Imidazol-2-one derivative and pharmaceutical use thereof

Abstract

Provided in the present invention are an imidazol-2-one derivative and the pharmaceutical use thereof. Specifically provided are a compound of general formula (I) or a racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, an intermediate thereof and a preparation method therefor, and the use thereof in the preparation of related drugs for treating diabetes or obesity.

Description

An imidazole-2-one derivative and its pharmaceutical applications Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a compound of general formula (I) or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, intermediates and preparation methods thereof, and its application in the preparation of drugs for treating diabetes and obesity. Background Technology

[0002] Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia. Hyperglycemia is caused by a deficiency in insulin secretion or impaired biological action, or both. The long-term hyperglycemia in diabetes leads to chronic damage and dysfunction of various tissues, especially the eyes, kidneys, heart, blood vessels, and nerves. It is mainly divided into two types: Type 1 diabetes: Destruction of pancreatic beta cells leads to an absolute lack of insulin. Type 2 diabetes: Primarily characterized by insulin resistance accompanied by a relative lack of insulin, or primarily characterized by impaired insulin secretion accompanied by insulin resistance.

[0003] Drugs for type 2 diabetes can be divided into six classes (insulin, insulin secretagogues, biguanides, glucosidase inhibitors, thiazolidinediones, and SGLT2 inhibitors), each of which works through different primary mechanisms.

[0004] GLP-1 is a 30-amino acid incretin hormone secreted by L cells in the intestine. GLP-1 stimulates insulin secretion in a physiological and glucose-dependent manner, reduces glucagon secretion, inhibits gastric emptying, reduces appetite, and stimulates β-cell proliferation. In non-clinical studies, GLP-1 promotes β-cell sustainability by stimulating the transcription of key genes involved in glucose-dependent insulin secretion and promoting β-cell regeneration. In healthy individuals, GLP-1 plays a crucial role in regulating postprandial blood glucose by stimulating glucose-dependent insulin secretion from the pancreas, leading to increased peripheral glucose uptake. GLP-1 also inhibits glucagon secretion, resulting in reduced hepatic glucose output. Furthermore, GLP-1 delays gastric emptying, slows small intestinal motility, and slows food absorption. Summary of the Invention

[0005] The purpose of this invention is to provide a compound that can activate the GLP-1 receptor, or its racemic, stereoisomer, tautomer, pharmaceutically acceptable salt, intermediates, and preparation method thereof, and its use in the preparation of drugs for treating diabetes or obesity.

[0006] The compounds of this invention have good pharmacokinetic properties and bioavailability, oral applicability, and good safety.

[0007] This invention provides a compound or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein the compound is selected from compounds represented by general formula (IA), wherein...

[0008] In some embodiments, the compound represented by formula (IA) is selected from formula (I).

[0009] In some embodiments, the compound represented by formula (I) is selected from the compounds represented by formulas (Ic) or (Id).

[0010] The compound represented by general formula (IA) is selected from the compound represented by general formula (Ia), (Ib), (Ie), (If), (Ig), and (Ih).

[0011] In some implementation schemes, k is selected from 0, 1, 2, 3, and 4;

[0012] In some implementation schemes, R k1 Each is independently selected from deuterium, F, Cl, methyl, ethyl, and CD3;

[0013] In some implementation schemes, R k2 Selected from H and deuterium;

[0014] In some implementation schemes, R k3 Selected from H and deuterium;

[0015] In some implementation schemes, R k4 Selected from H and deuterium;

[0016] In some implementations, p1 is selected from 0, 1, 2, 3, 4, or 5;

[0017] In some implementations, p2 is selected from 1 or 2;

[0018] In some implementations, p3 is selected from 0, 1, 2, 3, or 4;

[0019] In some implementation schemes, Indicates a single bond or a double bond;

[0020] In some implementation schemes, R f Selected from deuterium, CD3, and CH3;

[0021] In some implementations, T is selected from bonds, O, S, CH2, CH2CH2, CH2O, OCH2, CH2NH, NHCH2, CH2NHCH2, CH2OCH2;

[0022] In some implementations, Z1 is selected from O, S, NH or NR. 5d ;

[0023] In some implementations, Y is selected from C and N, Z is selected from CH or N, J is selected from N or C, and at least one of Y, Z, and J is selected from N;

[0024] In some implementations, Y is selected from C, Z is selected from N, and J is selected from N;

[0025] In some implementations, ring A is selected from C. 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Carbocyclic groups, 4- to 10-membered heterocyclic groups, C 11-15 aryl, 11 to 15-membered heterocyclic, 11 to 15-membered heteroaryl, wherein ring A is optionally surrounded by 1 to 5 R groups. a Alternatively, the nitrogen atom on the heteroaryl or heterocyclic group may be oxidized to form a nitrogen oxide;

[0026] In some implementations, ring A is selected from C. 6-10 aryl, 5 to 10-membered heteroaryl, wherein the ring A is optionally surrounded by 1 to 5 R groups. a replace;

[0027] In some embodiments, ring A is selected from phenyl, 5- to 6-membered heteroaryl, and said ring A is optionally surrounded by 1 to 5 R groups. a replace

[0028] In some embodiments, ring A is selected from phenyl, 5- to 6-membered heteroaryl, C 3-6 Monocyclic cycloalcohols, 4- to 8-membered monoheterocyclic cycloalcohols, benzo[a]C 7-8 A carbocyclic group, wherein ring A is optionally divided by 1 to 5 R groups. a Alternatively, the nitrogen atom on the heteroaryl or heterocyclic group may be oxidized to form a nitrogen oxide;

[0029] In some implementations, ring A is selected from 1 to 5 Rs. a The substituted group may be one of the following: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidine, piperidinyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, 1,3-dioxopentyl, 1,4-dioxohexyl, piperazine, morpholinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyrroleyl, thiophene, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, triazinyl,

[0030] In some embodiments, ring A is selected from phenyl, pyridyl, and Imidazole, pyrazol, thiazolyl, thiadiazole, oxazol, oxadiazole, or triazole, wherein ring A is optionally surrounded by 1 to 5 R groups.a replace;

[0031] In some embodiments, ring A is selected from phenyl, and ring A is optionally surrounded by 1 to 5 R atoms. a replace

[0032] In some implementations, ring A is selected from...

[0033] In some implementations, ring A is selected from...

[0034] In some implementation schemes, Selected from

[0035] In some implementations, ring A is selected from...

[0036] In some implementation schemes, Selected from k is selected from 0, 1, 2, 3, and 4;

[0037] R k1 Each element is independently selected from deuterium, F, Cl, methyl, ethyl, CD3. In some embodiments, ring B is selected from C. 6-10 Aryl, 5- to 6-membered heteroaryl, 5-5-membered heteroaryl, 5-6-membered heteroaryl, 6-6-membered heteroaryl, C 3-10 Carbocyclic groups, 4- to 10-membered heterocyclic groups, wherein ring B is optionally divided by 1 to 4 R groups. b replace;

[0038] In some embodiments, ring B is selected from 5-5-membered heteroaryl or 5-6-membered heteroaryl, wherein ring B is optionally surrounded by 1 to 4 R groups. b replace;

[0039] In some embodiments, ring B is selected from pyrrolothiophene, pyrrolopyrazol, pyrrolopyrrole, pyrroloimidazolyl, pyrrolothiophene, imidazothiophene, imidazoimidazolyl, pyrrolopyrazol, pyrrolothiazolyl, pyrrolofuranyl, indolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolotriazinyl, pyrrolophenyl, pyrrolopyridyl, pyrrolopyrimidinyl, imidazophenyl, imidazopyridyl, imidazopyrimidinyl, thiophenopyridyl, thiophenophenyl, furanopyridyl, furanophenyl, and said ring B is optionally surrounded by 1 to 4 R b replace;

[0040] In some implementations, ring B is selected from 1 to 4 Rs. bOne of the following groups is substituted:

[0041] Its right side is connected to Q;

[0042] In some implementations, ring B is selected from 1 to 4 Rs. b One of the following groups is substituted: Its right side is connected to Q;

[0043] In some implementation schemes, ring B is selected from... The ring B is arbitrarily divided by 1 to 4 Rs. b Replace it, and its right side is connected to Q;

[0044] In some implementation schemes, ring B is selected from... The ring B is arbitrarily divided by 1 to 4 Rs. b Replace it, and its right side is connected to Q;

[0045] In some implementation schemes, ring B is selected from... The ring B is arbitrarily divided by 1 to 4 Rs. b Replace it, and its right side is connected to Q;

[0046] In some implementation schemes, ring B is selected from... The ring B is arbitrarily divided by 1 to 4 Rs. b Replace it, and its right side is connected to Q;

[0047] In some embodiments, ring D is selected from benzo4- to 6-membered heterocyclic groups, 11- to 12-membered tricyclic heterocyclic groups, 13- to 16-membered tricyclic or tetracyclic heterocyclic groups, and 17- to 30-membered tricyclic or tetracyclic heterocyclic groups, wherein ring D is optionally surrounded by 1 to 6 R groups. d replace;

[0048] In some implementations, ring D is selected from... The ring D is arbitrarily divided by 1 to 4 Rs. d Replacement; and L1 is selected from -C(=S)-;

[0049] In some embodiments, ring D is selected from partially saturated rings such as: 11- to 12-membered tricyclic heterocyclic groups, 13- to 15-membered tricyclic heterocyclic groups, and 10-membered fused carbon cyclospirocyclic groups. 4-6 Carbon ring, 9-membered carbon ring screw C 4-6 Carbon ring, 11-membered carbon ring screw C 3-5 Carbon ring, 10-membered heterocyclic spiral C 4-6 Carbon ring, 11-membered heterocyclic spiral C 3-5 Carbon ring, 10-membered carbon ring screw with 4-6-membered heterocyclic ring, 11-membered carbon ring screw with 4-5-membered heterocyclic ring, 9-membered heterocyclic screw with 4-6-membered heterocyclic ring, 9-membered heterocyclic screw with 8-10-membered heterocyclic ring, 9-membered heterocyclic screw C3-6 Carbon ring, 10-membered mixed ring screw with 4 to 6-membered mixed ring, 11-membered mixed ring screw with 4 to 5-membered mixed ring, 11-membered mixed three-ring screw C 3-4 Carbon ring, wherein ring D is optionally divided by 1 to 4 R d replace;

