Tetrahydrothiophene derivatives and their pharmaceutical applications

Abstract

The present invention relates to compounds according to general formula (I) or stereoisomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, intermediates and processes for the preparation thereof, and their application in the manufacture of medicaments for the treatment of pain. [C1] TIFF2026503260000141.tif29156

Description

[Technical Field]

[0001] The present invention relates to compounds according to general formula (I) or stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, intermediates and processes for the preparation thereof, and their application in the manufacture of medicaments for treating or alleviating pain. [Background technology]

[0002] Pain originates from nociceptors in the peripheral nervous system, which convert perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials) that are transmitted via afferent nerve fibers to their cell bodies located in the dorsal root ganglia (DRG) and ultimately to higher-level nerve centers, resulting in a pain sensation. The generation and propagation of action potentials in neurons also depend on voltage-gated sodium channels (VGSCs) on the cell membrane. When the cell membrane is depolarized, sodium channels are activated, opening, allowing sodium ions to influx, further depolarizing the cell membrane and generating an action potential.

[0003] VGSCS consists of a single pore-forming α-subunit (approximately 260 kDa) and a related, smaller β-subunit (30-40 kDa). The related α-subunit family consists of 10 members, of which nine (Nav1.1-1.9) are voltage-dependent. Nav1.8, encoded by the gene SCN10A, is preferentially expressed in peripheral sensory neurons. It has been demonstrated that these neurons are capable of generating action potentials. Currently, Nav1.8 transcripts and protein 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 (brain and spinal cord).

[0004] The important role of Nav1.8 in pain signaling is already supported by a large body of evidence. A series of animal studies and human genetic evidence suggest that selective inhibition of Nav1.8 may be a potential new type of analgesic therapy. Clinical trials of drugs targeting this protein are currently underway. Summary of the Invention [Problem to be solved by the invention]

[0005] The object of the present invention is to provide a tetrahydrothiophene derivative having inhibitory activity against Nav1.8, which can selectively inhibit Nav1.8 and effectively reduce side effects, and has good analgesic activity, oral bioavailability, good inhibitory activity and selectivity against hNav1.8, excellent oral absorption in animals (e.g., mice, rats, dogs, and monkeys), weak inhibition of CYP enzymes, and good permeability. [Means for solving the problem]

[0006] The present invention provides a compound represented by general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, [ka] In some embodiments, [ka] teeth, [ka] B is trans relative to the ortho amide group; In some embodiments, [ka] teeth, [ka] is selected from In some embodiments, [ka] teeth, [ka] is selected from In some embodiments, the compound according to general formula (I) is selected from general formulas (Ia), (Ib), (Ic), (Id), (Ie), (If): [ka] In some embodiments, Q1 is C 6-10 Aryl group, 5- to 10-membered heteroaryl group, C 5-10 a carbocyclic group, a 5- to 10-membered heterocyclic group, or [ka] wherein the aryl, heteroaryl, carbocyclic or heterocyclic group is optionally selected from 1 to 5 R q is replaced by In some embodiments, Q1 is a phenyl group, a benzo C 4-6 a carbocyclic group, a 4- to 6-membered benzoheterocyclic group, a 5- to 6-membered heteroaryl group, an 8- to 10-membered fused ring heteroaryl group, or [ka] Preferably, Q1 is a phenyl group, a pyridyl group or [ka] wherein Q1 is optionally selected from 1 to 4 R q is replaced by In some embodiments, Q1 is [ka] Preferably, Q1 is selected from [ka] wherein Q1 is optionally selected from 1 to 5 R q is replaced by In some embodiments, R Q1 H, COOH, NR q1 R q2 , -C(=O)NR q1 R q2 , -S(=O)2NR q1 R q2 , OH, =O, -OR q1 , -C(=O)R q1 , -S(=O)2R q1 , -S(=O)(=NR q1 )R q2 or -P(=O)R q1 R q2 is selected from In some embodiments, R Q1 is selected from H, COOH, NH2, -C(=O)NH2, -S(=O)2NH2, OH, =O, -S(=O)2CH3, -S(=O)2-cyclopropyl group, -S(=O)(=NH)CH3, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl), In some embodiments, [ka] teeth, [ka] wherein Q1 is optionally selected from 1 to 3 R q is replaced by In some embodiments, [ka] teeth, [ka] Selected from R Q1is selected from COOH, -C(=O)NH2, -S(=O)2NH2, -S(=O)2CH3, -S(=O)(=NH)CH3, -P(=O)(CH3)2, and R qa teeth, [ka] —CHOH, and R q is selected from F, Cl or a methyl group, In some embodiments, R Q1 is selected from H, Q1 is selected from 1 to 5 R q and at least one R q is R qa Selected from R qa teeth, [ka] selected from -CHOH, -CFCHOH, NH, -P(=O)(CH), -P(=O)(CHCH), -P(=O)(CH)(cyclopropyl); In some embodiments, R qa teeth, [ka] —CHOH, In some embodiments, [ka] teeth, [ka] wherein Q1 is optionally selected from 1 to 3 R q is replaced by In some embodiments, R q1 , R q2 are independently H, C 1-6 Alkyl group, C 3-6 a carbocyclic group, a 4- to 7-membered heterocyclic group, and the alkyl group, carbocyclic group, or heterocyclic group may optionally be selected from the group consisting of 1 to 4 R kis replaced by As an option, R q1 , R q2 are directly linked to form a 4- to 7-membered heterocyclic group, said heterocyclic ring optionally containing 1 to 4 R k is replaced by In some embodiments, R q1 , R q2 are independently H, C 1-4 Alkyl group, C 3-6 a carbocyclic group, a 4- to 7-membered heterocyclic group, and the alkyl group, carbocyclic group, or heterocyclic group may optionally be selected from the group consisting of 1 to 4 R k is replaced by As an option, R q1 , R q2 are directly linked to form a 4- to 7-membered heterocyclic group, said heterocyclic ring optionally containing 1 to 4 R k is replaced by In some embodiments, R q1 , R q2 are each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl, and the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl groups are optionally selected from 1 to 4 R k is replaced by In some embodiments, B is C 6-10 Aryl group, 5- to 10-membered heteroaryl group, C 5-10 a carbocyclic group, a 5- to 10-membered heterocyclic group, and the aryl group, heteroaryl group, carbocyclic group, or heterocyclic group may optionally be selected from the group consisting of 1 to 4 R B is replaced by In some embodiments, B is a phenyl group, benzo C 4-6 A carbocyclic group, a 4- to 6-membered benzoheterocyclic group, a 5- to 6-membered heteroaryl group, an 8- to 10-membered fused ring heteroaryl group, and the B is optionally selected from 1 to 4 R B is replaced by In some embodiments, B is a phenyl group, [ka] wherein B is optionally selected from 1 to 4 R B is replaced by In some embodiments, B is [ka] or a phenyl group, wherein B is optionally selected from 1 to 4 R B is replaced by In some embodiments, B is [ka] is selected from, preferably [ka] and In some embodiments, R 1 , R 2 are each independently H, halogen, CN, OH, or C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-6 Alkyl group, -SC 1-6 Alkyl group, C 3-6 a carbocyclic group, a 3- to 7-membered heterocyclic group, and the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group may optionally be selected from the group consisting of 1 to 4 R k The condition is that R 1 , R 2 But at the same time, it's not H, In some embodiments, R 1 , R 2 are each independently H, halogen, CN, OH, or C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -SC 1-4 Alkyl group, C 3-6 a carbocyclic group, a 3- to 7-membered heterocyclic group, and the alkyl group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group may optionally be selected from the group consisting of 1 to 4 Rk The condition is that R 1 , R 2 But at the same time, it's not H, In some embodiments, R 1 , R 2 are each independently selected from H, F, Cl, Br, cyano, methyl, ethyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, vinyl, and ethynyl, and the methyl, ethyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, vinyl, and ethynyl groups are optionally selected from 1 to 4 R k The condition is that R 1 , R 2 But at the same time, it's not H, In some embodiments, R 1 , R 2 are each independently selected from H, a methyl group, an ethyl group, CH2F, CHF2, and CF3, with the proviso that R 1 , R 2 But at the same time, it's not H, In some embodiments, R 3 , R 4 , R q , R B are each independently H, deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl group, N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-6 Alkyl group, -SC 1-6 Alkyl group, C 3-7 Carbocyclic group, -OC 3-7 Carbocyclic group, 3- to 7-membered heterocyclic group, or -P(=O)R q1 R q2 wherein the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally selected from 1 to 4 R k is replaced by In some embodiments, R 3 , R 4 , R q , RB are each independently H, deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -SC 1-4 Alkyl group, C 3-7 Carbocyclic group, -OC 3-7 Carbocyclic group, 3- to 7-membered heterocyclic group, or -P(=O)R q1 R q2 wherein the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally selected from 1 to 4 R k is replaced by In some embodiments, R 3 , R 4 , R q , R B are each independently selected from H, deuterium, F, Cl, Br, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclopropyloxy, cyclobutyl, vinyl, ethynyl, -P(=O)(CH), -P(=O)(CHCH), -P(=O)(CH)(cyclopropyl), and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, vinyl, and ethynyl groups are optionally selected from the group consisting of 1 to 4 R k is replaced by In some embodiments, R 3 , R 4 are each independently selected from H, a methyl group, an ethyl group, CHF, CHF, and CF; In some embodiments, R q , R Bare each independently selected from H, F, Cl, Br, cyano, CH2F, CHF2, CF3, -OCH2F, -OCHF2, -OCF3, -OCD3, methyl, -S-methyl, -S-CF3, ethyl, isopropyl, ethynyl, methoxy, ethoxy, isopropyloxy, propyloxy, cyclopropyl, -O-cyclopropyl, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl), and the methyl, ethyl, isopropyl, ethynyl, methoxy, ethoxy, isopropyloxy, propyloxy, and cyclopropyl groups are optionally selected from the group consisting of 1 to 4 R k is replaced by In some embodiments, R B are each independently selected from F, Cl, Br, cyano, CHF, CHF, CF, -OCHF, -OCHF, -OCF, -OCD, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, propyloxy, cyclopropyl, and -O-cyclopropyl; In some embodiments, R q are each independently H, F, Cl, Br, a cyano group, CH2F, CHF2, CF3, -OCH2F, -OCHF2, -OCF3, -OCD3, a methyl group, an -S-methyl group, an -S-CF3, an ethyl group, an isopropyl group, an ethynyl group, a methoxy group, an ethoxy group, an isopropyloxy group, a propyloxy group, a cyclopropyl group, an -O-cyclopropyl group, [ka] -CHOH, -CFCHOH; In some embodiments, R q are each independently selected from F, Cl, Br, a cyano group, CHF, CHF, and CF; In some embodiments, any one of R q is R qa is selected from In some embodiments, R kDeuterium, =O, halogens, CN, OH, NH2, NHC 1-6 Alkyl group, N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-6 Alkyl group, -SC 1-6 Alkyl group, -OC 3-6 Carbocyclic group, -O-3 to 7-membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7-membered heterocyclic group, -C 1-4 Alkylene-C 3-6 carbocyclic group, -C 1-4 Alkylene-3 to 7-membered heterocyclic group, C 3-6 a carbocyclic group, a 3- to 7-membered heterocyclic group, and the alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group may optionally contain deuterium, halogen, ═O, CN, OH, NH, C 1-6 Alkyl group, C 1-6 substituted with 1 to 4 substituents selected from alkoxy groups; In some embodiments, R k Deuterium, =O, halogens, CN, OH, NH2, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -SC 1-4 Alkyl group, -OC 3-6 a carbocyclic group, -O-3 to 7-membered heterocyclic group, wherein the alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic group or heterocyclic group may optionally be selected from the group consisting of deuterium, halogen, CN, OH, NH, C 1-4 Alkyl group, C 1-4 substituted with 1 to 4 substituents selected from alkoxy groups; In some embodiments, R kis selected from deuterium, ═O, F, Cl, Br, I, CN, OH, NH, NH(CH), NH(CHCH), N(CH), N(CHCH), methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH-cyclopropyl, -CH-cyclobutyl, -CH-cyclopentyl, -CH-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups are optionally selected from deuterium, halogen, CN, OH, NH, C 1-4 Alkyl group, C 1-4 substituted with 1 to 4 substituents selected from alkoxy groups; In some embodiments, R k is selected from deuterium, F, Cl, Br, I, CN, OH, —CHOH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, —O-cyclopropyl, —NH-cyclopropyl, —CH-cyclopropyl, —CH-cyclobutyl, —CH-cyclopentyl, —CH-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0007] As a first embodiment of the present invention, there is provided a compound represented by the above-mentioned general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein Q1 is C 6-10 Aryl group, 5- to 10-membered heteroaryl group, C 5-10 a carbocyclic group, a 5- to 10-membered heterocyclic group, or [ka] wherein the aryl, heteroaryl, carbocyclic or heterocyclic group is optionally selected from 1 to 5 R q is replaced by R Q1H, COOH, NR q1 R q2 , -C(=O)NR q1 R q2 , -S(=O)2NR q1 R q2 , OH, =O, -OR q1 , -C(=O)R q1 , -S(=O)2R q1 , -S(=O)(=NR q1 )R q2 or -P(=O)R q1 R q2 is selected from R q1 , R q2 are independently H, C 1-6 Alkyl group, C 3-6 a carbocyclic group, a 4- to 7-membered heterocyclic group, and the alkyl group, carbocyclic group, or heterocyclic group may optionally be selected from the group consisting of 1 to 4 R k is replaced by As an option, R q1 , R q2 are directly linked to form a 4- to 7-membered heterocyclic group, said heterocyclic ring optionally containing 1 to 4 R k is replaced by B is C 6-10 Aryl group, 5- to 10-membered heteroaryl group, C 5-10 a carbocyclic group, a 5- to 10-membered heterocyclic group, and the aryl group, heteroaryl group, carbocyclic group, or heterocyclic group may optionally be selected from the group consisting of 1 to 4 R B is replaced by R 1 , R 2 are each independently H, halogen, CN, OH, or C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-6 Alkyl group, -SC 1-6 Alkyl group, C 3-6 a carbocyclic group, a 3- to 7-membered heterocyclic group, and the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group may optionally be selected from the group consisting of 1 to 4 R k The condition is that R 1 , R 2 But at the same time, it's not H, R 3 , R 4 , R q , R B are each independently H, deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl group, N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-6 Alkyl group, -SC 1-6 Alkyl group, C 3-7 Carbocyclic group, -OC 3-7 Carbocyclic group, 3- to 7-membered heterocyclic group, or -P(=O)R q1 R q2 wherein the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally selected from 1 to 4 R k is replaced by R k Deuterium, =O, halogens, CN, OH, NH2, NHC 1-6 Alkyl group, N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-6 Alkyl group, -SC 1-6 Alkyl group, -OC 3-6 Carbocyclic group, -O-3 to 7-membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7-membered heterocyclic group, -C 1-4 Alkylene-C 3-6 carbocyclic group, -C 1-4 Alkylene-3 to 7-membered heterocyclic group, C 3-6 a carbocyclic group, a 3- to 7-membered heterocyclic group, and the alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group may optionally contain deuterium, halogen, ═O, CN, OH, NH, C 1-6 Alkyl group, C 1-6 It is substituted with 1 to 4 substituents selected from alkoxy groups.

[0008] As a second embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein R q1 , R q2 are independently H, C 1-4 Alkyl group, C 3-6 a carbocyclic group, a 4- to 7-membered heterocyclic group, and the alkyl group, carbocyclic group, or heterocyclic group may optionally be selected from the group consisting of 1 to 4 R k is replaced by As an option, R q1 , R q2 are directly linked to form a 4- to 7-membered heterocyclic group, and the heterocyclic group optionally contains 1 to 4 R k is replaced by Q1 is a phenyl group, benzo C 4-6 a carbocyclic group, a 4- to 6-membered benzoheterocyclic group, a 5- to 6-membered heteroaryl group, an 8- to 10-membered fused ring heteroaryl group, or [ka] Preferably, Q1 is a phenyl group, a pyridyl group or [ka] wherein Q1 is optionally selected from 1 to 4 R q is replaced by B is a phenyl group, benzo C 4-6 A carbocyclic group, a 4- to 6-membered benzoheterocyclic group, a 5- to 6-membered heteroaryl group, an 8- to 10-membered fused ring heteroaryl group, and the B is optionally selected from 1 to 4 R B is replaced by R 1 , R 2 are each independently H, halogen, CN, OH, or C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -SC 1-4 Alkyl group, C 3-6a carbocyclic group, a 3- to 7-membered heterocyclic group, and the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group may optionally be selected from the group consisting of 1 to 4 R k The condition is that R 1 , R 2 But at the same time, it's not H, R 3 , R 4 , R q , R B are each independently H, deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -SC 1-4 Alkyl group, C 3-7 Carbocyclic group, -OC 3-7 Carbocyclic group, 3- to 7-membered heterocyclic group, or -P(=O)R q1 R q2 wherein the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally selected from 1 to 4 R k is replaced by R k Deuterium, =O, halogens, CN, OH, NH2, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -SC 1-4 Alkyl group, -OC 3-6 a carbocyclic group, -O-3 to 7-membered heterocyclic group, wherein the alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic group or heterocyclic group may optionally be selected from the group consisting of deuterium, halogen, CN, OH, NH, C 1-4 Alkyl group, C 1-4 substituted with 1 to 4 substituents selected from alkoxy groups; The definitions of the other groups are the same as in the first embodiment of the present invention.

[0009] As a third embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein R q1 , R q2 are each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl, and the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl groups are optionally selected from 1 to 4 R k is replaced by R 1 , R 2 are each independently selected from H, F, Cl, Br, cyano, methyl, ethyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, vinyl, and ethynyl, and the methyl, ethyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, vinyl, and ethynyl groups are optionally selected from 1 to 4 R k The condition is that R 1 , R 2 But at the same time, it's not H, B is [ka] or a phenyl group, preferably a phenyl group, [ka] and B optionally contains 1 to 4 R B is replaced by R 3 , R 4 , R q , R Bare each independently selected from H, deuterium, F, Cl, Br, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclopropyloxy, cyclobutyl, vinyl, ethynyl, -P(=O)(CH), -P(=O)(CHCH), -P(=O)(CH)(cyclopropyl), and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, vinyl, and ethynyl groups are optionally selected from the group consisting of 1 to 4 R k is replaced by R k is selected from deuterium, ═O, F, Cl, Br, I, CN, OH, NH, NH(CH), NH(CHCH), N(CH), N(CHCH), methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH-cyclopropyl, -CH-cyclobutyl, -CH-cyclopentyl, -CH-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups are optionally selected from deuterium, halogen, CN, OH, NH, C 1-4 Alkyl group, C 1-4 substituted with 1 to 4 substituents selected from alkoxy groups; The definitions of the other groups are the same as in the first or second embodiment of the present invention.

[0010] As a fourth embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein Q1 is, [ka] wherein Q1 is optionally selected from 1 to 5 R q is replaced by R3 , R 4 are each independently selected from H, a methyl group, an ethyl group, CHF, CHF, and CF; R 1 , R 2 are each independently selected from H, a methyl group, an ethyl group, CH2F, CHF2, and CF3, with the proviso that R 1 , R 2 But at the same time, it's not H, R q , R B are each independently selected from H, F, Cl, Br, cyano, CH2F, CHF2, CF3, -OCH2F, -OCHF2, -OCF3, -OCD3, methyl, -S-methyl, -S-CF3, ethyl, isopropyl, ethynyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, -O-cyclopropyl, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl), and the methyl, ethyl, isopropyl, ethynyl, methoxy, ethoxy, isopropyloxy, and cyclopropyl groups are optionally selected from the group consisting of 1 to 4 R k is replaced by R k is selected from deuterium, F, Cl, Br, I, CN, OH, -CHOH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH-cyclopropyl, -CH-cyclobutyl, -CH-cyclopentyl, -CH-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, The definitions of the other groups are the same as in the first, second or third embodiment of the present invention.

