Novel aryl ether-substituted heterocyclic compounds as GLP1R agonists

Abstract

Provided is a novel aryl ether-substituted heterocyclic compound having GLP1R agonist activity. 【Solution】Provided is a compound having the structure shown in formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isotope-substituted form, or isomer thereof. TIFF2026082907000718.tif69169 (A, B: C3-C18 monocyclic / polycyclic structure. X, X': CR d1 R d2 , O, S, etc. L: CR d1 R d2 , OCR d1 R d2 , etc. X1-X5, X8, X9: CR5, N. R0, R1, R4-R6: H, halogen, CN, etc. R2, R 2’ , R d1 , R d2 : H, halogen, etc. m: 1-4. n, q: 0-5.)

Description

Detailed description of the invention

[0001] This application claims priority to two prior applications filed with the China National Intellectual Property Administration on 30 August 2021, patent application number 202111017657.5, titled "Novel Aryl Ether-Substituted Heterocyclic Compounds as GLP1R Agonists," and filed with the China National Intellectual Property Administration on 29 September 2021, patent application number 202111168512.5, titled "Novel Aryl Ether-Substituted Heterocyclic Compounds as GLP1R Agonists." The entire text of these prior applications is incorporated herein by reference.

[0002] [Technical Field] The present invention belongs to the field of medicinal chemistry and specifically includes a novel aryl ether-substituted heterocyclic compound having GLP1R agonist activity, a composition containing the compound, and a method of applying the compound to the manufacture of a drug for treating or preventing a disease related to GLP1 / GLP1R.

[0003] [Background technology] As material living standards rise, overweight and obesity are becoming more common in modern society. The population of patients with obesity-related complications such as diabetes and fatty liver disease is steadily increasing. According to reports and projections issued by the World Health Organization (WHO) and Chiken Consulting, by 2030 there will be 3.26 billion obese people worldwide, by 2029 there will be over 500 million people with diabetes worldwide, and over 1.5 billion people with non-alcoholic fatty liver disease worldwide. Currently, there are no effective treatments for fatty liver disease, and only six obesity treatments have been approved by the FDA, many of which are regulated drugs with weak therapeutic effects and significant side effects. While several drugs for treating type 2 diabetes are already on the market, the adherence rate to current blood glucose-lowering drugs (<7%) is not very high, and even the most active combination drugs have an adherence rate of only about 45%. Therefore, regardless of whether it is fatty liver disease, obesity, or diabetes, the development of new drugs is necessary to meet the needs of a wider range of patients.

[0004] Glucagon-like peptide-1 (GLP-1) is a long peptide hormone containing 30 or 31 amino acids. It is produced and secreted by enteroendocrine L cells and several nerve cells in the nucleus tractus solitarius of the brainstem during feeding. GLP-1 physiologically and glucose-dependently stimulates insulin secretion, reduces glucagon secretion, suppresses gastric emptying, decreases appetite, and stimulates β-cell proliferation. In nonclinical studies, GLP-1 has been shown to promote the persistence of β-cells by stimulating the transcription of important genes for glucose-dependent insulin secretion and promoting β-cell regeneration (Meier, et al. Biodrugs. 2003; 17(2): 93-102). The GLP1 receptor is an ideal target that has proven useful in treating metabolic diseases such as obesity, diabetes, and fatty liver, and several GLP1R agonist polypeptide drugs, such as dulaglutide and semaglutide, are already commercially available overseas for the treatment of diabetes and obesity.

[0005] However, these polypeptides require injection, have low patient compliance, are expensive, are inaccessible, place a heavy burden on healthcare providers, require refrigeration, are inconvenient to transport and store, and are difficult to combine with existing oral small molecule drugs for diseases with complex etiologies, such as non-alcoholic fatty liver disease, which require treatment with multiple drugs. Therefore, the development of small molecule oral GLP1R agonists is urgently needed.

[0006] Currently, there are several publications and patent reports on oral small molecule GLP1 agonists. For example, Pfizer's PF-06882961 can achieve efficacy similar to, or even better than, GLP1 polypeptides (https: / / doi.org / 10.1101 / 2020.09.29.319483). Although its therapeutic efficacy and safety have been preliminaryly validated, PF-06882961 has poor oral absorption, extremely low bioavailability, a somewhat high clinical dose, high cost and burden on the patient's gastrointestinal tract, and the inability to achieve further improvements in blood glucose reduction and weight loss by further increasing the dose. Therefore, there is a need to develop new small molecule GLP1 agonists with better drug potential to meet the needs of a wider range of patients.

[0007] [Effects of the invention] The inventors have unexpectedly discovered that some of the novel aryl ether-substituted heterocyclic compounds of the structure of formula (I) of the present invention not only possess remarkable GLP1R agonist activity, but also exhibit superior pharmacokinetic properties (including a longer T1 / 2 and higher exposure) and bioavailability compared to the structurally known reference compound PF-06882961. They are expected to exhibit even better human PK properties and are therefore even more suitable for development as drug candidates for preventing or treating diseases related to GLP1 / GLP1R targets or signaling pathways.

[0008] [Summary of the Invention] The object of the present invention is to provide a compound represented by formula (I), or a pharmaceutically acceptable salt, solvate, enantiomer, and isotope-substituted compound thereof.

[0009] [ka]

[0010] Among them, A and B are each independently selected from monocyclic or polycyclic structures having 3 to 18 carbon atoms, and the monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a para ring, a spiro ring, or a bridged ring structure. X and X' are independently -C(R d1 )(R d2 )-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O)2-. L is independently -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O)2N(R d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O)2-. X1, X2, X3, X4, X5, X8, and X9 are independently selected from -CR5- or -N-. R0 is independently hydrogen, deuterium, halogen, -CN, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, C 1-10 alkoxy group, -NR d8 R d9 , a 6- to 10-member aryl group, a 5- to 8-member heteroaryl group, a 3- to 8-member saturated or partially saturated cycloalkyl group, and a 3- to 8-member saturated or partially saturated heterocyclyl group, among which the C 1-10 alkyl group, C 2-10 alkenyl group, C2-10 Alkynyl group, C 1-10 The alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group, and 3-8 membered saturated or partially saturated heterocyclyl group are optionally and most preferably substituted with one or more substituents, the substituents of which may optionally be hydrogen, deuterium, halogen, alkyl group, haloalkyl group, alkoxy group, alkylamino group, O=, CN, OH, -NR d8 R d9 , C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 A saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group are selected, and the aryl group, heteroaryl group, saturated or partially saturated cycloalkyl group, and saturated or partially saturated heterocyclyl group are further optionally substituted with one or more substituents, the substituents being optionally hydrogen, deuterium, halogen, alkyl group, haloalkyl group, cyano group, cyanoethyl group, O=, OH, C 1-3 Alkyl alkyl group, C 1-3 Selected from an alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, among which the above C 1-3 Alkyl alkyl group, C 1-3 The alkoxy group, saturated or partially saturated cycloalkyl group, or saturated or partially saturated heterocyclyl group is optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl group, cyano group, OCH3, and OH. Each R1 is homologous or homologous and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group substituted with an alkyl group, or a carboxyl group substituted product, is selected most preferably, optionally, the carboxyl group substituted product is

[0011] [ka]

[0012] And of those, C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 The alkylcarboxyl group or carboxyl group substituted is optionally most preferably H, deuterium, halogen, OCH3, carboxyl group, OH, CN, and NR d8 R d9 Substituted with one or more substituents selected from, or any two adjacent R1 atoms together with the attached carbon to form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the hydrogen atoms in the aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group can optionally be hydrogen, deuterium, halogen, -CN, -OH, CF3, or C 1-6 Alkyl alkyl group, C 1-6An alkoxy group, -NH2, -NHC 1-6 An alkyl group, -N(C 1-6 alkyl)2, =O, and a saturated or partially saturated C 3-6 Cycloalkyl group selected from the group consisting of groups substituted with, and C 1-6 The alkyl group and C 1-6 The alkoxy group is optionally hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, a saturated or partially saturated C 3-6 Cycloalkyl group substituted with one or more groups selected from the group consisting of.

[0013] R2, R 2' And R d1 , R d2 Are the same or different and are independently of each other hydrogen, deuterium, halogen, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkylamino group, N,N-di(C 1-10 alkyl)amino group, C 1-10 Alkyloxy group, C 1-10 Alkylacyl group, C 1-10 Alkyloxy group, C 1-10 Alkylsulfonyl group, C 1-10 Alkylsulfinyl group, C 3-10 Cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 Cycloalkoxy group, C 3-10 Cycloalkylacyl group, C 3-10 Cycloalkoxyacetyl group, C 3-10 Cycloalkylsulfonyl group and C 3-10 Cycloalkylsulfinyl group selected from the group consisting of, and the alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, heterocycloalkyl group are optionally hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl group, -N(C 1-6 alkyl)2, oxy group, and a saturated or partially saturated C3-6 Substituted with one or more groups selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be further composed of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C. 3-6 Substituted with one or more groups selected from cycloalkyl groups, or optionally R2 and R 2' , or R d1 and R d2 It may form a 5-6 membered aryl group or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group together with the carbon attached thereto, and among these, the cycloalkyl group and heterocycloalkyl group may be optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, and OCH2CH3. Each R4 is homologous or homologous and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon group, C 3-10 Cyclic hydrocarbon group, or C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Alkyl alkyl groups, and C 3-10 Cyclic hydrocarbon group, C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Selected from heteroalkyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10Substituted with one or more groups selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, Each of R5 and R6 is homologous or homologous, and independently of each other are hydrogen, deuterium, halogen, CN, OH, SH, and NR. d8 R d9 Selected from NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with a cycloalkyl group 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Heterocycloalkyl groups can optionally contain hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10The aryl group is substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, or any two adjacent R5 or R6 groups, together with the carbon attached to them, form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group may optionally consist of hydrogen, deuterium, halogen, -CN, -OH, CF3, or C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, oxy group, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 These are homologous or different, and can be arbitrarily and independently of each other: hydrogen, deuterium, NH2, C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the above C1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 The heterocyclyl group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, The above heteroatoms represent heteroatoms and their isotopes, arbitrarily and independently selected from O, N, S, and P. The above halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5.

[0014] In one embodiment of the present invention, the above compound, or a pharmaceutically acceptable salt thereof, an isotope-substituted compound, or an isomer thereof, has the structure of formula (IA),

[0015] [ka]

[0016] Eventually, A and B are arbitrarily and independently selected from monocyclic or polycyclic structures having 3 to 18 carbon atoms, and the above monocyclic or polycyclic structures may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, paracyclic rings, spirocyclic rings, or bridging ring structures. X and X' are independently -C(R d1 )(R d2 )-,-C(=O)N(R d3 )-,-N(R d4 )-, -C(=NR d5 )-,-S(=O)2N(R d6 )-,-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O)2- are selected, L is independently -C(R d1 )(R d2 )-,-OC(R d1 )(R d2 )-,-C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-,-N(R d4 )-, -C(=NR d5 )-,-S(=O)2N(R d6 )-,-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O)2- are selected, X1, X3, X8, and X9 are independently selected from -CR5- or -N-. R0 is independently hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkoxy group, -NR d8 R d9 , selected from 6-10 membered aryl groups, 5-8 membered heteroaryl groups, 3-8 membered saturated or partially saturated cycloalkyl groups, and 3-8 membered saturated or partially saturated heterocyclyl groups, of which R0 is represented by C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10The alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group, and 3-8 membered saturated or partially saturated heterocyclyl group are optionally and most preferably substituted with one or more substituents, the substituents of which may optionally be hydrogen, deuterium, halogen, alkyl group, haloalkyl group, alkoxy group, alkylamino group, O=, CN, OH, -NR d8 R d9 , C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 A saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group are selected, and the aryl group, heteroaryl group, saturated or partially saturated cycloalkyl group, and saturated or partially saturated heterocyclyl group are further optionally substituted with one or more substituents, the substituents being optionally hydrogen, deuterium, halogen, alkyl group, haloalkyl group, cyano group, cyanoethyl group, O=, OH, C 1-3 Alkyl alkyl group, C 1-3 Selected from an alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, among which the above C 1-3 Alkyl alkyl group, C 1-3 The alkoxy group, saturated or partially saturated cycloalkyl group, or saturated or partially saturated heterocyclyl group is optionally and most preferably substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl group, cyano group, OCH3, and OH. Each R1 is homologous or homologous and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group substituted with an alkyl group, or a carboxyl group substituted product, is selected most preferably, optionally, the carboxyl group substituted product is

[0017] [ka]

[0018] And of those, C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 The alkylcarboxyl group or carboxyl group substituted is optionally most preferably H, deuterium, halogen, OCH3, carboxyl group, OH, CN, and NR d8 R d9 R1 is substituted with one or more substituents selected from the above, or any two adjacent R1 atoms, together with the attached carbon, form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the hydrogen atoms in the above aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group may optionally be hydrogen, deuterium, halogen, -CN, -OH, CF3, or C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6Alkyl, -N(C 1-6 Alkyl)2, =O, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R2, R 2' and R d1 , R d2 They are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkylamino group, N,N-di(C 1-10 Alkyl)amino group, C 1-10 Alkyloxy group, C 1-10 Alkylacyl group, C 1-10 Alkyloxy group, C 1-10 Alkyl sulfonyl group, C 1-10 Alkyl sulfinyl group, C 3-10 Cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 Cycloalkoxy group, C 3-10 Cycloalkylacyl group, C 3-10 Cycloalkoxyacetyl group, C 3-10 Cycloalkylsulfonyl group and C 3-10 Selected from cycloalkylsulfinyl groups, and the alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, heterocycloalkyl group may optionally contain hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, oxy group, and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, and C 1-6Alkyl and C 1-6 The alkoxy group can optionally be hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C. 3-6 Substituted with one or more groups selected from cycloalkyl groups, or optionally R2 and R 2' , or R d1 and R d2 It may form a 5-6 membered aryl group or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group together with the carbon attached thereto, and among these, the cycloalkyl group and heterocycloalkyl group may be optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, and OCH2CH3. Each R4 is homologous or homologous and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon group, C 3-10 Cyclic hydrocarbon group, or C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Alkyl alkyl groups, and C 3-10 Cyclic hydrocarbon group, C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Selected from heteroalkyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more groups selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, Each of R5 and R6 is homologous or homologous, and independently of each other are hydrogen, deuterium, halogen, CN, OH, SH, and NR. d8 R d9 Selected from NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with a cycloalkyl group 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Heterocycloalkyl groups can optionally contain hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 The aryl group is substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, or any two adjacent R5 or R6 groups, together with the carbon attached to them, form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group may optionally consist of hydrogen, deuterium, halogen, -CN, -OH, CF3, or C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC1-6 Alkyl, -N(C 1-6 Alkyl)2, oxy group, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 These are homologous or different, and can be arbitrarily and independently of each other: hydrogen, deuterium, NH2, C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10C substituted with heterocycloalkyl groups 3-10 The heterocyclyl group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, The above heteroatoms represent heteroatoms and their isotopes, arbitrarily and independently selected from O, N, S, and P. The above halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. t is an integer arbitrarily chosen from 0, 1, 2, 3, and 4.

[0019] In one embodiment of the present invention, the above compound, or a pharmaceutically acceptable salt thereof, an isotope-substituted compound, or an isomer thereof, has the structure of formula (IB),

[0020] [ka]

[0021] Eventually, B is arbitrarily and independently selected from monocyclic or polycyclic structures having 3 to 18 carbon atoms, and the above monocyclic or polycyclic structures may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, paracyclic rings, spirocyclic rings, or bridging ring structures. X and X' are independently -C(R d1 )(R d2 )-,-C(=O)N(R d3 )-,-N(R d4 )-, -C(=NR d5 )-,-S(=O)2N(R d6 )-,-N(R d7)-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O)2- are selected, L is independently -C(R d1 )(R d2 )-,-OC(R d1 )(R d2 )-,-C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-,-N(R d4 )-, -C(=NR d5 )-,-S(=O)2N(R d6 )-,-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O)2- are selected, X1, X3, X8, X9, X 10 , X 11 and X 12 These are independently selected from -CR5- or -N-. R0 is independently hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkoxy group, -NR d8 R d9 , selected from 6-10 membered aryl groups, 5-8 membered heteroaryl groups, 3-8 membered saturated or partially saturated cycloalkyl groups, and 3-8 membered saturated or partially saturated heterocyclyl groups, of which R0 is represented by C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 The alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group, and 3-8 membered saturated or partially saturated heterocyclyl group are optionally substituted with one or more substituents, which may optionally be hydrogen, deuterium, halogen, alkyl group, haloalkyl group, carboxyl group, alkoxy group, alkylamino group, O=, CN, OH, -NR d8 R d9 , C 3-10Saturated or partially saturated cycloalkyl groups, C 3-10 A saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group are selected, and of these, the aryl group, heteroaryl group, saturated or partially saturated cycloalkyl group, and saturated or partially saturated heterocyclyl group are optionally substituted with one or more substituents, and the substituents may optionally be hydrogen, deuterium, halogen, alkyl group, haloalkyl group, cyano group, cyanoethyl group, O=, OH, C 1-3 Alkyl alkyl group, C 1-3 Selected from an alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, among which the above C 1-3 Alkyl alkyl group, C 1-3 The alkoxy group, saturated or partially saturated cycloalkyl group, or saturated or partially saturated heterocyclyl group is optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl group, cyano group, OCH3, and OH. Each R1 is homologous or homologous and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group substituted with an alkyl group, or a carboxyl group substituted product, is selected most preferably, optionally, the carboxyl group substituted product is

[0022] [ka]

[0023] And of those, C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 Alkylcarboxyl groups, or carboxyl group-substituted derivatives, can optionally include H, deuterium, halogen, OCH3, carboxyl group, OH, CN, and NR. d8 R d9 R1 is substituted with one or more substituents selected from the above, or any two adjacent R1 atoms, together with the attached carbon, form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the hydrogen atoms in the above aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group may optionally be hydrogen, deuterium, halogen, -CN, -OH, CF3, or C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, =O, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R2, R2' and R d1 , R d2 They are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkylamino group, N,N-di(C 1-10 Alkyl)amino group, C 1-10 Alkyloxy group, C 1-10 Alkylacyl group, C 1-10 Alkyloxy group, C 1-10 Alkyl sulfonyl group, C 1-10 Alkyl sulfinyl group, C 3-10 Cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 Cycloalkoxy group, C 3-10 Cycloalkylacyl group, C 3-10 Cycloalkoxyacetyl group, C 3-10 Cycloalkylsulfonyl group and C 3-10 Selected from cycloalkylsulfinyl groups, and the alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, heterocycloalkyl group may optionally contain hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, oxy group, and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C. 3-6 Substituted with one or more groups selected from cycloalkyl groups, or optionally R2 and R 2' , or R d1 and R d2It may form a 5-6 membered aryl group or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group together with the carbon attached thereto, and among these, the cycloalkyl group and heterocycloalkyl group may be optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, and OCH2CH3. Each R4 is homologous or homologous and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon group, C 3-10 Cyclic hydrocarbon group, or C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Alkyl alkyl groups, and C 3-10 Cyclic hydrocarbon group, C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Selected from heteroalkyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more groups selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, Each of R5 and R6 is homologous or homologous, and independently of each other are hydrogen, deuterium, halogen, CN, OH, SH, and NR. d8 R d9 Selected from NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with a cycloalkyl group 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Heterocycloalkyl groups can optionally contain hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 The aryl group is substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, or any two adjacent R5 or R6 groups, together with the carbon attached to them, form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group may optionally consist of hydrogen, deuterium, halogen, -CN, -OH, CF3, or C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, oxy group, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 These are homologous or different, and can be arbitrarily and independently of each other: hydrogen, deuterium, NH2, C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 The heterocyclyl group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, The above heteroatoms represent heteroatoms and their isotopes, arbitrarily and independently selected from O, N, S, and P. The above halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. t is an integer arbitrarily chosen from 0, 1, 2, 3, and 4.

[0024] In one embodiment of the present invention, the above compound, or a pharmaceutically acceptable salt thereof, an isotope-substituted compound, or an isomer thereof, has the structure of formula (IC),

[0025] [ka]

[0026] Eventually,

[0027] [ka]

[0028] This can represent a single bond or a double bond, X and X' are independently -C(R d1 )(R d2 )-,-C(=O)N(R d3 )-,-N(R d4 )-, -C(=NR d5 )-,-S(=O)2N(R d6 )-,-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O)2- are selected, L is independently -C(R d1 )(R d2 )-,-OC(R d1 )(R d2 )-,-C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-,-N(R d4 )-, -C(=NR d5 )-,-S(=O)2N(Rd6 )-,-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O)2- are selected, X1, X3, X8, X9, X 10 , X 11 , X 12 , X 13 , or X 14 These are independently selected from -CR5- or -N-. R0 is independently hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkoxy group, -NR d8 R d9 , selected from 6-10 membered aryl groups, 5-8 membered heteroaryl groups, 3-8 membered saturated or partially saturated cycloalkyl groups, and 3-8 membered saturated or partially saturated heterocyclyl groups, of which R0 is represented by C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 The alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group, and 3-8 membered saturated or partially saturated heterocyclyl group are optionally substituted with one or more substituents, the substituents being optionally hydrogen, deuterium, halogen, alkyl group, haloalkyl group, alkoxy group, alkylamino group, O=, CN, OH, -NR d8 R d9 , C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 A saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group are selected, and of these, the aryl group, heteroaryl group, saturated or partially saturated cycloalkyl group, and saturated or partially saturated heterocyclyl group are optionally substituted with one or more substituents, and the substituents may optionally be hydrogen, deuterium, halogen, alkyl group, haloalkyl group, cyano group, cyanoethyl group, O=, OH, C 1-3 Alkyl alkyl group, C 1-3Selected from an alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, among which the above C 1-3 Alkyl alkyl group, C 1-3 The alkoxy group, saturated or partially saturated cycloalkyl group, or saturated or partially saturated heterocyclyl group is optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl group, cyano group, OCH3, and OH. Each R1 is homologous or homologous and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group substituted with an alkyl group, or a carboxyl group substituted product, is selected most preferably, optionally, the carboxyl group substituted product is

[0029] [ka]

[0030] And of those, C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 Alkylcarboxyl groups, or carboxyl group-substituted derivatives, can optionally include H, deuterium, halogen, OCH3, carboxyl group, OH, CN, and NR. d8 R d9 R1 is substituted with one or more substituents selected from the above, or any two adjacent R1 atoms, together with the attached carbon, form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the hydrogen atoms in the above aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group may optionally be hydrogen, deuterium, halogen, -CN, -OH, CF3, or C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, =O, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R2, R 2' and R d1 , R d2 They are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkylamino group, N,N-di(C 1-10 Alkyl)amino group, C 1-10 Alkyloxy group, C 1-10Alkylacyl group, C 1-10 Alkyloxy group, C 1-10 Alkyl sulfonyl group, C 1-10 Alkyl sulfinyl group, C 3-10 Cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 Cycloalkoxy group, C 3-10 Cycloalkylacyl group, C 3-10 Cycloalkoxyacetyl group, C 3-10 Cycloalkylsulfonyl group and C 3-10 Selected from cycloalkylsulfinyl groups, and the alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, heterocycloalkyl group may optionally contain hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, oxy group, and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C. 3-6 Substituted with one or more groups selected from cycloalkyl groups, or optionally R2 and R 2' , or R d1 and R d2 It may form a 5-6 membered aryl group or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group together with the carbon attached thereto, and among these, the cycloalkyl group and heterocycloalkyl group may be optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, and OCH2CH3. Each R4 is homologous or homologous and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, or C 1-10 Alkyl alkyl group, C2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon group, C 3-10 Cyclic hydrocarbon group, or C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Alkyl alkyl groups, and C 3-10 Cyclic hydrocarbon group, C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Selected from heteroalkyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more groups selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, Each of R5 and R6 is homologous or homologous, and independently of each other are hydrogen, deuterium, halogen, CN, OH, SH, and NR. d8 R d9 Selected from NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with a cycloalkyl group 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Heterocycloalkyl groups can optionally contain hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 The aryl group is substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, or any two adjacent R5 or R6 groups, together with the carbon attached to them, form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group may optionally consist of hydrogen, deuterium, halogen, -CN, -OH, CF3, or C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, oxy group, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 These are homologous or different, and can be arbitrarily and independently of each other: hydrogen, deuterium, NH2, C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 The heterocyclyl group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, The above heteroatoms represent heteroatoms and their isotopes, arbitrarily and independently selected from O, N, S, and P. The above halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. t is an integer arbitrarily chosen from 0, 1, 2, 3, and 4.

[0031] In one embodiment of the present invention, the above compound, or a pharmaceutically acceptable salt thereof, an isotope-substituted compound, or an isomer thereof, has the structure of formula (ID),

[0032] [ka]

[0033] Eventually,

[0034] [ka]

[0035] This can represent a single bond or a double bond, X and X' are independently -C(R d1 )(R d2 )-,-C(=O)N(R d3 )-,-N(R d4 )-, -C(=NR d5 )-,-S(=O)2N(R d6 )-,-N(R d7 -C(=O)O-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O)2-, preferably -C(R d1 )(R d2 )-,-N(R d4 )-, -O-, -S-, -S(=O)-, or -S(=O)2-, L is independently -C(R d1 )(R d2 )-,-OC(R d1 )(R d2 )-,-C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-,-N(R d4 )-, -C(=NR d5 )-,-S(=O)2N(R d6 )-,-N(R d7 -OC(R d1 )(R d2 )-,-C(R d1 )(R d2)O-, -O-, -S-, or -N(R d4 )- and, X1, X3, X8 and X 13 These are independently selected from -CR5- or -N-. R0 is independently hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkoxy group, -NR d8 R d9 , selected from 6-10 membered aryl groups, 5-8 membered heteroaryl groups, 3-8 membered saturated or partially saturated cycloalkyl groups, and 3-8 membered saturated or partially saturated heterocyclyl groups, of which R0 is represented by C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 The alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group, and 3-8 membered saturated or partially saturated heterocyclyl group are optionally substituted with one or more substituents, the substituents being optionally hydrogen, deuterium, halogen, alkyl group, haloalkyl group, alkoxy group, alkylamino group, O=, CN, OH, -NR d8 R d9 , C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 A saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group are selected, and the aryl group, heteroaryl group, saturated or partially saturated cycloalkyl group, and saturated or partially saturated heterocyclyl group are further optionally substituted with one or more substituents, the substituents being optionally hydrogen, deuterium, halogen, alkyl group, haloalkyl group, cyano group, cyanoethyl group, O=, OH, C 1-3 Alkyl alkyl group, C 1-3 Selected from an alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, among which the above C 1-3 Alkyl alkyl group, C 1-3The alkoxy group, saturated or partially saturated cycloalkyl group, or saturated or partially saturated heterocyclyl group is optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl group, cyano group, OCH3, and OH. Each R1 is homologous or homologous and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group substituted with an alkyl group, or a carboxyl group substituted product, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 Alkylcarboxyl groups, or carboxyl group-substituted derivatives, can optionally include H, deuterium, halogen, OCH3, carboxyl group, OH, CN, and NR. d8 R d9R1 is substituted with one or more substituents selected from the above, or any two adjacent R1 atoms, together with the attached carbon, form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the hydrogen atoms in the above aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group may optionally be hydrogen, deuterium, halogen, -CN, -OH, CF3, or C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, =O, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R2, R 2' and R d1 , R d2 They are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkylamino group, N,N-di(C 1-10 Alkyl)amino group, C 1-10 Alkyloxy group, C 1-10 Alkylacyl group, C 1-10 Alkyloxy group, C 1-10 Alkyl sulfonyl group, C 1-10 Alkyl sulfinyl group, C 3-10 Cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 Cycloalkoxy group, C 3-10 Cycloalkylacyl group, C 3-10 Cycloalkoxyacetyl group, C 3-10 Cycloalkylsulfonyl group and C 3-10Selected from cycloalkylsulfinyl groups, and the above alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, heterocycloalkyl group are optionally hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 alkyl group, C 1-6 alkoxy group, -NH2, -NHC 1-6 alkyl group, -N(C 1-6 alkyl)2, oxy group, and saturated or partially saturated C 3-6 substituted with one or more groups selected from cycloalkyl groups, and C 1-6 alkyl group and C 1-6 alkoxy group are optionally further substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 substituted with one or more groups selected from cycloalkyl groups, or optionally R2 and R 2' , or R d1 and R d2 may form a 5- to 6-membered aryl group, or heteroaryl group, 3- to 8-membered saturated or partially saturated cycloalkyl group, 3- to 8-membered saturated or partially saturated heterocyclyl group together with the carbon to which they are attached, among which, the above cycloalkyl group, heterocycloalkyl group are optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, Each R4 is the same or different, and is optionally independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH, or C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 cyclic hydrocarbon group, C 3-10 heterocyclic hydrocarbon group, C 3-10 cyclic hydrocarbon group, or C 3-10 substituted with a heterocyclic hydrocarbon group of C 1-10 alkyl group, and C 3-10 ​​C substituted with a heterocyclic hydrocarbon group 1-10 selected from a heteroalkyl group, wherein the above C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, or C 1-10 alkoxy group is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 a saturated or partially saturated cycloalkyl group, or a heterosilyl group each R5 and R6 are the same or different and are independently of each other hydrogen, deuterium, halogen, CN, OH, SH, NR d8 R d9 , NH2, -COOH, or C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 cycloalkyl group, C 3-10 heterocycloalkyl group, C 3-10 C substituted with a cyclic hydrocarbon group 1-10 alkyl group, or C 3-10 cycloalkyl group, C 3-10 C substituted with a heterocycloalkyl group 3-10 selected from a heterosilyl group, wherein the above C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 cycloalkyl group, C 3-10 heterocycloalkyl group, C 3-10 C substituted with a cycloalkyl group 1-10 alkyl group, or C 3-10 cycloalkyl group, C 3-10 C substituted with a heterocycloalkyl group 3-10 heterocycloalkyl group is optionally hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10The aryl group is substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, or any two adjacent R5 or R6 groups, together with the carbon attached to them, form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group may optionally consist of hydrogen, deuterium, halogen, -CN, -OH, CF3, or C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, oxy group, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R d4 , R d8 and R d9 These are homologous or different, and can be arbitrarily and independently of each other: hydrogen, deuterium, NH2, C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10an alkylacyl group, C 1-10 an alkylsulfonyl group, a C2-10 heteroalkyl group, C 3-10 a cycloalkyl group, C 3-10 a heterocycloalkyl group, C 3-10 a C alkyl group substituted with a cyclic hydrocarbon group 1-10 or a C alkyl group, or C 3-10 a cycloalkyl group, C 3-10 a C alkyl group substituted with a heterocycloalkyl group 3-10 The heterocyclyl group is optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 a saturated or partially saturated cycloalkyl group, or a heterocyclyl group, wherein the hetero represents an heteroatom and its isotope optionally independently selected from O, N, S, P, wherein the halogen is optionally independently selected from F, Cl, Br, I, and their isotopes, m is an integer optionally selected from 1, 2, 3, and 4, n is an integer optionally selected from 0, 1, 2, 3, 4, and 5, q is an integer optionally selected from 0, 1, 2, 3, 4, and 5, t is an integer optionally selected from 0, 1, 2, 3, and 4.

[0036] In one embodiment of the present invention, the above compound, or a pharmaceutically acceptable salt, isotope-substituted form, or isomer thereof, has the structure of formula (IE),

[0037]

Chemical formula

[0038] Among them,

[0039]

Chemical formula

[0040] optionally represents a single bond or a double bond, X and X' are independently -C(R d1 )(R d2 )-,-N(R d4 )-,-N(R d7 -C(R d1 )(R d2 )-,-N(R d4 )-, -O-, -S-, -S(=O)-, or -S(=O)2-, L is independently -C(R d1 )(R d2 )-,-OC(R d1 )(R d2 )-,-C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-,-N(R d4 )-, -C(=NR d5 )-,-S(=O)2N(R d6 )-,-N(R d7 -OC(R d1 )(R d2 )-,-C(R d1 )(R d2 )O-, -O-, -S-, or -N(R d4 )- and, X1, X3, X8 and X 13 These are independently selected from -CR5- or -N-. R is independently hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkoxy group, -NR d8 R d9 , selected from 6-10 membered aryl groups, 5-8 membered heteroaryl groups, 3-8 membered saturated or partially saturated cycloalkyl groups, and 3-8 membered saturated or partially saturated heterocyclyl groups, of which R is represented by C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10The alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group, and 3-8 membered saturated or partially saturated heterocyclyl group are optionally substituted with one or more substituents, the substituents being optionally hydrogen, deuterium, halogen, alkyl group, haloalkyl group, alkoxy group, alkylamino group, O=, CN, OH, -NR d8 R d9 , C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 A saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group are selected, and of these, the aryl group, heteroaryl group, saturated or partially saturated cycloalkyl group, and saturated or partially saturated heterocyclyl group are optionally substituted with one or more substituents, and the substituents may optionally be hydrogen, deuterium, halogen, alkyl group, haloalkyl group, cyano group, cyanoethyl group, O=, OH, C 1-3 Alkyl alkyl group, C 1-3 Selected from an alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, among which the above C 1-3 Alkyl alkyl group, C 1-3 The alkoxy group, saturated or partially saturated cycloalkyl group, or saturated or partially saturated heterocyclyl group is optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl group, cyano group, OCH3, and OH. Each R1 is homologous or homologous and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group substituted with an alkyl group, or selected from carboxyl group substituted derivatives, or any two adjacent R1s, together with the carbon attached thereto, form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the hydrogen in the aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group can optionally be hydrogen, deuterium, halogen, -CN, -OH, CF3, or C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, =O, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R4 is homologous or homologous and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon group, C 3-10 Cyclic hydrocarbon group, or C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Alkyl alkyl groups, and C 3-10 Cyclic hydrocarbon group, C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Selected from heteroalkyl groups, of which the above C 1-10 Alkyl alkyl group, C2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more groups selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, Each of R5 and R6 is homologous or homologous, and independently of each other are hydrogen, deuterium, halogen, CN, OH, SH, and NR. d8 R d9 Selected from NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with a cycloalkyl group 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Heterocycloalkyl groups can optionally contain hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10The aryl group is substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, or any two adjacent R5 or R6 groups, together with the carbon attached to them, form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group may optionally consist of hydrogen, deuterium, halogen, -CN, -OH, CF3, or C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, oxy group, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R d1 , R d2 , R d4 , R d8 and R d These are homologous or different, and can be arbitrarily and independently of each other: hydrogen, deuterium, NH2, C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkylsulfonyl group, C2-10 heteroalkyl group, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 The heterocyclyl group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, The above heteroatoms represent heteroatoms and their isotopes, arbitrarily and independently selected from O, N, S, and P. The above halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. t is an integer arbitrarily chosen from 0, 1, 2, 3, and 4.

