Triazole derivative and pharmaceutical use thereof

Abstract

The present invention relates to a triazole derivative and a pharmaceutical use thereof.

Description

A triazole derivative and its pharmaceutical applications Technical Field

[0001] This invention relates to a triazole derivative or all its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts or cocrystals, pharmaceutical compositions thereof, and their use in medicine. Background Technology

[0002] APJ was first identified from a human genome library in 1993 and is a member of the family of seven transmembrane G protein-coupled receptors.

[0003] The apelin / APJ system is widely expressed in various tissues, especially in the cardiovascular system, including the heart, kidneys, and blood vessels. The apelin / APJ pathway is a key regulator of skeletal muscle aging. Sarcopenia, clinically known as "skeletal muscle aging" or "sarcopenia," refers to the decline in skeletal muscle mass and strength caused by aging. It generally manifests as denervation of skeletal muscle cells, mitochondrial dysfunction, inflammation, changes in hormone synthesis and secretion, and a series of consequences arising from these processes, such as decreased muscle strength, fatigue, metabolic disorders, and fractures. To date, no drugs targeting the apelin / APJ pathway have been marketed. Summary of the Invention

[0004] The object of this invention is to provide a triazole derivative, all its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts or cocrystals, pharmaceutical compositions thereof, and their use in medicine.

[0005] One or more embodiments of this application provide a compound of formula (I), or all of its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts, or cocrystals:

[0006] L1 is selected from

[0007] L2 is selected from NR3, O, C 1-6 Alkylene, C 2-6 Alynyl or 5-10 heteroaryl;

[0008] L3 does not exist; or

[0009] L3 is selected from H and C. 1-6 Alkylene, C 2-6 imidene group, C 2-6 Imyynyl group, the C 1-6 Alkylene, C2-6 imidene group, C 2-6 The ethynyl group may be further substituted by one or more R1 groups;

[0010] Ring A is selected from 5-12 membered carbocyclic groups and 5-12 membered heterocyclic groups;

[0011] R1 is independently selected from H, -OH, CN, carboxyl, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl may optionally be further surrounded by one or more OH, carboxyl, halogen, -CN, C 1-6 Halogenated alkyl, 3-10 membered heterocyclic alkyl, 5-10 membered aryl or 5-10 membered heteroaryl substitution;

[0012] R2 is independently selected from H, -OH, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 The alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl may optionally be further substituted by one or more substituents selected from -OH, -CN, halogen or carboxyl;

[0013] R3 is selected from H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, -NH2, carboxyl, amide, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 5-10 Aryl, 5-10 heteroaryl, -C 1-6 Alkylene-C 1-6 Alkoxy, -C 1-6 Alkylene -3 to 10-membered cycloalkyl, -C 1-6 Alkylene -3 to 10-membered heterocyclic alkyl, -C 1-6 Alkylene-C 5-10 Aryl or -C 1-6 alkylene-5 to 10-membered heteroaryl; the C 1-6The alkyl group is further substituted with one or more D molecules, namely, the 3-10 membered cycloalkyl group, the 3-10 membered heterocycloalkyl group, and the C alkyl group. 5-10 Aryl, 5-10 heteroaryl, -C 1-6 Alkylene-C 1-6 Alkoxy, -C 1- 6-alkylene-3 to 10-membered cycloalkyl, -C 1-6 Alkylene -3 to 10-membered heterocyclic alkyl, -C 1-6 Alkylene-C 5-10 Aryl or -C 1-6 alkylene-5 to 10-membered heteroaryl groups are further bounded by one or more C groups. 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkyl, -OH, -CN substitution;

[0014] R4 and R5 are each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered carbocyclic, 5-10 membered heteroaryl, 5-14 membered heterocyclic, -C 1-6 Alkylene-C 1-6 Alkoxy, -C 1-6 Alkylene -3 to 10-membered cycloalkyl, -C 1-6 Alkylene -3 to 10-membered heterocyclic alkyl, -C 1-6 alkylene-5 to 10-membered aryl, -C 1-6 alkylene-5 to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered carbocyclic, 5-10 membered heteroaryl, 5-14 membered heterocyclic, -C 1-6 Alkylene-C 1-6 Alkoxy, -C 1-6 Alkylene -3 to 10-membered cycloalkyl, -C 1-6 Alkylene -3 to 10-membered heterocyclic alkyl, -C 1-6 alkylene-5 to 10-membered aryl, -C 1-6 The alkylene-5 to 10-membered heteroaryl group is optionally further surrounded by one or more groups selected from -OH, -CN, halogen, carboxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -OC 1-6 Substitution with haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl;

[0015] R5 is selected from 5-12 membered carbon cyclogroups, wherein the 5-12 membered carbon cyclogroups are not substituted by 3 membered cycloalkyl groups;

[0016] m is selected from 0, 1, 2, 3, 4, 5 or 6.

[0017] It should be noted that when L3 is absent, L2 is directly connected to ring A.

[0018] In one or more embodiments of this application, L2 is selected from NR3, O, or C. 2-6 Alynyl group.

[0019] In one or more embodiments of this application, L2 is selected from NR3.

[0020] In one or more embodiments of this application, L2 is selected from NR3 or O.

[0021] In one or more embodiments of this application, R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, -C 1-6 Alkylene -3 to 10-membered cycloalkyl, -C 1-6 alkylene-3 to 10-membered heterocyclic alkyl; the C 1-6 The alkyl group is further substituted by one or more D atoms;

[0022] In one or more embodiments of this application, R3 is selected from C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -C 1-4 Alkylene-C 1-4 Alkoxy, -C 1-6 Alkylene - 3 to 6-membered cycloalkyl, -C 1-6 Alkylene-3 to 6-membered heterocyclic alkyl; the C 1-6 The alkyl group is further substituted with one or more D atoms.

[0023] In one or more embodiments of this application, R4 and R5 are each independently selected from C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered carbocyclic, 5-10 membered heteroaryl, -C 1-6 Alkylene -3 to 10-membered cycloalkyl, -C 1-6 Alkylene -3 to 10-membered heterocyclic alkyl, -C 1-6 alkylene-5 to 10-membered aryl, -C 1-6alkylene-5 to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered carbocyclic, 5-10 membered heteroaryl, 8-12 membered non-aromatic carbocyclic, -C 1-6 Alkylene -3 to 10-membered cycloalkyl, -C 1-6 Alkylene -3 to 10-membered heterocyclic alkyl, -C 1-6 alkylene-5 to 10-membered aryl, -C 1-6 The alkylene-5 to 10-membered heteroaryl group is optionally further surrounded by one or more groups selected from -OH, -CN, halogen, carboxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -OC 1-6 Substitution of alkyl halogens, 3-10 membered cycloalkyl groups, and 3-10 membered heterocycloalkyl groups.

[0024] In one or more embodiments of this application, R4 and R5 are each independently selected from C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered carbocyclic, 5-10 membered heterocyclic, -C 1-6 Alkylene -3 to 10-membered cycloalkyl, -C 1-6 Alkylene -3 to 10-membered heterocyclic alkyl, -C 1-6 alkylene-5 to 10-membered aryl, -C 1-6 alkylene-5 to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered carbocyclic, 5-10 membered heterocyclic, 8-12 membered non-aromatic carbocyclic, -C 1-6 Alkylene -3 to 10-membered cycloalkyl, -C 1-6 Alkylene -3 to 10-membered heterocyclic alkyl, -C 1-6 alkylene-5 to 10-membered aryl, -C 1-6 The alkylene-5 to 10-membered heteroaryl group is optionally further surrounded by one or more groups selected from -OH, -CN, halogen, carboxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -OC 1-6 Substitution of alkyl halogens, 3-10 membered cycloalkyl groups, and 3-10 membered heterocycloalkyl groups.

[0025] In one or more embodiments of this application, when L3 is present, L3 is selected from C. 1-6 Alkylene, the C 1-6 The alkylene group may optionally be further substituted with one or more R1s.

[0026] In one or more embodiments of this application, R1 is independently selected from H, -OH, -CN, halogen, carboxyl, C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 The alkoxy group may optionally be further substituted by one or more substituents selected from -OH, -CN, halogen, and carboxyl groups.

[0027] In one or more embodiments of this application, R1 is independently selected from H, -OH, -CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 The alkoxy group may optionally be further substituted by one or more substituents selected from -OH, -CN, halogen, and carboxyl groups.

[0028] In one or more embodiments of this application, ring A is selected from 6-10 aryl or 5-10 heteroaryl.

[0029] In one or more embodiments of this application, ring A is selected from 6-membered aromatic rings, 5-6-membered heteroaryl rings, and 8-10-membered bicyclic heteroaryl groups.

[0030] In one or more embodiments of this application, R2 is independently selected from H, -OH, halogen, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl.

[0031] In one or more embodiments of this application, R4 is selected from C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 5-10 aryl, 5-10 heteroaryl, -C 1-6 Alkylene -3 to 10-membered cycloalkyl, -C 1-6 alkylene-3 to 10-membered heterocyclic alkyl, wherein the 5-10-membered aryl, 5-10-membered heteroaryl, -C 1-6Alkylene -3 to 10-membered cycloalkyl, -C 1-6 Alkylene-3 to 10-membered heterocyclic alkyl groups optionally further selected from -OH, -CN, halogen, carboxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Substitution with alkoxy or 3-6 membered cycloalkyl groups.

[0032] In one or more embodiments of this application, R4 is selected from C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 5-8 Aryl, 5-8 membered heteroaryl, 5-10 membered heterocyclic, -C 1-4 Alkylene-C 1-4 Alkoxy, -C 1-6 Alkylene - 3 to 6-membered cycloalkyl, -C 1-6 alkylene-3 to 6-membered heterocyclic alkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 5-8 Aryl, 5-8 membered heteroaryl, 5-10 membered heterocyclic, -C 1-4 Alkylene-C 1-4 Alkoxy, -C 1-6 Alkylene - 3 to 6-membered cycloalkyl, -C 1-6 Alkylene-3 to 6-membered heterocyclic alkyl groups optionally further surrounded by one or more groups selected from -OH, -CN, halogen, carboxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Substitution with alkoxy or 3-6 membered cycloalkyl groups.

[0033] In one or more embodiments of this application, R5 is selected from C. 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl, C 5-6 Aryl, 5-6 membered heteroaryl, 12 membered carbocyclic or -C 1-4 alkylene-3 to 6-membered cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 5-6 Aryl, 5-6 membered heteroaryl, 12 membered carbocyclic or -C 1-4 Alkylene-3 to 6-membered cycloalkyl groups are optionally further surrounded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -OC 1-6 Substitution with haloalkyl, 3-6 membered cycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl groups.

[0034] In one or more embodiments of this application, R5 is selected from C. 5-6 When aryl, the C 5-8 The aryl group is not substituted by a 3-membered cycloalkyl group.

[0035] In one or more embodiments of this application, m is selected from 0, 1, 2, 3, 4, 5 or 6.

[0036] In one or more embodiments of this application, R3 is selected from C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -C 1-3 Alkylene-C 1-3 Alkoxy, -C 1-4 Alkylene - 3 to 6-membered cycloalkyl or -C 1-4 Alkylene-3 to 6-membered heterocyclic alkyl; the C 1-6 The alkyl group is further substituted with one or more D atoms.

[0037] In one or more embodiments of this application, when L3 is present, L3 is selected from the C-chain. 1-4 Alkylene, the C 1-4 The alkylene group may optionally be further substituted with one or more R1s.

[0038] In one or more embodiments of this application, R1 is independently selected from halogen or C. 1-6 Halogenated alkyl groups.

[0039] In one or more embodiments of this application, ring A is selected from phenyl, 6-membered monocyclic heteroaryl, and 9-membered bicyclic heteroaryl.

[0040] In one or more embodiments of this application, R2 is independently selected from H, halogen, -CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0041] In one or more embodiments of this application, R4 is selected from C. 1-6 Alkoxy, phenyl, 5-6 heteroaryl, -C 1-4 alkylene-3 to 6-membered heterocyclic alkyl, wherein the C 1-6 Alkoxy, 5-6 aryl, 5-6 heteroaryl, -C 1-4 Alkylene-3 to 6-membered heterocyclic alkyl groups optionally further comprising one or more C16 groups. 1-6 Alkyl, C 1-6 Substitution with alkoxy or 3-6 membered cycloalkyl groups.

[0042] In one or more embodiments of this application, R4 is selected from C.1-6 Alkyl, C 1-6 Alkoxy, C 5-6 Aryl, 5-6 membered heteroaryl, 8 membered bicyclic heterocyclic, -C 1-4 alkylene-azacyclobutane, -C 1-3 Alkylene-C 1-3 Alkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy, C 5-6 Aryl, 5-6 membered heteroaryl, 8 membered bicyclic heterocyclic, -C 1-4 alkylene-azacyclobutane, -C 1-3 Alkylene-C 1-3 The alkoxy group may optionally be further surrounded by one or more elements selected from halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Substitution with alkoxy or 3-5 membered cycloalkyl groups.

[0043] In one or more embodiments of this application, R5 is selected from C. 1-4 Alkyl, C 1-4 Alkoxy, 3-5 membered cycloalkyl, C 5-6 aryl, 6-membered heteroaryl, 12-membered fused carbocyclic or -C 1-4 alkylene-cyclopropyl, wherein C 1-4 Alkyl, C 1-4 Alkoxy, 3-5 membered cycloalkyl or -C 1-4 alkylene-cyclopropyl group is optionally further surrounded by one or more elements selected from halogen, C 1-4 Alkoxy, -OC 1-4 Halogenated alkyl, cyclopropyl, C 5-6 Substituents of aryl or 6-membered heteroaryl groups; the C 5-6 Aryl, 6-membered heteroaryl, and 12-membered fused carbocyclic groups are optionally further selected by one or more halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyl or -OC 1-4 Substitution of alkyl halogens.

[0044] In one or more embodiments of this application, m is selected from 0, 1 or 2.

[0045] In one or more embodiments of this application, group fragments Selected from

[0046] The definitions of R2 and m are the same as those in general formula (I).

[0047] In one or more embodiments of this application, ring A is selected from...

[0048] In one or more embodiments of this application, R2 is each independently selected from H, F, Cl, -CN, methyl or CF3.

[0049] In one or more embodiments of this application, R3 is selected from C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, cyclopropyl, cyclobutyl, cyclopentyl, -C 1-3 alkylene-cyclopropyl, -C 1-3 alkylene-cyclobutyl, -C 1-3 alkylene-cyclopentyl, -C 1- 3-alkylene-tetrahydrofuran.

[0050] In one or more embodiments of this application, R3 is selected from C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, cyclopropyl, cyclobutyl, cyclopentyl, -C 1-3 alkylene-methoxy, -C 1-3 alkylene-cyclopropyl, -C 1-3 alkylene-cyclobutyl, -C 1- 3-alkylene-oxehericyclic butyl, -C 1-3 alkylene-cyclopentyl, -C 1-3 Alkylene-tetrahydrofuranyl.

[0051] In one or more embodiments of this application, R4 is selected from C. 1-6 Alkyl, C 1-6 Alkoxy, pyridinyl, furanyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl The pyridyl, furanyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl groups mentioned above. Optionally further selected by one or more halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Substitution with alkoxy or 3-4 membered cycloalkyl groups.

[0052] In one or more embodiments of this application, R4 is selected from C. 1-4 Alkyl, -C 1-3 alkylene-ethoxy, pyridinyl, furanyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, methylene-azacyclobutane or The pyridyl, furanyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, methylene-azacyclobutane or Optionally further substituted with one or more substituents selected from F, Cl, methyl, ethyl, difluoromethyl, trifluoroethyl, methoxy or cyclopropyl.

[0053] In one or more embodiments of this application, R5 is selected from C. 1-6 Alkyl, C 1-6 Alkoxy, phenyl, pyridyl, pyrimidinyl, The C 1-6 Alkyl, C 1-6 Alkoxy, Optionally further substituted with one or more cyclopropyl, phenyl, or pyridyl substituents, wherein the phenyl, pyridyl, pyrimidinyl, or... Optionally further selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, -OC 1-4 Substituents of haloalkyl groups.

[0054] In one or more embodiments of this application, R5 is selected from C. 1-3 Alkyl, C 1-3 Alkoxy, phenyl, pyridyl, pyrimidinyl, The C 1-3 Alkyl, C 1-3 Alkoxy, Optionally further substituted with one or more cyclopropyl, phenyl, pyridyl, or methoxy substituents, wherein the phenyl, pyridyl, pyrimidinyl, or... Optionally further substituted with one or more substituents selected from F, Cl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, and -O-difluoromethyl haloalkyl.

[0055] In one or more embodiments of this application, the group fragment Selected from at least one of the following structures:

[0056] In one or more embodiments of this application, L2 is selected from at least one of the following structures: -O-,

[0057] In one or more embodiments of this application, R3 is selected from at least one of the following structures: methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, ...

[0058] In one or more embodiments of this application, R3 is preferably methyl.

[0059] In one or more embodiments of this application, R4 is selected from at least one of the following structures:

[0060] In one or more embodiments of this application, R5 is selected from at least one of the following structures:

[0061] In one or more embodiments of this application, the compound is a compound of formula (II), or any stereoisomer, tautomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal of a compound of formula (II).

[0062] The definitions of R4, R3, A, R2 and m are as described in any of the embodiments of this invention.

[0063] In one or more embodiments of the application, the compound is a compound of formula (II-1), or any stereoisomer, tautomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal of a compound of formula (II-1).

[0064] R4, A, R2 and m are defined as described in any of the embodiments of this invention.

[0065] In one or more embodiments of this application, the compound is a compound of formula (III), or any stereoisomer, tautomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal of a compound of formula (III).

[0066] Wherein, R4, R3, R2 and m are defined as described in any of the embodiments of the present invention;

[0067] X1, X2, and X3 are selected from C or N respectively, and at least one of X1, X2, and X3 is N.

[0068] In one or more embodiments of this application, the Selected from

[0069] In one or more embodiments of this application, the Selected from

[0070] In one or more embodiments of this application, the compound is a compound of formula (III-1), or any stereoisomer, tautomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal of a compound of formula (III-1).

[0071] Wherein, R4, R2 and m are defined as described in any of the embodiments of the present invention;

[0072] X1, X2, X 3、 The definition is the same as that of the compound shown in formula (III).

[0073] In one or more embodiments of this application, the compound is a compound of formula (IV), or any stereoisomer, tautomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal of a compound of formula (IV).

[0074] Wherein, R2, R3 and m are defined as described in any of the embodiments of the present invention;

[0075] X1, X2, and X3 are selected from C or N respectively, and at least one of X1, X2, and X3 is N;

[0076] X4, X5, and X6 are selected from C or N respectively, and at least one of X4, X5, and X6 is N;

[0077] R6 is selected from halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyl group.

[0078] In one or more embodiments of this application, X5 is N, and at least one of X4 and X6 is N.

[0079] In one or more embodiments of this application, the for

[0080] In one or more embodiments of this application, R6 is selected from methyl, ethyl, and...

[0081] In one or more embodiments of this application, the for

[0082] In one or more embodiments of this application, the compound is the compound represented by formula (IV-1), or any stereoisomer, tautomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal of the compound represented by formula (IV-1).

[0083] Wherein, R2, R3 and m are defined as described in any of the embodiments of the present invention;

[0084] X1, X2, X3, X4, X5, X6, R6, The definition is the same as that of the compound shown in formula (IV).

[0085] In one or more embodiments of this application, it is a compound of formula (V), or any stereoisomer, tautomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal of a compound of formula (V):

[0086] Wherein, R2, R3 and m are defined as described in any of the embodiments of the present invention;

[0087] X1, X2, and X3 are selected from C or N respectively, and at least one of X1, X2, and X3 is N;

[0088] X7, X8, and X9 are selected from C or N respectively, and at least one of X7, X8, and X9 is N;

[0089] R7 is selected from halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyl group.

[0090] In one or more embodiments of this application, the Selected from

[0091] In one or more embodiments of this application, R7 is selected from methyl, ethyl, Cl, and methoxy.

[0092] In one or more embodiments of this application, the Selected from

[0093] In one or more embodiments of this application, it is a compound of formula (V-1), or any stereoisomer, tautomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal of a compound of formula (V-1):

[0094] Wherein, R2 and m are defined as described in any of the embodiments of the present invention;

[0095] X1, X2, X3, X7, X8, X9, R7, The definition is the same as that of the compound shown in formula (V).

[0096] In one or more embodiments of this application, the compound is a compound of formula (VI), or any stereoisomer, tautomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal of a compound of formula (VI).

[0097] Wherein, R2, R3 and m are defined as described in any of the embodiments of the present invention;

[0098] R4 is selected from at least one of the following structures:

[0099] In one or more embodiments of this application, the compound is a compound of formula (VI-1), or any stereoisomer, tautomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal of a compound of formula (VI-1).

[0100] Wherein, R2 and m are defined as described in any of the embodiments of the present invention;

[0101] The definition of R4 is the same as that of the compound shown in formula (VI).

[0102] In one or more embodiments of this application, the compound is a compound of formula (VII), or any stereoisomer, tautomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal of a compound of formula (VII).

[0103] Wherein, R3 and R4 are defined as described in any of the embodiments of the present invention;

[0104] R 2-1 and R 2-2 Each has the definition of R2 as described in any of the embodiments of the present invention.

[0105] In one or more embodiments of this application, R 2-1 For H, methyl, Cl, CN, CF3; R 2-2 For H and F.

[0106] In one or more embodiments of this application, the compound is a compound of formula (VII-1), or any stereoisomer, tautomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal of a compound of formula (VII-1).

[0107] Wherein, R4 is defined as described in any of the embodiments of the present invention;

[0108] R 2-1 and R 2-2 The definition is the same as that of the compound shown in formula (VII).

[0109] In one or more embodiments of this application, a compound, or its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts, or cocrystals, wherein the compound is selected from:

[0110] In one or more embodiments of this application, a pharmaceutical composition is provided, the pharmaceutical composition comprising:

[0111] The above-mentioned compounds or their pharmaceutically acceptable salts, stereoisomers, hydrates, solvates, isotopes or tautomers;

[0112] One or more pharmaceutically acceptable carriers and / or excipients.

[0113] In one or more embodiments of this application, a pharmaceutical composition is provided, the pharmaceutical composition comprising: the above-mentioned compound, or all of its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts or cocrystals; and optionally one or more pharmaceutically acceptable carriers and / or excipients.

[0114] In one or more embodiments of this application, the above-described compound or its pharmaceutically acceptable salts, stereoisomers, hydrates, solvates, isotopes, and tautomers are used as APJ agonists.

[0115] In one or more embodiments of this application, the above-described compound, or all its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts or eutectics, or the above-described pharmaceutical compositions are used in the preparation of a medicament as an APJ agonist.

[0116] In one or more embodiments of this application, the above-described pharmaceutical composition or compound, or its pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, isotope, or tautomer, is used in the preparation of medicaments for treating and / or preventing aging-related diseases.

[0117] In one or more embodiments of this application, the above-described pharmaceutical composition, or the above-described compound, or all of its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts, or cocrystals are used in the preparation of medicaments for treating and / or preventing aging-related diseases.

[0118] In one or more embodiments of this application, the use of the above-described pharmaceutical composition or the compound or its pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, isotope, or tautomer in the preparation of a weight-loss medicament.

[0119] In one or more embodiments of this application, the use of the above-described pharmaceutical composition, or the above-described compound, or all of its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts, or eutectics in the preparation of a weight-loss medicament.

[0120] In one or more embodiments of this application, the use of the above-described pharmaceutical composition or the compound or its pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, isotope, or tautomer in the preparation of a muscle-building medicament is described.

[0121] In one or more embodiments of this application, the use of the above-described pharmaceutical composition, or the above-described compound, or all of its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts, or eutectics in the preparation of a muscle-building medicament.

[0122] In one or more embodiments of this application, the above-described pharmaceutical composition or the compound or its pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, isotope, or tautomer is used in the preparation of a medicament for treating and / or preventing cardiovascular diseases.

[0123] In one or more embodiments of this application, the above-described pharmaceutical composition, or the above-described compound, or all of its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts, or cocrystals are used in the preparation of medicaments for the treatment and / or prevention of cardiovascular diseases.

[0124] In one or more embodiments of this application, the above-described pharmaceutical composition or the compound or its pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, isotope, or tautomer is used in the preparation of a medicament for regulating pulmonary vascular resistance, regulating right ventricular afterload, and / or regulating mean pulmonary artery pressure.

[0125] In one or more embodiments of this application, the above-described pharmaceutical composition, or the above-described compound, or all of its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts, or cocrystals are used in the preparation of medicaments for regulating pulmonary vascular resistance, regulating right ventricular afterload, and / or regulating mean pulmonary artery pressure.

[0126] In one or more embodiments of this application, the above-described pharmaceutical composition or the compound or its pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, isotope, or tautomer is used in the preparation of a medicament for the prevention and / or treatment of pulmonary hypertension.

[0127] In one or more embodiments of this application, the above-described pharmaceutical composition, or the above-described compound, or all of its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts, or eutectics are used in the preparation of a medicament for the prevention and / or treatment of pulmonary hypertension.

[0128] In one or more embodiments of this application, the above-described pharmaceutical composition, or the above-described compound, or all of its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts, or cocrystals are used as APJ agonists.

[0129] In one or more embodiments of this application, the use of the above-described pharmaceutical composition, or the above-described compound, or all of its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts, or cocrystals in the treatment and / or prevention of age-related diseases.

[0130] In one or more embodiments of this application, the use of the above-described pharmaceutical composition, or the above-described compound, or all of its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts, or cocrystals in weight loss.

[0131] In one or more embodiments of this application, the use of the above-described pharmaceutical composition, or the above-described compound, or all of its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts, or cocrystals in muscle building.

[0132] In one or more embodiments of this application, the use of the above-described pharmaceutical composition, or the above-described compound, or all of its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts, or cocrystals in the treatment and / or prevention of cardiovascular diseases.

[0133] In one or more embodiments of this application, the use of the above-described pharmaceutical composition, or the above-described compound, or all of its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts, or cocrystals in regulating pulmonary vascular resistance, regulating right ventricular afterload, and / or regulating mean pulmonary artery pressure.

[0134] In one or more embodiments of this application, the use of the above-described pharmaceutical composition, or the above-described compound, or all of its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts, or cocrystals in the prevention and / or treatment of pulmonary hypertension.

[0135] In one or more embodiments of this application, a method for treating and / or preventing age-related diseases is provided. According to an embodiment of this application, the method includes administering to a subject an effective amount of the compound described above, or all its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts or cocrystals, or a pharmaceutical composition thereof.

[0136] In one or more embodiments of this application, this application provides a method for weight loss and / or muscle gain. According to an embodiment of this application, the method includes: administering to a subject an effective amount of the above-described compound, or all its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts or cocrystals, or the above-described pharmaceutical compositions.

[0137] In one or more embodiments of this application, this application provides a method for treating and / or preventing cardiovascular disease. According to an embodiment of this application, the method includes administering to a subject an effective amount of the above-described compound, or all its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts or cocrystals, or the above-described pharmaceutical compositions.

[0138] In one or more embodiments of this application, this application provides a method for regulating pulmonary vascular resistance, regulating right ventricular afterload, and / or regulating mean pulmonary artery pressure. According to embodiments of this application, the method includes administering to a subject an effective amount of the above-described compound, or all its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts or cocrystals, or the above-described pharmaceutical compositions.

[0139] In one or more embodiments of this application, a method for preventing and / or treating pulmonary hypertension is provided. According to an embodiment of this application, the method includes administering to a subject an effective amount of the above-described compound, or all its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts or cocrystals, or the above-described pharmaceutical compositions.

[0140] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0141] The carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I involved in the groups and compounds described in this invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, isotopes of fluorine include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0142] In this invention, when specifying the number of substituents, the term "one or more" refers to one substitution up to the maximum possible number of substitutions, that is, from substituting one hydrogen to substituting all hydrogens. When specifying the number of substituents, for example, the term "1-4" refers to 1, 2, 3, or 4 substitutions, that is, 1, 2, 3, or 4 hydrogens are substituted by substituents.

[0143] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group with 1 to 20 carbon atoms, preferably an alkyl group with 1 to 8 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8), more preferably an alkyl group with 1 to 6 carbon atoms, further preferably an alkyl group with 1 to 4 carbon atoms, and even more preferably an alkyl group with 1 to 3 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 isomers thereof; when the alkyl group is substituented, it may optionally be further substituted by one or more substituents.

[0144] "alkylene" refers to a divalent group derived from an alkane, which can be straight-chain or branched. The alkylene group preferably has 1 to 8 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8), more preferably 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, 6), even more preferably 1 to 4 carbon atoms (e.g., 1, 2, 3, 4), and even more preferably 1 to 3 carbon atoms (e.g., 1, 2, 3). Non-limiting examples include methylene, ethylene, etc.

[0145] "Alkoxy" refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy. The definition of alkyl is the same as that of "alkyl" as described above.

[0146] "Alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds, composed of 2 to 20 carbon atoms, preferably alkenyl groups with 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably alkenyl groups with 2 to 8 carbon atoms, and even more preferably alkenyl groups with 2 to 6 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl, and undecen-3-yl. The alkenyl group may optionally be further replaced by one or more substituents.

[0147] "Alkenyl" refers to a divalent group derived from an alkenyl group, which can be straight-chain or branched. The alkylene group preferably has 2 to 8 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8), more preferably 2 to 6 carbon atoms (e.g., 2, 3, 4, 5, 6), and even more preferably 2 to 4 carbon atoms (e.g., 2, 3, 4).

[0148] "Alynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon triple bonds, composed of 2 to 20 carbon atoms, preferably an alkynyl group with 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably an alkynyl group with 2 to 8 carbon atoms, and even more preferably an alkynyl group with 2 to 6 carbon atoms. Non-limiting embodiments include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, pentyne-1-yl, pentyne-2-yl, hexyn-1-yl, 1-heptyne-1-yl, heptyne-3-yl, heptyne-4-yl, octyne-3-yl, nonyne-3-yl, decanyne-4-yl, undecanyne-3-yl, and dodecanyne-4-yl. The ethynyl group may optionally be further substituted with one or more substituents.

[0149] "Alynylene" refers to a divalent group derived from alkynyl, which can be straight-chain or branched. The alkylene group preferably has 2 to 8 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8), more preferably 2 to 6 carbon atoms (e.g., 2, 3, 4, 5, 6), and even more preferably 2 to 4 carbon atoms (e.g., 2, 3, 4).

[0150] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a 5- to 8-membered (e.g., 5, 6, 7, 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system. It can be a bridged ring or a spirocyclic ring. Non-limiting examples include phenyl and naphthyl groups. The aryl group may optionally be further substituted by one or more substituents.

[0151] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic ring containing 1 to 3 (e.g., 1, 2, 3) heteroatoms selected from N, O, or S, or a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system containing 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O, or S, preferably a 5- to 8-membered heteroaryl ring, wherein the 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms selectively substituted in the heteroaryl ring can be oxidized to various oxidation states. The heteroaryl group can be attached to a heteroatom or a carbon atom. The heteroaryl group can be a bridged ring or a spiro ring. Non-limiting examples include cyclopyridyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, thiophenyl, pyranyl, pyrroloyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, and pyrrolopyridyl. The heteroaryl group may optionally be further substituted with one or more substituents. "Hypoaryl" refers to a divalent group derived from a heteroaryl group.

[0152] "Carbocyclic group" or "carbocyclic" refers to a saturated or unsaturated aromatic ring or non-aromatic ring. When it is an aromatic ring, its definition is the same as that of "aryl" above; when it is a non-aromatic ring, it can be a monocyclic ring of 3 to 10 members (e.g., 3, 4, 5, 6, 7, 8, 9, 10 members), a bicyclic ring of 4 to 12 members (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 members), or a tricyclic system of 10 to 15 members (e.g., 10, 11, 12, 13, 14, 15 members). It can be a bridged ring or a spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. The “carbocyclic group” or “carbocyclic” may optionally be further replaced by one or more substituents.

[0153] "Heterocyclic group" or "heterocycle" refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl" above. When it is a non-aromatic heterocycle, it can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic group. The selectively substituted 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms in the ring of the "heterocyclic group" or "heterocycle" can be oxidized to various oxidation states; the "heterocyclic group" or "heterocycle" can be attached to a heteroatom or a carbon atom; the "heterocyclic group" or "heterocycle" can be a bridged ring or a spirocycle. Non-limiting examples of the "heterocyclic group" or "heterocycle" include epoxyethyl, epoxypropyl, azirropropyl, oxacyclobutyl, azirrobutyl, thioheterobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxhexacycloyl, azirroheptyl, oxacycloheptyl, thioheterobutyl, oxazorphinyl, diazorphinyl, thioazorphinyl, pyridinyl, piperidinyl, homopiperidinyl, furfural, etc. nylonyl, thiophenyl, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxylalkyl, 1,3-dithiaalkyl, dihydrofuranyl, dithiapentanecycloyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiaranyl, tetrahydropyrroleyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidyl Azolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxopentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, dihydrothiophenyl, pyrazolyl, imidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3] [1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptyl. The “heterocyclic group” or “heterocycle” may optionally be further substituted with one or more substituents.

[0154] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, which can be a monocyclic system of 3 to 10 members (e.g., 3, 4, 5, 6, 7, 8, 9, 10 members), a bicyclic system of 4 to 12 members (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 members), or a polycyclic system of 10 to 20 members (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 members), preferably with 3 to 10 carbon atoms, more preferably with 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, and cyclohepttrienyl, etc. When the cycloalkyl group is substituted, it may optionally be further substituted by one or more substituents.

[0155] "Heterocyclic alkyl" refers to a substituted or unsubstituted saturated non-aromatic cyclic group, which can be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1, 2, or 3 heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic group. The 1, 2, or 3 N or S atoms selectively substituted in the ring of the "heterocyclic alkyl" can be oxidized to various oxidation states; the "heterocyclic alkyl" can be attached to a heteroatom or a carbon atom; the "heterocyclic alkyl" can be a bridged ring or a spirocyclic ring. Non-limiting examples of “heterocyclic alkyl” include epoxyethyl, aziridine, oxacyclobutyl, aziridine, 1,3-dioxolanecycloyl, 1,4-dioxolanecycloyl, 1,3-dioxahexacycloyl, aziridine, piperidinyl, piperinyl, morpholinyl, thiomorpholinyl, 1,3-dithiaalkyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, aziridine[3.2.1]octyl, aziridine[5.2.0]nonyl, oxacyclo[5.3.1.1]dodecyl, aziridine, and oxaspiro[3.3]heptyl.

[0156] When the terms "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclic", "carbocyclic", "heterocyclic", "cycloalkyl", and "heterocyclic" mentioned above are substituted, they can be further replaced by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 Alkylamino, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -NR q4 Rq5 =NR q6 -C(=O)OC 1-6 Alkyl group, -OC (=O)C 1-6 Alkyl, -C(=O)NR q4 R q5 C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -OC(=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl, -OC(=O)C 3-8 Heterocyclic alkyl, -C(=O)OC 3-8 Heterocyclic alkyl groups, -OC (=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 2-6 alkenyl or -NHC(=O)C 2-6 The alkynyl group is substituted by a substituent, and the substituent is C1. -6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 Heterocyclic alkyl groups or -NHC(=O)C 3-8 The cycloalkyl group may optionally be further surrounded by one to three elements selected from OH, F, Cl, Br, I, C. 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or replaced by the =O substituent; R q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl; Rq2 R q3 Each is independently selected from H or C1-6 alkyl groups; wherein, R q4 R q5 Each is independently selected from H and C. 1-6 Alkyl group, -NH (C=NR) q1 )NR q2 R q3 -S(=O)2NR q 2 R q3 -C(=O)R q1 Or -C(=O)NR q2 R q3 The C mentioned therein 1-6 The alkyl group may optionally be further influenced by one or more elements selected from OH, F, Cl, Br, I, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 heteroaryl, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups; or R q4 With R q5 The N atom forms a 3- to 8-membered heterocycle, which may contain one or more heteroatoms selected from N, O or S.

[0157] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this invention, their pharmaceutically acceptable salts or prodrugs, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0158] "Carrier" refers to a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the compound given.

[0159] "Excipients" are inert substances added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0160] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0161] "Optional" or "optionally" or "selectively" means that the event or condition described below may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which it does not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may or may not be present, and the description includes both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group.

[0162] "Effective amount" or "effective dose" refers to an amount that is functional or active in humans and / or animals and is acceptable to humans and / or animals.

