Novel aromatic ether-substituted heterocyclic compounds as GLP1R agonists

Abstract

The present invention discloses novel aromatic ether substituted heterocyclic compounds having GLP1R agonist activity, and specifically discloses a compound having a structure of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isotope substituted product or isomer thereof as a GLP1R agonist.

Description

[0001] This application claims priority to prior applications filed with the State Intellectual Property Office of China on August 30, 2021, with patent application number 202111017657.5, entitled “Novel Aryl Ether Substituted Heterocyclic Compounds as GLP1R Agonists,” and with patent application number 202111168512.5, entitled “Novel Aryl Ether Substituted Heterocyclic Compounds as GLP1R Agonists,” filed with the State Intellectual Property Office of China on September 29, 2021. The entire contents of the prior applications are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry and specifically includes novel aromatic ether-substituted heterocyclic compounds with GLP1R agonist activity, compositions containing such compounds, and methods for using such compounds to prepare drugs for treating or preventing diseases related to GLP1 / GLP1R.

[0003] Background: With the improvement of living standards, overweight and obesity are becoming increasingly common in modern society. The number of patients suffering from complications caused by obesity, such as diabetes and fatty liver disease, is increasing. Reports released by the World Health Organization (WHO) and Zhiyan Consulting predict that by 2030, the number of obese people worldwide will reach 3.26 billion; by 2029, the number of people with diabetes worldwide will exceed 500 million; and the number of people with non-alcoholic fatty liver disease worldwide will exceed 1.5 billion. Currently, there are no effective treatments for fatty liver disease. The FDA has approved only six drugs for the treatment of obesity, most of which are controlled drugs with limited efficacy and significant side effects. Although a number of drugs have been approved for the treatment of type 2 diabetes, the glucose-lowering rate achieved by existing drugs (<7%) remains low, with even the most active combination achieving a rate of only around 45%. Therefore, new drug development is needed to address the needs of a wider range of patients, whether it is fatty liver disease, obesity, or diabetes.

[0004] Glucagon-like peptide-1 (GLP-1) is a long peptide hormone containing 30 or 31 amino acids. It is produced and secreted by intestinal endocrine L cells and certain neurons in the nucleus tractus solitarius of the brainstem during feeding. GLP-1 stimulates insulin secretion in a physiological and glucose-dependent manner, reduces glucagon secretion, inhibits gastric emptying, reduces appetite, and stimulates β-cell proliferation. In nonclinical trials, GLP-1 promotes the sustainable capacity 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 has been proven to be an ideal target for the treatment of metabolic diseases such as obesity, diabetes, and fatty liver. Several GLP1R agonist peptide drugs such as dulaglutide and semaglutide have been approved for the treatment of diabetes and weight loss abroad.

[0005] However, these peptides require injections, resulting in poor patient compliance. They are also costly, inaccessible, and burdensome. They require refrigeration, making them inconvenient to carry and store. Furthermore, they are difficult to combine with existing oral small molecule drugs for complex diseases requiring multiple drug combinations, such as non-alcoholic fatty liver disease. Therefore, the development of small molecule oral GLP1R agonists is urgently needed.

[0006] There are currently a small number of literature or patent reports on oral small molecule GLP1 agonists: for example, Pfizer's PF-06882961 can achieve similar or better efficacy than GLP1 peptides (https: / / doi.org / 10.1101 / 2020.09.29.319483). Although the efficacy and safety have been preliminarily verified, PF-06882961 has major drugability deficiencies such as poor oral absorption, extremely low bioavailability, and large clinical dosages. It has a heavy cost and gastrointestinal burden on patients, and it is impossible to achieve better blood sugar and weight reduction effects by further increasing the dosage. Therefore, it is necessary to develop new small molecule GLP1 agonists with better drugability to meet the needs of a wider range of patients.

[0007] Technical Effects

[0008] The present inventors unexpectedly discovered that some of the novel aromatic ether-substituted heterocyclic compounds of formula (I) of the present invention not only have significant GLP1R agonist activity, but also have better pharmacokinetic properties (including longer T1 / 2, higher exposure) and bioavailability than the reference compound PF-06882961 with a known structure. These compounds are expected to have better human PK properties and be more suitable for development as candidate drugs for the prevention or treatment of diseases related to GLP1 / GLP1R targets or signaling pathways. Summary of the Invention

[0009] 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 product thereof.

[0010]

[0011] (I)

[0012] wherein A and B are arbitrarily and independently selected from monocyclic or polycyclic structures of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spiro rings or bridged ring structures;

[0013] X and X' are independently selected from -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-;

[0014] L is independently selected from -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-;

[0015] X1, X2, X3, X4, X5, X8 and X9 are independently selected from -CR5- or -N-;

[0016] R0 is independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d8 R d9 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl and 5-8 membered heteroaryl; wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, saturated or partially saturated heterocyclic group is further optionally substituted by 1 to multiple substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0017] Each R1 is the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2, -COOH or selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl substituted carboxyl or carboxyl surrogate, most preferably, the carboxyl surrogate is: or ; wherein the C 1-10 Alkyl, C2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 The alkylcarboxyl or carboxyl surrogate is optionally replaced by one or more alkylcarboxyl groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 or any two adjacent R1 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, and the hydrogen on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic alkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0018] R2, R 2' and R d1 、R d2 the same or different, independently selected from hydrogen, deuterium, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 or optionally R2 and R 2' or R d1 and R d2 It can form, together with the carbon to which it is attached, a 5-6 membered aryl or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the cycloalkyl group or heterocycloalkyl group is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3;

[0019] Each R4 is the same or different and is independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Heteroalkyl; wherein said C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 The alkoxy group is optionally substituted by 1 to 2 or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0020] Each R5 and R6 are the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NR d8 R d9 , NH2, -COOH or selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocycloalkyl is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 or any two adjacent R5 or R6 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, and the aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0021] R d3 、R d4 、Rd5 、R d6 、R d7 、R d8 、R d9 and R d10 The same or different, each independently selected from hydrogen, deuterium, NH2, C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0022] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0023] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0024] m is an integer arbitrarily selected from 1, 2, 3 and 4;

[0025] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0026] q is arbitrarily selected from integers of 0, 1, 2, 3, 4 and 5.

[0027] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has the structure of formula (IA):

[0028]

[0029] Formula (IA)

[0030] in,

[0031] A and B are arbitrarily and independently selected from monocyclic or polycyclic structures of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spiro rings or bridged ring structures;

[0032] X and X' are independently selected from -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-;

[0033] L is independently selected from -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-;

[0034] X1, X3, X8 and X9 are independently selected from -CR5- or -N-;

[0035] R0 is independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1-10Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d8 R d9 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl and 5-8 membered heteroaryl; wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, saturated or partially saturated heterocyclic group is further optionally substituted by 1 to multiple substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl are optionally substituted, preferably with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0036] Each R1 is the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2, -COOH or selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl substituted carboxyl or carboxyl surrogate, most preferably, the carboxyl surrogate is: or ; wherein the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 The alkylcarboxyl or carboxyl surrogate is optionally replaced by one or more alkylcarboxyl groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR. d8 R d9 or any two adjacent R1 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, and the hydrogen on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic alkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0037] Each R2, R 2' and R d1 、R d2 the same or different, independently selected from hydrogen, deuterium, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C3-10 Cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 or optionally R2 and R 2' or R d1 and R d2 It can form, together with the carbon to which it is attached, a 5-6 membered aryl or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the cycloalkyl group or heterocycloalkyl group is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3;

[0038] Each R4 is the same or different and is independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Heteroalkyl; wherein said C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 The alkoxy group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0039] Each R5 and R6 are the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NR d8 Rd9 , NH2, -COOH or selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocycloalkyl is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 or any two adjacent R5 or R6 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, and the aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0040] Each R d3 、R d4 、R d5 、R d6 、R d7 、R d8 、R d9and R d10 The same or different, each independently selected from hydrogen, deuterium, NH2, C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0041] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0042] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0043] m is an integer arbitrarily selected from 1, 2, 3 and 4;

[0044] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0045] q is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0046] t is an integer arbitrarily selected from 0, 1, 2, 3 and 4.

[0047] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has the structure of formula (IB),

[0048]

[0049] Formula (IB)

[0050] in,

[0051] B is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a fused ring, a spirocyclic ring or a bridged ring structure;

[0052] X and X' are independently selected from -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-;

[0053] L is independently selected from -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-;

[0054] X1, X3, X8, X9, X 10 、X 11 and X 12 independently selected from -CR5- or -N-;

[0055] R0 is independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, carboxyl, alkoxy, alkylamino, O=, CN, OH, -NR d8 R d9 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl and 5-8 membered heteroaryl; wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, saturated or partially saturated heterocyclic group is optionally substituted by 1 to multiple substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0056] Each R1 is the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2, -COOH or selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl substituted carboxyl or carboxyl surrogate, most preferably, the carboxyl surrogate is: or ; wherein the C 1-10 Alkyl, C2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 The alkylcarboxyl or carboxyl surrogate is optionally replaced by one or more alkyl groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 or any two adjacent R1 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, and the hydrogen on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic alkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0057] Each R2, R 2' and R d1 、R d2 the same or different, independently selected from hydrogen, deuterium, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 or optionally R2 and R 2' or R d1 and R d2 It can form, together with the carbon to which it is attached, a 5-6 membered aryl or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the cycloalkyl group or heterocycloalkyl group is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3;

[0058] Each R4 is the same or different and is independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Heteroalkyl; wherein said C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 The alkoxy group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0059] Each R5 and R6 are the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NR d8 R d9 , NH2, -COOH or selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocycloalkyl is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 or any two adjacent R5 or R6 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, and the aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0060] Each R d3 、R d4 、Rd5 、R d6 、R d7 、R d8 、R d9 and R d10 The same or different, each independently selected from hydrogen, deuterium, NH2, C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0061] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0062] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0063] m is an integer arbitrarily selected from 1, 2, 3 and 4;

[0064] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0065] q is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0066] t is an integer arbitrarily selected from 0, 1, 2, 3 and 4.

[0067] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IC),

[0068]

[0069] Formula (IC)

[0070] in,

[0071] Any represents a single bond or a double bond;

[0072] X and X' are independently selected from -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-;

[0073] L is independently selected from -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-;

[0074] X1, X3, X8, X9, X 10 、X 11 、X 12 、X 13 or X 14 independently selected from -CR5- or -N-;

[0075] R0 is independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NRd8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d8 R d9 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl and 5-8 membered heteroaryl; wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, saturated or partially saturated heterocyclic group is optionally substituted by 1 to multiple substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0076] Each R1 is the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2, -COOH or selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl substituted carboxyl or carboxyl surrogate, most preferably, the carboxyl surrogate is: or ; wherein the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 The alkylcarboxyl or carboxyl surrogate is optionally replaced by one or more alkyl groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 or any two adjacent R1 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, and the hydrogen on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic alkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0077] Each R2, R 2' and R d1 、R d2 the same or different, independently selected from hydrogen, deuterium, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 or optionally R2 and R 2' or R d1 and R d2 It can form, together with the carbon to which it is attached, a 5-6 membered aryl or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the cycloalkyl group or heterocycloalkyl group is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3;

[0078] Each R4 is the same or different and is independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Heteroalkyl; wherein said C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 The alkoxy group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0079] Each R5 and R6 are the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NR d8 R d9 , NH2, -COOH or selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocycloalkyl is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 or any two adjacent R5 or R6 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, and the aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0080] Each Rd3 、R d4 、R d5 、R d6 、R d7 、R d8 、R d9 and R d10 The same or different, each independently selected from hydrogen, deuterium, NH2, C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0081] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0082] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0083] m is an integer arbitrarily selected from 1, 2, 3 and 4;

[0084] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0085] q is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0086] t is an integer arbitrarily selected from 0, 1, 2, 3 and 4.

[0087] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (ID),

[0088]

[0089] Formula (ID)

[0090] in,

[0091] Any represents a single bond or a double bond;

[0092] X and X' are independently selected from -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-; priority is given to -C(R d1 )(R d2 )-、-N(R d4 )-, -O-, -S-, -S(=O)– or -S(=O)2-;

[0093] L is independently selected from -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-; priority is given to -OC(R d1 )(R d2 )-、-C(R d1 )(R d2 )O-, -O-, -S- or -N(R d4 )-;

[0094] X1, X3, X8 and X 13 independently selected from -CR5- or -N-;

[0095] R0 is independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R0 represents C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d8 R d9 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl and 5-8 membered heteroaryl; wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, saturated or partially saturated heterocyclic group is further optionally substituted by 1 to multiple substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0096] Each R1 is the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2, -COOH or selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl substituted carboxyl or carboxyl surrogate; wherein said C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 The alkylcarboxyl or carboxyl surrogate is optionally replaced by one or more alkyl groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN and NR d8 R d9 or any two adjacent R1 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, and the hydrogen on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic alkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0097] Each R2, R 2' and R d1 、R d2 the same or different, independently selected from hydrogen, deuterium, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkylamino, N,N-di(C 1-10 alkyl)amino, C1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 or optionally R2 and R 2' or R d1 and R d2 It can form, together with the carbon to which it is attached, a 5-6 membered aryl or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the cycloalkyl group or heterocycloalkyl group is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3;

[0098] Each R4 is the same or different and is independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10Heteroalkyl; wherein said C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 The alkoxy group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0099] Each R5 and R6 are the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NR d8 R d9 , NH2, -COOH or selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocycloalkyl is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 or any two adjacent R5 or R6 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, and the aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0100] Each R d4 、R d8 and R d9 The same or different, each independently selected from hydrogen, deuterium, NH2, C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0101] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0102] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0103] m is an integer arbitrarily selected from 1, 2, 3 and 4;

[0104] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0105] q is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0106] t is an integer arbitrarily selected from 0, 1, 2, 3 and 4.

[0107] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IE):

[0108]

[0109] Formula (IE)

[0110] in,

[0111] Any represents a single bond or a double bond;

[0112] X and X' are independently selected from -C(R d1 )(R d2 )-、-N(R d4 )-、-N(R d7 )-, -O-, -S-, -S(=O)– or -S(=O)2-; preferably -C(R d1 )(R d2 )-、-N(R d4 )-, -O-, -S-, -S(=O)–, or -S(=O)2-;

[0113] L is independently selected from -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-; priority is given to -OC(R d1 )(R d2 )-、-C(R d1 )(R d2 )O-, -O-, -S- or -N(R d4 )-;

[0114] X1, X3, X8 and X 13 independently selected from -CR5- or -N-;

[0115] R is independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R represents C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d8 R d9 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl and 5-8 membered heteroaryl; wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, saturated or partially saturated heterocyclic group is optionally substituted by 1 to multiple substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0116] Each R1 is the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2, -COOH or selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C3-10 Heterocyclic group, C 1-10 Alkyl substituted carboxyl or carboxyl substitute; or any two adjacent R1 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, and the hydrogen on the aryl, saturated or partially saturated cycloalkyl, or heterocyclic alkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0117] Each R4 is the same or different and is independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Heteroalkyl; wherein said C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 The alkoxy group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0118] Each R5 and R6 are the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NR d8 R d9 , NH2, -COOH or selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocycloalkyl is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 or any two adjacent R5 or R6 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, and the aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0119] Each R d1 、R d2 、R d4 、R d8 and R d The same or different, each independently selected from hydrogen, deuterium, NH2, C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0120] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0121] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0122] m is an integer arbitrarily selected from 1, 2, 3 and 4;

[0123] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0124] q is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0125] t is an integer arbitrarily selected from 0, 1, 2, 3 and 4.

[0126] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has the structure of formula (IF-1) or (IF-2),

[0127] Formula (IF-1)

[0128]

[0129] Formula (IF-2)

[0130] in,

[0131] Any represents a single bond or a double bond;

[0132] X and X' are independently selected from -C(R d1 )(R d2 )-、-N(R d4 )-, -O-, -S-, -S(=O)– or -S(=O)2-;

[0133] L is independently selected from -OC(R d1 )(R d2 )-、-C(R d1 )(R d2 )O-, -O-, -S- or -N(R d4 )-;

[0134] X1 and X8 are independently selected from -CR5- or -N-;

[0135] R is independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R represents C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d8 R d9 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl and 5-8 membered heteroaryl; wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, saturated or partially saturated heterocyclic group is further optionally substituted by 1 to multiple substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0136] Each R1 is the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2, -COOH or selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl or carboxyl surrogate;

[0137] Each R4 is the same or different and is independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Heteroalkyl; wherein said C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 The alkoxy group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0138] Each R5 and R6 are the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NR d8 R d9 , NH2, -COOH or selected from C 1-10 Alkyl, C2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocycloalkyl is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 or any two adjacent R5 or R6 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, and the aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0139] Each R d1 、R d2 、R d4 、R d8 and R d The same or different, each independently selected from hydrogen, deuterium, NH2, C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0140] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0141] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0142] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0143] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0144] q is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0145] t is an integer arbitrarily selected from 0, 1, 2, 3 and 4.

[0146] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IG),

[0147]

[0148] Formula (IG)

[0149] in,

[0150] X and X' are independently selected from -C(R d1 )(R d2 )-、-N(R d4 )-, -O-, -S-, -S(=O)– or -S(=O)2-;

[0151] L is independently selected from -OC(R d1 )(R d2 )-、-C(R d1 )(R d2 )O-, -O-, -S- or -N(R d4 )-;

[0152] X1 and X8 are independently selected from -CR5- or -N-;

[0153] R is independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR d8 R d9 , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group, wherein R represents C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, -NR d8 R d9 、C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic group, 6-10 membered aryl and 5-8 membered heteroaryl; wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, saturated or partially saturated heterocyclic group is optionally substituted by 1 to multiple substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is optionally substituted by 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3 and OH;

[0154] Each R1 is the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2, -COOH or selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl or carboxyl surrogate;

[0155] Each R4 is the same or different and is independently selected from hydrogen, deuterium, halogen, CN, OH, SH and NH2, -COOH or C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon group, composed of C 3-10 Cycloalkyl or C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Alkyl, and C 3-10 Cycloalkyl, C 3-10 Heterocyclic hydrocarbon-substituted C 1-10 Heteroalkyl; wherein said C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 The alkoxy group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic radical substitution;

[0156] Each R5 and R6 are the same or different and are independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NR d8 R d9 , NH2, -COOH or selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocycloalkyl is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH, and C 3-10 or any two adjacent R5 or R6 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, and the aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0157] Each R d1 、R d2 、R d4 、R d8 and R d The same or different, each independently selected from hydrogen, deuterium, NH2, C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0158] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0159] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0160] m is an integer arbitrarily selected from 1, 2, 3 and 4;

[0161] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0162] q is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0163] t is an integer arbitrarily selected from 0, 1, 2, 3 and 4.

[0164] According to an embodiment of the present invention,

[0165] A is selected from unsubstituted or substituted C 6-20 Aryl, 5-20 membered heteroaryl;

[0166] B is selected from unsubstituted or substituted 3-20 membered heterocyclic group, 6-18 membered spirocyclic group or bridged ring group, C 6-20 aryl;

[0167] X and X' are the same or different and are independently selected from -C(R d1 )(R d2)-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -S(=O)– or -S(=O)2-;

[0168] L is selected from -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-; R d1 、R d2 The same or different, each independently selected from hydrogen, deuterium, halogen, C 1-10 Alkyl, C 1-10 alkoxy;

[0169] X1, X2, X3, X4, X5, X8 and X9 are the same or different and are independently selected from -CR5- or -N-; each R5 is the same or different and is independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 1-10 alkoxy;

[0170] R0 is selected from unsubstituted or optionally substituted by one, two or more R 01 Substituted C 1-10 Alkyl; each R 01 The same or different, independently selected from unsubstituted or optionally substituted by one, two or more R 02 Substituted C 3-20 Cycloalkyl, 3-20 membered heterocyclyl and 5-20 membered heteroaryl; each R 02 the same or different, independently selected from halogen, deuterium, CN, oxo (=O), C 1-10 Alkyl, halogenated C 1-10 Alkyl, CN-C 1-10 Alkyl, C 3-6 Cycloalkyl-C 1-10 alkyl;

[0171] Each R1 is the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, COOH, unsubstituted or optionally substituted by one, two or more R 11 Substituted -C 1-10 Alkyl-COOH, -C 2-10 Alkenyl-COOH; each R 11 the same or different, independently selected from H, deuterium, halogen, C 1-10 Alkyl, C1-10 alkoxy;

[0172] R2, R 2' the same or different, independently selected from hydrogen, deuterium, halogen, oxo (=O), C 1-10 Alkyl, C 1-10 alkyloxy;

[0173] Each R4 is the same or different and is independently selected from hydrogen, deuterium, halogen, oxo (=O), CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 1-10 alkoxy;

[0174] Each R6 is the same or different and is independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NH2, -COOH, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkynyl, 5-14 membered heteroaryl;

[0175] R d3 、R d4 、R d5 、R d6 、R d7 、R d8 、R d9 and R d10 The same or different, each independently selected from hydrogen, deuterium, CN, OH, SH and NH2, -COOH, C 1-10 Alkyl, C 1-10 alkoxy;

[0176] m is an integer arbitrarily selected from 1, 2, 3 and 4;

[0177] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0178] q is arbitrarily selected from integers of 0, 1, 2, 3, 4 and 5.

[0179] According to an embodiment of the present invention, A is selected from unsubstituted or substituted C 6-14 Aryl, 5-14 membered heteroaryl;

[0180] B is selected from unsubstituted or substituted 3-14 membered heterocyclic group, 6-18 membered spirocyclic group or bridged ring group, C 6-14 aryl;

[0181] X and X' are the same or different and are independently selected from -C(R d1 )(R d2 )-, -O-, -S-;

[0182] L is selected from -C(Rd1 )(R d2 )-、-OC(R d1 )(R d2 )-、-C(R d1 )(R d2 )O-, -O-, -S-, -NH-; R d1 、R d2 The same or different, each independently selected from hydrogen, deuterium, C 1-10 alkyl;

[0183] X1, X2, X3, X4, X5, X8 and X9 are the same or different and are independently selected from -CR5- or -N-; each R5 is the same or different and is independently selected from hydrogen, deuterium, halogen, C 1-10 Alkyl, C 1-10 alkoxy;

[0184] R0 is selected from unsubstituted or optionally substituted by one, two or more R 01 Substituted C 1-10 Alkyl; each R 01 The same or different, independently selected from unsubstituted or optionally substituted by one, two or more R 02 Substituted C 3-14 Cycloalkyl, 3-14 membered heterocyclyl and 5-14 membered heteroaryl; each R 02 the same or different, independently selected from CN, deuterium, oxo (=O), C 1-10 Alkyl, CN-C 1-10 Alkyl, C 3-6 Cycloalkyl-C 1-10 alkyl;

[0185] Each R1 is the same or different and is independently selected from halogen, COOH, unsubstituted or optionally substituted by one, two or more R 11 Substituted -C 1-10 Alkyl-COOH, -C 2-10 Alkenyl-COOH; each R 11 the same or different, independently selected from H, deuterium, halogen, C 1-10 Alkyl, C 1-10 alkoxy;

[0186] R2, R 2' the same or different, independently selected from hydrogen, deuterium, halogen, oxo (=O), C 1-10 Alkyl, C 1-10 alkoxy;

[0187] Each R4 is the same or different and is independently selected from hydrogen, deuterium, halogen, oxo (=O), CN, OH, SH and NH2, -COOH, C 1-10Alkyl, C 1-10 alkoxy;

[0188] Each R6 is the same or different and is independently selected from hydrogen, deuterium, halogen, CN, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkynyl, 5-14 membered heteroaryl;

[0189] m is an integer arbitrarily selected from 1, 2 and 3;

[0190] n is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0191] q is an integer arbitrarily selected from 0, 1, 2, 3 and 4.