[0041] In one embodiment of the present invention, the above compound, or a pharmaceutically acceptable salt thereof, an isotope-substituted compound, or an isomer thereof, has the structure of formula (IF-1) or (IF-2),

[0042] [ka]

[0043] Eventually,

[0044] [ka]

[0045] This can represent a single bond or a double bond, X and X' are independently -C(R d1 )(R d2 )-,-N(R d4 )-, -O-, -S-, -S(=O)-, or -S(=O)2- are selected, L is independently -OC(R d1 )(R d2 )-,-C(R d1 )(R d2 )O-, -O-, -S-, or -N(R d4 )- Selected from, X1 and X8 are independently selected from -CR5- or -N-. R is independently hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkoxy group, -NR d8 R d9 , selected from 6-10 membered aryl groups, 5-8 membered heteroaryl groups, 3-8 membered saturated or partially saturated cycloalkyl groups, and 3-8 membered saturated or partially saturated heterocyclyl groups, of which R is represented by C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 The alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group, and 3-8 membered saturated or partially saturated heterocyclyl group are optionally substituted with one or more substituents, the substituents being optionally hydrogen, deuterium, halogen, alkyl group, haloalkyl group, alkoxy group, alkylamino group, O=, CN, OH, -NR d8 R d9 , C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10A saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group are selected, and the aryl group, heteroaryl group, saturated or partially saturated cycloalkyl group, and saturated or partially saturated heterocyclyl group are further optionally substituted with one or more substituents, the substituents being optionally hydrogen, deuterium, halogen, alkyl group, haloalkyl group, cyano group, cyanoethyl group, O=, OH, C 1-3 Alkyl alkyl group, C 1-3 Selected from an alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, among which the above C 1-3 Alkyl alkyl group, C 1-3 The alkoxy group, saturated or partially saturated cycloalkyl group, or saturated or partially saturated heterocyclyl group is optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl group, cyano group, OCH3, and OH. Each R1 is homologous or homologous and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group substituted with an alkyl group, or a carboxyl group-substituted product, is selected from these. Each R4 is homologous or homologous and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon group, C 3-10 Cyclic hydrocarbon group, or C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Alkyl alkyl groups, and C 3-10 Cyclic hydrocarbon group, C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Selected from heteroalkyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more groups selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, Each of R5 and R6 is homologous or homologous, and independently of each other are hydrogen, deuterium, halogen, CN, OH, SH, and NR. d8 R d9 Selected from NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10Heterocycloalkyl groups, C 3-10 C substituted with a cycloalkyl group 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Heterocycloalkyl groups can optionally contain hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 The aryl group is substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, or any two adjacent R5 or R6 groups, together with the carbon attached to them, form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group may optionally consist of hydrogen, deuterium, halogen, -CN, -OH, CF3, or C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, oxy group, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R d1 , R d2 , R d4 , R d8 and R d These are homologous or different, and can be arbitrarily and independently of each other: hydrogen, deuterium, NH2, C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkylsulfonyl group, C2-10 heteroalkyl group, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 The heterocyclyl group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, The above heteroatoms represent heteroatoms and their isotopes, arbitrarily and independently selected from O, N, S, and P. The above halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. t is an integer arbitrarily chosen from 0, 1, 2, 3, and 4.

[0046] In one embodiment of the present invention, the above compound, or a pharmaceutically acceptable salt thereof, an isotope-substituted compound, or an isomer thereof, has the structure of formula (IG),

[0047] [ka]

[0048] Eventually, X and X' are independently -C(R d1 )(R d2 )-,-N(R d4 )-, -O-, -S-, -S(=O)-, or -S(=O)2- are selected, L is independently -OC(R d1 )(R d2 )-,-C(R d1 )(R d2 )O-, -O-, -S-, or -N(R d4 )- Selected from, X1 and X8 are independently selected from -CR5- or -N-. R is independently hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkoxy group, -NR d8 R d9 , selected from 6-10 membered aryl groups, 5-8 membered heteroaryl groups, 3-8 membered saturated or partially saturated cycloalkyl groups, and 3-8 membered saturated or partially saturated heterocyclyl groups, of which R is represented by C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 The alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group, and 3-8 membered saturated or partially saturated heterocyclyl group are optionally substituted with one or more substituents, the substituents being optionally hydrogen, deuterium, halogen, alkyl group, haloalkyl group, alkoxy group, alkylamino group, O=, CN, OH, -NR d8 R d9 , C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10A saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group are selected, and of these, the aryl group, heteroaryl group, saturated or partially saturated cycloalkyl group, and saturated or partially saturated heterocyclyl group are optionally substituted with one or more substituents, and the substituents may optionally be hydrogen, deuterium, halogen, alkyl group, haloalkyl group, cyano group, cyanoethyl group, O=, OH, C 1-3 Alkyl alkyl group, C 1-3 Selected from an alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, among which the above C 1-3 Alkyl alkyl group, C 1-3 The alkoxy group, saturated or partially saturated cycloalkyl group, or saturated or partially saturated heterocyclyl group is optionally substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl group, cyano group, OCH3, and OH. Each R1 is homologous or homologous and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group substituted with an alkyl group, or a carboxyl group-substituted product, is selected from these. Each R4 is homologous or homologous and can be arbitrarily and independently selected from hydrogen, deuterium, halogen, CN, OH, SH, and NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon group, C 3-10 Cyclic hydrocarbon group, or C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Alkyl alkyl groups, and C 3-10 Cyclic hydrocarbon group, C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Selected from heteroalkyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more groups selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, Each of R5 and R6 is homologous or homologous, and independently of each other are hydrogen, deuterium, halogen, CN, OH, SH, and NR. d8 R d9 Selected from NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10Heterocycloalkyl groups, C 3-10 C substituted with a cycloalkyl group 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Heterocycloalkyl groups can optionally contain hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 The aryl group is substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, or any two adjacent R5 or R6 groups, together with the carbon attached to them, form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group may optionally consist of hydrogen, deuterium, halogen, -CN, -OH, CF3, or C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, oxy group, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R d1 , R d2 , R d4 , R d8 and R d These are homologous or different, and can be arbitrarily and independently of each other: hydrogen, deuterium, NH2, C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkylsulfonyl group, C2-10 heteroalkyl group, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 The heterocyclyl group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, The above heteroatoms represent heteroatoms and their isotopes, arbitrarily and independently selected from O, N, S, and P. The above halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. t is an integer arbitrarily chosen from 0, 1, 2, 3, and 4.

[0049] According to embodiments of the present invention, A is either unsubstituted or substituted C 6-20 Selected from aryl groups and 5-20 member heteroaryl groups, B is an unsubstituted or substituted 3-20 member heterocyclyl group, a 6-18 member spirocycle group, or a crosslinking ring group, C 6-20Selected from aryl groups, X and X' are homologous or different, and independently of each other -C(R d1 )(R d2 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -S(=O)-, or -S(=O)2- are selected, L is -C(R d1 )(R d2 )-, OC(R d1 )(R d2 )-,-C(R d1 )(R d2 )O-, -O-, -S-, -NH-, -C(=O)O-, -OC(=O)-, -C(=O)-, -S(=O)-, or -S(=O)2- are selected from R d1 , R d2 They are homologous or different, and can be any and all independently of each other: hydrogen, deuterium, halogen, C 1-10 Alkyl alkyl group, C 1-10 Selected from alkoxy groups, X1, X2, X3, X4, X5, X8, and X9 are homologous or different, independently selected from -CR5- or -N-, and each R5 is homologous or different, independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl alkyl group, C 1-10 Selected from alkoxy groups, R0 can be unsubstituted, or optionally contain one, two, or more Rs. 01 C replaced by 1-10 Selected from alkyl groups, each R 01 R are homologous or different, and are independently unsubstituted for each other, or optionally one, two, or more R. 02 C replaced by 3-20 Selected from cycloalkyl groups, 3-20 membered heterocyclyl groups, and 5-20 membered heteroaryl groups, each R 02 These are homologous or different, and are independently of each other: halogens, deuterium, CN, oxo (=O), and C. 1-10 Alkyl, halo C 1-10 Alkyl, CN-C 1-10 Alkyl alkyl group, C 3-6 Cycloalkyl-C 1-10 Selected from alkyl groups, Each R1 is homologous or homologous, and independently of each other, it can be hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, COOH, unsubstituted, or optionally one, two, or more Rs. 11 -C replaced by 1-10 alkyl-COOH, -C 2-10 Selected from alkenyl-COOH, each R 11 They are homologous or different, and independently of each other, H, deuterium, halogens, and C 1-10 Alkyl alkyl group, C 1-10 Selected from alkoxy groups, R2, R 2' These are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, oxo (=O), and C. 1-10 Alkyl alkyl group, C 1-10 Selected from alkyloxy groups, Each R4 is homologous or different, and can be hydrogen, deuterium, halogen, oxo (=O), CN, OH, SH, and NH2, -COOH, C, either independently or arbitrarily. 1-10 Alkyl alkyl group, C 1-10 Selected from alkoxy groups, Each R6 is homologous or different, and independently of each other, they are hydrogen, deuterium, halogen, CN, OH, SH, NH2, -COOH, and C. 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 2-10 Selected from alkynyl groups and 5-14 member heteroaryl groups, R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 These are homologous or different, and are arbitrarily and independently of each other: hydrogen, deuterium, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl alkyl group, C 1-10 Selected from alkoxy groups, m is an integer arbitrarily chosen from 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5.

[0050] According to embodiments of the present invention, A is either unsubstituted or substituted C 6-14 Selected from aryl groups and 5-14 member heteroaryl groups, B is an unsubstituted or substituted 3-14 member heterocyclyl group, a 6-18 member spirocyclic group, or a crosslinking ring group, C 6-14 Selected from aryl groups, X and X' are homologous or different, and independently of each other -C(R d1 )(R d2 )-, -O-, -S- are selected, L is -C(R d1 )(R d2 )-,-OC(R d1 )(R d2 )-,-C(R d1 )(R d2 ) Selected from O-, -O-, -S-, -NH-, R d1 , R d2 They are homologous or different, and can be arbitrarily and independently of each other: hydrogen, deuterium, and C 1-10 Selected from alkyl groups, X1, X2, X3, X4, X5, X8, and X9 are homologous or homologous, independently selected from -CR5- or -N-, and each R5 is homologous or homologous, independently selected from hydrogen, deuterium, halogen, or C 1-10 Alkyl alkyl group, C 1-10 Selected from alkoxy groups, R0 can be unsubstituted, or optionally contain one, two, or more Rs. 01 C replaced by 1-10 Selected from alkyl groups, each R 01 R are homologous or different, and are independently unsubstituted for each other, or optionally one, two, or more R. 02 C replaced by 3-14 Selected from cycloalkyl groups, 3-14 member heterocyclyl groups, and 5-14 member heteroaryl groups, each R 02 These are homologous or different, and are independent of each other as CN, deuterium, oxo (=O), and C. 1-10 Alkyl, CN-C 1-10 Alkyl alkyl group, C 3-6 Cycloalkyl-C 1-10Selected from alkyl groups, Each R1 is homologous or homologous, and independently of each other, it can be a halogen, COOH, unsubstituted, or optionally one, two, or more Rs. 11 -C replaced by 1-10 alkyl-COOH, -C 2-10 Selected from alkenyl-COOH, each R 11 They are homologous or different, and independently of each other, H, deuterium, halogens, and C 1-10 Alkyl alkyl group, C 1-10 Selected from alkoxy groups, R2, R 2' These are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, oxo (=O), and C. 1-10 Alkyl alkyl group, C 1-10 Selected from alkoxy groups, Each R4 is homologous or different, and can be hydrogen, deuterium, halogen, oxo (=O), CN, OH, SH, and NH2, -COOH, C, either independently or arbitrarily. 1-10 Alkyl alkyl group, C 1-10 Selected from alkoxy groups, Each R6 is homologous or different, and independently of each other, they are hydrogen, deuterium, halogen, CN, and C. 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 2-10 Selected from alkynyl groups and 5-14 member heteroaryl groups, m is an integer arbitrarily chosen from 1, 2, and 3. n is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. q is an integer arbitrarily chosen from 0, 1, 2, 3, and 4.

[0051] According to embodiments of the present invention, A is selected from a phenyl group or a pyridyl group. B is a piperidine group, an azetidinyl group, a phenyl group, a (1R,5S)-3-azabicyclo[3.2.1]octyl group, a spiro ring group, or a crosslinking ring group, wherein the spiro ring or crosslinking ring contains one or more heteroatoms, and the heteroatoms are arbitrarily and independently selected from N, O, or S. X and X' are homologous or different, and are independently selected from CH2, O, or S. L may be selected from O, S, NH, CH2, OCH2, and CH2O. X1, X2, X3, X4, X5, X8, and X9 are homologous or different, and are independently selected from CH, CF, or N. R0 is either unsubstituted or substituted with an imidazole group, pyrazolyl group, pyrrolyl group, azetidinyl group, oxetane group, pyrrolidinyl group, or cyclopropyl group. 1-3 Selected from alkyl groups, the above imidazole group, pyrazolyl group, pyrrolyl group, azetidinyl group, oxetane group, pyrrolidinyl group, or cyclopropyl group may be unsubstituted, oxo (=O), or C 1-3 Alkyl, CN-C 1-3 Alkyl alkyl group, C 3-6 Cycloalkyl-C 1-3 It may be replaced with an alkyl group. Each R1 is homologous or different, and is independent of COOH, F, and -C. 1-3 Alkyl-COOH, -C 2-3 Selected from alkenyl-COOH, R2, R 2' These are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, oxo (=O), and C. 1-3 Selected from alkyl groups, Each R4 is homologous or different, and can be hydrogen, deuterium, halogen, oxo (=O), or C, either independently or arbitrarily. 1-3 Selected from alkyl groups, Each R6 is homologous or different, and is independently selected from hydrogen, deuterium, F, Cl, Br, CN, ethynyl group, and imidazole group. m is arbitrarily selected from 1 or 2. n is arbitrarily selected from 0, 1, or 2. q can be arbitrarily selected from 0, 1, or 2.

[0052] According to embodiments of the present invention,

[0053] [ka]

[0054] The structure may be selected from the following:

[0055] [ka]

[0056] B may have the following structure:

[0057] [ka]

[0058] L may be selected from O, S, NH, CH2, OCH2, and CH2O.

[0059] [ka]

[0060] The structure may be selected from the following:

[0061] [ka]

[0062] R0 may be selected from the following structures:

[0063] [ka]

[0064] R1 is

[0065] [ka]

[0066] You can be chosen from among them. R2, R 2' All of them are H, R4 is H, F, or a methyl group, X8 is selected from CH or N, and X9 is selected from CH or N. m is selected from 1 or 2, and n is selected from 1 or 2.

[0067] In one embodiment of the present invention, the above compound, or a pharmaceutically acceptable salt thereof, or its enantiomer or isotope-substituted compound is a compound selected from the following structures:

[0068] [Table 1]

[0069] TIFF2026082907000026.tif182169

[0070] TIFF2026082907000027.tif177169

[0071] TIFF2026082907000028.tif181169

[0072] TIFF2026082907000029.tif177169

[0073] TIFF2026082907000030.tif181169

[0074] TIFF2026082907000031.tif177169

[0075] TIFF2026082907000032.tif181169

[0076] TIFF2026082907000033.tif177169

[0077] TIFF2026082907000034.tif181169

[0078] TIFF2026082907000035.tif177169

[0079] TIFF2026082907000036.tif181169

[0080] TIFF2026082907000037.tif178169

[0081] TIFF2026082907000038.tif181169

[0082] TIFF2026082907000039.tif177169

[0083] TIFF2026082907000040.tif181169

[0084] TIFF2026082907000041.tif227169

[0085] TIFF2026082907000042.tif222169

[0086] TIFF2026082907000043.tif231169

[0087] TIFF2026082907000044.tif226169

[0088] TIFF2026082907000045.tif222169

[0089] TIFF2026082907000046.tif231169

[0090] TIFF2026082907000047.tif226169

[0091] TIFF2026082907000048.tif222169

[0092] TIFF2026082907000049.tif231169

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[0128]

Table 2

[0129] TIFF2026082907000086.tif177169 <�

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[0131] TIFF2026082907000088.tif213169

[0132] TIFF2026082907000089.tif200169[

[25] ]

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[0143] TIFF2026082907000100.tif225169

[0144] TIFF2026082907000101.tif211169

[0145] TIFF2026082907000102.tif138169

[0146]

Table 3

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[0150] TIFF2026082907000107.tif222169

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[0153] TIFF2026082907000110.tif176169

[0154] TIFF2026082907000111.tif191169

[0155] TIFF2026082907000112.tif215169

[0156] TIFF2026082907000113.tif219169

[0157] TIFF2026082907000114.tif179169

[0158] TIFF2026082907000115.tif214169

[0159] TIFF2026082907000116.tif217169

[0160] TIFF2026082907000117.tif217169

[0161] TIFF2026082907000118.tif220169

[0162] TIFF2026082907000119.tif215169

[0163] TIFF2026082907000120.tif213169

[0164] TIFF2026082907000121.tif184169

[0165] TIFF2026082907000122.tif224169

[0166] TIFF2026082907000123.tif194169

[0167] TIFF2026082907000124.tif202169

[0168] TIFF2026082907000125.tif188169

[0169] TIFF2026082907000126.tif117169

[0170] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (I), and at least one of its pharmaceutically acceptable salts, solvates, enantiomers, and isotopic substitutions.

[0171] According to embodiments of the present invention, the pharmaceutical composition is formulated to be administered by a route selected from the group consisting of oral, injection, rectal, nasal, pulmonary, topical, oral and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural.

[0172] According to embodiments of the present invention, the pharmaceutical composition is preferably administered orally. The above oral dosage form is not particularly limited, and any oral dosage form known in the art may be used, preferably including oral dosage forms known in the art such as tablets, capsules, suspensions, or oral solutions. When used as an oral dosage form, the dosage reference used is, for example, 500 to 1500 mg / day, a preferred dose of 700 to 1200 mg / day, preferably 800 to 1000 mg / day, and most preferably 1000 mg / day. The administration time of the pharmaceutical composition according to the present invention is determined according to the severity of the disease, preferably at least one month, for example, one, two, three, four, five, or six months, and the longest period may be lifelong administration as required by the disease.

[0173] According to embodiments of the present invention, the pharmaceutical composition contains, but is not limited to, at least one selected from fillers, disintegrants, adhesives, lubricants, surfactants, flavorings, wetting agents, pH adjusters, solubilizers, or solubilizers and osmotic pressure adjusters, and may further contain other pharmaceutically acceptable adjuvants. Those skilled in the art can easily determine how to select the corresponding adjuvants and their corresponding doses according to the needs of a specific dosage form.

[0174] According to embodiments of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0175] Another object of the present invention is to provide applications of the above compounds in the manufacture of drugs for preventing and / or treating diseases related to the GLP1 / GLP1R signaling pathway. Diseases related to the GLP1 / GLP1R signaling pathway include overweight, obesity, diabetes (including T1D and / or T2DM, prediabetes), idiopathic T1D (type 1B), adult latent autoimmune diabetes (LADA), early-onset T2DM (EOD), juvenile atypical diabetes (YOAD), juvenile-onset adult-onset diabetes (MODY), diabetes associated with malnutrition, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, renal diseases (e.g., acute kidney disease, renal tubular dysfunction), (Pro-inflammatory changes in proximal tubules), diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, obesity (including hypothalamic obesity and monogenic obesity) and associated comorbidities (e.g., osteoarthritis and urinary incontinence), eating disorders (including binge eating syndromes such as Prader-Willi and Bardet-Biedl syndrome, bulimia nervosa, and symptomatic obesity), weight gain due to the use of other drugs (e.g., use of steroids and antipsychotics), hyperglycemia, dyslipidemia (hyperlipidemia, hypertriglyceridemia, increased total cholesterol, hypertrichosis) High-density lipoprotein cholesterol, low-density lipoprotein cholesterol, hyperinsulinemia, NAFLD (including related diseases such as fatty degeneration, NASH, fibrosis, cirrhosis, and hepatocellular carcinoma), cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction (e.g., necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipids, metabolic Acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, impaired fasting blood glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, hyperapolipoprotein B-lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease,This includes, but is not limited to, the prevention or treatment of conditions such as colitis, irritable bowel syndrome, polycystic ovary syndrome, and addiction (e.g., alcoholism and / or drug abuse).

[0176] The present invention further provides the use of the compound represented by formula (I) above, its pharmaceutically acceptable salts, solvates, enantiomers and isotopic substitutions, and the pharmaceutical compositions thereof in the prevention and / or treatment of diseases related to the GLP1 / GLP1R signaling pathway. The diseases related to the GLP1 / GLP1R signaling pathway are as defined above.

[0177] The present invention further provides a method for preventing and / or treating diseases related to the GLP1 / GLP1R signaling pathway, comprising administering to a patient a prophylactic or therapeutically effective amount of at least one of the compounds represented by formula (I), pharmaceutically acceptable salts, solvates, enantiomers, and isotopic substitutions thereof, or administering to a patient a prophylactic or therapeutically effective amount of the above pharmaceutical composition. The diseases related to the GLP1 / GLP1R signaling pathway are as defined above.

[0178] In some embodiments, the patient is a mammal, preferably a human.

[0179] [Brief explanation of the drawing] [Figure 1] This is a comparative curve showing the effects of the compound of the present invention and conventional drugs on IPGTT blood glucose in GLP-1R humanized mice.

[0180] [Figure 2] This figure compares the insulin secretion-promoting effects of the compound of the present invention and conventional drugs on IPGTT in GLP-1R humanized mice.

[0181] [Figure 3] Comparison curve of the effects of the compound of the present invention and conventional drugs on blood glucose in cynomolgus monkeys during IVGTT.

[0182] Definition and Description C 1-10This includes C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10 Selected from C 2-10 This includes C2, C3, C4, C5, C6, C7, C8, C9 and C 10 Selected from C 3-10 This includes C3, C4, C5, C6, C7, C8, C9 and C 10 Selected from, As used herein, the term “alkyl group” refers to a linear or branched monovalent hydrocarbon group. Non-limiting examples include methyl, ethyl, propyl, butyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, and hexyl groups.

[0183] As used herein, the term "alkylene group" refers to the group of the formula -(CH2) n - Refers to a straight-chain or branched-chain divalent hydrocarbon group. Non-limiting examples include ethylene and propylene.

[0184] As used herein, the term “one or more” means one or more, for example, one, two, three, four, five, or more.

[0185] The terms "carbocyclic (group)" or "cycloalkyl group" refer to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon groups that may contain 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12), and more preferably 3 to 6 carbon atoms. The carbocyclic group may be monocyclic or polycyclic, may be a saturated cycloalkyl group, or may optionally contain one, two, or more double and / or triple bonds on the ring, thereby forming a so-called cycloalkenyl group or cycloalkynyl group. If the carbocyclic group has multiple rings, these rings may form spirocyclic, fused, and bridging ring structures. For example, non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and cyclooctatetraenyl groups, while non-limiting examples of polycyclic carbocycles include decahydronaphthyl or isobornyl groups.

[0186] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms or groups of atoms selected from N, O, NH, S, S(O), or S(O)2, but not containing -OO-, -OS-, or -SS- ring portions, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms (e.g., 1, 2, 3, and 4), and more preferably, 3 to 6 ring atoms (e.g., 3, 4, 5, and 6). The heterocyclyl group may be linked to the rest of the molecule via any one of the carbon atoms, or a nitrogen atom (if present), or an oxygen or sulfur atom (especially if an onium salt is formed). The heterocyclyl group may contain condensed or bridging rings and / or spirocyclic rings. Non-limiting examples of monocyclic heterocyclyl groups include azetidinyl group, oxetane group, pyrrolidinyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydrothiophenyl group, dihydroimidazole group, dihydrofuranyl group, dihydropyrazolyl group, dihydropyrrolyl group, dioxolyl group, tetrahydropyranyl group, pyrrolidyl group, piperidine group, piperazine group, morpholinyl group, thiomorpholinyl group, dithianyl group, trithianyl group, homopiperazine group, diazepanyl group, etc., with piperidine group and pyrrolidinyl group being preferred. Polycyclic heterocyclyl groups include heterocyclyl groups of spiro rings, fused rings, and crosslinking rings, and may also be benzo-condensed heterocyclyl groups such as dihydroisoquinolinyl group. The heterocyclyl group described above may be bicyclic, and non-limiting examples include hexahydrocyclopenta[c]pyrrole-2(1H)-yl and hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl. The heterocyclyl group may be partially unsaturated, that is, it may contain one or more double bonds, and non-limiting examples include a dihydrofuranyl group, a dihydropyranyl group, a 2,5-dihydro-1H-pyrrolyl group, a 4H-[1,3,4]thiadiazine group, a 4,5-dihydroxazolyl group, or a 4H-[1,4]thiadinyl group.

[0187] The heterocyclyl group may be optionally substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylate groups.

[0188] In this specification, the term “heteroaryl group / heteroaromatic ring” refers to a heteroaromatic system comprising 1 to 4 heteroatoms and 5 to 20 ring atoms, of which the heteroatoms are selected from oxygen, sulfur, nitrogen, and phosphorus. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), and more preferably 5-membered or 6-membered. Non-limiting examples of heteroaryl groups include thienyl, furan, pyrrolyl, oxazolyl, thiazolyl, imidazole, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and their benzo derivatives such as benzofuranyl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzimidazole, benzotriazolyl, indazole, indole, isoindole, or pyridyl This includes, but is not limited to, yl groups, pyridadinyl groups, pyrimidinyl groups, pyrazinyl groups, triazinyl groups, and their benzo derivatives such as quinolinyl groups, quinazolinyl groups, isoquinolinyl groups, or azosinyl groups, indolidinyl groups, purinyl groups, and their benzo derivatives, or sinnolinyl groups, phthalazinyl groups, quinazolinyl groups, quinoxalinyl groups, naphthylidinyl groups, pteridinyl groups, carbazolyl groups, acridinyl groups, phenadinyl groups, phenothiazinyl groups and / or phenoxadinyl groups.

[0189] The heteroaryl group / heteroaromatic ring may be optionally substituted or unsubstituted. If substituted, the substituents are preferably one, two or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0190] Unless otherwise specified, heterocyclyl groups, heteroaryl groups, or heteroaromatic rings include all possible isomeric forms thereof, e.g., their positional isomers. Thus, non-limiting examples for some explanation include forms in which they are substituted at one, two or more positions, such as the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions (if any), or bonded to other groups, including thienyl groups containing pyridine-2-yl, pyridylidene-2-yl, pyridine-3-yl, pyridylidene-3-yl, pyridylidene-3-yl, pyridine-4-yl and pyridylidene-4-yl, thienyl groups containing thienyl-2-yl, thienylidene-2-yl, thienylidene-3-yl and thienylidene-3-yl, or thienylidenyl groups, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, and pyrazole-5-yl.

[0191] As used herein, the term “pharmaceutically acceptable” means a compound, material, composition and / or dosage form that, within the bounds of reliable medical judgment, is free from excessive toxicity, irritation, allergic reactions or other problems or complications, is reasonable in terms of the cost-benefit ratio, and is suitable for use in contact with human and animal tissues.

[0192] The term "pharmaceutically acceptable salt" refers to a salt of a compound according to the present invention, which is prepared from a compound found in the present invention having a specific substituent and a relatively non-toxic acid or base. If a compound according to the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of alkali in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia, or magnesium salts, or similar salts. If a compound according to the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, for example, inorganic salts containing hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, and phosphorous acid, and organic salts containing acids such as acetic acid, propionic acid, isobutanoic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid, and further include salts of amino acids (e.g., arginine), and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)). Some specific compounds according to the present invention can be converted to either a base or an acid addition salt by containing basic and acidic functional groups.

[0193] Preferably, the salt is contacted with a base or acid using conventional methods, and the parent compound is further isolated, thereby regenerating the neutral form of the compound. The difference between the parent form of the compound and its various salt forms lies in several physical properties, such as differences in solubility in polar solvents.

[0194] As used herein, "pharmaceutically acceptable salts" belong to derivatives of the compounds of the present invention, in which the parent compound is modified by salt formation with an acid or a base. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic acids or organic acid salts of bases such as amines, alkali metals of acidic groups such as carboxylic acids, or organic salts. pharmaceutically acceptable salts include conventional non-toxic salts such as sodium salts, potassium salts, amine salts, and quaternary ammonium salts of the parent compound. Conventional non-toxic salts include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate group, carbonic acid, citric acid, EDTA, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl group, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, and sulfate. This includes, but is not limited to, inorganic and organic acids selected from oxalic acid, embonic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturone, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, tartaric acid, and p-toluenesulfonic acid, as well as salts derived from inorganic and organic bases such as Na, potassium, magnesium, calcium, or amines, diethylamine, triethylamine, and ethanolamine.

[0195] The pharmaceutically acceptable salts according to the present invention can be synthesized by conventional chemical methods from parent compounds containing an acid group or a base. Generally, such salts are produced by reacting these compounds in the form of a free acid or base with a stoichiometrically appropriate base or acid in water, an organic solvent, or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0196] In addition to the salt form, the compounds provided by the present invention also exist in prodrug form. The prodrugs of the compounds described herein are readily converted to the compounds of the present invention by chemical reaction under physiological conditions. The prodrugs may be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0197] Some of the compounds of the present invention may exist in a non-solvated form or a solvated form, including a hydrated form. Generally, the solvated form corresponds to the non-solvated form, and both are included within the scope of the present invention. Some of the compounds of the present invention may exist in a polycrystalline form or an amorphous form.

[0198] In this specification, the term "solvate" refers to an aggregate formed by one or more solvent molecules and the compounds of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. Accordingly, the term "hydrate" refers to an aggregate formed by a solvent molecule that is water.

[0199] Some of the compounds of the present invention may have a chiral carbon atom (optical center) or a double bond. Exosomes, diastereoisomers, geometric isomers, and individual isomers are all included within the scope of the present invention.

[0200] In this specification, schematic diagrams of racemic, ambiscalemic and scalemic, or enantiopuric compounds are shown in Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise specified, the absolute configuration of stereocenters is indicated by wedge-shaped and dashed bonds. Where compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, these include E and Z geometric isomers unless otherwise specified. Similarly, all tautomers are included within the scope of the present invention.

[0201] The compounds according to the present invention may exist in specific geometric or stereoisomer forms. The present invention intends all compounds including cis-trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, and (L)-isomers, as well as racemic mixtures and other mixtures thereof, for example, all mixtures such as enantiomers or diastereomer-enriched mixtures, fall within the scope of the present invention. Substituents such as alkyl groups may have other chiral carbon atoms. All of these isomers and mixtures thereof are included within the scope of the present invention.

[0202] Optically active (R)- and (S)- isomers and D- and L isomers can be produced by chiral synthesis, chiral reagents, or other conventional techniques. To obtain one enantiomer of a certain compound according to the present invention, it can be produced by asymmetric synthesis or by induction with a chiral auxiliary agent, and the mixture of the obtained diastereomers is separated and the decomposition of the groups is assisted to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a salt of the diastereomer is formed with a suitable optically active acid or base, and then the diastereomer is separated by fractional crystallization or chromatography known in the art, and then recovered to obtain the pure enantiomer. The separation of enantiomers and diastereomers is generally completed by chromatography, which uses a chiral stationary phase and is optionally combined with a chemical induction method (e.g., producing a carbamate from an amide).

[0203] The compounds according to the present invention may contain non-natural atomic isotopes in one or more atoms constituting the compound. For example, tritium ( 3 H), Yo-125( 125 I), or C-14( 14 The compound may be labeled with a radioactive isotope such as C). Transformations involving all isotopes of the compound according to the present invention, whether radioactive or not, are all included within the scope of the present invention.

[0204] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and is free from toxicity and adverse effects to the host or patient. Typical carriers include water, oils, vegetables and minerals, creams, detergent substrates, ointment substrates, etc. These substrates include suspending agents, tackifiers, transdermal accelerators, etc. These formulations are well known to those skilled in the art in the fields of cosmetics or topical medicine. Further information regarding carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0205] If any of the variables (e.g., R) appear one or more times in the composition or structure of a compound, the definitions for each case are independent. Therefore, for example, if a group is substituted with 0 to 2 R molecules, the group can be optionally substituted with at most 2 R molecules, and each of the R molecules has an independent choice. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce stable compounds.

[0206] If the bond of one substituent can bridge to two atoms on a ring, then such substituent can bond to any atom on that ring. If it is not specified which atom a listed substituent will bond to a compound included in the chemical structure but not specifically mentioned, then such substituent can bond to any atom on that ring. Combinations of substituents and / or their variants are permitted only if such combinations produce stable compounds.

[0207] The term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0208] The present invention will be further illustrated below with reference to examples. The examples shown below are for illustrative purposes only and do not limit the scope of the present invention. The compounds of the present invention can be produced by many methods known in the field of organic synthesis. The examples of the present invention can be synthesized by the methods described below, and by synthetic methods known in the field of organic synthesis chemistry, or by improved methods based thereon. Preferred methods include, but are not limited to, the methods described below.

[0209] Unless otherwise specified, all solvents used in this invention are commercially available and therefore do not require further purification before use. Reactions are typically carried out in an inert atmosphere of nitrogen gas using anhydrous solvents. Nuclear magnetic resonance spectra are measured using a Bruker-Avance-400 (400 MHz) spectrometer, and chemical shifts are reported in the form of δ (ppm). Mass spectrometry is performed using an Agilent 1200 series (plus 6110 / and 1956A) LC / MS, or a Shimadzu MS (DAD: SPD-M20A(LC)) and Shimadzu Micromass 2020 detector. The mass spectrometer is equipped with an electrospray ion source (ESI) operating in positive and negative modes.

[0210] The abbreviations used are as follows: aq is aqueous solution, TLC is thin-layer chromatography, RT is room temperature, MeOH is methanol, EtOH is ethanol, Â is ethyl acetate, THF is tetrahydrofuran, equivalent is eq, CDI is carbonyldiimidazole, DCM is dichloromethane, PE is petroleum ether, DIAD is diisopropyl azodicarboxylic acid, DMF is N,N-dimethylformamide, DMSO is dimethyl sulfoxide, CBz is benzyloxycarbonyl group, and BOC is ter t-butylcarbonyl group, HOAc is acetic acid, Ms is a methylsulfonyl group, NMP is N-methylpyrrolidone, DMAP is 4-(dimethylamino)pyridine, Boc2O is di-tert-butyl dicarbonate, TFA is trifluoroacetic acid, DIPEA is diisopropylethylamine, SOCl2 is thionyl chloride, CS2 is carbon disulfide, TsOH is 4-toluenesulfonic acid, MTBE is tert-butyl methyl ether, FA is formic acid, ACN is acetonitrile, and i-PrOH is 2-propanol.