[0163] "Treatment" for any disease or condition refers to any treatment that can slow, interrupt, stop, control, or halt the progression of a disease or condition, but does not necessarily mean the complete disappearance of all symptoms of the disease or condition. It also includes preventative treatment of said symptoms, especially in patients susceptible to such disease or disorder. In some embodiments, "treatment" refers to improving a disease or condition (i.e., slowing, stopping, or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" refers to alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceptible to the patient. In still other embodiments, "treatment" refers to regulating a disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters), or both. In still other embodiments, "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0164] In many embodiments of the methods disclosed herein, the subject treated by the methods of this disclosure is ideally a human subject, although it should be understood that the various methods described herein are effective for all vertebrate species, which are intended to be included in the term "subject". Thus, a "subject" may include a human subject for various medical purposes, such as: for treating an existing condition or disease, or for a preventative treatment to prevent the onset of a condition or disease, or an animal (non-human) subject for medical, veterinary, or developmental purposes. Suitable animal subjects include: mammals, including but not limited to: primates, such as humans, monkeys, and apes; bovids, such as cattle and oxen; sheep, such as sheep; caprines, such as goats; hogs, such as pigs and hogs; equines, such as horses, donkeys, and zebras; felines, including wildcats and domestic cats; canines, including dogs; rabbits, including rabbits and hares; and rodents, including mice and rats. An animal may be a transgenic animal.

[0165] Nouns and representative reagents:

[0166] TEA: Triethylamine; TFA: Trifluoroacetic acid; EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; DCM: Dichloromethane; MeOH: Methanol; EA / EtOAc: Ethyl acetate; THF: Tetrahydrofuran; ACN: Acetonitrile; PE: Petroleum ether; DMAP: 4-Dimethylaminopyridine; DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene. Detailed Implementation

[0167] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0168] Preparation of intermediate J

[0169] 4-(2,6-Dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine J

[0170] 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine J

[0171] first step:

[0172] Nitrogen-(2,6-dimethoxyphenyl)-5-methylnicotinamide C

[0173] N-(2,6-dimethoxyphenyl)-5-methylnicotinamide

[0174] 5-Methylnicotinic acid A (13.7 g, 100 mmol) and 2,6-dimethoxyaniline B (18.2 g, 120 mmol) were added to dichloromethane (200 mL), followed by the sequential addition of DMAP (611 mg, 5 mmol) and EDCI (23.0 g, 120 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (200 mL), washed with water (3 × 50 mL) and brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was purified by rapid column chromatography (eluting with PE / EtOAc = 20 / 1 to 1 / 1) to give the title compound N-(2,6-dimethoxyphenyl)-5-methylnicotinamide C (22.0 g, yield 80.6%).

[0175] LC-MS m / z (ESI) = 273.2 [M+H] + .

[0176] Step Two:

[0177] Nitrogen-(2,6-dimethoxyphenyl)-5-methylpyridine-3-methylthioamide D

[0178] N-(2,6-dimethoxyphenyl)-5-methylpyridine-3-carbothioamide

[0179] Nitrogen-(2,6-dimethoxyphenyl)-5-methylnicotinamide C (1.0 g, 3.7 mmol) was added to toluene (10 ml), followed by Lawson's reagent (1.04 g, 2.6 mmol). The reaction mixture was kept under nitrogen protection and refluxed for 3 hours. After the reaction was completed, dichloromethane (20 ml) was added to dissolve the mixture, and then it was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15:1) to obtain nitrogen-(2,6-dimethoxyphenyl)-5-methylpyridine-3-methylthioamide D (430 mg, yield 40.3%).

[0180] LCMS m / z(ESI) = 289.1 [M+H] + .

[0181] Step 3:

[0182] Nitrogen-(2,6-dimethoxyphenyl)-5-methylnicotinamide E

[0183] N-(2,6-dimethoxyphenyl)-5-methylnicotinohydrazonamide

[0184] Nitrogen-(2,6-dimethoxyphenyl)-5-methylpyridine-3-methylthioamide D (430 mg, 1.49 mmol) was added to 1,4-dioxane (1.5 ml), followed by the addition of hydrazine hydrate (746 mg, 14.9 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 16 hours. After the reaction was completed, the mixture was directly lyophilized to obtain a light green solid, nitrogen-(2,6-dimethoxyphenyl)-5-methylnicotinamide E (430 mg, crude product), which was used directly in the next step.

[0185] LC-MS m / z (ESI) = 287.2 [M+H] + .

[0186] Step 4:

[0187] 4-(2,6-Dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4-hydro-1,2,4-triazol-3-carboxylic acid ethyl ester F

[0188] ethyl 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazole-3-carboxylate

[0189] Nitrogen-(2,6-dimethoxyphenyl)-5-methylnicotinamide E (430 mg, crude) was added to oxaloyl chloride monoethyl ester (3 ml). Under nitrogen protection, the mixture was heated to 130 °C and reacted for 3 hours. After the reaction was completed, the reaction mixture was evaporated to dryness and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give ethyl 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4-hydro-1,2,4-triazol-3-carboxylic acid ester F (120 mg, two-step yield 21.8%).

[0190] LC-MS m / z (ESI) = 369.2 [M+H] + .

[0191] Step 5:

[0192] 3-(4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-5-methylpyridine G

[0193] 3-(4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-5-methylpyridine

[0194] Ethyl 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-carboxylic acid ester F (1.5 g, 4.1 mmol) was added to a mixture of methanol (20 ml) and purified water (20 ml), followed by the addition of lithium hydroxide solid (195 mg, 8.2 mmol). The resulting mixture was stirred at room temperature for 2 h. After the reaction was complete, the pH was adjusted to 3 with 2 mol / L ethyl hydrochloride solution, and stirred at room temperature for 0.5 h. Then, saturated sodium bicarbonate aqueous solution was added to adjust the pH to 8, and finally, ethyl acetate was added for extraction three times (50 ml × 3). The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1 to 1:1) to give 3-(4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-5-methylpyridine G (950 mg, yield 78.1%).

[0195] LC-MS m / z (ESI) = 297.1 [M+H] + .

[0196] Step 6:

[0197] 3-(5-bromo-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-5-methylpyridine H

[0198] 3-(5-bromo-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-5-methylpyridine

[0199] The starting material 3-(4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-5-methylpyridine G (950 mg, 3.2 mmol) was added to tetrahydrofuran (20 ml), followed by N-bromosuccinimide (855 mg, 4.8 mmol). Under nitrogen protection, the reaction mixture was slowly heated to reflux for 2 hours. After the reaction was completed, the mixture was directly purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1 to 1:1) to obtain 3-(5-bromo-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-5-methylpyridine H (800 mg, yield 66.7%).

[0200] LC-MS m / z(ESI)=375.1[M+1]or 377.1[M+H] + .

[0201] Step 7:

[0202] N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-2-methylpropane-2-sulfonamide I

[0203] N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-2-methylpropane-2-sulfonamide

[0204] 3-(5-bromo-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-5-methylpyridine H (2 g, 5.33 mmol) was dissolved in 50 mL of 1,4-dioxane, and tert-butylsulfonamide (2.2 g, 16 mmol) and CuI (4.1 g, 21.3 mmol) were added. The reaction was carried out at 100 °C for 8 hours. The reaction was monitored by LCMS until it was complete. The reaction was quenched with ammonia until the system was clear. The mixture was then extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The mixture was purified by reverse phase to give the target compound N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridine-3-yl)-4H-1,2,4-triazol-3-yl)-2-methylpropane-2-sulfonamide I (yellow solid, 1.1 g, 44% yield).

[0205] LC-MS m / z (ESI) = 432.10 [M+H] + .

[0206] Step 8:

[0207] 4-(2,6-Dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine J

[0208] 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine

[0209] N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-2-methylpropane-2-sulfonamide I (1.1 g, 2.5 mmol) was dissolved in 5.5 mL of trifluoroacetic acid, and anisole (0.83 g, 7.5 mmol) was added. Nitrogen gas was added to replace the nitrogen atmosphere, and the reaction was carried out at 100 °C for 16 h. The reaction was monitored by LCMS until completion. The reaction solution was evaporated to dryness, and the mixture was purified by reverse phase to obtain the target compound 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine J (pale yellow solid, 450 mg, 57% yield).

[0210] LC-MS m / z (ESI) = 312.10 [M+H] + .

[0211] Example 1

[0212] N-(N-(5-chloropyridin-2-yl)methyl)sulfonyl)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine compound 1

[0213] N-(N-(5-chloropyridine-2-)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-methyl pyridine-3-)-4H-1,4-trichlorobenzene triazole-3-amine

[0214] first step:

[0215] (5-chloropyridin-2-yl)methyl)sulfonyl fluoride 1-2

[0216] ((5-chloropyridin-2-yl)methyl)sulfamoyl fluoride

[0217] (5-chloropyridin-2-yl)methylamine 1-1 (500 mg, 3.5 mmol) was dissolved in THF, and (4-acetamidophenyl)(fluorosulfonyl)sulfonyl fluoride (AISF) (1.32 g, 4.2 mmol) was added. DBU (1.2 g, 7.7 mmol) was then slowly added dropwise, and the reaction was allowed to proceed for 10 min. The reaction was monitored by LCMS and TLC until complete. The reaction was quenched with aqueous KHSO4 solution, extracted with EA, and the organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The positive purification yielded the target compound (5-chloropyridin-2-yl)methyl)sulfonyl fluoride 1-2 (white solid, 300 mg).

[0218] LC-MS m / z (ESI) = 225.10 [M+H] + .

[0219] Step Two:

[0220] N-(N-(5-chloropyridin-2-yl)methyl)sulfonyl)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine compound 1

[0221] N-(N-(5-chloropyridine-2-)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-methyl pyridine-3-)-4H-1,4-trichlorobenzene triazole-3–amine

[0222] 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine J (50 mg, 0.16 mmol) was dissolved in 1 mL of acetonitrile, and (5-chloropyridin-2-yl)methyl)sulfonyl fluoride 1-2 (45 mg, 0.19 mmol) and DBU (50 mg, 0.32 mmol) were added. The reaction was carried out at 80 °C for 3 hours. The reaction was monitored by LCMS until completion. Ethyl acetate and water were added for extraction. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. Normal phase purification was performed to obtain the target compound N-(N-(5-chloropyridin-2-yl)methyl)sulfonyl)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine compound 1 (off-white solid, 3 mg).

[0223] LC-MS m / z (ESI) = 544.10 [M+H] + .

[0224] 1 H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.32(s,1H),8.17(s,1H),7.92(s,1H),7 .54(s,2H),7.43(s,1H),6.79(m,2H),3.94(s,2H),3.66(s,6H),2.21(s,3H).

[0225] Example 2

[0226] N-(N-(4-chlorophenyl)sulfonyl)-4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine compound 2

[0227] N-(N-(4-chlorophenyl)sulfanilamide)-4-(2,6-dimethoxyphenyl)-5-(5-methylpyridine-3-yl)-4H-1,2,4-triazole-3-amine

[0228] first step:

[0229] (4-Chlorobenzyl)sulfanilamide fluoride 2-2

[0230] (4-chlorobenzyl)sulfamoyl fluoride

[0231] (4-Chlorophenyl)methylamine 2-1 (1 g, 7.1 mmol) was dissolved in THF, and (4-acetamidophenyl)(fluorosulfonyl)sulfonyl fluoride (AISF) (2.7 g, 8.5 mmol) was added. DBU (2.4 g, 15.5 mmol) was then slowly added dropwise, and the reaction was allowed to proceed for 10 min. The reaction was monitored by LCMS and TLC until complete. The reaction was quenched with aqueous KHSO4 solution, extracted with EA, and the organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The positive purification yielded the target compound (4-chlorobenzyl)sulfanyl fluoride 2-2 (pale yellow liquid, 800 mg).

[0232] LC-MS m / z (ESI) = 224.10 [M+H] + .

[0233] Step Two:

[0234] N-(N-(4-chlorophenyl)sulfonyl)-4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine compound 2

[0235] N-(N-(4-chlorophenyl)sulfanilamide)-4-(2,6-dimethoxyphenyl)-5-(5-methylpyridine-3-yl)-4h-1,2,4-triazole-3-amine

[0236] 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine J (50 mg, 0.16 mmol) was dissolved in 1 mL of acetonitrile, and (4-chlorobenzyl)sulfanilamide fluoride 2-2 (110 mg, 0.48 mmol) and DBU (75 mg, 0.48 mmol) were added. The reaction was carried out at 80 °C for 3 hours. The reaction was monitored by LCMS until completion. Ethyl acetate and water were added for extraction. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The normal phase was purified to give the target compound N-(N-(4-chlorophenyl)sulfanilamide)-4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine compound 2 (white solid, 7 mg).

[0237] LC-MS m / z (ESI) = 515.10 [M+H] + .

[0238] 1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.20(s,1H),7.59(s,1H),7.50(t,1H),7.3 6–7.28(m,5H),6.95(t,1H),6.83(d,2H),3.92(d,2H),3.70(s,6H),2.25(s,3H).

[0239] Example 3

[0240] N-(N-(1-(4-chlorophenyl)ethyl)sulfonyl)-4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine compound 3

[0241] N-(N-(1-(4-chlorophenyl)ethyl)sulfanilamide)-4-(2,6-dimethoxyphenyl)-5-(5-methylpyridine-3-yl)-4H-1,2,4-triazole-3-amine

[0242] first step:

[0243] (1-(4-chlorophenyl)ethyl)sulfonyl fluoride 3-2

[0244] (1-(4-chlorophenyl)ethyl)sulfamoyl fluoride

[0245] 1-(4-chlorophenyl)ethyl-1-amine 3-1 (500 mg, 3.2 mmol) was dissolved in THF, and (4-acetaminophenyl)(fluorosulfonyl)sulfonyl fluoride (AISF) (1.21 g, 3.8 mmol) was added. DBU (1.1 g, 7.1 mmol) was then slowly added dropwise, and the reaction was allowed to proceed for 10 min. The reaction was monitored by LCMS and TLC until completion. The reaction was quenched with aqueous KHSO4 solution, extracted with EA, and the organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The positive purification yielded the target compound (1-(4-chlorophenyl)ethyl)sulfonyl fluoride 3-2 (pale yellow liquid, 400 mg).

[0246] LC-MS m / z (ESI) = 238.10 [M+H] + .

[0247] Step Two:

[0248] N-(N-(1-(4-chlorophenyl)ethyl)sulfonyl)-4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine compound 3

[0249] N-(N-(1-(4-chlorophenyl)ethyl)sulfanilamide)-4-(2,6-dimethoxyphenyl)-5-(5-methylpyridine-3-yl)-4H-1,2,4-triazole-3-amine

[0250] 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine J (50 mg, 0.16 mmol) was dissolved in 1 mL of acetonitrile, and (1-(4-chlorophenyl)ethyl)sulfonyl fluoride 3-2 (80 mg, 0.35 mmol) and DBU (55 mg, 0.35 mmol) were added. The reaction was carried out at 80 °C for 3 hours. The reaction was monitored by LCMS until completion. Ethyl acetate and water were added for extraction. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. Normal phase purification was performed to obtain the target compound N-(N-(1-(4-chlorophenyl)ethyl)sulfonyl)-4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine compound 3 (white solid, 30 mg).

[0251] LC-MS m / z (ESI) = 529.10 [M+H] + .

[0252] 1 H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.20(s,1H),7.60(s,1H),7.53–7.47(m,1H),7 .36–7.28(m,4H),6.83(m,2H),4.27(t,1H),3.72(d,6H),2.25(s,3H),1.28(d,3H).

[0253] Example 4

[0254] N-(N-(4-chlorophenyl)sulfonyl)-4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine compound 4

[0255] N-(N-(4-chlorophenyl)sulfanilamide)-4-(2,6-dimethoxyphenyl)-5-(5-methylpyri dine-3-yl)-4H-1,2,4-triazole-3-amine

[0256] first step:

[0257] (5-Chlorimyrimidin-2-yl)methyl)sulfonyl fluoride 4-2

[0258] ((5-chloropyrimidin-2-yl)methyl)sulfamoyl fluoride

[0259] (5-Chloropremine-2-yl)methylamine 4-1 (0.5 g, 2.8 mmol) was dissolved in THF, and (4-acetaminophenyl)(fluorosulfonyl)sulfonyl fluoride (AISF) (1.1 g, 3.4 mmol) was added. DBU (1.3 g, 8.4 mmol) was then slowly added dropwise, and the reaction was allowed to proceed for 10 min. The reaction was monitored by LCMS and TLC until complete. The reaction was quenched with aqueous KHSO4 solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then evaporated to dryness. The positive purification yielded the target compound (5-chloropyrimidin-2-yl)methyl)sulfonyl fluoride 4-2 (off-white solid, 200 mg).

[0260] Step Two:

[0261] N-(N-(5-chloropyrimidin-2-yl)sulfonyl)-4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine compound 4

[0262] N-(N-(5-chloropyrimidine-2-group)sulfanilamide)-4-(2,6-dimethoxyphenyl)-5-(5-methylpyridine-3-yl)-4H-1,2,4-triazole-3-amine

[0263] 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine J (50 mg, 0.16 mmol) was dissolved in 1 mL of acetonitrile, and (5-chloropyrimidin-2-yl)methyl)sulfonyl fluoride 4-2 (110 mg, 0.48 mmol) and DBU (75 mg, 0.48 mmol) were added sequentially. The reaction was carried out at 80 °C for 3 hours. The reaction was monitored by LCMS until completion. The mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then evaporated to dryness. The mixture was purified under normal phase to give the target compound N-(N-(5-chloropyrimidin-2-yl)sulfanilamide)-4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine compound 4 (white solid, 7 mg).

[0264] LC-MS m / z (ESI) = 517.10 [M+H] + .

[0265] 1 H NMR(400MHz,DMSO-d6)δ13.32(s,1H),8.88(s,2H),8.47(s,1H),8.19(s,1H), 7.59(s,1H),7.49(d,1H),6.81(d,3H),4.19(d,2H),3.69(s,6H),2.24(s,3H).

[0266] Example 5

[0267] (N-((5-chloropyridin-2-yl)methyl)aminosulfonyl)(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)amide sodium (I) compound 5

[0268] (N-((5-chloropyridin-2-yl)methyl)sulfamoyl)(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)amide sodium(I)

[0269] N-(N-(5-chloropyridin-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine compound 1 (20 mg, 0.039 mmol) was dissolved in 1 mL of dichloromethane, followed by the addition of 2N sodium hydroxide solution. The mixture was stirred at room temperature for 15 minutes, resulting in the precipitation of a large amount of solid. The solid was filtered, washed twice with dichloromethane, and dried to obtain the target compound (N-((5-chloropyridin-2-yl)methyl)aminosulfonyl)(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)amide sodium (I) compound 5.

[0270] LC-MS m / z (ESI) = 516.97 [M+H] + .

[0271] 1 H NMR(400MHz,DMSO-d6)δ8.51(d,1H),8.25(d,1H),8.15(d,1H),7.87(dd,1H),7.56–7.4 8(m,2H),7.39(t,1H),6.78(d,2H),6.10(t,1H),3.94(d,2H),3.65(s,6H),2.19(s,3H).

[0272] Example 6

[0273] N-(N-(5-fluoropyridin-2-yl)methyl)sulfonyl)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine compound 6

[0274] N-(N-(5-fluoropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-methylpyridine-3-)-4H-1,4-trichlorobenzene triazole-3–amine

[0275] first step:

[0276] ((5-Fluoropyridin-2-yl)methyl)sulfonyl fluoride 6-2

[0277] ((5-fluoropyridin-2-yl)methyl)sulfamoyl fluoride

[0278] (5-Fluoropyridin-2-yl)methylamine 6-1 (0.9 g, 8.49 mmol) was dissolved in THF, and (4-acetamidophenyl)(fluorosulfonyl)sulfonyl fluoride (AISF) (3.1 g, 10 mmol) was added. DBU (2.8 g, 22 mmol) was then slowly added dropwise, and the reaction was allowed to proceed for 30 min. The reaction was monitored by TLC until complete, quenched with aqueous KHSO4 solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. Purification by silica gel column chromatography yielded the target compound ((5-fluoropyridin-2-yl)methyl)sulfonyl fluoride 6-2 (off-white solid, 346 mg).

[0279] LC-MS m / z (ESI) = 209.01 [M+H] + .

[0280] Step Two:

[0281] N-(N-(5-fluoropyridin-2-yl)methyl)sulfonyl)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine compound 6

[0282] N-(N-(5-fluoro pyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-methyl pyridine-3-)-4H-1,4-trichlorobenzene triazole-3–amine

[0283] 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine J (75 mg, 0.24 mmol) was dissolved in 1 mL of acetonitrile, and ((5-fluoropyridin-2-yl)methyl)sulfonyl fluoride 6-2 (150 mg, 0.72 mmol) and DBU (110 mg, 0.72 mmol) were added sequentially. The reaction was carried out at 80 °C for 3 hours. The reaction was monitored by LCMS until completion. Ethyl acetate and water were added for extraction. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The organic phase was purified by silica gel column chromatography to obtain the target N-(N-(5-fluoropyridin-2-yl)methyl)sulfonyl)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine compound 6 (white solid, 38 mg).

[0284] LC-MS m / z (ESI) = 500.10 [M+H] + .

[0285] 1 H NMR (400MHz, DMSO-d6) δ = 8.46 (s, 2H), 8.20 (d, 1H), 7.68 (td, 1H), 7.59 (s, 1H), 7. 53–7.43(m,2H),6.95(t,1H),6.82(d,2H),4.05(d,2H),3.70(s,6H),2.24(s,3H).

[0286] Example 7

[0287] N-(N-(1-(5-chloropyridin-2-yl)ethyl)sulfonyl)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine compound 7

[0288] N-(N-(1-(5-chloropyridine-2-yl)ethyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-methylpyridine-3-)-4H-1,4-trichlorobenzene triazole-3-amine

[0289] first step:

[0290] (1-(5-chloropyridin-2-yl)ethyl)sulfonyl fluoride 7-2

[0291] (1-(5-chloropyridin-2-yl)ethyl)sulfamoyl fluoride

[0292] 1-(5-chloropyridin-2-yl)ethane-1-amine 7-1 (0.4 g, 1.72 mmol) was dissolved in THF, and (4-acetamidophenyl)(fluorosulfonyl)sulfonyl fluoride (AISF) (640 mg, 5.76 mmol) was added. DBU (928 mg, 6.88 mmol) was then slowly added dropwise, and the reaction was allowed to proceed for 30 min. The reaction was monitored by TLC until complete. The reaction was quenched with aqueous KHSO4 solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then evaporated to dryness. The resulting silica gel column chromatography purified the target compound (1-(5-chloropyridin-2-yl)ethyl)sulfonyl fluoride 7-2 (off-white solid, 184 mg).

[0293] LC-MS m / z (ESI) = 239.00 [M+H] + .

[0294] Step Two:

[0295] N-(N-(1-(5-chloropyridin-2-yl)ethyl)sulfonyl)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine compound 7

[0296] N-(N-(1-(5-chloropyridine-2-yl)ethyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-methylpyridine-3-)-4H-1,4-trichlorobenzene triazole-3-amine

[0297] 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine J (50 mg, 0.18 mmol) was dissolved in 1 mL of acetonitrile, and (5-fluoropyridin-2-yl)ethylsulfonyl fluoride 7-2 (130 mg, 0.54 mmol) and DBU (83 mg, 0.54 mmol) were added. The reaction was carried out at 80 °C for 3 hours. The reaction was monitored by LCMS until completion. Ethyl acetate and water were added for extraction. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The solution was purified by silica gel column chromatography to obtain the target N-(N-(1-(5-chloropyridin-2-yl)ethyl)sulfonyl)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine compound 7 (white solid, 24 mg).

[0298] LC-MS m / z (ESI) = 531.10 [M+H] + .

[0299] 1 H NMR (400MHz, DMSO-d6) δ = 13.32 (s, 1H), 8.45 (s, 2H), 8.20 (d, 1H), 7.68 (td, 1H), 7.59 (s, 1H), 7. 53–7.43(m,2H),6.95(t,1H),6.82(d,2H),4.35(t,1H),3.70(s,6H),2.24(s,3H).1.24(s,3H).

[0300] Example 8

[0301] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 8

[0302] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-methylpyridine-3-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[0303] first step:

[0304] (5-chloropyridin-2-yl)methyl)tert-butyl carbamate 8-2

[0305] tert-butyl((5-chloropyridin-2-yl)methyl)carbamate

[0306] The starting material (5-chloropyridin-2-yl)methylamine 8-1 (1.43 g, 10 mmol) was added to dichloromethane (20 mL), followed by the slow dropwise addition of di-tert-butyl dicarbonate (3.27 g, 15 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction was confirmed by LCMS, and the solution was directly concentrated to give the title compound (5-chloropyridin-2-yl)methyl)carbamate tert-butyl 8-2 (2.43 g, 100.0% yield).

[0307] LCMS m / z(ESI) = 243.1[M+H] + .

[0308] Step Two:

[0309] (5-chloropyridin-2-yl)methyl)(methyl)tert-butyl carbamate 8-3

[0310] tert-butyl((5-chloropyridin-2-yl)methyl)(methyl)carbamate

[0311] The starting material (5-chloropyridin-2-yl)methyl)tert-butyl carbamate 8-2 (2.43 g, 10 mmol) was added to N,N-dimethylformamide (20 mL), followed by the addition of cesium carbonate (6.52 g, 20 mmol) and iodomethane (2.13 g, 15 mmol). The reaction solution was reacted at room temperature for 3 hours. After the reaction was completed, the product was purified by reverse chromatography to obtain (5-chloropyridin-2-yl)methyl)(methyl)tert-butyl carbamate 8-3 (2.0 g, yield 77.5%).

[0312] LCMS m / z(ESI) = 257.1 [M+H] + .

[0313] Step 3:

[0314] 1-(5-chloropyridin-2-yl)-N-methylmethylamine 8-4

[0315] 1-(5-chloropyridin-2-yl)-N-methylmethanamine

[0316] The starting material (5-chloropyridin-2-yl)methyl(methyl)carbamate tert-butyl ester 8-3 (2.0 g, 7.8 mmol) was added to dichloromethane (10 mL), followed by trifluoroacetic acid (10 mL). The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was directly concentrated to obtain 1-(5-chloropyridin-2-yl)-N-methylmethylamine 8-4 (1.0 g, yield 81.7%).

[0317] LCMS m / z(ESI) = 157.1 [M+H] + .

[0318] Step 4:

[0319] (N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)tert-butyl carbamate 8-5

[0320] tert-butyl(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)carbamate

[0321] The starting material, tert-butanol (370 mg, 5.0 mmol), was added to dichloromethane (10 mL). Under nitrogen protection, the mixture was cooled to 0 °C, followed by the addition of chlorosulfonyl isocyanate (708 mg, 5.0 mmol). The reaction mixture was reacted at 0 °C for 1 hour, followed by the addition of triethylamine (505 mg, 5.0 mmol), resulting in the precipitation of a large amount of solid. Then, the starting material, 1-(5-chloropyridin-2-yl)-N-methylmethylamine 8-4 (314 mg, 2.0 mmol), was added, and the reaction mixture was slowly heated to room temperature. The reaction was confirmed by LCMS, and the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain (N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)carbamate tert-butyl 8-5 (440 mg, yield 65.5%).

[0322] LC-MS m / z (ESI) = 336.1 [M+H] + .

[0323] Step 5:

[0324] N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonamide 8-6

[0325] N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonamide

[0326] The starting material (440 mg, 1.3 mmol) of N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)carbamate tert-butyl ester 8-5 was added to dichloromethane (4 mL), followed by trifluoroacetic acid (4 mL). The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was directly concentrated to obtain N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonamide 8-6 (287 mg, yield 93.5%).

[0327] LC-MS m / z (ESI) = 236.1 [M+H] + .

[0328] Step 6:

[0329] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)thiocarbamoyl 8-7

[0330] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)carbamimidothioic acid

[0331] The starting material N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonamide 8-6 (5.4 g, 22.9 mmol) was added to an acetonitrile (100 mL) solution, followed by 2-isothiocyano-1,3-dimethoxybenzene (4.92 g, 2.32 mmol) and cesium carbonate (9.7 g, 29.8 mmol). The resulting mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was filtered to obtain a filter cake of N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)thiocarbamoyl 8-7 (15.3 g, 100% yield). This was used directly in the next step.

[0332] LC-MS m / z(ESI) = 432.0 [M+1].

[0333] Step 7:

[0334] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-diethylphenyl)-2-(5-methylnicotinyl)hydrazine-1-carboxamide 8-8

[0335] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-diethylphenyl)-2-(5-methylnicotinoyl)hydrazine-1-carboximidamide

[0336] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)thiocarbamoyl 8-7 (15.3 g) was added to tetrahydrofuran (100 mL), followed by 5-methylnicotinamide (3.5 g, 23 mmol) and then EDCI (5.7 g, 29.9 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 h. After the reaction was complete, the solution was directly evaporated to dryness. The solution was then dissolved in a 10:1 DCM:MeOH mixture (100 mL), washed three times with a saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain a crude product. The crude product was then slurried with ACN to obtain a white solid N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-diethylphenyl)-2-(5-methylnicotinyl)hydrazine-1-carboxamide 8-8 (6.7 g, yield 53.2%).

[0337] LC-MS m / z (ESI) = 548.1 [M+1].

[0338] Step 8:

[0339] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 8

[0340] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine

[0341] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-diethylphenyl)-2-(5-methylnicotinyl)hydrazine-1-carboxamide 8-8 (6.7 g, 12.2 mmol) was dissolved in TFA (67 mL) and reacted at 80 °C for 8 h. The reaction was monitored by LCMS until it was complete. The reaction was quenched by adding sodium bicarbonate aqueous solution, and then extracted with a DCM:MeOH mixed solution (10:1) (100 mL) and water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The mixture was then slurried with acetonitrile to give the target compound 8 (white solid, 3.6 g, 51.2% yield).

[0342] LC-MS m / z (ESI) = 530.1 [M+H] + .

[0343] 1 H NMR(400MHz,DMSO-d6)δ13.55(s,1H),8.56(d,1H),8.48(d,1H),8.21(d,1H),7.92(dd,1H),7.63( d,1H),7.52(t,1H),7.43(d,1H),6.85(d,2H),4.13(s,2H),3.71(s,6H),3.33(s,3H),2.25(s,3H).

[0344] Example 9

[0345] N-(N-(1-(5-chloropyridin-2-yl)ethyl)sulfonyl)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 9

[0346] N-(N-(1-(5-chloropyridine-2-yl)ethyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-methylpyridine-3-)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[0347] first step:

[0348] 1-(5-chloropyridin-2-yl)-N-methylethyl-1-amine 9-2

[0349] 1-(5-chloropyridin-2-yl)-N-methylethan-1-amine

[0350] 1-(5-chloropyridin-2-yl)acetone 9-1 (1.0 g, 6.5 mmol) and methylamine hydrochloride (439 mg, 6.5 mmol) were dissolved in tetrahydrofuran (10 mL), and acetic acid (0.4 mL, 6.5 mmol) was added. The mixture was stirred at room temperature for 1 h, followed by the addition of sodium cyanoborohydride (816 mg, 13 mmol), and the reaction was continued for another 1 h. The reaction was confirmed to be complete by LCMS. The reaction was quenched with sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified directly by column chromatography to obtain the target compound 1-(5-chloropyridin-2-yl)-N-methylethyl-1-amine 9-2 (800 mg, 73% yield).

[0351] Step Two:

[0352] (N-(1-(5-chloropyridin-2-yl)ethyl)-N-methylaminosulfonyl)tert-butyl carbamate 9-3

[0353] tert-butyl(N-(1-(5-chloropyridin-2-yl)ethyl)-N-methylsulfamoyl)carbamate

[0354] The starting material, tert-butanol (370 mg, 5.0 mmol), was added to dichloromethane (10 mL). After nitrogen protection, the mixture was cooled to 0 °C, and then chlorosulfonyl isocyanate (708 mg, 5.0 mmol) was added. The reaction mixture was reacted at 0 °C for 1 hour, followed by the addition of triethylamine (505 mg, 5.0 mmol), resulting in the precipitation of a large amount of solid. Then, the starting material, 1-(5-chloropyridin-2-yl)-N-methylethyl-1-amine 9-2 (340 mg, 2.0 mmol), was added, and the reaction mixture was slowly heated to room temperature. The reaction was confirmed by LCMS, and the mixture was concentrated under reduced pressure and purified directly by column chromatography to obtain (N-(1-(5-chloropyridin-2-yl)ethyl)-N-methylaminosulfonyl)carbamate tert-butyl 9-3 (430 mg, yield 61.4%).

[0355] LCMS m / z(ESI) = 350.1[M+H] + .

[0356] Step 3:

[0357] N-((5-chloropyridin-2-yl)ethyl)-N-methylaminosulfonamide 9-4

[0358] N-((5-chloropyridin-2-yl)ethyl)-N-methylaminosulfonamide

[0359] The starting material (N-(1-(5-chloropyridin-2-yl)ethyl)-N-methylaminosulfonyl)carbamate tert-butyl 9-3 (430 mg, 1.2 mmol) was added to dichloromethane (4 mL), followed by trifluoroacetic acid (4 mL). The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was directly concentrated to obtain N-((5-chloropyridin-2-yl)ethyl)-N-methylaminosulfonamide 9-4 (255 mg, yield 83.1%).

[0360] LCMS m / z(ESI) = 250.1 [M+H] + .

[0361] Step 4:

[0362] N-(N-(1-(5-chloropyridin-2-yl)ethyl)sulfonyl)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 9

[0363] N-(N-(1-(5-chloropyridine-2-yl)ethyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-methylpyridine-3-)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[0364] The following substances were added: N-((5-chloropyridin-2-yl)ethyl)-N-methylaminosulfonamide 9-4 (255 mg, 1.02 mmol), 3-(5-bromo-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-5-methylpyridine (300 mg, 0.8 mmol), cesium carbonate (652 mg, 2.0 mmol), cuprous iodide (190 mg, 1.0 mmol), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (284 mg, 2.0 mmol). mmol) was added to 1,4-dioxane (3 mL), and reacted in a microwave at 110 °C for 2 hours. After the reaction was completed, dichloromethane (10 mL) and mercaptosilica (2 g) were added and stirred vigorously for 1 hour. After filtration and concentration, the product was purified by reverse column chromatography to obtain the target product N-(N-(1-(5-chloropyridin-2-yl)ethyl)sulfonyl)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 9 (95 mg, yield 21.8%).

[0365] LC-MS m / z (ESI) = 544.2 [M+H] + .

[0366] 1 H NMR(400MHz, DMSO-d6)δ=8.54(d,1H),8.39(s,1H),8.17(d,1H),7.84(dd,1H),7.58(d,1H),7.55(d,1H), 7.46(t,1H),6.80(dd,2H),5.08(q,1H),3.68(s,3H),3.63(s,3H),2.42(s,3H),2.23(s,3H),1.35(d,3H).

[0367] Example 10

[0368] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 10

[0369] N-(N-(5-chloro-3-fluoropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-methylpyridine-3-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[0370] first step:

[0371] 1-(5-chloropyridin-2-yl)-N-methylmethylamine 10-2

[0372] 1-(5-chloro-3-fluoropyridin-2-yl)-N-methylmethanamine

[0373] 5-Chloro-3-fluoropyridinaldehyde 10⁻¹ (2.0 g, 12.5 mmol) and methylamine hydrochloride (1.68 g, 25.2 mmol) were added to methanol / tetrahydrofuran = 1 / 1 (10 mL: 10 mL). After nitrogen protection, the reaction was carried out at 50 °C for 2 h. Then, sodium triacetylborohydride (15.9 g, 75 mol) was added, and the reaction was carried out for 4 h. After the reaction was completed, the mixture was directly filtered, the filtrate was concentrated, the residue was dissolved in dichloromethane, sodium bicarbonate was added and stirred for 2 h, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (PE:EA = 10%) to obtain a yellow solid 1-(5-chloro-3-fluoropyridin-2-yl)-N-methylmethylamine 10⁻² (1.5 g, yield 73%).

[0374] LC-MS m / z (ESI) = 175.2 [M+H] + .

