Pyrazolopiperidine-containing compound and use thereof

Abstract

Provided in the present disclosure are a compound as represented by formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. The compound of the present disclosure serves as a GLP-1R agonist, and the compound and a pharmaceutical composition thereof can be used in the preparation of a drug for treating and / or preventing conditions mediated by GLP-1R.

Description

A class of compounds containing pyrazolopiperidine and their uses

[0001] Cross-references to related applications

[0002] This application claims priority and benefit to Chinese Patent Application No. 202510487947.8, filed with the China National Intellectual Property Administration (CNIPA) on April 18, 2025; Chinese Patent Application No. 202510789975.5, filed with the CNIPA on June 13, 2025; and Chinese Patent Application No. 202511403300.9, filed with the CNIPA on September 28, 2025, the disclosures of which are incorporated herein by reference in their entirety. Technical Field

[0003] This application relates to the field of pharmaceutical technology, and more specifically, to a class of pyrazolopiperidine compounds, pharmaceutical compositions comprising the same, and their use as GLP-1R agonists. Background Technology

[0004] GLP-1 (glucagon-like peptide-1) is mainly synthesized and secreted by L cells located in the ileum and colon. Its function is related to GLP-1R (glucagon-like peptide-1 receptor), which is mainly distributed in pancreatic β and α cells, the gastrointestinal tract, the central nervous system, and the cardiovascular system. GLP-1R belongs to the glucagon receptor subfamily of the G protein-coupled receptor B cluster. Its key characteristics include a seven-transmembrane core domain and a relatively large extracellular domain.

[0005] In the pancreas, GLP-1 induces glucose-dependent insulin secretion, increases insulin secretion, and decreases glucagon levels. In the central nervous system, GLP-1R agonism increases satiety, reduces food intake, alleviates nausea, and promotes nerve cell survival. In other tissue systems, GLP-1R agonism also lowers blood pressure, improves microvascular function, reduces inflammation, reduces gastric emptying, lowers blood glucose, increases insulin sensitivity, and reduces gluconeogenesis. Therefore, GLP-1R agonism can lower blood glucose and / or lead to weight loss, thereby preventing and / or treating diabetes and / or obesity. Moreover, GLP-1R agonism can contribute to weight loss through various biological mechanisms. For example, smegglutide, a GLP-1R agonist, has been approved for the treatment of type 2 diabetes and weight management.

[0006] Furthermore, there is evidence that stimulating GLP-1 receptor agonists is also a promising strategy for the prevention and / or treatment of Alzheimer's disease (AD), non-alcoholic fatty liver disease (NAFLD, or, as its updated name, metabolic dysfunction-associated fatty liver disease (MASLD)). For example, studies have shown that in AD, when glucose metabolism is impaired and mitochondrial function is damaged, lactate shuttle during glial cell glycolysis becomes increasingly important for neuronal survival, acting as an energy substitute. GLP-1 can partially restore glycolytic function in astrocytes and increase lactate flux, which helps alleviate the energy crisis in neurons. Similarly, non-alcoholic fatty liver disease is divided into two main categories: non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH, or, as its updated name, metabolic dysfunction-associated steatohepatitis (MASH)). With an oversupply of metabolic substrates, excess fat accumulates in hepatocytes, accompanied by the gradual production of potentially toxic lipid species and a progressive increase in neoadipogenesis (DNL) in NAFLD. Obesity and type 2 diabetes are two major risk factors for NASH, and individuals with a history of NASH have a significantly increased likelihood of developing liver and cardiovascular disease. Furthermore, insulin resistance in the liver and adipose tissue is considered a key driver of NASH morbidity and mortality, and GLP-1 analogs can improve glycemic control, reduce weight, and activate liver enzymes in patients with type 2 diabetes mellitus (T2DM). Some evidence suggests that liraglutide acts directly on human hepatocytes in vitro, reducing steatosis by lowering DNL levels and increasing fatty acid oxidation. Notably, most patients showed improvement in steatosis and hepatocyte swelling after receiving liraglutide treatment. Summary of the Invention

[0007] In a first aspect, this disclosure provides a compound of formula (I), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

[0008] in,

[0009] Ring A is selected from C 3-15 Carbocyclic groups, 3-12 membered heterocyclic groups;

[0010] Ring B is selected from 3-12 membered heterocyclic groups and 5-12 membered heteroaryl groups;

[0011] Ring C is selected from C 3-15 Carbocyclic group, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-12 heteroaryl;

[0012] Ring D is selected from C 3-15 Carbocyclic group, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-12 heteroaryl;

[0013] R a Each time it appears, it is independently selected from hydrogen, deuterium, hydroxyl, amino, mercapto, cyano, oxo, -S(O)(NH)R a1 -S(O)(NCH3)R a1 -(CH2) m OR a1 -(CH2) m SR a1 -(CH2) m NHR a1 The following groups, or optionally substituted groups: C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 1-6 mercaptoalkyl, C 2-6 alkynyl or C 2-6 Alkenyl, wherein optional substitution refers to unsubstituted or substituted with one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R a1 replace;

[0014] R a1 Each time it appears, it is independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 1-6 Hydroxyalkyl, C 1-6 mercaptoalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, 5-12 heteroaryl, R a1 Optionally by one or more (e.g., 2, 3, 4, 5, or 6) R a2 replace;

[0015] R a2 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 1-6 Hydroxyalkyl, C 1-6 mercaptoalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, 5-12 heteroaryl, R a2 Optionally by one or more Ra3 replace;

[0016] R a3 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl groups, 3-10 membered heterocyclic groups;

[0017] Or, when R a When it appears twice or more, two of the R's a Linked together with their respective attached atoms, they form optionally substituted C 3-7 3-7 membered heterocyclic groups, C 6-10 Aryl or 5-7 heteroaryl, wherein optional substitution means unsubstituted or selected from one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R a1 replace;

[0018] R b Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylamine group;

[0019] R c Each time it appears, it is independently selected from hydroxyl, halogen, amino, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -S(O)(=NR c1 )R c1 C 1-6 Mercaptoalkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 3-15 Carbocyclic group, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-12 heteroaryl, -(CH2) m OR c1 -(CH2) m SR c1 Or -(CH2) m NHR c1 The R cFurther optionally by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R c1 replace;

[0020] R c1 Each time it appears, it is independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, 5-12 heteroaryl, R c1 Further optionally by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R c2 replace;

[0021] R c2 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups; R c2 Further optionally by one or more R c3 replace;

[0022] R c3 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, and C. 1- 6-alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl or 3-10 membered heterocyclic groups;

[0023] R d Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, or optionally substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 2-6 alkenyl, C 2-6 alkynyl group, C 3- 10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14Aryl, 5-12 heteroaryl; the optional substitution refers to one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituted sites of the unsubstituted or substituted group being independently replaced by R. d1 Replaced;

[0024] R d1 Each time it appears, it is independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 1-6 Hydroxyalkyl, C 1-6 mercaptoalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl and 5-12 heteroaryl groups;

[0025] R e Each time it appears, it is independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1- 6-alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, 5-12 heteroaryl;

[0026] X1 and X2 are each independently selected from CR x Or N, where R x Independently selected from hydrogen, halogen, hydroxyl, amino, nitro, mercapto, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, 5-12 heteroaryl;

[0027] Unless otherwise stated, the heteroatoms in the above heterocyclic groups and heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3, 4, 5 or 6;

[0028] Each time m, n, o, p, or q appears, it is independently selected from 0, 1, 2, 3, 4, or 5;

[0029] The prerequisite is that the combination of the definitions of the above variables forms a stable chemical structure.

[0030] In some embodiments, this disclosure provides a compound of formula (I), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

[0031] in,

[0032] Ring A is selected from C 3-15 Carbocyclic groups, 3-12 membered heterocyclic groups;

[0033] Ring B is selected from 3-12 membered heterocyclic groups and 5-12 membered heteroaryl groups;

[0034] Ring C is selected from C 3-15 Carbocyclic group, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-12 heteroaryl;

[0035] Ring D is selected from C 3-15 Carbocyclic group, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-12 heteroaryl;

[0036] R a Each time it appears, it is independently selected from hydrogen, deuterium, hydroxyl, amino, mercapto, cyano, oxo, -S(O)(NH)R a1 -S(O)(NCH3)R a1 -(CH2) m OR a1 -(CH2) m SR a1 -(CH2) m NHR a1 The following groups, or optionally substituted groups: C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 1-6 mercaptoalkyl, C 2-6 alkynyl or C 2-6 Alkenyl, wherein optional substitution refers to unsubstituted or substituted with one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R a1 replace;

[0037] R a1 Each time it appears, it is independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 1-6 Hydroxyalkyl, C 1-6 mercaptoalkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, 5-12 heteroaryl, R a1 Optionally by one or more (e.g., 2, 3, 4, 5, or 6) R a2 replace;

[0038] R a2 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 1-6 Hydroxyalkyl, C 1-6 mercaptoalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, 5-12 heteroaryl, R a2 Optionally by one or more R a3 replace;

[0039] R a3 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl groups, 3-10 membered heterocyclic groups;

[0040] Or, when R a When it appears twice or more, two of the R's a It forms an optional substitution with the atoms it is linked to: C 3-7 3-7 membered heterocyclic groups, C 6-10 Aryl or 5-7 heteroaryl, wherein optional substitution means unsubstituted or selected from one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R a1 replace;

[0041] R b Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylamine group;

[0042] R cEach time it appears, it is independently selected from hydroxyl, halogen, amino, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -S(O)(=NR c1 )R c1 C 1-6 Mercaptoalkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 3-15 Carbocyclic group, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-12 heteroaryl, -(CH2) m OR c1 -(CH2) m SR c1 Or -(CH2) m NHR c1 The R c Further optionally by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R c1 replace;

[0043] R c1 Each time it appears, it is independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, 5-12 heteroaryl, R c1 Further by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R c2 replace;

[0044] R c2 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups; R c2 Further by one or more R c3 replace;

[0045] R c3Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, and C. 1- 6-alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl or 3-10 membered heterocyclic groups;

[0046] R d Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, 5-12 heteroaryl; the optional substitution refers to one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituted sites of the unsubstituted or substituted group being independently replaced by R. d1 Replaced;

[0047] R d1 Each time it appears, it is independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 1-6 Hydroxyalkyl, C 1-6 mercaptoalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl and 5-12 heteroaryl groups;

[0048] R e Each time it appears, it is independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1- 6-alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, 5-12 heteroaryl;

[0049] X1 and X2 are each independently selected from CR x Or N, where R xIndependently selected from hydrogen, halogen, hydroxyl, amino, nitro, mercapto, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, 5-12 heteroaryl;

[0050] Unless otherwise stated, the heteroatoms in the above heterocyclic groups and heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3, 4, 5 or 6;

[0051] Each time m, n, o, p, or q appears, it is independently selected from 0, 1, 2, 3, 4, or 5;

[0052] The prerequisite is that the combination of the definitions of the above variables forms a stable chemical structure.

[0053] In some implementations, ring A is selected from C. 3-10 Carbocyclic group, 3-10 membered heterocyclic group; preferably, ring A is selected from C 3-8 Carbocyclic group, 3-8 membered heterocyclic group; more preferably, ring A is a monocyclic C 3-5 Carbocyclic groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl), C 5-8 Bicyclic carbocyclic groups (e.g., 5, 6, 7 or 8-membered bicyclic carbocyclic groups, preferably, the bicyclic carbocyclic groups are fused bicyclic carbocyclic groups, screwed bicyclic carbocyclic groups, or bridged bicyclic carbocyclic groups), 4-6-membered monocyclic heterocyclic groups (e.g., 4, 5, 6-membered monocyclic heterocyclic groups), or 5-8-membered bicyclic heterocyclic groups (e.g., 5, 6, 7 or 8-membered bicyclic heterocyclic groups, preferably, the bicyclic heterocyclic groups are fused bicyclic heterocyclic groups, screwed bicyclic heterocyclic groups, or bridged bicyclic heterocyclic groups);

[0054] Preferably, the heteroatom in the heterocyclic group is selected from N, O or S, and the number of heteroatoms is one or two.

[0055] In some embodiments, ring A is cyclopropyl or cyclobutyl; preferably cyclopropyl.

[0056] In some embodiments, ring B is selected from 3-10 membered heterocyclic groups (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered heterocyclic groups) and 5-10 membered heteroaryl groups (e.g., 5, 6, 7, 8, 9, 10 membered heteroaryl groups); preferably, ring B is selected from 5-6 membered heterocyclic groups and 5-6 membered heteroaryl groups; more preferably, ring B is selected from 5 membered heterocyclic groups or 5 membered heteroaryl groups; more preferably, the heteroatom in the heterocyclic group or heteroaryl group is selected from N, O or S, and the number of heteroatoms is 1 or 2.

[0057] In some implementation schemes, ring B is selected from... These represent the connection sites with the skeleton and the ring C, respectively.

[0058] In some implementation schemes, ring B is These represent the connection sites with the skeleton and loop C, respectively.

[0059] In some implementation schemes, ring B is These represent the connection sites with the skeleton and the ring C, respectively.

[0060] In some implementations, ring C is selected from C 3-10 Carbocyclic group, 3-12 membered heterocyclic group, C 6-14 aryl, 5-12-membered heteroaryl; preferably, the ring C is selected from 5-12-membered heterocyclic, 5-12-membered heteroaryl, C 6-10 aryl; preferably, the ring C is selected from 5-12 membered heteroaryl, C 6-10 Aryl (e.g., C6 aryl); preferably, the ring C is a 5-12 membered heteroaryl; more preferably, the ring C is a 9-membered bicyclic heteroaryl;

[0061] Preferably, the heteroatom in the heterocyclic group or heteroaryl group is selected from N, O or S, and the number of heteroatoms is 1, 2 or 3.

[0062] In some implementations, ring C is selected from...

[0063] Preferably, ring C is selected from

[0064] Indicates the connection site with ring B.

[0065] Preferably, ring C is selected from This indicates the connection point with ring B.

[0066] In some implementations, ring C is This indicates the connection point with ring B.

[0067] In some implementations, ring C is This indicates the connection point with ring B.

[0068] In some implementations, ring D is selected from C. 3-15 Carbocyclic groups, 3-12 membered heterocyclic groups (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered heterocyclic groups), C 6-14Aryl, 5-12 heteroaryl (e.g., 5, 6, 7, 8, 9, 10, 11, 12 heteroaryl); preferably, ring D is selected from C. 3-10 Carbocyclic group, 4-10 membered heterocyclic group, C 6-14 Aryl, 5-10 membered heteroaryl; preferably, ring D is selected from 5-10 membered heterocyclic groups (e.g., 5, 6, 7, 8, 9, 10 membered heterocyclic groups) and 5-6 membered heteroaryl groups;

[0069] Preferably, the heteroatom in the heterocyclic group or heteroaryl group is selected from N, O or S, and the number of heteroatoms is 1 or 2.

[0070] In some implementations, ring D is selected from... Preferably, ring D is

[0071] In some implementations, ring D is selected from... Indicates the connection site with the skeleton; preferably, ring D is Indicates the connection point with the skeleton.

[0072] In some implementation schemes, R a Each time it appears, it is independently selected from deuterium, hydroxyl, amino, mercapto, cyano, oxo, -S(O)(NH)R a1 -S(O)(NCH3)R a1 -(CH2) m OR a1 -(CH2) m SR a1 -(CH2) m NHR a1 , or optionally substituted with the following groups: C 1-4 Alkyl (preferably C) 1-3 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl), C 1-4 Hydroxyalkyl (preferably C) 1-3 Hydroxyalkyl groups (e.g., hydroxymethyl, hydroxyethyl, hydroxypropyl), C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), C 1-4 Alkylamine group (preferably C) 1-4 Alkyl NH-, preferably C 1-3 Alkylamine group, such as methyl-NH-, ethyl-NH-, propyl-NH-, isopropyl-NH-), C 1-4 Mercaptoalkyl (preferably C) 1-3Mercaptoalkyl, such as mercaptomethyl, mercaptoethyl, mercaptopropyl), C 2-4 Alkyne (e.g., ethynyl, propynyl, butynyl) or C 2-4 Alkenyl (e.g., vinyl, propenyl, butenyl), wherein the optional substitution refers to unsubstituted or substituted with one or more (e.g., 2, 3, 4, 5, or 6) R a1 replace.

[0073] In some implementation schemes, R a Selected from methyl, hydroxymethyl, -CH2O cyclopropyl, -CH2O methyl, C 2-4 alkynyl group, -OR a1 -CH2OR a1 -CH2OCH2R a1 -CH2NHR a1 -CH2NHCH2R a1 -CH2SR a1 -CH2SCH2R a1 -CH2S(O) 1-2 R a1 -CH2S(O) 1-2 CH2R a1 .

[0074] In some implementation schemes, R a Selected from methyl, hydroxymethyl, -CH2O cyclopropyl, -CH2O methyl.

[0075] In some implementations, or when R a When it appears twice or more, two of the R's a Linked together with their respective attached atoms, they form optionally substituted C 3-6 The group consists of a carbocyclic group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), a 3-7 membered heterocyclic group (e.g., 3, 4, 5, 6, or 7 membered heterocyclic groups; e.g., oxapentanoid, thiopentanoid, nitro(NH)apentanoid), a phenyl group, or a 5-7 membered heteroaryl group (e.g., 5, 6, or 7 membered heteroaryl), wherein the optional substitution refers to unsubstituted or selected from one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R groups. a1 replace;

[0076] Preferably, the heteroatom in the heterocyclic group or heteroaryl group is selected from N, O or S, and the number of heteroatoms is 1 or 2.

