Bicyclic fto inhibitors

Abstract

Disclosed herein are compounds of formula (I) and (II) as FTO inhibitors having novel structures. Also disclosed herein are pharmaceutical compositions comprising the compounds, and methods of inhibiting weight gain, promoting weight loss, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating obesity or obesity-related diseases (especially obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipidemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular diseases) or Alzheimer's disease by using the compounds disclosed herein to inhibit FTO.

Description

Technical Field

[0001] This document discloses compounds of formulas (I) and (II) having novel structures as FTO inhibitors. It also discloses pharmaceutical compositions comprising said compounds, and methods for inhibiting FTO by using the disclosed compounds to suppress weight gain, promote weight loss, reduce serum LDL, cholesterol, LDL-c, or triglycerides, or treat obesity or obesity-related diseases (especially obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipidemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease) or Alzheimer's disease. Background Technology

[0002] Obesity is a serious health problem worldwide, and many factors contribute to this chronic disease, including environmental and genetic factors. Genome-wide association studies investigating obese patients have revealed a strong association between the FTO (fat mass and obesity) gene and obesity. The functional role of FTO in obesity has been confirmed in transgenic animal models such as FTO knockout mice, FTO overexpression mice, and FTO-I367F mutant mice. More specifically, global-knockout and neuron-specific knockout of FTO induce weight loss, while FTO gene overexpression leads to obesity. A missense mutation was observed to inhibit FTO enzyme function and protect mice from obesity. However, FTO is expressed in many tissues, particularly in the hypothalamic nucleus, which controls energy expenditure, consistent with FTO's indication of affecting energy homeostasis. The FTO protein is an α-ketoglutarate and iron(II)-dependent nucleic acid demethylase. Its preferred substrate is N6-meA in messenger RNA, located near the stop codon and influencing gene translation.

[0003] WO 2016206573 A1 discloses entacapone analogues that exhibit FTO inhibition. However, FTO inhibitors inhibiting COMT are undesirable because COMT inhibition can affect the metabolism of important neurotransmitters in the body, including dopamine, adrenaline, and noradrenaline, which further leads to effects unrelated to FTO inhibition and potential side effects. Additionally, COMT inhibition may also affect the metabolism of drugs or small molecules containing catechol groups, leading to undesirable drug-drug interactions.

[0004] There is a need for novel FTO inhibitors with improved properties. Summary of the Invention

[0005] This document discloses compounds comprising a bicyclic moiety for use as FTO inhibitors, pharmaceutical compositions comprising said compounds, and methods of using said compounds. Specifically, the compounds disclosed herein are obtained by combining the bicyclic moiety, the hydroxyl group in formula (I), and R. 1 The group is structurally modified to exhibit comparable or improved FTO inhibition, as well as improved FTO inhibition selectivity relative to COMT inhibition, or even no COMT inhibition.

[0006] On the one hand, this paper provides a compound of formula (I).

[0007] (I)

[0008] Or its pharmaceutically acceptable salt, its stereoisomer, its tautomer, or its deuterated analogue.

[0009] in

[0010] X 1 X 2 and X 3 Each can be independently -O-, -S-, -NH-, -N=, -CH=, or -CH2-, provided that no two -O- and / or -S- are adjacent.

[0011] X 4 X 5 X 6 Each is independently either -CH= or -N=.

[0012] X 7 and X 8 Each is nitrogen and carbon independently;

[0013] m and n are each numbers from 0 to 3, provided that the valence theory is satisfied;

[0014] R 2 and R 3 Each of these groups independently represents a halogen, deuterium, cyano, oxo, nitro, hydroxyl, or C group. 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated, and halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Alkyl-S-, C 2-6 alkenyl, C 2-6 Alkynyl, -SO2R 2a -COOR2a or -NR 2a R 2b ,

[0015] Where R 2a and R 2b Each is independently hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated, and halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 alkyl;

[0016] R 1 It is -C(O)NR a1 R a2 -C(O)R a3 or R a4 ,

[0017] in

[0018] R a1 It is hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 1-6 Alkoxy;

[0019] R a2 yes

[0020] a)C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 cycloalkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 Each of the cycloalkyl groups is unsubstituted or is composed of one or more elements selected from deuterium, -OR b1 Halogen, C 1-6 Alkyl-S-, cyano, -NR b2 R b3 -C(O)NR b2 R b3 -OC(O)NR b2 R b3 -C(O)R b2 -NR b2 C(O)R b3 Substituents of phenyl, naphthyl, heteroaryl, or heterocyclic groups, wherein each of the phenyl or naphthyl groups is unsubstituted or substituted by one or more substituents R. c3 replace;

[0021] b)C 3-8 Cycloalkyl, phenyl, heteroaryl or heterocyclic, C 3-8 Each of the cycloalkyl, phenyl, heteroaryl, or heterocyclic groups is either unsubstituted or substituents R. c3 replace;

[0022] in

[0023] R b1 yes

[0024] 1) Hydrogen;

[0025] 2)C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-6 alkyl-;

[0026] 3) Phenyl, wherein the phenyl group is unsubstituted or modified by halogen, oxo group, C 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, Halogenated C 1-6 Alkyl, heterocyclic, -C 1-6 Alkyl C(O)NR c1 R c2 -C(O)NR c1 R c2 -NR c1 R c2 -NR c1 C(O)R c2 Or heteroaryl substitution; or

[0027] 4) Heteroaryl or heterocyclic groups, each of which is unsubstituted or C-substituted. 1-6 Alkyl, oxo, or heteroaryl substitutions;

[0028] R c1 and R c2 Each is independently hydrogen, C 1-6 Alkyl, phenyl, wherein the phenyl group is unsubstituted or is substituted with one or more groups selected from hydroxyl, halogen, oxo, C 1-6 Alkyl or C 1-6 Substitution of alkoxy groups;

[0029] R b2 and R b3 Each is independently hydrogen, C 1-6 Alkyl, phenyl, wherein the phenyl group is unsubstituted or is substituted with one or more groups selected from hydroxyl, halogen, oxo, C 1-6 Alkyl or C 1-6 Substitution of alkoxy groups;

[0030] Rc3 yes

[0031] -halogen;

[0032] -hydroxyl group;

[0033] -Cyano;

[0034] -Oxide group;

[0035] -C 1-6 Alkyl, the C 1-6 Alkyl groups are unsubstituted or converted by one or more halogens, hydroxyl groups, C... 1-6 Alkoxy, phenyl, or alkyl-substituted heteroaryl (pyrazolyl) substituted;

[0036] -C 2-6 alkenyl or C 2-6 alkynyl group;

[0037] -C 1-6 Alkyl-S-

[0038] -C 1-6 alkoxy or phenoxy, wherein the C 1-6 Each of the alkoxy or phenoxy groups is unsubstituted or converted by one or more halogens, C 1-6 Alkoxy, alkyl-substituted heteroaryl, or alkyl-substituted heterocyclic group;

[0039] --C 1-6 Alkyl C(O)NR e1 R e2 ;

[0040] --C(O)NR e1 R e2 ;

[0041] --NR e1 R e2 ;

[0042] --NR e1 C(O)R e2 ;

[0043] --NR e1 -C(O)-NR e2 R e3 ;

[0044] --NR e1 R e2 ;

[0045] - Heterocyclic group, said heterocyclic group is unsubstituted or halogenated, C 1-6 Alkyl or heterocyclic groups, via C 1-6 Alkyl-substituted heterocyclic substitution,

[0046] - Heteroaryl, wherein the heteroaryl group is unsubstituted or C-substituted. 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl- or heteroaryl substitution;

[0047] -C 3-8 cycloalkyl;

[0048] -phenyl; and

[0049] R e1 R e2 and R e3 Each is independently hydrogen, C 1-6 Alkyl, phenyl, C 1-6 Alkyl-substituted phenyl, heteroaryl (e.g., thiazolyl, pyrazolyl), or C-substituted phenyl groups 1-6 Alkyl-substituted heteroaryl (1-methyl-1H-1,2,3-triazol-4-yl).

[0050] Alternatively, R a1 and R a2 Together with the nitrogen atoms to which they are attached, they form 4- to 9-membered rings containing one or two additional heteroatoms selected from nitrogen, oxygen, or sulfur, and said rings are either unsubstituted or modified by one or more substituents R. b4 Substitution, or two substituents R on two adjacent atoms b4 Formation of 4- to 6-membered fused rings and / or two substituents R on the same carbon atom b4 Forming 3 to 6-membered spirorings, wherein the fused ring or spiroring is unsubstituted or composed of one or more elements selected from halogens or C. 1-6 Alkyl substituents,

[0051] R b4 It is a hydroxyl group; halogen; oxo group; cyano group; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkoxy C 1-6 Alkyl; Halogenated C 1-6 Alkoxy; NR c4 R c5 , where R c4 and R c5 Each is independently hydrogen, alkyl, or phenyl; phenyl, heterocyclic, or heteroaryl, wherein each of the phenyl, heterocyclic, or heteroaryl groups is unsubstituted or substituted with one or more halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -NRe4 R e5 or -COOR e4 Replace, where R e4 and R e5 It is hydrogen, C 1-6 Alkyl, phenyl, C 1-6 Alkyl-substituted phenyl, heteroaryl, or C-substituted phenyl 1-6 Alkyl-substituted heteroaryl groups;

[0052] R a3 It is C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-S-, C3-8 cycloalkyl, phenyl, heteroaryl, or heterocyclic, wherein each of the C3-8 cycloalkyl, phenyl, heteroaryl, or heterocyclic groups is unsubstituted or is selected from one or more halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Substitution of alkoxy groups;

[0053] R a4 It is a heteroaryl or heterocyclic group, each of which is unsubstituted or is composed of one or more compounds selected from halogens, C, and D. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, phenoxy, -NR c6 R c7 -C(O)NR c6 R c7 -OC(O)NR c6 R c7 -C(O)R c6 or -NR c6 C(O)R c7 Substituents of the substituents

[0054] R c6 and R c7 Each is independently hydrogen, C 1-6 Alkyl, phenyl, wherein the phenyl group is unsubstituted or is substituted with one or more groups selected from hydroxyl, halogen, oxo, C 1-6 Alkyl or C 1-6 Substitution of alkoxy groups,

[0055] The condition is a double-ring part. It belongs to the aromatic family.

[0056] Double ring section

[0057] In some implementation schemes, X 4 X 5 and X 6 Each is -CH=; and X 7 and X 8 It's carbon.

[0058] In some implementation schemes, X 1 It is O, S, or -NH-, X 2 It is -N= and X 3 It is -CH=. In some implementations, X 1 It is -N=, X 2 It is -CH= and X 3 It is O, S, or -NH-. In some implementations, X 1 Is it O or S, X 2 It is -N= and X 3 It is -CH=. In some implementations, X 1 It is -N=, X 2 It is -CH= and X 3 It is O or S. In some implementations, X 1 It is -N=, X 2 It is -N= and X 3 It is -NH-; or X 1 It is -N=, X 2 It is -NH- and X 3 Is -N=; or X 1 It is -NH-, X 2 It is -N= and X 3 It is -N=.

[0059] In some implementations, n is 0. In some implementations, n is 0 and m is 1 to 3, for example, 1, 2, or 3.

[0060] In some embodiments, the bicyclic moiety is benzofuranyl, benzo[b]thiophenyl, benzo[d]isoxazolyl, benzo[d]isothiazolyl, benzo[c]isoxazolyl, benzo[c]isothiazolyl, benzo[d]oxazolyl, 1H-benzo[d]imidazolyl, benzo[d]thiazolyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, [1,2,3]triazolo[1,5-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, [1,2,4]triazolo[1,5-a]pyridyl, benzo[d][1,2,3]oxadiazolyl, benzo[c][1,2,5]oxadiazolyl, benzo[d][1 [2,3]thiadiazolyl, 1H-benzo[d][1,2,3]triazolyl, 2H-benzo[d][1,2,3]triazolyl, tetrazo[1,5-a]pyridyl, isoindololinyl, 1H-[1,2,3]triazol[4,5-c]pyridyl, 3H-[1,2,3]triazol[4,5-b]pyridyl, 1H-[1,2,3]triazol[4,5-b]pyridyl, 1H-[1,2,3]triazol[4,5-b]pyrazinyl or 3H-[1,2,3]triazol[4,5-d]pyrimidinyl, each of which is unsubstituted or substituted by one or more substituents selected from: halogen, deuterium, oxo, nitro, hydroxyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 1-6 Alkyl SO2-, NR 2a R 2b C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, cyano, COOR 2a Or cycloalkyl.

[0061] In some embodiments, the bicyclic moiety is benzofuran-5-yl, benzo[b]thiophene-5-yl, benzo[d]isoxazole-5-yl, benzo[d]isoxazole-6-yl, benzo[d]isothiazol-5-yl, benzo[c]isoxazole-5-yl, benzo[c]isothiazol-5-yl, benzo[d]oxazole-5-yl, benzo[d]oxazole-6-yl, 1H-benzo[d]imidazol-6-yl, benzo[d]thiazol-6-yl, pyrazolo[ [1,5-a]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl, [1,2,3]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-7-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, benzo[d][1,2,3]oxadiazol-5-yl, benzo[c][1,2,5] Oxadiazole-5-yl, benzo[d][1,2,3]oxadiazole-6-yl, benzo[d][1,2,3]thiadiazole-6-yl, 1H-benzo[d][1,2,3]triazole-6-yl, 1H-benzo[d][1,2,3]triazole-5-yl, 2H-benzo[d][1,2,3]triazole-5-yl, tetrazo[1,5-a]pyridin-7-yl, tetrazo[1,5-a]pyridin-6-yl, isoindoline-5-yl, 1 H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, 3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl, or 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl, each of which is unsubstituted or substituted as defined above. In some embodiments, the substituent is an oxo group, fluorine, chlorine, bromine, nitro, methoxy, hydroxyl, difluoromethoxy, trifluoromethoxy, methylthio, methanesulfonyl, amino, methylamino, methyl, trifluoromethyl-d3, hydroxymethyl, cyano, methoxycarbonyl, carboxyl, or cyclopropyl.

[0062] In some embodiments, the bicyclic moiety is benzofuran-5-yl, benzo[b]thiophene-5-yl, benzo[d]isoxazole-5-yl, benzo[d]isoxazole-6-yl, benzo[d]isothiazol-5-yl, benzo[c]isoxazole-5-yl, benzo[c]isothiazol-5-yl, benzo[d]oxazole-5-yl, benzo[d]oxazole-6-yl, 1H-benzo[d]imidazol-6-yl, benzo[d]thiazol-6-yl, pyrazolo[1,5-a]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl, [1,2,3]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, [1,2,4]triazolo[1, [5-a]pyridin-7-yl, [1,2,4]triazol[1,5-a]pyridin-6-yl, benzo[d][1,2,3]oxadiazol-5-yl, benzo[c][1,2,5]oxadiazol-5-yl, benzo[d][1,2,3]oxadiazol-6-yl, benzo[d][1,2,3]thiadiazol-6-yl, 1H-benzo[d][1,2,3]triazol-6-yl, 1H-benzo[d][1,2,3]triazol-5-yl, 2H-benzo[d][1,2,3]triazol-5-yl, tetraazol[1,5-a]pyridin-7-yl, tetraazol[1,5-a]pyridin-6-yl, 2-oxo-2,3-dihydrobenzo[d]oxadiazol-5-yl, 2-oxo-2,3-dihydro Benz[d]oxazol-6-yl, 1,3-dioxoisoindoline-5-yl, 4-chloro-1H-benzo[d][1,2,3]triazol-6-yl, 4-nitro-1H-benzo[d][1,2,3]triazol-6-yl, 4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-bromo-1H-benzo[d][1,2,3]triazol-6-yl, 4-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-amino-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methylamino)-1H-benzo[d][1,2,3]triazol-6-yl, 4-( Trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-ethyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyano-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methylsulfonyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methoxycarbonyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-carboxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyclopropyl-1H-benzo[d][1,2,3]3] Triazol-6-yl, 7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 7-chloro-1H-benzo[d][1,2,3]triazol-6-yl, 7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 7-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 7-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 7-cyano-1H-benzo[d][1,2,3]triazol-6-yl, 7-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5-fluoro-1H-benzo[d][1,2,3] Triazol-6-yl, 5-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 5-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 5-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 5-cyano-1H-benzo[d][1,2,3]triazol-6-yl, 5-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4,7-dichloro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-methoxy 4-chloro-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyano-7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyano-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-chloro-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-methyl-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl 3] Triazol-6-yl, 7-methoxy-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-hydroxy-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 5-fluoro-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5-hydroxy-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5,7-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5,7-Difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-1H-[1,2,3]triazol[4,5-c]pyridin-6-yl, 7-chloro-3H-[1,2,3]triazol[4,5-b]pyridin-5-yl, 4-(trifluoromethyl)-1H-[1,2,3]triazol[4,5-b]pyridin-5-yl, 4-(trifluoromethyl)-1H-[1,2,3]triazol[d][1,2,3]triazol[d][1,2,3]triazol[d][1,2,3]triazol[d][1,2,3]pyridin-5-yl, 4-(trifluoromethyl)-1H-[ ...triazol[d][1,2,3]triazol[d][1,2,3]triazol[d][1,2,3]triazol[d][1,2,3]triazol[d][1,2,3]triazol[d][1,2,3 [3] Triazolo[4,5-c]pyridin-6-yl, 7-(trifluoromethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 7-cyano-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 4-cyano-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, 1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 4-(difluoromethoxy)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(trifluoromethoxy)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(hydroxymethyl) )-1H-benzo[d][1,2,3]triazol-6-yl, 5-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4,7-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-4-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-yl, 4-ethyl-7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4,5-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4,5-difluoro-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 5,7-difluoro-4- Methyl-1H-benzo[d][1,2,3]triazol-6-yl, 5,7-difluoro-4-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-yl, 1H-[1,2,3]triazol[4,5-c]pyridin-6-yl, 3H-[1,2,3]triazol[4,5-b]pyridin-5-yl, 1H-[1,2,3]triazol[4,5-b]pyrazin-6-yl, 3H-[1,2,3]triazol[4,5-d]pyrimidin-5-yl, 7-nitro-3H-[1,2,3]triazol[4,5-b]pyridin-5-yl, 7-methyl-3H-[1,2,3]triazol[4,5-b]pyridin-5-yl, 7-methoxy-3H-[1,2,3]triazol[4,5-b]pyridin-5-yl,3] Triazolo[4,5-b]pyridin-5-yl, 7-hydroxy-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 6-fluoro-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 4-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, 4-methoxy-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, 4-hydroxy-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, 7-fluoro-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, 5-methoxy-1H-[1,2,3]triazolo[ [4,5-b]pyridin-6-yl, 5-hydroxy-1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 7-methyl-1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 4-chloro-1H-benzo[d][1,2,3]triazol-6-yl, 7-chlorobenzo[d]isoxazole-5-yl, 7-methylbenzo[d]isoxazole-5-yl, 7-hydroxybenzo[d]isoxazole-5-yl, 7-methoxybenzo[d]isoxazole-5-yl, 1-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 3-methylbenzo[d]isoxazole-5-yl, or 6-fluorobenzo[d]isoxazole-5-yl.

[0063] In some embodiments, the bicyclic moiety is benzo[d]isoxazolyl, benzo[c][1,2,5]oxadiazolyl, 1H-benzo[d][1,2,3]triazolyl, or 2H-benzo[d][1,2,3]triazolyl, each of which is unsubstituted or substituted as defined above.

[0064] In some embodiments, the bicyclic moiety is benzo[d]isoxazole-5-yl, benzo[d]isoxazole-6-yl, benzo[c][1,2,5]oxadiazole-5-yl, benzo[d][1,2,3]oxadiazole-6-yl, 1H-benzo[d][1,2,3]triazole-6-yl, 1H-benzo[d][1,2,3]triazole-5-yl, or 2H-benzo[d][1,2,3]triazole-5-yl, each of which is unsubstituted or substituted as defined above.

[0065] In some embodiments, the bicyclic moiety is benzo[d]isoxazole-5-yl, benzo[d]isoxazole-6-yl, benzo[c][1,2,5]oxadiazole-5-yl, benzo[d][1,2,3]oxadiazole-6-yl, 1H-benzo[d][1,2,3]triazole-6-yl, 1H-benzo[d][1,2,3]triazole-5-yl, 2H-benzo[d][1,2,3]triazole-5-yl, 4-chloro-1H-benzo[d][1,2,3]triazole-6-yl, 4-nitro-1H-benzo[d][1,2,3]triazole-6-yl, 4-fluoro-1H-benzo[d][1,2,3]triazole-6-yl, 4-bromo-1H-benzo[d][1,2,3] ... 3] Triazol-6-yl, 4-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-amino-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methylamino)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-ethyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyano-1H- Benz[d][1,2,3]triazol-6-yl, 4-(methanesulfonyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methoxycarbonyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-carboxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyclopropyl-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 7-chloro-1H-benzo[d][1,2,3]triazol-6-yl, 7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 7-methoxy-1H-benzo[d][1,2,3]triazol-6-yl 7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 7-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 7-cyano-1H-benzo[d][1,2,3]triazol-6-yl, 7-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 5-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 5-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 5-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 5-cyano-1H-benzo[d][1,2,3]triazol-6-yl3] Triazol-6-yl, 5-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4,7-dichloro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyano-7-fluoro-1H-benzo[d][ [1,2,3]triazol-6-yl, 4-cyano-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-chloro-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-methyl-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-methoxy-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-hydroxy-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro ...chloro-5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-1H-benzo[d][1,2, 3] Triazol-6-yl, 4-chloro-5-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 5-fluoro-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5-hydroxy-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5,7-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5,7-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 4 -chloro-5-fluoro-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(difluoromethoxy)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(trifluoromethoxy)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(hydroxymethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4,7-difluoro-1H-benzo[d][1,2,3]triazol-6-yl3] Triazol-6-yl, 7-fluoro-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-4-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-yl, 4-ethyl-7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4,5-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4,5-difluoro-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 5,7-difluoro-4 5-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 5,7-difluoro-4-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-yl, 2-(4-chloro-1H-benzo[d][1,2,3]triazol-6-yl, 7-chlorobenzo[d]isoxazole-5-yl, 7-methylbenzo[d]isoxazole-5-yl, 7-hydroxybenzo[d]isoxazole-5-yl, 7-methoxybenzo[d]isoxazole-5-yl, or 6-fluorobenzo[d]isoxazole-5-yl.

[0066] R 1 As -C(O)NR a1 R a2

[0067] In some implementation schemes, R 1 It is -C(O)NR a1 R a2 ,

[0068] in

[0069] R a1 It is C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 1-6 Alkoxy;

[0070] R a2 yes

[0071] a)C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 cycloalkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 Each of the cycloalkyl groups is unsubstituted or is composed of one or more elements selected from deuterium, -OR b1 Halogen, C 1-6 Alkyl-S-, cyano, -NR b2 R b3 -C(O)NR b2 R b3 -OC(O)NR b2 R b3-C(O)R b2 -NR b2 C(O)R b3 Substituents of phenyl, naphthyl, heteroaryl, or heterocyclic groups, wherein each of the phenyl or naphthyl groups is unsubstituted or substituted by one or more substituents R. c3 replace;

[0072] b)C 3-8 Cycloalkyl, phenyl, heteroaryl, or heterocyclic, wherein the C 3-8 Each of the cycloalkyl, phenyl, heteroaryl, or heterocyclic groups is either unsubstituted or substituents R. c3 replace;

[0073] in

[0074] R b1 yes

[0075] 1) Hydrogen;

[0076] 2)C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-6 alkyl-;

[0077] 3) Phenyl, wherein the phenyl group is unsubstituted or modified by halogen, oxo group, C 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, Halogenated C 1-6 Alkyl, heterocyclic (e.g., azirrocyclobutane), -C 1-6 Alkyl C(O)NR c1 R c2 -C(O)NR c1 R c2 -NR c1 R c2 -NR c1 C(O)R c2 Or heteroaryl (e.g., pyridyl, pyrazolyl, pyrazinyl); or

[0078] 4) A heteroaryl group (e.g., pyrimidinyl, pyridinyl, 1H-benzo[d]imidazolyl, 1H-indazolyl) or a heterocyclic group (e.g., azacyclic butyl, pyrrolidinyl), wherein the heteroaryl or heterocyclic group is unsubstituted or C-substituted. 1-6 Alkyl, oxo, or pyridyl substitutions;

[0079] R c1 and R c2 Each is independently hydrogen, C 1-6 Alkyl, phenyl, wherein the phenyl group is unsubstituted or is substituted with one or more groups selected from hydroxyl, halogen, oxo, C 1-6Alkyl or C 1-6 Substitution of alkoxy groups;

[0080] R b2 and R b3 Each is independently hydrogen, C 1-6 Alkyl, phenyl, wherein the phenyl group is unsubstituted or is substituted with one or more groups selected from hydroxyl, halogen, oxo, C 1-6 Alkyl or C 1-6 Substitution of alkoxy groups;

[0081] R c3 yes

[0082] -halogen;

[0083] -hydroxyl group;

[0084] -Cyano;

[0085] -Oxide group;

[0086] -C 1-6 Alkyl, the C 1-6 Alkyl groups are unsubstituted or converted by one or more halogens, hydroxyl groups, C... 1-6 Alkoxy, phenyl, or alkyl-substituted heteroaryl (pyrazolyl) substituted;

[0087] -C 2-6 alkenyl or C 2-6 alkynyl group;

[0088] -C 1-6 Alkyl-S-

[0089] -C 1-6 alkoxy or phenoxy, wherein the C 1-6 Each of the alkoxy or phenoxy groups is unsubstituted or converted by one or more halogens, C 1-6 Alkoxy, alkyl-substituted heteroaryl (pyrazolyl) or alkyl-substituted heterocyclic (piperidinyl) substitution;

[0090] --C 1-6 Alkyl C(O)NR e1 R e2 ;

[0091] --C(O)NR e1 R e2 ;

[0092] --NR e1 R e2 ;

[0093] --NR e1 C(O)R e2 ;

[0094] --NR e1 -C(O)-NR e2 R e3 ;

[0095] --NR e1 R e2 ;

[0096] - Heterocyclic groups (e.g., azirmonobutan-1-yl, piperidin-4-yl, morpholino, piperazino, morpholino), said heterocyclic groups being unsubstituted or halogenated, C 1-6 Alkyl or heterocyclic groups, via C 1-6 Alkyl-substituted heterocyclic substitution,

[0097] - Heteroaryl (e.g., pyrazinyl, pyridyl, pyrimidinyl), said heteroaryl is unsubstituted or C-substituted. 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl- or heteroaryl (e.g., pyridyl) substitution

[0098] -C 3-8 cycloalkyl;

[0099] -phenyl,

[0100] R e1 R e2 and R e3 Each is independently hydrogen, C 1-6 Alkyl, phenyl, C 1-6 Alkyl-substituted phenyl, heteroaryl (e.g., thiazolyl, pyrazolyl), or C-substituted phenyl groups 1-6 Alkyl-substituted heteroaryl (1-methyl-1H-1,2,3-triazol-4-yl).

[0101] In some implementation schemes, R a1 It is C 1-6 Alkyl or deuterated C 1-6 Alkyl group. In some embodiments, R a1 It is C 1-6 Alkyl group. In some embodiments, R... a1 It is hydrogen, methyl, ethyl, CH3-d3, CF3, CHF2, or methoxy. In some embodiments, R a1 It is methyl or ethyl.

[0102] In some implementation schemes, R a2 It is C 1-6 Alkyl group. In some embodiments, R a2 It is methyl, ethyl, isopropyl, propyl, isobutyl, or butyl. In some embodiments, R a2It is CH3-d3, methoxyethyl, CF3CH2, methylthioethyl, cyanomethyl, trifluoromethyl.

[0103] In some implementation schemes, R a2 It is C 1-6 Alkyl (e.g., methyl, ethyl, or propyl), the C 1-6 Alkyl-OR b1 Replace, where R b1 It is hydrogen, methoxy, or phenyl, wherein the phenyl group is unsubstituted or substituted with one, two, or three substituents selected from fluorine, bromine, chlorine, methyl, hydroxymethyl, trifluoromethyl, azirmonobutan-1-yl, 2-amino-2-oxoethyl, acetamyl, pyridin-2-yl, 1H-pyrazol-1-yl, pyrazin-2-yl, N,N-dimethylamino, 2-(dimethylamino)-2-oxoethyl, 2-hydroxypropyl, or methylamino; pyrimidinyl, pyridinyl, 1H-benzo[d]imidazolyl, or 1H-indazolyl, each of which is unsubstituted or substituted with one, two, or three substituents selected from methyl, oxo, or pyridinyl.

[0104] In some implementation schemes, R a2 It is 2-(o-tolyloxy)ethyl, 2-(2-(hydroxymethyl)phenoxy)ethyl, 2-(2-(trifluoromethyl)phenoxy)ethyl, 2-(2-(hydroxymethyl)-3-methylphenoxy)ethyl, 2-phenoxyethyl, 2-(3-(azacyclobutan-1-yl)phenoxy)ethyl, 2-(4-(azacyclobutan-1-yl)phenoxy)ethyl, 2-(2-(2-amino-2-oxoethyl)phenoxy)ethyl, 2-(3-acetamidophenoxy)ethyl, 2-(4-(pyridin-2-yl)phenoxy)ethyl, 2-(4-methyl-3-(1H-pyrazol-1-yl)phenoxy)ethyl, 2-(3-(pyrazin-2-yl)phenoxy)ethyl, N,N-dimethylaminophenoxyethyl, 2-(3-( 2-(dimethylamino)-2-oxoethyl)phenoxy)ethyl, 2-(3-(2-hydroxypropyl)phenoxy)ethyl, 2-(4-methyl-3-methylaminophenoxy)ethyl, 2-(2-chlorophenoxy)ethyl, 2-fluoro-5-methylphenoxy, 2-(pyrimidin-2-yloxy)ethyl, 2-(pyridin-2-yloxy)ethyl, 2-(pyridin-3-yloxy)ethyl, 2-((2-oxo-2H-[1,2'-bipyridine]-4'-yl)oxy)ethyl, 2-((1-methyl-1H-benzimidazol-4-yl)oxy)ethyl, 2-((1-methyl-1H-indazol-4-yl)oxy)ethyl or 2-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)ethyl.

[0105] In some implementation schemes, R a2 It is C1-6 Alkyl (e.g., methyl, ethyl, or propyl), the C 1-6 Alkyl-NR b2 R b3 Replace, where R b2 Is it hydrogen or C? 1-6 Alkyl (e.g., methyl, ethyl, etc.) and R b3 It is C 1-6 Alkyl, phenyl, wherein the phenyl group is unsubstituted or substituted with one, two or three substituents selected from methyl, ethyl, oxo, or halogen. In some embodiments, R a2 It is 2-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)ethyl, N-methyl-N-(2-fluoro-5-methylphenyl)amino, N-(2-fluoro-5-methylphenyl)amino or dimethylamino.

[0106] In some implementation schemes, R a2 It is C 1-6 Alkyl (e.g., methyl, ethyl, or propyl), the C 1-6 The alkyl group is either unsubstituted or substituted with one or more halogens or hydroxyl groups and further substituted with a phenyl group, wherein the phenyl group is unsubstituted or substituted with one or more substituents R. c3 Replacement. In some implementations, R c3 It is a halogen; hydroxyl group; cyano group; oxo group; C 1-6 Alkyl, the C 1-6 Alkyl groups are unsubstituted or converted by one or more halogens, hydroxyl groups, C... 1-6 Alkoxy, phenyl, or alkyl-substituted heteroaryl groups (e.g., pyrazolyl); C 1-6 Alkyloxy; phenoxy, C 2-6 alkenyl; C 2-6 Alkyne group; hydroxyl group; C 1-6 Alkoxy, the C 1-6 Alkyl groups are unsubstituted or substituted with one or more halogens, C 1-6 Alkoxy, alkyl-substituted heteroaryl (pyrazolyl), or alkyl-substituted heterocyclic (piperidinyl) substitution; -C 1-6 Alkyl C(O)NR e2 R e3 ;-C(O)NR e1 R e2 ;-NR e1 R e2 ;-NR e1 C(O)R e2 ;-NR e1 -C(O)-NR e2 R e3 ;-NR e1 R e2 ;Re1 R e2 R e3 Each is independently hydrogen, C 1-6 Alkyl, heteroaryl (e.g., thiazolyl, pyrazolyl) or C-terminated 1-6 Alkyl-substituted heteroaryl groups (1-methyl-1H-1,2,3-triazol-4-yl); heterocyclic groups (e.g., aziridine-1-yl, piperidin-4-yl, morpholino, piperazine-yl, morpholino), said heterocyclic groups being unsubstituted or halogenated, C 1-6 Alkyl or heterocyclic or C 1-6 Alkyl-substituted heterocyclic groups; heteroaryl groups (pyrazinyl, pyridyl, pyrimidinyl), wherein the heteroaryl group is unsubstituted or C-substituted. 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl- or heteroaryl (e.g., pyridyl) substitution; C 3-8 cycloalkyl; phenyl; or C 1-6 Alkyl-S-. In some embodiments, R c3 Selected from chlorine, fluorine, bromine, methyl, ethyl, ethynyl, vinyltrifluoromethyl, methoxymethyl, (1-methyl-1H-pyrazol-4-yl)methyl, hydroxy, methoxy, (1-methylpiperidin-4-yl)methoxy, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, cyano, oxo, hydroxymethyl, 3-methylurea, thiazol-2-ylamino, (1-methyl-1H-pyrazol-4-yl)amino, aziridine-1-yl, 1- Methylpiperidin-4-yl, piperidin-4-yl, 4-methylpiperazin-1-yl, morpholino, pyrazin-2-yl, 3-(hydroxymethyl)pyridin-2-yl, pyridin-3-yl, phenyl, pyrimidin-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, 4'-methyl-[1,1'-bipiperazin]-4-yl, amino, acetamido, dimethylamino, methylthio, cyclopropyl, 2-amino-2-oxoethyl, or 2-(methylamino)-2-oxoethyl. a2It is 5-chloro-2-fluorobenzyl, 2-fluoro-5-methylbenzyl, 2-hydroxybenzyl, 2-fluoro-3-methylbenzyl, 2-fluoro-4-methylbenzyl, 2-hydroxy-3-methylbenzyl, 5-cyano-2-fluorobenzyl, 2-fluoro-5-(trifluoromethyl)benzyl, 2-chlorobenzyl, 2,6-difluorobenzyl, 3-chloro-2-fluorobenzyl, 2,5-difluorobenzyl, 2-fluoro-4-methoxybenzyl, 1-(5-chloro-2-fluorophenyl)ethyl, 2-fluoro-5-methoxybenzyl, 2,4,5-trifluorobenzyl, 2,4-difluorobenzyl, 2,4-difluoro-5-methylbenzyl, 2-fluoro-5-(methoxy) 2-(5-chloro-2-fluorophenyl)benzyl, 2-fluoro-3,5-dimethylbenzyl, benzyl, 4-chloro-2-fluorobenzyl, 2-(5-chloro-2-fluorophenyl)prop-2-yl, (5-chloro-2-fluorophenyl)fluoromethyl, (5-chloro-2-fluorophenyl)difluoromethyl, 1-(3-chlorophenyl)-2-hydroxyethyl, 1-(5-chloro-2-fluorophenyl)cyclopropyl, 2-fluorobenzyl, 2-fluoro-3-hydroxybenzyl, 2-fluoro-3-(hydroxymethyl)benzyl, 2-fluoro-3-(3-methylureido)benzyl, 2-fluoro-3-(thiazol-2-ylamino)benzyl, 2-fluoro-3-((1-methyl-1H-pyrazole-4-) 4-ethyl-2-fluorobenzyl, 4-(azacyclobutane-1-yl)-2-fluorobenzyl, 5-chloro-2-fluoro-4-(pyrazin-2-yl)benzyl, 2-fluoro-4-(3-(hydroxymethyl)pyridin-2-yl)benzyl, 2-fluoro-4-(1-methylpiperidin-4-yl)benzyl, 2-fluoro-4-(piperidin-4-yl)benzyl, 2-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)benzyl, 2-fluoro-4-(4-methylpiperidin-1-yl)benzyl, 2-fluoro-4-(4'-methyl-[1,1'-bipiperidin]-4-yl)benzyl, 5-chloro- 2-Fluoro-4-((1-methylpiperidin-4-yl)methoxy)benzyl, 2-Fluoro-4-((1-methylpiperidin-4-yl)methoxy)benzyl, 2-cyano-N-(4-cyano-2-fluorobenzyl), 3-chloro-2,6-difluorobenzyl, 5-chloro-2,4-difluorobenzyl, 3-amino-5-chloro-2-fluorobenzyl, 3-acetamido-5-chloro-2-fluorobenzyl, 5-chloro-2-hydroxybenzyl, 5-cyano-2-hydroxybenzyl, 2-cyano-5-methylbenzyl, 2-fluoro-5-(trifluoromethoxy)benzyl, 5-(difluoromethoxy)-2-fluorobenzyl, 2-fluoro-5-(2,2,2-Trifluoroethoxy)benzyl, 5-(dimethylamino)-2-fluorobenzyl, 2-fluoro-5-(methylthio)benzyl, 5-ethynyl-2-fluorobenzyl, 2-fluoro-5-vinylbenzyl, 2-fluoro-5-((trifluoromethoxy)methyl)benzyl, 2-fluoro-5-(hydroxymethyl)benzyl, 5-(azacyclobutane-1-yl)-2-fluorobenzyl, 5-cyclopropyl-2-fluorobenzyl, 2-fluoro-5-morpholinobenzyl, 2-amino-2-oxoethyl)-2-fluorobenzyl, 2-fluoro-5-(2-(methylamino)-2-oxoethyl)benzyl, 2-fluoro-5-((1-methyl-1H-pyridine) (Azol-4-yl)methyl)benzyl, 2-fluoro-4-(2-(methylamino)-2-oxoethyl)benzyl, 2-cyanobenzyl, (3-fluoronaphthyl-2-yl)methyl, 2-fluoro-4-(pyridin-3-yl)benzyl, (3-fluoro-[1,1'-biphenyl]-4-yl)methyl, (4-fluoro-[1,1'-biphenyl]-3-yl)methyl, 2-fluoro-5-(pyrimidin-4-yl)benzyl, 3-phenylpropyl, 3-(2-cyanophenyl)propyl, 3-(2-chlorophenyl)propyl, 3-(2-methoxyphenyl)propyl, 3-(2-fluorophenyl)propyl, or 3-oxo-3-phenylpropyl.

[0107] In some implementation schemes, R a2 It is C 1-6 Alkyl (e.g., methyl, ethyl, or propyl), the C 1-6 The alkyl group is either unsubstituted or substituted with one or more halogens or hydroxyl groups and further substituted with a heteroaryl or heterocyclic group, wherein the heteroaryl or heterocyclic group is unsubstituted or substituted with one or more substituents R. c3Substitution. In some embodiments, the heteroaryl or heterocyclic group is selected from triazolyl, isoquinolinyl, pyridyl, pyrazinyl, imidazolyl, pyrazolyl, dihydrobenzofuranyl, 2,3-dihydrobenzofuranyl, dihydrobenzofuranyl, 2,3-dihydrobenzofuranyl, benzo[b][1,4]dioxinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[b][1,4]oxazinyl, 2,3-dihydrobenzo[b][1,4]oxazinyl, benzo[b][1,4]thiazinyl or 3,4-dihydro-2H-benzo[b][1,4]thiazinyl, 1,2,3,4-tetrahydroquinoxalinyl or 1,2,3,4-tetrahydroquinoxalinyl, isochoryl or indazoleyl. In some embodiments, the heteroaryl or heterocyclic group is selected from 1H-1,2,3-triazol-4-yl, isoquinoline-6-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,4-triazol-3-yl, 2H-1,2,3-triazol-4-yl, 1H-imidazol-4-yl, 1H-pyrazol-4-yl, 1H-pyrazol-3-yl, dihydrobenzofuran-6-yl or 2,3-dihydrobenzofuran-6-yl, dihydrobenzofuran-5-yl or 2,3-di- Hydrobenzofuran-5-yl, benzo[b][1,4]dioxin-6-yl or 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, benzo[b][1,4]oxazin-7-yl or 2,3-dihydrobenzo[b][1,4]oxazin-7-yl, 2H-benzo[b][1,4]thiazin-7-yl or 3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl, 1,2,3,4-tetrahydroquinoxalin-6-yl or 1,2,3,4-tetrahydroquinoxalin-6-yl, isochoran-7-yl or 1H-indazole-6-yl. In some embodiments, R c3 Selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy; hydroxy, cyano, heterocyclic, NR e1 R e2 Oxide, heterocyclic group, or phenyl group. In some embodiments, R c3 Selected from fluorine, bromine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxyl, cyano, morpholino, (1-methyl-1H-1,2,3-triazol-4-yl)amino, oxo, pyridyl, or phenyl. In some embodiments, R a2It is (1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)methyl, (7-fluoroisoquinoline-6-yl)methyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyrazin-2-ylmethyl, (4-methylpyridin-2-yl)methyl, (4-methoxypyridin-2-yl)methyl, (2-chloro-5-methylpyridin-3-yl)methyl, (2-chloro-5-fluoropyridin-4-yl)methyl, (2-chloro-5-hydroxypyridin-4-yl)methyl, (5-fluoro-2-methylpyridin-4-yl)methyl (5-fluoro-2-methoxypyridin-4-yl)methyl, (2-cyano-5-fluoropyridin-4-yl)methyl, (2-cyano-5-hydroxypyridin-4-yl)methyl, (5-fluoro-2-morpholinopyridin-4-yl)methyl, (5-fluoro-2-((1-methyl-1H-1,2,3-triazol-4-yl)amino)pyridin-4-yl)methyl, 5-chloro-2-oxo-1,2-dihydropyridin-3-yl)methyl, (1-phenyl-1H-1,2,3-triazol-4-yl)methyl, (1-phenyl-1H-1,2,3-triazol-4-yl)methyl, (1-phenyl-1H- -1,2,4-triazol-3-yl)methyl, (2-phenyl-2H-1,2,3-triazol-4-yl)methyl, (1-phenyl-1H-imidazol-4-yl)methyl, 1-phenyl-1H-pyrazole-4-yl)methyl, (1-phenyl-1H-pyrazole-3-yl)methyl, (5-fluoro-2,3-dihydrobenzofuran-6-yl)methyl, (6-fluoro-2,3-dihydrobenzofuran-5-yl)methyl, (2,3-dihydrobenzofuran-6-yl)methyl, (7-fluoro-2,3-dihydrobenzo[b][1,4]) Dioxin-6-yl)methyl, (6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl, (6-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl, (6-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)methyl, (7-fluoro-1,2,3,4-tetrahydroquinoxalin-6-yl)methyl, (6-fluoroisochroman-7-yl)methyl, or (7-fluoro-1H-indazole-6-yl)methyl.