[0050] In some implementations, ring D is selected from... The ring D is arbitrarily divided by 1 to 4 Rs. d replace;

[0051] In some implementations, ring D is selected from... The ring D is arbitrarily divided by 1 to 4 Rs. d replace;

[0052] In some implementations, ring D is selected from... The ring D is arbitrarily divided by 1 to 4 Rs. d Replacement; and L1 is selected from -C (=S)-; in some embodiments, ring D is selected from The ring D is arbitrarily divided by 1 to 4 Rs. d replace;

[0053] In some implementations, ring D is selected from... The ring D is arbitrarily divided by 1 to 4 Rs. d Replacement; in some implementations, ring D is selected from The ring D is arbitrarily divided by 1 to 4 Rs. d replace;

[0054] In some implementations, ring D is selected from... T is selected from bond, O, S, CH2, CH2CH2, CH2O, OCH2, CH2NH, NHCH2, CH2NHCH2, CH2OCH2, and Z1 is selected from O, S, NH, or NR. 5d The ring D is arbitrarily divided by 1 to 4 Rs. d replace;

[0055] In some implementations, ring D is selected from... T is selected from bonds, O, S, CH2, CH2CH2, CH2O, OCH2, CH2NH, NHCH2, CH2NHCH2, CH2OCH2, and the ring D is optionally bounded by 1 to 4 Rs. d replace;

[0056] In some implementations, ring D is selected from... T is selected from bond, O, S, CH2, NH or NR. d3 ;

[0057] In some implementations, ring D is selected from... The ring D is arbitrarily divided by 1 to 4 Rs. d Replacement; and L1 is selected from -C(=S)-;

[0058] In some implementations, ring D is selected from... R d1 Selected from H or R d R d2 Selected from H or R d ;

[0059] In some implementations, ring D is selected from...

[0060] In some implementations, ring D is selected from... R d1 Selected from H or R d R d2 Selected from H or R d R d3 Selected from H or R d ;

[0061] In some implementations, ring D is selected from... The ring D is arbitrarily divided by 1 to 4 Rs. d replace;

[0062] In some implementations, ring D is selected from... In some implementations, ring D1 is selected from...

[0063] In some implementations, ring D is selected from... The ring D is arbitrarily divided by 1 to 4 Rs. d replace;

[0064] In some implementations, ring D1 is selected from...

[0065] In some implementations, Q is selected from bonds, O, S, NH, C. 1-4 Alkylene The alkylene group is optionally surrounded by 1 to 4 R groups. k replace;

[0066] In some implementations, Q is selected from bonds, O, S, NH, CH2, CH(CH3),

[0067] In some implementations, Q is selected from the key;

[0068] In some implementation schemes, R 6 Selected from C 1-6 Alkyl, -C 1-2 Alkylene-OC 1-4 Alkyl, C 3-10 Carbocyclic groups, 4- to 10-membered heterocyclic groups, the R 6 Choose from 1 to 10 R 6a replace;

[0069] In some implementation schemes, R 6 Selected from C 1-4 Alkyl, -C 1-2 Alkylene-OC 1-4 Alkyl, C 3-6 Single carbon cyclo group, C 6-10 And carbon cyclo group, C 6-10 Spirocarbon cyclo group, C 5-10 Bridged carbocyclic groups, 4- to 8-membered monoheterocyclic groups, 7- to 10-membered fused heterocyclic groups, 7- to 10-membered spiroheterocyclic groups, and 6- to 10-membered bridged heterocyclic groups, wherein R 6 Choose from 1 to 10 R 6a replace;

[0070] In some implementation schemes, R 6 Selected from 4- to 8-membered monoheterocyclic groups, the R 6 Choose from 1 to 10 R 6a replace;

[0071] In some implementation schemes, R 6 Selected from oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, aziroxybutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, wherein R 6 Choose from 1 to 10 R 6a replace;

[0072] In some implementation schemes, R 6Selected from methyl, ethyl, propyl, isopropyl, -CH2O-CH3, -CH2O-CH2CH3, -CH2O-CH(CH3)2, -CH2O-C(CH3)3, -CH2CH2O-CH3, -CH2CH2O-CH2CH3, -CH2CH2O-CH(CH3)2, -CH2CH2O-C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]cyclopentyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aziridine, pyrrolyl, piperidinyl, piperazine, morpholinyl, phenyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, pyrroleyl, thiophene, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or The R mentioned 6 Choose from 1 to 10 R 6a replace;

[0073] In some implementations, -QR 6 Selected from one of the following groups that may be substituted: ethyl, propyl, isopropyl, -CH2CH2CH2O-CH2CH3, -CH2CH2CH2O-CH(CH3)2, -CH2CH2CH2O-C(CH3)3, When substituted, it is replaced by 1 to 10 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy, or ethoxy; in some embodiments, R 6a Selected from deuterium, F, Cl, Br, I, =O, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl,

[0074] In some implementation schemes, R 6a Selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl,

[0075] In some implementations, -QR 6 Selected from one of the following groups that are substituted: When substituted, it is replaced by 1 to 10 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy, or ethoxy.

[0076] In some implementations, -QR 6 Selected from one of the following groups that are substituted:

[0077] In some implementations, -QR 6 Selected from optional replacements When substituted, it is replaced by 1 to 10 substituents selected from deuterium, F, Cl, Br, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy, or ethoxy.

[0078] In some implementations, -QR 6 Selected from

[0079] In some implementation schemes, R 7 Selected from H or deuterium, with H preferred;

[0080] In some implementation schemes, R 8 Selected from H or deuterium, with H preferred;

[0081] In some implementations, L1 is selected from -S(=O)2-, -C(=O)-, and -C(=S)-;

[0082] In some implementations, L1 is selected from -C(=O)- and -C(=S)-;

[0083] In some implementations, L1 is selected from -C(=O)- and -C(=S)-;

[0084] In some implementations, L2 is selected from -(CR L1 R L2 ) m -;

[0085] In some implementations, L2 is selected from -(CR L1 R L2 )-、-(CR L1 R L2 )2-;

[0086] In some implementations, L2 is selected from -CR L1 R L2 -or can be chosen by 1 to 4 Rsk One of the following groups is substituted:

[0087] In some implementations, L2 is selected from

[0088] In some implementations, L2 is selected from

[0089] In some implementations, X is selected from S or O, preferably O;

[0090] In some implementations, m is selected from 1, 2, 3 or 4, preferably 1;

[0091] In some implementation schemes, R 4 Selected from -C(=O)R 4a -C(=O)OR 4a -C(=O)NR 4a R 4b , In some implementation schemes, R 4 Selected from -C(=O)OH, -C(=O)OCH3, -C(=O)N(CH3)2, In some implementation schemes, R 4 Selected from

[0092] In some implementation schemes, R 4a R 4b R 4c R 4d R 4e R 4f Each element is independently selected from H, deuterium, and C. 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0093] In some implementation schemes, R 4a R 4b R 4c R 4d R 4e R 4f Each element is independently selected from H, deuterium, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0094] In some implementation schemes, R 4a R 4b R 4c R4d R 4e R 4f Each is independently selected from H, deuterium, methyl, ethyl, propyl, and isopropyl;

[0095] In some implementation schemes, R a R b R d R 6a Each element is independently selected from H, deuterium, halogens, =O, =S, CN, OH, NO2, COOH, CONH2, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic groups, -O-3 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-3 to 7-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 Alkyl-3 to 7-membered heterocyclic groups, -P(=O)R 5a R 5b -S (=O) 1-2 -R 5c -C(=O)R 5c =NR 5d -NH-R 5d -C(=O)NHR 5c C 3-6 Carbocyclic, 3- to 7-membered heterocyclic, wherein the alkyl, alkylene, alkenyl, ynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0096] In some implementation schemes, R a R b R d R 6a Each element is independently selected from H, deuterium, halogens, =O, =S, CN, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocyclic groups, -O-3 to 7-membered heterocyclic groups, -NH-C 3-6Carbocyclic groups, -NH-3 to 7-membered heterocyclic groups, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkyl-3 to 7-membered heterocyclic groups, -P(=O)R 5a R 5b -S (=O) 1-2 -R 5c -C(=O)R 5c -C(=O)NHR 5c C 3-6 Carbocyclic, 3 to 7-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0097] In some implementation schemes, R a R b R d R 6a Each element is independently selected from H, deuterium, F, Cl, Br, I, =O, =S, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, -P(=O)R 5a R 5b -C(=O)R 5c , -C(=O)CH3, -C(=O)CH2CH3, or optionally 1 to 3 R's k The substitution may be one of the following groups: methyl, ethyl, propyl, isopropyl, butyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, isopropoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylspirocyclobutyl, cyclopentylspirocyclobutyl, cyclopentylspirocyclopentyl, cyclohexylspirocyclobutyl, cyclohexylspirocyclohexyl, aziridine, oxacyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinylspirocyclohexyl, -C(=O)NHCH3, -C(=O)NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-aziridine, -CH2-piperidinyl, -C(=O)NHR 5c ;

[0098] In some implementation schemes, R a R b R 6a Each element is independently selected from H, deuterium, halogens, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 C-cyclohexane 3-6The alkyl group or carbocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0099] In some implementation schemes, R a R b R 6a Each element is independently selected from H, deuterium, halogens, and C. 1-4 Alkyl-OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 C-cyclohexane 3-6 The alkyl or carbocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0100] In some implementation schemes, R a R b R 6a Each element is independently selected from H, deuterium, F, Cl, Br, or arbitrarily selected from 1 to 3 R. k The substitution may be made with one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, or cyclopropyl;

[0101] In some implementation schemes, R d Each element is independently selected from H, deuterium, halogens, =O, =S, CN, OH, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 carbonyl group, =NR 5d -NH-R 5d C 3-6 The carbocyclic group, wherein the alkyl, alkylene, or carbocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0102] In some implementation schemes, R d Each element is independently selected from H, deuterium, halogens, =O, =S, CN, OH, and C. 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 carbonyl group, =NR 5d -NH-R 5d C 3-6 The carbocyclic group, wherein the alkyl, alkylene, or carbocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0103] In some implementation schemes, R d Each element is independently selected from H, deuterium, halogens, =O, =S, CN, OH, and C. 1-4 Alkyl, -OC1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 carbonyl group, C 3-6 The carbocyclic group, wherein the alkyl, alkylene, or carbocyclic group is optionally selected from one to four deuterium, halogen, CN, C 1-4 Alkyl or C 1-4 Substituents of alkoxy groups

[0104] In some implementation schemes, R d Choose from 1 to 3 Rs k Replace, R k Selected from R k1 ;

[0105] In some implementation schemes, R a Each of these groups is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, -CH2OH, -CH2CH2OH, -CH2CN, -CH2N(CH3)2, -CH2-cyclopropyl. Preferably, R a Each element is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, methoxy, cyclopropyl.