[0077] In some implementation schemes, R a1 Each time it appears, it is independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, C. 1-4 Alkyl (preferably C) 1-3Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl), C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), C 1-4 Alkylamine group (preferably C) 1-4 Alkyl NH-, preferably C 1-3 Alkylamine group, such as methyl-NH-, ethyl-NH-, propyl-NH-, isopropyl-NH-), C 1-4 Hydroxyalkyl (preferably C) 1-3 Hydroxyalkyl groups (e.g., hydroxymethyl, hydroxyethyl, hydroxypropyl), C 1-4 Mercaptoalkyl (preferably C) 1-3 Mercaptoalkyl, such as mercaptomethyl, mercaptoethyl, mercaptopropyl), C 2-4 Alkenyl (e.g., vinyl, propenyl, butenyl), C 2-4 Alkyne groups (e.g., ethynyl, propynyl, butynyl), C 3-7 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), 3-7 membered heterocyclic groups (e.g., 3, 4, 5, 6 or 7 membered heterocyclic groups), C 6-10 Aryl, 5-12 membered heteroaryl (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered heteroaryl), R a1 Optionally by one or more (e.g., 2, 3, 4, 5, or 6) R a2 replace;

[0078] Preferably, the heteroatom in the heterocyclic group or heteroaryl group is selected from N, O or S, and the number of heteroatoms is 1 or 2.

[0079] In some implementation schemes, R a1 Selected from hydrogen, deuterium, methyl, deuterated methyl (-CD3), deuterated methoxy (-OCD3), oxo, hydroxyl, -OR a2 -CH2R a2 C 3-4 Cycloalkyl.

[0080] In some implementation schemes, R a1 Selected from hydrogen, deuterium, hydroxyl, methoxy, oxo, methyl, deuterated methyl (-CD3), deuterated methoxy (-OCD3), cyclopropyl, cyclobutyl, -CH2cyclopropyl, -CH2cyclobutyl, Indicates the connection site.

[0081] In some implementation schemes, R a2 Each time it appears, it is independently selected from deuterium, halogens (e.g., fluorine, chlorine), hydroxyl, amino, mercapto, cyano, oxo, C1-4 Alkyl (preferably C) 1-3 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl), C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), C 1-4 Alkylamine group (preferably C) 1-4 Alkyl NH-, preferably C 1-3 Alkylamine group, such as methyl-NH-, ethyl-NH-, propyl-NH-, isopropyl-NH-), C 1-4 Hydroxyalkyl (preferably C) 1-3 Hydroxyalkyl groups (e.g., hydroxymethyl, hydroxyethyl, hydroxypropyl), C 1-4 Mercaptoalkyl (preferably C) 1-3 Mercaptoalkyl, such as mercaptomethyl, mercaptoethyl, mercaptopropyl), C 2-4 Alkenyl (e.g., vinyl, propenyl, butenyl), C 2-4 Alkyne groups (e.g., ethynyl, propynyl, butynyl), C 3-7 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), 3-7 membered heterocyclic groups (e.g., 3, 4, 5, 6 or 7 membered heterocyclic groups), C 6-10 Aryl, 5-12 heteroaryl (e.g., 5, 6, 7, 8, 9, 10, 11, 12 heteroaryl), R a2 Further optionally by one or more R a3 replace;

[0082] Preferably, the heteroatom in the heterocyclic group or heteroaryl group is selected from N, O or S, and the number of heteroatoms is 1 or 2.

[0083] In some implementation schemes, R a2 Each time it appears, it is independently selected from deuterium, fluorine, chlorine, cyclopropyl, cyclobutyl, and methyl.

[0084] In some implementation schemes, R a2 Each time it appears, it is independently selected from cyclopropyl.

[0085] In some implementation schemes, R a3 Each time it appears, it is independently selected from deuterium, halogens (e.g., fluorine, chlorine), hydroxyl, amino, mercapto, cyano, oxo, C 1-4 Alkyl (preferably C) 1-3 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl), C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), C 1-4 Alkylamine group (preferably C) 1-4 Alkyl NH-, preferably C1-3 Alkylamine group, such as methyl-NH-, ethyl-NH-, propyl-NH-, isopropyl-NH-), C 2-4 Alkenyl (e.g., vinyl, propenyl, butenyl), C 2-4 Alkyne groups (e.g., ethynyl, propynyl, butynyl), C 3-7 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), 3-7 membered heterocyclic groups (e.g., 3, 4, 5, 6 or 7 membered heterocyclic groups, preferably oxetane or hydrogenated furan);

[0086] Preferably, the heteroatom in the heterocyclic group is selected from N, O or S, and the number of heteroatoms is 1 or 2.

[0087] In some implementation schemes, R a3 Selected from fluorine, chlorine, and methyl.

[0088] In some implementation schemes, R a Selected from methyl, ethynyl, This indicates the connection point with ring A.

[0089] In some implementation schemes, R a Selected from methyl, This indicates the connection point with ring A.

[0090] In some implementation schemes, R a Selected from methyl.

[0091] In some implementation schemes, R a Selected from This indicates the connection point with ring A.

[0092] In some implementation schemes, Selected from

[0093] In some implementation schemes, for In some implementation schemes, for

[0094] In some implementation schemes, Selected from

[0095] In some implementation schemes, Selected from

[0096] In some implementation schemes, for In some implementation schemes, for

[0097] In some implementation schemes, Selected from

[0098] ; Indicates the connection site. This indicates a connection to an N atom.

[0099] In some implementation schemes, Selected from Indicates the connection site. This indicates a connection to an N atom.

[0100] In some implementation schemes, Selected from Indicates the connection site. This indicates a connection to an N atom.

[0101] In some implementation schemes, Selected from Indicates the connection site. This indicates a connection to an N atom.

[0102] In some implementation schemes, Selected from Indicates the connection site. This indicates a connection to an N atom.

[0103] In some implementation schemes, Selected from Indicates the connection site. This indicates a connection to an N atom.

[0104] In some implementation schemes, Selected from Indicates the connection site. This indicates a connection to an N atom.

[0105] In some implementation schemes, R b Each time it appears, it is independently selected from deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, and C. 1-4 Alkyl (preferably C) 1-3Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl), C 1-4 Hydroxyalkyl (preferably C) 1-3 Hydroxyalkyl groups (e.g., hydroxymethyl, hydroxyethyl, hydroxypropyl), C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), C 1-4 Alkylamine group (preferably C) 1-4 Alkyl NH-, preferably C 1-3 Alkylamine group, for example, methyl-NH-, ethyl-NH-, propyl-NH-, isopropyl-NH-).

[0106] In some implementation schemes, R b It is an oxo group.

[0107] In some implementation schemes, R b It is hydrogen.

[0108] In some implementation schemes, R c Each time it appears, it is independently selected from hydroxyl, halogen, amino, mercapto, cyano, oxo, C 1-4 Alkyl (preferably C) 1-3 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl), C 1-4 Hydroxyalkyl (preferably C) 1-3 Hydroxyalkyl groups, such as hydroxymethyl, hydroxyethyl, and hydroxypropyl, -S(O) (=NR) c1 )R c1 (Preferred -S(O)(=NC) 1-3 Alkyl)R c1 or -S(O)(=NH)R c1 Further optimization -S(O)(=NC) 1-3 Alkyl)C 3-6 cycloalkyl or -S(O)(=NH)C 3-6 Cycloalkyl; for example, -S(O) (=N-methyl)cyclopropyl or -S(O) (=NH)cyclopropyl), C 1-4 Mercaptoalkyl (preferably C) 1-3 Mercaptoalkyl groups, such as mercaptomethyl, mercaptoethyl, mercaptopropyl, and aminoC, are mentioned. 1-4 Alkyl (preferably amino C) 1-3 Alkyl groups, such as aminomethyl, aminoethyl, and aminopropyl, C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), C 1-4 Alkylthio (preferably C) 1-3 Alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio), C 1-4 Alkylamine group (preferably C)1-4 Alkyl NH-, preferably C 1-3 Alkylamine group, such as methyl-NH-, ethyl-NH-, propyl-NH-, isopropyl-NH-), C 3-12 Carbocyclic group (preferably C) 3-7 Carbocyclic group; further preferred C 3-6 Carbocyclic groups; for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), 3-12 membered heterocyclic groups (preferably 3-10 membered heterocyclic groups; more preferably 3-9 membered heterocyclic groups, such as 3, 4, 5, 6, 7, 8, 9 membered heterocyclic groups), C 6-10 Aryl, 5-12-membered heteroaryl (preferably 5-10-membered heteroaryl, more preferably 5-9-membered heteroaryl, such as 5, 6, 7, 8, 9-membered heteroaryl), -(CH2) m OR c1 -(CH2) m SR c1 Or -(CH2) m NHR c1 The R c Further optionally by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R c1 replace;

[0109] Preferably, the heteroatom in the heterocyclic group or heteroaryl group is selected from N, O or S, and the number of heteroatoms is 1 or 2.

[0110] In some implementation schemes, R c Each time it appears, it is independently selected from halogen (preferably fluorine), cyclopropyl, -S(O)(=N-methyl)cyclopropyl, methyl, ethyl, hydroxyethyl, -CH2CH2S(R) c1 ) 1-2 R c1 Tetrahydrofuranyl, -Ethylene R c1 ,-Ethylene OR c1 ,-EthyleneSR c1 ,-Ethylene NHR c1 -CH(R) c1 )2、-methylene R c1 ,-methylene OR c1 ,-methylene SR c1 ,-methylene NHR c1 .

[0111] In some implementation schemes, R c1 Each time it appears, it is independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, C. 1-4 Alkyl (preferably C) 1-3 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl), C1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), C 1-4 Alkylthio (preferably C) 1-3 Alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio), C 1-4 Alkylamine group (preferably C) 1-4 Alkyl NH-, preferably C 1-3 Alkylamine group, such as methyl-NH-, ethyl-NH-, propyl-NH-, isopropyl-NH-), C 2-4 Alkenyl (e.g., vinyl, propenyl, butenyl), C 2-4 Alkyne groups (e.g., ethynyl, propynyl, butynyl), C 3-10 cycloalkyl (preferably C) 3-7 Cycloalkyl groups; for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), 3-10 membered heterocyclic groups (preferably 3-9 membered heterocyclic groups, more preferably 3-7 membered heterocyclic groups, such as 3, 4, 5, 6, 7 membered heterocyclic groups), C 6-10 Aryl, 5-12-membered heteroaryl (preferably 5-10-membered heteroaryl, more preferably 5-9-membered heteroaryl, for example, 5, 6, 7, 8, 9-membered heteroaryl), R c1 Further optionally by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R c2 replace;

[0112] Preferably, the heteroatom in the heterocyclic group or heteroaryl group is selected from N, O or S, and the number of heteroatoms is 1 or 2.

[0113] In some implementation schemes, R c1 Selected from hydrogen, methyl, methoxy, hydroxy, oxo, -C(R) c2 3. C 2-4 Alkyne groups (e.g., ethynyl, propynyl, butynyl), -C 2-4 alkynyl R c2 Cyclopropyl CH2R c2 ; Indicates the connection site.

[0114] In some implementation schemes, R c1 Selected from hydrogen, methyl, oxo, methoxy, hydroxy, cyclopropyl, -CHF2, -CH2F, CF3, -CD3, ethynyl, propynyl, -CH2cyclopropyl Indicates the connection site.

[0115] In some implementation schemes, Rc2 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, C. 1-4 Alkyl (preferably C) 1-3 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl), C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), C 1-4 Alkylamine group (preferably C) 1-4 Alkyl NH-, preferably C 1-3 Alkylamine group, such as methyl-NH-, ethyl-NH-, propyl-NH-, isopropyl-NH-), C 2-4 Alkenyl (e.g., vinyl, propenyl, butenyl), C 2-4 Alkyne groups (e.g., ethynyl, propynyl, butynyl), C 3-10 cycloalkyl (preferably C) 3-7 Cycloalkyl groups; for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), 3-10 membered heterocyclic groups (preferably 3-9 membered heterocyclic groups, more preferably 3-7 membered heterocyclic groups, such as 3, 4, 5, 6, 7 membered heterocyclic groups); R c2 Further optionally by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R c3 replace;

[0116] Preferably, the heteroatom in the heterocyclic group is selected from N, O or S, and the number of heteroatoms is 1 or 2.

[0117] In some implementation schemes, R c2 Selected from hydrogen, C 1-3 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl) and C 3-5 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl); R c2 Further optionally by one or more (e.g., 2, 3, 4, 5, 6, or 7) R c3 replace.

[0118] In some implementation schemes, R c2 Selected from hydrogen, halogens (e.g., fluorine, chlorine, bromine, preferably fluorine), and deuterated C 1-3 Alkyl groups (e.g., deuterated methyl (-CD3), deuterated ethyl (-CH2CD3 or -CD2CD3), deuterated propyl (-CH2CH2CD3, -CH2CD2CD3 or -CD2CD2CD3), deuterated isopropyl (-CH(CD3)2 or -CD(CD3)2), halogenated C 1- 3-alkyl (preferably fluorinated C) 1-3 Alkyl, Chlorinated C 1-3 Alkyl; more preferably fluorinated C1-2 Alkyl, Chlorinated C 1-2 Alkyl groups; for example, -CF3, -CHF2, -CH2F), C 3-5 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl), C 1-3 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), hydroxyl, C 1-3 Alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy).

[0119] In some implementation schemes, R c2 Selected from hydrogen, deuterated methyl (-CD3), -CF3, -CHF2, cyclopropyl, Represents the connection site.

[0120] In some implementation schemes, R c2 Selected from hydrogen, deuterium, halogens (e.g., fluorine, chlorine, bromine, preferably fluorine), cyclopropyl, Methyl, hydroxyl, methoxy, cyclobutyl; Represents the connection site.

[0121] In some implementation schemes, R c3 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, and C. 1-4 Alkyl (preferably C) 1-3 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl), C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), C 1-4 Alkylamine group (preferably C) 1-4 Alkyl NH-, preferably C 1-3 Alkylamine group, such as methyl-NH-, ethyl-NH-, propyl-NH-, isopropyl-NH-), C 2-4 Alkenyl (e.g., vinyl, propenyl, butenyl), C 2-4 Alkyne groups (e.g., ethynyl, propynyl, butynyl), C 3-10 cycloalkyl (preferably C) 3-7 Cycloalkyl; for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) or 3-10 membered heterocyclic groups (preferably 3-9 membered heterocyclic groups, more preferably 3-7 membered heterocyclic groups, such as 3, 4, 5, 6, 7 membered heterocyclic groups, such as oxetane, hydrogenated furan);

[0122] Preferably, the heteroatom in the heterocyclic group is selected from N, O or S, and the number of heteroatoms is 1 or 2.

[0123] In some implementation schemes, R c3 It is selected from hydrogen, halogens (e.g., fluorine, chlorine, bromine; preferably fluorine) and methyl.

[0124] In some implementation schemes, R c3 It is selected from hydrogen, cyclopropyl, methyl, cyclobutyl, and halogen (preferably fluorine).

[0125] In some implementation schemes, R c Selected from F, cyclopropyl, methyl, Represents the connection site.

[0126] In some implementation schemes, R c Further include Represents the connection site.

[0127] In some implementation schemes, R c Further include Represents the connection site.

[0128] In some implementation schemes, Selected from Represents the connection site; preferably, Selected from Represents the connection site.

[0129] In some implementation schemes, Selected from Represents the connection site.

[0130] In some implementations, the Further include

[0131] In some implementation schemes, Selected from Represents the connection site.

[0132] In some implementations, the Further include Represents the connection site.

[0133] In some implementations, the Further include Represents the connection site.

[0134] In some implementation schemes, R d Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, or optionally substituted with the following groups: C 1-4 Alkyl (preferably C) 1-3 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl), C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), C 1-4 Alkylamine group (preferably C) 1-4 Alkyl NH-, preferably C 1-3 Alkylamine group, such as methyl-NH-, ethyl-NH-, propyl-NH-, isopropyl-NH-), C 2-4 Alkenyl (e.g., vinyl, propenyl, butenyl), C 2-4 Alkyne groups (e.g., ethynyl, propynyl, butynyl), C 3-10 cycloalkyl (preferably C) 3-7 Cycloalkyl groups; for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), 3-10 membered heterocyclic groups (preferably 3-9 membered heterocyclic groups, more preferably 3-7 membered heterocyclic groups, such as 3, 4, 5, 6, 7 membered heterocyclic groups), C 6-10 Aryl, 5-12 membered heteroaryl (preferably 5-10 membered heteroaryl, more preferably 5-9 membered heteroaryl, for example, 5, 6, 7, 8, 9 membered heteroaryl); the optional substitution refers to one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituted sites of unsubstituted or substituted groups being independently replaced by R. d1 Replaced;

[0135] Preferably, the heteroatom in the heterocyclic group or heteroaryl group is selected from N, O or S, and the number of heteroatoms is 1 or 2.

[0136] In some implementation schemes, R d Selected from hydrogen, methyl, hydroxyl, and oxo groups.