[0108] In some implementation schemes, R a2 It is C 1-6 Alkyl (e.g., methyl, ethyl, or propyl), the C 1-6 Alkyl groups are -C(O)NR b2 R b3 -OC(O)NR b2 R b3 -C(O)R b2 -NR b2 C(O)R b3 or -NR b2 R b3 Replace, where Rb1 and R b2 As defined in equation (I). In some implementations, R a2 It is 2-(methylamino)-2-oxoethyl, 2-(methoxyamino)-2-oxoethyl, 2-(dimethylamino)-2-oxoethyl, 2-oxo-2-(phenylamino)ethyl, 2-oxo-2-(pyridin-4-ylamino)ethyl, 2-((2-methoxyethyl)amino)-2-oxoethyl, dimethylaminocarbonyloxyethyl, carboxymethyl, methoxycarbonylmethyl, methylcarbonylaminoethyl, 3-(azacyclobutane-1-yl)-3-oxopropyl, 2-(methylamino)ethyl, or carbamoyl.

[0109] In some implementation schemes, R a2 It is C 3-8 Cycloalkyl, phenyl, heteroaryl, or heterocyclic groups, each of which is unsubstituted or substituted by one or more substituents selected from halogens; C 1-6 Alkyl, the C 1-6 Alkyl groups are unsubstituted or R-substituted. c3 Replacement. In some implementations, R a2 It is pyridin-2-yl, pyridin-3-yl, isoquinoline-4-yl, pyrimidin-5-yl, isoxazol-5-yl, isoxazol-3-yl, triazol-3-yl, benzo[c]isooxazol-3-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridyl, triazolo[4,3-a]pyridyl, 5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazinyl, triazolo[3,4-c][1,4]oxazinyl, 6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazinyl, triazolo[5,1-c][1,4]oxazinyl or phenyl, each of which is unsubstituted or R c3 Replacement. In some implementations, R c3 It is phenyl; C 1-6 Alkyl group; cyano group; oxo group; -NR e1 R e2 ;-NR e1 -C(O)-NR e2 R e3 ; phenoxy, phenyl, or heteroaryl. In some embodiments, R c3 It is fluorine, bromine, chlorine, methyl, methoxy, amino, cyano, oxo, acetamyl, 3-methylurea, benzyl, phenoxy, pyridin-2-yl, or phenyl. In some embodiments, R a2It is cyclopropyl, pyridin-3-yl, 4-methylpyridin-3-yl, 4,6-dimethylpyridin-3-yl, 4-methoxypyridin-3-yl, 6-amino-4-cyanopyridin-3-yl, isoquinoline-4-yl, 5-methyl-2-oxo-1,2-dihydropyridin-4-yl, 4-methylpyrimidin-5-yl, 5-fluoro-4-methylpyridin-3-yl, 6-amino-4-methylpyridin-3-yl, 6-acetamido-4-methylpyridin-3-yl -yl, 4-methyl-6-(3-methylureido)pyridin-3-yl, 5-methoxypyridin-3-yl, 4-benzylpyridin-3-yl, 5-phenoxypyridin-3-yl, isoxazol-5-yl, 4-methylisooxazol-5-yl, 3,4-dimethylisooxazol-5-yl, 4-methyl-3-phenylisooxazol-5-yl, 4-methyl-3-(pyridin-2-yl)isooxazol-5-yl, isoxazol-3-yl, 4-methyl-4H-1, 2,4-Triazol-3-yl, 4-Phenyloisoxazo-5-yl, 3-Methyl-4-phenylisoxazo-5-yl, Benzo[c]isoxazo-3-yl, 1-Methyl-2-oxo-1,2-dihydropyridin-3-yl, 3-Fluoro-6-methylpyridin-2-yl, 5-Methyl-2-oxo-1,2-dihydropyridin-3-yl, 4-Fluoro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 1-Pheny-1H-1,2, 3-Triazol-4-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl, 5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl, 6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-3-yl, 5-fluoro-2-methylphenyl, 2-chloro-5-fluorophenyl or 2-cyano-5-fluorophenyl.

[0110] In some implementation schemes, R a2 It is an alkenyl or alkynyl group, each of which is further substituted with a phenyl group, wherein the phenyl group is unsubstituted or substituted with one or more R groups. c3 Replacement. In some implementations, R a2It is butyl-2-yn-1-yl, 3-(1-methyl-1H-pyrazol-4-yl)prop-2-yn-1-yl, 4,4-dimethylpent-2-yn-1-yl, 3-cyclopropylprop-2-yn-1-yl, N,N-dimethylaminobut-2-yn-yl, N,N-dimethylamino-1-methyl-but-2-yn-yl, 5-hydroxyhex-2-yn-1-yl, 5,6-dihydroxyhex-2-yn-1 -yl, 5-hydroxy-4-methylpentan-2-yn-1-yl, 3-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)prop-2-yn-1-yl, 3-(1-methyl-2-oxopiridine-3-yl)prop-2-yn-1-yl, 4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)but-3-yn-2-yl, 4-(1-methyl-2-oxopiridine-3-yl)but-3-yn-2-yl, 4-(1-methyl-2-oxopiridine-3-yl) 3-(o-Tolyl)prop-2-yn-1-yl, 3-(2-fluorophenyl)prop-2-yn-1-yl, 3-(2-chlorophenyl)prop-2-yn-1-yl, 3-(3-fluorophenyl)prop-2-yn-1-yl, 3-(4-fluorophenyl)prop-2-yn-1-yl, 3-(2-hydroxyphenyl)prop-2-yn-1-yl 3-(pyridin-3-yl)prop-2-yn-1-yl, 4-(pyridin-3-yl)but-3-yn-2-yl, 3-(pyridin-4-yl)prop-2-yn-1-yl, 3-(2-cyanophenyl)prop-2-yn-1-yl, 4-(pyridin-2-yl)but-2-yn-1-yl, 4-(pyrazin-2-yl)but-2-yn-1-yl or 4-(pyridin-2-yl)pent-2-yn-1-yl.

[0111] R 1 As -C(O)NR a1 R a2 , where R a1 and R a2 Forming a ring

[0112] In some implementation schemes, R 1 As -C(O)NR a1 R a2 , where R a1 and R a2 Together with the nitrogen atoms to which they are attached, they form 4- to 9-membered rings containing one or two additional heteroatoms selected from nitrogen, oxygen, or sulfur, and said rings are either unsubstituted or modified by one or more substituents R. b4 Substitution, or two substituents R on two adjacent atoms b4 Formation of 4- to 6-membered fused rings and / or two substituents R on the same carbon atom b4 Forming 3 to 6-membered spirorings, wherein the fused ring or spiroring is unsubstituted or composed of one or more elements selected from halogens or C. 1-6 Alkyl substituents.

[0113] In some implementation schemes, R 1 As -C(O)NR a1 Ra2 , where R a1 and R a2 Together with the nitrogen atoms to which they are attached, they form rings selected from the following: piperidinyl, 6-azaspiro[2.5]octane-6-yl, 5-azaspiro[2.5]octane-5-yl, piperidinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, thiomorpholine, morpholine, azacyclobutane, azacycloheptane, azacyclooctane, 3-azabicyclo[3.1.0]hexane, and octahydrocyclopentadien[c]pyrrole, wherein each of the rings is unsubstituted or substituted as defined above.

[0114] In some implementation schemes, R b4 It is a hydroxyl group; halogen; oxo group; cyano group; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkoxy C 1-6 Alkyl; Halogenated C 1-6 Alkoxy; NR c4 R c5 (R) c4 and R c5 Each of the following groups is independently hydrogen, alkyl, or phenyl; phenyl, heterocyclic (e.g., pyrrolidine, aziridine) or heteroaryl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenoxy, cyclohexyl, 1H-pyrazol-4-yl, or 1-methyl-1H-pyrazol-4-yl), wherein each of the phenyl, heterocyclic, or heteroaryl groups is unsubstituted or substituted with one or more halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -NR e4 R e5 or -COOR e4 Replace, where R e4 and R e5 It is hydrogen, C 1-6 Alkyl, phenyl, C 1-6 Alkyl-substituted phenyl, heteroaryl, or C-substituted phenyl 1-6 Alkyl-substituted heteroaryl groups.

[0115] In some implementations, R is optionally further specified. b4It is 3-chlorophenyl, methoxymethyl, phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, m-tolyl, 3-(trifluoromethyl)phenyl, 3-(N,N-dimethylamino)phenyl, 3-(methylamino)phenyl, 3-(methoxycarbonyl, 3-(carboxyl)phenyl), methoxyphenyl), phenoxy, cyclohexyl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl, fluorine, bromine, chlorine, azacyclobutane, oxo, pyrrolidine, hydroxyl, amino, trifluoromethyl or phenylamino.

[0116] In some implementation schemes, R 1 It is 4-(3-chlorophenyl)piperidine-1-carbonyl, 6-azaspiro[2.5]octane-6-carbonyl, 5-azaspiro[2.5]octane-5-carbonyl, piperidine-1-carbonyl, 4-(methoxymethyl)piperidine-1-carbonyl, 4-phenylpiperidine-1-carbonyl, 4-phenylpiperazine-1-carbonyl, 4-phenyl-1,2,3,6-tetrahydropyridine-1-carbonyl, 4-(pyridin-2-yl)piperidine-1-carbonyl, 4-(pyridin-3-yl)piperidine-1-carbonyl, 4-(pyridin ... 4-Pyridine-1-carbonyl, 4-(m-Tolyl)piperidine-1-carbonyl, 4-(3-(trifluoromethyl)phenyl)piperidine-1-carbonyl, 4-(3-(N,N-dimethylamino)phenyl)piperidine-1-carbonyl, 4-(3-(methylamino)phenyl)piperidine-1-carbonyl, 4-(3-(methoxycarbonyl)phenyl)piperidine-1-carbonyl, 4-(3-(carboxyl)phenyl)piperidine-1-carbonyl, 4-(4-methoxyphenyl)piperidine-1-carbonyl 4-Phenoxypiperidine-1-carbonyl, 4-cyclohexylpiperidine-1-carbonyl, 3-phenylpiperidine-1-carbonyl, 3-(1H-pyrazol-4-yl)piperidine-1-carbonyl, 3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carbonyl, 3-(methoxymethyl)piperidine-1-carbonyl, 4,4-difluoropiperidine-1-carbonyl, 3,3-difluoropiperidine-1-carbonyl, 1,1-thiodimorpholine-4-carbonyl, morpholine-4-carbonyl, azacyclobutane-1-carbonyl , pyrrolidine-1-carbonyl, 3-fluoroazacyclobutane-1-carbonyl, 3,3-difluoroazacyclobutane-1-carbonyl, 3-hydroxyazacyclobutane-1-carbonyl, 3-aminoazacyclobutane-1-carbonyl, 3-(trifluoromethyl)azacyclobutane-1-carbonyl, azacycloheptane-1-carbonyl, azacyclooctane-1-carbonyl, 3-azabicyclo[3.1.0]hexane-3-carbonyl, octahydrocyclopentadien[c]pyrrole-2-carbonyl or 4-(phenylamino)piperidine-1-carbonyl.

[0117] In some implementation schemes, R 1 It is -C(O)R a3 , where R a3 It is C 1-6 Alkyl, Halogenated C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-S-, C3-8 cycloalkyl, phenyl, heteroaryl, or heterocyclic, wherein each of the C3-8 cycloalkyl, phenyl, heteroaryl, or heterocyclic groups is unsubstituted or substituted by one or more substituents selected from: halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl group. In some embodiments, R a3 It is methyl, ethyl, isopropyl, propyl, ethynyl, vinyl, methoxy, ethoxy, ethanethiol, 1-methylcyclopropane, 1-fluorocyclopropane, 2,2-difluorocyclopropane, 1-(trifluoromethyl)cyclopropane, cyclopropyl, cyclobutyl, thiazole-4-carbonyl, or 1H-imidazol-1-carbonyl.

[0118] R 1 As R a4

[0119] In some implementation schemes, R 1 It is a heteroaryl group, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents selected from the following: halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, phenoxy, -NR b2 R b3 -C(O)NR b2 R b3 -OC(O)NR b2 R b3 -C(O)R b2 or -NR b2 C(O)R b3 In some implementations, R 1 It is a thiazolyl, thiadiazolyl, imidazolyl, pyridyl, pyrazinyl, oxypyrazinyl, pyrimidinyl, oxypyrimidinyl, pyridazinyl, pyridinyl, or benzo[d]thiazolyl, each of which is unsubstituted or substituted as defined above. In some embodiments, R 1 It is thiazol-2-yl, thiazol-4-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1H-imidazol-2-yl, pyridin-2-yl, pyrazin-2-yl, pyrazinyl oxide, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidinyl oxide, pyridazin-3-yl, pyrimidin-5-yl, pyridin-2-yl, pyrazin-2-yl, pyridazin-3-yl, or benzo[d]thiazol-2-yl.

[0120] In some implementation schemes, R 1 It is thiazol-2-yl, thiazol-4-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1H-imidazol-2-yl, pyridin-2-yl, pyrazin-2-yl, pyrazin 1-oxide, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin 1-oxide, pyridazin-3-yl, 3-chloropyridin-2-yl, 3-fluoropyridin-2-yl, 3-methylpyridin-2-yl, 3-(trifluoromethyl)pyridin-2-yl, 5-bromopyrimidin-4-yl, 5-chloropyrimidin-4-yl, 5-fluoropyrimidin-4-yl, 5-methylpyrimidin- 4-yl, 5-(trifluoromethyl)pyrimidin-4-yl, 3-methylpyrazin-2-yl, 5-fluoropyridin-2-yl, 3,5-difluoropyridin-2-yl, 5-methylthiazol-4-yl, 1-methyl-1H-imidazol-2-yl, N,N-dimethylaminocarbonylpyrimidin-5-yl, N,N-dimethylaminocarbonylpyridin-2-yl, N,N-dimethylaminocarbonylpyrazin-2-yl, N,N-dimethylaminocarbonylpyridazin-3-yl, 5-phenoxypyridin-2-yl, 5-phenoxypyrazin-2-yl or benzo[d]thiazol-2-yl.

[0121] In one respect, this article provides a compound of formula (II).

[0122] (II)

[0123] Or its pharmaceutically acceptable salt, its stereoisomer, its tautomer, or its deuterated analogue.

[0124] in

[0125] X 1 and X 3 Each can be independently -O-, -S-, -NH-, -N=, or -CH=;

[0126] m and n are each numbers from 0 to 3, provided that the valence theory is satisfied;

[0127] R 2 and R 3 Each of these groups independently represents a halogen, deuterium, cyano, oxo, nitro, hydroxyl, or C group. 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated, and halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-8 cycloalkyl, C1-6 Alkyl-S-, C 2-6 alkenyl, C 2-6 Alkynyl, -SO2R 2a -COOR 2a or -NR 2a R 2b ,

[0128] Where R 2a and R 2b Each is independently hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated, and halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 alkyl;

[0129] R 1 yes

[0130] 1)-C(O)NR a1 R a2 , where R a1 and R a2 Each is C independently 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0131] 2)-C(O)NR a1 R a2 , where R a1 It is C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 Alkyl; and R a2 It is C 1-6 Alkyl, the C 1-6 The alkyl group is either unsubstituted or substituted with one or more halogens or hydroxyl groups and further substituted with a phenyl group, wherein the phenyl group is unsubstituted or substituted with one or more substituents R. c3 replace;

[0132] 3)-C(O)NR a1 R a2 , where R a1 It is C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 Alkyl; and R a2 It is C 1-6 Alkyl, the C 1-6 Alkyl groups are either unsubstituted or substituted with one or more halogens or hydroxyl groups and are further modified by -OR b1Replace, where R b1 It is a phenyl group, wherein the phenyl group is unsubstituted or modified by halogens, oxo groups, C... 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, Halogenated C 1-6 Alkyl, heterocyclic, -C 1-6 Alkyl C(O)NR c1 R c2 -C(O)NR c1 R c2 -NR c1 R c2 -NR c1 C(O)R c2 Or heteroaryl substitution; or

[0133] 4)-C(O)NR a1 R a2 , where R a1 It is C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 Alkyl; and R a2 It is C 2-6 alkenyl or C 2-6 The alkynyl group, each of which is further substituted with a phenyl group, wherein the phenyl group is unsubstituted or substituted with one or more substituents R. c3 replace;

[0134] 5)-C(O)NR a1 R a2 , where R a1 It is C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 Alkyl; and R a2 It is C 3-8 Cycloalkyl, phenyl, heteroaryl or heterocyclic, wherein C 3-8 Each of the cycloalkyl, phenyl, heteroaryl, or heterocyclic groups is either unsubstituted or substituents R. c3 replace;

[0135] 6)-C(O)NR a1 R a2 , where R a1 and R a2 Together with the nitrogen atoms to which they are attached, they form 4- to 9-membered rings containing one or two additional heteroatoms selected from nitrogen, oxygen, or sulfur, and said rings are either unsubstituted or modified by one or more substituents R. b4 Substitution, or two substituents R on two adjacent atoms b4 Formation of 4- to 6-membered fused rings and / or two substituents R on the same carbon atom b4Forming 3 to 6-membered spirorings, wherein the fused ring or spiroring is unsubstituted or composed of one or more elements selected from halogens or C. 1-6 Alkyl substituents,

[0136] 7) Heteroaryl or heterocyclic groups, each of which is unsubstituted or substituted by one or more substituents selected from: halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, phenoxy, -NR c6 R c7 -C(O)NR c6 R c7 -OC(O)NR c6 R c7 -C(O)R c6 or -NR c6 C(O)R c7 ,

[0137] in

[0138] R c1 and R c2 Each is independently hydrogen, C 1-6 Alkyl, phenyl, wherein the phenyl group is unsubstituted or is substituted with one or more groups selected from hydroxyl, halogen, oxo, C 1-6 Alkyl or C 1-6 Substitution of alkoxy groups;

[0139] R c3 yes

[0140] -halogen;

[0141] -hydroxyl group;

[0142] -Cyano;

[0143] -Oxide group;

[0144] -C 1-6 Alkyl, the C 1-6 Alkyl groups are unsubstituted or converted by one or more halogens, hydroxyl groups, C... 1-6 Alkoxy, phenyl, or alkyl-substituted heteroaryl (pyrazolyl) substituted;

[0145] -C 2-6 alkenyl or C 2-6 alkynyl group;

[0146] -hydroxyl group;

[0147] -C 1-6 Alkyl-S-

[0148] -C1-6 alkoxy or phenoxy, wherein the C 1-6 Each of the alkoxy or phenoxy groups is unsubstituted or converted by one or more halogens, C 1-6 Alkoxy, alkyl-substituted heteroaryl, or alkyl-substituted heterocyclic group;

[0149] --C 1-6 Alkyl C(O)NR e1 R e2 ;

[0150] --C(O)NR e1 R e2 ;

[0151] --NR e1 R e2 ;

[0152] --NR e1 C(O)R e2 ;

[0153] --NR e1 -C(O)-NR e2 R e3 ;

[0154] --NR e1 R e2 ;

[0155] - Heterocyclic group, said heterocyclic group is unsubstituted or halogenated, C 1-6 Alkyl or heterocyclic groups, via C 1-6 Alkyl-substituted heterocyclic substitution,

[0156] - Heteroaryl, wherein the heteroaryl group is unsubstituted or C-substituted. 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl- or heteroaryl substitution;

[0157] -C 3-8 cycloalkyl;

[0158] -phenyl; and

[0159] R e1 R e2 and R e3 Each is independently hydrogen, C 1-6 Alkyl, phenyl, C 1-6 Alkyl-substituted phenyl, heteroaryl (e.g., thiazolyl, pyrazolyl), or C-substituted phenyl groups 1-6 Alkyl-substituted heteroaryl (1-methyl-1H-1,2,3-triazol-4-yl).

[0160] R b4 It is a hydroxyl group; halogen; oxo group; cyano group; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkoxy C 1-6 Alkyl; Halogenated C 1-6 Alkoxy; NR c4 R c5 , where R c4 and R c5 Each is independently hydrogen, alkyl, or phenyl; phenyl, heterocyclic, or heteroaryl, wherein each of the phenyl, heterocyclic, or heteroaryl groups is unsubstituted or substituted with one or more halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -NR e4 R e5 or -COOR e4 Replace, where R e4 and R e5 It is hydrogen, C 1-6 Alkyl, phenyl, C 1-6 Alkyl-substituted phenyl, heteroaryl, or C-substituted phenyl 1-6 Alkyl-substituted heteroaryl groups;

[0161] R c6 and R c7 Each is independently hydrogen, C 1-6 Alkyl, phenyl, wherein the phenyl group is unsubstituted or is substituted with one or more groups selected from hydroxyl, halogen, oxo, C 1-6 Alkyl or C 1-6 Substitution of alkoxy groups,

[0162] The condition is a double-ring part. It belongs to the aromatic family.

[0163] Double ring section

[0164] In some implementations, the double-ring portion yes or Each of these is either unsubstituted or substituted with one or more substituents selected from the following: halogen, deuterium, oxo, nitro, hydroxyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 1-6 Alkyl SO2-, NR 2a R 2b C 1-6 Alkyl, Halogenated C1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, cyano, COOR 2a Or cycloalkyl.

[0165] In some implementations, n is 0. In some implementations, R 2 Selected from fluorine, chlorine, bromine, nitro, methoxy, hydroxyl, difluoromethoxy, trifluoromethoxy, methylthio, methanesulfonyl, amino, methylamino, methyl, trifluoromethyl-d3, hydroxymethyl, cyano, methoxycarbonyl, carboxyl, or cyclopropyl.

[0166] In some embodiments, the bicyclic moiety is benzo[d]isoxazole-5-yl, 1H-benzo[d][1,2,3]triazol-6-yl, 1H-benzo[d][1,2,3]triazol-5-yl, 2H-benzo[d][1,2,3]triazol-5-yl, 4-chloro-1H-benzo[d][1,2,3]triazol-6-yl, 4-nitro-1H-benzo[d][1,2,3]triazol-6-yl, 4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-bromo-1H-benzo[d][1,2,3]triazol-6-yl, 4-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl Azol-6-yl, 4-amino-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methylamino)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-ethyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyano-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methylsulfonyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methoxycarbonyl)-1 H-benzo[d][1,2,3]triazol-6-yl, 4-carboxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyclopropyl-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 7-chloro-1H-benzo[d][1,2,3]triazol-6-yl, 7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 7-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 7-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 7-cyano-1H-benzyl [d][1,2,3]triazol-6-yl, 7-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 5-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 5-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 5-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 5-cyano-1H-benzo[d][1,2,3]triazol-6-yl, 5-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4,7-Dichloro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyano-7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyano-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl 3] Triazol-6-yl, 7-chloro-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-methyl-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-methoxy-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-hydroxy-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 5-fluoro-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol -6-yl, 5-hydroxy-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5,7-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5,7-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-methoxy-1H-benzo[d][1,2,3]triazol-6-yl - yl, 4-(difluoromethoxy)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(trifluoromethoxy)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(hydroxymethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4,7-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-4-(methyl-d3)-1H-benzo[d][1,2,3]benzol[d][1,2,3]triazol-6-yl,3] Triazol-6-yl, 4-ethyl-7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4,5-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4,5-difluoro-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 5,7-difluoro-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 5,7-difluoro-4-(methyl-d3)-1H-benzo[d][1, 2,3]triazol-6-yl, 4-chloro-1H-benzo[d][1,2,3]triazol-6-yl, 7-chlorobenzo[d]isoxazo-5-yl, 7-methylbenzo[d]isoxazo-5-yl, 7-hydroxybenzo[d]isoxazo-5-yl, 7-methoxybenzo[d]isoxazo-5-yl, 1-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 3-methylbenzo[d]isoxazo-5-yl, or 6-fluorobenzo[d]isoxazo-5-yl. In some embodiments, the bicyclic moiety is benzo[d]isoxazolyl, benzo[c][1,2,5]oxadiazolyl, 1H-benzo[d][1,2,3]triazolyl, or 2H-benzo[d][1,2,3]triazolyl, each of which is unsubstituted or substituted as defined above. ,

[0167] In some embodiments, the bicyclic moiety is benzo[d]isoxazole-5-yl, 1H-benzo[d][1,2,3]triazol-6-yl, 1H-benzo[d][1,2,3]triazol-5-yl, or 2H-benzo[d][1,2,3]triazol-5-yl, each of which is unsubstituted or substituted as defined above.

[0168] In some embodiments, the bicyclic moiety is benzo[d]isoxazole-5-yl, 1H-benzo[d][1,2,3]triazol-6-yl, 1H-benzo[d][1,2,3]triazol-5-yl, 2H-benzo[d][1,2,3]triazol-5-yl, 4-chloro-1H-benzo[d][1,2,3]triazol-6-yl, 4-nitro-1H-benzo[d][1,2,3]triazol-6-yl, 4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-bromo-1H-benzo[d][1,2,3]triazol-6-yl, 4-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl Azol-6-yl, 4-amino-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methylamino)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-ethyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyano-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methylsulfonyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methoxycarbonyl)-1 H-benzo[d][1,2,3]triazol-6-yl, 4-carboxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyclopropyl-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 7-chloro-1H-benzo[d][1,2,3]triazol-6-yl, 7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 7-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 7-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 7-cyano-1H-benzyl [d][1,2,3]triazol-6-yl, 7-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 5-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 5-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 5-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 5-cyano-1H-benzo[d][1,2,3]triazol-6-yl, 5-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4,7-Dichloro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyano-7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyano-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl 3] Triazol-6-yl, 7-chloro-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-methyl-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-methoxy-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-hydroxy-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 5-fluoro-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol -6-yl, 5-hydroxy-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5,7-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5,7-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-methoxy-1H-benzo[d][1,2,3]triazol-6-yl - yl, 4-(difluoromethoxy)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(trifluoromethoxy)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(hydroxymethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4,7-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-4-(methyl-d3)-1H-benzo[d][1,2,3]benzol[d][1,2,3]triazol-6-yl,3] Triazol-6-yl, 4-ethyl-7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4,5-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4,5-difluoro-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 5,7-difluoro-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 5,7-difluoro-4 -(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-yl, 2-(4-chloro-1H-benzo[d][1,2,3]triazol-6-yl, 7-chlorobenzo[d]isoxazo-5-yl, 7-methylbenzo[d]isoxazo-5-yl, 7-hydroxybenzo[d]isoxazo-5-yl, 7-methoxybenzo[d]isoxazo-5-yl or 6-fluorobenzo[d]isoxazo-5-yl.

[0169] 1) to 5), where -C(O)NR a1 R a2

[0170] In some implementation schemes, R a1 It is C 1-6 Alkyl or deuterated C 1-6 Alkyl group. In some embodiments, R a1 It is C 1-6 Alkyl group. In some embodiments, R... a1 It is hydrogen, methyl, ethyl, CH3-d3, CF3, CHF2, or methoxy. In some embodiments, R a1 It is methyl or ethyl.

[0171] In some implementation schemes, R a2 It is C 1-6 Alkyl group. In some embodiments, R a2 It is methyl, ethyl, isopropyl, propyl, isobutyl, or butyl. In some embodiments, R a2 It is CH3-d3, methoxyethyl, CF3CH2, methylthioethyl, cyanomethyl, trifluoromethyl.

[0172] In some implementation schemes, R a2 It is C 1-6 Alkyl (e.g., methyl, ethyl, or propyl), the C 1-6 The alkyl group is either unsubstituted or substituted with one or more halogens or hydroxyl groups and further substituted with a phenyl group, wherein the phenyl group is unsubstituted or substituted with one or more substituents R. c3 Replacement. In some implementations, R c3 It is a halogen; hydroxyl group; cyano group; oxo group; C 1-6 Alkyl, the C 1-6 Alkyl groups are unsubstituted or converted by one or more halogens, hydroxyl groups, C... 1-6Alkoxy, phenyl, or alkyl-substituted heteroaryl groups (e.g., pyrazolyl); C 1-6 Alkyloxy; phenoxy, C 2-6 alkenyl; C 2-6 Alkyne group; hydroxyl group; C 1-6 Alkoxy, the C 1-6 Alkyl groups are unsubstituted or substituted with one or more halogens, C 1-6 Alkoxy, alkyl-substituted heteroaryl (pyrazolyl), or alkyl-substituted heterocyclic (piperidinyl) substitution; -C 1-6 Alkyl C(O)NR e2 R e3 ;-C(O)NR e1 R e2 ;-NR e1 R e2 ;-NR e1 C(O)R e2 ;-NR e1 -C(O)-NR e2 R e3 ;-NR e1 R e2 ;R e1 R e2 R e3 Each is independently hydrogen, C 1-6 Alkyl, heteroaryl (e.g., thiazolyl, pyrazolyl) or C-terminated 1-6 Alkyl-substituted heteroaryl groups (1-methyl-1H-1,2,3-triazol-4-yl); heterocyclic groups (e.g., aziridine-1-yl, piperidin-4-yl, morpholino, piperazine-yl, morpholino), said heterocyclic groups being unsubstituted or halogenated, C 1-6 Alkyl or heterocyclic or C 1-6 Alkyl-substituted heterocyclic groups; heteroaryl groups (pyrazinyl, pyridyl, pyrimidinyl), wherein the heteroaryl group is unsubstituted or C-substituted. 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl- or heteroaryl (e.g., pyridyl) substitution; C 3-8 cycloalkyl; phenyl; or C 1-6 Alkyl-S-. In some embodiments, R c3Selected from chlorine, fluorine, bromine, methyl, ethyl, ethynyl, vinyltrifluoromethyl, methoxymethyl, (1-methyl-1H-pyrazol-4-yl)methyl, hydroxy, methoxy, (1-methylpiperidin-4-yl)methoxy, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, cyano, oxo, hydroxymethyl, 3-methylurea, thiazol-2-ylamino, (1-methyl-1H-pyrazol-4-yl)amino, aziridine-1-yl, 1- Methylpiperidin-4-yl, piperidin-4-yl, 4-methylpiperazin-1-yl, morpholino, pyrazin-2-yl, 3-(hydroxymethyl)pyridin-2-yl, pyridin-3-yl, phenyl, pyrimidin-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, 4'-methyl-[1,1'-bipiperazin]-4-yl, amino, acetamido, dimethylamino, methylthio, cyclopropyl, 2-amino-2-oxoethyl, or 2-(methylamino)-2-oxoethyl. a2It is 5-chloro-2-fluorobenzyl, 2-fluoro-5-methylbenzyl, 2-hydroxybenzyl, 2-fluoro-3-methylbenzyl, 2-fluoro-4-methylbenzyl, 2-hydroxy-3-methylbenzyl, 5-cyano-2-fluorobenzyl, 2-fluoro-5-(trifluoromethyl)benzyl, 2-chlorobenzyl, 2,6-difluorobenzyl, 3-chloro-2-fluorobenzyl, 2,5-difluorobenzyl, 2-fluoro-4-methoxybenzyl, 1-(5-chloro-2-fluorophenyl)ethyl, 2-fluoro-5-methoxybenzyl, 2,4,5-trifluorobenzyl, 2,4-difluorobenzyl, 2,4-difluoro-5-methylbenzyl, 2-fluoro-5-(methoxy) 2-(5-chloro-2-fluorophenyl)benzyl, 2-fluoro-3,5-dimethylbenzyl, benzyl, 4-chloro-2-fluorobenzyl, 2-(5-chloro-2-fluorophenyl)prop-2-yl, (5-chloro-2-fluorophenyl)fluoromethyl, (5-chloro-2-fluorophenyl)difluoromethyl, 1-(3-chlorophenyl)-2-hydroxyethyl, 1-(5-chloro-2-fluorophenyl)cyclopropyl, 2-fluorobenzyl, 2-fluoro-3-hydroxybenzyl, 2-fluoro-3-(hydroxymethyl)benzyl, 2-fluoro-3-(3-methylureido)benzyl, 2-fluoro-3-(thiazol-2-ylamino)benzyl, 2-fluoro-3-((1-methyl-1H-pyrazole-4-) 4-ethyl-2-fluorobenzyl, 4-(azacyclobutane-1-yl)-2-fluorobenzyl, 5-chloro-2-fluoro-4-(pyrazin-2-yl)benzyl, 2-fluoro-4-(3-(hydroxymethyl)pyridin-2-yl)benzyl, 2-fluoro-4-(1-methylpiperidin-4-yl)benzyl, 2-fluoro-4-(piperidin-4-yl)benzyl, 2-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)benzyl, 2-fluoro-4-(4-methylpiperidin-1-yl)benzyl, 2-fluoro-4-(4'-methyl-[1,1'-bipiperidin]-4-yl)benzyl, 5-chloro- 2-Fluoro-4-((1-methylpiperidin-4-yl)methoxy)benzyl, 2-Fluoro-4-((1-methylpiperidin-4-yl)methoxy)benzyl, 2-cyano-N-(4-cyano-2-fluorobenzyl), 3-chloro-2,6-difluorobenzyl, 5-chloro-2,4-difluorobenzyl, 3-amino-5-chloro-2-fluorobenzyl, 3-acetamido-5-chloro-2-fluorobenzyl, 5-chloro-2-hydroxybenzyl, 5-cyano-2-hydroxybenzyl, 2-cyano-5-methylbenzyl, 2-fluoro-5-(trifluoromethoxy)benzyl, 5-(difluoromethoxy)-2-fluorobenzyl, 2-fluoro-5-(2,2,2-Trifluoroethoxy)benzyl, 5-(dimethylamino)-2-fluorobenzyl, 2-fluoro-5-(methylthio)benzyl, 5-ethynyl-2-fluorobenzyl, 2-fluoro-5-vinylbenzyl, 2-fluoro-5-((trifluoromethoxy)methyl)benzyl, 2-fluoro-5-(hydroxymethyl)benzyl, 5-(azacyclobutane-1-yl)-2-fluorobenzyl, 5-cyclopropyl-2-fluorobenzyl, 2-fluoro-5-morpholinobenzyl, 2-amino-2-oxoethyl)-2-fluorobenzyl, 2-fluoro-5-(2-(methylamino)-2-oxoethyl)benzyl, 2-fluoro-5-((1-methyl-1H-pyridine) (Azol-4-yl)methyl)benzyl, 2-fluoro-4-(2-(methylamino)-2-oxoethyl)benzyl, 2-cyanobenzyl, (3-fluoronaphthyl-2-yl)methyl, 2-fluoro-4-(pyridin-3-yl)benzyl, (3-fluoro-[1,1'-biphenyl]-4-yl)methyl, (4-fluoro-[1,1'-biphenyl]-3-yl)methyl, 2-fluoro-5-(pyrimidin-4-yl)benzyl, 3-phenylpropyl, 3-(2-cyanophenyl)propyl, 3-(2-chlorophenyl)propyl, 3-(2-methoxyphenyl)propyl, 3-(2-fluorophenyl)propyl, or 3-oxo-3-phenylpropyl.

[0173] In some implementation schemes, R a2 It is C 1-6 Alkyl (e.g., methyl, ethyl, or propyl), the C 1-6 The alkyl group is either unsubstituted or substituted with one or more halogens or hydroxyl groups and further substituted with a heteroaryl or heterocyclic group, wherein the heteroaryl or heterocyclic group is unsubstituted or substituted with one or more substituents R. c3Substitution. In some embodiments, the heteroaryl or heterocyclic group is selected from triazolyl, isoquinolinyl, pyridyl, pyrazinyl, imidazolyl, pyrazolyl, dihydrobenzofuranyl, 2,3-dihydrobenzofuranyl, dihydrobenzofuranyl, 2,3-dihydrobenzofuranyl, benzo[b][1,4]dioxinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[b][1,4]oxazinyl, 2,3-dihydrobenzo[b][1,4]oxazinyl, benzo[b][1,4]thiazinyl or 3,4-dihydro-2H-benzo[b][1,4]thiazinyl, 1,2,3,4-tetrahydroquinoxalinyl or 1,2,3,4-tetrahydroquinoxalinyl, isochoryl or indazoleyl. In some embodiments, the heteroaryl or heterocyclic group is selected from 1H-1,2,3-triazol-4-yl, isoquinoline-6-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,4-triazol-3-yl, 2H-1,2,3-triazol-4-yl, 1H-imidazol-4-yl, 1H-pyrazol-4-yl, 1H-pyrazol-3-yl, dihydrobenzofuran-6-yl or 2,3-dihydrobenzofuran-6-yl, dihydrobenzofuran-5-yl or 2,3-di- Hydrobenzofuran-5-yl, benzo[b][1,4]dioxin-6-yl or 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, benzo[b][1,4]oxazin-7-yl or 2,3-dihydrobenzo[b][1,4]oxazin-7-yl, 2H-benzo[b][1,4]thiazin-7-yl or 3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl, 1,2,3,4-tetrahydroquinoxalin-6-yl or 1,2,3,4-tetrahydroquinoxalin-6-yl, isochoran-7-yl or 1H-indazole-6-yl. In some embodiments, R c3 Selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy; hydroxy, cyano, heterocyclic, NR e1 R e2 Oxide, heterocyclic group, or phenyl group. In some embodiments, R c3 Selected from fluorine, bromine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxyl, cyano, morpholino, (1-methyl-1H-1,2,3-triazol-4-yl)amino, oxo, pyridyl, or phenyl. In some embodiments, R a2It is (1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)methyl, (7-fluoroisoquinoline-6-yl)methyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyrazin-2-ylmethyl, (4-methylpyridin-2-yl)methyl, (4-methoxypyridin-2-yl)methyl, (2-chloro-5-methylpyridin-3-yl)methyl, (2-chloro-5-fluoropyridin-4-yl)methyl, (2-chloro-5-hydroxypyridin-4-yl)methyl, (5-fluoro-2-methylpyridin-4-yl)methyl (5-fluoro-2-methoxypyridin-4-yl)methyl, (2-cyano-5-fluoropyridin-4-yl)methyl, (2-cyano-5-hydroxypyridin-4-yl)methyl, (5-fluoro-2-morpholinopyridin-4-yl)methyl, (5-fluoro-2-((1-methyl-1H-1,2,3-triazol-4-yl)amino)pyridin-4-yl)methyl, 5-chloro-2-oxo-1,2-dihydropyridin-3-yl)methyl, (1-phenyl-1H-1,2,3-triazol-4-yl)methyl, (1-phenyl-1H-1,2,3-triazol-4-yl)methyl, (1-phenyl-1H- -1,2,4-triazol-3-yl)methyl, (2-phenyl-2H-1,2,3-triazol-4-yl)methyl, (1-phenyl-1H-imidazol-4-yl)methyl, 1-phenyl-1H-pyrazole-4-yl)methyl, (1-phenyl-1H-pyrazole-3-yl)methyl, (5-fluoro-2,3-dihydrobenzofuran-6-yl)methyl, (6-fluoro-2,3-dihydrobenzofuran-5-yl)methyl, (2,3-dihydrobenzofuran-6-yl)methyl, (7-fluoro-2,3-dihydrobenzo[b][1,4]) Dioxin-6-yl)methyl, (6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl, (6-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl, (6-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)methyl, (7-fluoro-1,2,3,4-tetrahydroquinoxalin-6-yl)methyl, (6-fluoroisochroman-7-yl)methyl, or (7-fluoro-1H-indazole-6-yl)methyl.