[0211] Compounds may be named manually, using ChemDraw®, or, if commercially purchased, using the supplier's catalog name. Typically, TLC or LC-MS is used to determine if the reaction is complete.

[0212] [Modes for carrying out the invention] The following examples have been provided to illustrate the present invention in more detail, but the scope of the present invention is not limited to these.

[0213] Example 1-1, Synthesis of (S,E)-3-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-yl)methyl acrylate (intermediate A-1): 1) Preparation of methyl (E)-3-(3-fluoro-4-nitrophenyl)acrylate:

[0214] [ka]

[0215] At 0°C, sodium hydride (60% w / w dispersed in mineral oil, 210 mg, 5.24 mmol) was added to a dry THF (10 mL) solution of methyl diethylphosphonate (1 g, 4.76 mmol). The mixture was stirred at 0°C for 30 min, and then 3-fluoro-4-nitrobenzaldehyde (885 mg, 5.24 mmol) was gradually added while maintaining the reaction temperature at approximately 0°C. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred for 16 hours. The mixture was cooled to 0°C, quenched with water (50 mL), and extracted with ethyl acetate (2 × 30 mL). After concentration of the organic layer under reduced pressure, the residue was obtained by silica gel column chromatography (PE / EA = 3 / 1) to obtain (E)-3-(3-fluoro-4-nitrophenyl)methyl acrylate (800 mg, 74.8% yield).

[0216] 1 H NMR(400 MHz, DMSO-d6): δ 8.18(t, J=8.2 Hz, 1 H), 8.05(d, J=12.8 Hz, 1 H), 7.80(d, J=8.6 Hz, 1 H), 7.73(d, J=16.0 Hz, 1 H), 6.93(d, J=16.0 Hz, 1 H), 3.76(s, 3 H).

[0217] 2) Synthesis of (S,E)-3-(4-nitro-3-((oxetane-2-ylmethyl)amino)phenyl)methyl acrylate:

[0218] [ka]

[0219] A mixed solution of (E)-3-(3-fluoro-4-nitrophenyl)methyl acrylate (intermediate 1) (300 mg, 1.33 mmol), (S)-oxetane-2-ylmethylamine (116 mg, 1.33 mmol), and K2CO3 (368 mg, 2.67 mmol) in DMF (5 mL) was stirred at room temperature and reacted for 16 hours. The mixture was diluted with water (50 mL) and extracted with EA (3 × 10 mL). The organic phases were combined, washed with saline solution (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by TLC (PE / EA = 1 / 1) to obtain (S,E)-3-(4-nitro-3-((oxetane-2-ylmethyl)amino)phenyl)methyl acrylate (320 mg, 82.4% yield). LC-MS m / z: 293 [M+H] + .

[0220] 3) Synthesis of (S,E)-3-(4-amino-3-((oxetane-2-ylmethyl)amino)phenyl)methyl acrylate:

[0221] [ka]

[0222] A mixture of (S,E)-3-(4-nitro-3-((oxetane-2-ylmethyl)amino)phenyl)methyl acrylate (intermediate 2) (320 mg, 1.1 mmol), Fe (173 mg), and NH4Cl (164 mg) in ethanol / water (10 / 1, 5 mL) was heated to 80°C, stirred, and reacted for 16 hours. The reaction mixture was cooled to room temperature, injected into a saturated NaHCO3 (30 mL) solution, and extracted with EA (3 × 10 mL). After combining the organic phases and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain (S,E)-3-(4-amino-3-((oxetane-2-ylmethyl)amino)phenyl)methyl acrylate (270 mg, 93.7% yield). LC-MS m / z: 263 [M+H] + .

[0223] 4) Synthesis of (S,E)-3-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-yl)methyl acrylate (intermediate A-1):

[0224] [ka]

[0225] At 0°C, chloroacetic anhydride (173 mg, 1.01 mmol) was gradually added to a dry THF (5 mL) solution of (S,E)-3-(4-amino-3-((oxetan-2-ylmethyl)amino)phenyl)methyl acrylate (intermediate 3) (240 mg, 0.916 mmol). The reaction mixture was stirred at 0°C for 30 min, then heated to 60°C and stirred, and reacted for 3 hours. After cooling to room temperature, the mixture was quenched with water (20 mL) and extracted with EA (2 × 10 mL). The organic layers were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1) to obtain (S,E)-3-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1Hbenzo[d]imidazole-6-yl)methyl acrylate (intermediate A-1) (240 mg, 81.9% yield). LC-MS m / z: 321 [M+H] + .

[0226] Examples 1-2, Synthesis of 4-(2-chloroacetamide)-3-(((1-ethyl-1H-imidazole-5-yl)methyl)amino)methyl benzoate (intermediate A-2): 1) Synthesis of methyl 3-(((1-ethyl-1H-imidazole-5-yl)methyl)amino)-4-nitrobenzoate:

[0227] [ka]

[0228] TEA (1.2 g, 12.1 mmol) was added to a mixed solution of (1-ethyl-1H-imidazole-5-yl)methylamine (240 mg, 1.21 mmol) and methyl 3-fluoro-4-nitrobenzoate (241.2 mg, 1.21 mmol) in THF (6 mL) and MeOH (4 mL). The reaction mixture was heated to 60°C and stirred over the weekend to allow the reaction to proceed. The reaction mixture was injected into saturated saline (100 mL) and extracted with EA (2 × 80 mL). The organic layer was concentrated under reduced pressure and purified by silica gel column flash chromatography (EA / PE = 3 / 1 elution) to obtain methyl 3-(((1-ethyl-1H-imidazole-5-yl)methyl)amino)-4-nitrobenzoate (320 mg, 87.0% yield). LC-MS m / z: 305 [M+H] + .

[0229] 2) Synthesis of methyl 4-amino-3-(((1-ethyl-1H-imidazole-5-yl)methyl)aminobenzoate:

[0230] [ka]

[0231] Under N2 protection, 320 mg (1.05 mmol) of methyl 3-(((1-ethyl-1H-imidazole-5-yl)methyl)amino)-4-nitrobenzoate was added to a 10 mL solution of MeOH with 50 mg of 10% moistened Pd / C. After substitution with H2, the mixture was heated to 45°C under an H2 atmosphere and stirred for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column flash chromatography (DCM / MeOH = 10 / 1 elution) yielded methyl 4-amino-3-(((1-ethyl-1H-imidazole-5-yl)methyl)amino)benzoate (270 mg, 93.8% yield). LC-MS m / z: 275 [M+H] + .

[0232] 3) Synthesis of 4-(2-chloroacetamide)-3-(((1-ethyl-1H-imidazole-5-yl)methyl)amino)methyl benzoate (intermediate A-2):

[0233] [ka]

[0234] A solution of 4-amino-3-(((1-ethyl-1H-imidazole-5-yl)methyl)amino)methyl benzoate (230.0 mg, 0.84 mmol) and 2-chloroacetic anhydride (285.4 mg, 1.68 mmol) in THF (10 mL) was stirred at room temperature and allowed to react for 16 hours. The reaction mixture was poured into saturated saline (100 mL) and extracted with DCM (2 × 80 mL). After concentrating the organic phase under reduced pressure, 4-(2-chloroacetamide)-3-(((1-ethyl-1H-imidazole-5-yl)methyl)amino)methyl benzoate (230.0 mg, 78.2% yield) was obtained. LC-MS m / z: 351 [M+H] + .

[0235] Examples 1-3, (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl (intermediate A-3): 1) Synthesis of methyl (S)-4-nitro-3-((oxetane-2-ylmethyl)amino)benzoate:

[0236] [ka]

[0237] 4.0 g, 20 mmol of methyl 3-fluoro-4-nitrobenzoate and 1.7 g, 20 mmol of (S)-oxetane-2-ylmethylamine (S) were dissolved in DMA (40 mL) and K2CO3 (5.5 g, 40 mmol) was added. The mixture was stirred at room temperature and allowed to react for 12 hours. The reaction mixture was poured into saturated saline (200 mL) and extracted with ethyl acetate (2 × 80 mL). After combining the organic layers, the mixture was washed with saturated saline (2 × 200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain methyl (S)-4-nitro-3-((oxetane-2-ylmethyl)amino)benzoate (5.2 g). LC-MS m / z: 267 [M+H] + .

[0238] 2) Synthesis of (S)-4-amino-3-((oxetane-2-ylmethyl)amino)methyl benzoate:

[0239] [ka]

[0240] Under N2 protection, 520 mg of Pd / C was added to a 50 mL methanol solution of (S)-4-nitro-3-((oxetane-2-ylmethyl)amino)methyl benzoate, and after purging with H2, the reaction mixture was stirred at room temperature under an H2 atmosphere for 12 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain (S)-4-amino-3-((oxetane-2-ylmethyl)amino)methyl benzoate (3.9 g, 82.3% yield). LC-MS m / z: 237 [M+H] + .

[0241] 3) Synthesis of (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-methyl formate (intermediate A-3):

[0242] [ka]

[0243] At 0°C, 1.5 g, 6 mmol of methyl (S)-4-amino-3-((oxetane-2-ylmethyl)amino)benzoate was added in 12 mL of THF to a solution of 2-chloroacetic anhydride (1.1 g, 6.6 mmol) in several portions. The reaction mixture was stirred at room temperature for 12 hours. After concentrating the mixture under reduced pressure, it was separated by silica gel column chromatography (EA / PE = 1 / 1) to obtain methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-formate (intermediate A-3) (1.6 g, 90% yield). LC-MS m / z: 295 [M+H] + .

[0244] Examples 1-4, Synthesis of (E)-3-(4-(2-chloroacetamide)-3-(((1-ethyl-1H-imidazole-5-yl)methyl)amino)phenyl)methyl acrylate (intermediate A-4): 1) Synthesis of (E)-3-(3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)-4-nitrophenyl)methyl acrylate:

[0245] [ka]

[0246] (E)-3-(3-fluoro-4-nitrophenyl)methyl acrylate (intermediate 1) (400 mg, 1.78 mmol) and (1-ethyl-1H-imidazole-5-yl)methylamine (354 mg, 1.78 mmol) were mixed in THF (6 mL) and MeOH (4 mL) to which TEA (1.80 g, 17.80 mmol, 10.0 eq) was added. After homogeneous stirring, the reaction mixture was heated to 60°C and stirred, and the reaction was allowed to proceed for 48 hours. The resulting mixture was poured into saline solution (50 mL) and extracted with EA (2 × 20 mL). The organic phases were combined, concentrated under reduced pressure, and then purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain (E)-3-(3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)-4-nitrophenyl)methyl acrylate (400 mg, 68.1% yield). LC-MS m / z: 331 [M+H] + .

[0247] 2) Synthesis of (E)-3-(3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)-4-aminophenyl)methyl acrylate:

[0248] [ka]

[0249] (E)-3-(3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)-4-nitrophenyl)methyl acrylate (400 mg, 1.21 mmol), Fe powder (203 mg, 3.63 mmol), and NH4Cl (192 mg, 3.62 mmol) were homogeneously mixed in EtOH / H2O (10 / 1.5 mL), heated to 80°C, stirred, and reacted for 5 hours. The reaction mixture was cooled to room temperature, injected into saturated NaHCO3 (30 mL) solution, and extracted with EA (3 × 10 mL). After combining the organic phases and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain (E)-3-(3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)-4-aminophenyl)methyl acrylate (60 mg, 16.5% yield). LC-MS m / z: 301 [M+H] + .

[0250] 3) Synthesis of (E)-3-(4-(2-chloroacetamide)-3-(((1-ethyl-1H-imidazole-5-yl)methyl)amino)phenyl)methyl acrylate (intermediate A-4):

[0251] [ka]

[0252] (E)-3-(3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)-4-aminophenyl)methyl acrylate (50 mg, 0.17 mmol) and 2-chloroacetic anhydride (58 mg, 0.34 mmol) were homogeneously mixed in THF (2 mL), and the mixture was stirred at room temperature and reacted for 16 hours. The resulting mixture was poured into saline solution (10 mL) and extracted with DCM (2 × 5 mL). The organic phase was concentrated to obtain (E)-3-(4-(2-chloroacetamide)-3-(((1-ethyl-1H-imidazole-5-yl)methyl)amino)phenyl)methyl acrylate (intermediate A-4) (50 mg, 79.8% yield). LC-MS m / z: 377 [M+H] + .

[0253] Examples 1-5, Synthesis of (S)-2-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-yl)methyl acetate (intermediate A-5): 1) Synthesis of methyl 2-(3-fluoro-4-nitrophenyl)acetate:

[0254] [ka]

[0255] 957 mg (8.04 mmol) of thionyl chloride was gradually added to a methanol (10 mL) solution in which 2-(3-fluoro-4-nitrophenyl)acetic acid (800 mg, 4.02 mmol) was dissolved at 0°C. The mixture was stirred at room temperature for 3 hours, and then the reaction mixture was quenched with water (50 mL) at 0°C and extracted with ethyl acetate (2 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain the synthesis of methyl 2-(3-fluoro-4-nitrophenyl)acetate (840 mg, yield: 98.1%).

[0256] 1 H NMR (400 MHz, DMSO-d6): δ 8.13(t, J=8.2 Hz, 1H), 7.55(dd, J=12.4, 1.6 Hz, 1H), 7.37(dd, J = 8.4, 1.0 Hz, 1H), 3.90(s, 2H), 3.65(s, 3H).

[0257] 2) Synthesis of (S)-2-(4-nitro-3-((oxetane-2-ylmethyl)amino)phenyl)methyl acetate:

[0258] [ka]

[0259] A mixed solution of 2-(3-fluoro-4-nitrophenyl)acetate methyl (1.05 g, 4.93 mmol), (S)-oxetane-2-ylmethylamine (468 mg, 5.38 mmol), and potassium carbonate (1.35 g, 9.78 mmol) in DMF (10 mL) was stirred at room temperature for 3 hours. The resulting mixture was diluted with water (100 mL) and extracted with dichloromethane (3 × 10 mL). The organic phases were combined, washed with saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain (S)-2-(4-nitro-3-((oxetane-2-ylmethyl)amino)phenyl)acetate methyl (300 mg, yield: 21.9%). LC-MS m / z: 280 [M+H] + .

[0260] 3) Synthesis of (S)-2-(4-amino-3-((oxetane-2-ylmethyl)amino)phenyl)methyl acetate:

[0261] [ka]

[0262] Under N2 protection, 10% moistened Pd / C (116 mg) was added to a methanol (10 mL) solution of (S)-2-(4-nitro-3-((oxetane-2-ylmethyl)amino)phenyl)methyl acetate (300 mg, 1.07 mmol). After substitution with H2, the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) and reacted for 16 hours. The reaction mixture was filtered, and the solid was washed with methanol (50 mL). The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain (S)-2-(4-amino-3-((oxetane-2-ylmethyl)amino)phenyl)methyl acetate (120 mg, yield: 45.0%). LC-MS m / z: 251 [M+H] + .

[0263] 4) Synthesis of (S)-2-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-yl)methyl acetate (intermediate A-5):

[0264] [ka]

[0265] At 0°C, 120 mg, 0.48 mmol of methyl (S)-2-(4-amino-3-((oxetane-2-ylmethyl)amino)phenyl)acetate was dissolved in 5 mL of anhydrous tetrahydrofuran, to which 91 mg, 0.53 mmol of 2-chloroacetic acid (anhydrous chloroacetic acid) was gradually added. The mixture was stirred at 0°C for 30 minutes, then heated to 60°C and stirred further for 3 hours. The mixture was cooled to room temperature, quenched with 20 mL of water, and extracted with ethyl acetate (2 × 10 mL). After combining the organic phases and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1) to obtain methyl (S)-2-(2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-yl)acetate (intermediate A-5) (100 mg, 67.6% yield). LC-MS m / z: 309 [M+H] + .

[0266] Examples 1-6, Synthesis of 2-(chloromethyl)-1-(1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-formate methyl (intermediate A-6): 1) Synthesis of (1-(cyanomethyl)cyclopropyl)methanesulfonate:

[0267] [ka]

[0268] Triethylamine (4.00 g, 39.25 mmol) was added to a solution of anhydrous dichloromethane (20 mL) containing 2-(1-(hydroxymethyl)cyclopropyl)acetonitrile (2.00 g, 18.00 mmol). The resulting mixture was cooled to 0°C, and MsCl (3.12 g, 27.23 mmol) was added dropwise, stirring continuously at 0°C for 1 hour. The reaction mixture was then stirred at room temperature for a further 2 hours, diluted with dichloromethane (50 mL), and washed with saline solution (25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (1-(cyanomethyl)cyclopropyl)methanesulfonate (3.26 g, 17.23 mmol).

[0269] 1 HNMR(400 MHz, CDCl3)δ 4.15(s, 2H), 3.08(s, 3H), 2.59(s, 2H), 0.82(d, J = 4.0 Hz, 4H).

[0270] 2) Synthesis of 2-(1-(azidomethyl)cyclopropyl)acetonitrile:

[0271] [ka]

[0272] A 20 mL solution of DMF containing (1-(cyanomethyl)cyclopropyl)methanesulfonate (3.32 g, 17.54 mmol) and sodium azide (4.81 g, 73.99 mmol) was heated to 120°C, stirred, and reacted for 16 hours. The mixture was then cooled to room temperature, quenched with water, and extracted with dichloromethane (3 × 30 mL). The organic phases were combined, washed with saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-(1-(azidomethyl)cyclopropyl)acetonitrile (1.60 g, 11.75 mmol, 66.9% yield).

[0273] 1HNMR(400 MHz, CDCl3)δ 3.31(s, 2H), 2.53(s, 2H), 0.70(d, J = 1.2 Hz, 4H).

[0274] 3) Synthesis of 2-(1-(aminomethyl)cyclopropyl)acetonitrile:

[0275] [ka]

[0276] Tributylphosphine (7.13 g, 35.24 mmol) was added dropwise to a methanol (15 mL) / water (9 mL) mixture containing 2-(1-(azidomethyl)cyclopropyl)acetonitrile (1.60 g, 11.75 mmol) at room temperature. The resulting mixture was stirred and reacted for 3 hours under conditions of heating to 65°C. The mixture was filtered, and the filter cake was washed with methanol (10 mL). The filtrate was concentrated under reduced pressure to obtain 2-(1-(aminomethyl)cyclopropyl)acetonitrile (821 mg, 7.45 mmol, 63.5% yield).

[0277] 1 HNMR (400 MHz, DMSO- d6 )δ 2.39(s, 2H), 2.25(s, 2H), 0.22(t, J = 5.2 Hz, 2H), 0.17(t, J = 5.2 Hz, 2H).

[0278] 4) Synthesis of methyl 3-((1-(cyanomethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate:

[0279] [ka]

[0280] 300 mg, 1.51 mmol of methyl 3-fluoro-4-nitrobenzoate and 2-(1-(aminomethyl)cyclopropyl)acetonitrile (166 mg, 1.51 mmol) were dissolved in DMF (5 mL). Potassium carbonate (625 mg, 4.53 mmol) was added to the solution, and the mixture was stirred at room temperature and reacted for 16 hours. The solution was diluted with water (15 mL) and extracted with ethyl acetate (3 × 30 mL). The organic phases were combined and washed with saline solution (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain methyl 3-((1-(cyanomethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate (250 mg, 0.86 mmol, yield: 57.6%). LC-MS m / z: 290 [M+H] + .

[0281] 5) Synthesis of 4-amino-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)methyl benzoate:

[0282] [ka]

[0283] At room temperature, zinc powder (449 mg, 6.87 mmol) and acetic acid (415 mg, 6.91 mmol) were added to a methanol (8 mL) solution in which compound methyl 3-((1-(cyanomethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate (200 mg, 0.69 mmol) was dissolved. The mixture was stirred at room temperature and reacted for 1 hour. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 30 mL). The organic phases were washed together with saline solution, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (Spherical C18 column, 20–40 μm, 120 g, mobile phase A: water (with 10 mM HCOOH added), mobile phase B: acetonitrile, flow rate: 80 mL / min, gradient: 40%B–60%B within 20 min, detector: 254 nm). The mobile phase containing the required product was collected using a 52% B mobile phase and concentrated under reduced pressure to obtain methyl 4-amino-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate (141 mg, 0.54 mmol, yield: 78.6%). LC-MS m / z: 260 [M+H] + .

[0284] 6) Synthesis of 2-(chloromethyl)-1-(1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-methyl formate (intermediate A-6):

[0285] [ka]

[0286] At room temperature, methyl 4-amino-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate (140 mg, 0.54 mmol) was dissolved in a 5 mL solution of anhydrous THF, to which 92 mg, 0.54 mmol, 2-chloroacetic acid (anhydrous) was added in several portions. The mixture was stirred at 60°C and reacted for 16 hours. The mixture was quenched by adding water (5 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were washed together in brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column: Spherical C18, 20–40 μm, 120 g, mobile phase A: water (with 10 mM HCOOH added), mobile phase B: acetonitrile, flow rate: 80 mL / min, gradient: 40%B–60%B within 20 min, detector: 254 nm). The mobile phase containing the required product was collected using a 50% B mobile phase and concentrated under reduced pressure to obtain 2-(chloromethyl)-1-(1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-methyl formate (intermediate A-6) (90 mg, 0.54 mmol, yield: 52.5%). LC-MS m / z: 318 [M+H] + .

[0287] Examples 1-7, Synthesis of 4-(2-chloroacetamide)-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-methyl fluorobenzoate (intermediate A-7): 1) Synthesis of 2-(1-((5-bromo-3-fluoro-2-nitrophenyl)amino)methyl)cyclopropyl)acetonitrile:

[0288] [ka]

[0289] To a dimethyl sulfoxide (20 mL) solution containing 5-bromo-1,3-difluoro-2-nitrobenzene (1.00 g, 4.20 mmol) and 2-(1-(aminomethyl)cyclopropyl)acetonitrile (464.2 mg, 4.21 mmol), N,N-diisopropylethylamine (1.63 g, 12.61 mmol) was added, and the mixture was stirred at 70°C and reacted for 4 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 30 mL). The organic phases were combined and washed with saline solution (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=5 / 1) to obtain 2-(1-((5-bromo-3-fluoro-2-nitrophenyl)amino)methyl)cyclopropyl)acetonitrile (542.0 mg, 1.65 mmol, yield: 39.3%). LC-MS m / z: 328, 330 [M+H] + .

[0290] 2) Synthesis of 2-(1-((2-amino-5-bromo-3-fluorophenyl)amino)methyl)cyclopropyl)acetonitrile:

[0291] [ka]

[0292] At room temperature, zinc powder (1.08 g, 16.52 mmol) and acetic acid (996.0 mg, 16.59 mmol) were added to a methanol (10 mL) solution containing 2-(1-((5-bromo-3-fluoro-2-nitrophenyl)amino)methyl)cyclopropyl)acetonitrile (542.0 mg, 1.65 mmol). The mixture was stirred at room temperature for 30 min. The solution was diluted with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saline solution (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain 2-(1-((2-amino-5-bromo-3-fluorophenyl)amino)methyl)cyclopropyl)acetonitrile (358.0 mg, 1.21 mmol, yield: 72.9%). LC-MS m / z: 298 [M+H] + .

[0293] 3) Synthesis of methyl 4-amino-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-fluorobenzoate:

[0294] [ka]

[0295] At room temperature, a mixture of DMF (3 mL) and methanol (10 mL) containing 2-(1-((2-amino-5-bromo-3-fluorophenyl)amino)methyl)cyclopropyl)acetonitrile (358.0 mg, 1.21 mmol) was added to triethylamine (366.6 mg, 3.62 mmol) and 1,1'-bisdiphenylphosphinoferocenedichloropalladium (88.5 mg, 0.12 mmol). The mixture was heated to 90°C under carbon monoxide protection and stirred, reacting for 16 hours. After cooling to room temperature, the mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain methyl 4-amino-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-fluorobenzoate (100.0 mg, 0.36 mmol, yield: 29.8%). LC-MS m / z: 278 [M+H] + .

[0296] 4) Synthesis of 4-(2-chloroacetamide)-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-methyl fluorobenzoate (intermediate A-7):

[0297] [ka]

[0298] 85.0 mg, 0.31 mmol of methyl 4-amino-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-fluorobenzoate (methyl 4-amino-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-fluorobenzoate (methyl 4-amino-3-((1-(cyanomethyl)cyclopropyl)methyl)-methyl methyl 4-amino-3-((1-(cyanomethyl)cyclopropyl)methyl)-methyl methyl 4-amino-3-((1-(cyanomethyl)cyclopropyl)methyl)-methyl methyl 4-amino-3-((1-(cyanomethyl)cyclopropyl)methyl)-methyl methyl 4-amino-3-((1-(cyanomethyl)cyclopropyl)methyl)-methyl methyl 4-amino-3-((1-(cyanomethyl)cyclopropyl)methyl)-amino-5-fluorobenzoate (methyl 4-amino-3-3-((1-(cyanomethyl)cyclopropyl)methyl)-methyl methyl 4-amino-3-5-fluorobenzoate (methyl 4-amino-3 The mobile phase containing the required product was collected using a 52% B mobile phase and concentrated under reduced pressure to obtain 4-(2-chloroacetamide)-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-methyl fluorobenzoate (intermediate A-7) (141 mg, 0.54 mmol, yield: 78.6%). LC-MS m / z: 354 [M+H] + .

[0299] Examples 1-8, Synthesis of 2-(chloromethyl)-1-(oxetan-3-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl (intermediate A-8): 1) Synthesis of methyl 4-nitro-3-((oxetane-3-ylmethyl)amino)benzoate:

[0300] [ka]

[0301] A mixed solution of methyl 3-fluoro-4-nitrobenzoate (1.60 g, 8.05 mmol), compound oxetane-3-ylmethaneamine (700 mg, 8.05 mmol), and potassium carbonate (2.22 g, 16.10 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saline solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain methyl 4-nitro-3-((oxetane-3-ylmethyl)amino)benzoate (1.50 g, yield: 70.1%). LC-MS m / z: 267 [M+H] + .

[0302] 2) Synthesis of methyl 4-amino-3-((oxetane-3-ylmethyl)amino)benzoate:

[0303] [ka]

[0304] Palladium carbon (200 mg) was added to a methanol (30 mL) solution containing methyl 4-nitro-3-((oxetane-3-ylmethyl)amino)benzoate (1.50 g, 5.64 mmol). The resulting mixture was degassed, packed three times with hydrogen gas, and stirred at room temperature for 4 hours. The reaction product was filtered, and the filter cake was washed with methanol (20 mL). The filtrate was concentrated to obtain methyl 4-amino-3-((oxetane-3-ylmethyl)amino)benzoate (1.20 g, yield: 90.2%), which was used directly in the next reaction without purification. LC-MS m / z: 237 [M+H] + .

[0305] 3) Synthesis of 2-(chloromethyl)-1-(oxetan-3-ylmethyl)-1H-benzo[d]imidazole-6-methyl formate:

[0306] [ka]

[0307] At 0°C, 1.20 g, 5.08 mmol of methyl 4-amino-3-((oxetane-3-ylmethyl)amino)benzoate was dissolved in 20 mL of anhydrous tetrahydrofuran. 869 mg, 5.08 mmol of 2-chloroacetic acid was gradually added to this solution. The mixture was stirred at 0°C for 30 min, then heated to 70°C and stirred for 3 hours. The mixture was quenched with 100 mL of water at room temperature and extracted with 2 × 30 mL of ethyl acetate. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain methyl 2-(chloromethyl)-1-(oxetane-3-ylmethyl)-1H-benzo[d]imidazole-6-formate (1.00 g, yield: 67.0%). LC-MS m / z: 295 [M+H] + .

[0308] Examples 1-9, Synthesis of 2-(chloromethyl)-1-((3-methyloxetan-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl (intermediate A-9): 1) Synthesis of methyl 3-((3-methoxy-3-yl)methyl)amino)-4-nitrobenzoate:

[0309] [ka]

[0310] A mixture of methyl 3-fluoro-4-nitrobenzoate (2.00 g, 10.00 mmol), compound (3-methyloxan-3-yl)formamide (1.00 g, 10.00 mmol), and potassium carbonate (4.14 g, 30.00 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saline solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain methyl 3-((3-methoxy-3-yl)methyl)amino)-4-nitrobenzoate (1.96 g, yield: 70.4%). LC-MS m / z: 281 [M+H] + .

[0311] 2) Synthesis of methyl 4-amino-3-((3-methyloxetan-3-yl)methyl)amino)benzoate:

[0312] [ka]

[0313] Palladium carbon (400 mg) was added to a methanol (20 mL) solution containing methyl 3-((3-methoxy-3-yl)methyl)amino)-4-nitrobenzoate (1.96 g, 7.04 mmol). The resulting mixture was degassed and charged three times with hydrogen gas, then stirred at room temperature and reacted for 4 hours. The reaction product was filtered, and the filter cake was washed with methanol (20 mL). The filtrate was concentrated to obtain methyl 4-amino-3-((3-methyloxetan-3-yl)methyl)amino)benzoate (1.55 g, yield: 85.2%), which did not require purification and was used directly in the next reaction. LC-MS m / z: 251 [M+H] + .

[0314] 3) Synthesis of 2-(chloromethyl)-1-((3-methyloxetan-3-yl)methyl)-1H-benzo[d]imidazole-6-methyl formate:

[0315] [ka]

[0316] At 0°C, 2-chloromethyl-3-((3-methyloxetan-3-yl)methyl)amino)benzoate (200 mg, 0.80 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) solution to which 2-chloroacetic acid (137 mg, 0.80 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed by concentrating under reduced pressure, and the residue was reacted in dioxane (5 mL) by heating to 100°C for 3 hours. The mixture was quenched with water (20 mL) at room temperature and extracted with ethyl acetate (2 × 10 mL). The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 2-(chloromethyl)-1-((3-methyloxetan-3-yl)methyl)-1H-benzo[d]imidazole-6-formate methyl (200 mg, yield: 81.2%). LC-MS m / z: 309 [M+H] + .

[0317] Examples 1-10, Synthesis of 4-(2-chloroacetamide)-3-((1,2-dimethyl-1H-imidazole-5-yl)methyl)amino)methyl benzoate (intermediate A-10): 1) Synthesis of 1,2-dimethyl-1H-imidazole-5-carbonealdehyde:

[0318] [ka]

[0319] At -78°C, 5-bromo-1,2-dimethyl-1H-imidazole (500 mg, 2.86 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) solution. n-butyllithium (1.26 mL, 3.15 mmol, 2.5 M hexane) was added, and the mixture was stirred at -78°C for 30 minutes. Then, at 0°C, N,N-dimethylformamide (626 mg, 8.58 mmol) was gradually added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with water (50 mL) at 0°C and extracted with ethyl acetate (2 × 30 mL). The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain 1,2-dimethyl-1H-imidazole-5-carbonealdehyde (300 mg, yield: 84.6%). LC-MS m / z: 125 [M+H] + .

[0320] 2) Synthesis of (E)-N-((1,2-dimethyl-1H-imidazole-5-yl)methylene)-2-methylpropane-2-sulfoxideamide:

[0321] [ka]

[0322] A mixed solution of 1,2-dimethyl-1H-imidazole-5-carbonealdehyde (300 mg, 2.42 mmol), 2-methylpropane-2-sulfoxideamide (439 mg, 3.63 mmol), and tetraisopropyl titanate (2.06 g, 7.26 mmol) in tetrahydrofuran (5 mL) was stirred at room temperature and reacted for 16 hours. The resulting mixture was diluted with water (2 mL), filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane / methanol = 20 / 1) yielded (E)-N-((1,2-dimethyl-1H-imidazole-5-yl)methylene)-2-methylpropane-2-sulfoxideamide (500 mg, yield: 91.0%). LC-MS m / z: 228 [M+H] + .

[0323] 3) Synthesis of N-((1,2-dimethyl-1H-imidazole-5-yl)methyl)-2-methylpropane-2-sulfoxideamide:

[0324] [ka]

[0325] (E)-N-((1,2-dimethyl-1H-imidazole-5-yl)methylene)-2-methylpropane-2-sulfoxideamide (500 mg, 2.20 mmol) and sodium borohydride (167 mg, 4.40 mmol) were dissolved in methanol (10 mL). The resulting mixture was stirred at room temperature and reacted for 2 hours. After the reaction was complete, the reaction was quenched with water (50 mL) at room temperature and extracted with dichloromethane (2 × 20 mL). After concentrating the organic phase under reduced pressure, N-((1,2-dimethyl-1H-imidazole-5-yl)methyl)-2-methylpropane-2-sulfoxideamide (400 mg, yield: 55.3%) was obtained and used directly in the next reaction without purification. LC-MS m / z: 230 [M+H] + .

[0326] 4) Synthesis of (1,2-dimethyl-1H-imidazole-5-yl)methylamine hydrochloride:

[0327] [ka]

[0328] N-((1,2-dimethyl-1H-imidazole-5-yl)methyl)-2-methylpropane-2-sulfoxideamide (400 mg, 1.75 mmol) was dissolved in methanol hydrochloride solution (5 mL, 3 M). The mixture was stirred at room temperature and reacted for 1 hour. The reaction was filtered to obtain (1,2-dimethyl-1H-imidazole-5-yl)methylamine hydrochloride (200 mg, yield: 57.8%).

[0329] 1 H NMR (400 MHz, DMSO-d6): δ 8.86(s, 2H), 7.63(s, 1H), 4.19(s, 2H), 3.77(s, 3H), 2.63(s, 3H).

[0330] 5) Synthesis of methyl 3-((1,2-dimethyl-1H-imidazole-5-yl)methyl)amino)-4-nitrobenzoate:

[0331] [ka]

[0332] Triethylamine (510 mg, 5.05 mmol) was added to a stirred solution of tetrahydrofuran (3 mL) and methanol (2 mL) containing (1,2-dimethyl-1H-imidazole-5-yl)methylamine hydrochloride (200 mg, 1.01 mmol), 3-fluoro-4-nitrobenzoate methyl (201 mg, 1.01 mmol) dissolved in the mixture. The mixture was stirred at 60°C and reacted for 3 hours. The resulting mixture was injected into saline solution (50 mL) and extracted with ethyl acetate (2 × 20 mL). The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain 3-((1,2-dimethyl-1H-imidazole-5-yl)methyl)amino)-4-nitrobenzoate methyl (200 mg, yield: 65.1%). LC-MS m / z: 305 [M+H] + .

