Novel prodrug compound or fused ring compound as GLP1r agonist

Abstract

A novel prodrug compound having GLP1R agonist activity. Specifically disclosed is a compound having a structure represented by formula (I) as a GLP1R agonist, or a pharmaceutically acceptable salt, solvate, hydrate, isotopic substituent or isomer thereof.

Description

Novel prodrug compounds or fused ring compounds as GLP1R agonists

[0001] This application requires the applicant to:

[0002] Priority benefit of the prior application, patent application number 202310805684.1, filed with the State Intellectual Property Office of China on July 3, 2023, entitled “Novel Prodrug Compounds as GLP1R Agonists”;

[0003] Priority benefit of the prior application, patent application number 202311152034.8, filed with the State Intellectual Property Office of China on September 7, 2023, entitled “Novel Prodrug Compounds as GLP1R Agonists”;

[0004] Priority benefit of the prior application, patent application number 202311180743.7, filed with the State Intellectual Property Office of China on September 13, 2023, entitled “Novel Prodrug Compounds as GLP1R Agonists”;

[0005] Priority benefit of the prior application, patent application number 202410171113.1, filed with the State Intellectual Property Office of China on February 6, 2024, entitled “Novel prodrug compounds or fused ring compounds as GLP1R agonists”;

[0006] Priority benefit of the prior application, patent application number 202410464273.5, filed with the State Intellectual Property Office of China on April 17, 2024, entitled “Novel prodrug compounds or fused ring compounds as GLP1R agonists”;

[0007] The entirety of the prior application is incorporated into the present disclosure by reference. Technical Field

[0008] The present invention belongs to the field of medicinal chemistry and specifically includes novel fused ring compounds or prodrugs having GLP1R agonist activity, compositions comprising such fused ring compounds or prodrugs, and the use of such fused ring compounds or prodrugs in the preparation of drugs for treating or preventing diseases related to GLP1 / GLP1R. Background Art

[0009] With the improvement of material living standards, overweight or obesity is becoming more and more common in modern society. The number of patients with complications caused by obesity, such as diabetes and fatty liver, is increasing. A report released by the World Health Organization (WHO) and Zhiyan Consulting predicts that by 2030, the number of obese patients in the world will reach 3.26 billion; by 2029, the number of global diabetes patients will exceed 500 million; and the number of global non-alcoholic fatty liver disease patients will exceed 1.5 billion. Currently, there is no effective treatment for fatty liver disease; there are only six FDA-approved drugs for the treatment of obesity, and most of them are controlled drugs with weak efficacy and significant side effects; although many drugs for the treatment of type 2 diabetes have been approved for marketing, the blood sugar-lowering rate of existing hypoglycemic drugs (<7%) has always been low, and even the most active compound has a target-lowering rate of only around 45%. Therefore, whether it is fatty liver, obesity, or diabetes, new drugs need to be developed to meet the needs of a wider range of patients.

[0010] 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 non-clinical experiments, GLP-1 promotes the sustainable capacity of β cells by stimulating the transcription of important genes for glucose-dependent insulin secretion and promoting the regeneration of β cells (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.

[0011] 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.

[0012] There are currently numerous publications and patent reports on oral small-molecule GLP1 agonists. For example, Pfizer's PF-06882961 and PF-07081532 can achieve similar or superior efficacy to GLP1 peptides (https: / / doi.org / 10.1101 / 2020.09.29.319483). Although its efficacy and safety have been preliminarily verified, PF-06882961 has significant drugability deficiencies, such as poor oral absorption, extremely low bioavailability, and a high clinical dosage, which imposes a heavy burden on costs and the gastrointestinal tract of patients. PF-07081532, while well-absorbed orally, has a long half-life (more suitable for 2-3 day dosing), can accumulate with long-term use, and has significant gastrointestinal side effects, especially severe diarrhea, and potential hepatotoxicity. Therefore, there is an urgent need to develop small-molecule GLP1R agonists with good efficacy and minimal side effects.

[0013] The process of fat metabolism passes through a barrier: the mitochondrial membrane. While the mitochondria can burn fat, releasing energy for consumption, long-chain fatty acids cannot pass through this barrier. L-carnitine acts as a transporter, gradually moving long-chain fatty acids across the barrier and delivering them to the mitochondria for further oxidation. L-carnitine is an essential coenzyme in fat metabolism, facilitating the entry of fatty acids into the mitochondria for oxidation and decomposition.

[0014] Technical Effects

[0015] The inventors unexpectedly discovered that some of the novel fused ring compounds or prodrugs of formula (I) of the present invention not only significantly reduce gastrointestinal side effects and improve safety, especially gastrointestinal side effects, but also promote the synergistic mechanism due to mitochondrial fat transport, further enhancing efficacy, improving water solubility, bioavailability, and leakage (Cmax and AUC), and extending half-life. Lower doses in vivo can achieve better efficacy and significantly increase the safety window. Some compounds have the potential to be administered orally once a week, making them more suitable as candidate drugs for the prevention or treatment of diseases related to GLP1 / GLP1R targets or signaling pathways.

[0016] Summary of the Invention

[0017] 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.

[0018] 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;

[0019] Priority is given to

[0020] X and X' are independently selected from the group consisting of absence, a single bond, -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-;

[0021] Y is independently selected from -O-, -S-, -OC(R d1 )(R d2 )O-、-OC(R d1 )(R d2 )-、-OC(R d1 )(R d2 )OCO-、-OC(R d1 )(R d2 )OP=O[OC(R d1 )(R d2 )OR]2-;

[0022] L is independently selected from the group consisting of absence, a single bond, -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-;

[0023] X1 and X8 are independently selected from -CR5- or -N-;

[0024] 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 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;

[0025] R is arbitrarily and independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocycloalkyl, heterocyclyl, alkylacyl, cycloalkylacyl, haloalkylacyl, deuterated alkylacyl, heterocycloalkylacyl, heterocyclylacyl, hydroxyl, amino, substituted amino (disubstituted tertiary amine or trisubstituted quaternary amine), carboxyl, ester, amide, aminoacyl, substituted phosphonyl, or a combination of alkyl / alkenyl / alkynyl or the following structural groups:

[0026] The hydrogen on R is preferably optionally replaced by one or more selected from hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl and alkyl / alkenyl / alkynyl combination, oxo, CN, CF3, OH, OCH3, OCH2CH3, amino, substituted amino (disubstituted tertiary amine or trisubstituted quaternary amine), carboxyl, ester, amide, aminoacyl, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0027] 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; and the hydrogen on R1 is preferably optionally replaced by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0028] 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 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 C3-6 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;

[0029] 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;

[0030] Each R3, 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 C1-10 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;

[0031] 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, 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, C3-10 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;

[0032] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0033] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0034] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0035] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0036] t and q are arbitrarily selected from integers of 0, 1, 2, 3, 4 and 5.

[0037] 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):

[0038] wherein 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 spiro ring or a bridged ring structure;

[0039] Priority is given to

[0040] X and X' are independently selected from the group consisting of absence, a single bond, -C(R d1 )(Rd2 )-、-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-;

[0041] Y is independently selected from -O-, -S-, -OC(R d1 )(R d2 )O-、-OC(R d1 )(R d2 )-、-OC(R d1 )(R d2 )OCO-、-OC(R d1 )(R d2 )OP=O[OC(R d1 )(R d2 )OR]2-;

[0042] L is independently selected from the group consisting of absence, a single bond, -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-;

[0043] X0, X1, X2, X3, X4, X5 and X8 are independently selected from -CR5- or -N-;

[0044] 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;

[0045] R is arbitrarily and independently selected from alkyl, alkenyl, alkynyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocycloalkyl, heterocyclyl, alkylacyl, cycloalkylacyl, haloalkylacyl, deuterated alkylacyl, heterocycloalkylacyl, heterocyclylacyl, hydroxyl, amino, substituted amino (disubstituted tertiary amine or trisubstituted quaternary amine), carboxyl, ester, amide, aminoacyl, substituted phosphonyl, or a combination of alkyl / alkenyl / alkynyl or the following structural groups:

[0046] The hydrogen on R is preferably optionally replaced by one or more selected from hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl and alkyl / alkenyl / alkynyl combination, oxo, CN, CF3, OH, OCH3, OCH2CH3, amino, substituted amino (disubstituted tertiary amine or trisubstituted quaternary amine), carboxyl, ester, amide, aminoacyl, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0047] 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; and the hydrogen on R1 is preferably optionally replaced by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0048] 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 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 C3-6 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;

[0049] 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;

[0050] Each R3, 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 C1-10 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;

[0051] 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, 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, C3-10 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;

[0052] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0053] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0054] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0055] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0056] t and q are arbitrarily selected from integers of 0, 1, 2, 3, 4 and 5.

[0057] 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),

[0058] wherein 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 spiro ring or a bridged ring structure;

[0059] Priority is given to

[0060] Y is independently selected from -O-, -S-, -OC(R d1 )(Rd2 )O-、-OC(R d1 )(R d2 )-、-OC(R d1 )(R d2 )OCO-、-OC(R d1 )(R d2 )OP=O[OC(R d1 )(R d2 )OR]2-;

[0061] X1 and X8 are independently selected from -CR5- or -N-;

[0062] 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;

[0063] R is arbitrarily and independently selected from alkyl, alkenyl, alkynyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocycloalkyl, heterocyclyl, alkylacyl, cycloalkylacyl, haloalkylacyl, deuterated alkylacyl, heterocycloalkylacyl, heterocyclylacyl, hydroxyl, amino, substituted amino (disubstituted tertiary amine or trisubstituted quaternary amine), carboxyl, ester, amide, aminoacyl, substituted phosphonyl, or a combination of alkyl / alkenyl / alkynyl or the following structural groups:

[0064] The hydrogen on R is preferably optionally replaced by one or more selected from hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl and alkyl / alkenyl / alkynyl combination, oxo, CN, CF3, OH, OCH3, OCH2CH3, amino, substituted amino (disubstituted tertiary amine or trisubstituted quaternary amine), carboxyl, ester, amide, aminoacyl, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0065] 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; and the hydrogen on R1 is preferably optionally replaced by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0066] 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, C1-10 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;

[0067] 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 1-10Alkyl, 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;

[0068] Each of R3, R5, R6 and R7 is the same or different and is 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 1-6The 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;

[0069] 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, 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;

[0070] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0071] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0072] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0073] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0074] t and q are arbitrarily selected from integers of 0, 1, 2, 3, 4 and 5.

[0075] 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),

[0076] wherein 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 spiro ring or a bridged ring structure;

[0077] Priority is given to

[0078] Y is independently selected from -O-, -S-, -OC(R d1 )(R d2 )O-、-OC(R d1 )(R d2 )-、-OC(R d1 )(R d2 )OCO-、-OC(R d1 )(R d2 )OP=O[OC(R d1 )(R d2 )OR]2-;

[0079] Z is independently selected from the group consisting of absence, a single bond, -C(R d1 )(R d2 )-、-CH2 CH2-、-C(R d1 )(R d2 )CO-;

[0080] X1 and X8 are independently selected from -CR5- or -N-;

[0081] 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 1-10Alkoxy, 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;

[0082] R is arbitrarily and independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocycloalkyl, heterocyclyl, alkylacyl, cycloalkylacyl, haloalkylacyl, deuterated alkylacyl, heterocycloalkylacyl, heterocyclylacyl, hydroxyl, amino, substituted amino (disubstituted tertiary amine or trisubstituted quaternary amine), carboxyl, ester, amide, aminoacyl, substituted phosphonyl, or a combination of alkyl / alkenyl / alkynyl or the following structural groups: The hydrogen on R is preferably optionally replaced by one or more selected from hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl and alkyl / alkenyl / alkynyl combination, oxo, CN, CF3, OH, OCH3, OCH2CH3, amino, substituted amino (disubstituted tertiary amine or trisubstituted quaternary amine), carboxyl, ester, amide, aminoacyl, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0083] 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 3-10Saturated 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; and the hydrogen on R1 is preferably optionally replaced by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0084] 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 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 Rd1 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;

[0085] 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;

[0086] Each R3, R5, R6, R7 may be 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, 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 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, R6 or R7 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;

[0087] 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, 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, C2-10 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;

[0088] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0089] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0090] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0091] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0092] r is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0093] t and q are arbitrarily selected from integers of 0, 1, 2, 3, 4 and 5.