[0174] In some implementation schemes, R a2 It is C 3-8 Cycloalkyl, phenyl, heteroaryl, or heterocyclic groups, each of which is unsubstituted or substituted by one or more substituents selected from halogens; C 1-6 Alkyl, the C 1-6 Alkyl groups are unsubstituted or R-substituted. c3 Replacement. In some implementations, R a2It is pyridin-2-yl, pyridin-3-yl, isoquinoline-4-yl, pyrimidin-5-yl, isoxazol-5-yl, isoxazol-3-yl, triazol-3-yl, benzo[c]isooxazol-3-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridyl, triazolo[4,3-a]pyridyl, 5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazinyl, triazolo[3,4-c][1,4]oxazinyl, 6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazinyl, triazolo[5,1-c][1,4]oxazinyl or phenyl, each of which is unsubstituted or R c3 Replacement. In some implementations, R c3 It is phenyl; C 1-6 Alkyl group; cyano group; oxo group; -NR e1 R e2 ;-NR e1 -C(O)-NR e2 R e3 ; phenoxy, phenyl, or heteroaryl. In some embodiments, R c3 It is fluorine, bromine, chlorine, methyl, methoxy, amino, cyano, oxo, acetamyl, 3-methylurea, benzyl, phenoxy, pyridin-2-yl, or phenyl. In some embodiments, R a2It is cyclopropyl, pyridin-3-yl, 4-methylpyridin-3-yl, 4,6-dimethylpyridin-3-yl, 4-methoxypyridin-3-yl, 6-amino-4-cyanopyridin-3-yl, isoquinoline-4-yl, 5-methyl-2-oxo-1,2-dihydropyridin-4-yl, 4-methylpyrimidin-5-yl, 5-fluoro-4-methylpyridin-3-yl, 6-amino-4-methylpyridin-3-yl, 6-acetamido-4-methylpyridin-3-yl -yl, 4-methyl-6-(3-methylureido)pyridin-3-yl, 5-methoxypyridin-3-yl, 4-benzylpyridin-3-yl, 5-phenoxypyridin-3-yl, isoxazol-5-yl, 4-methylisooxazol-5-yl, 3,4-dimethylisooxazol-5-yl, 4-methyl-3-phenylisooxazol-5-yl, 4-methyl-3-(pyridin-2-yl)isooxazol-5-yl, isoxazol-3-yl, 4-methyl-4H-1, 2,4-Triazol-3-yl, 4-Phenyloisoxazo-5-yl, 3-Methyl-4-phenylisoxazo-5-yl, Benzo[c]isoxazo-3-yl, 1-Methyl-2-oxo-1,2-dihydropyridin-3-yl, 3-Fluoro-6-methylpyridin-2-yl, 5-Methyl-2-oxo-1,2-dihydropyridin-3-yl, 4-Fluoro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 1-Pheny-1H-1,2, 3-Triazol-4-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl, 5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl, 6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-3-yl, 5-fluoro-2-methylphenyl, 2-chloro-5-fluorophenyl or 2-cyano-5-fluorophenyl.

[0175] In some implementation schemes, R a2 It is an alkenyl or ynyl group, wherein the alkenyl or ynyl group is unsubstituted or is modified by one or more R groups. c3 Replacement. In some implementations, R a2It is butyl-2-yn-1-yl, 3-(1-methyl-1H-pyrazol-4-yl)prop-2-yn-1-yl, 4,4-dimethylpent-2-yn-1-yl, 3-cyclopropylprop-2-yn-1-yl, N,N-dimethylaminobut-2-yn-yl, N,N-dimethylamino-1-methyl-but-2-yn-yl, 5-hydroxyhex-2-yn-1-yl, 5,6-dihydroxyhex-2-yn-1 -yl, 5-hydroxy-4-methylpentan-2-yn-1-yl, 3-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)prop-2-yn-1-yl, 3-(1-methyl-2-oxopiridine-3-yl)prop-2-yn-1-yl, 4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)but-3-yn-2-yl, 4-(1-methyl-2-oxopiridine-3-yl)but-3-yn-2-yl, 4-(1-methyl-2-oxopiridine-3-yl) 3-(o-Tolyl)prop-2-yn-1-yl, 3-(2-fluorophenyl)prop-2-yn-1-yl, 3-(2-chlorophenyl)prop-2-yn-1-yl, 3-(3-fluorophenyl)prop-2-yn-1-yl, 3-(4-fluorophenyl)prop-2-yn-1-yl, 3-(2-hydroxyphenyl)prop-2-yn-1-yl 3-(pyridin-3-yl)prop-2-yn-1-yl, 4-(pyridin-3-yl)but-3-yn-2-yl, 3-(pyridin-4-yl)prop-2-yn-1-yl, 3-(2-cyanophenyl)prop-2-yn-1-yl, 4-(pyridin-2-yl)but-2-yn-1-yl, 4-(pyrazin-2-yl)but-2-yn-1-yl or 4-(pyridin-2-yl)pent-2-yn-1-yl.

[0176] 6) R 1 As -C(O)NR a1 R a2 , where R a1 and R a2 Forming a ring

[0177] In some implementation schemes, R 1 As -C(O)NR a1 R a2 , where R a1 and R a2 Together with the nitrogen atoms to which they are attached, they form 4- to 9-membered rings containing one or two additional heteroatoms selected from nitrogen, oxygen, or sulfur, and said rings are either unsubstituted or modified by one or more substituents R. b4 Substitution, or two substituents R on two adjacent atoms b4 Formation of 4- to 6-membered fused rings and / or two substituents R on the same carbon atom b4 Forming 3 to 6-membered spirorings, wherein the fused ring or spiroring is unsubstituted or composed of one or more elements selected from halogens or C. 1-6 Alkyl substituents.

[0178] In some implementation schemes, R 1 As -C(O)NR a1 Ra2 , where R a1 and R a2 Together with the nitrogen atoms to which they are attached, they form rings selected from the following: piperidinyl, 6-azaspiro[2.5]octane-6-yl, 5-azaspiro[2.5]octane-5-yl, piperidinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, thiomorpholine, morpholine, azacyclobutane, azacycloheptane, azacyclooctane, 3-azabicyclo[3.1.0]hexane, and octahydrocyclopentadien[c]pyrrole, wherein each of the rings is unsubstituted or substituted as defined above.

[0179] In some implementation schemes, R b4 It is a hydroxyl group; halogen; oxo group; cyano group; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkoxy C 1-6 Alkyl; Halogenated C 1-6 Alkoxy; NR c4 R c5 (R) c4 and R c5 Each of the following groups is independently hydrogen, alkyl, or phenyl; phenyl, heterocyclic (e.g., pyrrolidine, aziridine) or heteroaryl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenoxy, cyclohexyl, 1H-pyrazol-4-yl, or 1-methyl-1H-pyrazol-4-yl), wherein each of the phenyl, heterocyclic, or heteroaryl groups is unsubstituted or substituted with one or more halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -NR e4 R e5 or -COOR e4 Replace, where R e4 and R e5 It is hydrogen, C 1-6 Alkyl, phenyl, C 1-6 Alkyl-substituted phenyl, heteroaryl, or C-substituted phenyl 1-6 Alkyl-substituted heteroaryl groups.

[0180] In some implementations, R is optionally further specified. b4It is 3-chlorophenyl, methoxymethyl, phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, m-tolyl, 3-(trifluoromethyl)phenyl, 3-(N,N-dimethylamino)phenyl, 3-(methylamino)phenyl, 3-(methoxycarbonyl, 3-(carboxyl)phenyl), methoxyphenyl), phenoxy, cyclohexyl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl, fluorine, bromine, chlorine, azacyclobutane, oxo, pyrrolidine, hydroxyl, amino, trifluoromethyl or phenylamino.

[0181] In some implementation schemes, R 1 It is 4-(3-chlorophenyl)piperidine-1-carbonyl, 6-azaspiro[2.5]octane-6-carbonyl, 5-azaspiro[2.5]octane-5-carbonyl, piperidine-1-carbonyl, 4-(methoxymethyl)piperidine-1-carbonyl, 4-phenylpiperidine-1-carbonyl, 4-phenylpiperazine-1-carbonyl, 4-phenyl-1,2,3,6-tetrahydropyridine-1-carbonyl, 4-(pyridin-2-yl)piperidine-1-carbonyl, 4-(pyridin-3-yl)piperidine-1-carbonyl, 4-(pyridin ... 4-Pyridine-1-carbonyl, 4-(m-Tolyl)piperidine-1-carbonyl, 4-(3-(trifluoromethyl)phenyl)piperidine-1-carbonyl, 4-(3-(N,N-dimethylamino)phenyl)piperidine-1-carbonyl, 4-(3-(methylamino)phenyl)piperidine-1-carbonyl, 4-(3-(methoxycarbonyl)phenyl)piperidine-1-carbonyl, 4-(3-(carboxyl)phenyl)piperidine-1-carbonyl, 4-(4-methoxyphenyl)piperidine-1-carbonyl 4-Phenoxypiperidine-1-carbonyl, 4-cyclohexylpiperidine-1-carbonyl, 3-phenylpiperidine-1-carbonyl, 3-(1H-pyrazol-4-yl)piperidine-1-carbonyl, 3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carbonyl, 3-(methoxymethyl)piperidine-1-carbonyl, 4,4-difluoropiperidine-1-carbonyl, 3,3-difluoropiperidine-1-carbonyl, 1,1-thiodimorpholine-4-carbonyl, morpholine-4-carbonyl, azacyclobutane-1-carbonyl , pyrrolidine-1-carbonyl, 3-fluoroazacyclobutane-1-carbonyl, 3,3-difluoroazacyclobutane-1-carbonyl, 3-hydroxyazacyclobutane-1-carbonyl, 3-aminoazacyclobutane-1-carbonyl, 3-(trifluoromethyl)azacyclobutane-1-carbonyl, azacycloheptane-1-carbonyl, azacyclooctane-1-carbonyl, 3-azabicyclo[3.1.0]hexane-3-carbonyl, octahydrocyclopentadien[c]pyrrole-2-carbonyl or 4-(phenylamino)piperidine-1-carbonyl.

[0182] In some implementation schemes, R 1 It is -C(O)R a3 , where R a3 It is C 1-6 Alkyl, Halogenated C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-S-, C3-8 cycloalkyl, phenyl, heteroaryl, or heterocyclic, wherein each of the C3-8 cycloalkyl, phenyl, heteroaryl, or heterocyclic groups is unsubstituted or substituted by one or more substituents selected from: halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl group. In some embodiments, R a3 It is methyl, ethyl, isopropyl, propyl, ethynyl, vinyl, methoxy, ethoxy, ethanethiol, 1-methylcyclopropane, 1-fluorocyclopropane, 2,2-difluorocyclopropane, 1-(trifluoromethyl)cyclopropane, cyclopropyl, cyclobutyl, thiazole-4-carbonyl, or 1H-imidazol-1-carbonyl.

[0183] R 1 As a heteroaryl or heterocyclic group

[0184] In some implementation schemes, R 1 It is a heteroaryl group, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents selected from the following: halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, phenoxy, -NR b2 R b3 -C(O)NR b2 R b3 -OC(O)NR b2 R b3 -C(O)R b2 or -NR b2 C(O)R b3 In some implementations, R 1 It is a thiazolyl, thiadiazolyl, imidazolyl, pyridyl, pyrazinyl, oxypyrazinyl, pyrimidinyl, oxypyrimidinyl, pyridazinyl, pyridinyl, or benzo[d]thiazolyl, each of which is unsubstituted or substituted as defined above. In some embodiments, R 1 It is thiazol-2-yl, thiazol-4-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1H-imidazol-2-yl, pyridin-2-yl, pyrazin-2-yl, pyrazinyl oxide, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidinyl oxide, pyridazin-3-yl, pyrimidin-5-yl, pyridin-2-yl, pyrazin-2-yl, pyridazin-3-yl, or benzo[d]thiazol-2-yl.

[0185] In some implementation schemes, R 1 It is thiazol-2-yl, thiazol-4-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1H-imidazol-2-yl, pyridin-2-yl, pyrazin-2-yl, pyrazin 1-oxide, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin 1-oxide, pyridazin-3-yl, 3-chloropyridin-2-yl, 3-fluoropyridin-2-yl, 3-methylpyridin-2-yl, 3-(trifluoromethyl)pyridin-2-yl, 5-bromopyrimidin-4-yl, 5-chloropyrimidin-4-yl, 5-fluoropyrimidin-4-yl, 5-methylpyrimidin- 4-yl, 5-(trifluoromethyl)pyrimidin-4-yl, 3-methylpyrazin-2-yl, 5-fluoropyridin-2-yl, 3,5-difluoropyridin-2-yl, 5-methylthiazol-4-yl, 1-methyl-1H-imidazol-2-yl, N,N-dimethylaminocarbonylpyrimidin-5-yl, N,N-dimethylaminocarbonylpyridin-2-yl, N,N-dimethylaminocarbonylpyrazin-2-yl, N,N-dimethylaminocarbonylpyridazin-3-yl, 5-phenoxypyridin-2-yl, 5-phenoxypyrazin-2-yl or benzo[d]thiazol-2-yl.

[0186] In some embodiments, the compounds exemplified in this application are disclosed herein.

[0187] In one aspect, this article provides a method for inhibiting FTO or for treating diseases associated with excessive FTO activity, including obesity, obesity-related diseases, and Alzheimer's disease. Specifically, this article discloses a method for inhibiting weight gain in subjects; or promoting weight loss; or lowering serum LDL, cholesterol, LDL-c, or triglycerides; or treating obesity or obesity-related diseases (especially obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipidemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease), macular degeneration, or Alzheimer's disease; or treating injury or promoting wound healing or tissue regeneration, said method comprising administering an effective amount of the compound disclosed herein to a subject in need.

[0188] In one aspect, this document provides the use of the disclosed compounds in the manufacture of pharmaceutical agents for inhibiting weight gain; or promoting weight loss; or lowering serum LDL, cholesterol, LDL-c, or triglycerides; or treating obesity or obesity-related diseases (especially obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipidemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease), macular degeneration, or Alzheimer's disease; or treating injury or promoting wound healing or tissue regeneration.

[0189] In one aspect, this document provides any of the compounds disclosed herein, said compounds being used to: inhibit weight gain; or promote weight loss; or lower serum LDL, cholesterol, LDL-c, or triglycerides; or treat obesity or obesity-related diseases (especially obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipidemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease), macular degeneration, or Alzheimer's disease; or treat injury or promote wound healing or tissue regeneration.

[0190] In some embodiments of the above-described method or use, the method or use is characterized by FTO suppression. Detailed Implementation

[0191] definition

[0192] The following terms have indicative meanings throughout the specification:

[0193] As used herein (including the appended claims), unless the context clearly specifies otherwise, singular terms such as “a” and “the” include their corresponding plural referents.

[0194] Unless the context clearly specifies otherwise, the term “or” is used to mean the terms “and / or” and is used interchangeably with them.

[0195] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched saturated hydrocarbon groups containing 1 to 18 carbon atoms (such as 1 to 12, further such as 1 to 10, even further such as 1 to 8, 1 to 6, or 1 to 4). Alkyl groups containing 1 to 6 carbon atoms (i.e., C46) are also included. 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl, 2-propyl or isopropyl, 1-butyl or n-butyl, 2-methyl-1-propyl or isobutyl, 1-methylpropyl or sec-butyl (“s-Bu”), 1,1-dimethylethyl or tert-butyl (“t-Bu”), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl. Alkyl groups may optionally be substituted or enriched with deuterium, for example, -CD3 (methyl-d3), -CD2CD3 (ethyl-d5), etc.

[0196] The term "alkylene" refers to a divalent alkyl group as defined herein. For example, methylene refers to -CH2-.

[0197] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0198] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine, and iodine). Examples of haloalkyl groups include halogenated C264 alkyl groups. 1-8 Alkyl, Halogenated C 1-6 Alkyl or halogenated C 1-4 Alkyl groups, but not limited to -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0199] The term "alkyloxy" or "alkoxy" refers to an alkyl group as defined above, which is attached to a portion of the parent molecule by an oxygen atom. Alkoxy groups (e.g., C16) 1-6 Alkoxy or C 1-4 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy, and hexoxy.

[0200] The term "alkoxy-alkyl-" refers to an alkyl group as defined above, further substituted with an alkoxy group as defined above. Alkoxy-alkyl- (e.g., C10) 1-6 Alkoxy-C 1-6 Examples of alkyl- include, but are not limited to, methoxymethyl, ethoxymethyl, ethoxyethyl, isopropoxymethyl, or propoxymethyl.

[0201] The term "amino" refers to -NH2. The term "alkylamino" refers to -NH (alkyl). The term "dialkylamino" refers to -N (alkyl)2.

[0202] The term "alkenyl" in this document refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups, which contains at least one C=C double bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Alkenyl (e.g., C...) 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl (or vinyl), propenyl, propenyl-2-alkenyl, 2-methylpropenyl, butenyl, butenyl-2-alkenyl, butenyl-3-alkenyl, butenyl-1,3-dienyl, 2-methylbutenyl-1,3-dienyl, hexenyl-1-alkenyl, hexenyl-2-alkenyl, hexenyl-3-alkenyl, hexenyl-4-alkenyl, and hexenyl-1,3-dienyl.

[0203] The term "alkenyl" refers to a divalent alkenyl group as defined herein.

[0204] The term "alkynyl" in this document refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups, which contains at least one C≡C triple bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Alkynyl (e.g., C...) 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propynyl), 1-butynyl, 2-butynyl and 3-butynyl.

[0205] The term "ethynyl" refers to a divalent ethynyl group as defined herein.

[0206] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused cycloalkyl, bridged cycloalkyl, or spirocycloalkyl.

[0207] For example, cycloalkyl groups can contain 3 to 12 (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4) carbon atoms. Even further, for example, cycloalkyl groups can be selected from monocyclic groups containing 3 to 12 (such as 3 to 10, further such as 3 to 8, 3 to 6) carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Specifically, saturated monocyclic cycloalkyl groups (e.g., C16, C26 ... 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In a preferred embodiment, the cycloalkyl group is a monocyclic ring (abbreviated as C16) containing 3 to 6 carbon atoms. 3-6 Cycloalkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged in a fused bicyclic arrangement selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or bridging bicyclic groups selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those bicyclic arrangements selected from [5,6] and [6,6] ring systems. In some embodiments, the cycloalkyl group also contains at least one double bond or at least one triple bond.

[0208] The term "deuterated" in deuterated analogues is used herein to modify a chemical structure or organic group or radical in which one or more carbon-bonded hydrogen atoms are replaced by one or more deuterium atoms, such as "deuterated-alkyl," "deuterated-cycloalkyl," "deuterated-heterocycloalkyl," "deuterated-aryl," "deuterated-heteroaryl," "deuterated-heterocyclic," etc. For example, the term "deuterated-alkyl" as defined above refers to an alkyl group as defined herein, in which at least one carbon-bonded hydrogen atom is replaced by deuterium. In a deuterated alkyl group, at least one carbon atom is bonded to deuterium; and it is possible for a carbon atom to be bonded to more than one deuterium atom; it is also possible for more than one carbon atom in an alkyl group to be bonded to deuterium. For example, -CD3 and methyl-d3 are interchangeable and refer to a methyl group in which all three hydrogen atoms are replaced by deuterium. Other deuterated groups, such as deuterated alkyl groups, are interpreted accordingly.

[0209] The term "aryl" used alone or in combination with other terms refers to a group selected from the following:

[0210] -5- and 6-membered carbon rings, aromatic rings, such as phenyl;

[0211] - Bicyclic ring systems, such as 7- to 12-membered bicyclic ring systems, wherein at least one ring is a carbocyclic ring and aromatic, such as naphthyl and indanyl; and

[0212] - Tricyclic ring systems, such as decacyclic to 15-membered tricyclic ring systems, wherein at least one ring is a carbocyclic ring and an aromatic ring, such as a fluorene group.

[0213] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably in the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 cyclic carbon atoms (i.e., C5-10 aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthraceneyl, phenanthrene, etc. In some embodiments, the aromatic hydrocarbon ring is a naphthyl ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0214] The term "heteroaryl" in this article refers to a group selected from the following:

[0215] - A 5, 6 or 7-membered aromatic monocyclic ring containing at least one heteroatom, for example 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in some embodiments 1 to 2 heteroatoms, wherein the heteroatoms are selected from nitrogen (N), sulfur (S) and oxygen (O), and the remaining ring atoms are carbon.

[0216] - An 8- to 12-membered bicyclic ring comprising at least one heteroatom, for example, 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, wherein the heteroatom is selected from nitrogen, oxygen, or optionally oxidized sulfur (as one or more ring members), the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0217] -11 to 14-membered tricyclic rings containing at least one heteroatom, such as 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, wherein the heteroatom is selected from nitrogen, oxygen or optionally oxidized sulfur (as one or more ring members), the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0218] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group is no greater than 2. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is no greater than 1. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different. The nitrogen atom in one or more rings of a heteroaryl group can be oxidized to form an N-oxide.

[0219] The term “optionally oxidized sulfur” as used in this article refers to S, SO or SO2.

[0220] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 cyclic members, wherein 1, 2, 3, or 4 heteroatomic ring members are independently selected from nitrogen (N), sulfur (S), and oxygen (O), and the remaining ring members are carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring comprising 1 or 2 heteroatomic ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a 5- to 6-membered heteroaryl ring, wherein the heteroaryl ring is monocyclic and has 1 or 2 heteroatomic ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is an 8- to 10-membered heteroaryl ring, wherein the heteroaryl ring is bicyclic and has one or two heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0221] Examples of heteroaryl or monocyclic or bicyclic aromatic heterocycles include, but are not limited to (numbered from the connection position specified as priority 1), pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl), cyclophosphino, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (such as 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl), tetrazolium. Thiophene (such as thiophene-2-yl, thiophene-3-yl), triazine, benzothiophene, furanyl (furyl or furanyl), benzofuranyl, benzimidazolyl, indole, isoindole, indolinyl, oxadiazolyl (such as 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrroleyl, triazolyl (such as 1,2,3-triazolyl, 1,2,4-triazolyl or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrroleyl, triazolyl (such as 1,2,3-triazolyl, 1,2,4-triazolyl or 1,3,4-triazolyl), 4-triazolyl), quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridyl (such as 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (such as benzo[d]oxazol-6-yl), pteridylyl, purineyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thiazolyl -2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazanyl (such as furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothiophene, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxolinyl, naphthidyl, furan-pyridyl, benzothiazolyl (such as benzo[d]thiazolyl-6-yl), indazole (such as 1H-indazole-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0222] "Heterocyclic group", "heterocyclic" or "heterocyclic" are interchangeable and refer to a non-aromatic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, the remaining ring members being carbon, including monocyclic, fused, bridged and spirocyclic, i.e. monocyclic heterocyclic groups, bridged heterocyclic groups, spirocyclic groups and fused heterocyclic groups.

[0223] Exemplary monocyclic 4- to 9-membered heterocyclic groups include, but are not limited to (as numbered from the connection position specified as priority 1), pyrrolid-1-yl, pyrrolid-2-yl, pyrrolid-3-yl, imidazolidine-2-yl, imidazolidine-4-yl, pyrrolid-2-yl, pyrrolid-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholinoyl, morpholin-2-yl, morpholin-3-yl, ethylene oxide, aziridine-1-yl -yl, aziridin-2-yl, azircyclic octane-1-yl, azircyclic octane-2-yl, azircyclic octane-3-yl, azircyclic octane-4-yl, azircyclic octane-5-yl, cyclothioethane, azircyclic butane-1-yl, azircyclic butane-2-yl, azircyclic butane-3-yl, oxetane, thiobutane, 1,2-dithiobutane, 1,3-dithiobutane, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thiooxane, piperazine, homopiperazine High piperidinyl, aziridine-1-yl, aziridine-2-yl, aziridine-3-yl, aziridine-4-yl, oxacycloheptyl, thiocycloheptyl, 1,4-oxathiyl, 1,4-dioxacycloheptyl, 1,4-oxothiocycloheptyl, 1,4-oxacycloheptyl, 1,4-dithiocycloheptyl, 1,4-thiocycloheptyl and 1,4-diazacycloheptyl, 1,4-dithiyl, 1,4-oxacycloheptyl, oxacycloheptyl Zollyl, diazazollyl, thiazollyl, dihydrothiophenyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiaranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxane, 1,3-dioxolane, pyrazolinyl, pyrazolane, dithiane, dithiopentane, pyrazolane, imidazolinyl, pyrimidinoneyl, or 1,1-dioxo-thiomorpholinyl.

[0224] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other. Where the compounds disclosed herein have two or more asymmetric centers, they may also exist as diastereomers. Enantiomers and diastereomers fall within the broader category of stereoisomers. This is intended to include all such possible stereoisomers as substantially pure enantiomers, their racemic mixtures, and mixtures of diastereomers. This is intended to include all stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise explicitly stated, reference to one isomer applies to all possible isomers. Whenever an isomer composition is not specified, all possible isomers are included.

[0225] When the compounds disclosed herein contain alkene double bonds, such double bonds are intended to include both E and Z geometric isomers unless otherwise specified.

[0226] When the compounds disclosed herein contain a disubstituted cyclohexyl or cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring can be in cis or trans configurations. A cis configuration means that the two substituents are located above the two substituent positions on the carbon atom, while a trans configuration means that they are located on opposite sides.

[0227] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter separated) to the desired homogeneity using techniques commonly used in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve many methods, including, for example: reversed-phase and normal-phase; size exclusion; ion exchange; high, medium, and low-pressure liquid chromatography methods and apparatus; small-scale analytical; simulated moving bed (“SMB”) and preparative thin-layer or thick-layer chromatography; and techniques for small-scale thin-layer and rapid chromatography. Those skilled in the art will apply the techniques most likely to achieve the desired separation.

[0228] "Diarrhetinic isomers" refer to stereoisomers of compounds having two or more chiral centers, but which are not mirror images of each other. They can be separated into their individual diastereomers based on physicochemical differences, using methods well known to those skilled in the art (such as chromatography and / or stepwise crystallization). Enantiomers can be separated by reacting an enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting (e.g., hydrolyzing) the respective diastereomers into their corresponding pure enantiomers. Enantiomers can also be separated using a chiral HPLC column.

[0229] A single stereoisomer, such as a substantially pure enantiomer, can be obtained by resolving a racemic mixture using an optically active resolving agent using methods such as diastereomeric formation [Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH, et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113(3) (1975): pp. 283-302]. Racemic mixtures of the chiral compounds of the present invention can be separated and isolated by any suitable method, including: (1) forming ionic diastereomeric salts with the chiral compound and separating them by fractional crystallization or other methods; (2) forming diastereomeric compounds with a chiral derivatizing agent, separating the diastereomeric compounds and converting them into pure stereoisomers; and (3) directly separating substantially pure or enriched stereoisomers under chiral conditions. See: Wainer, Irving W. ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0230] A "tautomer" is a type of isomer that includes two or more interconvertible compounds resulting from at least one form of hydrogen atom migration and at least one change in valence (e.g., from single to double, triple to single, or vice versa). For example, a triazolyl group can have the following tautomeric forms: , or .

[0231] "Pharmaceutically acceptable salts" are salts that, within the bounds of reliable medical judgment, are suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and are proportionate to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or individually by reacting a free base functional group with a suitable organic acid or by reacting an acidic group with a suitable base.

[0232] Alternatively, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt (such as a pharmaceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and treating said solution with acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize that various synthetic methodologies can be used to prepare non-toxic, pharmaceutically acceptable addition salts without requiring excessive experimentation.

[0233] As defined herein, “pharmaceutically acceptable salts” include salts of at least one compound of formula (I) and salts of stereoisomers of the compound of formula (I), such as enantiomer salts and / or diastereomer salts.

[0234] When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, the terms “administration,” “administering,” “treating,” and “treatment” herein mean contact between an exogenous agent, therapeutic agent, diagnostic agent, or composition and said animal, human, subject, cell, tissue, organ, or biological fluid. Cellular treatment encompasses contact between the reagent and said cells, as well as contact between the reagent and a fluid, wherein the fluid contacts the cells. The terms “administration” and “treatment” also mean in vitro and ex vivo treatment of, for example, cells by means of a reagent, diagnostic agent, conjugated compound, or another cell. The term “subject” herein includes any biological entity, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit), and most preferably a human.

[0235] The term "effective amount" or "therapeutic effective amount" refers to an amount of active ingredient (such as a compound) that, when administered to a subject to treat a disease or at least one clinical symptom of a disease or disorder, is sufficient to affect such treatment of said disease, disorder, or symptom. "Therapeutic effective amount" can vary depending on: the compound; the disease, disorder, and / or the symptoms of the disease or disorder; the severity of the disease, disorder, and / or the symptoms of the disease or disorder; the age of the subject to be treated; and / or the weight of the subject to be treated. In any given example, appropriate amount will be clear to those skilled in the art or can be determined by routine experiments. In some embodiments, "therapeutic effective amount" is the amount of at least one compound disclosed herein and / or at least one stereoisomer thereof and / or at least one pharmaceutically acceptable salt thereof that is effective in "treating" (as defined above) a subject's disease or disorder. In the case of combination therapies, "therapeutic effective amount" refers to the total amount of the combination of substances used to effectively treat a disease, disorder, or symptom.

[0236] Throughout the specification and the subsequent claims, unless the context otherwise requires, the term "comprising" and its variations such as "comprises" are intended to describe the presence of the following feature, but do not exclude the presence or addition of one or more other features. When used herein, the term "comprising" may be replaced by the terms "containing," "including," or sometimes "having."

[0237] Throughout the specification and subsequent claims, the term "Cn-m" indicates a range including the endpoints, where n and m are integers and represent the number of carbon atoms. Examples include C1-8, C... 1-6 wait.

[0238] Expressing "unsubstituted or substituted", for example, "unsubstituted or substituted". d "Substitution" means that such a group is either unsubstituted or substituented by at least one substituent (e.g., R). d Replaced by. Regarding "replaced by," for example, "replaced by R..." d "Substitution" unless the number of substituents is specified, usually refers to a group being substituented by at least one substituent (e.g., 1 to 4, 1 to 3, 1 or 2, or 1 substituent) (e.g., selected from R). d The substitution condition is that it conforms to the valence theory.

[0239] The terms “at least one” and “one or more” are interchangeable and refer to one, two, three or more of the objects referred to by the terms. Specifically, the term “at least one substituent” refers to one, two, three or more substituents, such as 1 to 5, 1 to 4, 1 to 3, 1 or 2 or one substituent, as long as the valence theory is satisfied.

[0240] Example

[0241] Unless otherwise explicitly instructed, reagents and solvents are obtained from commercial sources (such as Sigma-Aldrich, Alfa, Sinopharm Chemical Reagent Co. (SCRC) or others).

[0242] As used herein, the symbols and conventions used in these methods, schemes, and embodiments, whether or not specific abbreviations are explicitly defined, are consistent with those used in contemporary scientific literature (e.g., the Journal of the American Chemical Society or the Journal of Biochemistry).

[0243] Specifically, but not limited to, the following abbreviations may be used in the embodiments and throughout the specification:

[0244]

[0245] The following examples are for illustrative purposes only, whether for intermediates or the final compound. However, the invention should not be limited thereto.

[0246]

[0247] Intermediate Aa1

[0248]

[0249] Step 1: Synthesis of 6-bromo-4-chloro-1H-benzo[d][1,2,3]triazole(2)

[0250] NaNO2 (1.6 g, 23.3 mmol) was added to a solution of 5-bromo-3-chlorophenyl-1,2-diamine (5 g, 22.6 mmol) in AcOH (30 mL) and H2O (15 mL). The mixture was stirred at room temperature for 6 h. The reaction mixture was then filtered to obtain the product (5 g, 95%). MS [M+H] + The calculated value for C6H3BrClN3 is 234.2, and the measured value is also 234.2.

[0251] Step 2: Synthesis of methyl 4-chloro-1H-benzo[d][1,2,3]triazole-6-carboxylate (3)

[0252] A solution of 6-bromo-4-chloro-1H-benzo[d][1,2,3]triazole (5 g, 21.6 mmol), TEA (6.5 g, 64.7 mmol), and Pd(dppf)Cl2•DCM (1.2 g, 1.1 mmol) in MeOH (40 mL) was stirred at 80ºC for 6 h under CO2. The reaction solution was removed under vacuum to give the crude product. Further purification by column chromatography (silica gel, PE / EA = 1 / 1) yielded the desired product (4 g, 88%). MS [M+H] + The calculated value for C8H6ClN3O2 is 212.2, and the measured value is also 212.2.

[0253] Step 3: Synthesis of 4-chloro-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (4)

[0254] LiOH (198 mg, 4.7 mmol) was added to a solution of methyl 4-chloro-1H-benzo[d][1,2,3]triazol-6-carboxylate (500 mg, 2.4 mmol) in THF / H₂O (5 / 5 mL) at 0°C. After addition, the reaction was warmed to room temperature and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted with EA (100 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum to give the desired product (300 mg, 64%). MS [M+H] + The calculated value for C7H4ClN3O2 is 198.2, and the measured value is also 198.2.

[0255] Intermediate Aa2

[0256]

[0257] Step 1: Synthesis of methyl 4-bromo-1H-benzo[d][1,2,3]triazole-6-carboxylate (2)

[0258] AcOH (3.1 g, 51.23 mmol) and NaNO₂ (2.8 g, 40.98 mmol) were added to a solution of methyl 3,4-diamino-5-bromobenzoate (5 g, 20.49 mmol) in H₂O (80 mL). The mixture was stirred at 25ºC for 1 h. The resulting solid was filtered, washed with water, and dried to obtain the product (5.1 g, crude). MS [M+2] + The calculated value for C8H6BrN3O2 is 258.0, and the measured value is also 258.0.

[0259] Step 2: Synthesis of 4-bromo-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (3)

[0260] LiOH (247 mg, 5.88 mmol) was added to a solution of methyl 7-chloro-1H-benzo[d][1,2,3]triazol-6-carboxylate (500 mg, 1.96 mmol) in THF / H₂O (3 / 3 mL) at 0°C. After addition, the reaction was warmed to room temperature and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted with EA (100 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum to give the desired product (400 mg, 85%). MS [M+2] + The calculated value for C7H4ClN3O2 is 244, and the measured value is also 244.

[0261] intermediate Aa3

[0262]

[0263] Step 1: Synthesis of 4-nitro-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (2)

[0264] HNO3 (40 mL) was added dropwise to a solution of 1H-benzo[d][1,2,3]triazol-6-carboxylic acid (1.8 g, 11.04 mmol) in H2SO4 (40 mL) at 0ºC. After the addition, the mixture was stirred at 90ºC for 2 hours. The reaction mixture was quenched with ice. It was filtered and the solid was collected. The solid was washed with water until neutral to obtain the product (600 mg, 26%). MS [M+H] + The calculated value for C7H4N4O4 is 209.0, and the measured value is also 209.0.

[0265] Intermediate Aa4 (Method 1)

[0266]

[0267] Step 1: Synthesis of 6-bromo-4-methyl-1H-benzo[d][1,2,3]triazole(2)

[0268] AcOH (1.42 mL, 24.88 mmol) was added to a solution of 5-bromo-3-methylphenyl-1,2-diamine (2 g, 9.95 mmol) and NaNO2 (1.37 g, 19.9 mmol) in H2O (20 mL). The mixture was stirred at room temperature for 2 h. The solution was concentrated to dryness under vacuum to give the desired product (1.5 g, 71%). MS [M+H] + The calculated value for C7H6BrN3 is 211.97, and the measured value is also 211.97.

[0269] Step 2: Synthesis of methyl 4-methyl-1H-benzo[d][1,2,3]triazole-6-carboxylate (3)

[0270] A solution of 6-bromo-4-methyl-1H-benzo[d][1,2,3]triazole (800 mg, 3.77 mmol), TEA (1.57 mL, 11.32 mmol), and Pd(dppf)Cl2 (310.1 mg, 0.38 mmol) in MeOH (10 mL) was stirred at 80ºC for 5 h under CO2. The mixture was extracted with EA (50 mL * 3), dried over Na2SO4, and concentrated to dryness under vacuum. The residue was purified by column chromatography (silica gel, PE / EA = 1 / 5) to give the desired product (350 mg, 48%). MS [M+H]+ The calculated value for C9H9N3O2 is 192.07, and the measured value is also 192.07.

[0271] Step 3: Synthesis of 4-methyl-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (4)

[0272] LiOH (131.94 mg, 3.14 mmol) was added to a solution of methyl 4-methyl-1H-benzo[d][1,2,3]triazol-6-carboxylate (300 mg, 1.57 mmol) in THF / H₂O (4 / 1 mL) at 0°C. After addition, the reaction was warmed to room temperature and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted with EA (30 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum to give the desired product (200 mg, 72%). MS [M+H] + The calculated value for C8H7N3O2 is 178.05, and the measured value is also 178.05.

[0273] Intermediate Aa4 (Method 2)

[0274]

[0275] Step 1: Synthesis of methyl 4-methyl-1H-benzo[d][1,2,3]triazole-6-carboxylate (2)

[0276] To a solution of methyl 4-bromo-1H-benzo[d][1,2,3]triazol-6-carboxylate (300 mg, 1.18 mmol) in dioxane (5 mL) and H₂O (1 mL), Pd(dppf)Cl₂ (86 g, 0.12 mmol), K₂CO₃ (407 g, 2.95 mmol), and 2,4,6-trimethyl-1,3,5,2,4,6-trioxaboranecyclohexane (1.78 g, 3.54 mmol) were added. The mixture was stirred at 100ºC for 18 h under N₂ atmosphere. The mixture was neutralized with hydrochloric acid, extracted with EA (20 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum to give the desired product (120 mg, 53%). MS [M+H] + The calculated value for C9H9N3O2 is 192.1, and the measured value is also 192.1.

[0277] Step 2: Synthesis of 4-methyl-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (3)

[0278] LiOH (79 mg, 1.88 mmol) was added to a solution of methyl 4-methyl-1H-benzo[d][1,2,3]triazol-6-carboxylate (120 mg, 0.63 mmol) in THF / H₂O (3 / 3 mL) at 0ºC. After addition, the reaction was warmed to room temperature and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted with EA (10 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum to give the desired product (90 mg, 81%). MS [M+H] + The calculated value for C8H7N3O2 is 178.1, and the measured value is also 178.1.

[0279] intermediate Aa5

[0280]

[0281] Step 1: Synthesis of 5-bromo-3-(trifluoromethyl)benzene-1,2-diamine (2)

[0282] To a solution of 4-bromo-2-nitro-6-(trifluoromethyl)aniline (1 g, 3.51 mmol), Zn (2.3 g, 35.09 mmol), and ammonium formate (2.2 g, 35.09 mmol) in MeOH (20 mL), the mixture was stirred at 60ºC for 1 h. The reaction solution was filtered and the mixture was extracted with EA (50 mL * 3) and dried over Na2SO4. The solution was concentrated to dryness under vacuum to give the desired product (890 mg, 99%). MS [MH] + The calculated value for C7H6BrF3N2 is 254.97, and the measured value is also 254.97.

[0283] Step 2: Synthesis of 6-bromo-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole (3)

[0284] AcOH (0.49 mL, 8.53 mmol) was added to a solution of 5-bromo-3-(trifluoromethyl)phenyl-1,2-diamine (870 mg, 3.41 mmol) and NaNO2 (470 mg, 6.82 mmol) in H2O (8 mL). The mixture was stirred at room temperature for 2 h. The solution was concentrated to dryness under vacuum to give the desired product (850 mg, 93%). MS [MH] + The calculated value for C7H3BrF3N3 is 265.95, and the measured value is also 265.95.

[0285] Step 3: Synthesis of methyl 4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole-6-carboxylate (4)

[0286] A solution of 6-bromo-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole (200 mg, 0.75 mmol), TEA (228 mg, 2.26 mmol), and Pd(dppf)Cl2•DCM (62 mg, 0.075 mmol) in MeOH (8 mL) was stirred at 100ºC for 8 h under CO2. The mixture was extracted with EA (50 mL * 3), dried over Na2SO4, and concentrated to dryness under vacuum. The residue was purified by column chromatography (silica gel, PE / EA = 4 / 1) to give the desired product (97 mg, 52.8%). MS [MH] - The calculated value for C9H6F3N3O2 is 246.04, and the measured value is also 246.04.

[0287] Step 4: Synthesis of 4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (5)

[0288] LiOH (83 mg, 1.98 mmol) was added to a solution of methyl 4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-carboxylate (97 mg, 0.40 mmol) in THF / H₂O (4 / 2 mL). After addition, the reaction was stirred at room temperature for 8 h. The mixture was neutralized with hydrochloric acid, extracted with EA (30 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum to give the desired product (67 mg, 72.5%). MS [MH] + The calculated value for C8H4F3N3O2 is 232.03, and the measured value is also 232.03.

[0289] Intermediate Aa6

[0290]

[0291] Step 1: Synthesis of methyl 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole-6-carboxylate (2)

[0292] DIEA (1.6 g, 9.43 mmol) and SEMCl (0.9 g, 5.19 mmol) were added to a solution of methyl 4-chloro-1H-benzo[d][1,2,3]triazol-6-carboxylate (1 g, 4.72 mmol) in DMF (10 mL) at 0ºC and stirred overnight at room temperature. The reaction mixture was cooled to 0ºC and a saturated aqueous solution of NaCl (30 mL) was added to the reaction mixture. Extraction was performed by EA (100 mL * 3), followed by drying with Na2SO4 and further purification by column chromatography (silica gel, PE / EA = 1 / 1) to give the desired product (1 g, 62%). MS [M+H] + For C 14 H 20 The calculated value of ClN3O3Si is 342.2, and the measured value is also 342.2.

