GLP-1R agonist compound and application thereof

Abstract

The invention relates to a GLP-1R agonist compound and application thereof, in particular to a compound as shown in a formula I, or an isotope label, a stereoisomer and pharmaceutically acceptable salt thereof, and application of the compound as a medicine. The compound shows excellent agonistic action and pharmacodynamic performance on GLP-1R, can be used as a regulator for preparing drugs for treating, improving or preventing metabolic diseases and related diseases, and has wide application prospects.

Description

A GLP-1R agonist compound and its application

[0001] Citation of Related Applications

[0002] The present invention claims priority to the invention patent application entitled “A GLP-1R agonist compound and its application” filed in China on November 10, 2023, with application number 202311497272.2, and the invention patent application entitled “A GLP-1R agonist compound and its application” filed in China on January 19, 2024, with application number 202410084261.X, and the entire contents of the patent application are incorporated herein by reference. Technical Field

[0003] The present invention belongs to the field of medicine and relates to a compound or its stereoisomers, or pharmaceutically acceptable salts, which can bind to and activate the glucagon-like peptide-1 receptor (GLP-1R) and may be used to treat metabolic disorders and related diseases, including but not limited to type 2 diabetes mellitus (T2DM), obesity, and non-alcoholic fatty liver disease (NASH). Background Art

[0004] Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted primarily by intestinal L cells after a meal. GLP-1 plays a key role in lowering glucose concentrations by enhancing insulin secretion and inhibiting glucagon release. Other functions of GLP-1 include delaying gastric emptying, suppressing appetite, and promoting beta-cell proliferation. The effects of GLP-1 are mediated by binding to GLP-1R, a glucose-dependent B-family G protein-coupled receptor. Binding of GLP-1 to GLP-1R activates the heterotrimeric Gs protein, which subsequently enhances adenylate cyclase activity, leading to an increase in intracellular cyclic adenosine monophosphate (cAMP) levels, thereby enhancing glucose-stimulated insulin secretion (Pflugers Arch. 1998, 435, 583-594; Basic Clin. Pharmacol. Toxicol. 2004, 95, 252-262). Due to its short half-life, GLP-1 is stable in the blood circulation for only 2-3 minutes and is inactivated by dipeptidyl peptidase 4 (DPP4).

[0005] GLP-1R agonists have been widely developed for the treatment of T2DM, obesity, and related metabolic diseases. GLP-1R agonists can be divided into short-acting GLP-1R agonists (exenatide and lixisenatide) or long-acting GLP-1R stimulators (exenatide-LAR, liraglutide, albiglutide, and dulaglutide) based on their pharmacological properties. However, the above-mentioned GLP-1R agonists are mainly administered by subcutaneous injection. GLP-1R agonists administered orally are easier to administer, but clinical options are very limited. Semaglutide, approved by the U.S. Food and Drug Administration in 2019, is the only oral GLP-1R agonist that only needs to be taken once a day.

[0006] Therefore, new GLP-1R agonists are urgently needed as alternatives for the treatment of metabolic disorders and related diseases, including but not limited to T2DM, obesity, and NASH.

[0007] Summary of the Invention

[0008] In one aspect, the present invention provides a class of novel compounds, or isotope-labeled compounds, stereoisomers, and pharmaceutically acceptable salts thereof.

[0009] More specifically, the compound provided by the present invention has the structure shown in Formula I:

[0010] in,

[0011] X 1 、X 2 and X 3 independently selected from N and C;

[0012] Rings A, B and C are independently selected from C 3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl groups;

[0013] Each R 1 independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl, -CN, -NO2, -NR A1 R B1 、-OR A1 、-C(O)R A1 、-C(O)OR A1 、-OC(O)R A1 、-C(O)NRA1 R B1 、-NR A1 C(O)R B1 、-OC(O)NR A1 R B1 、-S(O) r R A1 、-S(O)2OR A1 、-OS(O)2R A1 、-NR A1 S(O) r R B1 、-S(O) r NR A1 R B1 、-P(O)R A1 R B1 and-P(O)(OR A1 )(OR B1 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X1 Substituents substituted;

[0014] Each R 2 independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl, -(CH2) s CF3, -CN, -NO2, -NR A2 R B2 、-OR A2 、-C(O)R A2 、-C(O)OR A2 、-OC(O)R A2 、-C(O)NR A2 R B2 、-NR A2 C(O)R B2 、-OC(O)NR A2 R B2 、-NR A2 C(O)OR B2 、-S(O) r R A2 、-P(O)R A2 R B2 、-S(O) rNR A2 R B2 and-P(O)(OR A2 )(OR B2 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X2 Substituents substituted;

[0015] Each R 3 independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl, -CN, -NO2, -NR A3 R B3 、-OR A3 and -C(O)R A3 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X3 Substituents substituted;

[0016] Or two R 3 Together with the atoms they are connected to form a C 3-10 Cycloalkyl or 4-12 membered heterocyclic group containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted by 1, 2 or 3 groups independently selected from R X3 Substituents substituted;

[0017] R 4 is selected from -C(O)OH, heterocyclyl and heteroaryl;

[0018] R 5 Selected from hydrogen and C 1-6 alkyl;

[0019] R 6 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4Alkyl, -CN, -NO2, -NR A4 R B4 、-OR A4 and -C(O)R A4 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X4 Substituents substituted;

[0020] R 7 and R 8 Together with the atoms they are connected to form fragments R 9 and R 10 independently selected from hydrogen, halogen, C 1-3 alkyl;

[0021] or R 9 and R 10 Together with the atoms they are connected to form fragments R 7 and R 8 independently selected from hydrogen, halogen and C 1-3 alkyl;

[0022] or R 8 and R 9 Together with the carbon atoms to which they are attached, they form fragments R 7 and R 10 independently selected from hydrogen, halogen and C 1-3 alkyl;

[0023] Rings T, T' and W are independently selected from C 3-10 Cycloalkyl, C 3-8 Cycloalkenyl, 3-12 membered heterocyclyl and 5-6 membered heteroaryl, the ring is unsubstituted or substituted by 1, 2 or 3 independently selected R X Substituents substituted;

[0024] is a single bond or a double bond;

[0025] or R 8 and R 6 Together with the atoms they are connected to form a C 3-10 Cycloalkyl or 4-12 membered heterocyclic group containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, the ring is unsubstituted or substituted with 1, 2 or 3 R X Substituent substitution; R 7 、R 9 and R 10 are independently selected from hydrogen, halogen and C 1-3 alkyl;

[0026] or R 9 and R 6 Together with the atoms they are connected to form a C 3-10 Cycloalkyl or 4-12 membered heterocyclic group containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, the ring is unsubstituted or substituted with 1, 2 or 3 R X Substituent substitution; R 7 、R 8 and R 10 Each independently selected from hydrogen, halogen and C 1-3 alkyl;

[0027] Each R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 and R B4 independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from hydroxy, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Substitution with cycloalkyl, cyano, alkoxy, alkylamino, di(alkyl)amino, haloalkyl, acyl, sulfonyl, sulfonamido, and halogen;

[0028] or "R A1 and R B1 ” or “R A2 and R B2 ” or “R A3 and R B3 "Together with the atoms or atoms to which they are attached, they form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which is unsubstituted or substituted with 1, 2 or 3 groups selected from hydroxy, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6Substitution with cycloalkyl, cyano, alkoxy, alkylamino, di(alkyl)amino, haloalkyl, acyl, sulfonyl, sulfonamido, and halogen;

[0029] Each R X 、R X1 、R X2 、R X3 and R X4 Independently selected from hydroxyl, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, cyano, alkoxy, alkylamino, di(alkyl)amino, haloalkyl, acyl, sulfonyl, sulfonamido, and halogen;

[0030] m, n and p are independently selected from 0, 1, 2 and 3;

[0031] r and s are independently selected from 0, 1 and 2.

[0032] In some embodiments, the present invention relates to a compound of formula I, or an isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 7 and R 8 Together with the atoms they are connected to form fragments R 9 and R 10 independently selected from hydrogen, halogen, C 1-3 Alkyl; or R 9 and R 10 Together with the atoms they are connected to form fragments R 7 and R 8 independently selected from hydrogen, halogen, C 1-3 alkyl.

[0033] Further, in the above compounds, the rings T and T' are independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and oxocyclobutyl; or the rings T and T' are independently selected from oxacyclopropyl, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, azetidinyl and thietanyl. The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxocyclobutyl, oxacyclopropyl, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, azetidinyl and thietanyl are unsubstituted or replaced by 1-3 (e.g., 1, 2 or 3) independently selected from R X Substituents substituted, each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6Cycloalkyl, cyano, alkoxy, alkylamino, di(alkyl)amino, haloalkyl, acyl, sulfonyl, sulfonamido, and halogen.

[0034] Or in the above compound, the rings T and T' are independently selected from any one of the following structures:

[0035] Or ring T and ring T' are independently selected from any one of the following structures:

[0036] In some embodiments, the present invention relates to a compound of formula I, or an isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 9 and R 10 Together with the atoms they are connected to form fragments R 7 and R 8 independently selected from hydrogen, halogen and C 1-3 alkyl.

[0037] Furthermore, in the above compounds, the ring T' is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and C 4-8 The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and C 4-8 The cycloalkenyl group is unsubstituted or substituted by 1-3 (eg, 1, 2 or 3) independently selected from R X Substituents substituted, each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, alkylamino, -OC 1-6 Alkyl, -OC 1-6 Cycloalkyl and halogen, or each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Cycloalkyl and halogen.

[0038] Or in the above compounds, the ring T 'is selected from oxacyclopropyl, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, azetidinyl, thietanyl, thietanyl and thietanyl. The oxacyclopropyl, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, azetidinyl, azetidinyl, azetidinyl, thietanyl, thietanyl and thietanyl are unsubstituted or replaced by 1-3 (e.g., 1, 2 or 3) independently selected from R X Substituents substituted, each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, alkoxy, -C(O)H, -C(O)-C1-6 Alkyl, -C(O)-C 1-6 Cycloalkyl, -C(O)-C 1-6 Alkyl-C 1-6 Alkoxy, -C(O)-haloalkyl, -C(O)-C 1-6 Alkoxy, -C(O)-C 1-6 Alkylamino, -C(O)-aminoalkyl, -C(O)NH2, sulfonyl and halogen.

[0039] Preferably, in the above compounds, the ring T' is selected from any one of the following structures:

[0040] Or the ring T' is selected from any of the following structures:

[0041] Or ring T' is selected from any of the following structures:

[0042] In some embodiments, the present invention relates to a compound of formula I, or an isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 8 and R 9 Together with the carbon atoms to which they are attached, they form fragments R 7 and R 10 independently selected from hydrogen, halogen and C 1-3 alkyl.

[0043] Further, ring W is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxocyclohexyl, cyclohexenyl and oxocyclohexenyl; or ring W is selected from oxacyclopropyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, aziridine, azetidinyl and azetidinyl; or ring W is selected from furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl, and the ring Propyl, cyclobutyl, cyclopentyl, cyclohexyl, oxocyclohexyl, cyclohexenyl, oxocyclohexenyl, oxacyclopropyl, oxetanyl, oxolanyl, oxetanyl, aziridine, azetidinyl, azetidinyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl are unsubstituted or substituted by 1-3 (e.g., 1, 2 or 3) independently selected from R X Substituents substituted, each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, cyano, alkoxy, alkylamino, di(alkyl)amino, haloalkyl, acyl, sulfonyl, sulfonamido, and halogen. It is a single bond or a double bond.

[0044] Preferably, in the above compounds, the ring W is selected from any one of the following structures:

[0045] Or the ring W is selected from any one of the following structures:

[0046] Or the ring W is selected from any one of the following structures:

[0047] In some embodiments, the present invention relates to a compound of formula I, or an isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 8 and R 6 Together with the atoms they are connected to form a C 3-8 Cycloalkyl or a 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus; R 7 、R 9 and R 10 Each independently selected from hydrogen, halogen and C 1-3 Alkyl; or R 9 and R 6 Together with the atoms they are connected to form a C 3-8 Cycloalkyl or a 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus; R 7 、R 8 and R 10 Each independently selected from hydrogen, halogen and C 1-3 The ring is unsubstituted or substituted by 1-3 (e.g. 1, 2 or 3) independently selected from R X Substituents substituted, each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, cyano, alkoxy, alkylamino, di(alkyl)amino, haloalkyl, acyl, sulfonyl, sulfonamido, and halogen.

[0048] In some embodiments, the compound of formula I, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, wherein X 1 、X 2 and X 3 are independently selected from N and C, only one of which is N and the other two are C.

[0049] In some embodiments, the compound of formula I, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, wherein ring A is an aryl or heteroaryl group, preferably

[0050] In some embodiments, the compound of formula I, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, wherein each R 1 independently selected from hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy, wherein m is selected from 1, 2 and 3; each R 1 It is independently preferably hydrogen, fluorine, methyl or cyclopropyl, or preferably fluorine, methyl or cyclopropyl, and m is preferably 2 or 3.

[0051] In some embodiments, the compound of formula I, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, wherein ring B is selected from Preferably

[0052] In some embodiments, the compound of formula I, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, wherein each R 2 independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 3-6 Cycloalkyl, -CH2CF3, -S(O)2NR A2 R B2 、-S(O)2R A2 and-P(O)R A2 R B2 ; Each R A2 and R B2 Independently selected from C 1-4 Alkyl and C 3-6 Cycloalkyl, wherein n is 1, 2 or 3, or wherein n is 1 or 2; or wherein each R 2 independently selected from hydrogen, fluorine, methyl, -CH2CH3, -CH2CF3, -P(O)(CH3)2, -P(O)(CH2CH3)2, -NHCH3, -OCH3, -CH2S(O)2CH3 and Or the R 2 are independently hydrogen, fluorine, methyl, -CH2CF3, -P(O)(CH3)2, -P(O)(CH2CH3)2, -NHCH3, -OCH3, -CH2S(O)2CH3 or Or the R 2are independently fluoro, methyl, -CH2CH3, -CH2CF3, -P(O)(CH3)2, -P(O)(CH2CH3)2, -NHCH3, -OCH3, -CH2S(O)2CH3 or

[0053] In some embodiments, the compound of formula I, or its isotope label, stereoisomer, or pharmaceutically acceptable salt, wherein ring C is selected from heterocyclic and heteroaryl groups; each R 3 independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl; said p is 0, 1, 2 or 3, when p≥2, wherein two R 3 Optionally, together with the atoms to which they are attached, form a C 3-10 Cycloalkyl.

[0054] Furthermore, in the above compounds, ring C is Or ring C is The p is preferably 0; or the p is preferably 2, R 3 Preferably methyl; or said p is preferably 2, two R 3 Together with the atoms to which they are attached, they form a cyclopropyl group.

[0055] In some embodiments, the compound of formula I, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, wherein R 4 Selected from or R 4 for

[0056] In some embodiments, the compound of formula I, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, wherein R 5 Selected from hydrogen and C 1-3 Alkyl, or R 5 is hydrogen or methyl.

[0057] In some embodiments, the compound of formula I, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, wherein R 6 Selected from hydrogen and C 1-3 Alkyl, or R 6 It is a methyl group.

[0058] In some embodiments, the compound of formula I has any of the following structures:

[0059] in,

[0060] Selected from

[0061] Selected from or Selected from

[0062] Selected from or Selected from or Selected from

[0063] R 4 for

[0064] R 5 is hydrogen or methyl;

[0065] R 6 is methyl;

[0066] is a single bond or a double bond;

[0067] Rings T, T' and W are independently selected from C 3-10 Cycloalkyl, C 3-8 Cycloalkenyl, 3-12 membered heterocyclyl and 5-6 membered heteroaryl, the ring is unsubstituted or substituted by 1, 2 or 3 independently selected R X Substituents substituted;

[0068] or R 8 With R 6 Together with the atoms they are connected to form a C 3-8 Cycloalkyl or 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, the ring is unsubstituted or substituted with 1, 2 or 3 R X Substituent substitution; R 9 is hydrogen;

[0069] or R 9 With R 6 Together with the atoms they are connected to form a C 3-8 Cycloalkyl or 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted with 1, 2 or 3 R X Substituent substitution; R 8 is hydrogen;

[0070] Each R XIndependently selected from hydroxyl, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, cyano, alkoxy, alkylamino, di(alkyl)amino, haloalkyl, acyl, sulfonyl, sulfonamido, and halogen.

[0071] Further, in the above compounds, the rings T and T' are independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and oxocyclobutyl; or the rings T and T' are independently selected from oxacyclopropyl, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, azetidinyl and thietanyl; the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxocyclobutyl, oxacyclopropyl, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, azetidinyl and thietanyl are unsubstituted or replaced by 1, 2 or 3 groups independently selected from R X Substituents substituted, each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, cyano, alkoxy, alkylamino, di(alkyl)amino, haloalkyl, acyl, sulfonyl, sulfonamido, and halogen.

[0072] Or in the above compound, the rings T and T' are selected from Or the rings T and T' are selected from

[0073] Alternatively, further, in the above compounds, the ring W is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxocyclohexyl, cyclohexenyl and oxocyclohexenyl; or the ring W is selected from oxacyclopropyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, aziridine, azetidinyl and azetidinyl; or the ring W is selected from furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl. The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxocyclohexyl, cyclohexenyl, oxocyclohexenyl, oxacyclopropyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, aziridine, azetidinyl, azetidinyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl are unsubstituted or substituted by 1, 2 or 3 groups independently selected from R X Substituents substituted, each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-6 Cycloalkyl, cyano, alkoxy, alkylamino, di(alkyl)amino, haloalkyl, acyl, sulfonyl, sulfonamido, and halogen.

[0074] Preferably, in the above compounds, the ring W is selected from Or the ring W is selected from Or the ring W is selected from

[0075] In some embodiments, the compound of formula I has any of the following structures:

[0076] in,

[0077] Selected from

[0078] Selected from or Selected from

[0079] Selected from or Selected from or Selected from

[0080] R 4 for

[0081] R 5 is hydrogen or methyl;

[0082] R 6 is methyl;

[0083] Ring T' is independently selected from C 3-10 Cycloalkyl, C 3-8 Cycloalkenyl, 3-12 membered heterocyclyl and 5-6 membered heteroaryl, the ring is unsubstituted or substituted by 1, 2 or 3 independently selected R X Substituents substituted; each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6Cycloalkyl, cyano, alkoxy, alkylamino, di(alkyl)amino, haloalkyl, acyl, sulfonyl, sulfonamido, and halogen.

[0084] Furthermore, in the above compounds, the ring T' is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and C 4-8 Cycloalkenyl; the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and C 4-8 The cycloalkenyl group is unsubstituted or substituted by 1, 2 or 3 groups independently selected from R X Substituents substituted, each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, alkylamino, -OC 1-6 Alkyl, -OC 1-6 Cycloalkyl and halogen, or each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Cycloalkyl and halogen.