[0011] As a fifth embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein [ka] teeth, [ka] wherein Q1 is optionally selected from 1 to 3 R q is replaced by R qa teeth, [ka] selected from -CHOH, -CFCHOH, NH, -P(=O)(CH), -P(=O)(CHCH), -P(=O)(CH)(cyclopropyl); Preferably, [ka] teeth, [ka] wherein Q1 is optionally selected from 1 to 3 R q is replaced by B is [ka] is selected from, preferably [ka] and The definitions of the other groups are the same as in the first, second, third or fourth embodiment of the present invention.

[0012] As a sixth embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein The compound represented by general formula (I) is selected from the group consisting of general formulas (Ia), (Ib), (Ic), (Id), (Ie), and (If), [ka] The definitions of the other groups are the same as in the first, second, third, fourth or fifth embodiment of the present invention.

[0013] As a seventh embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein [ka] teeth, [ka] is selected from The definitions of the other groups are the same as in the first, second, third, fourth or fifth embodiment of the present invention.

[0014] The present invention relates to the compound shown below or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the structures shown below in Table E.

[0015] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0016] The present invention relates to pharmaceutical compositions comprising any of the above compounds or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.

[0017] The present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of the above-described compounds of the present invention or stereoisomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and a pharmaceutically acceptable carrier.

[0018] In some embodiments, the pharmaceutical compositions of the present invention may be in the form of a unit dosage form (the amount of active ingredient in a unit dosage form is also referred to as the "formulation specification").

[0019] As used herein, an "effective amount" or "therapeutically effective amount" refers to the administration of a sufficient amount of a compound disclosed herein that relieves to some extent one or more symptoms of the disease or condition being treated (e.g., treated and / or alleviated pain). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is that amount of a compound disclosed herein that is necessary to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include 1 to 1500 mg, 1 to 1200 mg, 1 to 1000 mg, 1 to 900 mg, 1 to 800 mg, 1 to 700 mg, 1 to 600 mg, 2 to 600 mg, 3 to 600 mg, 4 to 600 mg, 5 to 600 mg, 6 to 600 mg, 10 to 600 mg, 20 to 600 mg, 25 to 600 mg, 30 to 600 mg, 40 to 600 mg, 50 to 600 mg, 60 to 600 mg, 70 to 600 mg, 75 to 600 mg, 80 to 600 mg, 90 to 600 mg, 100 to 600 mg, 200 to 600 mg, 1 to 500 mg, and 2 to 500 mg , 3~500mg, 4~500mg, 5~500mg, 6~500mg, 10~500mg, 20~500mg, 25~500mg, 30~500mg, 40~500mg, 50~500mg, 60~500mg, 70~500mg, 75~500mg, 80~500m g, 90~500mg, 100~500mg, 125~500mg, 150~500mg, 200~500mg, 250~500mg, 300~500mg, 400~500mg, 5~400mg, 10~400mg, 20~400mg, 25~400mg, 30~40 0mg, 40~400mg, 50~400mg, 60~400mg, 70~400mg, 75~400mg, 80~400mg, 90~400mg, 100~400mg, 125~400mg, 150~400mg, 200~400mg, 250~400mg, 300~ 400mg, 1~300mg, 2~300mg, 5~300mg, 10~300mg, 20~300mg, 25~300mg, 30~300mg, 40~300mg, 50~300mg, 60~300mg, 70~300mg, 75~300mg, 80~300mg, 9 Including, but not limited to, 0-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, and 80-800mg.

[0020] In some embodiments, the pharmaceutical composition contains 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, 110 mg, 120 mg, 125 mg, 130 mg, Including, but not limited to, 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, 840 mg of a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof.

[0021] A method for treating a disease in a mammal, said method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and said disease is preferably treated or alleviated pain.

[0022]

[0023] A method for treating or alleviating a disease in a mammal, the method comprising administering to a subject a pharmaceutical compound of the present invention, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, in a daily dose of 1 to 1000 mg / day, which may be a single dose or divided doses, and in some embodiments, the daily dose is 10 to 1500 mg / day, 10 to 1000 mg / day, 10 to 800 mg / day, 25 to 800 mg / day, 50 to 800 mg / day, 100 to 800 mg / day, 20 In some embodiments, the daily dose includes, but is not limited to, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, and 1000 mg / day.

[0023] The present invention relates to a kit, which may comprise a composition in single-dose or multi-dose form, comprising a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the amount of the compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof is the same as the amount in the pharmaceutical composition.

[0024] The present invention relates to the application of any of the above compounds or stereoisomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof in the manufacture of a medicament for treating and / or alleviating pain.

[0025] The present invention relates to the application of the above pharmaceutical composition in the manufacture of a medicament for treating and / or alleviating pain.

[0026] Amounts of compounds of the invention or stereoisomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof are in each case calculated in terms of the free base form. Synthesis method 1: [ka]

[0027] The Wittig reaction of general formula (Z1) with general formula (Z2) gives the corresponding general formula (Z3), and the addition reaction of general formula (Z3) with ethyl thioglycolate gives the corresponding general formula (Z4), and the general formula (Z4) undergoes intramolecular ester condensation to give the corresponding general formula (Z5), and the protecting group on general formula (Z5) gives the corresponding general formula (Z6), and the coupling of general formula (Z6) with fragment (BX) gives the corresponding general formula (Z7), and the reduction of general formula (Z7) gives the corresponding general formula (Z8), and the coupling of general formula (Z8) with amino fragment (R Q1 -Q1-NH2) to obtain the corresponding general formula (Ia').

[0028] X is a halogen, a boronic acid, or a boronic ester.

[0029] Unless otherwise stated, terms used in the specification and claims have the following meanings:

[0030] Carbon, hydrogen, oxygen, sulfur, nitrogen, F, Cl, Br, and I in the groups and compounds described in the present invention all include their isotopic status, and carbon, hydrogen, oxygen, sulfur, or nitrogen in the groups and compounds described in the present invention are optionally substituted with one or more corresponding isotopes, where the carbon isotope is: 12 C and 13 C and 14 C, isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called tritium), and isotopes of oxygen include 16 O and 17 O and 18 Isotopes of sulfur include O and32 S and 33 S and 34 S and 36 S and nitrogen isotopes include 14 N and 15 N and fluorine isotopes include 17 F and 19 The isotopes of chlorine include F and 35 Cl and 37 The isotopes of bromine include Cl and 79 Br and, 81 Contains Br and

[0031] "Halogen" refers to F, Cl, Br or I.

[0032] "Halogen substitution" refers to F, Cl, Br, or I substitution, including, but not limited to, substitution with 1 to 10 substituents selected from F, Cl, Br, or I, substitution with 1 to 6 substituents selected from F, Cl, Br, or I, and substitution with 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen substitution" is abbreviated as "halogenation."

[0033] "Alkyl group" refers to a substituted or unsubstituted straight- or branched-chain saturated aliphatic hydrocarbon group, including, but not limited to, alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 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 various branched-chain isomers thereof, and definitions of alkyl groups described herein are consistent with this definition. Alkyl groups may be monovalent, divalent, trivalent, or tetravalent.

[0034] An "alkylene group" is a substituted or unsubstituted straight-chain or branched-chain divalent saturated hydrocarbon group, -(CH2) v - (where v is an integer from 1 to 10), and examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene groups.

[0035] "Cycloalkyl group" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms; non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl groups. The definition of cycloalkyl groups described herein is as set forth above. Cycloalkyl groups may be monovalent, divalent, trivalent, or tetravalent.

[0036] "Heterocycloalkyl group" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group, containing 3 to 10 atoms, 3 to 8 atoms, but not limited to, 1 to 3 heteroatoms selected from N, O, or S, and the optionally substituted N and S in the heterocycloalkyl ring can be oxidized to various oxidation states. The heterocycloalkyl group can be attached to a heteroatom or a carbon atom, can be attached to an aromatic or non-aromatic ring, or can be attached to a bridged or spiro ring; non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinanyl, morpholinyl, hexahydropyrimidinyl, and piperazinyl. The heterocycloalkyl group may be monovalent, divalent, trivalent, or tetravalent.

[0037] An "alkenyl group" is a substituted or unsubstituted straight- and branched-chain unsaturated hydrocarbon group that has at least one, and typically one, two, or three, carbon-carbon double bond and a backbone containing 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, and the like. The definition of an alkenyl group described herein is consistent with this definition, including, but not limited to, 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. The alkenyl group may be monovalent, divalent, trivalent, or tetravalent.

[0038] "Alkynyl group" refers to substituted or unsubstituted straight- and branched-chain unsaturated hydrocarbon groups having at least one, and typically one, two, or three, carbon-carbon triple bonds, and a backbone containing 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms, but is not limited to such. Examples of alkynyl groups include ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, and 1-methyl-1-butynyl. Alkynyl groups include, but are not limited to, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, and the like. The alkynyl groups may be monovalent, divalent, trivalent, or tetravalent.

[0039] "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-pentyloxy, n-hexyloxy, cyclopropoxy, and cyclobutoxy.

[0040] "Carbocyclic group" or "carbocycle" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic ring, where the aromatic or non-aromatic ring may be a 3- to 8-membered monocyclic, a 4- to 12-membered bicyclic, or a 10- to 15-membered tricyclic system, and the carbocyclic group may be linked to an aromatic or non-aromatic ring, which may optionally be a monocyclic, bridged, or spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, [ka] A "carbocyclic group" or "carbocycle" may be monovalent, divalent, trivalent or tetravalent.

[0041] The term "heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic ring, which may be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system, containing one or more (including, but not limited to, 2, 3, 4, or 5) heteroatoms selected from N, O, or S, and wherein the optionally substituted N, S in the ring of the heterocyclic group can be oxidized to various oxidation states. Heterocyclic groups may be attached at a heteroatom or carbon atom, may be attached at an aromatic or non-aromatic ring, may have bridged or spiro rings attached to them, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azacycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuryl, dihydropyranyl, dithiolanyl, tetrahydrofuran ... a hydropyrrolyl group, a tetrahydroimidazolyl group, a tetrahydrothiazolyl group, a tetrahydropyranyl group, a benzimidazolyl group, a benzopyridyl group, a pyrrolopyridyl group, a benzodihydrofuryl group, a pyrrolyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group, a pyrazinyl group, an indazolyl group, a benzothienyl group, a benzofuryl group, a benzopyrrolyl group, a benzimidazolyl group, a benzothiazolyl group, a benzoxazolyl group, a benzopyridyl group, a benzopyrimidinyl group, a benzopyrazinyl group, a piperazinyl group, an azabicyclo[3.2.1]octyl group, an azabicyclo[5.2.0]nonyl group, an oxatricyclo[5.3.1.1]dodecyl group, an azaadamantyl group, an oxaspiro[3.3]heptyl group, [ka] The "heterocyclic group" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

[0042] A "heteroaryl group" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 groups selected from or containing heteroatoms (including, but not limited to, N, O, or S(=O)n, where n is 0, 1, or 2), and the number of ring atoms in the heteroaromatic ring includes, but is not limited to, 5 to 15, 5 to 10, or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring can be fused with a saturated or unsaturated carbocyclic or heterocyclic ring, where the ring connected to the base skeleton is a heteroaryl ring. Non-limiting examples include: [ka] The definition of a heteroaryl group described herein is consistent with this definition. A heteroaryl group may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the linking site is on the heteroaryl ring.

[0043] "Substituted" or "unsubstituted" refers to substitution with one or more (including, but not limited to, 2, 3, 4, or 5) substituents, which substituents include H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged ring, spirocyclic, fused ring, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, formate, -(CH) m -C(=O)-R a , -O-(CH2) m -C(=O)-R a , -(CH2) m -C(=O)-NR b R c , -(CH2) m S(=O) n R a, -(CH2) m -Alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1, or 2), an arylthio group, a thiocarbonyl group, a silyl group, or —NR b R c and the like, where R b and R c are independently selected from H, a hydroxy group, an amino group, a carbonyl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group, and a trifluoromethanesulfonyl group; and optionally, R b and R c can form a 5- or 6-membered cycloalkyl group or a heterocyclic group, R a and R d are each independently selected from an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro ring group, or a fused ring group.

[0044] "Substituted with 1 to X substituents selected from" refers to substitution with 1, 2, 3, ..., X substituents selected from ..., where X is selected from any integer from 1 to 10. For example, "1 to 4 R k "Substituted with" means 1, 2, 3 or 4 R k For example, "substituted with 1 to 5 substituents selected from" refers to substitution with 1, 2, 3, 4, or 5 substituents selected from. For example, "a heterobridged ring is optionally substituted with 1 to 4 substituents selected from D or F" refers to substitution with 1, 2, 3, or 4 substituents selected from D or F.

[0045] The ring of X to Y members (where X is an integer and 3 ≤ X < Y, and Y is selected from any integer from 4 to 12) includes rings of X, X + 1, X + 2, X + 3, X + 4, …, Y members. The ring includes a complex ring, a carbon ring, an aromatic ring, an aryl group, a heteroaryl group, a cycloalkyl group, a complex monocyclic ring, a complex condensed ring, a complex spiro ring or a complex bridged ring. For example, "a 4- to 7-member complex monocyclic ring" refers to a 4-member, 5-member, 6-member or 7-member complex monocyclic ring, and "a 5- to 10-member complex condensed ring" refers to a 5-member, 6-member, 7-member, 8-member, 9-member or 10-member complex condensed ring.

[0046] "Optionally" or "optionally" means that the event or circumstance described thereafter may occur but does not necessarily occur, and the description includes both the case where the event or circumstance occurs and the case where it does not occur. For example, "an alkyl group optionally substituted by F" means that the alkyl group may be substituted by F but does not necessarily have to be substituted by F, indicating that it includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

[0047] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" refers to a salt obtained by the reaction of the compound of the present invention maintaining the biological effectiveness and properties of the free acid or free base with a non-toxic inorganic base or organic base for the free acid, or a non-toxic inorganic acid or organic acid for the free base.

[0048] "Pharmaceutical composition" refers to a mixture composed of one or more compounds described in the present invention, or its stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and other chemical components, where "other chemical components" refer to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0049] "Carrier" refers to a material that does not cause significant irritation to organisms and does not eliminate the biological activity and properties of the administered compound.

[0050] "Preparation specifications" refers to the weight of the active ingredient contained in one unit dosage form, one tablet, or each other unit dosage form.

[0051] "Animal" includes mammals such as humans, companion animals, zoo animals, and farm animals, and is preferably a human, horse, or dog.

[0052] "Stereoisomer" refers to isomers that result from differences in the way atoms in molecules are arranged in space, and includes cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0053] "Tautomer" refers to a functional isomer produced when an atom in a molecule rapidly shifts between two positions, such as keto-enol isomers and amide-imide alcohol isomers. DETAILED DESCRIPTION OF THE INVENTION

[0054] The following examples will illustrate the technical solutions of the present invention in detail, and the protection scope of the present invention includes but is not limited to them.

[0055] The structure of the compound was confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR displacements (δ) were 10 -6 The NMR data were given in units of ppm. NMR measurements were performed using nuclear magnetometers (Bruker Avance III 400 and Bruker Avance 300), and the solvents used were deuterated dimethyl sulfoxide (DMSO-d), deuterated chloroform (CDCl), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). MS measurements were performed using Agilent 6120B (ESI) and Agilent 6120B (APCI). HPLC measurements were performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM). Prep-HPLC (Condition 1): Instrument: Waters AutoP, Prep column: Sunfire C18 (19 mm x 250 mm). Preparation method: The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. Mobile phase: acetonitrile / water (0.1% trifluoroacetic acid), gradient elution, acetonitrile content 35% to 80%, flow rate: 15 mL / min, elution time: 20 min.

[0056] Prep-HPLC conditions (condition 2): Instrument: Waters 2767 preparative liquid, Preparative column: SunFire C18 (19 mm x 250 mm). The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. Mobile phase: acetonitrile / water (0.1% trifluoroacetic acid), gradient elution, acetonitrile content 10% to 70%, flow rate 17 mL / min, elution time 20 min.

[0057] Prep-HPLC (neutral preparative): Instrument: Waters AutoP, Preparative column: XSelect C18 (19 mm x 250 mm). Preparation method: The crude material was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. Mobile phase: acetonitrile / water (5 mM ammonium acetate), gradient elution, acetonitrile content 30% to 80%, flow rate: 15 mL / min, elution time: 20 min.

[0058] The silica gel plates used for thin layer chromatography are Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates. The silica gel plate specifications used for thin layer chromatography (TLC) are 0.15mm-0.20mm, and the specifications used for product separation and purification by chromatography are 0.4mm-0.5mm. For column chromatography, Yantai Yellow Sea silica gel 200-300 mesh silica gel was generally used as the carrier.

[0059] To achieve the objectives of the present invention, the compounds used in the reactions described herein are prepared based on organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature, where "commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aldington Biochemical Technology Co., Ltd., Shanghai McKinney Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Acer (China) Chemical Co., Ltd., Teijin Chemical (Shanghai) Chemical Industry Development Co., Ltd., Ananji Chemical, Shanghai Taitan Technology Co., Ltd., Kelong Chemical, Bailingwei Technology Co., Ltd., and the like.

[0060] TCFH: tetramethylchlorourea hexafluorophosphate, THF: tetrahydrofuran, DMF: N,N-dimethylcarboxamide, DIPEA: N,N-diisopropylethylamine, HATU: CAS 148893-10-1, T3P (50% wt in EtOAc): CAS 68957-94-8 Retention time: Unless otherwise specified in the examples, the retention time corresponds to the analytical method.

[0061] Example 1: Preparation of Compound 1-1a and Compound 1-1b [ka]

[0062] Step 1: Preparation of Compound 1b In an ice bath, 1a-1 (30.96 g, 129.95 mmol) was dissolved in tetrahydrofuran (130 mL), and sodium hydride (5.20 g, 130 mmol) was added portionwise. The mixture was allowed to react for 30 min under a nitrogen atmosphere and ice bath. 1a (11.20 g, 100 mmol) was dissolved in tetrahydrofuran (20 mL), and the mixture was added dropwise. The mixture was allowed to warm to room temperature under a nitrogen atmosphere and react for 18 h. In an ice bath, 1N hydrochloric acid was slowly added dropwise to the reaction mixture until the pH reached 7-8. The mixture was extracted with ether (150 mL × 3). The combined organic phases were 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, 71.88% yield, E / Z configuration mixture).

[0063] Step 2: Preparation of Compound 1c In an ice bath, 1b-1 (8.63 g, 71.88 mmol) was added to a round-bottom flask, piperidine (1.22 g, 14.38 mmol) was added dropwise, and 1b (6.0 g, 71.88 mmol) was added dropwise. The reaction was then carried out at 50 °C for 24 h under nitrogen gas protection. The reaction was quenched by adding 0.1 N hydrochloric acid (100 mL) in an ice bath, and extracted with ether (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated (at 25 °C) to give crude 1c. The crude product was purified by silica gel column chromatography to give 1c (6.3 g, 27.96% yield). LC-MS m / z=317.1[M+H] +

[0064] Step 3: Preparation of Compound 1d 1c (6.3 g, 19.92 mmol) was dissolved in ether (120 mL) under ice bath, and potassium tert-butoxide (2.91 g, 25.90 mmol) was slowly added dropwise to the system under nitrogen gas protection, followed by reaction in an ice bath for 2 h. The reaction was quenched by adding glacial acetic acid (1.56 mL) and water (100 mL) to the reaction system under ice bath, and the mixture was extracted with ether (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 1d.

