prep-HPLC to prepare compound 71c (50 mg, yield 76.50%).

[0619] Step 3: Preparation of compounds 71c-P1 and 71c-P2

[0620] Compound 71c (50 mg, 0.09 mmol) was chirally resolved to yield compounds 71c-P1 (21 mg, SFC retention time: 1.633 min) and 71c-P2 (19 mg, SFC retention time: 1.798 min). Purification methods: Instrument: CAS-05-ANA-SFC-D; Column: OD column; Mobile phase: A for CO2; B for 0.05% MNH3 in ethanol; Flow rate: 3 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm. (Compounds 71c-P1 and 71c-P2, one is compound 71, and the other is compound 72.)

[0621] Compound 71c-P1: LCMSm / z = 565.5 [M+H] +

[0622] Compound 71c-P2: LCMSm / z = 565.5 [M+H] +

[0623] Following the preparation method in 71, the target compounds listed in the table below were prepared (with configurations consistent with the substrates).

[0624]

[0625]

[0626] Example 77: Preparation of Compound 77

[0627]

[0628] Step 1: Preparation of compound 77b

[0629] Substrate 16b (200 mg, 0.47 mmol) was prepared according to the method in step one of Example 3 to obtain 77b (100 mg, yield 35.43%).

[0630] Step 2: Preparation of Compound 77

[0631] 77b (100 mg, 0.17 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (0.5 mL) was added dropwise. The reaction was carried out at room temperature for 2 hours. The reaction system was concentrated to obtain a crude product, which was then subjected to prep-HPLC to prepare compound 77 (100 mg, yield 53.55%).

[0632] LCMSm / z = 530.2 [M+H] +

[0633] Following the preparation method in 77, the target compounds listed in the table below were prepared (with configurations consistent with the substrates).

[0634]

[0635]

[0636] Example 87: Preparation of Compound 87

[0637]

[0638] Step 1: Preparation of compound 87a

[0639] Compound 87a (516 mg, 87.3%) was obtained from 1j (500 mg, 1.3 mmol) and 2-hydroxymethyloxetane (114 mg, 1.3 mmol) as starting materials, referring to the first step of Example 8.

[0640] LCMSm / z = 455.2[M+H] +

[0641] Step 2: Preparation of compound 87b

[0642] Using 87a (516 mg, 1.14 mmol) as the starting material, compound 87b (470 mg, 97.08% yield) was obtained in step 2 of Example 20.

[0643] LCMSm / z = 425.1 [MH] -

[0644] Step 3: Preparation of compound 87c

[0645] Compound 87c (113 mg, yield 53.3%) was obtained from 87b (150 mg, 0.35 mmol) using the method in step one of Example 3.

[0646] LCMSm / z = 603.2[M+H] +

[0647] Step 4: Preparation of Compound 87

[0648] Compound 87 (2.0 mg, yield 2.0%) was obtained from 87c (113 mg, 0.35 mmol) using the method in step 2 of Example 70.

[0649] LCMSm / z = 563.2 [M+H] +

[0650] The target compounds (with consistent substrate configuration) were prepared according to the preparation method of Example 70, as shown in the table below.

[0651]

[0652] Biological test cases

[0653] 1. Nav1.8 Manual Patch Clamp Test

[0654] (1) Cell Culture

[0655] The CHO cell line stably expressing human Nav1.8 was cultured in Ham's F-12 medium containing 10% fetal bovine serum and 10 μg / mL Blasticidin, 200 μg / mL Hygromycin B, and 100 μg / mL Zeocin. The cell culture temperature was 37°C and the carbon dioxide concentration was 5%. After removing the old medium and washing once with PBS, 1 mL of 0.25% Trypsin-EDTA solution was added, and the cells were incubated at 37°C for approximately 1.5 min. When the cells detached from the bottom of the dish, pre-warmed complete medium (37°C) was added. The cell suspension was gently pipetted to separate aggregated cells. The cell suspension was transferred to sterile centrifuge tubes and centrifuged at 1000 rpm for 5 min to collect the cells. The cells were seeded in 6 cm cell culture dishes at a density of 2.5 × 10⁶ cells per dish. 5 Cells (final volume 5 mL) were used for expansion or maintenance culture. To maintain cell electrophysiological activity, the cell density should not exceed 80%. Before patch-clamp detection, cells were separated with 0.25% Trypsin-EDTA, and 6.5 × 10⁶ cells were cultured. 3 Cells were seeded onto coverslips and cultured in 24-well plates (final volume 500 μL), and analyzed after 18 hours.