[0085] or the above compounds, wherein the ring T' is selected from oxirane, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, azetyl, azetyl, azetyl, thiol, thiol and thiol; the oxirane, oxetanyl, oxolanyl, oxhexyl, aziridine, azetyl, azetyl, azetyl, azetyl, azetyl, azetyl, thiol and thiol are unsubstituted or replaced by 1, 2 or 3 groups independently selected from R X Substituents substituted, each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, alkoxy, -C(O)H, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Cycloalkyl, -C(O)-C 1-6 Alkyl-C 1-6 Alkoxy, -C(O)-haloalkyl, -C(O)-C 1-6 Alkoxy, -C(O)-C 1-6 Alkylamino, -C(O)-aminoalkyl, -C(O)NH2, sulfonyl and halogen.

[0086] Preferably, in the above compounds, the ring T' is selected from Or the ring T' is selected from Or the ring T' is selected from

[0087] In some embodiments, the compound of formula I above has the following structure:

[0088] in,

[0089] Selected from

[0090] Selected from

[0091] Selected from

[0092] R 4 for

[0093] R 5 is methyl;

[0094] R 6 is methyl;

[0095] Ring T' is independently selected from C 3-10 Cycloalkyl, C 3-8 Cycloalkenyl, 3-12 membered heterocyclyl and 5-6 membered heteroaryl, the ring is unsubstituted or substituted by 1, 2 or 3 independently selected R X Substituents substituted; each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, cyano, alkoxy, alkylamino, di(alkyl)amino, haloalkyl, acyl, sulfonyl, sulfonamido, and halogen.

[0096] Furthermore, in the above compound, the ring T' is C 3-6 Cycloalkyl, preferably C 3-4 Cycloalkyl; the ring is unsubstituted or substituted by 1, 2 or 3, preferably 1 or 2, independently selected from R X Substituents substituted; each R X Independently selected from C 1-3 Alkyl, vinyl, -OC 1-6 Alkyl and halogen, preferably methyl, vinyl, methoxy and fluorine.

[0097] Preferably, in the above compounds, the ring T' is selected from

[0098] In some embodiments, the compound of formula I above has the following structure:

[0099] in,

[0100] Ring T' is independently selected from C 3-10 Cycloalkyl, C 3-8 Cycloalkenyl, 3-12 membered heterocyclyl and 5-6 membered heteroaryl, the ring is unsubstituted or substituted by 1, 2 or 3 independently selected R X Substituents substituted; each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, cyano, alkoxy, alkylamino, di(alkyl)amino, haloalkyl, acyl, sulfonyl, sulfonamido, and halogen.

[0101] Furthermore, in the above compound, the ring T' is C 3-6 Cycloalkyl, preferably C 3-4 Cycloalkyl; the ring is unsubstituted or substituted by 1, 2 or 3, preferably 1 or 2, independently selected from R X Substituents substituted; each R X Independently selected from C 1-3 Alkyl, vinyl, -OC 1-6 Alkyl and halogen, preferably methyl, vinyl, methoxy and fluorine.

[0102] Preferably, in the above compounds, the ring T' is selected from Preferred

[0103] Non-limiting illustrative compounds of the present invention are shown below:

[0104] The present invention also provides a method for preparing the compound of formula I, including but not limited to the following steps (the synthesis methods of some compounds are detailed in the Examples).

[0105] General preparation method 1

[0106] The above synthetic route successfully prepared the cyanoketone intermediate D. First, the bromocarboxylate compound A was prepared from commercial raw materials. This was then reacted with the aminonitrile compound B through a Buchwald-Hartwig coupling reaction to obtain the intermediate C. Subsequently, the ring was closed under alkaline conditions to obtain the important intermediate D.

[0107] General preparation method 2

[0108] The above synthetic route successfully prepared another type of cyanoketone intermediate D-1. First, the commercial raw material A-1 and the aminonitrile compound B were subjected to a reductive amination reaction to prepare the corresponding intermediate C-1. Subsequently, the ring closure reaction was carried out under alkaline conditions to obtain the important intermediate D-1.

[0109] General preparation method 3

[0110] The cyanoketone intermediate D-2 can be successfully prepared via the above synthetic route. First, commercial starting material A-2 (or prepared starting material) and aminonitrile compound B undergo a reductive amination reaction to produce intermediate C-2. This is followed by Boc protection and ring closure under alkaline conditions to yield the key intermediate D-2.

[0111] General preparation method 4

[0112] The cyanoketone intermediate D-3 can be successfully prepared via the above synthetic route. First, commercial starting material A-3 (or prepared) is reacted with aminonitrile compound B via a Michael addition reaction to produce intermediate C-3. This is followed by Boc protection and ring closure under alkaline conditions to yield the key intermediate D-3.

[0113] General preparation method 5

[0114] The above synthetic route can successfully prepare the important intermediate J. First, bromoaryl hydrocarbon E and di-tert-butyl azodicarboxylate undergo lithium halogen exchange and addition reaction to obtain intermediate F. This is then cyclized with the cyanoketone intermediate obtained by general preparation methods 1 and 2 to prepare compound G. This is followed by an addition reaction with an isocyanate and cyclization under acidic conditions to obtain urea compound I. Finally, the important intermediate J is prepared through a Buchwald-Hartwig or Ullmann coupling reaction with a substituted indazole compound.

[0115] General Preparation Method 6

[0116] The important intermediate J-1 can be successfully prepared by the above synthetic route and with reference to the synthesis of compound J.

[0117] General preparation method 7

[0118] The target compound T can be successfully prepared via the above synthetic route. First, the iodinated tetrahydropyran intermediate L is prepared using commercial raw material K and acetone as starting materials in the presence of an iodine source. Intermediate M is then obtained via a Negishi reaction, followed by hydrolysis and condensation to yield compound O. Subsequently, a cyano group is introduced via a nucleophilic substitution reaction, which reacts with a cyclic sulfate ester to form a three-membered ring. The exposed cyano group further reacts with hydroxylamine and carbonyldiimidazole to yield intermediate R. The acid S, obtained by hydrolysis of the amide from R, is condensed with the product of compound J after deprotection under acidic conditions to yield compound T.

[0119] General Preparation Method 8

[0120] The target compound T-1 can be successfully prepared through the above synthetic route. Compound S and J-1 can be prepared under condensation conditions to obtain compound T-1.

[0121] General Preparation Method 9

[0122] Compound T-2 can be prepared by using D-3 instead of D-2 and referring to general preparation methods 6 and 8.

[0123] General preparation method 10

[0124] The target compound T-3 can be successfully prepared through the above synthetic route. First, a cyano group is introduced into the commercial raw material U-1 under alkaline conditions to obtain the intermediate U-2. Subsequently, compound T-3 can be prepared by referring to general preparation methods 6 and 8.

[0125] General preparation method 11

[0126] The target compound T-4 can be successfully prepared via the above synthetic route. First, a cyano group is introduced into the commercial raw material V-1 (or prepared) under alkaline conditions to obtain the intermediate V-2. Subsequently, compound T-4 can be prepared by referring to general preparation methods 6 and 8.

[0127] On the other hand, the present invention provides a pharmaceutical composition comprising the above-mentioned compound, or its isotope-labeled substance, stereoisomer, pharmaceutically acceptable salt, and pharmaceutically acceptable excipients and / or carriers (eg, at least one pharmaceutically acceptable carrier).

[0128] In another aspect, the present invention provides a method for regulating GLP-1R, comprising administering an effective amount (e.g., a therapeutically effective amount) of the above-mentioned compound (e.g., a compound of Formula I), or its isotope label, stereoisomer, pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition to a system or subject in need thereof, thereby regulating the GLP-1R.

[0129] In another aspect, the present invention provides a method for treating, improving or preventing a disease or condition responsive to inhibition of GLP-1R, comprising administering an effective amount (e.g., a therapeutic, improving or preventing effective amount) of the above-mentioned compound (e.g., a compound of Formula I), or its isotope label, stereoisomer, pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition to a system or subject in need thereof, and optionally in combination with a second therapeutic agent, thereby treating, improving or preventing the disease or condition.

[0130] In another aspect, the present invention provides a method for treating, improving or preventing a GLP-1R-mediated disease or condition, comprising administering an effective amount (e.g., a therapeutic, improving or preventing effective amount) of the above-mentioned compound (e.g., a compound of Formula I), or its isotope label, stereoisomer, pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition to a system or subject in need thereof, and optionally in combination with a second therapeutic agent, thereby treating, improving or preventing the disease or condition.

[0131] In another aspect, the present invention provides use of the aforementioned compound (eg, compound of formula I) or its isotope-labeled substance, stereoisomer, pharmaceutically acceptable salt, or pharmaceutical composition in the preparation of a medicament for regulating GLP-1R.

[0132] In another aspect, the present invention provides the use of the above-mentioned compound (e.g., compound of Formula I) or its isotopically labeled substance, stereoisomer, pharmaceutically acceptable salt, or pharmaceutical composition in the preparation of a medicament for treating, ameliorating, or preventing a disease or condition responsive to inhibition of GLP-1R. In certain embodiments, the compound or pharmaceutical composition of the present invention can be used alone or in combination with a second therapeutic agent to treat, ameliorate, or prevent a disease or condition responsive to inhibition of GLP-1R.

[0133] In another aspect, the present invention provides the use of the above-mentioned compound (e.g., compound of Formula I) or its isotopically labeled substance, stereoisomer, pharmaceutically acceptable salt, or pharmaceutical composition in the preparation of a medicament for treating, ameliorating, or preventing a GLP-1R-mediated disease or condition. In certain embodiments, the compound or pharmaceutical composition of the present invention can be used alone or in combination with a second therapeutic agent to treat, ameliorate, or prevent a GLP-1R-mediated disease or condition.

[0134] In another aspect, the present invention provides the above-mentioned compound (eg, compound of formula I) or its isotope-labeled substance, stereoisomer, pharmaceutically acceptable salt or pharmaceutical composition, for use in regulating GLP-1R.

[0135] In another aspect, the present invention provides the above-mentioned compound (e.g., compound of formula I) or its isotope-labeled substance, stereoisomer, pharmaceutically acceptable salt or pharmaceutical composition, which is used to treat, improve or prevent diseases or conditions responsive to GLP-1R inhibition.

[0136] In another aspect, the present invention provides the above-mentioned compound (e.g., compound of formula I) or its isotope-labeled substance, stereoisomer, pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition, which is used to treat, improve or prevent GLP-1R-mediated diseases or conditions.

[0137] Specifically, the diseases or conditions described herein include, but are not limited to, autoimmune diseases, transplant diseases, infectious diseases, or other GLP-1R-mediated diseases or conditions, including, but not limited to, diabetes, diabetic complications, obesity, impaired glucose tolerance, overweight, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, arrhythmia, cerebral infarction, stroke, liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, dementia, Parkinson's disease, and diabetic nephropathy.

[0138] The present invention provides novel GLP-1R inhibitors having at least one advantageous property selected from the group consisting of ease of administration, solubility, drug-drug interaction, efficacy, stability, selectivity, toxicity, drug resistance, pharmacokinetic and pharmacodynamic properties.

[0139] Definition of terms

[0140] Unless otherwise specified in the present invention, the terms of the present invention have the following meanings:

[0141] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by persons skilled in the art. Unless otherwise indicated, all patents, patent applications, and publicly available materials referenced herein are incorporated by reference in their entirety. If multiple definitions of the same term are used herein, the definition in this section shall prevail.

[0142] It should be understood that the foregoing general description and the following detailed description are merely illustrative and are not limiting of any claims. In this application, the singular includes the plural unless otherwise indicated. It should be noted that throughout the specification and the appended claims, singular references such as "a," "an," and "the" include the plural unless the context indicates otherwise. Furthermore, the terms "include," "comprise," and similar terms are not limiting.

[0143] Unless otherwise indicated, the mass spectrometry (MS), nuclear magnetic resonance (NMR), high performance liquid chromatography (HPLC), infrared (IR) and ultraviolet / visible (UV / Vis) spectroscopy and conventional pharmacological techniques used in the present invention are prior art. Unless otherwise defined, the nomenclature, experimental methods and techniques involved in analytical chemistry, organic synthetic chemistry, pharmaceuticals and pharmaceutical chemistry in the present invention are all known. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, formulation and administration, and for treating patients. Reaction and purification techniques can be referred to the manufacturer's instructions, or to known conventional techniques, or to the methods described in the present invention. The above-mentioned techniques and operations can be implemented using known conventional methods and the methods cited in the literature in this specification. In the specification, groups and substituents can be selected by professionals in this field to form stable structures and compounds that meet the valence bond rules.

[0144] When referring to substituents by chemical formula, the substituents are written the same way from left to right as they are from right to left in the formula. For example, CHO is the same as OCH.

[0145] "Substituted" refers to the replacement of a hydrogen atom with a substituent. It should be noted that the substituents on a particular atom are limited by their valence.

[0146] The term "C i-j " or "ij member" means that the moiety has ij carbon atoms or ij atoms. For example, "C 1-6 "Alkyl" means that the alkyl group has 1 to 6 carbon atoms. 3-10 The cycloalkyl group means that the cycloalkyl group has 3 to 10 carbon atoms.

[0147] When any variable (such as R) appears more than once in the structure of a compound, it is independently defined in each case. Thus, for example, if a group is substituted with 0-2 R, then the group may optionally be substituted with up to two R, and R is independently selected in each case. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations will result in stable compounds.

[0148] "One or more" or "at least one" means one, two, three, four, five, six, seven, eight, nine or more.

[0149] Unless otherwise indicated, the term "hetero" refers to a heteroatom or heteroatom group (i.e., a group containing heteroatoms), i.e., an atom other than carbon and hydrogen atoms or a group containing these atoms. Preferably, the heteroatom is independently selected from O, N, S, P, etc. In embodiments involving two or more heteroatoms, the two or more heteroatoms may be the same, or the two or more heteroatoms may be different in part or in whole.

[0150] "Alkyl" whether used alone or in combination with other terms, refers to a branched or straight-chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms. Unless otherwise specified, "alkyl" refers to a C 1-10 Alkyl. For example, "C 1-6 "C" in "alkyl" 1-6 ” refers to an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched chain. For example, “C 1-8 "Alkyl" includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, and octyl.

[0151] "Cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic or tricyclic) hydrocarbon ring system, typically having 3 to 16 ring atoms, whether used alone or in combination with other terms. The ring atoms of a cycloalkyl are all carbon atoms, and the cycloalkyl contains zero heteroatoms and zero double bonds. In a polycyclic cycloalkyl, two or more rings may be fused, bridged, or spirocoupled. Examples of monocyclic ring systems include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A bridged cycloalkyl is a polycyclic ring system containing 3-10 carbon atoms, containing one or two alkylene bridges, each consisting of 1, 2, or 3 carbon atoms, connecting two non-adjacent carbon atoms on the ring system. A cycloalkyl may be fused to an aryl or heteroaryl group. In some embodiments, a cycloalkyl is benzofused. Examples of bridged cycloalkane systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, tricyclo[3.3.1.03,7]nonane, and tricyclo[3.3.1.13,7]decane (adamantane). Monocyclic and bridged cycloalkyl groups can be attached to the parent molecular moiety through any substitutable atom in the ring system.

[0152] "Cycloalkenyl" whether used alone or in combination with other terms, refers to a partially unsaturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms containing at least one carbon-carbon double bond, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged ring systems, and any ring of this system is non-aromatic. 3-8 The cycloalkenyl group includes cycloalkenyl groups of 3 to 8 carbon atoms, etc., which may be monovalent, divalent or polyvalent. 3-8 Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.

[0153] "Alkenyl" whether used alone or in combination with other terms, refers to a non-aromatic straight chain, branched or cyclic hydrocarbon group containing 2-10 carbon atoms and at least one carbon-carbon double bond. In some embodiments, there is one carbon-carbon double bond, and up to four non-aromatic carbon-carbon double bonds may be present. Therefore, "C 2-6 "Alkenyl" refers to an alkenyl group containing 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, vinyl (including the case where only one carbon atom in the carbon-carbon double bond is a ring atom, such as The straight-chain, branched, or cyclic portion of the alkenyl group may contain double bonds, and if a substituted alkenyl group is indicated, it may be substituted.

[0154] "Alkynyl," whether used alone or in combination with other terms, refers to a straight chain, branched, or cyclic hydrocarbon group containing 2-10 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, up to 3 carbon-carbon triple bonds may be present. Thus, "C 2-6 "Alkynyl" refers to an alkynyl group containing 2-6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, 3-methylbutynyl, and the like. The straight chain, branched, or cyclic portion of the alkynyl group may contain triple bonds, and if a substituted alkynyl group is indicated, it may be substituted.

[0155] "Halogen" whether used alone or in combination with other terms, refers to fluorine, chlorine, bromine, or iodine.

[0156] "Alkoxy" whether used alone or in combination with other terms, refers to an alkyl group as defined above that is attached to an oxygen atom by a single bond. The alkoxy group is attached to the rest of the molecule through the oxygen atom. The alkoxy group can be represented as -O-alkyl. "C 1-10 "Alkoxy" refers to an alkoxy group containing 1-10 carbon atoms, which may be a straight chain or branched structure. Alkoxy includes but is not limited to methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.

[0157] "Alkylamino" whether used alone or in combination with other terms, refers to an alkyl group as defined above that is attached to a nitrogen atom by a single bond. The alkylamino group is attached to the rest of the molecule through the nitrogen atom. The alkylamino group can be represented by -NH(alkyl). "C 1-10 "Alkylamino" refers to an alkylamino group containing 1 to 10 carbon atoms, which may be a straight chain or branched structure. Alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, butylamino, and hexylamino groups.

[0158] "Di(alkyl)amino" whether used alone or in combination with other terms, refers to two alkyl groups as defined above connected to a nitrogen atom by a single bond. The di(alkyl)amino group is connected to the rest of the molecule through the nitrogen atom. The di(alkyl)amino group can be represented as -N(alkyl)2. "Di(C 1-10 "Alkyl)amino" refers to a di(C 1-10 The amino group may be a straight chain or a branched structure.

[0159] "Aryl" whether used alone or in combination with other terms, refers to a group having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms ("C 6-14 a monovalent, monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system ("C6 aryl" group), in particular a ring having 6 carbon atoms (a "C6 aryl" group), for example phenyl; or a ring having 10 carbon atoms (a "C 10 an aryl group), such as naphthyl; or a ring having 14 carbon atoms ("C 14 The aryl group may be fused to a cycloalkyl or heterocyclic group.

[0160] Divalent radicals formed from substituted benzene derivatives with free valence electrons on ring atoms are named substituted phenylene groups. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals ending in "-" are formed by removing a hydrogen atom from a carbon atom with free valence electrons. Their names are obtained by adding "-idene" to the name of the monovalent radical. For example, naphthyl with two attachment sites is called naphthylene.