[0333] 6) Synthesis of methyl 4-amino-3-((1,2-dimethyl-1H-imidazole-5-yl)methyl)amino)benzoate:

[0334] [ka]

[0335] Palladium carbon (20 mg) was added to a methanol (10 mL) solution containing methyl 3-((1,2-dimethyl-1H-imidazole-5-yl)methyl)amino)-4-nitrobenzoate (200 mg, 0.66 mmol). The resulting mixture was degassed, packed three times with hydrogen gas, and stirred at room temperature for 3 hours. The mixture was filtered with methanol (50 mL), the reacted filter cake was washed, and the filtrate was concentrated under reduced pressure to obtain methyl 4-amino-3-((1,2-dimethyl-1H-imidazole-5-yl)methyl)amino)benzoate (150 mg, yield: 82.9%), which was used directly to the next step without purification. LC-MS m / z: 275 [M+H] + .

[0336] 7) Synthesis of 4-(2-chloroacetamide)-3-((1,2-dimethyl-1H-imidazole-5-yl)methyl)amino)methyl benzoate:

[0337] [ka]

[0338] A tetrahydrofuran (3 mL) solution containing 150 mg (0.55 mmol) and 142 mg (0.83 mmol) of 2-chloroacetic anhydride was stirred at room temperature and allowed to react for 2 hours. The resulting mixture was concentrated under reduced pressure and then separated and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain 150 mg (yield: 77.9%) of 4-(2-chloroacetamide)-3-(1,2-dimethyl-1H-imidazole-5-yl)methyl)amino)methyl benzoate. LC-MS m / z: 351 [M+H] + .

[0339] Examples 1-11, Synthesis of 5-(2-chloroacetamide)-6-(1-(cyanomethyl)cyclopropyl)methyl)aminopicolinate: 1) Synthesis of 6-((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-nitropicolinate methyl (intermediate A-11):

[0340] [ka]

[0341] N,N-diisopropylethylamine (1.52 g, 11.81 mmol) was added to a dimethyl sulfoxide (10 mL) solution containing methyl 6-chloro-5-nitropicolinate (850 mg, 3.94 mmol) and 2-(1-(aminomethyl)cyclopropyl)acetonitrile (433 mg, 3.94 mmol). The mixture was stirred at 60°C and reacted for 16 hours. The resulting mixture was injected into saline solution (20 mL) and extracted with ethyl acetate (2 × 20 mL). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain methyl 6-((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-nitropicolinate (190 mg, yield: 16.7%). LC-MS m / z: 291 [M+H] + .

[0342] 2) Synthesis of 5-amino-6-((1-(cyanomethyl)cyclopropyl)methyl)amino)picolinate methyl:

[0343] [ka]

[0344] At room temperature, zinc powder (428 mg, 6.55 mmol) and acetic acid (393 mg, 6.55 mmol) were added to a methanol (5 mL) solution containing methyl 6-((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-nitropicolinate (190 mg, 0.65 mmol). The mixture was stirred at room temperature and reacted for 2 hours. After the reaction, the resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain methyl 5-amino-6-((1-(cyanomethyl)cyclopropyl)methyl)amino)picolinate (130 mg, yield: 53.7%). LC-MS m / z: 261 [M+H] + .

[0345] 3) Synthesis of methyl 5-(2-chloroacetamide)-6-(1-(cyanomethyl)cyclopropyl)methyl)aminopicolinate:

[0346] [ka]

[0347] 5-amino-6-((1-(cyanomethyl)cyclopropyl)methyl)amino)picolinate (80 mg, 0.31 mmol) was dissolved in tetrahydrofuran (5 mL), to which 2-chloroacetic anhydride (79 mg, 0.46 mmol) was added. The mixture was stirred at room temperature and reacted for 2 hours. After the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 5-(2-chloroacetamide)-6-(1-(cyanomethyl)cyclopropyl)methyl)aminopicolinate (150 mg, yield 88%). LC-MS m / z: 337 [M+H] + .

[0348] Examples 1-12, Synthesis of (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-formate methyl (intermediate A-12):

[0349] [ka]

[0350] (S)-5-amino-6-((oxetane-2-ylmethyl)amino)methyl picolinate (100 mg, 0.42 mmol) was dissolved in tetrahydrofuran (10 mL), to which 2-anhydrous chloroacetic acid (101 mg, 0.63 mmol) was added, and the mixture was stirred at 60°C and reacted for 3 hours. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to obtain (S)-2-(chloromethyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-formate methyl (140 mg).

[0351] Examples 1-13, Synthesis of 5-(2-chloroacetamide)-6-(1-ethyl-1H-imidazole-5-yl)methyl)aminopicolinate methyl (intermediate A-13):

[0352] [ka]

[0353] At room temperature, 2-anhydrous chloroacetic acid (138 mg, 0.82 mmol) was added in several portions to a tetrahydrofuran (5 mL) solution containing 5-amino-6-((1-ethyl-1H-imidazole-5-yl)methyl)aminopicolinate (150 mg, 0.54 mmol). The mixture was stirred at 25°C and reacted for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 5-(2-chloroacetamide)-6-(1-ethyl-1H-imidazole-5-yl)methyl)aminopicolinate (180 mg, yield: 94.7%). LC-MS m / z: 352 [M+H] + .

[0354] Examples 1-14, Synthesis of 4-(2-chloroacetamide)-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)methyl benzoate (intermediate A-14):

[0355] [ka]

[0356] 494 mg (2.89 mmol) of 2-chloroacetic acid anhydrous was added to a 5 mL tetrahydrofuran mixture containing 500 mg (1.93 mmol) of methyl 4-amino-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate, and the mixture was stirred at room temperature and reacted for 2 hours. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 4-(2-chloroacetamide)-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)methyl benzoate (400 mg, yield: 61.8%). LC-MS m / z: 336 [M+H] + .

[0357] Examples 1-15, Synthesis of (S)-N-(4-bromo-2-fluoro-6-((oxetane-2-ylmethyl)amino)phenyl)-2-chloroacetamide (intermediate A-15):

[0358] [ka]

[0359] 2-Anhydrous chloroacetic acid (241 mg, 1.42 mmol) was added to a solution of (S)-5-bromo-3-fluoro-N1-(oxetane-2-ylmethyl)benzene-1,2-diamine (300 mg, 1.09 mmol) in anhydrous tetrahydrofuran (5 mL). The mixture was stirred at room temperature and reacted for 1 hour. Extraction was performed with ethyl acetate (3 × 10 mL). The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain (S)-N-(4-bromo-2-fluoro-6-((oxetane-2-ylmethyl)amino)phenyl)-2-chloroacetamide (230 mg, yield: 59.9%). LC-MS m / z: 353 [M+H] + .

[0360] Examples 1-16, Synthesis of N-(4-bromo-2-((1-(cyanomethyl)cyclopropyl)methyl)amino)-6-fluorophenyl)-2-chloroacetamide (intermediate A-16):

[0361] [ka]

[0362] 2-Anhydrous chloroacetic acid (129 mg, 0.76 mmol) was gradually added to a solution of 2-(1-((2-amino-5-bromo-3-fluorophenyl)amino)methyl)cyclopropyl)acetonitrile (150 mg, 0.50 mmol) in anhydrous tetrahydrofuran (5 mL). The mixture was stirred at room temperature and reacted for 1 hour. Extraction was performed with ethyl acetate (3 × 10 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain N-(4-bromo-2-((1-(cyanomethyl)cyclopropyl)methyl)amino)-6-fluorophenyl)-2-chloroacetamide (218 mg, crude product). LC-MS m / z: 376 [M+H] + .

[0363] Examples 1-17, Synthesis of 4-(2-chloroacetamide)-3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)-5-fluorobenzoate methyl (intermediate A-17): 1) Synthesis of methyl 4-amino-3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)-5-fluorobenzoate:

[0364] [ka]

[0365] Under carbon monoxide protection, potassium acetate (470 mg, 4.80 mmol) and 1,1'-bisdiphenylphosphinoferocenedichloropalladium (117 mg, 0.16 mmol) were added to a methanol / N,N-dimethylformamide (5 mL / 5 mL) mixture containing 5-bromo-N1-((1-ethyl-1H-imidazole-5-yl)methyl)-3-fluorobenzene-1,2-diamine (500 mg, 1.60 mmol), and the mixture was stirred at 90°C and reacted for 16 hours. After the reaction was complete, the mixture was diluted with water (30 mL), extracted with ethyl acetate (30 mL x 2), and the combined organic layer was washed with saline solution (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain methyl 4-amino-3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)-5-fluorobenzoate (150 mg, yield: 32.1%). LC-MS m / z: 293 [M+H] + .

[0366] 2) Synthesis of methyl 4-(2-chloroacetamide)-3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)-5-fluorobenzoate:

[0367] [ka]

[0368] At room temperature, 150 mg (0.51 mmol) of methyl 4-amino-3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)-5-fluorobenzoate was dissolved in 5 mL of anhydrous tetrahydrofuran, to which 176 mg (1.02 mmol) of chloroacetic acid (anhydrous 2) was gradually added. The mixture was stirred at room temperature and allowed to react for 3 hours. After the reaction was complete, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (2 × 20 mL). The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain methyl 4-(2-chloroacetamide)-3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)-5-fluorobenzoate (130 mg, yield: 69.3%). LC-MS m / z: 369 [M+H] + .

[0369] Examples 1-18, Synthesis of 4-(2-chloroacetamide)-3-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methyl)aminobenzoate methyl (intermediate A-18):

[0370] [ka]

[0371] At room temperature, compound 4-amino-3-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methyl)aminobenzoate methyl (500 mg, 1.67 mmol) was dissolved in anhydrous tetrahydrofuran solution (10 mL), and then anhydrous chloroacetic acid (715 mg, 4.18 mmol) was gradually added. The resulting mixture was stirred at room temperature and reacted for 2 hours. After the reaction was complete, the solvent was removed by reducing the pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain 4-(2-chloroacetamide)-3-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methyl)aminobenzoate methyl (400 mg, yield: 63.5%). LC-MS m / z: 377 [M+H] +.

[0372] Examples 1-19, Synthesis of 2-(chloromethyl)-1-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methyl)-1H-benzo[d]imidazole-6-formate methyl (intermediate A-19):

[0373] [ka]

[0374] At room temperature, 500 mg (1.67 mmol) of methyl 4-amino-3-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methyl)aminobenzoate was dissolved in 10 mL of anhydrous tetrahydrofuran, and then 715 mg (4.18 mmol) of 2-chloroacetic acid anhydrous was added. The resulting mixture was stirred at room temperature and reacted for 2 hours. The temperature was then raised to 60°C and stirred, and the mixture was reacted overnight. After the reaction was complete, the solvent was removed by reducing the pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain methyl 2-(chloromethyl)-1-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methyl)-1H-benzo[d]imidazole-6-formate (100 mg, yield: 16.7%). LC-MS m / z: 359 [M+H] + .

[0375] Examples 1-20: Synthesis of 2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole-6-methyl formate (intermediate A-20): 1) Synthesis of methyl 3-(methylamino)-4-nitrobenzoate:

[0376] [ka]

[0377] At room temperature, methyl 3-fluoro-4-nitrobenzoate (2.00 g, 10.00 mmol) and methylamine solution (10 mL of 2 M tetrahydrofuran solution) were added to tetrahydrofuran solution (30 mL). The resulting mixture was stirred at room temperature and reacted for 2 hours. After the reaction, the solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain methyl 3-(methylamino)-4-nitrobenzoate (1.80 g, yield: 85.0%). LC-MS m / z: 211 [M+H] + .

[0378] 2) Synthesis of methyl 4-amino-3-(methylamino)benzoate:

[0379] [ka]

[0380] At room temperature, methyl 3-(methylamino)-4-nitrobenzoate (1.80 g, 8.57 mmol) was dissolved in methanol (20 mL), and then palladium carbon (900 mg) was added. The resulting mixture was degassed and then packed three times with hydrogen gas, stirred at room temperature, and reacted for 3 hours. After the reaction was complete, the reaction solution was filtered, and the filter cake was washed with methanol (20 mL). The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 16 / 9) to obtain methyl 4-amino-3-(methylamino)benzoate (1.2 g, yield: 77.8%). LC-MS m / z: 181 [M+H] + .

[0381] 3) Synthesis of methyl 2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole-6-formate:

[0382] [ka]

[0383] At room temperature, methyl 4-amino-3-(methylamino)benzoate (1.2 g, 2.83 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran solution. Anhydrous chloroacetic acid (2.27 g, 5.66 mmol) was then added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then heated to 60°C, stirred, and stirred for 16 hours. After the reaction, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain methyl 2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole-6-formate (1.4 g, yield: 88.2%). LC-MS m / z: 239 [M+H] + .

[0384] Examples 1-21, Synthesis of 4-(2-chloroacetamide)-3-((1-isopropyl-1H-imidazole-5-yl)methyl)amino)methyl benzoate (intermediate A-21): 1) Synthesis of (E)-N-((1-isopropyl-1H-imidazole-5-yl)methylene)-2-methylpropane-2-sulfoxideamide:

[0385] [ka]

[0386] At room temperature, (E)-N-((1H-imidazole-5-yl)methylene)-2-methylpropane-2-sulfoxideamide (5.00 g, 25.12 mmol), potassium carbonate (10.40 g, 75.36 mmol), and 2-iodopropane (8.54 g, 50.25 mmol) were dissolved in N,N-dimethylacetamide (100 mL) solution, and the resulting mixture was stirred at room temperature and reacted for 16 hours. After the reaction was complete, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and back-extracted with saline solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 12 / 1) to obtain (E)-N-((1-isopropyl-1H-imidazole-5-yl)methylene)-2-methylpropane-2-sulfoxideamide (4.8 g, yield: 73.4%). LC-MS m / z: 242 [M+H] + .

[0387] 2) Synthesis of N-((1-isopropyl-1H-imidazole-5-yl)methyl)-2-methylpropane-2-sulfoxideamide:

[0388] [ka]

[0389] At room temperature, (E)-N-((1-isopropyl-1H-imidazole-5-yl)methylene)-2-methylpropane-2-sulfoxideamide (4.80 g, 19.92 mmol) was dissolved in methanol (30 mL) solution, and then sodium borohydride (2.28 g, 59.75 mmol) was gradually added. The resulting mixture was stirred at room temperature and reacted for 2 hours. After the reaction was complete, the reaction was quenched with water (200 mL x 2), extracted with ethyl acetate (200 mL), the organic phase was back-extracted with saline solution (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain N-((1-isopropyl-1H-imidazole-5-yl)methyl)-2-methylpropane-2-sulfoxideamide (4.5 g, yield: 87.5%). LC-MS m / z: 244 [M+H] + .

[0390] 3) Synthesis of (1-isopropyl-1H-imidazole-5-yl)methylamine:

[0391] [ka]

[0392] At room temperature, a mixture of N-((1-isopropyl-1H-imidazole-5-yl)methyl)-2-methylpropane-2-sulfoxideamide (4.50 g, 18.44 mmol) and acetic acid (50 mL, 3 mol / L methanol) was stirred for 16 hours. After the reaction was complete, the resulting reaction solution was concentrated under reduced pressure to obtain (1-isopropyl-1H-imidazole-5-yl)methylamine (2.4 g, yield: 93.6%). LC-MS m / z: 140 [M+H] + .

[0393] 4) Synthesis of 3-((1-isopropyl-1H-imidazole-5-yl)methyl)amino)-4-nitrobenzoate methyl:

[0394] [ka]

[0395] At room temperature, (1-isopropyl-1H-imidazole-5-yl)methylamine (2.40 g, 17.27 mmol), methyl 3-fluoro-4-nitrobenzoate (4.14 g, 20.72 mmol), and potassium carbonate (4.79 g, 34.53 mmol) were dissolved in 50 mL of N,N-dimethylformamide solution. The resulting mixture was stirred at room temperature and reacted for 16 hours. After the reaction was complete, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, back-extracted with saline solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 12 / 1) to obtain methyl 3-((1-isopropyl-1H-imidazole-5-yl)methyl)amino)-4-nitrobenzoate (1.2 g, yield: 21.9%). LC-MS m / z: 319 [M+H] + .

[0396] 5) Synthesis of methyl 4-amino-3-((1-isopropyl-1H-imidazole-5-yl)methyl)amino)benzoate:

[0397] [ka]

[0398] At room temperature, 1.2 g, 3.78 mmol of 3-((1-isopropyl-1H-imidazole-5-yl)methyl)amino)-4-nitrobenzoate methyl ester (1.2 g, 3.78 mmol) was dissolved in methanol (30 mL), and then 600 mg, 5.6 mmol of palladium carbon was added. The resulting mixture was degassed, packed three times with hydrogen gas, and stirred at room temperature for 3 hours. After the reaction was complete, the mixture was filtered, and the filter cake was washed with methanol (50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 13 / 1) to obtain 750 mg, yield: 69.0%, of 4-amino-3-((1-isopropyl-1H-imidazole-5-yl)methyl)amino)benzoate methyl ester (LC-MS m / z: 289 [M+H]). + .

[0399] 6) Synthesis of 4-(2-chloroacetamide)-3-((1-isopropyl-1H-imidazole-5-yl)methyl)amino)methyl benzoate:

[0400] [ka]

[0401] At room temperature, anhydrous chloroacetic acid (595 mg, 3.48 mmol) was added to a solution of anhydrous tetrahydrofuran (8 mL) containing 400 mg, 1.39 mmol of methyl 4-amino-3-((1-isopropyl-1H-imidazole-5-yl)methyl)amino)benzoate. The mixture was stirred at room temperature and reacted for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain methyl 4-(2-chloroacetamide)-3-((1-isopropyl-1H-imidazole-5-yl)methyl)amino)benzoate (450 mg, yield: 88.8%). LC-MS m / z: 365 [M+H] + .

[0402] Examples 1-22, Synthesis of 4-(2-chloroacetamide)-3-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methyl)aminobenzoate methyl (intermediate A-22): 1) Synthesis of (E)-N-((1H-imidazole-5-yl)methylene)-2-methylpropane-2-sulfoxideamide:

[0403] [ka]

[0404] At room temperature, 1H-imidazole-5-carbonealdehyde (5.00 g, 52.08 mmol) and 2-methylpropane-2-sulfoxideamide (9.39 g, 78.12 mmol) were dissolved in tetrahydrofuran (100 mL) solution, and then titanium tetraisopropoxide (44.40 g, 156.25 mmol) was gradually added. The resulting mixture was stirred at room temperature and reacted for 16 hours. After the reaction was complete, the solution was diluted with water (100 mL), filtered, and the filter cake was washed with ethyl acetate (150 mL). After the filtrate separated into layers, the aqueous layer was extracted with ethyl acetate (100 mL x 2). The organic phases were combined and back-extracted with saline solution (250 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 12 / 1) to obtain (E)-N-((1H-imidazole-5-yl)methylene)-2-methylpropane-2-sulfoxideamide (9.00 g, yield: 86.4%). LC-MS m / z: 200 [M+H] + .

[0405] 2) Synthesis of (E)-N-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methylene)-2-methylpropane-2-sulfoxideamide:

[0406] [ka]

[0407] (E)-N-((1H-imidazole-5-yl)methylene)-2-methylpropane-2-sulfoxideamide (3.00 g, 15.10 mmol) and potassium carbonate (6.25 g, 45.30 mmol) were dissolved in N,N-dimethylformamide (50 mL), and then (bromomethyl)cyclopropane (4.08 g, 30.20 mmol) was added. The resulting mixture was stirred at room temperature and reacted for 16 hours. After the reaction was complete, the resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (150 mL x 3). The organic phases were combined and back-extracted with saline solution (150 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 13 / 1) to obtain (E)-N-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methylene)-2-methylpropane-2-sulfoxideamide (2.8 g, yield: 73.4%). LC-MS m / z: 254 [M+H] + .

[0408] 3) Synthesis of N-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methyl)-2-methylpropane-2-sulfoxideamide:

[0409] [ka]

[0410] At room temperature, (E)-N-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methylene)-2-methylpropane-2-sulfoxideamide (2.80 g, 11.60 mmol) was dissolved in methanol (20 mL), and then sodium borohydride (1.26 g, 33.2 mmol) was gradually added. The mixture was stirred at room temperature and allowed to react for 2 hours. After the reaction was complete, water (200 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (300 mL). The organic phase was back-extracted with saline solution (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain N-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methyl)-2-methylpropane-2-sulfoxideamide (2.55 g, yield: 90.9%). LC-MS m / z: 256 [M+H] + .

[0411] 4) Synthesis of (1-(cyclopropylmethyl)-1H-imidazole-5-yl)methylamine:

[0412] [ka]

[0413] A mixed solution of N-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methyl)-2-methylpropane-2-sulfoxideamide (2.55 g, 10.00 mmol) and hydrochloric acid (30 mL, 3 M methanol) was stirred at room temperature for 16 hours. After the reaction was complete, the resulting mixture was concentrated to obtain (1-(cyclopropylmethyl)-1H-imidazole-5-yl)methylamine (1.5 g, yield: 99.3%). LC-MS m / z: 152 [M+H] + .

[0414] 5) Synthesis of 3-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methyl)amino)-4-nitrobenzoate methyl:

[0415] [ka]

[0416] (1-(cyclopropylmethyl)-1H-imidazole-5-yl)methylamine (1.50 g, 9.93 mmol), 3-fluoro-4-nitrobenzoate methyl (2.98 g, 14.90 mmol), and potassium carbonate (2.76 g, 19.87 mmol) were dissolved in N,N-dimethylformamide (30 mL) solution and stirred at room temperature for 16 hours. After the reaction was complete, the resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and back-extracted with saline solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 13 / 1) to obtain 3-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methyl)amino)-4-nitrobenzoate methyl (1.5 g, yield: 45.7%). LC-MS m / z: 331 [M+H] + .

[0417] 6) Synthesis of methyl 4-amino-3-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methyl)aminobenzoate:

[0418] [ka]

[0419] At room temperature, 1.50 g, 4.55 mmol of 3-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methyl)amino)-4-nitrobenzoate methyl was dissolved in 40 mL of methanol, and then 750 mg of palladium carbon was added. The resulting mixture was degassed and then packed three times with hydrogen gas, stirred at room temperature, and reacted for 4 hours. After the reaction was complete, the reaction was filtered, and the filter cake was washed with 50 mL of methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 13 / 1) to obtain 1.1 g, yield: 80.7% of 4-amino-3-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methyl)aminobenzoate methyl (LC-MS m / z: 301 [M+H]). + .

[0420] 7) Synthesis of methyl 4-(2-chloroacetamide)-3-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methyl)aminobenzoate:

[0421] [ka]

[0422] At room temperature, 150 mg, 0.50 mmol of 4-amino-3-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methyl)aminobenzoate methyl was dissolved in 5 mL of anhydrous tetrahydrofuran, to which 257 mg, 1.50 mmol of anhydrous chloroacetic acid was added. The mixture was stirred at room temperature and reacted for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to obtain 180 mg, yield: 95.5%, of 4-(2-chloroacetamide)-3-((1-(cyclopropylmethyl)-1H-imidazole-5-yl)methyl)aminobenzoate methyl. LC-MS m / z: 377 [M+H] + .

[0423] Examples 1-23, Synthesis of 4-(2-chloroacetamide)-3-((1-ethyl-5-oxopyrrolidine-2-yl)methyl)aminobenzoate methyl (intermediate A-23): 1) Synthesis of dimethylethyl-L-glutamic acid:

[0424] [ka]

[0425] At room temperature, dimethyl glutamate hydrochloride (5.00 g, 23.70 mmol) and potassium hydroxide (770 mg, 26.07 mmol) were dissolved in methanol (100 mL). The mixture was stirred at room temperature and reacted for 15 minutes. Next, acetaldehyde (1.56 g, 35.55 mmol) was added. The resulting mixture was stirred at room temperature and reacted for 2 hours. After the reaction was complete, the reaction was quenched with water (200 mL) at room temperature and extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain dimethylethyl-L-glutamic acid (3.50 g, yield: 72.7%).

[0426] 1 H NMR (400 MHz, CDCl3): δ 3.73 (s, 3 H), 3.67 (s, 3 H), 2.65-2.59 (m, 1 H), 2.50-2.42 (m, 3 H), 2.01-1.86 (m, 2 H), 1.07 (t, J=7.2 Hz, 3 H).

[0427] 2) Synthesis of methyl 1-ethyl-5-oxopyrrolidine-2-formate:

[0428] [ka]

[0429] Dimethylethyl-L-glutamic acid (3.50 g, 17.24 mmol) was dissolved in toluene (50 mL) at room temperature. The resulting mixture was stirred at 110°C and reacted for 16 hours. After the reaction was complete, the solvent was removed under vacuum to obtain methyl 1-ethyl-5-oxopyrrolidine-2-formate (2.00 g, yield: 67.8%). LC-MS m / z: 172 [M+H] + .

[0430] 3) Synthesis of 1-ethyl-5-(hydroxymethyl)pyrrolidine-2-one:

[0431] [ka]

[0432] At 0°C, lithium aluminum tetrahydrogen (222 mg, 5.85 mmol) was added to a tetrahydrofuran (10 mL) solution containing methyl 1-ethyl-5-oxopyrrolidine-2-formate (1.00 g, 5.85 mmol). The resulting mixture was stirred at room temperature and reacted for 1 hour. After the reaction was complete, water (2 mL) and aqueous sodium hydroxide solution (2 mL, 15%) were added to quench the reaction mixture. The mixture was filtered and then concentrated under reduced pressure to obtain 1-ethyl-5-(hydroxymethyl)pyrrolidine-2-one (600 mg, yield: 71.7%). LC-MS m / z: 144 [M+H] + .

[0433] 4) Synthesis of methyl (1-ethyl-5-oxopyrrolidine-2-yl)sulfonate:

[0434] [ka]

[0435] At 0°C, triethylamine (848 mg, 8.40 mmol) and methanesulfonyl chloride (580 mg, 5.04 mmol) were added to a 10 mL solution of dichloromethane containing 600 mg, 4.20 mmol of 1-ethyl-5-(hydroxymethyl)pyrrolidine-2-one. The resulting mixture was stirred at room temperature and reacted for 1 hour. After the reaction was complete, the reaction mixture was quenched with water (20 mL) at room temperature and extracted with dichloromethane (10 mL x 2). The organic layers were combined and concentrated under reduced pressure to obtain methyl (1-ethyl-5-oxopyrrolidine-2-yl)sulfonate (500 mg, yield: 53.9%). LC-MS m / z: 222 [M+H] + .

[0436] 5) Synthesis of 5-(azidomethyl)-1-ethylpyrrolidine-2-one:

[0437] [ka]

[0438] At room temperature, methyl (1-ethyl-5-oxopyrrolidine-2-yl)sulfonate (500 mg, 2.26 mmol) and sodium azide (220 mg, 3.39 mmol) were dissolved in N,N-dimethylformamide (10 mL) solution. The resulting mixture was stirred at 120°C and reacted for 16 hours. After the reaction was complete, the mixture was diluted at room temperature in saturated sodium bicarbonate (50 mL) solution and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and back-extracted with saline solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-(azidomethyl)-1-ethylpyrrolidine-2-one (500 mg, crude product). LC-MS m / z: 169 [M+H] + .

[0439] 6) Synthesis of 5-(aminomethyl)-1-ethylpyrrolidine-2-one:

[0440] [ka]

[0441] At room temperature, 5-(azidomethyl)-1-ethylpyrrolidine-2-one (500 mg, 2.98 mmol) was dissolved in a mixed solution of tetrahydrofuran / water (10 mL / 2 mL), and then triphenylphosphine (1.56 g, 5.96 mmol) was added. The resulting mixture was stirred at room temperature and reacted for 2 hours. After the reaction was complete, the solvent was removed by reducing the pressure, and the residue was purified by silica gel column chromatography to obtain 5-(aminomethyl)-1-ethylpyrrolidine-2-one (265 mg, yield: 99.9%). LC-MS m / z: 143.

[0442] 7) Synthesis of 3-((1-ethyl-5-oxopyrrolidine-2-yl)methyl)amino)-4-nitrobenzoate methyl:

[0443] [ka]

[0444] At room temperature, 5-(aminomethyl)-1-ethylpyrrolidine-2-one (500 mg, 3.52 mmol), methyl 3-fluoro-4-nitrobenzoate (700 mg, 3.52 mmol), and potassium carbonate (972 mg, 7.04 mmol) were dissolved in N,N-dimethylformamide (10 mL) solution. The resulting mixture was stirred at room temperature and reacted for 16 hours. After the reaction was complete, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (20 mL x 2). The organic phases were combined and back-extracted with saline solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain methyl 3-((1-ethyl-5-oxopyrrolidine-2-yl)methyl)amino)-4-nitrobenzoate (120 mg, yield: 10.6%).

[0445] 8) Synthesis of 4-amino-3-((1-ethyl-5-oxopyrrolidine-2-yl)methyl)amino)methyl benzoate:

[0446] [ka]

[0447] At room temperature, palladium carbon (20 mg) was added to a methanol (10 mL) solution containing methyl 3-((1-ethyl-5-oxopyrrolidine-2-yl)methyl)amino)-4-nitrobenzoate (120 mg, 0.37 mmol). The resulting mixture was degassed and charged three times with hydrogen gas, stirred at room temperature, and reacted for 16 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain methyl 4-amino-3-((1-ethyl-5-oxopyrrolidine-2-yl)methyl)amino)benzoate (100 mg, yield: 92.9%). LC-MS m / z: 292.

[0448] 9) Synthesis of 4-amino-3-((1-ethyl-5-oxopyrrolidine-2-yl)methyl)amino)methyl benzoate:

[0449] [ka]

[0450] At room temperature, 100 mg, 0.31 mmol of 4-amino-3-((1-ethyl-5-oxopyrrolidine-2-yl)methyl)amino)methyl benzoate was dissolved in 3 mL of anhydrous tetrahydrofuran, and then 106 mg, 0.62 mmol of anhydrous chloroacetic acid was gradually added. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated using a jiany to remove the solvent, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain 100 mg, yield: 87.9% of 4-(2-chloroacetamide)-3-((1-ethyl-5-oxopyrrolidine-2-yl)methyl)aminobenzoate. LC-MS m / z: 368.

[0451] Examples 1-24, Synthesis of (S)-4-(2-chloroacetamide)-3-((1-ethylpyrrolidine-2-yl)methyl)aminobenzoate methyl (intermediate A-24): 1) Synthesis of (S)-3-((1-ethylpyrrolidine-2-yl)methyl)amino)-4-nitrobenzoate methyl:

[0452] [ka]

[0453] At room temperature, methyl 3-fluoro-4-nitrobenzoate (7.77 g, 39.04 mmol), (S)-(1-ethylpyrrolidine-2-yl)formamide (5.00 g, 39.04 mmol), and potassium carbonate (16.16 g, 117.12 mmol) were dissolved in N,N-dimethylformamide (70 mL). The resulting mixture was stirred at room temperature and reacted for 16 hours. After the reaction was complete, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and back-extracted with saline solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain methyl (S)-3-((1-ethylpyrrolidine-2-yl)methyl)amino)-4-nitrobenzoate (9.30 g, yield: 77.7%). LC-MS m / z:308.

[0454] 2) Synthesis of (S)-4-amino-3-((1-ethylpyrrolidine-2-yl)methyl)aminobenzoate:

[0455] [ka]

[0456] At room temperature, 3.07 g, 10.00 mmol of (S)-3-((1-ethylpyrrolidine-2-yl)methyl)amino)-4-nitrobenzoate methyl (2.3 g, yield: 80.0%) was dissolved in methanol (50 mL), and then 1.50 g, 14.00 mmol of palladium carbon was added. The resulting mixture was degassed, packed three times with hydrogen gas, and stirred at room temperature for 4 hours. After the reaction was complete, the mixture was filtered, and the filter cake was washed with methanol (50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain 2.3 g, yield: 80.0%) of (S)-4-amino-3-((1-ethylpyrrolidine-2-yl)methyl)aminobenzoate methyl (2.3 g, yield: 80.0%). LC-MS m / z: 278.

[0457] 3) Synthesis of (S)-4-(2-chloroacetamide)-3-((1-ethylpyrrolidine-2-yl)methyl)aminobenzoate:

[0458] [ka]

[0459] At room temperature, anhydrous chloroacetic acid (111 mg, 0.65 mmol) was gradually added to a solution of anhydrous tetrahydrofuran (20 mL) containing (S)-4-amino-3-((1-ethylpyrrolidine-2-yl)methyl)aminobenzoate methyl (120 mg, 0.43 mmol). The mixture was stirred at room temperature and reacted for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain (S)-4-(2-chloroacetamide)-3-((1-ethylpyrrolidine-2-yl)methyl)aminobenzoate methyl (140 mg, yield: 91.5%). LC-MS m / z: 354.

[0460] Examples 1-25, Synthesis of (S)-N-(4-bromo-2-methyl-6-((oxetane-2-ylmethyl)amino)phenyl)-2-chloroacetamide (intermediate A-25): 1) Synthesis of (S)-5-bromo-3-methyl-2-nitro-N-(oxetan-2-ylmethyl)aniline:

[0461] [ka]

[0462] At room temperature, 5-bromo-1-fluoro-3-methyl-2-nitrobenzene (500 mg, 2.14 mmol), compound (S)-oxetane-2-ylmethaneamine (186 mg, 2.14 mmol), and potassium carbonate (590 mg, 4.28 mmol) were dissolved in N,N-dimethylformamide (5 mL). The resulting mixture was stirred at room temperature and reacted for 16 hours. After the reaction was complete, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with saline solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain (S)-5-bromo-3-methyl-2-nitro-N-(oxetane-2-ylmethyl)aniline (490 mg, yield: 76.2%). LC-MS m / z: 301.

[0463] 2) Synthesis of (S)-5-bromo-3-methyl-N-(oxetane-2-ylmethyl)benzene-1,2-diamine:

[0464] [ka]

[0465] At room temperature, zinc powder (1.06 g, 16.30 mmol) was added to a methanol (5 mL) solution containing (S)-5-bromo-3-methyl-2-nitro-N-(oxetan-2-ylmethyl)aniline (490 mg, 1.63 mmol). The resulting mixture was stirred at room temperature and reacted for 2 hours. After the reaction was complete, the reaction solution was filtered. The filtrate obtained with aqueous ammonia was then adjusted to a pH of 7-8. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain (S)-5-bromo-3-methyl-N-(oxetan-2-ylmethyl)benzene-1,2-diamine (269 mg, yield: 60.7%). LC-MS m / z: 271.

[0466] 3) Synthesis of (S)-N-(4-bromo-2-methyl-6-((oxetane-2-ylmethyl)amino)phenyl)-2-chloroacetamide:

[0467] [ka]

[0468] At room temperature, (S)-5-bromo-3-methyl-N-(oxetane-2-ylmethyl)benzene-1,2-diamine (109 mg, 0.40 mmol) was dissolved in tetrahydrofuran solution (3 mL), and then anhydrous chloroacetic acid (75 mg, 0.44 mmol) was added. The resulting mixture was stirred at room temperature and reacted for 1 hour. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain (S)-N-(4-bromo-2-methyl-6-((oxetane-2-ylmethyl)amino)phenyl)-2-chloroacetamide (98 mg, yield: 70.4%). LC-MS m / z: 349.