[0094] 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),

[0095] in,

[0096] 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;

[0097] Priority is given to

[0098] X and X' are independently selected from the group consisting of absence, a single bond, -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-;

[0099] Y is independently selected from -O-, -S-, -OC(R d1 )(R d2 )O-、-OC(R d1 )(R d2 )-、-OC(R d1 )(R d2 )OCO-、-OC(R d1 )(R d2 )OP=O[OC(R d1 )(R d2 )OR]2-;

[0100] L is independently selected from the group consisting of absence, a single bond, -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-;

[0101] X0, X1, X2, X3, X4 and X8 are independently selected from -CR5- or -N-;

[0102] 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 1-10Alkoxy, 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;

[0103] R is arbitrarily and independently selected from alkyl, alkenyl, alkynyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocycloalkyl, heterocyclyl, alkylacyl, cycloalkylacyl, haloalkylacyl, deuterated alkylacyl, heterocycloalkylacyl, heterocyclylacyl, hydroxyl, amino, substituted amino (disubstituted tertiary amine or trisubstituted quaternary amine), carboxyl, ester, amide, aminoacyl, substituted phosphonyl, or a combination of alkyl / alkenyl / alkynyl or the following structural groups:

[0104] The hydrogen on R is preferably optionally replaced by one or more selected from hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl and alkyl / alkenyl / alkynyl combination, oxo, CN, CF3, OH, OCH3, OCH2CH3, amino, substituted amino (disubstituted tertiary amine or trisubstituted quaternary amine), carboxyl, ester, amide, aminoacyl, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0105] 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, C3-10 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; and the hydrogen on R1 is preferably optionally replaced by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0106] 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 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 R2' 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;

[0107] 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;

[0108] Each R3, 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 C1-10 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;

[0109] 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, 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 C1-10 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;

[0110] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0111] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0112] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0113] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0114] t and q are arbitrarily selected from integers of 0, 1, 2, 3, 4 and 5.

[0115] 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):

[0116] in,

[0117] 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;

[0118] Priority is given to

[0119] X and X' are independently selected from the group consisting of absence, a single bond, -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-;

[0120] Y is independently selected from -O-, -S-, -OC(R d1 )(R d2 )O-、-OC(R d1 )(R d2 )-、-OC(R d1 )(R d2 )OCO-、-OC(R d1 )(R d2 )OP=O[OC(R d1 )(R d2 )OR]2-;

[0121] L is independently selected from the group consisting of absence, a single bond, -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-;

[0122] X5, X1, X2, X3, X4 and X8 are independently selected from -CR5- or -N-;

[0123] 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 1-10Alkoxy, 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;

[0124] R is arbitrarily and independently selected from alkyl, alkenyl, alkynyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocycloalkyl, heterocyclyl, alkylacyl, cycloalkylacyl, haloalkylacyl, deuterated alkylacyl, heterocycloalkylacyl, heterocyclylacyl, hydroxyl, amino, substituted amino (disubstituted tertiary amine or trisubstituted quaternary amine), carboxyl, ester, amide, aminoacyl, substituted phosphonyl, or a combination of alkyl / alkenyl / alkynyl or the following structural groups:

[0125] The hydrogen on R is preferably optionally replaced by one or more selected from hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl and alkyl / alkenyl / alkynyl combination, oxo, CN, CF3, OH, OCH3, OCH2CH3, amino, substituted amino (disubstituted tertiary amine or trisubstituted quaternary amine), carboxyl, ester, amide, aminoacyl, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0126] 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 2-10Heteroalkyl, 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 Alkyl substituted carboxyl or carboxyl surrogate; and the hydrogen on R1 is preferably optionally replaced by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0127] 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 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 3-6or 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;

[0128] 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;

[0129] Each R3, 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, C2-10 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;

[0130] 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, 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 3-10Heterocyclic 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;

[0131] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0132] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0133] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0134] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0135] t and q are arbitrarily selected from integers of 0, 1, 2, 3, 4 and 5.

[0136] 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 (IF),

[0137] wherein 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 spiro ring or a bridged ring structure;

[0138] Priority is given to

[0139] Y is independently selected from -O-, -S-, -OC(R d1 )(R d2 )O-、-OC(R d1 )(R d2 )-、-OC(R d1 )(R d2 )OCO-、-OC(R d1 )(R d2)OP=O[OC(R d1 )(R d2 )OR]2-;

[0140] Z is independently selected from the group consisting of absence, a single bond, -C(R d1 )(R d2 )-、-CH2 CH2-、-C(R d1 )(R d2 )CO-;

[0141] X1 and X8 are independently selected from -CR5- or -N-;

[0142] 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;

[0143] R is arbitrarily and independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocycloalkyl, heterocyclyl, alkylacyl, cycloalkylacyl, haloalkylacyl, deuterated alkylacyl, heterocycloalkylacyl, heterocyclylacyl, hydroxyl, amino, substituted amino (disubstituted tertiary amine or trisubstituted quaternary amine), carboxyl, ester, amide, aminoacyl, substituted phosphonyl, or a combination of alkyl / alkenyl / alkynyl or the following structural groups: The hydrogen on R is preferably optionally replaced by one or more selected from hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl and alkyl / alkenyl / alkynyl combination, oxo, CN, CF3, OH, OCH3, OCH2CH3, amino, substituted amino (disubstituted tertiary amine or trisubstituted quaternary amine), carboxyl, ester, amide, aminoacyl, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0144] 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; and the hydrogen on R1 is preferably optionally replaced by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0145] 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 1-10Alkyloxy, 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;

[0146] 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 C1-10 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;

[0147] Each R3, R5, R6, R7 may be 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, R6 or R7 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;

[0148] 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, 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;

[0149] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0150] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0151] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0152] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0153] t and q are arbitrarily selected from integers of 0, 1, 2, 3, 4 and 5.

[0154] 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 (1-IC),

[0155] wherein 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 spiro ring or a bridged ring structure;

[0156] Priority is given to

[0157] Y is independently selected from -O-, -S-, -OC(R d1 )(R d2 )O-、-OC(R d1 )(R d2 )-、-OC(R d1 )(R d2 )OCO-;

[0158] X1 and X8 are independently selected from -CR5- or -N-;

[0159] 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 3-10Saturated 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;

[0160] R is arbitrarily and independently selected from alkyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocycloalkyl, heterocyclyl, alkylacyl, cycloalkylacyl, haloalkylacyl, deuterated alkylacyl, heterocycloalkylacyl, heterocyclylacyl; and the hydrogen on R is preferably optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0161] 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: The hydrogen on R1 is preferably optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0162] R2, R 2' and R d1 、R d2the 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 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;

[0163] 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 3-10Heterocyclic 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;

[0164] Each of R3, R5, R6, R7 and R 7‘ may be 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 3-10or 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;

[0165] 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, 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, C3-10 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;

[0166] The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof;

[0167] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0168] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0169] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0170] t and q are arbitrarily selected from integers of 0, 1, 2, 3, 4 and 5.

[0171] According to an embodiment of the present invention, R is arbitrarily independently selected from alkyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocycloalkyl, heterocyclyl, alkylacyl, cycloalkylacyl, haloalkylacyl, deuterated alkylacyl, heterocycloalkylacyl, heterocyclylacyl; and the hydrogen on R is preferably optionally replaced by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0172] According to an embodiment of the present invention, 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: The hydrogen on R1 is preferably optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl group is substituted.

[0173] According to an embodiment of the present invention, ring A is selected from 5-10 membered heteroaryl or 5-10 membered heterocyclic group, such as 6 membered heteroaryl or 9-10 membered heterocyclic group, preferably pyridyl,

[0174] According to an embodiment of the present invention, ring A is selected from

[0175] According to an embodiment of the present invention, ring B is selected from 3-8 membered heterocyclic groups, such as 5-6 membered heterocyclic groups, preferably piperazinyl, According to an embodiment of the present invention,

[0176] Ring B is preferably selected from the following structures:

[0177] According to an embodiment of the present invention, X and X' are the same or different and are independently selected from the group consisting of absence, O, CH2, CD2; and D is deuterium.

[0178] According to an embodiment of the present invention, L is preferably selected from a single bond, O, S, NH, CH2, OCH2, CH2O;

[0179] According to an embodiment of the present invention, Y is selected from -O-, -S-, -OCH2O-, -OCH2-, -OCH2OC(O)-;

[0180] According to an embodiment of the present invention, R is selected from C 1-6 Alkyl-C(O)O-CH2-, (like ), Each R N may be the same or different and are independently selected from C 1-6 Alkyl, such as methyl; Z - Selected from anions, such as halogen anions (F - 、Cl - Br - , I - ).

[0181] According to an embodiment of the present invention, R0 is selected from H, unsubstituted or optionally substituted by one, two or more R 01 Substituted C 1-6 an alkyl group, such as a methyl group; each R 01may be the same or different and independently selected from H, unsubstituted or optionally substituted by one, two or more R 02 Substituted groups: 5-6 membered heteroaryl, 3-6 membered heterocyclic group, C 3-6 Cycloalkyl; each R 02 may be the same or different and independently selected from oxo (=O), C 1-6 Alkyl, C 3- 6-cycloalkyl-C 1-6 Alkyl, cyano C 1-6 alkyl;

[0182] According to an embodiment of the present invention, each R 01 may be the same or different and independently selected from H, unsubstituted or optionally substituted by one, two or more R 02 Substituted groups: imidazolyl, oxetanyl, cyclopropyl, tetrahydropyrrolyl, pyrazolyl;

[0183] According to an embodiment of the present invention, each R 02 They may be the same or different and independently selected from methyl, ethyl, isopropyl, oxo (=O), cyanomethyl, and cyclopropylmethyl.

[0184] According to an embodiment of the present invention, R0 is selected from the structure shown below:

[0185] methyl,

[0186] According to an embodiment of the present invention, each R3 is the same or different and is independently selected from H, C 1-6 Alkyl; for example, H or methyl.

[0187] According to an embodiment of the present invention, Selected from

[0188] According to an embodiment of the present invention, each R5 is selected from halogen, such as F.

[0189] According to an embodiment of the present invention, each R6 is the same or different and is independently selected from halogen (such as F or Cl), CN.

[0190] In one embodiment of the present invention, the above-mentioned compound or its pharmaceutically acceptable salt, or its corresponding isomer, isotope substitution, is a new compound selected from the structures disclosed in the embodiments of the present invention.

[0191] 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.

[0192] 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.

[0193] According to an embodiment of the present invention, the pharmaceutical composition is preferably administered orally.

[0194] The oral dosage form is not particularly limited and may be any oral dosage form known in the art, preferably tablets, capsules, suspensions or oral solutions, etc.

[0195] 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.

[0196] According to an embodiment of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0197] 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, heart failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, impaired glucose metabolism, impaired fasting blood glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, hyperlipoprotein B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, and addiction treatment (such as alcoholism and / or drug abuse).

[0198] 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 related to the GLP1 / GLP1R signaling pathway. The diseases related to the GLP1 / GLP1R signaling pathway are as defined above.

[0199] 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.

[0200] In some embodiments, the patient is a mammal, preferably a human.

[0201] Definition and Explanation:

[0202] 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 ;

[0203] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group, preferably a straight-chain or branched saturated hydrocarbon group (C 1-10 Alkyl). The alkyl group includes C 1-3 Alkyl, C 1-6 Alkyl, C 3-6 Alkyl, C 1-10 Alkyl, etc. "C 1-10 "Alkyl" means straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C 1-8 "Alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, "C 1-6The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0204] 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.

[0205] As used herein, the term "1 to a plurality of" means more than one, for example, 1, 2, 3, 4, 5 or more.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] The term "aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10aryl) such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl”), such as anthracenyl. When the C 6-20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the position of substitution, and for example, substitution may be at the ortho, para or meta position.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] The diagrammatic representations of racemic, ambiscalemic, scalemic, or enantiomerically pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise indicated, wedge-shaped and dashed bonds are used to represent the absolute configuration at a stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they are intended to include both E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are intended to be encompassed within the scope of this invention.