[0293] Step 2: Synthesis of methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-benzo[d][1,2,3]triazole-6-carboxylate (3)

[0294] To a solution of methyl 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-6-carboxylate (1 g, 2.92 mmol) in dry toluene (40 mL), LiCl (368 mg, 8.76 mmol), CuI (55 mg, 0.29 mmol), and Pd(PPh3)4 (335 mg, 0.29 mmol) were added, and the mixture was stirred at the same temperature and then microwaved at 130ºC for 2 h. The reaction mixture was extracted with EA (50 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 1 / 1) to obtain the product (660 mg, 68%). MS [M+H] + For C 16 H 23 The calculated value of N3O3Si is 334.2, and the measured value is also 334.2.

[0295] Step 3: Synthesis of methyl 4-vinyl-1H-benzo[d][1,2,3]triazole-6-carboxylate (4)

[0296] TFA (5 mL) was added to a solution of methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-benzo[d][1,2,3]triazol-6-carboxylate (660 mg, 1.98 mmol) in DCM (10 mL) at 0ºC for 4 h. The mixture was concentrated and purified by column chromatography (silica gel, PE / EA = 1 / 3) to give the desired product (350 mg, 87%). MS [M+H] + For C 10 The calculated value of H9N3O2 is 204.2, and the measured value is also 204.2.

[0297] Step 4: Synthesis of methyl 4-ethyl-1H-benzo[d][1,2,3]triazole-6-carboxylate (5)

[0298] A solution of methyl 4-vinyl-1H-benzo[d][1,2,3]triazole-6-carboxylate (350 mg, 1.72 mmol) and Pd / C (150 mg) in MeOH (10 mL) was stirred at room temperature under H2 for 2 h. The reaction solution was filtered to remove Pd / C and then removed under vacuum to give the desired product (200 mg, 57%). MS [M+H] + For C 10 H 11 The calculated value of N3O2 is 206.2, and the measured value is also 206.2.

[0299] Step 5: Synthesis of 4-ethyl-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (6)

[0300] LiOH (123 mg, 2.93 mmol) was added to a solution of methyl 4-ethyl-1H-benzo[d][1,2,3]triazol-6-carboxylate (200 mg, 0.98 mmol) in THF / H₂O (5 / 5 mL) at 0°C. After addition, the reaction was warmed to room temperature and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted with EA (100 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (DCM / MeOH = 10 / 1) to obtain the product (150 mg, 80%). MS [M+H] + The calculated value for C9H9N3O2 is 192.2, and the measured value is also 192.2.

[0301] Intermediate Aa7

[0302]

[0303] Step 1: Synthesis of 3-amino-5-bromo-2-nitrobenzenenitrile (2)

[0304] To a solution of 5-bromo-3-fluoro-2-nitroaniline (3 g, 12.77 mmol) in DMF (30 mL), NaCN (751 mg, 15.32 mmol) was added. After stirring overnight at 130ºC, the reaction mixture was cooled to 25ºC and water (60 mL) was added. Extraction was performed by EA (200 mL * 3), followed by drying over Na2SO4, and further purification by column chromatography (silica gel, DCM / MeOH = 25 / 1) to give the desired product (3 g, 97%). MS [M+H] + The calculated value for C7H4BrN3O2 is 242.2, and the measured value is also 242.2.

[0305] Step 2: Synthesis of 2,3-diamino-5-bromobenzonitrile (3)

[0306] Fe (3.5 g, 61.98 mmol) and NH₄Cl (3.3 g, 61.98 mmol) were added to a solution of 3-amino-5-bromo-2-nitrobenzenenitrile (3 g, 12.40 mmol) in MeOH (30 mL). After stirring at 50ºC for 4 h, the reaction mixture was filtered to obtain the product (1.6 g, 61%). MS [M+H] + The calculated value for C7H6BrN3 is 212.2, and the measured value is also 212.2.

[0307] Step 3: Synthesis of 6-bromo-1H-benzo[d][1,2,3]triazole-4-carboxylonitrile (4)

[0308] NaNO2 (547 mg, 7.92 mmol) was added to a solution of 2,3-diamino-5-bromobenzonitrile (1.6 g, 7.55 mmol) in AcOH (8 mL) and H2O (8 mL). The mixture was stirred at room temperature for 3 h. The reaction mixture was then filtered to obtain the product (1.5 g, 89%). MS [M+H] + The calculated value for C7H3BrN4 is 223.2, and the measured value is also 223.2.

[0309] Step 4: Synthesis of methyl 4-cyano-1H-benzo[d][1,2,3]triazole-6-carboxylate (5)

[0310] A solution of 6-bromo-1H-benzo[d][1,2,3]triazol-4-carboxynitrile (1.5 g, 6.73 mmol), TEA (2038 mg, 20.18 mmol), and Pd(dppf)Cl2·DCM (393 mg, 0.34 mmol) in MeOH (20 mL) was stirred at 120ºC for 6 h under CO2. The reaction solution was removed under vacuum to obtain the crude product. Further purification by column chromatography (silica gel, DCM / MeOH = 20 / 1) yielded the desired product (1.2 g, 88%). MS [M+H] + The calculated value for C9H6N4O2 is 203.2, and the measured value is also 203.2.

[0311] Step 5: Synthesis of 4-cyano-1H-benzo[d][1,2,3]triazole-6-carboxylic acid (6)

[0312] LiOH (499 mg, 11.88 mmol) was added to a solution of methyl 4-cyano-1H-benzo[d][1,2,3]triazol-6-carboxylate (1.2 g, 5.94 mmol) in THF / H₂O (5 / 5 mL) at 0°C. After addition, the reaction was warmed to room temperature and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted with EA (100 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum to give the desired product (800 mg, 72%). MS [M+H] + The calculated value for C8H4N4O2 is 189.2, and the measured value is also 189.2.

[0313] intermediate Aa8

[0314]

[0315] Step 1: Synthesis of 2-(difluoromethoxy)-6-nitroaniline (2)

[0316] A solution of 2-amino-3-nitrophenol (2 g, 12.98 mmol), sodium 2-chloro-2,2-difluoroacetate (I) (4.9 g, 32.44 mmol), and K₂CO₃ (2.1 g, 15.57 mmol) in DMF (15 mL) and H₂O (1.5 mL) was added. The mixture was stirred at 100ºC under N₂ for 2.5 h. The mixture was extracted with EA (50 mL * 3), the organic phase was washed with 1M NaOH (50 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum. The residue was purified by column chromatography (silica gel, PE / DCM = 3 / 1) to give the desired product (500 mg, 18%). MS [MH] + The calculated value for C7H6F2N2O3 is 205.03, and the measured value is also 205.03.

[0317] Step 2: Synthesis of 4-bromo-2-(difluoromethoxy)-6-nitroaniline (3)

[0318] Sodium acetate (259.3 mg, 3.16 mmol) and bromine (0.014 mL, 2.17 mmol) were added to a solution of 2-(difluoromethoxy)-6-nitroaniline (403 mg, 1.98 mmol) in AcOH (5 mL). The mixture was stirred at room temperature for 0.2 h. 5 mL of H₂O was added to the reaction solution. The reaction solution was filtered to give the desired product (500 mg, 89%). MS [MH] + The calculated value for C7H5BrF2N2O3 is 282.95, and the measured value is also 282.95.

[0319] Step 3: Synthesis of 5-bromo-3-(difluoromethoxy)benzene-1,2-diamine (4)

[0320] Add 4-bromo-2-(difluoromethoxy)-6-nitroaniline (492 mg, 1.74 mmol), Zn (1.14 g, 17.39 mmol), and ammonium formate (1.1 g, 17.39 mmol) to a solution of MeOH (8 mL). Stir the mixture at 60ºC for 1 h. Filter the reaction solution and extract the mixture by EA (50 mL * 3), drying over Na2SO4. Concentrate to dryness under vacuum to give the desired product (420 mg, 95%). MS [MH] + The calculated value for C7H7BrF2N2O is 252.97, and the measured value is also 252.97.

[0321] Step 4: Synthesis of 6-bromo-4-(difluoromethoxy)-1H-benzo[d][1,2,3]triazole(5)

[0322] AcOH (0.23 mL, 3.95 mmol) was added to a solution of 5-bromo-3-(difluoromethoxy)phenyl-1,2-diamine (400 mg, 1.58 mmol) and NaNO2 (218 mg, 3.16 mmol) in H2O (8 mL). The mixture was stirred at room temperature for 2 h. The solution was concentrated to dryness under vacuum to give the desired product (390 mg, 93%). MS [MH] + The calculated value for C7H4BrF2N3O is 263.95, and the measured value is also 263.95.

[0323] Step 5: Synthesis of methyl 4-methyl-1H-benzo[d][1,2,3]triazole-6-carboxylate (6)

[0324] A solution of 6-bromo-4-methyl-1H-benzo[d][1,2,3]triazole (390 mg, 1.48 mmol), TEA (450 mg, 4.45 mmol), and Pd(dppf)Cl2•DCM (121 mg, 0.15 mmol) in MeOH (16 mL) was stirred at 80ºC for 8 h under CO2. The mixture was extracted with EA (50 mL * 3), dried over Na2SO4, and concentrated to dryness under vacuum. The residue was purified by column chromatography (silica gel, DCM / MeOH = 9 / 1) to give the desired product (270 mg, 75%). MS [MH] - The calculated value for C9H7F2N3O3 is 244.05, and the measured value is also 244.05.

[0325] Step 6: Synthesis of 4-(difluoromethoxy)-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (7)

[0326] LiOH (216 mg, 5.14 mmol) was added to a solution of methyl 4-methyl-1H-benzo[d][1,2,3]triazol-6-carboxylate (250 mg, 1.03 mmol) in THF / H₂O (8 / 4 mL). After addition, the reaction was stirred at 60ºC for 8 h. The mixture was neutralized with hydrochloric acid, extracted with EA (30 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum to give the desired product (220 mg, 93%). MS [MH] + The calculated value for C8H5F2N3O3 is 230.03, and the measured value is also 230.03.

[0327] Intermediate Aa9

[0328]

[0329] Step 1: Synthesis of 5-bromo-3-methoxyphenyl-1,2-diamine (2)

[0330] Zn (2.34 g, 36.5 mmol) and HCOONH4 (2.55 g, 40.6 mmol) were added to a solution of 4-bromo-2-methoxy-6-nitroaniline (1.00 g, 4.06 mmol) in MeOH (15 mL). The mixture was stirred at 60ºC for 2 h. The mixture was filtered and concentrated to dryness under vacuum. Water (10 mL) was added, and the mixture was extracted with DCM (10 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum to give the desired product (800 mg, 91.2%). MS [M+H] + The calculated value for C7H9BrN2O is 217.1, and the measured value is also 217.1.

[0331] Step 2: Synthesis of 6-bromo-4-methoxy-1H-benzo[d][1,2,3]triazole(3)

[0332] AcOH (555 mg, 9.25 mmol) was added to a solution of 5-bromo-3-methoxyphenyl-1,2-diamine (800 mg, 3.70 mmol) and NaNO2 (511 mg, 7.40 mmol) in H2O (20 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness under vacuum to give the desired product (700 mg, 83.3%). MS [M+H] + The calculated value for C7H6BrN3O is 228.2, and the measured value is also 228.2.

[0333] Step 3: Synthesis of methyl 4-methoxy-1H-benzo[d][1,2,3]triazole-6-carboxylate (4)

[0334] TEA (934 mg, 9.25 mmol) and Pd(dppf)Cl2 (219 mg, 0.30 mmol) were added to a solution of 6-bromo-4-methoxy-1H-benzo[d][1,2,3]triazole (700 mg, 3.08 mmol) in MeOH (10 mL). The mixture was stirred at 80ºC for 5 h under CO2. The reaction mixture was quenched with water (10 mL), extracted with EA (10 mL x 3), dried over Na2SO4, and concentrated to dryness under vacuum. The residue was purified by column chromatography (PE / EA = 3 / 2) to give the desired product (600 mg, 94.1%). MS [M+H] + The calculated value for C9H9N3O3 is 208.2, and the measured value is also 208.2.

[0335] Step 4: 4-Methoxy-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (5)

[0336] LiOH (345 mg, 14.4 mmol) was added to a solution of methyl 4-methoxy-1H-benzo[d][1,2,3]triazole-6-carboxylate (600 mg, 2.89 mmol) in THF / H₂O (4 / 1 mL). The mixture was stirred overnight at room temperature. The mixture was adjusted to pH 5 with hydrochloric acid (1 N), filtered, and the cake was collected to give the desired product (400 mg, 71.4%). MS[M+H] + The calculated value for C8H7N3O3 is 194.1, and the measured value is also 194.1.

[0337] Intermediate Aa10

[0338]

[0339] Step 1: Synthesis of 5-bromo-3-fluorobenzene-1,2-diamine (2)

[0340] Zn (2.46 g, 38.4 mmol) and HCOONH4 (2.69 g, 42.7 mmol) were added to a solution of 4-bromo-2-fluoro-6-nitroaniline (1.00 g, 4.27 mmol) in MeOH (15 mL). The mixture was stirred at 60ºC for 2 h. The mixture was filtered and concentrated to dryness under vacuum. Water (10 mL) was added, and the mixture was extracted with DCM (15 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum to give the desired product (810 mg, 92.9%). MS [M+H] +The calculated value for C6H6BrFN2 is 205.1, and the measured value is also 205.1.

[0341] Step 2: Synthesis of 6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazole(3)

[0342] AcOH (595 mg, 9.92 mmol) was added to a solution of 5-bromo-3-fluorophenyl-1,2-diamine (810 mg, 3.97 mmol) and NaNO2 (547 mg, 7.94 mmol) in H2O (20 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness under vacuum to give the desired product (700 mg, 82.0%). MS [M+H] + The calculated value for C6H3BrFN3 is 216.1, and the measured value is also 216.1.

[0343] Step 3: Synthesis of methyl 4-fluoro-1H-benzo[d][1,2,3]triazole-6-carboxylate (4)

[0344] TEA (986 mg, 9.76 mmol) and Pd(dppf)Cl2 (234 mg, 0.32 mmol) were added to a solution of 6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazole (700 mg, 3.25 mmol) in MeOH (10 mL). The mixture was stirred at 80ºC for 16 h under CO2. The reaction mixture was quenched with water (10 mL), extracted with EA (10 mL x 3), dried over Na2SO4, and concentrated to dryness under vacuum. The residue was purified by column chromatography (PE / EA = 3 / 2) to give the desired product (590 mg, 93.0%). MS [M+H] + The calculated value for C8H6FN3O2 is 196.1, and the measured value is also 196.1.

[0345] Step 4: 4-Fluoro-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (5)

[0346] LiOH (363 mg, 15.1 mmol) was added to a solution of methyl 4-fluoro-1H-benzo[d][1,2,3]triazol-6-carboxylate (590 mg, 3.02 mmol) in THF / H₂O (4 / 1 mL). The mixture was stirred overnight at room temperature. The mixture was adjusted to pH 5 with hydrochloric acid (1 N), filtered, and the cake was collected to give the desired product (450 mg, 82.3%). MS [M+H] +The calculated value for C7H4FN3O2 is 182.1, and the measured value is also 182.1.

[0347] Intermediate Aa11

[0348]

[0349] Step 1: Synthesis of (6-bromo-1H-benzo[d][1,2,3]triazol-4-yl)methanol(2)

[0350] NaBH4 (3.0 g, 78.13 mmol) was added to a solution of methyl 6-bromo-1H-benzo[d][1,2,3]triazol-4-carboxylate (5 g, 19.53 mmol) in MeOH (50 mL) at 0°C and stirred at 60°C for 4 h. The reaction mixture was cooled to 0°C and a saturated aqueous solution of NH4Cl (50 mL) was added to the reaction mixture. Extraction was performed by EA (150 mL * 3), drying was performed by Na2SO4, and further purification was carried out by column chromatography (silica gel, PE / EA = 1 / 2) to give the desired product (2 g, 45%). MS [M+H] + The calculated value for C7H6BrN3O is 228.2, and the measured value is also 228.2.

[0351] Step 2: Synthesis of methyl 4-(hydroxymethyl)-1H-benzo[d][1,2,3]triazole-6-carboxylate (3)

[0352] A solution of (6-bromo-1H-benzo[d][1,2,3]triazol-4-yl)methanol (2 g, 8.77 mmol), TEA (2658 mg, 26.32 mmol), and Pd(dppf)Cl2·DCM (711 mg, 0.88 mmol) in MeOH (20 mL) was stirred at 120ºC for 6 h under CO2. The reaction solution was removed under vacuum to give the crude product. Further purification by column chromatography (silica gel, PE / EA = 1 / 2) yielded the desired product (1.5 g, 83%). MS [M+H] + The calculated value for C9H9N3O3 is 208.2, and the measured value is also 208.2.

[0353] Step 3: Synthesis of 4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole-6-carboxylic acid methyl ester (4)

[0354] A solution of methyl 4-(hydroxymethyl)-1H-benzo[d][1,2,3]triazole-6-carboxylate (1.5 g, 7.25 mmol) in DMF (10 mL) was added to DIEA (1.9 g, 14.49 mmol) and SEMCl (2.5 g, 14.49 mmol) and stirred overnight at room temperature. The reaction mixture was cooled to 0°C and a saturated aqueous solution of NaCl (30 mL) was added to the reaction mixture. Extraction was performed by EA (100 mL * 3), drying was performed over Na2SO4, and further purification was carried out by column chromatography (silica gel, PE / EA = 2 / 1) to give the desired product (2.6 g, 77%). MS [M+H] + For C 21 H 37 The calculated value of N3O5Si2 is 468.2, and the measured value is also 468.2.

[0355] Step 4: Synthesis of 4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (5)

[0356] LiOH (700 mg, 16.67 mmol) was added to a solution of methyl 4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-6-carboxylate (2.6 g, 5.56 mmol) in THF / H₂O (15 / 15 mL). After addition, the reaction was warmed to room temperature and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted with EA (100 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 1 / 2) to obtain the product (2 g, 79%). MS [M+H] + For C 20 H 35 The calculated value of N3O5Si2 is 454.2, and the measured value is also 454.2.

[0357] Intermediate Aa12

[0358]

[0359] Step 1: Synthesis of 6-bromo-7-chloro-1H-benzo[d][1,2,3]triazole(2)

[0360] AcOH (1.3 g, 21.6 mmol) and NaNO₂ (1.2 g, 17.28 mmol) were added to a solution of 4-bromo-3-chlorophenyl-1,2-diamine (1.9 g, 8.64 mmol) in H₂O (30 mL). The mixture was stirred at 25ºC for 1 h. The resulting solid was filtered, washed with water, and dried to obtain the product (2.1 g, crude). MS [M+H] + The calculated value for C6H3BrClN3 is 231.9, and the measured value is also 231.9.

[0361] Step 2: Synthesis of methyl 7-chloro-1H-benzo[d][1,2,3]triazole-6-carboxylate (3)

[0362] A solution of 6-bromo-7-chloro-1H-benzo[d][1,2,3]triazole (1.5 g, 6.49 mmol), TEA (1.98 mg, 19.48 mmol), and Pd(dppf)Cl2 (475 mg, 0.65 mmol) in MeOH (15 mL) was stirred at 90ºC for 6 h under CO2. The reaction solution was removed under vacuum to obtain the crude product. Further purification by column chromatography (silica gel, PE / EA = 5 / 1) yielded the desired product (400 mg, 29%). MS [M+H] + The calculated value for C8H6ClN3O2 is 212.0, and the measured value is also 212.0.

[0363] Step 3: Synthesis of 7-chlorobenzo[d]isoxazole-5-carboxylic acid (4)

[0364] LiOH (60 mg, 1.42 mmol) was added to a solution of methyl 7-chloro-1H-benzo[d][1,2,3]triazol-6-carboxylate (100 mg, 0.47 mmol) in THF / H₂O (3 / 3 mL) at 0ºC. After addition, the reaction was warmed to room temperature and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted with EA (100 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum to give the desired product (65 mg, 70%). MS [M+H] + The calculated value for C7H4ClN3O2 is 198.0, and the measured value is also 198.0.

[0365] Intermediate Aa13

[0366]

[0367] Step 1: Synthesis of 4-bromo-3-fluorophenyl-1,2-diamine (2)

[0368] Zn (2.5 g, 38.46 mmol) and HCOONH4 (2.68 g, 42.74 mmol) were added to a solution of 4-bromo-3-fluoro-2-nitroaniline (1 g, 4.27 mmol) in MeOH (30 mL). The mixture was stirred at 60ºC for 2 h. The resulting solid was filtered, washed with DCM, and dried to obtain the product (900 mg, crude). MS [M+H] + The calculated value for C6H6BrFN2 is 205.0, and the measured value is also 205.0.

[0369] Step 2: Synthesis of 6-bromo-7-fluoro-1H-benzo[d][1,2,3]triazole(3)

[0370] AcOH (602 mg, 11.03 mmol) and NaNO₂ (610 mg, 8.82 mmol) were added to a solution of 4-bromo-3-fluorophenyl-1,2-diamine (900 mg, 4.41 mmol) in H₂O (20 mL). The mixture was stirred at 25ºC for 1 h. The resulting solid was filtered, washed with water, and dried to obtain the product (700 mg, crude). MS [M+H] + The calculated value for C6H3BrFN3 is 215.9, and the measured value is also 215.9.

[0371] Step 3: Synthesis of methyl 7-fluoro-1H-benzo[d][1,2,3]triazole-6-carboxylate (4)

[0372] A solution of 6-bromo-7-fluoro-1H-benzo[d][1,2,3]triazole (700 mg, 3.26 mmol) / TEA (987 mg, 9.77 mmol) and Pd(dppf)Cl2 (241 mg, 0.33 mmol) in MeOH (10 mL) was stirred at 90ºC for 6 h under CO2. The reaction solution was removed under vacuum to give the crude product. Further purification by column chromatography (silica gel, PE / EA = 5 / 1) yielded the desired product (320 mg, 51%). MS [M+H] + The calculated value for C8H6FN3O2 is 196.0, and the measured value is also 196.0.

[0373] Step 4: Synthesis of 7-fluoro-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (5)

[0374] LiOH (207 mg, 4.92 mmol) was added to a solution of methyl 7-fluoro-1H-benzo[d][1,2,3]triazol-6-carboxylate (320 mg, 1.64 mmol) in THF / H₂O (3 / 3 mL) at 0°C. After addition, the reaction was warmed to room temperature and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted with EA (100 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum to give the desired product (180 mg, 61%). MS [M+H] + The calculated value for C7H4FN3O2 is 182.0, and the measured value is also 182.0.

[0375] Intermediate Aa14

[0376]

[0377] Step 1: Synthesis of methyl 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxylate (2)

[0378] A solution of 5-bromobenzo[d]isoxazole (900 mg, 4.24 mmol), TEA (1.29 g, 12.73 mmol), and Pd(dppf)Cl2 (155 mg, 0.21 mmol) in MeOH (20 mL) was stirred at 120ºC for 6 h under CO2. The reaction solution was removed under vacuum to obtain the crude product. Further purification by column chromatography (silica gel, PE / EA = 1 / 1) yielded the desired product (700 mg, 86%). MS [M+H] + The calculated value for C9H9N3O2 is 191.2, and the measured value is also 191.2.

[0379] Step 2: Synthesis of 1-methyl-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (3)

[0380] LiOH (176 mg, 7.32 mmol) was added to a solution of methyl 1-methyl-1H-benzo[d][1,2,3]triazol-6-carboxylate (700 mg, 3.66 mmol) in THF / H₂O (7 / 7 mL) at 0ºC. After addition, the reaction was warmed to room temperature and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted with EA (50 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum to give the desired product (300 mg, 46%). MS [M+H] + The calculated value for C8H7N3O2 is 177.2, and the measured value is also 177.2.

[0381] Intermediate Aa15

[0382]

[0383] Step 1: Synthesis of 4-bromo-2-chloro-5-methylaniline (2)

[0384] Br2 (28.14 g, 176.1 mmol) was added to a solution of 2-chloro-5-methylaniline (25 g, 176.1 mmol) in AcOH (250 mL). The reaction mixture was stirred at 100ºC for 3 h under N2. The reaction mixture was quenched with H2O (200 mL) and extracted with DCM (500 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 10 / 1) to obtain the product (21 g, 54.3%). MS [M+H] + The calculated value for C7H7BrClN is 219.9, and the measured value is also 219.9.

[0385] Step 2: Synthesis of N-(4-bromo-2-chloro-5-methylphenyl)acetamide (3)

[0386] Acetyl chloride (8.19 g, 105 mmol) was added to a solution of 4-bromo-2-chloro-5-methylaniline (21 g, 95.45 mmol) and TEA (14.46 g, 143.18 mmol) in THF (210 mL). The reaction was stirred at room temperature for 2 h. The mixture was quenched with ice water and extracted with DCM (300 mL * 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 4 / 1) to obtain the product (17.5 g, 69.7%). MS [M+H] + The calculated value for C9H9BrClNO is 262.0, and the measured value is also 262.0.

[0387] Step 3: Synthesis of N-(4-bromo-6-chloro-3-methyl-2-nitrophenyl)acetamide (4)

[0388] KNO3 (7.39 g, 73.19 mmol) was added to a solution of H2SO4 (175 mL) and N-(4-bromo-2-chloro-5-methylphenyl)acetamide (17.5 g, 66.54 mmol) at 0ºC. The reaction was stirred at room temperature for 2 h. The mixture was quenched with ice water and neutralized to pH = 6 with NaHCO3, and extracted with EA (200 mL * 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 4 / 1) to obtain the product (7.5 g, 36.6%). MS [M+H] + The calculated value for C9H8BrClN2O3 is 306.9, and the measured value is also 306.9.

[0389] Step 4: Synthesis of 4-bromo-6-chloro-3-methyl-2-nitroaniline (5)

[0390] MsOH (7 mL) was added to a solution of N-(4-bromo-6-chloro-3-methyl-2-nitrophenyl)acetamide (7 g, 22.87 mmol) in MeOH (70 mL), and the reaction was stirred at 60ºC for 2 h. The reaction mixture was concentrated to dryness under vacuum to give a crude product (5.5 g, 91.7%). MS [M+H] + The calculated value for C7H6BrClN2O2 is 264.9, and the measured value is also 264.9.

[0391] Step 5: Synthesis of 4-bromo-6-chloro-3-methylphenyl-1,2-diamine (6)

[0392] Zn (7.07 g, 108.75 mmol) and ammonium formate (6.85 g, 108.75 mmol) were added to a solution of 4-bromo-6-chloro-3-methyl-2-nitroaniline (5.5 g, 20.75 mmol) in EtOH (55 mL), and the reaction was stirred at 60ºC for 3 h. The reaction mixture was filtered to obtain a filtrate, which was concentrated to dryness under vacuum and extracted by EA (200 mL * 3), dried over Na2SO4, and concentrated to dryness under vacuum to give the desired product (4.5 g, 91.8%). MS [M+H] + The calculated value for C7H8BrClN2 is 235.0, and the measured value is also 235.0.

[0393] Step 6: Synthesis of 6-bromo-4-chloro-7-methyl-1H-benzo[d][1,2,3]triazole(7)

[0394] NaNO₂ (2.6 g, 38.2 mmol) was added to a solution of 4-bromo-6-chloro-3-methylphenyl-1,2-diamine (4.5 g, 19.1 mmol) in AcOH (25 mL) and H₂O (25 mL). The mixture was stirred at room temperature for 3 h. The reaction mixture was then filtered to obtain the product (3.6 g, 76.8%). MS [M+H] + The calculated value for C7H5BrClN3 is 245.9, and the measured value is also 245.9.

[0395] Step 7: Synthesis of methyl 4-chloro-7-methyl-1H-benzo[d][1,2,3]triazole-6-carboxylate (8)

[0396] A solution of 6-bromo-4-chloro-7-methyl-1H-benzo[d][1,2,3]triazole (200 mg, 0.81 mmol), TEA (245 mg, 2.43 mmol), and Pd(dppf)Cl2 (65 mg, 0.08 mmol) in MeOH (5 mL) was stirred at 100ºC for 16 h under CO2. The reaction solution was removed under vacuum to give the crude product. Further purification by column chromatography (silica gel, PE / EA = 1 / 1) yielded the desired product (120 mg, 65.6%). MS [M+H] + The calculated value for C9H8ClN3O2 is 226.0, and the measured value is also 226.0.

[0397] Step 8: Synthesis of 4-chloro-7-methyl-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (9)

[0398] LiOH (51 mg, 2.12 mmol) was added to a solution of methyl 4-chloro-7-methyl-1H-benzo[d][1,2,3]triazol-6-carboxylate (120 mg, 0.53 mmol) in THF / H₂O (2 / 2 mL) at 0°C. After addition, the reaction was carried out at 50°C for 16 h. The mixture was neutralized with hydrochloric acid, extracted with EA (10 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum to give the desired product (60 mg, 53.6%). MS [M+H] + The calculated value for C8H6ClN3O2 is 212.0, and the measured value is also 212.0.

[0399] Intermediate Aa16

[0400]

[0401] Step 1: Synthesis of 4-bromo-2-chloro-5-methoxyaniline (2)

[0402] 1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (22.47 g, 79.12 mmol) was added to a solution of 2-chloro-5-methoxyaniline (25 g, 158.23 mmol) in EA (250 mL) at -5ºC. The reaction mixture was stirred at room temperature under N2 for 1 h. The reaction mixture was quenched with K2CO3 (200 mL) and extracted with DCM (500 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 10 / 1) to obtain the product (31 g, 83.8%). MS [M+H] + The calculated value for C7H7BrClNO is 235.9, and the measured value is also 235.9.

[0403] Step 2: Synthesis of N-(4-bromo-2-chloro-5-methoxyphenyl)acetamide (3)

[0404] Acetyl chloride (11.27 g, 144.5 mmol) was added to a solution of 4-bromo-2-chloro-5-methoxyaniline (31 g, 131.4 mmol) and TEA (19.91 g, 197.1 mmol) in THF (310 mL). The reaction was stirred at room temperature for 2 h. The mixture was quenched with ice water and extracted with DCM (300 mL * 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 4 / 1) to obtain the product (19.4 g, 53.0%). MS [M+H] + The calculated value for C9H9BrClNO2 is 278.0, and the measured value is also 278.0.

[0405] Step 3: Synthesis of N-(4-bromo-6-chloro-3-methoxy-2-nitrophenyl)acetamide (4)

[0406] KNO3 (7.29 g, 72.16 mmol) was added to a solution of H2SO4 (183 mL) and N-(4-bromo-2-chloro-5-methylphenyl)acetamide (18.3 g, 65.6 mmol) at 0ºC. The reaction was stirred at room temperature for 2 h. The mixture was quenched with ice water and neutralized to pH = 6 with NaHCO3, and extracted with EA (200 mL * 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 4 / 1) to obtain the product (5.6 g, 26.7%). MS [M+H] + The calculated value for C9H8BrClN2O4 is 322.9, and the measured value is also 322.9.

[0407] Step 4: Synthesis of 4-bromo-6-chloro-3-methoxy-2-nitroaniline (5)

[0408] MsOH (5.5 mL) was added to a solution of N-(4-bromo-6-chloro-3-methoxy-2-nitrophenyl)acetamide (5.5 g, 16.98 mmol) in MeOH (55 mL), and the reaction was stirred at 60ºC for 2 h. The reaction mixture was concentrated to dryness under vacuum to give a crude product (4.7 g, 98.5%). MS [M+H] + The calculated value for C7H6BrClN2O3 is 280.9, and the measured value is also 280.9.

[0409] Step 5: Synthesis of 4-bromo-6-chloro-3-methoxyphenyl-1,2-diamine (6)

[0410] Zn (5.44 g, 83.65 mmol) and ammonium formate (5.27 g, 83.65 mmol) were added to a solution of 4-bromo-6-chloro-3-methoxy-2-nitroaniline (4.7 g, 16.73 mmol) in EtOH (47 mL), and the reaction was stirred at 60ºC for 3 h. The reaction mixture was filtered to obtain a filtrate, which was concentrated to dryness under vacuum and extracted by EA (200 mL * 3), dried over Na2SO4, and concentrated to dryness under vacuum to give the desired product (4.0 g, 95.2%). MS [M+H] + The calculated value for C7H8BrClN2O is 251.0, and the measured value is also 251.0.

[0411] Step 6: Synthesis of 6-bromo-4-chloro-7-methoxy-1H-benzo[d][1,2,3]triazole(7)

[0412] NaNO₂ (2.2 g, 31.88 mmol) was added to a solution of 4-bromo-6-chloro-3-methoxyphenyl-1,2-diamine (4 g, 15.94 mmol) in AcOH (40 mL) and H₂O (40 mL). The mixture was stirred at room temperature for 3 h. The reaction mixture was then filtered to obtain the product (2.3 g, 55.2%). MS [M+H] + The calculated value for C7H5BrClN3O is 261.9, and the measured value is also 261.9.

[0413] Step 7: Synthesis of methyl 4-chloro-7-methoxy-1H-benzo[d][1,2,3]triazole-6-carboxylate (8)

[0414] A solution of 6-bromo-4-chloro-7-methoxy-1H-benzo[d][1,2,3]triazole (800 mg, 3.05 mmol), TEA (924 mg, 9.15 mmol), and Pd(dppf)Cl2 (253 mg, 0.31 mmol) in MeOH (15 mL) was stirred at 110ºC for 24 h under CO2. The reaction solution was removed under vacuum to give the crude product. Further purification by column chromatography (silica gel, PE / EA = 1 / 1) yielded the desired product (200 mg, 27.1%). MS [M+H] + The calculated value for C9H8ClN3O3 is 242.0, and the measured value is also 242.0.

[0415] Step 8: Synthesis of 4-chloro-7-methoxy-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (9)

[0416] LiOH (80 mg, 3.32 mmol) was added to a solution of methyl 4-chloro-7-methoxy-1H-benzo[d][1,2,3]triazol-6-carboxylate (200 mg, 0.83 mmol) in THF / H₂O (2 / 2 mL) at 0°C. After addition, the reaction was carried out at 50°C for 16 h. The mixture was neutralized with hydrochloric acid, extracted with EA (10 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum to give the desired product (70 mg, 37.2%). MS [M+H] + The calculated value for C8H6ClN3O3 is 228.0, and the measured value is also 228.0.

[0417] intermediate Ab1

[0418]

[0419] Step 1: Synthesis of methyl benzo[d]isoxazole-5-carboxylate (2)

[0420] A solution of 6-bromo-4-chloro-1H-benzo[d][1,2,3]triazole (2 g, 10.1 mmol), TEA (3.1 g, 30.3 mmol), and Pd(dppf)Cl2·DCM (584 mg, 0.5 mmol) in MeOH (20 mL) was stirred at 120ºC for 6 h under CO2. The reaction solution was removed under vacuum to obtain the crude product. Further purification by column chromatography (silica gel, PE / EA = 1 / 1) yielded the desired product (1.2 g, 67%). MS [M+H] + The calculated value for C9H7NO3 is 178.2, and the measured value is also 178.2.

[0421] Step 2: Synthesis of benzo[d]isoxazole-5-carboxylic acid (3)

[0422] LiOH (569 mg, 13.6 mmol) was added to a solution of methyl benzo[d]isoxazole-5-carboxylate (1.2 g, 6.8 mmol) in THF / H₂O (5 / 5 mL) at 0°C. After addition, the reaction was warmed to room temperature and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted with EA (100 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum to give the desired product (1.05 g, 95%). MS [M+H] + The calculated value for C8H5NO3 is 164.2, and the measured value is also 164.2.

[0423] intermediate Ab2

[0424]

[0425] Step 1: Synthesis of 5-bromo-3-chloro-2-hydroxybenzaldehyde (2)

[0426] Hexamethylenetetramine (1.4 g, 9.66 mmol) was added fractionally to a solution of 4-bromo-2-chlorophenol (1 g, 4.83 mmol) in TFA (10 mL) over 1.5 h. After stirring at 90ºC for 15 h, the reaction mixture was cooled to room temperature and poured into water (20 mL) (exothermic). The mixture was allowed to cool to room temperature, and 50% H₂SO₄ aqueous solution (5 mL) was added. The mixture was allowed to cool to room temperature, and the precipitate was collected by vacuum filtration to obtain the product (1.045 g, 92%). MS [M+H] +The calculated value for C7H4BrClO2 is 237.2, and the measured value is also 237.2.

[0427] Step 2: Synthesis of 5-bromo-7-chlorobenzo[d]isoxazole (3)

[0428] Hydroxylamine hydrochloride (352 mg, 5.11 mmol), DDQ (1160 mg, 5.11 mmol), PPh3 (1339 mg, 5.11 mmol), and TEA (517 mg, 5.11 mmol) were added to a solution of 5-bromo-3-chloro-2-hydroxybenzaldehyde (1 g, 4.26 mmol) in EtOH (15 mL). After stirring at 80ºC for 1 h, water (20 mL) was added to the reaction mixture. The reaction mixture was filtered to obtain the product (479 mg, 49%). MS [M+H] + The calculated value for C7H3BrClNO is 234.2, and the measured value is also 234.2.

[0429] Step 3: Synthesis of methyl 7-chlorobenzo[d]isoxazole-5-carboxylate (4)

[0430] A solution of 5-bromo-7-chlorobenzo[d]isoxazole (479 mg, 2.06 mmol), TEA (626 mg, 6.19 mmol), and Pd(dppf)Cl2·DCM (82 mg, 0.10 mmol) in MeOH (10 mL) was stirred at 80ºC under CO for 6 h. The reaction solution was removed under vacuum to obtain the crude product. Further purification by column chromatography (silica gel, PE / EA = 1 / 1) yielded the desired product (361 mg, 82%). MS [M+H] + The calculated value for C9H6ClNO3 is 212.2, and the measured value is also 212.2.

[0431] Step 4: Synthesis of 7-chlorobenzo[d]isoxazole-5-carboxylic acid (5)

[0432] LiOH (143 mg, 3.41 mmol) was added to a solution of methyl 7-chlorobenzo[d]isoxazole-5-carboxylate (361 mg, 1.70 mmol) in THF / H₂O (3 / 3 mL) at 0°C. After addition, the reaction was warmed to room temperature and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted with EA (100 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum to give the desired product (156 mg, 46%). MS [M+H] +The calculated value for C8H4ClNO3 is 198.2, and the measured value is also 198.2.

[0433] intermediate Ab3

[0434]

[0435] Step 1: Synthesis of 5-bromo-2-hydroxy-3-methylbenzaldehyde (2)

[0436] Br2 (0.45 mL, 8.82 mmol) was added to a solution of 2-hydroxy-3-methylbenzaldehyde (1 g, 7.35 mmol) in AcOH (10 mL) at room temperature under a nitrogen atmosphere. After stirring overnight at room temperature, the reaction mixture was cooled to 0ºC and a saturated aqueous solution of Na2S2O3 (30 mL) was added. Extraction was performed by EA (100 mL * 3), followed by drying over Na2SO4, and further purification by column chromatography (silica gel, PE / EA = 1 / 2) to give the desired product (1.4 g, 89%). MS [M+H] + The calculated value for C8H7BrO2 is 215.2, and the measured value is also 215.2.

[0437] Step 2: Synthesis of 5-bromo-7-methylbenzo[d]isoxazole (3)

[0438] Hydroxylamine hydrochloride (539 mg, 7.81 mmol), DDQ (1774 mg, 7.81 mmol), PPh3 (2048 mg, 7.81 mmol), and TEA (790 mg, 7.81 mmol) were added to a solution of 5-bromo-2-hydroxy-3-methylbenzaldehyde (1.4 g, 6.51 mmol) in EtOH (20 mL). After stirring at 80ºC for 1 h, water (20 mL) was added to the reaction mixture. The reaction mixture was filtered to obtain the product (741 mg, 54%). MS [M+H] + The calculated value for C8H6BrNO is 212.2, and the measured value is also 212.2.

[0439] Step 3: Synthesis of methyl 7-methylbenzo[d]isoxazole-5-carboxylate (4)

[0440] A solution of 5-bromo-7-methylbenzo[d]isoxazole (741 mg, 3.50 mmol), TEA (1059 mg, 10.49 mmol), and Pd(dppf)Cl2·DCM (142 mg, 0.17 mmol) in MeOH (10 mL) was stirred at 120ºC for 6 h under CO2. The reaction solution was removed under vacuum to obtain the crude product. Further purification by column chromatography (silica gel, PE / EA = 1 / 1) yielded the desired product (356 mg, 53%). MS [M+H] + For C 10 The calculated value of H9NO3 is 192.2, and the measured value is also 192.2.

[0441] Step 4: Synthesis of 7-methylbenzo[d]isoxazole-5-carboxylic acid (5)

[0442] LiOH (157 mg, 3.73 mmol) was added to a solution of methyl 7-methylbenzo[d]isoxazole-5-carboxylate (356 mg, 1.86 mmol) in THF / H₂O (3 / 3 mL) at 0ºC. The reaction was then warmed to room temperature and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted with EA (50 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum to give the desired product (207 mg, 63%). MS [M+H] + The calculated value for C9H7NO3 is 178.2, and the measured value is also 178.2.

[0443] intermediate Ab4

[0444]

[0445] Step 1: Synthesis of 5-bromo-7-methoxybenzo[d]isoxazole (2)

[0446] A solution of 5-bromo-2-hydroxy-3-methoxybenzaldehyde (1 g, 4.33 mmol), TEA (0.66 mL, 4.76 mmol), and NH₂OH•HCl (358.5 mg, 5.20 mmol) in EtOH (20 mL) was stirred at 95ºC for 5 hours under N₂. The solution was then concentrated under vacuum to give a crude intermediate. DDQ (982.9 mg, 4.33 mmol) and PPh₃ (1.1 g, 4.33 mmol) were added dropwise to a solution of the above compound in THF (10 mL) at 0ºC under N₂ atmosphere. After addition, the mixture was stirred at the same temperature for another 1 hour. The reaction mixture was quenched with HCl and extracted with DCM (30 mL x 3). The combined organic phases were dried over Na₂SO₄ and concentrated to dryness under vacuum. The residue was purified by column chromatography (silica gel, PE / EA = 1 / 5) to obtain the desired product (500 mg, 51%). MS [M+H] + The calculated value for C8H6BrNO2 is 227.96, and the measured value is also 227.96.