[0375] Step Two:

[0376] (N-((5-chloro-3-fluoropyridin-2-yl)methyl)-N-methylaminosulfonyl)tert-butyl carbamate 10-3

[0377] tert-butyl(N-((5-chloro-3-fluoropyridin-2-yl)methyl)-N-methylsulfamoyl)carbamate

[0378] The starting material, tert-butanol (0.76 g, 10.03 mmol), was added to dichloromethane (10 mL). After nitrogen protection, the mixture was cooled to 0 °C, followed by the addition of chlorosulfonyl isocyanate (1.3 g, 10.3 mmol). The reaction mixture was reacted at 0 °C for 1 hour, followed by the addition of triethylamine (2.64 g, 25.7 mmol), resulting in the precipitation of a large amount of solid. Then, the starting material, 1-(5-chloropyridin-2-yl)-N-methylmethylamine 10⁻² (1.5 g, 8.5 mmol), was added, and the reaction mixture was slowly heated to room temperature. The reaction was confirmed by LCMS, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain (N-((5-chloro-3-fluoropyridin-2-yl)methyl)-N-methylaminosulfonyl)carbamate tert-butyl ester 10⁻³ (2.4 g, yield 70.5%).

[0379] LCMS m / z(ESI) = 336.1 [M+H] + .

[0380] Step 3:

[0381] N-((5-chloro-3-fluoropyridin-2-yl)methyl)-N-methylaminosulfonamide 10-4

[0382] N-((5-chloro-3-fluoropyridin-2-yl)methyl)-N-methylaminosulfonamide

[0383] The starting material (N-((5-chloropyridin-3-fluoropyridin-2-yl)methyl)-N-methylaminosulfonyl)carbamate tert-butyl ester 10-3 (2.4 g, 6.7 mmol) was added to dioxane hydrochloride (20 mL). The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was directly concentrated to obtain N-((5-chloro-3-fluoropyridin-2-yl)methyl)-N-methylaminosulfonamide 10-4 (1.2 g, yield 88%).

[0384] LCMS m / z(ESI) = 254.1 [M+H] + .

[0385] Step 4:

[0386] N-(N-((5-chloro-3-fluoropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)carbamoylthioic acid 10-5

[0387] N-(N-((5-chloro-3-fluoropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)carbamimidothioic acid

[0388] The starting material N-((5-chloro-3-fluoropyridin-2-yl)methyl)-N-methylaminosulfonamide 10⁻⁴ (1.2 g, 5.1 mmol) was added to an acetonitrile (12 mL) solution, followed by 2-isothiocyano-1,3-dimethoxybenzene (1.0 g, 1.01 mmol) and then cesium carbonate (2.1 g, 6.6 mmol). The resulting mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was filtered to obtain a filter cake of N-(N-((5-chloro-3-fluoropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)carbamoylthioic acid 10⁻⁵ (1.40 g, 100% yield). This was used directly in the next step.

[0389] LC-MS m / z (ESI) = 449.10 [M+H] + .

[0390] Step 5:

[0391] (N-(N-(5-chloro-3-fluoropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinyl)hydrazine-1-carboxamide 10-6

[0392] N-(N-((5-chloro-3-fluoropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinoyl)hydrazine-1-carboximidamide

[0393] 10⁻⁵ (1.40 g) of N-(N-((5-chloro-3-fluoropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)carbamoylthioic acid was added to tetrahydrofuran (15 mL), followed by 5-methylnicotinamide 5 (475 mg, 3.1 mmol), and then EDCI (774 mg, 4.05 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 h. After the reaction was complete, the solution was directly evaporated to dryness. The solution was then dissolved in a 10:1 DCM:MeOH mixed solution (100 mL), washed three times with a saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain a crude product. The crude product was then slurried with ACN to obtain a white solid (N-(N-(5-chloro-3-fluoropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinyl)hydrazine-1-carboxamide 10-6 (1.5 g, yield 76.2%).

[0394] LC-MS m / z (ESI) = 567.1 [M+H] + .

[0395] Step 6:

[0396] N-(N-(5-chloro-3-fluoropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 10

[0397] N-(N-(5-chloro-3-fluoropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine

[0398] N-(N-((5-chloro-3-fluoropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinyl)hydrazine-1-carboxamide 10-6 (1.5 g, 1.3 mmol) was dissolved in TFA (15 mL) and reacted at 80 °C for 8 h. The reaction was monitored by LCMS until completion. The reaction was quenched by adding sodium bicarbonate aqueous solution, followed by extraction with a DCM:MeOH = 10:1 mixed solution (100 mL) and water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The mixture was then slurried with acetonitrile to give the target compound 10 (white solid, 132 mg, 13% yield).

[0399] LC-MS m / z (ESI) = 548.10 [M+H] + .

[0400] 1 H NMR(400MHz,DMSO-d6)δ13.41(s,1H),8.48(dd,2.0Hz,2H),8.21(d,,1H),8.08(dd,,1H),7 .62(q,1H),7.52(t,1H),6.85(d,2H),4.15(d,2H),3.75(s,6H),2.48(s,3H),2.26(s,3H).

[0401] Example 11

[0402] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-ethyl-4H-1,2,4-triazol-3-amine compound 11

[0403] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-methylpyridine-3-yl)-N-ethyl-4H-1,4-trichlorobenzene triazole-3-amine

[0404] first step:

[0405] N-((5-chloropyridin-2-yl)methyl)ethylamine 11-2

[0406] N-((5-chloropyridin-2-yl)methyl)ethanamine

[0407] 5-Chloropyridine aldehyde 11-1 (3 g, 21.3 mmol) and ethylamine hydrochloride (1.73 g, 21.3 mol) were added to methanol / tetrahydrofuran = 1 / 1 (10 mL / 10 mL). After nitrogen protection, the reaction was carried out at 50 °C for 2 h. Then, sodium triacetylborohydride (4.5 g, 21.3 mol) was added, and the reaction was carried out for 4 h. After the reaction was completed, the mixture was directly filtered, the filtrate was concentrated, the residue was dissolved in dichloromethane, NaHCO3 solid was added and stirred for 2 h, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (PE:EA = 10%) to obtain yellow solid N-((5-chloropyridin-2-yl)methyl)ethylamine 11-2 (1.3 g, yield 60%).

[0408] LC-MS m / z(ESI) = 171.0 [M+1].

[0409] Step Two:

[0410] N-((5-chloropyridin-2-yl)methyl)-N-ethylaminosulfonyl)tert-butyl carbamate 11-3

[0411] tert-butyl(N-((5-chloropyridin-2-yl)methyl)-N-ethylsulfamoyl)carbamate

[0412] The starting material, tert-butanol (688 mg, 9.17 mmol), was added to dichloromethane (16 mL). After nitrogen protection, the mixture was cooled to 0 °C, followed by the addition of chlorosulfonyl isocyanate (1.17 g, 0.61 mmol). The reaction mixture was reacted at 0 °C for 1 hour, followed by the addition of triethylamine (4.8 g, 45.8 mmol), resulting in the precipitation of a large amount of solid. Then, the starting material, N-((5-chloropyridin-2-yl)methyl)ethylamine 11-2 (1.3 g, 7.6 mmol), was added, and the reaction mixture was slowly heated to room temperature. The reaction was confirmed by LCMS, and the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain N-((5-chloropyridin-2-yl)methyl)-N-ethylaminosulfonyl)carbamate tert-butyl 11-3 (1.4 g, yield 55.7%).

[0413] LC-MS m / z (ESI) = 350.1 [M+H] + .

[0414] Step 3:

[0415] N-((5-chloropyridin-2-yl)methyl)-N-ethylaminosulfonamide 11-4

[0416] N-((5-chloropyridin-2-yl)methyl)-N-ethylaminosulfonamide

[0417] The raw material N-((5-chloropyridin-2-yl)methyl)-N-ethylaminosulfonyl)carbamate tert-butyl ester 11-3 (1.4 g, 4 mmol) was added to dioxane hydrochloride (14 mL), and the reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was directly concentrated to obtain N-((5-chloropyridin-2-yl)methyl)-N-ethylaminosulfonamide 11-4 (1 g, yield 100%).

[0418] LC-MS m / z (ESI) = 250.1 [M+H] + .

[0419] Step 4:

[0420] N-(N-((5-chloropyridin-2-yl)methyl)-N-ethylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)carbamoylthioic acid 11-5

[0421] N-(N-((5-chloropyridin-2-yl)methyl)-N-ethylsulfamoyl)-N'-(2,6-dimethoxyphenyl)carbamoylthioic acid

[0422] The starting material N-((5-chloropyridin-2-yl)methyl)-N-ethylaminosulfonamide 11-4 (1 g, 4 mmol) was added to an acetonitrile (18 ml) solution, followed by 2-isothiocyano-1,3-dimethoxybenzene (863 mg, 4 mmol) and cesium carbonate (1.7 g, 5.22 mmol). The resulting mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was filtered to obtain crude N-(N-((5-chloropyridin-2-yl)methyl)-N-ethylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)carbamoylthioic acid 11-5 (2.68 g, 100% yield) as filter cake. This was used directly in the next step.

[0423] LC-MS m / z(ESI) = 445.0 [M+1].

[0424] Step 5:

[0425] N-(N-((5-chloropyridin-2-yl)methyl)-N-ethylaminosulfonyl)-N'-(2,6-diethylphenyl)-2-(5-methylnicotinyl)hydrazine-1-carboxamide 11-6

[0426] N-(N-((5-chloropyridin-2-yl)methyl)-N-ethylsulfamoyl)-N'-(2,6-diethylphenyl)-2-(5-methylnicotinoyl)hydrazine-1-carboxamide

[0427] Crude N-(N-((5-chloropyridin-2-yl)methyl)-N-ethylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)carbamoylthioic acid 11-5 (2.68 g) was added to tetrahydrofuran (27 ml), followed by 5-methylnicotinamide (617 mg, 4 mmol), and then EDCI (1 g, 5.27 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours. After the reaction was complete, the solution was directly evaporated to dryness. The solution was then dissolved in a 10:1 DCM:MeOH mixture (100 mL), washed three times with a saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain a crude product. The crude product was then slurried with ACN to obtain a white solid N-(N-((5-chloropyridin-2-yl)methyl)-N-ethylaminosulfonyl)-N'-(2,6-diethylphenyl)-2-(5-methylnicotinyl)hydrazine-1-carboxamide 11-6 (684 mg, yield 30.4%).

[0428] LC-MS m / z(ESI) = 562.1 [M+1].

[0429] Step 6:

[0430] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-ethyl-4H-1,2,4-triazol-3-amine compound 11

[0431] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-methylpyridine-3-yl)-N-ethyl-4H-1,4-trichlorobenzene triazole-3-amine

[0432] N-(N-((5-chloropyridin-2-yl)methyl)-N-ethylaminosulfonyl)-N'-(2,6-diethylphenyl)-2-(5-methylnicotinyl)hydrazine-1-carboxamide 11-6 (684 mg, 1.2 mmol) was dissolved in TFA (6 mL) and reacted at 80 °C for 8 h. The reaction was monitored by LCMS until it was complete. The reaction was quenched by adding sodium bicarbonate aqueous solution, followed by extraction with a DCM:MeOH = 10:1 mixed solution (50 mL) and water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The mixture was then slurried with acetonitrile to obtain the target compound 11 (white solid, 180 mg, 27.2% yield).

[0433] LC-MS m / z (ESI) = 544.10 [M+H] + .

[0434] 1 H NMR (400MHz, DMSO-d6)δ=13.64(s,1H),8.55(d,1H),8.48(d,1H),8.21(d,1H),7.89(dd,1H),7.63(d,1H) ,7.51(t,1H),7.46(d,1H),6.84(d,2H),4.29(s,2H),3.70(s,6H),3.05(m,2H),2.25(s,3H),0.92(t,3H).

[0435] Example 12

[0436] N-(N-methyl-1-(5-methylpyrimidin-2-yl)ethyl)sulfonyl)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 12

[0437] N-(N-methyl-1-(5-methylpyrimidin-2-yl)ethyl)sulfonamide)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0438] first step:

[0439] N-Methyl-1-(5-methylpyrimidin-2-yl)ethyl-1-amine 12-2

[0440] N-methyl-1-(5-methylpyrimidin-2-yl)ethan-1-amine

[0441] Compound 1-(5-methylpyrimidin-2-yl)ethyl-1-one 12-1 (1.36 g, 10 mmol) and methylamine hydrochloride (2.03 g, 30 mmol) were dissolved in tetrahydrofuran (10 mL), heated to 50 °C and stirred for 1 h. Then, sodium triacetoxyborohydride (6.36 g, 30 mmol) was added, and the reaction was continued for 2 h. The reaction was detected by LCMS to be complete. The reaction was quenched with sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified directly by column chromatography to obtain the target compound N-methyl-1-(5-methylpyrimidin-2-yl)ethyl-1-amine 12-2 (1.1 g, yield 72.3%).

[0442] LCMS m / z(ESI) = 152.1 [M+H] + .

[0443] Step Two:

[0444] (N-methyl-N-(1-(5-methylpyrimidin-2-yl)ethyl)aminosulfonyl)tert-butyl carbamate 12-3

[0445] tert-butyl(N-methyl-N-(1-(5-methylpyrimidin-2-yl)ethyl)sulfamoyl)carbamate

[0446] The starting material, tert-butanol (740 mg, 10 mmol), was added to dichloromethane (10 mL). After nitrogen protection, the mixture was cooled to 0 °C, and then chlorosulfonyl isocyanate (1.42 g, 10.0 mmol) was added. The reaction mixture was reacted at 0 °C for 1 hour, followed by the addition of triethylamine (1.01 g, 10.0 mmol), resulting in the precipitation of a large amount of solid. Then, the starting material, N-methyl-1-(5-methylpyrimidin-2-yl)ethyl-1-amine 12-2 (1.1 g, 7.2 mmol), was added, and the reaction mixture was slowly heated to room temperature. The reaction was confirmed by LCMS, and the mixture was concentrated under reduced pressure and purified directly by column chromatography to obtain (N-methyl-N-(1-(5-methylpyrimidin-2-yl)ethyl)aminosulfonyl)carbamate tert-butyl 12-3 (920 mg, yield 38.7%).

[0447] LCMS m / z(ESI) = 331.1[M+H] + .

[0448] Step 3:

[0449] N-Methyl-N-(1-(5-methylpyrimidin-2-yl)ethyl)aminosulfonamide 12-4

[0450] N-methyl-N-(1-(5-methylpyrimidin-2-yl)ethyl)aminosulfonamide

[0451] The starting material (N-methyl-N-(1-(5-methylpyrimidin-2-yl)ethyl)aminosulfonyl)carbamate tert-butyl ester 12-3 (920 mg, 2.8 mmol)) was added to dichloromethane (4 mL), followed by trifluoroacetic acid (4 mL). The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was directly concentrated to obtain N-methyl-N-(1-(5-methylpyrimidin-2-yl)ethyl)aminosulfonamide 12-4 (520 mg, yield 81.0%).

[0452] LCMS m / z(ESI) = 231.1[M+H] + .

[0453] Step 4:

[0454] N'-(2,6-Dimethoxyphenyl)-N-(N-methyl-N-(1-(5-methylpyrimidin-2-yl)ethyl)aminosulfonyl)thiocarbamoimine 12-5

[0455] N'-(2,6-dimethoxyphenyl)-N-(N-methyl-N-(1-(5-methylpyrimidin-2-yl)ethyl)sulfamoyl)carbamimidothioic acid

[0456] N-methyl-N-(1-(5-methylpyrimidin-2-yl)ethyl)aminosulfonamide 12-4 (230 mg, 1.0 mmol) and 2-isothiocyano-1,3-dimethoxybenzene (390 mg, 2.0 mmol) were added to anhydrous acetonitrile (20 mL), followed by cesium carbonate (978 mg, 3.0 mmol). The reaction mixture was incubated at room temperature for 2 hours. LC-MS analysis confirmed the reaction was complete. The mixture was then directly concentrated, and the crude product 12-5 was used directly in the next step.

[0457] LCMS m / z(ESI) = 426.1 [M+H] + .

[0458] Step 5:

[0459] N'-(2,6-Dimethoxyphenyl)-N-(N-methyl-N-(1-(5-methylpyrimidin-2-yl)ethyl)aminosulfonyl)-2-(5-methylnicotinyl)hydrazine-1-formamidin 12-6

[0460] N'-(2,6-dimethoxyphenyl)-N-(N-methyl-N-(1-(5-methylpyrimidin-2-yl)ethyl)sulfamoyl)-2-(5-methylnicotinoyl)hydrazine-1-carboximidamide

[0461] The crude product from the previous step was added to tetrahydrofuran (20 mL), followed by 5-methylnicotinamide (450 mg, 3.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (576 mg, 3.0 mmol). The reaction mixture was reacted overnight at room temperature. The target reaction was detected by LCMS. After the reaction was complete, the mixture was filtered directly, concentrated under reduced pressure, and purified by reverse column chromatography to obtain 12-6 (205 mg, two-step yield 37.8%).

[0462] LCMS m / z(ESI) = 543.2 [M+H] + .

[0463] Step 6:

[0464] N-(N-methyl-1-(5-methylpyrimidin-2-yl)ethyl)sulfonyl)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 12

[0465] N-(N-methyl-1-(5-methylpyrimidin-2-yl)ethyl)sulfonamide)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0466] The starting material 12-6 (205 mg, 0.37 mmol) was added to trifluoroacetic acid (5 mL), and under nitrogen protection, the mixture was heated to 70 °C and reacted for 6 hours. After the reaction was completed, the mixture was directly concentrated and purified by reverse column chromatography to obtain N-(N-methyl-1-(5-methylpyrimidin-2-yl)ethyl)sulfonyl)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 12 (178 mg, yield 89.9%).

[0467] LCMS m / z(ESI) = 525.2[M+H] + .

[0468] 1 H NMR(400MHz,DMSO-d6)δ8.66(s,2H),8.33(s,1H),8.19(d,1H),7.50(s,1H),7.44(t,1H),6.80(dd ,2H),5.18(q,1H),3.68(s,3H),3.64(s,3H),2.43(s,3H),2.28(s,3H),2.20(s,3H),1.40(d,3H).

[0469] Example 13

[0470] N-(N-methyl-1-(3-chloropyridin-5-yl)ethyl)sulfonyl)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 13

[0471] N-(N-methyl-1-(3-chloropyridin-5-yl)ethyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0472] first step:

[0473] 1,3-Diethyl-2-isothiocyanate benzene 13-2

[0474] 1,3-diethyl-2-isothiocyanatobenzene

[0475] The starting material 2,6-diethylaniline 13-1 (1.49 g, 10 mmol) was added to dichloromethane (20 mL), followed by 1,1-thiocarbonylDI-2(1H)-pyridine (2.33 g, 10 mmol). Under nitrogen protection, the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the product was directly purified by column chromatography to obtain 1,3-diethyl-2-isothiocyanate benzene 13-2 (1.2 g, yield 62.5%).

[0476] LC-MS m / z (ESI) = 192.1 [M+H] + .

[0477] Step Two:

[0478] N-(N-((5-chloro-3-fluoropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-diethylphenyl)thiocarbamoyl 13-3

[0479] N-(N-((5-chloro-3-fluoropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-diethylphenyl)carbamimidothioic acid

[0480] The raw materials 1,3-diethyl-2-isothiocyanate benzene 13-2 (960 mg, 5.0 mmol) and N-methyl-1-(3-chloropyridin-5-yl)ethyl)sulfonamide (944 mg, 4.0 mmol) were added to anhydrous acetonitrile (50 mL), followed by the addition of cesium carbonate (2.45 g, 7.5 mmol). The reaction mixture was reacted at room temperature for 2 hours. After the reaction was completed, the mixture was directly concentrated, and the crude product 13-3 was used directly in the next step.

[0481] LC-MS m / z (ESI) = 427.1 [M+H]+ .

[0482] Step 3:

[0483] N-(N-((5-chloro-3-fluoropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-diethylphenyl)-2-(5-methylnicotinyl)hydrazine-1-formamidinium 13-4

[0484] N-(N-((5-chloro-3-fluoropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-diethylphenyl)-2-(5-methylnicotinoyl)hydrazine-1-carboximidamide

[0485] Crude starting material 13-3 (2.14 g, 5.0 mmol) and 5-methylnicotinamide (756 mg, 5.0 mmol) were added to anhydrous tetrahydrofuran (20 mL), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 g, 10.0 mmol). The reaction mixture was reacted overnight at room temperature. The target reaction was detected by LCMS. After the reaction was complete, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to obtain 13-4 (267 mg, two-step yield 12.3%).

[0486] LCMS m / z(ESI) = 544.2 [M+H] + .

[0487] Step 4:

[0488] N-(N-methyl-1-(3-chloropyridin-5-yl)ethyl)sulfonyl)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 13

[0489] N-(N-methyl-1-(3-chloropyridin-5-yl)ethyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0490] The starting material 13-4 (267 mg, 0.45 mmol) was added to trifluoroacetic acid (5 ml), and under nitrogen protection, the mixture was heated to 70 °C and reacted for 6 hours. After the reaction was completed, the mixture was directly concentrated and purified by reverse column chromatography to obtain N-(N-methyl-1-(3-chloropyridin-5-yl)ethyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 13 (78 mg, yield 32.9%).

[0491] LC-MS m / z (ESI) = 526.2 [M+H] + .

[0492] 1 H NMR (400MHz, DMSO-d6)δ=13.91(s,1H),8.55(d,1H),8.46(d,1H),8.06(d,1H),7.87(dd,1H),7.59(d,1H) ,7.54(t,1H),7.43(d,1H),7.35(d,2H),4.19(s,2H),2.56(s,3H),2.28(q,4H),2.22(s,3H),1.02(t,6H).

[0493] Example 14

[0494] N-(N-methyl-1-(3-trifluoromethylpyridin-5-yl)ethyl)sulfonyl)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 14

[0495] N-(N-methyl-1-(3-trifluoromethylpyridin-5-yl)ethyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0496] first step:

[0497] (5-Trifluoromethylpyridin-2-yl)methyl)tert-butyl carbamate 14-2

[0498] (5-Trifluoromethylpyridin-2-yl)methyl)carbamate tert butyl ester

[0499] The starting material (5-trifluoromethylpyridin-2-yl)methylamine 14-1 (1.76 g, 10 mmol) was added to dichloromethane (20 mL), followed by the slow dropwise addition of di-tert-butyl dicarbonate (3.27 g, 15 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction was confirmed by LCMS, and the solution was directly concentrated to give the title compound (5-trifluoromethylpyridin-2-yl)methyl)carbamate tert-butyl 14-2 (2.43 g, 100.0% yield).

[0500] LC-MS m / z (ESI) = 277.1 [M+H] + .

[0501] Step Two:

[0502] (5-Trifluoromethylpyridin-2-yl)methyl)(methyl)tert-butyl carbamate 14-3

[0503] (5-Trifluoromethylpyridin-2-yl)methyl)(methyl)carbamate tert butyl ester

[0504] The starting material (5-trifluoromethylpyridin-2-yl)methyl)tert-butyl carbamate 14-2 (2.76 g, 10 mmol) was added to N,N-dimethylformamide (20 mL), then cooled to 0 °C, and sodium hydride (800 mg, 20 mmol, 60% mineral oil mixture) was added. Then, iodomethane (2.13 g, 15 mmol) was slowly added dropwise. The reaction solution was reacted at room temperature for 3 hours. After the reaction was completed, (5-trifluoromethylpyridin-2-yl)methyl)(methyl)tert-butyl carbamate 14-3 (1.1 g, yield 37.8%) was obtained by reverse chromatography.

[0505] LC-MS m / z(ESI) = 291.1 [M+H] + .

[0506] Step 3:

[0507] 1-(5-trifluoromethylpyridin-2-yl)-N-methylmethylamine 14-4

[0508] 1-(5-trifluoromethylpyridin-2-yl)-N-methylmethylamine

[0509] The starting material (5-trifluoromethylpyridin-2-yl)methyl(methyl)carbamate tert-butyl ester 14-3 (1.0 g, 3.4 mmol) was added to dichloromethane (10 mL), followed by trifluoroacetic acid (10 mL). The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was directly concentrated to obtain 1-(5-trifluoromethylpyridin-2-yl)-N-methylmethylamine 14-4 (567 mg, yield 87.4%).

[0510] LC-MS m / z (ESI) = 191.1 [M+H] + .

[0511] Step 4:

[0512] (N-((5-trifluoromethylpyridin-2-yl)methyl)-N-methylaminosulfonyl)tert-butyl carbamate 14-5

[0513] (N-((5-trifluoromethylpyridin-2-yl)methyl)-N-methylsulfonamide)tert butyl carbamate

[0514] The starting material, tert-butanol (370 mg, 5.0 mmol), was added to dichloromethane (10 mL). Under nitrogen protection, the mixture was cooled to 0 °C, followed by the addition of chlorosulfonyl isocyanate (708 mg, 5.0 mmol). The reaction mixture was reacted at 0 °C for 1 hour, followed by the addition of triethylamine (505 mg, 5.0 mmol), resulting in the precipitation of a large amount of solid. Then, the starting material, 1-(5-trifluoromethylpyridin-2-yl)-N-methylmethylamine 14-4 (382 mg, 2.0 mmol), was added, and the reaction mixture was slowly heated to room temperature. The reaction was confirmed by LCMS, and the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain (N-((5-trifluoromethylpyridin-2-yl)methyl)-N-methylaminosulfonyl)carbamate tert-butyl 14-5 (430 mg, yield 58.1%).

[0515] LC-MS m / z (ESI) = 370.1 [M+H] + .

[0516] Step 5:

[0517] N-((5-trifluoromethylpyridin-2-yl)methyl)-N-methylaminosulfonamide 14-6

[0518] N-((5-trifluoromethylpyridin-2-yl)methyl)-N-methylaminosulfonamide

[0519] The raw material N-((5-trifluoromethylpyridin-2-yl)methyl)-N-methylaminosulfonyl)carbamate tert-butyl ester 14-5 (430 mg, 1.16 mmol) was added to dichloromethane (4 mL), followed by trifluoroacetic acid (4 mL). The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was directly concentrated to obtain N-((5-trifluoromethylpyridin-2-yl)methyl)-N-methylaminosulfonamide 14-6 (260 mg, yield 83.1%).

[0520] LC-MS m / z (ESI) = 270.1 [M+H] + .

[0521] Step 6:

[0522] N-(N-methyl-1-(3-trifluoromethylpyridin-5-yl)ethyl)sulfonyl)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 14

[0523] N-(N-methyl-1-(3-trifluoromethylpyridin-5-yl)ethyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0524] The following substances were added: N-((5-trifluoromethylpyridin-2-yl)methyl)-N-methylaminosulfonamide 14-6 (260 mg, 0.96 mmol), 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine J (200 mg, 0.54 mmol), cesium carbonate (417 mg, 1.28 mmol), cuprous iodide (122 mg, 0.64 mmol), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (182 mg). 1.28 mmol) was added to 1,4-dioxane (3 mL), and the mixture was reacted in a microwave at 110 °C for 2 hours. After the reaction was completed, dichloromethane (10 mL) and mercaptosilica (2 g) were added and the mixture was stirred vigorously for 1 hour. After filtration and concentration, the mixture was purified by reverse column chromatography to obtain the target product N-(N-(5-chloropyridin-2-yl)methyl)sulfonamide)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 14 (15 mg, yield 10.5%).

[0525] LC-MS m / z (ESI) = 564.2 [M+H] + .

[0526] 1 H NMR(400MHz,DMSO-d6)δ13.56(s,1H),8.91(d,1H),8.48(d,1H),8.22(d,2H),7.64(d ,2H),7.52(t,1H),6.85(d,2H),4.24(s,2H),3.72(s,6H),2.62(d,3H),2.26(s,3H).

[0527] Example 15

[0528] N-(N-cyclopropylmethyl-1-(5-methylpyrimidin-2-yl)ethyl)sulfonyl)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 15

[0529] N-(N-cyclopropylmethyl-1-(5-methylpyrimidin-2-yl)ethyl)sulfonamide)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0530] first step:

[0531] 1-(5-chloropyridin-2-yl)-N-(cyclopropylmethyl)methylamine 15-2

[0532] N-methyl-1-(5-methylpyrimidin-2-yl)ethan-1-amine

[0533] The starting material 5-chloropyridinaldehyde 15-1 (1.0 g, 7.1 mmol) and cyclopropylmethylamine (775 mg, 10.6 mmol) were dissolved in tetrahydrofuran (10 mL), heated to 50 °C and stirred for 1 h. Then, sodium triacetoxyborohydride (3.01 g, 14.2 mmol) was added, and the reaction was continued for 2 h. The reaction was detected by LCMS and quenched with sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified directly by column chromatography to obtain the target compound 1-(5-chloropyridin-2-yl)-N-(cyclopropylmethyl)methylamine 15-2 (1.1 g, yield 78.6%).

[0534] LC-MS m / z (ESI) = 197.1 [M+H] + .

[0535] Step Two:

[0536] (N-((5-chloropyridin-2-yl)methyl)-N-(cyclopropylmethyl)aminosulfonyl)tert-butyl carbamate 15-3

[0537] tert-butyl(N-((5-chloropyridin-2-yl)methyl)-N-(cyclopropylmethyl)sulfamoyl)carbamate

[0538] The starting material, tert-butanol (740 mg, 10 mmol), was added to dichloromethane (10 mL). After nitrogen protection, the mixture was cooled to 0 °C, and then chlorosulfonyl isocyanate (1.42 g, 10.0 mmol) was added. The reaction mixture was reacted at 0 °C for 1 hour, followed by the addition of triethylamine (2.02 g, 20.0 mmol), resulting in the precipitation of a large amount of solid. Then, the starting material, 1-(5-chloropyridin-2-yl)-N-(cyclopropylmethyl)methylamine 15-2 (1.1 g, 5.5 mmol), was added, and the reaction mixture was slowly heated to room temperature. The reaction was confirmed by LCMS, concentrated under reduced pressure, and directly purified by column chromatography to obtain (N-((5-chloropyridin-2-yl)methyl)-N-(cyclopropylmethyl)aminosulfonyl)carbamate tert-butyl ester 15-3 (690 mg, yield 32.4%).

[0539] LC-MS m / z (ESI) = 376.1 [M+H] + .

[0540] Step 3:

[0541] N-((5-chloropyridin-2-yl)methyl)-N-(cyclopropylmethyl)aminosulfonamide 15-4

[0542] N-((5-chloropyridin-2-yl)methyl)-N-(cyclopropylmethyl)sulfonamide

[0543] The starting material (N-((5-chloropyridin-2-yl)methyl)-N-(cyclopropylmethyl)aminosulfonyl)carbamate tert-butyl ester 15-3 (690 mg, 1.8 mmol)) was added to dichloromethane (4 mL), followed by trifluoroacetic acid (4 mL). The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was directly concentrated to obtain N-((5-chloropyridin-2-yl)methyl)-N-(cyclopropylmethyl)aminosulfonamide 15-4 (497 mg, yield 97.8%).

[0544] LC-MS m / z (ESI) = 276.1 [M+H] + .

[0545] Step 4:

[0546] N-(N-((5-chloropyridin-2-yl)methyl)-N-(cyclopropylmethyl)aminosulfonyl)-N'-(2,6-dimethoxyphenyl)thiocarbamoimine 15-5

[0547] N-(N-((5-chloropyridin-2-yl)methyl)-N-(cyclopropylmethyl)sulfamoyl)-N'-(2,6-dimethoxyphenyl)carbamimidothioic acid

[0548] N-((5-chloropyridin-2-yl)methyl)-N-(cyclopropylmethyl)aminosulfonamide 15-4 (276 mg, 1.0 mmol) and 2-isothiocyano-1,3-dimethoxybenzene (234 mg, 1.2 mmol) were added to anhydrous acetonitrile (20 mL), followed by the addition of cesium carbonate (489 mg, 1.5 mmol). The reaction mixture was incubated at room temperature for 2 hours. LC-MS analysis confirmed the reaction was complete. The mixture was then directly concentrated, and the crude product 15-5 was used directly in the next step.

[0549] LC-MS m / z (ESI) = 471.1 [M+H] + .

[0550] Step 5:

[0551] N-(N-((5-chloropyridin-2-yl)methyl)-N-(cyclopropylmethyl)aminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinyl)hydrazine-1-formamidin 15-6

[0552] N-(N-((5-chloropyridin-2-yl)methyl)-N-(cyclopropylmethyl)sulfamoyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinoyl)hydrazine-1-carboximidamide

[0553] The crude product 15-5 from the previous step was added to tetrahydrofuran (20 mL), followed by 5-methylnicotinamide (206 mg, 1.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288 mg, 1.5 mmol). The reaction mixture was reacted overnight at room temperature. The target reaction was detected by LCMS. After the reaction was complete, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to obtain N-(N-((5-chloropyridin-2-yl)methyl)-N-(cyclopropylmethyl)aminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinamide)hydrazine-1-formamidinium 15-6 (430 mg, two-step yield 73.1%).

[0554] LC-MS m / z (ESI) = 588.2 [M+H] + .

[0555] Step 6:

[0556] N-(N-cyclopropylmethyl-1-(5-methylpyrimidin-2-yl)ethyl)sulfonyl)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 15

[0557] N-(N-cyclopropylmethyl-1-(5-methylpyrimidin-2-yl)ethyl)sulfonamide)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0558] The starting material 15-6 (430 mg, 0.73 mmol) was added to trifluoroacetic acid (5 mL), and under nitrogen protection, the mixture was heated to 70 °C and reacted for 6 hours. After the reaction was completed, the mixture was directly concentrated and purified by reverse column chromatography to obtain compound 15 (178 mg, yield 42.8%) of N-(N-cyclopropylmethyl-1-(5-methylpyrimidin-2-yl)ethyl)sulfonamide)-4-(2,6-dimethoxy)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine.

[0559] LC-MS m / z (ESI) = 570.2 [M+H] + .

[0560] 1H NMR(400MHz,DMSO-d6)δ13.86(s,1H),8.55(d,1H),8.47(d,1H),8.21(d,1H),7.89(dd,1H),7.63(s,1H),7.50(dt ,2H),6.83(d,2H),4.43(s,2H),3.69(s,6H),2.88(d,2H),2.25(s,3H),0.76(dd,1H),0.24(q,2H),-0.027(q,2H).

[0561] Example 16

[0562] N-(N-cyclopropyl-1-(3-chloropyridin-5-yl)ethyl)sulfonyl)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 16

[0563] N-(N-cyclopropyl-1-(3-chloropyridin-5-yl)ethyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0564] first step:

[0565] N-((5-chloropyridin-2-yl)methyl)cyclopropylamine 16-2

[0566] N-((5-chloropyridin-2-yl)methyl)cyclopropylamine

[0567] The starting material 5-chloropyridinaldehyde 16-1 (1.0 g, 7.1 mmol) and cyclopropylamine (604 mg, 10.6 mmol) were dissolved in tetrahydrofuran (10 mL), heated to 50 °C and stirred for 1 h. Then, sodium triacetoxyborohydride (3.01 g, 14.2 mmol) was added, and the reaction was continued for 2 h. The reaction was detected by LCMS and the reaction was quenched with sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified directly by column chromatography to obtain the target compound N-((5-chloropyridin-2-yl)methyl)cyclopropylamine 16-2 (1.1 g, yield 84.6%).

[0568] LC-MS m / z (ESI) = 183.1 [M+H] + .

[0569] Step Two:

[0570] (N-((5-chloropyridin-2-yl)methyl)-N-cyclopropylaminosulfonyl)tert-butyl carbamate 16-3

[0571] tert-butyl(N-((5-chloropyridin-2-yl)methyl)-N-cyclopropylsulfamoyl)carbamate

[0572] The starting material, tert-butanol (740 mg, 10 mmol), was added to dichloromethane (10 mL). After nitrogen protection, the mixture was cooled to 0 °C, and then chlorosulfonyl isocyanate (1.42 g, 10.0 mmol) was added. The reaction mixture was reacted at 0 °C for 1 hour, followed by the addition of triethylamine (2.02 g, 20.0 mmol), resulting in the precipitation of a large amount of solid. Then, the starting material, N-((5-chloropyridin-2-yl)methyl)cyclopropylamine 16-2 (1.1 g, 6.0 mmol), was added, and the reaction mixture was slowly heated to room temperature. The reaction was confirmed by LCMS, and the mixture was concentrated under reduced pressure and purified directly by column chromatography to obtain (N-((5-chloropyridin-2-yl)methyl)-N-cyclopropylaminosulfonyl)carbamate tert-butyl 16-3 (780 mg, yield 35.9%).

[0573] LC-MS m / z (ESI) = 362.1 [M+H] + .