[0656] (2) Compound preparation

[0657] The compound was dissolved in dimethyl sulfoxide (DMSO) to prepare a 30 mM DMSO stock solution. The stock solution was diluted to the test concentration with extracellular fluid (140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2·2H2O, 10 mM D-Glucose, 10 mM MEPES and 1.25 mM NaH2PO4·2H2O, pH adjusted to 7.4 with NaOH). The final DMSO concentration of all test samples was 0.1%.

[0658] (3) Electrophysiological tests

[0659] First, a capillary glass tube was drawn into a recording electrode using a microelectrode drawing device. Then, the electrode, filled with intracellular fluid (50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, and 20 mM EGTA, pH adjusted to 7.2 with CsOH), was placed into a microelectrode holder. Under an inverted microscope, the microelectrode manipulator was used to immerse the electrode in the extracellular fluid, and the electrode resistance (Rpip) was recorded. Next, the electrode was slowly brought into contact with the cell surface, and negative pressure was applied to aspirate and form a GΩ seal. Fast capacitance compensation was then performed, and negative pressure was continued to rupture the cell membrane, establishing a whole-cell recording mode. Finally, slow capacitance compensation was performed, and experimental parameters such as series resistance (Rs) were recorded. No leakage compensation was applied. Once the Nav1.8 current recorded in the whole cell stabilized, drug administration began, with each drug concentration acting for approximately 5 minutes (or until the current stabilized). A coverslip containing cells was placed in a recording bath under an inverted microscope. Blank control solution and the working solution of the test compound were perfused through the recording bath by gravity to act on the cells, with fluid exchange facilitated by a peristaltic pump. The current detected in the cells in the solution without the compound served as a control group. All electrophysiological experiments were performed at room temperature. The inhibitory rate of the compound on Nav1.8 was determined by calculating the relative percentage of peak currents generated before and after cell treatment.

[0660] The voltage stimulation protocol for whole-cell patch-clamp recording of Nav1.8 sodium current is as follows: After whole-cell sealing, the cell voltage is clamped at -120 mV. The voltage is first stepped from -110 mV to -30 mV in 10 mV increments, maintained for 5 seconds, and then a 0 mV depolarization pulse is applied to obtain the half-inactivation voltage (V). half Then with V halfThe stimulation voltage was maintained for 5 seconds, then restored to -120 mV and maintained for 20 ms. A depolarization pulse (TP2) was then applied to 0 mV for 50 ms to detect the sodium current in the semi-inactivated state. Finally, the voltage was restored to the clamp voltage of -120 mV, and data was collected every 20 ms to observe the effect of the drug on the peak sodium current. Experimental data were acquired using an EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0661] Table 1 shows the IC50 values ​​of the tested compounds for inhibiting Nav1.8. 50

[0662] Test compounds <![CDATA[IC 50 (nM)]]> Test compounds <![CDATA[IC 50 (nM)]]> Test compounds <![CDATA[IC 50 (nM)]]> Compound 1 ＜0.1 Compound 30 ＜1 Compound 61 ＜0.1 Compound 3 ＜1 Compound 31 ＜1 Compound 62 ＜1 Compound 4 ＜0.1 Compound 32 ＜0.1 Compound 63 ＜1 Compound 6 ＜0.1 Compound 33c-P2 ＜0.1 Compound 64 ＜1 Compound 8 ＜0.1 Compound 35a-P1 ＜0.1 Compound 65 ＜1 Compound 11 ＜1 Compound 35a-P2 ＜1 Compound 66 ＜1 Compound 12 ＜1 Compound 37b-P1 ＜0.1 Compound 67 ＜1 Compound 13 ＜1 Compound 37b-P2 ＜0.1 Compound 68 ＜1 Compound 14 ＜1 Compound 39c-P1 ＜1 Compound 69 ＜1 Compound 15 ＜1 Compound 39c-P2 ＜1 Compound 70 ＜1 Compound 16 ＜0.1 Compound 41c-P1 ＜1 Compound 71 ＜1 Compound 17 ＜1 Compound 41c-P2 ＜1 Compound 75 ＜1 Compound 18 ＜0.1 Compound 44 ＜1 Compound 76 ＜1 Compound 19 ＜1 Compound 45 ＜1 Compound 78 ＜1 Compound 20 ＜1 Compound 46 ＜1 Compound 79 ＜1 Compound 21 ＜0.1 Compound 49 ＜0.1 Compound 80 ＜1 Compound 22 ＜1 Compound 50 ＜1 Compound 82 ＜1 Compound 23 ＜1 Compound 55 ＜0.1 Compound 83 ＜1 Compound 24 ＜1 Compound 56c-P1 ＜1 Compound 84 ＜1 Compound 26 ＜1 Compound 56c-P2 ＜1 Compound 87 ＜1 Compound 27 ＜1 Compound 58c-P1 ＜1 Compound 88 ＜1 Compound 28 ＜1 Compound 58c-P2 ＜1 Compound 89 ＜1 Compound 29 ＜0.1 Compound 60 ＜1