[0469] Examples 1-26, Synthesis of (S)-2-(chloromethyl)-4-methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-methyl formate (intermediate A-26): 1) Synthesis of (S)-4-amino-3-methyl-5-((oxetan-2-ylmethyl)amino)methyl benzoate:

[0470] [ka]

[0471] At room temperature, (S)-5-bromo-3-methyl-N-(oxetan-2-ylmethyl)benzene-1,2-diamine (130 mg, 0.48 mmol), 1,1'-bisdiphenylphosphinoferocenedichloropalladium (37 mg, 0.05 mmol), and potassium acetate (141 mg, 1.44 mmol) were dissolved in a mixed solution of N,N-dimethylformamide / methanol (2 mL / 2 mL). The mixture was stirred at 90°C and under carbon monoxide protection at 58.76 psi and reacted for 16 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain (S)-4-amino-3-methyl-5-((oxetan-2-ylmethyl)amino)methyl benzoate (50 mg, yield: 41.5%). LC-MS m / z: 251.

[0472] 2) Synthesis of (S)-2-(chloromethyl)-4-methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-methyl formate:

[0473] [ka]

[0474] At room temperature, 50 mg, 0.20 mmol of (S)-4-amino-3-methyl-5-((oxetan-2-ylmethyl)amino)methyl benzoate was dissolved in 2 mL of tetrahydrofuran solution, and then 51 mg, 0.30 mmol of anhydrous chloroacetic acid was added. The resulting mixture was stirred at room temperature and reacted for 1 hour. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 20 mg, yield: 32.6% of (S)-2-(chloromethyl)-4-methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl4-methyl ((oxetan-2-ylmethyl

[0475] Examples 1-27, Synthesis of 4-(2-chloroacetamide)-3-(1-ethyl-1H-pyrazole-5-yl)methyl)aminobenzoate methyl (intermediate A-27): 1) Synthesis of methyl 1-ethyl-1H-pyrazole-5-formate:

[0476] [ka]

[0477] At 0°C, 1-ethyl-1H-pyrazole-5-formate (770 mg, 5.50 mmol) was dissolved in methanol (8 mL), and then (diazomethyl)trimethylsilane (2.0 M tetrahydrofuran solution, 27.5 mL, 55.00 mmol) was added. The resulting mixture was stirred at room temperature and reacted for 1 hour. After the reaction was complete, it was quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layer was back-extracted with saline (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl 1-ethyl-1H-pyrazole-5-formate (600 mg, yield: 70.8%). LC-MS m / z: 155.

[0478] 2) Synthesis of (1-ethyl-1H-pyrazole-5-yl)methanol:

[0479] [ka]

[0480] At 0°C, methyl 1-ethyl-1H-pyrazole-5-formate (600 mg, 3.90 mmol) was dissolved in anhydrous tetrahydrofuran solution (8 mL), and then lithium aluminum tetrahydrogen (296 mg, 7.80 mmol) was gradually added. The mixture was stirred at room temperature and allowed to react for 1 hour. After the reaction was complete, the reaction was quenched by adding water (2 mL) and aqueous sodium hydroxide solution (2 mL, 15%). The mixture was filtered and concentrated under reduced pressure to obtain (ethyl-1H-pyrazole-5-yl)methanol (400 mg, yield: 81.4%). LC-MS m / z: 127.

[0481] 3) Synthesis of 5-(chloromethyl)-1-ethyl-1H-pyrazole:

[0482] [ka]

[0483] At 0°C, (1-ethyl-1H-pyrazole-5-yl)methanol (400 mg, 3.17 mmol) was dissolved in dichloromethane (20 mL) solution, and then triethylamine (640 mg, 6.34 mmol) and methanesulfonyl chloride (729 mg, 6.34 mmol) were added. The mixture was stirred at room temperature and reacted for 2 hours. After the reaction was complete, the mixture was quenched with water (100 mL) and extracted with dichloromethane (50 mL x 2). The organic layer was back-extracted with saline (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-(chloromethyl)-1-ethyl-1H-pyrazole (400 mg, yield: 87.0%). LC-MS m / z: 145.

[0484] 4) Synthesis of 5-(azidomethyl)-1-ethyl-1H-pyrazole:

[0485] [ka]

[0486] At room temperature, 5-(chloromethyl)-1-ethyl-1H-pyrazole (400 mg, 2.76 mmol) and sodium azide (359 mg, 5.52 mmol) were dissolved in N,N-dimethylformamide (4 mL) solution. The resulting mixture was stirred at 120°C and reacted for 16 hours. After the reaction was complete, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and back-extracted with saline solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-(azidomethyl)-1-ethyl-1H-pyrazole (370 mg, yield: 88.8%). LC-MS m / z: 152.

[0487] 5) Synthesis of (1-ethyl-1H-pyrazole-5-yl)methylamine:

[0488] [ka]

[0489] At room temperature, 320 mg (2.12 mmol) of 5-(azidomethyl)-1-ethyl-1H-pyrazole was dissolved in a mixed and stirred solution of tetrahydrofuran / water (4 mL / 0.4 mL), and then triphenylphosphine (1.1 g, 4.24 mmol) was added. The reaction was stirred at room temperature for 5 hours. After the reaction was complete, the solvent was removed by concentrating under reduced pressure to obtain (1-ethyl-1H-pyrazole-5-yl)methylamine (265 mg, yield: 99.9%).

[0490] 6) Synthesis of methyl 3-((1-ethyl-1H-pyrazole-5-yl)methyl)amino)-4-nitrobenzoate:

[0491] [ka]

[0492] (1-ethyl-1H-pyrazole-5-yl)methylamine (265 mg, 2.12 mmol), methyl 3-fluoro-4-nitrobenzoate (422 mg, 2.12 mmol), and potassium carbonate (585 mg, 4.24 mmol) were dissolved in N,N-dimethylformamide (7 mL) solution and stirred at room temperature for 16 hours. After the reaction was complete, the mixture was diluted with water (60 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and back-extracted with saline solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain methyl 3-((1-ethyl-1H-pyrazole-5-yl)methyl)amino)-4-nitrobenzoate (100 mg, yield: 15.5%). LC-MS m / z: 346.

[0493] 7) Synthesis of methyl 4-amino-3-((1-ethyl-1H-pyrazole-5-yl)methyl)amino)benzoate:

[0494] [ka]

[0495] At room temperature, 130 mg, 0.43 mmol of methyl 3-((1-ethyl-1H-pyrazole-5-yl)methyl)amino)-4-nitrobenzoate was dissolved in 12 mL of methanol, and then 50 mg, 30.42 mmol of palladium carbon was added. The resulting mixture was degassed and then charged three times with hydrogen gas, stirred at room temperature, and reacted for 16 hours. After the reaction was complete, the reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to obtain 70 mg, yield: 59.4%, of methyl 4-amino-3-((1-ethyl-1H-pyrazole-5-yl)methyl)amino)benzoate. LC-MS m / z: 275.

[0496] 8) Synthesis of methyl 4-(2-chloroacetamide)-3-(1-ethyl-1H-pyrazole-5-yl)methyl)aminobenzoate:

[0497] [ka]

[0498] At room temperature, 70 mg, 0.26 mmol of methyl 4-amino-3-((1-ethyl-1H-pyrazole-5-yl)methyl)amino)benzoate was dissolved in tetrahydrofuran (3 mL) solution to which anhydrous chloroacetic acid (111 mg, 0.65 mmol) was gradually added. The mixture was stirred at room temperature and reacted for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain methyl 4-(2-chloroacetamide)-3-(1-ethyl-1H-pyrazole-5-yl)methyl)aminobenzoate (60 mg, yield: 65.7%). LC-MS m / z: 351.

[0499] Examples 1-28, Synthesis of 4-(2-chloroacetamide)-3-((1-ethyl-3-methyl-1H-pyrazole-5-yl)methyl)amino)methyl benzoate (intermediate A-28): 1) Synthesis of methyl 1-ethyl-3-methyl-1H-pyrazole-5-formate:

[0500] [ka]

[0501] At 0°C, 1-ethyl-3-methyl-1H-pyrazole-5-formate (1.00 g, 6.49 mmol) was dissolved in methanol (10 mL), and then (diazomethyl)trimethylsilane (2.0 M tetrahydrofuran solution, 32.45 mL, 64.90 mmol) was added. The resulting mixture was stirred at room temperature and reacted for 1 hour. After the reaction was complete, it was quenched with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was back-extracted with saline (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl 1-ethyl-3-methyl-1H-pyrazole-5-formate (800 mg, yield: 73.4%). LC-MS m / z: 169.

[0502] 2) Synthesis of (1-ethyl-3-methyl-1H-pyrazole-5-yl)methanol:

[0503] [ka]

[0504] At 0°C, methyl 1-ethyl-3-methyl-1H-pyrazole-5-formate (800 mg, 4.76 mmol) was dissolved in anhydrous tetrahydrofuran solution (10 mL), and then lithium aluminum tetrahydrogen (543 mg, 14.28 mmol) was gradually added. The mixture was stirred at room temperature and allowed to react for 1 hour. After the reaction was complete, water (2 mL) and aqueous sodium hydroxide solution (2 mL, 15%) were added to quench the reaction. The mixture was filtered and then concentrated under reduced pressure to obtain (ethyl-3-methyl-1H-pyrazole-5-yl)methanol (550 mg, yield: 82.5%). LC-MS m / z: 141.

[0505] 3) Synthesis of 5-(chloromethyl)-1-ethyl-3-methyl-1H-pyrazole:

[0506] [ka]

[0507] At 0°C, (1-ethyl-3-methyl-1H-pyrazole-5-yl)methanol (550 mg, 3.93 mmol) was dissolved in dichloromethane (20 mL) solution, and then triethylamine (794 mg, 7.86 mmol) and methanesulfonyl chloride (679 mg, 5.90 mmol) were added. The mixture was stirred at room temperature and reacted for 2 hours. After the reaction was complete, the mixture was quenched with water (100 mL) and extracted with dichloromethane (50 mL x 2). The organic layer was back-extracted with saline (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-(chloromethyl)-1-ethyl-3-methyl-1H-pyrazole (500 mg, yield: 80.0%). LC-MS m / z: 159.

[0508] 4) Synthesis of 5-(azidomethyl)-1-ethyl-3-methyl-1H-pyrazole:

[0509] [ka]

[0510] At room temperature, 5-(chloromethyl)-1-ethyl-3-methyl-1H-pyrazole (450 mg, 2.83 mmol) and sodium azide (368 mg, 5.66 mmol) were dissolved in N,N-dimethylformamide (4 mL) solution. The resulting mixture was stirred at 120°C and reacted for 16 hours. After the reaction was complete, the mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and back-extracted with saline solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-(azidomethyl)-1-ethyl-3-methyl-1H-pyrazole (350 mg, yield: 75.0%). LC-MS m / z: 166.

[0511] 5) Synthesis of (1-ethyl-3-methyl-1H-pyrazole-5-yl)methylamine:

[0512] [ka]

[0513] At room temperature, compound 5-(azidomethyl)-1-ethyl-3-methyl-1H-pyrazole (350 mg, 2.12 mmol) was dissolved in a mixed and stirred solution of tetrahydrofuran / water (7 mL / 0.7 mL), and then triphenylphosphine (1.1 g, 4.24 mmol) was added. The mixture was stirred at room temperature for 5 hours. After the reaction was complete, the solvent was removed under vacuum to obtain a colorless oily compound (1-ethyl-3-methyl-1H-pyrazole-5-yl)methylamine (286 mg, yield: 97.1%). LC-MS m / z: 140.

[0514] 6) Synthesis of methyl 3-((1-ethyl-3-methyl-1H-pyrazole-5-yl)methyl)amino)-4-nitrobenzoate:

[0515] [ka]

[0516] At room temperature, (1-ethyl-3-methyl-1H-pyrazole-5-yl)methylamine (286 mg, 2.06 mmol), methyl 3-fluoro-4-nitrobenzoate (410 mg, 2.06 mmol), and potassium carbonate (569 mg, 4.12 mmol) were dissolved in N,N-dimethylformamide (8 mL). The resulting mixture was stirred at room temperature and reacted for 16 hours. After the reaction was complete, it was diluted with water (50 mL) and extracted with ethyl acetate (25 mL x 2). The organic phases were combined and back-extracted with saline solution (25 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain 3-((1-ethyl-3-methyl-1H-pyrazole-5-yl)methyl)amino)-4-nitrobenzoate methyl (300 mg, yield: 45.8%). LC-MS m / z: 319.

[0517] 7) Synthesis of methyl 4-amino-3-((1-ethyl-3-methyl-1H-pyrazole-5-yl)methyl)amino)benzoate:

[0518] [ka]

[0519] At room temperature, 330 mg, 1.04 mmol of 3-((1-ethyl-3-methyl-1H-pyrazole-5-yl)methyl)amino)-4-nitrobenzoate methyl ester (330 mg, 1.04 mmol) was dissolved in methanol (24 mL), and then palladium carbon (50 mg, 30.42 mmol) was added. The resulting mixture was degassed and then packed three times with hydrogen gas and stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to obtain 4-amino-3-((1-ethyl-3-methyl-1H-pyrazole-5-yl)methyl)amino)benzoate methyl ester (200 mg, yield: 67.1%). LC-MS m / z: 289.

[0520] 8) Synthesis of 4-(2-chloroacetamide)-3-((1-ethyl-3-methyl-1H-pyrazole-5-yl)methyl)amino)methyl benzoate:

[0521] [ka]

[0522] At room temperature, 200 mg (0.69 mmol) of methyl 4-amino-3-((1-ethyl-3-methyl-1H-pyrazole-5-yl)methyl)amino)methyl benzoate was dissolved in tetrahydrofuran (4 mL), to which anhydrous chloroacetic acid (296 mg, 1.73 mmol) was gradually added. The mixture was stirred at room temperature and reacted for 2 hours. After the reaction was complete, the solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain methyl 4-(2-chloroacetamide)-3-((1-ethyl-3-methyl-1H-pyrazole-5-yl)methyl)amino)methyl benzoate (200 mg, yield: 79.4%). LC-MS m / z: 365.

[0523] Examples 1-29, synthesis of other parts of Class A intermediates: The following intermediates can be obtained by following synthesis steps similar to those for each intermediate in Examples 1-1 to 1-28.

[0524] [Table 4]

[0525] TIFF2026082907000229.tif225169

[0526] TIFF2026082907000230.tif220169

[0527] TIFF2026082907000231.tif216169

[0528] TIFF2026082907000232.tif132169

[0529] Example 2-1, Synthesis of 3-fluoro-4-((6-(piperidine-4-oxy)pyridine-2-yl)methoxy)benzonitrile (intermediate B-1): 1) Synthesis of tert-butyl 4-(6-bromopyridine-2-yl)oxy)piperidine-1-formate:

[0530] [ka]

[0531] Under conditions of 0°C, sodium hydride (60% w / w dispersed in mineral oil, 597 mg, 14.93 mmol) was added to a tetrahydrofuran (30 mL) solution in which compound 4-hydroxypiperidine-1-formate tert-butyl (2.00 g, 9.95 mmol) was dissolved. The mixture was stirred at 0°C for 30 min, and then 2-bromo-6-fluoropyridine (2.09 g, 11.94 mmol) was gradually added. The reaction mixture was stirred at 70°C for 4 hours, and after the reaction was complete, the reaction was quenched with water (30 mL) at room temperature, and then extracted twice with ethyl acetate (50 mL / batch). The organic layers were washed twice with saline solution (30 mL / wash), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 4-(6-bromopyridine-2-yl)oxy)piperidine-1-formate tert-butyl (1.80 g, 5.06 mmol, yield: 50.9%). LC-MS m / z: 356.9,358.9 [M+H] + .

[0532] 2) Synthesis of 6-((1-(tert-butoxycarbonyl)piperidine-4-yl)oxy)methyl picolinate:

[0533] [ka]

[0534] At room temperature and under CO protection at a pressure of 58.76 psi, a methanol (5 mL) solution containing compound 4-(6-bromopyridine-2-yl)oxy)piperidine-1-formate tert-butyl (1.80 g, 5.06 mmol) was prepared. Potassium acetate (1.49 g, 15.18 mmol) and 1,1'-bisdiphenylphosphinoferocenedichloropalladium (373 mg, 0.51 mmol) were added. The mixture was stirred at 90°C for 16 hours. The reaction was quenched with water (15 mL), and then extracted three times with ethyl acetate (30 mL / batch). The organic layers were washed twice with saline solution (30 mL / wash), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by reverse-phase flash chromatography under the following conditions (column: spherical C18, 20-40 μm, 120 g; mobile phase A: water (with 10 mM aqueous ammonia added); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 60%B-80%B within 20 min; detector: 254 nm). The mobile phase containing the desired product was collected at 70%B and concentrated under reduced pressure to obtain 6-((1-(tert-butoxycarbonyl)piperidine-4-yl)oxy)methyl picolinate (1.50 g, 4.46 mmol, yield: 88.1%). LC-MS m / z: 337 [M+H] + .

[0535] 3) Synthesis of 4-(6-(hydroxymethyl)pyridine-2-yl)oxy)piperidine-1-formate tert-butyl:

[0536] [ka]

[0537] At 0°C, methyl 6-((1-(tert-butoxycarbonyl)piperidine-4-yl)oxy)picolinate (500 mg, 1.49 mmol) was dissolved in methanol (5 mL), to which sodium borohydride (170 mg, 4.47 mmol) and lithium chloride (6 mg, 0.15 mmol) were added. The mixture was stirred at 50°C for 16 hours. Water (5 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (20 mL / batch). The combined organic layers were washed twice with saline solution (10 mL / wash), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by reverse-phase flash chromatography under the following conditions: (column: spherical C18, 20-40 μm, 120 g; mobile phase A: water (with 10 mM aqueous ammonia added); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 60%B-80%B within 20 min; detector: 254 nm). The mobile phase containing the desired product was collected and concentrated under reduced pressure to obtain 4-(6-(hydroxymethyl)pyridine-2-yl)oxy)piperidine-1-formate tert-butyl (200 mg, 0.65 mmol, yield: 43.6%). LC-MS m / z: 309 [M+H] + .

[0538] 4) Synthesis of 4-(6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)oxy)piperidine-1-formate tert-butyl:

[0539] [ka]

[0540] Under conditions of 0°C, triphenylphosphine (257 mg, 0.98 mmol) was added to a solution of tetrahydrofuran (10 mL) containing compound 4-(6-(hydroxymethyl)pyridine-2-yl)oxy)piperidine-1-formate tert-butyl (200 mg, 0.65 mmol) and 3-fluoro-4-hydroxybenzonitrile (89 mg, 0.65 mmol). Then, at 0°C, diisopropyl azodicarboxylic acid (198 mg, 0.98 mmol) was added dropwise. The mixture was then stirred at room temperature for 16 hours. The resulting mixture was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain 4-(6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)oxy)piperidine-1-formate tert-butyl (250 mg, 0.59 mmol, yield: 90.8%). LC-MS m / z: 428 [M+H] + .

[0541] 5) Synthesis of 3-fluoro-4-((6-(piperidine-4-oxy)pyridine-2-yl)methoxy)benzonitrile (intermediate B-1):

[0542] [ka]

[0543] At room temperature, 250 mg, 0.59 mmol of tert-butyl 4-(6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)oxy)piperidine-1-formate was dissolved in 15 mL of dichloromethane, to which trifluoroacetic acid (3 mL) was added dropwise. The solution was then stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to obtain the crude product, which was then further purified by reverse-phase flash chromatography under the following conditions: column: spherical C18, 20-40 μm, 120 g; mobile phase A: water (with 10 mM aqueous ammonia added); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 40%B-60%B within 20 min; detector: 254 nm. The mobile phase containing the required product was collected at 52% B and concentrated under reduced pressure to obtain 3-fluoro-4-((6-(piperidine-4-oxy)pyridine-2-yl)methoxy)benzonitrile (180 mg, 0.55 mmol, yield: 93.2%). LC-MS m / z: 328 [M+H] + .

[0544] Example 2-2, Synthesis of 3-fluoro-4-((6-((piperidine-4-yloxy)methyl)pyridine-2-yloxy)methyl)benzonitrile (intermediate B-2): 1) Synthesis of tert-butyl 4-(6-fluoropyridine-2-yl)methoxy)piperidine-1-formate:

[0545] [ka]

[0546] Under 0°C conditions, 1.06 g, 5.26 mmol of 4-hydroxypiperidine-1-formate tert-butyl was dissolved in tetrahydrofuran (15 mL). Sodium hydride (60% w / w dispersed in mineral oil, 252 mg, 6.31 mmol) was added, and the mixture was stirred for 30 minutes. Then, 500 mg, 2.63 mmol of 2-(bromomethyl)-6-fluoropyridine was gradually added. The mixture was then stirred at room temperature for 16 hours, the reaction was quenched with methanol (10 mL) at room temperature, and the mixture was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 4-(6-fluoropyridine-2-yl)methoxy)piperidine-1-formate tert-butyl (447 mg, yield: 54.8%). LC-MS m / z: 311 [M+H] + .

[0547] 2) Synthesis of 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)methoxy)piperidine-1-formate tert-butyl:

[0548] [ka]

[0549] At 0°C, sodium hydride (60% w / w dispersed in mineral oil, 185 mg, 4.62 mmol) was added to a tetrahydrofuran (10 mL) solution containing 3-fluoro-4-(hydroxymethyl)benzonitrile (581 mg, 3.85 mmol), and the mixture was stirred for 30 minutes. Then, at 0°C, compound 4-(6-fluoropyridine-2-yl)methoxy)piperidine-1-formate tert-butyl (240 mg, 0.77 mmol) was gradually added. The mixture was stirred at 70°C for 16 hours, the reaction was quenched with water (20 mL) at room temperature, and the organic phase was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)methoxy)piperidine-1-formate (281 mg, 82.4%). LC-MS m / z: 442 [M+H] + .

[0550] 3) Synthesis of 3-fluoro-4-((6-((piperidine-4-yloxy)methyl)pyridine-2-yloxy)methyl)benzonitrile:

[0551] [ka]

[0552] 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)methoxy)piperidine-1-formate tert-butyl (400 mg, 0.91 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was added. The solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the resulting mixture was adjusted to pH = 8-9 with a methanol solution of ammonia (7 M) and concentrated again. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 3-fluoro-4-((6-((piperidine-4-yloxy)methyl)pyridine-2-yloxy)methyl)benzonitrile (301 mg, yield: 97.4%). LC-MS m / z: 342 [M+H] + .

[0553] Examples 2-3, Synthesis of 3-fluoro-4-((6-(piperidine-4-ylmethoxy)pyridine-2-yl)oxy)methyl)benzonitrile (intermediate B-3): 1) Synthesis of 4-((6-fluoropyridine-2-yl)oxy)methyl)piperidine-1-formate tert-butyl:

[0554] [ka]

[0555] At 0°C, sodium hydride (60% w / w dispersion in mineral oil, 837 mg, 20.93 mmol) was added to a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-formate (3.0 g, 13.93 mmol) in anhydrous tetrahydrofuran (50 mL). The mixture was stirred at 0°C for 30 min, and then 2,6-difluoropyridine (2.41 g, 20.94 mmol) was gradually added at 0°C. The mixture was stirred at 70°C for 5 h. After the reaction was complete, the reaction was quenched with water (200 mL) at 0°C and extracted with dichloromethane (3 × 50 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=4 / 1) to obtain tert-butyl 4-((6-fluoropyridine-2-yl)oxy)methyl)piperidine-1-formate (2.0 g, 6.44 mmol, yield: 46.2%). LC-MS m / z: 311 [M+H] + .

[0556] 2) Synthesis of tert-butyl 4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)methyl)piperidine-1-formate ester

[0557] [ka]

[0558] At 0°C, 3-fluoro-4-(hydroxymethyl)benzonitrile (365 mg, 2.41 mmol) was dissolved in anhydrous THF (50 mL) solvent, to which sodium hydride (60% w / w dispersion in mineral oil, 97 mg, 2.42 mmol) was added. The mixture was stirred at 0°C for 30 min, and then compound 4-((6-fluoropyridine-2-yl)oxy)methyl)piperidine-1-formate tert-butyl (500 mg, 1.61 mmol) was gradually added at 0°C. The mixture was stirred at 70°C for 5 h, quenched with water (30 mL) at 0°C, and extracted with dichloromethane (3 × 10 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=5 / 1) to obtain tert-butyl 4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)methyl)piperidine-1-formate (400 mg, 0.91 mmol, yield 56.3%). LC-MS m / z: 442 [M+H] + .

[0559] 3) Synthesis of 3-fluoro-4-((6-(piperidine-4-ylmethoxy)pyridine-2-yl)oxy)methyl)benzonitrile

[0560] [ka]

[0561] 400 mg, 0.91 mmol of tert-butyl 4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)methyl)piperidine-1-formate (400 mg, 0.91 mmol) was dissolved in dichloromethane (5 mL), to which trifluoroacetic acid (1 mL) was added and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate (30 mL) solution and extracted with dichloromethane (10 mL x 2). The extract was concentrated and the residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain 3-fluoro-4-((6-(piperidine-4-ylmethoxy)pyridine-2-yl)oxy)methyl)benzonitrile (250 mg, 0.73 mmol, yield: 80.6%). LC-MS m / z: 342 [M+H] + .

[0562] Examples 2-4, Synthesis of 3-fluoro-4-((6-(piperidine-4-oxy)pyridine-2-yl)oxy)methyl)benzonitrile (intermediate B-4) 1) Synthesis of tert-butyl 4-(6-fluoropyridine-2-yl)oxy)piperidine-1-formate

[0563] [ka]

[0564] At 0°C, sodium hydride (60% w / w dispersion in mineral oil, 870 mg, 21.74 mmol) was added to a solution of tert-butyl 4-hydroxypiperidine-1-formate (3.50 g, 17.39 mmol) in anhydrous tetrahydrofuran (20 mL). The mixture was stirred at 0°C for 30 min, and then 2,6-difluoropyridine (2.00 g, 17.38 mmol) was gradually added at 0°C. The mixture was heated to 80°C and stirred for 4 hours, then quenched with water (20 mL) at room temperature, and extracted with ethyl acetate (20 mL x 2). The organic layers were washed together with saline solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain 4-(6-fluoropyridine-2-yl)oxy)piperidine-1-formate tert-butyl (5.10 g, 17.21 mmol, yield: 99.2%).

[0565] 1H NMR(400 MHz, DMSO-d6)δ 7.86(dd, J = 16.8, 8.0 Hz, 1H), 6.73(dd, J = 8.0, 1.6 Hz, 1H), 6.68(dd, J = 7.6, 2.4 Hz, 1H), 5.06 - 5.02(m, 1H), 3.70 - 3.64(m, 2H), 3.20 - 3.15(m, 2H), 1.96 - 1.90(m, 2H), 1.58 - 1.49(m, 2H), 1.40(s, 9H).

[0566] 2) Synthesis of 4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)piperidine-1-formate tert-butyl

[0567] [ka]

[0568] At 0°C, 3-fluoro-4-(hydroxymethyl)benzonitrile (1.22 g, 8.07 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) to which sodium hydride (60% w / w dispersion in mineral oil, 541 mg, 13.52 mmol) was added. The mixture was stirred at 0°C for 30 min, and then compound 4-(6-fluoropyridine-2-yl)oxy)piperidine-1-formate tert-butyl (2.00 g, 6.75 mmol) was gradually added at 0°C. The reaction mixture was then heated to 70°C and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and the reaction was quenched with water (20 mL) and extracted with EA (20 mL x 2). The combined organic layers were washed with saline solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain 4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)piperidine-1-formate tert-butyl (1.52 g, 3.56 mmol, yield: 55.6%). LC-MS m / z: 372 [M+H] + .

[0569] 3) Synthesis of 3-fluoro-4-((6-(piperidine-4-oxy)pyridine-2-yl)oxy)methyl)benzonitrile

[0570] [ka]

[0571] Compound 4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)piperidine-1-formate tert-butyl (1.52 g, 3.56 mmol) was dissolved in dichloromethane (15 mL), to which trifluoroacetic acid (3 mL) was added. The reaction mixture was then stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated, and the resulting mixture was adjusted to pH = 8-9 with a methanol solution of ammonia (7 M), and then concentrated again. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain 3-fluoro-4-((6-(piperidine-4-oxy)pyridine-2-yl)oxy)methyl)benzonitrile (1.00 g, 3.05 mmol, 86.2%). LC-MS m / z: 328 [M+H] + .

[0572] Examples 2-5, Synthesis of 3-fluoro-4-((6-((piperidine-4-oxy)methyl)pyridine-2-yl)methoxy)benzonitrile (intermediate B-5): 1) Synthesis of methyl 6-(chloromethyl)picolinate

[0573] [ka]

[0574] To a solution of methyl 6-(hydroxymethyl)picolinate (2.00 g, 11.98 mmol) in dichloromethane (20 mL), triethylamine (2.42 g, 23.96 mmol) was added, followed by the gradual addition of methanesulfonyl chloride (1.65 g, 14.38 mmol) at 0°C, and the mixture was stirred at room temperature for 3 hours. Water (10 mL) was then added, and the mixture was extracted with dichloromethane (20 mL x 2). The combined organic layer was washed with saline solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain methyl 6-(chloromethyl)picolinate (1.2 g, yield: 54.2%). LC-MS m / z: 188 [M+H] + .

[0575] 2) Synthesis of 6-((1-(tert-butoxycarbonyl)piperidine-4-yl)oxymethyl)pyridineformic acid

[0576] [ka]

[0577] At 0°C, sodium hydride (60% w / w dispersed in mineral oil, 1.18 g, 29.40 mmol) was added to a tetrahydrofuran (50 mL) solution in which compound 4-hydroxypiperidine-1-formate tert-butyl (4.92 g, 24.50 mmol) was dissolved. The mixture was stirred for 30 minutes, and then methyl 6-(chloromethyl)picolinate (454 mg, 2.45 mmol) was gradually added at 0°C. The reaction was then quenched with water (10 mL) at room temperature and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saline solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 6-((1-(tert-butoxycarbonyl)piperidine-4-yl)oxy)methyl)pyridinformic acid (356 mg, yield: 43.2%). LC-MS m / z: 337 [M+H] + .

[0578] 3) Synthesis of methyl 6-((piperidine-4-oxy)methyl)picolinate

[0579] [ka]

[0580] At 0°C, 6-((1-(tert-butoxycarbonyl)piperidine-4-yl)oxy)methyl)pyridineformic acid (356 mg, 1.06 mmol) was dissolved in methanol (5 mL), to which dichlorosulfoxide (189 mg, 1.59 mmol) was added. The mixture was stirred at 60°C for 2 hours, then quenched with water (10 mL) at room temperature, and extracted with ethyl acetate (10 mL x 2). The combined organic layer was washed with saturated sodium bicarbonate (10 mL) and saline solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain methyl 6-((piperidine-4-oxy)methyl)picolinate (260 mg, 98.1% yield). LC-MS m / z: 251 [M+H] + .

[0581] 4) Synthesis of 6-((1-(tert-butoxycarbonyl)piperidine-4-yl)oxy)methyl)picolinate

[0582] [ka]

[0583] At room temperature, 6-((piperidine-4-oxy)methyl picolinate (260 mg, 1.04 mmol) and triethylamine (315 mg, 3.12 mmol) were dissolved in tetrahydrofuran (3 mL), to which di-tert-butyl dicarbonate (453 mg, 2.08 mmol) was added. The mixture was stirred at room temperature for 16 hours, then quenched with water (10 mL) at room temperature, and extracted with ethyl acetate (10 mL × 2). The combined organic layer was washed with saline solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 6-((1-(tert-butoxycarbonyl)piperidine-4-yl)oxy)methyl picolinate (255 mg, 70.1% yield). LC-MS m / z: 351 [M+H]+ .

[0584] 5) Synthesis of 4-(6-(hydroxymethyl)pyridine-2-yl)methoxy)piperidine-1-formate tert-butyl

[0585] [ka]

[0586] At 0°C, lithium aluminum tetrahydride (27 mg, 0.70 mmol) was added to a solution of 6-((1-(tert-butoxycarbonyl)piperidine-4-yl)oxy)methyl)picolinate (244 mg, 0.70 mmol) in tetrahydrofuran (3 mL). The mixture was stirred at room temperature for 16 hours, then the reaction was quenched with water (10 mL) at room temperature and extracted with ethyl acetate (10 mL x 2). The combined organic layer was washed with saline solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 4-(6-(hydroxymethyl)pyridine-2-yl)methoxy)piperidine-1-formate tert-butyl (107 mg, yield: 39.6%). LC-MS m / z: 323 [M+H] + .

[0587] 6) Synthesis of 4-(6-(chloromethyl)pyridine-2-yl)methoxy)piperidine-1-formate tert-butyl

[0588] [ka]

[0589] To a solution of 4-(6-(hydroxymethyl)pyridine-2-yl)methoxy)piperidine-1-formate tert-butyl (47 mg, 0.15 mmol) dissolved in dichloromethane (1 mL), triethylamine (30 mg, 0.30 mmol) was added, followed by the addition of methanesulfonyl chloride (21 mg, 0.18 mmol) at 0°C. The mixture was stirred at room temperature for 16 hours. Water (10 mL) was then added. Extraction was performed using DCM (20 mL × 2). The combined organic layer was washed with saline solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 4-(6-(chloromethyl)pyridine-2-yl)methoxy)piperidine-1-formate tert-butyl (40 mg, yield: 80.6%). LC-MS m / z: 341 [M+H] + .

[0590] 7) Synthesis of 4-(6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)methoxy)piperidine-1-formate tert-butyl

[0591] [ka]

[0592] At room temperature, potassium carbonate (541 mg, 13.52 mmol) was added to a solution of N,N-dimethylformamide (1 mL) containing the compounds 4-(6-(chloromethyl)pyridine-2-yl)methoxy)piperidine-1-formate tert-butyl (40 mg, 0.12 mmol) and 3-fluoro-4-hydroxybenzonitrile (33 mg, 0.24 mmol). The mixture was stirred at 60°C for 16 hours, quenched with water (10 mL) at room temperature, and extracted with ethyl acetate (10 mL x 2). The combined organic layer was washed with saturated ammonium chloride (20 mL x 3) and saline solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain tert-butyl 4-(6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)methoxy)piperidine-1-formate (35 mg, yield: 67.4%). LC-MS m / z: 442 [M+H] + .