[0192] According to an embodiment of the present invention, A is selected from phenyl or pyridyl;

[0193] B is piperidinyl, azetidinyl, phenyl, (1R, 5S)-3-azabicyclo[3.2.1]octanyl, spirocyclic group or bridged ring group; the spirocyclic or bridged ring contains one or more heteroatoms, and the heteroatoms are arbitrarily and independently selected from N, O or S;

[0194] X and X' are the same or different and are independently selected from CH2, O or S;

[0195] L can be selected from O, S, NH, CH2, OCH2, CH2O;

[0196] X1, X2, X3, X4, X5, X8 and X9 are the same or different and are independently selected from CH, CF or N;

[0197] R0 is selected from C unsubstituted or substituted by imidazolyl, pyrazolyl, pyrrolyl, azetidinyl, oxetanyl, pyrrolidinyl or cyclopropyl 1-3 Alkyl; the imidazolyl, pyrazolyl, pyrrolyl, azetidinyl, oxetanyl, pyrrolidinyl or cyclopropyl group may be unsubstituted, substituted with oxo (=O) or substituted with C 1-3 Alkyl, CN-C 1-3 Alkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl substitution;

[0198] Each R1 is the same or different and is independently selected from COOH, F, -C 1-3 Alkyl-COOH, -C 2-3 alkenyl-COOH;

[0199] R2, R 2' the same or different, independently selected from hydrogen, deuterium, halogen, oxo (=O), C 1-3 alkyl;

[0200] Each R4 is the same or different and is independently selected from hydrogen, deuterium, halogen, oxo (=O), C 1-3 alkyl;

[0201] Each R6 is the same or different and is independently selected from hydrogen, deuterium, F, Cl, Br, CN, ethynyl, imidazolyl;

[0202] m is arbitrarily selected from 1 or 2;

[0203] n is arbitrarily selected from 0, 1 or 2;

[0204] q is arbitrarily selected from 0, 1 or 2.

[0205] According to an embodiment of the present invention, The structure can be selected from the following:

[0206] 、 、 、 、 、 、 、 、 、 、 、 、 ;

[0207] B can be the following structure: 、 、 、 ;

[0208] L can be selected from O, S, NH, CH2, OCH2, CH2O;

[0209] The structure can be selected from the following:

[0210] 、 、 、 、 、 ;

[0211] R0 can be selected from the following structures:

[0212] methyl, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ;

[0213] R1 can be selected from COOH, F, 、 ;

[0214] R2 and R2' are both H;

[0215] R4 is H, F, methyl; X8 is selected from CH or N; X9 is selected from CH or N;

[0216] m is selected from 1 or 2; n is selected from 1 or 2.

[0217] In one embodiment of the present invention, the above-mentioned compound or its pharmaceutically acceptable salt, or its corresponding isomer, isotope substitution, is a compound selected from the following structures:

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its pharmaceutically acceptable salts, solvates, enantiomers and isotope substitutions.

[0312] According to an embodiment of the present invention, the pharmaceutical composition is formulated for administration by a route selected from the group consisting of oral, parenteral, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural.

[0313] According to an embodiment of the present invention, the pharmaceutical composition is preferably administered orally.

[0314] The oral dosage form is not particularly limited and may be any oral dosage form known in the art, preferably including tablets, capsules, suspensions, oral solutions, and the like. When used as an oral dosage form, the dosage standard used is, for example, 500-1500 mg / day, preferably 700-1200 mg / day, more preferably 800-1000 mg / day, and most preferably 1000 mg / day.

[0315] The duration of administration of the pharmaceutical composition according to the present invention may depend on the severity of the disease, and is preferably at least 1 month, for example, 1, 2, 3, 4, 5 or 6 months, and may be lifelong depending on the disease condition.

[0316] According to an embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable excipient selected from at least one of the following excipients, including but not limited to a filler, a disintegrant, a binder, a lubricant, a surfactant, a flavoring agent, a wetting agent, a pH adjuster, a solubilizer or cosolvent, and an osmotic pressure regulator. Those skilled in the art can easily determine how to select the corresponding excipients and their corresponding amounts based on the requirements of the specific dosage form.

[0317] According to an embodiment of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0318] Another object of the present invention is to provide the use of the above-mentioned compound in the preparation of a drug for preventing and / or treating diseases related to the GLP1 / GLP1R signaling pathway. The diseases related to the GLP1 / GLP1R signaling pathway include but are not limited to overweight, obesity, diabetes (T1D and / or T2DM, including prediabetes), idiopathic T1D (type 1B), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., acute kidney disease, renal tubular dysfunction, proinflammatory changes in the proximal tubules), diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, obesity ( including hypothalamic obesity and monogenic obesity) and related comorbidities (such as osteoarthritis and urinary incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain caused by the use of other medications (e.g., steroids and antipsychotics), excessive sugar cravings, dyslipidemia (including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, hyperinsulinemia), NAFLD (including steatosis, NAS H, fibrosis, cirrhosis, hepatocellular carcinoma and other related diseases), cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction (such as necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipidosis, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure Prevention or treatment of cardiovascular disease, cardiovascular disease, cerebrovascular disease, myocardial ischemia ...

[0319] The present invention also provides the compound represented by formula (I), its pharmaceutically acceptable salts, solvates, enantiomers, and isotopic substitutions, and the use of the pharmaceutical composition in preventing and / or treating diseases associated with the GLP1 / GLP1R signaling pathway. The diseases associated with the GLP1 / GLP1R signaling pathway are as defined above.

[0320] The present invention also provides a method for preventing and / or treating diseases associated with the GLP1 / GLP1R signaling pathway, comprising administering to a patient a preventively or therapeutically effective amount of at least one of the compounds of Formula (I), pharmaceutically acceptable salts, solvates, enantiomers, and isotopic substitutions thereof, or administering to a patient a preventively or therapeutically effective amount of the aforementioned pharmaceutical composition. The diseases associated with the GLP1 / GLP1R signaling pathway are as defined above.

[0321] In some embodiments, the patient is a mammal, preferably a human. BRIEF DESCRIPTION OF THE DRAWINGS

[0322] Figure 1 This is a comparison curve of the effects of the compound of the present invention and existing drugs on IPGTT blood glucose in GLP-1R humanized mice.

[0323] Figure 2 This is a comparison chart of the effects of the compound of the present invention and existing drugs on insulin release in GLP-1R humanized mice IPGTT.

[0324] Figure 3 This is a comparison curve of the effects of the compound of the present invention and existing drugs on IVGTT blood glucose in cynomolgus monkeys.

[0325] Definition and description: C 1-10 Selected from C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10 ; C 2-10 Selected from C2, C3, C4, C5, C6, C7, C8, C9 and C 10 ; C 3-10 Selected from C3, C4, C5, C6, C7, C8, C9 and C 10 ;

[0326] As used herein, the term "alkyl" refers to a linear or branched monovalent hydrocarbon group. Non-limiting examples include methyl, ethyl, propyl, butyl, 2-methyl-propyl, 1,1-dimethylethyl, pentyl, and hexyl.

[0327] As used herein, the term "alkylene" refers to a group of the formula -(CH2) n -a linear or branched divalent hydrocarbon group. Non-limiting examples include ethylene and propylene.

[0328] As used herein, the term "1 to a plurality of" means more than one, for example, 1, 2, 3, 4, 5 or more.

[0329] The term "carbocycle" or "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, which may contain 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 3 to 6 carbon atoms. The carbocycle may be monocyclic or polycyclic, and may be a saturated cycloalkyl or may optionally contain one, two, or more double bonds and / or triple bonds on its ring, thereby forming a so-called cycloalkenyl or cycloalkynyl group. In the case of carbocycles having multiple rings, these rings may form spirocycles, fused rings, and bridged ring structures. For example, non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclooctatetraenyl, etc.; non-limiting examples of polycyclic carbocycles include decalinyl or isobornyl.

[0330] The term "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom or atomic group selected from N, O, NH, S, S(O) or S(O)2, but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, 1-4 of which are heteroatoms (e.g., 1, 2, 3, and 4); more preferably, it contains 3 to 6 ring atoms (e.g., 3, 4, 5, 6). The heterocyclic group can be connected to the rest of the molecule through any one of the carbon atoms or a nitrogen atom (if present) or an oxygen or sulfur atom (particularly in the case of forming an onium salt). The heterocyclic group can include fused or bridged rings and / or spirocyclic rings. Non-limiting examples of monocyclic heterocyclic groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, dioxolyl, tetrahydropyranyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, trithianyl, homopiperazinyl, diazepanyl etc., preferably piperidinyl, pyrrolidinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups, and can also be benzo-fused heterocyclic groups such as dihydroisoquinolinyl. The heterocyclic group can be bicyclic, and its non-limiting examples include hexahydrocyclopenta [c] pyrrole -2 (1H) - base, hexahydro pyrrolo [1,2-a] pyrazine -2 (1H) - base. The heterocyclyl group may also be partially unsaturated, i.e. it may contain one or more double bonds, non-limiting examples of which include dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl.

[0331] The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0332] As used herein, the term "heteroaryl / heteroaromatic ring" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, nitrogen and phosphorus. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan. Non-limiting examples of heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, etc. and their benzo derivatives, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, , isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, etc.; or acinyl, indolizinyl, purinyl, etc. and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and / or phenoxazinyl, etc.

[0333] The heteroaryl group / heteroaromatic ring may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one, two or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0334] Unless otherwise specified, heterocyclic groups, heteroaryls, or heteroaromatic rings include all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative, non-limiting examples, substituted or bonded to other groups at one, two, or more positions of the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) may include pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene, and pyridin-4-ylene; thienyl or thienylene include thien-2-yl, thien-2-ylene, thien-3-ylene, and thien-3-ylene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.

[0335] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0336] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric 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 salts of amino acids such as arginine, and organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0337] Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound. The parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

[0338] As used herein, "pharmaceutically acceptable salts" are derivatives of the compounds of the present invention, wherein the parent compound is modified by salification with an acid or alkali. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid radicals such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts such as sodium salts, potassium salts, amine salts, quaternary ammonium salts of the parent compound, and the like. Conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids, inorganic and organic bases, wherein the inorganic or organic acid is selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene The inorganic base and organic base described in the following examples are selected from sodium, potassium, magnesium, calcium, etc. or amines, diethylamine, triethylamine, ethanolamine, etc.

[0339] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0340] In addition to the form of salts, the compounds provided by the present invention also exist in prodrug form. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0341] Some compounds of the present invention may exist in unsolvated or solvated forms, including hydrate forms. Generally speaking, solvated forms are comparable to unsolvated forms and are included within the scope of the present invention. Some compounds of the present invention may exist in polycrystalline or amorphous forms.

[0342] As used herein, the term "solvate" refers to an association formed between one or more solvent molecules and a compound 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. Thus, the term "hydrate" refers to an association formed when the solvent molecule is water.

[0343] Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all within the scope of the present invention.

[0344] The diagrammatic representations of racemic, ambiscalemic and scalemic, or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by a wedge-shaped bond and a dashed bond. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise indicated, they include E, Z Geometric isomers. Likewise, all tautomeric forms are included within the scope of the present invention.

[0345] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, ( R )- and( S )-enantiomers, diastereomers, ( D )-isomer, ( L )-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are within the scope of the present invention.

[0346] Optically active ( R )-and( S )-isomers and D and L Isomers. If a single enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by fractional crystallization or chromatography as known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished using chromatography using a chiral stationary phase, optionally combined with chemical derivatization (e.g., formation of carbamates from amines).

[0347] The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0348] 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 has no toxic side effects on the host or patient. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity-increasing agents, transdermal enhancers, etc. Their preparations are well known to those skilled in the art of cosmetics or topical medicine. For additional information about carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0349] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0350] When a substituent's bond crosses two atoms in a ring, such substituent may be bonded to any atom in the ring. When a substituent is listed without specifying the atom through which it is bonded to a compound included in the general chemical formula but not specifically mentioned, such substituent may be bonded to any atom therein. Combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0351] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0352] The present invention will now be further described by way of examples. The examples given below are for illustrative purposes only and are not intended to limit the scope of this invention. The compounds of the present invention can be prepared using many methods known in the art of organic synthesis. The examples of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry, or by methods modified therefrom. Preferred methods include, but are not limited to, the methods described below.

[0353] Unless otherwise specified, all solvents used in this invention were commercially available and used without further purification. Reactions were typically carried out under an inert atmosphere of nitrogen using anhydrous solvents. Nuclear magnetic resonance spectra were measured on a Bruker Avance-400 (400 MHz) spectrometer, with chemical shifts reported as δ (ppm). Mass spectrometry was performed using an Agilent 1200 Series (Plus 6110 / and 1956A) LC / MS or a Shimadzu MS (DAD: SPD-M20A(LC)) and a Shimadzu Micromass 2020 detector. The mass spectrometer was equipped with an electrospray ionization (ESI) source operating in positive and negative modes.

[0354] 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; EtOAc is ethyl acetate; THF is tetrahydrofuran; equivalent is eq; CDI is carbonyldiimidazole; DCM is dichloromethane; PE is petroleum ether; DIAD is diisopropyl azodicarboxylate; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; CBz is benzyloxycarbonyl; BOC is tert-butyl benzoate. Butylcarbonyl; HOAc is acetic acid; Ms is methanesulfonyl; 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; i-PrOH is 2-propanol.

[0355] Compounds can be named manually, using ChemDraw®, or, if purchased commercially, using the supplier's catalog name. TLC or LC-MS is usually used to determine if the reaction is complete. DETAILED DESCRIPTION

[0356] In order to illustrate the present invention in more detail, the following examples are given, but the scope of the present invention is not limited thereto.

[0357] Example 1-1. Synthesis of (S,E)-methyl 3-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)acrylate (Intermediate A-1):

[0358] 1) Preparation of (E)-3-(3-fluoro-4-nitrophenyl) methyl acrylate:

[0359]

[0360] To a solution of methyl diethylphosphonate (1 g, 4.76 mmol) in dry THF (10 mL) at 0°C was added sodium hydride (60% w / w dispersion in mineral oil, 210 mg, 5.24 mmol). The mixture was stirred at 0°C for 30 minutes, followed by the slow addition of 3-fluoro-4-nitrobenzaldehyde (885 mg, 5.24 mmol), maintaining the reaction temperature around 0°C. After the addition, the mixture was allowed to warm 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). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 3 / 1) to afford methyl (E)-3-(3-fluoro-4-nitrophenyl)acrylate (800 mg, 74.8% yield).

[0361] 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.18(t, J =8.2 Hz, 1 H), 8.05(d, J =12.8 Hz, 1H), 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).

[0362] 2) Synthesis of (S, E)-3-(4-nitro-3-((oxetane-2-ylmethyl)amino)phenyl)acrylate:

[0363]

[0364] A mixture of (E)-methyl 3-(3-fluoro-4-nitrophenyl)acrylate (Intermediate 1) (300 mg, 1.33 mmol), (S)-oxetan-2-ylmethylamine (116 mg, 1.33 mmol), and KCO (368 mg, 2.67 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The mixture was diluted with water (50 mL) and extracted with EA (3 x 10 mL). The combined organic phases were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by TLC (PE / EA = 1 / 1) to afford methyl (S,E)-3-(4-nitro-3-((oxetan-2-ylmethyl)amino)phenyl)acrylate (320 mg, 82.4% yield). LC-MS m / z: 293 [M+H] + .

[0365] 3) Synthesis of (S, E)-3-(4-amino-3-((oxetane-2-ylmethyl)amino)phenyl)acrylate:

[0366]

[0367] A mixture of (S,E)-methyl 3-(4-nitro-3-((oxetan-2-ylmethyl)amino)phenyl)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 with stirring for 16 hours. The reaction mixture was cooled to room temperature, poured into saturated NaHCO3 (30 mL), and extracted with EA (3 × 10 mL). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to afford methyl (S,E)-3-(4-amino-3-((oxetan-2-ylmethyl)amino)phenyl)acrylate (270 mg, 93.7% yield). LC-MS m / z: 263 [M+H] + .

[0368] 4) Synthesis of (S,E)-3-(2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)methyl acrylate (Intermediate A-1):

[0369]

[0370] To a solution of (S,E)-methyl 3-(4-amino-3-((oxetan-2-ylmethyl)amino)phenyl)acrylate (Intermediate 3) (240 mg, 0.916 mmol) in dry THF (5 mL) at 0°C was slowly added chloroacetic anhydride (173 mg, 1.01 mmol). The reaction mixture was stirred at 0°C for 30 minutes and then heated to 60°C with stirring for 3 hours. After cooling to room temperature, the mixture was quenched with water (20 mL) and extracted with EA (2 × 10 mL). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1) to afford methyl (S,E)-3-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)acrylate (Intermediate A-1) (240 mg, 81.9% yield). LC-MS m / z: 321 [M+H] + .

[0371] Example 1-2, Synthesis of methyl 4-(2-chloroacetamide)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (Intermediate A-2):

[0372] 1) Synthesis of methyl 3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate:

[0373]

[0374] To a mixed solution of (1-ethyl-1H-imidazol-5-yl)methanamine (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) was added TEA (1.2 g, 12.1 mmol). The reaction mixture was heated to 60 o The reaction was stirred at 40°C over the weekend. The reaction mixture was poured into saturated brine (100 mL) and extracted with EA (2 × 80 mL). The organic layer was concentrated under reduced pressure and then purified by flash column chromatography on silica gel (EA / PE = 3 / 1) to afford methyl 3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate (320 mg, 87.0% yield). LC-MS m / z: 305 [M+H] + .

[0375] 2) Synthesis of methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate:

[0376]

[0377] Under N2 protection, 10% wet Pd / C (50 mg) was added to a solution of methyl 3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate (320 mg, 1.05 mmol) in MeOH (10 mL). After H2 replacement, the temperature was raised to 45°C under H2 atmosphere. o The reaction was stirred at C for 3 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by flash column chromatography on silica gel (DCM / MeOH = 10 / 1) to give methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (270 mg, 93.8% yield). LC-MS m / z: 275 [M+H] + .

[0378] 3) Synthesis of methyl 4-(2-chloroacetamide)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (Intermediate A-2):

[0379]

[0380] A solution of methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)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 for 16 h. The reaction solution was poured into saturated brine (100 mL) and extracted with DCM (2 × 80 mL). The organic phase was concentrated under reduced pressure to yield methyl 4-(2-chloroacetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (230.0 mg, 78.2% yield). LC-MS m / z: 351 [M+H] + .

[0381] Example 1-3, (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate A-3):

[0382] 1) Synthesis of methyl (S)-4-nitro-3-((oxetane-2-ylmethyl)amino)benzoate:

[0383]

[0384] To a solution of methyl 3-fluoro-4-nitrobenzoate (4.0 g, 20 mmol) and (S)-oxetane-2-ylmethylamine (1.7 g, 20 mmol) in DMA (40 mL) was added KCO (5.5 g, 40 mmol) and stirred at room temperature for 12 h. The reaction mixture was poured into saturated brine (200 mL) and extracted with ethyl acetate (2 × 80 mL). The combined organic layers were washed with saturated brine (2 × 200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield methyl (S)-4-nitro-3-((oxetane-2-ylmethyl)amino)benzoate (5.2 g). LC-MS m / z: 267 [M+H] + .

[0385] 2) Synthesis of methyl (S)-4-amino-3-((oxetane-2-ylmethyl)amino)benzoate:

[0386]

[0387] Under N₂ protection, palladium / carbon (520 mg) was added to a solution of methyl (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate (5.2 g, 20 mmol) in methanol (50 mL). After H₂ replacement, the reaction mixture was stirred at room temperature under an H₂ atmosphere for 12 h. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to yield methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (3.9 g, 82.3% yield). LC-MS m / z: 237 [M+H] + .

[0388] 3) Synthesis of (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Intermediate A-3):

[0389]

[0390] To a solution of (S)-methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (1.5 g, 6 mmol) in THF (12 mL) at 0 °C, 2-chloroacetic anhydride (1.1 g, 6.6 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure and then separated by silica gel column chromatography (EA / PE = 1 / 1) to afford (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate A-3) (1.6 g, 90% yield). LC-MS m / z: 295 [M+H] + .

[0391] Example 1-4, Synthesis of (E)-methyl 3-(4-(2-chloroacetamide)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)phenyl)acrylate (Intermediate A-4):

[0392] 1) Synthesis of (E)-3-(3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrophenyl)acrylate:

[0393]

[0394] To a solution of (E)-methyl 3-(3-fluoro-4-nitrophenyl)acrylate (Intermediate 1) (400 mg, 1.78 mmol) and (1-ethyl-1H-imidazol-5-yl)methanamine (354 mg, 1.78 mmol) in THF (6 mL) and MeOH (4 mL) was added TEA (1.80 g, 17.80 mmol, 10.0 eq). After stirring, the reaction mixture was heated to 60°C and stirred for 48 h. The resulting mixture was poured into brine (50 mL) and extracted with EA (2 × 20 mL). The combined organic phases were concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to afford methyl (E)-3-(3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrophenyl)acrylate (400 mg, 68.1% yield). LC-MS m / z: 331 [M+H] + .

[0395] 2) Synthesis of (E)-3-(3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-aminophenyl)acrylate:

[0396]

[0397] Methyl (E)-3-(3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrophenyl)acrylate (400 mg, 1.21 mmol), Fe powder (203 mg, 3.63 mmol), and NH4Cl (192 mg, 3.62 mmol) were mixed in EtOH / H2O (10 / 1.5 mL), heated to 80°C, and stirred for 5 h. The reaction mixture was cooled to room temperature, poured into saturated NaHCO3 (30 mL), and extracted with EA (3 × 10 mL). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to afford methyl (E)-3-(3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-aminophenyl)acrylate (60 mg, 16.5% yield). LC-MS m / z: 301 [M+H] + .

[0398] 3) Synthesis of (E)-methyl 3-(4-(2-chloroacetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)phenyl)acrylate (Intermediate A-4):

[0399]

[0400] Intermediate A-2

[0401] Methyl (E)-3-(3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-aminophenyl)acrylate (50 mg, 0.17 mmol) and 2-chloroacetic anhydride (58 mg, 0.34 mmol) were mixed in THF (2 mL) and stirred at room temperature for 16 h. The resulting mixture was poured into brine (10 mL) and extracted with DCM (2 × 5 mL). The organic phase was concentrated to afford methyl (E)-3-(4-(2-chloroacetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)phenyl)acrylate (Intermediate A-4) (50 mg, 79.8% yield). LC-MS m / z: 377 [M+H] + .

[0402] Example 1-5, Synthesis of (S)-methyl 2-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)acetate (Intermediate A-5):

[0403] 1) Synthesis of methyl 2-(3-fluoro-4-nitrophenyl) acetate:

[0404]

[0405] To a solution of 2-(3-fluoro-4-nitrophenyl)acetic acid (800 mg, 4.02 mmol) in methanol (10 mL) was slowly added thionyl chloride (957 mg, 8.04 mmol) at 0°C. The mixture was stirred at room temperature for 3 hours, then quenched with water (50 mL) at 0°C and extracted with ethyl acetate (2 × 20 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford methyl 2-(3-fluoro-4-nitrophenyl)acetate (840 mg, 98.1% yield).

[0406] 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.13(t, J =8.2 Hz, 1H), 7.55(dd, J =12.4, 1.6Hz, 1H), 7.37(dd, J = 8.4, 1.0 Hz, 1H), 3.90(s, 2H), 3.65(s, 3H).