[0065] Step 4: Preparation of Compound 1e 1d (4.05 g, 15 mmol) was dissolved in dichloromethane (40 mL) and pre-cooled at -78 °C for 15 min. Under a nitrogen atmosphere, N,N-diisopropylethylamine (2.32 g, 17.99 mmol) was added dropwise, and trifluoromethanesulfonic anhydride (4.23 g, 15 mmol) was dissolved in dichloromethane (10 mL) and slowly added dropwise to the system. After completion, the reaction was continued at -78 °C for 2 h. The reaction was quenched by slowly adding saturated aqueous sodium bicarbonate solution (50 mL) in an ice bath, followed by extraction with dichloromethane (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography to give 1e (5.2 g, 86.16% yield).

[0066] Step 5: Preparation of Compound 1f 1e (5.2 g, 12.92 mmol) was dissolved in toluene (50 mL), 1e-1 (2.67 g, 14.21 mmol) and Pd(PPh3)4 (0.75 g, 0.65 mmol) were added sequentially, and potassium phosphate (8.23 g, 38.71 mmol) was added to the mixture, which was then reacted at 100 °C for 6 h under a nitrogen atmosphere. The reaction was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (10 mL × 2). The filtrate was layered and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give 1f (5.1 g, 99.59% yield). LC-MS m / z=397.1[M+H] +

[0067] Step 6: Preparation of Compounds 1g-1a and 1g-1b 1f (3.7 g, 9.33 mmol) was dissolved in methanol (50 mL), palladium carbon (1.99 g, 18.56 mmol) was added, and after completion, the reaction mixture was pressurized to 2 MPa under a hydrogen gas atmosphere and reacted at room temperature for 24 h. The reaction mixture 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, 27.44% yield), and the unreacted mixture of 1f-2a and 1f-2b (0.148 g, 4.00% yield) was recovered.

[0068] Mixture of 1g-1a and 1g-1b: LC-MS m / z=399.4[M+H] + 1 H NMR (400MHz,CDCl3): δ 6.96 - 6.90 (m,1H),6.88 - 6.79 (m,1H),4.08 - 4.01 (m,4H),3.94 - 3.80 (m,2H),3.77 - 3.68 (m,1H),3.49 - 3.37 (m,1H),1.59 (s,3H),1.02 (t,3H),0.96 (d,3H). Mixture of 1f-2a and 1f-2b: LC-MS m / z=397.1[M+H] + 1 H NMR (400MHz,CDCl3): δ 6.90 - 6.81 (m,1H),6.77 - 6.71 (m,1H),4.13 - 4.04 (m,2H),3.92 (d,3H),3.42 - 3.34 (m,1H),1.77 (s,3H),1.13 (t,3H),1.09 - 1.04 (m,3H).

[0069] Step 7: Preparation of Compounds 1h-1a and 1h-1b A mixture of 1g-1a and 1g-1b (1.02 g, 2.56 mmol) was dissolved in tetrahydrofuran (25 mL) under nitrogen atmosphere and ice bath. The mixture was pre-cooled for 15 min. Potassium tert-butoxide (0.95 g, 8.46 mmol) was slowly added dropwise to the mixture (internal temperature <13 °C). After completion, the reaction was continued for 2 h under ice bath. 1N hydrochloric acid (internal temperature <13 °C) was slowly added dropwise to the mixture until pH = 1. Water (10 mL) was added and the mixture was extracted with ethyl acetate (25 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a mixture of 1h-1a and 1h-1b. LC-MS m / z=369.0[MH] -

[0070] Step 8: Preparation of Compounds 1i-1a and 1i-1b A mixture of 1h-1a and 1h-1b (0.90 g, 2.44 mmol) was dissolved in DMF (20 mL). 1h-2 (0.56 g, 3.68 mmol), TCFH (1.37 g, 4.88 mmol), and N-methylimidazole (0.40 g, 4.88 mmol) were added sequentially. After completion, the mixture was allowed to react at room temperature for 18 h under a nitrogen atmosphere. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (90 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give a mixture of 1i-1a and 1i-1b (0.526 g, 42.65% yield). LC-MS m / z=505.2[M+H] +

[0071] Step 9: Preparation of Compound 1-1a and Compound 1-1b A mixture of 1i-1a and 1i-1b (0.52 g, 1.04 mmol) was dissolved in 7 M ammonia methanol solution (5 mL) and reacted at room temperature for 18 h. The reaction mixture was concentrated to give a crude product, which was then purified by silica gel column chromatography to give a mixture of compound 1-1a and compound 1-1b (0.38 g, 74.50% yield).

[0072] LC-MS m / z=490.2[M+H] + , 1 H NMR (400MHz,DMSO-d6): δ 10.74 (s,1H),8.45 (d,1H),8.14 (d,1H),8.07 - 7.99 (m,1H),7.67 - 7.63 (m,1H),7.62 - 7.56 (m,1H),7.21 - 7.12 (m,2H),4.47 (d,1H),4.00 - 3.82 (m,4H),2.84 - 2.72 (m,1H),1.61 (s,3H),0.83 (d,3H). Example 2: Preparation of Compound 1-2a and Compound 1-2b [ka]

[0073] Step 1: Preparation of Compounds 1g-2a and 1g-2b 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 completion, the mixture was pressurized to 2.5 MPa under a hydrogen gas atmosphere and reacted 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, 34.35% yield).

[0074] Step 2: Preparation of Compounds 1h-2a and 1h-2b A mixture of 1g-2a and 1g-2b (0.052 g, 0.13 mmol) was dissolved in tetrahydrofuran (5 mL) under nitrogen atmosphere and ice bath. The mixture was pre-cooled for 15 min. Potassium tert-butoxide (0.048 g, 0.43 mmol) was slowly added dropwise to the mixture (internal temperature <13 °C). After completion, the mixture was allowed to react in an ice bath for 2 h. 1N hydrochloric acid (internal temperature <13 °C) was slowly added dropwise to the mixture until the pH reached 1. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a mixture of 1h-2a and 1h-2b. LC-MS m / z=369.0[MH] -

[0075] Step 3: Preparation of Compounds 1i-2a and 1i-2b A mixture of 1h-2a and 1h-2b (0.048 g, 0.13 mmol) was dissolved in DMF (3 mL). 1h-2 (0.03 g, 0.20 mmol), TCFH (0.073 g, 0.26 mmol), and N-methylimidazole (0.022 g, 0.26 mmol) were added sequentially and the mixture was allowed to react for 18 h at room temperature under a nitrogen atmosphere. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (30 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give a mixture of 1i-2a and 1i-2b (0.01 g, 15.25% yield). LC-MS m / z=505.2[M+H] +

[0076] Step 4: Preparation of Compounds 1-2a and 1-2b A mixture of 1i-2a and 1i-2b (0.01 g, 0.02 mmol) was dissolved in 7 M ammonia methanol solution (3 mL) and reacted at room temperature for 8 h. The reaction mixture was concentrated to give a crude product, which was then purified by silica gel column chromatography to give a mixture of compounds 1-2a and 1-2b (0.006 g, 61.91% yield). LC-MS m / z=490.2[M+H] + , 1 H NMR (400MHz,DMSO-d6): δ 10.92 (s,1H),8.47 (d,1H),8.17 (d,1H),8.06 - 8.00 (m,1H),7.70 - 7.64 (m,1H),7.63 - 7.57 (m,1H),7.22 - 7.06 (m,2H),4.86 (d,1H),4.54 - 4.46 (m,1H),4.01 (d,3H),2.66 - 2.58 (m,1H),1.85 (s,3H),0.83 - 0.75 (m,3H).

[0077] SFC preparative conditions: Instrument: Waters 150 Prep-SFC C, Preparative column: Chiralcel OX Column. Preparation method: The crude product was dissolved in acetonitrile to prepare a 10 mg / ml sample solution. Mobile phase: carbon dioxide / methanol, methanol content 30%, Elution time: 8 min.

[0078] A mixture of 504 mg of compounds 1-2a and 1-2b was purified by SFC preparative separation and lyophilized to give compounds 1-2P1 (193.8 mg, retention time: 1.137 min) and 1-2P2 (218 mg, retention time: 1.526 min). Chiral analysis method: (Instrument: SHIMADZU LC-30 AD sf, Chiral column: Chiralcel OX Column. Preparation method: The crude product was dissolved in acetonitrile to prepare the sample solution. Mobile phase: carbon dioxide / 0.05% DEA in methanol. Elution gradient: 5%-40%, flow rate: 3.0 mL / min, elution time: 3 min).

[0079] The structure of compound 1-2P1 is one of 1-2a and 1-2b, and is an enantiomer of compound 1-2P2. That is, when the structure of compound 1-2P1 is that of formula 1-2a, the structure of compound 1-2P2 is that of formula 1-2b, and when the structure of compound 1-2P1 is that of formula 1-2b, the structure of compound 1-2P2 is that of formula 1-2a. Compounds 1-2P1 and 1-2P2 are indistinguishable from each other in nuclear magnetic and mass spectrometry, and are consistent with a mixture of compounds 1-2a and 1-2b.

[0080] Example 3: Preparation of Compound 3-2a and Compound 3-2b [ka]

[0081] Step 1: Preparation of Compounds 3-1a and 3-1b A mixture of 1h-2a and 1h-2b (0.052 g, 0.14 mmol) was dissolved in ethyl acetate (3 mL), triethylamine (0.042 g, 0.42 mmol) and T3P (50% wt in EtOAc 0.36 g, containing 1-propylphosphonic anhydride 0.18 g, 0.56 mmol) were added sequentially, followed by the dropwise addition of a solution of 3-1a-1 (0.041 g, 0.21 mmol) in ethyl acetate (1 mL). The mixture was then reacted at room temperature for 18 h under a nitrogen atmosphere. The reaction was quenched by the addition of aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give a mixture of 3-1a and 3-1b (0.03 g, 39.21% yield). LCMS m / z=547.1[M+H] +

[0082] Step 2: Preparation of Compound 3-2a and Compound 3-2b A mixture of 3-1a and 3-1b (0.03 g, 0.027 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.6 mL) was added dropwise, and the mixture was allowed to react at room temperature for 2 h. The reaction mixture was concentrated to give a crude product, which was purified by prep-HPLC (condition 1) to give the trifluoroacetate salt of the mixture of 3-2a and 3-2b (0.016 g, 58.5% yield).

[0083] LCMS m / z=507.4[M+H] + , Example 4: Preparation of Compound 4-1a and Compound 4-1b [ka]

[0084] Step 1: Preparation of Compounds 4-1a and 4-1b A mixture of 1h-2a and 1h-2b (0.052 g, 0.14 mmol) was dissolved in ethyl acetate (3 mL), triethylamine (0.042 g, 0.42 mmol) and T3P (50% wt in EtOAc 0.36 g, containing 1-propylphosphonic anhydride 0.18 g, 0.56 mmol) were added sequentially, followed by 2C-1 (0.048 g, 0.28 mmol). The mixture was then reacted at room temperature for 18 h under a nitrogen atmosphere. The reaction was quenched with aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by prep-HPLC (condition 1) to give the trifluoroacetate salt of the mixture of 4-1a and 4-1b (0.006 g, 8.2% yield).

[0085] LCMS m / z=523.5[M+H] + 1H NMR (400MHz,DMSO-d6) δ 10.78 (d,1H),8.31 - 8.25 (m,1H),7.78 - 7.72 (m,1H),7.69 - 7.64 (m,1H),7.62 - 7.56 (m,1H),7.22 - 7.13 (m,1H),7.11 - 7.05 (m,1H),4.87 (d,1H),4.54 - 4.45 (m,1H),4.01 (d,3H),3.27 (d,3H),2.68 - 2.59 (m,1H),1.86 (s,3H),0.83 - 0.74 (m,3H). Example 5: Preparation of Compound 5-3a and Compound 5-3b [ka]

[0086] Step 1: Preparation of Compounds 5-1a and 5-1b A mixture of 1h-2a and 1h-2b (0.022 g, 0.06 mmol) was dissolved in ethyl acetate (3 mL). Triethylamine (0.036 g, 0.36 mmol) and T3P (50% wt in EtOAc 0.152 g, containing 1-propylphosphonic anhydride 0.076 g, 0.24 mmol) were added sequentially. Aqueous ammonia (0.008 g, 0.12 mmol) was then added and the mixture was allowed to react at room temperature for 18 h under a nitrogen atmosphere. The reaction was quenched by the addition of aqueous sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a mixture of 5-1a and 5-1b. LCMS m / z=370.1[M+H] +

[0087] Step 2: Preparation of Compounds 5-2a and 5-2b A mixture of 5-1a and 5-1b (0.06 mmol) was dissolved in 1,4-dioxane (3 mL) under a nitrogen atmosphere and ice bath. 5-1-1 (0.048 g, 0.09 mmol), Xantphos Pd G2 (CAS: 1375325-77-1) (0.006 g, 0.006 mmol), and cesium carbonate (0.057 g, 0.18 mmol) were added sequentially. The mixture was then reacted at 100 °C for 16 h under a nitrogen atmosphere. The reaction was cooled to room temperature and quenched with water (15 mL). The mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give the mixture of 5-2a and 5-2b (0.026 g, 52.47% yield).

[0088] Step 3: Preparation of Compounds 5-3a and 5-3b A mixture of 5-2a and 5-2b (0.026 g, 0.016 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.6 mL) was added dropwise, and the mixture was allowed to react at room temperature for 2 h. In an ice bath, saturated sodium bicarbonate solution (15 mL) was slowly added dropwise to the reaction mixture, followed by extraction with dichloromethane (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give a mixture of 5-3a and 5-3b (0.012 g, 71.36% yield).

[0089] LCMS m / z=526.0[M+H] + , Example 6: Preparation of Compound 6-2a and Compound 6-2b [ka]

[0090] Step 1: Preparation of Compounds 6-1a and 6-1b A mixture of 1h-2a and 1h-2b (0.049 g, 0.13 mmol) was dissolved in ethyl acetate (3 mL), triethylamine (0.079 g, 0.78 mmol) and T3P (50% wt in EtOAc 0.33 g, containing 1-propylphosphonic anhydride 0.165 g, 0.52 mmol) were added sequentially, followed by 6-1-1 (0.033 g, 0.20 mmol). The mixture was allowed to react at room temperature for 18 h under a nitrogen atmosphere. The reaction was quenched with aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give a mixture of 6-1a and 6-1b (0.056 g, 82.61% yield). LCMS m / z=522.2[M+H] +

[0091] Step 2: Preparation of Compounds 6-2a and 6-2b A mixture of 6-1a and 6-1b (0.056 g, 0.054 mmol) was dissolved in 7 M ammonia in methanol (5 mL) and reacted at room temperature for 18 h. The reaction mixture was concentrated to give a crude product, which was then purified by prep-HPLC (condition 1) to give a mixture of 6-2a and 6-2b (0.036 g, 65.82% yield).

[0092] LCMS m / z=507.2[M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 10.52 (s,1H),7.87 - 7.81 (m,1H),7.69 - 7.56 (m,3H),7.25 - 7.13 (m,2H),7.12 - 7.04 (m,1H),4.83 (d,1H),4.52 - 4.45 (m,1H),4.00 (d,3H),2.66 - 2.55 (m,1H),1.85 (s,3H),0.84 - 0.72 (m,3H). Example 7: Preparation of Compound 7-1a and Compound 7-1b [ka]

[0093] Preparation of Compounds 7-1a and 7-1b A mixture of 1h-2a and 1h-2b (0.050 g, 0.14 mmol) was dissolved in ethyl acetate (3 mL). Triethylamine (0.042 g, 0.42 mmol) and T3P (50% wt in EtOAc 0.35 g, containing 1-propylphosphonic anhydride 0.175 g, 0.55 mmol) were added sequentially. 7-1-1 (0.033 g, 0.20 mmol) was added and the mixture was allowed to react at room temperature for 18 h under a nitrogen atmosphere. The reaction was quenched with aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by prep-HPLC (condition 1) and lyophilized to give a mixture of 7-1a and 7-1b (0.020 g, 27.24% yield).

[0094] LCMS m / z=525.2[M+H] + Example 8: Preparation of Compound 8-1a and Compound 8-1b [ka]

[0095] Preparation of Compounds 8-1a and 8-1b A mixture of 1h-2a and 1h-2b (0.050 g, 0.14 mmol) was dissolved in ethyl acetate (3 mL), and triethylamine (0.042 g, 0.42 mmol) and T3P (50% wt in EtOAc 0.35 g, containing 1-propylphosphonic anhydride 0.175 g, 0.55 mmol) were added sequentially. 8-1-1 (0.040 g, 0.21 mmol, reference literature: WO2020 / 028724) was then added, and the mixture was allowed to react at room temperature for 18 h under a nitrogen gas atmosphere. The reaction was quenched by adding aqueous sodium bicarbonate (10 mL) to the reaction system, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by prep-HPLC fractionation (condition 1) and freeze-dried to give a mixture of 8-1a and 8-1b (0.007 g, yield 9.22%).

[0096] LCMS m / z=543.2[M+H] + 1 H NMR (400MHz,CDCl3) δ 8.11 (s,1H),7.98 - 7.92 (m,1H),7.81 - 7.76 (m,1H),7.17 (t,1H),7.05 - 6.98 (m,1H),6.91 - 6.83 (m,1H),5.04 (s,2H),4.57 (d,1H),4.46 (dd,1H),4.04 (d,3H),2.68 - 2.59 (m,1H),1.92 (s,3H),0.91 - 0.85 (m,3H). Example 9: Preparation of Compound 9-1a and Compound 9-1b [ka]

[0097] A mixture of 1h-1a and 1h-1b (50 mg, 0.14 mmol) was dissolved in DMF (3 mL), and 2C-1 (36 mg, 0.21 mmol), TCFH (79 mg, 0.28 mmol), and N-methylimidazole (34 mg, 0.41 mmol) were added sequentially. The mixture was reacted at room temperature under a nitrogen atmosphere for 18 h. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (5 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by prep-HPLC (condition 1) to give a mixture of compound 9-1a and compound 9-1b (15 mg, 20.95% yield).

[0098] LCMS m / z=523.5[M+H] + Example 10: Preparation of Compound 10-1a and Compound 10-1b [ka]

[0099] A mixture of 1h-1a and 1h-1b (50 mg, 0.14 mmol) was dissolved in DMF (3 mL). 10-1-1 (40 mg, 0.21 mmol), TCFH (79 mg, 0.28 mmol), and N-methylimidazole (34 mg, 0.42 mmol) were added sequentially. The mixture was reacted at room temperature under a nitrogen atmosphere for 18 h. Water (5 mL) was added to quench the reaction, followed by extraction with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (5 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by prep-HPLC (condition 1) to give a mixture of 10-1a and 10-1b (9.73 mg, 12.86% yield).

[0100] LCMS m / z=541.5[M+H] + Example 11: Preparation of Compound 11-1a and Compound 11-1b [ka]

[0101] A mixture of 1h-1a and 1h-1b (100 mg, 0.27 mmol) was dissolved in EA (3 mL). 4-amino-1-methylpyridine-ethanone (40 mg, 0.32 mmol), T3P (50% wt in EtOAc 680 mg, containing 1-propylphosphonic anhydride 340 mg, 1.08 mmol), and Et3N (82 mg, 0.81 mmol) were added sequentially and reacted at room temperature for 18 h under a nitrogen atmosphere. Water (5 mL) was added, followed by extraction with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (5 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by prep-HPLC (condition 1) to give a mixture of 11-1a and 11-1b (30 mg, 23.32% yield).