[0161] "Heteroaryl", whether used alone or in combination with other terms, refers to a monovalent, monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl" group), in particular 5, 6, 9 or 10 atoms, and containing at least one heteroatom which may be identical, partially different or completely different, selected from N, O and S. The heteroaryl group may be fused to a cycloalkyl or heterocyclyl group.

[0162] In some embodiments, "heteroaryl" refers to:

[0163] A 5- to 8-membered aromatic monocyclic ring containing 1-4, in certain embodiments 1-3, heteroatoms selected from N, O, and S, with the remainder being carbon atoms, wherein at least one heteroatom is present in the aromatic ring; and

[0164] An 8- to 12-membered aromatic bicyclic ring containing 1-6, in certain embodiments 1-4, or in certain embodiments 1-3 heteroatoms selected from N, O, and S, with the remainder being carbon atoms, wherein at least one heteroatom is present in the aromatic ring; and

[0165] An 11- to 14-membered aromatic tricyclic ring containing 1-8, in certain embodiments 1-6, or 1-4, or 1-3 heteroatoms selected from N, O, and S, with the remainder being carbon atoms, wherein at least one heteroatom is present in the aromatic ring.

[0166] When the total number of S and O in the heteroaryl group is greater than 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O in the heteroaryl group is no greater than 2. In some embodiments, the total number of S and O in the heteroaryl group is no greater than 1.

[0167] Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyridazinyl, triazinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, thienyl, and furanyl.

[0168] Further, heteroaryl includes but is not limited to indazolyl, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzotriazolyl, quinoxalinyl, quinolinyl and isoquinolinyl. "Heteroaryl" includes any N-oxidized derivative of a nitrogen-containing heteroaryl.

[0169] The name of a monovalent heteroaryl group ends with "-yl". The derived divalent group is obtained by removing a hydrogen atom from a carbon atom containing a free valence electron. The name of the divalent group is obtained by adding "-idene" to the name of the monovalent group. For example, a pyridyl group with two attachment sites is called a pyridylidene.

[0170] "Heterocycle" (and derivatives thereof such as "heterocyclic" or "heterocyclyl") refers generally to a saturated or unsaturated, monocyclic or polycyclic (e.g., bicyclic) cyclic aliphatic hydrocarbon system, typically having 3 to 12 ring atoms, containing at least one (e.g., 1, 2, 3, or 4) heteroatom independently selected from oxygen, sulfur, nitrogen, and phosphorus (preferably oxygen, sulfur, nitrogen). In a polycyclic system, two or more rings may be linked by fusion, bridging, or spiro, and the heterocycle may be fused to an aryl or heteroaryl group. In some embodiments, the heterocycle is benzofused. Heterocycles also include ring systems substituted with one or more oxo (=O) or imino (=NH) moieties. In some embodiments, the C, N, S, and P atoms in the heterocycle are optionally substituted with oxo. In some embodiments, the C, S, and P atoms in the heterocycle are optionally substituted with imino, and the imino group may be unsubstituted or substituted. Either a carbon atom or a heteroatom in the heterocycle may be a site of attachment, provided that a stable structure is formed. When a heterocyclic ring has a substituent, the substituent may be bonded to any heteroatom or carbon atom on the heterocyclic ring, provided that a stable chemical structure is formed that complies with the valence bond rules.

[0171] Suitable heterocycles include, for example, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and hexahydropyridazinyl. Examples of heterocycles having one or more oxo moieties include, but are not limited to, piperidinyl-N-oxide, morpholinyl-N-oxide, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Bicyclic heterocycles include, but are not limited to:

[0172] "Aryl-alkyl" (or "aralkyl") refers to an alkyl group as defined above substituted with an aryl group as defined above. Examples of aralkyl groups include, but are not limited to, benzyl, phenethyl, and naphthylmethyl. In some embodiments, the aralkyl group contains 7-20 or 7-11 carbon atoms. When "aryl-C 1-4 When "alkyl", "C 1-4 ” refers to the number of carbon atoms in the alkyl portion, not the aryl portion.

[0173] "Heterocyclyl-alkyl" refers to an alkyl group as defined above substituted with a heterocyclyl group as defined above. 1-4 When "alkyl", "C 1-4 ” refers to the number of carbon atoms in the alkyl portion, not the heterocyclyl portion.

[0174] "Cycloalkyl-alkyl" refers to an alkyl group as defined above substituted with a cycloalkyl group as defined above. 3-10 Cycloalkyl-C 1-4 When "alkyl", "C 3-10 " refers to the number of carbon atoms in the cycloalkyl portion rather than the alkyl portion, "C 1-4 ” refers to the number of carbon atoms in the alkyl portion, not the cycloalkyl portion.

[0175] "Heteroaryl-alkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above. 1-4 When "alkyl", "C 1-4 ” refers to the number of carbon atoms in the alkyl portion, not the heteroaryl portion.

[0176] For the avoidance of doubt, for example, when referring to alkyl, cycloalkyl, heterocyclyl, aryl and / or heteroaryl substitution, it is intended that each of these groups is substituted individually or that these groups are substituted in combination. 1-4 alkyl, and may be unsubstituted or substituted by at least one (e.g., 1, 2, 3 or 4) independently selected from R X It should be understood that the aryl moiety may be unsubstituted or substituted with at least one (e.g., 1, 2, 3, or 4) independently selected from R X The alkyl portion may also be unsubstituted or substituted with at least one (e.g., 1, 2, 3, or 4) independently selected from R X substituted by a substituent.

[0177] "Haloalkyl" refers to an alkyl group as defined above that is substituted with a halogen as defined above. 1-4 “Haloalkyl” refers to a haloalkyl group containing 1 to 4 carbon atoms and may be a straight chain or branched structure. Examples of haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl, 1,1,2-trifluoroethyl, 1,2,2-trifluoroethyl, and 2,2,2-trifluoroethyl.

[0178] "Hydroxyl," whether used alone or in combination with other terms, refers to a "-OH" group.

[0179] "Cyano," whether used alone or in combination with other terms, refers to a "-CN" group.

[0180] "Nitro," whether used alone or in combination with other terms, refers to a "-NO2" group.

[0181] "Carboxyl," whether used alone or in combination with other terms, refers to a "-C(O)OH (or -CO2H)" group.

[0182] "Carbonyl," whether used alone or in combination with other terms, refers to a "-C(O)-" group.

[0183] "Acyl" whether used alone or in combination with other terms refers to a "-C(O)-R" group, wherein the group R includes but is not limited to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, haloalkyl, heterocyclyl, aryl, heteroaryl, amino, alkylamino or a combination thereof to form a monovalent group, and is connected to the rest of the molecule through a carbonyl group.

[0184] "Pharmaceutically acceptable salts" refer to salts formed with pharmaceutically acceptable non-toxic bases or acids (including inorganic or organic bases and inorganic or organic acids). Pharmaceutically acceptable inorganic base salts can be selected from, for example, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, divalent manganese, potassium, sodium and zinc salts. Further, pharmaceutically acceptable inorganic base salts can be selected from ammonium, calcium, magnesium, potassium and sodium salts. Salts of pharmaceutically acceptable organic bases can be selected from, for example, primary, secondary and tertiary amine salts, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydralazine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine and tromethamine.

[0185] When compound of the present invention is alkali, need to form its salt with at least one pharmaceutically acceptable non-toxic acid, these acids are selected from inorganic acid and organic acid.For example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid and p-toluenesulfonic acid.In some embodiments, described acid can be selected from, for example: citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid and tartaric acid.

[0186] “Administering” or “administering” refers to providing a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, to a subject in need of treatment.

[0187] "Effective amount" refers to a dose of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, that can induce a biological or medical response in a tissue, system, animal or human that can be observed by researchers, veterinarians, clinicians or other clinical personnel.

[0188] "Composition" includes: a product containing specified ingredients in specified amounts, and any product resulting directly or indirectly from the combination of those specified ingredients in specified amounts. "Pharmaceutical composition" includes: a product containing an active ingredient (or pharmaceutically active ingredient) and an inert ingredient as a carrier, and any product made directly or indirectly (e.g., by combination, compounding, or aggregation) from two or more ingredients, or a product produced by the decomposition of one or more ingredients, or a product produced by some other type of reaction or interaction between one or more ingredients.

[0189] "Pharmaceutically acceptable" means compatible with the other ingredients of the formulation and not unacceptably deleterious to the user.

[0190] "Subject" refers to an individual suffering from a disease, condition, or the like, including mammals and non-mammals. Mammals include, but are not limited to, any member of the class mammalia: humans; non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. Non-mammals include, but are not limited to, birds and fish. In one embodiment of the present invention, the mammal is a human. When surgery, medication, or other procedures are administered to an individual, the individual may also be referred to as a "subject."

[0191] "Treatment" includes alleviating, reducing or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, for example, preventing the disease or symptom from developing, alleviating the disease or symptom, promoting remission of the disease or symptom, or stopping the symptoms of the disease or symptom, and extends to include prevention. "Treatment" also includes achieving a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit refers to the eradication or improvement of the condition being treated. In addition, a therapeutic benefit is achieved by eradicating or improving one or more physiological signs associated with the underlying disease, and although the patient may still have the underlying disease, an improvement in the patient's disease is observed. A prophylactic benefit refers to the use of the composition by a patient to prevent the risk of a certain disease, or when a patient develops one or more physiological signs of a disease, although the disease has not yet been diagnosed.

[0192] "Protecting group" (Pg) refers to a class of substituents used to block or protect a particular functional group by reacting with other functional groups on a compound. For example, an "amino protecting group" refers to a substituent attached to an amino group that blocks or protects the amino functionality on the compound. Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethoxycarbonyl protecting group (Fmoc). Similarly, a "hydroxy protecting group" refers to a class of hydroxy substituents that effectively block or protect the hydroxy function. Suitable hydroxy protecting groups include, but are not limited to, acetyl and silyl. A "carboxyl protecting group" refers to a class of carboxyl substituents that effectively block or protect the function of the carboxyl group. Commonly used carboxyl protecting groups include, but are not limited to: -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfinyl)ethyl, 2-(diphenylphosphine)-ethyl, nitroethyl, etc. For a general description and usage of protecting groups, see reference: Theodora W. Greene, Peter G.M. Wuts, Protective Groups in Organic Synthesis, 1999.

[0193] "NH" protecting groups include, but are not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butyloxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropyloxycarbonyl, isopropyloxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, di Benzyl, trityl, 2-nitrobenzenesulfonyl, methanesulfonyl, p-toluenesulfonyl, N,N-dimethylaminomethylene, benzylethylene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, cyclohexylene, 2-ethoxycarbonylcyclohexylene, 2-ethoxycarbonylcyclopentylene, 2-acetylcyclohexylene, 3,3-dimethyl-5-oxycyclohexylene, diphenylphosphoryl, dibenzylphosphoryl, 5-methyl-2-oxy-2H-1,3-dioxol-4-yl-methyl, trimethylsilyl, triethylsilyl and triphenylsilyl.

[0194] "C(O)OH" protecting groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl, acetylmethyl, phenacyl, p-nitrophenacyl, p-bromophenacyl, p-methylsulfonylphenacyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, o-phenyl dicarboximidomethyl, succinimidylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

[0195] The "OH or SH" protecting group includes, but is not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2 -(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonium)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formic acid, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, benzyl Oxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl(phenylmethyl), p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl, p-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

[0196] Geometric isomers may exist in the compounds of the present invention. For example, the compounds of the present invention may have carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, where, according to the Cahn-Ingold-Prelog priority rules, "E" represents a preferred substituent on the opposite side of the carbon-carbon double bond or carbon-nitrogen double bond, while "Z" represents a preferred substituent on the same side of the carbon-carbon double bond or carbon-nitrogen double bond. The compounds of the present invention may also exist as a mixture of "E" and "Z" isomers. Substituents around a cycloalkyl or heterocyclic group can be designated as cis or trans. In addition, the present invention includes different isomers and mixtures thereof formed by different arrangements of substituents around the adamantane ring system. Two substituents around a single ring in the adamantane ring system are designated as having a Z or E relative configuration. See, e.g., Cheryl D. Jones, Mira Kaselj, Ralph N. Salvatore, and William J. le Noble, J Org Chem 1998, 63, 8, 2758-2760.

[0197] The compounds of the present invention may contain asymmetrically substituted carbon atoms in the R or S configuration. "R" and "S" are defined in Rules for the Nomenclature of Organic Chemistry Section E: Stereochemistry (Recommendations 1974), Pure & Appl. Chem, (1976) 45, 11-30. Compounds containing asymmetrically substituted carbon atoms are racemates if the R and S configurations are present in equal amounts. If one configuration is present in greater amounts than the other, the configuration of the chiral carbon atom is represented by the configuration in greater amount, preferably with an enantiomeric excess (ee) of about 85-90%, more preferably about 95-99%, and further preferably about 99% or more. Therefore, the present invention encompasses racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

[0198] The compounds of the present invention may exist in an isotopically labeled or enriched form, containing one or more atoms having a mass or mass number different from the most common atomic mass found in nature. Isotopes may be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to: 2 H(D), 3 H(T), 13 C. 14 C. 15 N. 18 O. 32 P. 35 S. 18 F. 36 Cl and125 I. Other isotopes of these atoms and / or other atoms are also within the scope of the present invention.

[0199] In another embodiment, the isotopic label contains deuterium ( 2 H), tritium ( 3 H) or 14 C isotopes. The isotopically labeled compounds of the present invention can be obtained using methods well known to those skilled in the art. These isotopically labeled compounds can be obtained by replacing the non-labeled reagent with an isotopically labeled reagent, as described in the Examples and reaction diagrams of the present invention. In certain embodiments, a compound can be treated with an isotopically labeled reagent to replace an atom with an isotopic atom. For example, the replacement of hydrogen with deuterium can be achieved by the action of a deuterated acid such as D2SO4 / D2O.

[0200] The isotope-labeled compounds of the present invention can be used as standards for GLP-1R inhibitor pharmacodynamic binding assays. Compounds containing isotopes can be used in pharmaceutical research to evaluate the mechanism of action and metabolic pathways of non-isotope-labeled parent compounds and to study the in vivo metabolic turnover of compounds (Blake et al., J. Pharm. Sci. 1975, 64(3): 367-391). This type of metabolic study is very important for designing safe and effective therapeutic drugs, and can determine whether the in vivo active compound or the metabolite of the parent compound used by the patient is toxic or carcinogenic (Foster et al., Advances in Drug Research, Academic press, London, 1985, Vol. 14: 2-36; Kato et al., J Labelled Comp Radiopharm. 1995, 36(10): 927-932; Kushner et al., Can J Physiol Pharmacol, 1999, 77: 79-88).

[0201] In addition, drugs containing non-radioactive active isotopes, such as deuterated drugs, are called "heavy drugs" and can be used to treat, alleviate or prevent diseases and conditions associated with GLP-1R activity. A compound in which the ratio of an isotope exceeds its natural abundance is called enrichment. The amount of enrichment includes, but is not limited to, for example, from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96 to about 100%.

[0202] Stable isotope labeling of drugs can alter their physicochemical properties, such as pKa and liquid solubility. If isotope substitution affects regions associated with ligand-receptor interactions, these effects and changes may affect the pharmacodynamic response of the drug molecule. Some physical properties of stable isotope-labeled molecules differ from those of unlabeled molecules, while the chemical and biological properties are the same, with one important difference: due to the increased mass of the heavy isotope, any chemical bond involving the heavy isotope and another atom is stronger than that of the light isotope. Accordingly, the presence of the isotope at the metabolic or enzymatic conversion site will slow down the reaction, potentially changing its pharmacokinetic characteristics or efficacy compared to the non-isotope-labeled compound. DETAILED DESCRIPTION

[0203] To further illustrate the present invention, the compounds provided by the present invention, their preparation methods and applications are described in detail below with reference to the examples.

[0204] Where specific conditions are not specified in the examples, the experiments were conducted according to conventional conditions. The examples are provided to better illustrate the present invention, but should not be construed as limiting the present invention to these examples. Non-essential improvements and adjustments to the embodiments made by those skilled in the art based on the above-mentioned invention remain within the scope of protection of the present invention.

[0205] The full names corresponding to the abbreviations of the present invention are shown in Table 1.

[0206] Table 1

[0207] Example 1

[0208] Synthesis route

[0209] Synthesis of compound 1B

[0210] Compound 1A (commercially available) (0.50 g, 3.92 mmol) and (S)-3-aminobutyronitrile hydrochloride (0.47 g, 3.92 mmol) were weighed and added to 20 mL of dichloromethane. Anhydrous sodium acetate (0.33 g, 3.92 mmol) and sodium triacetoxyborohydride (0.83 g, 5.88 mmol) were then added at 0°C. The mixture was allowed to stand overnight at room temperature under nitrogen. The reaction was quenched with saturated sodium bicarbonate solution, the pH was adjusted to 8-9, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was used directly in the next step without purification. [M+H] + =197.

[0211] Synthesis of compound 1C

[0212] Compound 1B (0.76 g, 3.92 mmol) was dissolved in 18 mL of dichloromethane, followed by the addition of triethylamine (0.79 g, 7.84 mmol) and di-tert-butyl dicarbonate (1.28 g, 5.88 mmol) at room temperature, and stirred overnight at room temperature. After the reaction was complete, 20 mL of water was added to quench the reaction, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography to obtain compound 1C (0.85 g, colorless oil), [M+H] + =297.

[0213] Synthesis of compound 1D

[0214] Compound 1C (0.85 g, 2.87 mmol) was dissolved in 20 mL of tetrahydrofuran under nitrogen protection. NaHMDS (2.0 M THF solution, 2.9 mL, 5.74 mmol) was added dropwise at -20°C. The internal temperature was kept below -10°C during the addition. After the addition was complete, the mixture was slowly returned to room temperature and stirred for 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography to obtain compound 1D (0.57 g, light yellow oil). [M+H] + =265.

[0215] Synthesis of compound 1E

[0216] Compound 1D (0.13 g, 0.48 mmol), 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride (0.14 g, 0.72 mmol), and pyridine hydrochloride (5.8 mg, 0.05 mmol) were weighed and dissolved in 2 mL of ethanol. The mixture was heated to 80°C under nitrogen for 5 h. The solvent was concentrated to dryness, 20 mL of ethyl acetate was added, and the mixture was washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography to obtain compound 1E (0.16 g, light yellow oil). [M+H] + =401.

[0217] Synthesis of compound 1F

[0218] Compound 1E (0.16 g, 0.40 mmol) was dissolved in 15 mL of pyridine, and 2-isocyanato-1,1-dimethoxyethane (0.13 g, 1.00 mmol) was added under ice-water bath. The mixture was reacted at room temperature for 5 h. The mixture was directly dried and separated by silica gel column chromatography to obtain compound 1F (0.16 g, light yellow solid). [M+H] + =532.