[0407] 2) Synthesis of (S)-methyl 2-(4-nitro-3-((oxetane-2-ylmethyl)amino)phenyl)acetate:

[0408]

[0409] A mixture of methyl 2-(3-fluoro-4-nitrophenyl)acetate (1.05 g, 4.93 mmol), (S)-oxetan-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 combined organic phases were 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 = 2 / 1) to afford methyl (S)-2-(4-nitro-3-((oxetan-2-ylmethyl)amino)phenyl)acetate (300 mg, yield: 21.9%). LC-MS m / z: 280 [M+H] + .

[0410] 3) Synthesis of (S)-methyl 2-(4-amino-3-((oxetane-2-ylmethyl)amino)phenyl)acetate:

[0411]

[0412] Under N₂ protection, 10% wet Pd / C (116 mg) was added to a solution of methyl (S)-2-(4-nitro-3-((oxetan-2-ylmethyl)amino)phenyl)acetate (300 mg, 1.07 mmol) in methanol (10 mL). After H₂ replacement, the reaction was stirred at room temperature under a hydrogen atmosphere (1 atm) for 16 h. The reaction mixture was filtered, and the solid was washed with methanol (50 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 1 / 1) to afford methyl (S)-2-(4-amino-3-((oxetan-2-ylmethyl)amino)phenyl)acetate (120 mg, yield: 45.0%). LC-MS m / z: 251 [M+H] + .

[0413] 4) Synthesis of (S)-methyl 2-(2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)acetate (Intermediate A-5):

[0414]

[0415] To a solution of (S)-methyl 2-(4-amino-3-((oxetan-2-ylmethyl)amino)phenyl)acetate (120 mg, 0.48 mmol) in anhydrous tetrahydrofuran (5 mL) at 0°C was slowly added 2-chloroacetic anhydride (91 mg, 0.53 mmol). The mixture was stirred at 0°C for 30 minutes and then heated to 60°C and stirred for an additional 3 hours. The mixture was cooled to room temperature and quenched with water (20 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1) to afford methyl (S)-2-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)acetate (Intermediate A-5) (100 mg, 67.6% yield). LC-MS m / z:309 [M+H] + .

[0416] Example 1-6, Synthesis of methyl 2-(chloromethyl)-1-(1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate A-6):

[0417] 1) Synthesis of (1-(cyanomethyl)cyclopropyl)methanesulfonate:

[0418]

[0419] Triethylamine (4.00 g, 39.25 mmol) was added to a solution of 2-(1-(hydroxymethyl)cyclopropyl)acetonitrile (2.00 g, 18.00 mmol) in anhydrous dichloromethane (20 mL). The resulting mixture was cooled to 0°C, and MsCl (3.12 g, 27.23 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 1 h. The reaction mixture was then stirred at room temperature for an additional 2 h, diluted with dichloromethane (50 mL), and washed with brine (25 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield (1-(cyanomethyl)cyclopropyl)methanesulfonate (3.26 g, 17.23 mmol).

[0420] 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).

[0421] 2) Synthesis of 2-(1-(azidomethyl)cyclopropyl)acetonitrile:

[0422]

[0423] A solution of (1-(cyanomethyl)cyclopropyl)methanesulfonate (3.32 g, 17.54 mmol) and sodium azide (4.81 g, 73.99 mmol) in DMF (20 mL) was heated to 120°C and stirred for 16 hours. The mixture was then cooled to room temperature and quenched with water. The mixture was then extracted with dichloromethane (3 × 30 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 2-(1-(azidomethyl)cyclopropyl)acetonitrile (1.60 g, 11.75 mmol, 66.9% yield).

[0424] 1 HNMR(400 MHz, CDCl3)δ 3.31(s, 2H), 2.53(s, 2H), 0.70(d, J = 1.2 Hz,4H).

[0425] 3) Synthesis of 2-(1-(aminomethyl)cyclopropyl)acetonitrile:

[0426]

[0427] To a solution of 2-(1-(azidomethyl)cyclopropyl)acetonitrile (1.60 g, 11.75 mmol) in methanol (15 mL) / water (9 mL) was added tributylphosphine (7.13 g, 35.24 mmol) dropwise at room temperature. The resulting mixture was heated to 65°C and stirred for 3 h. The mixture was filtered, and the filter cake was washed with methanol (10 mL). The filtrate was concentrated under reduced pressure to yield 2-(1-(aminomethyl)cyclopropyl)acetonitrile (821 mg, 7.45 mmol, 63.5% yield).

[0428] 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).

[0429] 4) Synthesis of methyl 3-((1-(cyanomethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate:

[0430]

[0431] To a solution of methyl 3-fluoro-4-nitrobenzoate (300 mg, 1.51 mmol) and 2-(1-(aminomethyl)cyclopropyl)acetonitrile (166 mg, 1.51 mmol) in DMF (5 mL) was added potassium carbonate (625 mg, 4.53 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with brine (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 give methyl 3-((1-(cyanomethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate (250 mg, 0.86 mmol, yield: 57.6%). LC-MS m / z: 290 [M+H] + .

[0432] 5) Synthesis of methyl 4-amino-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate:

[0433]

[0434] To a solution of methyl 3-((1-(cyanomethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate (200 mg, 0.69 mmol) in methanol (8 mL) was added zinc powder (449 mg, 6.87 mmol) and acetic acid (415 mg, 6.91 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. Water (15 mL) was added for dilution and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with brine, 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, 120 g; mobile phase A: water (with 10 mM HCOOH); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 40% B to 60% B over 20 minutes; detector: 254 nm). The mobile phase containing the desired product was collected at 52% B and concentrated under reduced pressure to yield 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] + .

[0435] 6) Synthesis of methyl 2-(chloromethyl)-1-(1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate A-6):

[0436]

[0437] To a solution of methyl 4-amino-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate (140 mg, 0.54 mmol) in anhydrous THF (5 mL) was added portionwise 2-chloroacetic anhydride (92 mg, 0.54 mmol) at room temperature. The mixture was stirred at 60°C for 16 h. The reaction was quenched by the addition of water (5 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with 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); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 40% B to 60% B over 20 minutes; detector: 254 nm). The mobile phase containing the desired product was collected and concentrated under reduced pressure at 50% B mobile phase to yield methyl 2-(chloromethyl)-1-(1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate A-6) (90 mg, 0.54 mmol, yield: 52.5%). LC-MS m / z: 318 [M+H] + .

[0438] Example 1-7, Synthesis of methyl 4-(2-chloroacetamide)-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-fluorobenzoate (Intermediate A-7):

[0439] 1) Synthesis of 2-(1-((5-bromo-3-fluoro-2-nitrophenyl)amino)methyl)cyclopropyl)acetonitrile:

[0440]

[0441] To a solution of 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) in dimethyl sulfoxide (20 mL) was added N,N-diisopropylethylamine (1.63 g, 12.61 mmol), and the mixture was stirred at 70°C for 4 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with brine (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 provide 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] + .

[0442] 2) Synthesis of 2-(1-((2-amino-5-bromo-3-fluorophenyl)amino)methyl)cyclopropyl)acetonitrile:

[0443]

[0444] To a solution of 2-(1-((5-bromo-3-fluoro-2-nitrophenyl)amino)methyl)cyclopropyl)acetonitrile (542.0 mg, 1.65 mmol) in methanol (10 mL) at room temperature were added zinc powder (1.08 g, 16.52 mmol) and acetic acid (996.0 mg, 16.59 mmol). The mixture was stirred at room temperature for 30 minutes. Water (10 mL) was added for dilution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (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 provide 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] + .

[0445] 3) Synthesis of methyl 4-amino-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-fluorobenzoate:

[0446]

[0447] To a solution of 2-(1-((2-amino-5-bromo-3-fluorophenyl)amino)methyl)cyclopropyl)acetonitrile (358.0 mg, 1.21 mmol) in DMF (3 mL) / methanol (10 mL) at room temperature were added triethylamine (366.6 mg, 3.62 mmol) and 1,1'-bis(diphenylphosphinoferrocenepalladium)dichloride (88.5 mg, 0.12 mmol). The mixture was heated to 90°C under carbon monoxide protection and stirred 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 combined organic phases were 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 give 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] + .

[0448] 4) Synthesis of methyl 4-(2-chloroacetamide)-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-fluorobenzoate (Intermediate A-7):

[0449]

[0450] To a solution of methyl 4-amino-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-fluorobenzoate (85.0 mg, 0.31 mmol) in THF (4 mL) was added portionwise 2-chloroacetic anhydride (52.5 mg, 0.31 mmol) at room temperature. The mixture was stirred at 60°C for 16 hours. The mixture was quenched by the addition of water (5 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was 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 HCOOH); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 40% B to 60% B over 20 minutes; detector: 254 nm). The mobile phase containing the desired product was collected at 52% B and concentrated under reduced pressure to yield methyl 4-(2-chloroacetamido)-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-fluorobenzoate (Intermediate A-7) (141 mg, 0.54 mmol, yield: 78.6%). LC-MS m / z: 354 [M+H] + .

[0451] Example 1-8, Synthesis of 2-(chloromethyl)-1-(oxetan-3-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Intermediate A-8):

[0452] 1) Synthesis of methyl 4-nitro-3-((oxetane-3-ylmethyl)amino)benzoate:

[0453]

[0454] A mixture of methyl 3-fluoro-4-nitrobenzoate (1.60 g, 8.05 mmol), oxetan-3-ylmethanamine (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 combined organic phases were washed with brine (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 yield methyl 4-nitro-3-((oxetan-3-ylmethyl)amino)benzoate (1.50 g, yield: 70.1%). LC-MS m / z: 267 [M+H] + .

[0455] 2) Synthesis of methyl 4-amino-3-((oxetan-3-ylmethyl)amino)benzoate:

[0456]

[0457] Palladium on carbon (200 mg) was added to a solution of methyl 4-nitro-3-((oxetan-3-ylmethyl)amino)benzoate (1.50 g, 5.64 mmol) in methanol (30 mL). The resulting mixture was degassed and filled with hydrogen three times, then stirred at room temperature for 4 hours. The reaction mixture was filtered, and the filter cake was washed with methanol (20 mL). The filtrate was concentrated to afford methyl 4-amino-3-((oxetan-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] + .

[0458] 3) Synthesis of methyl 2-(chloromethyl)-1-(oxetane-3-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate:

[0459]

[0460] To a solution of methyl 4-amino-3-((oxetan-3-ylmethyl)amino)benzoate (1.20 g, 5.08 mmol) in dry tetrahydrofuran (20 mL) at 0°C was slowly added 2-chloroacetic anhydride (869 mg, 5.08 mmol). The mixture was stirred at 0°C for 30 minutes, then heated to 70°C and stirred for 3 hours. The mixture was quenched with water (100 mL) at room temperature and extracted with ethyl acetate (2 × 30 mL). The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford methyl 2-(chloromethyl)-1-(oxetan-3-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (1.00 g, yield: 67.0%). LC-MS m / z: 295 [M+H] + .

[0461] Example 1-9, Synthesis of methyl 2-(chloromethyl)-1-((3-methyloxetan-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate A-9):

[0462] 1) Synthesis of methyl 3-((3-methoxy-3-yl)methyl)amino)-4-nitrobenzoate:

[0463]

[0464] A mixture of methyl 3-fluoro-4-nitrobenzoate (2.00 g, 10.00 mmol), (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 combined organic phases were washed with brine (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 yield methyl 3-((3-methoxy-3-yl)methyl)amino)-4-nitrobenzoate (1.96 g, yield: 70.4%). LC-MS m / z: 281 [M+H] + .

[0465] 2) Synthesis of methyl 4-amino-3-((3-methyloxetane-3-yl)methyl)amino)benzoate:

[0466]

[0467] Palladium on carbon (400 mg) was added to a solution of methyl 3-((3-methoxy-3-yl)methyl)amino)-4-nitrobenzoate (1.96 g, 7.04 mmol) in methanol (20 mL). The resulting mixture was degassed and filled with hydrogen three times, then stirred at room temperature for 4 hours. The reaction mixture was filtered, and the filter cake was washed with methanol (20 mL). The filtrate was concentrated to afford methyl 4-amino-3-((3-methyloxetan-3-yl)methyl)amino)benzoate (1.55 g, yield: 85.2%), which was used directly in the next step without purification. LC-MS m / z: 251 [M+H] + .

[0468] 3) Synthesis of methyl 2-(chloromethyl)-1-((3-methyloxetane-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate:

[0469]

[0470] To a solution of methyl 4-amino-3-((3-methyloxetan-3-yl)methyl)amino)benzoate (200 mg, 0.80 mmol) in dry tetrahydrofuran (5 mL) at 0°C was added 2-chloroacetic anhydride (137 mg, 0.80 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure, and the residue was heated to 100°C in dioxane (5 mL) 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 afford methyl 2-(chloromethyl)-1-((3-methyloxetan-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (200 mg, yield: 81.2%). LC-MS m / z: 309 [M+H] + .

[0471] Example 1-10, Synthesis of Methyl 4-(2-chloroacetamide)-3-((1,2-dimethyl-1H-imidazol-5-yl)methyl)amino)benzoate (Intermediate A-10):

[0472] 1) Synthesis of 1,2-dimethyl-1H-imidazole-5-carbonaldehyde:

[0473]

[0474] To a solution of 5-bromo-1,2-dimethyl-1H-imidazole (500 mg, 2.86 mmol) in dry tetrahydrofuran (10 mL) at -78°C was added n-butyllithium (1.26 mL, 3.15 mmol, 2.5 M hexane). The mixture was stirred at -78°C for 30 minutes, followed by the slow addition of N,N-dimethylformamide (626 mg, 8.58 mmol) at 0°C. The mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the mixture was quenched with water (50 mL) at 0°C and extracted with ethyl acetate (2 x 30 mL). The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford 1,2-dimethyl-1H-imidazole-5-carboxaldehyde (300 mg, yield: 84.6%). LC-MS m / z: 125 [M+H] + .

[0475] 2) Synthesis of (E)-N-((1,2-dimethyl-1H-imidazol-5-yl)methylene)-2-methylpropane-2-sulfoxide amide:

[0476]

[0477] A mixture of 1,2-dimethyl-1H-imidazole-5-carboxaldehyde (300 mg, 2.42 mmol), 2-methylpropane-2-sulfoxide (439 mg, 3.63 mmol), and tetraisopropyl titanate (2.06 g, 7.26 mmol) in tetrahydrofuran (5 mL) was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (2 mL) and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain (E)-N-((1,2-dimethyl-1H-imidazol-5-yl)methylene)-2-methylpropane-2-sulfoxide (500 mg, yield: 91.0%). LC-MS m / z: 228 [M+H] + .

[0478] 3) Synthesis of N-((1,2-dimethyl-1H-imidazol-5-yl)methyl)-2-methylpropane-2-sulfoxide amide:

[0479]

[0480] (E)-N-((1,2-dimethyl-1H-imidazol-5-yl)methylene)-2-methylpropane-2-sulfoxide amide (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 for 2 hours. After completion of the reaction, the reaction was quenched with water (50 mL) at room temperature and extracted with dichloromethane (2 x 20 mL). The organic phase was concentrated under reduced pressure to afford N-((1,2-dimethyl-1H-imidazol-5-yl)methyl)-2-methylpropane-2-sulfoxide amide (400 mg, yield: 55.3%), which was used directly in the next step without purification. LC-MS m / z: 230 [M+H] + .

[0481] 4) Synthesis of (1,2-dimethyl-1H-imidazol-5-yl)methylamine hydrochloride:

[0482]

[0483] Dissolve N-((1,2-dimethyl-1H-imidazol-5-yl)methyl)-2-methylpropane-2-sulfoxide amide (400 mg, 1.75 mmol) in methanolic hydrochloric acid (5 mL, 3 M). Stir the mixture at room temperature for 1 hour. Filter the reaction mixture to obtain (1,2-dimethyl-1H-imidazol-5-yl)methanamine hydrochloride (200 mg, 57.8% yield).

[0484] 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.86(s, 2H), 7.63(s, 1H), 4.19(s, 2H), 3.77(s, 3H), 2.63(s, 3H).

[0485] 5) Synthesis of methyl 3-((1,2-dimethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate:

[0486]

[0487] Triethylamine (510 mg, 5.05 mmol) was added to a stirred solution of (1,2-dimethyl-1H-imidazol-5-yl)methanamine hydrochloride (200 mg, 1.01 mmol) and methyl 3-fluoro-4-nitrobenzoate (201 mg, 1.01 mmol) in tetrahydrofuran (3 mL) and methanol (2 mL). The mixture was stirred at 60°C for 3 hours. The resulting mixture was poured into brine (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 afford methyl 3-((1,2-dimethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate (200 mg, yield: 65.1%). LC-MS m / z: 305 [M+H] + .

[0488] 6) Synthesis of methyl 4-amino-3-((1,2-dimethyl-1H-imidazol-5-yl)methyl)amino)benzoate:

[0489]

[0490] To a solution of methyl 3-((1,2-dimethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate (200 mg, 0.66 mmol) in methanol (10 mL) was added palladium on carbon (20 mg). The resulting mixture was degassed and filled with hydrogen three times, and stirred at room temperature for 3 hours. The reaction cake was filtered and washed with methanol (50 mL), and the filtrate was concentrated under reduced pressure to afford methyl 4-amino-3-((1,2-dimethyl-1H-imidazol-5-yl)methyl)amino)benzoate (150 mg, yield: 82.9%), which was used in the next step without purification. LC-MS m / z: 275 [M+H] + .

[0491] 7) Synthesis of methyl 4-(2-chloroacetamido)-3-((1,2-dimethyl-1H-imidazol-5-yl)methyl)amino)benzoate:

[0492]

[0493] A solution of methyl 4-amino-3-((1,2-dimethyl-1H-imidazol-5-yl)methyl)amino)benzoate (150 mg, 0.55 mmol) and 2-chloroacetic anhydride (142 mg, 0.83 mmol) in tetrahydrofuran (3 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure and then purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain methyl 4-(2-chloroacetamido)-3-((1,2-dimethyl-1H-imidazol-5-yl)methyl)amino)benzoate (150 mg, yield: 77.9%). LC-MS m / z: 351 [M+H] + .

[0494] Example 1-11, Synthesis of methyl 5-(2-chloroacetamide)-6-(1-(cyanomethyl)cyclopropyl)methyl)aminopicolinate:

[0495] 1) Synthesis of methyl 6-((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-nitropyridine carboxylate (Intermediate A-11):

[0496]

[0497] To a solution of methyl 6-chloro-5-nitropyridine carboxylate (850 mg, 3.94 mmol) and 2-(1-(aminomethyl)cyclopropyl)acetonitrile (433 mg, 3.94 mmol) in dimethyl sulfoxide (10 mL) was added N,N-diisopropylethylamine (1.52 g, 11.81 mmol), and the mixture was stirred at 60°C for 16 hours. The resulting mixture was poured into brine (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 afford methyl 6-((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-nitropyridine carboxylate (190 mg, yield: 16.7%). LC-MS m / z: 291 [M+H] + .

[0498] 2) Synthesis of methyl 5-amino-6-((1-(cyanomethyl)cyclopropyl)methyl)amino)picolinate:

[0499]

[0500] Zinc powder (428 mg, 6.55 mmol) and acetic acid (393 mg, 6.55 mmol) were added to a solution of methyl 6-((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-nitropyridine carboxylate (190 mg, 0.65 mmol) in methanol (5 mL) at room temperature and stirred for 2 hours. After the reaction was complete, 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] + .

[0501] 3) Synthesis of methyl 5-(2-chloroacetamide)-6-(1-(cyanomethyl)cyclopropyl)methyl)aminopicolinate:

[0502]

[0503] To a solution of methyl 5-amino-6-((1-(cyanomethyl)cyclopropyl)methyl)amino)picolinate (80 mg, 0.31 mmol) in tetrahydrofuran (5 mL) was added 2-chloroacetic anhydride (79 mg, 0.46 mmol), and the mixture was stirred at room temperature for 2 hours. After completion of 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 afford methyl 5-(2-chloroacetamido)-6-(1-(cyanomethyl)cyclopropyl)methyl)aminopicolinate (150 mg, 88% yield). LC-MS m / z: 337 [M+H] + .

[0504] Example 1-12, Synthesis of (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (Intermediate A-12):

[0505]

[0506] To a solution of (S)-methyl 5-amino-6-((oxetan-2-ylmethyl)amino)picolinate (100 mg, 0.42 mmol) in tetrahydrofuran (10 mL) was added 2-chloroacetic anhydride (101 mg, 0.63 mmol), and the mixture was stirred at 60°C for 3 hours. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to afford methyl (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (140 mg).

[0507] Example 1-13, Synthesis of methyl 5-(2-chloroacetamide)-6-(1-ethyl-1H-imidazol-5-yl)methyl)aminopicolinate (Intermediate A-13):

[0508]

[0509] 2-Chloroacetic anhydride (138 mg, 0.82 mmol) was added portionwise to a solution of methyl 5-amino-6-((1-ethyl-1H-imidazol-5-yl)methyl)amino)picolinate (150 mg, 0.54 mmol) in tetrahydrofuran (5 mL) at room temperature. The mixture was stirred at 25°C 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 afford methyl 5-(2-chloroacetamido)-6-(1-ethyl-1H-imidazol-5-yl)methyl)aminopicolinate (180 mg, yield: 94.7%). LC-MS m / z: 352 [M+H] + .

[0510] Example 1-14, Synthesis of Methyl 4-(2-chloroacetamide)-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate (Intermediate A-14):

[0511]

[0512] 2-Chloroacetic anhydride (494 mg, 2.89 mmol) was added to a mixture of methyl 4-amino-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate (500 mg, 1.93 mmol) in tetrahydrofuran (5 mL) and stirred at room temperature 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 afford methyl 4-(2-chloroacetamido)-3-((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate (400 mg, yield: 61.8%). LC-MS m / z: 336 [M+H] + .

[0513] Example 1-15, Synthesis of (S)-N-(4-bromo-2-fluoro-6-((oxoalkyl-2-ylmethyl)amino)phenyl)-2-chloroacetamide (Intermediate A-15):

[0514]

[0515] 2-Chloroacetic anhydride (241 mg, 1.42 mmol) was added to a solution of (S)-5-bromo-3-fluoro-N1-(oxetan-2-ylmethyl)benzene-1,2-diamine (300 mg, 1.09 mmol) in dry tetrahydrofuran (5 mL). The mixture was stirred at room temperature 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 afford (S)-N-(4-bromo-2-fluoro-6-((oxetan-2-ylmethyl)amino)phenyl)-2-chloroacetamide (230 mg, yield: 59.9%). LC-MS m / z: 353 [M+H] + .

[0516] Example 1-16, Synthesis of N-(4-bromo-2-((1-(cyanomethyl)cyclopropyl)methyl)amino)-6-fluorophenyl)-2-chloroacetamide (Intermediate A-16):

[0517]

[0518] 2-Chloroacetic anhydride (129 mg, 0.76 mmol) was slowly added to a solution of 2-(1-((2-amino-5-bromo-3-fluorophenyl)amino)methyl)cyclopropyl)acetonitrile (150 mg, 0.50 mmol) in dry tetrahydrofuran (5 mL). The mixture was stirred at room temperature 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] + .

[0519] Example 1-17, Synthesis of methyl 4-(2-chloroacetamide)-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)-5-fluorobenzoate (Intermediate A-17):

[0520] 1) Synthesis of methyl 4-amino-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)-5-fluorobenzoate:

[0521]

[0522] Under carbon monoxide protection, potassium acetate (470 mg, 4.80 mmol) and 1,1'-bis(diphenylphosphinoferrocenedichloropalladium) (117 mg, 0.16 mmol) were added to a mixture of 5-bromo-N1-((1-ethyl-1H-imidazol-5-yl)methyl)-3-fluorobenzene-1,2-diamine (500 mg, 1.60 mmol) in methanol / N,N-dimethylformamide (5 mL / 5 mL). The mixture was stirred at 90°C for 16 hours. After the reaction was complete, water (30 mL) was added for dilution, and the resulting mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (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 = 20 / 1) to give methyl 4-amino-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)-5-fluorobenzoate (150 mg, yield: 32.1%). LC-MS m / z: 293 [M+H] + .