[0102] LCMS m / z=477.1[M+H] + Example 12: Preparation of Compound 12-1a and Compound 12-1b [ka]

[0103] A mixture of 1h-1a and 1h-1b (100 mg, 0.27 mmol) was dissolved in EA (3 mL). 4-aminopyridazine (31 mg, 0.33 mmol), T3P (50% wt in EtOAc 680 mg, containing 1-propylphosphonic anhydride 340 mg, 1.08 mmol), and Et3N (82 mg, 0.81 mmol) were added sequentially and reacted under a nitrogen atmosphere at room temperature for 18 h. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine (5 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by prep-HPLC (condition 1) to give a mixture of compound 12-1a and compound 12-1b (93.92 mg, 77.75% yield).

[0104] LCMS m / z=448.2[M+H] + Example 13: Preparation of Compound 13-1a and Compound 13-1b [ka]

[0105] A mixture of 1h-1a and 1h-1b (100 mg, 0.27 mmol) was dissolved in EA (3 mL). 3-aminopyridine (30 mg, 0.32 mmol), T3P (50% wt in EtOAc 680 mg, containing 1-propylphosphonic anhydride 340 mg, 1.08 mmol), and Et3N (82 mg, 0.81 mmol) were added sequentially and reacted at room temperature under a nitrogen atmosphere for 18 h. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (5 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by prep-HPLC (condition 1) to give a mixture of 13-1a and 13-1b (110 mg, 91.26% yield).

[0106] LCMS m / z=447.1[M+H] + Example 14: Preparation of Compound 14-2a and Compound 14-2b [ka]

[0107] Step 1: Preparation of Compound 14-1a and Compound 14-1b A mixture of 1h-1a and 1h-1b (100 mg, 0.27 mmol) was dissolved in DMF (3 mL), and 14-1-1 (see WO2022121517A1 for preparation method) (91 mg, 0.41 mmol), TCFH (150 mg, 0.53 mmol), and N-methylimidazole (67 mg, 0.82 mmol) were added sequentially. The mixture was reacted at room temperature for 18 h under a nitrogen atmosphere. Water (5 mL) was added to the reaction system to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (10 mL), and the organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a mixture of 14-1a and 14-1b (90 mg, 57.81% yield). LCMS m / z=577.2[M+H] +

[0108] Step 2: Preparation of Compound 14-2a and Compound 14-2b A mixture of Compound 14-1a and Compound 14-1b (40 mg, 0.07 mmol) was added to a solution of 4 M hydrochloric acid in dioxane (2 mL). After completion, the mixture was reacted at room temperature for 18 h under a nitrogen atmosphere. The crude product was concentrated and purified by prep-HPLC (Condition 1) to give a mixture of Compound 14-2a and Compound 14-2b (19.32 mg, 52.19% yield).

[0109] LCMS m / z=537.2[M+H] + Example 15: Preparation of Compound 15-2a and Compound 15-2b [ka]

[0110] Step 1: Preparation of Compound 15-1a and Compound 15-1b A mixture of 1h-1a and 1h-1b (100 mg, 0.27 mmol) was dissolved in EA (3 mL), and tert-butyl 5-aminopyridine-2-carbamate (68 mg, 0.32 mmol), T3P (50% wt in EtOAc 680 mg, containing 1-propylphosphonic anhydride 340 mg, 1.08 mmol), and Et3N (82 mg, 0.81 mmol) were added sequentially. After completion, the reaction was allowed to proceed at room temperature under a nitrogen atmosphere for 18 h. The reaction was quenched by adding water (5 mL) to the reaction system, extracted with ethyl acetate (5 mL × 3), the organic phases were combined and washed with saturated brine (5 mL), the organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by prep-HPLC fractionation (Condition 1) to give a mixture of Compound 15-1a and Compound 15-1b (140 mg, yield 92.34%). LCMS m / z=562.2[M+H] +

[0111] Step 2: Preparation of Compound 15-2a and Compound 15-2b A mixture of Compound 15-1a and Compound 15-1b (100 mg, 0.18 mmol) was added to a solution of 4 M hydrochloric acid in dioxane (2 mL). After completion, the mixture was allowed to react at room temperature for 18 h under a nitrogen atmosphere. The crude product was concentrated and purified by prep-HPLC (Condition 1) to give a mixture of Compound 15-2a and Compound 15-2b (81.11 mg, 97.65% yield).

[0112] LCMS m / z=462.2[M+H] + Example 16: Preparation of Compound 16-1a and Compound 16-1b [ka]

[0113] A mixture of 1h-1a and 1h-1b (100 mg, 0.27 mmol) was dissolved in EA (3 mL). 5-aminopyrimidine (31 mg, 0.32 mmol), T3P (50% wt in EtOAc 680 mg, containing 1-propylphosphonic anhydride 340 mg, 1.08 mmol), and Et3N (82 mg, 0.81 mmol) were added sequentially and reacted at room temperature under a nitrogen atmosphere for 18 h. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (5 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by prep-HPLC (condition 1) to give a mixture of compound 16-1a and compound 16-1b (28.78 mg, 23.82% yield).

[0114] LCMS m / z=448.4[M+H] + Example 17: Preparation of Compound 17-1a and Compound 17-1b [ka]

[0115] The synthesis method was the same as in Example 16, and 5-aminopyrimidine was used as the starting material to obtain a mixture of Compound 17-1a and Compound 17-1b (63.24 mg, yield 52.34%).

[0116] LCMS m / z=448.4[M+H] + Example 18: Preparation of Compound 18-2a and Compound 18-2b [ka]

[0117] Step 1: Preparation of Compound 18-1a and Compound 18-1b The synthesis method was the same as in Example 16, and a mixture of Compound 18-1a and Compound 18-1b (40 mg, yield 48.37%) was obtained. LCMS m / z=591.9[M+H] +

[0118] Step 2: Preparation of Compound 18-2a and Compound 18-2b A mixture of Compound 18-1a and Compound 18-1b (40 mg, 0.068 mmol) was added with methanol (1 mL) and hydrochloric acid (0.3 mL). After completion, the mixture was reacted at room temperature for 18 h under a nitrogen atmosphere. The crude product was concentrated and purified by prep-HPLC (Condition 1) to give a mixture of Compound 18-2a and Compound 18-2b (16 mg, 49.38% yield).

[0119] LCMS m / z=477.1[M+H] + Example 19: Preparation of Compound 19-2a and Compound 19-2b [ka]

[0120] Step 1: Preparation of Compound 19-1a and Compound 19-1b The synthesis method was the same as in Example 5, and a mixture of Compound 19-1a and Compound 19-1b (34 mg, yield 52.24%) was obtained. LCMS m / z=592.2[M+H] +

[0121] Step 2: Preparation of Compound 19-2a and Compound 19-2b Methanol (1 mL) and hydrochloric acid (0.3 mL) were added to a mixture of compound 19-1a and compound 19-1b (34 mg, 0.057 mmol). After completion, the mixture was allowed to react at room temperature for 18 h under a nitrogen atmosphere. The mixture was concentrated to give a crude product, which was then purified by prep-HPLC (condition 1) to give a mixture of compound 19-2a and compound 19-2b (20 mg, yield 73.49%).

[0122] LCMS m / z=478.50[M+H] + Example 20: Preparation of Compound 20-1a and Compound 20-1b [ka]

[0123] The synthesis method was the same as in Example 16, and a mixture of Compound 20-1a and Compound 20-1b (3 mg, yield 4.63%) was obtained.

[0124] LCMS m / z=463.1[M+H] + Example 21: Preparation of Compound 21-1a and Compound 21-1b [ka]

[0125] Step 1: Preparation of Compounds 1e-2a and 1e-2b 1e (51.0 g, 126.86 mmol) was purified by column chromatography to give a mixture of 1e-2a and 1e-2b (17.6 g, 34% yield).

[0126] Step 2: Preparation of compound 21-2 21-1 (350 mg, 1.63 mmol) (see WO2021093820A1 for preparation method), (Bpin)2 (496 mg, 1.96 mmol), potassium acetate (480 mg, 4.89 mmol), and Pd(dppf)Cl2·DCM (119 mg, 0.16 mmol) were added to 1,4-dioxane (10 mL) and reacted at 100 °C for 5 h under a nitrogen atmosphere. The reaction mixture was used directly in the next step.

[0127] Step 3: Preparation of Compounds 21-3a and 21-3b To the reaction mixture from the previous step, 1e-2a and 1e-2b (655 mg, 1.63 mmol), Pd(PPh3)4 (94 mg, 0.08 mmol), potassium phosphate (1.04 g, 4.90 mmol), and water (0.5 mL) were added, and the mixture was reacted at 100 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography to give a mixture of 21-3a and 21-3b (420 mg, 66.34% yield). LCMS m / z=389.2[M+H] +

[0128] Step 4: Preparation of 21-4a and 21-4b A mixture of 21-3a and 21-3b (220 mg, 0.57 mmol) was dissolved in methanol (8 mL), platinum oxide (52 mg) was added, and the mixture was reacted at room temperature for 18 h under a hydrogen gas atmosphere. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated and purified using a silica gel column to give a mixture of 21-4a and 21-4b (88 mg, 39.54% yield).

[0129] Step 5: Preparation of 21-5a and 21-5b A mixture of 21-4a and 21-4b (50 mg, 0.13 mmol) was dissolved in absolute ethanol (3 mL), and cesium carbonate (64 mg, 0.2 mmol) was added. The mixture was allowed to react at 50° C. for 3 h. The reaction mixture was cooled to room temperature, quenched by addition of 1 M hydrochloric acid (5 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated and purified by silica gel column separation to give a mixture of 21-5a and 21-5b (40 mg, 84.91% yield). LCMS m / z=361.1[MH] -

[0130] Step 6: Preparation of 21-6a and 21-6b A mixture of 21-5a and 21-5b (40 mg, 0.11 mmol) was dissolved in ethyl acetate (3 mL). Triethylamine (33 mg, 0.33 mmol), T3P (50% wt in EtOAc 280 mg, containing 1-propylphosphonic anhydride 140 mg, 0.44 mmol), and methyl 4-aminopyridine-2-carboxylate (40 mg, 0.11 mmol) were added sequentially and the mixture was allowed to react at room temperature for 18 h under a nitrogen atmosphere. The reaction was quenched by the addition of aqueous sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give a mixture of 21-6a and 21-6b (8 mg, 14.65% yield). LCMS m / z=497.6[M+H] +

[0131] Step 7: Preparation of Compound 21-7a and Compound 21-7b A mixture of 21-6a and 21-6b (8 mg, 0.039 mmol) was dissolved in 7 M ammonia methanol solution (1 mL) and reacted at room temperature for 18 h. The reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography to give a mixture of 21-7a and 21-7b (1 mg, 13.01% yield). LCMS m / z=482.2[M+H] +

[0132] A mixture of 110 mg of compound 21-7a and compound 21-7b was used as a starting material and subjected to chiral resolution to obtain compound 21-7P1 (38.3 mg, retention time: 1.576 min) and compound 21-7P2 (38 mg, retention time: 1.723 min).

[0133] Compound 21-7P1 is one of the above 21-7a and 21-7b, and is an enantiomer of compound 21-7P2. That is, when the structure of compound 21-7P1 is that of formula 21-7a, the structure of compound 21-7P2 is that of formula 21-7b, and when the structure of compound 21-7P1 is that of formula 21-7b, the structure of compound 21-7P2 is that of formula 21-7a.

[0134] SFC preparative conditions: Instrument: Waters 150 Prep-SFC C, Preparative column: Chiral IC column. Preparation method: The crude material was dissolved in acetonitrile to prepare a 10 mg / ml sample solution. Mobile phase: Carbon dioxide / 0.1% NH₃·H₂O methanol solution, methanol content 15%, Elution time: 15 min.

[0135] Chiral test method: (Instrument: SHIMADZU LC-30 AD sf, Preparative column: Chiral IC column. Preparation method: The crude product was dissolved in acetonitrile to prepare the sample solution. Mobile phase system: carbon dioxide / 0.05% DEA in methanol. Elution gradient: 5% to 40%, flow rate: 3.0 mL / min, elution time: 3 min).

[0136] Example 22: Preparation of Compound 22-1a and Compound 22-1b [ka]

[0137] A mixture of 1h-2a and 1h-2b (50 mg, 0.135 mmol) was dissolved in ethyl acetate (3 mL), triethylamine (42 mg, 0.42 mmol) and T3P (50% wt in EtOAc 350 mg, containing 1-propylphosphonic anhydride 175 mg, 0.55 mmol) were added sequentially, followed by 22-1a-1 (34 mg, 0.20 mmol). The mixture was then reacted at room temperature for 18 h under a nitrogen atmosphere. The reaction was quenched with aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give a mixture of 22-1a and 22-1b (42 mg, 59% yield).

[0138] LCMS m / z=524.0[M+H] + , 1 H NMR (400MHz,CDCl3) δ 8.44 (s,1H),8.02 (d,1H),7.95 (t,1H),7.67 (d,1H),7.52 (t,1H),7.04 - 6.95 (m,1H),6.89 - 6.80 (m,1H),4.63 (d,1H),4.56 - 4.45 (m,1H),4.05 (t,3H),3.10 (s,3H),2.72 - 2.56 (m,1H) ,1.93 (s,3H) ,0.94 - 0.80 (m,3H). Example 23: Preparation of Compounds 23-8a and 23-8b [ka]

[0139] Step 1: Preparation of compound 23-2 23-1 (7.9 g, 50.0 mmol), vinylboronic acid pinacol ester (8.47 g, 55.0 mmol), potassium carbonate (13.8 g, 100.0 mmol), and Pd(dppf)Cl₂·DCM (0.51 g, 0.75 mmol) were added to a mixture of 1,4-dioxane (120 mL) and water (30 mL) and reacted at 100 °C for 4 h under a nitrogen atmosphere. After cooling to room temperature, ethyl acetate (200 mL) was added and the mixture was washed with saturated brine (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give 23-2 (4.6 g, 61% yield). LCMS m / z=151.0[M+H] +

[0140] Step 2: Preparation of compound 23-3 23-2 (4.6 g, 30.66 mmol), silver benzoate (21.0 g, 91.98 mmol), and iodine (12.4 g, 49.05 mmol) were added to toluene (150 mL) and refluxed under nitrogen for 20 h. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give 23-3 (5.88 g, 49% yield). LCMS m / z=393.1[M+H] +

[0141] Step 3: Preparation of compound 23-4 23-3 (5.88 g, 15.0 mmol) and lithium hydroxide monohydrate (2.52 g, 60.0 mmol) were added to a mixture of tetrahydrofuran (80 mL) and water (20 mL) and reacted at room temperature for 3 h. The reaction mixture was extracted with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated, separated, and purified using a silica gel column to give 23-4 (117 mg, 4% yield). LCMS m / z=185.1[M+H] +

[0142] Step 4: Preparation of compound 23-5 23-4 (117 mg, 0.635 mmol), 2,2-dimethoxypropane (198 mg, 1.9 mmol), and p-toluenesulfonic acid monohydrate (18 mg, 0.095 mmol) were added to tetrahydrofuran (5 mL) and reacted at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, then purified by silica gel column chromatography to give 23-5 (110 mg, 76% yield).

[0143] Step 5: Preparation of compound 23-6 23-5 (110 mg, 0.486 mmol) and palladium carbon (10%) (22 mg) were added to ethyl acetate (3 mL) and ethanol (3 mL) and reacted under hydrogen gas at room temperature for 16 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The filtrate was then purified using a silica gel column to give 23-6 (89 mg, 94% yield). LCMS m / z=195.1[M+H] +

[0144] Step 6: Preparation of 23-7a and 23-7b A mixture of 1h-2a and 1h-2b (50 mg, 0.135 mmol) was dissolved in ethyl acetate (3 mL). Triethylamine (42 mg, 0.42 mmol), T3P (50% wt in EtOAc 350 mg, containing 1-propylphosphonic anhydride 175 mg, 0.55 mmol), and 23-6 (40 mg, 0.20 mmol) were added sequentially and reacted at room temperature under a nitrogen atmosphere for 18 h. The reaction was quenched by the addition of aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give a mixture of 23-7a and 23-7b (68 mg, 92% yield). LCMS m / z=547.1[M+H] +

[0145] Step 7: Preparation of Compound 23-8a and Compound 23-8b A mixture of 23-7a and 23-7b (68 mg, 0.124 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was allowed to react at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and then purified by preparative HPLC (condition 1) to give the trifluoroacetate salt of the mixture of compounds 23-8a and 23-8b (40 mg, 52% yield).

[0146] LCMS m / z=507.1[M+H] + , Example 24: Preparation of Compounds 24-9a and 24-9b [ka]

[0147] Step 1: Preparation of compound 24-2 24-1 (4.0 g, 15.6 mmol), 3-bromo-2-methylpropene (2.53 g, 18.74 mmol), and potassium carbonate (4.3 g, 31.2 mmol) were added to acetonitrile (60 mL) and reacted at 60 °C for 12 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and purified by column chromatography to give 24-2 (4.8 g, 99% yield).

[0148] Step 2: Preparation of compound 24-3 24-2 (4.8 g, 15.4 mmol) was added to dichloromethane (150 mL), placed in an ice bath, and aluminum trichloride (107 mg, 0.8 mmol) was added. The reaction was continued in the ice bath for 1 h. The reaction mixture was quenched by adding it to ice-cold aqueous sodium bicarbonate solution, extracted with ethyl acetate (200 mL), and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified using a silica gel column to give 24-3 (4.0 g, 83% yield).

[0149] Step 3: Preparation of compound 24-4 24-3 (2.02 g, 6.51 mmol), (Bpin)2 (CAS: 73183-34-3) (2.15 g, 8.46 mmol), potassium acetate (1.28 g, 13.0 mmol), and Pd(dppf)Cl2·DCM (265 mg, 0.32 mmol) were added to 1,4-dioxane (40 mL) and reacted at 100 °C for 5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and then purified using a silica gel column to give 24-4 (660 mg, 30% yield).

[0150] Step 4: Preparation of Compounds 24-5a and 24-5b 24-4 (286 mg, 0.8 mmol), 1e-2a and 1e-2b (300 mg, 0.746 mmol), Pd(PPh3)4 (43 mg, 0.04 mmol), and potassium phosphate (474 ​​mg, 2.4 mmol) were added to toluene (9 mL) and water (3 mL) and reacted at 100 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography to give a mixture of 24-5a and 24-5b (300 mg, 77% yield).

[0151] Step 5: Preparation of 24-6a and 24-6b A mixture of 24-5a and 24-5b (300 mg, 0.62 mmol) was dissolved in methanol (30 mL), palladium carbon (10%) (100 mg) was added, and the mixture was reacted under a hydrogen gas atmosphere at 2.5 MPa and 90°C for 70 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated and then purified using a silica gel column to give a mixture of 24-6a and 24-6b (180 mg, 60% yield).

[0152] Step 6: Fabrication of 24-7a and 24-7b A mixture of 24-6a and 24-6b (130 mg, 0.267 mmol) was dissolved in absolute ethanol (5 mL), and cesium carbonate (160 mg, 0.4 mmol) was added. The mixture was allowed to react at 50° C. for 3 h. The reaction mixture was cooled to room temperature, quenched by addition of 1 M hydrochloric acid (5 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then purified by silica gel column chromatography to give a mixture of 24-7a and 24-7b (120 mg, 98% yield). LCMS m / z=457.0[M−H] -

[0153] Step 7: Preparation of 24-8a and 24-8b A mixture of 24-7a and 24-7b (46 mg, 0.1 mmol) was dissolved in ethyl acetate (2 mL). Triethylamine (42 mg, 0.42 mmol), T3P (50% wt in EtOAc 350 mg, containing 1-propylphosphonic anhydride 175 mg, 0.55 mmol), and 1h-2 (40 mg, 0.20 mmol) were added sequentially and reacted at room temperature under a nitrogen atmosphere for 18 h. The reaction was quenched by the addition of aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give a mixture of 24-8a and 24-8b (23 mg, 39% yield). LCMS m / z=593.1[M+H] +

[0154] Step 8: Preparation of Compound 24-9a and Compound 24-9b A mixture of 24-8a and 24-8b (23 mg, 0.039 mmol) was dissolved in 7 M ammonia in methanol (3 mL) and reacted at room temperature for 18 h. The reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography to give a mixture of compounds 24-9a and 24-9b (14 mg, 62% yield).