[0447] Step 2: Synthesis of methyl 7-methoxybenzo[d]isoxazole-5-carboxylate (3)

[0448] A solution of 5-bromo-7-methoxybenzo[d]isoxazole (500 mg, 2.19 mmol), TEA (0.91 mL, 6.58 mmol), and Pd(dppf)Cl2 (179.5 mg, 0.22 mmol) in MeOH (10 mL) was stirred at 80ºC under CO for 5 h. The mixture was extracted with EA (50 mL * 3), dried over Na2SO4, and concentrated to dryness under vacuum. The residue was purified by column chromatography (silica gel, PE / EA = 1 / 5) to give the desired product (350 mg, 77%). MS [MH] - For C 10 The calculated value of H9NO4 is 208.05, and the measured value is also 208.05.

[0449] Step 3: Synthesis of 7-methoxybenzo[d]isoxazole-5-carboxylic acid (4)

[0450] NaOH (169 mg, 4.23 mmol) was added to a solution of 7-methoxybenzo[d]isoxazole-5-carboxylic acid (350 mg, 1.69 mmol) in THF / H₂O (4 / 1 mL) at 0°C. After addition, the reaction was warmed to room temperature and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted with EA (20 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum to give the desired product (270 mg, 83%). MS [M+H] + The calculated value for C9H7NO4 is 194.04, and the measured value is also 194.04.

[0451] intermediate Ab5

[0452]

[0453] Step 1: Synthesis of 3-methylbenzo[d]isoxazole-5-carboxylic acid (2)

[0454] n-BuLi (0.21 mL, 0.52 mmol) was added dropwise to a solution of 5-bromo-3-methylbenzo[d]isoxazole (100 mg, 0.47 mmol) in THF (5 mL) at -78ºC under a CO2 atmosphere. After addition, the mixture was stirred at the same temperature for another 1 hour. The mixture was then allowed to warm to ambient temperature and stirred overnight. The reaction mixture was quenched with H2O and acidified to pH = 1 with 1M HCl. It was then extracted with EA (30 mL x 3) and dried over Na2SO4. The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 1 / 3) to obtain the product (50 mg, 60%). MS [MH] + C9H7NO3 178.04, measured value is 178.04.

[0455] intermediate Ac1

[0456]

[0457] Step 1: Synthesis of [1,2,3]triazolo[1,5-a]pyridine-5-carboxylic acid methyl ester (2)

[0458] A solution of 5-bromo-[1,2,3]triazolo[1,5-a]pyridine (1 g, 5.05 mmol), TEA (1.5 g, 15.15 mmol), and Pd(dppf)Cl2·DCM (205 mg, 0.25 mmol) in MeOH (20 mL) was stirred at 120ºC for 6 h under CO2. The reaction solution was removed under vacuum to obtain the crude product. Further purification by column chromatography (silica gel, PE / EA = 1 / 1) yielded the desired product (390 mg, 44%). MS [MH] + The calculated value for C9H7NO3 is 178.2, and the measured value is also 178.2.

[0459] Step 2: Synthesis of [1,2,3]triazolo[1,5-a]pyridine-5-carboxylic acid (3)

[0460] LiOH (354 mg, 8.64 mmol) was added to a solution of methyl [1,2,3]triazolo[1,5-a]pyridine-5-carboxylate (510 mg, 2.88 mmol) in THF / H₂O (4 / 4 mL) at 0ºC. After addition, the reaction was warmed to room temperature and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted with EA (50 mL * 3), dried over Na₂SO₄, and concentrated to dryness under vacuum to give the desired product (400 mg, 85%). MS [MH] + The calculated value for C7H5N3O2 is 164.0, and the measured value is also 164.0.

[0461] Intermediate B1

[0462]

[0463] Step 1: Synthesis of 1-(5-chloro-2-fluorophenyl)-N-methylethyl-1-amine (2)

[0464] To a solution of compound 1 (600 mg, 3.47 mmol) and methylamine hydrochloride (259 mg, 3.82 mmol) in MeOH (10 mL), NaBH3CN (437 mg, 6.94 mmol) and ZnCl2 (566 mg, 4.16 mmol) were added. The mixture was stirred at 50ºC for 6 hours. The reaction mixture was quenched with ice water (20 mL), acidified to pH 7–8 with Na2CO3, and extracted with EA (50 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (DCM / MeOH = 20 / 1) to obtain the product (300 mg, 46%). MS [MH] + For C9H 11 The calculated value of ClFN is 188.1, and the measured value is also 188.1.

[0465] Step 2: Synthesis of N-(1-(5-chloro-2-fluorophenyl)ethyl)-2-cyano-N-methylacetamide (3)

[0466] T3P (761 mg, 2.39 mmol) and DIEA (618 mg, 4.79 mmol) were added to a solution of 1-(5-chloro-2-fluorophenyl)-N-methylethyl-1-amine (300 mg, 1.60 mmol) and 2-cyanoacetic acid (136 mg, 1.60 mmol) in DCM (10 mL). The mixture was stirred at 25ºC for 4 h. The reaction mixture was quenched with water (20 mL), extracted with DCM (50 mL x 3), and dried over Na2SO4. The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 3 / 2) to obtain the product (150 mg, 37%). MS [MH] + For C 12 H 12 The calculated value of ClFN2O is 254.9, and the measured value is also 254.9.

[0467] Intermediate B2

[0468]

[0469] Step 1: Synthesis of 1-(2-fluoro-5-(trifluoromethyl)phenyl)-N-methylmethylamine (2)

[0470] To a solution of compound 1 (700 mg, 3.65 mmol) and methylamine hydrochloride (297 mg, 4.37 mmol) in MeOH (10 mL), NaBH3CN (459 mg, 7.29 mmol) and ZnCl2 (594 mg, 4.37 mmol) were added. The mixture was stirred at 50ºC for 6 hours. The reaction mixture was quenched with ice water (20 mL), acidified to pH 7–8 with Na2CO3, and extracted with EA (50 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (DCM / MeOH = 20 / 1) to obtain the product (300 mg, 46%). MS [M+H] + The calculated value for C9H9F4N is 208.1, and the measured value is also 208.1.

[0471] Step 2: Synthesis of 2-cyano-N-(2-fluoro-5-(trifluoromethyl)benzyl)-N-methylacetamide (3)

[0472] T3P (691 mg, 2.17 mmol) and DIEA (561 mg, 4.35 mmol) were added to a solution of 1-(2-fluoro-5-(trifluoromethyl)phenyl)-N-methylmethylamine (300 mg, 1.45 mmol) and 2-cyanoacetic acid (123 mg, 1.45 mmol) in DCM (10 mL). The mixture was stirred at 25ºC for 4 h. The reaction mixture was quenched with water (20 mL) and extracted with DCM (50 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 3 / 2) to obtain the product (220 mg, 55%). MS [M+H] + For C 12 H 10 The calculated value of F4N2O is 274.9, and the measured value is also 274.9.

[0473] Intermediate B3

[0474]

[0475] Step 1: Synthesis of 1-(2-bromoethoxy)-2-chlorobenzene (2)

[0476] Compound 1 (1 g, 7.75 mmol) and 1,2-dibromoethane (2.9 g, 15.50 mmol) were added to a solution of NaOH (10 mL, 1.6 N). The mixture was stirred at 100ºC for 12 hours. The reaction mixture was quenched with ice water (20 mL) and extracted with EA (50 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 5 / 1) to obtain the product (1 g, 55%). MS [M+H] + The calculated value for C8H8BrClO is 237.1, and the measured value is also 237.1.

[0477] Step 2: Synthesis of 2-(2-chlorophenoxy)-N-methylethyl-1-amine (3)

[0478] To a solution of compound 2 (1 g, 4.24 mmol) and methylamine hydrochloride (346 mg, 5.08 mmol) in MeOH (10 mL), NaBH3CN (320 mg, 5.08 mmol) and ZnCl2 (1153 mg, 8.47 mmol) were added. The mixture was stirred at 50ºC for 6 hours. The reaction mixture was quenched with ice water (30 mL), acidified to pH 7–8 with Na2CO3, and extracted with EA (50 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (DCM / MeOH = 20 / 1) to obtain the product (600 mg, 76%). MS [M+H] + For C9H 12 The calculated value of ClNO is 186.1, and the measured value is also 186.1.

[0479] Step 3: Synthesis of N-(2-(2-chlorophenoxy)ethyl)-2-cyano-N-methylacetamide (4)

[0480] T3P (1539 mg, 4.84 mmol) and DIEA (1248 mg, 9.68 mmol) were added to a solution of 2-(2-chlorophenoxy)-N-methylethyl-1-amine (600 mg, 3.23 mmol) and 2-cyanoacetic acid (277 mg, 3.23 mmol) in DCM (10 mL). The mixture was stirred at 25ºC for 4 h. The reaction mixture was quenched with water (20 mL), extracted with DCM (50 mL x 3), and dried over Na2SO4. The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 2 / 3) to obtain the product (500 mg, 61%). MS [M+H] + For C 12 H 13 The calculated value of ClN2O2 is 252.9, and the measured value is also 252.9.

[0481] intermediate B4

[0482]

[0483] Step 1: Synthesis of 4-fluoro-3-((methylamino)methyl)benzonitrile (2)

[0484] To a solution of compound 1 (700 mg, 4.70 mmol) and methylamine hydrochloride (383 mg, 5.64 mmol) in MeOH (20 mL), NaBH3CN (592 mg, 9.40 mmol) and ZnCl2 (767 mg, 5.64 mmol) were added. The mixture was stirred at 50ºC for 6 hours. The reaction mixture was quenched with ice water (20 mL), acidified to pH 7–8 with Na2CO3, and extracted with EA (50 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (DCM / MeOH = 20 / 1) to obtain the product (500 mg, 65%). MS [M+H] + The calculated value for C9H9FN2 is 165.1, and the measured value is also 165.1.

[0485] Step 2: Synthesis of 2-cyano-N-(5-cyano-2-fluorobenzyl)-N-methylacetamide (3)

[0486] T3P (1454 mg, 4.57 mmol) and DIEA (1180 mg, 9.15 mmol) were added to a solution of 4-fluoro-3-((methylamino)methyl)benzonitrile (500 mg, 3.05 mmol) and 2-cyanoacetic acid (259 mg, 3.05 mmol) in DCM (10 mL). The mixture was stirred at 25ºC for 4 h. The reaction mixture was quenched with water (20 mL), extracted with DCM (50 mL x 3), and dried over Na2SO4. The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 3 / 2) to obtain the product (350 mg, 50%). MS [M+H] + For C 12 H 10 The calculated value of FN3O is 231.9, and the measured value is also 231.9.

[0487] Intermediate B5

[0488]

[0489] Step 1: Synthesis of 1-phenyl-1H-1,2,3-triazol-4-carboxaldehyde (2)

[0490] A mixture of (1-phenyl-1H-1,2,3-triazol-4-yl)methanol (1 g, 5.7 mmol) and MnO2 (7.4 g, 85.7 mmol) in EA (20 mL) was stirred at 80ºC for 2 hours. The reaction mixture was cooled to room temperature and diluted with H2O (30 mL). Extraction was performed with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. The product was purified by column chromatography (dichloromethane / methanol (10:1)) to give the product (900 mg, 91%). MS [M+H] + The calculated value for C9H7N3O is 174.1, and the measured value is also 174.1.

[0491] Step 2: Synthesis of N-methyl-1-(1-phenyl-1H-1,2,3-triazol-4-yl)methylamine (3)

[0492] To a solution of compound 2 (900 mg, 5.2 mmol) and methylamine hydrochloride (354 mg, 5.2 mmol) in MeOH (20 mL), NaBH3CN (393 mg, 6.2 mmol) and ZnCl2 (1415 mg, 10.4 mmol) were added. The mixture was stirred at 50ºC for 6 hours. The reaction mixture was quenched with ice water (20 mL), acidified to pH 7–8 with Na2CO3, and extracted with EA (50 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (DCM / MeOH = 20 / 1) to obtain the product (780 mg, 80%). MS [M+H] + For C 10 H 12 The calculated value of N4 is 189.1, and the measured value is also 189.1.

[0493] Step 3: Synthesis of 2-cyano-N-methyl-N-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)acetamide (4)

[0494] T3P (1979 mg, 6.2 mmol) and DIEA (1606 mg, 12.4 mmol) were added to a solution of N-methyl-1-(1-phenyl-1H-1,2,3-triazol-4-yl)methylamine (780 mg, 4.1 mmol) and 2-cyanoacetic acid (353 mg, 4.1 mmol) in DCM (20 mL). The mixture was stirred at 25ºC for 4 h. The reaction mixture was quenched with water (20 mL), extracted with DCM (50 mL x 3), and dried over Na2SO4. The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 2 / 3) to obtain the product (180 mg, 17%). MS [M+H] + For C 13 H 13 The calculated value of N5O is 255.9, and the measured value is also 255.9.

[0495] Intermediate B6

[0496]

[0497] Step 1: Synthesis of 2-cyano-N-methyl-N-(2-phenoxyethyl)acetamide (2)

[0498] T3P (376.8 mg, 1.2 mmol) and DIEA (203.8 mg, 1.58 mmol) were added to a solution of N-methyl-2-phenoxyethyl-1-amine (120 mg, 0.79 mmol) and 2-cyanoacetic acid (67.5 mg, 0.79 mmol) in DCM (6 mL). The mixture was stirred at 25ºC for 8 h. The reaction mixture was quenched with water (20 mL), extracted with DCM (15 mL x 3), and dried over Na2SO4. The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 1 / 3) to obtain the product (80 mg, 46%). MS [M+H] + C 12 H 14 N2O2219.11, measured value is 219.11.

[0499] Intermediate B7

[0500]

[0501] Step 1: Synthesis of 3-(4-(3-chlorophenyl)piperidin-1-yl)-3-oxopropionitrile (2)

[0502] T3P (1217 mg, 3.83 mmol) and DIEA (987 mg, 7.66 mmol) were added to a solution of 4-(3-chlorophenyl)piperidine (500 mg, 2.55 mmol) and 2-cyanoacetic acid (217 mg, 2.55 mmol) in DCM (10 mL). The mixture was stirred at 25ºC for 4 h. The reaction mixture was quenched with water (20 mL) and extracted with DCM (50 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 1 / 2) to obtain the product (400 mg, 60%). MS [M+H] + For C 14 H 14 The calculated value of ClN2O is 262.9, and the measured value is also 262.9.

[0503] Intermediate B8

[0504]

[0505] Step 1: Synthesis of N-phenylpiperidin-4-amine (2)

[0506] A mixture of tert-butyl 4-(phenylamino)piperidine-1-carboxylate (1 g, 3.6 mmol) and TFA (2 mL) in DCM (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness under vacuum to give the product (600 mg, 94%). MS [M+H] + For C 11 H 16 The calculated value of N2 is 177.1, and the measured value is also 177.1.

[0507] Step 2: Synthesis of 3-oxo-3-(4-(phenylamino)piperidin-1-yl)propionitrile (3)

[0508] T3P (1611 mg, 5.1 mmol) and DIEA (1319 mg, 10.2 mmol) were added to a solution of N-methyl-1-(1-phenyl-1H-1,2,3-triazol-4-yl)methylamine (600 mg, 3.4 mmol) and 2-cyanoacetic acid (290 mg, 4.1 mmol) in DCM (10 mL). The mixture was stirred at 25ºC for 4 h. The reaction mixture was quenched with water (20 mL), extracted with DCM (50 mL x 3), and dried over Na2SO4. The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 1 / 3) to obtain the product (180 mg, 22%). MS [M+H] + For C 14 H 17 The calculated value of N3O is 243.9, and the measured value is also 243.9.

[0509] Step 3: Synthesis of (1-(2-cyanoacetyl)piperidin-4-yl)(phenyl)carbamate tert-butyl ester (4)

[0510] DMAP (271 mg, 2.2 mmol) was added to a solution of compound 2 (180 mg, 0.7 mmol) and (Boc)₂O (807 mg, 3.7 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 6 hours. The reaction mixture was quenched with ice water (20 mL) and extracted with EA (50 mL x 3). The combined organic phases were dried over Na₂SO₄ and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 2 / 1) to obtain the product (130 mg, 51%). MS [M+H] + For C 19 H 25 The calculated value of N3O3 is 344.1, and the measured value is also 344.1.

[0511] Intermediate B9

[0512]

[0513] Step 1: Synthesis of 3-(3-azabicyclo[3.1.0]hex-3-yl)-3-oxopropionitrile (3)

[0514] T4P (9 g, 25.21 mmol) and DIEA (6.47 g, 50.43 mmol) were added to a solution of 3-azabicyclo[3.1.0]hexane hydrochloride (2 g, 16.81 mmol), 2-cyanoacetic acid (2.13 g, 25.21 mmol), and the mixture was stirred at 25ºC under N2 for 16 h. The reaction solution was removed under vacuum to obtain the crude product. Further purification by column chromatography (silica gel, PE / EA = 1 / 1) yielded the desired product (1.5 g, 60%). MS [M+H] + For C8H 10 The calculated value of N2O is 151.1, and the measured value is also 151.1.

[0515] Intermediate B10

[0516]

[0517] Step 1: Synthesis of 3-(2-chlorophenyl)-N-methylprop-2-yn-1-amine (2)

[0518] A solution of N-methylprop-2-yn-1-amine (400 mg, 5.8 mmol), 1-chloro-2-iodobenzene (1380 mg, 5.8 mmol), PdCl₂(PPh₃)₂ (81 mg, 0.1 mmol), and copper iodide (11 mg, 0.1 mmol) in anhydrous diethylamine (10 mL) was stirred at room temperature under N₂ for 22 h. The solvent was removed under vacuum to obtain the crude product. Further purification by column chromatography (silica gel, PE / EA = 1 / 2) yielded the desired product (250 mg, 24%). MS [M+H] + For C 10 H 10 The calculated value of ClN is 180.1, and the measured value is also 180.1.

[0519] Step 2: Synthesis of N-(3-(2-chlorophenyl)prop-2-yn-1-yl)-2-cyano-N-methylacetamide (3)

[0520] T3P (662 mg, 2.1 mmol) and DIEA (537 mg, 4.2 mmol) were added to a solution of 3-(2-chlorophenyl)-N-methylprop-2-yn-1-amine (250 mg, 1.4 mmol) and 2-cyanoacetic acid (118 mg, 1.4 mmol) in DCM (10 mL). The mixture was stirred at 25ºC for 4 h. The reaction mixture was quenched with water (20 mL), extracted with DCM (50 mL x 3), and dried over Na2SO4. The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 3 / 2) to obtain the product (150 mg, 44%). MS [M+H] + For C 13 H 11 The calculated value of ClN2O is 246.9, and the measured value is also 246.9.

[0521] Intermediate B11

[0522]

[0523] Step 1: Synthesis of 1-(5-chloro-2-fluorophenyl)-N-methylmethylamine (2)

[0524] Methylamine hydrochloride (42.7 g, 632.59 mmol) was added to a mixture of 5-chloro-2-fluorobenzaldehyde (50.0 g, 316.45 mmol) in MeOH (200 mL) and stirred at 0ºC for 30 min. NaBH3CN (29.8 g, 474.52 mmol) and ZnCl2 (86.1 g, 633.09 mmol) were added to the above mixture, and the mixture was then heated to 50ºC and stirred for 16 h. The reaction was quenched with ice water (200 mL), acidified to pH 7–8 with Na2CO3, extracted with EA (200 mL * 3), dried over Na2SO4, and concentrated to dryness under vacuum. The residue was purified by preparative HPLC (H2O / MeCN = 90 / 10, 0.1% TFA) to obtain the product (23.0 g, 41.8%). MS [M+H] + The calculated value for C8H9ClFN is 174.1, and the measured value is also 174.1.

[0525] Step 2: Synthesis of N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide (3)

[0526] To a mixture of (1-(5-chloro-2-fluorophenyl)-N-methylmethylamine) (23.0 g, 132.95 mmol) in DCM (200 mL), 2-cyanoacetic acid (12.43 g, 146.24 mmol), T3P (126.83 g, 199.42 mmol), and DIEA (51.45 g, 398.84 mmol) were added. The reaction was stirred at room temperature for 16 h. The reaction was quenched with ice water (200 mL), extracted with EA (200 mL * 3), dried over Na2SO4, and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 1 / 1) to obtain the product (18.0 g, 56.6%). MS [M+H] + For C 11 H 10 The calculated value of ClFN2O is 241.1, and the measured value is also 241.1.

[0527] Intermediate B12

[0528]

[0529] Step 1: Synthesis of 1-(2-fluoro-5-methylphenyl)-N-methylmethylamine (2)

[0530] NaBH4(OAc)3 (2.3 g, 10.86 mmol) was added to a solution of 2-fluoro-5-methylbenzaldehyde (1 g, 7.24 mmol) and methylamine (7.2 mL, 14.48 mmol) in DCE (20 mL). The mixture was stirred at room temperature for 5 h, and then quenched with 1N NaOH (20 mL). The mixture was extracted with DCM (20 mL x 3) and dried over Na2SO4, then filtered and concentrated under vacuum to give the crude product. Further purification by column chromatography (silica gel, PE / EA = 6 / 1) yielded the desired product (1.048 g, 94%). MS [M+H] + The calculated value for C9H12FN is 154.1, and the measured value is also 154.1.

[0531] Step 2: Synthesis of 2-cyano-N-(2-fluoro-5-methylbenzyl)-N-methylacetamide (3)

[0532] A solution of 1-(2-fluoro-5-methylphenyl)-N-methylmethylamine (1.048 g, 6.84 mmol), 2-cyanoacetic acid (582 mg, 6.84 mmol), HATU (3.12 g, 8.21 mmol), and DIPEA (1.33 g, 10.26 mmol) in DCM (20 mL) was stirred at room temperature for 5 h, and then quenched with water (25 mL). The mixture was extracted with ethyl acetate (20 mL x 3) and dried over Na2SO4, then filtered and concentrated under vacuum to give the crude product. Further purification by column chromatography (silica gel, PE / EA = 4 / 1) gave the desired product (980 mg, 65%). MS [M+H] + The calculated value for C12H13FN2O is 221.2, and the measured value is also 221.2.

[0533] Intermediate B13

[0534]

[0535] Step 1: Synthesis of N-(5-chloro-2-fluorobenzyl)ethylamine (2)

[0536] To a mixture of 5-chloro-2-fluorobenzaldehyde (900 mg, 5.7 mmol) in MeOH (500 mL), methylamine hydrochloride (775 mg, 11.4 mmol), NaBH3CN (428 mg, 6.8 mmol), and ZnCl2 (1.5 g, 11.4 mmol) were added, and the mixture was then heated to 50ºC and stirred for 6 hours. The reaction was quenched with ice water (50 mL), acidified to pH 7–8 with Na2CO3, extracted with EA (200 mL * 3), dried over Na2SO4, and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (DCM / MeOH = 20 / 1) to obtain the product (750 mg, 70%). MS [M+H] + For C9H 11 The calculated value of ClFN is 188.1, and the measured value is also 188.1.

[0537] Step 2: Synthesis of N-(5-chloro-2-fluorobenzyl)-2-cyano-N-ethylacetamide (3)

[0538] A solution of 4-fluoro-3-((methylamino)methyl)benzonitrile (650 mg, 3.5 mmol) and 2-cyanoacetic acid (294 mg, 3.5 mmol) in DCM (50 mL) was prepared at 25ºC. The flask was equipped with a magnetic stir bar and a three-way stopcock attached to a nitrogen-filled bulb. T3P (1.7 g, 5.2 mmol) and DIEA (1.3 g, 10.4 mmol) were added to the stirred solution. The flask was purged with nitrogen. The mixture was stirred at 25ºC for 8 h. The reaction was quenched with water (50 mL), extracted with DCM (200 mL * 3), and dried over Na2SO4. The residue was purified by silica gel chromatography (PE / EA = 2 / 3) to obtain the product (420 mg, 48%). MS [MH] + For C 12 H 12 The calculated value of ClFN2O is 254.9, and the measured value is also 254.9.

[0539] Intermediate B14

[0540]

[0541] T3P (884.5 mg, 2.78 mmol) and DIEA (477 mg, 3.7 mmol) were added to a solution of 4-(piperidin-4-yl)pyridine (300 mg, 1.85 mmol) and 2-cyanoacetic acid (157 mg, 1.85 mmol) in DCM (6 mL). The mixture was stirred at 25ºC for 8 h. The reaction mixture was quenched with water (20 mL), extracted with DCM (15 mL x 3), and dried over Na2SO4. The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 1 / 3) to obtain the product (250 mg, 58.9%). MS [MH] + C 13 H 15 N3O 230.12, measured value is 230.12.

[0542] Intermediate B15

[0543]

[0544] T3P (1.48 g, 4.67 mmol) and DIEA (942 mg, 9.33 mmol) were added to a solution of 4-phenylpiperidine (500 mg, 3.11 mmol) and 2-cyanoacetic acid (264 mg, 3.11 mmol) in DCM (10 mL). The mixture was stirred at 25ºC for 4 h. The reaction mixture was quenched with water (20 mL) and extracted with DCM (50 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 1 / 2) to obtain the product (160 mg, 23%). MS [M+H] + For C 14 H 16 The calculated value of N2O is 229.1, and the measured value is also 229.1.

[0545] Intermediate B16

[0546]

[0547] Step 1: Synthesis of tert-butyl (2-(2-chlorophenoxy)ethyl)carbamate (2)

[0548] A solution of 2-chlorophenol (1.0 g, 7.8 mmol) and NaH (187.5 mg, 7.8 mmol) in anhydrous THF (25 mL) was stirred at 0ºC for 30 min. Tert-butyl (2-bromoethyl)carbamate (1.7 g, 7.8 mmol) was added dropwise, and the reaction mixture was stirred at 0ºC for 15 min, then allowed to warm to room temperature and stirred overnight. The reaction was quenched with water (30 mL) and extracted with EtOAc (200 mL x 3), then dried over Na₂SO₄ and filtered. The solvent was removed under vacuum to give tert-butyl (2-(2-chlorophenoxy)ethyl)carbamate (1.1 g, 52%). MS [MH] + For C 13 H 18 The calculated value of ClNO3 is 272.1, and the measured value is also 272.1.

[0549] Step 2: Synthesis of (2-(2-chlorophenoxy)ethyl)(ethyl)carbamate tert-butyl ester (3)

[0550] A mixture of (2-(2-chlorophenoxy)ethyl)carbamate tert-butyl ester (1.1 g, 4.1 mmol) and NaH (0.2 g, 8.1 mmol) in THF (50 mL) was reacted at -20ºC for 30 min under N2 atmosphere. After the addition of iodoethane (0.6 g, 4.1 mmol), the mixture was stirred overnight. The above compound was added to the reaction mixture, warmed to room temperature, and stirred overnight. After the reaction was complete, the mixture was acidified to pH 5-6 with HCl, extracted with DCM (200 mL * 3), dried over Na2SO4, concentrated under vacuum, and the residue was purified by silica gel chromatography (DCM / MeOH = 50 / 1) to obtain the product (1.0 g, 83%). MS [MH] + For C 15 H 22 The calculated value of ClNO3 is 299.9, and the measured value is 299.9.

[0551] Step 3: Synthesis of 2-(2-chlorophenoxy)-N-ethylethyl-1-amine (4)

[0552] A mixture of (2-(2-chlorophenoxy)ethyl)(ethyl)carbamate tert-butyl ester (900 mg, 3.0 mmol) and TFA (0.5 mL) in DCM (20 mL) was stirred overnight at 25ºC. The reaction mixture was dried to obtain the product (500 mg, 83%). MS [MH] - For C 10 H 14 The calculated value of ClNO is 199.9, and the measured value is 199.9.

[0553] Step 4: Synthesis of N-(2-(2-chlorophenoxy)ethyl)-2-cyano-N-ethylacetamide (5)

[0554] A solution of 2-(2-chlorophenoxy)-N-ethylethyl-1-amine (500 mg, 2.5 mmol) and 2-cyanoacetic acid (213 mg, 2.5 mmol) in DCM (50 mL) was prepared at 25ºC. The flask was equipped with a magnetic stir bar and a three-way stopcock attached to a nitrogen-filled bulb. T3P (1.6 g, 5.0 mmol) and DIEA (1.3 g, 10.0 mmol) were added to the stirred solution. The flask was purged with nitrogen. The mixture was stirred at 25ºC for 8 h. The reaction was quenched with water (20 mL), extracted with DCM (150 mL * 3), and dried over Na2SO4. The residue was purified by silica gel chromatography (PE / EA = 2 / 3) to obtain the product (400 mg, 60%). MS [MH] + For C13 H 15 The calculated value of ClN2O2 is 266.9, and the measured value is also 266.9.

[0555] Intermediate B17

[0556]

[0557] To a mixture of diethylamine (1.0 g, 13.70 mmol) and DCM (20 mL), 2-cyanoacetic acid (1.28 g, 15.07 mmol), T3P (13.07 g, 20.55 mmol), and DIEA (5.3 g, 41.1 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was washed with ice water (50 mL) and extracted with EA (50 mL * 3). The combined extracts were dried over anhydrous Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 3 / 1) to obtain the product (900 mg, 46.9%). MS [M+H] + The calculated value for C7H12N2O is 141.2, and the measured value is also 141.2.

[0558] Compound 27

[0559] (Z)-3-(1H-benzo[d][1,2,3]triazol-6-yl)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-hydroxy-N-methylacrylamide (27)

[0560]

[0561] A solution of 1H-benzo[d][1,2,3]triazol-6-carboxylic acid (200 mg, 1.2 mmol) in SOCl2 (10 mL) was stirred at 80ºC for 2 hours. The solution was then concentrated under vacuum to give a crude intermediate. LiHMDS (3.1 mL, 3.1 mmol) was added dropwise to a solution of N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide (296 mg, 1.2 mmol) in THF (10 mL) at -78ºC under a N2 atmosphere. After the addition, the mixture was stirred at the same temperature for another 1 hour. The crude intermediate was then added to the above solution at -78ºC and stirred overnight at room temperature. The reaction mixture was quenched with HCl and extracted with DCM (30 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by preparative HPLC (H2O / MeCN = 7 / 3, 0.1% TFA, twice) to obtain the product (27.3 mg, HPLC: 95.563%). MS [MH] - For C 18 H 13 The calculated value of ClFN5O2 is 384.0, and the measured value is 383.6. 1 HNMR (400MHz, DMSO-d6) δ 8.02 (s, 1H), 7.58 (s, 2H), 7.38 – 7.34 (m, 1H), 7.23-7.20(m, 1H), 7.11 (s, 1H), 4.57 (s, 2H), 2.95 (s, 3H).

[0562] Compound 490

[0563] (Z)-3-(1H-benzo[d][1,2,3]triazol-6-yl)-3-hydroxy-2-(thiazolyl-2-yl)acrylonitrile (490)

[0564]

[0565] A solution of 1H-benzo[d][1,2,3]triazol-6-carboxylic acid (150 mg, 0.92 mmol) in SOCl2 (20 mL) was stirred at 80ºC for 2 hours. The solution was then concentrated under vacuum to give a crude intermediate. LiHMDS (2.3 mL, 2.3 mmol) was added dropwise to a solution of 2-(thiazol-2-yl)acetonitrile (114 mg, 0.92 mmol) in THF (10 mL) at -78ºC under a N2 atmosphere. After the addition, the mixture was stirred at the same temperature for another 1 hour. The crude intermediate was then added to the above solution at -78ºC and stirred overnight at room temperature. The reaction mixture was quenched with HCl and extracted with DCM (30 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by preparative HPLC (0.05% TFA; ACN-H2O) to obtain the product (1.2 mg, 0.5%). MS [MH] - For C 12 The calculated value for H7N5OS is 268.0, while the actual measured value is 268.1. 1 HNMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.95 – 7.79 (m,2H), 7.54 (d, J = 2.9 Hz, 1H), 7.14 (s, 1H).

[0566] Compound A1

[0567] (Z)-3-(1H-benzo[d][1,2,3]triazol-6-yl)-2-cyano-3-hydroxy-N-methylacrylamide (A1)

[0568]

[0569] A solution of 1H-benzo[d][1,2,3]triazol-6-carboxylic acid (150 mg, 0.92 mmol) in SOCl2 (20 mL) was stirred at 80ºC for 2 hours. The solution was then concentrated under vacuum to give a crude intermediate. LiHMDS (2.3 mL, 2.3 mmol) was added dropwise to a solution of 2-cyano-N-methylacetamide (90 mg, 0.92 mmol) in THF (10 mL) at -78ºC under a N2 atmosphere. After addition, the mixture was stirred at the same temperature for another 1 hour. The crude intermediate was then added to the above solution at -78ºC and stirred overnight at room temperature. The reaction mixture was quenched with HCl and extracted with DCM (30 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by preparative HPLC (0.05% TFA; ACN-H2O) to give the product (20 mg, 8.9%). MS [MH] + For C 11 The calculated value of H9N5O2 is 244.1, and the measured value is 243.9. 1 HNMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.49 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 2.81 (s, 3H).

[0570] Compound 439

[0571] (Z)-6-(2-cyano-3-cyclopropyl-1-hydroxy-3-oxopropyl-1-en-1-yl)-1H-benzo[d][1,2,3]triazol-4-carboxynitrile (439)

[0572]

[0573] Step 1: Synthesis of 4-cyano-1H-benzo[d][1,2,3]triazole-6-carbonyl fluoride

[0574] DAST (702 mg, 4.36 mmol) was added to a solution of 4-cyano-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (410 mg, 2.18 mmol) in DCM (10 mL). After stirring at 40ºC for 3 h, the mixture was extracted with EA (100 mL * 3), dried over Na2SO4, and concentrated to dryness under vacuum to give the desired product (320 mg, 77%). MS [M+H] +The calculated value for C8H3FN4O is 191.2, and the measured value is also 191.2.

[0575] Step 2: Synthesis of (Z)-6-(2-cyano-3-cyclopropyl-1-hydroxy-3-oxopropyl-1-en-1-yl)-1H-benzo[d][1,2,3]triazol-4-carboxynitrile (439)

[0576] LiHMDS (1.3 mL, 1.33 mmol) was added dropwise to a solution of 3-cyclopropyl-3-oxopropionitrile (166 mg, 1.53 mmol) in THF (10 mL) at -78°C under a N2 atmosphere. After addition, the mixture was stirred at the same temperature for another 1 hour. Then, 5 (290 mg, 1.53 mmol) was added to the above solution at -78°C and stirred overnight at room temperature. The reaction mixture was quenched with HCl and extracted with DCM (30 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by preparative HPLC (H2O / MeCN = 7 / 3, 0.1% TFA, twice) to obtain the product (1.01 mg, HPLC: 93.759%). MS [MH] - For C 14 The calculated value of H9N4O2 is 278.1, and the measured value is 278.2. 1 HNMR (400 MHz, DMSO-d6) δ 7.23 (s, 1H), 7.10 (s, 1H), 6.98 (s, 1H), 2.54 (s, 1H), 0.76-0.71 (m, 4H).

[0577] Compound 153

[0578] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-hydroxy-3-(4-(hydroxymethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-methylacrylamide (153)

[0579]

[0580] Step 1: Synthesis of (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-hydroxy-N-methyl-3-(4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide

[0581] A solution of 4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (600 mg, 1.32 mmol) in DCM (10 mL) was added to (COCl)₂ (502 mg, 3.96 mmol) and DMF (10 mg, 0.08 mmol), and stirred at 0ºC for 2 h. The solution was then concentrated under vacuum to obtain a crude intermediate. LiHMDS (3.3 mL, 3.31 mmol) was added dropwise to a solution of N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide (317 mg, 1.32 mmol) in THF (10 mL) at -78ºC under a N₂ atmosphere. After the addition, the mixture was stirred at the same temperature for another 1 h. The crude intermediate was then added to the above solution at -78ºC and stirred overnight at room temperature. The reaction mixture was quenched with AcOH and extracted with EA (50 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (DCM / MeOH = 25 / 1) to obtain the product (150 mg, 17%). MS [M+H] + For C 31 H 43 The calculated value of ClFN5O5Si2 is 675.9, and the measured value is also 675.9.

[0582] Step 2: Synthesis of (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-hydroxy-3-(4-(hydroxymethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-methacrylamide (153)

[0583] TFA (3 mL) was added to a solution of (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-hydroxy-N-methyl-3-(4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide (150 mg, 0.22 mmol) in DCM (10 mL) for 4 h. The mixture was concentrated and purified by preparative HPLC (H2O / MeCN = 7 / 3, 0.1% TFA, 2 times) to obtain the product (10.0 mg, HPLC: 100.00%). MS [MH] - For C 19 H 15 The calculated value of ClFN5O3 is 414.1, and the measured value is 413.7.1 HNMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.71 (s, 1H), 7.41 (s, 2H), 7.29 (d, J = 8.4 Hz, 1H), 4.92 (s, 2H), 4.74 (s, 2H), 3.16 (s, 3H).

[0584] Compound 152

[0585] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-hydroxy-N-methyl-3-(4-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide (152)

[0586]

[0587] Step 1: Synthesis of tert-butyl (2-(methyl-d3)phenyl)carbamate (2)

[0588] Zn (2.75 g, 42.3 mmol), NaI (3.17 g, 21.15 mmol), and NiCl2(dppp) (764.22 mg, 1.41 mmol) were added to a solution of tert-butyl (2-iodophenyl)carbamate (4.5 g, 14.1 mmol) and iodomethane-d3 (2.1 g, 14.1 mmol) in THF (50 mL). The reaction mixture was stirred at room temperature under N2 for 24 h. The reaction mixture was quenched with NH4Cl (200 mL) and extracted with DCM (500 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 50 / 1) to obtain the product (2 g, 59.7%). MS [M+H] + For C 12 H 14 The calculated value of D3NO2 is 211.2, and the measured value is also 211.2.

[0589] Step 2: Synthesis of 2-(methyl-d3)aniline (3)

[0590] HCl (2 mL) was added to a solution of tert-butyl (2 g, 9.48 mmol) in MeOH (20 mL), and the reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness under vacuum to give a crude product (1.3 g). MS [M+H] + The calculated value for C7H6D3N is 111.1, and the measured value is also 111.1.

[0591] Step 3: Synthesis of N-(2-(methyl-d3)phenyl)acetamide (4)

[0592] TEA (1.77 g, 17.57 mmol) was added to a solution of 2-(methyl-d3)aniline (1.3 g, 11.71 mmol) and acetyl chloride (1 g, 12.88 mmol) in THF (10 mL). The reaction was stirred at room temperature for 2 h. The mixture was quenched with ice water and extracted with DCM (20 mL * 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 4 / 1) to obtain the product (800 mg, 44.7%). MS [M+H] + The calculated value for C9H8D3NO is 153.2, and the measured value is also 153.2.

[0593] Step 4: Synthesis of N-(2-(methyl-d3)-6-nitrophenyl)acetamide (5)

[0594] HNO3 (428.4 mg, 6.8 mmol) was added to a solution of N-(2-(methyl-d3)phenyl)acetamide (800 mg, 5.23 mmol) in AcOH (5 mL) and Ac2O (5 mL) at 0ºC. The reaction was stirred overnight at room temperature. The mixture was quenched with ice water and neutralized to pH = 6 with NaHCO3, and extracted with EA (20 mL * 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 4 / 1) to obtain the product (350 mg, 59.2%). MS [M+H] + The calculated value for C9H7D3N2O3 is 198.2, and the measured value is also 198.2.

[0595] Step 5: Synthesis of 2-(methyl-d3)-6-nitroaniline (6)

[0596] HCl (1 mL) was added to a solution of N-(2-(methyl-d3)-6-nitrophenyl)acetamide (350 mg, 1.77 mmol) in MeOH (10 mL), and the reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness under vacuum to give a crude product (250 mg, 90.5%). MS [M+H] + The calculated value for C7H5D3N2O2 is 156.1, and the measured value is also 156.1.

[0597] Step 6: Synthesis of 4-bromo-2-(methyl-d3)-6-nitroaniline (7)

[0598] NBS (313.28 mg, 1.76 mmol) was added to a solution of 2-(methyl-d3)-6-nitroaniline (250 mg, 1.6 mmol) in HOAc (5 mL) at 0ºC. After addition, the reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 2 / 1) to obtain the product (260 mg, 91.7%). MS [M+H] + The calculated value for C7H4D3BrN2O2 is 235.0, and the measured value is also 235.0.

[0599] Step 7: Synthesis of 5-bromo-3-(methyl-d3)phenyl-1,2-diamine (8)

[0600] Zn (357.5 mg, 5.5 mmol) and ammonium formate (346.5 mg, 5.5 mmol) were added to a solution of 4-bromo-2-(methyl-d3)-6-nitroaniline (260 mg, 1.1 mmol) in EtOH (5 mL), and the reaction was stirred at 60ºC for 3 h. The reaction mixture was filtered to obtain a filtrate, which was concentrated to dryness under vacuum and extracted by EA (20 mL * 3), dried over Na2SO4, and concentrated to dryness under vacuum to give the desired product (180 mg, 79.8%). MS [M+H] + The calculated value for C7H6D3BrN2 is 205.0, and the measured value is also 205.0.