[0663] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good Nav1.8 inhibitory activity.

[0664] 2. Pharmacokinetic assays in mice

[0665] Experimental animals: C57 mice, 22-25g, 6 mice / compound.

[0666] Experimental design: On the day of the experiment, C57 mice were randomly divided into groups according to body weight. They were fasted for 12-14 hours before administration but allowed free access to water, and were fed 4 hours after administration.

[0667] Table 2. Dosage Information

[0668]

[0669] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Gavage administration solvent: 0.5% MC

[0670] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; MC: methylcellulose)

[0671] Blood samples of 0.06 mL were collected via the orbital cavity before and after isoflurane anesthesia, placed in EDTAK2 centrifuge tubes, and centrifuged at 5000 rpm for 10 min at 4°C to collect plasma. Blood collection time points for both the intravenous and gavage groups were 0, 5, 15, 30 min, 1, 2, 4, 7, 24, and 48 h. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0672] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral performance.

Claims

1. A compound or its stereoisomers, racemates, or pharmaceutically acceptable salts, wherein the compound is selected from compounds represented by general formula (I). X is selected from -S-, -S(=O)-, or -S(=O)2; A is selected from C 3-12 Carbocyclic rings, 5-12 membered heterocyclic rings, 5-10 membered heteroaryl rings, C 6-10 aryl or R 6 Each element is independently selected from H, deuterium, halogens, CN, OH, =O, -C(=O)OH, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbon rings, 3- to 7-membered heterocycles, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -NH-C 3-6 Carbon ring, -C(=O)NR a1 R a2 -S(=O)2NR a1 R a2 -C(=O)R a1 -C(=O)OR a1 -NH-C(=O)R a1 -S(=O)2R a1 -S(=O)(=NR) a1 )R a2 -P(=O)R a3 R a4 -NH-S(=O)2R a1 -NH-S(=O)2NR a1 R a2 -C(=O)NH-C(=NR) a3 )NR a1 R a2 -C(=NR) a3 )NR a1 R a2 The alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R a1 R a2 Each independently selected from H and C 1-6 Alkyl, C 3-6 Carbocyclic, 4- to 7-membered heterocyclic, wherein the alkyl, carbocyclic or heterocyclic is optionally surrounded by 1 to 4 R... k replace; As an option, R a1 R a2 Direct connection forms a 4- to 7-membered heterocycle, wherein the heterocycle is optionally bounded by 1 to 4 R... k replace; R 5 Selected from -YC 1-4 Alkylene-R 5a -YR 5b The alkylene group is optionally surrounded by 1 to 4 R groups. k replace; Y is selected from -O-, -NH-, and -S-. R 5a Selected from C 3-8 Carbocyclic rings, 3- to 8-membered heterocyclic rings, 5- to 6-membered heteroaryl groups, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -C (=NR) a3 )NR a1 R a2 -C(=NR) a3 )R a2 -S(=O)(=NR) a3 )R a4 -P(=O)R a3 R q4 -OP(=O)R a3 R a4 The alkyl, heteroaryl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R 5b Selected from C 4-10 Carbocyclic rings, 4- to 10-membered heterocyclic rings, 5- to 6-membered heteroaryl groups, wherein R 5b Choose from 1 to 4 Rs k replace; R a3 R a4 Each element is independently selected from H, OH, NH2, and C. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Carbocyclic, 4- to 7-membered heterocyclic, wherein the alkyl, carbocyclic or heterocyclic is optionally surrounded by 1 to 4 R... k replace; B1, B2, B3, and B4 are each independently selected from N or CR. B B1, B2, B3, and B4 are not all selected from N simultaneously; R B Each element is independently selected from H, deuterium, halogens, CN, OH, -C(=O)OH, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-7 Carbon ring, -OC 3-7 Carbon rings, 3- to 7-membered heterocycles, or -P(=O)R q1 R q2 The alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; m is selected from 0, 1, 2, 3, 4, 5 or 6; R 1 R 2 R 3 R 4 Each element is independently selected from H, deuterium, halogens, CN, OH, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 Carbocyclic, 3- to 7-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic is optionally surrounded by 1 to 4 R... k replace; As an option, R 1 R 4 Direct connection forms C 3-6 Carbon rings or 4- to 7-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 6 R... k replace; R k Each element is independently selected from deuterium, =O, halogens, CN, OH, -C(=O)OH, -C(=O)NH2, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -C(=O)-C 3-6 Carbon ring, -C(=O)-C 1-6 Alkyl, -NH-C 3-6 Carbon rings, -NH-3 to 7-membered heterocycles, -C 1-4 Alkylene-C 3-6 Carbon ring, -C 1-4 Alkylene-3 to 7-membered heterocycles, C 3-6 Carbocyclic rings, 3 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic rings are optionally selected from 1 to 4 deuterium, halogens, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 The alkoxy group is replaced by a substituent.