[0106] In some implementation schemes, R a Each element is independently selected from deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, methoxy, cyclopropyl.

[0107] In some implementation schemes, R b Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, and cyclopropyl.

[0108] In some implementation schemes, R bEach group is independently selected from deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, and cyclopropyl.

[0109] In some implementation schemes, R d Each is independently selected from deuterium, F, Cl, Br, I, =O, =S, CN, OH, NH2, NH(CH3), N(CH3)2, CD3, -CH2CH2OCH3, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CH2CH2F, -OCH2CH2OH, -C(=O)NHCH3, -C(=O)NH-cyclopropyl, Or choose 1 to 4 Rs k1 The substitution may be made with one of the following groups: methyl, ethyl, methoxy, ethoxy, cyclopropyl, oxetyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-oxetyl, -CH2-azacyclobutyl, -S(=O)2CH3, -S(=O)2cyclopropyl, -C(=O)NH-cyclopropyl, -C(=O)CH3, -C(=O)-vinyl, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O) -Cyclopentyl, -C(=O)-bicyclo[2.2.1]heptyl, -C(=O)-bicyclo[1.1.1]pentyl, -C(=O)-cyclobutylspirobutyl, -C(=O)-oxetanebutyl, -C(=O)-tetrahydrofuranyl, -C(=O)-oxetanehexyl, -C(=O)-azacyclobutyl, -C(=O)-pyrrolidinyl, -C(=O)-piperidinyl, -C(=O)-piperazinyl, -C(=O)-pyrazolyl, -C(=O)-phenyl;

[0110] R k1 Selected from deuterium, F, Cl, Br, OH, CN, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, -CH2-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or The methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, -CH2-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, CH2CN, methyl, ethyl, methoxy, or ethoxy groups;

[0111] In some implementation schemes, Rd Each is independently selected from deuterium, F, Cl, Br, I, =O, =S, CN, OH, NH2, NH(CH3), N(CH3)2, CHF2, CH2F, CF3, CD3, methyl, ethyl, methoxy, ethoxy, cyclopropyl, oxetyl, -CH2-cyclopropyl, -CH2-oxetyl, -C(=O)CH3, -C(=O)NHCH3, -C(=O)NH-cyclopropyl,

[0112] In some implementation schemes, R d Each of the following groups is independently selected from deuterium, F, Cl, Br, I, CN, OH, CHF2, CH2F, CF3, CD3, methyl, ethyl, methoxy, ethoxy, and cyclopropyl.

[0113] In some implementation schemes, R d1 Selected from H, CHF2, CD3, methyl, cyclopropyl, oxetyl, -CH2-cyclopropyl, -CH2-oxetyl;

[0114] In some implementation schemes, R d2 Selected from H, deuterium, F, Cl, Br, CHF2, CD3, methyl, cyclopropyl, oxetyl, -CH2-cyclopropyl, -CH2-oxetyl;

[0115] In some implementation schemes, R d3 Selected from H or methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-oxacyclobutyl, -CH2-tetrahydrofuranyl, -CH2-azacyclobutyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -S(=O) 1-2 -R 5c -C(=O)R 5c The methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-oxacyclobutyl, -CH2-tetrahydrofuranyl, -CH2-azacyclobutyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl group is optionally surrounded by 1 to 4 R groups. k Replace (R) k Preferably, each is independently selected from deuterium, F, Cl, Br, CN, OH, CHF2, CD3, methyl, ethyl, propyl, isopropyl, cyclopropyl, oxetine, -CH2-cyclopropyl, -CH2-oxetine, methoxy, methoxymethyl, methoxyethyl, CH2CN, vinyl, ), the R 5c Choose from 1 to 4 Rsk Replace (R) k Preferably, each element is independently selected from deuterium, F, Cl, Br, CN, OH, CHF2, CD3, methyl, ethyl, propyl, isopropyl, cyclopropyl, oxetyl, -CH2-cyclopropyl, -CH2-oxetyl, methoxy, methoxymethyl, methoxyethyl, CH2CN, vinyl, propenyl. );

[0116] In some implementation schemes, R 5a R 5b R 5c Each independently selected from C 1-6 Alkyl, -C 1-4 Alkyl-OC 1-4 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 3-12 A carbocyclic group, a 4- to 12-membered heterocyclic group, wherein the alkyl, alkenyl, alkoxy, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0117] In some implementation schemes, R 5a R 5b R 5c Each independently selected from C 1-4 Alkyl, -C 1-4 Alkyl-OC 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 3-6 cycloalkyl, C 5-8 Bridged cycloalkyl, C 5-11 Spirocycloalkyl, C 5-11 Circocycloalkyl, 4- to 7-membered monocyclic heterocycloalkyl, 6- to 10-membered bridged heterocycloalkyl, 6- to 11-membered spirocyclic heterocycloalkyl, 6- to 11-membered circocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace;

[0118] In some implementation schemes, R 5c Selected from 1 to 4 Rs kThe substitution may be made with one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyridine, piperidinyl, piperazine, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, oxacyclohexyl, phenyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyrazinyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, cyclopropylspirocyclobutyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylcyclopentyl, 3-oxabicyclo[3.1.0]hexyl, thienyl, furanyl, thiazolyl, oxazolyl, methoxymethyl, ethoxymethyl;

[0119] In some implementation schemes, R 5c Selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclobutyl, pyrrolyl, piperidinyl, piperazine, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, oxacyclohexyl, phenyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyridinyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, cyclopropylspirocyclobutyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylcyclopentyl, 3-oxabicyclo[3.1.0]hexyl, thienyl, furanyl, thiazolyl, oxazolyl, methoxymethyl, ethoxymethyl, wherein R 5c The following compounds are optionally selected from 1 to 4: deuterium, F, Cl, Br, CN, OH, CHF2, CD3, methyl, ethyl, propyl, isopropyl, cyclopropyl, oxetyl, -CH2-cyclopropyl, -CH2-oxetyl, methoxy, methoxymethyl, methoxyethyl, CH2CN, vinyl, propenyl. The substituents are replaced;

[0120] In some implementation schemes, R 5d Selected from CN, OH, -OC 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0121] In some implementation schemes, R 5d Selected from CN, OH, -OC 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0122] In some implementation schemes, R 5d Selected from CN, OH, methoxy, or ethoxy;

[0123] In some implementation schemes, R5a R 5b Each of the following is independently selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group is optionally marked with 1 to 3 R groups. k replace;

[0124] In some implementation schemes, R 1 R 2 R 3 R L1 R L2 Each element is independently selected from H, deuterium, halogens, CN, OH, NO2, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, wherein the alkyl, alkenyl, or ynyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0125] In some implementation schemes, R 1 R 2 R 3 R L1 R L2 Each element is independently selected from H, deuterium, halogens, CN, OH, NO2, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, wherein the alkyl, alkenyl, or ynyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0126] In some implementation schemes, R 1 R 2 R 3 R L1 R L2 Each element is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, or optionally influenced by 1 to 3 R atoms. k The substituted group is one of the following: methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio;

[0127] In some implementation schemes, R 1R 2 R 3 Each of the following is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, CD3, OCD3, CF3, CH2F, CHF2, CH2OH, OCF3, OCHF2, OCH2F, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio, preferably, R 1 Selected from H; preferably, R 2 Selected from H, methyl, or CD3; preferably, R 3 Selected from H, methyl, or CD3;

[0128] In some implementation schemes, R 1 R 2 Selected from H;

[0129] In some implementation schemes, R 3 Selected from C 1-6 Alkyl, preferably C 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0130] In some implementation schemes, R 3 Selected from methyl and ethyl;

[0131] In some implementation schemes, R L1 R L2 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, methyl, ethyl, methoxy, ethoxy, isopropoxy, and methylthio.

[0132] In some implementation schemes, R L1 R L2 Together with the atoms connected to it, they form C 3-8 Carbon rings or 4- to 8-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace;

[0133] In some implementation schemes, R L1 R L2 Together with the adjacent carbon atoms, they form C 3-6 Carbon rings or 4- to 6-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace;

[0134] In some implementation schemes, R L1 R L2 Together with the atoms connected to it, they form C 3-8 Carbon ring, wherein the carbon ring is optionally divided by 1 to 4 R k replace;

[0135] In some implementation schemes, R L1 R L2 Together with the adjacent carbon atoms, they form C 3-6 Carbon ring, wherein the carbon ring is optionally divided by 1 to 4 R k replace;

[0136] In some implementation schemes, R L1 R L2 Together with the adjacent carbon atoms, they form optional groups of 1 to 4 R atoms. k The following groups are substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidinyl, piperidinyl, oxacyclobutyl, tetrahydrofuranyl;

[0137] In some implementation schemes, R 5a R 5b Together with the attached phosphorus atom, they form a 5- to 8-membered heterocycle, which is optionally surrounded by 1 to 4 R atoms. k replace;

[0138] In some implementation schemes, R 5a R 5b Together with the attached phosphorus atom, they form a 5- to 8-membered monoheterocycle, which is optionally surrounded by 1 to 4 R atoms. k Replace; in some implementations, R 5a R 5b Together with the attached phosphorus atoms, they form an array optionally bounded by 1 to 3 R atoms. k The following groups are substituted:

[0139] In some implementation schemes, R k Each is independently selected from deuterium, halogens, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic groups, -O-3 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-3 to 7-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 alkylene-3 to 7-membered heterocyclic groups, C 3-6 Carbocyclic groups, 3- to 7-membered heterocyclic groups, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic groups are optionally selected from one to four groups chosen from deuterium, halogen, CN, OH, NH2, CH2CN, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0140] In some implementation schemes, R k Each element is independently selected from deuterium, halogens, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, and C. 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -OC 3-6 Carbocyclic groups, -O-3 to 6-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-3 to 6-membered heterocyclic groups, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 alkylene-3 to 6-membered heterocyclic groups, C 3-6 Carbocyclic groups, 3- to 6-membered heterocyclic groups, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic groups are optionally selected from one to four groups chosen from deuterium, halogen, CN, OH, NH2, CH2CN, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0141] In some implementation schemes, R k Each is independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrroleyl, morpholinyl. The methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrroleyl, and morpholinyl groups are optionally selected from 1 to 4 of the following: deuterium, F, Cl, Br, I, CN, OH, NH2, CH2CN, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0142] In some implementation schemes, R k Each is independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrroleyl, morpholinyl. The methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, aziroxybutyl, oxacyclobutyl, pyrrolyl, piperidinyl, pyrazolyl, pyrrolithyl, and morpholinyl groups are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, CH2CN, methyl, ethyl, methoxy, and ethoxy groups;

[0143] In some implementation schemes, R k Selected from R k1 ;

[0144] In some implementation schemes, R k1 Selected from deuterium, F, Cl, Br, OH, CN, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, -CH2-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl The methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, -CH2-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, CH2CN, methyl, ethyl, methoxy, or ethoxy groups;

[0145] In some implementation schemes, R k Each of the groups is independently selected from deuterium, F, Cl, Br, methyl, and ethyl, wherein the methyl and ethyl groups are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, CH2CN, methyl, ethyl, methoxy, and ethoxy.