[0601] Step 8: Synthesis of 6-bromo-4-(methyl-d3)-1H-benzo[d][1,2,3]triazole (9)

[0602] NaNO2 (60.72 mg, 0.88 mmol) was added to a solution of 5-bromo-3-(methyl-d3)phenyl-1,2-diamine (180 mg, 0.88 mmol) in AcOH (2 mL) and H2O (2 mL). The mixture was stirred at room temperature for 3 h. The reaction mixture was then filtered to obtain the product (130 mg, 68.4%). MS [M+H] + The calculated value for C7H3D3BrN3 is 216.0, and the measured value is also 216.0.

[0603] Step 9: Synthesis of methyl 4-(methyl-d3)-1H-benzo[d][1,2,3]triazole-6-carboxylate (10)

[0604] A solution of 6-bromo-4-(methyl-d3)-1H-benzo[d][1,2,3]triazole (130 mg, 0.6 mmol), TEA (181.8 mg, 1.8 mmol), and Pd(dppf)Cl2 (43.86 mg, 0.06 mmol) in MeOH (5 mL) was stirred at 80ºC under CO for 6 h. The reaction solution was removed under vacuum to give the crude product. Further purification by column chromatography (silica gel, PE / EA = 1 / 1) yielded the desired product (65 mg, 55.6%). MS [M+H] + The calculated value for C9H6D3N3O2 is 195.2, and the measured value is also 195.2.

[0605] Step 10: Synthesis of 4-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (11)

[0606] LiOH (23.76 mg, 0.99 mmol) was added to a solution of methyl 4-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-carboxylate (65 mg, 0.33 mmol) in THF / H2O (2 / 2 mL) at 0ºC. After addition, the reaction was warmed to room temperature and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted with EA (10 mL * 3), dried over Na2SO4, and concentrated to dryness under vacuum to give the desired product (45 mg, 75.3%). MS [M+H] + The calculated value for C8H4D3N3O2 is 181.1, and the measured value is also 181.1.

[0607] Step 11: Synthesis of (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-hydroxy-N-methyl-3-(4-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide (152)

[0608] A solution of 4-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (45 mg, 0.25 mmol) in SOCl2 (3 mL) was stirred at 80ºC for 2 hours. This solution was then concentrated under vacuum to give a crude intermediate. LiHMDS (0.7 mL, 0.63 mmol) was added dropwise to a solution of N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide (60 mg, 0.25 mmol) in THF (5 mL) at -78ºC under a N2 atmosphere. After the addition, the mixture was stirred at the same temperature for another 1 hour. The crude intermediate was then added to the above solution at -78ºC and stirred overnight at room temperature. The reaction mixture was quenched with HCl and extracted with EA (10 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by preparative HPLC (H2O / MeCN = 45 / 55, 0.1% TFA) to obtain the product (10.2 mg, HPLC: 99.39%). MS [M+H + For C 19 H 12 The calculated value of D3ClFN5O2 is 402.8, and the measured value is also 402.8. 1 HNMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.58 (s, 1H), 7.45 (s, 2H), 7.33 (d, J= 8.7 Hz, 1H), 4.78 (s, 2H), 3.18 (s, 3H).

[0609] Compound 40

[0610] (Z)-3-(4-chloro-1H-benzo[d][1,2,3]triazol-6-yl)-2-cyano-3-hydroxy-N,N-bis(methyl-d3)acrylamide

[0611]

[0612] Step 1: Synthesis of 2-cyano-N,N-bis(methyl-d3)acetamide

[0613] T4P (12.4 g, 58.8 mmol) and DIEA (6.47 g, 69.0 mmol) were added to a solution of bis(methyl-d3)amine hydrochloride (2 g, 23.0 mmol), 2-cyanoacetic acid (2.9 g, 34.5 mmol), and stirred at 25ºC under N2 for 16 h. The reaction solution was removed under vacuum to obtain the crude product. Further purification by column chromatography (silica gel, PE / EA = 1 / 1) yielded the desired product (1.1 g, 41%). MS [M+H] + The calculated value for C5H2D6N2O is 119.1, and the measured value is also 119.1.

[0614] Step 2: Synthesis of (Z)-3-(4-chloro-1H-benzo[d][1,2,3]triazol-6-yl)-2-cyano-3-hydroxy-N,N-bis(methyl-d3)acrylamide (40)

[0615] A solution of 4-chloro-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (300 mg, 1.52 mmol) in SOCl2 (10 mL) was stirred at 80ºC for 12 hours. This solution was then concentrated under vacuum to give a crude intermediate. LiHMDS (3.8 mL, 3.8 mmol) was added dropwise to a solution of 32-cyano-N,N-bis(methyl-d3)acetamide (216 mg, 1.83 mmol) in THF (5 mL) at -78ºC under a N2 atmosphere. After the addition, the mixture was stirred at the same temperature for another 1 hour. The crude intermediate was then added to the above solution at -78ºC and stirred overnight at room temperature. The reaction mixture was quenched with HCl and extracted with DCM (30 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by preparative HPLC (H2O / MeCN = 7 / 3, 0.1% TFA) to obtain the product (120 mg, 27%). MS [M+H] + For C 12 The calculated value of H4D6ClN5O2 is 298.1, and the measured value is also 298.1. 1 NMR (400 MHz, MeOD) δ 8.05 (s, 1H), 7.58 (s, 1H).

[0616] Compound 38

[0617] (Z)-3-(1H-benzo[d][1,2,3]triazol-6-yl)-2-cyano-3-hydroxy-N,N-dimethylacrylamide (38)

[0618] The title compounds were prepared in 48% yield from 1H-benzo[d][1,2,3]triazol-6-carboxylic acid and 2-cyano-N,N-dimethylacetamide, according to the preparation procedures for compounds 27, 490, and 33. MS [M+H] + For C 12 H 11 The calculated value of N5O2 is 258.1, and the measured value is 257.9. 1 HNMR (400 MHz, MeOD) δ 8.41 (s, 1H), 7.84 (s, 2H), 3.22– 3.08 (s, 6H).

[0619] Compound 438

[0620] (Z)-3-(1H-benzo[d][1,2,3]triazol-6-yl)-2-(cyclopropanecarbonyl)-3-hydroxyacrylonitrile (438)

[0621] The title compound was prepared in 8.7% yield from 1H-benzo[d][1,2,3]triazol-6-carboxylic acid and 3-cyclopropyl-3-oxopropionitrile according to the preparation procedure for compound 27. MS [MH] - For C 13 H 10 The calculated value of N4O2 is 253.1, and the measured value is also 253.1. 1 HNMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 2.46 – 2.46 (m, 1H), 1.17 (m, 4H).

[0622] Compound 146

[0623] (Z)-3-(4-chloro-1H-benzo[d][1,2,3]triazol-6-yl)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-hydroxy-N-methylacrylamide (146)

[0624] A solution of 4-chloro-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (100 mg, 0.5 mmol) in SOCl2 (10 mL) was stirred at 80ºC for 2 hours. This solution was then concentrated under vacuum to give a crude intermediate. LiHMDS (1.3 mL, 1.3 mmol) was added dropwise to a solution of N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide (122 mg, 0.5 mmol) in THF (20 mL) at -78ºC under a N2 atmosphere. After the addition, the mixture was stirred at the same temperature for another 1 hour. The crude intermediate was then added to the above solution at -78ºC and stirred overnight at room temperature. The reaction mixture was quenched with HCl and extracted with DCM (30 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by preparative HPLC (H2O / MeCN = 6 / 4, 0.1% TFA, twice) to obtain product 146 (61.4 mg, HPLC: 98.59%). MS [M+H + For C 18 H 12 The calculated value of Cl2FN5O2 is 420.2, and the measured value is 419.8. 1 HNMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.91 (s, 1H), 7.38 (m, 3H), 4.78 (s, 2H), 3.18 (s, 3H).

[0625] Compound 148

[0626] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-hydroxy-N-methyl-3-(4-methyl-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide (148)

[0627] The title compound was prepared in 35.9% yield from 4-methyl-1H-benzo[d][1,2,3]triazol-6-carboxylic acid and N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide according to the preparation procedure for compound 27. MS [M+H] + For C 19 H 15 The calculated value of ClFN5O2 is 400.1, and the measured value is also 400.1. 1HNMR (400 MHz, DMSO-d6) δ 16.17 (s,1H), 8.27 (s, 1H), 7.58 – 7.32 (m, 5H), 4.78 (s, 2H), 3.18 (s, 3H), 2.68 (s,3H).

[0628] Compound 149

[0629] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-(4-cyano-1H-benzo[d][1,2,3]triazol-6-yl)-3-hydroxy-N-methylacrylamide (149)

[0630] The title compound was prepared in 12.4% yield from 4-cyano-1H-benzo[d][1,2,3]triazol-6-carboxylic acid and N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide according to the preparation procedure for compound 27. MS [M+H] + For C 19 H 12 The calculated value of ClFN6O2 is 411.1, and the measured value is 411.0. 1 HNMR (400 MHz, DMSO-d6) δ 8.71 (s,1H), 8.39 (s, 1H), 7.40-7.28 (m, 5H), 4.72 (s, 2H), 3.11 (s, 3H).

[0631] Compound 150

[0632] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-(4-(difluoromethoxy)-1H-benzo[d][1,2,3]triazol-6-yl)-3-hydroxy-N-methylacrylamide (150)

[0633] The title compound was prepared in 0.7% yield from 4-(difluoromethoxy)-1H-benzo[d][1,2,3]triazol-6-carboxylic acid and N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide according to the preparation procedure for compound 27. MS [M+H] + For C 19 H 13 The calculated value of ClF3N5O3 is 452.1, and the measured value is 451.9. 1HNMR (400 MHz, DMSO-d6) δ 8.30-8.15 (m, 1H), 7.75 – 7.53 (m, 1H), 7.44 (s, 1H), 7.36 (dd, J = 7.9, 4.9 Hz,2H), 7.21 (t, J = 9.2 Hz, 1H), 4.69 (s, 2H), 3.12 (s, 3H).

[0634] Compound 155

[0635] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-hydroxy-3-(4-methoxy-1H-benzo[d][1,2,3]triazol-6-yl)-N-methylacrylamide (155)

[0636] The title compound was prepared in 5.9% yield from 4-methoxy-1H-benzo[d][1,2,3]triazol-6-carboxylic acid and N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide according to the preparation procedure for compound 27. MS [M+H] + For C 19 H 15 The calculated value of ClFN5O3 is 416.1, and the measured value is also 416.1. 1 HNMR (400 MHz, DMSO-d6) δ 8.03-8.06(m, 1H), 7.30-7.40 (m, 3H), 7.13-7.18 (m, 1H), 4.87 (s, 2H), 4.10 (s, 3H), 3.30 (s, 3H).

[0637] Compound 444

[0638] (Z)-3-(4-chloro-1H-benzo[d][1,2,3]triazol-6-yl)-2-(4-(3-chlorophenyl)piperidin-1-carbonyl)-3-hydroxyacrylonitrile (444)

[0639] A solution of 4-chloro-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (50 mg, 0.25 mmol) in SOCl2 (5 mL) was stirred at 80ºC for 2 hours. This solution was then concentrated under vacuum to give a crude intermediate. LiHMDS (0.6 mL, 0.63 mmol) was added dropwise to a solution of 3-(4-(3-chlorophenyl)piperidin-1-yl)-3-oxopropionitrile (79 mg, 0.30 mmol) in THF (5 mL) at -78ºC under a N2 atmosphere. After the addition, the mixture was stirred at the same temperature for another 1 hour. The crude intermediate was then added to the above solution at -78ºC and stirred overnight at room temperature. The reaction mixture was quenched with HCl and extracted with DCM (50 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by preparative HPLC (H2O / MeCN = 7 / 3, 0.1% TFA) to obtain product 444 (19 mg, HPLC: 95.757%). MS [M+H + For C 21 H 17 The calculated value of Cl2N5O2 is 442.1, and the measured value is also 442.1. 1 H NMR (400MHz, MeOD) δ 8.46 (s, 1H), 7.96 (s, 1H), 7.28 (d, J = 7.6 Hz, 2H), 7.21 (d, J= 7.3 Hz, 2H), 4.72 (d, J = 12.9 Hz, 2H), 3.19 (t, J = 12.6 Hz, 2H), 2.94 (t,J = 11.7 Hz, 1H), 2.00 (d, J = 12.7 Hz, 2H), 1.83-1.75 (m, 2H).

[0640] Compound 445

[0641] (Z)-2-(4-(3-chlorophenyl)piperidin-1-carbonyl)-3-(4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-3-hydroxyacrylonitrile (445)

[0642] The title compound was prepared in 12.2% yield from 4-fluoro-1H-benzo[d][1,2,3]triazol-6-carboxylic acid and 3-(4-(3-chlorophenyl)piperidin-1-yl)-3-oxopropionitrile according to the preparation procedure for compound 27. MS [M+H] + For C 21 H 17The calculated value of ClFN5O2 is 426.1, and the measured value is 426.0. 1 HNMR (400 MHz, DMSO-d6) δ 8.31 (s,1H), 7.63-7.65 (m, 1H), 7.18-7.27 (m, 4H), 4.68-4.71 (m, 2H), 3.14-3.29 (m,2H), 2.89-2.95 (m, 1H), 1.96-1.99 (m, 2H), 1.72-1.81 (m, 2H).

[0643] Compound 440

[0644] (Z)-3-(4-chloro-1H-benzo[d][1,2,3]triazol-6-yl)-2-(cyclopropanecarbonyl)-3-hydroxyacrylonitrile (440)

[0645] A solution of 4-chloro-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (100 mg, 0.51 mmol) in SOCl2 (10 mL) was stirred at 80ºC for 2 hours. The solution was then concentrated under vacuum to give a crude intermediate. LiHMDS (1.3 mL, 1.26 mmol) was added dropwise to a solution of 3-cyclopropyl-3-oxopropionitrile (55 mg, 0.51 mmol) in THF (10 mL) at -78ºC under a N2 atmosphere. After the addition, the mixture was stirred at the same temperature for another 1 hour. The crude intermediate was then added to the above solution at -78ºC and stirred overnight at room temperature. The reaction mixture was quenched with AcOH and extracted with EA (30 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by preparative HPLC (H2O / MeCN = 6 / 4, 0.1% TFA) to obtain product 440 (19.7 mg, HPLC: 98.559%). MS [M+H] + For C 13 The calculated value of H9ClN4O2 is 289.0, and the measured value is also 289.0. 1 HNMR (400 MHz, DMSO-d6) δ8.45 (s, 1H), 7.89 (s, 1H), 2.54 (s, 1H), 1.20 (s, 4H).

[0646] Compound 491

[0647] (Z)-3-(4-chloro-1H-benzo[d][1,2,3]triazol-6-yl)-3-hydroxy-2-(thiazolyl-2-yl)acrylonitrile (491)

[0648] A solution of 4-chloro-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (100 mg, 0.51 mmol) in SOCl2 (10 mL) was stirred at 80ºC for 2 hours. The solution was then concentrated under vacuum to give a crude intermediate. LiHMDS (1.3 mL, 1.26 mmol) was added dropwise to a solution of 2-(thiazol-2-yl)acetonitrile (63 mg, 0.51 mmol) in THF (10 mL) at -78ºC under a N2 atmosphere. After the addition, the mixture was stirred at the same temperature for another 1 hour. The crude intermediate was then added to the above solution at -78ºC and stirred overnight at room temperature. The reaction mixture was quenched with AcOH and extracted with EA (30 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by preparative HPLC (H2O / MeCN = 6 / 4, 0.1% TFA, twice) to obtain product 491 (8.6 mg, HPLC: 95.399%). MS [M+H + For C 12 The calculated value of H6ClN5OS is 304.0, and the measured value is also 304.0. 1 HNMR (400 MHz, DMSO-d6) δ 13.58 (s, 1H), 8.27 (s, 1H), 7.82 (s, 1H), 7.63 (s, 1H), 7.33 (s, 1H).

[0649] Compound 147

[0650] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-(4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-3-hydroxy-N-methylacrylamide (147)

[0651] The title compound was prepared in 12% yield from 4-fluoro-1H-benzo[d][1,2,3]triazol-6-carboxylic acid and N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide according to the preparation procedure for compound 27. MS [M+H] + For C 18 H 12 The calculated value of ClF2N5O2 is 404.1, and the measured value is also 404.1. 1HNMR (400 MHz, DMSO-d6) δ 8.25 (s,1H), 7.64 (s, 1H), 7.43-7.31 (m, 3H), 4.76 (s, 2H), 3.17 (s, 3H).

[0652] Compound 166

[0653] (Z)-3-(7-chloro-1H-benzo[d][1,2,3]triazol-6-yl)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-hydroxy-N-methylacrylamide (166)

[0654] The title compound was prepared in 2.2% yield from 7-chlorobenzo[d]isoxazole-5-carboxylic acid and N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide according to the preparation procedure for compound 27. MS [M+H] + For C 18 H 12 The calculated value of Cl2FN5O2 is 420.0, and the measured value is also 420.0. 1 HNMR (400 MHz, MeOD) δ 7.91 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.37 – 7.33 (m, 1H), 7.16 (t,J = 9.2 Hz, 1H), 3.25 (s, 2H), 1.28 (s, 3H).

[0655] Compound 167

[0656] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-(7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-3-hydroxy-N-methylacrylamide (167)

[0657] The title compound was prepared from 7-chlorobenzo[d]isoxazole-5-carboxylic acid and N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide in a yield of 1.4%, according to the preparation procedure for compound 27. MS [M+H] - For C 18 H 12 The calculated value of ClF2N5O2 is 404.1, and the measured value is 404.0. 1H NMR (400 MHz, MeOD) δ 7.69 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.38 – 7.36 (m, 2H), 7.31 (dd, J = 7.9, 3.5 Hz, 2H), 7.11 (s, 2H), 4.83 (s, 3H), 1.25 (s, 3H).

[0658] Compound 39

[0659] (Z)-3-(4-chloro-1H-benzo[d][1,2,3]triazol-6-yl)-2-cyano-3-hydroxy-N,N-dimethylacrylamide (39)

[0660] A solution of 4-chloro-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (50 mg, 0.25 mmol) in SOCl2 (5 mL) was stirred at 80ºC for 2 hours. This solution was then concentrated under vacuum to give a crude intermediate. LiHMDS (0.6 mL, 0.63 mmol) was added dropwise to a solution of 2-cyano-N,N-dimethylacetamide (34 mg, 0.30 mmol) in THF (5 mL) at -78ºC under a N2 atmosphere. After the addition, the mixture was stirred at the same temperature for another 1 hour. The crude intermediate was then added to the above solution at -78ºC and stirred overnight at room temperature. The reaction mixture was quenched with HCl and extracted with DCM (50 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by preparative HPLC (H2O / MeCN = 7 / 3, 0.1% TFA) to obtain product 39 (10.8 mg, HPLC: 96.604%). MS [M+H] + For C 12 H 10 The calculated value of ClN5O2 is 292.1, and the measured value is 292.0. 1 HNMR (400 MHz, MeOD-d4) δ8.43 (s, 1H), 7.94 (s, 1H), 3.27 (s, 6H)

[0661] Compound 36

[0662] (Z)-3-(4-chloro-1H-benzo[d][1,2,3]triazol-6-yl)-2-cyano-N,N-diethyl-3-hydroxyacrylamide (36)

[0663] The title compound was prepared in 14.9% yield from 4-chloro-1H-benzo[d][1,2,3]triazol-6-carboxylic acid and 2-cyano-N,N-diethylacetamide according to the preparation procedure for compound 27. MS [M+H] + For C 14 H 14 The calculated value of ClN5O2 is 320.1, and the measured value is also 320.1. 1 HNMR (400 MHz, MeOD) δ 8.41(s, 1H), 7.89 (s, 1H), 3.60(d, J = 6.3 Hz, 4H), 1.22 (t, J = 6.0 Hz, 6H).

[0664] Compounds B-1 and B-2

[0665] (Z)-3-(4-chloro-1H-benzo[d][1,2,3]triazol-6-yl)-2-cyano-N,N-diethylacrylamide (B-1) and (E)-3-(4-chloro-1H-benzo[d][1,2,3]triazol-6-yl)-2-cyano-N,N-diethylacrylamide (B-2)

[0666]

[0667] Step 1: Synthesis of 4-chloro-1H-benzo[d][1,2,3]triazole-6-carboxaldehyde (2)

[0668] To a solution of 6-bromo-4-chloro-1H-benzo[d][1,2,3]triazole (500 mg, 2.16 mmol) in dry DMF (10 mL), n-butylisocyanate (358 mg, 4.31 mmol), HCOOK (362 mg, 4.31 mmol), Johnphos (128 mg, 0.43 mmol), and Pd(OAc)₂ (49 mg, 0.22 mmol) were added, and the mixture was stirred overnight at 65ºC under the same temperature. The reaction mixture was extracted with EA (50 mL x 3). The combined organic phases were dried over Na₂SO₄ and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 1 / 2) to obtain the product (120 mg, 31%). MS [M+H] + The calculated value for C7H4ClN3O is 182.2, and the measured value is also 182.2.

[0669] Step 2: Synthesis of (Z)-3-(4-chloro-1H-benzo[d][1,2,3]triazol-6-yl)-2-cyano-N,N-diethylacrylamide (B-1) and (E)-3-(4-chloro-1H-benzo[d][1,2,3]triazol-6-yl)-2-cyano-N,N-diethylacrylamide (B-2)

[0670] To a solution of 4-chloro-1H-benzo[d][1,2,3]triazole-6-carboxaldehyde (120 mg, 0.66 mol) in i-PrOH (5 mL), 2-cyano-N,N-diethylacetamide (77 mg, 0.55 mmol) and piperidine (6 mg, 0.07 mmol) were added and stirred overnight at 85ºC. The reaction mixture was filtered to obtain the crude product. The residue was purified by preparative HPLC (H2O / MeCN = 7 / 3, 0.1% TFA, twice) to obtain product B-1 (4.4 mg, HPLC: 97.749%), MS [M+H]+, calculated value for C14H14ClN5O 304.0, found value 304.0. ¹H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.89 (s, 1H), 7.57 (s, 1H), 3.44 (q, J = 7.0 Hz, 2H), 3.26 (q, J = 7.0 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.1 Hz, 3H), and product B-2 (16.1 mg). mg (HPLC: 95.551%). MS [M+H]+, calculated value for C14H14ClN5O 304.0, measured value 304.0. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.05 (s, 1H), 7.93 (s, 1H), 3.45 (d, J = 6.9 Hz, 4H), 1.16 (d, J = 13.6 Hz, 6H).

[0671] Compound 41

[0672] (Z)-2-cyano-3-(4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-3-hydroxy-N,N-dimethylacrylamide (41)

[0673] The title compound was prepared in 3.6% yield from 4-fluoro-1H-benzo[d][1,2,3]triazol-6-carboxylic acid and 2-cyano-N,N-dimethylacetamide according to the preparation procedure for compound 27. MS [M+H] + For C 12 H 10 The calculated value of FN5O2 is 276.1, and the measured value is also 276.1. 1 HNMR (400 MHz, MeOD) δ 8.26 (s, 1H), 7.60-7.62 (m, 1H), 3.25 (s, 6H).

[0674] Compound 42

[0675] (Z)-3-(4-bromo-1H-benzo[d][1,2,3]triazol-6-yl)-2-cyano-3-hydroxy-N,N-dimethylacrylamide (42)

[0676] The title compound was prepared in 3.52% yield from 4-bromo-1H-benzo[d][1,2,3]triazol-6-carboxylic acid and 2-cyano-N,N-dimethylacetamide according to the preparation procedure for compound 27. MS[M+2] + For C 12 H 10 The calculated value of BrN5O2 is 338.0, and the measured value is also 338.0. 1 HNMR (400 MHz, MeOD) δ 8.47 (s, 1H), 8.09 (s, 1H), 3.27 (s, 6H).

[0677] Compound 48

[0678] (Z)-2-cyano-3-hydroxy-N,N-dimethyl-3-(4-methyl-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide (48)

[0679] The title compound was prepared in 3.3% yield from 4-methyl-1H-benzo[d][1,2,3]triazol-6-carboxylic acid and 2-cyano-N,N-dimethylacetamide according to the preparation procedure for compound 27. MS [M+H] + For C 13 H 13 The calculated value of N5O2 is 272.1, and the measured value is also 272.1. 1 HNMR (400 MHz, MeOD) δ 8.28 (s, 1H), 7.69 (s, 1H), 3.25 (s, 6H), 2.73 (s, 3H).

[0680] Compound 43

[0681] (Z)-2-cyano-3-hydroxy-3-(4-methoxy-1H-benzo[d][1,2,3]triazol-6-yl)-N,N-dimethylacrylamide (43)

[0682] The title compound was prepared in 21.5% yield from 4-methoxy-1H-benzo[d][1,2,3]triazol-6-carboxylic acid and 2-cyano-N,N-dimethylacetamide according to the preparation procedure for compound 27. MS [M+H] + For C 13 H 13 The calculated value of N5O3 is 288.1, and the measured value is also 288.1. 1 HNMR (400 MHz, DMSO-d6) δ 8.07-8.13 (m, 1H), 7.21 (s,1H), 4.06 (s, 3H), 3.17 (s, 6H).

[0683] Compound 154

[0684] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-(4-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-3-hydroxy-N-methylacrylamide (154)

[0685] The title compound was prepared in 2.73% yield from 4-ethyl-1H-benzo[d][1,2,3]triazol-6-carboxylic acid and N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide according to the preparation procedure for compound 27. MS [MH] - For C 20 H 17 The calculated value of ClFN5O2 is 412.1, and the measured value is 411.7. 1 HNMR (400 MHz, DMSO-d6) δ 8.07 (s,1H), 7.49 (s, 1H), 7.40 – 7.30 (m, 2H), 7.20 (t, J = 9.4 Hz, 1H), 4.67 (s,2H), 3.09 (s, 3H), 3.03 (d, J = 6.7 Hz, 2H), 1.32 (t, J = 7.4 Hz, 3H).

[0686] Compound 37

[0687] (Z)-2-cyano-N,N-diethyl-3-hydroxy-3-(4-nitro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide (37)

[0688] The title compound was prepared in 0.92% yield from 4-nitro-1H-benzo[d][1,2,3]triazol-6-carboxylic acid and 2-cyano-N,N-diethylacetamide according to the preparation procedure for compound 27. MS [M+H] + For C 14 H 14 The calculated value of N6O4 is 331.1, and the measured value is also 331.1. 1 HNMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.74 (s, 1H), 3.63 (s, 4H), 1.23 (s, 6H).

[0689] Compounds C-1 and C-2

[0690] (E)-2-cyano-N,N-diethyl-3-(4-nitro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide (C-1) and (Z)-2-cyano-N,N-diethyl-3-(4-nitro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide (C-2)

[0691]

[0692] Step 1: Synthesis of 6-bromo-4-nitro-1H-benzo[d][1,2,3]triazole(2)

[0693] A solution of 5-bromo-3-nitrobenzene-1,2-diamine (2 g, 8.62 mmol) and NaNO2 (595 mg, 8.62 mmol) in AcOH (20 mL) was stirred at room temperature under N2 for 30 min. After addition, the reaction was heated to 65ºC and stirred for 2.5 h. The reaction was extracted with EA (100 mL * 3) and dried over Na2SO4. The combined organic phases were concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 1 / 1) to obtain the product (600 mg, 29%). MS [M+H] + The calculated value for C6H3BrN4O2 is 242.9, and the measured value is also 242.9.

[0694] Step 2: Synthesis of 4-nitro-6-vinyl-1H-benzo[d][1,2,3]triazole(3)

[0695] A solution of 6-bromo-4-nitro-1H-benzo[d][1,2,3]triazole (340 mg, 1.40 mmol), potassium trifluoro(vinyl)borate(I) (399 mg, 4.20 mmol), K3PO4 (594 mg, 2.80 mmol), and Pd(dppf)Cl2·DCM (114 mg, 0.14 mmol) in dioxane (5 mL) and H2O (1 mL) was stirred at 100ºC for 3 h under N2. The reaction solution was removed under vacuum to give the crude product. Further purification by column chromatography (silica gel, PE / EA = 1 / 1) yielded the desired product (180 mg, 67%). MS [M+H] + The calculated value for C8H6N4O2 is 191.0, and the measured value is also 191.0.

[0696] Step 3: Synthesis of 4-nitro-1H-benzo[d][1,2,3]triazole-6-carboxaldehyde (5)

[0697] NaIO4 (1007 mg, 4.75 mmol) and K2OsO4 (69 mg, 0.19 mmol) were added dropwise to a solution of 4-nitro-6-vinyl-1H-benzo[d][1,2,3]triazole (180 mg, 0.95 mmol) in dioxane (2 mL) and H2O (5 mL) for 10 min at 0ºC. After addition, the reaction was warmed to room temperature and stirred for 1 h. The mixture was quenched with ice, extracted with EA (50 mL * 3), dried over Na2SO4, and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EA = 2 / 8) to obtain the product (65 mg, 36%). MS [M+H] + The calculated value for C7H4N4O3 is 193.0, and the measured value is also 193.0.

[0698] Step 4: Synthesis of (E)-2-cyano-N,N-diethyl-3-(4-nitro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide (C-1) and (Z)-2-cyano-N,N-diethyl-3-(4-nitro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide (C-2)

[0699] A solution of 4-nitro-1H-benzo[d][1,2,3]triazol-6-carboxaldehyde (65 mg, 0.34 mmol), piperidine (3 mg, 0.03 mmol), and 2-cyano-N,N-diethylacetamide (40 mg, 0.29 mmol) in i-PrOH (4 mL) was stirred at 85ºC for 16 h under N2. The reaction solution was removed under vacuum to obtain the crude product. The residue was purified by preparative HPLC (H2O / MeCN = 7 / 3, 0.1% FA) to obtain product C-1 (3.02 mg, HPLC: 96.327%). MS [M+H] + For C 14 H 14 The calculated value for N6O3 is 315.1, and the measured value is also 315.1. 1 ¹H NMR (400 MHz, DMSO-d6) δ 8.89–8.87 (m, 2H), 7.91 (s, 1H), 3.56–3.52 (m, 4H), 1.30–1.19 (m, 6H), and product C-2 (1.75 mg, HPLC: 96.486%). MS [M+H] + For C 14 H 14 The calculated value for N6O3 is 315.1, and the measured value is also 315.1. 1 H NMR(400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.39 (s, 1H), 7.98 (s, 1H), 3.46 (m, 2H), 3.17 (m, 2H), 1.15 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.1 Hz, 3H).

[0700] Compound 47

[0701] (Z)-2-cyano-3-hydroxy-N,N-dimethyl-3-(4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide (47)

[0702] The title compound was prepared in 5.06% yield from 4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-carboxylic acid and 2-cyano-N,N-dimethylacetamide according to the preparation procedure for compound 27. MS [M+H] + For C 13 H 10 The calculated value of F3N5O2 is 326.1, and the measured value is 326.0. 1HNMR (400 MHz, MeOD) δ 8.78 (s, 1H), 8.24 (s, 1H), 3.26 (s, 6H).

[0703] Compound 485

[0704] (Z)-2-(3-azabicyclo[3.1.0]hexane-3-carbonyl)-3-(4-chloro-1H-benzo[d][1,2,3]triazol-6-yl)-3-hydroxyacrylonitrile (485)

[0705] A solution of 4-chloro-1H-benzo[d][1,2,3]triazol-6-carboxylic acid (50 mg, 0.25 mmol) in SOCl2 (10 mL) was stirred at 80ºC for 2 hours. This solution was then concentrated under vacuum to give a crude intermediate. LiHMDS (0.6 mL, 0.63 mmol) was added dropwise to a solution of 3-(3-azabicyclo[3.1.0]hex-3-yl)-3-oxopropionitrile (46 mg, 0.30 mmol) in THF (5 mL) at -78ºC under a N2 atmosphere. After the addition, the mixture was stirred at the same temperature for another 1 hour. The crude intermediate was then added to the above solution at -78ºC and stirred overnight at room temperature. The reaction mixture was quenched with HCl and extracted with DCM (30 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by preparative HPLC (H2O / MeCN = 7 / 3, 0.1% TFA) to obtain product 485 (12.45 mg, HPLC: 96.491%). MS [M+H] + For C 15 H 12 The calculated value of ClN5O2 is 330.1, and the measured value is also 330.1. 1 NMR (400MHz, MeOD-d4) δ 8.42 (s, 1H), 7.93 (s, 1H), 4.15 (d, J = 10.5 Hz, 2H), 3.82(s, 2H), 1.76 (s, 2H), 0.87 (d, J = 5.7 Hz, 1H), 0.23 (d, J = 3.4 Hz, 1H).

[0706] Compound 73

[0707] (Z)-3-(4-chloro-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-2-cyano-3-hydroxy-N,N-dimethylacrylamide

[0708] The title compound was prepared in 13.8% yield from 4-chloro-7-methyl-1H-benzo[d][1,2,3]triazol-6-carboxylic acid and 2-cyano-N,N-dimethylacetamide according to the preparation procedure for compound 27. MS [M+H] + The calculated value for C13H12ClN5O2 is 306.1, while the measured value is 330.1. 1 NMR (400 MHz, MeOD-d4) δ 7.58 (s, 1H), 3.25 (s,6H), 2.77 (s, 3H).

[0709] Compound 74

[0710] (Z)-3-(4-chloro-7-methoxy-1H-benzo[d][1,2,3]triazol-6-yl)-2-cyano-3-hydroxy-N,N-dimethylacrylamide

[0711] The title compound was prepared in 9.2% yield from 4-chloro-7-methoxy-1H-benzo[d][1,2,3]triazol-6-carboxylic acid and 2-cyano-N,N-dimethylacetamide according to the preparation procedure for compound 27. MS [M+H] + The calculated value for C13H12ClN5O3 is 322.1, and the measured value is also 322.1. 1 NMR (400 MHz, MeOD-d4) δ 7.53 (s, 1H), 4.63 (s, 3H), 3.23 (s, 6H).

[0712] Compound 298

[0713] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-hydroxy-N-methyl-3-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide (298)

[0714] The title compound was prepared in 48.0% yield from 1-methyl-1H-benzo[d][1,2,3]triazol-6-carboxylic acid and N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide according to the preparation procedure for compound 27. MS [M+H] + For C 19 H 15 The calculated value of ClFN5O2 is 400.1, and the measured value is also 400.1. 1HNMR (400 MHz, DMSO-d6) δ 8.32 (s,1H), 8.15 (d, J = 6.6 Hz, 1H), 7.71 (s, 1H), 7.41 (s, 2H), 7.28 (s, 1H), 4.74(s, 2H), 4.34 (s, 5H), 3.14 (s, 3H).

[0715] Compound 526

[0716] (Z)-N-(5-chloro-2-fluorobenzyl)-3-(7-chlorobenzo[d]isoxazol-5-yl)-2-cyano-3-hydroxy-N-methacrylamide (526)

[0717] The title compound was prepared in 18.5% yield from 7-chlorobenzo[d]isoxazo-5-carboxylic acid and N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide according to the preparation procedure for compound 27. MS [MH] - For C 19 H 12 The calculated value of Cl2FN3O3 is 418.0, and the measured value is 418.1. 1 HNMR (400 MHz, DMSO-d6) δ 8.10 (s, 2H), 7.39-7.27 (m,4H), 4.70 (s, 2H), 3.09 (s, 3H).

[0718] Compound 533

[0719] (Z)-N-(1-(5-chloro-2-fluorophenyl)ethyl)-2-cyano-3-hydroxy-N-methyl-3-(7-methylbenzo[d]isoxazol-5-yl)acrylamide (533)

[0720] The title compound was prepared in 13.3% yield from 7-methylbenzo[d]isoxazole-5-carboxylic acid and N-(1-(5-chloro-2-fluorophenyl)ethyl)-2-cyano-N-methylacetamide according to the preparation procedure for compound 27. MS [MH] - For C 21 H 17 The calculated value of ClFN3O3 is 412.1, and the measured value is 412.0. 1HNMR (400 MHz, DMSO-d6) δ 11.14 (s,1H), 7.98 (s, 1H), 7.81 (s, 1H), 7.51 (s, 1H), 7.43 (s, 2H), 7.26 (s, 1H),5.76 (m, 1H), 2.87 (s, 3H), 2.24 (s, 3H), 1.55 (d, J = 5.8 Hz, 3H).

[0721] Compounds 534 and 535

[0722] (R,Z)-N-(1-(5-chloro-2-fluorophenyl)ethyl)-2-cyano-3-hydroxy-N-methyl-3-(7-methylbenzo[d]isoxazo-5-yl)acrylamide (535) and (S,Z)-N-(1-(5-chloro-2-fluorophenyl)ethyl)-2-cyano-3-hydroxy-N-methyl-3-(7-methylbenzo[d]isoxazo-5-yl)acrylamide (534)

[0723]

[0724] Compound 533 was purified by chiral HPLC to obtain product 535: MS [MH] - For C 21 H 17 The calculated value of ClFN3O3 is 412.1, and the measured value is also 412.1. 1 H NMR 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 7.92 (s, 1H), 7.77 (s, 1H), 7.50 (s, 1H), 7.42 (d, J = 2.8 Hz, 2H), 7.24 (t, J = 8.7 Hz, 1H), 5.73 (s, 1H), 2.85 (d, J = 4.9 Hz, 3H), 2.22 (s, 3H), 1.53 (s, 3H). And product 534: MS [MH] - For C 21 H 17 The calculated value of ClFN3O3 is 412.1, and the measured value is also 412.1. 1HNMR (400 MHz, DMSO-d6) δ 8.00 – 7.87 (m, 1H), 7.78 (s, 1H), 7.51 (s, 1H), 7.42 (s, 2H), 7.25 (s,1H), 5.75 (s, 1H), 2.85 (s, 3H), 2.22 (s, 3H), 1.54 (s, 3H).

[0725] Compound 4

[0726] (Z)-3-(benzo[d]isoxazol-5-yl)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-hydroxy-N-methacrylamide (4)

[0727] The title compound was prepared in 18.5% yield from benzo[d]isoxazole-5-carboxylic acid and N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide according to the preparation procedure for compound 27. MS [M+H] + For C 19 H 13 The calculated value of ClFN3O3 is 384.1, and the measured value is 383.6. 1 HNMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 7.89-8.22 (m,2H), 7.05-7.48 (m, 5H), 4.75 (s, 2H), 3.09 (s, 3H).

[0728] Compound 5

[0729] (Z)-3-(benzo[d]isoxazol-5-yl)-2-cyano-N-(2-fluoro-5-methylbenzyl)-3-hydroxy-N-methacrylamide (5)

[0730] The title compound was prepared in 11.0% yield from benzo[d]isoxazole-5-carboxylic acid and 2-cyano-N-(2-fluoro-5-methylbenzyl)-N-methylacetamide according to the preparation procedure for compound 27. MS [M+H] + For C 20 H 16 The calculated value of FN3O3 is 366.1, and the measured value is also 366.1. 1HNMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.94 (d, J = 7.7Hz, 1H), 7.19 – 7.07 (m, 5H), 4.74 (s, 2H), 3.13 (s, 3H), 2.28 (s, 3H).

[0731] Compound 527

[0732] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-hydroxy-N-methyl-3-(7-methylbenzo[d]isoxazol-5-yl)acrylamide (527)

[0733] The title compound was prepared in 10.1% yield from 7-methylbenzo[d]isoxazole-5-carboxylic acid and N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide according to the preparation procedure for compound 27. MS [MH] - For C 20 H 15 The calculated value of ClFN3O3 is 397.6, and the measured value is also 397.6. 1 HNMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.83 (s,1H), 7.43 (s, 3H), 7.32 (d, J = 9.0 Hz, 1H), 4.75 (s, 2H), 3.14 (s, 3H), 2.27(s, 3H).

[0734] Compound 542

[0735] (Z)-3-(benzo[d]isoxazol-5-yl)-N-(2-(2-chlorophenoxy)ethyl)-2-cyano-3-hydroxy-N-methylacrylamide (542)

[0736] The title compound was prepared in 19.1% yield from benzo[d]isoxazole-5-carboxylic acid and N-(2-(2-chlorophenoxy)ethyl)-2-cyano-N-methylacetamide according to the preparation procedure for compound 27. MS [MH] - For C 20 H 16 The calculated value of ClN3O4 is 396.1, and the measured value is also 396.1. 1HNMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 8.08 (s,1H), 7.89 (d, J = 8.2 Hz, 1H), 7.38 (dd, J = 7.9, 1.5 Hz, 1H), 7.31 – 7.24(m, 1H), 7.16-7.09 (m, 3H), 6.93 (td, J = 7.7, 1.3 Hz, 1H), 4.28 (s, 2H), 3.95 (s, 2H), 3.30 (s, 3H).