[0155] LCMS m / z=578.1[M+H]+ 1 H NMR (400MHz,CDCl3) δ 9.82(s,1H),8.46 (d,1H),8.39 - 8.27 (m,1H),8.16 (d,1H),8.00 (d,1H),7.06 (d,1H),6.68 (d,1H),5.88 (d,1H),5.09 (d,1H),4.43 - 4.29 (m,1H),3.02 (s,2H),2.83 - 2.70 (m,1H),1.90 (s,3H),1.48 (s,3H),1.42 (s,3H),1.00 - 0.90 (m,3H). Example 25: Preparation of Compound 25-1a and Compound 25-1b [ka]

[0156] A mixture of 1h-1a and 1h-1b (50 mg, 0.14 mmol) was dissolved in EA (1.5 mL). 2-(methylsulfonyl)pyridin-4-amine (45 mg, 0.26 mmol), T3P (50% wt in EtOAc 340 mg, containing 1-propylphosphonic anhydride 170 mg, 0.54 mmol), and Et3N (82 mg, 0.81 mmol) were added sequentially and reacted at room temperature under a nitrogen atmosphere for 18 h. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (5 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by prep-HPLC (Condition 1) to give a mixture of compound 25-1a and compound 25-1b (7.23 mg, 18.62% yield).

[0157] LCMS m / z=525.60[M+H] + Example 26: Preparation of Compound 26-1a and Compound 26-1b [ka]

[0158] A mixture of 1h-1a and 1h-1b (50 mg, 0.13 mmol) was dissolved in ethyl acetate (1.5 mL), and 4-fluoro-3-(methylsulfonyl)aniline (51 mg, 0.26 mmol), T3P (50% wt in EtOAc 340 mg, containing 1-propylphosphonic anhydride 170 mg, 0.54 mmol), and Et3N (82 mg, 0.81 mmol) were added sequentially. The reaction was allowed to proceed under a nitrogen atmosphere at room temperature for 18 h. The reaction was quenched by adding water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (5 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by prep-HPLC (condition 1) to give a mixture of compound 26-1a and compound 26-1b (37.21 mg, 33.95% yield).

[0159] LCMS m / z=542.60[M+H] + 1 H NMR (400MHz,CDCl3) δ 8.84 (s,1H),8.42 - 8.30 (m,1H),7.82 - 7.73 (m,1H),7.21 (t,1H),6.99 - 6.90 (m,1H),6.87 - 6.76 (m,1H),4.70 (d,1H),4.61 - 4.52 (m,1H),4.05 (d,3H),3.34 (s,3H),2.67 - 2.58 (m,1H),1.92 (s,3H),0.95 - 0.85 (m,3H). Example 27: Preparation of Compound 27-1a and Compound 27-1b [ka]

[0160] A mixture of 1h-2a and 1h-2b (0.052 g, 0.14 mmol) was dissolved in ethyl acetate (3 mL), triethylamine (0.085 g, 0.84 mmol) and T3P (50% wt in EtOAc 0.36 g, containing 1-propylphosphonic anhydride 0.18 g, 0.56 mmol) were added sequentially, and 27-1a-1 (0.040 g, 0.21 mmol) was added to the mixture and reacted at room temperature for 18 h under a nitrogen atmosphere. The reaction was quenched by adding aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by prep-HPLC (condition 1) to give the trifluoroacetate salt of the mixture of 27-1a and 27-1b.

[0161] LCMS m / z=541.1[M+H] + 1 H NMR (400MHz,DMSO-d6) δ 10.72 (s,1H),8.17 - 8.09 (m,1H),7.81 - 7.72 (m,1H),7.37 (t,1H),7.22 - 7.14 (m,1H),7.11 - 7.04 (m,1H),4.83 (d,1H),4.53 - 4.45 (m,1H),4.00 (d,3H),3.19 (s,3H),2.65 - 2.57 (m,1H),1.85 (s,3H),0.83 - 0.74 (m,3H). Example 28: Preparation of Compound 28-2a and Compound 28-2b [ka]

[0162] Step 1: Preparation of Compounds 28-1a and 28-1b A mixture of 1h-2a and 1h-2b (0.052 g, 0.14 mmol) was dissolved in ethyl acetate (3 mL), triethylamine (0.085 g, 0.84 mmol) and T3P (50% wt in EtOAc 0.36 g, containing 1-propylphosphonic anhydride 0.18 g, 0.56 mmol) were added sequentially, followed by 28-1a-1 (0.032 g, 0.21 mmol). The mixture was then reacted at room temperature for 18 h under a nitrogen atmosphere. The reaction was quenched with aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give a mixture of 28-1a and 28-1b (0.06 g, 85.12% yield). LCMS m / z=504.1[M+H] +

[0163] Step 2: Preparation of Compounds 28-2a and 28-2b A mixture of 28-1a and 28-1b (0.06 g, 0.12 mmol) was dissolved in 7 M ammonia methanol solution (5 mL), heated to 40 °C in a sealed tube, and reacted for 18 h. The reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography to give a mixture of 28-2a and 28-2b (0.02 g, 34.12% yield).

[0164] LCMS m / z=489.3[M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 10.46 (s,1H),7.99 (t,1H),7.90 (s,1H),7.66 - 7.61 (m,1H),7.56 - 7.51 (m,1H),7.39 - 7.27 (m,2H),7.23 - 7.06 (m,2H),4.87 (d,1H),4.53 - 4.45 (m,1H),4.00 (d,3H),2.65 - 2.56 (m,1H),1.86 (s,3H),0.82 - 0.75 (m,3H). Example 29: Preparation of Compound 29-1a and Compound 29-1b [ka]

[0165] Step 1: Preparation of compound 29b 29a (3.28 g, 15.0 mmol) was dissolved in methanol (50 mL), and triethylamine (1.52 g, 14.99 mmol) and (Boc)O (6.48 g, 29.98 mmol) were added sequentially. The mixture was reacted at 50 °C for 18 h. The reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography to give 29b (4.47 g, 93.38% yield). LCMS m / z=264.0[M-55] +

[0166] Step 2: Preparation of compound 29c 29b (4.46 g, 13.96 mmol) was dissolved in DMSO (50 mL), and 29b-1 (7.08 g, 34.90 mmol) and copper powder (2.22 g, 34.90 mmol) were added sequentially. The mixture was then reacted at 80 °C under a nitrogen atmosphere for 18 h. The reaction was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (10 mL × 3). The filtrate was quenched with water (500 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (200 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product. The crude product was purified by silica gel column chromatography to give 29c (3.3 g, 74.97% yield).

[0167] Step 3: Preparation of compound 29d 29c (0.50 g, 1.6 mmol) was dissolved in ethyl acetate (10 mL), p-toluenesulfonic acid (0.69 g, 4.0 mmol) was added, and the mixture was reacted at 45 °C for 18 h under a nitrogen atmosphere. The reaction mixture was concentrated to give a crude product, which was then dissolved in water (10 mL). Saturated sodium carbonate solution was added dropwise in an ice bath until the pH reached 9–10. The mixture was extracted with dichloromethane:methanol = 10:1 (15 mL × 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 29d (0.32 g, 92.94% yield). LCMS m / z=216.1[M+1] +

[0168] Step 4: Preparation of Compounds 29e-1a and 29e-1b A mixture of 1h-2a and 1h-2b (0.052 g, 0.14 mmol) was dissolved in ethyl acetate (3 mL), triethylamine (0.085 g, 0.84 mmol) and T3P (50% wt in EtOAc 0.36 g, 1-propylphosphonic anhydride 0.18 g, 0.56 mmol) were added sequentially, followed by 29d (0.045 g, 0.21 mmol). The mixture was then reacted at room temperature for 18 h under a nitrogen atmosphere. The reaction was quenched with aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give a mixture of 29e-1a and 29e-1b (0.048 g, 60.41% yield).

[0169] Step 5: Preparation of Compounds 29-1a and 29-1b A mixture of 29e-1a and 29e-1b (0.048 g, 0.084 mmol) was dissolved in methanol (3 mL) and pre-cooled in an ice bath for 10 min. Sodium borohydride (0.0032 g, 0.084 mmol) was added and the mixture was allowed to react in an ice bath for 2 h. Water (10 mL) was added to the reaction mixture in an ice bath to quench the reaction, followed by extraction with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sulfuric acid, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give a mixture of 29-1a and 29-1b (0.02 g, 45.31% yield).

[0170] LCMS m / z=524.1[M+H] - , 1 H NMR (400MHz,DMSO-d6) δ 10.52 (s,1H),7.60 (d,2H),7.43 (d,2H),7.22 - 7.13 (m,1H),7.11 - 7.05 (m,1H),5.52 (t,1H),4.87 (d,1H),4.52 - 4.44 (m,1H),3.99 (d,3H),3.84 - 3.73 (m,2H),2.65 - 2.57 (m,1H),1.85 (s,3H),0.82 - 0.74 (m,3H). Example 30: Preparation of Compound 30 [ka]

[0171] Step 1: Preparation of Compound 30b 30a (0.88 g, 6.28 mmol) was dissolved in tetrahydrofuran (15 mL) under ice bath conditions, and LiHMDS (2.53 g, 13.82 mmol) was added dropwise. Di-tert-butyl dicarbonate (1.51 g, 6.91 mmol) was dissolved in tetrahydrofuran (5 mL). The mixture was slowly added dropwise and allowed to warm to room temperature under a nitrogen atmosphere for 18 h. The reaction was quenched by adding saturated aqueous ammonium chloride (30 mL) under ice bath conditions, followed by extraction with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product 30b (1.4 g, 92.76% yield).

[0172] Step 2: Preparation of Compound 30c 30b (1.41 g, 5.87 mmol) was dissolved in methanol (10 mL), and ammonium carbamate (1.83 g, 23.48 mmol) and iodobenzene acetate (5.67 g, 17.61 mmol) were added sequentially. The mixture was allowed to react at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 30c (1.14 g, 71.57% yield).

[0173] Step 3: Preparation of Compound 30d 30c (0.054 g, 0.2 mmol) was dissolved in dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was reacted at room temperature for 2 h. The solvent was removed by concentration under reduced pressure to give crude product 30d. LCMS m / z=172.1[M+1] +

[0174] Step 4: Preparation of Compound 30 1h-2a (0.037 g, 0.1 mmol) was dissolved in ethyl acetate (3 mL), triethylamine (0.061 g, 0.60 mmol) and T3P (50% wt in EtOAc 0.25 g, containing 1-propylphosphonic anhydride 0.125 g, 0.40 mmol) were added sequentially, followed by 30d (0.026 g, 0.15 mmol). The reaction mixture was stirred at room temperature for 18 h under a nitrogen atmosphere. Aqueous sodium bicarbonate (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by prep-HPLC (condition 1) and then lyophilized to give compound 30 (0.003 g, 5.73% yield).

[0175] LCMS m / z=524.1[M+H] + , Example 31: Preparation of Compound 31-1a and Compound 31-1b [ka]

[0176] Step 1: Preparation of Compound 31b In an ice bath, 31a-1 (29.14 g, 130 mmol) was dissolved in tetrahydrofuran (100 mL), sodium hydride (5.2 g, 130 mmol) was added portionwise, and the mixture was allowed to react for 30 min under a nitrogen atmosphere and ice bath. A solution of 1a (11.20 g, 100 mmol) in tetrahydrofuran (20 mL) was added dropwise, and the mixture was allowed to warm to room temperature under a nitrogen atmosphere and react for 18 h. In an ice bath, 1N hydrochloric acid was slowly added dropwise to the reaction mixture until the pH reached 7-8. The mixture was extracted with ether (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated at room temperature to obtain crude product 31b (9.5 g, 52.16% yield). The crude product was purified by silica gel column chromatography to obtain 31b (9.5 g, 52.16% yield).

[0177] Step 2: Preparation of compound 31c In an ice bath, 31b (4.8 g, 26.37 mmol) was added to a round-bottom flask, piperidine (0.45 g, 5.27 mmol) was added dropwise, and 31b-1 (2.80 g, 26.37 mmol) was added dropwise. The mixture was then reacted at 30 °C for 48 h under nitrogen gas protection. The reaction was quenched by adding 0.1 N hydrochloric acid (50 mL) to the reaction mixture in an ice bath, and the mixture was extracted with ether (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated (25 °C) to give the crude product 31c (2.57 g, 33.81% yield). LCMS m / z=289.1[M+H] +

[0178] Step 3: Preparation of compound 31d Under a nitrogen atmosphere, 31c (2.57 g, 8.91 mmol) was dissolved in ether (30 mL) and pre-cooled in an ice bath for 10 min. A 1 M solution of potassium tert-butoxide in tetrahydrofuran (1.43 mL) was slowly added dropwise, and the reaction was continued in an ice bath for 2 h. The reaction was quenched by slowly adding glacial acetic acid (0.7 mL) and water (30 mL) to the system in an ice bath, followed by extraction with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated aqueous sodium bicarbonate (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 31d.

[0179] Step 4: Preparation of Compound 31e 31d (1.97 g, 8.13 mmol) was dissolved in dry dichloromethane (20 mL) and pre-cooled at −78 °C for 15 min. Under a nitrogen atmosphere, N,N-diisopropylethylamine (1.26 g, 9.76 mmol) and a solution of trifluoromethanesulfonic anhydride (2.29 g, 8.13 mmol) in dichloromethane (5 mL) were added dropwise and the reaction mixture was allowed to react at −78 °C for 2 h. The reaction mixture was quenched by slowly adding saturated aqueous sodium bicarbonate (30 mL) in an ice bath, followed by extraction with dichloromethane (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product. The crude product was purified by silica gel column chromatography to give 31e (0.680 g, 22.35% yield).

[0180] Step 5: Preparation of compound 31f 31e (0.68 g, 1.82 mmol) was dissolved in toluene (15 mL), 1e-1 (0.38 g, 2.00 mmol) and tetrakis(triphenylphosphine)palladium (0.11 g, 0.091 mmol) were added sequentially, and potassium phosphate (1.16 g, 5.46 mmol) was added as a 2 M aqueous solution. After completion, the reaction was carried out at 100 °C for 3 h under a nitrogen atmosphere. The reaction was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (10 mL × 2). The filtrate was layered 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 give crude product. The crude product was purified by silica gel column chromatography to give 31f (0.66 g, 98.46% yield).

[0181] Step 6: Preparation of Compound 31g 31f (0.55 g, 1.49 mmol) was dissolved in ethanol (15 mL), platinum dioxide (0.12 g, 0.51 mmol) was added, and the mixture was reacted under a hydrogen gas atmosphere at 25 °C for 18 h. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (5 mL × 2). The filtrate was collected and concentrated to give a crude product, which was purified by silica gel column chromatography to give 31g (0.53 g, yield 96.05%).

[0182] Step 7: Preparation of compound 31h 31g (0.53g, 1.43mmol) was dissolved in ethanol (15mL), cesium carbonate (0.70g, 2.15mmol) was added, and the mixture was reacted at 50°C for 2 hours. The reaction mixture was concentrated to give a crude product, which was then dissolved in water (15mL), adjusted to pH 1-2 with 1N hydrochloric acid, and extracted with ethyl acetate (20mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product 31h. LCMS m / z=355.3[MH] -

[0183] Step 8: Preparation of Compounds 31i-1a and 31i-1b 31h (0.51 g, 1.43 mmol) was dissolved in ethyl acetate (15 mL), triethylamine (0.87 g, 8.59 mmol) and T3P (50% wt in EtOAc 3.64 g, 1-propylphosphonic anhydride 1.82 g, 5.72 mmol) were added sequentially, followed by 1h-2 (0.33 g, 2.15 mmol). The reaction mixture was stirred at room temperature for 18 h under a nitrogen atmosphere. Aqueous sodium bicarbonate (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give a mixture of 31i-1a and 31i-1b (0.34 g, 48.43% yield). LCMS m / z=491.1[M+H] +

[0184] Step 9: Preparation of Compound 31-1a and Compound 31-1b A mixture of 31i-1a and 31i-1b (0.34 g, 0.70 mmol) was dissolved in 7 M ammonia in methanol (10 mL) and reacted at room temperature for 18 h. The reaction mixture was concentrated to give a crude product, which was purified by prep-HPLC (neutral fractionation) and lyophilized to give a mixture of compound 31-1a and compound 31-1b (0.21 g, 63.10% yield).

[0185] LCMS m / z=476.1[M+H] + , 1 H NMR(400MHz,CDCl3):δ 9.84 (s,1H),8.45 (d,1H),8.36 - 8.29 (m,1H),8.13 (d,1H),8.08 - 7.96 (m,1H),7.05 - 6.96 (m,1H),6.89 - 6.78 (m,1H),6.07 - 5.95 (m,1H),4.74 (d,1H),4.38 - 4.25 (m,1H),4.06 (d,3H),2.60 (t,1H),2.33 - 2.22 (m,1H),1.79 (s,3H).

[0186] A mixture of compounds 31-1a and 31-1b (0.21 g) was purified by SFC preparative separation and lyophilized to give compounds 31-1P1 (86.0 mg, retention time: 5.345 min) and 31-1P2 (90.0 mg, retention time: 7.364 min). Chiral analysis method: (instrument: Shimadzu LC-20AT, chiral column: Daicel AD-H. Preparation method: The crude product was dissolved in acetonitrile to prepare the sample solution. Mobile phase: n-hexane / ethanol, ethanol content 20%, flow rate: 1.0 mL / min, elution time: 30 min).

[0187] SFC preparative conditions: Instrument: SFC Prep 150 AP, Preparative column: Daicel IC-H (19 mm x 250 mm). Preparation method: The crude material was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. Mobile phase: carbon dioxide / methanol:isopropanol (1:1), methanol:isopropanol (1:1) content 18%, flow rate: 35 mL / min.

[0188] The structure of compound 31-1P1 is one of the above formulas 31-1a and 31-1b, and is an enantiomer of compound 31-1P2. That is, when the structure of compound 31-1P1 is that of formula 31-1a, the structure of compound 31-1P2 is that of formula 31-1b, and when the structure of compound 31-1P1 is that of formula 31-1b, the structure of compound 31-1P2 is that of formula 31-1a.

[0189] Example 32: Preparation of Compound 32-1a and Compound 32-1b [ka]

[0190] A mixture of 31h (0.18 g, 0.5 mmol) was dissolved in ethyl acetate (15 mL), triethylamine (0.30 g, 3 mmol) and T3P (50% wt in EtOAc 1.28 g, containing 1-propylphosphonic anhydride 0.64 g, 2 mmol) were added sequentially, followed by 32a-1 (0.10 g, 0.75 mmol). The mixture was allowed to react at room temperature for 18 h under a nitrogen atmosphere. The reaction was quenched by the addition of aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give 120 mg of a mixture of compounds 32-1a and 32-1b.

[0191] LCMS m / z=475.1[M+H] + 1H NMR(400MHz,CDCl3):δ 8.46 (s,1H),7.99 - 7.94 (m,1H),7.93 - 7.87 (m,1H),7.51 - 7.45 (m,1H),7.38 (t,1H),7.04 - 6.96 (m,1H),6.90 - 6.80 (m,1H),6.36 - 5.53 (m,2H),4.52 (d,1H),4.27 - 4.14 (m,1H),4.00 (d,3H),2.59 (t,1H),2.29 - 2.20 (m,1H),1.81 (s,3H).