[0223] 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)-isomers, (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 such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0224] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one 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 (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by fractional crystallization or chromatography as is known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0225] The compounds of the present invention may contain unnatural proportions of atomic isotopes at 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( 14C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0230] 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.

[0231] Unless otherwise specified, all solvents used in the present invention are commercially available and do not require further purification when used. The reaction is usually carried out using anhydrous solvents under an inert atmosphere of nitrogen. Nuclear magnetic resonance spectra are measured on a Bruker-Avance-400 (400 MHz) spectrometer, and chemical shifts are reported in the form of δ (ppm). Mass spectrometry is performed using an Agilent 1200 series (plus 6110 / and 1956A) LC / MS or Shimadzu MS (DAD: SPD-M20A (LC)) and Shimadzu Micromass 2020 detector. The mass spectrometer is equipped with an electrospray ionization source (ESI) operating in positive and negative modes.

[0232] 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.

[0233] Compounds can be named manually or using The product is named after the manufacturer. If purchased commercially, the supplier's catalog name can also be used. TLC or LC-MS is usually used to determine whether the reaction is complete. DETAILED DESCRIPTION

[0234] 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.

[0235] Example 1. Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (pivaloyloxy)methyl ester (Compound 1):

[0236] 1) Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester:

[0237] 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-oxy)pyridin-2-yl)methoxy)benzonitrile (184 mg, 0.56 mmol), and potassium carbonate (176 mg, 1.27 mmol) in N,N-dimethylformamide (8 mL) was stirred at 60°C for 3 hours, quenched with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic layer was back-extracted with saturated brine (10 mL × 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 give (S)-methyl 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, yield: 33.5%). LC-MS m / z: 586 [M+H] + .

[0238] 2) Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (original compound 55*):

[0239] To a solution of (S)-methyl 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.17 mmol) in tetrahydrofuran / water (2 mL / 2 mL) was added lithium hydroxide (13 mg, 0.51 mmol), and the reaction was stirred at room temperature for 16 hours. The resulting mixture was adjusted to pH 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-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (56.80 mg, yield: 58.6%). LC-MS m / z: 572 [M+H] + .

[0240] 1 HNMR (400MHz, DMSO-d6): δ8.23(s,1H),7.88(dd,J=2.0Hz,11.6Hz,1H),7.80(dd,J=1.6,8.8Hz,1H),7.73(t,J=8.0Hz,1H),7.6 7(d,J=8.4Hz,1H),7.60(d,J=8.8Hz,1H),7.45(t,J=8.4Hz,1H),7.06(d,J=7.6Hz,1H),6.74(d,J=8.4Hz,1H),5.31(s,2H),5.1 0-5.08(m,1H),4.92-4.90(m,1H),4.80-4.74(m,1H),4.65-4.61(m,1H),4.50-4.47(m,1H),4.40-4.35(m,1H),3.93(d,J=13.6 Hz,1H),3.78(d,J=13.6Hz,1H),2.79-2.67(m,3H),2.51-2.41(m,1H),2.32-2.27(m,2H),1.92-1.89(m,2H)1.63-1.58(m,2H).

[0241] 3) Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (pivaloyloxy)methyl ester (Compound 1):

[0242] To a solution of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (50 mg, 0.087 mmol) in N,N-dimethylformamide (1 mL) was added iodomethyl pivalate (42 mg, 0.174 mmol) and potassium carbonate (36 mg, 0.26 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was purified by reverse phase flash chromatography under the following conditions: Column: spherical C18, 2 0-40 μm, 40 g; mobile phase A: pure water containing 0.1% formic acid; mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 30% B to 80% B over 20 minutes; detector: 214 nm. Fractions containing 57% mobile phase B were collected and concentrated under reduced pressure to yield (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (pivaloyloxy)methyl ester (17.56 mg, 0.026 mmol, yield: 9.2%), LCMS m / z: 686 [M+H]. + .

[0243] 1H NMR(400MHz, DMSO-d6)δ8.33(s,1H),7.88(dd,J=11.2Hz,2.0Hz,1H),7.82(dd,J=8.4Hz,1.6Hz,1H),7.75-7.65(m,3H),7.45( t,J=8.4Hz,1H),7.06(d,J=7.2Hz,1H),6.74(d,J=8.0Hz,1H),6.01-5.97(m,2H),5.31(s,2H),5.10-5.07(m,1H),4.92-4.90(m ,1H),4.84-4.78(m,1H),4.66(dd,J=15.2Hz,2.4Hz,1H),4.51-4.47(m,1H),4.38-4.36(m,1H),3.95(d,J=13.6Hz,1H),3.79( d,J=13.6Hz,1H),2.78-2.67(m,3H),2.46-2043(m,1H),2.32-2.27(m,2H),1.90-1.88(m,2H),1.62-1.58(m,2H),1.16(s,9H).

[0244] 19 F NMR(377MHz,DMSO-d6)δ-132.41

[0245] Example 2. Synthesis of (R)-4-(((2-((4-((6-((4-cyano-2-fluorophenoxy)methyl-d2)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate)oxy)methoxy)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium (Compound 2):

[0246] 1) Synthesis of compound (S)-2-((4-((6-((4-nitrile-2-fluorophenoxy)methyl-d2)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid chloromethyl ester

[0247] To a solution of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl-d2)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (700 mg, 1.22 mmol) in dichloromethane (10 mL) and H2O (10 mL) was added sodium bicarbonate (379 mg, 4.51 mmol) and TBAHS (221 mg, 0.12 mmol) at room temperature. The mixture was stirred at room temperature for 5 minutes. A solution of chloromethylsulfonyl chloride (221 mg, 1.34 mmol) in dichloromethane (10 mL) was added at room temperature, and stirring was continued at room temperature for 2 hours. The reaction mixture was poured into water (60 mL) and extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated aqueous sodium bicarbonate (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 3 / 1) to give compound (S)-chloromethyl 2-((4-((6-((4-nitrile-2-fluorophenoxy)methyl-d2)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (530 mg, 0.85 mmol, yield: 69.9%), LCMS m / z: 622 [M+H]. +

[0248] 2) Synthesis of (R)-4-(((2-((4-((6-((4-cyano-2-fluorophenoxy)methyl-d2)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate)oxy)methoxy)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium

[0249] At room temperature, (R)-3-hydroxy-4-(trimethylamino)butyrate (644 mg, 4.00 mmol) was added to a solution of S)-2-((4-((6-((4-nitrile-2-fluorophenoxy)methyl-d2)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid chloromethyl ester (500 mg, 0.80 mmol) in dry acetonitrile (10 mL), and the mixture was heated at 80°C with stirring for 3 hours. The mixed reaction solution was purified by high performance liquid chromatography (chromatographic column: Spherical C18, 20-10mmol / L): spherical C18, 20-40um, 330g; mobile phase A: water (0.1% FA); mobile phase B: acetonitrile; flow rate: 120mL / min; gradient: 5%B-95%B, 30 minutes; detector: 214nm) purification, when the content of mobile phase B reached 31%, the fractions containing the product were collected and concentrated under reduced pressure to obtain compound (R)-4-(((2-( (4-((6-((4-cyano-2-fluorophenoxy)methyl-d2)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate)oxy)methoxy)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium (66.68 mg, 0.09 mmol, yield: 11.3%), LCMS m / z: 747 [M+H] + .

[0250] 1 H NMR(400MHz,DMSO-d6)δ8.43(s,1H),7.92-7.87(m,2H),7.85-7.83(m,1H),7.85-7.83(m,1H),7.81-7.77(m,1H),7.69-7 .67(m,1H),7.45(t,J=8.4Hz,8.8Hz,1H),7.13(d,J=7.2Hz,1H),6.81(d,J=8.4Hz,1H),6.02(q,J=6.0Hz,12.0Hz,2H),5. 81(d,J=4.0Hz,1H),5.14(s,1H),5.04-5.02(m,1H),4.86-4.80(m,2H),4.69(d,J=13.2Hz,1H),4.52-4.47(m,2H),4.37- 4.32(m,1H),3.39-3.30(m,6H),3.13(s,9H),2.75-2.54(m,4H),2.36-2.32(m,1H),2.15-2.14(m,2H),1.99-1.94(m,2H).

[0251] 19 F NMR(377MHz,DMSO-d6)δ-73.574,-132.307.

[0252] Example 3. Synthesis of (R)-4-(((2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carbonyl)oxy)methoxy)-2-hydroxy-N,N,N-trimethyl-4-oxobutane-1-ammonium (Compound 3):

[0253] 1) Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid chloromethyl ester

[0254] To a solution of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid (500 mg, 0.874 mmol) in dichloromethane (10 mL) and water (10 mL) at room temperature were added sodium bicarbonate (293 mg, 3.5 mmol) and tetrabutylammonium hydrogen sulfate (30 mg, 0.0874 mmol). The mixture was stirred at room temperature for 5 minutes, and then a solution of chloromethyl chloride sulfinate (158 mg, 0.962 mmol) dissolved in dichloromethane (10 mL) was slowly added dropwise, and stirred at room temperature for 2 hours. The mixed reaction solution was quenched with saturated aqueous ammonium chloride (5 mL) and extracted with dichloromethane (50 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 1 / 4) to give compound (S)-chloromethyl 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (400 mg, 0.645 mmol, yield: 73.8%), LCMS m / z: 620 [M+H]. +

[0255] 2) Synthesis of (R)-4-(((2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carbonyl)oxy)methoxy)-2-hydroxy-N,N,N-trimethyl-4-oxobutane-1-ammonium

[0256] To a solution of (S)-chloromethyl 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (400 mg, 0.645 mmol) in acetonitrile (10 mL) at room temperature was added (R)-3-hydroxy-4-(trimethylamino)butyrate (519 mg, 3.23 mmol). The mixture was heated at 80°C with stirring for 3 hours under nitrogen protection. The mixed reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography (chromatographic column: spherical C18, 20-40 μm, 330 g; mobile phase A: water (0.1% FA); mobile phase B: acetonitrile; flow rate: 120 mL / min; flow rate: 120 mL / min; gradient: 5% B-95% B, 30 minutes; detector: 214 nm). When the content of mobile phase B reached 30%, the fractions containing the desired product were collected and concentrated under reduced pressure to obtain compound ( R)-4-(((2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carbonyl)oxy)methoxy)-2-hydroxy-N,N,N-trimethyl-4-oxobutane-1-aminium (82.7 mg, 0.11 mmol, yield: 17.2%), LCMS m / z: 746 [M+H] + .

[0257] 1H NMR (400MHz, DMSO-d6) δ8.34 (s, 1H), 7.87-7.72 (m, 2H), 7.71-7.66 (m, 3H), 7.45 (t, J = 8.8Hz, 1H), 7.06(d,J=7.2Hz,1H),6.73(d,J=8.4Hz,1H),6.03-5.99(m,2H),5.31(s,2H),5.10-5 .08(m,1H),4.91-4.79(m,2H),4.68-4.65(m,1H),4.53-4.47(m,2H),4.39-4.34(m,1 H),3.98-3.94(m,1H),3.81-3.78(m,1H),3.48-3.23(m,3H),3.14(s,9H),2.79-2.55 (m,5H),2.48-2.41(m,1H),2.39-2.30(m,2H),1.90-1.88(m,2H),1.65-1.56(m,2H).

[0258] 19 F NMR(377MHz,DMSO-d6)δ-132.378.