[0137] In some implementation schemes, R d1 Each time it appears, it is independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, C. 1-4 Alkyl (preferably C) 1-3Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl), C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), C 1-4 Alkylamine group (preferably C) 1-4 Alkyl NH-, preferably C 1-3 Alkylamine group, such as methyl-NH-, ethyl-NH-, propyl-NH-, isopropyl-NH-), C 1-4 Hydroxyalkyl (preferably C) 1-3 Hydroxyalkyl groups (e.g., hydroxymethyl, hydroxyethyl, hydroxypropyl), C 1-4 Mercaptoalkyl (preferably C) 1-3 Mercaptoalkyl, such as mercaptomethyl, mercaptoethyl, mercaptopropyl), C 2-4 Alkenyl (e.g., vinyl, propenyl, butenyl), C 2-4 Alkyne groups (e.g., ethynyl, propynyl, butynyl), C 3-7 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), 3-7 membered heterocyclic groups (e.g., 3, 4, 5, 6 or 7 membered heterocyclic groups), C 6-10 Aryl, 5-12 heteroaryl (5, 6, 7, 8, 9, 10, 11, 12 heteroaryl);

[0138] Preferably, the heteroatom in the heterocyclic group or heteroaryl group is selected from N, O or S, and the number of heteroatoms is 1 or 2.

[0139] In some implementation schemes, R d1 Selected from methyl and hydrogen.

[0140] In some implementation schemes, R d Selected from hydrogen, methoxy, methyl, or oxo groups; or, when p is greater than or equal to 2, the two R groups are selected from hydrogen, methoxy, methyl, or oxo groups. d Together with the C atoms they are linked to, they form a cyclopropyl group. Preferably, R d Selected from hydrogen, methoxy, methyl, or oxo groups; or, when p is greater than or equal to 2, the two R groups are selected from hydrogen, methoxy, methyl, or oxo groups. d It links together with the C atoms that are connected to it to form in, Indicates the connection site.

[0141] In some implementation schemes, for Indicates the connection site; preferably, for Indicates the connection site; more preferably, for Indicates the connection site.

[0142] In some implementation schemes, Selected from

[0143] In some implementations, the Further include

[0144] In some implementation schemes, Selected from Indicates the connection site; preferably, Selected from Indicates the connection site.

[0145] In some implementation schemes, for Indicates the connection site; preferably, for Indicates the connection site.

[0146] In some implementations, the Further include Indicates the connection site.

[0147] In some implementation schemes, R e Each time it appears, it is independently selected from halogens (e.g., fluorine, chlorine), hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-4 Alkyl (preferably C) 1-3 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl), C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), C 1-4 Alkylamine group (preferably C) 1-4 Alkyl NH-, preferably C 1-3 Alkylamine group, such as methyl-NH-, ethyl-NH-, propyl-NH-, isopropyl-NH-), C 2-4 Alkenyl (e.g., vinyl, propenyl, butenyl), C 2-4 Alkyne groups (e.g., ethynyl, propynyl, butynyl), C 3-10 cycloalkyl (preferably C) 3-7Cycloalkyl groups; for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), 3-10 membered heterocyclic groups (preferably 3-9 membered heterocyclic groups, more preferably 3-7 membered heterocyclic groups, such as 3, 4, 5, 6, 7 membered heterocyclic groups), C 6-10 Aryl, 5-12-membered heteroaryl (preferably 5-10-membered heteroaryl, more preferably 5-9-membered heteroaryl, for example, 5, 6, 7, 8, 9-membered heteroaryl);

[0148] Preferably, the heteroatom in the heterocyclic group or heteroaryl group is selected from N, O or S, and the number of heteroatoms is 1 or 2.

[0149] In some implementation schemes, R e Selected from halogens (preferably fluorine or chlorine, more preferably fluorine) and methyl.

[0150] In some implementation schemes, for Represents the connection site.

[0151] In some implementations, X1 and X2 are each independently selected from CR x Or N, where R x Independently selected from hydrogen, halogen (e.g., fluorine, chlorine), hydroxyl, amino, nitro, mercapto, cyano, C 1-4 Alkyl (preferably C) 1-3 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl), C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), C 1-4 Alkylamine group (preferably C) 1-4 Alkyl NH-, preferably C 1-3 Alkylamine group, such as methyl-NH-, ethyl-NH-, propyl-NH-, isopropyl-NH-), C 2-4 Alkenyl (e.g., vinyl, propenyl, butenyl), C 2-4 Alkyne groups (e.g., ethynyl, propynyl, butynyl), C 3-10 cycloalkyl (preferably C) 3-7 Cycloalkyl groups; for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), 3-10 membered heterocyclic groups (preferably 3-9 membered heterocyclic groups, more preferably 3-7 membered heterocyclic groups, such as 3, 4, 5, 6, 7 membered heterocyclic groups), C 6-10 Aryl, 5-12-membered heteroaryl (preferably 5-10-membered heteroaryl, more preferably 5-9-membered heteroaryl, for example, 5, 6, 7, 8, 9-membered heteroaryl);

[0152] Preferably, the heteroatom in the heterocyclic group or heteroaryl group is selected from N, O or S, and the number of heteroatoms is 1 or 2.

[0153] In some implementations, X1 is CH and X2 is N; or, X1 is N and X2 is CH; or, X1 is CH and X2 is CH; or, X1 is N and X2 is N.

[0154] In some implementations, X1 and X2 are each independently selected from CH.

[0155] In some implementations, m, n, o, p, or q are each independently selected from 0, 1, 2, or 3 each time they appear; preferably, m, n, o, p, or q are each independently selected from 0, 1, or 2 each time they appear.

[0156] In some implementations, m is 0, 1, or 2; preferably, m is 1 or 2; more preferably, m is 1.

[0157] In some implementations, n is 0, 1, or 2; preferably, n is 0 or 1; more preferably, n is 1.

[0158] In some implementations, o is 0, 1, or 2; preferably, o is 1 or 2; more preferably, o is 2.

[0159] In some implementations, p is 0, 1, or 2; preferably, p is 0 or 2; more preferably, p is 2.

[0160] In some implementations, q is 0, 1, 2 or 3; preferably, q is 2 or 3; more preferably, q is 3.

[0161] In some implementations, the condition is that when ring B is Ring A is cyclopropyl, and ring D is... Ring C is When R is located on the N atom c for hour, Not for (Or, when R) c -(CH2) m OR c1 (e.g., -ethylene OR) c1 ,-methylene OR c1 When ), the R c Selected from ); or, when ring B is Ring D is Ring C is At that time, ring A and its substituents are not Or, when ring B is Ring A is cyclopropyl, and ring D is... Ring C is R a Selected from -CH2NH(CH2) 0-2 C 3-5 Cycloalkyl or -CH2S(CH2) 0-2 C 3-5 cycloalkyl;

[0162] Among them, m1 and n1 are each independently selected from 0, 1, 2, 3, 4 or 5.

[0163] In some implementations, the condition is that when ring B is for for Ring C is R c for hour, Not for (Or, when R) c -(CH2) m OR c1 (e.g., -ethylene OR) c1 ,-methylene OR c1 When ), the R c Selected from ); where m1 is selected from 1, 2, 3, 4 or 5, and n1 is selected from 0, 1, 2, 3, 4 or 5. Indicates the connection site.

[0164] In some implementations, the condition is that when ring B is Ring A is cyclopropyl, and ring D is... Meanwhile, ring C is When R c for hour, Not for (Or, when R) c -(CH2) m OR c1 (e.g., -ethylene OR) c1 ,-methylene OR c1 When ), the R c Selected from Preferably, at least one R c for And the R c lie in On the N atom, and Not for (or, the R) c Selected from );in, The connection sites are indicated by m1 and n1, which are each independently selected from 0, 1, 2, 3, 4 or 5.

[0165] In some implementations, when ring B is for for At that time, one of the following conditions must be met:

[0166] (1) When R c It is methyl or cyclopropyl, R a for When m1 is 1, 2, or 3, n1 is 1, 2, or 3; R a2 As defined by compound (I); preferably, m1 is 1 and n1 is 1;

[0167] (2) When for R c for At that time, the Not for Where m1 is 1, 2, 3, 4 or 5, and n1 is 0, 1, 2, 3, 4 or 5; R c2 As defined by compound (I); preferably, m1 is 2, n1 is 0 or 1; or, when for R c -(CH2) m OR c1 (e.g., -ethylene OR) c1 ,-methylene OR c1 When ), the R c Selected from

[0168] in, Indicates the connection site.

[0169] In some implementations, when ring B is Ring A is cyclopropyl, and ring D is... Meanwhile, ring C is At least one of the following conditions must be met:

[0170] (1)R a for m1 is 1, 2 or 3, and n1 is 1, 2 or 3;

[0171] (2)R c for and Not for Or, when R c -(CH2) m OR c1 (e.g., -ethylene OR) c1 ,-methylene OR c1 When ), the R c Selected from

[0172] in, The connection sites are indicated by m1 and n1, which are each independently selected from 0, 1, 2, 3, 4 or 5.

[0173] In some embodiments, the compound of formula (I) has the following structure:

[0174] Among them, rings A, B, D, C, and R a R b R c R d R e X1, X2, m, n, o, p, and q are defined as compounds of formula (I).

[0175] In some embodiments, the compound of formula (I) is a compound as shown below.

[0176] in, Indicates a single bond or a double bond;

[0177] Ring D, Ring C, R a R c R d X1, X2, m, o, and p are defined as compounds of formula (I).

[0178] In some embodiments, the compound of formula (I) is a compound as shown below.

[0179] in, Indicates a single bond or a double bond;

[0180] X3 is CH or N; preferably CH;

[0181] R c It can be located anywhere in the double-ring system;

[0182] Ring D, R a R c R d The compounds X1, X2, o, and p are defined as those of formula (I).

[0183] In some embodiments, the compound of formula (I) is a compound as shown below.

[0184] in, Indicates a single bond or a double bond;

[0185] X3 is CH or N; preferably CH;

[0186] Ring D, R a R c R d The compounds X1, X2 and p are defined as those of formula (I).

[0187] In some embodiments, the compound of formula (I) is a compound as shown below.

[0188] in, Indicates a single bond or a double bond;

[0189] Ring D, Ring C, R a R c R d X1, X2, p, m and o are defined as compounds of formula (I).

[0190] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of this application.

[0191] In some embodiments, this disclosure provides the following compounds, or tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compounds have the structures shown in Table 1' below:

[0192] Table 1'

[0193] In some embodiments, this disclosure provides the following compounds, or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compounds have the structures shown in Table 1 below:

[0194] Table 1

[0195] In some embodiments, this disclosure provides the following compounds, or their tautomers, stereoisomers, or pharmaceutically acceptable salts, as shown in Table 1-1.

[0196] Table 1-1

[0197] Secondly, this disclosure provides a method for preparing the compound represented by formula (I) or its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, comprising:

[0198] Intermediate 1.1 was deprotected to obtain intermediate 1.2;

[0199] Intermediate 1.2 and intermediate 1.3 undergo a condensation reaction to give the compound shown in formula (I);

[0200] PG is an amino protecting group, such as tert-butoxycarbonyl (Boc);

[0201] Among them, rings A, B, D, C, and R a R b R c R d R e X1, X2, m, n, o, p, and q are as defined in the compound of formula (I) above.

[0202] In some implementations, the preparation method of intermediate 1.1 includes:

[0203] Method 1: When ring B is hour, Indicates the connection site.

[0204] Intermediate 2.1 reacts with intermediate 2.2 to yield intermediate 1.1'; or,

[0205] Method 2: When ring B is hour, Indicates the connection site.

[0206] Intermediate 2.3 reacts with chloroethyl isocyanate to give intermediate 2.4, which then undergoes a substitution reaction to give cyclized intermediate 2.5, and finally reacts with intermediate 2.2 to give intermediate 1.1”;

[0207] Among them, rings C and R c R e o and q are as defined in the compound of formula (I) above.

[0208] In some embodiments, the preparation method of intermediate 1.3 includes:

[0209] Method 1: When ring D is hour, Indicates the connection site.

[0210] First, starting material 3.1 reacts with material 3.2 to obtain intermediate 3.3. Then, the cyano fragment undergoes transformation to obtain intermediate 3.4. Next, a cyclization reaction occurs to obtain intermediate 3.5. Finally, R is removed. y To obtain intermediate 1.3' containing a carboxyl group; or,

[0211] Method 2: When ring D is an aromatic ring,

[0212] First, a cyanomethyl fragment is introduced from starting material 3.6 to obtain intermediate 3.7. Then, ring A is constructed to obtain intermediate 3.8. Next, the cyano fragment undergoes transformation to obtain intermediate 3.9. Then, a ring-closing reaction occurs to obtain intermediate 3.10, and then R is removed. y Intermediate 3.11, containing a carboxyl group, is obtained, and finally undergoes a coupling reaction to give intermediate 1.3; or, method three: when ring D is an aromatic ring,

[0213] First, 3.11 is converted into boric acid or borate ester, and finally, intermediate 1.3 is obtained by Suzuki coupling.

[0214] Among them, the above-mentioned rings A, D, and R a R d X1, X2, m and p are as defined in the compound of formula (I) above.

[0215] In some embodiments, the above preparation method further includes a protection and partial deprotection reaction step.

[0216] In some implementations, the following exemplary preparation methods are provided:

[0217] First, compound 82 undergoes a substitution reaction to give compound 38-0. Finally, the hydroxyl group is converted into the corresponding structural fragment to obtain the final compound.

[0218] or,

[0219] The reaction steps are similar to those described above;

[0220] Among them, R c1 As defined by the compound of formula (I) above.

[0221] In aspect 2.1, this disclosure provides intermediates in the general route as described in the second aspect, as well as intermediates in the preparation examples or embodiments of this disclosure.

[0222] In some embodiments, this disclosure provides the following compounds,

[0223] PG is an amino protecting group, such as tert-butoxycarbonyl (Boc);

[0224] Ring A, Ring B, Ring D, Ring C, R a R b R c R d R e X1, X2, m, n, o, p, and q are as defined in the compound of formula (I) above.

[0225] Thirdly, this disclosure provides a pharmaceutical composition comprising the compounds described in this disclosure (compounds of formula I, I-1, I-2, I-3, I-4, II-1, II-2, II-3, II-4, III, III-1, III-2, III-3, III-4, III-5, or the compounds shown in Table 1 or Table 1') or their tautomers, stereoisomers or pharmaceutically acceptable salts thereof, optionally further comprising pharmaceutically acceptable excipients.

[0226] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound as described above (Formula I, I-1, I-2, I-3, I-4, II-1, II-2, II-3, II-4, III, III-1, III-2, III-3, III-4, III-5, or the compounds shown in Table 1 or Table 1') or its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, optionally further comprising pharmaceutically acceptable excipients.

[0227] The administration of the disclosed compounds (of formula I, I-1, I-2, I-3, I-4, II-1, II-2, II-3, II-4, III, III-1, III-2, III-3, III-4, III-5, or the compounds shown in Table 1 or Table 1') or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof can be carried out in pure form or as a suitable pharmaceutical composition by any acceptable route of administration of a medicament for similar use. The pharmaceutical compositions of this disclosure can be prepared by combining the disclosed compounds with suitable pharmaceutically acceptable excipients. The pharmaceutical compositions of this disclosure can be formulated into solid, semi-solid, liquid, or gaseous formulations. Generally, the above pharmaceutical compositions can be prepared using excipients conventional in the field of pharmaceutical preparations by conventional preparation methods.

[0228] Fourthly, this disclosure provides the use of the compounds as described above (compounds I, I-1, I-2, I-3, I-4, II-1, II-2, II-3, II-4, III, III-1, III-2, III-3, III-4, III-5, or the compounds shown in Table 1 or Table 1') or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of this disclosure, as pharmaceuticals or in the preparation of pharmaceuticals; preferably, the pharmaceutical is a GLP-1R agonist; more preferably, the pharmaceutical is for the treatment of and / or a drug for preventing GLP-1R-related conditions; more preferably, the drug is a drug for treating and / or preventing conditions mediated by GLP-1R; more preferably, the drug is a drug for treating and / or preventing conditions caused by or mediated by reduced GLP-1R activity; more preferably, the drug is a drug for preventing and / or treating conditions by activating GLP-1R-mediated cascade signals; more preferably, the conditions include diabetes, overweight or obesity, non-alcoholic fatty liver disease (or metabolic dysfunction-related fatty liver disease), Alzheimer's disease, etc.

[0229] In some embodiments, the use of the drug is to treat and / or prevent diabetes, overweight or obesity, non-alcoholic fatty liver disease (or metabolic disorder-related fatty liver disease) or Alzheimer's disease; preferably, the drug is to treat and / or prevent diabetes, overweight or obesity; preferably, the diabetes is type 2 diabetes.

[0230] Fifthly, this disclosure provides compounds as described above (compounds I, I-1, I-2, I-3, I-4, II-1, II-2, II-3, II-4, III, III-1, III-2, III-3, III-4, III-5, or compounds shown in Table 1 or Table 1') or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof, for the treatment and / or prevention of conditions; preferably, the conditions are GLP-1R-related conditions; more preferably, the conditions are GLP-1R-mediated conditions; more preferably, the conditions are conditions caused by or mediated by reduced GLP-1R activity; more preferably, the conditions include diabetes, overweight or obesity, non-alcoholic fatty liver disease (or metabolic dysfunction-related fatty liver disease), Alzheimer's disease, etc.; more preferably, the conditions include diabetes, overweight or obesity; preferably, the diabetes is type 2 diabetes.

[0231] In some embodiments, the condition is diabetes, overweight or obesity, non-alcoholic fatty liver disease (or metabolic disorder-related fatty liver disease) or Alzheimer's disease; preferably, the condition is diabetes, overweight or obesity; preferably, the diabetes is type 2 diabetes.