[0146] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or general formula (IA), or its racemic mixture, stereoisomer, tautomer, or pharmaceutically acceptable salt, is used.

[0147] Indicates a single bond or a double bond;

[0148] Y is selected from C and N, Z is selected from CH or N, J is selected from N or C, and at least one of Y, Z, and J is selected from N;

[0149] Ring A is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Carbocyclic groups, 4- to 10-membered heterocyclic groups, C 11-15 aryl, 11 to 15-membered heterocyclic, 11 to 15-membered heteroaryl, wherein ring A is optionally surrounded by 1 to 5 R groups. a Alternatively, the nitrogen atom on the heteroaryl or heterocyclic group may be oxidized to form a nitrogen oxide;

[0150] Ring B is selected from C 6-10 Aryl, 5- to 6-membered heteroaryl, 5-5-membered heteroaryl, 5-6-membered heteroaryl, 6-6-membered heteroaryl, C 3-10 Carbocyclic groups, 4- to 10-membered heterocyclic groups, wherein ring B is optionally divided by 1 to 4 R groups. b replace;

[0151] Ring D is selected from benzo4- to 6-membered heterocyclic groups, 11- to 12-membered tricyclic heterocyclic groups, 13- to 16-membered tricyclic or tetracyclic heterocyclic groups, and 17- to 30-membered tricyclic or tetracyclic heterocyclic groups, wherein ring D is optionally surrounded by 1 to 6 R groups. d replace;

[0152] L1 is selected from -S(=O)2-, -C(=O)-, and -C(=S)-;

[0153] L2 is selected from -(CR) L1 R L2 ) m -;

[0154] X is selected from S or O;

[0155] Q is selected from bonds, O, S, NH, C. 1-4 Alkylene The alkylene group is optionally surrounded by 1 to 4 R groups. k replace;

[0156] m is selected from 1, 2, 3, or 4;

[0157] R 4 Selected from -C(=O)R 4a -C(=O)OR 4a -C(=O)NR 4a R 4b ,

[0158] R 4a R 4b R4c R 4d R 4e R 4f Each element is independently selected from H, deuterium, and C. 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0159] R 6 Selected from C 1-6 Alkyl, -C 1-2 Alkylene-OC 1-4 Alkyl, C 3-10 Carbocyclic groups, 4- to 10-membered heterocyclic groups, the R 6 Choose from 1 to 10 R 6a replace;

[0160] R a R b R d R 6a Each element is independently selected from H, deuterium, halogens, =O, =S, CN, OH, NO2, COOH, CONH2, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic groups, -O-3 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-3 to 7-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 Alkyl-3 to 7-membered heterocyclic groups, -P(=O)R 5a R 5b -S (=O) 1-2 -R 5c -C(=O)R 5c -C(=O)NHR 5c =NR 5d -NH-R 5d C 3-6 Carbocyclic, 3- to 7-membered heterocyclic, wherein the alkyl, alkylene, alkenyl, ynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0161] R 5a R 5b R 5c Each independently selected from C 1-6 Alkyl, -C 1-4Alkyl-OC 1-4 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 3-12 A carbocyclic group, a 4- to 12-membered heterocyclic group, wherein the alkyl, alkenyl, alkoxy, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replace; R 5d Selected from CN, OH, -OC 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0162] R 1 R 2 R 3 R L1 R L2 Each element is independently selected from H, deuterium, halogens, CN, OH, NO2, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, wherein the alkyl, alkenyl, or ynyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0163] As an option, R L1 R L2 Together with the atoms connected to it, they form C 3-8 Carbocyclic or 4- to 8-membered heterocyclic groups, wherein the carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0164] As an option, R 5a R 5b Together with the attached phosphorus atom, they form a 5- to 8-membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0165] R k Each is independently selected from deuterium, halogens, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic groups, -O-3 to 7-membered heterocyclic groups, -NH-C 3-6Carbocyclic groups, -NH-3 to 7-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 alkylene-3 to 7-membered heterocyclic groups, C 3-6 Carbocyclic groups, 3- to 7-membered heterocyclic groups, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic groups are optionally selected from one to four groups chosen from deuterium, halogen, CN, OH, NH2, CH2CN, C 1-6 Alkyl, C 1-6 The alkoxy group is replaced by a substituent.

[0166] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I), or its racemic mixture, stereoisomer, tautomer, or pharmaceutically acceptable salt, is used.

[0167] Cycle B is selected from 5-5-membered heteroaryl or 5-6-membered heteroaryl, wherein cycle B is optionally surrounded by 1 to 4 R groups. b replace;

[0168] Ring D is selected from The ring D is arbitrarily divided by 1 to 4 Rs. d replace;

[0169] Ring D is selected from The ring D is arbitrarily divided by 1 to 4 Rs. d Replacement; and L1 is selected from -C(=S)-;

[0170] Ring A is selected from phenyl, 5- to 6-membered heteroaryl, C 3-6 Monocyclic cycloalcohols, 4- to 8-membered monoheterocyclic cycloalcohols, benzo[a]C 7-8 A carbocyclic group, wherein ring A is optionally divided by 1 to 5 R groups. a Alternatively, the nitrogen atom on the heteroaryl or heterocyclic group may be oxidized to form a nitrogen oxide;

[0171] R 6 Selected from C 1-4 Alkyl, -C 1-2 Alkylene-OC 1-4 Alkyl, C 3-6 Single carbon cyclo group, C 6-10 And carbon cyclo group, C 6-10 Spirocarbon cyclo group, C 5-10 Bridged carbocyclic groups, 4- to 8-membered monoheterocyclic groups, 7- to 10-membered fused heterocyclic groups, 7- to 10-membered spiroheterocyclic groups, and 6- to 10-membered bridged heterocyclic groups, wherein R 6 Choose from 1 to 10 R 6a replace;

[0172] R 4a R4b R 4c R 4d R 4e R 4f Each element is independently selected from H, deuterium, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace

[0173] R a R b R d R 6a Each element is independently selected from H, deuterium, halogens, =O, =S, CN, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocyclic groups, -O-3 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-3 to 7-membered heterocyclic groups, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkyl-3 to 7-membered heterocyclic groups, -P(=O)R 5a R 5b -S (=O) 1-2 -R 5c -C(=O)R 5c -C(=O)NHR 5c C 3-6 Carbocyclic, 3 to 7-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0174] R 5a R 5b R 5c Each independently selected from C 1-4 Alkyl, -C 1-4 Alkyl-OC 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 3-6 cycloalkyl, C 5-8 Bridged cycloalkyl, C 5-11 Spirocycloalkyl, C 5-11Circocycloalkyl, 4- to 7-membered monocyclic heterocycloalkyl, 6- to 10-membered bridged heterocycloalkyl, 6- to 11-membered spirocyclic heterocycloalkyl, 6- to 11-membered circocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace;

[0175] R 5d Selected from CN, OH, -OC 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0176] R 1 R 2 R 3 R L1 R L2 Each element is independently selected from H, deuterium, halogens, CN, OH, NO2, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, wherein the alkyl, alkenyl, or ynyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0177] As an option, R L1 R L2 Together with the adjacent carbon atoms, they form C 3-6 Carbocyclic or 4- to 6-membered heterocyclic groups, wherein the carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0178] As an option, R 5a R 5b Together with the attached phosphorus atom, they form a 5- to 8-membered monoheterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0179] The remaining definitions are the same as those in the first embodiment of the present invention.

[0180] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I), or its racemic mixture, stereoisomer, tautomer, or pharmaceutically acceptable salt, is used.

[0181] Ring B is selected from pyrrolothiophene, pyrrolopyrazol, pyrrolopyrrole, pyrroloimidazolyl, pyrrolothiophene, imidazothiophene, imidazoimidazolyl, pyrrolopyrazol, pyrrolothiazolyl, pyrrolofuranyl, indolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolotriazinyl, pyrrolophenyl, pyrrolopyridyl, pyrrolopyrimidinyl, imidazophenyl, imidazopyridyl, imidazopyrimidinyl, thiophenopyridyl, thiophenophenyl, furanopyridyl, furanophenyl, wherein ring B is optionally surrounded by 1 to 4 R b replace;

[0182] L2 is selected from -(CR) L1 R L2 )-、-(CR L1 R L2 )2-;

[0183] R k Each element is independently selected from deuterium, halogens, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, and C. 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -OC 3-6 Carbocyclic groups, -O-3 to 6-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-3 to 6-membered heterocyclic groups, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 alkylene-3 to 6-membered heterocyclic groups, C 3-6 Carbocyclic groups, 3- to 6-membered heterocyclic groups, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic groups are optionally selected from one to four groups chosen from deuterium, halogen, CN, OH, NH2, CH2CN, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0184] The remaining definitions are the same as those in the first and second embodiments of this invention.