[0593] 8) Synthesis of 3-fluoro-4-((6-((piperidine-4-oxy)methyl)pyridine-2-yl)methoxy)benzonitrile

[0594] [ka]

[0595] 35 mg, 0.08 mmol) of compound 4-(6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)methoxy)piperidine-1-formate tert-butyl was dissolved in dichloromethane (2 mL) to which trifluoroacetic acid (1 mL) was added. The solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the resulting mixture was adjusted to pH = 8-9 with a methanol solution of ammonia (7 M), and then concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 3-fluoro-4-((6-((piperidine-4-oxy)methyl)pyridine-2-yl)methoxy)benzonitrile (27 mg, yield >99%). LC-MS m / z: 342 [M+H] + .

[0596] Example 2-6, Synthesis of 4-((6-(azetidine-3-yloxy)pyridine-2-yloxy)methyl)-3-fluorobenzonitrile (intermediate B-6): 1) Synthesis of tert-butyl 3-(6-fluoropyridine-2-yl)oxy)azetidine-1-formate:

[0597] [ka]

[0598] At 0°C, sodium hydride (694 mg, 17.34 mmol, 60% w / w dispersed in mineral oil) was added to a 30 mL solution of anhydrous THF in which 2.00 g, 11.55 mmol of 3-hydroxyazetidine-1-formate tert-butyl was dissolved. The mixture was stirred at 0°C for 30 min, and then 2,6-difluoropyridine (1.60 g, 13.90 mmol) was gradually added at 0°C. The mixture was heated to 70°C and stirred for 4 hours. After the reaction was complete, the mixture was quenched with water (20 mL) at room temperature and extracted with ethyl acetate (2 × 20 mL). The mixture was washed with brine, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain tert-butyl 3-(6-fluoropyridine-2-yl)oxy)azetidine-1-formate (3.00 g, 11.18 mmol, yield 96.7%). LC-MS m / z: 269 [M+H] + .

[0599] 2) Synthesis of 3-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)azetidine-1-formate tert-butyl:

[0600] [ka]

[0601] At 0°C, 3-fluoro-4-(hydroxymethyl)benzonitrile (1.00 g, 6.62 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) solution to which sodium hydride (60% w / w dispersion in mineral oil, 397 mg, 9.93 mmol) was added. The mixture was stirred at 0°C for 30 min, and then 3-(6-fluoropyridine-2-yl)oxy)azetidine-1-formate tert-butyl (1.33 g, 4.96 mmol) was gradually added at 0°C. The mixture was stirred at 70°C for 4 h, quenched with water (20 mL) at room temperature, and extracted with ethyl acetate (2 × 20 mL). The organic phases were washed together in brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=5 / 1) to obtain 3-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)azetidine-1-formate tert-butyl (1.52 g, 3.81 mmol, yield: 57.4%). LC-MS m / z: 400 [M+H] + .

[0602] 3) Synthesis of 4-((6-(azetidine-3-yloxy)pyridine-2-yloxy)methyl)-3-fluorobenzonitrile:

[0603] [ka]

[0604] 3-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)azetidine-1-formate tert-butyl (900 mg, 2.25 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting mixture was adjusted to pH = 8-9 with methanol solution of ammonia (7 M). After concentration under reduced pressure, the mixture was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain 4-((6-(azetidine-3-yloxy)pyridine-2-yloxy)methyl)-3-fluorobenzonitrile (650 mg, 2.17 mmol, yield: 96.0%). LC-MS m / z: 300 [M+H] + .

[0605] Example 2-7, Synthesis of 3-fluoro-4-((3-(piperidine-4-oxy)phenoxy)methyl)benzonitrile (intermediate B-7): 1) Synthesis of 3-fluoro-4-((3-hydroxyphenoxy)methyl)benzonitrile:

[0606] [ka]

[0607] The mixture was stirred, and resorcinol (1.04 g, 9.52 mmol) and K2CO3 (1.31 g, 9.52 mmol) were added to a solution of 4-bromomethyl-3-fluorobenzonitrile (1.00 g, 4.76 mmol) in acetonitrile (10 mL). The mixture was heated to 100°C and stirred, and the reaction was allowed to proceed for 16 hours. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with EA (3 × 30 mL). The organic phases were combined and washed with saline solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain 3-fluoro-4-((3-hydroxyphenoxy)methyl)benzonitrile (514 mg, 44.0% yield). LC-MS m / z: 244 [M+H]+ .

[0608] 2) Synthesis of 4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-formate tert-butyl:

[0609] [ka]

[0610] The mixture was stirred, and 4-((methanesulfonyl)oxy)piperidine-1-formate tert-butyl (919 mg, 3.29 mmol) and Cs2CO3 (805 mg, 2.47 mmol) were added to a solution of 3-fluoro-4-((3-hydroxyphenoxy)methyl)benzonitrile (200 mg, 0.82 mmol) in DMF (5 mL). The reaction mixture was heated to 100°C and stirred, and the reaction was allowed to proceed for 16 hours. The mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography (column: Spherical C18, 20-40 μm, 120 g, mobile phase A: water (with 10 mM NH3.H2O added), mobile phase B: acetonitrile, flow rate: 80 mL / min, gradient: 40%B-80%B within 20 min, detector: 254 nm). The fraction containing the desired product was collected at 65% B and concentrated under reduced pressure to obtain 4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-formate tert-butyl (180.0 mg, 79.8% yield). LC-MS m / z: 371 [M+H] + .

[0611] 3) Synthesis of 3-fluoro-4-((3-(piperidine-4-oxy)phenoxy)methyl)benzonitrile:

[0612] [ka]

[0613] To a solution of 4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-formate tert-butyl (120.0 mg, 0.282 mmol) in DCM (3 mL), TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. Quenched with saturated NaHCO3 (30 mL) and extracted with DCM (2 × 10 mL). After combining the organic phases and concentrating under reduced pressure, the mixture was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain 3-fluoro-4-((3-(piperidine-4-oxy)phenoxy)methyl)benzonitrile (89.0 mg, 96.8% yield). LC-MS m / z: 327 [M+H] + .

[0614] Example 2-8, Synthesis of 2-((4-chloro-2-fluorobenzyl)oxy)-3-fluoro-6-(piperidine-4-oxy)pyridine (intermediate B-8): 1) Synthesis of 4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)oxypiperidine-1-formate tert-butyl

[0615] [ka]

[0616] At 0°C, sodium hydride (264 mg, 0.56 mmol) was added to a tetrahydrofuran (15 mL) stirring solution containing 4-hydroxypiperidine-1-formate tert-butyl (1.10 g, 5.50 mmol). The mixture was stirred at 0°C for 30 min. Next, at 0°C, 2-((4-chloro-2-fluorobenzyl)oxy)-3,6-difluoropyridine (100 mg, 0.28 mmol) was added. The mixture was heated to 70°C and stirred for 16 h. The desired product was detected by liquid chromatography-mass spectrometry, and the reaction was then quenched with methanol (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saline solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the product 4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)oxypiperidine-1-formate tert-butyl (447 mg, yield: 53.7%). LC-MS m / z: 399 [M+H] + .

[0617] 2) Synthesis of 2-((4-chloro-2-fluorobenzyl)oxy)-3-fluoro-6-(piperidine-4-oxy)pyridine:

[0618] [ka]

[0619] 4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)oxypiperidine-1-formate tert-butyl (447 mg, 0.98 mmol) was dissolved in dichloromethane (10 mL), to which trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. The desired product was detected by liquid chromatography-mass spectrometry, and the mixture was then quenched with water (5 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layer was washed with saline solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the product 2-((4-chloro-2-fluorobenzyl)oxy)-3-fluoro-6-(piperidine-4-oxy)pyridine (199 mg, yield: 57.2%). LC-MS m / z: 355 [M+H] + .

[0620] Example 2-9, Synthesis of 3-fluoro-4-((3-fluoro-6-(piperidine-4-oxy)pyridine-2-yl)methoxy)benzonitrile (intermediate B-9): 1) Synthesis of methyl 3,6-difluoropicolinate:

[0621] [ka]

[0622] Dichlorosulfoxide (4.0 g, 33.96 mmol) was added to a methanol (80 mL) solution containing 3,6-difluoropyridingivenic acid (3.6 g, 22.64 mmol). The solution was stirred at 60°C for 2 hours. The reaction mixture was concentrated. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) yielded methyl 3,6-difluoropicolinate (3.15 g, yield: 80.4%). LC-MS m / z: 174 [M+H] + .

[0623] 2) Synthesis of (3,6-difluoropyridine-2-yl)methanol:

[0624] [ka]

[0625] Sodium borohydride (2.07 g, 54.63 mmol) and lithium chloride (153 mg, 3.64 mmol) were added to a methanol (55 mL) solution containing methyl 3,6-difluoropicolinate (3.15 g, 18.21 mmol). The solution was stirred at 50°C for 4 hours. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain (3,6-difluoropyridine-2-yl)methanol (2.0 g, yield: 91.1%). LC-MS m / z: 146 [M+H] + .

[0626] 3) Synthesis of methyl (3,6-difluoropyridine-2-yl)methanesulfonate:

[0627] [ka]

[0628] Triethylamine (460 mg, 4.55 mmol) was added to a solution of (3,6-difluoropyridine-2-yl)methanol (300 mg, 2.07 mmol) in anhydrous dichloromethane (20 mL). The resulting mixture was cooled to 0°C, methanesulfonyl chloride (358 mg, 3.11 mmol) was gradually added dropwise, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was stirred further at room temperature for 2 hours, then diluted with dichloromethane (50 mL), and back-extracted with saline solution (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, after which it was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain methyl (3,6-difluoropyridine-2-yl)methanesulfonate (272 mg, yield: 58.9%). LC-MS m / z: 224 [M+H] + .

[0629] 4) Synthesis of 4-((3,6-difluoropyridine-2-yl)methoxy)-3-fluorobenzonitrile:

[0630] [ka]

[0631] Methyl (3,6-difluoropyridine-2-yl)methanesulfonate (272 mg, 1.22 mmol) and 3-fluoro-4-hydroxybenzonitrile (167 mg, 1.22 mmol) were dissolved in N,N-dimethylformamide (5 mL). Potassium carbonate (505 mg, 3.66 mmol) was added, and the mixture was stirred at 60°C and reacted for 2 hours. The reaction was quenched with water (15 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with saline solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 4-((3,6-difluoropyridine-2-yl)methoxy)-3-fluorobenzonitrile (270 mg, yield: 83.6%). LC-MS m / z: 265 [M+H] + .

[0632] 5) Synthesis of 4-(6-((4-cyano-2-fluorophenoxy)methyl)-5-fluoropyridine-2-yl)oxypiperidine-1-formate tert-butyl:

[0633] [ka]

[0634] At 0°C, 246 mg, 1.22 mmol of tert-butyl 4-hydroxypiperidine-1-formate was dissolved in 30 mL of tetrahydrofuran. Sodium hydride (60% w / w dispersed in mineral oil, 61 mg, 1.53 mmol) was added to this solution. The mixture was stirred at 0°C and reacted for 30 minutes. Then, 270 mg, 1.02 mmol of 4-((3,6-difluoropyridine-2-yl)methoxy)-3-fluorobenzonitrile was added. The mixture was then stirred at 70°C and reacted for 2 hours. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saline solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) yielded 4-(6-((4-cyano-2-fluorophenoxy)methyl)-5-fluoropyridine-2-yl)oxypiperidine-1-formate tert-butyl (200 mg, yield: 36.9%). LC-MS m / z: 390 [M+H] + .

[0635] 6) Synthesis of 3-fluoro-4-((3-fluoro-6-(piperidine-4-oxy)pyridine-2-yl)methoxy)benzonitrile:

[0636] [ka]

[0637] 4-(6-((4-cyano-2-fluorophenoxy)methyl)-5-fluoropyridine-2-yl)oxypiperidine-1-formate tert-butyl (200 mg, 0.45 mmol) was dissolved in dichloromethane (10 mL) to which trifluoroacetic acid (2 mL) was added. The solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the resulting mixture was adjusted to pH = 8-9 with a methanol solution of ammonia (7 M), and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 3-fluoro-4-((3-fluoro-6-(piperidine-4-oxy)pyridine-2-yl)methoxy)benzonitrile (140 mg, yield: 91.1%). LC-MS m / z: 346 [M+H] + .

[0638] Example 2-10, Synthesis of 2-((4-chloro-2-fluorophenylthio)methyl)-6-(piperidine-4-oxy)pyridine (intermediate B-10): 1) Synthesis of 1,2-bis(4-chloro-2-fluorophenyl)disulfane:

[0639] [ka]

[0640] Compound 4-chloro-1,2-difluorobenzene (1.00 g, 6.76 mmol) and sodium sulfide (1.05 g, 13.52 mmol, 2.0 equivalents) were dissolved in dimethyl sulfoxide (10 mL). The mixture was stirred at 80°C and reacted for 2 hours. The mixture was quenched with water (100 mL) and extracted with dichloromethane (50 mL x 2). The aqueous phase was acidified with hydrochloric acid water to pH=2 and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saline solution (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1,2-bis(4-chloro-2-fluorophenyl)disulfan (700 mg, yield: 32.1%).

[0641] 2) Synthesis of 4-chloro-2-fluorobenzenethiol:

[0642] [ka]

[0643] 1,2-Bis(4-chloro-2-fluorophenyl)disulfan (700 mg, 2.17 mmol) and zinc powder (423 mg, 6.51 mmol) were dissolved in methanol / hydrochloric acid (10% H2O) (10 mL / 10 mL). The mixture was stirred at room temperature and reacted for 2 hours. The resulting mixture was diluted with water (50 mL) and extracted with dichloromethane (20 mL × 3). The organic phase was concentrated under reduced pressure to obtain 4-chloro-2-fluorobenzenethiol (400 mg, yield: 56.9%). LC-MS m / z: 161 [M+H] + .

[0644] 3) Synthesis of 4-(6-((4-chloro-2-fluorophenyl)thio)methyl)pyridine-2-yl)oxypiperidine-1-formate tert-butyl:

[0645] [ka]

[0646] 4-chloro-2-fluorobenzenethiol (400 mg, 2.47 mmol), potassium carbonate (682 mg, 4.94 mmol), and 4-((6-((methylsulfonyl)oxy)methyl)pyridine-2-yl)oxy)piperidine-1-formate tert-butyl (956 mg, 2.47 mmol) were dissolved in N,N-dimethylformamide (20 mL). The mixture was stirred at room temperature and allowed to react for 16 hours. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to obtain 4-(6-((4-chloro-2-fluorophenyl)thio)methyl)pyridine-2-yl)oxypiperidine-1-formate tert-butyl (1.00 g, yield: 89.6%). LC-MS m / z: 453 [M+H] + .

[0647] 4) Synthesis of 2-((4-chloro-2-fluorophenylthio)methyl)-6-(piperidine-4-oxy)pyridine:

[0648] [ka]

[0649] 4-(6-((4-chloro-2-fluorophenylthio)methyl)pyridine-2-yl)oxypiperidine-1-formate tert-butyl (1.00 g, 2.21 mmol) was dissolved in a 10 mL dichloromethane solution to which trifluoroacetic acid (3 mL) was added. The solution was stirred at room temperature and reacted for 2 hours. The mixture was quenched with a 50 mL saturated sodium bicarbonate solution and extracted with dichloromethane (20 mL x 3). The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain 2-((4-chloro-2-fluorophenylthio)methyl)-6-(piperidine-4-oxy)pyridine (700 mg, yield: 90.0%). LC-MS m / z: 353 [M+H] + .

[0650] Example 2-11, Synthesis of 3-fluoro-4-((6-(piperidine-4-oxy)pyridine-2-yl)methyl)thio)benzonitrile (intermediate B-11): 1) Synthesis of 4,4'-dithiodiasylbis(3-fluorobenzonitrile):

[0651] [ka]

[0652] Sodium sulfide (11.22 g, 143.88 mmol) was added to a dimethyl sulfoxide (100 mL) solution containing 3,4-difluorobenzonitrile (10.00 g, 71.89 mmol), and the mixture was stirred at 80°C for 2 hours. After the reaction was complete, the reaction was quenched with water (500 mL) and extracted with dichloromethane (200 mL x 2). The aqueous phase was acidified with hydrochloric acid solution to pH=2 and then extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with saline solution (400 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4,4'-dithiodiasylbis(3-fluorobenzonitrile) (5.70 g, yield: 26.1%).

[0653] 2) Synthesis of 3-fluoro-4-sulfhydrylbenzonitrile:

[0654] [ka]

[0655] 4,4'-Dithiodiacylbis(3-fluorobenzonitrile) (2.00 g, 6.57 mmol) was dissolved in methanol / hydrochloric acid (10% aqueous solution) (10 mL / 10 mL). Zinc powder (1.28 g, 19.58 mmol) was added to this solution, and the mixture was stirred at room temperature and reacted for 2 hours. The resulting mixture was diluted with water (200 mL) and extracted with dichloromethane (80 mL × 3). The organic phase was concentrated to obtain 3-fluoro-4-sulfhydrylbenzonitrile (1.20 g, yield: 59.6%).

[0656] 3) Synthesis of 4-((6-((4-cyano-2-fluorophenyl)thio)methyl)pyridine-2-yl)oxy)piperidine-1-formate tert-butyl:

[0657] [ka]

[0658] 3-Fluoro-4-sulfhydrylbenzonitrile (474 ​​mg, 3.10 mmol) and 4-((6-((methylsulfonyl)oxy)methyl)pyridine-2-yl)oxy)piperidine-1-formate tert-butyl (1.20 g, 3.10 mmol) were dissolved in N,N-dimethylformamide (20 mL). Potassium carbonate (856 mg, 6.20 mmol) was added to the solution, and the mixture was stirred at room temperature and allowed to react for 16 hours. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (80 mL x 3). The organic phases were combined and back-extracted with saline solution (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to obtain 4-((6-((4-cyano-2-fluorophenylthio)methyl)pyridine-2-yl)oxy)piperidine-1-formate tert-butyl (600 mg, yield: 43.7%). LC-MS m / z: 444 [M+H] + .

[0659] 4) Synthesis of 3-fluoro-4-((6-(piperidine-4-oxy)pyridine-2-yl)methylthio)benzonitrile:

[0660] [ka]

[0661] At room temperature, 500 mg (1.13 mmol) of tert-butyl 4-((6-((4-cyano-2-fluorophenylthio)methyl)pyridine-2-yl)oxy)piperidine-1-formate was dissolved in 5 mL of dichloromethane, to which trifluoroacetic acid (1 mL) was added. The solution was stirred at room temperature and reacted for 2 hours. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate (10 mL) and extracted with dichloromethane (5 mL x 3). The extract was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain 3-fluoro-4-((6-(piperidine-4-oxy)pyridine-2-yl)methylthio)benzonitrile (334 mg, yield: 86.4%). LC-MS m / z: 344 [M+H] + .

[0662] Example 2-12, Synthesis of 3-fluoro-4-((3-(piperidine-4-oxy)benzyl)oxy)benzonitrile (intermediate B-12): 1) Synthesis of tert-butyl 4-(3-(methoxycarbonyl)phenoxy)piperidine-1-formate:

[0663] [ka]

[0664] At 0°C, methyl 3-hydroxybenzoate (3.00 g, 19.73 mmol), tert-butyl 4-hydroxypiperidine-1-formate (3.97 g, 19.73 mmol), and triphenylphosphine (7.76 g, 29.60 mmol) were dissolved in tetrahydrofuran (30 mL), to which diisopropyl azodicarboxylate (5.98 g, 29.60 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layer was back-extracted with saline solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain tert-butyl 4-(3-(methoxycarbonyl)phenoxy)piperidine-1-formate (2.44 g, yield: 36.9%). LC-MS m / z: 358 [M+H] + .

[0665] 2) Synthesis of tert-butyl 4-(3-(hydroxymethyl)phenoxy)piperidine-1-formate:

[0666] [ka]

[0667] At 0°C, lithium aluminum tetrahydrogen (238 mg, 6.27 mmol) was gradually added to a tetrahydrofuran (15 mL) solution containing 1.40 g, 4.18 mmol of 4-(3-(methoxycarbonyl)phenoxy)piperidine-1-formate tert-butyl. The resulting mixture was stirred at room temperature for 3 hours. After the reaction was complete, water (5 mL) was added to quench the reaction, and the solution was extracted with ethyl acetate (20 mL x 2). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 4-(3-(hydroxymethyl)phenoxy)piperidine-1-formate tert-butyl (400 mg, yield: 31.2%).

[0668] 3) Synthesis of 4-(3-((4-cyano-2-fluorophenoxy)methyl)phenoxy)piperidine-1-formate tert-butyl:

[0669] [ka]

[0670] At 0°C, 3-fluoro-4-hydroxybenzonitrile (178 mg, 1.30 mmol) and triphenylphosphine (409 mg, 1.56 mmol) were added to a tetrahydrofuran (15 mL) solution containing 4-(3-(hydroxymethyl)phenoxy)piperidine-1-formate tert-butyl (400 mg, 1.30 mmol), and then diisopropyl azodicarboxylic acid (315 mg, 1.56 mmol) was added at 0°C. The resulting mixture was stirred at room temperature and reacted for 3 hours. After the reaction was complete, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layer was back-extracted with saline solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 4-(3-((4-cyano-2-fluorophenoxy)methyl)phenoxy)piperidine-1-formate tert-butyl (312 mg, yield: 56.3%). Mass spectrometry (M+H-56) + ):371.

[0671] 4) Synthesis of 3-fluoro-4-((3-(piperidine-4-oxy)benzyl)oxy)benzonitrile:

[0672] [ka]

[0673] At room temperature, 312 mg, 0.73 mmol of tert-butyl 4-(3-((4-cyano-2-fluorophenoxy)methyl)phenoxy)piperidine-1-formate was dissolved in 5 mL of dichloromethane solution, to which trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature and reacted for 3 hours. After the reaction was complete, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layer was back-extracted with saline solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 3-fluoro-4-((3-(piperidine-4-oxy)benzyl)oxy)benzonitrile (230 mg, yield: 96.6%). LC-MS m / z: 327 [M+H] + .

[0674] Example 2-13, Synthesis of 4-(3-((4-chloro-2-fluorophenoxy)methyl)phenoxy)piperidine (intermediate B-13): 1) Synthesis of 4-(3-((4-chloro-2-fluorophenoxy)methyl)phenoxy)piperidine-1-formate tert-butyl:

[0675] [ka]

[0676] 4-chloro-2-fluorophenol (144 mg, 0.98 mmol) and triphenylphosphine (308 mg, 1.18 mmol) were added to a solution of tetrahydrofuran (8 mL) containing 4-(3-(hydroxymethyl)phenoxy)piperidine-1-formate tert-butyl (300 mg, 0.98 mmol), and then diisopropyl azodicarboxylate (238 mg, 1.18 mmol) was gradually added at 0°C. The resulting mixture was stirred at room temperature and reacted for 3 hours. After the reaction was complete, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layer was back-extracted with saline solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 4-(3-((4-chloro-2-fluorophenoxy)methyl)phenoxy)piperidine-1-formate tert-butyl (381 mg, yield: 89.2%).

[0677] 2) Synthesis of 4-(3-((4-chloro-2-fluorophenoxy)methyl)phenoxy)piperidine:

[0678] [ka]

[0679] At room temperature, 381 mg (0.88 mmol) of tert-butyl 4-(3-((4-chloro-2-fluorophenoxy)methyl)phenoxy)piperidine-1-formate was dissolved in a 5 mL dichloromethane solution to which trifluoroacetic acid (1 mL) was added. The resulting mixture was stirred at room temperature and reacted for 1 hour. After the reaction was complete, the pH of the mixture was adjusted to 7-8 with a methanol solution of ammonia (7 M). The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 271 mg (yield: 91.6%) of 4-(3-((4-chloro-2-fluorophenoxy)methyl)phenoxy)piperidine (LC-MS m / z: 336 [M+H]).+ .

[0680] Example 2-14, Synthesis of 2-(4-((6-((methylsulfonyl)oxy)methyl)pyridine-2-yl)oxy)phenyl)methyl acetate (intermediate B-14): 1) Synthesis of methyl 2-(4-((6-bromopyridine-2-yl)oxy)phenyl)acetate:

[0681] [ka]

[0682] At room temperature, 2-bromo-6-fluoropyridine (2.53 g, 14.46 mmol) and cesium carbonate (5.89 g, 18.07 mmol) were added to a 20 mL solution of acetonitrile containing 2.00 g, 12.05 mmol of methyl 2-(4-hydroxyphenyl)acetate. The resulting mixture was stirred at 90°C and reacted for 16 hours. After the reaction, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layer was back-extracted with saline solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain methyl 2-(4-((6-bromopyridine-2-yl)oxy)phenyl)acetate (3.17 g, yield: 81.7%). LC-MS m / z: 322, 324 [M+H] + .

[0683] 2) Synthesis of 2-(4-((6-bromopyridine-2-yl)oxy)phenyl)acetic acid:

[0684] [ka]

[0685] At room temperature, methyl 2-(4-((6-bromopyridine-2-yl)oxy)phenyl)acetate (3.17 g, 9.84 mmol) was dissolved in a mixed solution of tetrahydrofuran / water (20 mL / 15 mL), and then lithium hydroxide monohydrate (4.13 g, 98.40 mmol) was added. The resulting mixture was stirred at room temperature and reacted for 5 hours. After the reaction was complete, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layer was back-extracted with saline solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain 2-(4-((6-bromopyridine-2-yl)oxy)phenyl)acetic acid (1.8 g, yield: 59.4%). LC-MS m / z: 308, 310 [M+H] + .

[0686] 3) Synthesis of 2-(4-((6-(methyl formate)pyridine-2-yl)oxy)phenyl)acetic acid:

[0687] [ka]

[0688] At room temperature and under CO protection, 2-(4-((6-bromopyridine-2-yl)oxy)phenyl)acetic acid (900 mg, 2.92 mmol), 1,1'-bisdiphenylphosphinoferocenedichloropalladium (213 mg, 0.29 mmol), and potassium acetate (859 mg, 8.76 mmol) were dissolved in methanol (10 mL). The mixture was heated to 90°C and stirred under carbon monoxide protection at 58.76 psi for 16 hours. After the reaction was complete, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL x 3). The combined organic layers were back-extracted with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 2-(4-((6-(methyl formate)pyridine-2-yl)oxy)phenyl)acetic acid (385 mg, yield: 45.9%). LC-MS m / z: 288 [M+H] + .

[0689] 4) Synthesis of 2-(4-((6-(hydroxymethyl)pyridine-2-yl)oxy)phenyl)acetic acid:

[0690] [ka]

[0691] At 0°C, 2-(4-((6-(methylpyridine-2-yl formate)oxy)phenyl)acetic acid (385 mg, 1.34 mmol) was dissolved in tetrahydrofuran (5 mL), and then lithium aluminum tetrahydrogen (76 mg, 2.01 mmol) was added. The resulting mixture was stirred at room temperature and reacted for 2 hours. After the reaction was complete, the mixture was adjusted to pH 5-6 with 1 N hydrochloric acid and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed with saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 2-(4-((6-(hydroxymethyl)pyridine-2-yl)oxy)phenyl)acetic acid (118 mg, yield: 33.9%). LC-MS m / z: 260 [M+H] + .

[0692] 5) Synthesis of methyl 2-(4-(6-(hydroxymethyl)pyridine-2-yl)oxy)phenyl)acetate:

[0693] [ka]

[0694] At room temperature, 2-(4-((6-(hydroxymethyl)pyridine-2-yl)oxy)phenyl)acetic acid (118 mg, 0.45 mmol) was dissolved in methanol (3 mL), and then p-toluenesulfonic acid (12 mg, 0.32 mmol) was added. The resulting mixture was stirred at 60°C for 1 hour. After the reaction was complete, the reaction was quenched by adding water (5 mL). The mixture was then extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with saline solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to obtain methyl 2-(4-(6-(hydroxymethyl)pyridine-2-yl)oxy)phenyl)acetate (89 mg, yield: 72.4%). LC-MS m / z: 274 [M+H]+ .

[0695] 6) Synthesis of 2-(4-((6-((methylsulfonyl)oxy)methyl)pyridine-2-yl)oxy)phenyl)acetate methyl:

[0696] [ka]

[0697] At 0°C, 2-(4-(6-(hydroxymethyl)pyridine-2-yl)oxy)phenyl)methyl acetate (89 mg, 0.33 mmol) and triethylamine (74 mg, 0.73 mmol) were dissolved in dichloromethane (3 mL), and then methanesulfonyl chloride (49 mg, 0.50 mmol) was gradually added. The resulting mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction was quenched by adding water (5 mL), and then extracted with ethyl acetate (20 mL × 3). The combined organic layer was back-extracted with saline solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 2-(4-((6-((methylsulfonyl)oxy)methyl)pyridine-2-yl)oxy)phenyl)methyl acetate (56 mg, yield: 48.3%). LC-MS m / z: 352 [M+H] + .

[0698] Examples 2-15, Synthesis of other Class B intermediates: The following intermediates can be obtained by following synthesis steps similar to those for intermediate B in Examples 2-1 to 2-14.

[0699] [Table 5]

[0700] TIFF2026082907000290.tif230169

[0701] TIFF2026082907000291.tif233169

[0702] TIFF2026082907000292.tif200169

[0703] Example 3, Synthesis of 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)oxy)piperidine-1-yl)methyl)-1-((1-ethyl-1H-imidazole-5-yl)methyl)-1H-benzo[d]imidazole-6-formic acid (Compound 1): 1) Synthesis of 4-(2-(4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)oxy)piperidine-1-yl)acetamide)-3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)methyl benzoate:

[0704] [ka]

[0705] 3-Fluoro-4-((6-(piperidine-4-oxy)pyridine-2-yl)methoxy)benzonitrile (100 mg, 0.31 mmol) and compound 4-(2-chloroacetamide)-3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)methyl benzoate (109 mg, 0.31 mmol) were dissolved in N,N-dimethylformamide (2 mL), to which potassium carbonate (86 mg, 0.62 mmol) was added, and the mixture was stirred at 60°C for 3 hours. The resulting mixture was poured into saline solution (20 mL) and extracted twice with dichloromethane (5 mL / batch). The organic phase was concentrated under reduced pressure and then purified by reverse-phase flash chromatography under the following conditions (column: spherical C18, 20-40 μm, 120 g; mobile phase A: water (0.1% aqueous ammonia); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 0%B to 95%B within 30 min; detector: 254 nm). The mobile phase containing the desired product was collected at 72%B and concentrated under reduced pressure to obtain 4-(2-(4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)oxy)piperidine-1-yl)acetamide)-3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)methyl benzoate (40 mg, yield: 20.1%). LC-MS m / z: 642.5 [M+H] + .

[0706] 2) Synthesis of 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)oxy)piperidine-1-yl)methyl)-1-((1-ethyl-1H-imidazole-5-yl)methyl)-1H-benzo[d]imidazole-6-formate methyl:

[0707] [ka]

[0708] 4-(2-(4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)oxy)piperidine-1-yl)acetamide)-3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)methyl benzoate (40 mg, 0.06 mmol) was dissolved in toluene (1 mL), to which acetic acid (0.1 mL) was added, and the mixture was stirred at 110°C for 3 hours. After the reaction was complete, the resulting mixture was poured into saline solution (10 mL) and extracted twice with dichloromethane (5 mL / batch). The organic phase was concentrated under reduced pressure to obtain 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)oxy)piperidine-1-yl)methyl)-1-((1-ethyl-1H-imidazole-5-yl)methyl)-1H-benzo[d]imidazole-6-formate methyl (30 mg, yield: 80.3%). LC-MS m / z: 624 [M+H] + .

[0709] 3) Synthesis of 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)oxy)piperidine-1-yl)methyl)-1-((1-ethyl-1H-imidazole-5-yl)methyl)-1H-benzo[d]imidazole-6-formic acid:

[0710] [ka]

[0711] 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)oxy)piperidine-1-yl)methyl)-1-((1-ethyl-1H-imidazole-5-yl)methyl)-1H-benzo[d]imidazole-6-methyl (30 mg, 0.05 mmol) was dissolved in a tetrahydrofuran / water (1 mL / 1 mL) mixture to which lithium hydroxide (2.4 mg, 0.10 mmol) was added. The mixture was stirred at room temperature for 16 hours, and the residue was concentrated under reduced pressure to remove the solvent. Preparative high-performance liquid chromatography (Prep HPLC) was then performed (Waters 2767 / 2545 / 2489 system, SunFire Prep C8 OBD 10 μm 19×250 mm column, gradient elution with ACN / 0.1% FA in H2O solvent system, detection wavelength 254 nm / 214 nm, flow rate 20 The solution was purified by LC-MS (mL / min) to obtain 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)oxy)piperidine-1-yl)methyl)-1-((1-ethyl-1H-imidazole-5-yl)methyl)-1H-benzo[d]imidazole-6-formic acid (7.67 mg, yield: 25.2%). LC-MS m / z: 610 [M+H] + .

[0712] 1 H NMR(400 MHz, DMSO-d6): δ 8.04(s, 1 H), 7.89-7.80(m, 2 H), 7.74-7.60(m, 4 H), 7.43(m, 1 H), 7.04(d, J=7.2 Hz, 1 H), 6.72(d, J=8.0 Hz, 1 H), 6.39(s, 1 H), 5.69(s, 2 H), 5.30(s, 2 H), 4.88-4.83(m, 1 H), 4.01-4.00(m, 2 H), 3.79(s, 2 H), 2.68-2.65(m, 2 H), 2.25-2.20(m, 2H), 1.81-1.76(m, 2 H), 1.47-1.44(m, 2 H), 1.16(t, J=7.2 Hz, 3 H).

[0713] Example 4, Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)methoxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid (compound S22): 1) Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)methoxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl:

[0714] [ka]

[0715] A mixture of (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl (150 mg, 0.51 mmol), 3-fluoro-4-((6-((piperidine-4-oxy)methyl)pyridine-2-yloxy)methyl)benzonitrile (173 mg, 0.51 mmol), and potassium carbonate (140 mg, 1.02 mmol) in N,N-dimethylformamide (2 mL) was stirred at 60°C for 3 hours. The resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed sequentially with saturated ammonium chloride (20 mL × 3) and saline solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)methoxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl (100 mg, yield: 32.9%). LC-MS m / z: 600 [M+H] + .

[0716] 2) Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)methoxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid:

[0717] [ka]

[0718] (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)methoxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-methyl formate (100 mg, 0.17 mmol) was dissolved in a water / tetrahydrofuran (4 mL / 4 mL) mixture to which lithium hydroxide monohydrate (12 mg, 0.51 mmol) was added. The reaction mixture was stirred at 40°C for 16 hours. The reaction mixture was adjusted with formic acid until the pH was 5-6. The solvent was removed under vacuum, and the residue was purified by high-performance liquid chromatography (Prep HPLC) (Waters 2767 / 2545 / 2489 system, SunFire Prep C8 OBD 10 μm 19×250 mm column, gradient elution with ACN / 0.1% NH3-H2O in H2O solvent system, detection wavelength 254 nm / 214 nm, flow rate 20 mL / min) to obtain (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)methoxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid (compound S22) (19.26 mg, 19.7% yield). LC-MS m / z: 586 [M+H] + .