[0259] Example 4. Synthesis of (R)-4-(((2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carbonyl)oxy)methoxy)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium (Compound 4):

[0260] 1) Synthesis of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid chloromethyl ester

[0261] To a solution of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (1.00 g, 1.72 mmol) in dichloromethane (20 mL) and water (20 mL) was added chloromethyl chloride sulfinate (312 mg, 1.89 mmol), sodium bicarbonate (549 mg, 6.54 mmol), and tetrabutylammonium hydrogen sulfate (58 mg, 0.17 mmol) at room temperature and stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL) and extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 1 / 4) to give compound (S)-chloromethyl 2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (680 mg, 1.08 mmol, yield: 62.96%), LCMS m / z: 629 [M+H]. +

[0262] 2) Synthesis of (R)-4-(((2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carbonyl)oxy)methoxy)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium

[0263] To a solution of (S)-chloromethyl 2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (680 mg, 1.08 mmol) in acetonitrile (20 mL) was added (R)-3-hydroxy-4-(trimethylamino)butyrate (1.74 g, 10.80 mmol) at room temperature, and the mixture was heated at 70°C with stirring under nitrogen for 4 hours. The mixed reaction solution was concentrated under reduced pressure and purified by reverse phase flash column chromatography (chromatographic conditions: chromatographic column: spherical C18, 20-40 μm, 330 g; mobile phase A: water (0.1% FA); mobile phase B: acetonitrile; flow rate: 120 mL / min; gradient: 5% B to 50% B in 12 min; detector: 254 nm). When the content of mobile phase B reached 17.5%, the fractions containing the product were collected and concentrated under reduced pressure to obtain compound (R)-4-(((2-((4-((6-((4- (chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carbonyl)oxy)methoxy)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium (178.6 mg, 0.24 mmol, yield: 21.94%), LCMS m / z: 754 [M+H] + .

[0264] 1 H NMR (400MHz, DMSO-d6) δ8.34(s,1H),7.84-7.82(m,1H),7.74-7.70(m,2H),7.46-7.43(m,1H),7.28(t,J=8.8Hz,1H),7.20- 7.17(m,1H),7.05(d,J=7.6Hz,1H),6.72(d,J=8.4Hz,1H),6.03-5.99(m,2H),5.18(s,2H),5.12-5.06(m,1H),4.97-4.91(m, 1H),4.84-4.79(m,1H),4.69-4.64(m,1H),4.53-4.47(m,2H),4.39-4.34(m,1H),3.98-3.94(m,1H),3.81-3.78(m,1H),3.4 4-3.41(m,3H),3.13(s,9H),2.81-2.55(m,5H),2.48-2.41(m,1H),2.35-2.30(m,2H),1.93-1.90(m,2H),1.65-1.56(m,2H).

[0265] 19 F NMR(377MHz,DMSO-d6)δ-131.370.

[0266] Example 5. Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (isobutyryloxy)methyl ester (Compound 5):

[0267] To a solution of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (500 mg, 0.87 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (360 mg, 2.61 mmol) and chloromethyl isobutyrate (596 mg, 4 0.35 mmol) and stirred at room temperature for 16 hours. The mixed reaction solution was then subjected to reverse-phase flash chromatography (chromatographic column: spherical C18, 20-100 mmol / L): spherical C18, 20-40 μm, 120 g; mobile phase A: water (0.1% NH3.H2O); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 5.0 equation: 80 mL / min; gradient: 60% B to 95% B over 30 minutes; detector: 214 nm). When the content of mobile B reached 75%, the product was collected and concentrated under reduced pressure to give (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (isobutyryloxy)methyl ester (402.00 mg, 0.60 mmol, yield: 68.5%), LCMS m / z: 672 [M+H] + .

[0268] 1H NMR (400MHz, DMSO-d6) δ8.33 (s, 1H), 7.88 (dd, J = 11.2Hz, 1.6Hz, 1H), 7.83-7.81 (m, 1H), 7.75-7.70 (m, 2H), 7.68-7.65 (m, 1H), 7. 45(t,J=8.4Hz,1H),7.06(d,J=7.2Hz,1H),6.74(d,J=8.4Hz,1H),6.00-5.97(m,2H),5.31(s,2H),5.10-5.08(m,1H),4.93-4.89( m,1H),4.84-4.78(m,1H),4.68-4.64(m,1H),4.52-4.47(m,1H),4.39-4.34(m,1H),3.97-3.77(m,2H),2.79-2.76(m,1H),2.74-2 .67(m,2H),2.66-2.59(m,1H),2.46-2.41(m,1H),2.33-2.27(m,2H),1.91-1.89(m,2H),1.62-1.58(m,2H),1.10(d,J=7.2Hz,6H).

[0269] 19 F NMR(377MHz,DMSO-d6)δ-132.37.

[0270] Example 6. Synthesis of (S)-(pivaloyloxy)methyl 2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Compound 6):

[0271] To a solution of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 49#) (200 mg, 0.34 mmol) in N,N-dimethylformamide (5 mL) were added potassium carbonate (141 mg, 1.02 mmol) and chloromethyl pivalate (257 mg, 1.70 mmol) at room temperature, and the reaction was stirred at room temperature for 16 hours. The mixed reaction solution was subjected to reverse phase flash chromatography (chromatographic column: spherical C18, 20-100 mmol / L): spherical C18, 20-40 um, 120 g; mobile phase A: water (0.1% NH3.H2O); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 5.0 equation: 80 mL / min; gradient: 60% B-95% B, 30 minutes; detector: 214 nm). When the content of mobile B reached 86%, the product was collected and concentrated under reduced pressure to give (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (pivaloyloxy)methyl ester (154.48 mg, 0.22 mmol, yield: 64.7%), LCMS m / z: 695 [M+H] + .

[0272] 1 H NMR (400MHz, DMSO-d6) δ8.33(d,J=1.2Hz,1H),7.82(dd,J=8.4Hz,1.6Hz,1H),7.74-7.00(m,2H),7.45(dd,J=10.8Hz,2.4Hz,1H), 7.28(t,J=8.8Hz,1H),7.20-7.17(m,1H),7.04(d,J=6.8Hz,1H),6.72(d,J=8.0Hz,1H),6.01-5.97(m,2H),5.18(s,2H),5.10-5.08 (m,1H),4.95-4.93(m,1H),4.84-4.78(m,1H),4.69-4.64(m,1H),4.50-4.49(m,1H),4.38-4.36(m,1H),3.96(d,J=13.6Hz,1H),3 .79(d,J=13.6Hz,1H),2.78-2.67(m,3H),2.46-2.43(m,1H),2.33-2.32(m,2H),1.92-1.90(m,2H),1.63-1.59(m,2H),1.16(s,9H)

[0273] 19 F NMR(377MHz,DMSO-d6)δ-131.38.

[0274] Example 7. Synthesis of (S)-(isobutyryloxy)methyl 2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Compound 7):

[0275] At room temperature, (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (400 mg, 0.69 mmol) was dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (286 mg, 2.07 mmol) and chloromethyl isobutyrate (473 mg, 3.45 mmol) were added, and the reaction was stirred at room temperature for 16 hours. The mixed reaction mixture was filtered and analyzed by reverse flash column chromatography (chromatographic column: spherical C18, 20-100 mmol / L): spherical C18, 20-40 um, 120 g; mobile phase A: water (0.1% NH3.H2O); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 5.0 equation: 80 mL / min; gradient: 60% B-95% B, 30 minutes; detector: 214 nm). At 86% B concentration, the fractions containing the desired product were collected and concentrated under reduced pressure to give ((S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid isobutyryloxy)methyl ester (336.90 mg, 0.49 mmol, yield: 71.7%), LCMS: m / z: 681 [M+H] + .

[0276] 1H NMR (400MHz, DMSO-d6) δ8.33(d,J=1.2Hz,1H),7.82(dd,J=1.2Hz,8.4Hz,1H),7.74-7.70(m,2H),7.45(dd,J=2.4Hz,11.2Hz,1H),7.30-7.25(m ,1H),7.20-7.17(m,1H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.4Hz,1H),5.98(dd,J=6.0Hz,8.4Hz,2H),5.18(s,2H),5.09(dd,J=2.4Hz,6.8Hz,1 H),4.96–4.92(m,1H),4.84-4.78(m,1H),4.69-4.65(m,1H),4.51-4.49(m,1H),4.38-4.35(m,1H),3.87(dd,J=13.6Hz,66.0Hz,1H),2.80-2.7 6(m,1H),2.71–2.67(m,2H),2.64–2.60(m,1H),2.46–2.41(m,1H),2.33 –2.32(m,2H),1.92–1.90(m,2H),1.63–1.61(m,2H),1.11-1.09(m,6H).

[0277] 19 F NMR(377MHz,DMSO-d6)δ-131.387.

[0278] Example 8. Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl-d2)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (isobutyryloxy)methyl ester (Compound 8):

[0279] To a solution of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl-d2)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (500 mg, 0.87 mmol) and potassium carbonate (240 mg, 1.74 mmol) in N,N-dimethylformamide (5 mL) was added chloromethyl isobutyrate (179 mg, 1.31 mmol) at 0°C. The mixture was stirred at 0°C for 2 hours under argon. The reaction mixture was diluted with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (chromatographic conditions: spherical C18, 20-40 μm, 120 g; mobile phase A: water (0.1% NH 3 .H 2 O); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 20% B to 80% B in 25 minutes; detector: 214 nm). At 80% B, the fractions containing the desired product were collected and concentrated under reduced pressure to give (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl-d 2 )pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (isobutyryloxy)methyl ester (317.93 mg, 0.47 mmol, yield: 54.1%), LCMS m / z: 674 [M+H] + .

[0280] 1 H NMR (400MHz, DMSO-d6) δ8.32(s,1H),7.89-7.80(m,2H),7.75-7.65(m,3H),7.45(t,J=8.4Hz,1H),7.06(d,J=7 .2Hz,1H),6.74(d,J=8.4Hz,1H),6.00-5.97(m,2H),5.09-5.08(m,1H),4.93-4.89(m,1H),4.84-4.78(m,1H),4 .68-4.67(m,1H),4.52-4.47(m,1H),4.39-4.34(m,1H),3.95(d,J=13.6Hz,1H),3.79(d,J=14.0Hz,1H),2.85-2 .55(m,4H),2.49-2.38(m,1H),2.36-2.24(m,2H),1.95-1.84(m,2H),1.67-1.54(m,2H),1.10(d,J=6.8Hz,6H).

[0281] 19 F NMR(377MHz,DMSO-d6)δ-132.42.

[0282] Example 9. Synthesis of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (5-methyl-2-oxo-1,3-dioxo-4-yl)methyl ester (Compound 9):

[0283] To a solution of (S)-2-((4-(((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl-1-(oxetan-2-ylmethyl)-1-(2-ylmethyl)-1-benzo[d]imidazole-6-carboxylic acid (800 mg, 1.38 mmol) in DMA (10 mL) was added 4-(chloromethyl)-5-methyl-13-dioxol-2-one (613 mg, 4.14 mmol) and KCO (571 mg, 4.14 mmol) at room temperature. The mixture was stirred at room temperature for 16 h, and the residue was purified by reverse phase flash chromatography (conditions as follows: column: spherical C18, 20-4 0 μm, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 5% B to 100% B in 20 minutes; detector: 214 nm. ) Purification. At 75% B, fractions containing the desired product were collected and concentrated under reduced pressure to give (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (790.29 mg, 1.14 mmol, yield: 82.79%), LCMS m / z: 693 [M+H]. +

[0284] 1H NMR (400MHz, DMSO-d6) δ8.32(d,J=1.2Hz,1H),7.83(dd,J=8.4,1.6Hz,1H),7.74-7.67(m,2H),7.45(dd,J=11.2,2.4Hz,1H),7.28 (t,J=9.2Hz,1H),7.21-7.16(m,1H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.4Hz,1H),5.24(s,2H),5.18(s,2H),5.12-5.05(m,1H),4. 99-4.90(m,1H),4.86-4.78(m,1H),4.66(dd,J=15.2,2.4Hz,1H),4.56-4.45(m,1H),4.41-4.33(m,1H),3.96(d,J=13.6Hz,1H),3. 79(d,J=13.6Hz,1H),2.84-2.66(m,3H),2.47-2.40(m,1H),2.37-2.27(m,2H),2.24(s,3H),1.97-1.86(m,2H),1.69-1.56(m,2H).

[0285] 19 F NMR(377MHz,DMSO-d6)δ-131.372.