[0232] In a sixth aspect, this disclosure provides a method for treating a condition, the method comprising: administering to an individual in need a therapeutically effective amount of the compound as described above (compounds of formula I, I-1, I-2, I-3, I-4, II-1, II-2, II-3, II-4, III, III-1, III-2, III-3, III-4, III-5, or the compounds shown in Table 1 or Table 1') or its tautomers, stereoisomers or pharmaceutically acceptable salts thereof or the pharmaceutical composition of this disclosure; preferably, the condition is a GLP-1R-related condition; more preferably, the condition is a GLP-1R-mediated condition; more preferably, the condition is a condition caused by or mediated by reduced GLP-1R activity; more preferably, the condition includes diabetes, overweight or obesity, non-alcoholic fatty liver disease (or metabolic dysfunction-related fatty liver disease), Alzheimer's disease, etc.; more preferably, the condition includes diabetes, overweight or obesity; preferably, the diabetes is type 2 diabetes.

[0233] In some embodiments, the condition is diabetes, overweight or obesity, non-alcoholic fatty liver disease (or metabolic disorder-related fatty liver disease) or Alzheimer's disease; preferably, the condition is diabetes, overweight or obesity; preferably, the diabetes is type 2 diabetes.

[0234] In some embodiments, the uses or methods provided in this disclosure include the use of the compounds described in this disclosure (Formula I, I-1, I-2, I-3, I-4, II-1, II-2, II-3, II-4, III, III-1, III-2, III-3, III-4, III-5, or the compounds shown in Table 1 or Table 1') or their tautomers, stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of this disclosure, in combination with another, two or more compounds or pharmaceuticals having the same or similar indications.

[0235] This disclosure also provides a composition comprising the compounds described in this disclosure (compounds of formula I, I-1, I-2, I-3, I-4, II-1, II-2, II-3, II-4, III, III-1, III-2, III-3, III-4, III-5, or the compounds shown in Table 1 or Table 1') or their tautomers, stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described in this disclosure, as well as another, two or more compounds having the same or similar indications.

[0236] This disclosure also provides the use of the compounds as described above (compounds of formula I, I-1, I-2, I-3, I-4, II-1, II-2, II-3, II-4, III, III-1, III-2, III-3, III-4, III-5, or those shown in Table 1 or Table 1') or their tautomers, stereoisomers or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof as GLP-1R agonists.

[0237] This disclosure also provides a composition comprising the compound (of formula I, formula I-1, formula I-2, formula I-3, formula I-4, formula II-1, formula II-2, formula II-3, formula II-4, formula III, formula III-1, formula III-2, formula III-3, formula III-4, formula III-5, the compound shown in Table 1, the compound shown in Table 1', or the compound shown in Table 1-1) or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

[0238] definition

[0239] Unless otherwise stated, the following terms as used in this disclosure have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0240] C in this article m-nThis refers to the part having an integer number of carbon atoms within a given range. For example, "C 1-6 "" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0241] When any variable (e.g., R) a When a group, a site, or an atom appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group, a site, or an atom is represented by two R... a Replaced, then each R a Each has its own independent options.

[0242] In this document, "multiple" refers to 2 to 10, for example, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 2, 3, 4, 5, 6, 7, 8 or 9; preferably 2, 3, 4, 5, 6, 7 or 8; preferably 2, 3, 4 or 5; preferably 2 or 3.

[0243] The terms “optional,” “arbitrary,” “optionally,” or “arbitrarily” refer to events or conditions that are subsequently described but are not required to occur, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0244] The term "optional substitution" means that the specified group is unsubstituted or substituted by one or more substituents independently selected from possible substituents, that is, one or more hydrogens on the specified group are replaced by substituents.

[0245] The term "oxo group" refers to a double bond (=O) formed when two hydrogen atoms at the same substitution position are replaced by the same oxygen atom.

[0246] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group comprising 1-20 carbon atoms, preferably comprising 1-10 carbon atoms (i.e., C10). 1-10 Alkyl groups, more preferably containing 1-8 carbon atoms (C64- ... 1-8 Alkyl groups, more preferably containing 1-6 carbon atoms (i.e., C64-C ... 1-6 Alkyl), for example, "C 1-6 "Alkyl" refers to a group that is alkyl and has 1 to 6 carbon atoms in its carbon chain (specifically, 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0247] Unless otherwise specified, the term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Alkenyl groups may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C2H2O). 2-10 Alkenyl), further preferably containing 2-8 carbon atoms (C 2-8 Alkenyl), more preferably containing 2-6 carbon atoms (i.e., C14-C2 ... 2-6 alkenyl), 2-5 carbon atoms (i.e., C) 2-5 alkenyl), 2-4 carbon atoms (i.e., C) 2-4 alkenyl), 2-3 carbon atoms (i.e., C) 2-3 Alkenyl), 2 carbon atoms (i.e., C2 alkenyl), for example "C 2-6 "Alkenyl" refers to a group that is alkenyl and has 2 to 6 carbon atoms in its carbon chain (specifically, 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.

[0248] Unless otherwise specified, the term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond. The alkynyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C2H2O). 2-10 Alkyne group), further preferably containing 2-8 carbon atoms (C 2-8 Alkyne group), more preferably containing 2-6 carbon atoms (i.e., C64-C ... 2-6 acetylsyl group), 2-5 carbon atoms (i.e., C64) 2-5 acetylsyl group), 2-4 carbon atoms (i.e., C64) 2-4 acetylsyl group), 2-3 carbon atoms (i.e., C64) 2-3 Alkynyl group), 2 carbon atoms (i.e., C2 alkynyl group), for example "C 2-6 "Alynyl" refers to a group that is alkynyl and has 2 to 6 carbon atoms in its carbon chain (specifically 2, 3, 4, 5, or 6). Non-limiting examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.

[0249] Unless otherwise specified, the term "alkoxy" refers to -O-alkyl, which is defined as above, i.e., containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, and even more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc.

[0250] Unless otherwise specified, the term "alkylamine" refers to -NR′R″, where R′ and R″ are the same or different, i.e., both are alkyl groups as defined above, or R′ is H and R″ is an alkyl group as defined above, i.e., containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, and even more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). For example, "C 1-6 "Alkylamine group" refers to -NHC 1-6 Alkyl or -N(C) 1-6 Alkyl group 2, preferably -NHC 1-6 Alkyl groups. Examples include, but are not limited to, -NH(CH3), -N(CH3)(CH3), -N(CH2CH3)(CH3), -N(CH2CH3)[CH(CH3)2], etc.

[0251] Unless otherwise specified, the term "hydroxyalkyl" refers to -alkyl-OH, and the definition of alkyl is the same as above, for example, "C 1-6 "Hydroxyalkyl" refers to -C 1-6 Alkyl-OH. The term "mercaptoalkyl" refers to -alkyl-SH, where the alkyl group is defined as above. For example, "C 1-6 "Mercaptoalkyl" refers to -C 1-6 Alkyl-SH.

[0252] Unless otherwise specified, the term "hydroxyl" refers to -OH. The term "mercapto" refers to -SH. The term "amino" refers to -NH2. The term "cyano" refers to -CN.

[0253] Unless otherwise specified, -S(O)(NH)R a1 This refers to -S(=O)(=NH)R a1 -S(O)(NCH3)R a1 This refers to -S(=O)(=NCH3)R a1 .

[0254] Unless otherwise specified, the terms "halogen" or "halogenated" refer to F, Cl, Br, and I. The term "halogenated alkyl" refers to an alkyl group as defined above in which one, two, or more hydrogen atoms, or all hydrogen atoms, are replaced by a halogen. Representative examples of halogenated alkyl groups include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, and CF2CF3.

[0255] Unless otherwise specified, the term "carbocyclic group" or "carbocyclic" refers to a non-aromatic cyclic hydrocarbon group ("C") having 3 to 15 ring carbon atoms. 3-15 A carbocyclic group (“C”) or a non-aromatic cyclic hydrocarbon group consisting of 3 to 14 carbon atoms in a ring (“C”). 3-14 The carbocyclic group (“C”) has 3-12 ring carbon atoms (“C”). 3-12 (Carbon cyclo group), or 4-12 ring carbon atoms ("C") 4-12 ("Carbocyclic group") or 3 to 10 ring carbon atoms ("C") 3-10 (Carbocyclic group), or 3 to 8 ring carbon atoms ("C") 3-8 (Carbocyclic group), or 3 to 7 ring carbon atoms ("C") 3-7 (Carbocyclic group), or 3 to 5 ring carbon atoms ("C") 3-5 (Carbocyclic group), or 4 to 6 ring carbon atoms ("C") 4-6 (Carbocyclic group), or 5 to 8 ring carbon atoms ("C") 5-8 (Carbocyclic group), or 5 to 7 ring carbon atoms ("C") 5-7 (Carbocyclic group). Example C 3-6 Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. As illustrated in the examples above, in some embodiments, the carbocyclic group is monocyclic (“monocyclic carbocyclic”) or a fused (paracyclic), bridged (bridged), or spirocyclic (spirocyclic) ring system, such as a bicyclic system (“bicyclic carbocyclic”), and may be saturated or partially unsaturated. “Carbocyclic” also includes ring systems in which the carbocyclic ring as defined above is fused with one or more aryl, heterocyclic, or heteroaryl groups, wherein the attachment point is on the carbocyclic or aryl ring, and in such cases, the number of ring atoms in the carbocyclic ring system is the number of ring atoms in the fused carbocyclic system. In some embodiments, each example of the carbocyclic group is independently optionally substituted, for example, unsubstituted (an "unsubstituted carbocyclic group") or substituted with one or more substituents (a "substituted carbocyclic group"). In some embodiments, the carbocyclic group is an unsubstituted C 3-10Carbocyclic group. In some embodiments, the carbocyclic group is a substituted C 3-10 Carbon cyclic group.

[0256] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, preferably containing 3-12 carbon atoms (i.e., C12-C12). 3-12 cycloalkyl), more preferably containing 3-10 carbon atoms (C 3-10 cycloalkyl groups, more preferably 3-7 carbon atoms (C 3-7 cycloalkyl groups), 4-6 carbon atoms (C 4-6 cycloalkyl groups), 5-6 carbon atoms (C 5-6 Cycloalkyl. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc. As illustrated in the examples above, in some embodiments, the cycloalkyl group is a monocyclic (“monocyclic cycloalkyl”) or a fused or fused (fused cycloalkyl), bridged (bridged cycloalkyl), or spirocyclic (spirocyclic alkyl) ring system, such as a bicyclic system (“bicyclic cycloalkyl”), and may be saturated or partially unsaturated. “Cycloalkyl” also includes ring systems in which the cycloalkyl ring as defined above is fused with one or more aryl, heterocyclic, or heteroaryl groups, wherein the attachment point is on the cycloalkyl or aryl ring, and in such cases, the cycloalkyl ring system is the number of ring atoms in the fused ring system.

[0257] Unless otherwise specified, the term "heterocyclic group" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic substituent having a ring carbon atom and 1 to 6 or 1 to 4 ring heteroatoms, comprising 3 to 20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. Preferably, it comprises 3 to 12 ring atoms (3-12 membered heterocyclic group), more preferably 3 to 10 ring atoms (3-10 membered heterocyclic group), or 3 to 8 ring atoms (3-8 membered heterocyclic group), or 3 to 6 ring atoms (3-6 membered heterocyclic group), or 4 to 6 ring atoms (4-6 membered heterocyclic group), or 5 to 6 ring atoms (5-6 membered heterocyclic group). The number of heteroatoms is preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, pyranyl, etc. Polycyclic heterocyclic groups include fused, spirocyclic, and bridged heterocyclic groups. A "heterocyclic group" can be a monocyclic ("monocyclic heterocyclic group") or a fused (fused heterocyclic group), bridged ("heterobridged heterocyclic group" or "bridged heterocyclic group") or spirocyclic ("heterospirocyclic group", "spiroheterocyclic group" or "spirocyclic heterocyclic group") ring system, such as a bicyclic system ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. A heterocyclic bicyclic system can include one or more heteroatoms in one or both rings. "Heterocyclic group" also includes a ring system in which the heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the attachment point is on the carbocyclic or heterocyclic ring; or "heterocyclic group" also includes a ring system in which the heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, or a ring system in which a cycloalkyl ring as defined above is fused with one or more heteroaryl groups, wherein the attachment point is on the heterocyclic ring or cycloalkyl ring or aryl ring or heteroaryl ring, and in such cases, the number of atoms in the heterocyclic ring system is the number of atoms in the fused ring system. In some embodiments, each example of a heterocyclic group is independently optionally substituted, for example, unsubstituted (an "unsubstituted heterocyclic group") or substituted with one or more substituents (an "substituted heterocyclic group"). Exemplary heterocyclic groups include, but are not limited to, aziridine, oxiridine, thiorenyl, aziridine, oxiridine, thiorenyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidine, dihydropyrrolyl, pyrrolyl-2,5-dione, dioxopentyl, oxiridine-thiocyclopentyl, dithiocyclopentyl, imidazolidin-2-one, and oxazolidin-2-one.

[0258] Unless otherwise specified, the terms "fused" or "combined" refer to aromatic, non-aromatic, saturated, or partially unsaturated polycyclic systems formed by two or more cyclic structures sharing two adjacent atoms, including cyclic systems formed by the fusion or combination of cycloalkyl, heterocyclic, aryl, or heteroaryl groups with cycloalkyl, heteroaryl, aryl, or heteroaryl groups, respectively. "Non-aromatic" means that the entire cyclic system is non-aromatic.

[0259] Unless otherwise specified, the term "aryl" or "aromatic ring group" refers to a monocyclic, bicyclic, or tricyclic aromatic carbocyclic system containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, preferably 6-10 carbon atoms. The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthracene, phenanthrene, or pyrene. "Aryl" can be monocyclic ("monocyclic aryl") or a fused or fused (fused aryl) ring system, such as a bicyclic system ("bicyclic aryl"), which may be partially unsaturated or unsaturated, or a tricyclic system ("tricyclic aryl"), wherein two ring systems may be fused or fused, and a third ring is fused to one or both of the two ring systems, or the third ring is screwed to one of the other two ring systems. "Aryl" also includes ring systems in which the aryl ring as defined above is fused or combined with one or more cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the attachment point is on the aryl ring, and in such cases, the number of atoms in the aryl ring system is the number of atoms in the fused or combined ring system.

[0260] Unless otherwise specified, the terms "heteroaryl" or "heterocyclic aryl" refer to an aromatic monocyclic or polycyclic system containing a 5-14 member structure, or preferably a 5-12 member structure, or preferably a 5-10 member structure, or preferably a 5-8 member structure, more preferably a 5-6 member structure, wherein one, two, three or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, the heteroatoms being independently selected from O, N or S, and the number of heteroatoms is preferably one, two or three. Polycyclic heteroaryl is a fused heteroaryl. Examples of heteroaryl groups include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, and benzo[] Pyrazinyl, benzimidazolyl, benziphthalazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc. "Heteroaryl" can be a monocyclic ("monocyclic heteroaryl") or a fused or merging (fused heteroaryl) ring system, such as a bicyclic system ("bicyclic heteroaryl"), which can be partially unsaturated or unsaturated, or a tricyclic system ("tricyclic heteroaryl"), wherein two ring systems can be fused or merging, and a third ring is fused to one or both of the two ring systems, or the third ring is screwed to one of the other two ring systems. "Heteroaryl" also includes ring systems in which the heteroaryl ring as defined above is fused or merging with one or more cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the attachment point is on the heteroaryl group, and in such cases, the number of atoms in the heteroaryl ring system is the number of atoms in the fused or merging ring system.

[0261] In this article, Represents o R c It can arbitrarily replace any site in the bicyclic system, as long as a stable structure can be formed, for example, It can be represented as This rule applies to any ring system of this disclosure, which is used herein for illustrative purposes.

[0262] In this article, R represents d These are substituents on ring D, which can replace hydrogen atoms on ring D, and the number of such substituents is p. dIt can be located at any position on ring D, as long as a stable chemical structure can be formed. When p is 0, it indicates that the hydrogen on ring D has not been substituted, or when p is not 0, if R d When the value is H, it also indicates that ring D has not been replaced. Other sites are defined similarly.

[0263] In the general formulas described herein, for example, in general formula I, ring C is selected from... When o is not 0, it indicates that there are o R values. c It can be arbitrarily replaced in At any position, for example, the following structure can be formed: Other sites are defined similarly.

[0264] For rings A, B, and / or D, in equation I... It forms the skeleton.

[0265] Unless otherwise specified, the terms "pharmaceutically acceptable salt" or "medicinal salt" refer to a salt that, to the extent of reasonable medical judgment, is suitable for contact with the tissues of mammals, particularly humans, without excessive toxicity, irritation, allergic reactions, etc., and in a manner commensurate with a reasonable benefit / risk ratio. Medically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or solely by reacting a free base or free acid with a suitable reagent.

[0266] Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), blocked isomers, and rotational isomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0267] Unless otherwise specified, the term "geometric isomer (cis / trans) isomer" may contain an E or Z configuration of a carbon-carbon or carbon-nitrogen double bond, wherein the term "E" represents a higher-order substituent on the opposite side of the carbon-carbon or carbon-nitrogen double bond, and the term "Z" represents a higher-order substituent on the same side of the carbon-carbon or carbon-nitrogen double bond (determined using the Cahn-Ingold Prelog priority rule). The compounds disclosed herein may also exist in mixtures of "E" and "Z" isomers.

[0268] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0269] Unless otherwise indicated, the structural formulas described in this disclosure include all isomers (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this disclosure, or its enantiomers, diastereomers, geometric isomers, conformational isomers, rotational isomers, or mixtures of hindered isomers, are within the scope of this disclosure.

[0270] The compounds described in this disclosure (e.g., Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula II-1, Formula II-2, Formula II-3, Formula II-4, Formula III, Formula III-1, Formula III-2, Formula III-3, Formula III-4, Formula III-5, the compounds shown in Table 1, the compounds shown in Table 1', or the compounds shown in Table 1-1) can be prepared in vitro or generated by in vivo metabolism.