[0737] Compound 531

[0738] (Z)-3-(benzo[d]isoxazol-5-yl)-2-cyano-N-(2-fluoro-5-(trifluoromethyl)benzyl)-3-hydroxy-N-methacrylamide (531)

[0739] The title compound was prepared in 5.2% yield from benzo[d]isoxazole-5-carboxylic acid and 2-cyano-N-(2-fluoro-5-(trifluoromethyl)benzyl)-N-methylacetamide according to the preparation procedure for compound 27. MS [MH] - For C 20 H 13 The calculated value of F4N3O3 is 418.1, and the measured value is also 418.1. 1 HNMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 8.14 (s,1H), 7.91-7.73 (m, 4H), 7.50 (t, J = 9.0 Hz, 1H), 7.14 (d, J = 5.7 Hz, 1H), 4.83 (s, 2H), 3.14 (s, 3H).

[0740] Compound 532

[0741] (Z)-2-cyano-N-(5-cyano-2-fluorobenzyl)-3-hydroxy-N-methyl-3-(7-methylbenzo[d]isoxazol-5-yl)acrylamide (532)

[0742] The title compound was prepared in 34.6% yield from benzo[d]isoxazole-5-carboxylic acid and 2-cyano-N-(5-cyano-2-fluorobenzyl)-N-methylacetamide according to the preparation procedure for compound 27. MS [MH] - For C 21 H 15 The calculated value of FN4O3 is 389.1, and the measured value is also 389.1.1 HNMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 7.96 (s, 1H), 7.88 (dd, J = 7.1, 4.1 Hz, 2H), 7.79 (t, J = 13.9 Hz, 2H), 7.46 (t, J = 9.1Hz, 1H), 4.72 (d, J = 26.4 Hz, 2H), 3.13 (s, 3H), 2.24 (s, 3H).

[0743] Compound 529

[0744] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-hydroxy-3-(7-methoxybenzo[d]isoxazol-5-yl)-N-methacrylamide (529)

[0745] The title compound was prepared in 5.3% yield from 7-methoxybenzo[d]isoxazole-5-carboxylic acid and N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide according to the preparation procedure for compound 27. MS [MH] - For C 20 H 15 The calculated value of ClFN3O4 is 414.1, and the measured value is also 414.1. 1 HNMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 7.73 –7.61 (m, 2H), 7.43-7.29 (m, 4H), 4.75 (s, 2H), 3.91 (s, 3H), 3.16 (s, 3H).

[0746] Compound 528

[0747] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-hydroxy-3-(7-hydroxybenzo[d]isoxazo-5-yl)-N-methacrylamide (528)

[0748]

[0749] BBr3 (0.80 mL, 0.72 mmol) was added dropwise to a solution of (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-hydroxy-3-(7-methoxybenzo[d]isoxazol-5-yl)-N-methacrylamide (60 mg, 0.14 mmol) in DCM (10 mL) for 15 min at 0ºC. After addition, the reaction was warmed to room temperature and stirred overnight. The mixture was quenched with ice, extracted with EA (50 mL * 3), dried over Na2SO4, and concentrated to dryness under vacuum. The residue was purified by preparative HPLC (H2O / MeCN = 7 / 3, 0.1% TFA, 2 times) to obtain the product (33.2 mg, HPLC: 95.176%). MS[MH] - For C 19 H 13 The calculated value of ClFN3O4 is 400.1, and the measured value is 399.6. 1 H NMR (400 MHz, DMSO) δ10.78 (s, 1H), 7.57 (t, J = 12.1 Hz, 1H), 7.42 (s, 3H), 7.32 (d, J = 8.3 Hz, 2H), 4.74 (s, 2H), 3.14 (s, 3H).

[0750] Compound 536

[0751] (Z)-2-cyano-3-hydroxy-N-methyl-3-(7-methylbenzo[d]isoxazol-5-yl)-N-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)acrylamide (536)

[0752] The title compound was prepared in 0.86% yield from 7-methoxybenzo[d]isoxazole-5-carboxylic acid and 2-cyano-N-methyl-N-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)acetamide according to the preparation procedure for compound 27. MS [MH] - For C 21 H 18 The calculated value of ClN3O4 is 413.1, and the measured value is also 413.1. 1HNMR (400 MHz, DMSO-d6) δ 8.77(s, 1H), 7.99 (s, 1H), 7.88 (d, J = 7.9 Hz, 2H), 7.82 (s, 1H), 7.57 (dd, J =10.7, 5.0 Hz, 3H), 7.46 (t, J = 7.4 Hz, 1H), 4.81 (s, 2H), 3.23 (s, 3H), 2.24 (s, 3H).

[0753] Compound 545

[0754] (Z)-N-(3-(2-chlorophenyl)prop-2-yn-1-yl)-2-cyano-3-hydroxy-N-methyl-3-(7-methylbenzo[d]isoxazol-5-yl)acrylamide (545)

[0755] The title compound was prepared in 0.86% yield from 7-methoxybenzo[d]isoxazole-5-carboxylic acid and N-(3-(2-chlorophenyl)prop-2-yn-1-yl)-2-cyano-N-methylacetamide according to the preparation procedure for compound 27. MS [MH] - For C 21 H 18 The calculated value of ClN3O4 is 414.1, and the measured value is 403.9. 1 HNMR (400 MHz, DMSO-d6) δδ 7.56 (d, J= 8.1 Hz, 3H), 7.43 (td, J = 7.8, 1.8 Hz, 2H), 7.36 (dd, J = 8.0, 7.0 Hz, 2H), 4.63 (s, 2H), 3.27 (s, 3H), 2.27 (s, 3H).

[0756] Compound 543

[0757] (Z)-N-(2-(2-chlorophenoxy)ethyl)-2-cyano-3-hydroxy-N-methyl-3-(7-methylbenzo[d]isoxazol-5-yl)acrylamide (543)

[0758] The title compound was prepared in 1.6% yield from 7-methoxybenzo[d]isoxazole-5-carboxylic acid and N-(2-(2-chlorophenoxy)ethyl)-2-cyano-N-methylacetamide according to the preparation procedure for compound 27. MS [MH] - For C 21 H 18 The calculated value of ClN3O4 is 412.1, and the measured value is also 412.1.1 HNMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.79 (s, 1H), 7.31-7.41 (m, 1H), 7.20-7.29 (m, 3H), 6.95-6.99 (m, 1H), 4.31 (s,2H), 3.97 (s, 2H), 3.33 (s, 3H), 2.26 (s, 3H).

[0759] Compound 538

[0760] (Z)-3-(benzo[d]isoxazol-5-yl)-2-(4-(3-chlorophenyl)piperidin-1-carbonyl)-3-hydroxyacrylonitrile (538)

[0761] The title compound was prepared in 35.9% yield from benzo[d]isoxazo-5-carboxylic acid and 3-(4-(3-chlorophenyl)piperidin-1-yl)-3-oxopropionitrile according to the preparation procedure for compound 27. MS [M+H] + For C 22 H 18 The calculated value of ClN3O3 is 406.1, and the measured value is also 406.1. 1 HNMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.95 (s, 1H),7.36–7.26 (m, 5H), 7.15(d, J = 8.0 Hz,1H), 4.49 (s, 2H), 3.11 (s, 2H), 2.91(s, 1H), 1.88 (s, 2H), 1.69 (s, 2H).

[0762] Compound 541

[0763] (Z)-3-(benzo[d]isoxazol-5-yl)-2-cyano-3-hydroxy-N-methyl-N-(2-phenoxyethyl)acrylamide (541)

[0764] The title compound was prepared in 2.2% yield from benzo[d]isoxazole-5-carboxylic acid and 2-cyano-N-methyl-N-(2-phenoxyethyl)acetamide according to the preparation procedure for compound 27. MS [M+H] + For C 20 H 17 The calculated value of N3O4 is 364.1, and the measured value is 364.2. 1HNMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 8.07 (d, J = 91.9Hz, 1H), 7.31 – 7.27 (m, 2H), 7.14 – 7.12 (m, 1H), 6.97 – 6.93 (m, 4H), 4.22(s, 2H), 3.91(s, 2H), 3.25(s, 3H).

[0765] Compound 3

[0766] (Z)-3-(benzo[d]isoxazo-5-yl)-N-(5-chloro-2-fluorobenzyl)-2-cyano-N-ethyl-3-hydroxyacrylamide (3)

[0767] The title compound was prepared in 34.6% yield from benzo[d]isoxazole-5-carboxylic acid and N-(5-chloro-2-fluorobenzyl)-2-cyano-N-ethylacetamide according to the preparation procedure for compound 27. MS [MH] - For C 20 H 15 The calculated value of ClFN3O3 is 398.1, and the measured value is 397.6. 1 HNMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 8.12 (s, 1H),7.90 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 9.6 Hz, 2H), 7.30 (t, J = 9.1 Hz, 2H),7.14 (d, J = 8.6 Hz, 1H), 4.75 (s, 2H), 3.58 (s, 2H), 1.19 (s, 3H).

[0768] Compound 544

[0769] (Z)-3-(benzo[d]isoxazol-5-yl)-N-(2-(2-chlorophenoxy)ethyl)-2-cyano-N-ethyl-3-hydroxyacrylamide (544)

[0770] The title compound was prepared in 29.1% yield from benzo[d]isoxazole-5-carboxylic acid and N-(2-(2-chlorophenoxy)ethyl)-2-cyano-N-ethylacetamide according to the preparation procedure for compound 27. MS [MH] - For C 12 H 18 The calculated value of ClN3O4 is 410.1, and the measured value is also 410.1. 1HNMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.88 (d, J= 8.2 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 7.5 Hz, 1H), 7.16-7.09(m, 3H), 6.95 (d, J = 7.3 Hz, 1H), 4.28 (s, 2H), 3.93 (s, 2H), 3.75 (s, 2H), 1.21 (d, J = 6.5 Hz, 3H).

[0771] Compound 323

[0772] (Z)-3-(benzo[d]isoxazo-5-yl)-3-hydroxy-2-(4-phenylpiperidin-1-carbonyl)acrylonitrile (323)

[0773] The title compound was prepared in 1.7% yield from benzo[d]isoxazol-5-carboxylic acid and 3-oxo-3-(4-phenylpiperidin-1-yl)propionitrile according to the preparation procedure for compound 27. MS [M+H] + For C 22 H 19 The calculated value of N3O3 is 374.1, and the measured value is 374.2. 1 HNMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 8.20 (s, 1H), 7.96 (d, J =7.5 Hz, 1H), 7.29-6.97 (m, 7H), 4.49 (d, J = 12.7 Hz, 2H), 3.13 (s, 2H), 2.88(s, 1H), 1.90 (d, J = 10.9 Hz, 2H), 1.66 (d, J = 11.1 Hz, 2H).

[0774] Compound 537

[0775] (Z)-3-(benzo[d]isoxazo-5-yl)-3-hydroxy-2-(4-(pyridin-4-yl)piperidine-1-carbonyl)acrylonitrile(537)

[0776] The title compound was prepared in 13.9% yield from benzo[d]isoxazo-5-carboxylic acid and 3-oxo-3-(4-(pyridin-4-yl)piperidin-1-yl)propionitrile according to the preparation procedure for compound 27. MS [MH] - For C 22 H 19The calculated value of N3O3 is 373.1, and the measured value is 372.8. 1 HNMR (400 MHz, DMSO-d6) 1 H NMR (400 MHz, DMSO-d6) δ 8.49(d, J = 5.0 Hz, 2H), 7.97-7.88 (m, 2H), 7.26-6.97 (m, 4H), 3.03-2.94 (m, 4H),2.08-1.73 (m, 4H), 1.23 (s, 1H).

[0777] Compound 539

[0778] (Z)-2-(4-(3-chlorophenyl)piperidin-1-carbonyl)-3-hydroxy-3-(7-methylbenzo[d]isoxazol-5-yl)acrylonitrile (539)

[0779] The title compound was prepared in 11.7% yield from 7-methylbenzo[d]isoxazol-5-carboxylic acid and 3-(4-(3-chlorophenyl)piperidin-1-yl)-3-oxopropionitrile according to the preparation procedure for compound 27. MS [MH] - For C 23 H 20 The calculated value of ClN3O3 is 420.1, and the measured value is also 420.1. 1 HNMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.83 (s, 1H),7.31 (t, J = 7.5 Hz, 2H), 7.28 – 7.06 (m, 3H), 4.45 (d, J = 12.3 Hz, 2H),3.08 (t, J = 12.0 Hz, 2H), 2.91 – 2.81 (m, 1H), 2.25 (s, 3H), 1.86 (d, J =11.1 Hz, 2H), 1.64 (d, J = 11.4 Hz, 2H).

[0780] Compound 525

[0781] (Z)-3-(benzo[d]isoxazol-5-yl)-2-cyano-3-hydroxy-N,N-dimethylacrylamide (525)

[0782] The title compound was prepared in 3.5% yield from benzo[d]isoxazole-5-carboxylic acid and 2-cyano-N-(2-fluoro-5-methylbenzyl)-N-methylacetamide according to the preparation procedure for compound 27. MS [M+H] +For C 13 H 11 The calculated value of N3O3 is 258.1, and the measured value is 258.2. 1 HNMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 8.18 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H), 3.15 (s, 6H).

[0783] Compound 34

[0784] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-hydroxy-N-methyl-3-(3-methylbenzo[d]isoxazol-5-yl)acrylamide (34)

[0785] The title compound was prepared in 22.4% yield from 3-methylbenzo[d]isoxazole-5-carboxylic acid and N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide according to the preparation procedure for compound 27. MS [M+H] + For C 20 H 15 The calculated value of ClFN3O3 is 400.1, and the measured value is 400.0. 1 HNMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.03 (s,1H), 7.87 (s, 1H), 7.44-7.31 (m, 3H), 4.77 (s, 2H), 3.17 (s, 3H), 2.60 (s,3H).

[0786] Compound 32

[0787] (Z)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-(1,3-dioxoisoindoline-5-yl)-3-hydroxy-N-methylacrylamide (32)

[0788] The title compound was prepared in 22.4% yield from 1,3-dioxoisoindoline-5-carboxylic acid and N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide according to the preparation procedure for compound 27. MS [M+Na] + For C 20 H 13 The calculated value of ClFN3O4 is 436.1, and the measured value is 436.0. 1H NMR (400 MHz, DMSO) δ 11.56 (s, 1H), 8.15 (s,2H), 7.98 (s, 1H), 7.43 (s, 2H), 7.31 (s, 1H), 4.75 (s, 2H), 3.14 (s, 3H).

[0789] Compound 30

[0790] (Z)-2-cyano-N-(2-fluoro-5-methylbenzyl)-3-hydroxy-N-methyl-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide (30)

[0791] The title compound was prepared in 7.2% yield from 2-oxo-2,3-dihydrobenzo[d]oxazol-5-carboxylic acid and 2-cyano-N-(2-fluoro-5-methylbenzyl)-N-methylacetamide according to the preparation procedure for compound 27. MS [M+H] + For C 20 H 16 The calculated value of FN3O4 is 382.1, and the measured value is also 382.1. 1 HNMR (400 MHz, DMSO-d6) δ 11.96 (s,1H), 7.55 (s, 1H), 7.47 (s, 2H), 7.16-7.08 (m, 3H), 4.73 (s, 2H), 3.13 (s,3H), 2.28 (s, 3H).

[0792] Compound 10

[0793] (Z)-3-(benzo[d]oxazol-5-yl)-2-cyano-N-(2-fluoro-5-methylbenzyl)-3-hydroxy-N-methacrylamide (10)

[0794] The title compound was prepared from benzo[d]oxazol-5-carboxylic acid and 2-cyano-N-(2-fluoro-5-methylbenzyl)-N-methylacetamide according to the method used to prepare compound 27, with a yield of 21.4%. MS [MH] - For C 20 H 16 The calculated value of FN3O3 is 364.1, and the measured value is 363.6. 1HNMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.02 (s, 1H), 7.76 (s, 1H), 7.22 – 6.99 (m, 4H), 4.60 (s, 2H), 2.97 (s, 3H), 2.28 (s, 3H).

[0795] Compound 11

[0796] (Z)-3-(benzo[d]oxazol-6-yl)-2-cyano-N-(2-fluoro-5-methylbenzyl)-3-hydroxy-N-methacrylamide (11)

[0797] The title compound was prepared from benzo[d]oxazol-6-carboxylic acid and 2-cyano-N-(2-fluoro-5-methylbenzyl)-N-methylacetamide according to the method used to prepare compound 27, in a yield of 9.6%. MS [MH] - For C 20 H 16 The calculated value of FN3O3 is 364.1, and the measured value is 364.0. 1 HNMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 7.79 (s, 1H), 7.24 – 6.98 (m, 5H), 4.60 (s, 2H), 2.98 (s, 3H), 2.27 (s, 3H).

[0798] Compound 21

[0799] (Z)-3-(benzo[c][1,2,5]oxadiazol-5-yl)-2-cyano-N-(2-fluoro-5-methylbenzyl)-3-hydroxy-N-methacrylamide (21)

[0800] The title compound was prepared in 21.6% yield from benzo[c][1,2,5]oxadiazole-5-carboxylic acid and 2-cyano-N-(2-fluoro-5-methylbenzyl)-N-methylacetamide according to the preparation procedure for compound 27. MS [MH] + For C 19 H 15 The calculated value of FN4O3 is 365.1, and the measured value is 364.7. 1HNMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.25 (s,1H), 7.83 (s, 1H), 7.22-7.10 (m, 3H), 4.74 (s, 2H), 3.12 (s, 3H), 2.28 (s,3H).

[0801] Compound 16

[0802] (Z)-3-([1,2,3]triazolo[1,5-a]pyridin-5-yl)-N-(5-chloro-2-fluorobenzyl)-2-cyano-3-hydroxy-N-methylacrylamide (16)

[0803] The title compound was prepared in 4.1% yield from [1,2,3]triazolo[1,5-a]pyridine-5-carboxylic acid and N-(5-chloro-2-fluorobenzyl)-2-cyano-N-methylacetamide according to the preparation procedure for compound 27. MS [MH] + For C 18 H 13 The calculated value of ClFN5O2 is 386.0, and the measured value is also 386.0. 1 H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.42 (s, 2H), 7.42-7.29 (m, 4H), 4.74 (s, 2H), 3.13 (s, 3H).

[0804] Compound 35

[0805] (Z)-3-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-(4-(3-chlorophenyl)piperidin-1-carbonyl)-3-hydroxyacrylonitrile (35)

[0806] The title compound was prepared in 15.2% yield from [1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid and 3-(4-(3-chlorophenyl)piperidin-1-yl)-3-oxopropionitrile according to the preparation procedure for compound 27. MS [M+H] + For C 21 H 18 The calculated value of ClN5O2 is 408.1, and the measured value is also 408.1. 1HNMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.70 (s, 1H), 7.33-6.96 (m, 7H), 4.24 (d, J = 9.6 Hz, 2H), 2.77 (m, 3H), 1.74 (m,4H)

[0807] Compound 540

[0808] (Z)-3-(benzo[d]isoxazol-5-yl)-3-hydroxy-2-(4-(phenylamino)piperidine-1-carbonyl)acrylonitrile

[0809]

[0810] Step 1: Synthesis of (Z)-(1-(3-(benzo[d]isoxazol-5-yl)-2-cyano-3-hydroxyacryloyl)piperidin-4-yl)(phenyl)carbamate tert-butyl ester (2)

[0811] A solution of benzo[d]isoxazole-5-carboxylic acid (62 mg, 0.4 mmol) in SOCl2 (10 mL) was stirred at 80ºC for 2 hours. This solution was then concentrated under vacuum to give a crude intermediate. LiHMDS (0.9 mL, 0.9 mmol) was added dropwise to a solution of (1-(2-cyanoacetyl)piperidin-4-yl)(phenyl)carbamate tert-butyl ester (130 mg, 0.4 mmol) in THF (15 mL) under a N2 atmosphere at -78ºC. After the addition, the mixture was stirred at the same temperature for another 1 hour. The crude intermediate was then added to the above solution at -78ºC and stirred overnight at room temperature. The reaction mixture was quenched with HCl and extracted with DCM (20 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (DCM / MeOH = 15 / 1) to obtain the product (50 mg, 27%). MS [M+H] + For C 27 H 28 The calculated value of N4O5 is 488.9, and the measured value is also 488.9.

[0812] Step 2: Synthesis of (Z)-3-(benzo[d]isoxazol-5-yl)-3-hydroxy-2-(4-(phenylamino)piperidine-1-carbonyl)acrylonitrile (540)

[0813] A mixture of tert-butyl 4-(phenylamino)piperidin-1-carboxylate (1 g, 3.6 mmol) and TFA (2 mL) in DCM (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness under vacuum and then purified by preparative HPLC (H2O / MeCN = 5 / 5, 0.1% TFA, twice) to obtain the product (5 mg, HPLC: 98.62%). MS [M+H + For C 22 H 20 The calculated value of N4O3 is 389.1, and the measured value is 389.0. 1 HNMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H),7.86 (s, 1H), 7.07 – 6.99 (m, 4H), 6.56 (d, J = 7.9 Hz, 2H), 6.48 (d, J = 7.2Hz, 1H), 4.14 (s, 2H), 3.49 (s, 1H), 3.17 (s, 2H), 1.94 (d, J = 7.0 Hz, 2H), 1.34-1.31 (m, 2H).

[0814] The following compounds were synthesized in a similar manner.

[0815]

[0816] Biological assay

[0817] FTO inhibition assay (enzyme inhibition)The inhibition assay was adapted from a publication on the assay of Maz-F coupled FTO demethylase activity (Chem Commun. 2017 Nov 30;53(96):12930-12933. doi: 10.1039 / c7cc07699a). FTO-catalyzed demethylation activity was measured in 10 μl of a reaction mixture containing 20 mM HEPES buffer (pH 7.5), 20 μM α-KG, 10 μM (NH4)2Fe(SO4)2, 1.5 mM L-ascorbic acid, 2 μM m6A-containing DRNA (5'-FAM-d(CAT)r(GG-m6A-CA)d(TATGT)-BHQ1-3'), and 0.15 μM FTO protein. The reaction mixture was incubated at 32ºC for 45 min. Add an equal amount of MazF (40 μL 1×Maz-F + 10 μL reactant / well) to each well to a final concentration of 50 nM, and incubate the reaction mixture at 37ºC for 25 min. MazF cleaves only unmethylated DRNA (-ACA-), allowing for specific detection of DRNA methylation status. Maz-F readily cleaves DRNA and ultimately releases 5'-FAM, emitting a strong fluorescence signal near 535 nm (485 nm excitation - 535 nm emission).

[0818] COMT inhibition assay. The inhibition of COMT by the compound was measured using a reaction kinetic model. The test compound was diluted to the desired concentration with assay buffer. The COMT enzyme was also diluted with assay buffer. Then, 5 μL of the diluted test compound, 5 μL of diluted COMT, and 5 μL of aescin were added to the plate and incubated at 37ºC for 5 min, and sealed with TopSeal-A384 transparent adhesive (PE). Then, 5 μL of AdoMet was added to the plate. The reaction system contained 1 U COMT enzyme, test compound, 4 μM aescin, 0.6 mM AdoMet, 50 mM K3PO4, and 10 mM MgCl2. The plate was read using a kinetic model (excitation at 360 nm and emission at 460 nm). Inhibition was calculated from the slope.

[0819] As expected, deuteration did not alter the in vitro enzyme inhibition of the compounds of the present invention.

[0820] Table 1: FTO IC50 of representative compounds

[0821]

[0822] Inactive means that the compound does not have an inhibitory response curve, even at levels as high as 10 μM or higher.

[0823] Although the foregoing invention has been described in considerable detail by way of illustration and example for the purpose of clarity, it will be apparent to those skilled in the art that certain minor changes and modifications may be made. Therefore, the description and embodiments should not be construed as limiting the scope of the invention.

Claims

1. A compound of formula (I) (I) Or its pharmaceutically acceptable salt, its stereoisomer, its tautomer, or its deuterated analogue. in X 1 X 2 and X 3 Each can be independently -O-, -S-, -NH-, -N=, -CH=, or -CH2-, provided that no two -O- and / or -S- are adjacent. X 4 X 5 X 6 Each is independently either -CH= or -N=. X 7 and X 8 Each is nitrogen and carbon independently; m and n are each numbers from 0 to 3, provided that the valence theory is satisfied; R 2 and R 3 Each of these groups independently represents a halogen, deuterium, cyano, oxo, nitro, hydroxyl, or C group. 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated, and halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Alkyl-S-, C 2-6 alkenyl, C 2-6 Alkynyl, -SO2R 2a -COOR 2a or -NR 2a R 2b , Where R 2a and R 2b Each is independently hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated, and halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 alkyl; R 1 It is -C(O)NR a1 R a2 -C(O)R a3 or R a4 , in R a1 It is hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 1-6 Alkoxy; R a2 yes a)C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 cycloalkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 Each of the cycloalkyl groups is unsubstituted or is composed of one or more elements selected from deuterium, -OR b1 Halogen, C 1-6 Alkyl-S-, cyano, -NR b2 R b3 -C(O)NR b2 R b3 -OC(O)NR b2 R b3 -C(O)R b2 -NR b2 C(O)R b3 Substituents of phenyl, naphthyl, heteroaryl, or heterocyclic groups, wherein each of the phenyl or naphthyl groups is unsubstituted or substituted by one or more substituents R. c3 replace; b)C 3-8 Cycloalkyl, phenyl, heteroaryl, or heterocyclic, wherein the C 3-8 Each of the cycloalkyl, phenyl, heteroaryl, or heterocyclic groups is either unsubstituted or substituents R. c3 replace; in R b1 yes 1) Hydrogen; 2)C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-6 alkyl-; 3) Phenyl, wherein the phenyl group is unsubstituted or modified by halogen, oxo group, C 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, Halogenated C 1-6 Alkyl, heterocyclic, -C 1-6 Alkyl C(O)NR c1 R c2 -C(O)NR c1 R c2 -NR c1 R c2 -NR c1 C(O)R c2 Or heteroaryl substitution; or 4) Heteroaryl or heterocyclic groups, each of which is unsubstituted or C-substituted. 1-6 Alkyl, oxo, or heteroaryl substitutions; R c1 and R c2 Each is independently hydrogen, C 1-6 Alkyl, phenyl, wherein the phenyl group is unsubstituted or is substituted with one or more groups selected from hydroxyl, halogen, oxo, C 1-6 Alkyl or C 1-6 Substitution of alkoxy groups; R b2 and R b3 Each is independently hydrogen, C 1-6 Alkyl, phenyl, wherein the phenyl group is unsubstituted or is substituted with one or more groups selected from hydroxyl, halogen, oxo, C 1-6 Alkyl or C 1-6 Substitution of alkoxy groups; R c3 yes -halogen; -hydroxyl group; -Cyano; -Oxide group; -C 1-6 Alkyl, the C 1-6 Alkyl groups are unsubstituted or converted by one or more halogens, hydroxyl groups, C... 1-6 Alkoxy, phenyl, or alkyl-substituted heteroaryl (pyrazolyl) substituted; -C 2-6 alkenyl or C 2-6 alkynyl group; -hydroxyl group; -C 1-6 Alkyl-S- -C 1-6 alkoxy or phenoxy, wherein the C 1-6 Each of the alkoxy or phenoxy groups is unsubstituted or converted by one or more halogens, C 1-6 Alkoxy, alkyl-substituted heteroaryl, or alkyl-substituted heterocyclic group; --C 1-6 Alkyl C(O)NR e1 R e2 ; --C(O)NR e1 R e2 ; --NO e1 R e2 ; --NR e1 C(O)R e2 ; --NO e1 -C(O)-NR e2 R e3 ; --NO e1 R e2 ; - Heterocyclic group, said heterocyclic group is unsubstituted or halogenated, C 1-6 Alkyl or heterocyclic groups, via C 1-6 Alkyl-substituted heterocyclic substitution, - Heteroaryl, wherein the heteroaryl group is unsubstituted or C-substituted. 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl- or heteroaryl substitution; -C 3-8 cycloalkyl; -phenyl; and R e1 R e2 and R e3 Each is independently hydrogen, C 1-6 Alkyl, phenyl, C 1-6 Alkyl-substituted phenyl, heteroaryl (e.g., thiazolyl, pyrazolyl), or C-substituted phenyl groups 1-6 Alkyl-substituted heteroaryl (1-methyl-1H-1,2,3-triazol-4-yl). Alternatively, R a1 and R a2 Together with the nitrogen atoms to which they are attached, they form 4- to 9-membered rings containing one or two additional heteroatoms selected from nitrogen, oxygen, or sulfur, and said rings are either unsubstituted or modified by one or more substituents R. b4 Substitution, or two substituents R on two adjacent atoms b4 Formation of 4- to 6-membered fused rings and / or two substituents R on the same carbon atom b4 Forming 3 to 6-membered spirorings, wherein the fused ring or spiroring is unsubstituted or composed of one or more elements selected from halogens or C. 1-6 Alkyl substituents, R b4 It is a hydroxyl group; halogen; oxo group; cyano group; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkoxy C 1-6 Alkyl; Halogenated C 1-6 Alkoxy; NR c4 R c5 , where R c4 and R c5 Each is independently hydrogen, alkyl, or phenyl; phenyl, heterocyclic, or heteroaryl, wherein each of the phenyl, heterocyclic, or heteroaryl groups is unsubstituted or substituted with one or more halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -NR e4 R e5 or -COOR e4 Replace, where R e4 and R e5 It is hydrogen, C 1-6 Alkyl, phenyl, C 1-6 Alkyl-substituted phenyl, heteroaryl, or C-substituted phenyl 1-6 Alkyl-substituted heteroaryl groups; R a3 It is C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-S-, C3-8 cycloalkyl, phenyl, heteroaryl, or heterocyclic, wherein each of the C3-8 cycloalkyl, phenyl, heteroaryl, or heterocyclic groups is unsubstituted or is selected from one or more halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Substitution of alkoxy groups; R a4 It is a heteroaryl or heterocyclic group, each of which is unsubstituted or is composed of one or more compounds selected from halogens, C, and D. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, phenoxy, -NR c6 R c7 -C(O)NR c6 R c7 -OC(O)NR c6 R c7 -C(O)R c6 or -NR c6 C(O)R c7 Substituents of the substituents R c6 and R c7 Each is independently hydrogen, C 1-6 Alkyl, phenyl, wherein the phenyl group is unsubstituted or is substituted with one or more groups selected from hydroxyl, halogen, oxo, C 1-6 Alkyl or C 1-6 Substitution of alkoxy groups, The condition is a double-ring part. It belongs to the aromatic family.

2. The compound according to claim 1, wherein X 4 X 5 and X 6 Each is -CH=; and X 7 and X 8 It's carbon.

3. The compound according to claim 1 or 2, wherein... (a)X 1 It is O, S, or -NH-, X 2 It is -N= and X 3 Is -CH=; or (b)X 1 It is -N=, X 2 It is -CH=, and X 3 It is O, S, or -NH-; or (c)X 1 Is it O or S, X 2 It is -N= and X 3 Is -CH=; or (d)X 1 It is -N=, X 2 It is -CH= and X 3 Is it O or S; or (e)X 1 It is -N=, X 2 It is -N= and X 3 It is -NH-; or X 1 It is -N=, X 2 It is -NH- and X 3 Is it -N=; or X 1 It is -NH-, X 2 It is -N= and X 3 It is -N=.

4. The compound according to any one of claims 1 to 3, wherein The bicyclic moiety is benzofuranyl, benzo[b]thiophenyl, benzo[d]isoxazolyl, benzo[d]isothiazolyl, benzo[c]isoxazolyl, benzo[c]isothiazolyl, benzo[d]oxazolyl, 1H-benzo[d]imidazolyl, benzo[d]thiazolyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, [1,2,3]triazolo[1,5-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, [1,2,4]triazolo[1,5-a]pyridyl, benzo[d][1,2,3]oxadiazolyl, benzo[c][1,2,5]oxadiazolyl, benzo[d][1,2,3] Thiadiazolyl, 1H-benzo[d][1,2,3]triazolyl, 2H-benzo[d][1,2,3]triazolyl, tetrazo[1,5-a]pyridyl, isoindolinyl, 1H-[1,2,3]triazol[4,5-c]pyridyl, 3H-[1,2,3]triazol[4,5-b]pyridyl, 1H-[1,2,3]triazol[4,5-b]pyridyl, 1H-[1,2,3]triazol[4,5-b]pyrazinyl or 3H-[1,2,3]triazol[4,5-d]pyrimidinyl, each of which is unsubstituted or substituted by one or more substituents selected from: halogen, deuterium, oxo, nitro, hydroxyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 1-6 Alkyl SO2-, NR 2a R 2b C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, cyano, COOR 2a Or cycloalkyl; Optionally further, the bicyclic moiety is benzofuran-5-yl, benzo[b]thiophene-5-yl, benzo[d]isoxazole-5-yl, benzo[d]isoxazole-6-yl, benzo[d]isothiazol-5-yl, benzo[c]isoxazole-5-yl, benzo[c]isothiazol-5-yl, benzo[d]oxazole-5-yl, benzo[d]oxazole-6-yl, 1H-benzo[d]imidazol-6-yl, benzo[d]thiazol-6-yl, pyrazolo[1] [,5-a]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl, [1,2,3]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-7-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, benzo[d][1,2,3]oxadiazol-5-yl, benzo[c][1,2,5]oxadiazol-5-yl Diazol-5-yl, benzo[d][1,2,3]oxadiazol-6-yl, benzo[d][1,2,3]thiadiazol-6-yl, 1H-benzo[d][1,2,3]triazol-6-yl, 1H-benzo[d][1,2,3]triazol-5-yl, 2H-benzo[d][1,2,3]triazol-5-yl, tetrazol[1,5-a]pyridin-7-yl, tetrazol[1,5-a]pyridin-6-yl, isoindolin-5-yl, 1 H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, 3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl or 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl, each of which is unsubstituted or substituted as defined above; Optionally further, wherein the bicyclic moiety is benzofuran-5-yl, benzo[b]thiophene-5-yl, benzo[d]isoxazole-5-yl, benzo[d]isoxazole-6-yl, benzo[d]isothiazol-5-yl, benzo[c]isoxazole-5-yl, benzo[c]isothiazol-5-yl, benzo[d]oxazole-5-yl, benzo[d]oxazole-6-yl, 1H-benzo[d]imidazol-6-yl, benzo[d]thiazol-6-yl, pyrazolo[1,5-a]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl, [1,2,3]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [-a]pyridin-7-yl, [1,2,4]triazol[1,5-a]pyridin-6-yl, benzo[d][1,2,3]oxadiazol-5-yl, benzo[c][1,2,5]oxadiazol-5-yl, benzo[d][1,2,3]oxadiazol-6-yl, benzo[d][1,2,3]thiadiazol-6-yl, 1H-benzo[d][1,2,3]triazol-6-yl, 1H-benzo[d][1,2,3]triazol-5-yl, 2H-benzo[d][1,2,3]triazol-5-yl, tetrazol[1,5-a]pyridin-7-yl, tetrazol[1,5-a]pyridin-6-yl, 2-oxo-2,3-dihydrobenzo[d]oxadiazol-5-yl, 2-oxo-2,3-dihydrobenzyl [d]oxazol-6-yl, 1,3-dioxoisoindoline-5-yl, 4-chloro-1H-benzo[d][1,2,3]triazol-6-yl, 4-nitro-1H-benzo[d][1,2,3]triazol-6-yl, 4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-bromo-1H-benzo[d][1,2,3]triazol-6-yl, 4-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-amino-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methylamino)-1H-benzo[d][1,2,3]triazol-6-yl, 4-( Trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-ethyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyano-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methylsulfonyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methoxycarbonyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-carboxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyclopropyl-1H-benzo[d][1,2,3]3] Triazol-6-yl, 7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 7-chloro-1H-benzo[d][1,2,3]triazol-6-yl, 7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 7-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 7-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 7-cyano-1H-benzo[d][1,2,3]triazol-6-yl, 7-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5-fluoro-1H-benzo[d][1,2,3] Triazol-6-yl, 5-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 5-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 5-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 5-cyano-1H-benzo[d][1,2,3]triazol-6-yl, 5-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4,7-dichloro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-methoxy 4-chloro-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyano-7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyano-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-chloro-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-methyl-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl 3] Triazol-6-yl, 7-methoxy-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-hydroxy-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 5-fluoro-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5-hydroxy-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5,7-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5,7-Difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-1H-[1,2,3]triazol[4,5-c]pyridin-6-yl, 7-chloro-3H-[1,2,3]triazol[4,5-b]pyridin-5-yl, 4-(trifluoromethyl)-1H-[1,2,3]triazol[4,5-b]pyridin-5-yl, 4-(trifluoromethyl)-1H-[1,2,3]triazol[d][1,2,3]triazol[d][1,2,3]triazol[d][1,2,3]triazol[d][1,2,3]pyridin-5-yl, 4-(trifluoromethyl)-1H-[ ...triazol[d][1,2,3]triazol[d][1,2,3]triazol[d][1,2,3]triazol[d][1,2,3]triazol[d][1,2,3]triazol[d][1,2,3 [3] Triazolo[4,5-c]pyridin-6-yl, 7-(trifluoromethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 7-cyano-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 4-cyano-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, 1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 4-(difluoromethoxy)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(trifluoromethoxy)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(hydroxymethyl) )-1H-benzo[d][1,2,3]triazol-6-yl, 5-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4,7-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-4-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-yl, 4-ethyl-7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4,5-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4,5-difluoro-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 5,7-difluoro-4- Methyl-1H-benzo[d][1,2,3]triazol-6-yl, 5,7-difluoro-4-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-yl, 1H-[1,2,3]triazol[4,5-c]pyridin-6-yl, 3H-[1,2,3]triazol[4,5-b]pyridin-5-yl, 1H-[1,2,3]triazol[4,5-b]pyrazin-6-yl, 3H-[1,2,3]triazol[4,5-d]pyrimidin-5-yl, 7-nitro-3H-[1,2,3]triazol[4,5-b]pyridin-5-yl, 7-methyl-3H-[1,2,3]triazol[4,5-b]pyridin-5-yl, 7-methoxy-3H-[1,2,3]triazol[4,5-b]pyridin-5-yl,3] Triazolo[4,5-b]pyridin-5-yl, 7-hydroxy-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 6-fluoro-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 4-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, 4-methoxy-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, 4-hydroxy-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, 7-fluoro-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl 5-Methoxy-1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 5-hydroxy-1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 7-methyl-1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 4-chloro-1H-benzo[d][1,2,3]triazol-6-yl, 7-chlorobenzo[d]isoxazo-5-yl, 7-methylbenzo[d]isoxazo-5-yl, 7-hydroxybenzo[d]isoxazo-5-yl, 7-methoxybenzo[d]isoxazo-5-yl, or 6-fluorobenzo[d]isoxazo-5-yl; Optionally further, the bicyclic moiety is benzo[d]isoxazolyl, benzo[c][1,2,5]oxadiazolyl, 1H-benzo[d][1,2,3]triazolyl or 2H-benzo[d][1,2,3]triazolyl, each of which is unsubstituted or substituted as defined above; Optionally further, the bicyclic moiety is benzo[d]isoxazole-5-yl, benzo[d]isoxazole-6-yl, benzo[c][1,2,5]oxadiazole-5-yl, benzo[d][1,2,3]oxadiazole-6-yl, 1H-benzo[d][1,2,3]triazole-6-yl, 1H-benzo[d][1,2,3]triazole-5-yl or 2H-benzo[d][1,2,3]triazole-5-yl, each of which is unsubstituted or substituted as defined above; Optionally, the bicyclic moiety is further wherein the bicyclic moiety is benzo[d]isoxazole-5-yl, benzo[d]isoxazole-6-yl, benzo[c][1,2,5]oxadiazole-5-yl, benzo[d][1,2,3]oxadiazole-6-yl, 1H-benzo[d][1,2,3]triazole-6-yl, 1H-benzo[d][1,2,3]triazole-5-yl, 2H-benzo[d][1,2,3]triazole-5-yl, 4-chloro-1H-benzo[d][1,2,3]triazole-6-yl, 4-nitro-1H-benzo[d][1,2,3]triazole-6-yl, 4-fluoro-1H-benzo[d][1,2,3]triazole-6-yl, 4-bromo-1H-benzo[d][1,2,3] ... Triazol-6-yl, 4-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-amino-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methylamino)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-ethyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyano-1H- Benz[d][1,2,3]triazol-6-yl, 4-(methanesulfonyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methoxycarbonyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-carboxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyclopropyl-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 7-chloro-1H-benzo[d][1,2,3]triazol-6-yl, 7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 7-methoxy-1H-benzo[d][1,2,3]triazol-6-yl 7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 7-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 7-cyano-1H-benzo[d][1,2,3]triazol-6-yl, 7-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 5-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 5-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 5-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 5-cyano-1H-benzo[d][1,2,3]triazol-6-yl3] Triazol-6-yl, 5-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4,7-dichloro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-7-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 4-cyano-7-fluoro-1H-benzo[d][ [1,2,3]triazol-6-yl, 4-cyano-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-chloro-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-methyl-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-methoxy-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 7-hydroxy-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro ...chloro-5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-1H-benzo[d][1,2, 3] Triazol-6-yl, 4-chloro-5-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 5-fluoro-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5-hydroxy-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5,7-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5,7-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-methoxy-1H-benzo[d][1,2,3]triazol-6-yl, 4 -chloro-5-fluoro-7-hydroxy-1H-benzo[d][1,2,3]triazol-6-yl, 4-chloro-5-fluoro-7-(methylthio)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(difluoromethoxy)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(trifluoromethoxy)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-yl, 4-(hydroxymethyl)-1H-benzo[d][1,2,3]triazol-6-yl, 5-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 4,7-difluoro-1H-benzo[d][1,2,3]triazol-6-yl3] Triazol-6-yl, 7-fluoro-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 7-fluoro-4-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-yl, 4-ethyl-7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4,5-difluoro-1H-benzo[d][1,2,3]triazol-6-yl, 4,5-difluoro-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 5,7-difluoro-4 5-methyl-1H-benzo[d][1,2,3]triazol-6-yl, 5,7-difluoro-4-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6-yl, 2-(4-chloro-1H-benzo[d][1,2,3]triazol-6-yl, 7-chlorobenzo[d]isoxazole-5-yl, 7-methylbenzo[d]isoxazole-5-yl, 7-hydroxybenzo[d]isoxazole-5-yl, 7-methoxybenzo[d]isoxazole-5-yl, or 6-fluorobenzo[d]isoxazole-5-yl.