[0574] Step 3:

[0575] N-((5-chloropyridin-2-yl)methyl)-N-(cyclopropyl)aminosulfonamide 16-4

[0576] N-((5-chloropyridin-2-yl)methyl)-N-cyclopropylsulfonamide

[0577] The starting material (N-((5-chloropyridin-2-yl)methyl)-N-cyclopropylaminosulfonyl)carbamate tert-butyl ester 16-3 (550 mg, 1.5 mmol)) was added to dichloromethane (4 mL), followed by trifluoroacetic acid (4 mL). The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was directly concentrated to obtain N-((5-chloropyridin-2-yl)methyl)-N-(cyclopropyl)aminosulfonamide 16-4 (320 mg, yield 80.4%).

[0578] LC-MS m / z (ESI) = 262.1 [M+H] + .

[0579] Step 4:

[0580] N-(N-((5-chloropyridin-2-yl)methyl)-N-(cyclopropyl)aminosulfonyl)-N'-(2,6-dimethoxyphenyl)thiocarbamoyl 16-5

[0581] N-(N-((5-chloropyridin-2-yl)methyl)-N-cyclopropylsulfamoyl)-N'-(2,6-dimethoxyphenyl)carbamimidothioic acid

[0582] N-((5-chloropyridin-2-yl)methyl)-N-(cyclopropyl)aminosulfonamide 16-4 (262 mg, 1.0 mmol) and 2-isothiocyano-1,3-dimethoxybenzene (234 mg, 1.2 mmol) were added to anhydrous acetonitrile (20 mL), followed by cesium carbonate (489 mg, 1.5 mmol). The reaction mixture was incubated at room temperature for 2 hours. LC-MS analysis confirmed the reaction was complete. The mixture was then directly concentrated, and the crude product 16-5 was used directly in the next step.

[0583] LC-MS m / z (ESI) = 457.1 [M+H] + .

[0584] Step 5:

[0585] N-(N-((5-chloropyridin-2-yl)methyl)-N-cyclopropylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinyl)hydrazine-1-formamidin 16-6

[0586] N-(N-((5-chloropyridin-2-yl)methyl)-N-cyclopropylsulfamoyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinoyl)hydrazine-1-carboximidamide

[0587] The crude product 16-5 from the previous step was added to tetrahydrofuran (20 mL), followed by 5-methylnicotinamide (206 mg, 1.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288 mg, 1.5 mmol). The reaction mixture was reacted overnight at room temperature. The target reaction was detected by LCMS. After the reaction was complete, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to give compound 16-6 (270 mg, two-step yield 47.0%).

[0588] LC-MS m / z (ESI) = 574.2 [M+H] + .

[0589] Step 6:

[0590] N-(N-cyclopropyl-1-(3-chloropyridin-5-yl)ethyl)sulfonyl)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 16

[0591] N-(N-cyclopropyl-1-(3-chloropyridin-5-yl)ethyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0592] The starting material 16-6 (270 mg, 0.47 mmol) was added to trifluoroacetic acid (5 mL), and under nitrogen protection, the mixture was heated to 70 °C and reacted for 6 hours. After the reaction was completed, the mixture was directly concentrated and purified by reverse column chromatography to obtain N-(N-cyclopropyl-1-(3-chloropyridin-5-yl)ethyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 16 (55 mg, yield 21.1%).

[0593] LC-MS m / z (ESI) = 556.2 [M+H] + .

[0594] 1 H NMR(400MHz,DMSO-d6)δ13.68(s,1H),8.53(d,1H),8.48(d,1H),8.21(d,1H),7.84(dd,1H),7.64(d,1H),7.5 3(t,1H),7.44(d,1H),6.85(d,2H),4.36(s,2H),3.72(s,6H),2.28(dd,1H),2.26(s,3H),0.57–0.44(m,4H).

[0595] Example 17

[0596] N-(N-methyl-d3-1-(3-chloropyridin-5-yl)ethyl)sulfonyl)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 17

[0597] N-(N-methyl-d3-1-(3-chloropyridin-5-yl)ethyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0598] first step:

[0599] N-((5-chloropyridin-2-yl)methyl)methane-d3-amine 17-2

[0600] N-((5-chloropyridin-2-yl)methyl)methan-d3-amine

[0601] The starting material 5-chloropyridinaldehyde 17-1 (2.8 g, 20 mmol) and deuterated methylamine (2.2 g, 30 mmol) were dissolved in tetrahydrofuran (10 mL), heated to 50 °C and stirred for 1 h. Then, sodium triacetoxyborohydride (6.3 g, 3 mmol) was added, and the reaction was continued for 2 h. The reaction was detected by LCMS to be complete. The reaction was quenched with sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified directly by column chromatography to obtain the target compound N-((5-chloropyridin-2-yl)methyl)methane-d3-amine 17-2 (2.0 g, yield 62.5%).

[0602] LC-MS m / z (ESI) = 160.0 [M+H] + .

[0603] Step Two:

[0604] (N-((5-chloropyridin-2-yl)methyl)-N-(methyl-d3)aminosulfonyl)tert-butyl carbamate 17-3

[0605] tert-butyl(N-((5-chloropyridin-2-yl)methyl)-N-(methyl-d3)sulfamoyl)carbamate

[0606] 1.1 g (15 mmol) of tert-butanol was added to 10 mL of dichloromethane under nitrogen protection and cooled to 0 °C. Then, 2.1 g (15.0 mmol) of chlorosulfonyl isocyanate was added, and the reaction mixture was reacted at 0 °C for 1 hour. Triethylamine (2.02 g (20.0 mmol) was then added, resulting in the precipitation of a large amount of solid. Next, N-((5-chloropyridin-2-yl)methyl)methane-d3-amine 17-2 (1.6 g (10.0 mmol)) was added, and the reaction mixture was slowly heated to room temperature. The reaction was confirmed by LCMS, concentrated under reduced pressure, and purified directly by column chromatography to obtain tert-butyl (N-((5-chloropyridin-2-yl)methyl)-N-(methyl-d3)aminosulfonyl)carbamate 17-3 (2.7 g, yield 79.6%).

[0607] LC-MS m / z (ESI) = 339.1 [M+H] + .

[0608] Step 3:

[0609] N-((5-chloropyridin-2-yl)methyl)-N-(methyl-d3)aminosulfonamide 17-4

[0610] N-((5-chloropyridin-2-yl)methyl)-N-(methyl-d3)sulfonamide

[0611] The starting material (N-((5-chloropyridin-2-yl)methyl)-N-(methyl-d3)aminosulfonyl)carbamate tert-butyl ester 17-3 (2.7 g, 8.0 mmol)) was added to dichloromethane (4 mL), followed by trifluoroacetic acid (4 mL). The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was directly concentrated to obtain N-((5-chloropyridin-2-yl)methyl)-N-(methyl-d3)aminosulfonamide 17-4 (1.5 g, yield 78.5%).

[0612] LC-MS m / z (ESI) = 239.1 [M+H] + .

[0613] Step 4:

[0614] N-(N-((5-chloropyridin-2-yl)methyl)-N-(methyl-d3)aminosulfonyl)-N'-(2,6-dimethoxyphenyl)thiocarbamoimine 17-5

[0615] N-(N-((5-chloropyridin-2-yl)methyl)-N-(methyl-d3)sulfamoyl)-N'-(2,6-dimethoxyphenyl)carbamimidothioic acid

[0616] N-((5-chloropyridin-2-yl)methyl)-N-(methyl-d3)aminosulfonamide 17-4 (956 g, 4.0 mmol) and 2-isothiocyano-1,3-dimethoxybenzene (780 mg, 4.0 mmol) were added to anhydrous acetonitrile (20 mL), followed by the addition of cesium carbonate (2.0 g, 6.0 mmol). The reaction mixture was incubated at room temperature for 2 hours. LC-MS analysis confirmed the reaction was complete. The mixture was then directly concentrated, and the crude product 17-5 was used directly in the next step.

[0617] LC-MS m / z (ESI) = 434.1 [M+H] + .

[0618] Step 5:

[0619] N-(N-((5-chloropyridin-2-yl)methyl)-N-(methyl-d3)aminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinyl)hydrazine-1-formamidin 17-6

[0620] N-(N-((5-chloropyridin-2-yl)methyl)-N-(methyl-d3)sulfamoyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinoyl)hydrazine-1-carboximidamide

[0621] The crude product 17-5 from the previous step was added to tetrahydrofuran (20 mL), followed by 5-methylnicotinamide (604 mg, 4.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.15 g, 6.0 mmol). The reaction mixture was reacted overnight at room temperature. The target reaction was detected by LCMS. After the reaction was complete, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to obtain N-(N-((5-chloropyridin-2-yl)methyl)-N-(methyl-d3)aminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinamide)hydrazine-1-formamidinium 17-6 (710 mg, two-step yield 32.3%).

[0622] LC-MS m / z (ESI) = 551.2 [M+H] + .

[0623] Step 6:

[0624] N-(N-methyl-d3-1-(3-chloropyridin-5-yl)ethyl)sulfonyl)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 17

[0625] N-(N-methyl-d3-1-(3-chloropyridin-5-yl)ethyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0626] The starting material 17-6 (710 mg, 1.3 mmol) was added to trifluoroacetic acid (15 mL), and under nitrogen protection, the mixture was heated to 70 °C and reacted for 6 hours. After the reaction was completed, the mixture was directly concentrated and purified by reverse column chromatography to obtain N-(N-methyl-d3-1-(3-chloropyridin-5-yl)ethyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 17 (415 mg, yield 43.3%).

[0627] LC-MS m / z (ESI) = 533.2 [M+H] + .

[0628] 1 H NMR(400MHz,DMSO-d6)δ13.54(s,1H),8.55(d,1H),8.44(d,1H),8.21(d,1H),7.91(dd,1 H),7.61(d,1H),7.57–7.38(m,2H),6.83(d,2H),4.15(s,2H),3.70(s,6H),2.24(s,3H).

[0629] Example 18

[0630] N-(N-trifluoroethyl-1-(3-chloropyridin-5-yl)ethyl)sulfonyl)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 18

[0631] N-(N-trifluoroethyl-1-(3-chloropyridin-5-yl)ethyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0632] first step:

[0633] N-((5-chloropyridin-2-yl)methyl)trifluoroethylamine 18-2

[0634] N-((5-chloropyridin-2-yl)methyl)trifluoroethylamine

[0635] Compound 5-chloropyridinaldehyde 18-1 (4.3 g, 30 mmol) and trifluoroethylamine (4.2 g, 42 mmol) were dissolved in tetrahydrofuran (10 mL), heated to 50 °C and stirred for 1 h. Then, sodium triacetoxyborohydride (7.0 g, 33 mmol) was added, and the reaction was continued for 2 h. The reaction was detected by LCMS to be complete. The reaction was quenched with sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified directly by column chromatography to obtain the target compound N-((5-chloropyridin-2-yl)methyl)trifluoroethylamine 18-2 (2.5 g, yield 84.6%).

[0636] LC-MS m / z (ESI) = 225.0 [M+H] + .

[0637] Step Two:

[0638] (N-((5-chloropyridin-2-yl)methyl)-N-(2,2,2-trifluoroethyl)aminosulfonyl)tert-butyl carbamate 18-3

[0639] tert-butyl(N-((5-chloropyridin-2-yl)methyl)-N-(2,2,2-trifluoroethyl)sulfamoyl)carbamate

[0640] 1.1 g (15 mmol) of tert-butanol was added to 10 mL of dichloromethane under nitrogen protection and cooled to 0 °C. Then, 2.1 g (15.0 mmol) of chlorosulfonyl isocyanate was added, and the reaction mixture was reacted at 0 °C for 1 hour. Then, 2.02 g (20.0 mmol) of triethylamine was added, resulting in the precipitation of a large amount of solid. Then, 2.25 g (10.0 mmol) of N-((5-chloropyridin-2-yl)methyl)trifluoroethylamine 18-2 was added, and the reaction mixture was slowly heated to room temperature. The reaction was confirmed by LCMS, concentrated under reduced pressure, and purified directly by column chromatography to obtain tert-butyl (N-((5-chloropyridin-2-yl)methyl)-N-(2,2,2-trifluoroethyl)aminosulfonyl)carbamate 18-3 (2.5 g, yield 61.9%).

[0641] LC-MS m / z (ESI) = 404.1 [M+H] + .

[0642] Step 3:

[0643] N-((5-chloropyridin-2-yl)methyl)-N-trifluoroethylaminesulfonamide 18-4

[0644] N-((5-chloropyridin-2-yl)methyl)-N-trifluoroethylsulfonamide

[0645] The starting material (N-((5-chloropyridin-2-yl)methyl)-N-(2,2,2-trifluoroethyl)aminosulfonyl)carbamate tert-butyl ester 18-3 (2.5 g, 6.2 mmol)) was added to dichloromethane (4 mL), followed by trifluoroacetic acid (4 mL). The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was directly concentrated to obtain N-((5-chloropyridin-2-yl)methyl)-N-trifluoroethylaminosulfonamide 18-4 (1.6 g, yield 84.9%).

[0646] LC-MS m / z (ESI) = 304.1 [M+H] + .

[0647] Step 4:

[0648] N-(N-((5-chloropyridin-2-yl)methyl)-N-(2,2,2-trifluoroethyl)aminosulfonyl)-N'-(2,6-dimethoxyphenyl)thiocarbamoyl 18-5

[0649] N-(N-((5-chloropyridin-2-yl)methyl)-N-(2,2,2-trifluoroethyl)sulfamoyl)-N'-(2,6-dimethoxyphenyl)carbamimidothioic acid

[0650] N-((5-chloropyridin-2-yl)methyl)-N-trifluoroethylaminesulfonamide 18-4 (1.3 g, 4.3 mmol) and 2-isothiocyano-1,3-dimethoxybenzene (1.1 g, 5.7 mmol) were added to anhydrous acetonitrile (20 mL), followed by cesium carbonate (2.1 g, 6.5 mmol). The reaction mixture was incubated at room temperature for 2 hours. The reaction was confirmed to be complete by LCMS. The mixture was then directly concentrated, and the crude product 18-5 was used directly in the next step.

[0651] LC-MS m / z (ESI) = 499.0 [M+H] + .

[0652] Step 5:

[0653] N-(N-((5-chloropyridin-2-yl)methyl)-N-(2,2,2-trifluoroethyl)aminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinyl)hydrazine-1-formamidinium 18-6

[0654] N-(N-((5-chloropyridin-2-yl)methyl)-N-(2,2,2-trifluoroethyl)sulfamoyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinoyl)hydrazine-1-carboximidamide

[0655] The crude product 18-5 from the previous step was added to tetrahydrofuran (20 mL), followed by 5-methylnicotinamide (650 mg, 4.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (826 mg, 4.3 mmol). The reaction mixture was reacted overnight at room temperature. The target reaction was detected by LCMS. After the reaction was complete, the mixture was filtered directly, concentrated under reduced pressure, and purified by reverse column chromatography to obtain (Z)-N-(N-((5-chloropyridin-2-yl)methyl)-N-(2,2,2-trifluoroethyl)aminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinamide)hydrazine-1-formamidinium 18-6 (1.1 g, two-step yield 41.5%).

[0656] LC-MS m / z (ESI) = 616.1 [M+H] +.

[0657] Step 6:

[0658] N-(N-trifluoroethyl-1-(3-chloropyridin-5-yl)ethyl)sulfonyl)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 18

[0659] N-(N-trifluoroethyl-1-(3-chloropyridin-5-yl)ethyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0660] The starting material 18-6 (1.1 g, 1.8 mmol) was added to trifluoroacetic acid (15 mL), and under nitrogen protection, the mixture was heated to 70 °C and reacted for 6 hours. After the reaction was completed, the mixture was directly concentrated and purified by reverse column chromatography to obtain N-(N-trifluoroethyl-1-(3-chloropyridin-5-yl)ethyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 18 (405 mg, yield 40%).

[0661] LC-MS m / z (ESI) = 598.2 [M+H] + .

[0662] 1 H NMR(400MHz,DMSO-d6)δ8.51(d,1H),8.41(d,1H),8.20(d,1H),7.88(dd,1H),7.59(d,1H), 7.54(d,1H),7.47(t,1H),6.81(d,2H),4.49(s,2H),4.00(q,2H),3.68(s,6H),2.24(s,3H)

[0663] Example 19

[0664] N-(N-methyl-1-(5-chloropyrimidin-2-yl)ethyl)sulfonyl)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 19

[0665] N-(N-methyl-1-(5-chloropyrimidin-2-yl)ethyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0666] first step:

[0667] 5-Chloroprene-2-formaldehyde 19-2

[0668] 5-chloropyrimidine-2-carbaldehyde

[0669] Oxaloyl chloride (3.5 g, 27.7 mmol) was added to dichloromethane (60 mL), and after nitrogen protection, the mixture was cooled to -70 °C. Then, dimethyl sulfoxide (2.37 g, 30.4 mmol) was slowly added dropwise. The reaction mixture was reacted at -65 °C for 30 minutes, followed by the addition of 5-chloropyrimidine-2-methanol 19-1 (2.0 g, 13.8 mmol). The reaction mixture was reacted at -70 °C for 1 hour, followed by the addition of triethylamine (8.4 g, 82.8 mmol) in a single batch. The mixture was then slowly heated to room temperature and reacted overnight. Extraction was performed with saturated sodium bicarbonate solution, followed by separation, drying over anhydrous sodium sulfate, concentration under reduced pressure, and column purification to obtain 5-chloropyrimidine-2-carboxaldehyde 19-2 (788 mg, yield 40.0%).

[0670] LC-MS m / z (ESI) = 143.0 [M+H] + .

[0671] Step Two:

[0672] 1-(5-Chloropremine-2-yl)-N-methylmethylamine 19-3

[0673] 1-(5-chloropyrimidin-2-yl)-N-methylmethanamine

[0674] 5-Chloroprene-2-carboxaldehyde 19-2 (788 mg, 5.0 mmol) and methylamine hydrochloride (1.01 g, 15.0 mmol) were dissolved in tetrahydrofuran (30 mL), heated to 50 °C and stirred for 1 h. Then, sodium triacetoxyborohydride (3.18 g, 15.0 mmol) was added, and the reaction was continued for 2 h. The reaction was detected by LCMS to be complete. The reaction was quenched with sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified directly by column chromatography to obtain the target compound 1-(5-chloropyrimidin-2-yl)-N-methylmethylamine 19-3 (570 mg, yield 72.1%).

[0675] LC-MS m / z (ESI) = 158.1 [M+H] + .

[0676] Step 3:

[0677] (N-((5-chloropyrimidin-2-yl)methyl)-N-methylaminosulfonyl)tert-butyl carbamate 19-4

[0678] tert-butyl(N-((5-chloropyrimidin-2-yl)methyl)-N-methylsulfamoyl)carbamate

[0679] The starting material, tert-butanol (445 mg, 6.0 mmol), was added to dichloromethane (10 mL). Under nitrogen protection, the mixture was cooled to 0 °C, followed by the addition of chlorosulfonyl isocyanate (852 mg, 6.0 mmol). The reaction mixture was reacted at 0 °C for 1 hour, followed by the addition of triethylamine (909 mg, 9.0 mmol), resulting in the precipitation of a large amount of solid. Then, the starting material, 1-(5-chloropyrimidin-2-yl)-N-methylmethylamine 19-3 (474 ​​mg, 3.0 mmol), was added, and the reaction mixture was slowly heated to room temperature. The reaction was confirmed by LCMS, and the mixture was concentrated under reduced pressure and purified directly by column chromatography to obtain (N-((5-chloropyrimidin-2-yl)methyl)-N-methylaminosulfonyl)carbamate tert-butyl 19-4 (340 mg, yield 33.6%).

[0680] LC-MS m / z (ESI) = 337.1 [M+H] + .

[0681] Step 4:

[0682] N-((5-chloropyrimidin-2-yl)methyl)-N-methylaminosulfonamide 19-5

[0683] N-((5-chloropyrimidin-2-yl)methyl)-N-methylsulfonamide

[0684] The starting material (N-((5-chloropyrimidin-2-yl)methyl)-N-methylaminosulfonyl)carbamate tert-butyl ester 19-4 (337 mg, 1.0 mmol)) was added to dichloromethane (4 mL), followed by trifluoroacetic acid (4 mL). The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was directly concentrated to obtain N-((5-chloropyrimidin-2-yl)methyl)-N-methylaminosulfonamide 19-5 (233 mg, yield 98.3%).

[0685] LC-MS m / z (ESI) = 237.1 [M+H] + .

[0686] Step 5:

[0687] N-(N-((5-chloropyrimidin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)thiocarbamoimine 19-6

[0688] N-(N-((5-chloropyrimidin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)carbamimidothioic acid

[0689] N-((5-chloropyrimidin-2-yl)methyl)-N-methylaminosulfonamide 19-5 (233 mg, 1.0 mmol) and 2-isothiocyano-1,3-dimethoxybenzene (234 mg, 1.2 mmol) were added to anhydrous acetonitrile (20 mL), followed by cesium carbonate (489 mg, 1.5 mmol). The reaction mixture was incubated at room temperature for 2 hours. LC-MS analysis confirmed the reaction was complete. The mixture was then directly concentrated, and the crude product 19-6 was used directly in the next step.

[0690] LC-MS m / z (ESI) = 432.1 [M+H] + .

[0691] Step 6:

[0692] N-(N-((5-chloropyrimidin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinyl)hydrazine-1-formamidinium 19-7

[0693] N-(N-((5-chloropyrimidin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinoyl)hydrazine-1-carboximidamide

[0694] The crude product 19-6 from the previous step was added to tetrahydrofuran (20 mL), followed by 5-methylnicotinamide (206 mg, 1.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288 mg, 1.5 mmol). The reaction mixture was reacted overnight at room temperature. The target reaction was detected by LCMS. After the reaction was complete, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to obtain N-(N-((5-chloropyrimidin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinamide)hydrazine-1-formamidinium 19-7 (150 mg, two-step yield 27.3%).

[0695] LC-MS m / z (ESI) = 549.2 [M+H] + .

[0696] Step 7:

[0697] N-(N-methyl-1-(5-chloropyrimidin-2-yl)ethyl)sulfonyl)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 19

[0698] N-(N-methyl-1-(5-chloropyrimidin-2-yl)ethyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0699] The starting material 19-7 (150 mg, 0.27 mmol) was added to trifluoroacetic acid (5 mL), and under nitrogen protection, the mixture was heated to 70 °C and reacted for 6 hours. After the reaction was completed, the mixture was directly concentrated and purified by reverse column chromatography to obtain N-(N-methyl-1-(5-chloropyrimidin-2-yl)ethyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 19 (55 mg, yield 38.4%).

[0700] LC-MS m / z (ESI) = 531.2 [M+H] + .

[0701] 1 H NMR(400MHz,DMSO-d6)δ13.52(s,1H),8.92(s,2H),8.48(d,1H),8.22(d,1H),7.63(d ,1H),7.52(t,1H),6.85(d,2H),4.26(s,2H),3.74(s,6H),2.60(s,3H),2.26(s,3H).

[0702] Example 20

[0703] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-cyclopropylthiazo-2-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 20

[0704] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-cyclopropylthiazole-2-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[0705] first step:

[0706] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-2-(5-cyclopropylthiazole-2-carbonyl)-N'-(2,6-dimethoxyphenyl)hydrazine-1-formamidinium 20-2

[0707] (Z)-N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-2-(5-cyclopropylthiazole-2-carbonyl)-N'-(2,6-dimethoxyphenyl)hydrazine-1-carboximidamide

[0708] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)thiocarbamoyl 8-7 (2.37 g, 5.5 mmol) was added to tetrahydrofuran (10 mL), followed by 5-cyclopropylthiazolyl-2-carbazide 20-1 (1.0 g, 5.46 mmol), and then EDCI (1.35 g, 7.1 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours. The reaction solution was directly evaporated to dryness, then dissolved in a 10:1 DCM:MeOH mixed solution (100 mL), washed three times with saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain a crude product. The crude product was then slurried with ACN to obtain a white solid N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-2-(5-cyclopropylthiazolyl-2-carbonyl)-N'-(2,6-dimethoxyphenyl)hydrazine-1-formamidin 20-2 (1.1 g, yield 76.2%).

[0709] LC-MS m / z (ESI) = 580.1 [M+1].

[0710] Step Two:

[0711] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-cyclopropylthiazo-2-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 20

[0712] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-cyclopropylthiazole-2-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[0713] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-2-(5-cyclopropylthiazol-2-carbonyl)-N'-(2,6-dimethoxyphenyl)hydrazine-1-formamidin 20-2 (1.1 g, 1.3 mmol) was dissolved in TFA (15 mL) and reacted at 80 °C for 8 hours. The reaction was monitored by LCMS until completion. The reaction was quenched by adding sodium bicarbonate aqueous solution, followed by extraction with a DCM:MeOH = 10:1 mixed solution (100 mL) and water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The mixture was then slurried with acetonitrile to obtain the target compound N-(N-(5-chloropyridin-2-yl)methyl)sulfonamide)-4-(2,6-dimethoxy)-5-(5-cyclopropylthiazol-2-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 20 (white solid, 312 mg, 23% yield).

[0714] LC-MS m / z (ESI) = 563.10 [M+H] + .

[0715] 1 H NMR(400MHz,DMSO-d6)δ13.57(s,1H),8.56(d,1H),7.90(dd,1H),7.52(t,1H),7.49(s,1H),7.42(d, 1H),6.83(d,2H),4.12(s,2H),3.68(s,6H),2.00–1.86(m,1H),0.76–0.68(m,2H),0.38–0.24(m,2H).

[0716] Example 21

[0717] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-methylfuran-2-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 21

[0718] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-methylfuran-2-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[0719] first step:

[0720] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,6-dimethoxyphenyl)-2-(5-methylfuran-2-carbonyl)hydrazone-1-carboxamide 21-2

[0721] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylfuran-2-carbonyl)hydrazine-1-carboximidamide

[0722] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)thiocarbamoyl 8-7 (3.1 g, 7.21 mmol) was added to tetrahydrofuran (10 mL), followed by 5-methylfuran-2-carbazide 21-1 (1.0 g, 7.14 mmol), and then EDCI (1.77 g, 9.28 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours until completion. Afterwards, the reaction solution was directly evaporated to dryness, then dissolved in a 10:1 DCM:MeOH mixed solution (100 mL), washed three times with saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain the crude product. The crude product was then slurried with ACN to obtain a white solid (N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,6-dimethoxyphenyl)-2-(5-methylfuran-2-carbonyl)hydrazone-1-carboxamide 21-2 (1.1 g, yield 76.2%).

[0723] LC-MS m / z (ESI) = 537.1 [M+1].

[0724] Step Two:

[0725] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-methylfuran-2-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 21

[0726] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-methylfuran-2-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[0727] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,6-dimethoxyphenyl)-2-(5-methylfuran-2-carbonyl)hydrazone-1-carboxamide 21-2 (1.1 g, 1.3 mmol) was dissolved in TFA (15 mL) and reacted at 80 °C for 8 hours. The reaction was monitored by LCMS until completion. The reaction was quenched by adding sodium bicarbonate aqueous solution, followed by extraction with a DCM:MeOH mixture of 10:1 (100 L) and water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The mixture was then slurried with acetonitrile to obtain the target compound N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-methylfuran-2-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 21 (white solid, 214 mg, 20% yield).

[0728] LC-MS m / z (ESI) = 519.10 [M+H] + .

[0729] 1 H NMR(400MHz,DMSO-d6)δ8.52(d,1H),7.89(dd,1H),7.53–7.45(m,2H),6.84(d,2H) ),6.05(dd,1H),5.63(d,1H),4.16(s,2H),3.65(s,6H),2.48(s,3H),2.24(s,3H).

[0730] Example 22

[0731] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-methylthiazo-2-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 22

[0732] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-methylthiazole-2-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[0733] first step:

[0734] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-2-(5-methylthiazolyl-2-carbonyl)-N'-(2,6-dimethoxyphenyl)hydrazine-1-formamidinium 22-2

[0735] (Z)-N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-2-(5-methylthiazole-2-carbonyl)-N'-(2,6-dimethoxyphenyl)hydrazine-1-carboximidamide

[0736] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)thiocarbamoyl 8-7 (3.1 g, 7.21 mmol) was added to tetrahydrofuran (10 mL), followed by 5-methylthiazolyl-2-carbazide 22-1 (1.0 g, 7.14 mmol), and then EDCI (1.77 g, 9.28 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours. The reaction solution was directly evaporated to dryness, then dissolved in a 10:1 DCM:MeOH mixed solution (100 mL), washed three times with saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain a crude product. The crude product was then slurried with ACN to obtain a white solid N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-2-(5-methylthiazolyl-2-carbonyl)-N'-(2,6-dimethoxyphenyl)hydrazine-1-formamidin 22-2 (1.5 g, yield 78.2%).

[0737] LC-MS m / z (ESI) = 554.1 [M+H] + .

[0738] Step Two:

[0739] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-methylthiazo-2-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 22

[0740] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-methylthiazole-2-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[0741] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-2-(5-methylthiazol-2-carbonyl)-N'-(2,6-dimethoxyphenyl)hydrazine-1-formamidin 22-2 (900 mg, 1.7 mmol) was dissolved in TFA (15 mL) and reacted at 80 °C for 8 hours. The reaction was monitored by LCMS until completion. The reaction was quenched by adding sodium bicarbonate aqueous solution, followed by extraction with a DCM:MeOH = 10:1 mixed solution (100 L) and water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The mixture was then slurried with acetonitrile to obtain the target compound N-(N-(5-chloropyridin-2-yl)methyl)sulfonamide)-4-(2,6-dimethoxy)-5-(5-methylthiazol-2-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 22 (white solid, 321 mg, 30% yield).

[0742] LC-MS m / z (ESI) = 536.10 [M+H] + .

[0743] 1 H NMR(400MHz,DMSO-d6)δ13.62(s,1H),8.56(d,1H),7.91(dd,1H),7.53(t,1H),7. 49–7.40(m,2H),6.85(d,2H),4.13(s,2H),3.69(s,6H),2.52(s,3H),2.23(s,3H).

[0744] Example 23

[0745] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1-methyl-1H-pyrazole-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 23

[0746] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(1-methyl-1H-pyrazole-3-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[0747] first step:

[0748] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboxamide 23-2

[0749] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboximidamide

[0750] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)thiocarbamoyl 8-7 (3.1 g, 7.21 mmol) was added to tetrahydrofuran (10 mL), followed by 1-methyl-1H-pyrazole-3-carbazide 23-1 (1.0 g, 7.14 mmol), and then EDCI (1.77 g, 9.28 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours. The reaction solution was directly evaporated to dryness, then dissolved in a 10:1 DCM:MeOH mixed solution (100 mL), washed three times with saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain a crude product. The crude product was then slurried with ACN to obtain a white solid N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,6-dimethoxyphenyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboxamide 23-2 (1.5 g, yield 78.2%).

[0751] LC-MS m / z (ESI) = 537.1 [M+H] + .

[0752] Step Two:

[0753] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1-methyl-1H-pyrazole-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 23

[0754] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(1-methyl-1H-pyrazole-3-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[0755] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,6-dimethoxyphenyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboxamide 23-2 (1.5 g, 2.8 mmol) was dissolved in TFA (15 mL) and reacted at 80 °C for 8 hours. The reaction was monitored by LCMS until completion. The reaction was quenched by adding sodium bicarbonate aqueous solution, followed by extraction with a DCM:MeOH = 10:1 mixed solution (100 mL) and water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The mixture was then slurried with acetonitrile to obtain the target compound N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1-methyl-1H-pyrazole-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 23 (white solid, 1.0 g, 70% yield).

[0756] LC-MS m / z (ESI) = 519.10 [M+H] + .

[0757] 1 H NMR(400MHz,DMSO-d6)δ8.56(dd,1H),7.92(dd,1H),7.69(d,1H),7.50(t,1H),7. 47–7.40(m,1H),6.83(d,2H),6.07(d,1H),4.13(s,2H),3.74(s,3H),3.69(s,5H).

[0758] Example 24

[0759] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(6-methoxypyridinyl)-N-methyl-4H-1,2,4-triazol-3-amine compound 24

[0760] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(6-methoxypicolinoyl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[0761] first step:

[0762] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(6-methoxypyridinyl)hydrazine-1-formamidin 24-2

[0763] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)-2-(6-methoxypicolinoyl)hydrazine-1-carboximidamide

[0764] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)thiocarbamoyl 8-7 (3.08 g, 7.18 mmol) was added to tetrahydrofuran (10 mL), followed by 6-methoxypyridinyl hydrazide 24-1 (1.0 g, 5.98 mmol), and then EDCI (1.77 g, 9.28 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours. The reaction solution was directly evaporated to dryness, then dissolved in a 10:1 DCM:MeOH mixed solution (100 mL), washed three times with saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain a crude product. The crude product was then slurried with ACN to obtain a white solid N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(6-methoxypyridinyl)hydrazine-1-formamidin 24-2 (1.1 g, yield 76.2%).

[0765] LC-MS m / z (ESI) = 564.1 [M+H] + .

[0766] Step Two:

[0767] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(6-methoxypyridinyl)-N-methyl-4H-1,2,4-triazol-3-amine compound 24

[0768] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(6-methoxypicolinoyl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[0769] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(6-methoxypyridinyl)hydrazine-1-formamidin 24-2 (1.1 g, 2.0 mmol) was dissolved in TFA (15 mL) and reacted at 80 °C for 8 hours. The reaction was monitored by LCMS until completion. The reaction was quenched by adding sodium bicarbonate aqueous solution, followed by extraction with a DCM:MeOH = 10:1 mixed solution (100 mL) and water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The mixture was then slurried with acetonitrile to obtain the target compound N-(N-(5-chloropyridin-2-yl)methyl)sulfonamide)-4-(2,6-dimethoxy)-5-(6-methoxypyridinyl)-N-methyl-4H-1,2,4-triazol-3-amine compound 24 (white solid, 235 mg, 20% yield).

[0770] LC-MS m / z (ESI) = 562.10 [M+H] + .

[0771] 1 H NMR(400MHz,DMSO-d6)δ13.47(s,1H),8.56(d,1H),7.92(dd,1H),7.87–7.77(m,1H),7.6 0(d,1H),7.43(dt,2H),6.84(d,1H),6.81(d,2H),4.12(s,2H),3.66(s,6H),3.11(s,3H).

[0772] Example 25

[0773] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(2-methylthiazo-5-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 25

[0774] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(2-methylthiazole-5-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[0775] first step:

[0776] 2-Methylthiazole-5-carbonylhydrazine 25-2

[0777] 2-methylthiazole-5-carbohydrazide

[0778] 4.5 g (28.6 mmol) of methyl 2-methylthiazole-5-carboxylic acid 25-1 and hydrazine hydrochloride (3.92 g (57.2 mmol) were added to methanol (120 mL), followed by DBU (13 mL (85.9 mmol)). The mixture was reacted at room temperature for 8 hours. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in ethyl acetate (50 mL), washed with water (50 mL × 3), washed with saturated sodium chloride (50 mL × 3), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain a brown liquid, 2-methylthiazole-5-carbazide 25-2 (3 g, yield 66.6%).

[0779] LC-MS m / z (ESI) = 158.10 [M+H] + .

[0780] Step Two:

[0781] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(2-methylthiazolyl-5-carbonyl)hydrazine-1-formimide 25-3

[0782] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)-2-(2-methylthiazole-5-carbonyl)hydrazine-1-carboximidamide

[0783] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)carbamic acid 8-7 (1.15 g, 2.6 mmol) and 2-methylthiazolyl-5-carbazide 25-2 (1.1 g, 6.9 mmol) were added to tetrahydrofuran (15 mL), followed by 1-ethyl-(3-dimethylaminopropyl)carbazide diimide hydrochloride (1.02 mg, 5.3 mmol). The mixture was reacted at room temperature for 8 hours. After the reaction was completed as monitored by TLC, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give a white solid N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(2-methylthiazolyl-5-carbonyl)hydrazine-1-carboximide 25-3 (500 mg, yield 33.8%).

[0784] LC-MS m / z (ESI) = 554.10 [M+H] + .

[0785] Step 3:

[0786] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(2-methylthiazo-5-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 25

[0787] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(2-methylthiazole-5-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[0788] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(2-methylthiazolyl-5-carbonyl)hydrazide-1-carboximide 25-3 (500 mg, 0.9 mmol) was added to trifluoroacetic acid (15 mL), and the reaction was carried out at 70 °C for 36 hours. After the reaction was completed by TLC monitoring, the system was diluted with water (40 mL) and extracted with ethyl acetate (40 mL × 3). The organic phase was washed with saturated sodium chloride (60 mL), dried over anhydrous sodium sulfate, and filtered. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 50:1) to give a white solid N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(2-methylthiazolyl-5-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 25 (46 mg, yield 10%).

[0789] LC-MS m / z (ESI) = 536.10 [M+H] + .