[0185] As a fourth embodiment of the present invention, the compound represented by the above general formula (I), or its racemic mixture, stereoisomer, tautomer, or pharmaceutically acceptable salt, is used.

[0186] Ring B is selected from any 1 to 4 Rs. b One of the following groups is substituted: Its right side is connected to Q;

[0187] Q is selected from bonds, O, S, NH, CH2, CH(CH3).

[0188] R 6 Selected from methyl, ethyl, isopropyl, propyl, -CH2O-CH3, -CH2O-CH2CH3, -CH2O-CH(CH3)2, -CH2O-C(CH3)3, -CH2CH2O-CH3, -CH2CH2O-CH2CH3, -CH2CH2O-CH(CH3)2, -CH2CH2O-C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]cyclopentyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aziridine, pyrrolyl, piperidinyl, piperazine, morpholinyl, phenyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, pyrroleyl, thiophene, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or The R mentioned 6 Choose from 1 to 10 R 6a replace;

[0189] R 4a R 4b R 4c R 4d R 4e R 4f Each is independently selected from H, deuterium, methyl, ethyl, propyl, and isopropyl;

[0190] R a R b R d R 6a Each element is independently selected from H, deuterium, F, Cl, Br, I, =O, =S, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, -P(=O)R 5a R 5b -C(=O)R 5c , -C(=O)CH3, -C(=O)CH2CH3, or optionally 1 to 3 R's kThe substituted group is one of the following: methyl, ethyl, propyl, isopropyl, butyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylspirocyclobutyl, cyclopentylspirocyclobutyl, cyclopentylspirocyclopentyl, cyclohexylspirocyclobutyl, cyclohexylspirocyclopentyl, aziridine, oxacyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinyl Spirocyclohexyl, -C(=O)NHCH3, -C(=O)NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-azacyclobutyl, -CH2-azacyclopentyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-oxacyclobutyl, -CH2-tetrahydrofuranyl, -CH2-oxacyclohexyl, -C(=O)NHR 5c ;

[0191] R 5c Selected from 1 to 4 Rs k The substitution may be made with one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyridine, piperidinyl, piperazine, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, oxacyclohexyl, phenyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyrazinyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, cyclopropylspirocyclobutyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylcyclopentyl, 3-oxabicyclo[3.1.0]hexyl, thienyl, furanyl, thiazolyl, oxazolyl, methoxymethyl, ethoxymethyl;

[0192] R 5a R 5b Each of the following is independently selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group is optionally marked with 1 to 3 R groups. k replace;

[0193] R 5d Selected from CN, OH, methoxy, or ethoxy;

[0194] R 1 R 2 R 3 R L1 R L2 Each element is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, or optionally influenced by 1 to 3 R atoms.k The substituted group is one of the following: methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio;

[0195] As an option, R L1 R L2 Together with the adjacent carbon atoms, they form optional groups of 1 to 4 R atoms. k The following groups are substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidinyl, piperidinyl, oxacyclobutyl, tetrahydrofuranyl;

[0196] As an option, R 5a R 5b Together with the attached phosphorus atoms, they form an array optionally bounded by 1 to 3 R atoms. k The following groups are substituted:

[0197] R k Each is independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrroleyl, morpholinyl. The methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrrolidinyl, and morpholinyl groups are optionally selected from 1 to 4 of the following: deuterium, F, Cl, Br, I, CN, OH, NH2, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0198] The remaining definitions are the same as those in the first, second, and third embodiments of this invention.

[0199] As a fifth embodiment of the present invention, the compound represented by the above general formula (I), or its racemic mixture, stereoisomer, tautomer, or pharmaceutically acceptable salt, is used.

[0200] R 4 Selected from -C(=O)OH, -C(=O)OCH3, -C(=O)N(CH3)2,

[0201] Ring A is selected from 1 to 5 R's.a The substituted group may be one of the following: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidine, piperidinyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, 1,3-dioxopentyl, 1,4-dioxohexyl, piperazine, morpholinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyrroleyl, thiophene, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, triazinyl,

[0202] L2 is selected from -CR L1 R L2 -or can be chosen by 1 to 4 Rs k One of the following groups is substituted:

[0203] R L1 R L2 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, methyl, ethyl, methoxy, ethoxy, isopropoxy, and methylthio.

[0204] R k Each is independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrroleyl, morpholinyl. The methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, aziroxybutyl, oxacyclobutyl, pyrrolyl, piperidinyl, pyrazolyl, pyrrolithyl, and morpholinyl groups are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, CH2CN, methyl, ethyl, methoxy, and ethoxy groups;

[0205] The remaining definitions are the same as those in the first, second, third, and fourth embodiments of this invention.

[0206] As a sixth embodiment of the present invention, the compound represented by the above general formula (I), or its racemic mixture, stereoisomer, tautomer, or pharmaceutically acceptable salt, is used.

[0207] X is selected from O or S;

[0208] L1 is selected from -C(=O)- and -C(=S)-;

[0209] L2 is selected from Preferred

[0210] R 4 Selected from

[0211] Ring A is selected from phenyl, pyridyl, Imidazole, pyrazol, thiazolyl, thiadiazole, oxazol, oxadiazole, wherein ring A is optionally surrounded by 1 to 5 R groups. a Substitution; preferably, ring A is selected from phenyl, said ring A is optionally replaced by 1 to 5 R... a replace;

[0212] Ring B is selected from The ring B is arbitrarily divided by 1 to 4 Rs. b Replace it, and its right side is connected to Q;

[0213] Preferably, ring B is selected from The ring B is arbitrarily divided by 1 to 4 Rs. b Replace it, and its right side is connected to Q;

[0214] -QR 6 Selected from one of the following groups that may be substituted: ethyl, propyl, isopropyl,

[0215] -CH2CH2CH2O-CH2CH3, -CH2CH2CH2O-CH(CH3)2, -CH2CH2CH2O-C(CH3)3, When substituted, it is replaced by 1 to 10 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy, or ethoxy.

[0216] R 6a Selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl,

[0217] Preferably, -QR 6 Selected from one of the following groups that are substituted: When substituted, it is replaced by 1 to 10 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy, or ethoxy.

[0218] Preferably, -QR 6 Selected from optional replacements When substituted, it is replaced by 1 to 10 substituents selected from deuterium, F, Cl, Br, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy, or ethoxy.

[0219] R 1 R 2 R 3 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, CD3, OCD3, CF3, CH2F, CHF2, CH2OH, OCF3, OCHF2, OCH2F, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio;

[0220] Preferably, R 1 Selected from H;

[0221] Preferably, R 2 Selected from H, methyl, or CD3;

[0222] Preferably, R 3 Selected from H, methyl, or CD3;

[0223] R a Each of these groups is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, -CH2OH, -CH2CH2OH, -CH2CN, -CH2N(CH3)2, -CH2-cyclopropyl.

[0224] Preferably, R a Each element is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, methoxy, cyclopropyl.

[0225] Rb Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, and cyclopropyl.

[0226] R d Each is independently selected from deuterium, F, Cl, Br, I, =O, =S, CN, OH, NH2, NH(CH3), N(CH3)2, CHF2, CH2F, CF3, CD3, methyl, ethyl, methoxy, ethoxy, cyclopropyl, oxetyl, -CH2-cyclopropyl, -CH2-oxetyl, -C(=O)CH3, -C(=O)-cyclopropyl, -C(=O)NHCH3, -C(=O)NH-cyclopropyl;

[0227] Preferably, ring A is selected from

[0228] Preferably, Selected from k is selected from 0, 1, 2, 3, 4; R k1 Each is independently selected from deuterium, F, Cl, methyl, ethyl, and CD3;

[0229] Preferably, ring D is selected from...

[0230] R d1 Selected from H, CHF2, CD3, methyl, and cyclopropyl;

[0231] R d2 Selected from H, deuterium, F, Cl, Br, CHF2, CD3, methyl, and cyclopropyl;

[0232] The remaining definitions are the same as those in the first, second, third, fourth, or fifth embodiments of this invention.

[0233] As a seventh embodiment of the present invention, the compound represented by the above general formula (I), or its racemic mixture, stereoisomer, tautomer, or pharmaceutically acceptable salt, is used.

[0234] Indicates a double bond;

[0235] Y is selected from C, Z is selected from N, and J is selected from N;

[0236] Ring A is selected from C 6-10 aryl, 5 to 10-membered heteroaryl, wherein the ring A is optionally surrounded by 1 to 5 R groups. a replace;

[0237] Ring B is selected from C 6-10Aryl, 5- to 6-membered heteroaryl, 5-5-membered heteroaryl, 5-6-membered heteroaryl, 6-6-membered heteroaryl, C 3-10 Carbocyclic groups, 4- to 10-membered heterocyclic groups, wherein ring B is optionally divided by 1 to 4 R groups. b replace;

[0238] Ring D is selected from benzo4- to 6-membered heterocyclic groups, 11- to 12-membered tricyclic heterocyclic groups, 13- to 16-membered tricyclic or tetracyclic heterocyclic groups, and 17- to 30-membered tricyclic or tetracyclic heterocyclic groups, wherein ring D is optionally surrounded by 1 to 6 R groups. d replace;

[0239] L1 is selected from -C(=O)- and -C(=S)-;

[0240] L2 is selected from -(CR) L1 R L2 ) m -;

[0241] X is selected from O;

[0242] Q is selected from key;

[0243] m is selected from 1;

[0244] R 4 Selected from

[0245] R 4d Selected from H;

[0246] R 6 Selected from 4- to 10-membered heterocyclic groups, the R 6 Choose from 1 to 10 R 6a replace;

[0247] R a R b R 6a Each element is independently selected from H, deuterium, halogens, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 C-cyclohexane 3-6 The alkyl group or carbocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0248] R d Each element is independently selected from H, deuterium, halogens, =O, =S, CN, OH, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 carbonyl group, =NR 5d -NH-R 5d C3-6 The carbocyclic group, wherein the alkyl, alkylene, or carbocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0249] R 5d Selected from CN, OH, -OC 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0250] R 1 R 2 Selected from H;

[0251] R 3 Selected from C 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0252] R L1 R L2 Together with the atoms connected to it, they form C 3-8 A carbocyclic group, wherein the carbocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0253] R k Each is independently selected from deuterium, halogens, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic groups, -O-3 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-3 to 7-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 alkylene-3 to 7-membered heterocyclic groups, C 3-6 Carbocyclic groups, 3- to 7-membered heterocyclic groups, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic groups are optionally selected from one to four groups chosen from deuterium, halogen, CN, OH, NH2, CH2CN, C 1-6 Alkyl, C 1-6 The alkoxy group is replaced by a substituent.