2. The compound according to claim 1, or its stereoisomers, racemates, or pharmaceutically acceptable salts, A is selected from phenyl, 5-6-membered heteroaryl, benzo[C] 4-7 Benzyl 5-7-membered heterocyclic group, benzo5-6-membered heteroaryl group, 5-membered 5-membered heterocyclic group, 5-membered 6-membered heterocyclic group, 6-membered 6-membered heterocyclic group or R 6 Each element is independently selected from H, deuterium, halogens, CN, OH, =O, -C(=O)OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Carbon rings, 3- to 7-membered heterocycles, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -NH-C 3-6 Carbon ring, -C(=O)NR a1 R a2 -S(=O)2NR a1 R a2 -C(=O)R a1 -C(=O)OR a1 -NH-C(=O)R a1 -S(=O)2R a1 -S(=O)(=NR) a1 )R a2 -P(=O)R a3 R a4 -NH-S(=O)2R a1 -NH-S(=O)2NR a1 R a2 -C(=O)NH-C(=NR) a3 )NR a1 R a2 -C(=NR) a3 )NR a1 R a2 The alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R a1 R a2 Each independently selected from H and C 1-4 Alkyl, C 3-6 Carbocyclic, 4- to 7-membered heterocyclic, wherein the alkyl, carbocyclic or heterocyclic is optionally surrounded by 1 to 4 R... k replace; As an option, R a1 R a2 Direct connection forms a 4- to 7-membered heterocycle, wherein the heterocycle is optionally bounded by 1 to 4 R... k replace; R 5a Selected from phenyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclic, 5- to 6-membered heteroaryl, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -C (=NR) a3 )NR a1 R a2 -C(=NR) a3 )R a2 -S(=O)(=NR) a3 )R a4 -P(=O)R a3 R q4 -OP(=O)R a3 R a4 The alkyl, phenyl, cycloalkyl, heteroaryl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R 5b Selected from C 4-6 Monocycloalkyl, C 4-10 cycloalkyl, C 5-10 Spirocycloalkyl, C 5-10 Bridged cycloalkyl, 4- to 8-membered monoheterocyclic, 4- to 10-membered fused heterocyclic, 5- to 10-membered spiroheterocyclic, 5- to 10-membered bridged heterocyclic, 5- to 6-membered heteroaryl, wherein R 5b Choose from 1 to 4 Rs k replace; R a3 R a4 Each element is independently selected from H, OH, NH2, and C. 1-4 Alkyl, -OC 1-4 Alkyl, C 3-6 Carbocyclic, 4- to 7-membered heterocyclic, wherein the alkyl, carbocyclic or heterocyclic is optionally surrounded by 1 to 4 R... k replace; R 1 R 2 R 3 R 4 Each element is independently selected from H, deuterium, halogens, CN, OH, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 3-6 Carbocyclic, 3- to 7-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic is optionally surrounded by 1 to 4 R... k replace; As an option, R 1 R 4 Direct connection forms C 3-6 Carbon rings or 4- to 7-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace; R B Each element is independently selected from H, deuterium, halogens, CN, OH, -C(=O)OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 3-7 Carbon ring, -OC 3-7 Carbon rings, 3- to 7-membered heterocycles, or -P(=O)R q1 R q2 The alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R k Each element is independently selected from deuterium, =O, halogens, CN, OH, -C(=O)OH, -C(=O)NH2, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -C(=O)-C 3-6 Carbon ring, -C(=O)-C 1-4 Alkyl, -NH-C 3-6 Carbon rings, -NH-3 to 7-membered heterocycles, -C 1-2 Alkylene-C 3-6 Carbon ring, -C 1-2 Alkylene-3 to 7-membered heterocycles, C 3-6 Carbocyclic rings, 3 to 7-membered heterocycles, wherein the alkylene group, alkyl group, alkenyl group, alkynyl group, carbocyclic ring or heterocycle is optionally selected from 1 to 4 elements selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 The alkoxy group is replaced by a substituent.