[0219] Synthesis of compound 1G

[0220] Compound 1F (160.1 mg, 0.30 mmol) was weighed and dissolved in 6 mL of tetrahydrofuran. Methanesulfonic acid (28.9 mg, 0.30 mmol) was added under nitrogen and stirred at 60°C for 4 h. After cooling to room temperature, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain compound 1G (131.1 mg, light yellow semisolid). [M+H] + =468.

[0221] Synthesis of compound 1H

[0222] Compound 1G (130.1 mg, 0.28 mmol) was dissolved in 12 mL of N-methylpyrrolidone, followed by the addition of 5-bromo-4-fluoro-1-methylindazole (128.5 mg, 0.56 mmol), potassium carbonate (116.2 mg, 0.84 mmol), cuprous iodide (61.3 mg, 0.32 mmol), and (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (91.6 mg, 0.64 mmol). The mixture was reacted at 130°C for 3 h under nitrogen protection. 50 mL of purified water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with purified water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography to obtain compound 1H (170.3 mg, light yellow oil), [M+H] + =616.

[0223] Synthesis of compound 1I

[0224] Compound 1H (50.0 mg, 0.08 mmol) was weighed and dissolved in 1 mL of dichloromethane. 2 mL of a 4 M solution of hydrogen chloride in dioxane was added under ice-cooling and allowed to react at room temperature for 1 h. The reaction solution was concentrated to obtain a crude product, which was used directly in the next step without purification. [M+H] + =516.

[0225] Synthesis of compound 1

[0226] The crude compound 1I (31.6 mg, 0.057 mmol) obtained in the previous step was weighed and dissolved in 2 mL of N,N-dimethylformamide. Compound 1J (23.5 mg, 0.057 mmol), HATU (28.2 mg, 0.074 mmol), DIPEA (29.4 mg, 0.23 mmol), and DMAP (2.1 mg, 0.017 mmol) were then added in that order and allowed to react at room temperature for 5 h. The mixture was extracted with purified water and ethyl acetate. The organic phase was concentrated and separated by silica gel column chromatography to yield compound 1 (30.1 mg, off-white solid) with an HPLC purity of 99.8%. [M+H] +=909; 1 H NMR (400MHz, DMSO-d6) δ11.56(s,1H),8.19(s,1H),7.53(s,2H),7.38(d,J=8.5Hz,2H),7 .24(dd,J=8.6,1.7Hz,1H),7.11(d,J=6.3Hz,2H),6.91(s,1H),6.78(d,J=25.4Hz,2H),5 .65(s,1H),4.08(s,3H),3.94(s,1H),3.77–3.65(m,3H),3.03–2.97(m,1H),2.23(s,6H) ,1.74–1.66(m,4H),1.65–1.45(m,7H),1.39(d,J=7.5Hz,2H),1.27(s,5H),1.18(s,5H).

[0227] Example 2

[0228] Synthesis route

[0229] Synthesis of compound 43B

[0230] Compound 43A (commercially available) (5.07 g, 35.14 mmol) was weighed and added to 80 mL of tetrahydrofuran. The mixture was cooled to -75°C under nitrogen and lithium diisopropylamide (2 M, 21.1 mL) was slowly added dropwise, maintaining the internal temperature above -70°C. After the addition was complete, the mixture was stirred at -70°C for 1.5 h, and paraformaldehyde (5.0 g, 166.50 mmol) was added all at once. The mixture was slowly warmed to room temperature overnight. The reaction system was slowly added to 2N HCl (30.0 mL), extracted with ethyl acetate, and the organic phases were combined and washed with saturated sodium bicarbonate solution until the pH was 8-9. The mixture was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was separated by column chromatography to obtain compound 43B (0.89 g, yellow oil).

[0231] Synthesis of compound 43C

[0232] Compound 43B (0.89 g, 5.11 mmol) was dissolved in 20 mL of dichloromethane. (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzidoxyl-3(1H)-one (3.25 g, 7.67 mmol) was then added under an ice-water bath and stirred at room temperature for 4 h. The reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phases were combined and washed with saturated sodium bicarbonate solution and saturated sodium thiosulfate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. This crude product was separated by column chromatography to yield compound 43C (0.52 g, light yellow liquid).

[0233] Synthesis of compound 43

[0234] Referring to Example 1, compound 43 was prepared by substituting 43C for 1A (20.1 mg, off-white solid) with an HPLC purity of 98%. [M+H] + =953; 1 H NMR (600MHz, CDCl3) δ11.20(s,1H),8.13(s,1H),7.60(dd,J=13.2,8.5Hz,1H),7.53(d,J=3.8Hz,2H),7.28(d,J =10.7Hz,2H),7.16(d,J=6.8Hz,2H),6.86(s,1H),6.62(d,J=3.0Hz,1H),6.31(d,J=3.2Hz,1H),5.70(q,J=6.6H z,1H),4.12(s,3H),4.04–3.94(m,2H),3.94–3.79(m,3H),3.35(d,J=13.5Hz,1H),3.18(d,J=13.4Hz,1H),3.08 –3.00(m,2H),2.30(s,6H),1.80–1.73(m,8H),1.68–1.59(m,2H),1.57(d,J=6.5Hz,3H),1.35(d,J=4.6Hz,10H).

[0235] Example 3

[0236] Synthesis route

[0237] Synthesis of compound 57B

[0238] 57B was synthesized by referring to the preparation method of intermediate R42 in patent WO2018071454 A1. [M+H] + =288.

[0239] Synthesis of compound 57C

[0240] The crude product, compound 57B (7.16 g, 24.91 mmol), obtained in the previous step, was weighed and dissolved in dichloromethane (120 mL). Dess-Martin periodinane (15.84 g, 37.36 mmol) was added portionwise under an ice bath. After the addition, the ice bath was removed and the mixture was stirred at room temperature for 5 h. The reaction was quenched by the addition of saturated NaHCO₃ solution (200 mL). The mixture was extracted with dichloromethane (200 mL), separated, and the organic phase was washed with NaHCO₃ solution (200 mL) and saturated brine (200 mL). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography to yield compound 57C (1.20 g). [M+H] + =286.

[0241] Synthesis of compound 57D

[0242] Referring to the preparation method of compound 1B in Example 1, 57D was synthesized by substituting 57C for 1A. [M+H] + =354.

[0243] Synthesis of compound 57E

[0244] 57D (0.81 g, 2.28 mmol) was weighed into a 100 mL single-necked flask and dissolved in tetrahydrofuran (8 mL). The mixture was cooled to -25°C with dry ice / ethanol. HMDSNa (2.30 mL, 4.56 mmol) was slowly added to the reaction solution using a syringe and allowed to warm to room temperature. After 1 h, the reaction was quenched with saturated ammonium chloride in an ice bath. The pH was adjusted to 8-9 with saturated NaHCO solution, and benzyl chloroformate (0.58 g, 3.42 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction was stopped and the pH was adjusted to 6-7 with 10% citric acid in an ice bath. The mixture was extracted with ethyl acetate (50 mL), separated, and the organic phase was washed with saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to yield compound 57E (0.86 g). [M+H] + =442.

[0245] Synthesis of compound 57F

[0246] Referring to the preparation method of compound 1E in Example 1, 57F was synthesized by replacing 1D with 57E. [M+H] + =578.

[0247] Synthesis of compound 57G

[0248] Referring to the preparation method of compound 57F, 57F was used to replace 1E to synthesize 57G. [M+H] + =709.

[0249] Synthesis of compound 57H

[0250] Referring to the preparation method of compound 1G in Example 1, 57H was synthesized by replacing 1F with 57G. [M+H] + =645.

[0251] Synthesis of compound 57I

[0252] Referring to the preparation method of compound 1H in Example 1, 57H was substituted for 1G to synthesize 57H. [M+H] + =793.

[0253] Synthesis of compound 57J

[0254] 57I (0.21 g, 0.27 mmol), PdCl2 (0.05 g, 0.27 mmol), and TEA (0.11 g, 1.08 mmol) were weighed into a 50 mL single-necked flask with dichloromethane (5 mL) as the solvent. Et3SiH (0.09 g, 0.81 mmol) was added under nitrogen. After stirring at room temperature for 1 h, methanol (5 mL) was added and stirring continued for 20 min. The mixture was filtered through celite and the filtrate was concentrated to obtain compound 57J (0.29 g), which was used directly in the next reaction. [M+H] + =659.

[0255] Synthesis of compound 57K

[0256] Referring to the preparation method of compound 1 in Example 1, 57K was synthesized by replacing 1I with 57J. [M+H] + =1052.

[0257] Synthesis of compound 57

[0258] 57K (0.20 g, 0.19 mmol) was weighed into a 50 mL single-necked flask and a solution of hydrochloric acid in dioxane (5 mL) was added at room temperature. The mixture was stirred at room temperature for 1 h. The reaction was stopped, and the reaction solution was concentrated. Dichloromethane (20 mL) and saturated NaHCO3 solution (20 mL) were added. The organic phase was separated and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain compound 57 (0.17 g). [M+H] + =952.

[0259] Example 4

[0260] Synthesis route

[0261] Synthesis of compound 59

[0262] 57 (19 mg, 0.02 mmol) and formaldehyde hydrate (10 mg, 0.12 mmol) were weighed into a 50 mL single-necked flask with dichloromethane (2 mL) as the solvent and stirred at room temperature for 20 min. NaBH(OAc)3 (6.5 mg, 0.03 mmol) was added under ice-cooling and stirring continued for 20 min. The reaction was quenched with saturated NaHCO3 solution (2 mL), extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified on a preparative silica gel plate to obtain compound 59 (15 mg). [M+H] + =966.

[0263] Example 5

[0264] Synthesis route

[0265] Synthesis of compound 15A

[0266] Referring to patent WO2021102314A1, 15A was prepared and synthesized. [M+H] + =260.

[0267] Synthesis of compound 15B

[0268] Compound 15A (0.28 g, 1.07 mmol) was dissolved in 10 mL of dichloromethane. (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzidoxyl-3(1H)-one (0.68 g, 1.62 mmol) was then added under an ice-water bath and stirred at room temperature for 4 h. The reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phases were combined and washed with saturated sodium bicarbonate solution and saturated sodium thiosulfate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was separated by column chromatography to yield compound 15B (0.2 g, colorless liquid).

[0269] Synthesis of compound 15

[0270] Referring to the preparation method of compound 1 in Example 1, 15 was synthesized by replacing 1A with 15B. [M+H] + =924.

[0271] Example 6

[0272] Synthesis route

[0273] Synthesis of compound 21C

[0274] 21C was synthesized according to the method of Example 22 of patent CN115353512 A. [M+H] + =355.

[0275] Synthesis of compound 21D

[0276] Referring to the preparation method of compound 1B in Example 1, 21C was used to replace 1A to synthesize 21D. [M+H] + =423.

[0277] Synthesis of compound 21E

[0278] 21D (0.46 g, 1.08 mmol) was weighed into a 100 mL round-bottom flask with acetonitrile (5 mL) and water (5 mL) as solvents. Potassium phosphate (0.69 g, 3.26 mmol) and Boc2O (0.71 g, 3.26 mmol) were added sequentially at room temperature, and the mixture was stirred overnight in a 36°C oil bath. After completion of the reaction, the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain compound 21E (0.37 g). [M+H] + =523.

[0279] Synthesis of compound 21F

[0280] 21E (1.90 g, 3.64 mmol) was weighed into a 100 mL round-bottom flask, and THF (20 mL) was added as solvent. TBAF (7.3 mL, 7.30 mmol) was added at room temperature and stirred overnight. After completion of the reaction, the mixture was extracted with DCM (50 mL x 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain crude compound 21F (1.80 g), which was used directly in the next reaction. [M+H] + =285.

[0281] Synthesis of compound 21G

[0282] Crude 21F (0.57 g, 2.0 mmol), NaHCO₃ (0.34 g, 4.0 mmol), and KBr (0.48 g, 4.0 mmol) were weighed into a 100 mL round-bottom flask. Acetonitrile (10 mL) and water (5 mL) were added as solvents. TEMPO (0.03 g, 0.2 mmol) and 7% sodium hypochlorite solution (0.75 g, 10.0 mmol) were added sequentially at room temperature and stirred at room temperature for 0.5 h. After completion of the reaction, the pH was adjusted to 10-11 with 10% NaOH solution under ice-cooling. The mixture was extracted with methyl tert-butyl ether (30 mL x 2) and the organic phase was discarded. The aqueous phase was adjusted to pH 4-5 with 50% H₂SO₄ under ice-cooling and extracted with dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford crude compound 21G (0.46 g), which was used directly in the next reaction. [M+H] + =299.

[0283] Synthesis of compound 21H

[0284] The crude product 21G (0.46 g, 1.54 mmol) and K2CO3 (0.43 g, 3.08 mmol) were weighed into a 100 mL round-bottom flask. DMF (5 mL) was added as solvent, and iodomethane (0.55 g, 3.85 mmol) was added at room temperature. The mixture was stirred overnight at room temperature. After completion, the reaction was quenched with water and extracted with methyl tert-butyl ether (25 mL x 4). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain compound 21H (0.18 g). [M+H] + =312.

[0285] Synthesis of compound 21

[0286] Referring to the preparation method of compound 1 in Example 1, 21 was synthesized by replacing 1C with 21H. [M+H] + =925.

[0287] Example 7

[0288] Synthesis of compound 23

[0289] Referring to the preparation method of compound 15 in Example 5, ethyl 1-(hydroxymethyl)cyclobutanecarboxylate (commercially available) was used instead of 15A to synthesize compound 23. [M+H] + =923.

[0290] Example 8

[0291] Synthesis route

[0292] Synthesis of compound 25A

[0293] Compound 3-cyclopentene-1,1-dicarboxylic acid diethyl ester (commercially available) (1.65 g, 8.95 mmol) was dissolved in 16.5 mL of tetrahydrofuran, cooled to 0-5°C in an ice-water bath, and a tetrahydrofuran solution of lithium tri-tert-butoxyaluminum hydride (22.7 mL, 1.0 mol / L, 22.7 mmol) was added dropwise. After the addition was complete, the mixture was heated to 65°C and reacted for 5 h. The mixture was cooled to room temperature, diluted with methyl tert-butyl ether, and quenched with saturated sodium bisulfate solution. The mixture was extracted with methyl tert-butyl ether, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 25A (1.81 g, colorless oil), [M+H] + =157.

[0294] Synthesis of compound 25B

[0295] Referring to the preparation method of compound 15B in Example 5, 25A was used to replace 15A to synthesize 25B, [M+H] + =169.

[0296] Synthesis of compound 25E

[0297] Referring to the preparation method of compound 1E in Example 1, 25B was used to replace 1A to synthesize 25E, [M+H] + =427.

[0298] Synthesis of compound 25F

[0299] Compound 25E (200.0 mg, 0.47 mmol) was dissolved in 20 mL of ethyl acetate, 10% palladium on carbon (0.14 g, 50% wet basis) was added, and hydrogenation was carried out under a hydrogen balloon at normal pressure for 2 h at room temperature. Filtering and concentrating the filtrate gave compound 25F (0.18 g, white solid), [M+H] + =429.

[0300] Synthesis of compound 25

[0301] Referring to the preparation method of Example 1, compound 25 was synthesized by substituting 25F for 1E. The HPLC purity was 99.4%. [M+H] + =937; 1 H NMR (600MHz, CDCl3) δ11.27(s,1H),8.13(s,1H),7.60(dd,J=12.4,8.5Hz,1H),7.50(t,J=12.4Hz,2H),7 .29(s,1H),7.25(s,1H),7.14(d,J=6.7Hz,2H),6.81(s,1H),6.60(d,J=3.1Hz,1H),6.32(d,J=3.0Hz,1H) ,5.72(q,J=6.5Hz,1H),4.11(s,3H),3.84(dd,J=10.0,4.4Hz,2H),3.33(d,J=13.5Hz,1H),2.57–2.44(m, 2H), 2.28 (s, 6H), 1.81–1.71 (m, 8H), 1.70–1.62 (m, 6H), 1.57 (t, J = 5.7Hz, 3H), 1.34 (s, 5H), 1.26 (s, 5H).

[0302] Example 9

[0303] Synthesis route

[0304] Synthesis of compound 31A

[0305] The compound Boc-L-proline methyl ester (commercially available) (5.0 g, 21.8 mmol) was dissolved in 40 mL of tetrahydrofuran, cooled to -70 ° C (N2 protection), and LiHMDS (43.6 mL, 43.6 mmol) was added dropwise. After the addition was complete, the mixture was stirred at -70 ° C for 1 hour, and then benzyl (chloromethyl) ether (5.12 g, 32.7 mmol) was added dropwise. After the addition was complete, the temperature was slowly raised to -20 ° C and stirred for 2 hours. The temperature was raised to 0 ° C and the reaction was quenched with saturated ammonium chloride solution. Extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography to obtain compound 31A (6.9 g, colorless oil), [M+H] + =350.

[0306] Synthesis of compound 31B

[0307] Compound 31A (2.5 g, 7.2 mmol) was dissolved in 25 mL of methanol, 10% palladium on carbon (0.51 g, 50% wet basis) was added, and hydrogenation was carried out under a hydrogen balloon at normal pressure for 2 h at room temperature. Filtering and concentrating the filtrate gave compound 31B (1.9 g, colorless oil), [M+H] + =260.

[0308] Synthesis of compound 31

[0309] Referring to the preparation method of compound 25 in Example 8, compound 31 was synthesized by replacing 25A with 31B. [M+H] + =938.

[0310] Example 10

[0311] Referring to the preparation method of compound 15 in Example 5, ethyl 1-(hydroxymethyl)cyclohexanecarboxylate (commercially available) was used instead of 15A to synthesize compound 37. [M+H] + =951.

[0312] Example 11

[0313] Synthesis route

[0314] Synthesis of compound 39B

[0315] 39A (commercially available) was used as the starting material and synthesized according to the method of US20130183269A1. [M+H] + =229.

[0316] Synthesis of compound 39C

[0317] Compound 39B (0.61 g, 2.67 mmol) was dissolved in 16 mL of tetrahydrofuran and cooled to 0-5°C in an ice-water bath. A solution of lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran (6.8 mL, 1.0 mol / L, 6.80 mmol) was added dropwise. After the addition was complete, the mixture was heated to 65°C and reacted for 5 h. The mixture was cooled to room temperature, diluted with methyl tert-butyl ether, and quenched with 20% sodium bisulfate solution. The mixture was extracted with methyl tert-butyl ether, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography to obtain compound 39C (0.40 g, colorless oil). [M+H] + =187.

[0318] Synthesis of compound 39D

[0319] Referring to the preparation method of compound 15B in Example 5, 39C was used to replace 15A to synthesize 39D, [M+H] + =185.

[0320] Synthesis of compound 39G

[0321] Referring to the preparation method of compound 1E in Example 1, 39G was synthesized by replacing 1A with 39D. [M+H] + =443.