[0523] 2) Synthesis of methyl 4-(2-chloroacetamide)-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)-5-fluorobenzoate:

[0524]

[0525] To a solution of methyl 4-amino-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)-5-fluorobenzoate (150 mg, 0.51 mmol) in dry tetrahydrofuran (5 mL) at room temperature, 2-chloroacetic anhydride (176 mg, 1.02 mmol) was slowly added. The reaction was stirred at room temperature for 3 hours. Upon completion, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford methyl 4-(2-chloroacetamido)-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)-5-fluorobenzoate (130 mg, yield: 69.3%). LC-MS m / z: 369 [M+H] + .

[0526] Example 1-18, Synthesis of methyl 4-(2-chloroacetamido)-3-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)aminobenzoate (Intermediate A-18);

[0527]

[0528] Methyl 4-amino-3-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)aminobenzoate (500 mg, 1.67 mmol) was dissolved in dry tetrahydrofuran (10 mL) at room temperature, and chloroacetic anhydride (715 mg, 4.18 mmol) was slowly added. The resulting mixture was stirred at room temperature for another 2 hours. After the reaction was complete, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford methyl 4-(2-chloroacetamido)-3-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)aminobenzoate (400 mg, yield: 63.5%). LC-MS m / z: 377 [M+H] + .

[0529] Example 1-19, Synthesis of methyl 2-(chloromethyl)-1-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate A-19);

[0530]

[0531] Methyl 4-amino-3-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)aminobenzoate (500 mg, 1.67 mmol) was dissolved in dry tetrahydrofuran (10 mL) at room temperature, followed by the addition of 2-chloroacetic anhydride (715 mg, 4.18 mmol). The resulting mixture was stirred at room temperature for 2 hours. The temperature was then raised to 60°C and the reaction was stirred overnight. After the reaction was complete, the solvent was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to yield methyl 2-(chloromethyl)-1-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, yield: 16.7%). LC-MS m / z: 359 [M+H] + .

[0532] Example 1-20, Synthesis of methyl 2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole-6-carboxylate (Intermediate A-20);

[0533] 1) Synthesis of methyl 3-(methylamino)-4-nitrobenzoate:

[0534]

[0535] Methyl 3-fluoro-4-nitrobenzoate (2.00 g, 10.00 mmol) and methylamine solution (2 M in tetrahydrofuran, 10 mL) were added to a tetrahydrofuran (30 mL) solution at room temperature. The resulting mixture was stirred and reacted at room temperature for 2 hours. After the reaction was complete, 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 methyl 3-(methylamino)-4-nitrobenzoate (1.80 g, yield: 85.0%). LC-MS m / z: 211 [M+H] + .

[0536] 2) Synthesis of methyl 4-amino-3-(methylamino)benzoate:

[0537]

[0538] Methyl 3-(methylamino)-4-nitrobenzoate (1.80 g, 8.57 mmol) was dissolved in methanol (20 mL) at room temperature, and palladium on carbon (900 mg) was added. The resulting mixture was degassed and filled with hydrogen three times, and the reaction was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture 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] + .

[0539] 3) Synthesis of methyl 2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole-6-carboxylate:

[0540]

[0541] Methyl 4-amino-3-(methylamino)benzoate (1.2 g, 2.83 mmol) was dissolved in dry tetrahydrofuran (20 mL) at room temperature. Chloroacetic anhydride (2.27 g, 5.66 mmol) was then added and stirred at room temperature for 2 hours. The reaction mixture was then heated to 60°C and stirred for 16 hours. After the reaction was complete, 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-carboxylate (1.4 g, yield: 88.2%). LC-MS m / z: 239 [M+H] + .

[0542] Example 1-21, Synthesis of methyl 4-(2-chloroacetamide)-3-((1-isopropyl-1H-imidazol-5-yl)methyl)amino)benzoate (Intermediate A-21):

[0543] 1) Synthesis of (E)-N-((1-isopropyl-1H-imidazol-5-yl)methylene)-2-methylpropane-2-sulfoxide amide:

[0544]

[0545] (E)-N-((1H-imidazol-5-yl)methylene)-2-methylpropane-2-sulfoxide amide (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) at room temperature. The resulting mixture was stirred at room temperature 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 combined organic phases were back-extracted with brine (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 give (E)-N-((1-isopropyl-1H-imidazol-5-yl)methylene)-2-methylpropane-2-sulfoxide amide (4.8 g, yield: 73.4%). LC-MS m / z: 242 [M+H] + .

[0546] 2) Synthesis of N-((1-isopropyl-1H-imidazol-5-yl)methyl)-2-methylpropane-2-sulfoxide amide:

[0547]

[0548] (E)-N-((1-isopropyl-1H-imidazol-5-yl)methylene)-2-methylpropane-2-sulfoxide amide (4.80 g, 19.92 mmol) was dissolved in methanol (30 mL) at room temperature, and sodium borohydride (2.28 g, 59.75 mmol) was slowly added. The resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, water (200 mL x 2) was added to quench the reaction and the mixture was extracted with ethyl acetate (200 mL). The organic phase was back-extracted with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield N-((1-isopropyl-1H-imidazol-5-yl)methyl)-2-methylpropane-2-sulfoxide amide (4.5 g, yield: 87.5%). LC-MS m / z: 244 [M+H] + .

[0549] 3) Synthesis of (1-isopropyl-1H-imidazol-5-yl)methylamine:

[0550]

[0551] A mixture of N-((1-isopropyl-1H-imidazol-5-yl)methyl)-2-methylpropane-2-sulfoxide amide (4.50 g, 18.44 mmol) and acetic acid (50 mL, 3 mol / L methanol) was stirred at room temperature for 16 hours. Upon completion of the reaction, the resulting solution was concentrated under reduced pressure to yield (1-isopropyl-1H-imidazol-5-yl)methanamine (2.4 g, yield: 93.6%). LC-MS m / z: 140 [M+H] + .

[0552] 4) Synthesis of methyl 3-((1-isopropyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate:

[0553]

[0554] (1-Isopropyl-1H-imidazol-5-yl)methanamine (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 N,N-dimethylformamide (50 mL) at room temperature. The resulting mixture was stirred at room temperature 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 combined organic phases were back-extracted with brine (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-imidazol-5-yl)methyl)amino)-4-nitrobenzoate (1.2 g, yield: 21.9%). LC-MS m / z: 319 [M+H] + .

[0555] 5) Synthesis of methyl 4-amino-3-((1-isopropyl-1H-imidazol-5-yl)methyl)amino)benzoate:

[0556]

[0557] Methyl 3-((1-isopropyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate (1.2 g, 3.78 mmol) was dissolved in methanol (30 mL) at room temperature, followed by the addition of palladium on carbon (600 mg, 5.6 mmol). The resulting mixture was degassed and filled with hydrogen three times, 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 afford methyl 4-amino-3-((1-isopropyl-1H-imidazol-5-yl)methyl)amino)benzoate (750 mg, yield: 69.0%). LC-MS m / z: 289 [M+H] + .

[0558] 6) Synthesis of methyl 4-(2-chloroacetamide)-3-((1-isopropyl-1H-imidazol-5-yl)methyl)amino)benzoate:

[0559]

[0560] Chloroacetic anhydride (595 mg, 3.48 mmol) was added to a solution of methyl 4-amino-3-((1-isopropyl-1H-imidazol-5-yl)methyl)amino)benzoate (400 mg, 1.39 mmol) in dry tetrahydrofuran (8 mL) at room temperature. The reaction was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give methyl 4-(2-chloroacetamido)-3-((1-isopropyl-1H-imidazol-5-yl)methyl)amino)benzoate (450 mg, yield: 88.8%). LC-MS m / z: 365 [M+H] + .

[0561] Example 1-22, Synthesis of Methyl 4-(2-chloroacetamide)-3-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)aminobenzoate (Intermediate A-22):

[0562] 1) Synthesis of (E)-N-((1H-imidazol-5-yl)methylene)-2-methylpropane-2-sulfoxide amide:

[0563]

[0564] At room temperature, 1H-imidazole-5-carboxaldehyde (5.00 g, 52.08 mmol) and 2-methylpropane-2-sulfoxide amide (9.39 g, 78.12 mmol) were dissolved in tetrahydrofuran (100 mL). Titanium tetraisopropoxide (44.40 g, 156.25 mmol) was then slowly added. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was diluted with water (100 mL), filtered, and the filter cake was washed with ethyl acetate (150 mL). The filtrate was separated, and the aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic phases were back-extracted with brine (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 afford (E)-N-((1H-imidazol-5-yl)methylene)-2-methylpropane-2-sulfoxide amide (9.00 g, yield: 86.4%). LC-MS m / z: 200 [M+H] + .

[0565] 2) Synthesis of (E)-N-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methylene)-2-methylpropane-2-sulfoxide amide:

[0566]

[0567] Dissolve (E)-N-((1H-imidazol-5-yl)methylene)-2-methylpropane-2-sulfoxide amide (3.00 g, 15.10 mmol) and potassium carbonate (6.25 g, 45.30 mmol) in N,N-dimethylformamide (50 mL), then add (bromomethyl)cyclopropane (4.08 g, 30.20 mmol). The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phases were back-extracted with brine (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 give (E)-N-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methylene)-2-methylpropane-2-sulfoxide amide (2.8 g, yield: 73.4%). LC-MS m / z: 254 [M+H] + .

[0568] 3) Synthesis of N-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)-2-methylpropane-2-sulfoxide amide:

[0569]

[0570] (E)-N-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methylene)-2-methylpropane-2-sulfoxide amide (2.80 g, 11.60 mmol) was dissolved in methanol (20 mL) at room temperature, and sodium borohydride (1.26 g, 33.2 mmol) was slowly added. The reaction was stirred at room temperature for 2 hours. After completion of the reaction, 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 brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford N-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)-2-methylpropane-2-sulfoxide amide (2.55 g, yield: 90.9%). LC-MS m / z: 256 [M+H] + .

[0571] 4) Synthesis of (1-(cyclopropylmethyl)-1H-imidazol-5-yl)methylamine:

[0572]

[0573] A mixture of N-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)-2-methylpropane-2-sulfoxide amide (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 yield (1-(cyclopropylmethyl)-1H-imidazol-5-yl)methanamine (1.5 g, yield: 99.3%). LC-MS m / z: 152 [M+H] + .

[0574] 5) Synthesis of methyl 3-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate:

[0575]

[0576] (1-(Cyclopropylmethyl)-1H-imidazol-5-yl)methanamine (1.50 g, 9.93 mmol), methyl 3-fluoro-4-nitrobenzoate (2.98 g, 14.90 mmol), and potassium carbonate (2.76 g, 19.87 mmol) were dissolved in N,N-dimethylformamide (30 mL) and stirred at room temperature for 16 hours. After the reaction, the resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were back-extracted with brine (50 mL × 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 yield methyl 3-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate (1.5 g, yield: 45.7%). LC-MS m / z: 331 [M+H] + .

[0577] 6) Synthesis of methyl 4-amino-3-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)aminobenzoate:

[0578]

[0579] Methyl 3-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate (1.50 g, 4.55 mmol) was dissolved in methanol (40 mL) at room temperature, and palladium on carbon (750 mg) was added. The resulting mixture was degassed and filled with hydrogen three times, then stirred at room temperature for 4 hours. After the reaction was complete, the reaction 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 provide methyl 4-amino-3-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)aminobenzoate (1.1 g, yield: 80.7%). LC-MS m / z: 301 [M+H] + .

[0580] 7) Synthesis of methyl 4-(2-chloroacetamide)-3-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)aminobenzoate:

[0581]

[0582] Chloroacetic anhydride (257 mg, 1.50 mmol) was added to a solution of methyl 4-amino-3-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)aminobenzoate (150 mg, 0.50 mmol) in dry tetrahydrofuran (5 mL) at room temperature. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to afford methyl 4-(2-chloroacetamido)-3-((1-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)aminobenzoate (180 mg, yield: 95.5%). LC-MS m / z: 377 [M+H] + .

[0583] Example 1-23, Synthesis of methyl 4-(2-chloroacetamide)-3-((1-ethyl-5-oxypyrrolidin-2-yl)methyl)aminobenzoate (Intermediate A-23):

[0584] 1) Synthesis of dimethylethyl-L-glutamate:

[0585]

[0586] At room temperature, dimethyl L-glutamate hydrochloride (5.00 g, 23.70 mmol) and potassium hydroxide (770 mg, 26.07 mmol) were dissolved in methanol (100 mL). The reaction was stirred at room temperature for 15 minutes. Acetaldehyde (1.56 g, 35.55 mmol) was then added. The resulting mixture was stirred at room temperature 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 yield dimethylethyl-L-glutamic acid (3.50 g, yield: 72.7%).

[0587] 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).

[0588] 2) Synthesis of 1-ethyl-5-oxopyrrolidine-2-carboxylic acid methyl ester:

[0589]

[0590] Dimethylethyl-L-glutamic acid (3.50 g, 17.24 mmol) was dissolved in toluene (50 mL) at room temperature, and the resulting mixture was stirred at 110°C for 16 hours. After the reaction was complete, the solvent was removed in vacuo to yield methyl 1-ethyl-5-oxopyrrolidine-2-carboxylate (2.00 g, yield: 67.8%). LC-MS m / z: 172 [M+H] + .

[0591] 3) Synthesis of 1-ethyl-5-(hydroxymethyl)pyrrolidin-2-one:

[0592]

[0593] To a solution of methyl 1-ethyl-5-oxopyrrolidine-2-carboxylate (1.00 g, 5.85 mmol) in tetrahydrofuran (10 mL) at 0°C, lithium aluminum tetrahydride (222 mg, 5.85 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. Upon completion, the reaction mixture was quenched by the addition of water (2 mL) and aqueous sodium hydroxide solution (2 mL, 15%). The product was filtered and concentrated under reduced pressure to yield 1-ethyl-5-(hydroxymethyl)pyrrolidin-2-one (600 mg, yield: 71.7%). LC-MS m / z: 144 [M+H] + .

[0594] 4) Synthesis of (1-ethyl-5-oxopyrrolidin-2-yl)sulfonic acid methyl ester:

[0595]

[0596] To a solution of 1-ethyl-5-(hydroxymethyl)pyrrolidin-2-one (600 mg, 4.20 mmol) in dichloromethane (10 mL) at 0°C, triethylamine (848 mg, 8.40 mmol) and methanesulfonyl chloride (580 mg, 5.04 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour. Upon completion of the reaction, 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 yield methyl (1-ethyl-5-oxopyrrolidin-2-yl)sulfonate (500 mg, yield: 53.9%). LC-MS m / z: 222 [M+H] + .

[0597] 5) Synthesis of 5-(azidomethyl)-1-ethylpyrrolidin-2-one:

[0598]

[0599] Methyl (1-ethyl-5-oxopyrrolidin-2-yl)sulfonate (500 mg, 2.26 mmol) and sodium azide (220 mg, 3.39 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature. The resulting mixture was stirred at 120°C for 16 hours. After the reaction was complete, the mixture was diluted with saturated sodium bicarbonate (50 mL) at room temperature and extracted with ethyl acetate (10 mL x 3). The combined organic phases were back-extracted with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 5-(azidomethyl)-1-ethylpyrrolidin-2-one (500 mg, crude product). LC-MS m / z: 169 [M+H] + .

[0600] 6) Synthesis of 5-(aminomethyl)-1-ethylpyrrolidin-2-one:

[0601]

[0602] 5-(Azidomethyl)-1-ethylpyrrolidin-2-one (500 mg, 2.98 mmol) was dissolved in a mixture of tetrahydrofuran and water (10 mL / 2 mL) at room temperature, followed by the addition of triphenylphosphine (1.56 g, 5.96 mmol). The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography to yield 5-(aminomethyl)-1-ethylpyrrolidin-2-one (265 mg, yield: 99.9%). LC-MS m / z: 143.

[0603] 7) Synthesis of methyl 3-((1-ethyl-5-oxypyrrolidin-2-yl)methyl)amino)-4-nitrobenzoate:

[0604]

[0605] 5-(Aminomethyl)-1-ethylpyrrolidin-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) at room temperature. The resulting mixture was stirred at room temperature 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 combined organic phases were back-extracted with brine (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 yield methyl 3-((1-ethyl-5-oxopyrrolidin-2-yl)methyl)amino)-4-nitrobenzoate (120 mg, yield: 10.6%).

[0606] 8) Synthesis of methyl 4-amino-3-((1-ethyl-5-oxypyrrolidin-2-yl)methyl)amino)benzoate:

[0607]

[0608] Palladium on carbon (20 mg) was added to a solution of methyl 3-((1-ethyl-5-oxopyrrolidin-2-yl)methyl)amino)-4-nitrobenzoate (120 mg, 0.37 mmol) in methanol (10 mL) at room temperature. The resulting mixture was degassed and filled with hydrogen three times, then stirred at room temperature for 16 hours. The reaction solution was filtered and concentrated under reduced pressure to yield methyl 4-amino-3-((1-ethyl-5-oxopyrrolidin-2-yl)methyl)amino)benzoate (100 mg, yield: 92.9%). LC-MS m / z: 292.

[0609] 9) Synthesis of methyl 4-amino-3-((1-ethyl-5-oxypyrrolidin-2-yl)methyl)amino)benzoate:

[0610]

[0611] Methyl 4-amino-3-((1-ethyl-5-oxopyrrolidin-2-yl)methyl)amino)benzoate (100 mg, 0.31 mmol) was dissolved in dry tetrahydrofuran (3 mL) at room temperature, and then chloroacetic anhydride (106 mg, 0.62 mmol) was slowly added. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was concentrated and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to yield methyl 4-(2-chloroacetamido)-3-((1-ethyl-5-oxopyrrolidin-2-yl)methyl)aminobenzoate (100 mg, yield: 87.9%). LC-MS m / z: 368.

[0612] Example 1-24, Synthesis of (S)-methyl 4-(2-chloroacetamido)-3-((1-ethylpyrrolidin-2-yl)methyl)aminobenzoate (Intermediate A-24):

[0613] 1) Synthesis of methyl (S)-3-((1-ethylpyrrolidin-2-yl)methyl)amino)-4-nitrobenzoate:

[0614]

[0615] Methyl 3-fluoro-4-nitrobenzoate (7.77 g, 39.04 mmol), (S)-(1-ethylpyrrolidin-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) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were back-extracted with brine (50 mL × 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 afford methyl (S)-3-((1-ethylpyrrolidin-2-yl)methyl)amino)-4-nitrobenzoate (9.30 g, yield: 77.7%). LC-MS m / z:308.

[0616] 2) Synthesis of methyl (S)-4-amino-3-((1-ethylpyrrolidin-2-yl)methyl)aminobenzoate:

[0617]

[0618] Methyl (S)-3-((1-ethylpyrrolidin-2-yl)methyl)amino)-4-nitrobenzoate (3.07 g, 10.00 mmol) was dissolved in methanol (50 mL) at room temperature, followed by the addition of palladium on carbon (1.50 g, 14.00 mmol). The resulting mixture was degassed and filled with hydrogen three times, and stirred at room temperature for 4 hours. After the reaction was complete, the mixture was filtered, and the filter cake was rinsed 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 afford methyl (S)-4-amino-3-((1-ethylpyrrolidin-2-yl)methyl)aminobenzoate (2.3 g, yield: 80.0%). LC-MS m / z: 278.

[0619] 3) Synthesis of methyl (S)-4-(2-chloroacetamido)-3-((1-ethylpyrrolidin-2-yl)methyl)aminobenzoate:

[0620]

[0621] Chloroacetic anhydride (111 mg, 0.65 mmol) was slowly added to a solution of (S)-methyl 4-amino-3-((1-ethylpyrrolidin-2-yl)methyl)aminobenzoate (120 mg, 0.43 mmol) in dry tetrahydrofuran (20 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford methyl (S)-4-(2-chloroacetamido)-3-((1-ethylpyrrolidin-2-yl)methyl)aminobenzoate (140 mg, yield: 91.5%). LC-MS m / z: 354.

[0622] Example 1-25, Synthesis of (S)-N-(4-bromo-2-methyl-6-((oxetan-2-ylmethyl)amino)phenyl)-2-chloroacetamide (Intermediate A-25):

[0623] 1) Synthesis of (S)-5-bromo-3-methyl-2-nitro-N-(oxetane-2-ylmethyl)aniline:

[0624]

[0625] 5-Bromo-1-fluoro-3-methyl-2-nitrobenzene (500 mg, 2.14 mmol), (S)-oxetane-2-yl-methaneamine (186 mg, 2.14 mmol), and potassium carbonate (590 mg, 4.28 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. After completion, the reaction was quenched with water (5 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (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 afford (S)-5-bromo-3-methyl-2-nitro-N-(oxetane-2-ylmethyl)aniline (490 mg, yield: 76.2%). LC-MS m / z: 301.

[0626] 2) Synthesis of (S)-5-bromo-3-methyl-N-(oxetane-2-ylmethyl)benzene-1,2-diamine:

[0627]

[0628] Zinc powder (1.06 g, 16.30 mmol) was added to a solution of (S)-5-bromo-3-methyl-2-nitro-N-(oxetan-2-ylmethyl)aniline (490 mg, 1.63 mmol) dissolved in methanol (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered. The filtrate was then adjusted to pH 7-8 with aqueous ammonia. The product was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford (S)-5-bromo-3-methyl-N-(oxetan-2-ylmethyl)benzene-1,2-diamine (269 mg, yield: 60.7%). LC-MS m / z: 271.

[0629] 3) Synthesis of (S)-N-(4-bromo-2-methyl-6-((oxetane-2-ylmethyl)amino)phenyl)-2-chloroacetamide:

[0630]

[0631] (S)-5-Bromo-3-methyl-N-(oxetan-2-ylmethyl)benzene-1,2-diamine (109 mg, 0.40 mmol) was dissolved in tetrahydrofuran (3 mL) at room temperature, followed by the addition of chloroacetic anhydride (75 mg, 0.44 mmol). The resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford (S)-N-(4-bromo-2-methyl-6-((oxetan-2-ylmethyl)amino)phenyl)-2-chloroacetamide (98 mg, yield: 70.4%). LC-MS m / z: 349.

[0632] Example 1-26, Synthesis of (S)-2-(chloromethyl)-4-methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Intermediate A-26):

[0633] 1) Synthesis of methyl (S)-4-amino-3-methyl-5-((oxetane-2-ylmethyl)amino)benzoate:

[0634]

[0635] (S)-5-Bromo-3-methyl-N-(oxetan-2-ylmethyl)benzene-1,2-diamine (130 mg, 0.48 mmol), 1,1'-bis(diphenylphosphinoferrocenepalladium)dichloride (37 mg, 0.05 mmol), and potassium acetate (141 mg, 1.44 mmol) were dissolved in a mixture of N,N-dimethylformamide and methanol (2 ml / 2 ml) at room temperature. The mixture was stirred at 90°C under a carbon monoxide atmosphere at 58.76 psi for 16 hours. After completion of the reaction, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford (S)-methyl-4-amino-3-methyl-5-((oxetan-2-ylmethyl)amino)benzoate (50 mg, yield: 41.5%). LC-MS m / z: 251.

[0636] 2) Synthesis of (S)-2-(chloromethyl)-4-methyl-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester:

[0637]

[0638] Methyl (S)-4-amino-3-methyl-5-((oxetan-2-ylmethyl)amino)benzoate (50 mg, 0.20 mmol) was dissolved in tetrahydrofuran (2 mL) at room temperature, followed by the addition of chloroacetic anhydride (51 mg, 0.30 mmol). The resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford methyl (S)-2-(chloromethyl)-4-methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (20 mg, yield: 32.6%). LC-MS m / z: 309.