[0286] Example 10. Synthesis of methyl (5-methyl-2-oxo-1,3-dioxol-4-yl)-2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Compound 10):

[0287] 1) Synthesis of 2-bromo-1-(4-chloro-2-fluorophenyl)ethan-1-one:

[0288] To a solution of 1-(4-chloro-2-fluorophenyl)ethan-1-one (20.00 g, 115.61 mmol) in acetonitrile (500 mL) at room temperature were added p-toluenesulfonic acid monohydrate (32.95 g, 173.42 mmol) and NBS (20.58 g, 115.61 mmol). The mixture was heated at 80°C under a nitrogen atmosphere and stirred for 6 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel (PE / EA = 10 / 1) column chromatography to give 2-bromo-1-(4-chloro-2-fluorophenyl)ethan-1-one (26.00 g, 103.59 mmol, yield: 89.6%). LCMS not shown.

[0289] 1 H NMR (400MHz, DMSO-d6): δ7.95 (t, J = 8.4 Hz, 1H), 7.69-7.66 (m, 1H), 7.49-7.47 (m, 1H), 4.84 (d, J = 2.0 Hz, 2H).

[0290] 2) Synthesis of 2-(3-bromo-2-iodophenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-one

[0291] To a solution of 2-bromo-1-(4-chloro-2-fluorophenyl)ethan-1-one (28.00 g, 111.55 mmol) in acetone (300 mL) was added 3-bromo-2-iodophenol (33.35 g, 111.55 mmol) and anhydrous potassium carbonate (30.79 mg, 223.10 mmol) at room temperature. The mixture was heated at 60°C and stirred for 3 hours under a nitrogen atmosphere. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel (PE / EA=15 / 1) column chromatography to give 2-(3-bromo-2-iodophenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-one (33.00, 70.36 mmol, yield: 63.0%), LCMS m / z: 471 [M+H+2]. + .

[0292] 3) Synthesis of (S)-2-(3-bromo-2-iodophenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-ol

[0293] To a solution of RuCl(p-cymene)[(S,S)-Ts-DPEN] (1.63 g, 2.56 mmol) in TEA (120 mL) at room temperature was added formic acid (12 mL). The mixture was stirred at room temperature for 1 hour, followed by the addition of 2-(3-bromo-2-iodophenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-one (12 g, 25.59 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate (300 mL), washed with anhydrous sodium carbonate (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel (PE:EA = 10:1) column chromatography to provide (S)-2-(3-bromo-2-iodophenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-ol (11.00 g, 23.35 mmol, yield: 91.2%).

[0294] 1H NMR (400MHz, DMSO-d6): δ7.70(t,J=8.4Hz,1H),7.40-7.37(m,1H),7.34-7.25(m,3H) ,6.99-6.97(m,1H),5.89(t,J=4.8Hz,1H),5.23(t,J=4.8Hz,1H),4.23-4.13(m,2H).

[0295] 4) Synthesis of (S)-8-bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin

[0296] To a solution of (S)-2-(3-bromo-2-iodophenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-ol (11.00 g, 23.35 mmol) in toluene (110 mL) were added CuI (447 mg, 2.34 mmol), anhydrous cesium carbonate (22.84 g, 70.05 mmol), and 1,10-phenanthroline (1.26 g, 7.01 mmol) at room temperature. The mixture was stirred at 120°C under a nitrogen atmosphere for 16 hours. The mixed reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to afford (S)-8-bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin (6.10 g, 17.73 mmol, yield: 75.9%).

[0297] 1 H NMR (400MHz, DMSO-d6): δ7.59-7.53(m,2H),7.44-7.41(m,1H),7.21-7.19(m,1H),6.99(d,J =1.2Hz,1H),6.86(t,J=8.0Hz,1H),5.60-5.58(m,1H),4.54-4.50(m,1H),4.23-4.18(m,1H).

[0298] 5) Preparation of tert-butyl (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0299] To a solution of (S)-8-bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin (6.32 g, 18.37 mmol) in dioxane (60 mL) and water (6 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5.68 g, 18.37 mmol), anhydrous sodium carbonate (3.82 g, 36.74 mmol), and Pd(dppf)Cl2 (1.35 g, 1.84 mmol) at room temperature. The mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel (PE / EA=10 / 1) column chromatography to give (S)-tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.10 g, 6.95 mmol, yield: 37.8%), LCMS m / z: 390 [M+H-56] + .

[0300] 6) Synthesis of tert-butyl (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate

[0301] To a solution of tert-butyl (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (4.00 g, 8.97 mmol) in THF (60 mL) was added Pd / C (4.00 g, 5% Pd on Carbon, wetted with ca. 55% water) at room temperature. The mixture was stirred under a hydrogen atmosphere for 3 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel (PE / EA=10 / 1) column chromatography to give (S)-tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate (2.60 g, 5.80 mmol, yield: 64.6%), LCMS m / z: 392 [M-56+H] + .

[0302] 7) Synthesis of (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine

[0303] To a solution of tert-butyl (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate (1.00 g, 2.23 mmol) in DCM (10 mL) was added TFA (2 mL) and stirred at room temperature for 2 hours. The mixture was concentrated to give a colorless oily crude compound (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine (777 mg, 2.23 mmol, yield: >99%), LCMS m / z: 348 [M+H] + .

[0304] 8) Synthesis of methyl 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0305] To a solution of (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine (777 mg, 2.23 mmol) in acetonitrile (10 mL) were added (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (988 mg, 3.35 mmol) and DIEA (1.44 g, 11.15 mmol) at room temperature, and the mixture was stirred with heating at 60°C for 2 hours. The mixed reaction solution was purified by reverse phase flash column chromatography (chromatographic column: spherical C18, 20-40 μm, 40 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 5% B to 50% B in 15 minutes; detector: 214 nm). At 40% B, the fractions containing the product were collected and concentrated under reduced pressure to give methyl 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (1.20 g, 1.98 mmol, yield: 88.8%), LCMS m / z: 606 [M+H] + .

[0306] 9) Synthesis of 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0307] To a solution of methyl 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (1.20 g, 1.98 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was added LiOH (475 mg, 19.80 mmol) and stirred at room temperature for 6 hours. The residue was purified by reverse phase flash column chromatography (column: spherical C18, 20-40 μm, 40 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 5% B to 80% B over 20 minutes; detector: 214 nm). At 36% B, the fractions containing the product were collected and concentrated under reduced pressure to give 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (808 mg, 1.36 mmol, yield 69.0%), LCMS m / z: 592 [M+H] + .

[0308] 1 H NMR (400MHz, DMSO-d6): δ8.26 (d, J = 1.2Hz, 1H), 7.81-7.78 (m, 1H), 7.64-7.51 (m, 3H), 7.44-7.42 (m, 1H), 6.86-6. 77(m,3H),5.48-5.46(m,1H),5.10-5.04(m,1H),4.81-4.76(m,1H),4.66-4.62(m,1H),4.50-4.42(m,2H),4.38-4 .33(m,1H),4.13-4.08(m,1H),3.91(d,J=13.6Hz,1H),3.78(d,J=13.6Hz,1H),2.98(d,J=11.6Hz,1H),2.85(d,J= 10.4Hz,2H),2.72-2.64(m,1H),2.44-2.33(m,1H),2.24-2.10(m,2H),,1.80(d,J=11.6Hz,1H),1.69-1.58(m,3H).

[0309] 19 F NMR (377MHz, DMSO-d6): δ-115.07.

[0310] 10) Synthesis of the compound (5-methyl-2-oxo-1,3-dioxol-4-yl)-2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

[0311] To a solution of 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (777 mg, 1.31 mmol) in DMF (5 mL) at room temperature were added 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (586 mg, 3.93 mmol) and DIEA (845 mg, 6.55 mmol), and the mixture was heated at 50°C with stirring under a nitrogen atmosphere for 2 hours. The mixed reaction solution was purified by reverse phase flash column chromatography (chromatographic column: spherical C18, 20-40 μm, 120 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B-80% B in 40 minutes; detector: 214 nm). At 86% B, the fractions containing the product were collected and concentrated under reduced pressure to give (5-methyl-2-oxo-1,3-dioxol-4-yl)-2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (748.05 mg, 1.06 mmol, yield: 81%), LCMS m / z: 704 [M+H] + .

[0312] 1H NMR (400MHz, DMSO-d6): δ8.31(d,J=1.2Hz,1H),7.84-7.81(m,1H),7.69(d,J=8.8Hz,1H),7.59-7.51(m,2H),7.44-7.41 (m,1H),6.86-6.77(m,3H),5.48-5.24(m,1H),5.10(s,2H),5.08-5.04(m,1H),4.68-4.63(m,1H),4.50-4.22(m,2H),4. 37-4.32(m,1H),4.13-4.08(m,1H),3.92(d,J=13.6Hz,1H),3.79(d,J=13.6Hz,1H),2.98(d,J=11.2Hz,1H),2.84(d,J=1 0.0Hz,2H),2.72-2.64(m,1H),2.51-2.39(m,1H),2.19(s,3H),2.11-1.81(m,2H),1.78-1.67(m,1H),1.64-1.58(m,3H).

[0313] 19 F NMR (377MHz, DMSO-d6): δ-115.07.

[0314] Example 11. Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Compound 11):

[0315] 1) Synthesis of tert-butyl (S)-4-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidine-1-carboxylate

[0316] To a solution of tert-butyl (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidine-1-carboxylate (1.1 g, 2.45 mmol) in DMA (20 mL) were added K4Fe(CN)6·3H2O (3.1 g, 7.36 mmol), Na2CO3 (780 mg, 7.36 mmol), and Xphos Pd G3 (103 mg, 0.12 mmol). The mixture was heated at 120°C and stirred under nitrogen for 16 hours. The resulting reaction mixture was diluted with saturated NH4Cl (50 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=1 / 1) to give (S)-tert-butyl 4-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidine-1-carboxylate (700 mg, 1.6 mmol, yield: 65%), LCMS m / z: 424 [M-56+ACN] + .

[0317] 2) Synthesis of (S)-3-fluoro-4-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dihydroxy-2-yl)benzonitrile p-toluenesulfonate

[0318] To a solution of tert-butyl (S)-4-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidine-1-carboxylate (700 mg, 1.6 mmol) in EA (15 mL) was added TsOH (608 mg, 3.2 mmol) at room temperature and stirred at 30°C for 16 hours. The resulting mixture was diluted with saturated NaHCO₃ (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford (S)-3-fluoro-4-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dihydroxy-2-yl)benzonitrile p-toluenesulfonate (650 mg, crude), which was used directly in the next step without further purification. LCMS m / z: 339 [M+H] + .

[0319] 3) Synthesis of methyl 2-((4-(((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidin-1-yl)methyl)-1-((((S)-oxetane-2-yl)methyl]-1H-benzo[d]imidazole-6-carboxylate

[0320] To a solution of (S)-3-fluoro-4-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dihydroxy-2-yl)benzonitrile p-toluenesulfonate (650 mg, 1.92 mmol) in ACN (10 mL) was added (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (567 mg, 1.92 mmol) and DIEA (495 mg, 3.84 mmol) at room temperature. The mixture was heated at 60°C with stirring for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=1 / 3) to give methyl 2-((4-(((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidin-1-yl)methyl)-1-((((S)-oxetan-2-yl)methyl]-1H-benzo[d]imidazole-6-carboxylate (700 mg, 1.17 mmol, yield 90%), LCMS m / z: 597 [M+H] +

[0321] 4) Synthesis of 2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0322] To a solution of methyl 2-((4-(((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidin-1-yl)methyl)-1-((((S)-oxetane-2-yl)methyl]-1H-benzo[d]imidazole-6-carboxylate (700 mg, 1.17 mmol) in THF (10 mL) and H2O (5 mL) was added a solution of LiOH (140 mg, 5.86 mmol) and stirred at room temperature for 16 hours. The mixture reaction solution was adjusted to pH 7 with acetic acid and extracted with EA (50 mL×3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue The product was purified by reverse phase column chromatography (column: spherical C18, 20-40 μm, 120 g; mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 5% B to 100% B, 15 minutes; detector: 254 nm). At 45% B, fractions containing the product were collected and concentrated under reduced pressure to give 2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (450 mg, 0.77 mmol, yield: 65.88%), LCMS m / z: 583 [M+H] + .