[0254] As an eighth embodiment of the present invention, the compound represented by the above general formula (I), or its racemic mixture, stereoisomer, tautomer, or pharmaceutically acceptable salt, is used.

[0255] Cycle B is selected from 5-5-membered heteroaryl or 5-6-membered heteroaryl, wherein cycle B is optionally surrounded by 1 to 4 R groups. b replace;

[0256] Preferably, ring B is selected from pyrrolothiophene, pyrrolopyrazol, pyrrolopyrrole, pyrroloimidazolyl, pyrrolothiophene, imidazothiophene, imidazoimidazolyl, pyrrolothiazolyl, pyrrolothiazolyl, pyrrolofuran, indolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolotriazinyl, pyrrolophenyl, pyrrolopyridyl, pyrrolopyrimidinyl, imidazophenyl, imidazopyridyl, imidazopyrimidinyl, thiophenopyridyl, thiophenophenyl, furanopyridyl, furanophenyl, and optionally divided by 1 to 4 R b replace;

[0257] Ring D is selected from The ring D is arbitrarily divided by 1 to 4 Rs. d replace;

[0258] Or ring D is selected from The ring D is arbitrarily divided by 1 to 4 Rs. d Replacement; and L1 is selected from -C(=S)-;

[0259] Ring A is selected from phenyl, 5- to 6-membered heteroaryl, and said ring A is optionally surrounded by 1 to 5 R groups. a replace;

[0260] R 6 Selected from 4- to 8-membered monoheterocyclic groups, the R 6 Choose from 1 to 10 R 6a replace;

[0261] R a R b R 6a Each element is independently selected from H, deuterium, halogens, and C. 1-4 Alkyl-OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 C-cyclohexane 3-6 The alkyl or carbocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0262] R d Each element is independently selected from H, deuterium, halogens, =O, =S, CN, OH, and C. 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6carbonyl group, =NR 5d -NH-R 5d C 3-6 The carbocyclic group, wherein the alkyl, alkylene, or carbocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0263] R 5d Selected from CN, OH, -OC 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0264] R 3 Selected from C 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0265] R L1 R L2 Together with the adjacent carbon atoms, they form C 3-6 A carbocyclic group, wherein the carbocyclic group is optionally surrounded by 1 to 4 R groups. k replace.

[0266] R k Each element is independently selected from deuterium, halogens, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, and C. 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -OC 3-6 Carbocyclic groups, -O-3 to 6-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-3 to 6-membered heterocyclic groups, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 alkylene-3 to 6-membered heterocyclic groups, C 3-6 Carbocyclic groups, 3- to 6-membered heterocyclic groups, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic groups are optionally selected from one to four groups chosen from deuterium, halogen, CN, OH, NH2, CH2CN, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0267] The definitions of the remaining groups are the same as in the seventh implementation scheme.

[0268] As a ninth embodiment of the present invention, the compound represented by the above general formula (I), or its racemic mixture, stereoisomer, tautomer, or pharmaceutically acceptable salt, is used.

[0269] Ring B is selected from any 1 to 4 Rs. b One of the following groups is substituted: Its right side is connected to Q;

[0270] R 6 Selected from oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, aziroxybutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, wherein R 6 Choose from 1 to 10 R 6a replace;

[0271] R a R b R 6a Each element is independently selected from H, deuterium, F, Cl, Br, or arbitrarily selected from 1 to 3 R. k The substitution may be made with one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, or cyclopropyl;

[0272] R d Each element is independently selected from H, deuterium, F, Cl, Br, or arbitrarily selected from 1 to 3 R. k The substitution may be made with one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, or cyclopropyl;

[0273] R 5d Selected from CN, OH, methoxy, or ethoxy;

[0274] R 3 Selected from methyl and ethyl;

[0275] R L1 R L2 Together with the adjacent carbon atoms, they form optional groups of 1 to 4 R atoms. k The following groups are substituted: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

[0276] R k Each is independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrroleyl, morpholinyl. The methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrrolidinyl, and morpholinyl groups are optionally selected from 1 to 4 of the following: deuterium, F, Cl, Br, I, CN, OH, NH2, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups

[0277] The definitions of the remaining groups are the same as in the seventh or eighth embodiment.

[0278] As a tenth embodiment of the present invention, the compound represented by the above general formula (I), or its racemic mixture, stereoisomer, tautomer, or pharmaceutically acceptable salt, is used.

[0279] R 4 Selected from

[0280] Ring A is selected from 1 to 5 R's. a Substituted phenyl;

[0281] L2 is selected from 1 to 4 R's. k One of the following groups is substituted:

[0282] Preferably, L2 is selected from

[0283] R k2 Selected from H or deuterium;

[0284] R k3 Selected from H or deuterium;

[0285] R k4 Selected from H or deuterium;

[0286] R k Each is independently selected from deuterium, F, Cl, Br, methyl, and ethyl, wherein the methyl or ethyl group is optionally substituted by one to four substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, CH2CN, methyl, ethyl, methoxy, and ethoxy.

[0287] The definitions of the remaining groups are the same as in the seventh, eighth, or ninth embodiments.

[0288] As an eleventh embodiment of the present invention, the compound represented by the above general formula (I), or its racemic mixture, stereoisomer, tautomer, or pharmaceutically acceptable salt, is used.

[0289] L2 is selected from

[0290] Ring A is selected from phenyl, wherein ring A is optionally surrounded by 1 to 5 R groups. a replace;

[0291] Ring B is selected from The ring B is arbitrarily divided by 1 to 4 Rs. b Replace it, and its right side is connected to Q;

[0292] -QR 6 Selected from optional replacements When substituted, it is replaced by 1 to 10 substituents selected from deuterium, F, Cl, Br, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy, or ethoxy.

[0293] R a Each element is independently selected from deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, methoxy, cyclopropyl.

[0294] R b Each is independently selected from deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, and cyclopropyl.

[0295] R d Each of the following groups is independently selected from deuterium, F, Cl, Br, I, CN, OH, CHF2, CH2F, CF3, CD3, methyl, ethyl, methoxy, ethoxy, and cyclopropyl.

[0296] The definitions of the remaining groups are the same as in the seventh, eighth, ninth, or tenth implementation schemes.

[0297] As a twelfth embodiment of the present invention, the compound represented by the above general formula (I) or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein ring A is selected from...

[0298] Selected from

[0299] k is selected from 0, 1, 2, 3, and 4;

[0300] R k1 Each is independently selected from deuterium, F, Cl, methyl, ethyl, and CD3;

[0301] Ring D is selected from

[0302] Or ring D is selected from L1 is selected from -C(=S)-;

[0303] R d1 Selected from H, CD3, methyl, and cyclopropyl;

[0304] R d2 Selected from H, deuterium, F, Cl, Br, CHF2, CF3, CD3, methyl, ethyl, and cyclopropyl;

[0305] The definitions of the remaining groups are the same as in embodiments seven, eight, nine, ten, or eleven.

[0306] As a thirteenth embodiment of the present invention, the compound represented by the above general formula (I), or its racemic mixture, stereoisomer, tautomer, or pharmaceutically acceptable salt, is used.

[0307] The compounds described in formula (I) are selected from formulas (Ig) or (Ih).

[0308] R k1 Each is independently selected from deuterium, F, Cl, methyl, ethyl, and CD3;

[0309] R k2 Selected from H or deuterium;

[0310] R k3 Selected from H or deuterium;

[0311] R k4 Selected from H or deuterium;

[0312] Ring D1 is selected from

[0313] Preferably, ring D is selected from... The ring D is arbitrarily divided by 1 to 4 Rs. d replace;

[0314] R d Each element is independently selected from H, deuterium, halogens, =O, =S, CN, OH, and C. 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 carbonyl group, C 3-6 The carbocyclic group, wherein the alkyl, alkylene, or carbocyclic group is optionally selected from one to four deuterium, halogen, CN, C 1-4 Alkyl or C 1-4 Substituents of alkoxy groups;

[0315] Preferably, ring D is selected from...

[0316] Preferably, ring D1 is selected from

[0317] R 5d Selected from CN, OH, methoxy, or ethoxy;

[0318] R d1 Selected from H, CD3, methyl, and cyclopropyl;

[0319] R d2 Selected from H, deuterium, F, Cl, Br, CHF2, CF3, CD3, methyl, ethyl, and cyclopropyl;

[0320] p1 is selected from 0, 1, 2, 3, 4 or 5;

[0321] k is selected from 0, 1, 2, 3, and 4;

[0322] R a Each element is independently selected from deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, methoxy, cyclopropyl.

[0323] This invention relates to a compound or its racemate, stereoisomer, tautomer, deuterated derivative, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal, wherein the compound is selected from one of the structures in Table E-1 below:

[0324] Table E-1

[0325] This invention relates to a pharmaceutical composition comprising the above-described compound or its racemic, stereoisomer, tautomer, pharmaceutically acceptable salt, and pharmaceutically acceptable carrier.

[0326] This invention relates to the use of the above-mentioned compounds or their racemates, stereoisomers, tautomers, pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions in the preparation of medicaments for treating diseases related to GLP-1R activity or expression levels.

[0327] This invention relates to the use of the above-mentioned compounds or their racemates, stereoisomers, tautomers, pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions in the preparation of medicaments for treating diabetes or obesity.

[0328] This invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of the compound of the invention or its racemic mixture, stereoisomer, pharmaceutically acceptable salt, and pharmaceutical excipient. The pharmaceutical composition may be in unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as a "dosage strength").

[0329] The present invention also provides a method for treating diseases in mammals, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or its racemic mixture, stereoisomer, pharmaceutically acceptable salt, or pharmaceutical composition. In some embodiments, the mammals described in the present invention include humans.

[0330] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition being treated (e.g., diabetes or obesity). In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1000 mg, 1-800 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3-500 mg. g, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg , 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 25 0-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 7 5-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200 mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg;.