[0639] Example 1-27, Synthesis of methyl 4-(2-chloroacetamide)-3-(1-ethyl-1H-pyrazol-5-yl)methyl)aminobenzoate (Intermediate A-27):

[0640] 1) Synthesis of 1-ethyl-1H-pyrazole-5-carboxylic acid methyl ester:

[0641]

[0642] 1-Ethyl-1H-pyrazole-5-carboxylic acid (770 mg, 5.50 mmol) was dissolved in methanol (8 mL) at 0°C, followed by the addition of (diazomethyl)trimethylsilane (2.0 M in tetrahydrofuran, 27.5 mL, 55.00 mmol). The resulting mixture was stirred at room temperature for 1 hour. Upon completion, the reaction was quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were back-extracted with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford methyl 1-ethyl-1H-pyrazole-5-carboxylate (600 mg, yield: 70.8%). LC-MS m / z: 155.

[0643] 2) Synthesis of (1-ethyl-1H-pyrazol-5-yl)methanol:

[0644]

[0645] At 0°C, dissolve methyl 1-ethyl-1H-pyrazole-5-carboxylate (600 mg, 3.90 mmol) in dry tetrahydrofuran (8 mL), then slowly add lithium aluminum tetrahydride (296 mg, 7.80 mmol). Stir the reaction at room temperature for 1 hour. Upon completion, quench the reaction by adding water (2 mL) and aqueous sodium hydroxide solution (2 mL, 15%). Filter and concentrate under reduced pressure to yield (1-ethyl-1H-pyrazol-5-yl)methanol (400 mg, yield: 81.4%). LC-MS m / z: 127.

[0646] 3) Synthesis of 5-(chloromethyl)-1-ethyl-1H-pyrazole:

[0647]

[0648] At 0°C, (1-ethyl-1H-pyrazol-5-yl)methanol (400 mg, 3.17 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (640 mg, 6.34 mmol) and methanesulfonyl chloride (729 mg, 6.34 mmol) were then added. The reaction was stirred at room temperature for 2 hours. Upon completion, the mixture was quenched with water (100 mL) and extracted with dichloromethane (50 mL x 2). The organic layer was back-extracted with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 5-(chloromethyl)-1-ethyl-1H-pyrazole (400 mg, yield: 87.0%). LC-MS m / z: 145.

[0649] 4) Synthesis of 5-(azidomethyl)-1-ethyl-1H-pyrazole:

[0650]

[0651] 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) at room temperature. The resulting mixture was stirred at 120°C 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 combined organic phases were back-extracted with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 5-(azidomethyl)-1-ethyl-1H-pyrazole (370 mg, yield: 88.8%). LC-MS m / z: 152.

[0652] 5) Synthesis of (1-ethyl-1H-pyrazol-5-yl)methylamine:

[0653]

[0654] 5-(Azidomethyl)-1-ethyl-1H-pyrazole (320 mg, 2.12 mmol) was dissolved in a stirred mixture of tetrahydrofuran and water (4 mL / 0.4 mL) at room temperature, followed by the addition of triphenylphosphine (1.1 g, 4.24 mmol). The reaction was stirred at room temperature for 5 hours. Upon completion of the reaction, the solvent was removed by concentration under reduced pressure to yield (1-ethyl-1H-pyrazol-5-yl)methanamine (265 mg, 99.9% yield).

[0655] 6) Synthesis of methyl 3-((1-ethyl-1H-pyrazol-5-yl)methyl)amino)-4-nitrobenzoate:

[0656]

[0657] (1-Ethyl-1H-pyrazol-5-yl)methanamine (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) and stirred at room temperature for 16 hours. After completion of the reaction, the mixture was diluted with water (60 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were back-extracted with brine (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 yield methyl 3-((1-ethyl-1H-pyrazol-5-yl)methyl)amino)-4-nitrobenzoate (100 mg, yield: 15.5%). LC-MS m / z: 346.

[0658] 7) Synthesis of methyl 4-amino-3-((1-ethyl-1H-pyrazol-5-yl)methyl)amino)benzoate:

[0659]

[0660] Methyl 3-((1-ethyl-1H-pyrazol-5-yl)methyl)amino)-4-nitrobenzoate (130 mg, 0.43 mmol) was dissolved in methanol (12 mL) at room temperature, followed by the addition of palladium on carbon (50 mg, 30.42 mmol). The resulting mixture was degassed and purged with hydrogen three times, then stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered, the filter cake rinsed with methanol, and the filtrate was concentrated under reduced pressure to yield methyl 4-amino-3-((1-ethyl-1H-pyrazol-5-yl)methyl)amino)benzoate (70 mg, yield: 59.4%). LC-MS m / z: 275.

[0661] 8) Synthesis of methyl 4-(2-chloroacetamide)-3-(1-ethyl-1H-pyrazol-5-yl)methyl)aminobenzoate:

[0662]

[0663] Chloroacetic anhydride (111 mg, 0.65 mmol) was slowly added to a solution of methyl 4-amino-3-((1-ethyl-1H-pyrazol-5-yl)methyl)amino)benzoate (70 mg, 0.26 mmol) in tetrahydrofuran (3 mL) at room temperature. The reaction was stirred at room temperature for 2 hours. Upon completion of the reaction, the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford methyl 4-(2-chloroacetamido)-3-(1-ethyl-1H-pyrazol-5-yl)methyl)amino)benzoate (60 mg, yield: 65.7%). LC-MS m / z: 351.

[0664] Example 1-28, Synthesis of Methyl 4-(2-chloroacetamide)-3-((1-ethyl-3-methyl-1H-pyrazol-5-yl)methyl)amino)benzoate (Intermediate A-28):

[0665] 1) Synthesis of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid methyl ester:

[0666]

[0667] 1-Ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (1.00 g, 6.49 mmol) was dissolved in methanol (10 mL) at 0°C, followed by the addition of (diazomethyl)trimethylsilane (2.0 M in tetrahydrofuran, 32.45 mL, 64.90 mmol). The resulting mixture was stirred at room temperature for 1 hour. Upon completion, the reaction was quenched with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were back-extracted with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to yield methyl 1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (800 mg, yield: 73.4%). LC-MS m / z: 169.

[0668] 2) Synthesis of (1-ethyl-3-methyl-1H-pyrazol-5-yl)methanol:

[0669]

[0670] At 0°C, methyl 1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (800 mg, 4.76 mmol) was dissolved in dry tetrahydrofuran (10 mL), and lithium aluminum tetrahydride (543 mg, 14.28 mmol) was slowly added. The reaction was stirred at room temperature for 1 hour. Upon completion, 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 yield (1-ethyl-3-methyl-1H-pyrazol-5-yl)methanol (550 mg, yield: 82.5%). LC-MS m / z: 141.

[0671] 3) Synthesis of 5-(chloromethyl)-1-ethyl-3-methyl-1H-pyrazole:

[0672]

[0673] At 0°C, (1-ethyl-3-methyl-1H-pyrazol-5-yl)methanol (550 mg, 3.93 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (794 mg, 7.86 mmol) and methanesulfonyl chloride (679 mg, 5.90 mmol) were then added. The reaction was stirred at room temperature for 2 hours. Upon completion, the mixture was quenched with water (100 mL) and extracted with dichloromethane (50 mL x 2). The organic layer was back-extracted with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 5-(chloromethyl)-1-ethyl-3-methyl-1H-pyrazole (500 mg, yield: 80.0%). LC-MS m / z: 159.

[0674] 4) Synthesis of 5-(azidomethyl)-1-ethyl-3-methyl-1H-pyrazole:

[0675]

[0676] 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) at room temperature. The resulting mixture was stirred at 120°C 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 combined organic phases were back-extracted with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 5-(azidomethyl)-1-ethyl-3-methyl-1H-pyrazole (350 mg, yield: 75.0%). LC-MS m / z: 166.

[0677] 5) Synthesis of (1-ethyl-3-methyl-1H-pyrazol-5-yl)methylamine:

[0678]

[0679] 5-(Azidomethyl)-1-ethyl-3-methyl-1H-pyrazole (350 mg, 2.12 mmol) was dissolved in a stirred mixture of tetrahydrofuran and water (7 mL / 0.7 mL) at room temperature, followed by the addition of triphenylphosphine (1.1 g, 4.24 mmol). The mixture was stirred at room temperature for 5 hours. Upon completion of the reaction, the solvent was removed in vacuo to yield (1-ethyl-3-methyl-1H-pyrazol-5-yl)methanamine (286 mg, 97.1% yield) as a colorless oil. LC-MS m / z: 140.

[0680] 6) Synthesis of methyl 3-((1-ethyl-3-methyl-1H-pyrazol-5-yl)methyl)amino)-4-nitrobenzoate:

[0681]

[0682] (1-Ethyl-3-methyl-1H-pyrazol-5-yl)methanamine (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) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic phases were back-extracted with brine (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 afford methyl 3-((1-ethyl-3-methyl-1H-pyrazol-5-yl)methyl)amino)-4-nitrobenzoate (300 mg, yield: 45.8%). LC-MS m / z:319.

[0683] 7) Synthesis of methyl 4-amino-3-((1-ethyl-3-methyl-1H-pyrazol-5-yl)methyl)amino)benzoate:

[0684]

[0685] Methyl 3-((1-ethyl-3-methyl-1H-pyrazol-5-yl)methyl)amino)-4-nitrobenzoate (330 mg, 1.04 mmol) was dissolved in methanol (24 mL) at room temperature, followed by the addition of palladium on carbon (50 mg, 30.42 mmol). The resulting mixture was degassed and purged with hydrogen three times, then stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was filtered, the filter cake rinsed with methanol, and the filtrate was concentrated under reduced pressure to yield methyl 4-amino-3-((1-ethyl-3-methyl-1H-pyrazol-5-yl)methyl)amino)benzoate (200 mg, yield: 67.1%). LC-MS m / z: 289.

[0686] 8) Synthesis of methyl 4-(2-chloroacetamido)-3-((1-ethyl-3-methyl-1H-pyrazol-5-yl)methyl)amino)benzoate:

[0687]

[0688] Chloroacetic anhydride (296 mg, 1.73 mmol) was slowly added to a solution of methyl 4-amino-3-((1-ethyl-3-methyl-1H-pyrazol-5-yl)methyl)amino)benzoate (200 mg, 0.69 mmol) in tetrahydrofuran (4 mL) at room temperature. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford methyl 4-(2-chloroacetamido)-3-((1-ethyl-3-methyl-1H-pyrazol-5-yl)methyl)amino)benzoate (200 mg, yield: 79.4%). LC-MS m / z: 365.

[0689] Example 1-29, Synthesis of other Class A intermediates:

[0690] The following intermediates can be obtained by similar synthetic steps to those of the intermediates in Examples 1-1 to 1-28:

[0691]

[0692]

[0693]

[0694]

[0695] Example 2-1, Synthesis of 3-fluoro-4-((6-(piperidin-4-oxy)pyridin-2-yl)methoxy)benzonitrile (Intermediate B-1):

[0696] 1) Synthesis of tert-butyl 4-(6-bromopyridin-2-yl)oxy)piperidine-1-carboxylate:

[0697]

[0698] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.00 g, 9.95 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (60% w / w dispersion in mineral oil, 597 mg, 14.93 mmol) at 0°C. The mixture was stirred at 0°C for 30 minutes, followed by the slow addition of 2-bromo-6-fluoropyridine (2.09 g, 11.94 mmol). The reaction mixture was stirred at 70°C for another 4 hours. Upon completion of the reaction, the reaction was quenched with water (30 mL) at room temperature and extracted twice with ethyl acetate (50 mL each). The combined organic layers were washed twice with brine (30 mL each time), 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 afford tert-butyl 4-(6-bromopyridin-2-yl)oxy)piperidine-1-carboxylate (1.80 g, 5.06 mmol, yield: 50.9%). LC-MS m / z: 356.9, 358.9 [M+H] + .

[0699] 2) Synthesis of methyl 6-((1-(tert-butyloxycarbonyl)piperidin-4-yl)oxy)picolinate:

[0700]

[0701] To a solution of tert-butyl 4-(6-bromopyridin-2-yl)oxy)piperidine-1-carboxylate (1.80 g, 5.06 mmol) in methanol (5 mL) was added potassium acetate (1.49 g, 15.18 mmol) and 1,1'-bis(diphenylphosphinoferrocenedichloropalladium) (373 mg, 0.51 mmol) at room temperature under 58.76 psi of CO. The mixture was stirred at 90°C for 16 hours. The reaction was quenched by the addition of water (15 mL) and extracted three times with ethyl acetate (30 mL each). The combined organic layers were washed twice with brine (30 mL each time), 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 (supplemented with 10 mM ammonia); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 60% B to 80% B over 20 minutes; detector: 254 nm). The mobile phase containing the desired product was collected at 70% B and concentrated under reduced pressure to yield methyl 6-((1-(tert-butyloxycarbonyl)piperidin-4-yl)oxy)picolinate (1.50 g, 4.46 mmol, yield: 88.1%). LC-MS m / z: 337 [M+H] + .

[0702] 3) Synthesis of tert-butyl 4-(6-(hydroxymethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate:

[0703]

[0704] To a solution of methyl 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)picolinate (500 mg, 1.49 mmol) in methanol (5 mL) at 0°C was added sodium borohydride (170 mg, 4.47 mmol) and lithium chloride (6 mg, 0.15 mmol). The mixture was stirred at 50°C for 16 hours. The reaction was quenched by adding water (5 mL) and extracted three times with ethyl acetate (20 mL each). The combined organic layers were washed twice with brine (10 mL each), 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 (supplemented with 10 mM ammonia); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 60% B to 80% B over 20 minutes; detector: 254 nm). The mobile phase containing the desired product was collected and concentrated under reduced pressure to yield tert-butyl 4-(6-(hydroxymethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (200 mg, 0.65 mmol, yield: 43.6%). LC-MS m / z: 309 [M+H] + .

[0705] 4) Synthesis of tert-butyl 4-(6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidine-1-carboxylate:

[0706]

[0707] Triphenylphosphine (257 mg, 0.98 mmol) was added to a solution of tert-butyl 4-(6-(hydroxymethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (200 mg, 0.65 mmol) and 3-fluoro-4-hydroxybenzonitrile (89 mg, 0.65 mmol) in tetrahydrofuran (10 mL) at 0°C. Diisopropyl azodicarboxylate (198 mg, 0.98 mmol) was then added dropwise at 0°C. 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 afford tert-butyl 4-(6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (250 mg, 0.59 mmol, yield: 90.8%). LC-MS m / z: 428 [M+H] + .

[0708] 5) Synthesis of 3-fluoro-4-((6-(piperidin-4-oxy)pyridin-2-yl)methoxy)benzonitrile (Intermediate B-1):

[0709]

[0710] To a solution of tert-butyl 4-(6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (250 mg, 0.59 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (3 mL) dropwise at room temperature. 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 further purified by reverse-phase flash chromatography under the following conditions: (column: spherical C18, 20-40 μm, 120 g; mobile phase A: water (supplemented with 10 mM ammonia); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 40% B to 60% B over 20 minutes; detector: 254 nm.) The mobile phase containing the desired product was collected at 52% B and concentrated under reduced pressure to obtain 3-fluoro-4-((6-(piperidin-4-oxy)pyridin-2-yl)methoxy)benzonitrile (180 mg, 0.55 mmol, yield: 93.2%). LC-MS m / z: 328 [M+H] + .

[0711] Example 2-2, Synthesis of 3-fluoro-4-((6-((piperidin-4-yloxy)methyl)pyridin-2-yloxy)methyl)benzonitrile (Intermediate B-2):

[0712] 1) Synthesis of tert-butyl 4-(6-fluoropyridin-2-yl)methoxy)piperidine-1-carboxylate:

[0713]

[0714] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1.06 g, 5.26 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (60% w / w dispersion in mineral oil, 252 mg, 6.31 mmol) at 0°C. The mixture was stirred for 30 minutes, followed by the slow addition of 2-(bromomethyl)-6-fluoropyridine (500 mg, 2.63 mmol). The mixture was then stirred at room temperature for 16 hours, quenched with methanol (10 mL) at room temperature, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to afford tert-butyl 4-(6-fluoropyridin-2-yl)methoxypiperidine-1-carboxylate (447 mg, 54.8% yield). LC-MS m / z: 311 [M+H] +.

[0715] 2) Synthesis of tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)methoxy)piperidine-1-carboxylate

[0716]

[0717] To a solution of 3-fluoro-4-(hydroxymethyl)benzonitrile (581 mg, 3.85 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (60% w / w dispersion in mineral oil, 185 mg, 4.62 mmol) at 0°C. The mixture was stirred for 30 minutes, followed by the slow addition of tert-butyl 4-(6-fluoropyridin-2-yl)methoxypiperidine-1-carboxylate (240 mg, 0.77 mmol) at 0°C. The mixture was stirred at 70°C for 16 hours, 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 give tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)methoxy)piperidine-1-carboxylate (281 mg, 82.4%). LC-MS m / z: 442 [M+H] + .

[0718] 3) Synthesis of 3-fluoro-4-((6-((piperidin-4-yloxy)methyl)pyridin-2-yloxy)methyl)benzonitrile:

[0719]

[0720] Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)methoxy)piperidine-1-carboxylate (400 mg, 0.91 mmol) in dichloromethane (2 mL). 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 7 M solution of ammonia in methanol and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give 3-fluoro-4-((6-((piperidin-4-yloxy)methyl)pyridin-2-yloxy)methyl)benzonitrile (301 mg, yield: 97.4%). LC-MS m / z: 342 [M+H] + .

[0721] Example 2-3, Synthesis of 3-fluoro-4-((6-(piperidin-4-ylmethoxy)pyridin-2-yl)oxy)methyl)benzonitrile (Intermediate B-3):

[0722] 1) Synthesis of tert-butyl 4-((6-fluoropyridin-2-yl)oxy)methyl)piperidine-1-carboxylate:

[0723]

[0724] To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (3.0 g, 13.93 mmol) in anhydrous tetrahydrofuran (50 mL) was added sodium hydride (60% w / w dispersion in mineral oil, 837 mg, 20.93 mmol) at 0°C. The mixture was stirred at 0°C for 30 minutes, followed by the slow addition of 2,6-difluoropyridine (2.41 g, 20.94 mmol) at 0°C. The mixture was stirred at 70°C for 5 hours. After completion of the reaction, 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 afford tert-butyl 4-((6-fluoropyridin-2-yl)oxy)methyl)piperidine-1-carboxylate (2.0 g, 6.44 mmol, yield: 46.2%). LC-MS m / z: 311 [M+H] + .

[0725] 2) Synthesis of tert-butyl 4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)methyl)piperidine-1-carboxylate

[0726]

[0727] To a solution of 3-fluoro-4-(hydroxymethyl)benzonitrile (365 mg, 2.41 mmol) in anhydrous THF (50 mL) was added sodium hydride (97 mg, 2.42 mmol, 60% w / w dispersion in mineral oil) at 0°C. The mixture was stirred at 0°C for 30 minutes, followed by the slow addition of tert-butyl 4-((6-fluoropyridin-2-yl)oxy)methyl)piperidine-1-carboxylate (500 mg, 1.61 mmol) at 0°C. The mixture was stirred at 70°C for 5 hours, 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 give tert-butyl 4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)methyl)piperidine-1-carboxylate (400 mg, 0.91 mmol, 56.3% yield). LC-MS m / z: 442 [M+H] + .

[0728] 3) Synthesis of 3-fluoro-4-((6-(piperidin-4-ylmethoxy)pyridin-2-yl)oxy)methyl)benzonitrile

[0729]

[0730] To a solution of tert-butyl 4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)methyl)piperidine-1-carboxylate (400 mg, 0.91 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL), followed by stirring at room temperature for 16 hours. After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate solution (30 mL) and extracted with dichloromethane (10 mL × 2). The extract was concentrated and the residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give 3-fluoro-4-((6-(piperidin-4-ylmethoxy)pyridin-2-yl)oxy)methyl)benzonitrile (250 mg, 0.73 mmol, yield: 80.6%). LC-MS m / z: 342 [M+H] + .

[0731] Example 2-4. Synthesis of 3-fluoro-4-((6-(piperidin-4-oxy)pyridin-2-yl)oxy)methyl)benzonitrile (Intermediate B-4)

[0732] 1) Synthesis of tert-butyl 4-(6-fluoropyridin-2-yl)oxy)piperidine-1-carboxylate

[0733]

[0734] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (3.50 g, 17.39 mmol) in anhydrous tetrahydrofuran (20 mL) was added sodium hydride (60% w / w dispersion in mineral oil, 870 mg, 21.74 mmol) at 0°C. The mixture was stirred at 0°C for 30 minutes, followed by the slow addition of 2,6-difluoropyridine (2.00 g, 17.38 mmol) at 0°C. The mixture was warmed 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 combined organic layers were washed with brine (10 mL × 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 give tert-butyl 4-(6-fluoropyridin-2-yl)oxy)piperidine-1-carboxylate (5.10 g, 17.21 mmol, yield: 99.2%).

[0735] 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).

[0736] 2) Synthesis of tert-butyl 4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidine-1-carboxylate

[0737]

[0738] To a solution of 3-fluoro-4-(hydroxymethyl)benzonitrile (1.22 g, 8.07 mmol) in anhydrous tetrahydrofuran (20 mL) at 0°C was added sodium hydride (60% w / w dispersion in mineral oil, 541 mg, 13.52 mmol). The mixture was stirred at 0°C for 30 minutes, followed by the slow addition of tert-butyl 4-(6-fluoropyridin-2-yl)oxy)piperidine-1-carboxylate (2.00 g, 6.75 mmol) at 0°C. The reaction mixture was then heated to 70°C and stirred for 3 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, quenched with water (20 mL), and extracted with EA (20 mL x 2). The combined organic layers were washed with brine (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 tert-butyl 4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidine-1-carboxylate (1.52 g, 3.56 mmol, yield: 55.6%). LC-MS m / z: 372 [M+H] + .

[0739] 3) Synthesis of 3-fluoro-4-((6-(piperidin-4-oxy)pyridin-2-yl)oxy)methyl)benzonitrile

[0740]

[0741] To a solution of tert-butyl 4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidine-1-carboxylate (1.52 g, 3.56 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (3 mL), and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated and the resulting mixture was adjusted to pH 8-9 with a 7M solution of ammonia in methanol, followed by further concentration. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to yield 3-fluoro-4-((6-(piperidin-4-oxy)pyridin-2-yl)oxy)methyl)benzonitrile (1.00 g, 3.05 mmol, 86.2%). LC-MS m / z: 328 [M+H] + .

[0742] Example 2-5, Synthesis of 3-fluoro-4-((6-((piperidin-4-oxy)methyl)pyridin-2-yl)methoxy)benzonitrile (Intermediate B-5):

[0743] 1) Synthesis of methyl 6-(chloromethyl)picolinate

[0744]

[0745] To a solution of methyl 6-(hydroxymethyl)picolinate (2.00 g, 11.98 mmol) in dichloromethane (20 mL) was added triethylamine (2.42 g, 23.96 mmol), followed by the slow addition of methanesulfonyl chloride (1.65 g, 14.38 mmol) at 0°C, and stirred at room temperature for 3 hours. Water (10 mL) was then added, and the mixture was extracted with dichloromethane (20 mL × 2). The combined organic layers were washed with brine (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 = 4 / 1) to obtain methyl 6-(chloromethyl)picolinate (1.2 g, yield: 54.2%). LC-MS m / z: 188 [M+H] + .