[0790] 1 H NMR (400MHz, DMSO-d6) δ13.49(s,1H),8.55(d,J=2.4Hz,1H),7.91(dd,J=8.4,2.4Hz,1H),7.61(t,J=8.4Hz,1H) ,7.51(s,1H),7.43(d,J=8.4Hz,1H),6.92(d,J=8.4Hz,2H),4.12(s,2H),3.74(s,6H),2.62(s,3H),2.51(s,3H).

[0791] Example 26

[0792] N-(N-methyl-1-(6-chloropyridazin-3-yl)ethyl)sulfonyl)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 26

[0793] N-(N-methyl-1-(6-chloropyridazin-3-yl)ethyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0794] first step:

[0795] 1-(6-Chlorpyridazine-3-yl)-N-methylmethylamine 26-2

[0796] 1-(6-chloropyridazin-3-yl)-N-methylmethanamine

[0797] 6-Chlorpyridazine-3-carboxaldehyde 26-1 (1.81 g, 12.7 mmol) and methylamine hydrochloride (1.71 g, 25.4 mmol) were added to methanol / tetrahydrofuran = 1 / 1 (10 mL: 10 mL). After nitrogen protection, the reaction was carried out at 50 °C for 2 h. Then, sodium triacetylborohydride (15.9 g, 75 mol) was added, and the reaction was carried out for 4 h. After the reaction was completed, the mixture was directly filtered, the filtrate was concentrated, the residue was dissolved in dichloromethane, sodium bicarbonate was added and stirred for 2 h, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (DCM:MeOH = 10%) to obtain a yellow solid 1-(6-chloropyridazine-3-yl)-N-methylmethylamine 26-2 (1.4 g, yield 70%).

[0798] LC-MS m / z (ESI) = 158.10 [M+H] + .

[0799] Step Two:

[0800] (N-((6-chloropyridazin-3-yl)methyl)-N-methylaminosulfonyl)tert-butyl carbamate 26-3

[0801] tert-butyl(N-((6-chloropyridazin-3-yl)methyl)-N-methylsulfamoyl)carbamate

[0802] The starting material, tert-butanol (0.725 g, 9.77 mmol), was added to dichloromethane (10 mL). After nitrogen protection, the mixture was cooled to 0 °C, followed by the addition of chlorosulfonyl isocyanate (1.38 g, 9.77 mmol). The reaction mixture was reacted at 0 °C for 1 hour, followed by the addition of triethylamine (2.7 g, 26.64 mmol), resulting in the precipitation of a large amount of solid. Then, the starting material, 1-(6-chloropyridazin-3-yl)-N-methylmethylamine 26-2 (1.4 g, 8.88 mmol), was added, and the reaction mixture was slowly heated to room temperature. The reaction was confirmed by LCMS, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain (N-((6-chloropyridazin-3-yl)methyl)-N-methylaminosulfonyl)carbamate tert-butyl ester 26-3 (600 mg, yield 20.2%).

[0803] LC-MS m / z (ESI) = 337.1 [M+H] + .

[0804] Step 3:

[0805] (N-(6-chloropyridazine-3-yl)methyl)-N-methylaminosulfonamide 26-4

[0806] (N-(6-chloropyridazin-3-yl)methyl)N-methylsulfonamide

[0807] The starting material (N-((6-chloropyridazin-3-yl)methyl)-N-methylaminosulfonyl)carbamate tert-butyl ester 26-3 (600 mg, 1.78 mmol)) was added to dioxane hydrochloride (10 mL). The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was directly concentrated to obtain (N-(6-chloropyridazin-3-yl)methyl)-N-methylaminosulfonamide 26-4 (600 mg). This was used directly in the next step.

[0808] LC-MS m / z (ESI) = 237.1 [M+H] + .

[0809] Step 4:

[0810] N-(N-((6-chloropyridazin-3-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)carbamoylthioic acid 26-5

[0811] N-(N-((6-chloropyridazin-3-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)carbamimidothioic acid

[0812] The starting material (N-(6-chloropyridazin-3-yl)methyl)-N-methylaminosulfonamide 26-4 (600 mg, 1.78 mmol) was added to an acetonitrile (10 mL) solution, followed by 2-isothiocyano-1,3-dimethoxybenzene (382 mg, 1.96 mmol) and cesium carbonate (756 mg, 2.32 mmol). The resulting mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was filtered to obtain filter cake (E)-N-(N-((6-chloropyridazin-3-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)carbamoylthioic acid 26-5 (760 mg). This was used directly in the next step.

[0813] LC-MS m / z (ESI) = 432.10 [M+H] + .

[0814] Step 5:

[0815] N-(N-((6-chloropyridazin-3-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinyl)hydrazine-1-carboxamide 26-6

[0816] N-(N-((6-chloropyridazin-3-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinoyl)hydrazine-1-carboximidamide

[0817] N-(N-((6-chloropyridazin-3-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)carbamoylthioic acid 26-5 (760 mg) was added to tetrahydrofuran (10 mL), followed by 5-methylnicotinamide (405 mg, 2.67 mmol), and then EDCI (443 mg, 2.31 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours. After the reaction was complete, the reaction mixture was directly evaporated to dryness, and then... Dissolved in a 10:1 DCM:MeOH mixed solution (100 mL), washed three times with saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain the crude product. Column chromatography (DCM:MeOH = 4%) yielded a white solid (Z)-N-(N-((6-chloropyridazin-3-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinyl)hydrazine-1-carboxamide 26-6 (300 mg, three-step yield 30.7%).

[0818] LC-MS m / z (ESI) = 549.1 [M+H] +.

[0819] Step 6:

[0820] N-(N-methyl-1-(6-chloropyridazin-3-yl)ethyl)sulfonyl)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 26

[0821] N-(N-methyl-1-(6-chloropyridazin-3-yl)ethyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0822] N-(N-((6-chloropyridazin-3-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinyl)hydrazine-1-carboxamide 26-6 (300 mg, 0.541 mmol) was dissolved in TFA (10 mL) and reacted at 70 °C for 8 h. The reaction was monitored by LCMS until completion. The reaction was quenched by adding sodium bicarbonate aqueous solution, followed by extraction with DCM:MeOH = 10:1 mixed solution (100 mL) and water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. Column chromatography (DCM:MeOH = 3%) yielded the target compound 26 (white solid, 120 mg, yield 41.3%).

[0823] LC-MS m / z (ESI) = 531.10 [M+H] + .

[0824] 1 H NMR(400MHz,DMSO-d6)δ13.52(s,1H),8.49(d,1H),8.21(d,1H),7.87(d,1H),7.72(d,1H),7.6 5–7.61(m,1H),7.53(t,1H),6.85(d,2H),4.33(s,2H),3.73(s,6H),2.53(s,3H),2.26(s,3H).

[0825] Example 27

[0826] N-(imidazo[1,2-a]pyridin-2-yl-methyl)sulfonyl)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 27

[0827] N-(N-(imidazo[1,2-a]pyridin-2-yl-methyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0828] first step:

[0829] 1-(imidazo[1,2-a]pyridin-2-yl)-N-methylmethylamine 27-2

[0830] 1-(imidazo[1,2-a]pyridin-2-yl)-N-methylmethanamine

[0831] Imidazolo[1,2-a]pyridin-2-carboxaldehyde 27-1 (4 g, 27.37 mmol) and methylamine hydrochloride (3.7 g, 54.7 mmol) were added to methanol:tetrahydrofuran = 1:1 (150 mL:150 mL). After nitrogen protection, the reaction was carried out at 50 °C for 2 hours. Then, sodium triacetylborohydride (34.8 g, 1.642 mol) was added, and the reaction was carried out for 4 hours. After the reaction was completed, the mixture was directly filtered, the filtrate was concentrated, the residue was dissolved in dichloromethane, 50 g of NaHCO3 solid was added, and the mixture was stirred for 2 hours. After filtration, the filtrate was concentrated to obtain a white solid 1-(imidazo[1,2-a]pyridin-2-yl)-N-methylmethylamine 27-2 (4.4 g, 99% yield).

[0832] LC-MS m / z(ESI) = 162.2 [M+1].

[0833] Step Two:

[0834] N-(imidazo[1,2-a]pyridin-2-ylmethyl)-N-methylsulfonylcarbamate tert-butyl ester 27-3

[0835] tert-butyl(N-(imidazo[1,2-a]pyridin-2-ylmethyl)-N-methylsulfamoyl)carbamate

[0836] 2.23 g (30 mmol) of tert-butanol was added to 200 mL of dichloromethane. Under nitrogen protection, the mixture was cooled to 0 °C, followed by the addition of 4.26 g (30 mmol) of chlorosulfonyl isocyanate. The reaction mixture was reacted at 0 °C for 1 hour. Then, 11.5 mL (82.1 mol) of triethylamine was added, resulting in the precipitation of a large amount of solid. Next, 4.4 g (27.36 mmol) of 1-(imidazo[1,2-a]pyridin-2-yl)-N-methylmethylamine 27-2 was added, and the reaction mixture was slowly heated to room temperature. The reaction was confirmed by LCMS. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 3 g (3 g, 26% yield) of N-(imidazo[1,2-a]pyridin-2-ylmethyl)-N-methylsulfonylcarbamate tert-butyl ester 27-3.

[0837] LCMS m / z(ESI) = 341.1[M+H] + .

[0838] Step 3:

[0839] N-(imidazo[1,2-a]pyridin-2-ylmethyl)-N-methylaminosulfonamide 27-4

[0840] N-(Imidazo[1,2-a]pyridin-2-ylmethyl)-N-methylsulfamamide

[0841] The starting material N-(imidazo[1,2-a]pyridin-2-ylmethyl)-N-methylsulfonylcarbamate tert-butyl ester 27-3 (2.9 g, 8.53 mmol) was added to dioxane hydrochloride (50 mL), and the reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was directly concentrated to obtain N-(imidazo[1,2-a]pyridin-2-ylmethyl)-N-methylaminosulfonamide 27-4 (2.4 g, yield 99%).

[0842] LCMS m / z(ESI) = 241.1[M+H] + .

[0843] Step 4:

[0844] N'-(2,6-dimethoxyphenyl)-N-(N-(imidazo[1,2-a]pyridin-2-ylmethyl)-N-methylsulfonylcarbamoyl)thiocarbamoamide 27-5

[0845] N'-(2,6-dimethoxyphenyl)-N-(N-(imidazo[1,2-a]pyridin-2-ylmethyl)-N-methylsulfamoyl)carbamimidothioic acid

[0846] The starting material N-(imidazo[1,2-a]pyridin-2-ylmethyl)-N-methylaminosulfonamide 27-4 (1 g, 3.62 mmol) was added to an acetonitrile (15 mL) solution, followed by 2-isothiocyano-1,3-dimethoxybenzene (780 mg, 4 mmol) and cesium carbonate (1.535 g, 4.7 mmol). The resulting mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was filtered to obtain the filter cake N'-(2,6-dimethoxyphenyl)-N-(N-(imidazo[1,2-a]pyridin-2-ylmethyl)-N-methylsulfonylcarbamoyl)thiocarbamoyl crude product 27-5 (1.8 g, 99% yield). This was used directly in the next step.

[0847] LC-MS m / z(ESI) = 436.0 [M+1].

[0848] Step 5:

[0849] N'-(2,6-dimethoxyphenyl)-N-(N-(imidazo[1,2-a]pyridin-2-ylmethyl)-N-methylsulfonylcarbamoyl)-2-(5-methylnicotinyl)hydrazine-1-carbamate 27-6

[0850] N'-(2,6-dimethoxyphenyl)-N-(N-(imidazo[1,2-a]pyridin-2-ylmethyl)-N-methylsulfamoyl)-2-(5-methylnicotinoyl)hydrazine-1-carboximidamide

[0851] Crude N'-(2,6-dimethoxyphenyl)-N-(N-(imidazo[1,2-a]pyridin-2-ylmethyl)-N-methylsulfonylcarbamoyl)thiocarbamoyl 27-5 (1.8 g) was added to tetrahydrofuran (40 ml), followed by 5-methylnicotinamide (755 mg, 5 mmol), and then EDCI (1.04 g, 5.41 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours. After the reaction was complete, the solution was directly evaporated to dryness. The solution was then dissolved in a 10:1 DCM:MeOH mixture (200 mL), washed three times with a saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain a crude product. The crude product was then slurried with ACN to obtain a white solid N'-(2,6-dimethoxyphenyl)-N-(N-(imidazo[1,2-a]pyridin-2-ylmethyl)-N-methylsulfonylcarbamoyl)-2-(5-methylnicotinyl)hydrazine-1-carbonylamidinium 27-6 (1.765 g, yield 78%).

[0852] LC-MS m / z(ESI) = 553.1 [M+1].

[0853] Step 6:

[0854] N-(imidazo[1,2-a]pyridin-2-yl-methyl)sulfonyl)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 27

[0855] N-(N-(imidazo[1,2-a]pyridin-2-yl-methyl)sulfonamide)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[0856] N'-(2,6-dimethoxyphenyl)-N-(N-(imidazo[1,2-a]pyridin-2-ylmethyl)-N-methylsulfonylcarbamoyl)-2-(5-methylnicotinyl)hydrazine-1-carbamoylamine 27-6 (2 g, 3.6 mmol) was dissolved in TFA (30 mL) and reacted at 80 °C for 8 hours. The reaction was monitored by LCMS until completion. The reaction was quenched by adding sodium bicarbonate aqueous solution, followed by extraction with a DCM:MeOH = 10:1 mixed solution (1 mL) and water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The mixture was then slurried with acetonitrile to obtain the target compound N-(imidazo[1,2-a]pyridin-2-yl-methyl)sulfonyl)-4-(2,6-ethyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine 27 (white solid, 160 mg, 8.3% yield).

[0857] LC-MS m / z (ESI) = 535.10 [M+H] + .

[0858] 1 H NMR (400MHz, DMSO-d6) δ13.56(s,1H),8.85(dd,J=6.8,1.1Hz,1H),8.50(d,J=2.0Hz,1H),8.28(s,1H),8.21(d,J=2.1Hz,1H),7.97 –7.86(m,2H),7.62(d,J=2.3Hz,1H),7.55–7.42(m,2H),6.82(d,J=8.5Hz,2H),4.31(s,2H),3.75(s,6H),2.60(s,3H),2.26(s,3H).

[0859] Example 28

[0860] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2,6-difluorophenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 28

[0861] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2,6-difluorophenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[0862] first step:

[0863] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,6-difluorophenyl)amino]thionylmethyl}-1-methylazanesulfonamide 28-2

[0864] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,6-difluorophenyl)amino]thioxomethyl}-1-methylazanesulfonamide

[0865] The starting material [(2,6-difluorophenyl)azineyl]methylthione 28-1 (850 mg, 5.0 mmol) was added to acetonitrile (30 mL), followed by [(5-chloropyridin-2-yl)methyl](methyl)azinesulfonamide intermediate 8-6 (1.16 g, 5.0 mmol) and cesium carbonate (1.96 g, 6.0 mmol). The reaction mixture was reacted at room temperature for 3 hours, then concentrated under reduced pressure. The crude product 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,6-difluorophenyl)amino]thionylmethyl}-1-methylazinesulfonamide 28-2 was used directly in the next step.

[0866] LCMS m / z(ESI) = 407.0 [M+H] + .

[0867] Step Two:

[0868] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,6-difluorophenyl)amino][(1E)-2-[(1-methylpyrazol-3-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 28-3

[0869] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,6-difluorophenyl)amino][2-[(1-methylpyrazol-3-yl)carbonyl]diazanylidene]methyl}-1-methylazanesulfonamide

[0870] Crude 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,6-difluorophenyl)amino]thionylmethyl}-1-methylazanesulfonamide 28-2 (2.0 g, 5.0 mmol) was added to tetrahydrofuran (30 mL), followed by 1-methylpyrazol-3-carboxyhydrazide (700 mg, 5.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.0 mmol). The reaction mixture was allowed to react overnight at room temperature, and the target reaction was detected by LC-MS. After the reaction was completed, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to obtain 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,6-difluorophenyl)amino][2-[(1-methylpyrazol-3-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 28-3 (610 mg, two-step yield 23.8%).

[0871] LCMS m / z(ESI) = 513.10 [M+H] + .

[0872] Step 3:

[0873] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2,6-difluorophenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 28

[0874] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2,6-difluorophenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[0875] The starting material 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,6-difluorophenyl)amino][2-[(1-methylpyrazol-3-yl)carbonyl]ethazineyl]methyl}-1-methylazanesulfonamide 28-3 (610 mg, 1.2 mmol) was added to trifluoroacetic acid (15 mL), and the reaction mixture was heated to 75 °C and reacted for 4 hours. The reaction was confirmed by LCMS. After direct concentration, the mixture was purified by reversed-phase chromatography to obtain 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2,6-difluorophenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 28 (40 mg, yield 6.7%).

[0876] LC-MS m / z (ESI) = 495.10 [M+H] + .

[0877] 1 H NMR(400MHz,DMSO-d6)δ13.63(s,1H),8.53(d,1H),7.89(dd,1H),7.81(d,1H),7. 78–7.60(m,1H),7.39(q,3H),6.65(d,1H),4.15(s,2H),3.66(s,3H),2.54(s,3H).

[0878] Example 29

[0879] 1-[(5-chloropyridin-2-yl)methyl]-N-[5-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-2-yl)-4-(2,6-dimethoxyphenyl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 29

[0880] 1-[(5-chloropyridin-2-yl)methyl]-N-[5-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-2-yl)-4-(2,6-dimethoxyphenyl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[0881] first step:

[0882] 5,6-Dihydro-4H-pyrrolo[2,1-e]pyrazole-2-formylhydrazine 29-2

[0883] 5,6-dihydro-4H-pyrrolo[2,1-e]pyrazole-2-carbohydrazide

[0884] Methyl 5,6-dihydro-4H-pyrrolo[2,1-e]pyrazole-2-carboxylate 29-1 (1.0 g, 6.0 mmol) was added to methanol (30 mL), followed by hydrazine hydrochloride (617 mg, 9.0 mmol) and sodium methoxide (486 mg, 9.0 mmol). The reaction mixture was heated to reflux for 5 hours, then concentrated under reduced pressure. The crude product was purified by normal chromatography to obtain 5,6-dihydro-4H-pyrrolo[2,1-e]pyrazole-2-carboxylhydrazine 29-2 (568 mg, yield 56.8%).

[0885] LC-MS m / z (ESI) = 167.10 [M+H] + .

[0886] Step Two:

[0887] N-{[2-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-2-ylcarbonyl)ethazine][(2,6-dimethoxyphenyl)amino]methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazinesulfonamide 29-3

[0888] N-{[(1Z)-2-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-2-ylcarbonyl)diazanylidene][(2,6-dimethoxyphenyl)amino]methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazanesulfonamide

[0889] The starting material 5,6-dihydro-4H-pyrrolo[2,1-e]pyrazole-2-carboxylhydrazide 29-2 (501 mg, 3.0 mmol) was added to tetrahydrofuran (30 mL), followed by 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino]thionylmethyl}-1-methylazanesulfonamide 8-7 (862 mg, 2.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (576 mg, 3.0 mmol). The reaction mixture was allowed to react overnight at room temperature, and the target reaction was detected by LC-MS. After the reaction was completed, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to obtain N-{[2-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-2-ylcarbonyl)ethazinediyl][(2,6-dimethoxyphenyl)amino]methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazanesulfonamide 29-3 (620 mg, two-step yield 55.1%).

[0890] LC-MS m / z (ESI) = 563.20 [M+H] + .

[0891] Step 3:

[0892] 1-[(5-chloropyridin-2-yl)methyl]-N-[5-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-2-yl)-4-(2,6-dimethoxyphenyl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 29

[0893] 1-[(5-chloropyridin-2-yl)methyl]-N-[5-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-2-yl)-4-(2,6-dimethoxyphenyl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[0894] The starting material N-{[2-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-2-ylcarbonyl)ethazinedimethyl][(2,6-dimethoxyphenyl)amino]methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazanesulfonamide 29-3 (620 mg, 1.1 mmol) was added to trifluoroacetic acid (15 mL), and the reaction mixture was heated to 75 °C and reacted for 4 hours. The reaction was detected by LCMS. After direct concentration, the product was purified by reversed-phase chromatography to obtain compound 29 (138 mg, yield 23.0%) of 1-[(5-chloropyridin-2-yl)methyl]-N-[5-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-2-yl)-4-(2,6-dimethoxyphenyl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide.

[0895] LC-MS m / z (ESI) = 545.10 [M+H] + .

[0896] 1 H NMR(400MHz,DMSO-d6)δ13.23(s,1H),8.55(d,1H),7.91(dd,1H),7.62–7.30(m,2H),6.83(d,2H) ),5.87(s,1H),4.12(s,2H),3.97(t,2H),3.69(s,6H),2.76(t,2H),2.50(s,3H),2.46(dd,2H).

[0897] Example 30

[0898] 1-[(5-chloropyridin-2-yl)methyl]-N-[5-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-3-yl)-4-(2,6-dimethoxyphenyl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 30

[0899] 1-[(5-chloropyridin-2-yl)methyl]-N-[5-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-3-yl)-4-(2,6-dimethoxyphenyl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[0900] first step:

[0901] [2-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-3-ylcarbonyl)ethazol]methane-2-methylpropyl-2-yl ester 30-2

[0902] 2-methylpropan-2-yl[2-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-3-ylcarbonyl)diazanyl]methanoate

[0903] The starting material, 5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-3-carboxylic acid 30-1 (2.0 g, 13.1 mmol), was added to dichloromethane (50 mL), followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (7.5 g, 19.7 mmol) and triethylamine (2.7 g, 26.2 mmol). After stirring for 15 minutes, tert-butyl hydrazinoformate (2.6 g, 19.7 mmol) was added. The reaction mixture was reacted overnight at room temperature. The reaction was confirmed by LCMS and purified directly by normal column chromatography to obtain [2-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-3-ylcarbonyl)ethazol]methane-2-methylpropyl-2-yl ester 30-2 (2.2 g, yield 62.9%).

[0904] LCMS m / z(ESI) = 267.10 [M+H] + .

[0905] Step Two:

[0906] 5,6-Dihydro-4H-pyrrolo[2,1-e]pyrazole-3-carboxylhydrazine 30-3

[0907] 5,6-dihydro-4H-pyrrolo[2,1-e]pyrazole-3-carbohydrazide

[0908] The starting material [2-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazole-3-ylcarbonyl)ethazolyl]methane-2-methylpropyl-2-yl ester 30-2 (2.2 g, 8.2 mmol) was added to 20 mL of hydrochloric acid solution (4 mol / L HCl in 1,4-dioxane solution). The reaction mixture was reacted at room temperature for 4 hours. After the reaction was completed, it was directly concentrated under reduced pressure. The crude product 5,6-dihydro-4H-pyrrolo[2,1-e]pyrazole-3-formylhydrazide 30-3 was directly used in the next step (1.37 g, 100% yield).

[0909] LC-MS m / z (ESI) = 167.10 [M+H] + .

[0910] Step 3:

[0911] N-{[2-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-3-ylcarbonyl)ethazine][(2,6-dimethoxyphenyl)amino]methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazinesulfonamide 30-4

[0912] N-{[2-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-3-ylcarbonyl)diazanylidene][(2,6-dimethoxyphenyl)amino]methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazanesulfonamide

[0913] Crude 5,6-dihydro-4H-pyrrolo[2,1-e]pyrazole-3-carboxylhydrazide 30-3 (499 mg, 3.0 mmol) was added to tetrahydrofuran (30 mL), followed by 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino]thionylmethyl}-1-methylazanesulfonamide 8-7 (862 mg, 2.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (576 mg, 3.0 mmol). The reaction mixture was allowed to react overnight at room temperature, and the target reaction was detected by LCMS. After the reaction was completed, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to obtain N-{[2-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-3-ylcarbonyl)ethazinediyl][(2,6-dimethoxyphenyl)amino]methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazanesulfonamide 30-4 (610 mg, yield 54.2%).

[0914] LC-MS m / z (ESI) = 563.20 [M+H] + .

[0915] Step 4:

[0916] 1-[(5-chloropyridin-2-yl)methyl]-N-[5-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-3-yl)-4-(2,6-dimethoxyphenyl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 30

[0917] 1-[(5-chloropyridin-2-yl)methyl]-N-[5-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-3-yl)-4-(2,6-dimethoxyphenyl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[0918] The starting material N-{[2-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-3-ylcarbonyl)ethazinediyl][(2,6-dimethoxyphenyl)amino]methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazanesulfonamide 30-4 (610 mg, 1.1 mmol) was added to trifluoroacetic acid (15 mL), and the reaction mixture was heated to 75 °C and reacted for 4 hours. The reaction was detected by LC-MS to indicate completion. After direct concentration, the mixture was purified by reversed-phase chromatography to obtain 1-[(5-chloropyridin-2-yl)methyl]-N-[5-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-3-yl)-4-(2,6-dimethoxyphenyl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 30 (45 mg, yield 7.6%).

[0919] LC-MS m / z (ESI) = 545.10 [M+H] + .

[0920] 1 H NMR(400MHz,DMSO-d6)δ13.09(s,1H),8.55(d,1H),7.91(dd,1H),7.58(t,1H),7.42(d,1H),6.90( d,2H),6.74(s,1H),4.11(s,2H),4.05(t,2H),3.72(s,6H),2.77(t,2H),2.53(q,2H),2.49(s,3H).

[0921] Example 31

[0922] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-4-(1-phenylpropyl)-1,2,4-triazacyclopentan-3-yl]azine sulfonamide compound 31

[0923] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-4-(1-phenylpropyl)-1,2,4-triazol-3-yl]azanesulfonamide

[0924] first step:

[0925] [(1-Phenylacetyl)aza-ylidene]methylthione 31-2

[0926] [(1-phenylpropyl)azanylidene]methanethione

[0927] The starting material 1-phenylpropyl-1-amine 31-1 (2.7 g, 20.0 mmol) was dissolved in dichloromethane (100 mL), and then 1,1-thiocarbonylDI-2(1H)-pyridine (5.6 g, 24.0 mmol) was added in portions. The reaction mixture was reacted at room temperature for 3 hours. The target reaction was detected by LC-MS. After the reaction was completed, it was directly purified by normal column chromatography to obtain [(1-phenylpropyl)aza-dimethyl]meththione 31-2 (2.5 g, yield 71.9%).

[0928] LC-MS m / z (ESI) = 178.1 [M+H] + .

[0929] Step Two:

[0930] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-{[(1-phenylpropyl)amino]thionylmethyl}azaalkylsulfonamide 31-3

[0931] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-{[(1-phenylpropyl)amino]thioxomethyl}azanesulfonamide

[0932] The starting material [(1-phenylpropyl)azineyl]methylthionone 31-2 (1.77 g, 10.0 mmol) was added to acetonitrile (30 mL), followed by [(5-chloropyridin-2-yl)methyl](methyl)azinesulfonamide intermediate 8-7 (2.36 g, 10.0 mmol) and cesium carbonate (4.89 g, 15.0 mmol). The reaction mixture was reacted at room temperature for 3 hours, then concentrated under reduced pressure. The crude product 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-{[(1-phenylpropyl)amino]thionylmethyl}azinesulfonamide 31-3 was used directly in the next step.

[0933] LC-MS m / z (ESI) = 413.1 [M+H] + .

[0934] Step 3:

[0935] N-{[2-[(1-methylpyrazol-3-yl)carbonyl]acetazinediyl][(1-phenylpropyl)amino]methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazinesulfonamide 31-4

[0936] N-{[2-[(1-methylpyrazol-3-yl)carbonyl]diazanylidene][(1-phenylpropyl)amino]methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazanesulfonamide

[0937] Crude 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-{[(1-phenylpropyl)amino]thionylmethyl}azaalkylsulfonamide 31-3 (2.1 g, 5.0 mmol) was added to tetrahydrofuran (30 mL), followed by 1-methylpyrazol-3-carboxylhydrazide (700 mg, 5.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.0 mmol). The reaction mixture was reacted overnight at room temperature, and the target reaction was detected by LC-MS. After the reaction was completed, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to obtain N-{[2-[(1-methylpyrazol-3-yl)carbonyl]ethazineyl][(1-phenylpropyl)amino]methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazaalkylsulfonamide 31-4 (1.9 g, two-step yield 73.1%).

[0938] LC-MS m / z (ESI) = 519.10 [M+H] + .

[0939] Step 4:

[0940] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-4-(1-phenylpropyl)-1,2,4-triazacyclopentan-3-yl]azine sulfonamide compound 31

[0941] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-4-(1-phenylpropyl)-1,2,4-triazol-3-yl]azanesulfonamide

[0942] The starting material N-{[2-[(1-methylpyrazol-3-yl)carbonyl]ethazinediyl][(1-phenylpropyl)amino]methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazanesulfonamide 31-4 (520 mg, 1.0 mmol) was added to isopropanol (5 mL), followed by 2 mol / L sodium hydroxide aqueous solution (5 mL). The reaction mixture was placed in a microwave reactor and heated to 110 °C for 4 hours. The reaction was completed by LCMS. After direct concentration, the mixture was purified by reversed-phase chromatography to obtain 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-4-(1-phenylpropyl)-1,2,4-triazacyclopentan-3-yl]azanesulfonamide compound 31 (95 mg, yield 19.0%).

[0943] LC-MS m / z (ESI) = 501.20 [M+H] + .

[0944] 1 H NMR(400MHz,DMSO-d6)δ13.16(s,1H),8.54(d,1H),7.91(dd,2H),7.54–7.06(m,6H),6.29(dd ,1H),3.97(d,5H),2.88–2.57(m,1H),2.37(s,3H),2.27(ddd,1H),2.07(s,1H),0.85(t,3H).

[0945] Example 32

[0946] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-4-(phenylcyclopropyl)-1,2,4-triazacyclopentan-3-yl]azine sulfonamide compound 32

[0947] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-4-(phenylcyclopropyl)-1,2,4-triazol-3-yl]azanesulfonamide

[0948] first step:

[0949] [(phenylcyclopropyl)aza-ylidene]methionine 32-2

[0950] [(phenylcyclopropyl)azanylidene]methanethione

[0951] The starting material 1-phenylcyclopropyl-1-amine 32-1 (2.0 g, 15.0 mmol) was dissolved in dichloromethane (100 mL), and then 1,1-thiocarbonylDI-2(1H)-pyridine (4.2 g, 18.0 mmol) was added in portions. The reaction mixture was reacted at room temperature for 3 hours. The target reaction was detected by LC-MS. After the reaction was completed, it was directly purified by normal column chromatography to obtain [(phenylcyclopropyl)aza-dimethyl]meththione 32-2 (2.5 g, yield 71.9%).

[0952] LC-MS m / z (ESI) = 176.1 [M+H] + .

[0953] Step Two:

[0954] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-{[(phenylcyclopropyl)amino]thionylmethyl}azaalkylsulfonamide 32-3

[0955] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-{[(phenylcyclopropyl)amino]thioxomethyl}azanesulfonamide

[0956] The starting material [(phenylcyclopropyl)azineyl]methionine 32-2 (1.05 g, 6.0 mmol) was added to acetonitrile (30 mL), followed by [(5-chloropyridin-2-yl)methyl](methyl)azinesulfonamide intermediate 8-7 (1.40 g, 6.0 mmol) and cesium carbonate (2.9 g, 9.0 mmol). The reaction mixture was reacted at room temperature for 3 hours, then concentrated under reduced pressure. The crude product 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-{[(phenylcyclopropyl)amino]thionylmethyl}azinesulfonamide 32-3 was used directly in the next step.

[0957] LCMS m / z(ESI) = 411.1[M+H] + .

[0958] Step 3:

[0959] N-{[(1E)-2-[(1-methylpyrazol-3-yl)carbonyl]ethazinediyl][(phenylcyclopropyl)amino]methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazinesulfonamide 32-4

[0960] N-{[(1E)-2-[(1-methylpyrazol-3-yl)carbonyl]diazanylidene][(phenylcyclopropyl)amino]methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazanesulfonamide

[0961] Crude 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-{[(phenylcyclopropyl)amino]thionylmethyl}azaalkylsulfonamide 32-3 (2.5 g, 6.0 mmol) was added to tetrahydrofuran (30 mL), followed by 1-methylpyrazol-3-carboxylhydrazide (840 mg, 6.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.0 mmol). The reaction mixture was reacted overnight at room temperature, and the target reaction was detected by LC-MS. After the reaction was completed, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to obtain N-{[2-[(1-methylpyrazol-3-yl)carbonyl]ethazineyl][(phenylcyclopropyl)amino]methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazaalkylsulfonamide 32-4 (1.5 g, two-step yield 48.4%).

[0962] LCMS m / z(ESI) = 517.20 [M+H] + .

[0963] Step 4:

[0964] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-4-(phenylcyclopropyl)-1,2,4-triazacyclopentan-3-yl]azine sulfonamide compound 32

[0965] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-4-(phenylcyclopropyl)-1,2,4-triazol-3-yl]azanesulfonamide

[0966] The starting material N-{[2-[(1-methylpyrazol-3-yl)carbonyl]ethazinediyl][(phenylcyclopropyl)amino]methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazanesulfonamide 32-4 (520 mg, 1.0 mmol) was added to isopropanol (5 mL), followed by 2 mol / L sodium hydroxide aqueous solution (5 mL). The reaction mixture was placed in a microwave reactor and heated to 110 °C for 4 hours. The reaction was completed by LCMS. After direct concentration, the product was purified by reversed-phase chromatography to obtain 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-4-(phenylcyclopropyl)-1,2,4-triazacyclopentan-3-yl]azanesulfonamide compound 32 (157 mg, yield 31.5%).

[0967] LC-MS m / z (ESI) = 499.20 [M+H] + .

[0968] 1 H NMR(400MHz,DMSO-d6)δ13.17(s,1H),8.52(d,1H),7.86(dd,1H),7.78(d,1H),7.46(d,1H),7.28(dd,2H),7 .24–7.14(m,1H),7.08–7.00(m,2H),6.36(d,1H),4.20(s,2H),3.85(s,3H),2.56(s,3H),1.75–1.36(m,4H).

[0969] Example 33

[0970] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-methylisoxazol-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 33

[0971] N-(N-(5-Chloropyridin-2-yl)methyl)sulfonylamino)-4-(2,6-dimethoxy)-5-(5-methylisoxazole-3-yl)-N-methyl-4H-1,2,4-triazole-3-amide

[0972] first step:

[0973] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,6-dimethoxyphenyl)-2-(5-methylisoxazol-3-carbonyl)hydrazine-1-formamidin 33-2

[0974] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylisoxazole-3-carbonyl)hydrazine-1-carboximidamide

[0975] 5-Methylisoxazole-3-carbamoylhydrazide 33-1 (220 mg, 1.6 mmol) was added to tetrahydrofuran (10 mL), followed by 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino]thionylmethyl}-1-methylazanesulfonamide 8-7 (650 mg, 1.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (480 mg, 2.5 mmol). The reaction mixture was allowed to react overnight at room temperature, and the target reaction was detected by LC-MS. After the reaction was completed, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to obtain N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamide)-N'-(2,6-dimethoxyphenyl)-2-(5-methylisoxazol-3-carbonyl)hydrazine-1-formamidinium 33-2 (600 mg, yield 73.3%).

[0976] LC-MS m / z (ESI) = 538.2 [M+H] + .

[0977] Step Two:

[0978] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-methylisoxazol-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 33

[0979] N-(N-(5-Chloropyridin-2-yl)methyl)sulfonylamino)-4-(2,6-dimethoxy)-5-(5-methylisoxazole-3-yl)-N-methyl-4H-1,2,4-triazole-3-amide

[0980] The starting material N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,6-dimethoxyphenyl)-2-(5-methylisoxazol-3-carbonyl)hydrazine-1-formamidin 33-2 (600 mg, 1.1 mmol) was added to trifluoroacetic acid (15 mL), and the reaction mixture was heated to 85 °C and reacted for 8 hours. The reaction was detected by LC-MS to indicate completion. After direct concentration, the mixture was purified by reversed-phase chromatography to obtain N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-methylisoxazol-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 33 (40 mg, yield 6.9%).

[0981] LC-MS m / z (ESI) = 520.10 [M+H] + .

[0982] 1 H NMR (400MHz, DMSO-d6) δ = 8.54 (d, 1H), 7.90 (dd, 1H), 7.56–7.25 (m, 2H), 6. 82(d,2H),6.51(s,1H),4.13(s,2H),3.69(s,6H),2.46(s,3H),2.4(s,3H).