[0323] 1 H NMR (400MHz, DMSO-d6) δ8.27(s,1H),7.98(d,J=10.8Hz,1H),7.81(d,J=8.4Hz,1H),7.76–7.68(m,2 H),7.63(d,J=8.4Hz,1H),6.85–6.68(m,3H),5.15–5.04(m,1H),4.83–4.74(m,1H),4.70–4.62(m,1 H),4.53–4.45(m,1H),4.39–4.31(m,1H),3.96(d,J=13.2Hz,1H),3.78(d,J=13.2Hz,1H),3.06–2.9 7(m,1H),2.90–2.82(m,1H),2.76–2.60(m,3H),2.32–2.14(m,2H),2.05(s,3H),1.81–1.59(m,4H).

[0324] 19 F NMR(377MHz,DMSO-d6)δ-111.083.

[0325] 5) Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0326] To a solution of 2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (800 mg, 1.37 mmol) in DMF (10 mL) were added 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (612 mg, 4.11 mmol) and DIEA (530 mg, 4.11 mol) at room temperature, and the mixture was heated at 50°C with stirring for 2 hours. The mixed reaction solution was purified by reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40 μm, 80 g; mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B to 100% B, 15 min; detector: 254 nm). Fractions containing the product were collected at 40% B and concentrated under reduced pressure to give 2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (521 mg, 0.75 mmol, yield: 54.66%). LCMS m / z:695[M+H] +

[0327] 1H NMR(400MHz, DMSO-d6)δ8.33(s,1H),7.98(d,J=11.2Hz,1H),7.86–7.80(m,1H),7.77–7.65(m,3H),6.8 7–6.72(m,3H),5.24(s,2H),5.14–5.06(m,1H),4.89–4.78(m,1H),4.74–4.63(m,1H),4.52–4.44(m,1H ),4.40–4.31(m,1H),3.98(d,J=13.6Hz,1H),3.79(d,J=13.6Hz,1H),3.02(d,J=11.6Hz,1H),2.86(d,J =10.8Hz,1H),2.77–2.64(m,2H),2.47–2.41(m,1H),2.29–2.14(m,5H),2.05(s,3H),1.85–1.64(m,4H).

[0328] 19 F NMR(377MHz,DMSO-d6)δ-111.084.

[0329] Example 12, Synthesis of (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (5-methyl-2-oxo-1,3-dioxo-4-yl)methyl ester (Compound 12):

[0330] 1) Synthesis of 3-(((6-bromopyridin-2-yl)oxy)methyl)-4-fluorobenzonitrile

[0331] To a solution of 2-bromo-6-fluoropyridine (10.00 g, 56.82 mmol) in DMF (200 mL) were added 4-fluoro-3-(hydroxymethyl)benzonitrile (8.58 g, 56.82 mmol) and K2CO3 (15.68 g, 113.64 mmol), and the mixture was heated at 70°C with stirring for 16 hours. The mixed reaction solution was diluted with ethyl acetate (300 mL) and washed with saline (200 mL x 3). 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 3-(((6-bromopyridin-2-yl)oxy)methyl)-4-fluorobenzonitrile (10.7 g, 34.85 mmol, yield: 61.3%), LCMS m / z: 307 [M+H]. +

[0332] 2) Synthesis of tert-butyl 6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate

[0333] To a solution of 3-(((6-bromopyridin-2-yl)oxy)methyl)-4-fluorobenzonitrile (4.57 g, 14.89 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5.98 g, 19.36 mmol) in 1,4-dioxane (110 mL) and H2O (11 mL) was added K2CO3 (4.11 g, 29.78 mmol) and Pd(dppf)Cl2·CH2Cl2 (0.60 g, 0.74 mmol) at room temperature. The mixture was heated at 90°C with stirring under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with saturated brine (100 mL x 3). 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=4:1) to give tert-butyl 6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (5.33 g, 13.03 mmol, yield 87.5%), LCMS m / z: 410 [M+H] +

[0334] 3) Synthesis of 3-fluoro-4-(((1',2',3',6'-tetrahydro-[2,4'-bipyridyl]-6-yl)oxy)methyl)benzonitrile

[0335] At room temperature, trifluoroacetic acid (13 mL) was added to a solution of tert-butyl 6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylate (5.33 g, 13.03 mmol) in dichloromethane (40 mL), and the mixture was stirred at room temperature for 2 hours. The mixed reaction solution was diluted with ethyl acetate (300 mL), washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-fluoro-4-(((1',2',3',6'-tetrahydro-[2,4'-bipyridyl]-6-yl)oxy)methyl)benzonitrile (2.78 g, 9.00 mmol, yield: 69.%), LCMS m / z: 310 [M+H] +

[0336] 4) Synthesis of (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

[0337] To a solution of 3-fluoro-4-(((1',2',3',6'-tetrahydro-[2,4'-bipyridyl]-6-yl)oxy)methyl)benzyl (2.78 g, 9.00 mmol) and (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (2.92 g, 9.90 mmol) in acetonitrile (50 mL) was added N,N-diisopropylethylamine (2.32 g, 18.00 mmol) at room temperature and heated at 60°C with stirring for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was added with ethyl acetate (20 mL) and slurried at room temperature for 2 hours. The filter cake was filtered and washed with ethyl acetate (10 mL), and dried under vacuum to give (S)-methyl 2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (3.26 g, 5.74 mmol, yield: 64%), LCMS m / z: 568 [M+H] + .

[0338] 5) Synthesis of (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0339] To a solution of (S)-methyl 2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (3.26 g, 5.74 mmol) in THF (150 mL) and H2O (75 mL) was added LiOH (0.69 g, 28.7 mmol) and stirred at room temperature for 16 hours. The reaction mixture was adjusted to pH ~5 with glacial acetic acid and extracted with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (2.78 g, 5.02 mmol, yield: 87.4%), LCMS m / z: 554 [M+H] +

[0340] 1 H NMR (400MHz, DMSO-d6): δ8.26(s,1H),7.88(d,J=10.4Hz,1H),7.81(d,J=8.4Hz,1H),7.72-7.65(m,4H),7.10(d ,J=7.2Hz,1H),6.77(d,J=8.0Hz,1H),6.70(s,1H),5.49(s,2H),5.06(q,J=6.8Hz,2.4Hz,1H),4.79(dd,J=15.2H z,7.2Hz,1H),4.65(d,J=15.2Hz,1H),4.46(q,J=13.2Hz,6.0Hz,1H),4.36(q,J=15.2Hz,6.0Hz,1H),4.07(d,J=1 3.6Hz,1H),3.91(d,J=13.6Hz,1H),3.23-3.21(m,2H),2.75-2.72(m,2H),2.67-2.63(m,1H),2.41-2.37(m,1H).

[0341] 19 F NMR (377MHz, DMSO-d6): δ-115.51.

[0342] 6) Synthesis of (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (5-methyl-2-oxo-1,3-dioxo-4-yl)methyl ester

[0343] To a solution of (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (2.78 g, 5.02 mmol) and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (2.24 g, 15.06 mmol) in dry DMF (60 mL) was added anhydrous sodium carbonate (2.13 g, 20.08 mmol). The mixture was heated at 50°C with stirring for 2 hours. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with saturated brine (200 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (conditions as follows: column: spherical C18, 20-40 μm, 120 g; mobile phase A: H 2 O; mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 5% B 5 min, 5-70% B 40 min; detector: 214 nm). At 70% B, the product-containing fraction was collected and concentrated under reduced pressure to give (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (1.57 g, 2.36 mmol, yield: 47.2%), LCMS m / z: 666 [M+H] +

[0344] 1H NMR (400MHz, DMSO-d6): 8.31(s,1H),7.88(d,J=10.0Hz,1H),7.84(d,J=8.8Hz,1H),7.72-7.68(m,4H),7.10(d,J=7.6H z,1H),6.77(d,J=8.0Hz,1H),6.70(s,1H),5.49(s,2H),5.24(s,2H),5.05(q,J=14.0Hz,6.8Hz,1H),4.83(dd,J=15.2H z,7.6Hz,1H),4.67(d,J=14.8Hz,1H),4.46(q,J=13.2Hz,7.2Hz,1H),4.34(q,J=14.8Hz,6.0Hz,1H),4.08(d,J=13.2Hz ,1H),3.92(d,J=13.2Hz,1H),3.28-3.17(m,2H),2.76-2.72(m,2H),2.67-2.63(m,1H),2.43-2.37(m,1H),2.24(s,3H).

[0345] 19 F NMR (377MHz, DMSO-d6): δ-115.52.

[0346] Example 13. Synthesis of (5-methyl-2-oxo-1,3-dioxo-4-yl)methyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Compound 13):

[0347] 1) Synthesis of 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole

[0348] To a solution of 3-bromobenzene-1,2-diol (40 g, 211.64 mmol) in toluene (1000 mL) at room temperature were added 1-(4-chloro-2-fluorophenyl)ethane-1-one (40.27 g, 232.80 mmol) and p-toluenesulfonic acid (1.82 g, 10.58 mmol). The mixture was heated to 148°C and allowed to react for 72 hours to remove water. After completion of the reaction, the mixed reaction solution was concentrated. The residue was purified by silica gel column chromatography to afford 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole (17.0 g, 49.42 mmol, yield: 23.4%).

[0349] 1 H NMR (400MHz, CDCl3): δ7.56-7.52(m,1H),6.17-6.12(m,2H),6.97-6.94(m,1H),6.76-6.68(m,2H),2.11(s,3H).

[0350] 2) Synthesis of tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0351] To a solution of 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole (16 g, 46.51 mmol) in 1,4-dioxane (400 mL) and H₂O (40 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (17.25 g, 55.81 mmol), K₂CO₃ (12.84 g, 93.02 mmol), and Pd(dppf)Cl₂ (1.9 g, 2.33 mmol) at room temperature. The mixture was stirred at 90°C under a nitrogen atmosphere for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was diluted with ethyl acetate (200 mL), washed with saturated brine (100 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 = 20 / 1) to give tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (17.7 g, 39.69 mmol, yield: 84%). LCMS m / z: 390 [M+H-56]. + .

[0352] 3) Synthesis of tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidine-1-carboxylate

[0353] To a solution of tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (17.7 g, 39.69 mmol) in tetrahydrofuran (200 mL) was added 5% Pd / C (3.56 g) at room temperature. The mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The mixed reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=10 / 1) to give tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidine-1-carboxylate (11.8 g, 26.34 mmol, yield: 66.4%). LCMS m / z: 392 [M+H-56]. + .

[0354] 4), (R)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidine-1-carboxylic acid tert-butyl ester and (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidine-1-carboxylic acid tert-butyl ester

[0355] Compound 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidine-1-carboxylic acid tert-butyl ester (11.8 g, 26.34 mmol) was separated and purified by SFC (specific conditions are as follows: system: Waters SFC 150; column: Chromatographic column dimensions: 250*40mm 10μm; mobile phase A: supercritical CO; mobile phase B: IPA (+0.1% 7.0mol / L ammonia in methanol) A:B=80:20; wavelength: 214nm; flow rate: 140mL / min; column temperature: RT; back pressure: 100bar: 3.0mL: cycle time: 5.0min) to obtain two isomers: compounds 103-7A and 103-7:

[0356] Compound 103-7A: Peak 1: Chiral-HPLC, 1.305 min; (R)-tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidine-1-carboxylate (5.7 g, yield: 48.3%).

[0357] Compound 103-7: Peak 2: Chiral-HPLC, 2.543 min; (S)-tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidine-1-carboxylate (5.7 g, yield: 48.3%).