[0746] 2) Synthesis of 6-((1-(tert-butyloxycarbonyl)piperidin-4-yl)oxy)methyl)picolinic acid

[0747]

[0748] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (4.92 g, 24.50 mmol) in tetrahydrofuran (50 mL) was added sodium hydride (60% w / w dispersion in mineral oil, 1.18 g, 29.40 mmol) at 0°C. The mixture was then stirred for 30 minutes, followed by the slow addition of methyl 6-(chloromethyl)picolinate (454 mg, 2.45 mmol) 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 brine (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 yield 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)methyl)picolinic acid (356 mg, yield: 43.2%). LC-MS m / z: 337 [M+H] + .

[0749] 3) Synthesis of methyl 6-((piperidin-4-oxy)methyl)picolinate

[0750]

[0751] To a solution of 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)methyl)picolinic acid (356 mg, 1.06 mmol) in methanol (5 mL) at 0°C was added thionyl chloride (189 mg, 1.59 mmol). 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 layers were washed with saturated sodium bicarbonate (10 mL) and brine (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 give methyl 6-((piperidin-4-oxy)methyl)picolinate (260 mg, 98.1% yield). LC-MS m / z: 251 [M+H] + .

[0752] 4) Synthesis of methyl 6-((1-(tert-butyloxycarbonyl)piperidin-4-yl)oxy)methyl)picolinate

[0753]

[0754] To a solution of methyl 6-((piperidin-4-oxy)methyl)picolinate (260 mg, 1.04 mmol) and triethylamine (315 mg, 3.12 mmol) in tetrahydrofuran (3 mL) was added di-tert-butyl dicarbonate (453 mg, 2.08 mmol) at room temperature. 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 layers were washed with brine (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 give methyl 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)methyl)picolinate (255 mg, 70.1% yield). LC-MS m / z: 351 [M+H] + .

[0755] 5) Synthesis of tert-butyl 4-(6-(hydroxymethyl)pyridin-2-yl)methoxy)piperidine-1-carboxylate

[0756]

[0757] Lithium aluminum tetrahydride (27 mg, 0.70 mmol) was added to a solution of methyl 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)methyl)picolinate (244 mg, 0.70 mmol) in tetrahydrofuran (3 mL) at 0°C. 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 layers were washed with brine (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 give tert-butyl 4-(6-(hydroxymethyl)pyridin-2-yl)methoxy)piperidine-1-carboxylate (107 mg, yield: 39.6%). LC-MS m / z: 323 [M+H] + .

[0758] 6) Synthesis of tert-butyl 4-(6-(chloromethyl)pyridin-2-yl)methoxy)piperidine-1-carboxylate

[0759]

[0760] To a solution of tert-butyl 4-(6-(hydroxymethyl)pyridin-2-yl)methoxy)piperidine-1-carboxylate (47 mg, 0.15 mmol) in dichloromethane (1 mL) was added triethylamine (30 mg, 0.30 mmol), followed by methanesulfonyl chloride (21 mg, 0.18 mmol) at 0°C, and the mixture was stirred at room temperature for 16 hours. Water (10 mL) was then added. Extraction was performed with DCM (20 mL × 2). The combined organic layers were washed with brine (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 tert-butyl 4-(6-(chloromethyl)pyridin-2-yl)methoxy)piperidine-1-carboxylate (40 mg, yield: 80.6%). LC-MS m / z: 341 [M+H] + .

[0761] 7) Synthesis of tert-butyl 4-(6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)methoxy)piperidine-1-carboxylate

[0762]

[0763] Potassium carbonate (541 mg, 13.52 mmol) was added to a solution of tert-butyl 4-(6-(chloromethyl)pyridin-2-yl)methoxy)piperidine-1-carboxylate (40 mg, 0.12 mmol) and 3-fluoro-4-hydroxybenzonitrile (33 mg, 0.24 mmol) in N,N-dimethylformamide (1 mL) at room temperature. 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 × 2). The combined organic layers were washed with saturated ammonium chloride (20 mL × 3) and brine (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 = 4 / 1) to obtain tert-butyl 4-(6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)methoxy)piperidine-1-carboxylate (35 mg, yield: 67.4%). LC-MS m / z: 442 [M+H] + .

[0764] 8) Synthesis of 3-fluoro-4-((6-((piperidin-4-oxy)methyl)pyridin-2-yl)methoxy)benzonitrile

[0765]

[0766] Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 4-(6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)methoxy)piperidine-1-carboxylate (35 mg, 0.08 mmol) in dichloromethane (2 mL). 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 7 M solution of ammonia in methanol and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 3-fluoro-4-((6-((piperidin-4-oxy)methyl)pyridin-2-yl)methoxy)benzonitrile (27 mg, yield >99%). LC-MS m / z: 342 [M+H] + .

[0767] Example 2-6, Synthesis of 4-((6-(azetidin-3-yloxy)pyridin-2-yloxy)methyl)-3-fluorobenzonitrile (Intermediate B-6):

[0768] 1) Synthesis of tert-butyl 3-(6-fluoropyridin-2-yl)oxy)azetidine-1-carboxylate:

[0769]

[0770] To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (2.00 g, 11.55 mmol) in anhydrous THF (30 mL) at 0°C was added sodium hydride (60% w / w dispersion in mineral oil, 694 mg, 17.34 mmol). The mixture was stirred at 0°C for 30 minutes, followed by the slow addition of 2,6-difluoropyridine (1.60 g, 13.90 mmol) at 0°C. The mixture was warmed to 70°C and stirred for 4 hours. After completion of the reaction, 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, and the combined organic phases were 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 give tert-butyl 3-(6-fluoropyridin-2-yl)oxy)azetidine-1-carboxylate (3.00 g, 11.18 mmol, 96.7% yield). LC-MS m / z: 269 [M+H] + .

[0771] 2) Synthesis of tert-butyl 3-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)azetidine-1-carboxylate:

[0772]

[0773] To a solution of 3-fluoro-4-(hydroxymethyl)benzonitrile (1.00 g, 6.62 mmol) in anhydrous tetrahydrofuran (20 mL) was added sodium hydride (60% w / w dispersion in mineral oil, 397 mg, 9.93 mmol) at 0°C. The mixture was stirred at 0°C for 30 minutes, followed by the slow addition of tert-butyl 3-(6-fluoropyridin-2-yl)oxy)azetidine-1-carboxylate (1.33 g, 4.96 mmol) at 0°C. The mixture was stirred at 70°C for 4 hours, quenched with water (20 mL) at room temperature, and extracted with ethyl acetate (2 × 20 mL). The combined organic phases were 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 = 5 / 1) to give tert-butyl 3-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)azetidine-1-carboxylate (1.52 g, 3.81 mmol, yield: 57.4%). LC-MS m / z: 400 [M+H] + .

[0774] 3) Synthesis of 4-((6-(azetidin-3-yloxy)pyridin-2-yloxy)methyl)-3-fluorobenzonitrile:

[0775]

[0776] To a solution of tert-butyl 3-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)azetidine-1-carboxylate (900 mg, 2.25 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL). 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 a 7M solution of ammonia in methanol. After concentration under reduced pressure, the product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give 4-((6-(azetidin-3-yloxy)pyridin-2-yloxy)methyl)-3-fluorobenzonitrile (650 mg, 2.17 mmol, yield: 96.0%). LC-MS m / z: 300 [M+H] + .

[0777] Example 2-7, Synthesis of 3-fluoro-4-((3-(piperidin-4-oxy)phenoxy)methyl)benzonitrile (Intermediate B-7):

[0778] 1) Synthesis of 3-fluoro-4-((3-hydroxyphenoxy)methyl)benzonitrile:

[0779]

[0780] 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) with stirring. The mixture was heated to 100°C and stirred for 16 hours. The mixture was cooled to room temperature, diluted with water (20 mL), and extracted with EA (3 × 30 mL). The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 4 / 1) to afford 3-fluoro-4-((3-hydroxyphenoxy)methyl)benzonitrile (514 mg, 44.0% yield). LC-MS m / z: 244 [M+H] + .

[0781] 2) Synthesis of tert-butyl 4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-carboxylate:

[0782]

[0783] To a stirred solution of 3-fluoro-4-((3-hydroxyphenoxy)methyl)benzonitrile (200 mg, 0.82 mmol) in DMF (5 mL) were added tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (919 mg, 3.29 mmol) and Cs2CO3 (805 mg, 2.47 mmol). The reaction was heated to 100°C and stirred 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); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 40% B to 80% B over 20 minutes; detector: 254 nm). Fractions containing the desired product were collected at 65% B and concentrated under reduced pressure to afford tert-butyl 4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-carboxylate (180.0 mg, 79.8% yield). LC-MS m / z: 371 [M+H] + .

[0784] 3) Synthesis of 3-fluoro-4-((3-(piperidin-4-oxy)phenoxy)methyl)benzonitrile:

[0785]

[0786] To a solution of tert-butyl 4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidine-1-carboxylate (120.0 mg, 0.282 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 2 hours. It was quenched with saturated NaHCO₃ (30 mL) and extracted with DCM (2 × 10 mL). The combined organic phases were concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to provide 3-fluoro-4-((3-(piperidin-4-oxy)phenoxy)methyl)benzonitrile (89.0 mg, 96.8% yield). LC-MS m / z: 327 [M+H] + .

[0787] Example 2-8, Synthesis of 2-((4-chloro-2-fluorobenzyl)oxy)-3-fluoro-6-(piperidin-4-oxy)pyridine (Intermediate B-8):

[0788] 1) Synthesis of tert-butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)oxypiperidine-1-carboxylate

[0789]

[0790] Sodium hydride (264 mg, 0.56 mmol) was added to a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1.10 g, 5.50 mmol) in tetrahydrofuran (15 mL) at 0°C. The mixture was stirred at 0°C for 30 minutes. 2-((4-chloro-2-fluorobenzyl)oxy)-3,6-difluoropyridine (100 mg, 0.28 mmol) was then added at 0°C. The mixture was warmed to 70°C and stirred for 16 hours. The desired product was detected by liquid chromatography-mass spectrometry. 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 brine (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 tert-butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)oxypiperidine-1-carboxylate (447 mg, yield: 53.7%). LC-MS m / z: 399 [M+H] + .

[0791] 2) Synthesis of 2-((4-chloro-2-fluorobenzyl)oxy)-3-fluoro-6-(piperidin-4-oxy)pyridine:

[0792]

[0793] To a solution of tert-butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)oxypiperidine-1-carboxylate (447 mg, 0.98 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3 mL), 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 quenched by addition of water (5 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 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-(piperidin-4-oxy)pyridine (199 mg, yield: 57.2%). LC-MS m / z: 355 [M+H] + .

[0794] Example 2-9, Synthesis of 3-fluoro-4-((3-fluoro-6-(piperidin-4-oxy)pyridin-2-yl)methoxy)benzonitrile (Intermediate B-9):

[0795] 1) Synthesis of methyl 3,6-difluoropicolinate:

[0796]

[0797] Thionyl chloride (4.0 g, 33.96 mmol) was added to a solution of 3,6-difluoropicolinic acid (3.6 g, 22.64 mmol) in methanol (80 mL). 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) afforded methyl 3,6-difluoropicolinate (3.15 g, yield: 80.4%). LC-MS m / z: 174 [M+H] + .

[0798] 2) Synthesis of (3,6-difluoropyridin-2-yl)methanol:

[0799]

[0800] To a solution of methyl 3,6-difluoropicolinate (3.15 g, 18.21 mmol) in methanol (55 mL) was added sodium borohydride (2.07 g, 54.63 mmol) and lithium chloride (153 mg, 3.64 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-difluoropyridin-2-yl)methanol (2.0 g, yield: 91.1%). LC-MS m / z: 146 [M+H]+ .

[0801] 3) Synthesis of methyl (3,6-difluoropyridin-2-yl)methanesulfonate:

[0802]

[0803] To a solution of (3,6-difluoropyridin-2-yl)methanol (300 mg, 2.07 mmol) in anhydrous dichloromethane (20 mL) was added triethylamine (460 mg, 4.55 mmol). The resulting mixture was cooled to 0°C, and methanesulfonyl chloride (358 mg, 3.11 mmol) was slowly added dropwise. The mixture was stirred at 0°C for 1 hour. The reaction mixture was stirred at room temperature for an additional 2 hours, then diluted with dichloromethane (50 mL) and back-extracted with brine (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. It was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford methyl (3,6-difluoropyridin-2-yl)methanesulfonate (272 mg, yield: 58.9%). LC-MS m / z: 224 [M+H] + .

[0804] 4) Synthesis of 4-((3,6-difluoropyridin-2-yl)methoxy)-3-fluorobenzonitrile:

[0805]

[0806] To a solution of methyl (3,6-difluoropyridin-2-yl)methanesulfonate (272 mg, 1.22 mmol) and 3-fluoro-4-hydroxybenzonitrile (167 mg, 1.22 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (505 mg, 3.66 mmol), and the mixture was stirred at 60°C for 2 hours. The reaction was quenched by adding water (15 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed 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 (petroleum ether / ethyl acetate = 2 / 1) to give 4-((3,6-difluoropyridin-2-yl)methoxy)-3-fluorobenzonitrile (270 mg, yield: 83.6%). LC-MS m / z: 265 [M+H] + .

[0807] 5) Synthesis of tert-butyl 4-(6-((4-cyano-2-fluorophenoxy)methyl)-5-fluoropyridin-2-yl)oxypiperidine-1-carboxylate:

[0808]

[0809] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (246 mg, 1.22 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (61 mg, 1.53 mmol, 60% w / w dispersion in mineral oil) at 0°C. The mixture was stirred at 0°C for 30 minutes, followed by the addition of 4-((3,6-difluoropyridin-2-yl)methoxy)-3-fluorobenzonitrile (270 mg, 1.02 mmol). The reaction was then stirred at 70°C for 2 hours, quenched with water (20 mL), and 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, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford tert-butyl 4-(6-((4-cyano-2-fluorophenoxy)methyl)-5-fluoropyridin-2-yl)oxypiperidine-1-carboxylate (200 mg, yield: 36.9%). LC-MS m / z: 390 [M+H] + .

[0810] 6) Synthesis of 3-fluoro-4-((3-fluoro-6-(piperidin-4-oxy)pyridin-2-yl)methoxy)benzonitrile:

[0811]

[0812] To a solution of tert-butyl 4-(6-((4-cyano-2-fluorophenoxy)methyl)-5-fluoropyridin-2-yl)oxypiperidine-1-carboxylate (200 mg, 0.45 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL). 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 ammonia in methanol (7 M), then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give 3-fluoro-4-((3-fluoro-6-(piperidin-4-oxy)pyridin-2-yl)methoxy)benzonitrile (140 mg, yield: 91.1%). LC-MS m / z: 346 [M+H] + .

[0813] Example 2-10, Synthesis of 2-((4-chloro-2-fluorophenylthio)methyl)-6-(piperidin-4-oxy)pyridine (Intermediate B-10):

[0814] 1) Synthesis of 1,2-bis(4-chloro-2-fluorophenyl)disulfane:

[0815]

[0816] 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 for 2 hours. The mixture was quenched with water (100 mL) and extracted with dichloromethane (50 mL x 2). The aqueous phase was acidified to pH 2 with hydrochloric acid and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 1,2-bis(4-chloro-2-fluorophenyl)disulfane (700 mg, yield: 32.1%).

[0817] 2) Synthesis of 4-chloro-2-fluorobenzenethiol:

[0818]

[0819] Dissolve 1,2-bis(4-chloro-2-fluorophenyl)disulfane (700 mg, 2.17 mmol) and zinc powder (423 mg, 6.51 mmol) in a solution of methanol / hydrochloric acid (10% in H2O) (10 mL / 10 mL). Stir the mixture at room temperature for 2 hours. The resulting mixture is diluted with water (50 mL) and extracted with dichloromethane (20 mL x 3). The organic phase is concentrated under reduced pressure to yield 4-chloro-2-fluorobenzenethiol (400 mg, yield: 56.9%). LC-MS m / z: 161 [M+H] + .

[0820] 3) Synthesis of tert-butyl 4-(6-((4-chloro-2-fluorophenyl)thio)methyl)pyridin-2-yl)oxypiperidine-1-carboxylate:

[0821]

[0822] 4-Chloro-2-fluorobenzenethiol (400 mg, 2.47 mmol), potassium carbonate (682 mg, 4.94 mmol), and tert-butyl 4-((6-((methylsulfonyl)oxy)methyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (956 mg, 2.47 mmol) were dissolved in N,N-dimethylformamide (20 mL). The mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic phases were 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 yield tert-butyl 4-(6-((4-chloro-2-fluorophenyl)thio)methyl)pyridin-2-yl)oxypiperidine-1-carboxylate (1.00 g, yield: 89.6%). LC-MS m / z: 453 [M+H] + .

[0823] 4) Synthesis of 2-((4-chloro-2-fluorophenylthio)methyl)-6-(piperidin-4-oxy)pyridine:

[0824]

[0825] To a solution of tert-butyl 4-(6-((4-chloro-2-fluorophenylthio)methyl)pyridin-2-yl)oxypiperidine-1-carboxylate (1.00 g, 2.21 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3 mL). The solution was stirred at room temperature for 2 hours. The reaction was quenched with saturated sodium bicarbonate (50 mL) 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 afford 2-((4-chloro-2-fluorophenylthio)methyl)-6-(piperidin-4-oxy)pyridine (700 mg, yield: 90.0%). LC-MS m / z: 353 [M+H] + .

[0826] Example 2-11, Synthesis of 3-fluoro-4-((6-(piperidin-4-oxy)pyridin-2-yl)methyl)thio)benzonitrile (Intermediate B-11):

[0827] 1) Synthesis of 4,4'-disulfide diacetyl bis(3-fluorobenzonitrile):

[0828]

[0829] Sodium sulfide (11.22 g, 143.88 mmol) was added to a solution of 3,4-difluorobenzonitrile (10.00 g, 71.89 mmol) in dimethyl sulfoxide (100 mL), and the mixture was stirred at 80°C for 2 hours. After the reaction was completed, the reaction was quenched with water (500 mL) and extracted with dichloromethane (200 mL × 2). The aqueous phase was acidified to pH = 2 with aqueous hydrochloric acid and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (400 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4,4'-dithiodicarbonylbis(3-fluorobenzonitrile) (5.70 g, yield: 26.1%).

[0830] 2) Synthesis of 3-fluoro-4-mercaptobenzonitrile:

[0831]

[0832] Zinc powder (1.28 g, 19.58 mmol) was added to a solution of 4,4'-dithiodicarbonylbis(3-fluorobenzonitrile) (2.00 g, 6.57 mmol) in methanol / hydrochloric acid (10% aqueous solution) (10 mL / 10 mL). The mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (200 mL) and extracted with dichloromethane (80 mL x 3). The organic phase was concentrated to yield 3-fluoro-4-mercaptobenzonitrile (1.20 g, yield: 59.6%).

[0833] 3) Synthesis of tert-butyl 4-((6-((4-cyano-2-fluorophenyl)thio)methyl)pyridin-2-yl)oxy)piperidine-1-carboxylate:

[0834]

[0835] To a solution of 3-fluoro-4-mercaptobenzonitrile (474 ​​mg, 3.10 mmol) and tert-butyl 4-((6-((methylsulfonyl)oxy)methyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (1.20 g, 3.10 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (856 mg, 6.20 mmol), and the mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic phases were back-extracted with 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 yield tert-butyl 4-((6-((4-cyano-2-fluorophenylthio)methyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (600 mg, yield: 43.7%). LC-MS m / z: 444 [M+H]+ .

[0836] 4) Synthesis of 3-fluoro-4-((6-(piperidin-4-oxy)pyridin-2-yl)methylthio)benzonitrile:

[0837]

[0838] Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 4-((6-((4-cyano-2-fluorophenylthio)methyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (500 mg, 1.13 mmol) in dichloromethane (5 mL) at room temperature. The solution was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate (10 mL) and extracted with dichloromethane (5 mL × 3). The extract was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to provide 3-fluoro-4-((6-(piperidin-4-oxy)pyridin-2-yl)methylthio)benzonitrile (334 mg, yield: 86.4%). LC-MS m / z: 344 [M+H] + .

[0839] Example 2-12, Synthesis of 3-fluoro-4-((3-(piperidin-4-oxy)benzyl)oxy)benzonitrile (Intermediate B-12):

[0840] 1) Synthesis of tert-butyl 4-(3-(methoxycarbonyl)phenoxy)piperidine-1-carboxylate:

[0841]

[0842] To a solution of methyl 3-hydroxybenzoate (3.00 g, 19.73 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (3.97 g, 19.73 mmol), and triphenylphosphine (7.76 g, 29.60 mmol) in tetrahydrofuran (30 mL) at 0°C was added diisopropyl azodicarboxylate (5.98 g, 29.60 mmol). The mixture was stirred at room temperature for 3 hours. Upon completion of the reaction, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were back-extracted with brine (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 afford tert-butyl 4-(3-(methoxycarbonyl)phenoxy)piperidine-1-carboxylate (2.44 g, yield: 36.9%). LC-MS m / z: 358 [M+H] + .

[0843] 2) Synthesis of tert-butyl 4-(3-(hydroxymethyl)phenoxy)piperidine-1-carboxylate:

[0844]

[0845] To a solution of tert-butyl 4-(3-(methoxycarbonyl)phenoxy)piperidine-1-carboxylate (1.40 g, 4.18 mmol) in tetrahydrofuran (15 mL) was slowly added lithium aluminum tetrahydride (238 mg, 6.27 mmol) at 0°C. The resulting mixture was stirred at room temperature for 3 hours. Upon completion, the reaction was quenched by adding water (5 mL) and extracted with ethyl acetate (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 afford tert-butyl 4-(3-(hydroxymethyl)phenoxy)piperidine-1-carboxylate (400 mg, yield: 31.2%).

[0846] 3) Synthesis of tert-butyl 4-(3-((4-cyano-2-fluorophenoxy)methyl)phenoxy)piperidine-1-carboxylate:

[0847]

[0848] At 0°C, 3-fluoro-4-hydroxybenzonitrile (178 mg, 1.30 mmol) and triphenylphosphine (409 mg, 1.56 mmol) were added to a solution of tert-butyl 4-(3-(hydroxymethyl)phenoxy)piperidine-1-carboxylate (400 mg, 1.30 mmol) in tetrahydrofuran (15 mL). Diisopropyl azodicarboxylate (315 mg, 1.56 mmol) was also added at 0°C. The resulting mixture was stirred at room temperature 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 layers were back-extracted with brine (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 give tert-butyl 4-(3-((4-cyano-2-fluorophenoxy)methyl)phenoxy)piperidine-1-carboxylate (312 mg, yield: 56.3%). Mass spectrum (M+H-56 + ):371.

[0849] 4) Synthesis of 3-fluoro-4-((3-(piperidin-4-oxy)benzyl)oxy)benzonitrile:

[0850]

[0851] To a solution of tert-butyl 4-(3-((4-cyano-2-fluorophenoxy)methyl)phenoxy)piperidine-1-carboxylate (312 mg, 0.73 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) at room temperature. The mixture was stirred at room temperature for 3 hours. Upon completion of the reaction, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were back-extracted with brine (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 provide 3-fluoro-4-((3-(piperidin-4-oxy)benzyl)oxy)benzonitrile (230 mg, yield: 96.6%). LC-MS m / z: 327 [M+H] + .

[0852] Example 2-13, Synthesis of 4-(3-((4-chloro-2-fluorophenoxy)methyl)phenoxy)piperidine (Intermediate B-13):

[0853] 1) Synthesis of tert-butyl 4-(3-((4-chloro-2-fluorophenoxy)methyl)phenoxy)piperidine-1-carboxylate:

[0854]

[0855] 4-Chloro-2-fluorophenol (144 mg, 0.98 mmol) and triphenylphosphine (308 mg, 1.18 mmol) were added to a solution of tert-butyl 4-(3-(hydroxymethyl)phenoxy)piperidine-1-carboxylate (300 mg, 0.98 mmol) in tetrahydrofuran (8 mL). Diisopropyl azodicarboxylate (238 mg, 1.18 mmol) was slowly added at 0°C. The resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, 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 back-extracted with brine (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 give tert-butyl 4-(3-((4-chloro-2-fluorophenoxy)methyl)phenoxy)piperidine-1-carboxylate (381 mg, yield: 89.2%).