[0322] Synthesis of compound 39H

[0323] Compound 39G (50.0 mg, 0.11 mmol) was dissolved in 5 mL of ethyl acetate, 10% palladium on carbon (0.15 g, 50% wet basis) was added, and hydrogenation was carried out under normal pressure and room temperature for 2 h. Filtering and concentrating the filtrate gave compound 39H (51.2 mg, light yellow oil), [M+H] + =445.

[0324] Synthesis of compound 39L

[0325] Referring to the preparation method of compound 1I in Example 1, 39H was used instead of 1G to synthesize 39L. [M+H] + =560.

[0326] Synthesis of compound 39P

[0327] Compound 39O (203.4 mg, 0.74 mmol) was weighed and dissolved in 5 mL of N,N-dimethylformamide. Trimethylsilyl alcohol (109.2 mg, 0.92 mmol), HATU (359.0 mg, 0.94 mmol), DIPEA (159.0 mg, 1.23 mmol), and DMAP (209.2 mg, 1.71 mmol) were then added in sequence and reacted at 50°C for 2 h. Purified water was added to precipitate the precipitate, which was collected by filtration and dried in vacuo to obtain compound 39P (216.6 mg, yellow solid). [M+H] + =374.

[0328] Synthesis of compound 39Q

[0329] Compound 39P (216.6 mg, 0.58 mmol) was weighed and dissolved in 5 mL of N,N-dimethylformamide. The mixture was cooled to 0-5°C in an ice-water bath, and 60% sodium hydride (31.6 mg, 0.79 mmol) was added portionwise. After addition, the mixture was stirred at room temperature for 1 hour. Chloroacetonitrile (57.0 mg, 0.75 mmol) was added dropwise and allowed to react at room temperature for 1 hour. Purified water was added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography to obtain compound 39Q (199.8 mg, white solid). [M+H] + =413.

[0330] Synthesis of compound 39M

[0331] Compound 39Q (199.8 mg, 0.48 mmol) and (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (133.0 mg, 0.96 mmol) were weighed and dissolved in 5 mL of tetrahydrofuran. The mixture was cooled to 0-5°C in an ice-water bath, and a solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (2.4 mL, 1.0 mol / L, 2.40 mmol) was added dropwise. After addition, the mixture was allowed to react at 0-5°C for 3 h. 5% citric acid solution was added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography to obtain compound 39M (63.0 mg, light yellow solid). [M+H] + =353.

[0332] Synthesis of compound 39N

[0333] Compounds 39L (20.0 mg, 0.033 mmol) and 39M (20.0 mg, 0.056 mmol) and N-methylimidazole (25.0 mg, 0.305 mmol) were weighed and dissolved in 1 mL of acetonitrile. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (33.0 mg, 0.117 mmol) was added under nitrogen protection and allowed to react at room temperature overnight. Purified water was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated on a preparative silica gel plate to obtain compound 39N (19.1 mg, light yellow solid). [M+H] + =894.

[0334] Synthesis of compound 39

[0335] Compound 39N (19.1 mg, 0.021 mmol) was weighed and dissolved in 1.5 mL of isopropanol. 50% aqueous hydroxylamine solution (55.6 mg, 0.84 mmol) was added and reacted at 80°C for 1 h. Purified water was added, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was dissolved in 1 mL of dimethyl sulfoxide, CDI (10.1 mg, 0.062 mmol) and DBU (11.2 mg, 0.073 mmol) were added, and reacted at room temperature for 1 h. Purified water was added to quench the reaction, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated on a preparative silica gel plate to obtain compound 39 (6.0 mg). [M+H] + =953.

[0336] Example 12

[0337] “*” indicates a chiral center with R or S configuration. Compounds 51-A and 51-B are two single stereoisomer compounds, collectively represented by compound 51.

[0338] Synthesis route

[0339] Synthesis of compound 51B

[0340] Compound 51A (commercially available) (6.00 g, 23.32 mol) was weighed and added to 90 mL of tetrahydrofuran. The temperature was cooled to -78°C, followed by the dropwise addition of LiHMDS (1 M THF solution), maintaining the temperature at -60°C for 30 min. Paraformaldehyde (2.10 g, 69.95 mol) was weighed and added to the system. The temperature was slowly raised to -10-0°C, and the reaction was continued for 2 h. The reaction was then quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous Na2SO4. The mixture was concentrated under reduced pressure and purified by column chromatography to obtain 3.96 g of 51B as a colorless oily liquid. [M+H] + =288.

[0341] Synthesis of compound 51C

[0342] Compound 51B (1.5 g, 5.22 mmol) was dissolved in 15 mL of dichloromethane, and DMP (5.53 g, 13.05 mmol) was added under ice-cooling. The mixture was allowed to return to room temperature and stirred for 2 h. The reaction was quenched by adding 50 mL of saturated aqueous NaHCO₃ solution, extracted with dichloromethane, washed with saturated aqueous NaHCO₃ solution, washed with water, washed with saturated brine, and dried over anhydrous Na₂SO₄. The mixture was filtered, concentrated, and separated by column chromatography to obtain compound 51C (0.91 g, colorless oily liquid). [M+H] + =286.

[0343] Synthesis of compound 51D

[0344] Compound 51C (0.91 g, 3.19 mmol) was dissolved in 20 mL of dichloromethane, and (S)-3-aminobutyronitrile hydrochloride (0.42 g, 3.51 mmol) and anhydrous sodium acetate (0.29 g, 3.51 mmol) were added. After stirring at room temperature for 30 min, sodium triacetoxyborohydride (1.35 g, 6.37 mmol) was added and stirred at room temperature overnight. The reaction was quenched with saturated aqueous NaHCO3 solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain compound 51D (0.51 g, light yellow oil). [M+H] + =354.

[0345] Synthesis of compound 51E

[0346] Compound 51D (0.51 g, 1.45 mmol) was dissolved in 10 mL of tetrahydrofuran under nitrogen protection. NaHMDS (2.0 M in THF, 1.44 mL, 2.89 mmol) was added dropwise at 0°C. After the addition was complete, the mixture was slowly returned to room temperature and stirred for 1 hour. The pH was adjusted to 8 with 5% citric acid, and benzyl chloroformate (0.37 g, 2.17 mmol) was added. The mixture was reacted at room temperature for 1 hour, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography. Among the isolated products, the less polar compound was 51E-A (0.17 g, light yellow oil), [M+H] + =442, the more polar compound is 51E-B (0.35 g, light yellow oil), [M+H] + =442.

[0347] Synthesis of compound 51F-A

[0348] Compound 51E-A (132.3 mg, 0.30 mmol), 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride (171.4 mg, 0.90 mmol), and pyridine hydrochloride (3.5 mg, 0.03 mmol) were weighed and dissolved in 2.6 mL of ethanol and heated to 80°C under nitrogen for two days. The mixture was quenched with water, extracted with ethyl acetate, and washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was dissolved in ACN, and TEA (90.9 mg, 0.90 mmol) and (Boc)2O (97.2 mg, 0.45 mmol) were added. The mixture was stirred at room temperature for 1 h. After concentration under reduced pressure, the mixture was separated by column chromatography to obtain compound 51F-A (71.3 mg, brown solid). [M+H] + =578.

[0349] Synthesis of compound 51I-A

[0350] Referring to the synthesis method of compound 1H in Example 1, 51F-A was substituted for 1G to synthesize 51I-A, [M+H] + =793.

[0351] Synthesis of compound 51J-A

[0352] Compound 51H-A (68.5 mg, 0.086 mmol) was weighed and dissolved in 1 mL of dichloromethane. TEA (34.9 mg, 0.346 mmol) was added. After nitrogen substitution, triethylsilane (30.1 mg, 0.259 mmol) was added dropwise and allowed to react at room temperature for 3 h. The mixture was quenched by adding 0.5 mL of methanol and filtered. The filter cake was eluted three times with DCM / MeOH = 5:1. After vacuum distillation, column chromatography purification was performed to obtain 60.8 mg of a brown solid. [M+H] + =659.

[0353] Synthesis of compound 51K-A

[0354] The synthesis method of compound 51K-A refers to the synthesis method of compound 1, [M+H] + =1051.

[0355] Synthesis of compound 51-A

[0356] Compound 51K-A (50.4 mg, 0.048 mmol) was weighed and dissolved in 1 mL of dichloromethane, and then 1 mL of a 4 M solution of hydrogen chloride in dioxane was added. The mixture was stirred at room temperature for 1 h, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by thin layer chromatography to obtain compound 51-A (42.0 mg), [M+H] + =951.

[0357] Synthesis of compound 51-B

[0358] Referring to the preparation method of compound 51-A, 51-B was synthesized by replacing 51E-A with 51E-B. [M+H] + =951.

[0359] Example 13

[0360] The compound of this example has four stereoisomers. The four single stereoisomer compounds are 53-A, 53-B, 53-C and 53-D, collectively represented by compound 53.

[0361] Synthesis of compounds 53-A and 53-B

[0362] Compound 51-A (8.5 mg, 0.0089 mmol) was weighed and dissolved in dichloromethane. 37% aqueous formaldehyde solution (4.3 mg, 0.1071 mmol) and sodium triacetoxyborohydride (2.9 mg, 0.0268 mmol) were added. The mixture was stirred at room temperature overnight and quenched by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin layer chromatography. Among the purified products, the one with the largest Rf value was compound 53-A (5.0 mg), [M+H] + =965, the compound with the smaller Rf value is 53-B (5.7 mg), [M+H] + =965.

[0363] Synthesis of compounds 53-C and 53-D

[0364] Compound 51-B (8.5 mg, 0.0089 mmol) was weighed and dissolved in dichloromethane. 37% aqueous formaldehyde solution (4.3 mg, 0.1071 mmol) and sodium triacetoxyborohydride (2.9 mg, 0.0268 mmol) were added. The mixture was stirred at room temperature overnight and quenched by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin layer chromatography. Among the purified products, compound 53-C (5.0 mg) had the largest Rf value, [M+H] + =965, the compound with the smaller Rf value is 53-D (5.7 mg), [M+H] + =965.

[0365] Example 14

[0366] The compound of this example exists in two single stereoisomer compounds: 55-A and 55-B, collectively represented by compound 55.

[0367] Synthesis of compound 55-A

[0368] Compound 51-A (8.7 mg, 0.0091 mmol) was weighed and dissolved in isopropyl formate, and the mixture was heated and stirred at 90°C in a sealed tube for 40 h. After concentration under reduced pressure, it was purified by thin layer chromatography to obtain compound 55-A (6.4 mg). [M+H] + =979.

[0369] Synthesis of compound 55-B

[0370] Referring to the synthesis method of compound 55-A, 55-B was synthesized by replacing 51-A with 51-B. [M+H] + =979.

[0371] Example 15

[0372] Synthesis route

[0373] Synthesis of compound 64

[0374] 57 (9.5 mg, 0.01 mmol) was weighed into a 10 mL sealed tube with isopropyl formate (1 mL) as solvent. The reaction was carried out at 75°C overnight. The reaction solution was cooled to room temperature, concentrated, and purified on a preparative silica gel plate to obtain compound 64 (7.5 mg). [M+H] + =980.

[0375] Example 16

[0376] Synthesis route

[0377] Synthesis of compound 79C

[0378] Referring to the preparation method of Compound 31 in Example 9, Compound 79C was synthesized by substituting 1-Boc-pyrrolidine-3-carboxylic acid methyl ester for Boc-L-proline methyl ester. [M+H] + =938.

[0379] Synthesis of compound 79

[0380] Referring to the preparation method of Compound 59 in Example 4, Compound 79 was synthesized by substituting Compound 57 with Compound 79C. [M+H] + =952.

[0381] Example 17

[0382] Synthesis of compound 83

[0383] Referring to the preparation method of compound 64 in Example 15, compound 83 was synthesized by replacing compound 57 with compound 79C. [M+H] + =966.

[0384] Example 18

[0385] Synthesis route

[0386] Synthesis of compound 91

[0387] 57 (10.1 mg, 0.01 mmol) was weighed into a 10 mL reaction tube with dichloromethane (1 mL) as the solvent. Pyridine (4.1 mg, 0.05 mmol) and acetyl chloride (1.8 mg, 0.02 mmol) were added sequentially under ice-cooling, and the mixture was naturally heated and stirred for 2 h. Methanol (0.5 mL) was added under ice-cooling to quench the reaction. The system was concentrated and purified on a preparative silica gel plate to obtain compound 91 (8.1 mg). [M+H] + =994.

[0388] Example 19

[0389] Synthesis route

[0390] Synthesis of compound 151A

[0391] N-Boc-9-azabicyclo[3.3.1]nonan-3-one (1.0 g, 4.2 mmol) was weighed and dissolved in THF (15 mL). LiHMDS (1 M, 8.2 mL, 8.2 mmol) was added under ice-cooling. The mixture was stirred at -70°C for 30 min, followed by a solution of p-toluenesulfonyl nitrile (1.0 g, 5.8 mmol) in THF (6 mL). The mixture was stirred for 30 min, then naturally warmed to room temperature and stirred for 20 min. The reaction was quenched with aqueous citric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified on a preparative silica gel plate to yield compound 151A (0.8 g, colorless oil). [M+H] + =265.

[0392] Synthesis of compound 151

[0393] Referring to the preparation method of Compound 1 in Example 1, Compound 151 was synthesized by substituting 151A and 3-cyclopropyl-4-fluorophenylhydrazine hydrochloride for 1D and 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride. [M+H] + =921.

[0394] Example 20

[0395] Synthesis route

[0396] Synthesis of compound 155

[0397] 57 (9.8 mg, 0.01 mmol) was weighed into a 10 mL reaction tube with dichloromethane (1 mL) as the solvent. Pyridine (4.5 mg, 0.05 mmol) and TFAA (6.5 mg, 0.03 mmol) were added sequentially under an ice bath. The ice bath was removed and the mixture was stirred at room temperature for 4 h. Methanol (0.5 mL) was added under an ice bath to quench the reaction. The system was concentrated and purified on a preparative silica gel plate to afford compound 155 (8.4 mg). [M+H] + =1048.

[0398] Example 21

[0399] Synthesis route

[0400] Synthesis of compound 156

[0401] 57 (9.8 mg, 0.01 mmol) was weighed into a 10 mL reaction tube and dichloromethane (1 mL) was used as the solvent. Pyridine (8.1 mg, 0.1 mmol) and Ms2O (8.6 mg, 0.05 mmol) were added sequentially and stirred at room temperature for 5 h. The reaction was quenched by adding water under ice-cooling. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified on a preparative silica gel plate to obtain compound 156 (5.1 mg). [M+H] + =1030.

[0402] Example 22

[0403] Synthesis route

[0404] Synthesis of compound 157

[0405] Compound 57 (5.5 mg, 0.006 mmol) was weighed into a 10 mL reaction tube and dichloromethane (1 mL) was used as the solvent. Pyridine (16.0 mg, 0.2 mmol) and cyclopropylcarbonyl chloride (5.1 mg, 0.048 mmol) were added sequentially under ice-cooling and stirred for 1 h. Water was added to quench the reaction under ice-cooling and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified on a preparative silica gel plate to obtain compound 157 (2.8 mg). [M+H] + =1020.

[0406] Example 23

[0407] Synthesis route

[0408] Synthesis of compound 158

[0409] 57 (5.5 mg, 0.006 mmol) and methoxyacetic acid (4.5 mg, 0.05 mmol) were weighed into a 10 mL reaction tube and DMF (0.25 mL) was used as solvent. Triethylamine (20.0 mg, 0.2 mmol) and HATU (4.5 mg, 0.012 mmol) were added sequentially at room temperature and stirred at room temperature for 1 h. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified on a preparative silica gel plate to obtain compound 158 (3.5 mg). [M+H] + =1024.

[0410] Example 24

[0411] Synthesis route

[0412] Synthesis of compound 159

[0413] Referring to the preparation method of compound 91 in Example 18, 159 was synthesized by replacing acetyl chloride with methyl chloroformate. [M+H] + =1010.

[0414] Example 25

[0415] Synthesis route

[0416] Synthesis of compound 160A

[0417] Compound 57 (6.7 mg, 0.007 mmol) was weighed and dissolved in 1 mL of N,N-dimethylformamide. N-tert-Butyloxycarbonyl-L-alanine (5.7 mg, 0.030 mmol), HATU (15.3 mg, 0.040 mmol), TEA (10.0 mg, 0.098 mmol), and DMAP (6.0 mg, 0.049 mmol) were then added in sequence. The mixture was reacted at room temperature for 1 h. Purified water and ethyl acetate were added for extraction. The organic phase was concentrated to obtain a crude product of compound 160A (18.1 mg, off-white solid). [M+H] + =1123.

[0418] Synthesis of compound 160

[0419] The crude compound 160A (18.1 mg) was dissolved in 0.6 mL of dichloromethane, followed by the addition of 0.6 mL of a 4 mol / L solution of hydrogen chloride in dioxane. The mixture was allowed to react at room temperature for 1 h. 10% potassium phosphate solution was added for quenching, and the mixture was extracted with ethyl acetate. The organic phase was concentrated and separated on a preparative silica gel plate to afford compound 160 (3.1 mg). [M+H] + =1023.

[0420] Example 26

[0421] Synthesis of compound 161

[0422] Referring to the preparation method of compound 160 in Example 25, 161 was synthesized by replacing N-tert-butyloxycarbonyl-L-alanine with BOC-glycine. [M+H] + =1009.

[0423] Example 27

[0424] Synthesis route

[0425] Synthesis of compound 162

[0426] 57 (9.1 mg, 0.01 mmol), TMSNCO (34.5 mg, 0.2 mmol), and triethylamine (20.1 mg, 0.2 mmol) were weighed into a 10 mL reaction tube with DCM (1.5 mL) as solvent and stirred at room temperature for 48 h. After completion of the reaction, the reaction solution was concentrated and purified on a silica gel plate to obtain compound 162 (6.1 mg). [M+H] + =995.

[0427] Example 28

[0428] Synthesis route

[0429] Synthesis of compound 163

[0430] 57 (6.0 mg, 0.006 mmol), N-succinimidyl-N-methylcarbamate (3.1 mg, 0.018 mmol), and triethylamine (10.1 mg, 0.1 mmol) were weighed into a 10 mL reaction tube with ACN (1.0 mL) as the solvent and stirred at room temperature for 48 h. After completion of the reaction, the reaction solution was concentrated and purified on a silica gel plate to afford compound 163 (4.0 mg). [M+H] + =1009.

[0431] Example 29

[0432] Compounds 164-171, 173-177 and 221-224 listed in Table 2 were prepared substantially according to synthetic methods or strategies similar to those of Examples 1-28, or using appropriate intermediates, which can be readily synthesized by methods known in the art and sequentially modified when necessary.

[0433] Table 2

[0434] Example 30

[0435] Synthesis route

[0436] Synthesis of compound 178F

[0437] Referring to the preparation method of compound 25E in Example 8, compound 178A (commercially available) was used instead of diethyl 3-cyclopentene-1,1-dicarboxylate to synthesize 178F. [M+H] + =537.