[0983] Example 34

[0984] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1-ethyl-1H-pyrazole-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 34

[0985] N-(N-(5-Chloropyridin-2-yl)methyl)sulfonylamino)-4-(2,6-dimethoxy)-5-(1-ethyl-1H-pyrazol-3-yl)-N-methyl-4H-1,2,4-triazole-3-amide

[0986] first step:

[0987] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(1-ethyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboxamide 34-2

[0988] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)-2-(1-ethyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboximidamide

[0989] 1-Ethyl-1H-pyrazole-3-carboxycarbamoylhydrazide 34-1 (300 mg, 2.0 mmol) was added to tetrahydrofuran (10 mL), followed by 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino]thionylmethyl}-1-methylazanesulfonamide 8-7 (650 mg, 1.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (480 mg, 2.5 mmol). The reaction mixture was allowed to react overnight at room temperature, and the target reaction was detected by LC-MS. After the reaction was completed, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to obtain N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(1-ethyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboxamide 34-2 (600 mg, yield 72.2%).

[0990] LC-MS m / z (ESI) = 551.2 [M+H] + .

[0991] Step Two:

[0992] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1-ethyl-1H-pyrazole-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 34

[0993] N-(N-(5-Chloropyridin-2-yl)methyl)sulfonylamino)-4-(2,6-dimethoxy)-5-(1-ethyl-1H-pyrazol-3-yl)-N-methyl-4H-1,2,4-triazole-3-amide

[0994] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(1-ethyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboxamide 34-2 (600 mg, 1.1 mmol) was added to trifluoroacetic acid (15 mL), and the reaction mixture was heated to 85 °C and reacted for 8 hours. The reaction was detected by LC-MS and the product was directly concentrated and purified by reversed-phase chromatography to obtain N-(N-(5-chloropyridin-2-yl)methyl)sulfonamide)-4-(2,6-dimethoxy)-5-(1-ethyl-1H-pyrazole-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 34 (160 mg, yield 26.7%).

[0995] LC-MS m / z (ESI) = 533.10 [M+H] + .

[0996] 1 H NMR(400MHz,DMSO-d6)δ8.56(d,1H),7.91(dd,1H),7.74(d,1H),7.49(t,1H),7.44(d,1H),6.8 2(d,2H),6.18(d,1H),4.13(s,2H),4.00(q,2H),3.68(s,6H),2.46(s,3H),1.32–1.11(m,3H).

[0997] Example 35

[0998] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-4-phenyl-1,2,4-triazol-3-yl] sulfonamide compound 35

[0999] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-4-phenyl-1,2,4-triazol-3-yl]azanesulfonamide

[1000] first step

[1001] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[(phenylamino)thiazolylmethyl]pyrimidinesulfonamide 35-2

[1002] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[(phenylamino)thioxomethyl]azanesulfonamide

[1003] [(5-chloropyridin-2-yl)methyl](methyl)azinesulfonamide (1.00 g, 4.24 mmol) was dissolved in ACN (10 mL), and Cs₂CO₃ (1.38 g, 4.24 mmol) was added. Phenyl isothiocyanate (631 mg, 4.67 mmol) was added with stirring. The reaction was carried out at room temperature for 3 hours under nitrogen protection. The reaction solution was concentrated, and the crude product was used directly in the next step: 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[(phenylamino)thiazolylmethyl]pyrimidinesulfonamide 35-2 (1.72 g, 100% yield).

[1004] LC-MS m / z (ESI) = 371.03 [M+H] + .

[1005] Step 2

[1006] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-({2-[(1-methylpyrazol-3-yl)carbonyl]diazatyl}[phenylazamethylene]methyl)azasulfonamide compound 35-3

[1007] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-({2-[(1-methylpyrazol-3-yl)carbonyl]diazanyl}[phenylazanylidene]methyl)azanesulfonamide

[1008] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[(phenylamino)thiazolylmethyl]pyrimidinesulfonamide (1.72 g, 4.24 mmol) 35-2 and 1-methylpyrazol-3-carboxyhydrazide (654 mg, 4.67 mmol) were dissolved in THF (20 mL), and EDCI (1.34 g, 7.00 mmol) was added with stirring. The reaction was carried out at room temperature for 2 hours, and the reaction was monitored by LCMS until complete. After the reaction solution was dried, it was extracted with EA and H2O. The organic phases were combined, washed four times with saturated ammonium chloride aqueous solution, concentrated, and purified by reverse phase to obtain 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-({2-[(1-methylpyrazol-3-yl)carbonyl]diazatyl}[phenylazamethylene]methyl)azasulfonamide 35-3 (800 mg, yield 36.8%).

[1009] LC-MS m / z (ESI) = 477.11 [M+H] + .

[1010] Step 3

[1011] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-4-phenyl-1,2,4-triazol-3-yl] sulfonamide compound 35

[1012] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-4-phenyl-1,2,4-triazol-3-yl]azanesulfonamide

[1013] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-({2-[(1-methylpyrazol-3-yl)carbonyl]diazatyl}[phenylazamethylene]methyl)azasulfonamide 35-3 (800 mg, 1.67 mmol) was dissolved in TFA (16 mL) and reacted at 80 °C for 12 hours with stirring. The reaction was monitored by LC-MS until complete. The reaction solution was dried and diluted with water. The pH was adjusted to approximately 10 with NaOH. The solution was extracted with ethyl acetate. The organic phases were combined, concentrated, and purified by reverse phase to give 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-4-phenyl-1,2,4-triazol-3-yl]azasulfonamide 35 (125 mg, yield 16.2%).

[1014] LC-MS m / z (ESI) = 459.10 [M+H] + .

[1015] 1 H NMR(400MHz,DMSO-d6)δ13.35(s,1H),8.59–8.46(m,1H),7.89(dd,1H),7.69(s,1H),7.61–7.53(m,1H), 7.53–7.48(m,2H),7.44(t,1H),7.41–7.34(m,2H),6.07(s,1H),4.18(d,2H),3.73(s,3H),2.55(s,3H).

[1016] Example 36

[1017] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2-methoxyphenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 36

[1018] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2-methoxyphenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[1019] first step

[1020] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2-methoxyphenyl)amino]thionylmethyl}-1-methylazinesulfonamide compound 36-2

[1021] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2-methoxyphenyl)amino]thioxomethyl}-1-methylazanesulfonamide

[1022] [(5-chloropyridin-2-yl)methyl](methyl)azanesulfonamide (1.00 g, 4.24 mmol) was dissolved in ACN (10 mL), and Cs₂CO₃ (1.38 g, 4.24 mmol) was added. 2-methoxyphenyl isocyanate (771 mg, 4.67 mmol) was added with stirring. The reaction was carried out at room temperature for 3 hours under nitrogen protection. The reaction solution was concentrated, and the crude product was used directly in the next step: 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2-methoxyphenyl)amino]thionylmethyl}-1-methylazanesulfonamide 36-2 (1.82 g, 100% yield).

[1023] LCMS m / z(ESI) = 401.03[M+1].

[1024] Step 2

[1025] N-{[(2-methoxyphenyl)aza-ylidene]{2-[(1-methylpyrazol-3-yl)carbonyl]ethazyl}methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazinesulfonamide compound 36-3

[1026] N-{(2-methoxyphenyl)azanylidene]{2-[(1-methylpyrazol-3-yl)carbonyl]diazanyl}methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazanesulfonamide

[1027] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2-methoxyphenyl)amino]thionylmethyl}-1-methylazanesulfonamide 36-2 (1.82 g, 4.24 mmol) and 1-methylpyrazol-3-carboxyhydrazide (654 mg, 4.67 mmol) were dissolved in THF (20 mL), and EDCI (1.34 g, 7.00 mmol) was added with stirring. The reaction was carried out at room temperature for 2 hours, and the reaction was monitored by LCMS until complete. After the reaction solution was dried, it was extracted with EA and H2O. The organic phases were combined, washed four times with saturated ammonium chloride aqueous solution, concentrated, and purified by reverse phase to obtain N-{(2-methoxyphenyl)azionyl]{2-[(1-methylpyrazol-3-yl)carbonyl]ethazyl}methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazanesulfonamide 36-3 (600 mg, yield 26.0%).

[1028] LC-MS m / z (ESI) = 507.13 [M+H] + .

[1029] Step 3

[1030] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2-methoxyphenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 36

[1031] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2-methoxyphenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[1032] N-{[(2-methoxyphenyl)azapyridyl]{2-[(1-methylpyrazol-3-yl)carbonyl]ethazyl}methyl}-1-[(5-chloropyridin-2-yl)methyl]-1-methylazaalkylsulfonamide 36-3 (600 mg, 1.18 mmol) was dissolved in TFA (12 mL) and reacted at 80 °C for 16 hours with stirring. The reaction was monitored by LC-MS until complete. The reaction solution was dried and diluted with water. The pH was adjusted to approximately 10 with NaOH. Ethyl acetate was added and water was extracted. The organic phases were combined, concentrated, and purified by reverse phase to obtain 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2-methoxyphenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazaalkylsulfonamide 36-4 (170 mg, yield 29.3%).

[1033] LC-MS m / z (ESI) = 489.11 [M+H] + .

[1034] 1 H NMR(400MHz,DMSO-d6)δ13.35(s,1H)8.55(s,1H),7.90(m,1H),7.69(m,1H),7.59–7.50(m,1H),7.42(m,1H),7.30(m,1H),7.28–7.14 (m,1H),7.15–7.04(m,1H),6.08(s,1H),4.15(s,1H),4.15(s,1H),3.76(s,1H),3.73(s,1H),3.66(s,1H),3.33(s,3H),2.52(s,3H).

[1035] Example 37

[1036] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1-(difluoromethyl)-1H-pyrazole-3-carbonyl)-N-methyl-4H-1,2,4-triazol-3-amine compound 37

[1037] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(1-(difluoromethyl)-1H-pyrazole-3-carbonyl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[1038] first step:

[1039] 1-(difluoromethyl)-1H-pyrazole-3-carbazide 37-2

[1040] 1-(difluoromethyl)-1H-pyrazole-3-carbohydrazide

[1041] 1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid methyl ester (1.0 g, 5.7 mmol) was added to methanol (10 ml), followed by DBU (2.6 g, 17 mmol), and then hydrazine hydrochloride (0.97 g, 14 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours. After the reaction was completed, the reaction mixture was evaporated to dryness and then slurryed to obtain 1-(difluoromethyl)-1H-pyrazole-3-carbohydrazide 37-2 (800 mg, yield 80.3%).

[1042] LC-MS m / z (ESI) = 177.0 [M+H] + .

[1043] Step Two:

[1044] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-2-(1-(difluoromethyl)-1H-pyrazole-3-carbonyl)-N'-(2,6-dimethoxyphenyl)hydrazine-1-formamidinium 37-3

[1045] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-2-(1-(difluoromethyl)-1H-pyrazole-3-carbonyl)-N'-(2,6-dimethoxyphenyl)hydrazine-1-carboximidamide

[1046] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)carbamoylthioic acid 8-7 (2.02 g, 4.7 mmol) was added to tetrahydrofuran (10 mL), followed by 1-(difluoromethyl)-1H-pyrazole-3-carbazide 37-2 (800 mg, 4.7 mmol), and then EDCI (897 mg, 4.7 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours. After completion, the reaction solution was directly evaporated to dryness, then dissolved in a 10:1 DCM:MeOH mixed solution (100 mL), washed three times with saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain the crude product. The crude product was then slurried with ACN to obtain N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-2-(1-(difluoromethyl)-1H-pyrazole-3-carbonyl)-N'-(2,6-dimethoxyphenyl)hydrazine-1-formamidinium 37-3 (1.0 g, yield 37%).

[1047] LC-MS m / z (ESI) = 573.1 [M+H] + .

[1048] Step 3:

[1049] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1-(difluoromethyl)-1H-pyrazole-3-carbonyl)-N-methyl-4H-1,2,4-triazol-3-amine compound 37

[1050] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(1-(difluoromethyl)-1H-pyrazole-3-carbonyl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[1051] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-2-(1-(difluoromethyl)-1H-pyrazole-3-carbonyl)-N'-(2,6-dimethoxyphenyl)hydrazine-1-formamidinium 37-3 (1.0 g, 1.7 mmol) was dissolved in TFA (15 mL) and reacted at 80 °C for 8 hours. The reaction was monitored by LCMS until completion. The reaction was quenched by adding sodium bicarbonate aqueous solution, followed by the addition of DCM:Me. Extracted with a 10:1 OH mixture (100 mL) and water, the organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The mixture was then slurried with acetonitrile to give the target compound N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1-(difluoromethyl)-1H-pyrazole-3-carbonyl)-N-methyl-4H-1,2,4-triazol-3-amine compound 37 (120 mg, 13% yield).

[1052] LC-MS m / z (ESI) = 555.10 [M+H] + .

[1053] 1 H NMR(400MHz,DMSO-d6)δ13.51(s,1H),8.55(s,1H),8.28(s,1H),7.91(d,1H),7.75(d,1 H),7.58–7.39(m,2H),6.83(d,2H),6.47(s,1H),4.13(s,2H),3.68(s,6H),1.23(s,3H).

[1054] Example 38

[1055] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-chloropyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 38

[1056] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-chlorylpyridin-3-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[1057] first step:

[1058] 2-(5-chloronicotinyl)-N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)hydrazine-1-formamidinium 38-1

[1059] 2-(5-chloronicotinoyl)-N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)hydrazine-1-carboximidamide

[1060] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)carbamoylthioic acid 8-7 (1.25 g, 2.9 mmol) was added to tetrahydrofuran (10 mL), followed by 5-chloronicotinamide hydrazone (500 mg, 2.9 mmol) and then EDCI (726 mg, 3.8 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours until completion. Afterwards, the reaction solution was directly evaporated to dryness, then dissolved in a 10:1 DCM:MeOH mixed solution (100 mL), washed three times with saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain the crude product. The crude product was then pulped with ACN to obtain 2-(5-chloronicotinyl)-N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)hydrazine-1-formamidinium 38-1 (400 mg, yield 76%).

[1061] LC-MS m / z (ESI) = 568.1 [M+H] + .

[1062] Step Two:

[1063] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(5-chloropyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 38

[1064] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(5-chlorylpyridin-3-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[1065] 2-(5-chloronicotinamide)-N-(N-((5-chloropyridin-2-yl)methyl)-N-methylamido)-N'-(2,6-dimethoxyphenyl)hydrazone-1-carboxamide anhydride 38-1 (400 mg, 0.7 mmol) was dissolved in TFA (5 mL) and reacted at 80 °C for 8 hours. The reaction was monitored by LC-MS until completion. The reaction was quenched by adding sodium bicarbonate aqueous solution, followed by extraction with a DCM:MeOH = 10:1 mixed solution (100 mL) and water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The mixture was then slurried with acetonitrile to obtain the target compound 38 (120 mg, 23% yield).

[1066] LC-MS m / z (ESI) = 550.10 [M+H] + .

[1067] 1 H NMR(400MHz,DMSO-d6)δ8.74(d,1H),8.56(d,1H),8.41(d,1H),7.92(dd,1H),7.83(t ,1H),7.55(t,1H),7.43(d,1H),6.87(d,2H),4.14(s,2H),3.73(s,6H),2.52(s,3H).

[1068] Example 39

[1069] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1-methyl-1H-pyrazole-4-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 39

[1070] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(1-methyl-1H-pyrazole-4-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[1071] first step:

[1072] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,-dimethoxyphenyl)-2-(1-methyl-1H-pyrazole-4-carbonyl)hydrazone-1-carboxamide 39-2

[1073] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)-2-(1-methyl-1H-pyrazole-4-carbonyl)hydrazine-1-carboximidamide

[1074] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)carbamoylthioic acid 8-7 (1.52 g, 3.5 mmol) was added to tetrahydrofuran (10 ml), followed by 1-methyl-1H-pyrazole-4-carboxyhydrazone anhydride (500 mg, 3.5 mmol), and then EDCI (880 mg, 4.6 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours until completion. Afterwards, the reaction solution was directly evaporated to dryness, then dissolved in a 10:1 DCM:MeOH mixed solution (100 mL), washed three times with saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain the crude product. The crude product was then slurried with ACN to obtain N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,6-dimethoxyphenyl)-2-(1-methyl-1H-pyrazole-4-carbonyl)hydrazone-1-carboxamide 39-2 (387 mg, yield 20%).

[1075] LC-MS m / z (ESI) = 537.1 [M+H] + .

[1076] Step Two:

[1077] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1-methyl-1H-pyrazole-4-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 39

[1078] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(1-methyl-1H-pyrazole-4-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[1079] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,6-dimethoxyphenyl)-2-(1-methyl-1H-pyrazole-4-carbonyl)hydrazone-1-carboxamide 39-2 (387 mg, 0.7 mmol) was dissolved in TFA (4 mL) and reacted at 80 °C for 8 hours. The reaction was monitored by LC-MS until it was complete. The reaction was quenched by adding sodium bicarbonate aqueous solution, and then extracted with a DCM:MeOH = 10:1 mixed solution (100 mL) and water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The mixture was then slurried with acetonitrile to obtain the target compound 39 (176 mg, 23% yield).

[1080] LC-MS m / z (ESI) = 519.10 [M+H] + .

[1081] 1 H NMR(400MHz,DMSO-d6)δ13.15(s,1H),8.55(d,1H),7.91(dd,1H),7.69(s,1H),7.57(t,1H) ,7.42(d,1H),7.13(s,1H),6.90(d,2H),4.11(s,2H),3.78(s,3H),3.72(s,6H),2.49(s,3H)

[1082] Example 40

[1083] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 41

[1084] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(1,3-dimethyl-1H-pyrazole-4-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[1085] first step:

[1086] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,-dimethoxyphenyl)-2-(1-ethyl-1H-pyrazole-4-carbonyl)hydrazone-1-carboxamide 40-2

[1087] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)-2-(1-ethyl-1H-pyrazole-4-carbonyl)hydrazine-1-carboximidamide

[1088] Crude N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)carbamoylthioic acid (1.40 g, 3.24 mmol) was added to tetrahydrofuran (10 ml), followed by 1-ethyl-1H-pyrazole-4-carboxyhydrazone anhydride (500 mg, 3.24 mmol), and then EDCI (806 mg, 4.22 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours until completion. Afterwards, the reaction solution was directly evaporated to dryness, then dissolved in a 10:1 DCM:MeOH mixed solution (100 mL), washed three times with saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain the crude product. The crude product was then slurried with ACN to obtain N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,-dimethoxyphenyl)-2-(1-ethyl-1H-pyrazole-4-carbonyl)hydrazone-1-carboxamide 40-2 (421 mg, yield 23.6%).

[1089] LC-MS m / z (ESI) = 551.1 [M+H] + .

[1090] Step Two:

[1091] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1-ethyl-1H-pyrazole-4-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 40

[1092] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(1-Ethyl-1H-pyrazole-4-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[1093] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,-dimethoxyphenyl)-2-(1-ethyl-1H-pyrazole-4-carbonyl)hydrazone-1-carboxamide 40-2 (387 mg, 0.7 mmol) was dissolved in TFA (4 mL) and reacted at 80 °C for 8 hours. The reaction was monitored by LC-MS until completion. The reaction was quenched by adding sodium bicarbonate aqueous solution, followed by extraction with a DCM:MeOH = 10:1 mixed solution (100 mL) and water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The mixture was then slurried with acetonitrile to obtain the target compound N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1-ethyl-1H-pyrazole-4-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 40 (213 mg, 57% yield).

[1094] LC-MS m / z (ESI) = 533.10 [M+H] + .

[1095] 1 H NMR(400MHz,DMSO-d6)δ8.55(dd,1H),7.91(dd,1H),7.77(d,1H),7.58(t,1H),7.46–7.41(m,1H) ,7.09(d,1H),6.90(d,2H),4.13(s,2H),4.124.05(m,2H),3.72(s,6H),2.50(s,4H),1.28(t,3H).

[1096] Example 41

[1097] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 41

[1098] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(1,3-dimethyl-1H-pyrazole-4-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[1099] first step:

[1100] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,-dimethoxyphenyl)-2-(1,3-dimethyl-1H-pyrazole-4-carbonyl)hydrazone-1-carboxamide 41-2

[1101] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)-2-(1,3-dimethyl-1H-pyrazole-4-carbonyl)hydrazine-1-carboximidamide

[1102] Crude N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)carbamoylthioic acid (1.40 g, 3.24 mmol) was added to tetrahydrofuran (10 mL), followed by 1,3-dimethyl-1H-pyrazole-4-carboxyhydrazone anhydride (500 mg, 3.24 mmol), and then EDCI (806 mg, 4.22 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours. After the reaction was completed, the reaction solution was directly evaporated to dryness, then dissolved in a 10:1 DCM:MeOH mixed solution (100 mL), washed three times with a saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain the crude product. The crude product was then slurried with ACN to obtain N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,-dimethoxyphenyl)-2-(1-ethyl-1H-pyrazole-4-carbonyl)hydrazone-1-carboxamide 41-2 (400 mg, yield 62%).

[1103] LC-MS m / z (ESI) = 551.1 [M+H] + .

[1104] Step Two:

[1105] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 41

[1106] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(1,3-dimethyl-1H-pyrazole-4-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[1107] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,-dimethoxyphenyl)-2-(1,3-dimethyl-1H-pyrazole-4-carbonyl)hydrazone-1-carboxamide 41-2 (387 mg, 0.7 mmol) was dissolved in TFA (4 mL) and reacted at 80 °C for 8 hours. The reaction was monitored by LC-MS until completion. The reaction was quenched by adding sodium bicarbonate aqueous solution, followed by the addition of DCM:M Extracted with a 10:1 eOH mixture (100 mL) and water, the organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The mixture was then slurried with acetonitrile to give the target compound N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 41 (195 mg, 52% yield).

[1108] LC-MS m / z (ESI) = 533.10 [M+H] + .

[1109] 1 H NMR(400MHz,DMSO-d6)δ13.18(s,1H),8.54(dd,1H),7.90(dd,1H),7.53(t,1H),7.42(d,1H) ,6.91(s,1H),6.86(d,2H),4.11(s,2H),3.71(s,6H),3.63(s,3H),2.49(s,3H),2.26(s,3H).

[1110] Example 42

[1111] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-difluorophenyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 42

[1112] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-difluorophenyl)-5-(5-methylpyridine-3-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[1113] first step:

[1114] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,6-difluorophenyl)thiourea 42-2

[1115] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-difluorophenyl)carbamimidothioic acid

[1116] The starting material N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonamide (1.38 g, 5.8 mmol) was added to an acetonitrile (12 mL) solution, followed by 2-isothiocyano-1,3-difluorobenzene 42-1 (1.0 g, 5.8 mmol) and cesium carbonate (2.47 g, 7.6 mmol). The resulting mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was filtered to obtain filter cake N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamide)-N'-(2,6-difluorophenyl)thioureic acid 42-2 (1.40 g, 100% yield). This was used directly in the next step.

[1117] LC-MS m / z (ESI) = 407.10 [M+H] + .

[1118] Step Two:

[1119] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,-difluorophenyl)-2-(5-methylnicotinamide)hydrazone-1-carboxamide 42-3

[1120] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-difluorophenyl)-2-(5-methylnicotinoyl)hydrazine-1-carboximidamide

[1121] Crude N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,6-difluorophenyl)thioureic acid 42-2 (1.40 g) was added to tetrahydrofuran (15 mL), followed by 5-methylnicotinamide (875 mg, 5.8 mmol) and then EDCI (1.44 g, 7.5 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours. After the reaction was complete, the solution was directly evaporated to dryness. The reaction solution was then dissolved in a 10:1 DCM:MeOH mixture (100 mL), washed three times with a saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain a crude product. The crude product was then slurried with ACN to obtain N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,-difluorophenyl)-2-(5-methylnicotinamide)hydrazone-1-carboxamide 42-3 (1.5 g, yield 76.2%).

[1122] LC-MS m / z (ESI) = 523.1 [M+H] + .

[1123] Step 3:

[1124] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-difluorophenyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 42

[1125] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-difluorophenyl)-5-(5-methylpyridine-3-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[1126] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2,-difluorophenyl)-2-(5-methylnicotinamide)hydrazone-1-carboxamide (1.5 g, 2.8 mmol) was dissolved in TFA (15 mL) and reacted at 80 °C for 8 hours. The reaction was monitored by LC-MS until it was complete. The reaction was quenched by adding sodium bicarbonate aqueous solution, and then extracted with a DCM:MeOH = 10:1 mixed solution (100 mL) and water. The organic phase was dried with anhydrous sodium sulfate and then evaporated to dryness. The mixture was then slurried with acetonitrile to obtain the target compound 42 (140 mg, 17.4% yield).

[1127] LC-MS m / z (ESI) = 505.10 [M+H] + .

[1128] 1 H NMR (400MHz, DMSO-d6) δ13.91(s,1H),8.54(d,2H),8.28(d,1H),7.90(dd,1H),7.76(tt,1H),7.69(q,1H),7.44(td,3H),4.17(s,2H),2.57(s,3H).

[1129] Example 43

[1130] first step:

[1131] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2-methoxyphenyl)-thiouric acid 43-2

[1132] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-((2-methoxyphenyl))carbamimidothioic acid

[1133] The starting material N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonamide (1.71 g, 7.2 mmol) was added to an acetonitrile (12 mL) solution, followed by 1-isothiocyanate-2-methoxybenzene 43-1 (1.2 g, 7.2 mmol) and cesium carbonate (3.08 g, 9.4 mmol). The resulting mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was filtered to obtain filter cake N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamide)-N'-(2,6-difluorophenyl)thioureic acid 43-2 (2.9 g, crude product). This was used directly in the next step.

[1134] LC-MS m / z (ESI) = 401.10 [M+H] + .

[1135] Step Two:

[1136] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2-methoxybenzene)-2-(5-methylnicotinamide)hydrazone-1-carboxamide 43-3

[1137] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2-methoxyphenyl)-2-(5-methylnicotinoyl)hydrazine-1-carboximidamide

[1138] Crude N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2-methoxyphenyl)thioureic acid 43-2 (2.90 g) was added to tetrahydrofuran (30 mL), followed by 5-methylnicotinamide (1.08 g, 7.2 mmol) and then EDCI (1.78 g, 9.36 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours. After the reaction was complete, the solution was directly evaporated to dryness. The reaction solution was then dissolved in a 10:1 DCM:MeOH mixture (100 mL), washed three times with a saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain a crude product. The crude product was then slurried with ACN to obtain N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2-methoxybenzene)-2-(5-methylnicotinamide)hydrazone-1-carboxamide 43-3 (1.1 g, yield 29.5%).

[1139] LC-MS m / z (ESI) = 518.1 [M+H] + .

[1140] Step 3:

[1141] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2-methoxyphenyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 43

[1142] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2-methoxyphenyl)-5-(5-methylpyridine-3-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[1143] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2-methoxyphenyl)-2-(5-methylnicotinamide)hydrazone-1-carboxamide 43-3 (1.1 g, 2.1 mmol) was dissolved in TFA (15 mL) and reacted at 80 °C for 8 hours. The reaction was monitored by LCMS until completion. The reaction was quenched by adding sodium bicarbonate aqueous solution, followed by extraction with a DCM:MeOH = 10:1 mixed solution (100 mL) and water. The organic phase was dried with anhydrous sodium sulfate and then evaporated to dryness. The mixture was then slurried with acetonitrile to obtain the target compound N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2-methoxyphenyl)-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine 43 (800 mg, 84.3% yield).

[1144] LC-MS m / z (ESI) = 500.10 [M+H] + .

[1145] 1 H NMR(400MHz,DMSO-d6)δ13.55(s,1H),8.56(dd,1H),8.46(dd,1H),8.23(d,1H),7.91(dd,1H),7.62(td,1H),7.58–7 .50(m,2H),7.44(d,1H),7.24–7.16(m,1H),7.12(td,1H),4.17(s,2H),3.63(s,3H),2.55(s,3H),2.27–2.20(m,3H).

[1146] Example 44

[1147] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(1,3-dimethoxypropane-2-yl))-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 44

[1148] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(1,3-dimethoxypropan-2-yl)-5-(5-methylpyridine-3-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[1149] first step:

[1150] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(1,3-dimethoxypropane-2-yl)-thiouric acid 44-2

[1151] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(1,3-dimethoxypropan-2-yl)carbamimidothioic acid

[1152] The starting material N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonamide (1.75 g, 7.4 mmol) was added to an acetonitrile (20 mL) solution, followed by 2-isothiocyanate-1,3-dimethoxypropane 44-1 (1.2 g, 7.4 mmol) and cesium carbonate (3.15 g, 9.6 mmol). The resulting mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was filtered, and N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamide)-N'-(1,3-dimethoxypropane-2-yl)-thiourea acid 44-2 (2.95 g, crude product) was used directly for the next step.

[1153] LC-MS m / z (ESI) = 397.10 [M+H] + .

[1154] Step Two:

[1155] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(1,3-dimethoxypropane-2-yl)-2-(5-methylnicotinamide)hydrazone-1-carboxamide 44-3

[1156] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(1,3-dimethoxypropan-2-yl)-2-(5-methylnicotinoyl)hydrazine-1-carboximidamide

[1157] Crude N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(2-methoxyphenyl)thioureic acid 44-2 (2.95 g) was added to tetrahydrofuran (30 mL), followed by 5-methylnicotinamide (1.15 g, 7.4 mmol) and then EDCI (1.87 g, 9.4 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours. After the reaction was complete, the reaction mixture was directly evaporated to dryness. Then, it was dissolved in a DCM:MeOH = 10:1 mixed solution (100 mL), washed three times with saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain the crude product. The crude product was then slurried with ACN to obtain N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(1,3-dimethoxypropane-2-yl)-2-(5-methylnicotinamide)hydrazone-1-carboxamide 44-3 (1.2 g, yield 31.6%).

[1158] LC-MS m / z (ESI) = 514.1 [M+H] + .

[1159] Step 3:

[1160] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(1,3-dimethoxypropane-2-yl))-5-(5-methylpyridin-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 44

[1161] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(1,3-dimethoxypropan-2-yl)-5-(5-methylpyridine-3-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[1162] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonamido)-N'-(1,3-dimethoxypropane-2-yl)-2-(5-methylnicotinamide)hydrazone-1-carboxamide 44-3 (1.2 g, 2.3 mmol) was dissolved in TFA (15 mL) and reacted at 80 °C for 8 hours. The reaction was monitored by LC-MS until it was complete. The reaction was quenched by adding sodium bicarbonate aqueous solution, and then extracted with a DCM:MeOH = 10:1 mixed solution (100 mL) and water. The organic phase was dried with anhydrous sodium sulfate and then evaporated to dryness. The mixture was then slurried with acetonitrile to obtain the target compound 44 (80 mg, 9.23% yield).

[1163] LC-MS m / z (ESI) = 496.10 [M+H] + .

[1164] 1 H NMR(400MHz,DMSO-d6)δ13.40(s,1H),8.63(dd,2H),8.58(d,1H),7.98(dd,1H),7.91–7.85(m,1H),7.5 0(d,1H),4.36(tt,1H),4.29(s,2H),4.03(t,2H),3.49(dd,2H),3.18(s,6H),2.66(s,3H),2.40(s,3H).

[1165] Example 45

[1166] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2,4-dimethoxypyridin-3-yl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 45

[1167] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2,4-dimethoxypyridin-3-yl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[1168] first step:

[1169] [(2,4-Dimethoxypyridin-3-yl)aza-ylidene]methylthione 45-2

[1170] [(2,4-dimethoxypyridin-3-yl)azanylidene]methanethione

[1171] The starting material 2,4-dimethoxypyridin-3-amine 45-1 (770 mg, 5.0 mmol) was dissolved in dichloromethane (20 mL), and then 1,1-thiocarbonylDI-2(1H)-pyridine (1.38 g, 6.0 mmol) was added in portions. The reaction mixture was reacted at room temperature for 3 hours. The target reaction was detected by LC-MS. After the reaction was completed, it was directly purified by normal column chromatography to obtain [(2,4-dimethoxypyridin-3-yl)aza-dimethyl]meththione 45-2 (810 mg, yield 82.2%).

[1172] LC-MS m / z (ESI) = 197.0 [M+H] + .

[1173] Step Two:

[1174] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,4-dimethoxypyridin-3-yl)amino]thionylmethyl}-1-methylazanesulfonamide 45-3

[1175] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,4-dimethoxypyridin-3-yl)amino]thioxomethyl}-1-methylazanesulfonamide

[1176] The starting material [(2,4-dimethoxypyridin-3-yl)azineyl]methylthionone 45-2 (810 mg, 4.1 mmol) was added to acetonitrile (20 mL), followed by [(5-chloropyridin-2-yl)methyl](methyl)azinesulfonamide intermediate 1 (944 mg, 4.0 mmol) and cesium carbonate (1.3 g, 4.0 mmol). The reaction mixture was reacted at room temperature for 3 hours, then concentrated under reduced pressure. The crude product 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,4-dimethoxypyridin-3-yl)amino]thionylmethyl}-1-methylazinesulfonamide 45-3 was used directly in the next step.

[1177] LCMS m / z(ESI) = 432.0 [M+H] + .

[1178] Step 3:

[1179] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,4-dimethoxypyridin-3-yl)amino][2-[(1-methylpyrazol-3-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 45-4

[1180] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,4-dimethoxypyridin-3-yl)amino][(1E)-2-[(1-methylpyrazol-3-yl)carbonyl]diazanylidene]methyl}-1-methylazanesulfonamide

[1181] Crude 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,4-dimethoxypyridin-3-yl)amino]thionylmethyl}-1-methylazanesulfonamide 45-3 (1.73 g, 4.0 mmol) was added to tetrahydrofuran (30 mL), followed by 1-methylpyrazol-3-carboxyhydrazide (700 mg, 5.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.0 mmol). The reaction mixture was allowed to react overnight at room temperature, and the target reaction was detected by LCMS. After the reaction was completed, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to obtain 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,4-dimethoxypyridin-3-yl)amino][2-[(1-methylpyrazol-3-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 45-4 (850 mg, two-step yield 39.5%).

[1182] LC-MS m / z (ESI) = 538.20 [M+H] + .

[1183] Step 4:

[1184] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2,4-dimethoxypyridin-3-yl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 45

[1185] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2,4-dimethoxypyridin-3-yl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[1186] The starting material 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,4-dimethoxypyridin-3-yl)amino][2-[(1-methylpyrazol-3-yl)carbonyl]ethazineide]methyl}-1-methylazanesulfonamide 45-4 (850 mg, 1.58 mmol) was added to trifluoroacetic acid (15 mL), and the reaction mixture was heated to 70 °C and reacted for 4 hours. The reaction was detected by LCMS to indicate completion. After direct concentration, the mixture was purified by reversed-phase chromatography to obtain 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2,4-dimethoxypyridin-3-yl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 45 (126 mg, yield 15.3%).

[1187] LC-MS m / z (ESI) = 520.20 [M+H] + .

[1188] 1 H NMR(400MHz,DMSO-d6)δ13.35(s,1H),8.55(d,1H),8.26(d,1H),7.91(dd,1H),7.75(d,1H),7.43( d,1H),7.00(d,1H),6.41(d,1H),4.12(s,2H),3.80(s,3H),3.77(s,3H),3.69(s,3H),2.51(s,3H).

[1189] Example 46

[1190] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(dicyclopropylmethyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 46

[1191] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(dicyclopropylmethyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[1192] first step:

[1193] 1-Cyclopropyl-N-[(2-methylpropyl-2-yl)(oxonyl)-λ] 4 [-Thio]methaneimine 46-2

[1194] 1-cyclopropyl-N-[(2-methylprop-2-yl)(oxo)-λ 4 -sulfanyl]methanimine

[1195] Cyclopropaneformaldehyde 46-1 (10.0 g, 142.7 mmol) was added to dichloromethane (150 mL), followed by S-tert-butylsulfinamide (8.6 g, 71.3 mmol) and magnesium sulfate (86.0 g, 713.5 mmol), and then pyridine 4-methylbenzenesulfonate (1.8 g, 7.13 mmol). The reaction mixture was reacted overnight at room temperature. After the reaction was complete, the mixture was filtered, and the filtrate was purified by silica gel column chromatography to give 1-cyclopropyl-N-[(2-methylpropyl-2-yl)(oxonyl)-λ]. 4⁻¹Thio[methaneimine]46-2 (10.0 g, yield 81.0%).

[1196] LCMS m / z(ESI) = 174.10 [M+H] + .