[0192] A mixture of 120 mg of compounds 32-1a and 32-1b was purified by SFC preparative separation and lyophilized to give compounds 32-1P1 (48 mg, retention time: 5.732 min) and 32-1P2 (50 mg, retention time: 5.168 min). Chiral analysis method: (instrument: Shimadzu LC-20AT, chiral column: Daicel AD-H. Preparation method: The crude product was dissolved in acetonitrile to prepare the sample solution. Mobile phase: n-hexane / ethanol, ethanol content 20%, flow rate: 1.0 mL / min, elution time: 30 min).

[0193] SFC preparative conditions: Instrument: SFC Prep 150 AP, Preparative column: Daicel IC-H (19 mm x 250 mm). Preparation method: The crude material was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. Mobile phase: carbon dioxide / methanol:isopropanol (9:1), methanol:isopropanol (9:1) content 20%, flow rate: 40 mL / min.

[0194] The structure of compound 32-1P1 is one of the above formulas 32-1a and 32-1b, and is an enantiomer of compound 32-1P2. That is, when the structure of compound 32-1P1 is that of formula 32-1a, the structure of compound 32-1P2 is that of formula 32-1b, and when the structure of compound 32-1P1 is that of formula 32-1b, the structure of compound 32-1P2 is that of formula 32-1a.

[0195] Example 33: Preparation of Compound 33-1a and Compound 33-1b [ka]

[0196] Step 1: Preparation of Compound 33-1a and Compound 33-1b A mixture of 1h-2a and 1h-2b (0.05 g, 0.13 mmol) was dissolved in oxalyl chloride (1 mL), and DMF (0.002 g, 0.028 mmol) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 2 h. After concentration, the crude product was added to a solution of 33-1a-1 (see WO 2022121517A1 for preparation method) (0.044 g, 0.20 mmol) and triethylamine (0.039 g, 0.39 mmol) in dichloromethane (1 mL) and allowed to react overnight at room temperature. The mixture was concentrated to give a crude product, which was purified by silica gel column chromatography to give a mixture of 33a-1a and 33a-1b (0.036 g, 48.03% yield).

[0197] Step 2: Preparation of Compound 33-1a and Compound 33-1b A mixture of 33a-1a and 33a-1b (0.036 g, 0.062 mmol) was added to a 4 M solution of hydrochloric acid in dioxane (1 mL), and the mixture was reacted at room temperature for 18 h under a nitrogen atmosphere. The mixture was concentrated to give a crude product, which was then purified by prep-HPLC (condition 1) to give a mixture of compounds 33-1a and 33-1b (0.01 g, 30.06% yield).

[0198] LCMS m / z=537.5[M+H] + Example 34: Preparation of Compound 34-1a and Compound 34-1b [ka]

[0199] Step 1: Preparation of compound 34a 1e (0.5 g, 1.29 mmol) was dissolved in toluene (5 mL), 34-1a-1 (0.24 g, 1.42 mmol) and Pd(PPh3)4 (0.075 g, 0.065 mmol) were added sequentially, and potassium phosphate (0.82 g, 3.87 mmol) was added to the system as a 2 M aqueous solution. The reaction was then heated at 100 °C under a nitrogen atmosphere for 6 h. The reaction was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (10 mL × 2). The filtrate was layered and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product. The crude product was purified by silica gel column chromatography to give 34a (0.45 g, 91.72% yield).

[0200] Step 2: Preparation of Compounds 34b-1a and 34b-1b 34a (0.45 g, 1.24 mmol) was dissolved in methanol (5 mL), palladium carbon (0.3 g, 0.29 mmol) was added, and the mixture was pressurized to 2.5 MPa under a hydrogen gas atmosphere and reacted at 90 °C for 72 h. The reaction mixture 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 34b-1a and 34b-1b (0.26 g, 57.55% yield).

[0201] Step 3: Preparation of Compounds 34c-1a and 34c-1b A mixture of 34b-1a and 34b-1b (0.25 g, 0.69 mmol) was dissolved in ethanol (3 mL), and cesium carbonate (0.34 g, 1.03 mmol) was added. The mixture was allowed to react at 50° C. for 4 h. 1N hydrochloric acid was slowly added dropwise to the mixture in an ice bath until the pH reached 1. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude mixture of 34c-1a and 34c-1b.

[0202] Step 4: Preparation of Compounds 34d-1a and 34d-1b A mixture of 34c-1a and 34c-1b (0.1 g, 0.28 mmol) was dissolved in dichloromethane (1 mL). Oxalyl chloride (0.36 g, 2.80 mmol) was slowly added dropwise in an ice bath, followed by DMF (0.002 g, 0.028 mmol). The mixture was allowed to react at room temperature for 2 h. After concentration, the crude product was added to a solution of 1h-2 (0.062 g, 0.41 mmol) and triethylamine (0.082 g, 0.81 mmol) in dichloromethane (1 mL) and the mixture was allowed to react overnight at room temperature. The mixture was concentrated to give the crude product, which was purified by silica gel column chromatography to give a mixture of 34d-1a and 34d-1b (0.078 g, 59.38% yield).

[0203] Step 5: Preparation of Compound 34-1a and Compound 34-1b A mixture of 34d-1a and 34d-1b (0.078 g, 0.16 mmol) was dissolved in 7 M ammonia in methanol (5 mL) and reacted at room temperature for 18 h. The reaction mixture was concentrated to give a crude product, which was purified by prep-HPLC (condition 1) and lyophilized to give a mixture of compounds 34-1a and 34-1b (0.034 g, 45.07% yield).

[0204] LCMS m / z=472.1[M+H] + 1 H NMR(400MHz,CDCl3):δ 9.60 (s,1H),8.45 (d,1H),8.30 (d,1H),8.11 (s,1H),8.06 (s,1H),7.25 - 7.18 (m,1H),6.62 (ddd,2H),5.88 (s,1H),4.87 (d,1H),4.55 (dd,1H),3.85 (s,3H),2.76 (q,1H),1.93 (s,3H),0.86 (dd,J=6.9,2.3 Hz,3H). Example 35: Preparation of Compound 35-8a and Compound 35-8b [ka]

[0205] Step 1: Preparation of compound 35-2 35-1 (2 g, 9.57 mmol) was dissolved in DMF (40 mL), and NaH (574 mg, 14.36 mmol) was added in an ice bath. The reaction was continued for 30 min. Deuterated iodomethane (2.77 g, 19.14 mmol) was added, and the reaction was continued at room temperature for 5 h under a nitrogen atmosphere. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a silica gel column to give 35-2 (1.1 g, 50.85% yield).

[0206] Step 2: Preparation of compound 35-3 35-1 (400 mg, 1.77 mmol), (Bpin)2 (539.4 mg, 2.12 mmol), potassium acetate (521.1 mg, 5.31 mmol), and Pd(dppf)Cl2·DCM (114.6 mg, 0.18 mmol) were added to 1,4-dioxane (10 mL) and reacted at 100 °C for 5 h under a nitrogen atmosphere to obtain reaction solution 35-3.

[0207] Step 3: Preparation of Compounds 35-4a and 35-4b To the reaction mixture of 35-3 from the previous step, 1e-2a and 1e-2b (713 mg, 1.77 mmol), Pd(PPh3)4 (102.3 mg, 0.09 mmol), potassium phosphate (1.13 g, 5.33 mmol), and water (1 mL) were added and reacted at 100 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography to give a mixture of 35-4a and 35-4b (500 mg, 70.73% yield). LCMS m / z=400.1[M+H] +

[0208] Step 4: Preparation of Compounds 35-5a and 35-5b A mixture of 35-4a and 35-4b (300 mg, 0.75 mmol) was dissolved in methanol (8 mL), platinum oxide (52 mg) was added, and the mixture was reacted at room temperature for 18 h under a hydrogen atmosphere. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated and purified using a silica gel column to give a mixture of 35-5a and 35-5b (80 mg, 26.57% yield).

[0209] Step 5: Preparation of Compounds 35-6a and 35-6b A mixture of 35-5a and 35-5b (80 mg, 0.20 mmol) was dissolved in absolute ethanol (3 mL), and cesium carbonate (98 mg, 0.3 mmol) was added. The mixture was allowed to react at 50° C. for 3 h. The reaction mixture was cooled to room temperature, quenched by addition of 1 M hydrochloric acid (5 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography to give a mixture of 35-6a and 35-6b (69 mg, 92.41% yield). LCMS m / z=372.3[MH] -

[0210] Step 6: Preparation of Compounds 35-7a and 35-7b A mixture of 35-6a and 35-6b (50 mg, 0.13 mmol) was dissolved in a 2 M solution of oxalyl chloride in dichloromethane (2 mL), and DMF (0.002 g, 0.028 mmol) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 2 h. After concentration, the crude product was added to a solution of methyl 4-aminopyridine-2-carboxylate (30 mg, 0.20 mmol) and triethylamine (39 mg, 0.39 mmol) in dichloromethane (2 mL) and allowed to react overnight at room temperature. The mixture was concentrated to give the crude product, which was purified by silica gel column chromatography to give a mixture of 35-7a and 35-7b (15 mg, 22.74% yield). LCMS m / z=508.3[M+H] +

[0211] Step 7: Preparation of Compounds 35-8a and 35-8b A mixture of 35-7a and 35-7b (15 mg, 0.03 mmol) was dissolved in 7 M ammonia in methanol (1 mL) and reacted at room temperature for 18 h. The reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography to give a mixture of compounds 35-8a and 35-8b (5.64 mg, 38.17% yield).

[0212] LCMS m / z=493.4[M+H] + Example 36: Preparation of Compound 36-1a and Compound 36-1b [ka]

[0213] Step 1: Preparation of Compounds 36-1a and 36-1b A mixture of 1h-2a and 1h-2b (50 mg, 0.14 mmol) was dissolved in a 2 M solution of oxalyl chloride in dichloromethane (2 mL), and DMF (0.002 g, 0.028 mmol) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 2 h. After concentration, the crude product was added to a solution of 4-amino-2-methoxypyridine (26 mg, 0.21 mmol) and triethylamine (42 mg, 0.42 mmol) in dichloromethane (2 mL) and allowed to react overnight at room temperature. The mixture was concentrated to give the crude product, which was purified by silica gel column chromatography to give a mixture of 36-1a and 36-1b (55 mg, 82.45% yield). LCMS m / z=477.1[M+H] +

[0214] Step 2: Preparation of Compounds 36-2a and 36-2b A mixture of 36-1a and 36-1b (45 mg, 0.10 mmol) was dissolved in THF (1 mL) and HCl (1 mL) and reacted at 60° C. for 18 h. The reaction mixture was concentrated to give a crude product, which was purified by prep-HPLC (condition 1) to give a mixture of compound 36-2a and compound 36-2b (4 mg, yield 8.65%).

[0215] LCMS m / z=463.1[M+H] + Example 37: Preparation of Compound 37-1a and Compound 37-1b [ka]

[0216] A mixture of 21-5a and 21-5b (70 mg, 0.19 mmol) was dissolved in tetrahydrofuran (3 mL), triethylamine (120 mg, 1.14 mmol), and T3P (50% wt in EtOAc 480 mg, containing 1-propylphosphonic anhydride 240 mg, 0.76 mmol) were added sequentially. 3-Aminobenzamide (26 mg, 0.19 mmol) was added, and the mixture was allowed to react under a nitrogen atmosphere at room temperature for 18 h. The reaction was quenched by the addition of aqueous sodium bicarbonate (10 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by prep-HPLC (Condition 1) to give a mixture of compound 37-1a and compound 37-1b (43 mg, 47.1% yield).

[0217] LCMS m / z=481.2[M+H] + Example 38: Preparation of Compound 1-2a [ka]

[0218] Step 1: Preparation of compounds 1h-2a A 3.0 g mixture of compounds 1h-2a and 1h-2b was purified by SFC preparative separation and lyophilized to give compounds 1h-2a (1.28 g, chiral HPLC retention time: 0.760 min) and 1h-2b (1.11 g, chiral HPLC retention time: 0.966 min). Chiral HPLC analysis: (instrument: Shimadzu LC-30 AD, chiral column: Chiralcel IG column. Preparation: 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).

[0219] SFC preparative conditions: Instrument: Waters 150 Prep-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: carbon dioxide / ethanol, ethanol content 10%, flow rate: 100 mL / min, elution time: 2 min.

[0220] Compound 1h-2a: 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),1.85(s,3H),0.88-0.75(m,3H).

[0221] Step 2: Preparation of Compounds 1i-2a 1h-2a (1.0 g, 2.7 mmol) was dissolved in tetrahydrofuran (20 mL), triethylamine (1.64 g, 16.20 mmol) and T3P (50% wt in EtOAc 6.88 g, 1-propylphosphonic anhydride 3.44 g, 10.79 mmol) were added sequentially, and the mixture was stirred at room temperature for 15 min. 1h-2 (0.62 g, 4.07 mmol) was added and the mixture was stirred at room temperature for 18 h under a nitrogen atmosphere. Saturated aqueous sodium bicarbonate (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give compound 1i-2a (0.919 g, 67.47% yield).

[0222] Step 3: Preparation of Compound 1-2a Compound 1-2a (0.87 g) was obtained by referring to Step 4 of Example 2. The absolute configuration of compound 1-2a was verified by Micro-ED.

[0223] Example 39: Preparation of Compound 6-2a [ka]

[0224] 1h-2a (0.037 g, 0.1 mmol) was dissolved in tetrahydrofuran (3 mL), triethylamine (0.061 g, 0.60 mmol), T3P (50% wt in EtOAc 0.26 g, 1-propylphosphonic anhydride 0.13 g, 0.40 mmol), and 6-2a-1 (0.023 g, 0.15 mmol) were added sequentially, and the reaction was allowed to proceed under a nitrogen atmosphere at room temperature for 18 h. Aqueous sodium bicarbonate (10 mL) was added, followed by extraction with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give compound 6-2a (0.036 g, 71.08% yield).

[0225] 1HNMR(400MHz,CDCl3):δ9.69 (s,1H),8.45-8.37 (m,1H),8.10-8.04 (m,1H),7.15-7.06 (m,1H),6.98 -6.88 (m,2H),6.87-6.78 (m,1H),6.47(s,1H),4.84(d,1H),4.63-4.54 (m,1H),4.08(d,3H),2.73-2.63(m,1H),1.93(s,3H),0.93-0.83(m,3H). LCMS m / z=507.2[M+H] + Example 40: Preparation of Compound 28-2a [ka]

[0226] 1h-2a (0.037 g, 0.1 mmol) was dissolved in tetrahydrofuran (5 mL), triethylamine (0.061 g, 0.60 mmol) and T3P (50% wt in EtOAc 0.26 g, containing 1-propylphosphonic anhydride 0.13 g, 0.40 mmol) were added sequentially, followed by 28-2a-1 (0.055 g, 0.41 mmol). The mixture was then reacted at room temperature for 18 h under a nitrogen atmosphere. Aqueous sodium bicarbonate (10 mL) was added, followed by extraction with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give compound 28-2a (0.106 g, 80.37% yield).

[0227] Example 41: Preparation of Compound 8-1a [ka]

[0228] 1h-2a (100 mg, 0.27 mmol) was separated and purified using a silica gel column according to the synthesis method of Example 8 to obtain compound 8-1a (95 mg, yield 62.9%).

[0229] LCMS m / z=543.2[M+H] + 1 H NMR(400MHz,CDCl3):δ 8.54 (s,1H),8.14 - 8.05 (m,1H),7.74 - 7.65 (m,1H),7.13 (t,1H),7.04 - 6.95 (m,1H),6.89 - 6.79 (m,1H),5.33 (s,2H),4.67 (d,1H),4.59 - 4.47 (m,1H),4.04 (d,3H),2.69 - 2.55 (m,1H),1.91 (s,3H),0.93 - 0.85 (m,3H). Example 42: Preparation of Compound 26-1a [ka]

[0230] 1h-2a (100 mg, 0.27 mmol) was dissolved in tetrahydrofuran (5 mL), triethylamine (164 mg, 1.62 mmol), T3P (50% wt in EtOAc 686 mg, containing 1-propylphosphonic anhydride 343 mg, 1.08 mmol), and 4-fluoro-3-(methylsulfonyl)aniline (76 mg, 0.405 mmol) were added sequentially, and the reaction was allowed to proceed under a nitrogen atmosphere at room temperature for 18 h. The reaction was quenched by the addition of aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The residue was purified by silica gel column separation to give compound 26-1a (132 mg, 90% yield).

[0231] Example 43: Preparation of Compound 27-1a [ka]

[0232] Using 1h-2a as a substrate, synthesis was carried out under the synthesis conditions of Example 27 to obtain 27-1a.

[0233] LCMS m / z=541.1[M+H] + Example 44: Preparation of Compound 25-1a [ka]

[0234] 1h-2a (0.10 g, 0.27 mmol) was dissolved in tetrahydrofuran (5 mL), triethylamine (0.16 g, 1.62 mmol) and T3P (50% wt in EtOAc 0.69 g, containing 1-propylphosphonic anhydride 0.345 g, 1.08 mmol) were added sequentially, followed by 2-(methylsulfonyl)pyridin-4-amine (0.070 g, 0.41 mmol). The reaction was quenched with aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product 25-1a (0.05 g, 35.31% yield). The crude product was purified by silica gel column chromatography to give 25-1a (0.05 g, 35.31% yield).

[0235] Example 45: Preparation of Compound 5-3a [ka]

[0236] Using 1h-2a as a substrate, synthesis was carried out in accordance with the synthesis method of Example 5 to obtain 5-3a.

[0237] LCMS m / z=526.0[M+H] + Example 46: Preparation of Compound 7-1a [ka]

[0238] Using 1h-2a as a substrate, compound 7-1a was synthesized according to the synthesis method of Example 7.

[0239] Example 47: Preparation of Compound 19-2a [ka]

[0240] Using 1h-2a as a substrate, compound 19-2a was synthesized according to the synthesis method of Example 19.

[0241] LCMS m / z=478.50[M+H] + Example 48: Preparation of Compound 48-1a [ka]

[0242] 1h-2a (0.037 g, 0.1 mmol) was dissolved in tetrahydrofuran (3 mL), triethylamine (0.061 g, 0.60 mmol) and T3P (50% wt in EtOAc 0.25 g, containing 1-propylphosphonic anhydride 0.125 g, 0.40 mmol) were added sequentially, and 48-1a-1 (0.021 g, 0.15 mmol) was added. The mixture was then reacted at room temperature for 18 h under a nitrogen atmosphere. Aqueous sodium bicarbonate (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give 48-1a (0.02 g, 40.53% yield).

[0243] LCMS m / z=494.2[M+H] + 1H NMR (400MHz,DMSO-d6): δ 10.38 (s,1H),7.66 - 7.62 (m,1H),7.45 - 7.38 (m,1H),7.22 - 7.14 (m,1H),7.11 - 7.01 (m,1H),5.26 (t,1H),4.83 (d,1H),4.52 - 4.44 (m,3H),3.99 (d,3H),2.65 - 2.56 (m,1H),1.85 (s,3H),0.82 - 0.74 (m,3H). Example 49: Preparation of Compound 18-2a [ka]

[0244] Using 1h-2a as a substrate, compound 18-2a was synthesized according to the synthesis method of Example 18.