[0331] In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1500 mg, 1-1000 mg, 1-800 mg, 1-600 mg, 20-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg of the compound of the present invention or its racemate, stereoisomer, or pharmaceutically acceptable salt.

[0332] A method for treating a disease in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its racemic, stereoisomer, or pharmaceutically acceptable salt, preferably 1-1500 mg, wherein the disease is preferably a disease related to GLP-1R activity or expression (such as diabetes or obesity).

[0333] A method for treating a disease in mammals, the method comprising administering a drug, a compound of the present invention or its racemic mixture, stereoisomer, or pharmaceutically acceptable salt, to a subject at a daily dose of 1-1500 mg / day, said daily dose being a single dose or multiple doses, and in some embodiments, the daily dose including but not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100 mg / day, etc. -800mg / day, 200-800mg / day, 25-400mg / day, 50-400mg / day, 100-400mg / day, 200-400mg / day, and in some embodiments, the daily dose includes, but is not limited to, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 400mg / day, 600mg / day, and 800mg / day.

[0334] This invention relates to a kit that may include a single-dose or multi-dose composition comprising a compound of the present invention or its racemate, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the amount of the compound of the present invention or its racemate, stereoisomer, or pharmaceutically acceptable salt thereof is the same as the amount in the aforementioned pharmaceutical composition.

[0335] In this invention, the amount of the compound of the invention or its racemate, stereoisomer, or pharmaceutically acceptable salt is converted in each case as a free base.

[0336] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0337] Synthesis Method 1:

[0338] General formula (Z1) and general formula (Z2) undergo a coupling reaction under the catalysis of a heavy metal catalyst to obtain the corresponding general formula (Z3). General formula (Z3) is deprotected under acidic conditions to obtain the corresponding general formula (Z4). General formula (Z4) and general formula (Z5) are combined with a condensing agent (such as HATU) to obtain the corresponding general formula (I).

[0339] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0340] The carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I involved in the groups and compounds described in this invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, isotopes of fluorine include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0341] “CN” refers to cyano.

[0342] "Halogen" refers to F, Cl, Br or I.

[0343] "Halogen-substituted" refers to substitution with F, Cl, Br, or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br, or I, 1 to 6 substituents selected from F, Cl, Br, or I, and 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen-substituted" is abbreviated as "halogenated".

[0344] "alkyl" refers to a substituted or unsubstituted straight-chain or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups with 1 to 20 carbon atoms, alkyl groups with 1 to 8 carbon atoms, alkyl groups with 1 to 6 carbon atoms, and alkyl groups with 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and their various branched isomers; the alkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0345] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2). v - (v is an integer from 1 to 10), alkylene examples include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0346] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-co-cyclobutyl, cyclobutyl-spirobutyl, adamantane, etc. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0347] "Heterocyclic alkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms or 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, S, P, or Se. The C, N, S, and P atoms on the ring of the heterocyclic alkyl group can be oxidized to various oxidation states. Heterocyclic alkyl groups can be monocyclic, fused, bridged, or spirocyclic. Heterocyclic alkyl groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, aziridinepropyl, oxacyclobutyl, aziridinebutyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxopentyl, dioxohexyl, pyrrolylalkyl, piperidinyl, imidazoalkyl, oxazolidinyl, oxazinylalkyl, morpholinyl, hexahydropyrimidinyl, piperazineyl, etc. Heterocyclic alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0348] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, usually one, two or three, carbon-carbon double bond. The main chain has, but is not limited to, 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, etc. Alkenyl groups can be monovalent, divalent, trivalent or tetravalent.

[0349] "Alynyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, usually one, two or three, carbon-carbon triple bond, with the main chain comprising 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms on the main chain, or having 2 to 4 carbon atoms on the main chain. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, etc.; the alkynyl group can be monovalent, divalent, trivalent or tetravalent.

[0350] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

[0351] "Carbocyclic group" or "carbocyclic ring" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system. The carbocyclic group can be attached to an aromatic or non-aromatic ring, and the ring can be optionally a monocyclic, fused, bridged, or spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, etc. "Carbocyclic group" or "carbon ring" can be monovalent, divalent, trivalent or tetravalent.

[0352] "Heterocyclic group" or "heterocyclic" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S, P or Se. The C, N, S, P or Se selectively substituted in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused, or spirocyclic ring. Non-limiting examples include epoxyethyl, aziridinepropyl, oxacyclobutyl, aziridinebutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexane, aziridineheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithioyl, dihydrofuranyl, dihydropyranyl, dithiapentylcycloyl. Tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophene, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl, "Heterocyclic group" or "heterocyclic" can be monovalent, divalent, trivalent or tetravalent.

[0353] "Spirocyclic" or "spirocyclic group" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share a single atom (called a spiro atom). The number of ring atoms in a spirocyclic system includes, but is not limited to, 5 to 20, 6 to 14, 6 to 12, or 6 to 10. One or more rings may contain 0 or more (including but not limited to 1, 2, 3, or 4) double bonds, and optionally may contain 0 to 5 double bonds selected from N, O, or S (=O). n heteroatoms (n is 0, 1 or 2).

[0354] "Spirocyclic" or "spirocyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0355] "Circular fused" or "circular fused group" refers to a polycyclic group in which each ring in a system shares a pair of adjacent atoms with other rings in the system. One or more rings may contain zero or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted. Each ring in a circular fused system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to those selected from N, S (=O)). n Or O, where n is 0, 1, or 2). The number of ring atoms in a cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include:

[0356] "Cyclone" or "cyclone base" can be monovalent, divalent, trivalent, or tetravalent.

[0357] A “bridged ring” or “bridged ring group” refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in a bridged ring system may contain 0 to 5 groups selected from heteroatoms or containing heteroatoms (including but not limited to N, S(=O)n, or O, where n is 0, 1, or 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include… Cubicane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0358] "Carbon spirocyclic", "spirocyclic carbon cyclic", "spirocarbon cyclic", or "carbon spirocyclic" refers to a spirocyclic system composed only of carbon atoms.

[0359] "Carbon fused ring", "fused cyclic carbon cyclic group", "fused carbon cyclic group" or "carbon fused cyclic group" refers to a ring system composed only of carbon atoms.

[0360] "Carbon bridged ring", "bridged ring carbon cyclo group", "bridged carbon cyclo group" or "carbon bridged ring group" refers to a ring system composed only of carbon atoms.

[0361] "Hybrid monocyclic", "monocyclic heterocyclic group" or "hybrid monocyclic group" refers to the "heterocyclic group" or "heterocyclic" in a monocyclic system.

[0362] "Hydrocyclic ring", "hydrocyclic cyclic group", "fused cyclic heterocyclic group" or "fused heterocyclic group" refers to a "fused ring" containing heteroatoms.

[0363] "Heterospirocyclic", "heterospirocyclic group", "spirocyclic heterocyclic group" or "spiroheterocyclic group" refers to a "spirocycle" containing heteroatoms.

[0364] "Hybrid-bridged ring", "hybrid-bridged ring group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing heteroatoms.

[0365] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring. Non-limiting embodiments include benzene rings, naphthalene rings, etc. The "aryl" or "aryl ring" can be monovalent, divalent, trivalent, or tetravalent. When it is divalent, trivalent, or tetravalent, the linking site is located on the aryl ring.

[0366] "Heteroaryl" or "heteroary ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or a group containing heteroatoms (including but not limited to N, O, S(=O)n or Se(=O)n, where n is 0, 1, or 2). The number of ring atoms in the heteroaryl ring includes, but is not limited to, 5 to 15, 5 to 10, or 5 to 6. The atoms C, N, and S on the ring may be optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1 or 2). Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furanyl, thiophenyl, selenyl, pyridyl, pyranyl, N-alkylpyrrolithyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazoleyl, benzopyrazolyl, benzimidazoleyl, benzopyridyl, pyrrolopyridyl, pyridinoneyl, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbon ring or heterocycle, wherein the ring connected to the parent structure is an aryl ring. Non-limiting embodiments include... The heteroaryl groups mentioned in this article are defined in accordance with this definition. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the linkage site is located on an aromatic ring.

[0367] "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4, or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged cyclic, spirocyclic, fused cyclic, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, and -(CH2). m -C(=O)-R a -O-(CH2) m -C(=O)-R a -(CH2) m -C(=O)-NR b R c -(CH2) m S(=O) n R a -(CH2)m -Alkenyl-R a OR d Or -(CH2) m -alkynyl-R a (where m and n are 0, 1, or 2), arylthio, thiocarbonyl, silyl, or -NR b R c Groups, wherein R b With R c Independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, R b With R c It can form five- or six-membered cycloalkyl or heterocyclic groups, R a With R d Each group is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic, carbonyl, ester, bridged cyclic, spirocyclic, or fused cyclic groups.

[0368] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from..., where X is any integer between 1 and 10. For example, "1 to 4 R..." k "Replace" refers to being replaced by 1, 2, 3, or 4 Rs. k Substitution. For example, "1 to 5 substituents selected from ..." means that the ring is substituted by 1, 2, 3, 4 or 5 substituents selected from ... . For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

[0369] The XY-membered rings (where X and Y are integers, and 3 ≤ X < Y, X < Y ≤ 20, selected from any integer between 4 and 20) include rings of the X, X+1, X+2, X+3, X+4…Y-membered elements. These rings include heterocyclic groups, carbocyclic groups, aryl groups, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic groups, heterofused rings, heterospirocyclic groups, or heterobridged rings. For example, "4-7-membered heteromonocyclic rings" refers to heteromonocyclic rings of 4, 5, 6, or 7 members, and "5-10-membered heterofused rings" refers to heterofused rings of 5, 6, 7, 8, 9, or 10 members.

[0370] C x-y Carbocyclic groups (including aryl, cycloalkyl, monocyclic, spirocyclic, fused, or bridged carbocyclic groups) include C x C x+1 C x+2 C x+3 C x+4 ….C y A ring of elements (x is an integer, and 3 ≤ x < y, where y is any integer between 4 and 20), for example, C. 3-6"Cycloalkyl" refers to C3, C4, C5, or C6 cycloalkyl groups.