[0719] 1HNMR(400 MHz, DMSO-d6): 8.08-8.06(m, 1 H), 7.90(d, J=10.0 Hz, 1 H), 7.77-7.70(m, 4 H), 7.46-7.44(m, 1 H), 7.07(d, J=7.2 Hz, 1 H), 6.80(d, J=8.4 Hz, 1 H), 5.44(s, 2 H), 5.10-5.05(m, 1 H), 4.73-4.68(m, 1 H), 4.59-4.51(m, 1 H), 4.49-4.46(m, 3 H), 4.39-4.34(m, 1 H), 3.86(d, J=13.2 Hz, 1 H), 3.73-3.69(m, 1 H), 3.47-3.41(m, 1 H), 2.76-2.64(m, 3 H), 2.49-2.41(m, 1 H), 2.23-2.17(m, 2 H), 1.89-1.85(m, 2 H), 1.56-1.49(m, 2H).

[0720] Example 5, Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)methyl)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid (compound S1): 1) Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)methyl)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl

[0721] [ka]

[0722] A solution of 3-fluoro-4-((6-(piperidine-4-ylmethoxy)pyridine-2-yl)oxy)methyl)benzonitrile (100 mg, 0.29 mmol), compound (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl (85 mg, 0.29 mmol), and potassium carbonate (80 mg, 0.58 mmol) in N,N-dimethylformamide (2 mL) was heated to 50°C and stirred for 3 hours. After the reaction was complete, the resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saline solution (30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)methyl)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl (100 mg, 0.17 mmol, yield: 57.6%). LC-MS m / z: 600 [M+H] + .

[0723] 2) Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)methyl)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid:

[0724] [ka]

[0725] Compound (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)methyl)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl (100 mg, 0.17 mmol) was dissolved in a water / tetrahydrofuran (1.0 mL / 1.0 mL) mixed solvent to which lithium hydroxide (8 mg, 0.33 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum, and the residue was purified by preparative high-performance liquid chromatography (Prep HPLC) (Waters 2767 / 2545 / 2489 system, SunFire Prep C8 OBD 10 μm 19×250 mm column, gradient elution with ACN / 0.1% FA in H2O solvent system, detection wavelength 254 nm / 214 nm, flow rate 20 mL / min) to obtain (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)methyl)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid (15.48 mg, yield: 15.6%). LC-MS m / z: 586 [M+H] + .

[0726] 1H NMR(400 MHz, DMSO-d6): δ8.28(s, 1 H), 8.24(s, 1 H), 7.92-7.87(m, 1 H), 7.80(d, J=8.4 Hz, 1 H), 7.71(dd, J=7.6, 1.2 Hz, 1 H), 7.66(d, J=6.4 Hz, 1 H), 7.64-7.60(m, 2 H), 6.46(d, J=8.0 Hz, 1 H), 6.37(d, J=8.0 Hz, 1 H), 5.45(s, 2 H), 5.11-5.03(m, 1 H), 4.80-4.72(m, 1H), 4.66-4.58(m, 1H), 4.52-4.45(m, 1 H), 4.40-4.33(m, 1 H), 4.00(d, J=6.0 Hz, 2 H), 3.89(d, J=13.6 Hz, 1 H), 3.73(d, J= 13.6 Hz, 1 H), 2.90(d, J=10.4 Hz, 1 H), 2.80-2.70(m, 1 H), 2.72-2.64(m, 1 H), 2.45-2.37(m, 1 H), 2.13-1.95(m, 2 H), 1.70-1.60(m, 3 H), 1.27-1.13(m, 2 H).

[0727] Example 6, Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid (compound S2): 1) Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl:

[0728] [ka]

[0729] (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl (200 mg, 0.68 mmol), 3-fluoro-4-((6-(piperidine-4-oxy)pyridine-2-yl)oxy)methyl)benzonitrile (245 mg, 0.75 mmol), and potassium carbonate (188 mg, 1.36 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at 60°C for 3 hours. The resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed sequentially with saturated ammonium chloride (20 mL × 3) and saline solution (10 mL × 2), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl (205 mg, 0.35 mmol, yield: 51.5%). LC-MS m / z: 586 [M+H] + .

[0730] 2) Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid:

[0731] [ka]

[0732] (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-formate (150 mg, 0.26 mmol) was dissolved in a water / tetrahydrofuran (1 mL / 1 mL) mixed solvent to which lithium hydroxide (62 mg, 2.59 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was adjusted with formic acid until the pH was 5-6. The solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative HPLC (Waters 2767 / 2545 / 2489 system, SunFire Prep C8 OBD 10 μm 19×250 mm column, gradient elution with ACN / 0.1% FA in H2O solvent system, detection wavelength 254 nm / 214 nm, flow rate 20 mL / min) to obtain (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid (38.01 mg, 0.07 mmol, yield: 26.0%). LC-MS m / z: 572 [M+H] + .

[0733] 1H NMR(400 MHz, DMSO-d6): δ 8.26(s, 1 H), 7.93-7.90(m, 1 H), 7.80(d, J=8.0 Hz, 1 H), 7.72-7.69(m, 1 H), 7.65-7.61(m, 3 H), 6.46(d, J=7.6 Hz, 1 H), 6.36(d, J=8.0 Hz, 1 H), 5.45(s, 2 H), 5.09-5.07(m, 1 H), 4.81-4.75(m, 2 H), 4.66-4.61(m, 1 H), 4.52-4.47(m, 1 H), 4.40-4.36(m, 1 H), 3.94(d, J = 13.6 Hz, 1 H), 3.78(d, J = 13.6 Hz, 1 H), 2.78-2.67(m, 3 H), 2.45-2.41(m, 1 H), 2.31-2.27(m, 2 H), 1.86-1.83(m, 2 H), 1.58-1.53(m, 2 H).

[0734] Example 7, Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)methoxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid (compound C1): 1) Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)methoxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl:

[0735] [ka]

[0736] A solution of 3-fluoro-4-((6-((piperidine-4-oxy)methyl)pyridine-2-yl)methoxy)benzonitrile (27 mg, 0.08 mmol), (S)-2-(chloromethyl)-1-(oxyethane-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl (24 mg, 0.08 mmol), and potassium carbonate (22 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL) was stirred at 60°C for 3 hours. The resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated ammonium chloride (20 mL x 3) and saline solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)methoxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl (23 mg, yield: 47.0%). LC-MS m / z: 600 [M+H] + .

[0737] 2) Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)methoxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid

[0738] [ka]

[0739] (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)methoxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl (23 mg, 0.04 mmol) was dissolved in water / tetrahydrofuran (1 mL / 1 mL) to which lithium hydroxide (10 mg, 0.40 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was adjusted with formic acid until the pH was 5-6. The solvent was removed by concentrating under reduced pressure. The residue was purified by preparative HPLC (Waters 2767 / 2545 / 2489 system, SunFire Prep C8 OBD 10 μm 19×250 mm column, gradient elution with ACN / 0.1% FA in H2O solvent system, detection wavelength 254 nm / 214 nm, flow rate 20 mL / min) to obtain (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridine-2-yl)methoxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid (14.73 mg, yield: 65.5%). LC-MS m / z: 586 [M+H] + .

[0740] 1H NMR(400 MHz, DMSO-d6)δ 8.26(s, 1 H), 8.22(s, 1 H), 7.91-7.86(m, 2H), 7.82-7.79(m, 1H), 7.69(d, J=8.8 Hz, 1H), 7.63(d, J=8.4 Hz, 1H), 7.46-7.42(m, 3H), 5.35(s, 2H), 5.10-5.08(m, 1H), 4.81-4.76(m, 1H), 4.66-4.59(m, 3H), 4.52-4.47(m, 1H), 4.40-4.35(m, 1H), 3.92(d, J=13.6 Hz, 1H), 3.75(d, J=13.6 Hz, 1H), 3.51-3.46(m, 1H), 2.79-2.67(m, 3H), 2.46-2.41(m, 1H), 2.27-2.24(m, 2H), 1.91-1.89(m, 2H), 1.56-1.51(m, 2H).

[0741] Example 8, Synthesis of (S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)azetidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid (compound S3): 1) Synthesis of (S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)azetidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl:

[0742] [ka]

[0743] A solution of (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl (150 mg, 0.51 mmol), compound 4-((6-(azetidine-3-oxy)pyridine-2-yloxy)methyl)-3-fluorobenzonitrile (153 mg, 0.51 mmol), and potassium carbonate (211 mg, 1.530 mmol) in DMF (2 mL) was heated to 60°C and stirred, and the mixture was reacted for 4 hours. The resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The organic phases were combined and washed sequentially with saturated ammonium chloride solution and saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain (S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)azetidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1Hbenzo[d]imidazole-6-formate methyl (180.0 mg, 0.32 mmol, yield: 63.3%). LC-MS m / z: 558 [M+H] + .

[0744] 2) Synthesis of (S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)azetidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid

[0745] [ka]

[0746] (S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)azetidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-methyl formate (90 mg, 0.16 mmol) was dissolved in a water / THF (4 mL / 4 mL) mixture to which lithium monohydrate hydroxide (68 mg, 1.63 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was adjusted with formic acid until the pH was 5-6. The solvent was removed under reduced pressure. The residue was purified by Prep HPLC (Waters 2767 / 2545 / 2489 system, SunFire Prep C8 OBD 10 μm 19×250 mm column, gradient elution with ACN / 0.1% NH4OH in H2O solvent system, detection wavelength 254 nm / 214 nm, flow rate 20 mL / min) to obtain (S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)azetidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid (compound S3) (10.23 mg, yield: 11.7%). LC-MS m / z: 544 [M+H] + .

[0747] 1HNMR(400 MHz, DMSO-d6): δ 12.56(brs, 1H), 8.24(d, J=0.8 Hz, 1 H), 7.86-7.78(m, 2 H), 7.71-7.63(m, 4 H), 6.49(d, J=7.6 Hz, 1 H), 6.42(d, J=7.6 Hz, 1 H), 5.41(s, 2 H), 5.08-5.02(m, 2 H), 4.72(dd, J = 15.4, 7.2 Hz, 1 H), 4.59(dd, J=15.4, 2.8 Hz, 1 H), 4.47-4.43(m, 1H), 4.33-4.28(m, 1H), 4.05(d, J=13.6 Hz, 1 H), 3.95(d, J=13.6 Hz, 1 H), 3.77-3.69(m, 2 H), 3.20-3.16(m, 2 H), 2.70-2.66(m, 1 H), 2.40-2.35(m, 1 H).

[0748] Example 9, (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid (compound S5) 1) Synthesis of (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl:

[0749] [ka]

[0750] At room temperature, K2CO3 (113.0 mg, 0.819 mmol) was added to a mixed solution of 3-fluoro-4-((6-(piperidine-4-oxy)pyridine-2-yl)oxy)methyl)benzonitrile (89.0 mg, 0.273 mmol) and (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-methyl formate (80.3 mg, 0.273 mmol, 1.0 eq) in DMF (4 mL). After homogeneous stirring, the mixture was heated to 60°C and stirred for 3 hours. The solution was diluted with water (5 mL) and extracted with EA (3 × 20 mL). The organic phases were washed together in saline solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl (94 mg, 59.0%). LC-MS m / z: 585 [M+H] + .

[0751] 2) Synthesis of (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid:

[0752] [ka]

[0753] After stirring, LiOH·H2O (68 mg, 1.60 mmol) was added to a THF / H2O (4 mL / 4 mL) mixture of (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl (94 mg, 0.16 mmol) and mixed with THF / H2O (4 mL / 4 mL). After stirring thoroughly, the mixture was heated to 40°C and stirred for 16 hours. The resulting mixture was adjusted to pH 5-6 with HCl (1 N) and extracted with EA (3 × 10 mL). The organic phases were combined, washed with saline solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (Spherical C18 column, 20-40 μm, 40 g, mobile phase A: water (with 10 mM NH3-H2O added), mobile phase B: acetonitrile, flow rate: 40 mL / min, gradient: 20%B-50%B within 20 min, detector: 254 nm). The mobile phase containing the desired product was collected using the 32%B mobile phase and concentrated under reduced pressure to obtain (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid (26.27 mg, 28.6%). LC-MS m / z: 571 [M+H] + .

[0754] 1H NMR(400 MHz, DMSO-d6)δ 8.16(s, 1 H), 7.92(d, J=8.0 Hz, 1 H), 7.80-7.77(m, 1 H), 7.76-7.75(m, 2 H), 7.53-7.51(m, 1 H), 7.17(t, J=8.0 Hz, 1 H), 6.62-6.57(m, 3 H), 5.21(s, 2 H), 5.11-5.06(m, 1 H), 4.77-4.71(m, 1 H), 4.63-4.59(m, 1 H), 4.52-4.47(m, 1 H), 4.40-4.36(m, 2H), 3.90(d, J=13.6 Hz, 1 H), 3.76(d, J=13.5 Hz, 1 H), 2.78-2.68(m, 3 H), 2.50-2.33(m, 3 H), 1.93-1.91(m, 2 H), 1.62-1.58(m, 2 H).

[0755] Example 10, Synthesis of 2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)piperidine-1-yl)methyl)-1-((1-ethyl-1H-imidazole-5-yl)methyl)-1H-benzo[d]imidazole-6-formic acid (compound S4): 1) Synthesis of 4-(2-(4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)piperidine-1-yl)acetamide)-3-(((1-ethyl-1H-imidazole-5-yl)methyl)amino)methyl benzoate:

[0756] [ka]

[0757] After stirring, K2CO3 (110 mg, 0.80 mmol) was added to the mixed solution of intermediates A-2 (140 mg, 0.40 mmol) and B-2 (131 mg, 0.40 mmol) in DMF (3 mL). After homogeneous stirring, the temperature was raised to 60°C and the mixture was stirred and reacted for 3 hours. The resulting mixture was poured into saline solution (50 mL) and extracted with DCM (2 × 10 mL). After combining the organic phases and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain 4-(2-(4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)piperidine-1-yl)acetamide)-3-(((1-ethyl-1H-imidazole-5-yl)methyl)amino)methyl benzoate (140 mg, 54.6% yield). LC-MS m / z: 642 [M+H] + .

[0758] 2) Synthesis of 4-(2-(4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)piperidine-1-yl)acetamide)-3-(((1-ethyl-1H-imidazole-5-yl)methyl)amino)benzoic acid:

[0759] [ka]

[0760] After stirring, LiOH (11 mg, 0.46 mmol) was added to a mixture of 4-(2-(4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)piperidine-1-yl)acetamide)-3-(((1-ethyl-1H-imidazole-5-yl)methyl)amino)methyl benzoate (140 mg, 0.22 mmol) in THF / H2O (1 mL / 1 mL), and the mixture was stirred at room temperature for 5 hours. The resulting mixture was poured into saline solution (10 mL) and extracted with DCM (2 × 5 mL). After combining the organic phases and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain 4-(2-(4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)piperidine-1-yl)acetamide)-3-(((1-ethyl-1H-imidazole-5-yl)methyl)amino)benzoic acid (80 mg, 58.0% yield). LC-MS m / z: 628 [M+H] + .

[0761] 3) Synthesis of 2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)piperidine-1-yl)methyl)-1-((1-ethyl-1H-imidazole-5-yl)methyl)-1H-benzo[d]imidazole-6-formic acid (compound 4):

[0762] [ka]

[0763] 4-(2-(4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)piperidine-1-yl)acetamide)-3-(((1-ethyl-1H-imidazole-5-yl)methyl)amino)benzoic acid (80 mg, 0.13 mmol) was homogeneously mixed with toluene (1 mL) and AcOH (0.2 mL), then the mixture was heated to 110°C and stirred for 3 hours. The solvent was removed by reducing the pressure. The residue was purified by Prep HPLC (Waters 2767 / 2545 / 2489 system, SunFire Prep C8 OBD 10 μm 19×250 mm column, gradient elution with ACN / 0.1% NH4OH in H2O solvent system, detection wavelength 254 nm / 214 nm, flow rate 20 mL / min) to obtain 2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)oxy)piperidine-1-yl)methyl)-1-((1-ethyl-1H-imidazole-5-yl)methyl)-1H-benzo[d]imidazole-6-formic acid (compound S4) (20.72 mg, 26.2% yield). LC-MS m / z: 610 [M+H] + .

[0764] 1 H NMR(400 MHz, DMSO-d6): δ 8.07(s, 1 H), 7.92-7.89(m, 1 H), 7.83-7.80(m, 1 H), 7.71-7.67(m, 3 H), 7.64-7.59(m, 2 H), 6.45(d, J=8.0 Hz, 1 H), 6.41(s, 1 H), 6.34(d, J=8.0 Hz, 1 H), 5.71(s, 2 H), 5.43(s, 2 H), 4.73-4.71(m, 1 H), 4.03-3.97(m, 2 H), 3.81(s, 2H), 2.68-2.65(m, 2H), 2.25-2.20(m, 2H), 1.75-1.71(m, 2H), 1.43-1.39(m, 2H), 1.16(t, J = 7.2Hz, 3H).

[0765] Example 11, Synthesis of 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-yl)methyl)-1-((1-ethyl-1H-imidazole-5-yl)methyl)-1H-benzo[d]imidazole-6-formic acid (compound S23): 1) Synthesis of 4-(2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-yl)acetamide)-3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)methyl benzoate:

[0766] [ka]

[0767] At room temperature, methyl 4-(2-chloroacetamide)-3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)benzoate (100 mg, 0.29 mmol) and 3-fluoro-4-((3-(piperidine-4-oxy)phenoxy)methyl)benzonitrile (95 mg, 0.29 mmol) were dissolved in a stirred solution of N,N-dimethylformamide (5 mL), to which potassium carbonate (120 mg, 0.87 mmol) was added. The mixture was stirred at 60°C for 3 hours. Water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saline solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to obtain 4-(2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-yl)acetamide)-3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)methyl benzoate (45 mg, yield: 24.1%). LC-MS m / z: 641 [M+H] + .

[0768] 2) Synthesis of 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-yl)methyl-1-((1-ethyl-1H-imidazole-5-yl)methyl)-1H-benzo[d]imidazole-6-formate methyl:

[0769] [ka]

[0770] 4-(2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-yl)acetamide)-3-((1-ethyl-1H-imidazole-5-yl)methyl)amino)methyl benzoate (45 mg, 0.07 mmol) was dissolved in toluene (10 mL) to which acetic acid (2 mL) was added. The resulting mixture was stirred at 110 °C for 16 hours. The resulting solution was concentrated to obtain the crude product, which was then further purified by reverse-phase flash chromatography under the following conditions (column: spherical C18, 20-40, 120 g; mobile phase A: water (with 10 mM aqueous ammonia added); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 60%B-80%B within 20 min; monitor: 254 nm). The mobile phase containing the required product was collected at 72% B and concentrated under reduced pressure to obtain 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-yl)methyl-1-((1-ethyl-1H-imidazole-5-yl)methyl)-1H-benzo[d]imidazole-6-formate methyl (22 mg, yield: 57.1%). LC-MS m / z: 623 [M+H] + .

[0771] 3) Synthesis of 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-yl)methyl)-1-((1-ethyl-1H-imidazole-5-yl)methyl)-1H-benzo[d]imidazole-6-formic acid:

[0772] [ka]

[0773] 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-yl)methyl-1-((1-ethyl-1H-imidazole-5-yl)methyl)-1H-benzo[d]imidazole-6-methyl formate (22 mg, 0.04 mmol) was dissolved in a stirred solution of tetrahydrofuran / water (4 mL / 4 mL), to which lithium hydroxide monohydrate (17 mg, 0.40 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The resulting mixture was adjusted to pH = 5-6 with hydrochloric acid solution (1 N), and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saline solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Reverse-phase flash chromatography was performed under the following conditions (column: spherical C18, 20-40 μm, 40 g, mobile phase A: water (10 The residue was purified by adding mM aqueous ammonia, mobile phase B: acetonitrile, flow rate: 40 mL / min, gradient: 20%B to 50%B within 20 min, monitor: 254 nm). The mobile phase containing the desired product was collected at 29%B and concentrated under reduced pressure to obtain 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-yl)methyl)-1-((1-ethyl-1H-imidazole-5-yl)methyl)-1H-benzo[d]imidazole-6-formic acid (11.42 mg, 0.019 mmol, yield: 47.5%). LC-MS m / z: 609 [M+H] + .

[0774] 1H NMR(400 MHz, DMSO-d6)δ 8.00(s, 1 H), 7.91(d, J=9.6 Hz, 1 H), 7.80-7.73(m, 3 H), 7.66(s, 1 H), 7.52(d, J=8.0 Hz, 1 H), 7.16(t, J=8.0 Hz ,1H), 6.60-6.54(m, 3 H), 6.37(s, 1H), 5.66(s, 2 H), 5.20(s, 2 H), 4.36-4.32(m, 1H), 4.00(q, J=7.2 Hz, 2 H), 3.76(s, 2 H), 2.67-2.65(m, 2H), 2.31-2.26(m, 2 H), 1.82-1.79(m, 2 H), 1.49-1.37(m, 2 H), 1.17(t, J =7.2 Hz, 3 H).

[0775] Example 12, Synthesis of formate of (S,E)-3-(2-((4-((6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)oxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-yl)acrylic acid (compound S36): 1) Synthesis of (S,E)-3-(2-((4-((6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)oxy)piperidine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-yl)methyl acrylate:

[0776] [ka]

[0777] At room temperature, potassium carbonate (78 mg, 0.56 mmol) was added to a stirred solution of N,N-dimethylformamide (3 mL) containing (S,E)-3-(2-(chloromethyl)-1-(oxyethane-2-ylmethyl)-1H-benzo[d]imidazole-6-yl)acrylate (90 mg, 0.28 mmol) and 2-((4-chloro-2-fluorobenzyl)oxy)-3-fluoro-6-(piperidine-4-oxy)pyridine (100 mg, 0.28 mmol). The mixture was stirred at 60°C for 3 hours. The desired product was detected by liquid chromatography-mass spectrometry, the mixture was quenched by adding water (5 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saline soluti...

Claims

1. A compound represented by formula (I), a pharmaceutically acceptable salt, solvate, enantiomer, or isotope-substituted compound thereof, 【Chemistry 1】 Of these, A and B are arbitrarily and independently selected from monocyclic or polycyclic structures of 3 to 18 carbon atoms, and the monocyclic or polycyclic structures may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, paracyclic rings, spirocyclic rings, or bridging ring structures. X and X’ are independently -C(R d1 )(R d2 )-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S(=O) 2 N(R d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O) 2 - selected from, L is independently -C(R d1 ) (R d2 )-,-OC(R d1 ) (R d2 )-, -C(R d1 ) (R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S (=O) 2 N(R) d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O) 2 - Selected from, X 1 , X 2 , X 3 , X 4 , X 5 , X 8 and X 9 Independently, -CR 5 -, or -N-, R 0 These are independently hydrogen, deuterium, halogen, -CN, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkoxy group, -NR d8 R d9 , selected from 6-10 membered aryl groups, 5-8 membered heteroaryl groups, 3-8 membered saturated or partially saturated cycloalkyl groups, and 3-8 membered saturated or partially saturated heterocyclyl groups, of which R 0 C represented by 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 The alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group, and 3-8 membered saturated or partially saturated heterocyclyl group are optionally substituted with one or more substituents, the substituents being optionally hydrogen, deuterium, halogen, alkyl group, haloalkyl group, alkoxy group, alkylamino group, O=, CN, OH, -NR d8 R d9 , C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 A saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group are selected, and the aryl group, heteroaryl group, saturated or partially saturated cycloalkyl group, and saturated or partially saturated heterocyclyl group are further optionally substituted with one or more substituents, and the substituents may optionally be hydrogen, deuterium, halogen, alkyl group, haloalkyl group, cyano group, cyanoethyl group, O=, OH, C 1-3 Alkyl alkyl group, C 1-3 Selected from an alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, among which the C 1-3 Alkyl alkyl group, C 1-3 The alkoxy group, saturated or partially saturated cycloalkyl group, or saturated or partially saturated heterocyclyl group may optionally be H, deuterium, halogen, haloalkyl group, cyano group, or OCH 3 And substituted with 1 to 3 substituents selected from OH, Each R 1 These are homologous or different, and independently of each other are hydrogen, deuterium, halogen, -CN, -OH, -SH, and -NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group substituted with an alkyl group, or a carboxyl group substituted product, is selected most preferably, optionally, the carboxyl group substituted product is 【Chemistry 2】 and among them, the above C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, C 3-10 saturated or partially saturated heterocycloalkyl group, C 3-10 cycloalkyl group, or C 3-10 alkyl group substituted with a heterocycloalkyl group, C 1-10 alkyl group, C 3-10 alkyl group substituted with a cycloalkyl group, C 2-10 heteroalkyl group, C 3-10 heterocyclyl group, C 1-10 alkyl carboxy group, or carboxy group substituent is optionally H, deuterium, halogen, OCH 3 , carboxy group, OH, CN and NR d8 R d9 is substituted with one or more substituents selected from, or any two adjacent Rs 1 together with the carbon to which it is attached form a 5- to 6-membered heteroaryl group, 3- to 8-membered saturated or partially saturated cycloalkyl group, 3- to 8-membered saturated or partially saturated heterocyclyl group, and the hydrogen in the above aryl group, saturated or partially saturated cycloalkyl group, heterocycloalkyl group is optionally hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl group, C 1-6 alkoxy group, -NH 2 , -NHC 1-6 alkyl group, -N(C 1-6 alkyl) 2 , =O, and is substituted with a group selected from saturated or partially saturated C 3-6 cycloalkyl group, and C 1-6 alkyl group and C 1-6 alkoxy group are optionally hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, R 2 , R 2' and R d1 , R d2 They are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkylamino group, N,N-di(C 1-10 alkyl)amino group, C 1-10 Alkyloxy group, C 1-10 Alkylacyl group, C 1-10 Alkyloxy group, C 1-10 Alkyl sulfonyl group, C 1-10 Alkyl sulfinyl group, C 3-10 Cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 Cycloalkoxy group, C 3-10 Cycloalkylacyl group, C 3-10 Cycloalkoxyacetyl group, C 3-10 Cycloalkylsulfonyl group and C 3-10 Selected from cycloalkylsulfinyl groups, and the alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, heterocycloalkyl group may optionally contain hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , oxy group, and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be further modified with hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, or optionally R 2 and R 2' , or R d1 and R d2 It may form a 5-6 membered aryl group, a heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group together with the carbon attached thereto, of which the cycloalkyl group and heterocycloalkyl group may optionally consist of hydrogen, deuterium, halogen, oxo, CN, and CF. 3 , OH, OCH 3 OCH 2 CH 3 Substituted by one or more groups selected from, Each R 4 These are homologous or different, and are arbitrarily and independently of each other: hydrogen, deuterium, halogens, CN, OH, SH, and NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon group, C 3-10 Cyclic hydrocarbon group, or C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Alkyl alkyl groups, and C 3-10 Cyclic hydrocarbon group, C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Selected from heteroalkyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more groups selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, Each R 5 and R 6 These are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, CN, OH, SH, NR d8 R d9 NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with a cycloalkyl group 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Heterocycloalkyl groups can optionally contain hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, or any two adjacent R groups 5 , or R 6 Together with the carbon attached thereto, it forms a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group can optionally be hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , oxy group, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 , saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 They are homologous or different, and can be arbitrarily and independently of each other: hydrogen, deuterium, NH 2 , C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 The heterocyclyl group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, The aforementioned heteroatoms represent heteroatoms and their isotopes, which are arbitrarily and independently selected from O, N, S, and P. The halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. The compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer, or isotope-substituted derivative.

2. It has the structure of formula (IA), 【Transformation 3】 Eventually, A and B are arbitrarily and independently selected from monocyclic or polycyclic structures having 3 to 18 carbon atoms, and the monocyclic or polycyclic structures may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, paracyclic rings, spirocyclic rings, or bridging ring structures. X and X' are independently -C(R d1 ) (R d2 )-,-C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S (=O) 2 N(R) d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O) 2 - Selected from, L is independently -C(R d1 ) (R d2 )-,-OC(R d1 ) (R d2 )-, -C(R d1 ) (R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S (=O) 2 N(R) d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O) 2 - Selected from, X 1 , X 3 , X 8 and X 9 Independently, -CR 5 -, or -N-, R 0 These are independently hydrogen, deuterium, halogen, -CN, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkoxy group, -NR d8 R d9 , selected from 6-10 membered aryl groups, 5-8 membered heteroaryl groups, 3-8 membered saturated or partially saturated cycloalkyl groups, and 3-8 membered saturated or partially saturated heterocyclyl groups, of which R 0 C represented by 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 The alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group, and 3-8 membered saturated or partially saturated heterocyclyl group are optionally substituted with one or more substituents, the substituents being optionally hydrogen, deuterium, halogen, alkyl group, haloalkyl group, alkoxy group, alkylamino group, O=, CN, OH, -NR d8 R d9 , C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 A saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group are selected, and the aryl group, heteroaryl group, saturated or partially saturated cycloalkyl group, and saturated or partially saturated heterocyclyl group are further optionally substituted with one or more substituents, and the substituents may optionally be hydrogen, deuterium, halogen, alkyl group, haloalkyl group, cyano group, cyanoethyl group, O=, OH, C 1-3 Alkyl alkyl group, C 1-3 Selected from an alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, among which the C 1-3 Alkyl alkyl group, C 1-3 The alkoxy group, saturated or partially saturated cycloalkyl group, or saturated or partially saturated heterocyclyl group may optionally be H, deuterium, halogen, haloalkyl group, cyano group, or OCH 3 And substituted with 1 to 3 substituents selected from OH, Each R 1 These are homologous or different, and independently of each other are hydrogen, deuterium, halogen, -CN, -OH, -SH, and -NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group substituted with an alkyl group, or a carboxyl group substituted product, is selected most preferably, optionally, the carboxyl group substituted product is 【Chemistry 4】 And of which C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 The alkylcarboxyl group, or the carboxyl group-substituted compound, can optionally contain H, deuterium, halogen, or OCH. 3 carboxyl group, OH, CN and NR d8 R d9 Substituted with one or more substituents selected from, or any two adjacent R 1 Together with the carbon attached thereto, it forms a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the hydrogen in the aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group can optionally be hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , =O, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 , saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R 2 , R 2' and R d1 , R d2 They are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkylamino group, N,N-di(C 1-10 alkyl)amino group, C 1-10 Alkyloxy group, C 1-10 Alkylacyl group, C 1-10 Alkyloxy group, C 1-10 Alkyl sulfonyl group, C 1-10 Alkyl sulfinyl group, C 3-10 Cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 Cycloalkoxy group, C 3-10 Cycloalkylacyl group, C 3-10 Cycloalkoxyacetyl group, C 3-10 Cycloalkylsulfonyl group and C 3-10 Selected from cycloalkylsulfinyl groups, and the alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, heterocycloalkyl group may optionally contain hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , oxy group, and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be further modified with hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, or optionally R 2 and R 2' , or R d1 and R d2 It may form a 5-6 membered aryl group, a heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group together with the carbon attached thereto, of which the cycloalkyl group and heterocycloalkyl group may optionally consist of hydrogen, deuterium, halogen, oxo, CN, and CF. 3 , OH, OCH 3 OCH 2 CH 3 Substituted by one or more groups selected from, Each R 4 These are homologous or different, and are arbitrarily and independently of each other: hydrogen, deuterium, halogens, CN, OH, SH, and NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon group, C 3-10 Cyclic hydrocarbon group, or C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Alkyl alkyl groups, and C 3-10 Cyclic hydrocarbon group, C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Selected from heteroalkyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more groups selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, Each R 5 and R 6 These are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, CN, OH, SH, NR d8 R d9 NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with a cycloalkyl group 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Heterocycloalkyl groups can optionally contain hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, or any two adjacent R groups 5 , or R 6 Together with the carbon attached thereto, it forms a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group can optionally be hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , oxy group, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be further modified with hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 , saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 They are homologous or different, and can be arbitrarily and independently of each other: hydrogen, deuterium, NH 2 , C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 The heterocyclyl group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, The aforementioned heteroatoms represent heteroatoms and their isotopes, which are arbitrarily and independently selected from O, N, S, and P. The halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. t is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. The compound according to feature 1.

3. It has the structure of formula (IB), 【Transformation 5】 Eventually, B is arbitrarily and independently selected from monocyclic or polycyclic structures having 3 to 18 carbon atoms, and the monocyclic or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, paracyclic rings, spirocyclic rings, or bridging ring structures. X and X' are independently -C(R d1 ) (R d2 )-,-C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S (=O) 2 N(R) d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O) 2 - Selected from, L is independently -C(R d1 ) (R d2 )-,-OC(R d1 ) (R d2 )-, -C(R d1 ) (R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S (=O) 2 N(R) d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O) 2 - Selected from, X 1 , X 3 , X 8 , X 9 , X 10 , X 11 and X 12 Independently, -CR 5 -, or -N-, R 0 These are independently hydrogen, deuterium, halogen, -CN, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkoxy group, -NR d8 R d9 , selected from 6-10 membered aryl groups, 5-8 membered heteroaryl groups, 3-8 membered saturated or partially saturated cycloalkyl groups, and 3-8 membered saturated or partially saturated heterocyclyl groups, of which R 0 C represented by 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 The alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group, and 3-8 membered saturated or partially saturated heterocyclyl group are optionally substituted with one or more substituents, the substituents being optionally hydrogen, deuterium, halogen, alkyl group, haloalkyl group, carboxyl group, alkoxy group, alkylamino group, O=, CN, OH, -NR d8 R d9 , C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 A saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group are selected, and the aryl group, heteroaryl group, saturated or partially saturated cycloalkyl group, and saturated or partially saturated heterocyclyl group are further optionally substituted with one or more substituents, and the substituents may optionally be hydrogen, deuterium, halogen, alkyl group, haloalkyl group, cyano group, cyanoethyl group, O=, OH, C 1-3 Alkyl alkyl group, C 1-3 Selected from an alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, among which the C 1-3 Alkyl alkyl group, C 1-3 The alkoxy group, saturated or partially saturated cycloalkyl group, or saturated or partially saturated heterocyclyl group may optionally be H, deuterium, halogen, haloalkyl group, cyano group, or OCH 3 And substituted with 1 to 3 substituents selected from OH, Each R 1 These are homologous or different, and independently of each other are hydrogen, deuterium, halogen, -CN, -OH, -SH, and -NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group substituted with an alkyl group, or a carboxyl group substituted product, is selected most preferably, optionally, the carboxyl group substituted product is 【Transformation 6】 And of which C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 The alkylcarboxyl group, or the carboxyl group-substituted compound, can optionally contain H, deuterium, halogen, or OCH. 3 carboxyl group, OH, CN and NR d8 R d9 Substituted with one or more substituents selected from, or any two adjacent R 1 Together with the carbon attached thereto, it forms a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the hydrogen in the aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group can optionally be hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , =O, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 , saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R 2 , R 2' and R d1 , R d2 They are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkylamino group, N,N-di(C 1-10 alkyl)amino group, C 1-10 Alkyloxy group, C 1-10 Alkylacyl group, C 1-10 Alkyloxy group, C 1-10 Alkyl sulfonyl group, C 1-10 Alkyl sulfinyl group, C 3-10 Cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 Cycloalkoxy group, C 3-10 Cycloalkylacyl group, C 3-10 Cycloalkoxyacetyl group, C 3-10 Cycloalkylsulfonyl group and C 3-10 Selected from cycloalkylsulfinyl groups, and the alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, heterocycloalkyl group may optionally contain hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , oxy group, and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be further modified with hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, or optionally R 2 and R 2' , or R d1 and R d2 It may form a 5-6 membered aryl group, a heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group together with the carbon attached thereto, of which the cycloalkyl group and heterocycloalkyl group may optionally consist of hydrogen, deuterium, halogen, oxo, CN, and CF. 3 , OH, OCH 3 OCH 2 CH 3 Substituted by one or more groups selected from, Each R 4 These are homologous or different, and are arbitrarily and independently of each other: hydrogen, deuterium, halogens, CN, OH, SH, and NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon group, C 3-10 Cyclic hydrocarbon group, or C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Alkyl alkyl groups, and C 3-10 Cyclic hydrocarbon group, C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Selected from heteroalkyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more groups selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, Each R 5 and R 6 These are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, CN, OH, SH, NR d8 R d9 NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with a cycloalkyl group 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Heterocycloalkyl groups can optionally contain hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, or any two adjacent R groups 5 , or R 6 Together with the carbon attached thereto, it forms a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group can optionally be hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , oxy group, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 , saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 They are homologous or different, and can be arbitrarily and independently of each other: hydrogen, deuterium, NH 2 , C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 The heterocyclyl group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, The aforementioned heteroatoms represent heteroatoms and their isotopes, which are arbitrarily and independently selected from O, N, S, and P. The halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. t is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. The compound according to feature 1.