[0271] The compounds disclosed herein also include isotopic derivatives thereof. Unless otherwise specified, the term "isotopic derivative" refers to compounds of this disclosure that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the largest number of atoms found in nature. For example, one or more atoms in the structure of the compound are replaced or substituted with atoms having atomic weights or mass numbers different from those typically found in nature (i.e., naturally occurring). Suitable isotopes that can be incorporated into the compounds of this disclosure include, but are not limited to, those that are not included in the present disclosure. 2 H (also written as D, representing deuterium), 3 H, 13 C 14 C 35 Cl、 37 Cl、 18 F, 123 I, 125 I, 13 N、 15 N、 15 O、 17 O、 18 O and35 S. Isotopes can be radioactive or non-radioactive. The isotopes commonly used for isotopic labeling are: hydrogen isotopes, 2 H and 3 H; Carbon isotopes: 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially 3 H and 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2 Substitution with H can enhance metabolic stability and prolong half-life, thereby providing therapeutic advantages by reducing dosage. Isotope-labeled compounds are generally synthesized from a labeled starting material using known synthetic techniques, similar to the synthesis of non-isotope-labeled compounds. The compounds disclosed herein may also include all isotopes of atoms appearing in intermediates or final compounds. Isotopes include those atoms having the same number of atoms but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0272] The disclosed compounds also include their solvates or solvent compounds. Unless otherwise specified, the terms "solvate" or "solvate" refer to the physical association of the disclosed compound with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. Solvent molecules in a solvate may be present in a regular and / or disordered arrangement. Solvates may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both solution phases and separable solvates. Solvation methods are well known in the art.

[0273] The disclosed compounds also include their cocrystals. Unless otherwise specified, the term "cocrystal" is used to describe a situation in which neutral molecular components are present in a definite stoichiometric ratio within a crystalline compound. The preparation of pharmaceutical cocrystals allows for alteration of the crystal form of the active pharmaceutical ingredient, which in turn alters its physicochemical properties without impairing its desired biological activity (see Pharmaceutical Salts and Cocrystals, eds. J. Wouters and L. Quere, RSC Publishing, 2012).

[0274] The disclosed compounds also include their polymorphs. Unless otherwise specified, the term "polymorph" refers to different arrangements of chemical drug molecules, generally manifested as the form in which the drug raw material exists in a solid state. A drug can exist in multiple crystalline states. Different crystalline forms of the same drug may have different solubility and absorption in the body, thus affecting the dissolution and release of the formulation.

[0275] This disclosure also includes metabolites of compounds. Unless otherwise specified, the term "metabolite" refers to a product obtained in vivo by the metabolic processes of a specific compound or its salt. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this disclosure. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this disclosure includes metabolites of compounds, including metabolites produced by prolonged exposure of the compounds of this disclosure to mammals.

[0276] This disclosure also includes prodrugs of compounds. Unless otherwise specified, the term "prodrug" refers to a drug that is converted into a parent drug in vivo. Prodrugs are generally useful because they can improve certain, undesirable physical or biological properties. Physical properties are generally related to solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological properties include metabolism that is too rapid or poor bioavailability, which may itself be related to physicochemical properties. For example, they can be bioavailable orally, whereas the parent drug cannot. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An example of a prodrug, but not limited to, is any compound of this disclosure that is administered as an ester ("prodrug") to facilitate transmembrane transport, where water solubility is detrimental to migration but beneficial once inside the cell, and is subsequently metabolized and hydrolyzed into a carboxylic acid, the active entity. Another example of a prodrug can be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to exhibit the active moiety.

[0277] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0278] The term “individual” can also be called “object” or “subject” and refers to a cell or animal, including but not limited to mammals such as laboratory animals or humans.

[0279] Some of the compounds disclosed herein are optically active. The compounds disclosed herein can be racemic, optical isomers, or mixtures thereof. The optical isomers of the compounds disclosed herein can be synthesized either from the starting materials of the optical isomers or by separating the racemic mixtures.

[0280] The above embodiments represent exemplary embodiments of this disclosure, but this disclosure is not limited to the above embodiments. Furthermore, the various technical features in the above embodiments of this disclosure can be combined with each other to constitute one or more new technical solutions, which also fall within the scope of this disclosure, provided that such new technical solutions are technically feasible.

[0281] Unless otherwise specified, the term “treatment” covers any treatment of a patient’s disease, symptom, and condition, including: (a) suppressing the symptoms of the disease, symptom, and condition, i.e., preventing its development; or (b) alleviating the symptoms of the disease, symptom, and condition, i.e., causing the disease or symptoms to subside; or (c) improving or eliminating the disease, symptom, and condition or one or more symptoms associated with said disease.

[0282] Preparation Examples, Examples, and other abbreviations used herein are: DCM (dichloromethane), DCE (1,2-dichloroethane), DIPEA (N,N-diisopropylethylamine), DMF (N,N-dimethylformamide), HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate), NMP (N-methylpyrrolidone), THF (tetrahydrofuran), EA (ethyl acetate), PE (petroleum ether).

[0283] The beneficial effects of this disclosure are as follows:

[0284] This disclosure presents a novel class of compounds that offer a new direction for the treatment of diseases such as diabetes, non-alcoholic fatty liver disease, Alzheimer's disease, and overweight and obesity.

[0285] The compounds disclosed herein achieve one or more of the following beneficial effects:

[0286] 1. In vitro experiments show that the compound disclosed herein has a strong agonistic effect on GLP-1R;

[0287] 2. In vivo pharmacokinetic studies have shown that the compound disclosed herein has good pharmacokinetic properties, especially oral absorption properties.

[0288] 3. In vitro experiments show that the compounds disclosed herein have good cell safety.

[0289] 4. The compounds disclosed herein do not exhibit significant inhibitory activity against transporters.

[0290] 5. In vivo experiments show that the compounds disclosed herein have good weight loss effects.

[0291] 6. In vivo studies have shown that the compounds disclosed herein can effectively lower blood sugar.

[0292] 7. The compounds disclosed herein do not exhibit significant off-target effects.

[0293] The present disclosure is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the disclosure. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this disclosure. The preferred embodiments and materials shown herein are for illustrative purposes only.

[0294] The following are examples and embodiments of the preparation of exemplary compounds of this disclosure.

[0295] The structures of the compounds disclosed herein were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS), and / or high-resolution mass spectrometry (HPLC), and / or high-resolution mass spectrometry (HRMS). The instruments used for NMR determination were a Bruker Avance neo 400MHz and / or a Bruker AVANCEIII 600; the instruments used for LC-MS were an Agilent 1260Infinity II-6120 / 6125MSD and / or a Waters ACQUITY QDa; the instruments used for HPLC were a Waters e2695-2998 (column: Waters XBridge C18 4.6*250mm, 5μm; column temperature: 40℃; flow rate: 1mL / min; wavelength: 216nm; mobile phase A: water (containing 0.1% trifluoroacetic acid); mobile phase B: methanol).

[0296] The starting materials used in the embodiments of this disclosure are known and commercially available, or can be synthesized using methods known in the art.

[0297] Preparation Example 1: Synthesis of 5-bromo-1-(2-(cyclopropylmethoxy)ethyl)-4-fluoro-1H-indazole (intermediate 2,2-A)

[0298] Step 1: Synthesis of 2-(5-bromo-4-fluoro-1H-indazol-1-yl)ethyl-1-ol

[0299] 5-Bromo-4-fluoro-1H-indazole (1.00 g, 4.65 mmol), 2-bromoethanol (1.16 g), sodium carbonate (1.48 g), and N,N-dimethylformamide (10 mL) were added to a round-bottom flask and heated to 80 °C for 12 h. After the reaction was complete, the mixture was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography (n-hexane:ethyl acetate = 1:1, the bands with the same molecular weight were observed on the top) to give the product (514 mg). ESI-MS (m / z): 259.0 [M+H] + .

[0300] Step Two:

[0301] Take the product from the previous step (514 mg, 1.98 mmol) and anhydrous N,N-dimethylformamide (10 mL), add them to a round-bottom flask, add sodium hydride (135 mg) under ice bath, react under ice bath for 30 min, add (bromomethyl)cyclopropane (402 mg), transfer to room temperature and react for 2 h. After the reaction is complete, add 100 mL of water, extract with ethyl acetate, wash the organic phase once with saturated sodium chloride, dry with anhydrous sodium sulfate, and purify the crude product by column chromatography (n-hexane:ethyl acetate = 2:1) to obtain the product (360 mg). ESI-MS (m / z): 313.0 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ8.23(s,1H),7.61-7.54(m,2H),4.59(t,J=5.3Hz,2H),3.81(t,J=5 .3Hz,2H),3.16(d,J=6.7Hz,2H),0.92-0.75(m,1H),0.40-0.30(m,2H),0.07-0.02(m,2H).

[0302] Preparation Example 2: 5-Bromo-2-(2-(cyclopropylmethoxy)ethyl)-4-fluoro-2H-indazole (Intermediate 2,2-B)

[0303] Step 1: Synthesis of 2-(5-bromo-4-fluoro-2H-indazol-2-yl)ethyl-1-ol

[0304] The crude product from step one of Preparation Example 1 was purified by column chromatography (n-hexane:ethyl acetate = 1:1, the lower bands with the same molecular weight) to obtain the product (394 mg). ESI-MS (m / z): 259.0 [M+H] + .

[0305] Step Two:

[0306] Following the preparation method in step two of Preparation Example 1, the product from the previous step of this preparation example (394 mg, 1.52 mmol) was used as the starting material to prepare and separate the product (220 mg). ESI-MS (m / z): 313.0 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.62(s,1H),7.45(d,J=9.0Hz,1H),7.38(dd,J=8.8,6.9Hz,1H),4.60(t,J=5.3Hz,2H ),3.90(t,J=5.3Hz,2H),3.22(d,J=6.8Hz,2H),0.95-0.86(m,1H),0.44-0.37(m,2H),0.09(q,J=4.8Hz,2H).

[0307] Preparation Example 3: Synthesis of 5-bromo-1-cyclopropyl-4-fluoro-1H-indazole (intermediate 2,2-C)

[0308] 5-Bromo-4-fluoro-1H-indazole (1.0 g), cyclopropylboronic acid (0.8 g), anhydrous copper acetate (0.85 g), 2,2'-bipyridine (0.73 g), sodium carbonate (1.0 g), and 1,2-dichloroethane (20 mL) were added to a flask, heated to 70 °C, and stirred for two hours. The mixture was filtered, and the filtrate was diluted with dichloromethane, washed with water, and the solvent was removed under reduced pressure. The product was purified by column chromatography (n-hexane:ethyl acetate = 5:1) to obtain 0.8 g of product. ESI-MS (m / z): 254.9 [M+H] + .

[0309] Preparation Example 4: Synthesis of 5-bromo-1-(2-cyclopropoxyethyl)-4-fluoro-1H-indazole (intermediate 2,2-D)

[0310] Step 1: Synthesis of 2-cyclopropoxyethyl 4-methylbenzenesulfonic acid

[0311] 160 mg of 2-cyclopropoxyethanol, 590 mg of p-toluenesulfonyl chloride, and 480 mg of triethylamine were added to 3 mL of dichloromethane and stirred at room temperature for 15 hours. After the reaction was complete, 20 mL of water was added, and the mixture was extracted with 3 x 20 mL ethyl acetate. The solvent was removed under reduced pressure, and the product (280 mg) was obtained by column chromatography (n-hexane:ethyl acetate = 10:1).

[0312] Step Two:

[0313] The product from the previous step (260 mg), 5-bromo-4-fluoro-1H-indazole (388 mg), and potassium carbonate (418 mg) were added to N,N-dimethylformamide (5 mL), heated to 100 °C, and stirred for 5 hours. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL × 2), and the solvent was removed under reduced pressure. Column chromatography (n-hexane:ethyl acetate = 5:1, bands with the same molecular weight were observed) yielded the product (210 mg). ESI-MS (m / z): 299.0 [M+H] + .

[0314] Preparation Example 5: Synthesis of 5-bromo-4-fluoro-1-(2-(1-methylcyclopropoxy)ethyl)-1H-indazole (intermediate 2,2-E)

[0315] Phase 1:

[0316] Step 1: Add 500 mg of 1-methylcyclopropoxy-1-ol, 790 mg of ethyl diazonyl acetate, and 30 mg of rhodium dimer acetate to 10 mL of dichloromethane in an ice bath, and stir at room temperature for 4 hours. After the reaction is complete, filter under vacuum and remove the filtrate under reduced pressure to obtain crude 2-(1-methylcyclopropoxy)ethyl acetate (700 mg).

[0317] Step 2: Crude 2-(1-methylcyclopropoxy)ethyl acetate (600 mg) and lithium aluminum hydride (96 mg) were added to tetrahydrofuran (5 mL) in an ice bath, and the mixture was stirred at 0 °C for 1 hour. After the reaction was completed, water (96 mg), 15% sodium hydroxide aqueous solution (96 mg), and water (288 mg) were added successively. The mixture was filtered, the filtrate was removed under reduced pressure, and 2-(1-methylcyclopropoxy)ethanol (60 mg) was obtained by column chromatography (n-hexane:ethyl acetate = 5:1).

[0318] Phase Two:

[0319] Following the preparation method of intermediate 2,2-D, intermediate 2,2-E (30 mg) was obtained from 2-(1-methylcyclopropoxy)ethanol. ESI-MS (m / z): 313.0 [M+H]+ , 1 H NMR (600MHz, DMSO-d6) δ8.22 (s, 1H), 7.58-7.54 (m, 1H), 7.48 (dd, J = 8.9, 0.5Hz, 1H), 4.51 ( t,J=5.2Hz,2H),3.80(t,J=5.2Hz,2H),1.13(s,3H),0.28-0.24(m,2H),0.24-0.22(m,2H).

[0320] Preparation Example 6: Synthesis of 5-bromo-4-fluoro-1-(2-((1-fluorocyclopropyl)methoxy)ethyl)-1H-indazole (intermediate 2,2-F)

[0321] Following the preparation method of intermediate 2,2-E, intermediate 2,2-F (35 mg) was obtained from (1-fluorocyclopropyl)methanol. ESI-MS (m / z): 331.1 [M+H] + , 1 H NMR (600MHz, DMSO-d6) δ8.24 (s, 1H), 7.62-7.54 (m, 2H), 4.62 (t, J = 5.3Hz, 2H), 3.9 2(t,J=5.3Hz,2H),3.64(s,1H),3.60(s,1H),0.94-0.84(m,2H),0.59-0.49(m,2H).

[0322] Preparation Example 7: Synthesis of 5-bromo-4-fluoro-1-(2-(methoxy-d3)ethyl)-1H-indazole (intermediate 2.2-M)

[0323] 2-(5-bromo-4-fluoro-1H-indazol-1-yl)ethyl-1-ol (200 mg, 0.77 mmol), sodium hydroxide (92 mg), deuterated iodomethane (336 mg), and anhydrous N,N-dimethylformamide (4 mL) were added to a round-bottom flask and reacted at room temperature for 30 min. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography (n-hexane:ethyl acetate = 2:1) to give intermediate 2.2-M (192 mg), ESI-MS (m / z): 276.0 [M+H]. + , 1 H NMR (600MHz, DMSO-d6) δ8.22 (s, 1H), 7.59-7.52 (m, 2H), 4.59 (t, J = 5.2Hz, 2H), 3.74 (t, J = 5.2Hz, 2H).

[0324] Preparation Example 8: Synthesis of (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-imidazolidine-1-yl]-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (intermediate 1,2-A)

[0325] Step 1: Synthesis of (S)-3-(3-(2-chloroethyl)ureo)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0326] (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazole[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (2 g), chloroethyl isocyanate (734 mg), and tetrahydrofuran (40 mL) were added to a flask, followed by triethylamine (1.6 g). The mixture was heated to 60 °C and stirred for 8 hours. After the reaction was complete, the temperature was lowered, and the mixture was added to water (40 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered and concentrated. The crude product was purified by column chromatography (n-hexane:ethyl acetate = 3:1) to give the product (700 mg), ESI-MS (m / z): 480.2 [M+H). + .

[0327] Step 2: Synthesis of (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxoimidazolidine-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0328] The product from the previous step (700 mg) and N,N-dimethylformamide (10 mL) were added to a flask, along with NaH (88 mg). The mixture was stirred at room temperature for 4 hours. After the reaction was complete, water (40 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (n-hexane:ethyl acetate = 1:1) to obtain the product (300 mg). ESI-MS (m / z): 444.2 [M+H] + .

[0329] Step 3: Synthesis of (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxoimidazolidine-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (intermediate 1.1-A)

[0330] The product from the previous step (60 mg), 5-bromo-4-fluoro-1-methyl-1H-indazole (62 mg), cuprous iodide (24 mg), (1S,2S)-(+)-N,N-dimethylcyclohexanediamine (18 mg), potassium phosphate (61 mg), and 1,4-dioxane (5 mL) were added to a flask. The mixture was heated to 120 °C and stirred for 4 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled, water (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered and concentrated. The crude product was purified by preparative thin-plate chromatography (n-hexane:ethyl acetate = 1:2) to obtain the product (50 mg). ESI-MS (m / z): 592.3 [M+H] + .