[0245] LCMS m / z=477.1[M+H] + Example 50: Preparation of Compound 50 [ka]

[0246] Step 1: Preparation of Compound 50b 50a (524 mg, 4.26 mmol) and imidazole (0.44 g, 6.39 mmol) were added to DMF (10 mL), and TBSCl (0.77 g, 5.11 mmol) was added. The mixture was allowed to react at room temperature for 3 h. The reaction mixture was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 50b (451 mg, 44.4% yield). LCMS m / z=239.3[M+H] +

[0247] Step 2: Preparation of compound 50c 1h-2a (50 mg, 0.14 mmol), 50b (67 mg, 0.28 mmol), T3P (50% wt in EtOAc 362 mg, containing 1-propylphosphonic anhydride 181 mg, 0.57 mmol), and TEA (85 mg, 0.84 mmol) were added to ethyl acetate (5 mL) and reacted at room temperature for 16 h. The reaction was quenched by addition of aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give 50c (24 mg, 29.02% yield). LCMS m / z=591.5[M+H] +

[0248] Step 3: Preparation of Compound 50 50c (24 mg, 0.041 mmol) was added to methanol (5 mL), and concentrated hydrochloric acid (1 mL) was slowly added. The mixture was allowed to react at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (50 mL) was added. Saturated aqueous sodium bicarbonate was added and the mixture was extracted. The organic phase was separated, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound 50 (8 mg, 38.90% yield).

[0249] LCMS m / z=477.2[M+H] + Example 51: Preparation of Compound 33-1a [ka]

[0250] Step 1: Fabrication of 33a-1a 1h-2a (100 mg, 0.27 mmol) was dissolved in a 2 M solution of oxalyl chloride in dichloromethane (2 mL), and DMF (0.002 g, 0.028 mmol) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 2 h. After concentration, the crude product was added to a solution of 33-1a-1 (see WO2022121517A1 for preparation) (61 mg, 0.27 mmol) and triethylamine (82 mg, 0.81 mmol) in dichloromethane (2 mL), and the mixture was allowed to react overnight at room temperature. The mixture was concentrated to give the crude product, which was purified by silica gel column chromatography to give 33a-1a (100 mg, 64.24% yield).

[0251] Step 2: Preparation of compound 33-1a Compound 33a-1a (100 mg, 0.17 mmol) was added to a 4 M solution of hydrochloric acid in dioxane (1 mL), and the mixture was reacted at room temperature for 18 h under a nitrogen atmosphere. The mixture was concentrated to give a crude product, which was then purified by prep-HPLC (condition 2) to give compound 33-1a (70 mg, 76.75% yield).

[0252] Example 52: Preparation of Compound 36-2a [ka]

[0253] Using 1h-2a as a substrate, compound 36-2a was synthesized according to the synthesis method of Example 36.

[0254] LCMS m / z=463.1[M+H] + Example 53: Preparation of Compound 20-1a [ka]

[0255] 1h-2a (100 mg, 0.27 mmol) was dissolved in tetrahydrofuran (5 mL), triethylamine (164 mg, 1.62 mmol) and T3P (50% wt in EtOAc 686 mg, containing 1-propylphosphonic anhydride 343 mg, 1.08 mmol) were added sequentially, followed by 3-aminopyridine oxide (60 mg, 0.53 mmol). The reaction mixture was allowed to react at room temperature for 18 h under a nitrogen atmosphere. The reaction mixture was quenched by addition to aqueous sodium bicarbonate, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Compound 20-1a (25 mg, 19.84% yield) was obtained by separation and purification using a silica gel column.

[0256] LCMS m / z=463.1[M+H] + Example 54: Preparation of Compound 54 [ka]

[0257] Compound 54 (90 mg, 63.4% yield) was obtained by synthesizing 1h-2a (100 mg, 0.27 mmol) and 54-1 (69 mg, 0.40 mmol) according to the synthesis method of Example 22.

[0258] LCMS m / z=524.1[M+H] + , Example 55: Preparation of Compound 55 [ka]

[0259] 6-1a (40 mg, 0.077 mmol) was added to 1 mL of an aqueous solution of lithium hydroxide (5 mg, 0.19 mmol), and 1 mL of methanol was added, followed by a reaction at 40° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by prep-HPLC (condition 2) to obtain compound 55 (10 mg, yield 25.56%).

[0260] LCMS m / z=508.1[M+H]+ Example 56: Preparation of Compound 56 [ka]

[0261] 1h-2a (100 mg, 0.27 mmol) and 56-1 (68 mg, 0.405 mmol) were separated and purified using a silica gel column according to the synthesis method of Example 22 to obtain compound 56 (137 mg, yield 94.4%).

[0262] LCMS m / z=522.5[M+H] + , Example 57: Preparation of Compound 57 [ka]

[0263] Preparation of compound 57 1h-2a (74 mg, 0.2 mmol) and 57-1 (50.7 mg, 0.3 mmol) were separated and purified using a silica gel column according to the synthesis method of Example 22 to obtain compound 57 (87 mg, yield 81.7%).

[0264] LCMS m / z=522.5[M+H] + , Example 58: Preparation of Compound 58 [ka]

[0265] Preparation of compound 58 1h-2a (100 mg, 0.27 mmol) and 58-1 (69 mg, 0.41 mmol) were purified by preparative HPLC (condition 2) according to the synthesis method of Example 22 to give the trifluoroacetate salt of compound 58 (36 mg, yield 25.5%).

[0266] LCMS m / z=523.1[M+H] + , 1 H NMR (400MHz,CDCl3) δ 11.37 (s,1H),8.71 (d,1H),8.61 - 8.52 (m,1H),8.16 - 8.07 (m,1H),6.91- 6.75 (m,2H),4.81 (d,1H),4.65 - 4.57 (m,1H),4.09 (d,3H),2.78 - 2.65 (m,1H),2.06 - 1.96 (m,6H),1.93 (s,3H),0.94 - 0.82 (m,3H).

[0267] 1h-2a (254 mg, 0.69 mmol), 58-1 (180 mg, 1.03 mmol), triethylamine (420 mg, 4.14 mmol), and T3P (50% wt in EtOAc 1.73 g, containing 1-propylphosphonic anhydride 0.87 g, 2.76 mmol) were added to tetrahydrofuran (10 mL) and reacted at room temperature for 16 h. Aqueous sodium bicarbonate (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give compound 58 (220 mg, 60.4% yield).

[0268] Example 59: Preparation of compound 59-a [ka]

[0269] Step 1: Preparation of Compounds 21-5P1 and 21-5P2 A 1.3 g mixture of compound 21-5a and compound 21-5b was separated by SFC preparative separation to give compound 21-5P1 (552 mg, chiral HPLC retention time: 0.736 min) and compound 21-5P2 (504 mg, chiral HPLC retention time: 1.033 min).

[0270] Compound 21-5P1 is one of the above 21-5a and 21-5b, and is an enantiomer of compound 21-5P2. That is, when the structure of compound 21-5P1 is that of formula 21-5a, the structure of compound 21-5P2 is that of formula 21-5b, and when the structure of compound 21-5P1 is that of formula 21-5b, the structure of compound 21-5P2 is that of formula 21-5a.

[0271] SFC preparative conditions: Instrument: Waters 150 Prep-SFC C; Preparative column: Chiral IC column. Preparation method: The crude material was dissolved in acetonitrile to prepare a 10 mg / ml sample solution. Mobile phase: Carbon dioxide / 0.1% NH₃·H₂O methanol solution, methanol content 15%, Elution time: 8 min.

[0272] Chiral test method: (Instrument: SHIMADZU LC-30 AD sf, Preparative column: Chiral IC column. Preparation method: The crude product was dissolved in acetonitrile to prepare the sample solution. Mobile phase system: carbon dioxide / 0.05% DEA in methanol. Elution gradient: 5% to 40%, flow rate: 3.0 mL / min, elution time: 3 min).

[0273] Step 2: Preparation of compound 59-a 21-5P1 (50 mg, 0.14 mmol) was dissolved in a 2 M solution of oxalyl chloride in dichloromethane (2 mL), and DMF (0.002 g, 0.028 mmol) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 2 h. After concentration, the crude product was added to a solution of 8-1a-1 (40 mg, 0.21 mmol) and triethylamine (42.5 mg, 0.42 mmol) in dichloromethane (2 mL) and the mixture was allowed to react overnight at room temperature. The crude product was concentrated and purified by silica gel column chromatography to give 59-a (50 mg, 66.8% yield). The chiral orientation of compound 59-a was the same as that of 21-5P1. LCMS m / z=535.0[M+H] +

[0274] By referring to the preparation method of 59-a (no change in configuration occurred in the amidation reaction), the target compounds (consistent with the substrate configuration) were prepared as shown in the table below.

[0275] [Table 2-1] [Table 2-2]

[0276] Example 70: Preparation of compound 70-a [ka]

[0277] Step 1: Compounds 31h-1P1 and 31h-1P2 The mixture 1gg of compounds 31h-1a and 31h-1b was separated by SFC preparative separation to give compound 31h-1P1 (412 mg, retention time: 1.589 min) and compound 31h-1P2 (430 mg, retention time: 1.778 min).

[0278] Compound 31h-1P1 is one of the above formulas 31h-1a and 31h-1b, and is an enantiomer of compound 31h-1P2. That is, when the structure of compound 31h-1P1 is that of formula 31h-1a, the structure of compound 31h-1P2 is that of formula 31h-1b, and when the structure of compound 31h-1P1 is that of formula 31h-1b, the structure of compound 31h-1P2 is that of formula 31h-1a.

[0279] SFC preparative conditions: Instrument: SFC Prep 150 AP, Preparative column: Daicel AD-H (19 mm x 250 mm). Preparation method: The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. Mobile phase: carbon dioxide / ethanol, ethanol content 8%, flow rate 40 ml / min.

[0280] Step 2: Preparation of compound 70-a 31h-1P1 (50 mg, 0.14 mmol) was dissolved in ethyl acetate (3 mL), triethylamine (85 mg, 0.84 mmol), T3P (50% wt in EtOAc 360 mg, containing 1-propylphosphonic anhydride 180 mg, 0.56 mmol), and 6-2a-1 (43 mg, 0.28 mmol) were added sequentially, and the reaction was allowed to proceed under a nitrogen atmosphere at room temperature for 18 h. Aqueous sodium bicarbonate (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give 70-a (6.28 mg, 9.11% yield). LCMS m / z=493.2[M+H] +

[0281] By referring to the preparation method of 70-a (no change in configuration occurred in the amidation reaction), the target compounds (which match the substrate configuration) as shown in the table below were prepared.

[0282] [Table 3]

[0283] Example 76: Preparation of Compounds 76-8a and 76-8b [ka]

[0284] Step 1: Preparation of compound 76-2 76-1 (3.8 g, 20.0 mmol), 3-bromo-2-methylpropene (3.24 g, 24.0 mmol), and potassium carbonate (5.53 g, 40.09 mmol) were added to acetonitrile (80 mL) and reacted at 60 °C for 12 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give 76-2 (4.5 g, 91.8% yield).

[0285] Step 2: Preparation of compound 76-3 76-2 (4.5 g, 18.36 mmol) was added to dichloromethane (180 mL), and aluminum trichloride (120 mg, 0.9 mmol) was added in an ice bath. The reaction mixture was then reacted for 2 h in an ice bath. The reaction mixture was quenched by adding aqueous sodium bicarbonate solution, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, separated, and purified using a silica gel column to give 76-3 (3.07 g, 68.2% yield).

[0286] Step 3: Preparation of Compounds 76-4a and 24-4b 76-3 (290 mg, 1.2 mmol), (Bpin)2 (370 mg, 1.44 mmol), potassium acetate (240 mg, 2.4 mmol), and Pd(dppf)Cl2·DCM (49 mg, 0.06 mmol) were added to 1,4-dioxane (8 mL) and reacted at 100 °C for 6 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth to obtain the filtrate. Water (3 mL), a mixture of 1e-2a and 1e-2b (480 mg, 1.2 mmol), potassium phosphate (760 mg, 3.58 mmol), and Pd(PPh3)4 (57.8 mg, 0.05 mmol) were added to the filtrate and reacted at 100 °C for 4 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and separated and purified using a silica gel column to obtain a mixture of 76-4a and 76-4b (280 mg, yield 55.7%).

[0287] Step 4: Fabrication of 76-5a and 76-5b A mixture of 76-4a and 76-4b (240 mg, 0.57 mmol) was dissolved in methanol (15 mL), platinum dichloride (50 mg, 0.19 mmol) was added, and the mixture was reacted at room temperature for 20 h under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated and purified using a silica gel column to give a mixture of 76-5a and 76-5b (133 mg, 55.5% yield).

[0288] Step 5: Fabrication of 76-6a and 76-6b A mixture of 76-5a and 76-5b (143 mg, 0.34 mmol) was dissolved in absolute ethanol (5 mL), and cesium carbonate (170 mg, 0.51 mmol) was added. The mixture was allowed to react at 50° C. for 5 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, quenched by addition of 1 M hydrochloric acid (5 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then purified by silica gel column chromatography to give a mixture of 76-6a and 76-6b (124 mg, 92.9% yield). LCMS m / z=391-3[MH] -

[0289] Step 6: Fabrication of 76-7a and 76-7b A mixture of 76-6a and 76-6b (124 mg, 0.32 mmol) was dissolved in ethyl acetate (6 mL). Triethylamine (200 mg, 1.95 mmol), T3P (50% wt in EtOAc 788 mg, containing 1-propylphosphonic anhydride 394 mg, 1.29 mmol), and 1h-2 (73 mg, 0.48 mmol) were added sequentially and reacted at room temperature under a nitrogen atmosphere for 20 h. The reaction was quenched by the addition of aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give a mixture of 76-7a and 76-7b (50 mg, 29.7% yield). LCMS m / z=527.2[M+H] +

[0290] Step 7: Preparation of a mixture of compound 76-8a and compound 76-8b A mixture of 76-7a and 76-7b (50 mg, 0.095 mmol) was dissolved in 7M ammonia in methanol (3 mL) and reacted at room temperature for 4 h. The reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography to give a mixture of 76-8a and 76-8b (18 mg, 36.8% yield).

[0291] LCMS m / z=512.2[M+H] + 1 H NMR (400MHz,CDCl3) δ 9.91(s,1H),8.45 (d,1H),8.40 - 8.30 (m,1H),8.18 (d,1H),8.00 (d,1H),7.07 - 6.92 (m,1H),6.51 (t,1H),5.91 (s,1H),5.11 (d,1H),4.44 - 4.29 (m,1H),3.00 (s,2H),2.79 - 2.68 (m,1H),1.90 (s,3H),1.47 (s,3H),1.42 (s,3H),1.00 - 0.92 (m,3H). Example 77: Preparation of Compound 77 [ka]

[0292] Step 1: Preparation of compound 77b 77a (3.04 g, 20.0 mmol), (Boc)O (4.8 g, 22 mmol), and 4-dimethylaminopyridine (244 mg, 2.0 mmol) were added to dichloromethane (70 mL) and reacted at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to give 77b (2.38 g, 33.8% yield). LCMS m / z=353.4[M+H] +

[0293] Step 2: Preparation of compound 77c 77b (352 mg, 1.0 mmol) was added to dichloromethane (10 mL), the mixture was placed in an ice bath, metachloroperbenzoic acid (516 mg, 3.0 mmol) was added, and the reaction was continued at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and then purified by silica gel column chromatography to give 77c (211 mg, 57.3% yield). LCMS m / z=369.2[M+H] +

[0294] Step 3: Preparation of compound 77d 77c (134 mg, 0.364 mmol) was added to dichloromethane (2 mL), and hydrogen chloride-1,4-dioxane solution (4 M, 4 mL) was added to the system. The reaction was allowed to proceed at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then dichloromethane (2 mL) was added. Hydrogen chloride-1,4-dioxane solution (4 M, 4 mL) was added to the system. The reaction mixture was cooled and concentrated under reduced pressure to give 77d (71 mg). LCMS m / z=169.1[M+H] +

[0295] Step 4: Preparation of compound 77e 77d (71 mg) was dissolved in tetrahydrofuran (8 mL), and triethylamine (121.4 mg, 1.2 mmol) and T3P (509 mg 50% wt in EtOAc, containing 1-propylphosphonic anhydride, 254.5 mg, 0.8 mmol) were added sequentially. Finally, substrate 1h-2a (74 mg, 0.2 mmol) was added to the reaction mixture. After completion, the reaction mixture was allowed to react at room temperature for 20 h under a nitrogen atmosphere. The reaction mixture was quenched with aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product 77e (81 mg, 77.8% yield). The crude product was purified by silica gel column chromatography to give 77e (81 mg, 77.8% yield). LCMS m / z=521.1[M+H] +

[0296] Step 5: Preparation of Compound 77 Substrate 77e (81 mg, 0.155 mmol) was dissolved in 7 M ammonia in methanol (10 mL) and reacted at room temperature for 2 h. The reaction mixture was concentrated to give a crude product, which was then purified by silica gel column chromatography to give compound 77 (42 mg, 53.6% yield). LCMS m / z=506.1[M+H] +

[0297] Biological Test Example 1 Nav1.8 manual patch clamp test (1) Cell culture A CHO cell line stably expressing human Nav1.8 was cultured in Ham's F-12 medium containing 10% fetal bovine serum, 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%. The old medium was removed, rinsed once with PBS, and 1 mL of 0.25% trypsin-EDTA solution was added and incubated at 37°C for approximately 1.5 min. Once the cells detached from the bottom of the dish, complete medium preheated to 37°C was added. The cell suspension was gently pipetted to separate clumped cells. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1000 rpm for 5 min to collect the cells. The cells were seeded into 6 cm cell culture dishes, with each dish containing 2.5 × 10 cells. 5 The cells were cultured in a final volume of 5 mL for expansion or maintenance. To maintain the electrophysiological activity of the cells, the cell density should not exceed 80%. Before patch clamp detection, the cells were detached with 0.25% Trypsin-EDTA and cultured at 6.5 × 10 3 The cells were plated on cover slips and cultured in 24-well plates (final volume 500 μL), and detection was carried out after 18 hours.

[0298] (2) Preparation of compounds Compounds were dissolved in dimethyl sulfoxide (DMSO) to prepare 30 mM DMSO stock solutions. The stock solutions were diluted to test concentrations in extracellular solution (140 mM NaCl, 3.5 mM KCl, 1 mM MgCl₂·6H₂O, 2 mM CaCl₂·2H₂O, 10 mM D-glucose, 10 mM HEPES, and 1.25 mM NaH₂PO₄·2H₂O, pH adjusted to 7.4 with NaOH). The final DMSO concentration in all test samples was 0.1%.

[0299] (3) Electrophysiological testing First, a glass capillary tube was pulled using a microelectrode puller to form a recording electrode. The electrode, filled with intracellular solution (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 in a microelectrode holder. Using a microelectrode puller under an inverted microscope, the electrode was immersed in the extracellular solution and the electrode resistance (Rpip) was recorded. The electrode was then slowly brought into contact with the cell surface, and negative pressure was applied to form a GΩ seal. Fast capacitance compensation was then performed, and continuous negative pressure was applied to disrupt the cell membrane, forming 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. Administration began after the Nav1.8 current of the whole-cell recording stabilized. Each drug concentration was administered for approximately 5 min (or until the current stabilized). The cell-plated coverslip was placed in a recording bath under an inverted microscope, and blank control external solution and test compound working solution were perfused into the recording bath by gravity perfusion. Fluid exchange was performed using a peristaltic pump. Cell currents detected in compound-free external solution served as the control. All electrophysiological tests were performed at room temperature. The inhibitory rate of the compound against Nav1.8 was determined by calculating the relative percentage of peak currents generated before and after treatment of the cells with the compound.