[0438] Synthesis of compound 178

[0439] Referring to the preparation method of compound 57K in Example 3, compound 178F was used instead of 57F to synthesize 178. [M+H] + =937.

[0440] Example 31

[0441] Synthesis route

[0442] Synthesis of compound 179A

[0443] 178I (63.2 mg, 0.1 mmol) was weighed into a 25 mL round-bottom flask and tetrahydrofuran (2 mL) was used as the solvent. Methylmagnesium bromide (0.1 mL, 0.3 mmol) was added under ice-cooling and stirred for 1 h. After completion, the reaction was quenched with saturated aqueous ammonium chloride under ice-cooling and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain compound 179A (38.0 mg). [M+H] + =694.

[0444] Synthesis of compound 179

[0445] Referring to the preparation method of compound 57K in Example 3, compound 179 was synthesized by replacing 57I with compound 179A. [M+H] + =953.

[0446] Example 32

[0447] Synthesis of compound 180

[0448] Compound 178 (0.090 g, 0.096 mmol) was dissolved in dichloromethane (3 mL) and DAST (0.015 g, 0.96 mmol) was added dropwise at -78 ° C. After the addition was complete, the mixture was returned to room temperature and stirred at room temperature for 12 h. After the reaction was complete, the system was poured into a sodium bicarbonate solution, extracted with dichloromethane (10 mL * 3), and washed twice with brine (10 mL). The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 30, V / V) to give compound 180 (0.057 g) with an HPLC purity of 97.80%. [M+H] + =959; 1H NMR (600MHz, CDCl3) δ11.10(s,1H),8.13(s,1H),7.59(d,J=8.6Hz,1H),7.53(s,2H),7.28(d,J=10.2Hz,1H),7.23(s,1 H),7.14(dd,J=17.4,7.4Hz,2H),6.79(d,J=10.6Hz,1H),6.61(d,J=3.1Hz,1H),6.29(d,J=3.0Hz,1H),5.75(d,J=6.7H z,1H),4.12(s,3H),3.85–3.80(m,2H),3.41–3.33(m,1H),3.33–3.22(m,1H),2.84(q,J=13.3Hz,1H),2.28(d,J=21.9H z, 6H), 1.82–1.74 (m, 6H), 1.71 (d, J = 6.7Hz, 3H), 1.65 (d, J = 13.2Hz, 2H), 1.53–1.47 (m, 2H), 1.34 (s, 5H), 1.26 (s, 5H).

[0449] Example 33

[0450] Synthesis route

[0451] Synthesis of compound 181

[0452] Compound 178 (0.043 g, 0.045 mmol) and sodium borohydride (0.009 g, 0.23 mmol) were added to THF (2 mL), and methanol (0.5 mL) was added dropwise at 0°C. After the addition was complete, the mixture was stirred at 25°C for 1 h. After the reaction was completed, the system was poured into water, and the mixture was extracted with ethyl acetate (20 mL*3) and washed twice with brine (60 mL). The organic phase was concentrated under reduced pressure to obtain a crude product. Compound 181 (0.025 g) was then purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, V / V). [M+H] + =939.

[0453] Example 34

[0454] Synthesis route

[0455] Synthesis of compound 182

[0456] Compound 181 (0.009 g, 0.0095 mmol) was dissolved in dichloromethane (1 mL) and DAST (0.015 g, 0.96 mmol) was added dropwise at -78 ° C. After the addition was complete, the mixture was returned to room temperature and stirred at room temperature for 5 h. After the reaction was completed, the system was poured into a sodium bicarbonate solution, extracted with dichloromethane (10 mL * 3), and washed twice with brine (10 mL). The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 30, V / V) to give compound 182 (0.005 g). [M + H] + =941.

[0457] Example 35

[0458] Synthesis route

[0459] Synthesis of compound 183A

[0460] Compound 178I (0.100 g, 0.73 mmol) and tetraisopropyl titanate (0.042 g, 0.0014 mol) were dissolved in a solution of ammonia in methanol (4 mL), and the reaction mixture was stirred at room temperature for 12 h. After the reaction was complete, the mixture was diluted with dichloromethane (20 mL) and washed twice with brine (50 mL). The organic layer was concentrated under reduced pressure to give compound 183A (0.090 g). [M+H] + =679.

[0461] Synthesis of compound 183B

[0462] Compound 183A (0.090 g, 0.13 mmol), (Boc)2O (0.144 g, 0.65 mmol) and triethylamine (0.067 g, 0.65 mmol) were dissolved in tetrahydrofuran (1 ml) and dichloromethane (2 ml) and stirred at room temperature for 3 h. After the reaction was completed, the system was concentrated under reduced pressure and then purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 40, V / V) to give compound 183B (0.092 g). [M+H] + =779.

[0463] Synthesis of compound 183

[0464] Referring to the preparation method of compound 57 in Example 3, compound 183B was used instead of 57I to synthesize 183. [M+H] + =938.

[0465] Example 36

[0466] Synthesis route

[0467] Synthesis of compound 184A

[0468] Compound 178I (0.050 g, 0.073 mmol) and sodium borohydride (0.014 g, 0.36 mmol) were added to THF (2 mL), and methanol (0.4 mL) was added dropwise at 0°C. After the addition was complete, the mixture was stirred at 25°C for 1 hour. After the reaction was completed, the system was poured into water, and the mixture was extracted with ethyl acetate (20 mL*3) and washed twice with brine (60 mL). The organic phase was concentrated under reduced pressure to obtain a crude product. Compound 184A (0.033 g) was then purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, V / V) to obtain compound 184A. [M+H] + =680.

[0469] Synthesis of compound 184B

[0470] Compound 184A (0.033 g, 0.050 mmol) was added to THF (4 mL), and sodium hydride (0.003 g, 0.075 mmol) was added at 0°C. The mixture was stirred at 25°C for 30 min, and then iodomethane (0.012 g, 0.090 mmol) was added. The mixture was stirred at 25°C for 1 h. After the reaction was completed, the system was poured into water, and the mixture was extracted with ethyl acetate (20 mL*3) and washed twice with brine (60 mL). The organic phase was concentrated under reduced pressure to obtain a crude product. Compound 184B (0.036 g) was then purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, V / V) to obtain compound 184B. [M+H] + =694.

[0471] Synthesis of compound 184

[0472] Referring to the preparation method of compound 57K in Example 3, compound 183B was used instead of 57I to synthesize 184. [M+H] + =953.

[0473] Example 37

[0474] Compounds 187, 192-194, 204, 207 and 216-220 listed in Table 3 were prepared essentially according to a synthetic method or strategy similar to that of Example 36, or using appropriate intermediates, which can be easily synthesized by methods known in the art and sequentially modified when necessary.

[0475] Table 3

[0476] Example 38

[0477] "*" indicates a chiral center with R or S configuration. 185-A and 185-B are two single stereoisomeric compounds, collectively represented by compound 185.

[0478] Synthesis route

[0479] Synthesis of compound 185-AA

[0480] Compound 185-AA was obtained by referring to the preparation method of intermediate 31-P1 in patent WO2022017338A1. [M+H] + =339.

[0481] Synthesis of compound 185-A

[0482] Referring to the preparation method of compound 39 in Example 11, 185-AA and 1I were used to replace 39L and 39M to synthesize 185-A. [M+H] + =895.

[0483] Synthesis of compound 185-BA

[0484] Compound 185-BA was obtained by referring to the preparation method of intermediate 31-P2 in patent WO2022017338A1. [M+H] + =339.

[0485] Synthesis of compound 185-B

[0486] Referring to the preparation method of compound 39 in Example 11, 185-B was synthesized by substituting 185-BA and 1I for 39L and 39M. [M+H] + =895.

[0487] Example 39

[0488] “*” indicates a chiral center with R or S configuration. 186-A and 186-B are two single stereoisomer compounds, collectively represented by compound 186.

[0489] Synthesis route

[0490] Synthesis of compound 186E

[0491] Referring to the preparation method of compound 1E in Example 1, 186E was synthesized by using 3-cyclopropyl-4-fluorophenylhydrazine hydrochloride instead of 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride.

[0492] Synthesis of compound 186I

[0493] Referring to the preparation method of compound 1I in Example 1, 186I was synthesized by replacing 1E with 186E.

[0494] Synthesis of compound 186-A

[0495] Referring to the method of Example 38, compound 185-A, 186-A was synthesized by replacing 1I with 186I. [M+H] + =907.

[0496] Synthesis of compound 186-B

[0497] Referring to the method of Example 38, compound 185-B, 186-A was synthesized by replacing 1I with 186I. 186-B was synthesized, [M+H] + =907.

[0498] Example 40

[0499] Synthesis route

[0500] Synthesis of compound 188A

[0501] 25E (210.2 mg, 0.49 mmol) was weighed and dissolved in 6 mL of DCM. Triethylamine (225.7 mg, 2.23 mmol) was added, and a dichloromethane solution of trifluoroacetic anhydride (205.3 mg, 0.95 mmol, 0.7 mL) was added dropwise. The reaction was allowed to react at room temperature for 0.5 h. Purified water was added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography to obtain compound 188A (277.6 mg, light brown solid). [M+H] + =523.

[0502] Synthesis of compound 188B

[0503] Compound 188A (277.6 mg, 0.53 mmol) was weighed and added to 8 mL of 1,4-dioxane and 5 mL of pure water, sodium periodate (568.1 mg, 2.66 mmol), and potassium osmate dihydrate (32 mg, 0.1 mmol). The mixture was reacted at room temperature for 2 h. Purified water was added for dilution, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude product 188B (350.6 mg, brown oil). [M+H] + =555.

[0504] Synthesis of compound 188C

[0505] The crude compound 188B (350.6 mg) was dissolved in 5 mL of methanol, and sodium borohydride (400 mg, 10.57 mmol) was added portionwise at room temperature. The mixture was allowed to react for 1 h. Purified water was added for dilution, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by column chromatography to obtain compound 188C (216.1 mg, light yellow solid). [M+H] + =559.

[0506] Synthesis of compound 188D

[0507] Compound 188C (183.8 mg, 0.33 mmol) was weighed and dissolved in 5 mL of DCM. Triethylamine (390.1 mg, 3.86 mmol) was added, and a solution of methanesulfonic anhydride in dichloromethane (230.5 mg, 1.32 mmol, 1.5 mL) was added dropwise. The reaction was allowed to react at room temperature for 0.5 h. Purified water was added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography to obtain compound 188D (54.7 mg, light brown solid). [M+H] + =715.

[0508] Synthesis of compound 188E

[0509] Compound 188D (54.7 mg, 0.076 mmol) was dissolved in 2 mL of ethanol, and 0.2 mL of pyridine and anhydrous sodium sulfide (49.8 mg, 0.64 mmol) were added. The mixture was reacted at 80°C for 2 h. Purified water was added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by column chromatography to obtain compound 188E (29.5 mg, white solid). [M+H] + =557.

[0510] Synthesis of compound 188F

[0511] Compound 188E (39.2 mg, 0.07 mmol) was weighed and dissolved in 5 mL of ethanol. 1.0 mL of 5 mol / L sodium hydroxide solution was added, and the mixture was sealed and reacted at 100°C for 30 h. Purified water was added dropwise to dilute the reaction mixture, and the pH was adjusted to 7 with 10% citric acid solution. The mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain compound 188F (38.1 mg, light yellow solid). [M+H] + =461.

[0512] Synthesis of compound 188

[0513] Referring to the preparation method of compound 1 in Example 1, 188 was synthesized by replacing 1E with 188F. [M+H] +=969.

[0514] Example 41

[0515] Synthesis route

[0516] Synthesis of compound 189A

[0517] Diethyl bis(hydroxymethyl)malonate (2.2 g, 10 mmol) was weighed and dissolved in dichloromethane (35 mL). TEA (8.4 mL, 60 mmol) was then added. The mixture was cooled to 0-5°C in an ice-water bath. A solution of Ms2O (5.23 g, 30 mmol) in dichloromethane (15 mL) was added dropwise and stirred at room temperature overnight. After completion of the reaction, the mixture was washed twice with 10% citric acid. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain compound 189A (3.8 g). [M+H] + =377.

[0518] Synthesis of compound 189B

[0519] Compound 189A (1.5 g, 4.0 mmol) and Na2S·9H2O (1.05 g, 4.4 mmol) were dissolved in 30 mL of DMSO and heated to 100°C for 6 h. Water was added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by column chromatography to obtain compound 189B, [M+H] + =219.

[0520] Synthesis of compound 189C

[0521] Referring to the preparation method of compound 25A in Example 8, 189C was synthesized by substituting 189B for diethyl 3-cyclopentene-1,1-dicarboxylate. [M+H] + =177.

[0522] Synthesis of compound 189

[0523] Referring to the preparation method of compound 57K in Example 3, 189 was synthesized by replacing 57B with 189C. [M+H] + =941.

[0524] Example 42

[0525] Synthesis route

[0526] Synthesis of compounds 190 and 191

[0527] Compound 189 (17.6 mg, 0.0187 mmol) and m-CPBA (11.4 mg, 0.0561 mmol) were dissolved in 2.5 mL of dichloromethane and reacted at room temperature for 6 h. The reaction was quenched by dropwise addition of water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by column chromatography. Among the isolated products, the less polar compound 191 was identified, and the more polar compound 190 was identified. [M+H] + =973 and [M+H] + =957.

[0528] Example 43

[0529] Synthesis of compound 195

[0530] Referring to the preparation method of compound 31 in Example 9, compound 195 was synthesized by replacing Boc-L-proline methyl ester with 1-Boc-pyrrolidine-3-carboxylic acid methyl ester (commercially available). [M+H] + =938.

[0531] Example 44

[0532] Synthesis route

[0533] Synthesis of compound 29A

[0534] Prepared by referring to the method of Example 111 of US2002 / 94989,2002. [M+H] + =235.

[0535] Synthesis of compound 29

[0536] Referring to the preparation method of compound 1 in Example 1, compound 29 was synthesized by replacing 1A with 29A. [M+H] + =939.

[0537] Example 45

[0538] Synthesis of compound 196

[0539] Referring to the preparation method of compound 185-A in Example 39, 196 was synthesized by substituting 185-AA with 1-(1-cyanocyclopropyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizine-2-carboxylic acid (intermediate 28-P1 of WO2022017338A1). [M+H] + =895.

[0540] Example 46

[0541] Synthesis route

[0542] Synthesis of compound 198A

[0543] Weigh ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (2.02 g, 9.41 mmol) and dissolve it in THF (20 ml). Replace the air with nitrogen three times, cool to -70°C, and slowly add LDA (2.0 M, 6.1 mL) dropwise. Stir at -70°C for 1 h, then transfer to 0°C and stir for 1 h. Cool the mixture to -70°C again and add a solution of ethyl formate (1.05 g, 14.19 mmol) in THF (4 mL) dropwise. Stir at -70°C for 1 h, then transfer to room temperature and stir for 30 min. The reaction was quenched with saturated aqueous ammonium chloride (30 mL) and stirred at room temperature for 30 min. Purified water (30 mL) was then added and extracted with 30 mL of ethyl acetate. The organic phases were combined, washed with 0.5 N HCl (20 mL), water (30 mL), and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford crude product 198A (2.21 g, yellow oil). The crude product was used directly in the next reaction without further purification.

[0544] Synthesis of compound 198B

[0545] 198A (2.21 g, 4.13 mmol) and (S)-3-aminobutyronitrile hydrochloride (0.55 g, 4.54 mmol) were weighed and added to dichloromethane (20 mL). Anhydrous sodium acetate (0.37 g, 4.54 mmol) and sodium triacetoxyborohydride (1.31 g, 6.19 mmol) were then added at 0°C. The mixture was allowed to stand overnight at room temperature under nitrogen. The reaction was quenched with saturated sodium bicarbonate solution, the pH was adjusted to 8-9, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with water (30 mL), then with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 100-1 / 50, v / v) to obtain product 198B (1.15 g, yield: 39%). LC / MS(ESI)m / z:311(M+H) + .

[0546] Synthesis of compound 198C

[0547] 198B (1.00 g, 3.23 mmol) was weighed and dissolved in tetrahydrofuran (20 mL). Under nitrogen, NaHMDS (2.0 M in THF, 3.2 mL, 6.45 mmol) was added dropwise at -20°C, maintaining the internal temperature above -10°C. After addition, the mixture was slowly returned to room temperature and stirred for 30 min. The reaction was quenched with 10% aqueous citric acid and the pH was adjusted to 9-10. Benzyl chloroformate (0.66 g, 3.87 mmol) was added dropwise in an ice-water bath. After addition, the mixture was stirred at room temperature for 30 min. Water (30 mL) was added, and the pH was adjusted to 5-6 with 3N HCl. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with water (20 mL x 2), then with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to yield the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-heptane = 1 / 4 to 1 / 2, V / V) to give product 198C (0.58 g, yield: 45%). LC / MS (ESI) m / z: 399 (M+H) + .

[0548] Synthesis of compound 198D

[0549] Compound 198C (0.58 g, 1.46 mmol), 4-fluoro-3,5-dimethylphenylhydrazine trifluoroacetate (0.83 g, 4.37 mmol), and pyridine (1.41 g, 17.82 mmol) were weighed and dissolved in 20 mL of ethanol. The mixture was heated to 80°C under nitrogen for 5 h. The solvent was concentrated to dryness, and ethyl acetate (30 mL) and saturated sodium bicarbonate solution (20 mL) were added for washing. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-heptane = 1 / 4 to 1 / 2, V / V) to obtain product 198D (0.33 g, yield: 42%). LC / MS (ESI) m / z: 535 (M+H) + .

[0550] Synthesis of compound 198E

[0551] Compound 198D (1.07 g, 2.00 mmol) was weighed and dissolved in 10 mL of pyridine. 2-Isocyanato-1,1-dimethoxyethane (1.62 g, 12.46 mmol) was added to the mixture under an ice-water bath and stirred at room temperature overnight. Methanol (5 mL) was added to the system and stirred for 30 min. The solvent was concentrated to dryness, ethyl acetate (30 mL) was added, and the mixture was washed with 10% aqueous citric acid solution (15 mL), saturated aqueous sodium bicarbonate solution (15 mL), and saturated brine (15 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-heptane = 1 / 3 to 1 / 1.5, V / V) to obtain product 198E (1.05 g, yield: 79%). LC / MS (ESI) m / z: 666 (M+H) + .

[0552] Synthesis of compound 198F

[0553] Compound 198E (1.05 g, 1.58 mmol) was weighed and dissolved in 20 mL of tetrahydrofuran. Methanesulfonic acid (0.19 g, 1.90 mmol) was added and stirred at 60°C under nitrogen for 2 h. After cooling to room temperature, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution (10 mL). The mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with water (20 mL*2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-heptane = 1 / 4-1 / 2, V / V) to obtain product 198F (1.00 g, yield: 100%). LC / MS (ESI) m / z: 602 (M+H) + .