[0331] Step 4: Synthesis of intermediate 1.2-A

[0332] The product from the previous step (50 mg) and 4M dioxane hydrochloride (2 mL) were added to a flask and stirred at room temperature for 4 hours. After the reaction was complete, the mixture was evaporated to dryness, and then washed with dichloromethane (30 mL) and saturated sodium bicarbonate aqueous solution (20 mL). After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated to obtain the product (40 mg). ESI-MS (m / z): 492.2 [M+H] + Preparation Example 9: Synthesis of (S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine (intermediate 1.2-B)

[0333] Following the preparation method of intermediate 1.2-A, using 5-bromo-1-cyclopropyl-4-fluoro-1H-indazole (intermediate 2.2-C, 220 mg) and (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (200 mg) as starting materials, intermediate 1.2-B (202 mg) was obtained through a two-step reaction. ESI-MS (m / z): 516.3 [M+H] + .

[0334] Preparation Example 10: Synthesis of (S)-3-(3-(1-(2-(cyclopropylmethoxy)ethyl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine (intermediate 1.2-B1)

[0335] Following the preparation method of intermediate 1.2-A, intermediate 1.2-B1 (193 mg) was prepared from 5-bromo-1-(2-(cyclopropylmethoxy)ethyl)-4-fluoro-1H-indazole (intermediate 2.2-A, 270 mg) and (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (200 mg) through a two-step reaction. ESI-MS (m / z): 574.3 [M+H] + , 1 H NMR(600MHz,DMSO-d6)δ8.32(d,J=0.5Hz,1H),7.66(d,J=8.9Hz,1H),7.36(t,J=7.3Hz,1H) ,7.13(d,J=6.2Hz,2H),7.01(s,1H),6.84(s,1H),4.62(t,J=5.3Hz,2H),3.94-3.88(m,1H), 3.83(t,J=5.3Hz,2H),3.22-3.15(m,3H),2.88-2.81(m,1H),2.68-2.58(m,2H),2.23(d,J= 1.7Hz, 6H), 1.14 (t, d = 6.5Hz, 3H), 0.89-0.81 (m, 1H), 0.39-0.34 (m, 2H), 0.07-0.03 (m, 2H).

[0336] Preparation Example 11: Synthesis of (S)-3-(3-(1-(2-(methoxy-d3)ethyl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine (intermediate 1,2-Q)

[0337] Following the preparation method of intermediate 1.2-A, intermediate 1.2-Q (180 mg) was obtained from 5-bromo-4-fluoro-1-(2-(methoxy-d3)ethyl)-1H-indazole (intermediate 2.2-M, 236 mg) and (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (200 mg). ESI-MS (m / z): 537.3 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ8.31(s,1H),7.64(d,J=8.9Hz,1H),7.40–7.32(m,1H) ,7.13(d,J=6.1Hz,2H),7.01(s,1H),6.84(s,1H),4.63(t,J=5.2Hz,2H),3.92– 3.84(m,1H),3.75(t,J=5.2Hz,2H),3.73–3.63(m,1H),3.22–3.15(m,1H),2.88 –2.79(m,1H),2.69–2.58(m,2H),2.23(d,J=0.9Hz,6H),1.14(d,J=6.5Hz,3H).

[0338] Preparation Example 12:

[0339] Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 82)

[0340] Following the preparation method of Example 1, the product (340 mg) was prepared from (S)-1-(4-fluoro-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (intermediate 1.2-U) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid. ESI-MS (m / z): 869.4 [M+H] + .

[0341] Preparation Example 13:

[0342] Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-(2-hydroxyethyl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 38-0)

[0343] Referring to Example 1, compound 38-0 was obtained from compound 82 and 2-bromoethanol. ESI-MS (m / z): 913.4 [M+H] + .

[0344] Referring to the preparation methods of intermediates 1.2-A and 1.2-B above or those disclosed in the literature, the following intermediates were synthesized using the corresponding intermediates as raw materials:

[0345] Preparation Example 14: Synthesis of 1-((1S,2S)-2-((cyclopropylmethoxy)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (Intermediate 1,3-A)

[0346] Step 1: (R)-4-((cyclopropylmethoxy)methyl)-2,2-dimethyl-1,3-dioxolane

[0347] (R)-(2,2-dimethyl-1,3-dioxolane-4-yl)methanol (500 mg, 3.79 mmol) was dissolved in DMSO (5 mL), followed by the addition of bromomethylcyclopropane (507 mg) and potassium tert-butoxide (850 mg). The mixture was stirred at 100 °C for 5 hours. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (n-hexane:ethyl acetate = 3:1) to give the product (353 mg).

[0348] Step 2: (2S)-3-(cyclopropylmethoxy)-1,2-propanediol

[0349] The product from the previous step (353 mg, 1.90 mmol) was dissolved in anhydrous methanol (10 mL), and then p-toluenesulfonic acid (36 mg) was added and stirred at room temperature for half an hour. After the reaction was completed, the product was concentrated directly and separated by column chromatography (n-hexane:ethyl acetate = 1:2) to obtain the product (220 mg).

[0350] Step 3: (4R)-4-((cyclopropylmethoxy)methyl)-1,3,2-dioxothiacyclopentane-2-oxide

[0351] Dissolve the product from the previous step in tetrahydrofuran, then add thionyl chloride (215 mg, 1.81 mmol), and stir at 60 °C for one hour. After the reaction is complete, filter and concentrate directly; no further purification (250 mg) is required, and the product can be used directly in the next step.

[0352] Step 4: (R)-4-((cyclopropylmethoxy)methyl)-1,3,2-dioxothiacyclopentane-2,2-dioxide

[0353] The crude product (250 mg) from the previous step was dissolved in acetonitrile and water (1:1, 20 mL), then sodium periodate (561 mg) and anhydrous ruthenium chloride (13.5 mg) were added, and the mixture was stirred at room temperature for two hours. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate (3 x 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (n-hexane:ethyl acetate = 2:1) to give the product (197 mg).

[0354] Step 5: 1-((1S,2S)-1-cyano-2-((cyclopropylmethoxy)methyl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0355] 1-Cyanomethyl-N-methyl-N-phenyl-5-[(4S)-tetrahydro-2,2-dimethyl-pyran-4-yl]-1H-indole-2-carboxamide (253 mg, 0.63 mmol) and the product from the previous step (197 mg) were dissolved in anhydrous tetrahydrofuran (20 mL). Then, N,N-dimethylpropenylurea (161 mg) was added. Finally, under nitrogen protection in an ice-water bath, lithium bis(trimethylsilyl)amino (1 M, 1.85 mL) was slowly added dropwise with stirring for one hour. After the reaction was completed, the mixture was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate (3 x 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (n-hexane:ethyl acetate = 1:1) to give the product (177 mg). ESI-MS (m / z): 512.31 [M+H] + .

[0356] Step Six: 1-((1S,2S)-2-((cyclopropylmethoxy)methyl)-1-((Z)-N'-hydroxymethamidinyl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0357] The product from the previous step (177 mg, 0.35 mmol) was dissolved in anhydrous ethanol (15 mL), then hydroxylamine hydrochloride (121 mg) and DIPEA (451 mg) were added, and the mixture was stirred at 60 °C for one hour. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate (3 x 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product (200 mg). ESI-MS (m / z): 545.30 [M+H] + .

[0358] Step 7: 1-((1S,2S)-2-((cyclopropylmethoxy)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0359] The product from the previous step (200 mg) was dissolved in dimethyl sulfoxide (20 mL), followed by the addition of N,N'-carbonyldiimidazole (599 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (562 mg). The mixture was stirred at room temperature for six hours. After the reaction was complete, water was added and the pH was adjusted to 3-4 with formic acid. The mixture was then extracted with ethyl acetate (3 x 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (n-hexane:ethyl acetate = 1:2) to obtain the product (149 mg). ESI-MS (m / z): 571.32 [M+H]. + .

[0360] Step 8: Synthesis of intermediate 1.3-A

[0361] The product from the previous step (149 mg, 0.26 mmol) was dissolved in ethylene glycol methyl ether (3 mL), and then potassium hydroxide (145 mg) was added. The mixture was stirred at 100 °C for one hour. After the reaction was complete, water was added and the pH was adjusted to 2-3 with dilute hydrochloric acid. The mixture was then extracted with ethyl acetate (3 x 15 mL). The organic phases were combined, dissolved in anhydrous sodium sulfate, filtered, and concentrated. The product was then separated by thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain 72 mg of the product. ESI-MS (m / z): 482.24 [M+H] + ; 1 H NMR (600MHz, CDCl3) δ10.45(s,1H),7.68(d,J=9.0Hz,1H),7.50(s,1H),7.33(dd,J=9.0 Hz,1.8Hz,1H),7.29(s,1H),3.98-3.83(m,3H),3.57-3.54(m,1H),3.31-3.28(m,1H),3. 25-3.22(m,1H),3.06-3.01(m,1H),2.29-2.27(m,1H),2.04-1.99(m,1H),1.83-1.59(m, 5H),1.37(s,3H),1.31(s,3H),1.00-0.96(m,1H),0.56-0.53(m,2H),0.19-0.15(m,2H).

[0362] Preparation Example 15: Synthesis of 5-(1,1-thiomorpholine)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (intermediate 1,3-B)

[0363] Step 1: Synthesis of 5-bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0364] Oxaloyl chloride (2.6 g) was added to a solution of 5-bromo-1H-indole-2-carboxylic acid (4 g, 16.7 mmol) in acetonitrile (40 mL) at 20-30 °C, followed by a solution of DMF (0.6 g) in acetonitrile (5 mL). The mixture was stirred for 1 hour. Then, N-methylaniline (2.1 g) was added to the reaction mixture, and the mixture was stirred for another 10 minutes. Triethylamine (4.4 g) was then added, and the reaction was continued for 2 hours, with the reaction temperature controlled to not exceed 20 °C. After the reaction was complete, water (10 mL) was added to the reaction mixture, and the mixture was stirred for 1 hour. The mixture was then filtered, and the filter cake was washed with acetonitrile and water. The product (5 g) was dried at 50 °C. ESI-MS (m / z): 329.0 [M+H] + .

[0365] Step 2: Synthesis of 5-bromo-1-(cyanomethyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0366] The product from the previous step (5 g) was dissolved in DMF (50 mL), and then NaH (1.8 g, 60%) was added. The mixture was stirred at room temperature for 0.5 hours, followed by the addition of chloroacetonitrile (3.4 g), and the reaction was continued for 3 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride aqueous solution, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM:EA = 60:1) to obtain the product (3.8 g), ESI-MS (m / z): 368.1 / 370.1 [M+H]. + .

[0367] Step 3: Synthesis of 5-bromo-1-((1S,2S)-1-cyano-2-methylcyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0368] The product from the previous step (3.8 g, 10.3 mmol) and (4R)-4-methyl-1,3,2-dioxane 2,2-dioxide (3.5 g) were dissolved in tetrahydrofuran (40 mL), degassed under reduced pressure, and the reaction system was cooled to 0 °C. Under a nitrogen atmosphere, a 1.0 M solution of potassium bis(trimethylsilyl)amino in tetrahydrofuran (41 mL) was slowly added dropwise, and the mixture was stirred at 0 °C for 2 hours. After the reaction was complete, a saturated ammonium chloride aqueous solution was added, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Finally, the product (1.5 g) was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:6), ESI-MS (m / z): 408.1 / 410.1 [M+H] + .

[0369] Step 4: Synthesis of 5-bromo-1-((1S,2S)-1-(N-hydroxymethylamidinyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0370] The product from the previous step (1.5 g, 3.7 mmol) was dissolved in DMSO (15 mL), and then 50% aqueous hydroxylamine solution (2.4 g) was added. The mixture was stirred at room temperature for 17 hours. After the reaction was complete, ethyl acetate was added, followed by washing with water and brine, drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain the product (1.4 g). ESI-MS (m / z): 441.1 [M+H] + .

[0371] Step 5: Synthesis of 5-bromo-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1H-indole-2-carboxamide

[0372] The product from the previous step (1.4 g) was dissolved in DMSO (15 mL), followed by the addition of carbonyl diimidazole (1.04 g, 6.4 mmol) and 1,8-diazabicycloundec-7-ene (1.22 g, 8 mmol). The mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction system was cooled to 0 °C, and 2N HCl was added. A solid precipitated, and the mixture was stirred at 0 °C for 0.5 hours. The mixture was then filtered, the filter cake was washed with water, and dried at 50 °C to obtain the crude product (1.5 g). ESI-MS (m / z): 467.0 / 469.0 [M+H] + .

[0373] Step Six: Synthesis of 5-bromo-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid

[0374] The product from the previous step (1.5 g, 3.2 mmol) was dissolved in ethylene glycol monomethyl ether (5 mL), and potassium hydroxide (1.8 g) was added. The mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the mixture was cooled to 0 °C, and the pH was adjusted to 1-2 with 6 N HCl. The mixture was stirred at room temperature for 0.5 hours, filtered, the filter cake was washed with water, and dried at 50 °C to obtain the product (1.0 g). ESI-MS (m / z): 376.1 / 378.1 [MH] - .

[0375] Step 7: Synthesis of intermediate 1.3-B

[0376] The NMP (2 mL) suspension of the product from the previous step (60 mg, 0.16 mmol), thiomorpholine-1,1-dioxide (28.35 mg), tris(dibenzylacetone)dipalladium (0) (15 mg), 2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl (15 mg), and sodium tert-butoxide (61 mg) was degassed under reduced pressure at room temperature. The mixture was then heated to 100 °C and stirred for 3 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, and formic acid was added to the mixture. The solution was then directly purified by reversed-phase chromatography (acetonitrile / water, 0.1% formic acid) to give the product (30 mg), ESI-MS (m / z): 431.1 [MH]. - .

[0377] Preparation Example 16: Synthesis of 5-(2-methoxy-3-methylpyridin-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (intermediate 1,3-C)

[0378] Step 1: Synthesis of 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indole-2-carboxylic acid

[0379] A suspension of 5-bromo-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (150 mg, 0.40 mmol), palladium acetate (9 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (38 mg), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhecyclopentane) (152 mg), and potassium phosphate (254 mg) in DMSO (2 mL) was degassed under reduced pressure at room temperature, and then heated to 100 °C and stirred for 3 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, and formic acid was added to the reaction system. The product (70 mg) was then directly purified by reversed-phase chromatography (acetonitrile / water, 0.1% formic acid), ESI-MS (m / z): 424.4 [MH]. - .

[0380] Step 2: Synthesis of intermediate 1,3-C

[0381] The product from the previous step (70 mg, 0.16 mmol), palladium acetate (7 mg), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphonane (29 mg), 4-iodo-2-methoxy-3-methylpyridine (40 mg), potassium phosphate (102 mg), and a suspension of DMSO (3 mL) and water (0.5 mL) were degassed under reduced pressure at room temperature. The mixture was heated to 100 °C and stirred for 3 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature. Formic acid was added to the mixture, and the resulting product was directly purified by reversed-phase chromatography (acetonitrile / water, 0.1% formic acid) to give the product (25 mg). ESI-MS (m / z): 419.4 [MH] - .

[0382] The following intermediates were prepared using intermediates 1.3-A, 1.3-B, 1.3-C, or methods disclosed in the literature:

[0383] Example 1: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(3-methoxypyrrolidine-1-yl)-1H-indol-1-yl)2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 1)

[0384] Intermediate 1,3-F (30 mg, 0.075 mmol), intermediate 1,2-B (38 mg), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (43 mg), N,N-diisopropylethylamine (39 mg), and N,N-dimethylformamide (2 mL) were added to a round-bottom flask and reacted at room temperature for 5 h. After the reaction was complete, 100 mL of water was added, and the mixture was extracted twice with 50 mL of EA solution, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the crude product was subjected to thin-layer chromatography (DCM:MeOH = 20:1) to obtain the product (14 mg). ESI-MS (m / z): 896.5 [M+H] + .

[0385] Example 2: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(1-(2-((cyclopropylmethyl)amino)ethyl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 38)

[0386] Step 1: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(4-fluoro-1-(2-hydroxyethyl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 38-0)

[0387] Referring to Example 1, an intermediate (1.2 g) was prepared from (S)-1-(4-fluoro-1-(2-hydroxyethyl)-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (intermediate 1.2-T) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid. ESI-MS (m / z): 913.4 [M+H] + .

[0388] Step 2: Synthesis of intermediate 38-1

[0389] The product from the previous step (50 mg, synthesized according to Example 1), methanesulfonyl chloride (12.5 mg), triethylamine (16.5 mg), and dichloromethane (2 mL) were added to a round-bottom flask and stirred at room temperature. After the reaction was complete, an appropriate amount of water was added, followed by extraction with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to thin-layer chromatography (DCM:MeOH = 30:1, v / v) to obtain the product (31 mg). ESI-MS (m / z): 991.4 [M+H] + .

[0390] Step 3: Synthesis of Compound 38

[0391] The product from the previous step (31 mg), cyclopropyl methylamine (4.3 mg), potassium carbonate (12.5 mg), and N,N-dimethylformamide (2 mL) were added to a round-bottom flask and reacted at 100 °C for 5 h. After the reaction was complete, an appropriate amount of water was added, followed by extraction with ethyl acetate, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentration under reduced pressure. The crude product was then subjected to thin-layer chromatography (DCM:MeOH = 20:1) to obtain the target product (9 mg). ESI-MS (m / z): 966.5 [M+H] + .

[0392] Example 3: Synthesis of 3-((1S,2R)-1-(2-((S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-(((cyclopropylmethyl)amino)methyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 41)

[0393] Step 1: Synthesis of 3-((1S,2S)-2-((benzyloxy)methyl)-1-(2-((S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0394] The product (554 mg) was prepared according to Example 1, ESI-MS (m / z): 1015.4 [M+H] + .