[1197] Step Two:

[1198] (dicyclopropylmethyl)[(2-methylpropyl-2-yl)(oxonyl)-λ 4 -Thio[amine]46-3

[1199] (dicyclopropylmethyl)[(2-methylprop-2-yl)(oxo)-λ 4 -sulfanyl]amine

[1200] The raw material 1-cyclopropyl-N-[(2-methylpropyl-2-yl)(oxo-ylidene)-λ 4 [-thio]methaneimine 46-2 (10.0 g, 57.5 mmol) was added to dichloromethane (100 mL), and after nitrogen protection, the mixture was cooled to -70 °C. Then, cyclopropylmagnesium bromide (80 mL, 1 mol / L tetrahydrofuran solution) was slowly added dropwise. After the addition was complete, the mixture was reacted at -70 °C for 2 hours, and then slowly heated to room temperature. The mixture was extracted with saturated ammonium chloride aqueous solution and dichloromethane. The organic phases were combined, washed with saturated experimental water, and dried over anhydrous sodium sulfate. The solution was purified by silica gel column chromatography to obtain (dicyclopropylmethyl)[(2-methylpropyl-2-yl)(oxonyl)-λ] 4 46-3 thio[thio]amine (5.7 g, yield 45.9%).

[1201] LC-MS m / z (ESI) = 216.10 [M+H] + .

[1202] Step 3:

[1203] Dicyclopropylmethaneamine 46-4

[1204] Dicyclopropylmethanamine

[1205] The raw material (dicyclopropylmethyl)[(2-methylpropyl-2-yl)(oxonyl)-λ 4[-Thio]amine 46-3 (5.7 g, 26.4 mmol) was added to methanol (20 mL), followed by a 1,4-dioxane solution of hydrogen chloride (60 mL). The reaction mixture was reacted at room temperature for 4 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and then ethyl acetate and 1N sodium hydroxide aqueous solution were added to adjust the pH to 8-9. The mixture was extracted multiple times, and the organic phases were combined, washed with saturated experimental water, and dried over anhydrous sodium sulfate. The mixture was then concentrated under reduced pressure to give dicyclopropylmethaneamine 46-4 (1.8 g, yield 60.8%).

[1206] LC-MS m / z (ESI) = 112.10 [M+H] + .

[1207] Step 4:

[1208] [(dicyclopropylmethyl)aza-dimethyl]methionine 46-5

[1209] [(dicyclopropylmethyl)azanylidene]methanethione

[1210] The starting material, dicyclopropylmethaneamine 46-4 (1.1 g, 10.0 mmol), was dissolved in dichloromethane (20 mL), and then 1,1-thiocarbonylDI-2(1H)-pyridine (2.3 g, 10.0 mmol) was added in portions. The reaction mixture was reacted at room temperature for 3 hours. The target reaction was detected by LCMS. After the reaction was completed, the mixture was directly purified by normal column chromatography to obtain [(dicyclopropylmethyl)azinedimethyl]meththione 46-5 (0.7 g, yield 45.5%).

[1211] LC-MS m / z (ESI) = 154.1 [M+H] + .

[1212] Step 5:

[1213] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(dicyclopropylmethyl)amino]thionylmethyl}-1-methylazanesulfonamide 46-6

[1214] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(dicyclopropylmethyl)amino]thioxomethyl}-1-methylazanesulfonamide

[1215] The starting material [(dicyclopropylmethyl)azineyl]methionine 46-5 (1.54 g, 10.0 mmol) was added to acetonitrile (30 mL), followed by [(5-chloropyridin-2-yl)methyl](methyl)azinesulfonamide intermediate 1 (2.36 g, 10.0 mmol) and cesium carbonate (4.89 g, 15.0 mmol). The reaction mixture was reacted at room temperature for 3 hours, then concentrated under reduced pressure. The crude product 1-[(5-chloropyridin-2-yl)methyl]-N-{[(dicyclopropylmethyl)amino]thionylmethyl}-1-methylazinesulfonamide 46-6 was used directly in the next step.

[1216] LC-MS m / z (ESI) = 389.1 [M+H] + .

[1217] Step 6:

[1218] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(dicyclopropylmethyl)amino][2-[(1-methylpyrazol-3-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 46-7

[1219] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(dicyclopropylmethyl)amino][2-[(1-methylpyrazol-3-yl)carbonyl]diazanylidene]methyl}-1-methylazanesulfonamide

[1220] Crude 1-[(5-chloropyridin-2-yl)methyl]-N-{[(dicyclopropylmethyl)amino]thiazidemethyl}-1-methylazanesulfonamide 46-6 (1.95 g, 5.0 mmol) was added to tetrahydrofuran (30 mL), followed by 1-methylpyrazol-3-carbamoylhydrazide (700 mg, 5.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.0 mmol). The reaction mixture was reacted overnight at room temperature, and the target reaction was detected by LCMS. After the reaction was complete, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to give 1-[(5-chloropyridin-2-yl)methyl]-N-{[(dicyclopropylmethyl)amino][2-[(1-methylpyrazol-3-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 46-7 (1.1 g, two-step yield 44.4%).

[1221] LC-MS m / z (ESI) = 495.20 [M+H] + .

[1222] Step 7:

[1223] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(dicyclopropylmethyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 46

[1224] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(dicyclopropylmethyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[1225] The starting material 1-[(5-chloropyridin-2-yl)methyl]-N-{[(dicyclopropylmethyl)amino][2-[(1-methylpyrazol-3-yl)carbonyl]ethazinediyl]methyl}-1-methylazanesulfonamide 46-7 (495 mg, 1.0 mmol) was added to isopropanol (5 mL), followed by 2 mol / L sodium hydroxide aqueous solution (5 mL). The reaction mixture was placed in a microwave reactor and heated to 110 °C for 4 hours. The reaction was confirmed by LCMS. After direct concentration, the mixture was purified by reversed-phase chromatography to obtain 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(dicyclopropylmethyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 46 (126 mg, yield 26.4%).

[1226] LC-MS m / z (ESI) = 477.20 [M+H] + .

[1227] 1 H NMR(400MHz,DMSO-d6)δ13.19(s,1H),8.56(d,1H),7.95(dd,1H),7.87(d,1H),7.49(d,1H),6.75–6.56(m,1H), 4.27(s,2H),3.92(s,3H),3.55(t,1H),2.62(s,3H),1.90(d,2H),0.69(s,2H),0.49–0.18(m,4H),0.06(dq,2H).

[1228] Example 47

[1229] 1-[(5-cyanopyridin-2-yl)methyl]-N-[5-(1-methylpyrazol-3-yl)-4-(2,6-dimethoxyphenyl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 47

[1230] 1-[(5-Cyanopyridin-2-yl)methyl]-N-[5-methylpyridin-3-yl)-4-(2,6-dimethoxyphenyl)-1,2,4-triazentan-3-yl]-1-methylazanesulfonamide

[1231] first step:

[1232] 6-((methylamino)methyl)nicotinamide 47-2

[1233] 6-((methylamino)methyl)nicotinotrile

[1234] 6-Formylnicotinic acid 47-1 (2 g, 15.13 mmol) and methylamine hydrochloride (2.04 g, 30.27 mmol) were added to methanol:tetrahydrofuran = 1:1 (150 mL:150 mL). After nitrogen protection, the reaction was carried out at 50 °C for 2 hours. Then, sodium triacetylborohydride (19.25 g, 90.82 mmol) was added, and the reaction was carried out for 4 hours. After the reaction was completed, the mixture was directly filtered, the filtrate was concentrated, the residue was dissolved in dichloromethane, 50 g of NaHCO3 solid was added, and the mixture was stirred for 2 hours. After filtration, the filtrate was concentrated to obtain 6-((methylamino)methyl)nicotinamide 47-2 (2.1 g, yield 98%).

[1235] LC-MS m / z (ESI) = 148.0 [M+H] + .

[1236] Step Two:

[1237] (N-((5-cyanopyridin-2-yl)methyl)-N-methylaminosulfonyl)tert-butyl carbamate 47-3

[1238] tert-butyl(N-((5-cyanopyridin-2-yl)methyl)-N-methylsulfamoyl)carbamate

[1239] 2.23 g (30 mmol) of tert-butanol was added to 200 mL of dichloromethane. Under nitrogen protection, the mixture was cooled to 0 °C, followed by the addition of 2.6 mL (29.8 mmol) of chlorosulfonyl isocyanate. The reaction mixture was reacted at 0 °C for 1 hour, followed by the addition of 11.5 mL (82.1 mol) of triethylamine, resulting in the precipitation of a large amount of solid. Then, 2.9 g (14.9 mmol) of 6-((methylamino)methyl)nicotinamide 47-2 was added, and the reaction mixture was slowly heated to room temperature. The reaction was confirmed by LCMS, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain tert-butyl (N-((5-cyanopyridin-2-yl)methyl)-N-methylaminosulfonyl)carbamate 47-3 (2.46 g, 51% yield).

[1240] LC-MS m / z (ESI) = 327.1 [M+H] + .

[1241] Step 3:

[1242] (N-((5-cyanopyridin-2-yl)methyl)-N-methylaminosulfonamide 47-4

[1243] (N-((5-cyanopyridin-2-yl)methyl)-N-methylsulfonamide

[1244] (N-((5-cyanopyridin-2-yl)methyl)-N-methylaminosulfonyl)carbamate tert-butyl ester 47-3 (2.46 g, 7.57 mmol) was added to dioxane hydrochloride (50 mL), and the reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was directly concentrated to obtain (N-((5-cyanopyridin-2-yl)methyl)-N-methylaminosulfonamide 47-4 (1.71 g, yield 99%).

[1245] LCMS m / z(ESI) = 227.0 [M+H] + .

[1246] Step 4:

[1247] N-(N-((5-cyanopyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)carbamoylthioic acid 47-5

[1248] N-(N-((5-cyanopyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)carbamimidothioic acid

[1249] The starting material (N-((5-cyanopyridin-2-yl)methyl)-N-methylaminosulfonamide 47-4 (800 mg, 3.54 mmol)) was added to an acetonitrile (15 mL) solution, followed by 2-isothiocyano-1,3-dimethoxybenzene (900 mg, 4.6 mmol) and cesium carbonate (1.5 g, 4.7 mmol). The resulting mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was filtered to obtain filter cake N-(N-((5-cyanopyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)carbamoylthioic acid 47-5 (1.428 g, 96% yield). This was used directly in the next step.

[1250] LC-MS m / z(ESI) = 422.0 [M+H] + .

[1251] Step 5:

[1252] N-(N-((5-cyanopyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-formimide 47-6

[1253] N-(N-((5-cyanopyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboximidamide

[1254] N-(N-((5-cyanopyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)carbamoylthioic acid 47-5 (1.428 g, 3.39 mmol) was added to tetrahydrofuran (40 ml), followed by 5-methylnicotinamide (950 mg, 6.78 mmol), and then EDCI (1.3 g, 6.78 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours. After the reaction was complete, the solution was directly... The reaction solution was evaporated to dryness, then dissolved in a 10:1 DCM:MeOH mixed solution (200 mL), washed three times with saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain the crude product. The crude product was then slurried with ACN to obtain N-(N-((5-cyanopyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboximide 47-6 (150 mg, yield 34%).

[1255] LC-MS m / z (ESI) = 528.1 [M+H] + .

[1256] Step 6:

[1257] 1-[(5-chlorocyano-2-yl)methyl]-N-[5-(1-methylpyrazol-3-yl)-4-(2,6-dimethoxyphenyl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 47

[1258] 1-[(5-Chlorocyano-2-yl)methyl]-N-[5-methylpyridin-3-yl)-4-(2,6-dimethoxyphenyl)-1,2,4-triazentan-3-yl]-1-methylazanesulfonamide

[1259] N-(N-((5-cyanopyridin-2-yl)methyl)-N-methylaminosulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazide-1-carboximide 47-6 (150 mg, 0.23 mmol) was dissolved in TFA (30 mL) and reacted at 80 °C for 8 hours. The reaction was monitored by LCMS until completion. The reaction was quenched by adding sodium bicarbonate aqueous solution, and then DCM was added. Extracted with a 10:1 mixture of MeOH (1 mL) and water, the organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The mixture was then slurried with acetonitrile to give the target compound 1-[(5-chlorocyano-2-yl)methyl]-N-[5-(1-methylpyrazol-3-yl)-4-(2,6-dimethoxyphenyl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 47 (22 mg, 18.8% yield).

[1260] LC-MS m / z (ESI) = 510.10 [M+H] + .

[1261] 1 H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.96(d,1H),8.28(dd,1H),7.68(d,1H),7.59( d,1H),7.49(t,1H),6.83(d,2H),6.07(d,1H),4.22(s,2H),3.73(s,3H),3.68(s,6H).

[1262] Example 48

[1263] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-N′-(cyclopropyl(pyridin-4-yl)-1,2,4-triazacyclopentan-3-yl]azine sulfonamide compound 48

[1264] 2-1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-N'-(cyclopropyl(pyridin-4-yl)-1,2,4-triazolepan-3-yl)azobenzenesulfonamide

[1265] first step:

[1266] 4-(cyclopropyl(isothiocyanate)methyl)pyridine 48-2

[1267] 4-(cyclopropyl(isothiocyanato)methyl)pyridine

[1268] The starting material, cyclopropyl(pyridin-4-yl)methylamine 48-1 (1.0 g, 6.75 mmol), was dissolved in dichloromethane (30 mL), followed by the addition of 1,1-thiocarbonylDI-2(1H)-pyridine (1.57 g, 6.75 mmol) in portions. The reaction mixture was reacted at room temperature for 3 hours. The target reaction was detected by LC-MS. After the reaction was completed, the mixture was directly purified by normal chromatography to obtain 4-(cyclopropyl(isothiocyanate)methyl)pyridine 48-2 (850 mg, yield 66%).

[1269] LC-MS m / z(ESI) = 191.0 [M+H] + .

[1270] Step Two:

[1271] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N′-(cyclopropyl(pyridin-4-yl)methyl ester)carbamoylthioic acid 48-3

[1272] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(cyclopropyl(pyridin-4-yl)methyl)carbamimidothioic acid

[1273] The starting material 4-(cyclopropyl(isothiocyanate)methyl)pyridine 48-2 (850 mg, 4.47 mmol) was added to acetonitrile (30 mL), followed by [(5-chloropyridin-2-yl)methyl](methyl)azanesulfonamide intermediate 8-7 (1.26 g, 5.36 mmol) and cesium carbonate (1.75 g, 5.36 mmol). The reaction mixture was reacted at room temperature for 3 hours, then concentrated under reduced pressure. The crude product N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N′-(cyclopropyl(pyridin-4-yl)methyl ester)carbamoylthioic acid 48-3 was used directly in the next step.

[1274] LC-MS m / z (ESI) = 426.0 [M+H] + .

[1275] Step 3:

[1276] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N′-(cyclopropyl(pyridin-4-yl)methyl ester)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-formimide 48-4

[1277] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(cyclopropyl(pyridin-4-yl)methyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboximidamide

[1278] Crude N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N′-(cyclopropyl(pyridin-4-yl)methyl ester)carbamoylthioic acid 48-3 (1.382 g, 1.626 mmol) was added to tetrahydrofuran (30 mL), followed by 1-methylpyrazole-3-carbamoylhydrazine (300 mg, 2.11 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (406 mg, 2.11 mmol). The reaction mixture was allowed to react overnight at room temperature, and the target reaction was detected by LC-MS. After the reaction was completed, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to obtain N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N′-(cyclopropyl(pyridin-4-yl)methyl ester)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazide-1-carboximide 48-4 (680 mg, two-step yield 56%).

[1279] LC-MS m / z (ESI) = 532.1 [M+H] +.

[1280] Step 4:

[1281] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-N′-(cyclopropyl(pyridin-4-yl)-1,2,4-triazacyclopentan-3-yl]azine sulfonamide compound 48

[1282] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-N'-(cyclopropyl(pyridin-4-yl)-1,2,4-triazolepan-3-yl)azobenzenesulfonamide

[1283] The starting material N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N′-(cyclopropyl(pyridin-4-yl)methyl ester)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazide-1-carboximide 48-4 (680 mg, 1.28 mmol) was added to isopropanol (5 mL), followed by 2 mol / L sodium hydroxide aqueous solution (5 mL). The reaction mixture was placed in a microwave reactor and heated to 110 °C for 4 hours. The reaction was detected by LCMS. After direct concentration, the product was purified by reversed-phase chromatography to obtain 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-N′-(cyclopropyl(pyridin-4-yl)-1,2,4-triazacyclopentan-3-yl]azine sulfonamide compound 48 (154 mg, yield 23.5%).

[1284] LC-MS m / z (ESI) = 514.1 [M+H] + .

[1285] 1 H NMR(400MHz,DMSO-d6)δ13.35(s,1H),8.75(d,2H),8.54(d,1H),8.03–7.84(m,2H),7.77(d,2H),7.37(d,1H),6.7 7(s,1H),3.89(s,2H),3.84(s,3H),2.33(s,3H),2.15(m,1H),1.24(m,1H),1.02(m,1H),0.62(m,2H),0.42(m,1H).

[1286] Example 49

[1287] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-N′-(cyclopropyl(pyridin-3-yl)-1,2,4-triazacyclopentan-3-yl]azine sulfonamide compound 49

[1288] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-N'-(cyclopropyl(pyridin-3-yl)-1,2,4-triazolepan-3-yl)azobenzenesulfonamide

[1289] first step:

[1290] 3-(cyclopropyl(isothiocyanate)methyl)pyridine 49-2

[1291] 3-(cyclopropyl(isothiocyanato)methyl)pyridine

[1292] The starting material, cyclopropyl(pyridin-3-yl)methylamine 49-1 (1.0 g, 6.75 mmol), was dissolved in dichloromethane (30 mL), followed by the addition of 1,1-thiocarbonylDI-2(1H)-pyridine (1.57 g, 6.75 mmol) in portions. The reaction mixture was reacted at room temperature for 3 hours. The target reaction was detected by LC-MS. After the reaction was completed, the mixture was directly purified by normal column chromatography to obtain 3-(cyclopropyl(isothiocyanate)methyl)pyridine 49-2 (1.28 g, 99% yield).

[1293] LC-MS m / z(ESI) = 191.0 [M+H] + .

[1294] Step Two:

[1295] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N′-(cyclopropyl(pyridin-3-yl)methyl ester)carbamoylthioic acid 49-3

[1296] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(cyclopropyl(pyridin-3-yl)methyl)carbamimidothioic acid

[1297] The starting material 3-(cyclopropyl(isothiocyanate)methyl)pyridine 49-2 (1.28 g, 6.73 mmol) was added to acetonitrile (30 mL), followed by [(5-chloropyridin-2-yl)methyl](methyl)azanesulfonamide intermediate 8-7 (1.22 g, 5.18 mmol) and cesium carbonate (2.2 g, 6.73 mmol). The reaction mixture was reacted at room temperature for 3 hours, then concentrated under reduced pressure. The crude product N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N′-(cyclopropyl(pyridin-3-yl)methyl ester)carbamoylthioic acid 49-3 was used directly in the next step.

[1298] LC-MS m / z (ESI) = 426.0 [M+H] + .

[1299] Step 3:

[1300] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N′-(cyclopropyl(pyridin-3-yl)methyl ester)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-formimide 49-4

[1301] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfamoyl)-N'-(cyclopropyl(pyridin-3-yl)methyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboximidamide

[1302] Crude N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N′-(cyclopropyl(pyridin-3-yl)methyl ester)carbamoylthioic acid 49-3 (953 mg, 2.24 mmol) was added to tetrahydrofuran (30 mL), followed by 1-methylpyrazol-3-carbamoylhydrazine (377 mg, 2.7 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (406 mg, 2.11 mmol). The reaction mixture was allowed to react overnight at room temperature, and the target reaction was detected by LC-MS. After the reaction was completed, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to obtain N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N′-(cyclopropyl(pyridin-3-yl)methyl ester)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazide-1-carboximide 49-4 (600 mg, 50% yield in two steps).

[1303] LC-MS m / z (ESI) = 532.1 [M+H] + .

[1304] Step 4:

[1305] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-N′-(cyclopropyl(pyridin-3-yl)-1,2,4-triazacyclopentan-3-yl]azine sulfonamide compound 49

[1306] 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazol-3-yl)-N'-(cyclopropyl(pyridin-3-yl)-1,2,4-triazolepan-3-yl)azobenzenesulfonamide

[1307] The starting material N-(N-((5-chloropyridin-2-yl)methyl)-N-methylaminosulfonyl)-N′-(cyclopropyl(pyridin-3-yl)methyl ester)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazide-1-carboximide 49-4 (680 mg, 1.28 mmol) was added to isopropanol (5 mL), followed by 2 mol / L sodium hydroxide aqueous solution (5 mL). The reaction mixture was placed in a microwave reactor and heated to 110 °C for 4 hours. The reaction was confirmed by LCMS. After direct concentration, the mixture was purified by reversed-phase chromatography to obtain 1-[(5-chloropyridin-2-yl)methyl]-1-methyl-N-[5-(1-methylpyrazole-3-yl)-N′-(cyclopropyl(pyridin-3-yl)-1,2,4-triazacyclopentan-3-yl]azanesulfonamide compound 49 (170 mg, yield 29%).

[1308] LC-MS m / z (ESI) = 514.1 [M+H] + .

[1309] 1 H NMR (400MHz, DMSO-d6) δ12.61(s,1H),8.64(d,J=2.3Hz,1H),8.53(d,1H),8.47(dd,1H),7.94–7.85(m,2H),7.78(d,J= 8.0Hz,1H),7.38(dd,2H),6.73(s,1H),5.55(s,1H),3.89(s,5H),2.33(s,4H),0.94(m,1H),0.55(m,2H),0.39(m,1H).

[1310] Example 50

[1311] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(2-methyl-1,3-oxazacyclopentan-5-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 50

[1312] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(2-methyl-1,3-oxazol-5-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[1313] first step:

[1314] {2-[(2-methyl-1,3-oxazacyclopentan-5-yl)carbonyl]acetazono}methane-2-methylpropyl-2-yl ester 50-2

[1315] 2-methylpropan-2-yl{2-[(2-methyl-1,3-oxazol-5-yl)carbonyl]diazanyl}methanoate

[1316] 12.7 g (100 mmol) of 2-methyl-1,3-oxazacyclopentan-5-carboxylic acid 50-1 was added to N,N-dimethylformamide (150 mL), followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (57.0 g, 150 mmol) and triethylamine (20.2 g, 200 mmol), and finally tert-butyl hydrazinoformate (14.5 g, 110 mmol). The reaction mixture was reacted at room temperature for 4 hours. After the reaction was completed, a large amount of purified water was added, and a large amount of solid precipitated. The solid was filtered, and the filter cake was washed several times with purified water. After filtration, the solid was concentrated under reduced pressure to obtain {2-[(2-methyl-1,3-oxazacyclopentan-5-yl)carbonyl]ethazyl}methanecarboxylic acid-2-methylpropyl-2-yl ester 50-2 (14.5 g, yield 59.9%).

[1317] LC-MS m / z (ESI) = 242.10 [M+H] + .

[1318] Step Two:

[1319] 2-Methyl-1,3-oxazacyclopentane-5-formylhydrazine 50-3

[1320] 2-methyl-1,3-oxazole-5-carbohydrazide

[1321] The starting material {2-[(2-methyl-1,3-oxazacyclopentan-5-yl)carbonyl]ethazyl}methane-2-methylpropyl-2-yl ester 50-2 (14.5 g, 59.9 mmol) was added to 1,4-dioxane (150 mL) containing 4 mol / L HCl. The reaction mixture was reacted at room temperature for 3 hours. After the reaction was completed, it was directly concentrated under reduced pressure to obtain 2-methyl-1,3-oxazacyclopentan-5-formylhydrazide 50-3 (8.5 g, 100% yield).

[1322] LC-MS m / z (ESI) = 142.10 [M+H] + .

[1323] Step 3:

[1324] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino][(1E)-2-[(2-methyl-1,3-oxazacyclopentan-5-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 50-4

[1325] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino][(1E)-2-[(2-methyl-1,3-oxazol-5-yl)carbonyl]diazanylidene]methyl}-1-methylazanesulfonamide

[1326] The starting materials 2-methyl-1,3-oxazacyclopentane-5-carbamoylhydrazide 50-3 (282 mg, 2.0 mmol) and 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino]thionylmethyl}-1-methylazanesulfonamide 8-7 (862 mg, 2.0 mmol) were added to tetrahydrofuran (10 mL), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (576 mg, 3.0 mmol). The reaction mixture was reacted at room temperature for 4 hours. After the reaction was completed, the solution was directly concentrated and then purified by reverse chromatography to obtain 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino][(1E)-2-[(2-methyl-1,3-oxazacyclopentan-5-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 50-4 (620 mg, yield 57.6%).

[1327] LC-MS m / z (ESI) = 538.10 [M+H] + .

[1328] Step 4:

[1329] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(2-methyl-1,3-oxazacyclopentan-5-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 50

[1330] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(2-methyl-1,3-oxazol-5-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[1331] The starting material 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino][(1E)-2-[(2-methyl-1,3-oxazacyclopentan-5-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 50-4 (620 mg, 1.15 mmol) was added to trifluoroacetic acid (10 mL). The reaction mixture was reacted at 80 °C for 3 hours. After the reaction was completed, the mixture was directly concentrated and then purified by reversed-phase chromatography to obtain 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(2-methyl-1,3-oxazacyclopentan-5-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 50 (97 mg, yield 16.2%).

[1332] LC-MS m / z (ESI) = 520.10 [M+H] + .

[1333] 1 H NMR(400MHz,DMSO-d6)δ13.42(s,1H),8.55(d,1H),7.91(dd,1H),7.55(t,1H),7. 51–7.38(m,2H),6.87(d,2H),4.12(s,2H),3.72(s,6H),2.50(s,3H),2.38(s,3H).

[1334] Example 51

[1335] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2-fluoro-6-methoxyphenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 51

[1336] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2-fluoro-6-methoxyphenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[1337] first step:

[1338] [(6-Fluoro-2-methoxyphenyl)aza-ylidene]methylthione 51-2

[1339] [(6-fluoro-2-methoxyphenyl)azanylidene]methanethione

[1340] The starting material 6-fluoro-2-methoxyaniline 51-1 (1.4 g, 10.0 mmol) was dissolved in dichloromethane (30 mL), and then 1,1-thiocarbonylDI-2(1H)-pyridine (2.3 g, 10.0 mmol) was added in portions. The reaction mixture was reacted at room temperature for 3 hours. The target reaction was detected by LCMS. After the reaction was completed, it was directly purified by normal column chromatography to obtain [(6-fluoro-2-methoxyphenyl)aza-dimethylthionone 51-2 (1.4 g, yield 76.1%).

[1341] LC-MS m / z (ESI) = 184.10 [M+H] + .

[1342] Step Two:

[1343] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(6-fluoro-2-methoxyphenyl)amino]thionylmethyl}-1-methylazinesulfonamide 51-3

[1344] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(6-fluoro-2-methoxyphenyl)amino]thioxomethyl}-1-methylazanesulfonamide

[1345] The starting material [(6-fluoro-2-methoxyphenyl)azineyl]methylthionone 51-2 (920 mg, 5.0 mmol) was added to acetonitrile (30 mL), followed by [(5-chloropyridin-2-yl)methyl](methyl)azinesulfonamide intermediate 1 (1.18 g, 5.0 mmol) and cesium carbonate (1.63 g, 5.0 mmol). The reaction mixture was reacted at room temperature for 3 hours, then concentrated under reduced pressure. The crude product 1-[(5-chloropyridin-2-yl)methyl]-N-{[(6-fluoro-2-methoxyphenyl)amino]thionylmethyl}-1-methylazinesulfonamide 51-3 was used directly in the next step.

[1346] LC-MS m / z (ESI) = 419.10 [M+H] + .

[1347] Step 3:

[1348] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(6-fluoro-2-methoxyphenyl)amino][2-[(1-methylpyrazol-3-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 51-4

[1349] 1-[(5-chloropyridin-2-yl)methyl]-N-{[(6-fluoro-2-methoxyphenyl)amino][(1E)-2-[(1-methylpyrazol-3-yl)carbonyl]diazanylidene]methyl}-1-methylazanesulfonamide

[1350] Crude 1-[(5-chloropyridin-2-yl)methyl]-N-{[(6-fluoro-2-methoxyphenyl)amino]thionylmethyl}-1-methylazanesulfonamide 51-3 (2.10 g, 5.0 mmol) was added to tetrahydrofuran (30 mL), followed by 1-methylpyrazol-3-carboxyhydrazide (700 mg, 5.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.0 mmol). The reaction mixture was allowed to react overnight at room temperature, and the target reaction was detected by LCMS. After the reaction was completed, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to obtain 1-[(5-chloropyridin-2-yl)methyl]-N-{[(6-fluoro-2-methoxyphenyl)amino][2-[(1-methylpyrazol-3-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 51-4 (1.1 g, two-step yield 41.8%).

[1351] LC-MS m / z (ESI) = 525.20 [M+H] + .

[1352] Step 4:

[1353] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2-fluoro-6-methoxyphenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 51

[1354] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2-fluoro-6-methoxyphenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[1355] The starting material 1-[(5-chloropyridin-2-yl)methyl]-N-{[(6-fluoro-2-methoxyphenyl)amino][(1E)-2-[(1-methylpyrazol-3-yl)carbonyl]ethazineide]methyl}-1-methylazanesulfonamide 51-4 (525 mg, 1.0 mmol) was added to trifluoroacetic acid (15 mL). The reaction mixture was heated to 70 °C and reacted for 4 hours. The reaction was detected by LCMS to indicate completion. After direct concentration, the product was purified by reversed-phase chromatography to obtain 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(2-fluoro-6-methoxyphenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 51 (116 mg, yield 22.9%).

[1356] LC-MS m / z (ESI) = 507.10 [M+H] + .

[1357] 1 H NMR(400MHz,Chloroform-d)δ13.91(s,1H),8.74(d,1H),7.69(dd,1H),7.43(td,1H),7.34(d,1H),7.31–7. 24(m,1H),6.90–6.74(m,2H),6.13(d,1H),4.59(d,1H),4.44(d,1H),3.83(s,3H),3.74(s,3H),2.74(s,3H).

[1358] Example 52

[1359] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(1,2,3,5,6,7-hexahydrocyclopenta[1,2-f]indene-4-yl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazinesulfonamide compound 52

[1360] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(1,2,3,5,6,7-hexahydrocyclopenta[1,2-f]inden-4-yl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[1361] first step:

[1362] (1,2,3,5,6,7-hexahydrocyclopenta[1,2-f]inden-4-ylazine) meththione 52-2

[1363] (1,2,3,5,6,7-hexahydrocyclopenta[1,2-f]inden-4-ylazanylidene)methanethione

[1364] The starting material 1,2,3,5,6,7-hexahydrocyclopentano[1,2-f]indene-4-amine 52-1 (1.73 g, 10.0 mmol) was dissolved in dichloromethane (30 mL), and then 1,1-thiocarbonylDI-2(1H)-pyridine (2.3 g, 10.0 mmol) was added in portions. The reaction mixture was reacted at room temperature for 3 hours. The target reaction was detected by LCMS. After the reaction was completed, it was directly purified by normal column chromatography to obtain (1,2,3,5,6,7-hexahydrocyclopentano[1,2-f]indene-4-ylazine)methylthione 52-2 (1.8 g, yield 83.3%).

[1365] LC-MS m / z (ESI) = 216.10 [M+H] + .

[1366] Step Two:

[1367] 1-[(5-chloropyridin-2-yl)methyl]-N-[(1,2,3,5,6,7-hexahydrocyclopenta[1,2-f]indene-4-ylamino)thionylmethyl]-1-methylazanesulfonamide 52-3

[1368] 1-[(5-chloropyridin-2-yl)methyl]-N-[(1,2,3,5,6,7-hexahydrocyclopenta[1,2-f]inden-4-ylamino)thioxomethyl]-1-methylazanesulfonamide

[1369] The starting material (1,2,3,5,6,7-hexahydrocyclopentano[1,2-f]indene-4-ylazineyl)methylthionone 52-2 (1.08 g, 5.0 mmol) was added to acetonitrile (30 mL), followed by [(5-chloropyridin-2-yl)methyl](methyl)azinesulfonamide (1.18 g, 5.0 mmol) and cesium carbonate (1.63 g, 5.0 mmol). The reaction mixture was reacted at room temperature for 3 hours, then concentrated under reduced pressure. The crude product 1-[(5-chloropyridin-2-yl)methyl]-N-[(1,2,3,5,6,7-hexahydrocyclopentano[1,2-f]indene-4-ylamino)thionylmethyl]-1-methylazinesulfonamide 52-3 was used directly in the next step.

[1370] LC-MS m / z (ESI) = 451.10 [M+H] + .

[1371] Step 3:

[1372] 1-[(5-chloropyridin-2-yl)methyl]-N-[(1,2,3,5,6,7-hexahydrocyclopenta[1,2-f]indene-4-ylamino)[(1E)-2-[(1-methylpyrazol-3-yl)carbonyl]ethazine]methyl]-1-methylazanesulfonamide 52-4

[1373] 1-[(5-chloropyridin-2-yl)methyl]-N-[(1,2,3,5,6,7-hexahydrocyclopenta[1,2-f]inden-4-ylamino)[(1E)-2-[(1-methylpyrazol-3-yl)carbonyl]diazanylidene]methyl]-1-methylazanesulfonamide

[1374] Crude 1-[(5-chloropyridin-2-yl)methyl]-N-[(1,2,3,5,6,7-hexahydrocyclopenta[1,2-f]indene-4-ylamino)thionylmethyl]-1-methylazanesulfonamide 52-3 (2.25 g, 5.0 mmol) was added to tetrahydrofuran (30 mL), followed by 1-methylpyrazol-3-carboxyhydrazide (700 mg, 5.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.0 mmol). The reaction mixture was allowed to react overnight at room temperature, and the target reaction was detected by LCMS. After the reaction was completed, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to obtain 1-[(5-chloropyridin-2-yl)methyl]-N-[(1,2,3,5,6,7-hexahydrocyclopenta[1,2-f]indene-4-ylamino)[(1E)-2-[(1-methylpyrazol-3-yl)carbonyl]ethazineyl]methyl]-1-methylazanesulfonamide 52-4 (1.1 g, two-step yield 39.4%).

[1375] LC-MS m / z (ESI) = 557.20 [M+H] + .

[1376] Step 4:

[1377] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(1,2,3,5,6,7-hexahydrocyclopenta[1,2-f]indene-4-yl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazinesulfonamide compound 52

[1378] 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(1,2,3,5,6,7-hexahydrocyclopenta[1,2-f]inden-4-yl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[1379] The starting material 1-[(5-chloropyridin-2-yl)methyl]-N-[(1,2,3,5,6,7-hexahydrocyclopenta[1,2-f]indene-4-ylamino)[(1E)-2-[(1-methylpyrazol-3-yl)carbonyl]ethazine]methyl]-1-methylazanesulfonamide 52-4 (557 mg, 1.0 mmol) was added to trifluoroacetic acid (15 mL). The mixture was placed in a microwave reactor and heated to 100 °C for 2 hours. The reaction was detected by LCMS. After direct concentration, the product was purified by reversed-phase chromatography to obtain 1-[(5-chloropyridin-2-yl)methyl]-N-[4-(1,2,3,5,6,7-hexahydrocyclopenta[1,2-f]indene-4-yl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 52 (117 mg, yield 21.7%).

[1380] LC-MS m / z (ESI) = 539.20 [M+H] + .

[1381] 1 H NMR(400MHz,DMSO-d6)δ13.51(s,1H),8.55(d,1H),7.88(dd,1H),7.69(d,1H),7.43(d,1H),7.25(s ,1H),5.91(d,1H),4.20(s,2H),3.76(s,3H),2.89(q,4H),2.55(d,5H),2.41(dt,2H),1.96(tt,4H).

[1382] Example 53

[1383] 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentane-3-yl]-1-methylazanesulfonamide compound 53

[1384] 1-[(6-chloro-1,2-diazin-3-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[1385] first step:

[1386] 3-Chloro-6-[(methylamino)methyl]-1,2-diazacyclohexane 53-2

[1387] 3-chloro-6-[(methylamino)methyl]-1,2-diazine

[1388] The starting material, 6-chloro-1,2-diazacyclohexane-3-carboxaldehyde 53-1 (10.0 g, 70 mmol), was added to a mixed solution of tetrahydrofuran (100 mL) and methanol (100 mL), followed by the addition of methylamine hydrochloride (14.2 g, 210 mmol). The reaction mixture was heated to 60 °C and reacted for 2 hours, then cooled to 0 °C. Triacetoxyborohydride sodium (29.6 g, 140 mmol) was slowly added in portions, and the reaction mixture was slowly heated to room temperature for 4 hours. After the reaction was complete, the mixture was extracted with saturated sodium bicarbonate aqueous solution and dichloromethane. After multiple extractions, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness. The crude product was subjected to normal column chromatography to obtain 3-chloro-6-[(methylamino)methyl]-1,2-diazacyclohexane 53-2 (7.8 g, yield 70.9%).