[0358] 5) Synthesis of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidine

[0359] To a solution of tert-butyl (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidine-1-carboxylate (2.5 g, 5.58 mmol) in ethyl acetate (100 mL) was added p-toluenesulfonic acid (2.12 g, 11.16 mmol) and stirred at 30°C for 16 hours. The reaction was filtered and concentrated under reduced pressure to give (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidine (1.74 g, 5.00 mmol, yield: 89.6%). LCMS m / z: 348 [M+H] +

[0360] 6) Synthesis of methyl 2-((4-(((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidin-1-yl)methyl)-1-((((S)-oxetane-2-yl)methyl]-1H-benzo[d]imidazole-6-carboxylate

[0361] To a solution of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidine (1.74 g, 5.00 mmol) and (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (1.47 g, 5.00 mmol) in acetonitrile (50 mL) was added DIEA (1.94 g, 15.00 mmol). The mixture was heated at 60°C with stirring for 4 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH=20 / 1) to give methyl 2-((4-(((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidin-1-yl)methyl)-1-((((S)-oxetan-2-yl)methyl]-1H-benzo[d]imidazole-6-carboxylate (1.5 g, 2.48 mmol, yield: 49.6%), LCMS m / z: 606 [M+H] +

[0362] 7) Synthesis of 2-((4-(((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidin-1-yl)methyl)-1-((((S)-oxetane-2-yl)methyl]-1H-benzo[d]imidazole-6-carboxylic acid

[0363] To a solution of methyl 2-((4-(((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidin-1-yl)methyl)-1-((((S)-oxetan-2-yl)methyl]-1H-benzo[d]imidazole-6-carboxylate (1.5 g, 2.48 mmol) in THF (150 mL) and H2O (150 mL) was added LiOH (0.24 g, 9.92 mmol) and stirred at room temperature for 16 h. The mixed reaction solution was heated to 40°C. The pH was adjusted to 5-6 with glacial acetic acid and extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-((4-(((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidin-1-yl)methyl)-1-((((S)-oxetane-2-yl)methyl]-1H-benzo[d]imidazole-6-carboxylic acid (1.3 g, 2.20 mmol, yield 88.7%), LCMS m / z: 592 [M+H]. + .

[0364] 1H NMR (400MHz, DMSO-d6): δ12.64(s,1H),8.28(s,1H),7.80(d,J=8.4Hz,1H),7.65(d,J=8.4Hz,1H),7.58-7.54(m,2H),7.33(d,J=8. 0Hz,1H),6.79(d,J=5.2Hz,2H),6.76-6.73(m,1H),5.14-5.08(m,1H),4.79(dd,J=15.2Hz,7.2Hz,1H),4.66(d,J=15.2Hz,1H),4.4 8(q,J=13.2Hz,7.6Hz,1H),4.38(q,J=14.8Hz,5.6Hz,1H),3.96(d,J=13.2Hz,1H),3.78(d,J=13.2Hz,1H),3.02(d,J=9.6Hz,1H),2 .87(d,J=10.8Hz,1H),2.73-2.64(m,2H),2.47-2.41(m,1H),2.25-2.18(m,2H),2.02(s,3H),1.81-1.77(m,2H),1.70-1.67(m,2H).

[0365] 19 F NMR (377MHz, DMSO-d6): δ-110.785.

[0366] 8) Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0367] To a mixture of 2-((4-(((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dihydroxy-4-yl)piperidin-1-yl)methyl)-1-((((S)-oxetan-2-yl)methyl]-1H-benzo[d]imidazole-6-carboxylic acid (1.0 g, 1.69 mmol) and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (0.76 g, 5.07 mmol) in dry DMF (20 mL) was added 2% paraformaldehyde (5% guanidine-3-yl)propanediol (4% guanidine-3-yl)propanediol (5% guanidine-3-yl)propanediol (6% guanidine-3-yl)propanediol (7% guanidine-3-yl)propanediol (8% guanidine-3-yl)propanediol (9% guanidine-3-yl)propanediol (1% guanidine-3-yl)propanediol (1% guanidine-3-yl)propanediol (2% guanidine-3-yl)propanediol ( To the solution, Na2CO3 (0.54 g, 5.07 mmol) was added and heated at 50°C with stirring for 2 hours. The mixed reaction solution was diluted with ethyl acetate (100 mL) and washed with saturated brine (100 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (conditions as follows: column: spherical C18, 20-40 μm, 330 g; mobile phase A: H2O; mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 5% B 5 min, 5-90% B 50 min; detector: 214 nm). At 90% B, the fractions containing the product were collected and concentrated under reduced pressure to yield (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (1.14 g, 1.62 mmol, 95.8% yield), LCMS m / z: 704 [M+H]. +

[0368] 1H NMR (400MHz, DMSO-d6): δ8.32(s,1H),7.83(d,J=8.8Hz,1H),7.79(d,J=8.4Hz,1H),7.58-7.53(m,2H),7.33(d,J=8.4Hz,1H),6.79(d,J=5 .6Hz,2H),6.76-6.73(m,1H),5.24(s,2H),5.10(q,J=14.0Hz,4.0Hz,1H),4.82(dd,J=15.2Hz,7.2Hz,1H),4.67(dd,J=15.2Hz,2.4Hz,1H) ,4.50-4.45(m,1H),4.39-4.34(m,1H),3.97(d,J=13.6Hz,1H),3.78(d,J=13.6Hz,1H),3.02(d,J=11.2Hz,1H),2.86(d,J=11.2Hz,1H),2. 73-2.65(m,2H),2.47-2.41(m,1H),2.24-2.21(m,1H),2.21(s,3H),2 .18-2.15(m,1H),2.02(s,3H),1.81-1.77(m,2H),1.70-1.66(m,2H).

[0369] 19 F NMR (377MHz, DMSO-d6): δ-110.787.

[0370] Example 14. Synthesis of bis(methylene)bis(2-((4-(6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid)(2-oxo-1,3-dioxo-4,5-diyl)ester (Compound 14):

[0371] 1) Synthesis of 4,5-bis(bromomethyl)-1,3-dihydroxy-2-ketone

[0372] To a solution of 4,5-dimethyl-1,3-dioxol-2-one (2.0 g, 17.5 mmol) in CCl4 (50 mL) was added NBS (6.5 g, 36.8 mmol) and AlBN (574 mg, 2.5 mmol), and the mixture was heated at 80°C with stirring for 16 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 2 / 1) to give 4,5-bis(bromomethyl)-1,3-dihydroxy-2-one (3.5 g, 12.9 mmol, yield: 73.68%).

[0373] 1 H NMR (400MHz, CDCl3) δ4.21 (s, 4H).

[0374] 2) Synthesis of bis(methylene)bis(2-((4-(6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl-1-(((S)-oxetane-2-yl)methyl ester)-1H-benzo[d]imidazole-6-carboxylic acid)(2-oxo-1,3-dioxo-4,5-diyl) ester

[0375] To a solution of 4,5-bis(bromomethyl)-1,3-dihydroxy-2-one (600 mg, 2.2 mmol) in DMF (20 mL) was added (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl]-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (2.56 g, 4.4 mmol) and DIEA (567 mg, 4.4 mmol), and the mixture was heated at 40°C with stirring for 3 hours. The reaction mixture was purified by reverse phase flash column chromatography (conditions as follows: column: spherical C18, 20-40 μm, 330 g; mobile phase A: 10 The product was purified by HPLC-MS / MS (HPLC-MS / MS): 5.5747 / 0.7300; 5.022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627; 1.0022 / 0.6627 + .

[0376] 1H NMR(400MHz, DMSO-d6)δ8.33(s,2H),7.83(dd,J=8.4,1.4Hz,2H),7.73–7.65(m,4H),7.44(dd,J=11.2,2.4Hz,2H),7 .30–7.24(m,2H),7.21–7.16(m,2H),7.05(d,J=7.2Hz,2H),6.72(d,J=8.4Hz,2H),5.44(s,4H),5.19(s,4H),5.09–5 .01(m,2H),4.99–4.90(m,2H),4.84–4.74(m,2H),4.70–4.59(m,2H),4.51–4.42(m,2H),4.39–4.26(m,2H),3.96(d, J=13.6Hz,2H),3.80(d,J=13.6Hz,2H),2.84–2.65(m,6H),2.44–2.28(m,6H),1.98–1.87(m,4H),1.68–1.56(m,4H).

[0377] 19 F NMR(377MHz,DMSO-d6)δ-131.347.

[0378] Example 15: Synthesis of the following compounds:

[0379] The following compounds can be obtained by similar steps to those in Example 1-14:

[0380] Test Example 1: Pharmacokinetic study of the test substance in mice:

[0381] The prodrug compounds of the present invention are rapidly metabolized into the corresponding prodrug compounds in mice. Therefore, the pharmacokinetic properties of some of the compounds of the present invention were evaluated by testing the prodrug compounds in mice. SPF-grade male ICR mice (3 per group) were obtained from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. The test compounds were dissolved in 5% DMSO, 10% solutol, and 85% saline. A single intravenous dose of 1 mg / kg was administered in a volume of 5 mL / kg. A single oral dose of 5 mg / kg was administered in a volume of 10 mL / kg. Animals were fasted overnight prior to the experiment but were not allowed to drink water. Food intake was resumed 4 hours after dosing. Blood samples were collected at 0.0830 (IV), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing. About 0.1 mL of whole blood was collected from the animal's saphenous vein and placed in an EDTA-K2 anticoagulant tube. The sample was centrifuged at 4°C and 4200 rpm for 5 minutes. The plasma was transferred to a centrifuge tube and stored at -80°C until analysis. Plasma sample analysis used acetonitrile protein precipitation to extract the prodrug compound or original drug compound and internal standard (Labetalol & tolbutamide & Verapamil & dexamethasone & glyburide & Celecoxib) in mouse plasma, and the extract was analyzed by LC / MS / MS. The measured plasma concentration-time data of individual animals were analyzed according to the non-compartmental model using Phoenix WinNonlin 7.0 (Pharsight, USA) software, and the mouse pharmacokinetic parameters were obtained as shown in the following table: Maximum (peak) plasma drug concentration C max ; Peak time T max ; half-life T 1 / 2 and the area under the plasma concentration-time curve (AUC) extrapolated to an infinite time 0-inf .

[0382] Table 1

[0383] Compound 49# is the technical drug of compounds 6, 7, and 9; Compound 55* is the technical drug of compound 1;

[0384] From the results in the table above, it can be seen that compared with the original drug compound 55* and compound 49#, the representative new prodrug compounds of the present invention have higher exposure doses and longer half-lives T 1 / 2 and greater oral bioavailability, which is much higher than that of the reference molecule PF-06882961, making it more suitable for drug development.

[0385] Test Example 2: Gastrointestinal reaction test of representative prodrug compounds in rats

[0386] The original drug compound 49# and representative prodrug compounds 7 and 9 were dissolved in a solvent (5% DMSO / 5% Solutol / 90% Water) to prepare a 25 mg / ml homogeneous suspension. Three SD rats (SPF, Beijing Vital River Laboratory Animal Technology Co., Ltd.) per group were gavage-administered with suspensions of the original drug compound 49# and representative prodrug compounds 7 and 9 at a dose of 500 mg / kg (20 ml / kg). Salivation symptoms were continuously observed and recorded after administration. The results are shown in the following table:

[0387] Table 2. Gastrointestinal reaction test of representative compounds in rats

[0388] As can be seen from the results in the above table, compared with the original drug compounds, the novel prodrug compounds 7 and 9 of the present invention have lower gastrointestinal side effects, and therefore have better safety and are more suitable for drug development.

[0389] Test Example 3: Pharmacokinetic study of the test substance in monkeys:

[0390] The prodrug compounds of the present invention are rapidly metabolized into the corresponding prodrug compounds in vivo. Therefore, the pharmacokinetic properties of some of the compounds of the present invention were evaluated by testing the prodrug compounds in cynomolgus monkeys. Three male eluting cynomolgus monkeys were used per group. The compounds were dissolved in 5% DMSO, 10% solutol, and 85% saline. A single intravenous dose of 1 mg / kg was administered in a volume of 2 mL / kg. A single oral gavage dose of 5 mg / kg was administered in a volume of 5 mL / kg. Animals were fasted overnight prior to the experiment but were allowed to resume food intake 4 hours after dosing. Blood samples were collected at 0.0830 (IV), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after dosing. Approximately 1 mL of whole blood was collected from the forearm vein of the animals and placed in EDTA-K2 anticoagulant tubes. The blood was centrifuged at 4200 rpm for 5 minutes at 4°C. The plasma was transferred to a centrifuge tube and stored at -80°C until analysis. Plasma sample analysis: The test compound and internal standards (Labetalol, tolbutamide, Verapamil, dexamethasone, glyburide, and Celecoxib) were extracted from monkey plasma using acetonitrile protein precipitation. The extracts were analyzed by LC / MS / MS. The plasma concentration-time data for individual animals were analyzed using Phoenix WinNonlin 7.0 (Pharsight, USA) software using a non-compartmental model to obtain the following pharmacokinetic parameters: maximum (peak) plasma concentration, C max ; Peak time T max ; half-life T 1 / 2 and the area under the plasma concentration-time curve (AUC) extrapolated to an infinite time 0-inf .