[0300] The voltage stimulation protocol for recording Nav1.8 sodium currents using whole-cell patch clamp was as follows: After forming a whole-cell seal, the cell voltage was clamped at -120 mV. First, the voltage was stepped from -110 mV to -30 mV in 10 mV increments and maintained for 5 s. After that, a 0 mV depolarizing pulse was applied to obtain the half-inactivation voltage (Vhalf). Vhalf was then used as the stimulation voltage and maintained for 5 s. The voltage was then returned to -120 mV and maintained for 20 ms. A further depolarizing pulse (TP2) was applied to 0 mV and maintained for 50 ms to detect the half-inactivation state of sodium currents. Finally, the clamp voltage was returned to -120 mV, and data collection was repeated every 20 ms to observe the effects of pharmaceuticals on the peak sodium current. Experimental data were acquired using an EPC10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0301] [Table 4-1] [Table 4-2]

[0302] Conclusion: The compounds of the present invention, for example, the compounds of the Examples, have good Nav1.8 inhibitory activity. Specifically, for example, compound 31-1P1 had an IC50 of 0.0412 nM against hNav1.8.

[0303] Biological test example 2: Pharmacokinetics test in rats Test animals: male SD rats, approximately 220 g, 6 to 8 weeks old, 6 rats per compound.

[0304] Experimental design: On the day of the experiment, 24 SD rats were randomly divided into groups according to their weight. One day before administration, they were fasted for 12-14 hours without water restriction, and fed 4 hours after administration.

[0305] [Table 5] Note: Vehicle for intravenous administration: 5% DMA + 5% Solutol + 90% Saline. Vehicle for oral gavage administration: 0.5% MC. (DMA: dimethylacetamide, Solutol: polyethylene glycol-15-hydroxyhydroxystearate, Saline: physiological saline, MC: methylcellulose)

[0306] Before and after administration, 0.10 mL of blood was collected from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected at 0, 5, 15, and 30 minutes, and 1, 2, 4, 6, 8, and 24 hours for both the intravenous and gavage groups. All samples were stored at -80°C before analytical detection, and quantitative analysis of the samples was performed by LC-MS / MS.

[0307] Conclusion: The compounds of the present invention, for example, the compounds of the Examples, had good oral efficacy in rats.

[0308] Biological test example 3: Pharmacokinetic test in mice Test animals: C57 mice, 22-25 g, 6 mice / compound.

[0309] Experimental design: On the day of the experiment, C57 mice were randomly divided into groups according to their weight. One day before administration, they were fasted for 12-14 hours without water restriction, and fed 4 hours after administration.

[0310] [Table 6] Note: Vehicle for intravenous administration: 5% DMA + 5% Solutol + 90% Saline. Vehicle for oral gavage administration: 0.5% MC. (DMA: dimethylacetamide, Solutol: polyethylene glycol-15-hydroxyhydroxystearate, Saline: physiological saline, MC: methylcellulose)

[0311] Before and after administration, 0.06 mL of blood was collected from the orbit under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm for 10 minutes at 4°C to collect plasma. Blood was collected at 0, 5, 15, and 30 minutes, and 1, 2, 4, 7, 24, and 48 hours for both the intravenous and gavage groups. All samples were stored at -80°C before analytical detection. Quantitative analysis of the samples was performed using LC-MS / MS.

[0312] [Table 7]

[0313] Conclusion: The compounds of the present invention, for example, the compounds of the Examples, had good oral efficacy in mice.

[0314] Biological test example 4: Pharmacokinetics test in beagle dogs Test animals: male beagle dogs, approximately 8-11 kg, 6 dogs / compound, purchased from Beijing Masu Biotechnology Co., Ltd.

[0315] Test method: On the day of the test, 12 beagle dogs were randomly assigned to groups according to their weight. One day before administration, they were fasted for 12-14 hours without water restriction, and fed 4 hours after administration. The doses were administered according to Table 4.

[0316] [Table 8] Note: Vehicle for intravenous administration: 5% DMA + 5% Solutol + 90% Saline. Vehicle for oral gavage administration: 0.5% MC. (DMA: dimethylacetamide, Solutol: polyethylene glycol-15-hydroxyhydroxystearate, Saline: physiological saline, MC: methylcellulose solution)

[0317] Before and after administration, 1 ml of blood was collected from the jugular or limb vein and placed in an EDTAK2 centrifuge tube. Plasma was collected by centrifugation at 5000 rpm for 10 minutes at 4°C. Blood was collected at 0, 5, 15, and 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 hours for both the intravenous and gavage groups. All samples were stored at -80°C before analytical detection, and quantitative analysis of the samples was performed by LC-MS / MS.

[0318] Conclusion: The compounds of the present invention, for example the compounds of the Examples, had good oral performance in dogs.

[0319] Biological Test Example 5: Pharmacokinetics Test in Monkeys Test animals: male cynomolgus monkeys, 3-5 kg, 3-6 years old, 6 animals / compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0320] Test method: On the day of the test, six monkeys were randomly assigned to groups according to their weight. One day before administration, they were fasted for 14 to 18 hours without water restriction, and were fed 4 hours after administration.

[0321] [Table 9] Note: Vehicle for intravenous administration: 5% DMA + 5% Solutol + 90% Saline. Vehicle for oral gavage administration: 0.5% MC (containing 0.5% Tween 80). *Dose is as free base.

[0322] Before and after administration, 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 minutes. Blood was collected at 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, 10, 12, and 24 hours for both the intravenous and intragastric administration groups. All samples were stored at -80°C before analytical detection, and quantitative analysis of the samples was performed by LC-MS / MS.

[0323] Conclusion: The compounds of the present invention, such as the compounds of the Examples, had good oral efficacy in monkeys.

[0324] Biological Test Example 6: CYP450 Enzyme Inhibition Test The purpose of this study was to evaluate the effects of test substances on the activity of five cytochrome P450 (CYP) isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) in human liver microsomes using an in vitro test system. Specific probe substrates for CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of test substances, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction was completed, the metabolites generated by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS) after sample processing. The changes in CYP enzyme activity were measured and the IC was calculated. 50 The values ​​were calculated to evaluate the potential inhibitory ability of the test substance against each CYP enzyme subtype.

[0325] Conclusion: The compounds of the present invention, for example, the compounds of the Examples, have weak CYP inhibitory activity. For example, compound 58 had an IC50 of greater than 30 μM against five CYP isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4).

[0326] Biological Test Example 7: Caco2 Permeability Test The test was performed using monolayers of Caco-2 cells incubated in triplicate in a 96-well Transwell plate. Transport buffer solution (HBSS, 10 mM HEPES, pH 7.4 ± 0.05) containing a compound of the present invention (2 μM) or control compounds digoxin (10 μM), nadolol (2 μM), and metoprolol (2 μM) was placed in the apical or basal wells of the dosing end. The corresponding wells of the receiving end were filled with transport buffer solution containing DMSO. After 2 hours of incubation at 37 ± 1°C, the cell plate was removed, and appropriate samples were taken from the apical and basal wells and placed in a new 96-well plate. Proteins were then precipitated by adding acetonitrile containing an internal standard. The samples were analyzed by LC-MS / MS to measure the concentrations of the compounds of the present invention and the control compounds. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to the basal side of the monolayer cells and from the basal to the apical side, thereby calculating the efflux rates. The integrity of the cell monolayer after 2 hours of incubation was assessed by fluorescein leakage.

[0327] Conclusion: The compounds of the present invention, such as the compounds of the Examples, had good permeability.

[0328] Biological Test Example 8: Spinal nerve ligation (SNL)-induced neuralgia model in mice Male C57BL / 6J mice purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd. were acclimatized and raised for one week before preparation of the model. The specific preparation method was as follows.

[0329] (1) Disinfect surgical instruments and ligatures. (2) Anesthetize the mouse with isoflurane and place it in the prone position on the operating table. (3) Cut the mouse's hair near the hipbone, disinfect the skin, and make an incision approximately 2 cm long along the spine. (4) Separate the fascia along the spine, bluntly separate the muscles, and expose the L5 transverse process. (5) Using forceps, carefully bite off the L5 transverse process to expose the L5 spinal nerve. (6) Carefully isolate the L5 nerve using a glass isolation needle and ligate the L5 nerve with a 5-0 ligature. (7) The muscles and skin are sutured and disinfected with iodophor. The day after model creation, mice that were not successfully created were removed (signs of successful model creation: the mouse's hind legs were curled). After model creation, mice were stroked for 3-5 minutes every day to allow the animals to become accustomed to the experimenter, and then placed on a metal pain measurement frame for 40-60 minutes of adaptation. After environmental adaptation was completed on the third day, Von Frey filaments (Aesthesio) were used. (R) The animals were tested for baseline values ​​(Ascending test) using 0.16, 0.4, 0.6, 1.0, 1.4, and 2.0 grams (0.16, 0.4, 0.6, 1.0, 1.4, and 2.0 grams). Each animal was measured twice, with an interval of at least 5 minutes, and the average value was calculated. The animals were grouped according to their baseline values ​​(10 animals per group). After grouping, the test compound (3 and 30 mg / kg) or vehicle (0.5% methylcellulose) was administered orally by gavage, and the mechanical pain threshold (MPT) of the mice was tested at different time points after administration. Time-MPT curves were plotted using GraphPad 8.3.0, and statistical analysis was performed.

[0330] Conclusion: According to the area under the time-MPT curve analysis, the compounds of the present invention, such as the compounds of the Examples, have significant analgesic effects, for example, compound 6-2a has significant analgesic effects at doses of 3 mg / kg or 30 mg / kg.

Claims

1. A compound selected from the compounds represented by general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, 【Chemistry 1】 Q １ is C ６－１０ aryl group, 5- to 10-membered heteroaryl group, C ５－１０ a carbocyclic group, a 5- to 10-membered heterocyclic group, or 【Chemistry 2】 wherein the aryl, heteroaryl, carbocyclic or heterocyclic group is optionally selected from 1 to 5 R ｑ is replaced by R Ｑ１ is H, COOH, NR ｑ１ R ｑ２ , —C(═O)NR ｑ１ R ｑ２ , -S(=O) ２ NR ｑ１ R ｑ２ ,OH,=O,-OR ｑ１ , -C(=O)R ｑ１ , -S(=O) ２ R ｑ１ , -S(=O)(=NR ｑ１ ) R ｑ２ or -P(=O)R ｑ１ R ｑ２ is selected from R ｑ１ , R ｑ２ are each independently H, C １－６ Alkyl group, C ３－６ a carbocyclic group, a 4- to 7-membered heterocyclic group, and the alkyl, carbocyclic or heterocyclic group optionally has 1 to 4 R ｋ is replaced by As an option, ｑ１ , R ｑ２ are directly linked to form a 4- to 7-membered heterocyclic group, said heterocyclic group optionally containing 1 to 4 R ｋ is replaced by B is C ６－１０ aryl group, 5- to 10-membered heteroaryl group, C ５－１０ a carbocyclic group, a 5- to 10-membered heterocyclic group, wherein the aryl, heteroaryl, carbocyclic or heterocyclic group optionally comprises 1 to 4 R Ｂ is replaced by R １ , R ２ are each independently H, halogen, CN, OH, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, —OC １－６ Alkyl group, —SC １－６ Alkyl group, C ３－６ a carbocyclic group, a 3- to 7-membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group optionally comprises 1 to 4 R ｋ It is replaced by, and as a condition, R １ , R ２ But at the same time, it's not H, R ３ , R ４ , R ｑ , R Ｂ are each independently H, deuterium, halogen, CN, OH, or NH ２ , N.H.C. １－６ Alkyl group, N(C １－６ alkyl) ２ , C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, —OC １－６ Alkyl group, —SC １－６ Alkyl group, C ３－７ Carbocyclic group, —OC ３－７ a carbocyclic group, a 3- to 7-membered heterocyclic group, or -P(=O)R ｑ１ R ｑ２ wherein the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally selected from 1 to 4 R ｋ is replaced by R ｋ is deuterium, ═O, halogen, CN, OH, NH ２ , N.H.C. １－６ Alkyl group, N(C １－６ alkyl) ２ , C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, —OC １－６ Alkyl group, —SC １－６ Alkyl group, —O—C ３－６ Carbocyclic group, —O-3 to 7-membered heterocyclic group, —NH—C ３－６ Carbocyclic group, —NH-3 to 7-membered heterocyclic group, —C １－４ Alkylene-C ３－６ Carbocyclic group, -C １－４ alkylene-3 to 7-membered heterocyclic group, C ３－６ a carbocyclic group, a 3- to 7-membered heterocyclic group, wherein said alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic group optionally contains deuterium, halogen, ═O, CN, OH, NH ２ , C １－６ Alkyl group, C １－６ A compound or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, substituted with 1 to 4 substituents selected from alkoxy groups.

2. R ｑ１ , R ｑ２ are each independently H, C １－４ Alkyl group, C ３－６ a carbocyclic group, a 4- to 7-membered heterocyclic group, and the alkyl, carbocyclic or heterocyclic group optionally has 1 to 4 R ｋ is replaced by As an option, ｑ１ , R ｑ２ are directly linked to form a 4- to 7-membered heterocyclic group, said heterocyclic group optionally containing 1 to 4 R ｋ is replaced by Q １ is a phenyl group, benzo C ４－６ a carbocyclic group, a 4- to 6-membered benzoheterocyclic group, a 5- to 6-membered heteroaryl group, an 8- to 10-membered fused ring heteroaryl group, or 【Transformation 3】 wherein Q is selected from １ optionally 1 to 4 R ｑ is replaced by B is a phenyl group, benzo C ４－６ A is selected from a carbocyclic group, a 4- to 6-membered benzoheterocyclic group, a 5- to 6-membered heteroaryl group, and an 8- to 10-membered fused ring heteroaryl group, and B is optionally selected from 1 to 4 R Ｂ is replaced by R １ , R ２ are each independently H, halogen, CN, OH, C １－４ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, —OC １－４ Alkyl group, —SC １－４ Alkyl group, C ３－６ a carbocyclic group, a 3- to 7-membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group optionally comprises 1 to 4 R ｋ It is replaced by, and as a condition, R １ , R ２ But at the same time, it's not H, R ３ , R ４ , R ｑ , R Ｂ are each independently H, deuterium, halogen, CN, OH, or NH ２ , N.H.C. １－４ Alkyl group, N(C １－４ alkyl) ２ , C １－４ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, —OC １－４ Alkyl group, —SC １－４ Alkyl group, C ３－７ Carbocyclic group, —OC ３－７ a carbocyclic group, a 3- to 7-membered heterocyclic group, or -P(=O)R ｑ１ R ｑ２ wherein the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally selected from 1 to 4 R ｋ is replaced by R ｋ is deuterium, ═O, halogen, CN, OH, NH ２ , N.H.C. １－４ Alkyl group, N(C １－４ alkyl) ２ , C １－４ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, —OC １－４ Alkyl group, —SC １－４ Alkyl group, —O—C ３－６ a carbocyclic group, an -O-3 to 7 membered heterocyclic group, wherein said alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic group or heterocyclic group optionally contains deuterium, halogen, CN, OH, NH ２ , C １－４ Alkyl group, C １－４ 2. The compound of claim 1, or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, substituted with 1 to 4 substituents selected from alkoxy groups.

3. R ｑ１ , R ｑ２ are each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl, and the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl groups are optionally selected from 1 to 4 R ｋ is replaced by R １ , R ２ are each independently selected from H, F, Cl, Br, cyano, methyl, ethyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, vinyl, and ethynyl, and the methyl, ethyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, vinyl, and ethynyl groups are optionally selected from 1 to 4 R ｋ It is replaced by, and as a condition, R １ , R ２ But at the same time, it's not H, B is, 【Chemistry 4】 or a phenyl group, wherein B is optionally selected from 1 to 5 R Ｂ is replaced by R ３ , R ４ , R ｑ , R Ｂ are each independently H, deuterium, F, Cl, Br, a cyano group, a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, an isopropyloxy group, a methylthio group, a cyclopropyl group, a cyclopropyloxy group, a cyclobutyl group, a vinyl group, an ethynyl group, -P(=O)(CH ３ ) ２ , -P(=O)(CH ２ CH ３ ) ２ , -P(=O)(CH ３ ) (cyclopropyl), and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, vinyl, and ethynyl groups are optionally selected from the group consisting of 1 to 4 R ｋ is replaced by R ｋ is deuterium, ═O, F, Cl, Br, I, CN, OH, NH ２ , NH(CH ３ ), NH(CH ２ CH ３ ), N(CH ３ ) ２ , N(CH ２ CH ３ ) ２ , methyl group, ethyl group, vinyl group, ethynyl group, methoxy group, ethoxy group, methylthio group, —O-cyclopropyl group, —NH-cyclopropyl group, —CH ２ -cyclopropyl group, -CH ２ -cyclobutyl group, -CH ２ -cyclopentyl group, -CH ２ - selected from cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein said methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups are optionally selected from deuterium, halogen, CN, OH, NH ２ , C １－４ Alkyl group, C １－４ 3. The compound of claim 2, or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, substituted with 1 to 4 substituents selected from alkoxy groups.

4. Q １ teeth, 【Transformation 5】 wherein Q is selected from １ optionally 1 to 5 R ｑ is replaced by R ３ , R ４ are each independently H, a methyl group, an ethyl group, or CH ２ F, CHF ２ , C.F. ３ is selected from R １ , R ２ are each independently H, a methyl group, an ethyl group, or CH ２ F, CHF ２ , C.F. ３ is selected from the following conditions: １ , R ２ But at the same time, it's not H, R ｑ , R Ｂ are each independently H, F, Cl, Br, a cyano group, or CH ２ F, CHF ２ , C.F. ３ , -OCH ２ F, -OCHF ２ , -OCF ３ , -OCD ３ , methyl group, —S-methyl group, —S—CF ３ , ethyl group, isopropyl group, ethynyl group, methoxy group, ethoxy group, isopropyloxy group, propyloxy group, cyclopropyl group, —O-cyclopropyl group, —P(═O)(CH ３ ) ２ , -P(=O)(CH ２ CH ３ ) ２ , -P(=O)(CH ３ ) (cyclopropyl), and the methyl, ethyl, isopropyl, ethynyl, methoxy, ethoxy, isopropyloxy, propyloxy, and cyclopropyl groups are optionally selected from the group consisting of 1 to 4 R ｋ is replaced by R ｋ is deuterium, F, Cl, Br, I, CN, OH, -CH ２ OH, methyl group, ethyl group, vinyl group, ethynyl group, methoxy group, ethoxy group, methylthio group, -O-cyclopropyl group, -NH-cyclopropyl group, -CH ２ -cyclopropyl group, -CH ２ -cyclobutyl group, -CH ２ -cyclopentyl group, -CH ２ - a cyclohexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof. [Request Item 5] [Transformation 6] teeth, 【Transformation 7】 wherein Q is selected from １ optionally, 1 to 3 R ｑ is replaced by R ｑａ teeth, 【Transformation 8】 -CH ２ OH, -CF ２ CH ２ OH, NH ２ , -P(=O)(CH ３ ) ２ , -P(=O)(CH ２ CH ３ ) ２ , -P(=O)(CH ３ ) (cyclopropyl), preferably R ｑａ teeth, 【Chemistry 9】 -CH ２ OH, Preferably, 【Chemistry 10】 teeth, 【Chemistry 11】 wherein Q is selected from １ optionally, 1 to 3 R ｑ is replaced by B is, 【Chemistry 12】 is selected from, preferably 【Chemistry 13】 5. The compound of claim 4, wherein:

6. 10. The compound of claim 1, or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the structures shown in Table E.

7. 10. A pharmaceutical composition comprising the compound of any one of claims 1 to 6 or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier, preferably the pharmaceutical composition comprising 1 to 1500 mg of the compound of any one of claims 1 to 6 or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.

8. 10. The use of a compound according to any one of claims 1 to 6 or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof in the manufacture of a medicament for treating and / or alleviating pain.

9. 10. A method for treating or alleviating a disease in a mammal, said method comprising administering to a subject a therapeutically effective amount of a compound of any one of claims 1 to 6, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and wherein the disease is preferably pain.

Images