[1389] LC-MS m / z (ESI) = 158.10 [M+H] + .

[1390] Step Two:

[1391] [({[(6-chloro-1,2-diazacyclohexane-3-yl)methyl](methyl)amino}dioxane-λ6-thio)amino]methane-2-methylpropyl-2-yl ester 53-3

[1392] 2-methylpropan-2-yl[({[(6-chloro-1,2-diazin-3-yl)methyl](methyl)amino}dioxo-λ6-sulfanyl)amino]methanoate

[1393] tert-butanol (5.5 g, 75 mmol) was added to dichloromethane (100 mL) under nitrogen protection, and then cooled to 0 °C. Next, chlorosulfonyl isocyanate (10.6 g, 75 mmol) was slowly added dropwise to the reaction mixture. After reacting the mixture at 0 °C for 1 hour, triethylamine (10.1 g, 100 mol) and 3-chloro-6-[(methylamino)methyl]-1,2-diazacyclohexane 53-2 (7.8 g, 50 mmol) were slowly added dropwise. The reaction mixture was slowly heated to room temperature and reacted for 3 hours. After the reaction was complete, the mixture was directly purified by a normal column to obtain [({[(6-chloro-1,2-diazacyclohexane-3-yl)methyl](methyl)amino}dioxane-λ6-thio)amino]methane-2-methylpropyl-2-yl ester 53-3 (9.2 g, yield 54.6%).

[1394] LC-MS m / z (ESI) = 337.10 [M+H] + .

[1395] Step 3:

[1396] [(6-chloro-1,2-diazacyclohexane-3-yl)methyl](methyl)azinesulfonamide 53-4

[1397] [(6-chloro-1,2-diazin-3-yl)methyl](methyl)azanesulfonamide

[1398] The starting material [({[(6-chloro-1,2-diazacyclohexane-3-yl)methyl](methyl)amino}dioxane-λ6-thio)amino]methane-2-methylpropyl-2-yl ester 53-3 (9.2 g, 27.3 mmol) was added to dichloromethane (75 mL) and trifluoroacetic acid (25 mL). The reaction mixture was reacted at room temperature for 3 hours. After the reaction was completed, the mixture was directly concentrated, and then saturated sodium bicarbonate aqueous solution and ethyl acetate were added. After extraction, the mixture was separated, and the aqueous phase was extracted multiple times. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain [(6-chloro-1,2-diazacyclohexane-3-yl)methyl](methyl)azanesulfonamide 53-4 (4.7 g, yield 72.6%).

[1399] LC-MS m / z (ESI) = 237.10 [M+H] + .

[1400] Step 4:

[1401] 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino]thionylmethyl}-1-methylazanesulfonamide 53-5

[1402] 1-[(6-chloro-1,2-diazin-3-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino]thioxomethyl}-1-methylazanesulfonamide

[1403] The starting material [(6-chloro-1,2-diazacyclohexane-3-yl)methyl](methyl)azinesulfonamide 53-4 (711 mg, 3.0 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of [(2,6-dimethoxyphenyl)azapyridyl]methylthionone (585 mg, 3.0 mmol) and cesium carbonate (978 mg, 3.0 mmol). The reaction mixture was reacted at room temperature for 4 hours. After the reaction was completed, the mixture was directly concentrated under reduced pressure, and the crude product 53-5 was used directly in the next step.

[1404] LC-MS m / z (ESI) = 432.10 [M+H] + .

[1405] Step 5:

[1406] 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino][2-[(1-methylpyrazol-3-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 53-6

[1407] 1-[(6-chloro-1,2-diazin-3-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino][2-[(1-methylpyrazol-3-yl)carbonyl]diazanylidene]methyl}-1-methylazanesulfonamide

[1408] Tetrahydrofuran (20 mL) was added to the crude product 53-5 from the previous step, followed by 1-methylpyrazol-3-carboxyhydrazide (420 mg, 3.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (864 mg, 4.5 mmol). The reaction mixture was reacted overnight at room temperature. After the reaction was complete, saturated ammonium chloride aqueous solution and ethyl acetate were added, and the organic phase was washed several times with saturated ammonium chloride aqueous solution. After separation, the organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography to give 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino][(2-[(1-methylpyrazol-3-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 53-6 (410 mg, two-step yield 25.4%).

[1409] LC-MS m / z (ESI) = 538.20 [M+H] + .

[1410] Step 6:

[1411] 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentane-3-yl]-1-methylazanesulfonamide compound 53

[1412] 1-[(6-chloro-1,2-diazin-3-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[1413] The starting material 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino][(1Z)-2-[(1-methylpyrazol-3-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 53-6 (410 mg, 0.76 mmol) was added to trifluoroacetic acid (5 mL). The reaction mixture was heated to 80 °C and reacted for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and then purified by column chromatography to obtain 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(1-methylpyrazol-3-yl)-1,2,4-triazacyclopentane-3-yl]-1-methylazanesulfonamide compound 53 (87 mg, yield 22.0%).

[1414] LC-MS m / z (ESI) = 520.10 [M+H] + .

[1415] 1 H NMR(400MHz,DMSO-d6)δ13.24(s,1H),7.86(d,1H),7.79–7.61(m,2H),7.50(t,1H) ),6.83(d,2H),6.06(d,1H),4.31(s,2H),3.73(s,3H),3.69(s,6H),2.51(d,3H).

[1416] Example 54

[1417] 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(2-methyl-1,3-thiazacyclopentan-5-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 54

[1418] 1-[(6-chloro-1,2-diazin-3-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(2-methyl-1,3-thiazol-5-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[1419] first step:

[1420] 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino]thionylmethyl}-1-methylazanesulfonamide 54-2

[1421] 1-[(6-chloro-1,2-diazin-3-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino]thioxomethyl}-1-methylazanesulfonamide

[1422] The starting material [(6-chloro-1,2-diazacyclohexane-3-yl)methyl](methyl)azinesulfonamide 54-1 (711 mg, 3.0 mmol) was dissolved in acetonitrile (20 ml), followed by the addition of [(2,6-dimethoxyphenyl)azapyridyl]methylthione (585 mg, 3.0 mmol) and cesium carbonate (978 mg, 3.0 mmol). The reaction mixture was reacted at room temperature for 4 hours. After the reaction was completed, the mixture was directly concentrated under reduced pressure, and the crude product 54-2 was used directly in the next step.

[1423] LC-MS m / z (ESI) = 432.10 [M+H] + .

[1424] Step Two:

[1425] 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino][2-[(2-methyl-1,3-thiazacyclopentane-5-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 54-3

[1426] 1-[(6-chloro-1,2-diazin-3-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino][2-[(1-methylpyrazol-3-yl)carbonyl]diazanylidene]methyl}-1-methylazanesulfonamide

[1427] Add 20 mL of tetrahydrofuran to the crude product 54-2 from the previous step, followed by 2-methyl-1,3-thiazacyclopentane-5-carboxylhydrazide (471 mg, 3.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (864 mg, 4.5 mmol). The reaction mixture was allowed to react overnight at room temperature. After the reaction was complete, a saturated aqueous solution of ammonium chloride and ethyl acetate were added, and the organic phase was washed several times with the saturated aqueous solution of ammonium chloride. After separation, the organic phase was dried with anhydrous sodium sulfate, filtered, and then evaporated to dryness. The solution was purified by column chromatography to give 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino][2-[(2-methyl-1,3-thiazacyclopentane-5-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 54-3 (395 mg, two-step yield 23.7%).

[1428] LC-MS m / z (ESI) = 555.10 [M+H] + .

[1429] Step 3:

[1430] 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(2-methyl-1,3-thiazacyclopentan-5-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 54

[1431] 1-[(6-chloro-1,2-diazin-3-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(2-methyl-1,3-thiazol-5-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[1432] The raw material 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino][(1Z)-2-[(2-methyl-1,3-thiazacyclopentane-5-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 54-3 (395 mg, 0.71 mmol) was added to trifluoroacetic acid (5 mL). The reaction mixture was heated to 80°C and reacted for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and then purified by column chromatography to obtain 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(2-methyl-1,3-thiazacyclopentan-5-yl)-1,2,4-triazacyclopentan-3-yl]-1-methylazanesulfonamide compound 54 (67 mg, yield 17.6%).

[1433] LC-MS m / z (ESI) = 537.10 [M+H] + .

[1434] 1 H NMR(400MHz,DMSO-d6)δ13.40(s,1H),7.97–7.81(m,1H),7.76(d,1H),7.60(t,1H ),7.47(s,1H),6.91(d,2H),4.32(s,2H),3.75(s,6H),2.61(s,3H),2.51(d,3H).

[1435] Example 55

[1436] 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(1-methylpyrazol-4-yl)-1,2,4-triazacyclopentane-3-yl]-1-methylazanesulfonamide compound 55

[1437] 1-[(6-chloro-1,2-diazin-3-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(1-methylpyrazol-4-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[1438] first step:

[1439] 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino]thionylmethyl}-1-methylazanesulfonamide 55-2

[1440] 1-[(6-chloro-1,2-diazin-3-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino]thioxomethyl}-1-methylazanesulfonamide

[1441] The starting material [(6-chloro-1,2-diazacyclohexane-3-yl)methyl](methyl)azinesulfonamide 55-1 (711 mg, 3.0 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of [(2,6-dimethoxyphenyl)azapyridyl]methylthione (585 mg, 3.0 mmol) and cesium carbonate (978 mg, 3.0 mmol). The reaction mixture was reacted at room temperature for 4 hours. After the reaction was completed, the mixture was directly concentrated under reduced pressure, and the crude product 55-2 was used directly in the next step.

[1442] LC-MS m / z (ESI) = 432.10 [M+H] + .

[1443] Step Two:

[1444] 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino][2-[(1-methylpyrazol-4-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 55-3

[1445] 1-[(6-chloro-1,2-diazin-3-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino][2-[(1-methylpyrazol-4-yl)carbonyl]diazanylidene]methyl}-1-methylazanesulfonamide

[1446] Tetrahydrofuran (20 mL) was added to the crude product 55-2 from the previous step, followed by 1-methylpyrazol-4-carboxyhydrazide (420 mg, 3.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (864 mg, 4.5 mmol). The reaction mixture was reacted overnight at room temperature. After the reaction was complete, saturated ammonium chloride aqueous solution and ethyl acetate were added, and the organic phase was washed several times with saturated ammonium chloride aqueous solution. After separation, the organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography to give 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino][2-[(1-methylpyrazol-4-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 55-3 (405 mg, two-step yield 25.1%).

[1447] LC-MS m / z (ESI) = 538.20 [M+H] + .

[1448] Step 3:

[1449] 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(1-methylpyrazol-4-yl)-1,2,4-triazacyclopentane-3-yl]-1-methylazanesulfonamide compound 55

[1450] 1-[(6-chloro-1,2-diazin-3-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(1-methylpyrazol-4-yl)-1,2,4-triazol-3-yl]-1-methylazanesulfonamide

[1451] The starting material 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-{[(2,6-dimethoxyphenyl)amino][2-[(1-methylpyrazol-4-yl)carbonyl]ethazine]methyl}-1-methylazanesulfonamide 55-3 (405 mg, 0.75 mmol) was added to trifluoroacetic acid (5 mL). The reaction mixture was heated to 80 °C and reacted for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and then purified by column chromatography to obtain 1-[(6-chloro-1,2-diazacyclohexane-3-yl)methyl]-N-[4-(2,6-dimethoxyphenyl)-5-(1-methylpyrazol-4-yl)-1,2,4-triazacyclopentane-3-yl]-1-methylazanesulfonamide compound 55 (71 mg, yield 18.2%).

[1452] LC-MS m / z (ESI) = 520.10 [M+H]+ .

[1453] 1 H NMR(400MHz,DMSO-d6)δ13.06(s,1H),8.73(d,1H),8.45(d,1H),7.70(s,1H),7.58(t ,1H),7.12(s,1H),6.89(d,2H),4.18(s,2H),3.79(s,3H),3.73(s,6H),2.55(s,3H).

[1454] Example 56

[1455] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-diethyl)-5-(1-methyl-1H-pyrazole-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 56

[1456] N-(N-(5-chloro-2-pyridinyl)methyl)sulfamoyl)-4-(2,6-diethyl)-5-(1-methyl-1H-pyrazol-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine

[1457] first step:

[1458] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonyl)-N'-(2,6-diethylphenyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboxamide 56-3

[1459] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonyl)-N'-(2,6-diethylphenyl)-2-(1-methyl-1H-pyrazol-3-carbonyl)hydrazine-1-carboxamide

[1460] 1-Methyl-1H-pyrazole-3-carboxycarbamoylhydrazide 56-1 (6.0 g, 0.15 mol) was added to tetrahydrofuran (120 mL), followed by 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,6-diethylphenyl)amino]thionylmethyl}-1-methylazanesulfonamide 56-2 (2.0 g, 0.15 mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.8 mg, 0.25 mol). The reaction mixture was allowed to react overnight at room temperature, and the target reaction was detected by LC-MS. After the reaction was completed, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to obtain N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonyl)-N'-(2,6-diethylphenyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboxamide 56-3 (1.1 g, yield 13.3%).

[1461] LC-MS m / z (ESI) = 533.2 [M+H] + .

[1462] Step Two:

[1463] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-diethyl)-5-(1-methyl-1H-pyrazole-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 56

[1464] N-(N-(5-chloro-2-pyridinyl)methyl)sulfamoyl)-4-(2,6-diethyl)-5-(1-methyl-1H-pyrazol-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine

[1465] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonyl)-N'-(2,6-diethylphenyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboxamide 56-3 (600 mg, 1.1 mmol) was added to trifluoroacetic acid (15 mL), and the reaction mixture was heated to 85 °C and reacted for 8 hours. The reaction was detected by LC-MS and the product was directly concentrated and purified by reversed-phase chromatography to obtain N-(N-(5-chloropyridin-2-yl)methyl)sulfonamide)-4-(2,6-diethyl)-5-(1-methyl-1H-pyrazole-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 56 (18 mg, yield 2.8%).

[1466] LC-MS m / z (ESI) = 515.10 [M+H] + .

[1467] 1 H NMR(400MHz,DMSO-d6)δ8.55(d,1H),7.89(dd,1H),7.67(d,1H),7.47(q,2H),7.29(t ,2H),5.84(d,1H),4.19(s,2H),3.73(s,3H),2.55(s,3H),2.24(q,4H),0.99(t,6H).

[1468] Example 57

[1469] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-isopropyl)-5-(1-methyl-1H-pyrazole-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 57

[1470] N-(N-(5-chloro-2-pyridyl)methyl)sulfamoyl)-4-(2,6-diisopropyl)-5-(1-methyl-1H-pyrazol-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[1471] first step:

[1472] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonyl)-N'-(2,6-diisopropylphenyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboxamide 57-3

[1473] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonyl)-N'-(2,6-dipropylphenyl)-2-(1-methyl-1H-pyrazol-3-carbonyl)hydrazine-1-carboxamide

[1474] 1-Methyl-1H-pyrazole-3-carboxycarbamoylhydrazide 57-1 (6.0 g, 0.15 mol) was added to tetrahydrofuran (120 mL), followed by 1-[(5-chloropyridin-2-yl)methyl]-N-{[(2,6-diethylphenyl)amino]thionylmethyl}-1-methylazanesulfonamide 57-2 (2.0 g, 0.15 mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.8 mg, 0.25 mol). The reaction mixture was allowed to react overnight at room temperature, and the target reaction was detected by LC-MS. After the reaction was completed, the mixture was directly filtered, concentrated under reduced pressure, and purified by reverse column chromatography to obtain N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonyl)-N'-(2,6-isopropylphenyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboxamide 57-3 (9 g).

[1475] LC-MS m / z (ESI) = 561.2 [M+H] + .

[1476] Step Two:

[1477] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-isopropyl)-5-(1-methyl-1H-pyrazole-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 57

[1478] N-(N-(5-chloro-2-pyridyl)methyl)sulfamoyl)-4-(2,6-diisopropyl)-5-(1-methyl-1H-pyrazol-3-yl)-N-methyl-4H-1,2,4-triazole-3-amine

[1479] N-(N-((5-chloropyridin-2-yl)methyl)-N-methylsulfonyl)-N'-(2,6-diethylphenyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboxamide 57-3 (600 mg, 1.1 mmol) was added to trifluoroacetic acid (15 mL), and the reaction mixture was heated to 85 °C and reacted for 8 hours. The reaction was detected by LC-MS and the product was directly concentrated and purified by reversed-phase chromatography to obtain N-(N-(5-chloropyridin-2-yl)methyl)sulfonamide)-4-(2,6-isopropyl)-5-(1-methyl-1H-pyrazole-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 57 (16 mg, yield 2.7%).

[1480] LC-MS m / z (ESI) = 543.10 [M+H] + .

[1481] 1 H NMR(400MHz,DMSO-d6)δ8.54(d,1H),7.87(dd,1H),7.66(d,1H),7.52(t,1H),7.46(d,1H),7.32(d,2H), 5.85(d,1H),4.19(s,2H),3.70(s,3H),2.54(s,3H),2.42(p,2H),1.23(s,2H),1.11(d,6H),0.90(d,6H).

[1482] Example 58

[1483] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1-methyl-1H-pyrazole-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 58

[1484] N-(N-(5-chloropyridine-2-yl)methyl)sulfanilamide)-4-(2,6-dimethoxy)-5-(1-methyl-1H-pyrazole-3-yl)-N-methyl-4H-1,4-trichlorobenzene triazole-3-amine

[1485] first step:

[1486] N-(N-(1-(5-chloropyridin-2-yl)ethyl)-N-methylsulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboxamide 58-3

[1487] N-(N-(1-(5-chloropyridin-2-yl)ethyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboximidamide

[1488] N-(N-(1-(5-chloropyridin-2-yl)ethyl)-N-methylsulfonyl)-N'-(2,6-dimethoxyphenyl)aminothiocarboxylic acid 58-2 (3.1 g, 7.21 mmol) was added to tetrahydrofuran (10 mL), followed by 1-methyl-1H-pyrazole-3-carbazide 58-1 (1.0 g, 7.14 mmol), and then EDCI (1.77 g, 9.28 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours. The reaction solution was directly evaporated to dryness, then dissolved in a 10:1 DCM:MeOH mixed solution (100 mL), washed three times with saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain a crude product. The crude product was then slurried with ACN to obtain a white solid N-(N-(1-(5-chloropyridin-2-yl)ethyl)-N-methylsulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboxamide 58-3 (0.5 g, yield 39.1%).

[1489] LC-MS m / z (ESI) = 551.1 [M+H] + .

[1490] Step Two:

[1491] N-(N-(5-chloropyridin-2-yl)ethyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1-methyl-1H-pyrazole-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 58

[1492] N-(N-(5-Chloropyridin-2-yl)ethyl)sulfonylamino)-4-(2,6-dimethoxy)-5-(1-methyl-1H-pyrazol-3-yl)-N-methyl-4H-1,2,4-triazole-3-amide

[1493] N-(N-(1-(5-chloropyridin-2-yl)ethyl)-N-methylsulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(1-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboxamide 58-3 (1.1 g, 1.6 mmol) was dissolved in TFA (15 mL) and reacted at 80 °C for 8 hours. The reaction was monitored by LCMS until completion. The reaction was quenched by adding sodium bicarbonate aqueous solution, and then DCM:MeOH was added. Extracted with a 10:1 mixture of water (100 mL), the organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. MPLC was used to separate the target compound N-(N-(5-chloropyridin-2-yl)ethyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1-methyl-1H-pyrazole-3-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 58 (white solid, 200 mg, 20% yield).

[1494] LC-MS m / z (ESI) = 533.10 [M+H] + .

[1495] 1 H NMR(400MHz,DMSO-d6)δ13.12(s,1H),8.56(dd,1H),7.86(dd,1H),7.68(d,1H),7.49(t,1H),7.42( d,1H),6.81(d,2H),6.04(d,1H),5.07(q,1H),3.74(s,3H),3.67(d,6H),2.42(s,3H),1.35(d,3H).

[1496] Example 59

[1497] N-(N-(5-chloropyridin-2-yl)methyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1-methyl-1H-pyrazole-4-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 59

[1498] N-(N-(5-Chloropyridin-2-yl)methyl)sulfonylamino)-4-(2,6-dimethoxy)-5-(1-methyl-1H-pyrazol-4-yl)-N-methyl-4H-1,2,4-triazole-3-amide

[1499] first step:

[1500] N-(N-(1-(5-chloropyridin-2-yl)ethyl)-N-methylsulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(1-methyl-1H-pyrazole-4-carbonyl)hydrazine-1-carboxamide 59-3

[1501] N-(N-(1-(5-chloropyridin-2-yl)ethyl)-N-methylsulfamoyl)-N'-(2,6-dimethoxyphenyl)-2-(1-methyl-1H-pyrazole-4-carbonyl)hydrazine-1-carboximidamide

[1502] N-(N-(1-(5-chloropyridin-2-yl)ethyl)-N-methylsulfonyl)-N'-(2,6-dimethoxyphenyl)aminothiocarboxylic acid 59-2 (3.1 g, 7.21 mmol) was added to tetrahydrofuran (10 mL), followed by 1-methyl-1H-pyrazole-4-carbazide 59-1 (1.0 g, 7.14 mmol), and then EDCI (1.77 g, 9.28 mmol). The reaction mixture was kept under nitrogen protection and reacted at room temperature for 3 hours. The reaction solution was directly evaporated to dryness, then dissolved in a 10:1 DCM:MeOH mixed solution (100 mL), washed three times with saturated ammonium chloride aqueous solution, and the organic phase was evaporated to dryness to obtain a crude product. The crude product was then slurried with ACN to obtain a white solid N-(N-(1-(5-chloropyridin-2-yl)ethyl)-N-methylsulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(1-methyl-1H-pyrazole-4-carbonyl)hydrazine-1-carboxamide 59-3 (0.5 g, yield 39.1%).

[1503] LC-MS m / z (ESI) = 551.1 [M+H] + .

[1504] Step Two:

[1505] N-(N-(5-chloropyridin-2-yl)ethyl)sulfonamido)-4-(2,6-dimethoxy)-5-(1-methyl-1H-pyrazole-4-yl)-N-methyl-4H-1,2,4-triazol-3-amine compound 59

[1506] N-(N-(5-Chloropyridin-2-yl)methyl)sulfonylamino)-4-(2,6-dimethoxy)-5-(1-methyl-1H-pyrazol-4-yl)-N-methyl-4H-1,2,4-triazole-3-amide

[1507] N-(N-((5-chloropyridin-2-yl)ethyl)-N-methylsulfonamido)-N'-(2,6-dimethoxyphenyl)-2-(1-methyl-1H...

Claims

1. A compound that is a compound of formula (I), or any stereoisomer, tautomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal of a compound of formula (I): L1 is selected from L2 is selected from NR3, O, C 1-6 Alkylene, C 2-6 Alynyl or 5-10 heteroaryl; L3 does not exist; or L3 is selected from C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Imyynyl group, the C 1-6 Alkylene, C 2-6 imidene group, C 2-6 The ethynyl group may be further substituted by one or more R1 groups; Ring A is selected from 5-12 membered carbocyclic groups and 5-12 membered heterocyclic groups; R1 is independently selected from H, -OH, CN, carboxyl, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl may optionally be further surrounded by one or more OH, carboxyl, halogen, -CN, C 1-6 Halogenated alkyl, 3-10 membered heterocyclic alkyl, 5-10 membered aryl or 5-10 membered heteroaryl substitution; R2 is independently selected from H, -OH, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 The alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl may optionally be further substituted by one or more substituents selected from -OH, -CN, halogen or carboxyl; R3 is selected from H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, -NH2, carboxyl, amide, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 5-10 Aryl, 5-10 heteroaryl, -C 1-6 Alkylene-C 1-6 Alkoxy, -C 1-6 Alkylene -3 to 10-membered cycloalkyl, -C 1-6 Alkylene -3 to 10-membered heterocyclic alkyl, -C 1-6 Alkylene-C 5-10 Aryl or -C 1-6 alkylene-5 to 10-membered heteroaryl; the C 1-6 The alkyl group is further substituted with one or more D molecules, namely, the 3-10 membered cycloalkyl group, the 3-10 membered heterocycloalkyl group, and the C alkyl group. 5-10 Aryl, 5-10 heteroaryl, -C 1-6 Alkylene-C 1-6 Alkoxy, -C 1- 6-alkylene-3 to 10-membered cycloalkyl, -C 1-6 Alkylene -3 to 10-membered heterocyclic alkyl, -C 1-6 Alkylene-C 5-10 Aryl or -C 1-6 alkylene-5 to 10-membered heteroaryl groups are further bounded by one or more C groups. 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkyl, -OH, -CN substitution; R4 and R5 are each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered carbocyclic, 5-10 membered heteroaryl, 5-14 membered heterocyclic, -C 1-6 Alkylene-C 1-6 Alkoxy, -C 1-6 Alkylene -3 to 10-membered cycloalkyl, -C 1-6 Alkylene -3 to 10-membered heterocyclic alkyl, -C 1-6 alkylene-5 to 10-membered aryl, -C 1-6 alkylene-5 to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered carbocyclic, 5-10 membered heteroaryl, 5-14 membered heterocyclic, -C 1-6 Alkylene-C 1-6 Alkoxy, -C 1-6 Alkylene -3 to 10-membered cycloalkyl, -C 1-6 Alkylene -3 to 10-membered heterocyclic alkyl, -C 1-6 alkylene-5 to 10-membered aryl, -C 1-6 The alkylene-5 to 10-membered heteroaryl group is optionally further surrounded by one or more groups selected from -OH, -CN, halogen, carboxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -OC 1-6 Substitution with haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl; R5 is selected from 5-12 membered carbocyclic groups, wherein the 5-12 membered carbocyclic group is not substituted by a 3-membered cycloalkyl group; m is selected from 0, 1, 2, 3, 4, 5 or 6.

2. The compound according to claim 1, or all its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, wherein, At least one of the following conditions must be met: (1) L2 is selected from NR3; (2) When L3 exists, L3 is selected from C. 1-6 Alkylene, the C 1-6 The alkylene group may optionally be further substituted with one or more R1s; (3) Ring A is selected from 6-membered aromatic rings, 5-6-membered heteroaryl rings, and 8-10-membered bicyclic heteroaryl groups; (4) R1 is independently selected from H, -OH, -CN, halogen, carboxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 The alkoxy group may optionally be further substituted by one or more substituents selected from -OH, -CN, halogen, and carboxyl groups; Preferably, R1 is independently selected from H, -OH, -CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 The alkoxy group may optionally be further substituted by one or more substituents selected from -OH, -CN, halogen, and carboxyl groups; (5) R2 is independently selected from H, -OH, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl; (6) R3 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -C 1-4 Alkylene-C 1-4 Alkoxy, -C 1-6 Alkylene - 3 to 6-membered cycloalkyl, -C 1-6 Alkylene-3 to 6-membered heterocyclic alkyl; the C 1-6 The alkyl group is further substituted by one or more D atoms; (7) R4 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 5-8 Aryl, 5-8 membered heteroaryl, 5-10 membered heterocyclic, -C 1-4 Alkylene-C 1-4 Alkoxy, -C 1-6 Alkylene - 3 to 6-membered cycloalkyl, -C 1-6 alkylene-3 to 6-membered heterocyclic alkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 5-8 Aryl, 5-8 membered heteroaryl, 5-10 membered heterocyclic, -C 1-4 Alkylene-C 1-4 Alkoxy, -C 1-6 Alkylene - 3 to 6-membered cycloalkyl, -C 1-6 Alkylene-3 to 6-membered heterocyclic alkyl groups optionally further surrounded by one or more groups selected from -OH, -CN, halogen, carboxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Substitution with alkoxy or 3-6 membered cycloalkyl groups; (8) R5 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl, C 5-6 Aryl, 5-6 membered heteroaryl, 12 membered carbocyclic or -C 1-4 alkylene-3 to 6-membered cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 5-6 Aryl, 5-6 membered heteroaryl, 12 membered carbocyclic or -C 1-4 Alkylene-3 to 6-membered cycloalkyl groups are optionally further surrounded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -OC 1-6 Substitution with haloalkyl, 3-6 membered cycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl groups; R5 is selected from C 5-6 When aryl, the C 5-6 The aryl group is not substituted by a 3-membered cycloalkyl group.

3. The compound according to claim 1 or 2, or all its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, wherein, At least one of the following conditions must be met: (1) L2 is selected from NR3; (2) L3 is selected from the straight-chain C 1-4 Alkylene, the C 1-4 The alkylene group may optionally be further substituted with one or more R1s; (3) Ring A is selected from phenyl, 6-membered monocyclic heteroaryl, and 9-membered bicyclic heteroaryl; (4) R1 is independently selected from halogen or C 1-6 Halogenated alkyl groups; (5) R2 is independently selected from H, halogen, -CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; (6) R3 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -C 1-3 Alkylene-C 1-3 Alkoxy, -C 1-4 Alkylene - 3 to 6-membered cycloalkyl or -C 1-4 Alkylene-3 to 6-membered heterocyclic alkyl; the C 1-6 The alkyl group is further substituted by one or more D atoms; (7) R4 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 5-6 Aryl, 5-6 membered heteroaryl, 8 membered bicyclic heterocyclic, -C 1-4 alkylene-azacyclobutane, -C 1-3 Alkylene-C 1-3 Alkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy, C 5-6 Aryl, 5-6 membered heteroaryl, 8 membered bicyclic heterocyclic, -C 1-4 alkylene-azacyclobutane, -C 1-3 Alkylene-C 1-3 The alkoxy group may optionally be further surrounded by one or more elements selected from halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Substitution with alkoxy or 3-5 membered cycloalkyl groups; (8) R5 is selected from C 1-4 Alkyl, C 1-4 Alkoxy, 3-5 membered cycloalkyl, C 5-6 aryl, 6-membered heteroaryl, 12-membered fused carbocyclic or -C 1-4 alkylene-cyclopropyl, wherein C 1-4 Alkyl, C 1-4 Alkoxy, 3-5 membered cycloalkyl or -C 1-4 alkylene-cyclopropyl group is optionally further surrounded by one or more elements selected from halogen, C 1-4 Alkoxy, -OC 1-4 Halogenated alkyl, cyclopropyl, C 5-6 Substituents of aryl or 6-membered heteroaryl groups; the C 5-6 Aryl, 6-membered heteroaryl, and 12-membered fused carbocyclic groups are optionally further selected by one or more halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyl or -OC 1-4 Substituents of haloalkyl groups; (9) m is selected from 0, 1 or 2.

4. The compound according to any one of claims 1-3, or all its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts, or cocrystals, wherein, At least one of the following conditions must be met: (1) Ring A is selected from (2) R2 is independently selected from H, F, Cl, -CN, methyl or CF3; (3) R3 is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, cyclopropyl, cyclobutyl, cyclopentyl, -C 1-3 alkylene-methoxy, -C 1-3 alkylene-cyclopropyl, -C 1-3 alkylene-cyclobutyl, -C 1-3 alkylene-oxoheterobutyl, -C 1-3 alkylene-cyclopentyl, -C 1-3 alkylene-tetrahydrofuranyl; (4) R4 is selected from C 1-4 Alkyl, -C 1-3 alkylene-ethoxy, pyridinyl, furanyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, methylene-azacyclobutane or The pyridyl, furanyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, methylene-azacyclobutane or Optionally further substituted with one or more substituents selected from F, Cl, methyl, ethyl, difluoromethyl, trifluoroethyl, methoxy or cyclopropyl; (5) R5 is selected from C 1-3 Alkyl, C 1-3 Alkoxy, phenyl, pyridyl, pyrimidinyl, The C 1-3 Alkyl, C 1-3 Alkoxy, Optionally further substituted with one or more cyclopropyl, phenyl, pyridyl, or methoxy substituents, wherein the phenyl, pyridyl, pyrimidinyl, or... Optionally further substituted with one or more substituents selected from F, Cl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, and -O-difluoromethyl haloalkyl.

5. The compound according to any one of claims 1-3, or all its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts, or cocrystals, wherein, At least one of the following conditions must be met: (1) Group fragment Selected from at least one of the following structures: (2) L2 is selected from at least one of the following structures: -O-, (3) R3 is selected from at least one of the following structures: methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, (4) R4 is selected from at least one of the following structures: (5) R5 is selected from at least one of the following structures:

6. The compound according to claim 1, wherein it is a compound of formula (II), or any stereoisomer, tautomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal of a compound of formula (II). in, The definitions of R2, R3, R4, A, and m are as described in any one of claims 1-5; Preferably, R3 is a methyl group.

7. The compound according to claim 1, wherein it is a compound of formula (III), or any stereoisomer, tautomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal of a compound of formula (III): in, The definitions of R2, R3, R4 and m are as described in any one of claims 1-5; X1, X2, and X3 are selected from C or N respectively, and at least one of X1, X2, and X3 is N; Preferably, the Selected from More preferably Preferably, R3 is a methyl group.

8. The compound according to claim 1, wherein it is a compound of formula (IV), or any stereoisomer, tautomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal of a compound of formula (IV): in, The definitions of R2, R3 and m are as described in any one of claims 1-5; X1, X2, and X3 are selected from C or N respectively, and at least one of X1, X2, and X3 is N; X4, X5, and X6 are each selected from C or N, and at least one of X4, X5, and X6 is N; preferably, X5 is N, and at least one of X4 and X6 is N; more preferably, the... for R6 is selected from halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyl group; preferably, R6 is selected from methyl, ethyl, ... More preferably, the for Preferably, R3 is a methyl group.

9. The compound according to claim 1, wherein it is a compound of formula (V), or any stereoisomer, tautomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal of a compound of formula (V): in, The definitions of R2, R3 and m are as described in any one of claims 1-5; X1, X2, and X3 are selected from C or N respectively, and at least one of X1, X2, and X3 is N; X7, X8, and X9 are each selected from C or N, and at least one of X7, X8, and X9 is N; preferably, the... Selected from The R7 is selected from halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyl group; preferably, R7 is selected from methyl, ethyl, Cl, and methoxy groups; The Selected from Preferably, R3 is a methyl group.

10. The compound according to claim 1, wherein it is a compound of formula (VI), or any stereoisomer, tautomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal of a compound of formula (VI): in, The definitions of R2, R3 and m are as described in any one of claims 1-5; R4 is selected from at least one of the following structures: Preferably, R3 is a methyl group.

11. The compound according to claim 1, wherein it is a compound of formula (VII), or any stereoisomer, tautomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt, or cocrystal of a compound of formula (VII): in, The definitions of R3 and R4 are as described in any one of claims 1-5 and 10; R 2-1 and R 2-2 Each has the definition of R2 as described in any one of claims 1-5; preferably, the R 2-1 The components are H, methyl, Cl, CN, and CF3; the R... 2-2 For H and F; Preferably, R3 is a methyl group.

12. A compound, or its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, wherein the compound is selected from:

13. A pharmaceutical composition comprising: The compound according to any one of claims 1-12, or all of its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts or cocrystals; And optionally one or more pharmaceutically acceptable carriers and / or excipients.

14. The use of the compound of any one of claims 1-12, or all its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts or cocrystals, or the use of the pharmaceutical composition of claim 13 in the preparation of a medicament, wherein the use of the medicament includes at least one of the following: Application as an APJ agonist; Applications in the treatment and / or prevention of age-related diseases; Applications in weight loss; Applications in muscle building; Applications in the treatment and / or prevention of cardiovascular diseases; Applications in regulating pulmonary vascular resistance, right ventricular afterload, and / or mean pulmonary artery pressure; Application in the prevention and / or treatment of pulmonary hypertension.

15. Use of the pharmaceutical composition of claim 13, or the compound of any one of claims 1-12, or all of its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, said use comprising at least one of the following: Use as an APJ agonist; Use in the treatment and / or prevention of age-related diseases; Its uses in weight loss; Its uses in muscle building; Use in the treatment and / or prevention of cardiovascular diseases; Uses in regulating pulmonary vascular resistance, regulating right ventricular afterload, and / or regulating mean pulmonary artery pressure; Use in the prevention and / or treatment of pulmonary hypertension.

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