[0395] Step 2: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-(hydroxymethyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0396] The product from the previous step (554 mg) and trifluoroacetic acid (10 mL) were added to a round-bottom flask and reacted at 80 °C for 2 h. The solvent was removed under reduced pressure, ethyl acetate was added, and the mixture was washed with sodium bicarbonate solution and saturated sodium chloride solution. The solvent was removed under reduced pressure, potassium carbonate (228 mg) and methanol (10 mL) were added, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, 100 mL of water was added, and the mixture was extracted twice with ethyl acetate, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally subjected to thin-layer chromatography (DCM:MeOH = 40:1) to obtain the product (360 mg). ESI-MS (m / z): 925.4 [M+H] +

[0397] Step 3:

[0398] Synthesis of methanesulfonic acid ((1S,2S)-2-(2-((S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)methyl ester

[0399] Take 120 mg of the product from the previous step and add 2 mL of dichloromethane to a round-bottom flask. Then add triethylamine (39 mg) and methanesulfonyl chloride (30 mg), and react at room temperature for 0.5 h. After the reaction is complete, add ethyl acetate, then wash with water and saturated sodium chloride solution, dry to anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain the product (100 mg). ESI-MS (m / z): 1003.4 [M+H] + Proceed directly to the next step.

[0400] Step 4: Synthesis of Compound 41

[0401] The product from the previous step (50 mg), cyclopropyl methylamine (500 μL), and tetrahydrofuran (2 mL) were added to a round-bottom flask and reacted at room temperature for 12 h. After the reaction was complete, an appropriate amount of water was added, followed by extraction with ethyl acetate, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and finally obtaining the product (7 mg) by thin-layer chromatography (DCM:MeOH = 10:1). ESI-MS (m / z): 978.5 [M+H] + The retention time by HPLC was 10.7 min.

[0402] Example 4: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(1-(but-2-yn-1-yl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 43)

[0403] Take 23 mg of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid and (S)-1-(1-(but-2-yn-1-yl)-4-fluoro-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4- Methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (1,2-H, 30 mg), N,N,N',N',-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (33 mg), N,N-diisopropylethylamine (22 mg), and N,N-dimethylformamide (1 mL) were added to a round-bottom flask and reacted at room temperature for 5 h. After the reaction was complete, 100 mL of water was added, and the mixture was extracted twice with EA (50 mL), washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the crude product was subjected to thin-layer chromatography (DCM:MeOH = 20:1) to obtain the product (15 mg). ESI-MS (m / z): 921.4 [M+H] + The retention time by HPLC was 17.6 min.

[0404] Following the preparation methods described in the above embodiments and / or in conjunction with the preparation methods described in the literature, the following compounds were prepared, and their structures and characterization data are as follows:

[0405] Experimental Example 1: In vitro agonist activity assay (reporter gene method)

[0406] 1. Experimental objective: To determine the agonistic effect of the test compound on GLP-1R using GLP1R-cAmp-Luc cells.

[0407] 2. Experimental steps:

[0408] 1) The test compounds were dissolved in DMSO to prepare a stock solution with a concentration of 10 mM. All test compounds were cultured in DMEM medium (high glucose, Puromycin). + Hygromycin B + Dilute to an initial concentration of 1250 nM, and then serially dilute 5-fold to create a total of 7 concentration gradients. Using white-walled 96-well cell culture plates, culture GLP1R-cAmp-Luc cells at a concentration of 1 × 10⁻⁶ cells / well. 5 Seed at a density of 90 μL / ml, with 90 μL of cell suspension per well; add 10 μL of the test compound to each well according to all 7 concentration gradients. The actual working starting concentration of the test compound is 125 nM. The cells are placed in a 37°C, 5% CO2 cell culture incubator for 4 h.

[0409] 2) Add 100 μL of fluorescein potassium salt solution diluted to 300 μg / mL with PBS to each well. The working concentration is 150 μg / mL. Incubate at room temperature for 30 min.

[0410] 3) The fluorescence signal of firefly luciferin was measured using a multi-functional microplate reader (PerkinElmer, Nivo); the fluorescence values ​​were processed, and the EC was calculated. 50 value.

[0411] 3. Experimental Results

[0412] The compounds disclosed herein exhibit good GLP-1R agonist activity, with preferred compounds having ≤20 nM agonist activity (EC). 50More preferably, the compound has ≤10 nM agonist activity (EC). 50 More preferably, the compounds have ≤5 nM agonistic activity (EC). 50 More preferably, the compounds have ≤2 nM agonistic activity (EC). 50 More preferably, the compounds have ≤1 nM agonistic activity (EC). 50 The activity results of exemplary compounds are shown in the table below.

[0413] Table 2 Note: A represents EC 50 ≤10nM.

[0414] Experimental Example 2: In vitro agonist activity assay (cAMP method)

[0415] 1. Experimental objective: To determine the agonistic effect of test compounds (including compounds disclosed herein and control compounds) on GLP-1R using GLP1R-cAmp-Luc cells.

[0416] 2. Experimental preparation:

[0417] 1) cAMP experimental buffer: Dilute HEPES to 5mM with HBSS, and add IBMX and BSA to a final concentration of 0.5mM and 0.1% respectively. Prepare fresh before use.

[0418] 2) cAMP detection reagent: Add 40×cAMP-D2 and 40×Anti-cAMP-Cryptate Reagent to Lysis & Detection Buffer, mix gently, and use immediately.

[0419] 3) Drug preparation:

[0420] a) Dissolve the precisely weighed analyte in DMSO to prepare a 10 mM stock solution, and then dilute the 10 mM DMSO stock solution with DMSO to a working concentration of 50 μM.

[0421] b) Weigh the reference compound GLP-1(7-37) and dissolve it in ultrapure water to prepare a 1 mM stock solution.

[0422] 3. cAMP experiment

[0423] 1) The working concentrations of the test compound and the reference compound were serially diluted 4-fold to 10 concentration points using ECHO, and 100 nmol of each solution was transferred to the compound plate. 100 nmol of DMSO was transferred as a low-signal control, and 100 nmol of the highest concentration reference compound was transferred as a high-signal control. The initial and final concentrations of the test compound were 500 nM, the initial concentrations of the reference compounds were all 20 nM, and the final concentration of BSA was 0.1%.

[0424] 2) Cell preparation: Thaw the frozen cells rapidly in a 37°C water bath. Transfer the thawed cells to a centrifuge tube, add 10 mL of HBSS to resuspend the cells, centrifuge at 1000 rpm for 5 minutes, and discard the supernatant. Wash the cells again with 10 mL of HBSS, centrifuge at 1000 rpm for 5 minutes, and discard the supernatant. Resuspend the cells in experimental buffer and count them using a cell counter.

[0425] 3) Add 10 μL of experimental buffer containing cells to the compound plate, with 1000 cells per well, and centrifuge at 1000 rpm for 1 minute. Incubate in an incubator at 37°C with 5% CO2 for 1 hour.

[0426] 4) Preparation of cAMP standard curve: Prepare 800 nM starting material and 10-point cAMP standard diluted 4 times. Add 10 μL to each well of the compound plate according to the compound arrangement diagram.

[0427] 5) Add 10 μL of the detection reagent solution to the corresponding well of the compound plate and centrifuge at 1000 rpm for 1 minute. Incubate at room temperature in the dark for 1 hour.

[0428] 6) Place the reaction plate in an EnVision microplate reader and take the reading. The final value is the ratio of the emitted light at 665 nm to that at 615 nm.

[0429] 7) Data analysis: Calculate the actual cAMP level (nM) of each sample well using the cAMP standard curve; Agonist: Activation rate % = 100 - 100 × (sample well cAMP value - low signal control group cAMP average value) / (high signal control group cAMP average value - low signal control group cAMP average value).

[0430] Calculate the EC of each test sample 50 The values ​​and results are shown in the table below.

[0431] Table 3 Note: A represents EC 50 ≤20nM.

[0432] Experimental Example 3: Pharmacokinetic Experiment in Mice

[0433] 1. Experimental animals: ICR mice (female, 22-25g) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0434] 2. Experimental Procedure: ICR mice were administered the test compound via tail vein injection / gavage. Whole blood samples were collected from mice at 5 min (intravenous only), 15 min, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. Plasma was separated by centrifugation, and the compound concentration was detected by LC-MS / MS. Pharmacokinetic parameters such as plasma clearance (Cl), elimination half-life (T1 / 2), peak time (Tmax), peak concentration (Cmax), area under the curve (AUC), and oral bioavailability (F) were calculated.

[0435] Intravenous dose: 2 mg / kg; oral gavage dose: 10 mg / kg. Alternatively, intravenous dose: 0.03–2 mg / kg (e.g., 0.3 mg / kg), oral gavage dose: 0.03–10 mg / kg (e.g., 0.3 mg / kg).

[0436] Oral gavage solvent: 2.5% DMSO + 10% EL+15% PEG400+72.5% (100mM glycine-NaOH buffer, pH=10); Intravenous solvent: 2% DMSO+98% 0.2g / mL HP-β-CD.

[0437] Assay method: After pretreatment by protein precipitation, quantitative analysis was performed using an LC / MS / MS system.

[0438] 3. Experimental Results

[0439] The compounds disclosed herein possess excellent PK properties, such as oral administration performance. The PK parameters of exemplary compounds are listed in the table below.

[0440] Table 4

[0441] Table 4-2

[0442] Table 4-3

[0443] Experimental Example 4: In vivo pharmacokinetics in monkeys

[0444] 1. Laboratory animal: Crab-eating macaque.

[0445] 2. Experimental procedure: The test compound was administered, and whole blood samples were collected from monkeys at 15 min, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h after administration. The plasma was separated by centrifugation, and the concentration of the compound was detected by LC-MS / MS. Pharmacokinetic parameters such as elimination half-life T1 / 2, peak time Tmax, peak concentration Cmax, and area under the curve (AUC) were calculated.

[0446] Oral dosage: 0.05–2 mg / kg (e.g., 0.5 mg / kg), prepared as a solution for administration.

[0447] Solvent: 2.5% DMSO+10% EL+15% PEG400+72.5% (100mM glycine-NaOH buffer, pH=10)

[0448] Assay method: After pretreatment by protein precipitation, quantitative analysis was performed using an LC / MS / MS system.

[0449] 3. Experimental Results

[0450] The compounds disclosed herein (e.g., compounds 2 to 61) have excellent oral administration properties, and the PK parameters of the exemplary compounds are listed in the table below.

[0451] Table 5

[0452] Experimental Example 5: Cytotoxicity Experiment

[0453] 1. Experimental materials:

[0454] Human umbilical vein endothelial cells (HUVECs): purchased from Nanjing Kebai Biotechnology Co., Ltd., cultured in BEGM kit containing 10% FBS.

[0455] Human normal hepatocytes HL-7702: purchased from Nanjing Kebai Biotechnology Co., Ltd., culture medium was RPMI Medium 1640 containing 10% FBS.

[0456] Human colon cancer cells Caco-2: purchased from Nanjing Kebai Biotechnology Co., Ltd., culture medium was MEM containing 20% ​​FBS + 1% MEM-NEAA + 1% sodium pyruvate.

[0457] Human embryonic kidney cells HEK-293T: purchased from Nanjing Kebai Biotechnology Co., Ltd., cultured in RPMI Medium 1640 containing 10% FBS.

[0458] All four cell lines were cultured at 37°C and 5% CO2.

[0459] 2. Experimental Procedure

[0460] Cell lines in the logarithmic growth phase were inoculated into 96-well plates at a certain number (100 μL / well). 100 μL of culture medium containing different concentration gradients of the test compound was added to each well. Three replicates were set for each drug concentration, along with corresponding blank wells (culture medium only) and normal wells (drug concentration of 0). After 72 hours of drug treatment, cell viability was assessed using the MTT and CTG methods, and the inhibition rate at each concentration was calculated.

[0461] The inhibition rate of cell growth is calculated using the following formula: Inhibition rate (%) = (OD value) / (OD value) 正常孔 - OD value 给药孔 ) / (OD value) 正常孔 - OD value 空白孔 )×100%

[0462] Calculate the half-maximal inhibitory concentration (IC50) of the drug based on the inhibition rate at each concentration. 50 .

[0463] IC 50 IC50 is used to evaluate the extent of a drug's inhibitory activity against tumor cell proliferation in vitro. 50 The smaller the value, the stronger the drug's inhibitory activity.

[0464] 3. Experimental Results

[0465] The results showed that the compounds disclosed herein have good cellular safety, and the preferred compounds have ≥15 μM inhibitory activity (IC50). 50 More preferably, the compound has ≥20 μM inhibitory activity (IC50). 50 More preferably, the compound has an inhibitory activity of ≥30 μM (IC50). 50 More preferably, the compound has ≥60 μM of inhibitory activity (IC50). 50 More preferably, the compound has an inhibitory activity of ≥65 μM (IC50). 50 More preferably, the compound has ≥90 μM inhibitory activity (IC50). 50 More preferably, the compound has an inhibitory activity of ≥100 μM (IC50). 50 The results for exemplary compounds are shown in the table below:

[0466] Experiment 6: Transporter Experiment

[0467] 1. Experimental Objective: To evaluate the inhibitory effect of the compound on the transporters OATP1B1 and OATP1B3.

[0468] 2. Experimental steps:

[0469] 1) Preparation of test stock solution: Weigh an appropriate amount of the test compound and dissolve it in DMSO to prepare a 20mM stock solution.

[0470] 2) Preparation of intermediate solutions of different concentrations: The 20 mM stock solution was released sequentially with DMSO to produce intermediate solutions of 10.0, 3.33, 1.11, 0.37, 0.123, 0.041 and 0.014 mM.

[0471] 3) Preparation of test sample or positive control working solution: Dilute the 10 mM stock solution with DMSO to 200 times the final concentration (50.0, 16.67, 5.56, 1.85, 0.617, 0.206 and 0.0687 μM).

[0472] 4) Preparation of probe substrate delivery solution: Dilute the stock solution to the final concentration with transport buffer (TB) (OATP1B1 / OATP1B3: pH 7.40±0.05), and the final concentration of DMSO shall not exceed 1%.

[0473] 5) Preparation of test sample or positive control solution: Add 2.5 μL of test sample or positive control working solution to 497.5 μL of probe substrate solution.

[0474] 6) Preparation of OATP1B1 / OATP1B3 pre-drug solution: Add 2.5 μL of the test sample or positive control working solution to 497.5 μL of LTB.

[0475] 7) Remove the transporter cells and Mock cells (HEK293-OATP1B1, HEK293-OATP1B3, HEK293-MOCK) from liquid nitrogen, revive them at 37°C, and transfer them to 10 mL of DMEM medium (containing 10.0% (v / v) fetal bovine serum). Centrifuge at 800 rpm for 5 minutes at room temperature, then remove the medium and dilute to 8 × 10⁻⁶ with DMEM medium (containing 10.0% fetal bovine serum and penicillin-streptomycin solution (100 U / mL and 0.100 mg / mL)). 5 Cells / mL. 100 μL was seeded into each well of a 96-well plate pre-coated with poly-L-lysine and incubated overnight at 37°C and 5% CO2.

[0476] 8) Subsequently, the Mock cells and transporter cells undergo the same operation.

[0477] 9) Remove the culture medium from the cell plate, wash the cells once with 100 μL of preheated TB, and incubate the cell plate at 37°C and 5% CO2 for 5 minutes.

[0478] 10) Pre-incubation of OATP1B1 and OATP1B3: Remove TB, add 50 μL of pre-warmed pre-drug solution to the cell plate, and incubate at 37°C and 5% CO2 for 30 minutes.

[0479] 11) Remove the buffer solution, add 50 μL of preheated test sample or positive control solution, and begin the transport experiment. Place the OATP1B1 and OATP1B3 cell culture plates in a 37°C, 5% CO2 incubator for 10 minutes.

[0480] 12) Immediately remove the drug solution from each well to stop the transport, and add 100 μL of pre-cooled TB to the cell plate, and quickly wash the cells three times.

[0481] 13) Add 100 μL of distilled water and lyse the cells by repeatedly freezing and thawing (-196℃ to 37℃) three times.

[0482] 14) Transfer 60 μL of cell lysis buffer to 240 μL of stop solution. Centrifuge all samples at 6000 rpm for 10 minutes and collect 100 μL of supernatant for LC-MS / MS analysis.

[0483] 15) Take 25.0 μL of cell lysis buffer for use. The BCA protein assay kit measures protein content.

[0484] 16) The inhibitory effect of the test compound on the corresponding transporter was obtained through data processing. The smaller the IC50 value, the stronger the inhibitory effect on the transporter.

[0485] 3. Experimental Results

[0486] The results showed that the compounds disclosed herein had no significant or weak inhibitory activity against OATP1B1 and OATP1B3, while the preferred compounds exhibited ≥0.2 μM inhibitory activity (IC50). 50 More preferably, the compound has ≥1 μM inhibitory activity (IC50). 50 More preferably, the compound has ≥5 μM inhibitory activity (IC50). 50 The results for exemplary compounds are shown in the table below:

[0487] Experimental Example 7: BCRP Transporter Experiment

[0488] 1. Experimental objective: To evaluate the inhibitory effect of the compound on the BCRP transporter.

[0489] 2. Experimental steps:

[0490] 1) Caco-2 cells (passaged batch: P49) were cultured at a rate of 1×10^5 cells / cm². 2 The cells were seeded at a density in 96-well Transwell plates and cultured for 14-28 days to form a dense cell monolayer. The culture medium was changed every 2-5 days.

[0491] 2) Wash the cell plate twice with transfer buffer (TB: HBSS containing 10.0mM HEPES and 0.5% BSA, pH 7.40±0.05), equilibrate at room temperature (25℃) for 10 minutes, and then measure the TEER value of each well.