[0391] Table 3. Pharmacokinetic parameters of representative compounds detected after metabolism in cynomolgus monkeys

[0392] As can be seen from the results in the above table, compared with the original drug compound (for the structure and specific data of the original drug compound, see compound 49 in WO2023029380A1), at the same dose, the novel prodrug compounds 7 and 9 of the present invention have higher exposure and longer T1 / 2 in cynomolgus monkeys, while also eliminating the gastrointestinal irritation caused by the carboxyl group. Therefore, they have better safety and are more suitable for drug development.

[0393] Test Example 3: GLP-1R humanized mouse intraperitoneal glucose tolerance test (IPGTT) experiment:

[0394] 1) Compound preparation

[0395] The test compound was dissolved in 10% Solutol HS15 + 90% Saline and vortexed with ultrasound until dissolved.

[0396] 2) Experimental animals

[0397] Male SPF C57BL6J (human-GLP-1R) mice, 6-9 weeks old, weighing 20g-25g.

[0398] 3) Animal acclimation and grouping

[0399] The experiment began after the animals had been acclimated to the facility for 7 days. The body weight and random blood glucose levels of the animals were measured one day before administration, and the animals were divided into groups based on body weight and random blood glucose levels, with 6 animals in each group.

[0400] 4) IPGTT experiment

[0401] The animals were fasted overnight. The next day, the corresponding test drug was orally instilled in each group at a volume of 10 ml / kg. Thirty minutes later, glucose (2 g / kg, 10 ml / kg) was injected intraperitoneally. Blood glucose was measured at -30, 0, 15, 30, 60, and 120 min using a glucometer. Plasma samples were collected at 0 and 15 min for insulin detection using a Rat / Mouse Insulin Elisa Kit.

[0402] 5) Data Analysis

[0403] AUC 0-120min The area under the blood glucose-time curve is the area under the blood glucose-time curve. Insulin change is the difference in plasma insulin concentration between 15 and 0 minutes. Data were analyzed using GraphPad Prism 6 software using a one-way ANOVA Dunnett test. A significant difference was considered when compared with the vehicle group at p < 0.05. * indicates p < 0.05, ** indicates p < 0.01, and *** indicates p < 0.001.

[0404] Test Example 4: Cynomolgus Monkey Intravenous Glucose Tolerance (IVGTT) Experiment:

[0405] 1) Compound preparation

[0406] Ultrasonic vortex oscillation until the test compound is evenly dispersed in 10% Solutol HS15 + 90% Saline. Vehicle is 10% Solutol HS15 + 90% Saline

[0407] 2) Experimental animals

[0408] Male cynomolgus monkeys, 10-15 weeks old, weighing 6-13 kg, were selected for efficacy studies based on alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), glycated hemoglobin (HbA1c), and body weight (BW).

[0409] 3) Adaptation and grouping

[0410] After one week of adaptive training, the animals were measured for baseline IVGTT before dosing. The animals were then divided into groups based on the insulin and blood glucose results from the IVGTT. Details of the disposition of the animals in each group are shown in the table below.

[0411] 4) IVGTT

[0412] The IVGTT was started 2 hours after the animals were orally gavaged, and blood was collected at: -15 min, 0 min (before sugar administration), and 2, 5, 7, 10, 20, and 30 min after sugar administration.

[0413] 5) Data Analysis

[0414] Data were analyzed using GraphPad Prism 6 software using one-way ANOVA and Dunnett's test. A significant difference was considered when p < 0.05 compared with the vehicle group. * indicates p < 0.05, ** indicates p < 0.01, and *** indicates p < 0.001.

[0415] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A compound represented by formula (I), a pharmaceutically acceptable salt, solvate, enantiomer or isotope-substituted product thereof, in, 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; Preferred X and X' are independently selected from absence, a single bond, -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-; Y is independently selected from -O-, -S-, -OC(R d1 )(R d2 )O-、-OC(R d1 )(R d2 )-、-OC(R d1 )(R d2 )OCO-、-OC(R d1 )(R d2 )OP=O[OC(R d1 )(R d2 )OR]2-; L is independently selected from the group consisting of absence, a single bond, -C(R d1 )(R d2 )-、-OC(R d1 )(R d2 )-、-C(R d1 )(R d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)– or -S(=O)2-; X1 and X8 are independently selected from -CR5- or -N-; 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 group and 5-8 membered heteroaryl group; wherein the aryl group, heteroaryl group, saturated or partially saturated cycloalkyl group, saturated or partially saturated heterocyclic group are further optionally substituted by 1 to more 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; R is arbitrarily and independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocycloalkyl, heterocyclyl, alkylacyl, cycloalkylacyl, haloalkylacyl, deuterated alkylacyl, heterocycloalkylacyl, heterocyclylacyl, hydroxyl, amino, substituted amino (disubstituted tertiary amine or trisubstituted quaternary amine), carboxyl, ester, amide, aminoacyl, substituted phosphonyl or a combination of alkyl / alkenyl / alkynyl or the following structural groups: The hydrogen on R is preferably optionally replaced by one or more selected from hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl and alkyl / alkenyl / alkynyl combination, oxo, CN, CF3, OH, OCH3, OCH2CH3, amino, substituted amino (disubstituted tertiary amine or trisubstituted quaternary amine), carboxyl, ester, amide, aminoacyl, saturated or partially saturated C 3-6 The cycloalkyl groups are substituted. 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 heterocycloalkyl, 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 substitute; and the hydrogen on R1 is preferably optionally replaced by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 The cycloalkyl groups are substituted. R2, R 2' and R d1 , R d2 are the same or different and are 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 C 3-10 Cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, The heterocycloalkyl group is optionally substituted by 1 to more cycloalkyl groups 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 with one to more substituted ions 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 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 together with the carbon to which it is attached, wherein the cycloalkyl group or heterocyclic group is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3; Each R4 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 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 the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 The alkoxy group is optionally substituted with 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; Each R3, 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 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 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 heterocycloalkyl group is optionally substituted by 1 to 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, 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, 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; 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, 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 said 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 1 to more than one atom 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; The heteroatom represents any heteroatom independently selected from O, N, S, P and isotopes thereof; The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m is an integer arbitrarily selected from 0, 1, 2, 3 and 4; n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; t and q are arbitrarily selected from integers of 0, 1, 2, 3, 4 and 5.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, characterized in that: It has the structure of formula (IA), wherein X0, X1, X2, X3, X4 and X5 are independently selected from -CR5- or -N-; Ring B, X, X', Y, L, R0, R, R1, R2, R 2' , R3, R4, R5, R6, m, n, t, q, and The definitions of claim 1 apply independently of one another.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product thereof, characterized in that: It has the structure of formula (IB), Wherein, R7 is 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 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 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 heterocycloalkyl group is optionally substituted by 1 to 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, 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, 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; Ring B, X1, Y, R0, R, R1, R2, R 2' , R3, R4, R6, m, n, t, q and Independently of each other, the definitions in claim 1 or 2 apply.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, characterized in that: It has the structure of formula (IC), wherein Z is independently selected from absence, a single bond, -C(R d1 )(R d2 )-、-CH2CH2-、-C(R d1 )(R d2 )CO-; r is arbitrarily selected from an integer of 0, 1, 2, 3, 4 and 5; Ring B, X1, Y, R0, R, R1, R2, R 2' , R3, R4, R6, R7, m, n, t, q and Independently of each other, it has the definition of any one of claims 1 to 3; Preferably, it has the structure of formula (1-IC), Among them, R 7‘ may be 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 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 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 heterocycloalkyl group is optionally substituted by 1 to 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, 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, 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; Ring B, X1, Y, R0, R, R1, R2, R 2' , R3, R4, R6, R7, m, n, t, q and Independently of each other, it has the definitions in any one of claims 1 to 3.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, characterized in that: It has the structure of formula (ID), Among them, ring B, X, X', X0, X1, X2, X3, X4, Y, L, R0, R, R1, R2, R 2' , R3, R4, R5, R6, m, n, t, q and Independently of each other, it has the definitions in any one of claims 1 to 4.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, characterized in that: It has the structure of formula (IE), Among them, ring B, X, X', X0, X2, X3, X4, X5, Y, L, R0, R, R1, R2, R 2' , R3, R4, R5, R6, m, n, t, q and Independently of each other, it has the definitions in any one of claims 1 to 5.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, characterized in that: It has the structure of formula (IF), Among them, ring B, X1, Y, R0, R, R1, R2, R 2' , R3, R4, R6, R7, m, n, t, q and Independently of each other, it has the definitions in any one of claims 1 to 6.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, characterized in that: R is arbitrarily and independently selected from alkyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocycloalkyl, heterocyclyl, alkylacyl, cycloalkylacyl, haloalkylacyl, deuterated alkylacyl, heterocycloalkylacyl, heterocyclylacyl; and the hydrogen on R is preferably optionally replaced by 1 to more selected from hydrogen, deuterium, halogen, element, oxygenate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups; Preferably, 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 heterocycloalkyl, 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: The hydrogen on R1 is preferably optionally replaced by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups; Preferably, ring A is selected from 5-10 membered heteroaryl or 5-10 membered heterocyclic group, such as 6 membered heteroaryl or 9-10 membered heterocyclic group, preferably pyridyl, Preferably, ring A is selected from Preferably, ring B is selected from 3-8 membered heterocyclic groups, such as 5-6 membered heterocyclic groups, preferably piperazinyl, Preferably, the B ring is selected from the following structures: Preferably, X and X' are the same or different and are independently selected from absence, O, CH2, CD2; D is deuterium; Preferably, L is selected from a single bond, O, S, NH, CH2, OCH2, CHO; Preferably, Y is selected from -O-, -S-, -OCH2O-, -OCH2-, -OCH2OC(O)-; Preferably, R is selected from C 1-6 Alkyl-C(O)O-CH2-, (like )、 Each R N may be the same or different and are independently selected from C 1-6 Alkyl, such as methyl; Z - Selected from anions, such as halogen anions (F - , Cl - Br - ,I - ); Preferably, R0 is selected from H, unsubstituted or optionally substituted with one, two or more R 01 Substituted C 1-6 an alkyl group, such as a methyl group; each R 01 may be the same or different and independently selected from H, unsubstituted or optionally substituted with one, two or more R 02 Substituted with the following groups: 5-6 membered heteroaryl, 3-6 membered heterocyclic group, C 3-6 Cycloalkyl; each R 02 may be the same or different and independently selected from oxo (=O), C 1-6 Alkyl, C 3-6 Cycloalkyl-C 1-6 Alkyl, cyano C 1-6 alkyl; Preferably, each R 01 may be the same or different and independently selected from H, unsubstituted or optionally substituted with one, two or more R 02 Substituted from the following groups: imidazolyl, oxetanyl, cyclopropyl, tetrahydropyrrolyl, pyrazolyl; Preferably, each R 02 may be the same or different and independently selected from methyl, ethyl, isopropyl, oxo (=O), cyanomethyl, cyclopropylmethyl; Preferably, R0 is selected from the structure shown below: methyl, Preferably, each R3 is the same or different and is independently selected from H, C 1-6 Alkyl; such as H or methyl; Preferably, Selected from Preferably, each R5 is selected from halogen, such as F; Preferably, each R6 is the same or different and is independently selected from halogen (eg F or Cl), CN.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, characterized in that: The compound is selected from the novel compounds disclosed in the examples of the present invention.

10. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof.

11. Use of at least one of the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, in the preparation of a medicament for preventing and / or treating a disease related to the GLP1 / GLP1R signaling pathway; Preferably, 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, tubular dysfunction, proinflammatory changes in the proximal tubules), diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, obesity (including 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., use of 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 artery disease, macular degeneration, cataract, glomerulosclerosis, chronic renal Failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, impaired glucose metabolism, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, hyperlipoprotein B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, prevention or treatment of polycystic ovary syndrome and addiction treatment (such as alcoholism and / or drug abuse).

Images