5. The compound according to any one of claims 1 to 4, wherein R 1 It is -C(O)NR a1 R a2 , in R a1 It is hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 1-6 Alkoxy; R a2 yes a)C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 cycloalkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 Each of the cycloalkyl groups is unsubstituted or is composed of one or more elements selected from deuterium, -OR b1 Halogen, C 1-6 Alkyl-S-, cyano, -NR b2 R b3 -C(O)NR b2 R b3 -OC(O)NR b2 R b3 -C(O)R b2 -NR b2 C(O)R b3 Substituents of phenyl, naphthyl, heteroaryl, or heterocyclic groups, wherein each of the phenyl or naphthyl groups is unsubstituted or substituted by one or more substituents R. c3 replace; b)C 3-8 Cycloalkyl, phenyl, heteroaryl or heterocyclic, wherein C 3-8 Each of the cycloalkyl, phenyl, heteroaryl, or heterocyclic groups is either unsubstituted or substituents R. c3 replace; in R b1 yes 1) Hydrogen; 2)C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-6 alkyl-; 3) Phenyl, wherein the phenyl group is unsubstituted or modified by halogen, oxo group, C 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, Halogenated C 1-6 Alkyl, heterocyclic (e.g., azirrocyclobutane), -C 1-6 Alkyl C(O)NR c1 R c2 -C(O)NR c1 R c2 -NR c1 R c2 -NR c1 C(O)R c2 Or heteroaryl (e.g., pyridyl, pyrazolyl, pyrazinyl); or 4) A heteroaryl group (e.g., pyrimidinyl, pyridinyl, 1H-benzo[d]imidazolyl, 1H-indazolyl) or a heterocyclic group (e.g., azacyclic butyl, pyrrolidinyl), wherein the heteroaryl or heterocyclic group is unsubstituted or C-substituted. 1-6 Alkyl, oxo, or pyridyl substitutions; R c1 and R c2 Each is independently hydrogen, C 1-6 Alkyl, phenyl, wherein the phenyl group is unsubstituted or is substituted with one or more groups selected from hydroxyl, halogen, oxo, C 1-6 Alkyl or C 1-6 Substitution of alkoxy groups; R b2 and R b3 Each is independently hydrogen, C 1-6 Alkyl, phenyl, wherein the phenyl group is unsubstituted or is substituted with one or more groups selected from hydroxyl, halogen, oxo, C 1-6 Alkyl or C 1-6 Substitution of alkoxy groups; R c3 yes -halogen; -hydroxyl group; -Cyano; -Oxide group; -C 1-6 Alkyl, the C 1-6 Alkyl groups are unsubstituted or converted by one or more halogens, hydroxyl groups, C... 1-6 Alkoxy, phenyl, or alkyl-substituted heteroaryl (pyrazolyl) substituted; -C 2-6 alkenyl or C 2-6 alkynyl group; -hydroxyl group; -C 1-6 Alkyl-S- -C 1-6 alkoxy or phenoxy, wherein the C 1-6 Each of the alkoxy or phenoxy groups is unsubstituted or converted by one or more halogens, C 1-6 Alkoxy, alkyl-substituted heteroaryl (pyrazolyl) or alkyl-substituted heterocyclic (piperidinyl) substitution; --C 1-6 Alkyl C(O)NR e1 R e2 ; --C(O)NR e1 R e2 ; --NO e1 R e2 ; --NR e1 C(O)R e2 ; --NO e1 -C(O)-NR e2 R e3 ; --NO e1 R e2 ; - Heterocyclic groups (e.g., azirmonobutan-1-yl, piperidin-4-yl, morpholino, piperazino, morpholino), said heterocyclic groups being unsubstituted or halogenated, C 1-6 Alkyl or heterocyclic groups, via C 1-6 Alkyl-substituted heterocyclic substitution, - Heteroaryl (e.g., pyrazinyl, pyridyl, pyrimidinyl), said heteroaryl is unsubstituted or C-substituted. 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl- or heteroaryl (e.g., pyridyl) substitution -C 3-8 cycloalkyl; -phenyl, R e1 R e2 and R e3 Each is independently hydrogen, C 1-6 Alkyl, phenyl, C 1-6 Alkyl-substituted phenyl, heteroaryl (e.g., thiazolyl, pyrazolyl), or C-substituted phenyl groups 1-6 Alkyl-substituted heteroaryl (1-methyl-1H-1,2,3-triazol-4-yl).

6. The compound according to any one of claims 1 to 4, wherein R a1 It is C 1-6 Alkyl or deuterated C 1-6 alkyl.

7. The compound according to any one of claims 1 to 4, wherein R a1 It is hydrogen, methyl, ethyl, CH3-d3, CF3, CHF2, methoxy.

8. The compound according to any one of claims 1 to 7, wherein (a)R a2 It is C 1-6 Alkyl, the C 1-6 Alkyl-OR b1 Replace, where R b1 It is hydrogen, methoxy, or phenyl, wherein the phenyl group is unsubstituted or substituted with one, two, or three substituents selected from fluorine, bromine, chlorine, methyl, hydroxymethyl, trifluoromethyl, azirmonobutan-1-yl, 2-amino-2-oxoethyl, acetamyl, pyridin-2-yl, 1H-pyrazol-1-yl, pyrazin-2-yl, N,N-dimethylamino, 2-(dimethylamino)-2-oxoethyl, 2-hydroxypropyl, or methylamino; pyrimidinyl, pyridinyl, 1H-benzo[d]imidazolyl, or 1H-indazolyl, each of which is unsubstituted or substituted with one, two, or three substituents selected from methyl, oxo, or pyridinyl. (b)R a2 It is C 1-6 Alkyl, the C 1-6 Alkyl-NR b2 R b3 Replace, where R b2 Is it hydrogen or C? 1-6 Alkyl (e.g., methyl, ethyl, etc.) and R b3 It is C 1-6 Alkyl, phenyl, wherein the phenyl group is unsubstituted or substituted with one, two or three substituents selected from methyl, ethyl, oxo or halogen. (c)R a2 It is C 1-6 Alkyl (e.g., methyl, ethyl, or propyl), the C 1-6 The alkyl group is either unsubstituted or substituted with one or more halogens or hydroxyl groups and further substituted with a phenyl group, wherein the phenyl group is unsubstituted or substituted with one or more substituents R. c3 replace; Optionally further, where R c3 It is a halogen; hydroxyl group; cyano group; oxo group; C 1-6 Alkyl, the C 1-6 Alkyl groups are unsubstituted or converted by one or more halogens, hydroxyl groups, C... 1-6 Alkoxy, phenyl, or alkyl-substituted heteroaryl groups (e.g., pyrazolyl); C 1-6 Alkyloxy; phenoxy, C 2-6 alkenyl; C 2-6 Alkyne group; hydroxyl group; C 1-6 Alkoxy, the C 1-6 Alkyl groups are unsubstituted or substituted with one or more halogens, C 1-6 Alkoxy, alkyl-substituted heteroaryl (pyrazolyl), or alkyl-substituted heterocyclic (piperidinyl) substitution; -C 1-6 Alkyl C(O)NR e2 R e3 ;-C(O)NR e1 R e2 ;-NR e1 R e2 ;-NR e1 C(O)R e2 ;-NR e1 -C(O)-NR e2 R e3 ;-NR e1 R e2 ;R e1 R e2 R e3 Each is independently hydrogen, C 1-6 Alkyl, heteroaryl (e.g., thiazolyl, pyrazolyl) or C-terminated 1-6 Alkyl-substituted heteroaryl groups (1-methyl-1H-1,2,3-triazol-4-yl); heterocyclic groups (e.g., aziridine-1-yl, piperidin-4-yl, morpholino, piperazine-yl, morpholino), said heterocyclic groups being unsubstituted or halogenated, C 1-6 Alkyl or heterocyclic or C 1-6 Alkyl-substituted heterocyclic groups; heteroaryl groups (pyrazinyl, pyridyl, pyrimidinyl), wherein the heteroaryl group is unsubstituted or C-substituted. 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl- or heteroaryl (e.g., pyridyl) substitution; C 3-8 cycloalkyl; phenyl; or C 1-6 Alkyl-S-; Optionally further, where R c3 Selected from chlorine, fluorine, bromine, methyl, ethyl, ethynyl, vinyltrifluoromethyl, methoxymethyl, (1-methyl-1H-pyrazol-4-yl)methyl, hydroxy, methoxy, (1-methylpiperidin-4-yl)methoxy, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, cyano, oxo, hydroxymethyl, 3-methylurea, thiazol-2-ylamino, (1-methyl-1H-pyrazol-4-yl)amino, aziridine-1-yl, 1- Methylpiperidin-4-yl, piperidin-4-yl, 4-methylpiperazin-1-yl, morpholino, pyrazin-2-yl, 3-(hydroxymethyl)pyridin-2-yl, pyridin-3-yl, phenyl, pyrimidin-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, 4'-methyl-[1,1'-bipiperazin]-4-yl, amino, acetamido, dimethylamino, methylthio, cyclopropyl, 2-amino-2-oxoethyl or 2-(methylamino)-2-oxoethyl; (d)R a2 It is C 1-6 Alkyl (e.g., methyl, ethyl, or propyl), the C 1-6 The alkyl group is either unsubstituted or substituted with one or more halogens or hydroxyl groups and further substituted with a heteroaryl or heterocyclic group, wherein the heteroaryl or heterocyclic group is unsubstituted or substituted with one or more substituents R. c3 replace; Optionally, the heteroaryl or heterocyclic group is further selected from triazolyl, isoquinolinyl, pyridyl, pyrazinyl, imidazolyl, pyrazolyl, dihydrobenzofuranyl, 2,3-dihydrobenzofuranyl, dihydrobenzofuranyl, 2,3-dihydrobenzofuranyl, benzo[b][1,4]dioxinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[b][1,4]oxazinyl, 2,3-dihydrobenzo[b][1,4]oxazinyl, benzo[b][1,4]thiazinyl or 3,4-dihydro-2H-benzo[b][1,4]thiazinyl, 1,2,3,4-tetrahydroquinoxalinyl or 1,2,3,4-tetrahydroquinoxalinyl, isochoryl or indazoleyl; Optionally, the heteroaryl or heterocyclic group is further selected from 1H-1,2,3-triazol-4-yl, isoquinoline-6-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,4-triazol-3-yl, 2H-1,2,3-triazol-4-yl, 1H-imidazol-4-yl, 1H-pyrazol-4-yl, 1H-pyrazol-3-yl, dihydrobenzofuran-6-yl or 2,3-dihydrobenzofuran-6-yl, dihydrobenzofuran-5-yl or 2,3-dihydrobenzofuran-5-yl. Benzofuran-5-yl, benzo[b][1,4]dioxin-6-yl or 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, benzo[b][1,4]oxazin-7-yl or 2,3-dihydrobenzo[b][1,4]oxazin-7-yl, 2H-benzo[b][1,4]thiazin-7-yl or 3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl, 1,2,3,4-tetrahydroquinoxaline-6-yl or 1,2,3,4-tetrahydroquinoxaline-6-yl, isochoran-7-yl or 1H-indazole-6-yl; Optionally further, where R c3 Selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy; hydroxy, cyano, heterocyclic, NR e1 R e2 , oxo group, heterocyclic group or phenyl; Optionally further, where R c3 Selected from fluorine, bromine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxyl, cyano, morpholino, (1-methyl-1H-1,2,3-triazol-4-yl)amino, oxo, pyridyl, or phenyl; (e)R a2 It is C 1-6 Alkyl (e.g., methyl, ethyl, or propyl), the C 1-6 Alkyl groups are -C(O)NR b2 R b3 -OC(O)NR b2 R b3 -C(O)R b2 -NR b2 C(O)R b3 or -NR b2 R b3 Replace, where R b1 and R b2 As defined in equation (I); (f)R a2 It is C 3-8 Cycloalkyl, phenyl, heteroaryl, or heterocyclic groups, each of which is unsubstituted or substituted by one or more substituents selected from halogens; C 1-6 Alkyl, the C 1-6 Alkyl groups are unsubstituted or R-substituted. c3 replace, Optionally further, where R a2 It is pyridin-2-yl, pyridin-3-yl, isoquinoline-4-yl, pyrimidin-5-yl, isoxazol-5-yl, isoxazol-3-yl, triazol-3-yl, benzo[c]isooxazol-3-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridyl, triazolo[4,3-a]pyridyl, 5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazinyl, triazolo[3,4-c][1,4]oxazinyl, 6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazinyl, triazolo[5,1-c][1,4]oxazinyl or phenyl, each of which is unsubstituted or R c3 replace, Optionally further, where R c3 It is phenyl; C 1-6 Alkyl group; cyano group; oxo group; -NR e1 R e2 ;-NR e1 -C(O)-NR e2 R e3 ;phenoxy, phenyl or heteroaryl; Optionally further, where R c3 It is fluorine, bromine, chlorine, methyl, methoxy, amino, cyano, oxo, acetamyl, 3-methylurea, benzyl, phenoxy, pyridin-2-yl, or phenyl; or (g)R a2 It is an alkenyl or alkynyl group, each of which is further substituted with a phenyl group, wherein the phenyl group is unsubstituted or substituted with one or more R groups. c3 replace.

9. The compound according to any one of claims 1 to 8, wherein (a) R a2 It is 2-(o-tolyloxy)ethyl, 2-(2-(hydroxymethyl)phenoxy)ethyl, 2-(2-(trifluoromethyl)phenoxy)ethyl, 2-(2-(hydroxymethyl)-3-methylphenoxy)ethyl, 2-phenoxyethyl, 2-(3-(azacyclobutan-1-yl)phenoxy)ethyl, 2-(4-(azacyclobutan-1-yl)phenoxy)ethyl, 2-(2-(2-amino-2-oxoethyl)phenoxy)ethyl, 2-(3-acetamidophenoxy)ethyl, 2-(4-(pyridin-2-yl)phenoxy)ethyl, 2-(4-methyl-3-(1H-pyrazol-1-yl)phenoxy)ethyl, 2-(3-(pyrazin-2-yl)phenoxy)ethyl, N,N-dimethylaminophenoxyethyl, 2-(3-( 2-(dimethylamino)-2-oxoethyl)phenoxy)ethyl, 2-(3-(2-hydroxypropyl)phenoxy)ethyl, 2-(4-methyl-3-methylaminophenoxy)ethyl, 2-(2-chlorophenoxy)ethyl, 2-fluoro-5-methylphenoxy, 2-(pyrimidin-2-yloxy)ethyl, 2-(pyridin-2-yloxy)ethyl, 2-(pyridin-3-yloxy)ethyl, 2-((2-oxo-2H-[1,2'-bipyridin]-4'-yl)oxy)ethyl, 2-((1-methyl-1H-benzimidazol-4-yl)oxy)ethyl, 2-((1-methyl-1H-indazol-4-yl)oxy)ethyl or 2-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)ethyl; (b) R a2 It is 2-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)ethyl, N-methyl-N-(2-fluoro-5-methylphenyl)amino, N-(2-fluoro-5-methylphenyl)amino or dimethylamino; (c) R a2 It is 5-chloro-2-fluorobenzyl, 2-fluoro-5-methylbenzyl, 2-hydroxybenzyl, 2-fluoro-3-methylbenzyl, 2-fluoro-4-methylbenzyl, 2-hydroxy-3-methylbenzyl, 5-cyano-2-fluorobenzyl, 2-fluoro-5-(trifluoromethyl)benzyl, 2-chlorobenzyl, 2,6-difluorobenzyl, 3-chloro-2-fluorobenzyl, 2,5-difluorobenzyl, 2-fluoro-4-methoxybenzyl, 1-(5-chloro-2-fluorophenyl)ethyl, 2-fluoro-5-methoxybenzyl, 2,4,5-trifluorobenzyl, 2,4-difluorobenzyl, 2,4-difluoro-5-methylbenzyl, 2-fluoro-5-(methoxy) 2-(5-chloro-2-fluorophenyl)benzyl, 2-fluoro-3,5-dimethylbenzyl, benzyl, 4-chloro-2-fluorobenzyl, 2-(5-chloro-2-fluorophenyl)prop-2-yl, (5-chloro-2-fluorophenyl)fluoromethyl, (5-chloro-2-fluorophenyl)difluoromethyl, 1-(3-chlorophenyl)-2-hydroxyethyl, 1-(5-chloro-2-fluorophenyl)cyclopropyl, 2-fluorobenzyl, 2-fluoro-3-hydroxybenzyl, 2-fluoro-3-(hydroxymethyl)benzyl, 2-fluoro-3-(3-methylureido)benzyl, 2-fluoro-3-(thiazol-2-ylamino)benzyl, 2-fluoro-3-((1-methyl-1H-pyrazole-4-) 4-ethyl-2-fluorobenzyl, 4-(azacyclobutane-1-yl)-2-fluorobenzyl, 5-chloro-2-fluoro-4-(pyrazin-2-yl)benzyl, 2-fluoro-4-(3-(hydroxymethyl)pyridin-2-yl)benzyl, 2-fluoro-4-(1-methylpiperidin-4-yl)benzyl, 2-fluoro-4-(piperidin-4-yl)benzyl, 2-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)benzyl, 2-fluoro-4-(4-methylpiperidin-1-yl)benzyl, 2-fluoro-4-(4'-methyl-[1,1'-bipiperidin]-4-yl)benzyl, 5-chloro- 2-Fluoro-4-((1-methylpiperidin-4-yl)methoxy)benzyl, 2-Fluoro-4-((1-methylpiperidin-4-yl)methoxy)benzyl, 2-cyano-N-(4-cyano-2-fluorobenzyl), 3-chloro-2,6-difluorobenzyl, 5-chloro-2,4-difluorobenzyl, 3-amino-5-chloro-2-fluorobenzyl, 3-acetamido-5-chloro-2-fluorobenzyl, 5-chloro-2-hydroxybenzyl, 5-cyano-2-hydroxybenzyl, 2-cyano-5-methylbenzyl, 2-fluoro-5-(trifluoromethoxy)benzyl, 5-(difluoromethoxy)-2-fluorobenzyl, 2-fluoro-5-(2,2,2-Trifluoroethoxy)benzyl, 5-(dimethylamino)-2-fluorobenzyl, 2-fluoro-5-(methylthio)benzyl, 5-ethynyl-2-fluorobenzyl, 2-fluoro-5-vinylbenzyl, 2-fluoro-5-((trifluoromethoxy)methyl)benzyl, 2-fluoro-5-(hydroxymethyl)benzyl, 5-(azacyclobutane-1-yl)-2-fluorobenzyl, 5-cyclopropyl-2-fluorobenzyl, 2-fluoro-5-morpholinobenzyl, 2-amino-2-oxoethyl)-2-fluorobenzyl, 2-fluoro-5-(2-(methylamino)-2-oxoethyl)benzyl, 2-fluoro-5-((1-methyl-1H-pyridine) (Azol-4-yl)methyl)benzyl, 2-fluoro-4-(2-(methylamino)-2-oxoethyl)benzyl, 2-cyanobenzyl, (3-fluoronaphthyl-2-yl)methyl, 2-fluoro-4-(pyridin-3-yl)benzyl, (3-fluoro-[1,1'-biphenyl]-4-yl)methyl, (4-fluoro-[1,1'-biphenyl]-3-yl)methyl, 2-fluoro-5-(pyrimidin-4-yl)benzyl, 3-phenylpropyl, 3-(2-cyanophenyl)propyl, 3-(2-chlorophenyl)propyl, 3-(2-methoxyphenyl)propyl, 3-(2-fluorophenyl)propyl or 3-oxo-3-phenylpropyl; (d) R a2 It is (1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)methyl, (7-fluoroisoquinoline-6-yl)methyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyrazin-2-ylmethyl, (4-methylpyridin-2-yl)methyl, (4-methoxypyridin-2-yl)methyl, (2-chloro-5-methylpyridin-3-yl)methyl, (2-chloro-5-fluoropyridin-4-yl)methyl, (2-chloro-5-hydroxypyridin-4-yl)methyl, (5-fluoro-2-methylpyridin-4-yl)methyl (5-fluoro-2-methoxypyridin-4-yl)methyl, (2-cyano-5-fluoropyridin-4-yl)methyl, (2-cyano-5-hydroxypyridin-4-yl)methyl, (5-fluoro-2-morpholinopyridin-4-yl)methyl, (5-fluoro-2-((1-methyl-1H-1,2,3-triazol-4-yl)amino)pyridin-4-yl)methyl, 5-chloro-2-oxo-1,2-dihydropyridin-3-yl)methyl, (1-phenyl-1H-1,2,3-triazol-4-yl)methyl, (1-phenyl-1H-1,2,3-triazol-4-yl)methyl, (1-phenyl-1H- -1,2,4-triazol-3-yl)methyl, (2-phenyl-2H-1,2,3-triazol-4-yl)methyl, (1-phenyl-1H-imidazol-4-yl)methyl, 1-phenyl-1H-pyrazole-4-yl)methyl, (1-phenyl-1H-pyrazole-3-yl)methyl, (5-fluoro-2,3-dihydrobenzofuran-6-yl)methyl, (6-fluoro-2,3-dihydrobenzofuran-5-yl)methyl, (2,3-dihydrobenzofuran-6-yl)methyl, (7-fluoro-2,3-dihydrobenzo[b][1,4]) Dioxin-6-yl)methyl, (6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl, (6-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl, (6-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)methyl, (7-fluoro-1,2,3,4-tetrahydroquinoxalin-6-yl)methyl, (6-fluoroisochroman-7-yl)methyl or (7-fluoro-1H-indazole-6-yl)methyl; (e) R a2 It is 2-(methylamino)-2-oxoethyl, 2-(methoxyamino)-2-oxoethyl, 2-(dimethylamino)-2-oxoethyl, 2-oxo-2-(phenylamino)ethyl, 2-oxo-2-(pyridin-4-ylamino)ethyl, 2-((2-methoxyethyl)amino)-2-oxoethyl, dimethylaminocarbonyloxyethyl, carboxymethyl, methoxycarbonylmethyl, methylcarbonylaminoethyl, 3-(azacyclobutane-1-yl)-3-oxopropyl, 2-(methylamino)ethyl or carbamoyl; (f) R a2 It is cyclopropyl, pyridin-3-yl, 4-methylpyridin-3-yl, 4,6-dimethylpyridin-3-yl, 4-methoxypyridin-3-yl, 6-amino-4-cyanopyridin-3-yl, isoquinoline-4-yl, 5-methyl-2-oxo-1,2-dihydropyridin-4-yl, 4-methylpyrimidin-5-yl, 5-fluoro-4-methylpyridin-3-yl, 6-amino-4-methylpyridin-3-yl, 6-acetamido-4-methylpyridin-3-yl -yl, 4-methyl-6-(3-methylureido)pyridin-3-yl, 5-methoxypyridin-3-yl, 4-benzylpyridin-3-yl, 5-phenoxypyridin-3-yl, isoxazol-5-yl, 4-methylisooxazol-5-yl, 3,4-dimethylisooxazol-5-yl, 4-methyl-3-phenylisooxazol-5-yl, 4-methyl-3-(pyridin-2-yl)isooxazol-5-yl, isoxazol-3-yl, 4-methyl-4H-1,2 ,4-triazol-3-yl, 4-phenylisoxazol-5-yl, 3-methyl-4-phenylisoxazol-5-yl, benzo[c]isoxazol-3-yl, 1-methyl-2-oxo-1,2-dihydropyridin-3-yl, 3-fluoro-6-methylpyridin-2-yl, 5-methyl-2-oxo-1,2-dihydropyridin-3-yl, 4-fluoro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 1-phenyl-1H-1,2,3 -triazol-4-yl, 5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyridin-3-yl, 5,6-dihydro-8H-[1,2,4]triazol[3,4-c][1,4]oxazin-3-yl, 6,7-dihydro-4H-[1,2,3]triazol[5,1-c][1,4]oxazin-3-yl, 5-fluoro-2-methylphenyl, 2-chloro-5-fluorophenyl or 2-cyano-5-fluorophenyl; or (g) R a2 It is butyl-2-yn-1-yl, 3-(1-methyl-1H-pyrazol-4-yl)prop-2-yn-1-yl, 4,4-dimethylpent-2-yn-1-yl, 3-cyclopropylprop-2-yn-1-yl, N,N-dimethylaminobut-2-yn-yl, N,N-dimethylamino-1-methyl-but-2-yn-yl, 5-hydroxyhex-2-yn-1-yl, 5,6-dihydroxyhex-2-yn-1 -yl, 5-hydroxy-4-methylpentan-2-yn-1-yl, 3-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)prop-2-yn-1-yl, 3-(1-methyl-2-oxopiridine-3-yl)prop-2-yn-1-yl, 4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)but-3-yn-2-yl, 4-(1-methyl-2-oxopiridine-3-yl)but-3-yn-2-yl, 4-(1-methyl-2-oxopiridine-3-yl) 3-(o-Tolyl)prop-2-yn-1-yl, 3-(2-fluorophenyl)prop-2-yn-1-yl, 3-(2-chlorophenyl)prop-2-yn-1-yl, 3-(3-fluorophenyl)prop-2-yn-1-yl, 3-(4-fluorophenyl)prop-2-yn-1-yl, 3-(2-hydroxyphenyl)prop-2-yn-1-yl 3-(pyridin-3-yl)prop-2-yn-1-yl, 4-(pyridin-3-yl)but-3-yn-2-yl, 3-(pyridin-4-yl)prop-2-yn-1-yl, 3-(2-cyanophenyl)prop-2-yn-1-yl, 4-(pyridin-2-yl)but-2-yn-1-yl, 4-(pyrazin-2-yl)but-2-yn-1-yl or 4-(pyridin-2-yl)pent-2-yn-1-yl.

10. The compound according to any one of claims 1 to 7, wherein R 1 As -C(O)NR a1 R a2 , where R a1 and R a2 Together with the nitrogen atoms to which they are attached, they form 4- to 9-membered rings containing one or two additional heteroatoms selected from nitrogen, oxygen, or sulfur, and said rings are either unsubstituted or modified by one or more substituents R. b4 Substitution, or two substituents R on two adjacent atoms b4 Formation of 4- to 6-membered fused rings and / or two substituents R on the same carbon atom b4 Forming 3 to 6-membered spirorings, wherein the fused ring or spiroring is unsubstituted or composed of one or more elements selected from halogens or C. 1-6 Alkyl substituents; Optionally further, where R 1 As -C(O)NR a1 R a2 , where R a1 and R a2 Together with the nitrogen atoms to which they are attached, they form rings selected from the following: piperidinyl, 6-azaspiro[2.5]octane-6-yl, 5-azaspiro[2.5]octane-5-yl, piperidinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, thiomorpholine, morpholine, azacyclobutane, azacycloheptane, azacyclooctane, 3-azabicyclo[3.1.0]hexane, and octahydrocyclopentadien[c]pyrrole, wherein each of the rings is unsubstituted or substituted as defined above; Optionally further, where R b4 It is a hydroxyl group; halogen; oxo group; cyano group; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkoxy C 1-6 Alkyl; Halogenated C 1-6 Alkoxy; NR c4 R c5 (R) c4 and R c5 Each of the following groups is independently hydrogen, alkyl, or phenyl; phenyl, heterocyclic (e.g., pyrrolidine, aziridine) or heteroaryl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenoxy, cyclohexyl, 1H-pyrazol-4-yl, or 1-methyl-1H-pyrazol-4-yl), wherein each of the phenyl, heterocyclic, or heteroaryl groups is unsubstituted or substituted with one or more halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -NR e4 R e5 or -COOR e4 Replace, where R e4 and R e5 It is hydrogen, C 1-6 Alkyl, phenyl, C 1-6 Alkyl-substituted phenyl, heteroaryl, or C-substituted phenyl 1-6 Alkyl-substituted heteroaryl groups. Optionally further, where R b4 It is 3-chlorophenyl, methoxymethyl, phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, m-tolyl, 3-(trifluoromethyl)phenyl, 3-(N,N-dimethylamino)phenyl, 3-(methylamino)phenyl, 3-(methoxycarbonyl, 3-(carboxyl)phenyl), methoxyphenyl), phenoxy, cyclohexyl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl, fluorine, bromine, chlorine, azacyclobutane, oxo, pyrrolidine, hydroxyl, amino, trifluoromethyl or phenylamino. Optionally further, where R 1 It is 4-(3-chlorophenyl)piperidine-1-carbonyl, 6-azaspiro[2.5]octane-6-carbonyl, 5-azaspiro[2.5]octane-5-carbonyl, piperidine-1-carbonyl, 4-(methoxymethyl)piperidine-1-carbonyl, 4-phenylpiperidine-1-carbonyl, 4-phenylpiperazine-1-carbonyl, 4-phenyl-1,2,3,6-tetrahydropyridine-1-carbonyl, 4-(pyridin-2-yl)piperidine-1-carbonyl, 4-(pyridin-3-yl)piperidine-1-carbonyl, 4-(pyridin ... 4-Pyridine-1-carbonyl, 4-(m-Tolyl)piperidine-1-carbonyl, 4-(3-(trifluoromethyl)phenyl)piperidine-1-carbonyl, 4-(3-(N,N-dimethylamino)phenyl)piperidine-1-carbonyl, 4-(3-(methylamino)phenyl)piperidine-1-carbonyl, 4-(3-(methoxycarbonyl)phenyl)piperidine-1-carbonyl, 4-(3-(carboxyl)phenyl)piperidine-1-carbonyl, 4-(4-methoxyphenyl)piperidine-1-carbonyl 4-Phenoxypiperidine-1-carbonyl, 4-cyclohexylpiperidine-1-carbonyl, 3-phenylpiperidine-1-carbonyl, 3-(1H-pyrazol-4-yl)piperidine-1-carbonyl, 3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carbonyl, 3-(methoxymethyl)piperidine-1-carbonyl, 4,4-difluoropiperidine-1-carbonyl, 3,3-difluoropiperidine-1-carbonyl, 1,1-thiodimorpholine-4-carbonyl, morpholine-4-carbonyl, azacyclobutane-1-carbonyl , pyrrolidine-1-carbonyl, 3-fluoroazacyclobutane-1-carbonyl, 3,3-difluoroazacyclobutane-1-carbonyl, 3-hydroxyazacyclobutane-1-carbonyl, 3-aminoazacyclobutane-1-carbonyl, 3-(trifluoromethyl)azacyclobutane-1-carbonyl, azacycloheptane-1-carbonyl, azacyclooctane-1-carbonyl, 3-azabicyclo[3.1.0]hexane-3-carbonyl, octahydrocyclopentadien[c]pyrrole-2-carbonyl or 4-(phenylamino)piperidine-1-carbonyl.

11. The compound according to any one of claims 1 to 7, wherein R 1 It is -C(O)R a3 , where R a3 It is C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-S-, C3-8 cycloalkyl, phenyl, heteroaryl, or heterocyclic, wherein each of the C3-8 cycloalkyl, phenyl, heteroaryl, or heterocyclic groups is unsubstituted or substituted by one or more substituents selected from: halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy; Optionally further, where R a3 It is methyl, ethyl, isopropyl, propyl, ethynyl, vinyl, methoxy, ethoxy, ethanethiol, 1-methylcyclopropane, 1-fluorocyclopropane, 2,2-difluorocyclopropane, 1-(trifluoromethyl)cyclopropane, cyclopropyl, cyclobutyl, thiazole-4-carbonyl, or 1H-imidazol-1-carbonyl.

12. The compound according to any one of claims 1 to 7, wherein R 1 It is a heteroaryl group, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents selected from the following: halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, phenoxy, -NR b2 R b3 -C(O)NR b2 R b3 -OC(O)NR b2 R b3 -C(O)R b2 or -NR b2 C(O)R b3 ; Optionally further, where R 1 It is thiazolyl, thiadizolyl, imidazolyl, pyridinyl, pyrazinyl, oxypyrazinyl, pyrimidinyl, oxypyrimidinyl, pyridazinyl, pyridinyl, or benzo[d]thiazolyl, each of which is unsubstituted or substituted as defined above; Optionally further, where R 1 It is thiazol-2-yl, thiazol-4-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1H-imidazol-2-yl, pyridin-2-yl, pyrazin-2-yl, pyrazinyl oxide, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidinyl oxide, pyridazin-3-yl, pyrimidin-5-yl, pyridin-2-yl, pyrazin-2-yl, pyridazin-3-yl, or benzo[d]thiazol-2-yl; Optionally further, where R 1 It is thiazol-2-yl, thiazol-4-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1H-imidazol-2-yl, pyridin-2-yl, pyrazin-2-yl, pyrazin 1-oxide, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin 1-oxide, pyridazin-3-yl, 3-chloropyridin-2-yl, 3-fluoropyridin-2-yl, 3-methylpyridin-2-yl, 3-(trifluoromethyl)pyridin-2-yl, 5-bromopyrimidin-4-yl, 5-chloropyrimidin-4-yl, 5-fluoropyrimidin-4-yl, 5-methylpyrimidin- 4-yl, 5-(trifluoromethyl)pyrimidin-4-yl, 3-methylpyrazin-2-yl, 5-fluoropyridin-2-yl, 3,5-difluoropyridin-2-yl, 5-methylthiazol-4-yl, 1-methyl-1H-imidazol-2-yl, N,N-dimethylaminocarbonylpyrimidin-5-yl, N,N-dimethylaminocarbonylpyridin-2-yl, N,N-dimethylaminocarbonylpyrazin-2-yl, N,N-dimethylaminocarbonylpyridazin-3-yl, 5-phenoxypyridin-2-yl, 5-phenoxypyrazin-2-yl or benzo[d]thiazol-2-yl.

13. A compound of formula (II) (II) Or its pharmaceutically acceptable salt, its stereoisomer, its tautomer, or its deuterated analogue. in X 1 and X 3 Each can be independently -O-, -S-, -NH-, -N=, or -CH=; m and n are each numbers from 0 to 3, provided that the valence theory is satisfied; R 2 and R 3 Each of these groups independently represents a halogen, deuterium, cyano, oxo, nitro, hydroxyl, or C group. 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated, and halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Alkyl-S-, C 2-6 alkenyl, C 2-6 Alkynyl, -SO2R 2a -COOR 2a or -NR 2a R 2b , Where R 2a and R 2b Each is independently hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated, and halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 alkyl; R 1 yes 1)-C(O)NR a1 R a2 , where R a1 and R a2 Each is C independently 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 alkyl; 2)-C(O)NR a1 R a2 , where R a1 It is C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 Alkyl; and R a2 It is C 1-6 Alkyl, the C 1-6 The alkyl group is either unsubstituted or substituted with one or more halogens or hydroxyl groups and further substituted with a phenyl group, wherein the phenyl group is unsubstituted or substituted with one or more substituents R. c3 replace; 3)-C(O)NR a1 R a2 , where R a1 It is C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 Alkyl; and R a2 It is C 1-6 Alkyl, the C 1-6 Alkyl groups are either unsubstituted or substituted with one or more halogens or hydroxyl groups and are further modified by -OR b1 Replace, where R b1 It is a phenyl group, wherein the phenyl group is unsubstituted or modified by halogens, oxo groups, C... 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, Halogenated C 1-6 Alkyl, heterocyclic, -C 1-6 Alkyl C(O)NR c1 R c2 -C(O)NR c1 R c2 -NR c1 R c2 -NR c1 C(O)R c2 Or heteroaryl substitution; or 4)-C(O)NR a1 R a2 , where R a1 It is C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 Alkyl; and R a2 It is C 2-6 alkenyl or C 2-6 The alkynyl group, each of which is further substituted with a phenyl group, wherein the phenyl group is unsubstituted or substituted with one or more substituents R. c3 replace; 5)-C(O)NR a1 R a2 , where R a1 It is C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 Alkyl; and R a2 It is C 3-8 Cycloalkyl, phenyl, heteroaryl or heterocyclic, wherein C 3-8 Each of the cycloalkyl, phenyl, heteroaryl, or heterocyclic groups is either unsubstituted or substituents R. c3 replace; 6)-C(O)NR a1 R a2 , where R a1 and R a2 Together with the nitrogen atoms to which they are attached, they form 4- to 9-membered rings containing one or two additional heteroatoms selected from nitrogen, oxygen, or sulfur, and said rings are either unsubstituted or modified by one or more substituents R. b4 Substitution, or two substituents R on two adjacent atoms b4 Formation of 4- to 6-membered fused rings and / or two substituents R on the same carbon atom b4 Forming 3 to 6-membered spirorings, wherein the fused ring or spiroring is unsubstituted or composed of one or more elements selected from halogens or C. 1-6 Alkyl substituents, 7) Heteroaryl or heterocyclic groups, each of which is unsubstituted or substituted by one or more substituents selected from: halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, phenoxy, -NR c6 R c7 -C(O)NR c6 R c7 -OC(O)NR c6 R c7 -C(O)R c6 or -NR c6 C(O)R c7 , in R c1 and R c2 Each is independently hydrogen, C 1-6 Alkyl, phenyl, wherein the phenyl group is unsubstituted or is substituted with one or more groups selected from hydroxyl, halogen, oxo, C 1-6 Alkyl or C 1-6 Substitution of alkoxy groups; R c3 yes -halogen; -hydroxyl group; -Cyano; -Oxide group; -C 1-6 Alkyl, the C 1-6 Alkyl groups are unsubstituted or converted by one or more halogens, hydroxyl groups, C... 1-6 Alkoxy, phenyl, or alkyl-substituted heteroaryl (pyrazolyl) substituted; -C 2-6 alkenyl or C 2-6 alkynyl group; -hydroxyl group; -C 1-6 Alkyl-S- -C 1-6 alkoxy or phenoxy, wherein the C 1-6 Each of the alkoxy or phenoxy groups is unsubstituted or converted by one or more halogens, C 1-6 Alkoxy, alkyl-substituted heteroaryl, or alkyl-substituted heterocyclic group; --C 1-6 Alkyl C(O)NR e1 R e2 ; --C(O)NR e1 R e2 ; --NO e1 R e2 ; --NR e1 C(O)R e2 ; --NO e1 -C(O)-NR e2 R e3 ; --NO e1 R e2 ; - Heterocyclic group, said heterocyclic group is unsubstituted or halogenated, C 1-6 Alkyl or heterocyclic groups, via C 1-6 Alkyl-substituted heterocyclic substitution, - Heteroaryl, wherein the heteroaryl group is unsubstituted or C-substituted. 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl- or heteroaryl substitution; -C 3-8 cycloalkyl; -phenyl; and R e1 R e2 and R e3 Each is independently hydrogen, C 1-6 Alkyl, phenyl, C 1-6 Alkyl-substituted phenyl, heteroaryl (e.g., thiazolyl, pyrazolyl), or C-substituted phenyl groups 1-6 Alkyl-substituted heteroaryl (1-methyl-1H-1,2,3-triazol-4-yl). R b4 It is a hydroxyl group; halogen; oxo group; cyano group; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkoxy C 1-6 Alkyl; Halogenated C 1-6 Alkoxy; NR c4 R c5 , where R c4 and R c5 Each is independently hydrogen, alkyl, or phenyl; phenyl, heterocyclic, or heteroaryl, wherein each of the phenyl, heterocyclic, or heteroaryl groups is unsubstituted or substituted with one or more halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -NR e4 R e5 or -COOR e4 Replace, where R e4 and R e5 It is hydrogen, C 1-6 Alkyl, phenyl, C 1-6 Alkyl-substituted phenyl, heteroaryl, or C-substituted phenyl 1-6 Alkyl-substituted heteroaryl groups; R c6 and R c7 Each is independently hydrogen, C 1-6 Alkyl, phenyl, wherein the phenyl group is unsubstituted or is substituted with one or more groups selected from hydroxyl, halogen, oxo, C 1-6 Alkyl or C 1-6 Substitution of alkoxy groups, The condition is a double-ring part. It belongs to the aromatic family.

14. The compound according to claim 1, wherein the compound is selected from compound numbers 1-549.

15. A pharmaceutical composition comprising a compound according to any one of claims 1-14 or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a deuterated analog thereof, and a pharmaceutically acceptable excipient.

16. A method for inhibiting weight gain in a subject; or promoting weight loss; or lowering serum LDL, cholesterol, LDL-c, or triglycerides; or treating obesity or obesity-related diseases (especially obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipidemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease), macular degeneration, or Alzheimer's disease; or treating injury or promoting wound healing or tissue regeneration, said method comprising administering to a subject in need an effective amount of the compound of any one of claims 1-14 or a pharmaceutically acceptable salt thereof, its stereoisomer, or its deuterated analogue.

17. The method of claim 16, wherein the method is characterized by FTO suppression.

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