[0554] Synthesis of compound 198G

[0555] Compound 198F (1.00 g, 1.67 mmol) was weighed and dissolved in 14 mL of N-methylpyrrolidone. 5-Bromo-4-fluoro-1-methylindazole (0.76 g, 3.34 mmol), potassium carbonate (0.69 g, 5.00 mmol), cuprous iodide (0.37 g, 1.92 mmol), and (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (0.55 g, 3.83 mmol) were then added sequentially. The reaction was incubated at 130°C under nitrogen for 2 h. After cooling the reaction system to room temperature, purified water (100 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with water (30 mL x 2) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to afford crude product 198G (1.63 g, brown oil). The crude product was used directly in the next reaction without further purification. LC / MS (ESI) m / z: 750 (M+H) + .

[0556] Synthesis of compound 198H

[0557] Compound 198G (1.63 g) was weighed and added to THF (10 mL), followed by 3N HCl (20 mL) and stirred at 50°C for 2 h. Under an ice-water bath, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL*3), and the organic phases were combined, washed with water (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-heptane = 1 / 2-1 / 1, V / V) to obtain product 198H (0.70 g, yield: 62.7%). LC / MS (ESI) m / z: 706 (M+H) + .

[0558] Synthesis of compound 198I

[0559] 198H (91.8 mg, 0.013 mmol) was weighed and added to dichloromethane (2.0 mL). Palladium chloride (46.5 mg, 0.026 mmol) and triethylamine (53.5 mg, 0.052 mmol) were then added. The atmosphere was replaced with nitrogen three times. Triethylsilane (45.9 mg, 0.039 mmol) was added dropwise under an ice-water bath. After the addition was complete, the mixture was stirred at room temperature for 2 h. Methanol (2 mL) was added and stirred for 30 min. The mixture was filtered through celite, washed with methanol (10 mL), and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-heptane = 1 / 4 to 3 / 1, V / V) to obtain the product 198I (52.4 mg, yield: 70%). LC / MS (ESI) m / z: 572 (M+H) + .

[0560] Synthesis of compound 198

[0561] Compound 198I (52.4 mg, 0.092 mmol) was weighed and dissolved in N,N-dimethylformamide (2 mL). Subsequently, 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 (37.7 mg, 0.092 mmol), HATU (45.3 mg, 0.119 mmol), DIPEA (35.6 mg, 0.275 mmol) and DMAP (3.9 mg, 0.028 mmol) were added in sequence, and the mixture was stirred at room temperature overnight. Purified water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with water (20 mL*2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by preparative thin-layer chromatography (developing solvent: methanol / dichloromethane / ethyl acetate = 1 / 50 / 5, V / V) to obtain product 198 (18.3 mg, yield: 21%). LC / MS (ESI) m / z: 965 (M+H) + .

[0562] Example 47

[0563] Compounds 199-203 listed in Table 4 were prepared using 198H as the starting material and were easily synthesized by synthetic methods similar to those of Examples 32-36 or methods known in the art, and were sequentially modified when necessary.

[0564] Table 4

[0565] Example 48

[0566] Synthesis of compound 205

[0567] Referring to the preparation method of compound 185-A in Example 38, 1-(1-cyanocyclopropyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-8-fluoroindolizine-2-carboxylic acid (intermediate 73 of WO2022017338A1) was used to synthesize 205 instead of 185-AA. [M+H] + =913.

[0568] Example 49

[0569] Synthesis of compound 206

[0570] Referring to the preparation method of compound 185-A in Example 38, 206 was synthesized using 5-(1-cyanocyclopropyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolo[1,2-b]pyridazine-6-carboxylic acid (intermediate 70 of WO2022017338A1) instead of 185-AA. [M+H] + =896.

[0571] Example 50

[0572] Synthesis route

[0573] Synthesis of compound 172

[0574] Referring to Example 2, 25E ​​was used instead of 43G to obtain compound 172, [M+H] + =935.

[0575] Example 51

[0576] Synthesis route

[0577] Synthesis of compound 208A

[0578] Compound 172C (400 mg, 0.62 mmol) was dissolved in 20 mL of tetrahydrofuran and cooled to 0-5°C in an ice-water bath. A solution of borane dimethyl sulfide complex in tetrahydrofuran (0.25 mL, 10 mol / L, 2.50 mmol) was added dropwise. After the addition was complete, the mixture was allowed to react at 0-5°C for 1 h. 1 mL of 10% sodium hydroxide solution was added dropwise, followed by 0.5 mL of 30% hydrogen peroxide solution. The mixture was allowed to react at 0-5°C for 2 h. Water and ethyl acetate were added for extraction, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography to obtain compound 208A (400 mg, light yellow solid). [M+H] + =660.

[0579] Synthesis of compound 208B

[0580] Compound 208A (179 mg, 0.27 mmol) was dissolved in 5 mL of dichloromethane, and Dess-Martin periodinane (230 mg, 0.54 mmol) was added portionwise at room temperature. After the addition was complete, the reaction was allowed to react at room temperature for 0.5 h. Saturated sodium bicarbonate solution was added dropwise to quench the reaction, and the mixture was stirred for 10 min. Water and ethyl acetate were added for extraction, and the mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography to obtain compound 208B (75 mg, white solid). [M+H] + =658.

[0581] Synthesis of compound 208

[0582] Referring to Example 1, 208B was used instead of 1H to prepare compound 208, [M+H] + =951.

[0583] Example 52

[0584] Compounds 197, 209-215 and 229 listed in Table 5 were easily synthesized using 172C as the starting material, referring to the preparation method of 208A and 208B in Example 51, and then by synthetic methods similar to those of Examples 30-36 or methods known in the art, and sequentially modified when necessary.

[0585] Table 5

[0586] Example 53

[0587] Synthesis route

[0588] Synthesis of compound 225A

[0589] At room temperature, compound (S)-3-aminobutyronitrile hydrochloride (2.05 g, 17.0 mmol) was weighed and dissolved in THF (20 mL) and water (20 mL). Sodium carbonate (3.56 g, 33.6 mmol) and Boc2O (4.56 g, 20.9 mmol) were added. The reaction was allowed to react at room temperature for 2 h. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic phase was washed once with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 1 / 0 to 1 / 1, V / V) to obtain product 225A (2.36 g, yield: 77%). [M+H] + =185.

[0590] Synthesis of compound 225B

[0591] At room temperature, 225A (0.31 g, 1.6 mmol) was weighed and dissolved in DMF (5 mL). The mixture was cooled to 0-5°C in an ice-water bath, and 60% sodium hydride (0.096 g, 2.4 mmol) was added and stirred for 0.5 h. Methyl 2-bromomethylacrylate (0.52 g, 2.90 mmol) was added and allowed to react for 5 min. Water and ethyl acetate were added to the reaction mixture and the layers were separated. The organic phase was washed once with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography (eluent: n-heptane / ethyl acetate = 1 / 50 to 1 / 5, v / v) to obtain product 225B (0.35 g, yield: 70%). [M+H] + =283.

[0592] Synthesis of compound 225C

[0593] At room temperature, 225B (0.100 g, 0.35 mmol) was weighed and dissolved in Diglyme (1 ml). The mixture was heated to 150°C, and a solution of sodium difluorobromosulfonate (0.300 g, 1.39 mmol) in Diglyme (1 ml) was slowly added dropwise to the system. After complete addition, the mixture was incubated for 1 hour. The crude product was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-heptane = 1 / 5, v / v) to afford product 225C (0.110 g). [M+H] + =333(M+H) + .

[0594] Synthesis of compound INT-225

[0595] At room temperature, 225C (0.110 g, 0.38 mmol) was weighed and added to THF (60 mL). The atmosphere was then replaced with nitrogen three times, the temperature was lowered to -40°C, and NaHMDS (0.2 mL, 0.49 mmol) was added dropwise. After the addition was complete, the mixture was allowed to warm to room temperature and allowed to react for 2 h. 1 mL of water was added dropwise to the system, and the mixture was extracted with 10 mL of ethyl acetate twice. After washing with brine, the organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 40 / 1, v / v) to obtain the product INT-225 (0.092 g, yield: 80%). [M+H] + =301.

[0596] Example 54

[0597] Synthesis route

[0598] Synthesis of compound 226A

[0599] Sodium hydride (0.62 g, 15.48 mmol) was added to ethylene glycol dimethyl ether (20 mL), replaced with nitrogen, and cooled to 0-5°C in an ice bath. Subsequently, a mixed solution of dibenzyl malonate (2.00 g, 7.04 mmol) and (4R)-4-methyl-1,3,2-dioxathiazolin 2,2-dioxide (0.97 g, 7.04 mmol) in ethylene glycol dimethyl ether (6 mL) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 30 min, and then at 40°C for 30 min. The reaction system was poured into ice water (50 mL) and extracted with ethyl acetate (30 mL*2). The organic phases were combined, washed with purified water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. Compound 226A (1.78 g, colorless liquid) was obtained by column chromatography. [M+H] + =325.

[0600] Synthesis of compound INT-226

[0601] Referring to the synthesis method of compound 39F in Example 11, 226A was used instead of 39B to prepare compound INT-226, [M+H] + =279.

[0602] Example 55

[0603] Synthesis route

[0604] Referring to the synthesis method of Example 54, (4R)-4-methyl-1,3,2-dioxathiaridine 2,2-dioxide was replaced with (4S)-4-methyl-1,3,2-dioxathiaridine 2,2-dioxide to obtain compound INT-226, [M+H] + =279.

[0605] Example 56

[0606] Synthesis route

[0607] Synthesis of compound 228A

[0608] At room temperature, 225B (485.4 mg, 1.7 mmol) was weighed and dissolved in THF (8 mL). 228B (J. Org. Chem. 2021, 86, 3196-3212) (915.7 mg, 2.5 mmol) was added and cooled to 0-5°C in an ice-water bath. 60% sodium hydride (343.8 mg, 8.6 mmol) was slowly added and reacted for 0.5 h. Water and ethyl acetate were added to the reaction solution and the layers were separated. The organic phase was washed once with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography (eluent: n-heptane / ethyl acetate = 1 / 10 to 1 / 1, V / V) to obtain the product 228A (468.2 mg, yield: 87.5%). [M+H] + =315.

[0609] Synthesis of compound INT-228

[0610] Compound 228A (468.2 mg, 1.48 mmol) was dissolved in 20 mL of tetrahydrofuran under nitrogen protection and cooled to 0-5°C in an ice-water bath. NaHMDS (2.0 M THF solution, 1.6 mL, 3.20 mmol) was added dropwise and stirred for 30 minutes after the addition was complete. The reaction was quenched with 10% aqueous citric acid solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography to obtain compound INT-228 (448.7 mg, 107%), [MH] - =281.

[0611] Example 57

[0612] Compounds 225-228 listed in Table 6 were prepared using INT-225 to INT-228 as starting materials, and were easily synthesized by a synthetic method similar to that of Example 1 or a method known in the art, and were sequentially modified when necessary.

[0613] Table 6

[0614] Example 58 Biological Evaluation

[0615] The agonist activity of the compounds of the present invention on GLP-1R was evaluated by detecting the generation of cAMP.

[0616] 1. Cells and reagents

[0617] (1) Cell line: HEK293-GLP-1R-luc stable cell line (Cobioer, CBP71117);

[0618] (2) Culture medium: DMEM + 10% FBS (Gibco);

[0619] (3) Kit: cAMP detection kit (PerkinElmer).

[0620] 2. Experimental operation

[0621] (1) HEK293-GLP1R cells were seeded in a 384-well plate at a density of 2000 cells per well;

[0622] (2) Prepare 4X compound working solution;

[0623] (3) Add 5 μL of 4X compound working solution to each well and incubate at 37°C for 30 min;

[0624] (4) Add 10 μL of Eu-cAMP tracer (1 / 50) diluted with Lysis Buffer to each well;

[0625] (5) Add 10 μL of Ulight-anti-cAMP (1 / 150) diluted in Lysis Buffer to each well;

[0626] (6) Incubate at room temperature for 1 h;

[0627] (7) The plate was read using a multifunctional microplate reader (excitation wavelength: 320 nm; emission wavelengths: 665 nm and 620 nm).

[0628] 3. Data Analysis

[0629] (1) The formula for calculating %Activity is as follows:

[0630] %Activity=100-(Signal cmpd -Signal Ave-PC ) / (Signal Ave-VC -Signal Ave-PC )×100

[0631] (2) Draw the effect-dose curve and calculate EC 50 :

[0632] Y=Bottom+(Top-Bottom) / (1+10^(LogEC 50 -X)*HillSlope))

[0633] X: log of agonist concentration; Y: Activity.

[0634] 4. Experimental results

[0635] Table 7

[0636] Remark:

[0637] A stands for EC 50 ≤0.1nM; B represents 0.1nM <EC 50 ≤1nM; C represents 1nM <EC 50 ≤10nM.

[0638] Example 59 Biological Evaluation

[0639] The agonist activity of the compounds of the present invention on GLP-1R was evaluated by detecting the generation of cAMP.

[0640] 1. Cells and reagents

[0641] (1) Cell line: HEK293-GLP-1R-luc stable cell line (Cobioer, CBP71117);

[0642] (2) Culture medium: DMEM + 10% FBS (Gibco);

[0643] (3) Kit: One-Lite TM kit Luciferase Assay System(Vazyme).

[0644] 2. Experimental operation

[0645] (1) HEK293-GLP1R cells were seeded in a 96-well plate at a density of 30,000 cells per well;

[0646] (2) Prepare 10X compound working solution;

[0647] (3) Add 10 μL of 10X compound working solution to each well and incubate at 37°C for 6 h;

[0648] (4) Add 100 μL of One-Lite Luciferase Assay Substrate prepared with One-Lite Luciferase Assay Buffer to each well;

[0649] (5) Incubate at room temperature for 3 minutes;

[0650] (6) Detect chemiluminescence by reading the plate using a multifunctional microplate reader.

[0651] 3. Data Analysis

[0652] (1) The formula for calculating %Activity is as follows:

[0653] %Activity=100-(Signalcmpd -Signal Ave-PC ) / (Signal Ave-VC -Signal Ave-PC )×100

[0654] (2) Draw the effect-dose curve and calculate EC 50 :

[0655] Y=Bottom+(Top-Bottom) / (1+10^(LogEC 50 -X)*HillSlope))

[0656] X: log of agonist concentration; Y: Activity.

[0657] 4. Experimental results

[0658] Table 8

[0659] Remark:

[0660] ++++ means EC 50 ≤20nM; +++ indicates 20nM <EC 50 ≤100nM; ++ means 100nM <EC 50 ≤300nM; + indicates EC 50 >300nM.

[0661] The above results show that the compounds of the present invention have good agonist activity on GLP-1R.

[0662] Example 60 Pharmacokinetic Evaluation in Rats

[0663] The compound of the present invention was formulated in 10% PEG 400 + 90% 100 mM glycine-64 mM NaOH and administered orally to fasted SD rats at either 1 mg / kg or 5 mg / kg. Approximately 50 μL of blood was collected venously at various time points (0.25, 0.5, 1.0, 2.0, 4.0, 5.0, 6.0, 7.0, 8.0, and 24 hours post-dose), placed in tubes containing EDTA-K2, and centrifuged to separate plasma. Compound plasma concentrations were determined using LC-MS / MS, and pharmacokinetic parameters were calculated using a non-compartmental model using WinNonlin. The results are shown in Table 9.

[0664] Table 9

[0665] The above rat pharmacokinetic test results show that the half-life of some representative compounds of the present invention is T 1 / 2The results are longer than those of the control compound (Compound 67 in Example WO2018056453), while Compound 1 and Compound 228 have higher oral exposure AUC and higher maximum blood concentration C max , indicating that the compounds of the present invention have better pharmacokinetic properties and oral administration characteristics, and are more suitable for drug development.

[0666] Example 61 Pharmacokinetic Evaluation in Cynomolgus Monkeys

[0667] A clear solution of 10% PEG / 90% 100 mM glycine-NaOH "Compound 67 of Example WO2018056453" and a clear solution of 10% PEG / 90% 100 mM glycine-NaOH "Compound 1" were prepared and injected subcutaneously into the forelimb of male cynomolgus monkeys (n=2) at a dose of 0.12 mg / kg.

[0668] Blood samples were collected from the vein at different time points after administration (0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 24.0 and 36 hours), placed in tubes containing EDTA-K2 anticoagulant, and centrifuged to separate plasma.

[0669] The drug concentration in plasma was determined by LC-MS / MS, and the relevant pharmacokinetic parameters were calculated using the non-compartmental linear logarithmic trapezoidal method using pharmacokinetic software (such as winNonlin Version 6.3) as shown in Table 10.

[0670] Table 10

[0671] The above cynomolgus monkey pharmacokinetic test results show that compared with the control compound (WO2018056453 Example Compound 67), the representative compound 1 of the present invention has a lower clearance rate Cl and a longer half-life T 1 / 2 and higher exposure AUC, better pharmacokinetic properties, and more suitable for drug development.

[0672] Example 62 Evaluation of drug efficacy in mice

[0673] 1. Experimental Purpose

[0674] The effects of long-term administration of the compound of the present invention on the body weight and food intake of GLP-1R humanized C57BL / 6N mice fed a high-fat diet were evaluated.

[0675] 2. Experimental reagents and instruments

[0676] C57BL / 6N_hGLP-1R mice, male, 5 weeks;

[0677] 60% high-fat diet (HFD);

[0678] Electronic balance.

[0679] 3. Experimental methods

[0680] (1) C57BL / 6N_hGLP-1R mice were fed with 60% high-fat diet until the end of the experiment.

[0681] (2) After the 10th week of HFD feeding, the model mice were randomly divided into groups according to body weight, with 6-7 mice per group. The mice were then individually caged for 2 weeks of adaptive feeding. The first group was the vehicle group (Vehicle: 10% PEG 400 + 10% propylene glycol + 80% glycine-NaOH buffer), which was given the vehicle; the remaining groups were the drug-treated groups. The drug-treatment cycle was 27 days.

[0682] (3) The day of drug administration was defined as Day 0. At each drug administration, the animals were weighed and the data were recorded, and the drug was administered according to the body weight.

[0683] (4) Starting from day 0 of the experiment, the food intake of each group of mice was measured once a day. Specifically, the feed was replaced after each dose and the added and remaining amounts were recorded.

[0684] 4. Experimental data processing and statistical analysis

[0685] The weight change rate of mice after administration was summarized and statistically analyzed.

[0686] Calculation of vehicle-corrected weight change rate: (((BW t / BW0)-1)-(BW t-vec-avg ))*100%;

[0687] BW t represents the weight of mice in the treatment group on day t; BW0 represents the weight of mice in the treatment group on day 0; BW t-vec-avg represents the average body weight of mice in the Vehicle group on day t of the drug-treated group.