[0492] 3) Dilute the osmotic control (atenolol / propranolol) with TB from 10 mM stock solution (DMSO) to 10 μM as the dosing solution. Incubate all dosing solutions at 37 ± 1 °C for 20 min. For transport experiments in the top-to-bottom direction (A→B): add 100 μL of the dosing solution containing the osmotic control (atenolol / propranolol) to the top-side well and add 300 μL of TB containing DMSO to the bottom-side well;

[0493] 4) Substrate control and test substance transport studies: The substrate control (estrone sulfate) was diluted from 10 mM stock solution (DMSO) to 10 μM with TB, and 10 μM / 30 μM positive inhibitor KO143 / neomyomycin was added or not added as the dosing solution.

[0494] The test substance was diluted with TB from 100 mM stock solution (DMSO) to concentrations of 50, 16.7, 5.56, 1.85, 0.206, and 0.023 μM (containing 10.0 μM estrone sulfate) to prepare dosing solutions. All dosing solutions were incubated at 37 ± 1 °C for 20 minutes.

[0495] For the top-to-base A→B transport experiment: 100 μL of drug solution containing different concentrations of test substance / positive inhibitor and estrone sulfate was added to the top-side well, and 300 μL of TB containing test substance / positive inhibitor was added to the base-side well.

[0496] For the basal-to-apex (B→A) transport experiment: 300 μL of drug solution containing different concentrations of test substance / positive inhibitor and estrone sulfate was added to the basal-side well, and 100 μL of TB containing test substance / positive inhibitor was added to the apex-side well.

[0497] 5) At time point T0: Take 8 μL of the drug solution (N=2), dilute it 10 times with TB to 80 μL, and immediately mix it with 320 μL of the stop solution;

[0498] 6) Incubate the culture plate at 37±1℃, 5% CO2 and saturated humidity for 120 minutes;

[0499] 7) After incubation, separate the top side plate from the base side plate and collect samples as follows:

[0500] A→B receptor side: Take 80 μL of solution (N=2) from the A→B basal side well and immediately mix it with 320 μL of stop solution.

[0501] A→B donor side: Take 8 μL of solution (N=2) from the top side hole of A→B, dilute it 10 times with TB to 80 μL, and immediately mix it with 320 μL of stop solution.

[0502] B→A receptor side (estrone sulfate with / without 10μM / 30μM positive inhibitor KO143 / neomyomycin, and estrone sulfate with different concentrations of the test substance): Take 80μL of solution (N=2) from the top side well of B→A and immediately mix it with 320μL of stop solution.

[0503] B→A donor side (estrone sulfate with / without 10μM / 30μM positive inhibitor KO143 / neomyomycin, and estrone sulfate with different concentrations of the test substance): Take 8μL of solution (N=2) from the B→A base side well, dilute 10 times with TB to 80μL, and immediately mix with 320μL of stop solution.

[0504] 8) Seal all sample plates, mix thoroughly, centrifuge at 6000 rpm for 10 minutes, take 100 μL of supernatant and mix thoroughly with 100 μL of water, and analyze the compound concentration using LC-MS / MS.

[0505] 3. Data Analysis

[0506] The apparent permeability coefficient Papp (cm / s) is calculated using the formula: Papp = (dCr / dt) × Vr / (A × C0), where dCr / dt is the rate of change of the cumulative concentration of the compound in the acceptor compartment over time (μM / s); Vr is the volume of the solution in the acceptor compartment (0.1 mL on the top side and 0.3 mL on the base side); and A is the surface area of ​​the monolayer cells (0.143 cm²). 2 C0 represents the initial concentration (μM) in the donor chamber.

[0507] Formula for calculating the efflux ratio: Efflux ratio = Papp(B→A) / Papp(A→B)

[0508] Recovery rate calculation formula: Recovery rate (%) = 100 × [(Vr × Cr) + (Vd × Cd)] / (Vd × C0), where Vd is the donor chamber volume (0.1 mL on the top side and 0.3 mL on the base side); Cd and Cr are the final concentrations (μM) of the compounds in the donor and acceptor chambers, respectively.

[0509] 4. Experimental Results

[0510] The results showed that the compounds disclosed herein had no significant inhibitory activity or weak inhibitory activity against BCRP, while the preferred compounds had ≥10 μM inhibitory activity (IC50). 50 More preferably, the compound has ≥20 μM inhibitory activity (IC50). 50 More preferably, the compound has an inhibitory activity of ≥30 μM (IC50). 50More preferably, the compound has ≥50 μM inhibitory activity (IC50). 50 The results for exemplary compounds are shown in the table below:

[0511] Experimental Example 8: Study on the weight loss efficacy of DIO hGLP1R mice

[0512] 1. Purpose of the experiment: To compare the weight-loss efficacy of the test compound and the control compound (e.g., LY3502970) in obese mice at the same dose.

[0513] 2. Experimental animals

[0514] Animals (species: C57BL / 6 humanized transgenic hGLP1R mice; age: 6 weeks; sex: male) were purchased and induced to consume high-fat diet (60kcal% Fat) for at least 12 weeks until their weight reached 40g or more.

[0515] 3. Experimental Grouping

[0516] Each group contains 5-8 animals (e.g., 5, 6, 7, or 8 animals per group).

[0517] Oral administration dosage: 0.03–10 mg / kg (e.g., 0.03 mpk, 0.3 mpk, 1 mpk, 3 mpk), once daily.

[0518] Solvent: 10% DMSO + 10% EL35 + 15% PEG400 + 65% (100mM glycine-NaOH buffer, pH=10).

[0519] 4. Test methods

[0520] Mice were weighed before administration, and the food intake of each mouse in one day (one full night + daytime) was measured. Mice were then evenly divided into groups based on their weight and food intake. Mouse weight was measured at fixed times daily, and the rate of weight change was calculated. After measurement, mice were administered the appropriate drug according to their current weight based on their group assignments. Daily mouse weight was recorded, the rate of weight change was calculated, and the data was plotted until the end of the experiment (administration was stopped when the weight stabilized; alternatively, the time to stop administration could be determined based on the actual situation).

[0521] 5. Test Results:

[0522] After continuous administration to the endpoint, the weight change rate of mice in each group was statistically analyzed. Compared with the Vehicle group, the disclosed compounds (e.g., compounds 2 to 61) achieved significantly (p<0.05) better weight loss effects (e.g., average weight change rate ≥10%; preferred compounds have an average weight change rate ≥13%; more preferred compounds have an average weight change rate ≥15%; more preferred compounds have an average weight change rate ≥18%; more preferred compounds have an average weight change rate ≥19%; more preferred compounds have an average weight change rate ≥20%; more preferred compounds have an average weight change rate ≥25%).

[0523] Experimental Example 9: Efficacy Study of Intraperitoneal Injection of IPGTT in hGLP-1R Transgenic Mice

[0524] 1. Experimental objective: To investigate the effect of a single gavage administration of different doses of the test compound or control compound (e.g., LY3502970) to hGLP-1R transgenic mice on blood glucose levels at different time points after glucose loading.

[0525] 2. Experimental animals: C57BL / 6 humanized transgenic hGLPIR mice, male, approximately 25g.

[0526] 3. Experimental grouping: Before the experiment, the mice were fasted for about 16 hours but allowed to drink water. The baseline blood glucose level of the mice was measured. The animals were randomly divided into groups of 5-8 mice each (e.g., 5, 6, 7 or 8 mice per group).

[0527] 4. Experimental Methods: Each group was administered the test compound or control compound via gavage at doses ranging from 0.01 mg / kg to 10 mg / kg (e.g., 0.01 mg / kg, 0.03 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg), with a volume of 10 mL / kg. The vehicle group, as a solvent control, received the same frequency and simultaneously with the test compound in 2.5% DMSO + 10% DMSO solution. EL + 15% PEG400 + 72.5% (100mM glycine-NaOH buffer, pH 10) buffer was administered intraperitoneally at a dose of 2 g / kg based on mouse body weight 60 min after drug administration (ip glucose solution, injection volume 10 mL / kg, with the glucose administration time set at 0 min). Blood glucose levels were measured before glucose administration and at 15 min, 30 min, 60 min, 120 min, and 180 min after glucose administration.

[0528] 5. Experimental Results: Blood glucose test results showed that, at the test dose, the blood glucose levels of the test compound group in mice at 15, 30, 60, 120, and 180 minutes after glucose loading showed a decreasing trend, significantly lower than those in the vehicle group. The area under the glucose curve (AUC) calculation results showed that, compared to the vehicle group, the AUC of the test compound group in mice after glucose loading was significantly lower. 0-180min Glu A significant (p<0.05) decrease indicates that the compounds of this disclosure (e.g., compounds 2 to 61) can effectively lower blood glucose (mean AUC of the tested compounds). 0-180min Glu Decrease rate ≥ 20%; average AUC of preferred compounds 0-180min Glu The rate of decrease is ≥30%; the average AUC of more preferred compounds 0-180min Glu The rate of decrease is ≥40%; the average AUC of more preferred compounds 0-180min Glu (The rate of decline is ≥50%).

[0529] Experimental Example 10: Study on the weight loss effect of drugs on cynomolgus monkeys

[0530] 1. Purpose of the experiment: To compare the weight-loss efficacy of the test compound and the control compound (e.g., LY3502970) in cynomolgus monkeys at the same dosage.

[0531] 2. Experimental animals

[0532] Species: Crab-eating macaque; Age: 3–6 years; Sex: Female

[0533] 3. Experimental Grouping

[0534] Each group contains 3-6 animals (e.g., 3, 4, 5, or 6 animals per group).

[0535] Gavage administration dosage: 0.5–10 MPa (e.g., 0.5 MPa, 1 MPa, 2 MPa, 3 MPa), once daily.

[0536] Solvent 2.5% DMSO+10% EL+15% PEG400+72.5% (100mM glycine-NaOH buffer, pH 10).

[0537] 4. Test methods

[0538] All experimental animals underwent at least 3 days of acclimatization before drug administration. During this period, they were administered acclimatization via gavage (2 mL / kg, solvent), and their weight was measured every other day. Clinical observation and food intake were conducted daily (over a full night and day). Animals were grouped according to weight and food intake. During the drug administration period, monkey weight was measured at fixed time points every other day, and the rate of weight change was calculated, recorded, and plotted. Food intake was measured at fixed time points daily, and the rate of food intake inhibition was calculated, recorded, and plotted. On the day of the last administration (when weight was essentially stable, drug administration was discontinued; or, the discontinuation time could be determined based on actual conditions), TK blood samples were collected from the veins of the limbs, approximately 0.5 mL per time point, and collected into K2EDTA-containing blood collection tubes. The blood was centrifuged at 4°C and 3000×g for 10 min. Plasma was collected and temporarily stored at -60°C or below for blood drug concentration testing.

[0539] 5. Test Results

[0540] After continuous administration, statistical analysis was performed on the weight change rate of each group of monkeys. Compared with the Vehicle group, the disclosed compounds (e.g., compounds 2 to 61) achieved significantly better weight loss effects. (e.g., average weight change rate ≥5%; preferred compounds have an average weight change rate ≥6%; more preferred compounds have an average weight change rate ≥7%; even more preferred compounds have an average weight change rate ≥8%; even more preferred compounds have an average weight change rate ≥9%).

[0541] Test Example 11: Safety Assessment Test of Off-Target Effects

[0542] 1. Experimental objective: To evaluate in vitro the potential off-target effects of the test compound on 90 targets, including G protein-coupled receptors, ion channels, transporters, kinases, enzymes, and nuclear hormone receptors.

[0543] 2. Experimental Methods: Calcium flow detection using a high-throughput real-time fluorescence detection and analysis system (FLIPR), cyclic adenosine monophosphate (cAMP) detection using time-resolved fluorescence resonance energy transfer (TR-FRET), ADP-Glo ​​fluorescence polarization assay, and fluorescence or chemiluminescence assays were employed to detect the effects of the test compounds (including the test compound or control compound) on 90 targets such as G protein-coupled receptors and ion channels (e.g., Ca2+ ... 2+ Binding, inhibitory or agonistic effects of (-L, 5HT2B, op-delta, etc.).

[0544] 3. Experimental results: The compounds disclosed herein (e.g., compounds 2 to 61) did not have any potential agonist or inhibitory effects on the 90 targets selected in this screening at a concentration of 10 μM.

[0545] The above description is merely a specific embodiment of this disclosure, but the scope of protection of this disclosure is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in this disclosure should be included within the scope of protection of this disclosure.

Claims

1. The compound represented by formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts: in, Cyclone A is selected from cyclopropyl; Ring B is selected from These represent the connection sites with the skeleton and loop C, respectively; Ring C is selected from Ring D is selected from R a Each time it appears, it is independently selected from deuterium, hydroxyl, amino, mercapto, cyano, oxo, -S(O)(NH)R a1 -S(O)(NCH3)R a1 -(CH2) m OR a1 -(CH2) m SR a1 -(CH2) m NHR a1 , or optionally substituted with the following groups: C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 alkylamine group, C 1-4 mercaptoalkyl, C 2-4 alkynyl or C 2-4 Alkenyl, wherein the optional substitution refers to unsubstituted or substituted with one or more R a1 replace; R a1 Selected from hydrogen, deuterium, methyl, deuterated methyl, deuterated methoxy, oxo, hydroxyl, -OR a2 -CH2R a2 C 3-4 cycloalkyl; R a2 Each time it appears, it is independently selected from deuterium, halogens (e.g., fluorine, chlorine), hydroxyl, amino, mercapto, cyano, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 alkylamine group, C 1-4 Hydroxyalkyl, C 1-4 mercaptoalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, R a2 Further optionally by one or more R a3 replace; R a3 Selected from fluorine, chloro, and methyl; R b Selected from hydrogen; R c Selected from halogens, cyclopropyl, -S(O)(=N-methyl)cyclopropyl, methyl, ethyl, hydroxyethyl, -CH2CH2S(R) c1 ) 1- 2R c1 Tetrahydrofuranyl, -Ethylene R c1 ,-Ethylene OR c1 ,-EthyleneSR c1 ,-Ethylene NHR c1 -CH(R) c1 )2、-methylene R c1 ,-methylene OR c1 ,-methylene SR c1 ,-methylene NHR c1 ; R c1 Selected from hydrogen, methyl, methoxy, hydroxy, oxo, -C(R) c2 3. C 2-4 alkynyl group, -C 2-4 alkynyl R c2 Cyclopropyl CH2R c2 ; Indicates the connection site; R c2 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, oxo, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 alkylamine group, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups; R c2 Further optionally by one or more R c3 replace; R c3 Selected from hydrogen, halogens, and methyl; R d Selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamine group; R e Selected from halogens and methyl groups; X1 is CH, X2 is N; or, X1 is N, X2 is CH; or, X1 is CH, X2 is CH; or, X1 is N, X2 is N; Unless otherwise stated, the heteroatoms in the above heterocyclic groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3, 4, 5 or 6; Each time m, n, o, p, or q appears, it is independently selected from 0, 1, 2, 3, 4, or 5.

2. The compound according to claim 1, its stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein, When ring B is for for At that time, one of the following conditions must be met: (1) When R c It is methyl or cyclopropyl, R a for When m1 is 1, 2, or 3, n1 is 1, 2, or 3; R a2 As defined by compound (I); preferably, m1 is 1 and n1 is 1; (2) When for R c for At that time, the Not for Where m1 is 1, 2, 3, 4 or 5, and n1 is 0, 1, 2, 3, 4 or 5; R c2 As defined by compound (I); preferably, m1 is 2 and n1 is 0 or 1; in, Indicates the connection site.

3. The compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt according to claim 1 or 2, wherein, Ring D is selected from Indicates the connection point with the skeleton.

4. The compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt according to any one of claims 1-3, wherein, Selected from Indicates the connection site.

5. The compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt according to any one of claims 1-4, wherein, R a Selected from methyl, ethynyl, This indicates the connection point with ring A.

6. The compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt according to any one of claims 1-5, wherein, Selected from ； Indicates the connection site. This indicates a connection to an N atom.

7. The compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt according to any one of claims 1-6, wherein, Selected from Represents the connection site.

8. The compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt according to any one of claims 1-7, wherein, R c Selected from F, cyclopropyl, methyl, Represents the connection site.

9. The compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt according to any one of claims 1-8, wherein, Selected from Represents the connection site.

10. The compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt according to any one of claims 1-9, wherein, for 11. The compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt according to any one of claims 1-10, wherein, The compound is: in, Indicates a single bond or a double bond; X3 is CH or N; preferably, X3 is CH; R c It can be located at any position in a double-ring system; Ring A, Ring B, Ring D, Ring C, R a R b R c R d R e X1, X2, m, n, o, p, and q are as defined in any one of claims 1-10.

12. A compound, its stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein, The compound has the structure described in Table 1 or Table 1' of the specification.

13. A pharmaceutical composition comprising a compound, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-12, optionally further comprising a pharmaceutically acceptable excipient.

14. The use of the compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt, or the pharmaceutical composition according to any one of claims 1-12 as a drug or in the preparation of a drug; preferably, the drug is a GLP-1R agonist; more preferably, the drug is a drug for treating and / or preventing GLP-1R-related conditions; more preferably, the drug is a drug for treating and / or preventing conditions mediated by GLP-1R; more preferably, the drug is a drug for treating and / or preventing conditions caused by or mediated by reduced GLP-1R activity; more preferably, the drug is a drug for preventing and / or treating conditions by activating GLP-1R-mediated cascade signaling; more preferably, the conditions include diabetes, overweight or obesity, non-alcoholic fatty liver disease, and Alzheimer's disease.

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