3. The compound according to claim 2, or its stereoisomers, racemates, or pharmaceutically acceptable salts, R a1 R a2 Each is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R a1 R a2 Direct connection forms an optional 1 to 4 R k The following groups are substituted: aziridine, pyrrolidinyl, piperidinyl; R a3 R a4 Each is independently selected from H, OH, NH2, or optionally influenced by 1 to 4 Rs. k The following groups may be substituted: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, or cyclopentyl; R 1 R 2 R 3 R 4 Each of the following groups is independently selected from H, deuterium, F, Cl, Br, CN, OH, methyl, ethyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, vinyl, and ethynyl, wherein the methyl, ethyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, vinyl, and ethynyl groups are optionally prefixed with 1 to 4 R groups. k replace; or, Selected from The ring C is selected from 1 to 4 Rs. k The following groups are substituted: cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, piperidinyl, oxecyclopentyl, oxecyclopentyl, dioxocyclopentyl; A is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridinoneyl, pyridazinoneyl, pyrroleyl, pyrazolyl, imidazoleyl, and thiazolyl. Quinolinyl, isoquinolinyl, benzopyridinyl, quinoxalinyl, quinazolinyl, indole, isoindole, benzimidazolyl, benzopyrazolyl, benzothiophenyl, benzothiazolyl, pyridinopyridinyl, pyridinopyrroleyl, pyridinopyrazolyl, pyridinotriazolyl, pyrimidinopyrroleyl, pyrimidinopyrazolyl, pyrimidinoimidazolyl, pyrimidinotriazolyl, pyrazinoimidazolyl, pyrazinopyrroleyl, pyrazinopyrazolyl, triazinopyrazolyl, benzocyclobutenyl, benzocyclopentenyl, benzooxacyclopentenyl, benzodioxacyclopentenyl, indoleketone, quinolinone, isoindoleketone, isoquinolinone R 5 Selected from -γ-methylene-R 5a γ-Ethylene-R 5a γ-Propylene-R 5a -YR 5b The methylene, ethylene, and propylene groups are optionally coated with 1 to 4 R groups. k replace; R B Each of the following groups is independently selected from H, deuterium, F, Cl, Br, cyano, OH, -C(=O)OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, -O-cyclopropyl, cyclobutyl, vinyl, ethynyl, propynyl, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl), wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, vinyl, ethynyl, and propynyl groups are optionally prefixed with 1 to 4 R groups. k replace; R k Each of the following groups is independently selected from deuterium, F, Cl, Br, I, CN, OH, -C(=O)OH, -C(=O)NH2, NH2, -C(=O)methyl, -C(=O)CH(CH3)2, -C(=O)cyclopropyl, -C(=O)cyclobutyl, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy The methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally selected from one to four elements selected from deuterium, halogens, CN, OH, NH2, and C. 1-4 Alkyl, C 1-4 The alkoxy group is replaced by a substituent.