[0688] The cumulative food intake of mice after drug administration was summarized and statistically analyzed.

[0689] Calculation of cumulative food intake: added amount (g) - remaining amount (g);

[0690] The cumulative food intake was the sum of the daily food intake of each animal during the dosing period.

[0691] 5. Experimental results

[0692] Table 11

[0693] According to the above experimental results, it can be seen that long-term administration of Example Compound 1 of the present invention has excellent weight reduction and food intake suppression effects on GLP-1R humanized C57BL / 6 mice fed a high-fat diet, and is superior to the control compound at doses of 0.3 mpk and 1.5 mpk. It also reduces mouse body weight and suppresses food intake in a dose-dependent manner within the dose range of 0.3-3 mpk.

[0694] The above embodiments are only intended to help understand the method and core concept of the present invention. It should be noted that, without departing from the principles of the present invention, a number of improvements and modifications may be made to the present invention by those skilled in the art, and such improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A compound of formula I, or an isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt thereof: in, X 1 , X 2 and X 3 independently selected from N and C; Rings A, B and C are independently selected from C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl; Each R 1 independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, -CN, -NO2, -NR A1 R B1 、-OR A1 、-C(O)R A1 、-C(O)OR A1 、-OC(O)R A1 、-C(O)NR A1 R B1 、-NR A1 C(O)R B1 、-OC(O)NR A1 R B1 、-S(O) r R A1 、-S(O)2OR A1 、-OS(O)2R A1 、-NR A1 S(O) r R B1 、-S(O) r NR A1 R B1 、-P(O)R A1 R B1 AND-P(O)(OR A1 )(OR B1 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X1 Substituents are substituted; Each R 2 independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, -(CH2) s CF3, -CN, -NO2, -NR A2 R B2 、-OR A2 、-C(O)R A2 、-C(O)OR A2 、-OC(O)R A2 、-C(O)NR A2 R B2 、-NR A2 C(O)R B2 、-OC(O)NR A2 R B2 、-NR A2 C(O)OR B2 、-S(O) r R A2 、-P(O)R A2 R B2 、-S(O) r NR A2 R B2 AND-P(O)(OR A2 )(OR B2 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X2 Substituents are substituted; Each R 3 independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, -CN, -NO2, -NR A3 R B3 、-OR A3 and -C(O)R A3 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X3 Substituents are substituted; Or two R 3 Together with the atoms they are connected to form a C 3-10 Cycloalkyl or a 4-12 membered heterocyclic group containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted by 1, 2 or 3 independently selected from R X3 Substituents are substituted; R 4 is selected from -C(O)OH, heterocyclyl and heteroaryl; R 5 Selected from hydrogen and C 1-6 alkyl; R 6 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, -CN, -NO2, -NR A4 R B4 、-OR A4 and -C(O)R A4 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X4 Substituents are substituted; R 7 and R 8 Together with the atoms they are connected to form fragments R 9 and R 10 independently selected from hydrogen, halogen and C 1-3 alkyl; or R 9 and R 10 Together with the atoms they are connected to form fragments R 7 and R 8 independently selected from hydrogen, halogen and C 1-3 alkyl; or R 8 and R 9 Together with the carbon atoms to which they are attached, they form fragments R 7 and R 10 independently selected from hydrogen, halogen and C 1-3 alkyl; Rings T, T' and W are independently selected from C 3-10 Cycloalkyl, C 3-8 Cycloalkenyl, 3-12 membered heterocyclyl and 5-6 membered heteroaryl, the ring is unsubstituted or substituted by 1, 2 or 3 independently selected from R X Substituents are substituted; is a single bond or a double bond; or R 8 and R 6 Together with the atoms they are connected to form a C 3-10 Cycloalkyl or a 4-12 membered heterocyclic group containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted with 1, 2 or 3 R X Substituent substitution; R 7 , R 9 and R 10 are independently selected from hydrogen, halogen and C 1-3 alkyl; or R 9 and R 6 Together with the atoms they are connected to form a C 3-10 Cycloalkyl or a 4-12 membered heterocyclic group containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted with 1, 2 or 3 R X Substituent substitution; R 7 , R 8 and R 10 are independently selected from hydrogen, halogen and C 1-3 alkyl; Each R A1 , R A2 , R A3 , R A4 , R B1 , R B2 , R B3 and R B4 independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from hydroxy, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Substitution with cycloalkyl, cyano, alkoxy, alkylamino, di(alkyl)amino, haloalkyl, acyl, sulfonyl, sulfonamido and halogen substituents; or "R A1 and R B1 ” or "R A2 and R B2 ” or "R A3 and R B3 "Together with the atoms or atoms to which they are attached, they form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 groups selected from hydroxy, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Substitution with cycloalkyl, cyano, alkoxy, alkylamino, di(alkyl)amino, haloalkyl, acyl, sulfonyl, sulfonamido and halogen substituents; Each R X , R X1 , R X2 , R X3 and R X4 Independently selected from hydroxyl, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, cyano, alkoxy, alkylamino, di(alkyl)amino, haloalkyl, acyl, sulfonyl, sulfonamido and halogen; m, n and p are independently selected from 0, 1, 2 and 3; r and s are independently selected from 0, 1 and 2.

2. The compound according to claim 1, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The rings T and T' are independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and oxocyclobutyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and oxocyclobutyl are unsubstituted or substituted by 1, 2 or 3 independently selected from R X Substituents are substituted; R X As defined in claim 1.

3. The compound according to claim 2, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The rings T and T' are independently selected from 4. The compound according to claim 1, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The rings T and T' are independently selected from oxirane, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, azetidinyl and thietanyl, and the oxirane, oxetanyl, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, azetidinyl and thietanyl are unsubstituted or substituted by 1, 2 or 3 groups independently selected from R X Substituents are substituted; R X As defined in claim 1.

5. The compound according to claim 1, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The rings T and T' are independently selected from 6. The compound according to claim 1, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring T' is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and C 4-8 Cycloalkenyl, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and C 4-8 The cycloalkenyl group is unsubstituted or substituted with 1, 2 or 3 groups independently selected from R X Substituents are substituted; Each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, alkylamino, -OC 1-6 Alkyl, -OC 1-6 Cycloalkyl and halogen, or each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Cycloalkyl and halogen.

7. The compound according to claim 6, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring T' is selected from Or the ring T' is selected from 8. The compound according to claim 1, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring T' is selected from oxirane, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, aziridine, azetyl, azetyl, thiol, thiolanyl and thiohexyl, and the oxirane, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, azetyl, azetyl, azetyl, azetyl, thiolanyl and thiohexyl are unsubstituted or substituted by 1, 2 or 3 groups independently selected from R X Substituents are substituted; Each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, alkoxy, -C(O)H, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Cycloalkyl, -C(O)-C 1-6 Alkyl-C 1-6 Alkoxy, -C(O)-haloalkyl, -C(O)-C 1-6 Alkoxy, -C(O)-C 1-6 Alkylamino, -C(O)-aminoalkyl, -C(O)NH2, sulfonyl and halogen.

9. The compound according to claim 8, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring T' is selected from 10. The compound according to claim 1, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring W is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxycyclohexyl, cyclohexenyl and oxycyclohexenyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxycyclohexyl, cyclohexenyl and oxycyclohexenyl are unsubstituted or substituted by 1, 2 or 3 independently selected from R X Substituents are substituted; R X As defined in claim 1.

11. The compound according to claim 10, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring W is selected from 12. The compound according to claim 1, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring W is selected from oxacyclopropyl, oxetane, oxolanyl, oxhexyl, aziridine, azetidinyl and aziridine, and the oxacyclopropyl, oxetane, oxolanyl, oxhexyl, aziridine, azetidinyl and azetidinyl are unsubstituted or replaced by 1-3 independently selected R X Substituents are substituted; R X As defined in claim 1.

13. The compound according to claim 12, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring W is selected from 14. The compound according to claim 1, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring W is selected from furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl, and the furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl are unsubstituted or substituted by 1, 2 or 3 independently selected R X Substituents are substituted; R X As defined in claim 1.

15. The compound according to claim 14, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring W is selected from 16. The compound according to claim 1, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The R 8 and R 6 Together with the atoms they are connected to form a C 3-8 Cycloalkyl or 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted with 1, 2 or 3 R X Substituent substitution; R 7 , R 9 and R 10 are independently selected from hydrogen, halogen and C 1-3 alkyl; R X As defined in claim 1.

17. The compound according to claim 1, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The R 9 and R 6 Together with the atoms they are connected to form a C 3-8 Cycloalkyl or 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted with 1, 2 or 3 R X Substituent substitution; R 7 , R 8 and R 10 are independently selected from hydrogen, halogen and C 1-3 alkyl; R X As defined in claim 1.

18. The compound according to any one of claims 1 to 17, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The X 1 , X 2 and X 3 are independently selected from N and C, only one of which is N and the other two are C.

19. The compound according to any one of claims 1 to 17, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring A is an aryl group or a heteroaryl group.

20. The compound according to any one of claims 1 to 17, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring A is The R 1 independently selected from hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy, wherein m is selected from 1, 2 and 3.

21. The compound according to claim 20, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The R 1 are independently hydrogen, fluorine, methyl or cyclopropyl, or each of the R 1 are independently fluoro, methyl or cyclopropyl, and m is 2 or 3.

22. The compound according to any one of claims 1 to 17, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring B is 23. The compound according to any one of claims 1 to 17, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring B is The R 2 independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 3-6 Cycloalkyl, -CH2CF3, -S(O)2NR A2 R B2 、-S(O)2R A2 and-P(O)R A2 R B2 ; Each R A2 and R B2 Independently selected from C 1-4 Alkyl and C 3-6 Cycloalkyl; wherein n is 1, 2 or 3.

24. The compound according to claims 1-17, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring B is The n is 1 or 2; the R 2 independently selected from hydrogen, fluorine, methyl, -CH2CH3, -CH2CF3, -P(O)(CH3)2, -P(O)(CH2CH3)2, -NHCH3, -OCH3, -CH2S(O)2CH3 and Or the R 2 are independently hydrogen, fluorine, methyl, -CH2CF3, -P(O)(CH3)2, -P(O)(CH2CH3)2, -NHCH3, -OCH3, -CH2S(O)2CH3 or Or the R 2 are independently fluorine, methyl, -CH2CH3, -CH2CF3, -P(O)(CH3)2, -P(O)(CH2CH3)2, -NHCH3, -OCH3, -CH2S(O)2CH3 or 25. The compound according to any one of claims 1 to 17, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring C is selected from a heterocyclic group or a heteroaryl group; The R 3 independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl; wherein p is 0, 1, 2 or 3, when p≥2, two R 3 Optionally, together with the atoms to which they are attached, form a C 3-10 Cycloalkyl.

26. The compound according to claim 25, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring C is 27. The compound according to claim 26, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring C is The p is 0; or p is 2, R 3 is methyl; Or if p is 2, two R 3 Together with the atoms to which they are attached they form a cyclopropyl group.

28. The compound according to any one of claims 1 to 17, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The R 4 for Or the R 4 for 29. The compound according to any one of claims 1 to 17, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The R 5 is hydrogen or C 1-3 Alkyl, or the R 5 It is hydrogen or methyl.

30. The compound according to any one of claims 1 to 17, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The R 6 is hydrogen or C 1-3 Alkyl, or the R 6 It is methyl.

31. The compound according to claim 1, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The compound has any of the following structures: in, Selected from Selected from or Selected from Selected from or Selected from or Selected from R 4 for R 5 is hydrogen or methyl; R 6 is methyl; is a single bond or a double bond; Rings T, T' and W are independently selected from C 3-10 Cycloalkyl, C 3-8 Cycloalkenyl, 3-12 membered heterocyclyl and 5-6 membered heteroaryl, the ring is unsubstituted or substituted by 1, 2 or 3 independently selected from R X Substituents are substituted; or R 8 With R 6 Together with the atoms they are connected to form a C 3-8 Cycloalkyl or 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted with 1, 2 or 3 R X Substituent substitution; R 9 is hydrogen; or R 9 With R 6 Together with the atoms they are connected to form a C 3-8 Cycloalkyl or 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted with 1, 2 or 3 R X Substituent substitution; R 8 is hydrogen; Each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, cyano, alkoxy, alkylamino, di(alkyl)amino, haloalkyl, acyl, sulfonyl, sulfonamido and halogen.

32. The compound according to claim 1, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The compound has any of the following structures: in, Selected from Selected from or Selected from Selected from or Selected from or Selected from R 4 for R 5 is hydrogen or methyl; R 6 is methyl; Ring T and ring T′ are as defined in claim 1 .

33. The compound according to claim 32, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The rings T and T' are independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and oxocyclobutyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and oxocyclobutyl are unsubstituted or substituted by 1, 2 or 3 independently selected from R X Substituents are substituted; R X As defined in claim 1.

34. The compound according to claim 33, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The rings T and T' are independently selected from 35. The compound according to claim 32, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The rings T and T' are independently selected from oxirane, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, azetidinyl and thietanyl, and the oxirane, oxetanyl, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, azetidinyl and thietanyl are unsubstituted or substituted by 1, 2 or 3 groups independently selected from R X Substituents are substituted; R X As defined in claim 1.

36. The compound according to claim 32, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The rings T and T' are independently selected from 37. The compound according to claim 1, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The compound has any of the following structures: in, Selected from Selected from or Selected from Selected from or Selected from or Selected from R 4 for R 5 is hydrogen or methyl; R 6 is methyl; Ring T' is as defined in claim 1.

38. The compound according to claim 37, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring T' is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and C 4-8 Cycloalkenyl, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and C 4-8 The cycloalkenyl group is unsubstituted or substituted with 1, 2 or 3 groups independently selected from R X Substituents are substituted; Each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, alkylamino, -OC 1-6 Alkyl, -OC 1-6 Cycloalkyl and halogen, or each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Cycloalkyl and halogen.

39. The compound according to claim 38, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring T' is selected from Or the ring T' is selected from 40. The compound according to claim 37, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring T' is selected from oxirane, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, aziridine, azetyl, azetyl, thiol, thiolanyl and thiohexyl, and the oxirane, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, azetyl, azetyl, azetyl, azetyl, thiolanyl and thiohexyl are unsubstituted or substituted by 1, 2 or 3 groups independently selected from R X Substituents are substituted; Each R X Independently selected from hydroxyl, oxo, C 1-6 Alkyl, alkoxy, -C(O)H-, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Cycloalkyl, -C(O)-C 1-6 Alkyl-C 1-6 Alkoxy, -C(O)-haloalkyl, -C(O)-C 1-6 Alkoxy, -C(O)-C 1-6 Alkylamino, -C(O)-aminoalkyl, -C(O)NH2, sulfonyl and halogen.

41. The compound according to claim 40, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring T' is selected from 42. The compound according to claim 1, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The compound has the following structure: in, Selected from Selected from Selected from R 4 for R 5 is methyl; R 6 is methyl; Ring T' is as defined in claim 1.

43. The compound according to claim 42, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring T' is C 3-6 Cycloalkyl, the ring is unsubstituted or substituted by 1, 2 or 3 independently selected from R X Substituents are substituted; Each R X Independently selected from C 1-3 Alkyl, vinyl, -OC 1-3 Alkyl and halogen.

44. The compound according to claim 43, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring T' is C 3-4 Cycloalkyl, the ring is unsubstituted or substituted by 1 or 2 independently selected from R X Substituents are substituted; R X Selected from methyl, vinyl, methoxy and fluorine.

45. The compound according to claim 44, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring T' is selected from 46. ​​The compound according to claim 1, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The compound has the following structure: in, Ring T' is as defined in claim 1.

47. The compound according to claim 46, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring T' is C 3-6 Cycloalkyl, preferably C 3-4 Cycloalkyl; the ring is unsubstituted or substituted by 1, 2 or 3, preferably 1 or 2 independently selected from R X Substituents are substituted; Each R X Independently selected from C 1-3 Alkyl, vinyl, -OC 1-6 Alkyl and halogen, preferably methyl, vinyl, methoxy and fluorine.

48. The compound according to claim 47, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring T' is selected from Best 49. The compound according to claim 1, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The compound has any of the following structures: in, Selected from Selected from Selected from R 4 for R 5 is hydrogen or methyl; R 6 is methyl; is a single bond or a double bond; Ring W is as defined in claim 1.

50. The compound according to claim 49, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring W is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxycyclohexyl, cyclohexenyl and oxycyclohexenyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxycyclohexyl, cyclohexenyl and oxycyclohexenyl are unsubstituted or substituted by 1, 2 or 3 independently selected from R X Substituents are substituted; R X As defined in claim 1.

51. The compound according to claim 50, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring W is selected from 52. The compound according to claim 49, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring W is selected from oxacyclopropyl, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl and aziridine, and the oxetanyl, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl and azetidinyl groups are unsubstituted or substituted by 1, 2 or 3 groups independently selected from R X Substituents are substituted; R X As defined in claim 1.

53. The compound according to claim 52, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring W is selected from 54. The compound according to claim 49, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring W is selected from furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl, and the furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl are unsubstituted or substituted by 1, 2 or 3 independently selected R X Substituents are substituted; R X As defined in claim 1.

55. The compound according to claim 54, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The ring W is selected from 56. The compound according to claim 1, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt, characterized in that: The compound has any of the following structures: in, Selected from Selected from Selected from R 4 for R 5 is hydrogen or methyl; R 8 With R 6 Together with the atoms they are connected to form a C 3-8 Cycloalkyl or 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted with 1, 2 or 3 R X Substituent substitution; R 9 is hydrogen; or R 9 With R 6 Together with the atoms they are connected to form a C 3-8 Cycloalkyl or 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted with 1, 2 or 3 R X Substituent substitution; R 8 is hydrogen; R X As defined in claim 1.

57. The following compound, or its isotope-labeled substance, stereoisomer, or pharmaceutically acceptable salt:

58. A pharmaceutical composition comprising the compound of any one of claims 1-57, or its isotope-labeled substance, stereoisomer, pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier.

59. Use of the compound of any one of claims 1-57, or its isotope-labeled substance, stereoisomer, pharmaceutically acceptable salt, or the pharmaceutical composition of claim 58 in the preparation of a medicament for treating, ameliorating or preventing a disease or condition responsive to inhibition of GLP-1R.

60. Use of the compound of any one of claims 1-57, or its isotope-labeled substance, stereoisomer, pharmaceutically acceptable salt, or the pharmaceutical composition of claim 58 in the preparation of a medicament for treating, ameliorating or preventing a GLP-1R-mediated disease or condition or regulating GLP-1R.

61. The use according to claim 59 or 60, characterized in that The diseases or conditions include diabetes, diabetic complications, obesity, impaired glucose tolerance, overweight, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, arrhythmia, cerebral infarction, stroke, liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, dementia, Parkinson's disease and diabetic nephropathy.

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