[0856] 2) Synthesis of 4-(3-((4-chloro-2-fluorophenoxy)methyl)phenoxy)piperidine:

[0857]

[0858] To a solution of tert-butyl 4-(3-((4-chloro-2-fluorophenoxy)methyl)phenoxy)piperidine-1-carboxylate (381 mg, 0.88 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. Upon completion of the reaction, the pH of the resulting mixture was adjusted to 7-8 using a 7 M solution of ammonia in methanol. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to provide 4-(3-((4-chloro-2-fluorophenoxy)methyl)phenoxy)piperidine (271 mg, yield: 91.6%). LC-MS m / z: 336 [M+H] + .

[0859] Example 2-14, Synthesis of methyl 2-(4-((6-((methylsulfonyl)oxy)methyl)pyridin-2-yl)oxy)phenyl)acetate (Intermediate B-14):

[0860] 1) Synthesis of methyl 2-(4-((6-bromopyridin-2-yl)oxy)phenyl)acetate:

[0861]

[0862] 2-Bromo-6-fluoropyridine (2.53 g, 14.46 mmol) and cesium carbonate (5.89 g, 18.07 mmol) were added to a solution of methyl 2-(4-hydroxyphenyl)acetate (2.00 g, 12.05 mmol) in acetonitrile (20 mL) at room temperature. The resulting mixture was stirred at 90°C for 16 hours. After the reaction was complete, the mixture was diluted with water (5 mL) and 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 (petroleum ether / ethyl acetate = 10 / 1) to yield methyl 2-(4-((6-bromopyridin-2-yl)oxy)phenyl)acetate (3.17 g, yield: 81.7%). LC-MS m / z: 322, 324 [M+H] + .

[0863] 2) Synthesis of 2-(4-((6-bromopyridin-2-yl)oxy)phenyl)acetic acid:

[0864]

[0865] Methyl 2-(4-((6-bromopyridin-2-yl)oxy)phenyl)acetate (3.17 g, 9.84 mmol) was dissolved in a mixture of tetrahydrofuran and water (20 mL / 15 mL) at room temperature, followed by the addition of lithium hydroxide monohydrate (4.13 g, 98.40 mmol). The resulting mixture was stirred at room temperature for 5 hours. Upon completion of the reaction, the mixture was diluted with water (5 mL) and 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 = 20 / 1) to yield 2-(4-((6-bromopyridin-2-yl)oxy)phenyl)acetic acid (1.8 g, yield: 59.4%). LC-MS m / z: 308, 310 [M+H] + .

[0866] 3) Synthesis of 2-(4-((6-(methyl formate)pyridin-2-yl)oxy)phenyl)acetic acid:

[0867]

[0868] At room temperature and under CO protection, 2-(4-((6-bromopyridin-2-yl)oxy)phenyl)acetic acid (900 mg, 2.92 mmol), 1,1'-bis(diphenylphosphinoferrocenepalladium)dichloride (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 protected with 58.76 psi of carbon monoxide, and stirred for 16 hours. Upon completion, the reaction was quenched with water (5 mL) and 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 yield 2-(4-((6-(methylformate)pyridin-2-yl)oxy)phenyl)acetic acid (385 mg, yield: 45.9%). LC-MS m / z: 288 [M+H] + .

[0869] 4) Synthesis of 2-(4-((6-(hydroxymethyl)pyridin-2-yl)oxy)phenyl)acetic acid:

[0870]

[0871] 2-(4-((6-(methylformate)pyridin-2-yl)oxy)phenyl)acetic acid (385 mg, 1.34 mmol) was dissolved in tetrahydrofuran (5 mL) at 0°C, and lithium aluminum tetrahydride (76 mg, 2.01 mmol) was added. The resulting mixture was stirred at room temperature for another 2 hours. After the reaction was complete, the resulting mixture was adjusted to pH 5-6 with 1N hydrochloric acid and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (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 give 2-(4-((6-(hydroxymethyl)pyridin-2-yl)oxy)phenyl)acetic acid (118 mg, yield: 33.9%). LC-MS m / z: 260 [M+H] + .

[0872] 5) Synthesis of methyl 2-(4-(6-(hydroxymethyl)pyridin-2-yl)oxy)phenyl)acetate:

[0873]

[0874] At room temperature, 2-(4-((6-(hydroxymethyl)pyridin-2-yl)oxy)phenyl)acetic acid (118 mg, 0.45 mmol) was dissolved in methanol (3 mL), and 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 completed, the reaction was quenched by adding water (5 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layer was washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to give methyl 2-(4-(6-(hydroxymethyl)pyridin-2-yl)oxy)phenyl)acetate (89 mg, yield: 72.4%). LC-MS m / z: 274 [M+H] + .

[0875] 6) Synthesis of methyl 2-(4-((6-((methylsulfonyl)oxy)methyl)pyridin-2-yl)oxy)phenyl)acetate:

[0876]

[0877] Methyl 2-(4-(6-(hydroxymethyl)pyridin-2-yl)oxy)phenyl)acetate (89 mg, 0.33 mmol) and triethylamine (74 mg, 0.73 mmol) were dissolved in dichloromethane (3 mL) at 0°C, and methylsulfonyl chloride (49 mg, 0.50 mmol) was slowly added. The resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction was quenched by adding water (5 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were back-extracted with brine (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 = 4 / 1) to give methyl 2-(4-((6-((methylsulfonyl)oxy)methyl)pyridin-2-yl)oxy)phenyl)acetate (56 mg, yield: 48.3%). LC-MS m / z: 352 [M+H] + .

[0878] Example 2-15, Synthesis of other Class B intermediates:

[0879] The following intermediates can be obtained by similar synthetic steps to those of intermediate B in Examples 2-1 to 2-14:

[0880]

[0881]

[0882]

[0883]

[0884] Example 3. Synthesis of 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 1):

[0885] 1) Synthesis of methyl 4-(2-(4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)acetamide)-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate:

[0886]

[0887] To a solution of 3-fluoro-4-((6-(piperidin-4-oxy)pyridin-2-yl)methoxy)benzonitrile (100 mg, 0.31 mmol) and methyl 4-(2-chloroacetamido)-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (109 mg, 0.31 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (86 mg, 0.62 mmol), and the mixture was stirred at 60°C for 3 hours. The resulting mixture was poured into brine (20 mL) and extracted twice with dichloromethane (5 mL each). The organic phase was concentrated under reduced pressure and purified by reverse-phase flash chromatography under the following conditions: (column: spherical C18, 20-40 μm, 120 g; mobile phase A: water (0.1% ammonia); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 0% B to 95% B over 30 minutes; detector: 254 nm). The mobile phase containing the desired product was collected at 72% B and concentrated under reduced pressure to provide methyl 4-(2-(4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)acetamide)-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (40 mg, yield: 20.1%). LC-MS m / z: 642.5 [M+H] + .

[0888] 2) Synthesis of methyl 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate:

[0889]

[0890] To a solution of methyl 4-(2-(4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)acetamide)-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (40 mg, 0.06 mmol) in toluene (1 mL) was added acetic acid (0.1 mL), and the mixed solution was stirred at 110°C for 3 hours. After the reaction was complete, the resulting mixture was poured into brine (10 mL) and extracted twice with dichloromethane (5 mL each). The organic phase was concentrated under reduced pressure to afford methyl 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (30 mg, yield: 80.3%). LC-MS m / z: 624 [M+H]+ .

[0891] 3) Synthesis of 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid:

[0892]

[0893] To a solution of methyl 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (30 mg, 0.05 mmol) in tetrahydrofuran / water (1 mL / 1 mL) was added lithium hydroxide (2.4 mg, 0.10 mmol). The mixture was stirred at room temperature for 16 h. The residue was concentrated under reduced pressure to remove the solvent and purified by preparative HPLC (Waters 2767 / 2545 / 2489 system; SunFire Prep C8 OBD 10 μm 19 × 250 mm Column; ACN / 0.1% FA in H2O solvent system gradient elution; detection wavelength 254 nm / 214 nm; flow rate 20 ml / min) to give 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (7.67 mg, yield: 25.2%). LC-MS m / z: 610 [M+H] + .

[0894] 1 H NMR (400 MHz, DMSO- d 6 ): 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, 2 H), 1.81-1.76(m, 2 H), 1.47-1.44(m, 2 H), 1.16(t, J =7.2 Hz, 3 H).

[0895] Example 4. Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)methoxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound S22):

[0896] 1) Synthesis of (S)-methyl 2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)methoxy)piperidin-1-yl)methyl)-1-(oxoalkane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate:

[0897]

[0898] A mixture of (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (150 mg, 0.51 mmol), 3-fluoro-4-((6-((piperidin-4-yloxy)methyl)pyridin-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 combined organic phases were washed sequentially with saturated ammonium chloride (20 mL × 3) and brine (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 give (S)-methyl 2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)methoxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, yield: 32.9%). LC-MS m / z: 600 [M+H] + .

[0899] 2) Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)methoxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid:

[0900]

[0901] To a mixture of (S)-methyl 2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)methoxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.17 mmol) in water / tetrahydrofuran (4 mL / 4 mL) was added lithium hydroxide monohydrate (12 mg, 0.51 mmol). The reaction mixture was stirred at 40°C for 16 hours. The pH of the reaction mixture was adjusted to 5-6 with formic acid. The solvent was removed in vacuo, and the residue was purified by Prep HPLC (Waters 2767 / 2545 / 2489 system; SunFire Prep C8 OBD10um 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 give (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)methoxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound S22) (19.26 mg, 19.7% yield). LC-MS m / z: 586 [M+H] + .

[0902] 1 HNMR(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, 1H), 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, 2H), 1.89-1.85(m, 2 H), 1.56-1.49(m, 2 H).

[0903] Example 5. Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)methyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound S1):

[0904] 1) Synthesis of (S)-methyl 2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)methyl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0905]

[0906] A solution of 3-fluoro-4-((6-(piperidin-4-ylmethoxy)pyridin-2-yl)oxy)methyl)benzonitrile (100 mg, 0.29 mmol), compound (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (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. Upon completion of the reaction, the resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give (S)-methyl 2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)methyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.17 mmol, yield: 57.6%). LC-MS m / z: 600 [M+H] + .

[0907] 2) Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)methyl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid:

[0908]

[0909] To a mixture of water / tetrahydrofuran (1.0 mL / 1.0 mL) containing (S)-methyl 2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)methyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.17 mmol) was added lithium hydroxide (8 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo, 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 an ACN / 0.1% FA in H O solvent system; detection wavelengths at 254 nm / 214 nm; flow rate at 20 ml / min) to afford (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)methyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (15.48 mg, yield: 15.6%). LC-MS m / z: 586 [M+H] + .

[0910] 1 H NMR (400 MHz, DMSO- d 6 ): δ8.28(s, 1 H), 8.24(s, 1 H), 7.92-7.87(m, 1H), 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, 1H), 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, 1 H), 4.66-4.58(m, 1 H), 4.52-4.45(m, 1H), 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, 1H), 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, 2H).

[0911] Example 6. Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound S2):

[0912] 1) Synthesis of (S)-methyl 2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate:

[0913]

[0914] A solution of (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (200 mg, 0.68 mmol), 3-fluoro-4-((6-(piperidin-4-oxy)pyridin-2-yl)oxy)methyl)benzonitrile (245 mg, 0.75 mmol), and potassium carbonate (188 mg, 1.36 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 x 2). The combined organic phases were washed sequentially with saturated ammonium chloride (20 mL x 3) and brine (10 mL x 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 give (S)-methyl 2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (205 mg, 0.35 mmol, yield: 51.5%). LC-MS m / z: 586 [M+H] + .

[0915] 2) Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid:

[0916]

[0917] To a solution of (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (150 mg, 0.26 mmol) in a water / tetrahydrofuran (1 mL / 1 mL) mixture was added lithium hydroxide (62 mg, 2.59 mmol). The reaction mixture was stirred at room temperature for 16 hours. The pH of the reaction mixture was adjusted to 5-6 with formic acid. The solvent was removed by concentration under reduced pressure, 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 an ACN / 0.1% FA in H O solvent system; detection wavelengths at 254 nm / 214 nm; flow rate at 20 ml / min) to afford (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (38.01 mg, 0.07 mmol, yield: 26.0%). LC-MS m / z: 572 [M+H] + .

[0918] 1 H NMR (400 MHz, DMSO- d 6 ): 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, 1H), 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).

[0919] Example 7. Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)methoxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound C1):

[0920] 1) Synthesis of (S)-methyl 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)methoxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate:

[0921]

[0922] A solution of 3-fluoro-4-((6-((piperidin-4-oxy)methyl)pyridin-2-yl)methoxy)benzonitrile (27 mg, 0.08 mmol), (S)-methyl 2-(chloromethyl)-1-(oxyethane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (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 × 2). The combined organic phases were washed with saturated ammonium chloride (20 mL × 3) and brine (10 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 give (S)-methyl 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)methoxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (23 mg, yield: 47.0%). LC-MS m / z: 600 [M+H] + .

[0923] 2) Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)methoxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0924]

[0925] To a solution of (S)-methyl 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)methoxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (23 mg, 0.04 mmol) in water / tetrahydrofuran (1 mL / 1 mL) was added lithium hydroxide (10 mg, 0.40 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was adjusted to pH 5-6 with formic acid. The solvent was removed by concentration 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 an ACN / 0.1% FA in H O solvent system; detection wavelengths at 254 nm / 214 nm; flow rate at 20 ml / min) to afford (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)methoxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (14.73 mg, yield: 65.5%). LC-MS m / z: 586 [M+H] + .

[0926] 1 H NMR (400 MHz, DMSO- d 6 )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).

[0927] Example 8. Synthesis of (S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)azetidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound S3):

[0928] 1) Synthesis of (S)-methyl 2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)azetidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate:

[0929]

[0930] A solution of (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (150 mg, 0.51 mmol), 4-((6-(azetidin-3-yloxy)pyridin-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 for 4 hours. The resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic phases were washed sequentially with saturated ammonium chloride solution and brine, 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 give (S)-methyl 2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)azetidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (180.0 mg, 0.32 mmol, yield: 63.3%). LC-MS m / z: 558 [M+H] + .

[0931] 2) Synthesis of (S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)azetidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0932]

[0933] To a solution of (S)-methyl 2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)azetidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (90 mg, 0.16 mmol) in water / THF (4 mL / 4 mL) was added monohydrate and lithium hydroxide (68 mg, 1.63 mmol). The reaction mixture was stirred at room temperature for 16 hours. The pH of the reaction mixture was adjusted to 5-6 with formic acid. The solvent was removed under reduced pressure. The residue was purified by PrepHPLC (Waters 2767 / 2545 / 2489 system; SunFire Prep C8 OBD 10 μm 19 × 250 mm Column; gradient elution with an ACN / 0.1% NH₄OH in H₂O solvent system; detection wavelengths at 254 nm / 214 nm; flow rate at 20 ml / min) to afford (S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)azetidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound S3) (10.23 mg, yield: 11.7%). LC-MS m / z: 544 [M+H] + .

[0934] 1 HNMR(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, 1 H), 4.33-4.28(m, 1 H), 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).

[0935] Example 9, (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound S5)

[0936] 1) Synthesis of (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester:

[0937]

[0938] K2CO3 (113.0 mg, 0.819 mmol) was added to a mixture of 3-fluoro-4-((6-(piperidin-4-oxy)pyridin-2-yl)oxy)methyl)benzonitrile (89.0 mg, 0.273 mmol) and (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (80.3 mg, 0.273 mmol, 1.0 eq) in DMF (4 mL) at room temperature. After stirring until homogeneous, the mixture was heated to 60°C and stirred for 3 hours. The mixture was diluted with water (5 mL) and extracted with EA (3 × 20 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give (S)-methyl 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (94 mg, 59.0%). LC-MS m / z: 585 [M+H] + .

[0939] 2) Synthesis of (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid:

[0940]

[0941] To a stirred solution of (S)-methyl 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (94 mg, 0.16 mmol) in THF / H₂O (4 mL / 4 mL) was added LiOH•H₂O (68 mg, 1.60 mmol). The mixture was stirred thoroughly and then heated to 40°C and stirred for 16 h. The resulting mixture was adjusted to pH 5-6 with HCl (1 N) and extracted with EA (3 × 10 mL). The combined organic phases were washed with brine (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); mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 20% B to 50% B over 20 minutes; detector: 254 nm). The mobile phase containing the desired product was collected at 32% B and concentrated under reduced pressure to yield (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (26.27 mg, 28.6%). LC-MS m / z: 571 [M+H] + .

[0942] 1 H 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, 2 H), 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, 2H), 1.62-1.58(m, 2 H).

[0943] Example 10. Synthesis of 2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound S4):

[0944] 1) Synthesis of methyl 4-(2-(4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)acetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate:

[0945]

[0946] To a stirred mixture of Intermediate A-2 (140 mg, 0.40 mmol) and Intermediate B-2 (131 mg, 0.40 mmol) in DMF (3 mL) was added K₂CO₃ (110 mg, 0.80 mmol). After stirring, the mixture was heated to 60°C and stirred for 3 h. The resulting mixture was poured into brine (50 mL) and extracted with DCM (2 × 10 mL). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to afford methyl 4-(2-(4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)acetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (140 mg, 54.6% yield). LC-MS m / z: 642 [M+H] + .

[0947] 2) Synthesis of 4-(2-(4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)acetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoic acid:

[0948]

[0949] To a stirred solution of methyl 4-(2-(4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)acetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (140 mg, 0.22 mmol) in a mixture of THF / H₂O (1 mL / 1 mL) was added LiOH (11 mg, 0.46 mmol), and the mixture was stirred at room temperature for 5 h. The resulting mixture was poured into brine (10 mL) and extracted with DCM (2 × 5 mL). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give 4-(2-(4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)acetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoic acid (80 mg, 58.0% yield). LC-MS m / z: 628 [M+H] + .

[0950] 3) Synthesis of 2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 4):

[0951]

[0952] 4-(2-(4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)acetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoic acid (80 mg, 0.13 mmol) was mixed in toluene (1 mL) and AcOH (0.2 mL). The mixture was heated to 110°C and stirred for 3 h. The solvent was removed under reduced pressure. The residue was purified by PrepHPLC (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 afford 2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound S4) (20.72 mg, 26.2% yield). LC-MS m / z: 610 [M+H]+ .

[0953] 1 H NMR (400 MHz, DMSO- d 6 ): 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, 1H), 4.03-3.97(m, 2 H), 3.81(s, 2 H), 2.68-2.65(m, 2 H), 2.25-2.20(m, 2 H),1.75-1.71(m, 2 H), 1.43-1.39(m, 2 H), 1.16(t, J = 7.2 Hz, 3 H).

[0954] Example 11. Synthesis of 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound S23):

[0955] 1) Synthesis of methyl 4-(2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidin-1-yl)acetamide)-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate:

[0956]

[0957] To a stirred solution of methyl 4-(2-chloroacetamido)-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (100 mg, 0.29 mmol) and 3-fluoro-4-((3-(piperidin-4-oxy)phenoxy)methyl)benzonitrile (95 mg, 0.29 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (120 mg, 0.87 mmol) at room temperature. The mixture was stirred at 60°C for 3 hours. The reaction was quenched by adding water (5 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (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 give methyl 4-(2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidin-1-yl)acetamide)-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (45 mg, yield: 24.1%). LC-MS m / z: 641 [M+H] + .

[0958] 2) Synthesis of methyl 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidin-1-yl)methyl-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate:

[0959]

[0960] To a solution of methyl 4-(2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidin-1-yl)acetamide)-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (45 mg, 0.07 mmol) in toluene (10 mL) was added acetic acid (2 mL). The resulting mixture was stirred at 110°C for 16 hours. The resulting solution was concentrated to afford the crude product, which was further purified by reverse phase flash chromatography under the following conditions: (column: spherical C18, 20-40, 120 g; mobile phase A: water (supplemented with 10 mM ammonia); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 60% B to 80% B over 20 minutes; detector: 254 nm.) The mobile phase containing the desired product was collected at 72% B and concentrated under reduced pressure to afford methyl 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidin-1-yl)methyl-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (22 mg, 57.1% yield). LC-MS m / z: 623 [M+H] + .

[0961] 3) Synthesis of 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid:

[0962]

[0963] To a stirred solution of methyl 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidin-1-yl)methyl-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (22 mg, 0.04 mmol) in tetrahydrofuran / water (4 mL / 4 mL) was added lithium hydroxide monohydrate (17 mg, 0.40 mmol), 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 extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: (column: spherical C18, 20-40 μm, 40 g; mobile phase A: water (added with 10 mM Ammonia water); mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 20% B-50% B in 20 minutes; detector: 254 nm. The mobile phase containing the desired product was collected at 29% B and concentrated under reduced pressure to give 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenoxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (11.42 mg, 0.019 mmol, yield: 47.5%). LC-MS m / z: 609 [M+H] + .

[0964] 1 H 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, 2 H), 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).

[0965] Example 12. Synthesis of the formate salt of (S,E)-3-(2-((4-((6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxoalkane-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)acrylic acid (Compound S36):

[0966] 1) Synthesis of methyl (S,E)-3-(2-((4-((6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxoalkane-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)acrylate:

[0967]

[0968] To a stirred solution of (S,E)-methyl 3-(2-(chloromethyl)-1-(oxyethane-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)acrylate (90 mg, 0.28 mmol) and 2-((4-chloro-2-fluorobenzyl)oxy)-3-fluoro-6-(piperidin-4-oxy)pyridine (100 mg, 0.28 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (78 mg, 0.56 mmol) at room temperature. 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 the addition of water (5 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give (S,E)-methyl 3-(2-((4-((6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxoalkane-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)acrylate (60 mg, yield: 33.5%). LC-MS m / z: 639 [M+H] + .

[0969] 2) Synthesis of (S,E)-3-(2-((4-((6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxoalkane-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)acrylic acid (formate)

[0970]

[0971] To a mixed solution of (S,E)-methyl 3-(2-((4-((6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxoalkane-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)acrylate (60 mg) was added lithium hydroxide monohydrate (6 mg, 0.24 mmol), and the mixture was stirred at room temperature for 5 hours. The resulting mixture was adjusted to pH 5-6 with formic acid and concentrated under reduced pressure. The residue was then 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% FA in H₂O solvent system; detection wavelengths at 254 nm / 214 nm; flow rate at 20 ml / min) to afford (S,E)-3-(2-((4-((6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)acrylic acid formate (13.10 mg, approximately 27% yield). LC-MS m / z: 625 [M+H] + .

[0972] 1 H NMR(400 MHz, DMSO-d6): δ 8.27(s, 1 H), 8.00(s, 1 H), 7.66-7.47(m, 6H), 7.32(dd, J =10.0 Hz, 2.0 Hz, 1 H), 6.54(d, J =15.6 Hz, 1 H), 6.34(dd, J =8.8Hz, 2.0 Hz, 1 H), 5.44(s, 2 H), 5.11-5.09(m, 1 H), 4.79-4.75(m, 2 H), 4.62-4.58(m, 1 H), 4.51-4.40(m, 2 H), 3.95-3.92(m, 1 H), 3.80-3.76(m, 1 H), 2.80-2.68(m, 3 H), 2.50-2.41(m, 1 H), 2.36-2.29(m, 2 H), 1.91-1.89(m, 2 H), 1.62-1.57(m, 2 H).