4. It has the structure of formula (IC), 【Transformation 7】 Eventually, 【Transformation 8】 This can represent a single bond or a double bond, X and X' are independently -C(R d1 ) (R d2 )-,-C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S (=O) 2 N(R) d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O) 2 - Selected from, L is independently -C(R d1 ) (R d2 )-,-OC(R d1 ) (R d2 )-, -C(R d1 ) (R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S (=O) 2 N(R) d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O) 2 - Selected from, X 1 , X 3 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , or X 14 Independently, -CR 5 -, or -N-, R 0 These are independently hydrogen, deuterium, halogen, -CN, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkoxy group, -NR d8 R d9 , selected from 6-10 membered aryl groups, 5-8 membered heteroaryl groups, 3-8 membered saturated or partially saturated cycloalkyl groups, and 3-8 membered saturated or partially saturated heterocyclyl groups, of which R 0 C represented by 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 The alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group, and 3-8 membered saturated or partially saturated heterocyclyl group are optionally substituted with one or more substituents, the substituents being optionally hydrogen, deuterium, halogen, alkyl group, haloalkyl group, alkoxy group, alkylamino group, O=, CN, OH, -NR d8 R d9 , C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 A saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group are selected, and the aryl group, heteroaryl group, saturated or partially saturated cycloalkyl group, and saturated or partially saturated heterocyclyl group are optionally substituted with one or more substituents, and the substituents may optionally be hydrogen, deuterium, halogen, alkyl group, haloalkyl group, cyano group, cyanoethyl group, O=, OH, C 1-3 Alkyl alkyl group, C 1-3 Selected from an alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, among which the C 1-3 Alkyl alkyl group, C 1-3 Alkoxy groups, saturated or partially saturated cycloalkyl groups, or saturated or partially saturated heterocyclyl groups include H, deuterium, halogens, haloalkyl groups, cyano groups, and OCH2. 3 And substituted with 1 to 3 substituents selected from OH, Each R 1 These are homologous or different, and independently of each other are hydrogen, deuterium, halogen, -CN, -OH, -SH, and -NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group substituted with an alkyl group, or a carboxyl group substituted product, is selected most preferably, optionally, the carboxyl group substituted product is 【Chemistry 9】 And of which C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 The alkylcarboxyl group, or the carboxyl group substituted, is most preferably H, deuterium, halogen, or OCH. 3 carboxyl group, OH, CN and NR d8 R d9 Substituted with one or more substituents selected from, or any two adjacent R 1 Together with the carbon attached thereto, it forms a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the hydrogen in the aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group can optionally be hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , =O, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 , saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R 2 , R 2' and R d1 , R d2 They are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkylamino group, N,N-di(C 1-10 alkyl)amino group, C 1-10 Alkyloxy group, C 1-10 Alkylacyl group, C 1-10 Alkyloxy group, C 1-10 Alkyl sulfonyl group, C 1-10 Alkyl sulfinyl group, C 3-10 Cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 Cycloalkoxy group, C 3-10 Cycloalkylacyl group, C 3-10 Cycloalkoxyacetyl group, C 3-10 Cycloalkylsulfonyl group and C 3-10 Selected from cycloalkylsulfinyl groups, and the alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, heterocycloalkyl group may optionally contain hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , oxy group, and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be further modified with hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, or optionally R 2 and R 2' , or R d1 and R d2 It may form a 5-6 membered aryl group, a heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group together with the carbon attached thereto, of which the cycloalkyl group and heterocycloalkyl group may optionally consist of hydrogen, deuterium, halogen, oxo, CN, and CF. 3 , OH, OCH 3 OCH 2 CH 3 Substituted by one or more groups selected from, Each R 4 is the same or different and is independently of each other hydrogen, deuterium, halogen, CN, OH, SH and NH 2 , -COOH, or is selected from C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 cyclic hydrocarbon group, C 3-10 heterocyclic hydrocarbon group, C 3-10 cyclic hydrocarbon group, or C 3-10 alkyl group substituted with a heterocyclic hydrocarbon group, and C 1-10 alkyl group, and C 3-10 cyclic hydrocarbon group, C 3-10 alkyl group substituted with a heterocyclic hydrocarbon group, C 1-10 heteroalkyl group, wherein the C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, or C 1-10 alkoxy group is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl group, or heterosilyl group, Each R 5 and R 6 are the same or different and each independently is hydrogen, deuterium, halogen, CN, OH, SH, NR d8 R d9 , NH 2 , -COOH, or is selected from a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, or a C 1-10 alkoxy group, a C 2-10 heteroalkyl group, a C 3-10 cycloalkyl group, a C 3-10 heterocycloalkyl group, a C 3-10 alkyl group substituted with a cyclic hydrocarbon group, or a C 1-10 alkyl group, or a C 3-10 cycloalkyl group, a C 3-10 heterocycloalkyl group substituted with a C 3-10 heterocyclyl group, wherein the C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, or a C 1-10 alkoxy group, a C 2-10 heteroalkyl group, a C 3-10 cycloalkyl group, a C 3-10 heterocycloalkyl group, a C 3-10 alkyl group substituted with a cycloalkyl group, or a C 1-10 alkyl group, or a C 3-10 cycloalkyl group, a C 3-10 heterocycloalkyl group substituted with a C 3-10 heterocycloalkyl group is optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and a C 3-10 saturated or partially saturated cycloalkyl group, or a heterocyclyl group, or any two adjacent Rs 5 , or R 6 Together with the carbon attached thereto, it forms a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group can optionally be hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , oxy group, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 , saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R d3 、R d4 、R d5 、R d6 、R d7 、R d8 、R d9 and R d10 are the same or different and are each independently, optionally, hydrogen, deuterium, NH 2 、C 1-10 alkyl group, C 2-10 alkynyl group, or C 1-10 alkoxy group, C 1-10 alkylacyl group, C 1-10 alkylsulfonyl group, C 2-10 heteroalkyl group, C 3-10 cycloalkyl group, C 3-10 heterocycloalkyl group, C 3-10 alkyl group substituted with a cyclic hydrocarbon group, or C 1-10 cycloalkyl group, C 3-10 heterocycloalkyl group substituted with a C 3-10 heterocyclyl group, where the C 3-10 alkyl group, C 1-10 alkynyl group, or C 2-10 alkoxy group, C 1-10 alkylacyl group, C 1-10 alkylsulfonyl group, C 1-10 heteroalkyl group, C 2-10 cycloalkyl group, C 3-10 heterocycloalkyl group, C 3-10 alkyl group substituted with a cyclic hydrocarbon group, or C 3-10 cycloalkyl group, C 1-10 heterocycloalkyl group substituted with a C 3-10 heterocyclyl group, and the C 3-10 heterocyclyl group is optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 saturated or partially saturated cycloalkyl group, or heterocyclyl group, 3-10 and is substituted with one or more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C The aforementioned heteroatoms represent heteroatoms and their isotopes, which are arbitrarily and independently selected from O, N, S, and P. The halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. t is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. The compound according to feature 1.

5. It has the structure of an expression (ID), 【Chemistry 10】 Eventually, 【Chemistry 11】 This can represent a single bond or a double bond, X and X' are independently -C(R d1 ) (R d2 )-,-C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S (=O) 2 N(R) d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O) 2 -Selected from, preferably -C(R d1 ) (R d2 )-, -N(R d4 )-, -O-, -S-, -S(=O)-, or -S(=O) 2 -and, L is independently -C(R d1 ) (R d2 )-,-OC(R d1 ) (R d2 )-, -C(R d1 ) (R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S (=O) 2 N(R) d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O) 2 -Selected from, preferably -OC(R d1 ) (R d2 )-, -C(R d1 ) (R d2 ) O-, -O-, -S-, or -N(R d4 )-and, X 1 , X 3 , X 8 and X 13 Independently, -CR 5 -, or -N-, R 0 These are independently hydrogen, deuterium, halogen, -CN, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkoxy group, -NR d8 R d9 , selected from 6-10 membered aryl groups, 5-8 membered heteroaryl groups, 3-8 membered saturated or partially saturated cycloalkyl groups, and 3-8 membered saturated or partially saturated heterocyclyl groups, of which R 0 C represented by 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 The alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group, and 3-8 membered saturated or partially saturated heterocyclyl group are optionally substituted with one or more substituents, the substituents being optionally hydrogen, deuterium, halogen, alkyl group, haloalkyl group, alkoxy group, alkylamino group, O=, CN, OH, -NR d8 R d9 , C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 A saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group are selected, and the aryl group, heteroaryl group, saturated or partially saturated cycloalkyl group, and saturated or partially saturated heterocyclyl group are further optionally substituted with one or more substituents, and the substituents may optionally be hydrogen, deuterium, halogen, alkyl group, haloalkyl group, cyano group, cyanoethyl group, O=, OH, C 1-3 Alkyl alkyl group, C 1-3 Selected from an alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, among which the C 1-3 Alkyl alkyl group, C 1-3 The alkoxy group, saturated or partially saturated cycloalkyl group, or saturated or partially saturated heterocyclyl group may optionally be H, deuterium, halogen, haloalkyl group, cyano group, or OCH 3 And substituted with 1 to 3 substituents selected from OH, Each R 1 These are homologous or different, and independently of each other are hydrogen, deuterium, halogen, -CN, -OH, -SH, and -NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group substituted with an alkyl group, or a carboxyl group substituted product, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 The alkylcarboxyl group, or the carboxyl group-substituted compound, can optionally contain H, deuterium, halogen, or OCH. 3 carboxyl group, OH, CN and NR d8 R d9 Substituted with one or more substituents selected from, or any two adjacent R 1 Together with the carbon attached thereto, it forms a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the hydrogen in the aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group can optionally be hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , =O, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 , saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R 2 , R 2' and R d1 , R d2 They are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkylamino group, N,N-di(C 1-10 alkyl)amino group, C 1-10 Alkyloxy group, C 1-10 Alkylacyl group, C 1-10 Alkyloxy group, C 1-10 Alkyl sulfonyl group, C 1-10 Alkyl sulfinyl group, C 3-10 Cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 Cycloalkoxy group, C 3-10 Cycloalkylacyl group, C 3-10 Cycloalkoxyacetyl group, C 3-10 Cycloalkylsulfonyl group and C 3-10 Selected from cycloalkylsulfinyl groups, and the alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, heterocycloalkyl group may optionally contain hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , oxy group, and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be further modified with hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, or optionally R 2 and R 2' , or R d1 and R d2 It may form a 5-6 membered aryl group, a heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group together with the carbon attached thereto, of which the cycloalkyl group and heterocycloalkyl group may optionally consist of hydrogen, deuterium, halogen, oxo, CN, and CF. 3 , OH, OCH 3 OCH 2 CH 3 Substituted by one or more groups selected from, Each R 4 These are homologous or different, and are arbitrarily and independently of each other: hydrogen, deuterium, halogens, CN, OH, SH, and NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon group, C 3-10 Cyclic hydrocarbon group, or C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Alkyl alkyl groups, and C 3-10 Cyclic hydrocarbon group, C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Selected from heteroalkyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more groups selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, Each R 5 and R 6 These are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, CN, OH, SH, NR d8 R d9 NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with a cycloalkyl group 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Heterocycloalkyl groups can optionally contain hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, or any two adjacent R groups 5 , or R 6 Together with the carbon attached thereto, it forms a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group can optionally be hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , oxy group, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 , saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R d4 , R d8 and R d9 They are homologous or different, and can be arbitrarily and independently of each other: hydrogen, deuterium, NH 2 , C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 The heterocyclyl group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, The aforementioned heteroatoms represent heteroatoms and their isotopes, which are arbitrarily and independently selected from O, N, S, and P. The halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. t is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. The compound according to feature 1.

6. It has the structure of formula (IE), 【Chemistry 12】 Eventually, 【Chemistry 13】 This can represent a single bond or a double bond, X and X' are independently -C(R d1 ) (R d2 )-, -N(R d4 )-, -N(R d7 )-, -O-, -S-, -S(=O)-, or -S(=O) 2 -Selected from, preferably -C(R d1 ) (R d2 )-, -N(R d4 )-, -O-, -S-, -S(=O)-, or -S(=O) 2 -and, L is independently -C(R d1 ) (R d2 )-,-OC(R d1 ) (R d2 )-, -C(R d1 ) (R d2 )O-, -C(=O)N(R d3 )-, -N(R d4 )-, -C(=NR d5 )-, -S (=O) 2 N(R) d6 )-, -N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O) 2 -Selected from, preferably -OC(R d1 ) (R d2 )-, -C(R d1 ) (R d2 ) O-, -O-, -S-, or -N(R d4 )-and, X 1 , X 3 , X 8 and X 13 Independently, -CR 5 -, or -N-, R is independently hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkoxy group, -NR d8 R d9 , selected from 6-10 membered aryl groups, 5-8 membered heteroaryl groups, 3-8 membered saturated or partially saturated cycloalkyl groups, and 3-8 membered saturated or partially saturated heterocyclyl groups, of which R is represented by C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 The alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group, and 3-8 membered saturated or partially saturated heterocyclyl group are optionally substituted with one or more substituents, the substituents being optionally hydrogen, deuterium, halogen, alkyl group, haloalkyl group, alkoxy group, alkylamino group, O=, CN, OH, -NR d8 R d9 , C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 A saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group are selected, and the aryl group, heteroaryl group, saturated or partially saturated cycloalkyl group, and saturated or partially saturated heterocyclyl group are further optionally substituted with one or more substituents, and the substituents may optionally be hydrogen, deuterium, halogen, alkyl group, haloalkyl group, cyano group, cyanoethyl group, O=, OH, C 1-3 Alkyl alkyl group, C 1-3 Selected from an alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, among which the C 1-3 Alkyl alkyl group, C 1-3 The alkoxy group, saturated or partially saturated cycloalkyl group, or saturated or partially saturated heterocyclyl group may optionally be H, deuterium, halogen, haloalkyl group, cyano group, or OCH 3 And substituted with 1 to 3 substituents selected from OH, Each R 1 These are homologous or different, and independently of each other are hydrogen, deuterium, halogen, -CN, -OH, -SH, and -NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group substituted with an alkyl group, or selected from carboxyl group substituted derivatives, or any two adjacent R 1 Together with the carbon attached thereto, it forms a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the hydrogen in the aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group can optionally be hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , =O, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 , saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R 4 These are homologous or different, and are arbitrarily and independently of each other: hydrogen, deuterium, halogens, CN, OH, SH, and NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon group, C 3-10 Cyclic hydrocarbon group, or C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Alkyl alkyl groups, and C 3-10 Cyclic hydrocarbon group, C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Selected from heteroalkyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more groups selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, Each R 5 and R 6 These are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, CN, OH, SH, NR d8 R d9 NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with a cycloalkyl group 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Heterocycloalkyl groups can optionally contain hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, or any two adjacent R groups 5 , or R 6 Together with the carbon attached thereto, it forms a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group can optionally be hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , oxy group, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 , saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R d1 , R d2 , R d4 , R d8 and R d They are homologous or different, and can be arbitrarily and independently of each other: hydrogen, deuterium, NH 2 , C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkylsulfonyl group, C2-10 heteroalkyl group, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 The heterocyclyl group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, The aforementioned heteroatoms represent heteroatoms and their isotopes, which are arbitrarily and independently selected from O, N, S, and P. The halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. t is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. The compound according to feature 1.

7. Having the structure of formula (IF-1) or (IF-2), 【Chemistry 14】 Eventually, 【Chemistry 15】 This can represent a single bond or a double bond, X and X' are independently -C(R d1 ) (R d2 )-, -N(R d4 )-, -O-, -S-, -S(=O)-, or -S(=O) 2 - Selected from, L independently -OC(R d1 ) (R d2 )-, -C(R d1 ) (R d2 ) O-, -O-, -S-, or -N(R d4 ) - Selected from, X 1 and X 8 Independently, -CR 5 -, or -N-, R is independently hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkoxy group, -NR d8 R d9 , selected from 6-10 membered aryl groups, 5-8 membered heteroaryl groups, 3-8 membered saturated or partially saturated cycloalkyl groups, and 3-8 membered saturated or partially saturated heterocyclyl groups, of which R is represented by C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 The alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group, and 3-8 membered saturated or partially saturated heterocyclyl group are optionally substituted with one or more substituents, the substituents being optionally hydrogen, deuterium, halogen, alkyl group, haloalkyl group, alkoxy group, alkylamino group, O=, CN, OH, -NR d8 R d9 , C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 A saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group are selected, and the aryl group, heteroaryl group, saturated or partially saturated cycloalkyl group, and saturated or partially saturated heterocyclyl group are further optionally substituted with one or more substituents, and the substituents may optionally be hydrogen, deuterium, halogen, alkyl group, haloalkyl group, cyano group, cyanoethyl group, O=, OH, C 1-3 Alkyl alkyl group, C 1-3 Selected from an alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, among which the C 1-3 Alkyl alkyl group, C 1-3 The alkoxy group, saturated or partially saturated cycloalkyl group, or saturated or partially saturated heterocyclyl group may optionally be H, deuterium, halogen, haloalkyl group, cyano group, or OCH 3 And substituted with 1 to 3 substituents selected from OH, Each R 1 These are homologous or different, and independently of each other are hydrogen, deuterium, halogen, -CN, -OH, -SH, and -NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group substituted with an alkyl group, or a carboxyl group-substituted product, is selected from these. Each R 4 These are homologous or different, and are arbitrarily and independently of each other: hydrogen, deuterium, halogens, CN, OH, SH, and NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon group, C 3-10 Cyclic hydrocarbon group, or C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Alkyl alkyl groups, and C 3-10 Cyclic hydrocarbon group, C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Selected from heteroalkyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more groups selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, Each R 5 and R 6 These are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, CN, OH, SH, NR d8 R d9 NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with a cycloalkyl group 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Heterocycloalkyl groups can optionally contain hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, or any two adjacent R groups 5 , or R 6 Together with the carbon attached thereto, it forms a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group can optionally be hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , oxy group, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 , saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R d1 , R d2 , R d4 , R d8 and R d They are homologous or different, and can be arbitrarily and independently of each other: hydrogen, deuterium, NH 2 , C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkylsulfonyl group, C2-10 heteroalkyl group, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 The heterocyclyl group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, The aforementioned heteroatoms represent heteroatoms and their isotopes, which are arbitrarily and independently selected from O, N, S, and P. The halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. t is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. The compound according to feature 1.

8. Having the structure of formula (IG), 【Chemistry 16】 Eventually, X and X' are independently -C(R d1 ) (R d2 )-, -N(R d4 )-, -O-, -S-, -S(=O)-, or -S(=O) 2 - Selected from, L independently -OC(R d1 ) (R d2 )-, -C(R d1 ) (R d2 ) O-, -O-, -S-, or -N(R d4 ) - Selected from, X 1 and X 8 Independently, -CR 5 -, or -N-, R is independently hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkoxy group, -NR d8 R d9 , selected from 6-10 membered aryl groups, 5-8 membered heteroaryl groups, 3-8 membered saturated or partially saturated cycloalkyl groups, and 3-8 membered saturated or partially saturated heterocyclyl groups, of which R is represented by C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 The alkoxy group, 6-10 membered aryl group, 5-8 membered heteroaryl group, 3-8 membered saturated or partially saturated cycloalkyl group, and 3-8 membered saturated or partially saturated heterocyclyl group are optionally substituted with one or more substituents, the substituents being optionally hydrogen, deuterium, halogen, alkyl group, haloalkyl group, alkoxy group, alkylamino group, O=, CN, OH, -NR d8 R d9 , C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 A saturated or partially saturated heterocyclyl group, a 6-10 membered aryl group, and a 5-8 membered heteroaryl group are selected, and the aryl group, heteroaryl group, saturated or partially saturated cycloalkyl group, and saturated or partially saturated heterocyclyl group are further optionally substituted with one or more substituents, and the substituents may optionally be hydrogen, deuterium, halogen, alkyl group, haloalkyl group, cyano group, cyanoethyl group, O=, OH, C 1-3 Alkyl alkyl group, C 1-3 Selected from an alkoxy group, a saturated or partially saturated cycloalkyl group, or a saturated or partially saturated heterocyclyl group, among which the C 1-3 Alkyl alkyl group, C 1-3 The alkoxy group, saturated or partially saturated cycloalkyl group, or saturated or partially saturated heterocyclyl group may optionally be H, deuterium, halogen, haloalkyl group, cyano group, or OCH 3 And substituted with 1 to 3 substituents selected from OH, Each R 1 These are homologous or different, and independently of each other are hydrogen, deuterium, halogen, -CN, -OH, -SH, and -NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups, or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group substituted with an alkyl group, or a carboxyl group-substituted product, is selected from these. Each R 4 These are homologous or different, and are arbitrarily and independently of each other: hydrogen, deuterium, halogens, CN, OH, SH, and NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cyclic hydrocarbon group, C 3-10 Heterocyclic hydrocarbon group, C 3-10 Cyclic hydrocarbon group, or C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Alkyl alkyl groups, and C 3-10 Cyclic hydrocarbon group, C 3-10 C substituted with heterocyclic hydrocarbon groups 1-10 Selected from heteroalkyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more groups selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, Each R 5 and R 6 These are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, CN, OH, SH, NR d8 R d9 NH 2 , selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with a cycloalkyl group 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Heterocycloalkyl groups can optionally contain hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, or any two adjacent R groups 5 , or R 6 Together with the carbon attached thereto, it forms a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group can optionally be hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , oxy group, and saturated or partially saturated C 3-6 Substituted with a group selected from cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 , saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, Each R d1 , R d2 , R d4 , R d8 and R d They are homologous or different, and can be arbitrarily and independently of each other: hydrogen, deuterium, NH 2 , C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group, or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkylsulfonyl group, C2-10 heteroalkyl group, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group, or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 The heterocyclyl group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially saturated cycloalkyl groups or heterocyclyl groups, The aforementioned heteroatoms represent heteroatoms and their isotopes, which are arbitrarily and independently selected from O, N, S, and P. The halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. t is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. The compound according to feature 1.

9. A is either unsubstituted or substituted C 6-20 Selected from aryl groups and 5-20 member heteroaryl groups, B is an unsubstituted or substituted 3-20 member heterocyclyl group, a 6-20 member crosslinking ring group, or a spiro ring group, C 6-20 Selected from aryl groups, X and X' are homologous or different, and independently of each other -C(R d1 ) (R d2 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -S(=O)-, or -S(=O) 2 - Selected from, L is -C(R d1 ) (R d2 )-, OC(R d1 ) (R d2 )-, -C(R d1 ) (R d2 )O-, -O-, -S-, -NH-, -C(=O)O-, -OC(=O)-, -C(=O)-, -S(=O)-, or -S(=O) 2 - Selected from, R d1 , R d2 They are homologous or different, and can be any and all independently of each other: hydrogen, deuterium, halogen, C 1-10 Alkyl alkyl group, C 1-10 Selected from alkoxy groups, X 1 , X 2 , X 3 , X 4 , X 5 , X 8 and X 9 They are homologous or different, and independently of each other, they are -CR 5 -, or -N-, each R 5 These are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, CN, OH, SH, and NH. 2 , -COOH, C 1-10 Alkyl alkyl group, C 1-10 Selected from alkoxy groups, R 0 This is either no substitution, or one, two, or more Rs of any choice. 01 C replaced by 1-10 Selected from alkyl groups, each R 01 R are homologous or different, and are independently unsubstituted for each other, or optionally one, two, or more R. 02 C replaced by 3-20 Selected from cycloalkyl groups, 3-20 membered heterocyclyl groups, and 5-20 membered heteroaryl groups, each R 02 These are homologous or different, and are independently of each other: halogens, deuterium, CN, oxo (=O), and C. 1-10 Alkyl, halo C 1-10 Alkyl, CN-C 1-10 Alkyl alkyl group, C 3-6 Cycloalkyl-C 1-10 Selected from alkyl groups, Each R 1 These are homologous or different, and independently of each other are hydrogen, deuterium, halogen, -CN, -OH, -SH, and -NH. 2 COOH, unsubstituted, or optionally one, two, or more R 11 -C replaced by 1-10 alkyl-COOH, -C 2-10 Selected from alkenyl-COOH, each R 11 They are homologous or different, and independently of each other, H, deuterium, halogens, and C 1-10 Alkyl alkyl group, C 1-10 Selected from alkoxy groups, R 2 , R 2' These are homologous or different, and are independently of each other: hydrogen, deuterium, halogen, oxo (=O), and C. 1-10 Alkyl alkyl group, C 1-10 Selected from alkyloxy groups, Each R 4 These are homologous or different, and are arbitrarily and independently of each other: hydrogen, deuterium, halogen, oxo (=O), CN, OH, SH, and NH. 2 , -COOH, C 1-10 Alkyl alkyl group, C 1-10 Selected from alkoxy groups, Each R 6 These are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, CN, OH, SH, and NH. 2 , -COOH, C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 2-10 Selected from alkynyl groups and 5-14 member heteroaryl groups, R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 and R d10 These are homologous or different, and are arbitrarily and independently of each other: hydrogen, deuterium, CN, OH, SH, and NH 2 , -COOH, C 1-10 Alkyl alkyl group, C 1-10 Selected from alkoxy groups, m is an integer arbitrarily chosen from 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. Preferably, A is either unsubstituted or substituted C 6-14 Selected from aryl groups and 5- to 14-membered heteroaryl groups, B is an unsubstituted or substituted 3- to 14-membered heterocyclyl group, or a crosslinking ring group, C 6-14 Selected from aryl groups, X and X' are homologous or different, and independently of each other -C(R d1 ) (R d2 ) -, -O-, -S- are selected, L is -C(R d1 ) (R d2 )-,-OC(R d1 ) (R d2 )-, -C(R d1 ) (R d2 ) Selected from O-, -O-, -S-, -NH-, R d1 , R d2 They are homologous or different, and can be arbitrarily and independently of each other: hydrogen, deuterium, and C 1-10 Selected from alkyl groups, X 1 , X 2 , X 3 , X 4 , X 5 , X 8 and X 9 They are homologous or different, and independently of each other, they are -CR 5 -, or -N-, each R 5 They are homologous or different, and are independently of each other: hydrogen, deuterium, halogens, and C 1-10 Alkyl alkyl group, C 1-10 Selected from alkoxy groups, R 0 This is either no substitution, or one, two, or more Rs of any choice. 01 C replaced by 1-10 Selected from alkyl groups, each R 01 R are homologous or different, and are independently unsubstituted for each other, or optionally one, two, or more R. 02 C replaced by 3-14 Selected from cycloalkyl groups, 3-14 member heterocyclyl groups, and 5-14 member heteroaryl groups, each R 02 These are homologous or different, and are independent of each other as CN, deuterium, oxo (=O), and C. 1-10 Alkyl, CN-C 1-10 Alkyl alkyl group, C 3-6 Cycloalkyl-C 1-10 Selected from alkyl groups, Each R 1 These are homologous or different, and independently of each other, they are halogen, COOH, unsubstituted, or optionally one, two, or more R atoms. 11 -C replaced by 1-10 alkyl-COOH, -C 2-10 Selected from alkenyl-COOH, each R 11 They are homologous or different, and independently of each other, H, deuterium, halogens, and C 1-10 Alkyl alkyl group, C 1-10 Selected from alkoxy groups, R 2 , R 2' These are homologous or different, and are independently of each other: hydrogen, deuterium, halogen, oxo (=O), and C. 1-10 Alkyl alkyl group, C 1-10 Selected from alkoxy groups, Each R 4 These are homologous or different, and are arbitrarily and independently of each other: hydrogen, deuterium, halogen, oxo (=O), CN, OH, SH, and NH. 2 , -COOH, C 1-10 Alkyl alkyl group, C 1-10 Selected from alkoxy groups, Each R 6 They are homologous or different, and independently of each other are hydrogen, deuterium, halogens, CN, and C. 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, C 2-10 Selected from alkynyl groups and 5-14 member heteroaryl groups, m is an integer arbitrarily chosen from 1, 2, and 3. n is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. q is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. Preferably, A is selected from a phenyl group or a pyridyl group. B is a piperidine group, an azetidinyl group, a phenyl group, a (1R,5S)-3-azabicyclo[3.2.1]octyl group, a spiro ring group, or a crosslinking ring group, wherein the spiro ring or crosslinking ring contains one or more heteroatoms, and the heteroatoms are arbitrarily and independently selected from N, O, or S. X and X' are homologous or different, and are CH independently of each other. 2 Selected from O or S, L stands for O, S, NH, CH 2 OCH 2 CH 2 Selected from O, X 1 , X 2 , X 3 , X 4 , X 5 , X 8 and X 9 They are homologous or different, and are independently selected from CH, CD, CF, or N. R 0 C is either unsubstituted or substituted with an imidazole group, pyrazolyl group, pyrrolyl group, azetidinyl group, oxetane group, pyrrolidinyl group, or cyclopropyl group. 1-3 Selected from alkyl groups, the imidazole group, pyrazolyl group, pyrrolyl group, azetidinyl group, oxetane group, pyrrolidinyl group, or cyclopropyl group may be unsubstituted, substituted with oxo (=O), or C 1-3 Alkyl, CN-C 1-3 Alkyl alkyl group, C 3-6 Cycloalkyl-C 1-3 It may be replaced with an alkyl group. Each R 1 COOH, F, and -C are homologous or different, and are independent of each other. 1-3 Alkyl alkyl group -COOH, -C 2-3 Selected from alkenyl-COOH, R 2 , R 2' These are homologous or different, and are independently of each other: hydrogen, deuterium, halogen, oxo (=O), and C. 1-3 Selected from alkyl groups, Each R 4 These are homologous or different, and can be arbitrarily and independently of each other: hydrogen, deuterium, halogen, oxo (=O), and C. 1-3 Selected from alkyl groups, Each R 6 These are homologous or different, and are independently selected from hydrogen, deuterium, F, Cl, Br, CN, ethynyl group, and imidazole group. m is arbitrarily selected from 1 or 2. n is arbitrarily selected from 0, 1, or 2. q can be arbitrarily selected from 0, 1, or 2. Preferably, 【Chemistry 17】 The structure may be selected from the following: [Chemistry 18] B is 【Chemistry 19】 It was chosen based on this structure, L stands for O, S, NH, CH 2 OCH 2 CH 2 Selected from O, 【Chemistry 20】 The structure may be selected from the following: 【Chemistry 21】 R 0 The structure is selected from the following: 【Chemistry 22】 R 1 teeth, 【Chemistry 23】 Selected from, R 2 , R 2' All of them are H, R 4 H, F, and methyl groups, X 8 is selected from CH or N, X 9 is selected from CH or N, m is selected from 1 or 2, and n is selected from 1 or 2. The compound according to any one of claims 1 to 8.

10. The aforementioned compound is selected from compounds having the following structure: The compound according to any one of claims 1 to 9. Table 1 Table 2 Table 3

11. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds described in any one of claims 1 to 10, a pharmaceutically acceptable salt thereof, a solvate, an enantiomer, or an isotope-substituted compound.

12. An application of a compound according to any one of claims 1 to 10, a pharmaceutically acceptable salt, solvate, enantiomer, or isotope substitution thereof, in the manufacture of a drug for preventing and / or treating a disease related to the GLP1 / GLP1R signaling pathway, Preferably, diseases related to the GLP1 / GLP1R signaling pathway include overweight, obesity, diabetes (including T1D and / or T2DM, prediabetes), idiopathic T1D (type 1B), adult latent autoimmune diabetes (LADA), early-onset T2DM (EOD), juvenile atypical diabetes (YOAD), juvenile-onset adult-onset diabetes (MODY), diabetes associated with malnutrition, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, and kidney disease (e.g., acute kidney disease, renal tubular dysfunction, proximal tubular changes). Diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, obesity (including hypothalamic obesity and monogenic obesity) and associated comorbidities (e.g., osteoarthritis and urinary incontinence), eating disorders (including binge eating syndromes such as Prader-Willi and Bardet-Biedl syndrome, bulimia nervosa, and symptomatic obesity), weight gain due to the use of other drugs (e.g., use of steroids and antipsychotics), excessive glucose, dyslipidemia (hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol) (including hyperinsulinemia), NAFLD (including related diseases such as fatty degeneration, NASH, fibrosis, cirrhosis, and hepatocellular carcinoma), cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction (e.g., necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipids, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, macular degeneration, cataracts This includes conditions such as disorders, glomerulosclerosis, chronic renal failure, metabolic syndromes, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, impaired fasting blood glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, hyperapolipoprotein B-lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, prevention or treatment of addictions (alcohol dependence and / or drug abuse),Applications that are not limited to these.

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