4. The compound according to claim 3, or its stereoisomers, racemates, or pharmaceutically acceptable salts, wherein, A is selected from Its left end is connected to -CO-NH-; R 6 Each is independently selected from H, deuterium, F, Cl, Br, CN, OH, =O, -C(=O)OH, -C(=O)NH2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, vinyl, ethynyl, propynyl, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl) -O-cyclopropyl, -O-cyclobutyl, -C(=O)methyl, -C(=O)O-methyl, -C(=O)ethyl, -C(=O)O-ethyl, -S(=O)2-methyl, -S(=O)2NH2, -NH-S(=O)2NH2, -C(=N)(OH)NH2, -C(=N)(O-methyl)NH2, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, vinyl, ethynyl, propynyl are optionally prefixed with 1 to 3 R. k replace; R 5a Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, azacyclobutyl, oxacyclohexyl, pyrrolyl, piperidinyl, pyrazolyl, pyrroleyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, thiophene, -O-cyclopropyl, -O-cyclobutyl, -C(=NR) a3 )NR a1 R a2 -C(=NR) a3 )R a2 -S(=O)(=NH)methyl, -P(=O)(OH)2, -OP(=O)(OH)2, -P(=O)(NH2)2, -OP(=O)(NH2)2, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -OP(=O)(methyl)2, -OP(=O)(ethyl)2, -P(=O)(CH3)(cyclopropyl), wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aziridine, pyrrolyl, piperidinyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, thiophene group is optionally surrounded by 1 to 3 R groups. k replace; R 5b Selected from bicyclic [1.1.1]pentyl, cyclobutyl, cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, aziroxybutyl, pyrrolyl, piperidinyl, pyrazolyl, pyrroleyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, thiophenyl, wherein R 5b Choose from 1 to 4 Rs k replace; Selected from B1 and B2 are each independently selected from N or CR. B ; R B Each of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, CH2F, CHF2, CF3, -OCH2F, -OCHF2, -OCF3, -OCD3, methyl, -S-methyl, -S-CF3, ethyl, isopropyl, ethynyl, propynyl, methoxy, ethoxy, isopropyloxy, propyloxy, cyclopropyl, -O-cyclopropyl, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl), wherein the methyl, ethyl, isopropyl, ethynyl, propynyl, methoxy, ethoxy, isopropyloxy, propyloxy, and cyclopropyl groups are optionally prefixed with 1 to 3 R groups. k replace; R k Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, -C(=O)OH, -C(=O)NH2, -C(=O)CH3, -C(=O)CH(CH3)2, -C(=O)cyclopropyl, -CH2OH, methyl, ethyl, CD3, OCD3, CH2F, CHF2, CF3, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

5. The compound according to claim 4, or its stereoisomers, racemates, or pharmaceutically acceptable salts, wherein, R 1 R 2 R 3 R 4 Each is independently selected from H, deuterium, methyl, ethyl, CD3, CH2F, CHF2, CF3; or, Selected from The ring C is arbitrarily divided by 1 to 4 Rs. k replace; Selected from Selected from R 5 Selected from -O-methylene-R 5a -S-methylene-R 5a -O-ethylene-R 5a -OR 5b -SR 5b The methylene and ethylene groups are optionally substituted with 1 to 4 substituents selected from H, deuterium, F, Cl, methyl, ethyl, CD3, CH2F, CHF2, and CF3; R 5a Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrroleyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, thiophene, -O-cyclopropyl, -O-cyclobutyl, -C(=N-OH)NH2, -C(=N-OH)NH-methyl, -C(=N-OH)NH-(methyl)2, -C(=N-OH)methyl, -C(=N-OH)cyclopropyl, -C(=NO-methyl)-methyl, -S(=O)(=NH)methyl, -P(=O)(OH)2, -OP(=O)(OH)2, -P(=O)(NH2)2, -OP(=O) (NH2)2, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl), wherein the methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aziridine, pyrrolyl, piperidinyl, pyrazolyl, pyrroloyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, or thiophene group is optionally substituted with 1 to 3 substituents of deuterium, F, Cl, Br, CN, OH, -C(=O)OH, -C(=O)NH2, -C(=O)CH3, -C(=O)cyclopropyl, -CH2OH, methyl, ethyl, CD3, OCD3, CH2F, CHF2, or CF3.

6. The compound according to claim 5, or its stereoisomers, racemates, or pharmaceutically acceptable salts, wherein, Selected from R k Each is independently selected from deuterium, F, Cl, Br, CN, OH, -CH2OH, methyl, ethyl, CD3, OCD3, CH2F, CHF2, CF3; Selected from Selected from R 5 Selected from 7. The compound according to claim 1, or its stereoisomers, racemates, or pharmaceutically acceptable salts, wherein the compound is selected from one of the structures shown in Table E below:

8. A pharmaceutical composition comprising the compound or its stereoisomer, racemate, pharmaceutically acceptable salt as claimed in any one of claims 1-7, and a pharmaceutically acceptable carrier, preferably, the pharmaceutical composition comprising 1-1500 mg of the compound or its stereoisomer, racemate, or pharmaceutically acceptable salt as claimed in any one of claims 1-7.

9. The use of the compound or its stereoisomer, racemate, pharmaceutically acceptable salt, or composition according to any one of claims 1-7 in the preparation of a medicament for treating and / or relieving pain.

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