[0973] Example 13, ( ESynthesis of 3-(2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazol-6-yl)acrylic acid (Compound C2):

[0974] 1), ( E Synthesis of methyl 3-(4-(2-(4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)acetamide)-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)phenyl)acrylate:

[0975]

[0976] To dissolve ( E To a solution of methyl 3-(4-(2-chloroacetamido)-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)phenyl)acrylate (100 mg, 0.27 mmol) and 3-fluoro-4-((6-(piperidin-4-yloxy)pyridin-2-yl)oxy)methyl)benzonitrile (88 mg, 0.27 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (75 mg, 0.54 mmol), and the mixture was stirred at room temperature for 16 hours. The resulting mixture was poured into brine (50 mL) and extracted with ethyl acetate (2 × 15 mL). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain ( E )-methyl 3-(4-(2-(4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)acetamide)-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)phenyl)acrylate (100 mg, yield: 55.5%). LC-MS m / z: 668 [M+H] + .

[0977] 2) Synthesis of (E)-methyl 3-(2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazol-6-yl)acrylate:

[0978]

[0979] The dissolved EA mixed solution of methyl 3-(4-(2-(4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)acetamide)-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)phenyl)acrylate (100 mg, 0.15 mmol) in toluene (2 mL) and acetic acid (0.2 mL) was stirred at 110°C for 3 hours. The resulting mixture was poured into brine (20 mL) and extracted with dichloromethane (3 × 5 mL). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give (E)-methyl 3-(2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazol-6-yl)acrylate (70 mg, yield: 71.9%). LC-MS m / z: 650 [M+H] + .

[0980] 3) ( E Synthesis of 3-(2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazol-6-yl)acrylic acid:

[0981]

[0982] To dissolve ( E To a solution of methyl 3-(2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazol-6-yl)acrylate (70 mg, 0.11 mmol) in tetrahydrofuran / water (2 mL / 2 mL) was added lithium hydroxide (5 mg, 0.21 mmol), and the mixture was stirred at room temperature for 16 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by Prep HPLC (Waters 2767 / 2545 / 2489 system; SunFire Prep C8 OBD 10 μm 19 × 250 mm Column; ACN / 0.1% FA in H2O solvent system gradient elution; detection wavelength 254 nm / 214 nm; flow rate 20 ml / min) to obtain ( E)-3-(2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazol-6-yl)acrylic acid (13.86 mg, yield: 19.8%). LC-MS m / z: 636 [M+H] + .

[0983] 1H NMR (400 MHz, DMSO- d 6 ): δ 7.91(d, J =9.6 Hz, 1H), 7.81(s, 1 H), 7.71-7.69(m, 2 H), 7.64-7.59(m, 4 H), 7.52-7.50(m, 1 H), 6.50(d, J =8.4 Hz, 1H),6.45(d, J =7.6 Hz, 1H), 6.34(d, J =8.0 Hz, 1H), 5.66(s, 2 H), 5.43(s, 2 H), 4.74-4.70(m, 1 H), 4.00-3.95(m, 2 H), 3.76(s, 2 H), 2.67-2.64(m, 2 H), 2.23-2.19(m, 2 H), 1.76-1.73(m, 2 H), 1.44-1.38(m, 2 H), 1.14-1.10(m, 3H).

[0984] Example 14. Synthesis of 2-((4-((6-((4-bromo-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound C3):

[0985] 1) Synthesis of methyl 4-(2-(4-((6-((4-bromo-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)acetamide)-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate:

[0986]

[0987] A solution of methyl 4-(2-chloroacetamido)-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (540 mg, 1.54 mmol), 2-((4-bromo-2-fluorophenoxy)methyl)-6-(piperidin-4-oxy)pyridine (586 mg, 1.54 mmol), and potassium carbonate (637 mg, 4.62 mmol) in dry N,N-dimethylformamide (15 mL) was stirred at room temperature for 16 hours. Upon completion, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give methyl 4-(2-(4-((6-((4-bromo-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)acetamide)-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (500 mg, yield: 46.8%).

[0988] 2) Synthesis of methyl 2-((4-((4-bromo-2-fluorophenoxy)methyl)pyridin-2-yl)oxypiperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate:

[0989]

[0990] A solution of methyl 4-(2-(4-((6-((4-bromo-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)acetamide)-3-((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (500 mg, 0.72 mmol) in toluene (6 mL) / acetic acid (1 mL) was stirred at 110°C for 3 hours. The product was separated and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain methyl 2-((4-((4-bromo-2-fluorophenoxy)methyl)pyridin-2-yl)oxypiperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (470 mg, yield: 96.5%). LC-MS m / z: 679 [M+H] + .

[0991] 3) Synthesis of 2-((4-((6-((4-bromo-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid:

[0992]

[0993] To a solution of methyl 2-((4-((4-bromo-2-fluorophenoxy)methyl)pyridin-2-yl)oxypiperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (80 mg, 0.12 mmol) in tetrahydrofuran / water (1 mL / 1 mL) was added lithium hydroxide (9 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 16 hours. The pH of the reaction mixture was adjusted to 5-6 using formic acid. The solvent was removed by concentration under reduced pressure, and the residue was purified by PrepHPLC (Waters 2767 / 2545 / 2489 system; SunFire Prep C8 OBD 10 μm 19 × 250 mm Column; gradient elution with an ACN / 0.1% FA in H O solvent system; detection wavelengths at 254 nm / 214 nm; flow rate at 20 ml / min) to afford 2-((4-((6-((4-bromo-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (30.96 mg, yield: 39%). LC-MS m / z: 665 [M+H] + .

[0994] 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.19(s, 1 H), 8.07(s, 1 H), 7.81(dd, J =8.8Hz, 1.6 Hz, 1 H), 7.72-7.67(m, 3 H), 7.54(dd, J =6.8 Hz, 2.4 Hz,1 H), 7.30(d, J =8.8 Hz, 1 H), 7.21(t, J =8.8 Hz, 1 H), 7.03(d, J =7.2 Hz, 1 H), 6.70(d, J=8.4 Hz,1 H), 6.41(s, 1 H), 5.72(s, 2 H), 5.17(s, 2 H), 4.88-4.86(m, 1 H), 4.03-3.98(m, 2 H), 3.81(s, 2 H), 2.69-2.67(m, 2 H), 2.33-2.23(m, 2 H), 1.81-1.78(m, 2H), 1.47-1.44(m, 2 H), 1.16(t, J =7.2 Hz, 3 H).

[0995] Example 15. Synthesis of (S)-2-((4-((6-((4-bromo-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound C4)

[0996] 1) Synthesis of (S)-2-((4-((6-((4-bromo-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

[0997]

[0998] A solution of (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.34 mmol), 2-((4-bromo-2-fluorophenoxy)methyl)-6-(piperidin-4-oxy)pyridine (130 mg, 0.34 mmol), and potassium carbonate (140 mg, 1.02 mmol) in dry N,N-dimethylformamide (4 mL) was stirred at 60°C for 3 hours. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layer was concentrated under reduced pressure and then purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give (S)-methyl 2-((4-((6-((4-bromo-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, yield: 46.1%). LC-MS m / z: 639 [M+H] + .

[0999] 2) Synthesis of (S)-2-((4-((6-((4-bromo-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid:

[1000]

[1001] To a solution of (S)-methyl 2-((4-((6-((4-bromo-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.16 mmol) in tetrahydrofuran / water (2 mL / 2 mL) was added lithium hydroxide (12 mg, 0.48 mmol). The reaction mixture was stirred at room temperature for 16 hours. The pH of the reaction mixture was adjusted to 5-6 using formic acid. The solvent was removed by concentration under reduced pressure, and 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% FA in H O solvent system; detection wavelength 254 nm / 214 nm; flow rate 20 ml / min) to afford (S)-2-((4-((6-((4-bromo-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (20.08 mg, yield: 20.5%). LC-MS m / z: 627 [M+H] + .

[1002] 1H NMR (400 MHz, DMSO- d 6 ): δ 8.28-8.23(m, 1 H), 7.80(d, J =8.8 Hz, 1 H),7.71(t, J =7.6 Hz, 1 H), 7.63(d, J =8.4 Hz, 1 H), 7.54(dd, J =10.4 Hz, 2.0 Hz, 1H), 7.31(d, J =9.2 Hz, 1 H), 7.22(t, J =8.8 Hz, 1 H), 7.04(d, J =7.2 Hz, 1 H), 6.72(d, J=8.4 Hz, 1 H), 5.18(s, 2 H), 5.13-5.06(m, 1 H), 4.97-4.89(m, 1 H), 4.83-4.73(m, 1 H), 4.68-4.60(m, 1 H), 4.54-4.46(m, 1 H), 4.41-4.33(m, 1 H), 3.98-3.90(m, 1 H), 3.82-3.75(m, 1 H), 2.82-2.66(m, 4 H), 2.46-2.36(m, 1 H), 2.33-2.26(m, 2 H), 1.97-1.88(m, 2 H), 1.66-1.56(m, 2 H).

[1003] Example 16. Synthesis of 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-3-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound C82):

[1004] 1) Synthesis of methyl 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-3-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate:

[1005]

[1006] A mixture of methyl 2-(chloromethyl)-1-(oxetan-3-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.34 mmol), 3-fluoro-4-((6-(piperidin-4-oxy)pyridin-2-yl)methoxy)benzonitrile (111 mg, 0.34 mmol), and potassium carbonate (94 mg, 0.68 mmol) in N,N-dimethylformamide (2 mL) was stirred at 60°C for 3 hours. The resulting mixture was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were back-extracted with brine (30 mL) and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford methyl 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-3-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, yield: 50.3%). LC-MS m / z: 586 [M+H] + .

[1007] 2) Synthesis of 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-3-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid:

[1008]

[1009] To a solution of 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-3-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.17 mmol) in tetrahydrofuran / water (1.0 mL / 1.0 mL) was added lithium hydroxide (8 mg, 0.34 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed by concentration under reduced pressure, and 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% FA in H O; detection wavelength: 254 nm / 214 nm; flow rate: 20 ml / min) to afford 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-3-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (25.81 mg, yield: 26.6%). LC-MS m / z: 572 [M+H] + .

[1010] 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.22(s, 1 H), 7.88(dd, J =11.2, 2.0 Hz, 1H), 7.81(dd, J =8.4, 1.2 Hz, 1 H), 7.73(t, J =8.0 Hz, 1 H), 7.67-7.61(m, 2 H),7.45(t, J =8.4 Hz, 1 H), 7.06(d, J =7.2 Hz, 1 H), 6.74(d, J =8.4 Hz, 1 H), 5.31(s,2 H), 4.94-4.91(m, 1 H), 4.72(d, J=7.6 Hz, 2 H), 4.64-4.61(m, 2 H), 4.56-4.53(m, 2 H), 3.81(s, 2 H), 3.67-3.61(m, 1 H), 2.80-2.77(m, 2 H), 2.33-2.27(m, 2H), 1.93-1.90(m, 2 H), 1.64-1.59(m, 2 H).

[1011] Example 17. Synthesis of 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((3-methyloxetanyl-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound C5):

[1012] 1) Synthesis of methyl 2-((4-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxypiperidin-1-yl)methyl)-1-((3-methyloxetanyl-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate:

[1013]

[1014] A solution of methyl 2-(chloromethyl)-1-((3-methyloxetan-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.32 mmol), 3-fluoro-4-((6-(piperidin-4-oxy)pyridin-2-yl)methoxy)benzonitrile (105 mg, 0.32 mmol), and potassium carbonate (88 mg, 0.64 mmol) in N,N-dimethylformamide (2 mL) was stirred at 60°C for 3 hours. The resulting mixture was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and back-extracted with saturated brine (30 mL). The organic phase was concentrated under reduced pressure and purified via silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford methyl 2-((4-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxypiperidin-1-yl)methyl)-1-((3-methyloxetanyl-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (50 mg, yield: 26.0%). LC-MS m / z: 600 [M+H] + .

[1015] 2) Synthesis of 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((3-methyloxetanyl-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid:

[1016]

[1017] Lithium hydroxide (10 mg, 0.42 mmol) was added to a mixture of methyl 2-((4-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxypiperidin-1-yl)methyl)-1-((3-methyloxy-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (50 mg, 0.08 mmol) in water / tetrahydrofuran (5 mL / 5 mL). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed by concentration under reduced pressure, and 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 an ACN / 0.1% FA in H O solvent system; detection wavelengths at 254 nm / 214 nm; flow rate at 20 ml / min) to afford 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((3-methyloxetanyl-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (9.50 mg, yield: 20.3%). LC-MS m / z: 586 [M+H] + .

[1018] 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.21(s, 1 H), 7.88(dd, J =11.2, 1.6 Hz, 1H), 7.81(d, J =9.2 Hz, 1 H), 7.73(t, J =8.0 Hz, 1 H), 7.66(d, J =8.4 Hz, 2 H), 7.44(t, J =8.8 Hz, 1 H), 7.05(d, J =7.2 Hz, 1 H), 6.73(d, J =8.4 Hz, 1 H), 5.30(s, 2H), 4.92-4.90(m, 1 H), 4.65-4.61(m, 4 H), 4.22(d, J=6.0 Hz, 1 H), 3.78(s, 2H), 2.76-2.74(m, 2 H), 2.31-2.26(m, 2 H), 1.92-1.87(m, 2 H), 1.62-1.58(m, 2H), 1.25(s, 3 H).

[1019] Example 18. Synthesis of (S)-2-((4-(3-((4-cyano-2-fluorophenoxy)methyl)phenoxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 67):

[1020] 1) Synthesis of (S)-methyl 2-((4-(3-((4-cyano-2-fluorophenoxy)methyl)phenoxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate:

[1021]

[1022] Potassium carbonate (94 mg, 0.68 mmol) was added to a solution of (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.34 mmol) and 3-fluoro-4-((3-(piperidin-4-oxy)benzyl)oxy)benzonitrile (122 mg, 0.37 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred at room temperature for 16 hours. The mixture was quenched by the addition of water (5 mL) and extracted with ethyl acetate (40 mL x 3). The product was back-extracted with brine (30 mL x 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was then purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give (S)-methyl 2-((4-(3-((4-cyano-2-fluorophenoxy)methyl)phenoxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (71 mg, yield: 35.8%). LC-MS m / z: 585 [M+H] + .

[1023] 2) Synthesis of (S)-2-((4-(3-((4-cyano-2-fluorophenoxy)methyl)phenoxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid:

[1024]

[1025] Lithium hydroxide monohydrate (50 mg, 1.20 mmol) was added to a mixture of (S)-methyl 2-((4-(3-((4-cyano-2-fluorophenoxy)methyl)phenoxy)piperidin-1-yl)methyl)-1-(oxoalkane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (71 mg, 0.12 mmol) in tetrahydrofuran / water (2 mL / 2 mL) at room temperature. The reaction was stirred at room temperature for 5 hours. The resulting mixture was adjusted to pH 5-6 with hydrochloric acid (1 N) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were back-extracted with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase flash chromatography under the following conditions (column: spherical C18, 20-40 μm, 40 g; mobile phase A: water (supplemented with 10 mM ammonia); mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 20% B to 50% B over 20 minutes; detector: 254 nm). (S)-2-((4-(3-((4-cyano-2-fluorophenoxy)methyl)phenoxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (4.69 mg, yield: 7.3%) was obtained. LC-MS m / z: 571 [M+H] + .

[1026] 1 H NMR (400 MHz, DMSO- d 6)8.25(s, 1 H), 7.88-7.80(m, 2 H), 7.68(d, J =8.4Hz, 1H), 7.61(d, J =8.0 Hz, 1 H), 7.42(t, J =8.4 Hz, 1 H), 7.30(t, J =7.6 Hz, 1H), 7.05-6.93(m, 3 H), 5.25(s, 2 H), 5.10-5.07(m, 1 H), 4.80-4.75(m, 1 H),4.63(d, J =13.2 Hz, 1 H), 4.52-4.47(m, 1 H), 4.42-4.35(m, 2 H), 3.94(d, J =13.2Hz, 1H), 3.78(d, J=13.2 Hz, 1 H), 2.79-2.67(m, 3 H), 2.46-2.35(m, 3 H), 1.95-1.93(m,2H), 1.64-1.60(m,2 H).

[1027] Example 19. Synthesis of 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1,2-dimethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound C6):

[1028] 1) Synthesis of methyl 4-(2-(4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)acetamido)-3-((1,2-dimethyl-1H-imidazol-5-yl)methyl)amino)benzoate:

[1029]

[1030] To a solution of methyl 4-(2-chloroacetamido)-3-((1,2-dimethyl-1H-imidazol-5-yl)methyl)amino)benzoate (150 mg, 0.43 mmol) and 3-fluoro-4-((6-(piperidin-4-oxy)pyridin-2-yl)methoxy)benzonitrile (141 mg, 0.43 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (119 mg, 0.86 mmol), and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the resulting mixture was poured into brine (50 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phase was concentrated under reduced pressure and purified via silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford methyl 4-(2-(4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)acetamido)-3-((1,2-dimethyl-1H-imidazol-5-yl)methyl)amino)benzoate (150 mg, yield: 54.3%). LC-MS m / z: 642 [M+H] + .

[1031] 2) Synthesis of methyl 2-((4-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxypiperidin-1-yl)methyl)-1-((1,2-dimethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate:

[1032]

[1033] Methyl 4-(2-(4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)acetamido)-3-((1,2-dimethyl-1H-imidazol-5-yl)methyl)amino)benzoate (150 mg, 0.08 mmol) was dissolved in a mixture of toluene (5 mL) and acetic acid (1 mL) and stirred at 110°C for 3 hours. The resulting mixture was poured into brine (20 mL) and extracted with dichloromethane (2 × 10 mL). The organic phase was concentrated under reduced pressure to afford methyl 2-((4-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxypiperidin-1-yl)methyl)-1-((1,2-dimethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, yield: 69.8%). LC-MS m / z: 624 [M+H] + .

[1034] 3) Synthesis of the formate salt of 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1,2-dimethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid:

[1035]

[1036] To a solution of 2-((4-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxypiperidin-1-yl)methyl)-1-((1,2-dimethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.17 mmol) in tetrahydrofuran / water (5 mL / 5 mL) was added lithium hydroxide (8 mg, 0.34 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed by concentration under reduced pressure, and 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 an ACN / 0.1% FA in H O solvent system; detection wavelengths at 254 nm / 214 nm; flow rate at 20 ml / min) to afford the formate salt of 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1,2-dimethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (71.07 mg, yield: 68.6%). LC-MS m / z: 610 [M+H] + .

[1037] 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.16(s, 2 H), 8.09(s, 1 H), 7.88(dd, J =11.2, 1.6 Hz, 1 H), 7.81(dd, J =8.4, 1.2 Hz, 1 H), 7.74-7.65(m, 3 H), 7.44(t, J =8.4 Hz, 1 H), 7.05(d, J =7.2 Hz, 1 H), 6.72(d, J =8.4 Hz, 1 H), 6.41(s, 1 H),5.67(s, 2 H), 5.30(s, 2 H), 4.90-4.86(m, 1 H), 3.82(s, 2 H), 3.44(s, 3 H),2.72-2.69(m, 2 H), 2.33-2.24(m, 5 H), 1.84-1.82(m, 2 H), 1.54-1.47(m, 2 H).

[1038] Example 20. Synthesis of 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)-5-fluoropyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 135):

[1039] 1) Synthesis of methyl 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)-5-fluoropyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate:

[1040]

[1041] Potassium carbonate (207 mg, 1.50 mmol) was added to a mixture of methyl 2-(chloromethyl)-1-(1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (160 mg, 0.50 mmol) and 3-fluoro-4-((3-fluoro-6-(piperidin-4-oxy)pyridin-2-yl)methoxy)benzonitrile (173 mg, 0.50 mmol) in N,N-dimethylformamide (4 mL) at room temperature. The mixture was stirred at 60°C for 2 hours. The mixture was quenched by the addition of water (5 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were back-extracted with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give methyl 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)-5-fluoropyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (17 mg, yield: 6.0%). LC-MS m / z: 627 [M+H] + .

[1042] 2) Synthesis of 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)-5-fluoropyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid:

[1043]

[1044] To a mixture of methyl 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)-5-fluoropyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (17 mg, 0.03 mmol) in tetrahydrofuran / water (3 mL / 3 mL) was added lithium hydroxide monohydrate (12 mg, 0.30 mmol), and the reaction was stirred at room temperature for 3 hours. The resulting mixture was adjusted to pH 5-6 with hydrochloric acid (1 N) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were back-extracted with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase flash chromatography under the following conditions (column: spherical C18, 20-40 μm, 120 g; mobile phase A: water (supplemented with 10 mM ammonia); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 30% B to 50% B over 20 minutes; detec...

Claims

1. A compound represented by formula (IE), a pharmaceutically acceptable salt or enantiomer thereof: Formula (IE) in, represents a single bond; X stands for -O-; X' represents -C(R d1 )(R d2 )-; L stands for -O-; X1 represents -N-; X3 or X8 represents -CR5- or N; R is independently selected from 5-8 membered heteroaryl or 3-8 membered saturated or partially saturated heterocyclic group, optionally substituted by 1 to more substituents, wherein the substituents are methyl, ethyl, propyl, butyl, 2-methyl-propyl, 1,1-dimethylethyl, pentyl and hexyl; Each R1 is the same or different and is independently selected from hydrogen, deuterium, halogen, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl or -COOH; Each R4 is the same or different and is independently selected from hydrogen, deuterium, halogen, C 1-10 Alkyl or C 1-10 Alkoxy; Each R5 and R6 are the same or different and are independently selected from hydrogen, deuterium, halogen, CN, C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy; Each R d1 , R d2 are the same or different and are independently selected from hydrogen, deuterium, halogen or C 1-10 alkyl; m is arbitrarily selected from an integer between 1 and 2; n is an integer arbitrarily selected from 0, 1 or 2; q is an integer arbitrarily selected from 0, 1 or 2; Provided that the following compounds are not contained:

2. The compound according to claim 1, its pharmaceutically acceptable salt or enantiomer, characterized in that: X3 or X8 represents -CH- or N.

3. The compound according to claim 1 or 2, its pharmaceutically acceptable salt or enantiomer, characterized in that: Each R1 is the same or different and is independently selected from hydrogen, F or -COOH; Each R4 is the same or different and is independently selected from hydrogen, deuterium, F or methyl; Each R5 is the same or different and is independently selected from hydrogen, deuterium or F; Each R6 is the same or different and is independently selected from hydrogen, deuterium, halogen, C 2-10 Alkynyl or CN.

4. A compound having the following structure, or a pharmaceutically acceptable salt or enantiomer thereof:

5. A compound having the following structure or a pharmaceutically acceptable salt thereof:

6. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt or an enantiomer thereof, or the compound according to claim 5 or a pharmaceutically acceptable salt thereof.

7. Use of the compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt or enantiomer thereof, or the compound according to claim 5 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating diseases related to the GLP1 / GLP1R signaling pathway.

8. The use as claimed in claim 7, wherein the disease related to the GLP1 / GLP1R signaling pathway is selected from overweight, diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, obesity, eating disorders, weight gain caused by the use of other drugs, excessive sugar addiction, dyslipidemia, hyperinsulinemia, NAFLD, cardiovascular disease, atherosclerosis or peripheral vascular disease.

9. The use according to claim 8, wherein: The diabetes is selected from T1D or T2DM, prediabetes, latent autoimmune diabetes in adults, atypical diabetes of youth, juvenile diabetes of maturity, malnutrition-related diabetes or gestational diabetes; The eating disorder is selected from binge eating syndrome, bulimia nervosa or syndromic obesity; The dyslipidemia is selected from hyperlipidemia, hypertriglyceridemia or increased total cholesterol; The NAFLD is selected from steatosis, NASH, fibrosis, cirrhosis or hepatocellular carcinoma.

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