[0371] When a functional group has one or more connectable sites, any one or more of these sites can be linked to other functional groups via chemical bonds. When the chemical bond connection is non-directional and a hydrogen atom is present at the connectable site, the number of hydrogen atoms at that site decreases accordingly with the number of bonds being formed, resulting in a functional group with a corresponding valence. For example... This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... These four connection methods, even if an H atom is drawn on -N-, This also includes For example This indicates that the R group on the piperidinyl group can be located on C or N, and at least includes [missing information].

[0372] When the listed linking groups do not specify their linking direction, the linking direction includes the direction of the reading order from left to right and from right to left. For example, when ALB is selected from -MW-, it includes AMWB and AWMB.

[0373] "Carrier" refers to a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the compound given.

[0374] "Animals" refers to mammals, such as humans, companion animals, zoo animals, and livestock, with humans, horses, or dogs being preferred.

[0375] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0376] "Tautomers" refer to functional group isomers that are produced by the rapid movement of an atom in two positions within a molecule, such as keto-enol isomers and amide-imine alcohol isomers. Detailed Implementation

[0377] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0378] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0379] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0380] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0381] Thin-layer chromatography silica gel plates used were from Yantai Huanghai HSGF. 254 Or Qingdao GF 254 Silica gel plates: The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15mm-0.20mm, while those used for TLC separation and purification of products have a diameter of 0.4mm-0.5mm.

[0382] Column chromatography typically uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0383] An asterisk (*) next to a chemical bond indicates that the chiral center has an unknown, single configuration.

[0384] HATU: CAS148893-10-1; LiHMDS: Lithium bis(trimethylsilyl)amino; DBU: CAS 6674-22-2.

[0385] Preparation of intermediate 1-E

[0386] Step 1: Preparation of 1-B

[0387] 1-A (280 mg, 0.99 mmol) was dissolved in ultradry THF (5 mL), and iodomethane (156 mg, 1.10 mmol) and anhydrous potassium carbonate (200 mg, 1.45 mmol) were added, respectively. The mixture was reacted at 45 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 5:1) to obtain 1-B (175 mg, yield: 60%).

[0388] LCMS m / z = 296.0 [M+H] +

[0389] Step 2: Preparation of 1-D

[0390] 1-B (175 mg, 0.59 mmol) and 1-C (218 mg, 0.49 mmol) were dissolved in N-methylpyrrolidone (5 mL). Cuprous iodide (142.5 mg, 0.75 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (107 mg, 0.75 mmol), and anhydrous potassium carbonate (138 mg, 1 mmol) were added to the system. The reaction was carried out at 130 °C for 2 h under a nitrogen atmosphere. After cooling to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The mixture was washed with saturated sodium chloride aqueous solution (10 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 1 / 1) to obtain 1-D (288 mg, yield: 89%).

[0391] LCMS m / z = 657.4 [M+H] +

[0392] Step 3: Preparation of 1-E

[0393] 1-D (200 mg, 0.3 mmol) was dissolved in dichloromethane (2 mL), and 4 M HCl-dioxane solution (2 mL) was added. The mixture was reacted at room temperature for 16 h. The system was concentrated under reduced pressure. 2 mL of saturated potassium carbonate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane: methanol (v / v) = 10 / 1) to obtain 1-E (105 mg, yield: 62%).

[0394] LCMS m / z = 557.8 [M+H] +

[0395] Preparation of intermediate 2-L

[0396] Step 1: Preparation of 2-B

[0397] Methyltriphenylphosphine bromide (20.0 g, 55.99 mmol) was dissolved in ultradry THF (100 mL) under ice bath conditions. 1 M potassium tert-butoxide-tetrahydrofuran solution (60.0 mL, 60.0 mmol) was added to the system, and the reaction was carried out under a nitrogen atmosphere for 0.5 h. Then 2-A (8.0 g, 39.41 mmol) was added, and the system was heated to room temperature and reacted for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (eluent: petroleum ether) to obtain 2-B (3.46 g, yield 43.67%).

[0398] Step 2: Preparation of 2-C

[0399] 2-B (2.0 g, 9.95 mmol) was dissolved in dichloromethane (20 mL), and bromosuccinimide (4.4 g, 24.72 mmol) and triethylamine trihydrofluoride (4.8 g, 29.77 mmol) were added under ice bath conditions. The mixture was heated to room temperature and reacted for 16 h. 50 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether) to obtain 2-C (600 mg, yield 20.11%).

[0400] Step 3: Preparation of 2-D

[0401] 2-C (550 mg, 1.83 mmol) was dissolved in petroleum ether (10 mL), potassium tert-butoxide (1.2 g, 10.69 mmol) was added, and the mixture was reacted at room temperature for 16 h. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether) to obtain 2-D (400 mg, yield 99.59%).

[0402] Step 4: Preparation of 2-E

[0403] 1M diethylzinc n-hexane solution (4 mL, 4 mmol) was dissolved in ultra-dry dichloromethane (4 mL) under ice bath conditions. Trifluoroacetic acid (0.3 mL, 4.04 mmol) was slowly added dropwise to the system, and the reaction was carried out under a nitrogen atmosphere for 0.5 h. Then, diiodomethane (0.35 mL, 4.34 mmol) was added, and the mixture was stirred for 20 min. 2-D (400 mg, 1.83 mmol) was added, and the mixture was heated to room temperature and reacted for 16 h. 10 mL of saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether) to obtain 2-E (370 mg, yield 86.94%).

[0404] Step 5: Preparation of 2-F

[0405] 2-E (370 mg, 1.59 mmol) was dissolved in ultradry THF (5 mL), and 2.5 M n-butyllithium tetrahydrofuran solution (0.7 mL, 1.75 mmol) was added at -78 °C and reacted for 1 h. Di-tert-butyl azodicarbonate (400 mg, 1.74 mmol) was added, and the mixture was heated to room temperature and reacted for 2 h. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 10:1) to obtain 2-F (239 mg, yield 39.16%).

[0406] Step 6: Preparation of 2-G

[0407] 2-F (230 mg, 0.60 mmol) was dissolved in N-methylpyrrolidone (2 mL), and methanesulfonic acid (0.3 mL, 4.62 mmol) was added. The mixture was reacted at 80 °C for 16 h. 5 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (5 mL × 3). The mixture was washed with saturated sodium chloride aqueous solution (5 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain 2-G (100 mg, yield 90.74%), which was used directly in the next reaction without further purification.

[0408] Step 7: Preparation of 2-H

[0409] 2-G (100 mg, 0.54 mmol) was dissolved in toluene (2 mL), and 2-G-1 (145 mg, 0.61 mmol) and pyridine hydrochloride (10 mg, 0.087 mmol) were added. The mixture was reacted at 90 °C for 1 h. The system was concentrated under reduced pressure, and the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 5:1) to obtain 2-H (54 mg, yield 24.59%).

[0410] LCMS m / z = 405.3 [M+H] +

[0411] Step 8: Preparation of 2-I

[0412] 2-H (50 mg, 0.12 mmol) was dissolved in pyridine (1 mL), and 2-H-1 (40 mg, 0.31 mmol) and diethylamine (20 mg, 0.27 mmol) were added. The mixture was reacted at room temperature for 0.5 h. 5 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (5 mL × 3). The mixture was washed with saturated sodium chloride aqueous solution (5 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain 2-I (60 mg, yield 90.62%), which was used directly in the next reaction without further purification.

[0413] Step 9: Preparation of 2-J

[0414] 2-I (60 mg, 0.11 mmol) was dissolved in ultradry THF (2 mL), and methanesulfonic acid (0.1 mL, 1.54 mmol) was added. The mixture was reacted at 60 °C for 0.5 h. 5 mL of saturated sodium bicarbonate aqueous solution was added to the mixture, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give 2-J (50 mg, yield 94.66%).

[0415] LCMS m / z = 472.2 [M+H] +

[0416] Step 10: Preparation of 2-K

[0417] 2-J (80 mg, 0.17 mmol) and 2-J-1 (55 mg, 0.19 mmol) (synthetic method referred to WO2018229079) were dissolved in N-methylpyrrolidone (2 mL). Cuprous iodide (30 mg, 0.16 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (30 mg, 0.21 mmol), and anhydrous potassium carbonate (120 mg, 0.87 mmol) were added to the system. The reaction was carried out at 130 °C for 2 h under a nitrogen atmosphere and then cooled to room temperature. 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The mixture was washed with saturated sodium chloride aqueous solution (10 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 5:1) to obtain 2-K (100 mg, yield 85.82%).

[0418] LCMS m / z = 687.3 [M+H] +

[0419] Step 11: Preparation of 2-L

[0420] 2-K (100 mg, 0.15 mmol) was dissolved in dichloromethane (1 mL), and 4 M HCl-dioxane solution (1 mL) was added. The mixture was reacted at room temperature for 3 h. The system was concentrated to dryness, and 2 mL of saturated potassium carbonate aqueous solution was added to the reaction solution. The organic layers were extracted with ethyl acetate (2 mL × 3) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane:methanol (v / v) = 10:1) to obtain 2-L (80 mg, yield 93.65%).

[0421] LCMS m / z = 587.2 [M+H] +

[0422] Example 1: Preparation of Compound 1

[0423] Step 1: Preparation of 1b

[0424] 1a (3.23 g, 11.87 mmol) was dissolved in a mixed solution of 1,4-dioxane (40 mL) and water (8 mL). Under a nitrogen atmosphere, 1A (3.1 g, 13.02 mmol), potassium carbonate (3.27 g, 23.66 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (972 mg, 1.19 mmol) were added, and the reaction was carried out at 80 °C for 4 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to give 1b (3.15 g, yield: 88%).

[0425] LCMS m / z = 304.1[M+1] +

[0426] Step 2: Preparation of 1c

[0427] Dissolve 1b (3.15 g, 10.39 mmol) in methanol (100 mL), add 10% palladium on carbon (1.2 g), and react at 30 °C for 16 h under a hydrogen balloon atmosphere. Filter the reaction mixture through a diatomaceous earth liner, and concentrate the filtrate under reduced pressure to obtain crude product 1c (3.1 g).

[0428] LCMS m / z = 306.1 [M+1] +

[0429] Step 3: Preparation of chiral isomer 1 and chiral isomer 2 of 1c

[0430] The crude product 1c was subjected to chiral resolution under the following conditions:

[0431] 1. Instrument: CAS-05-Prep-SFC-F; Column: OD column.

[0432] 2. The sample was dissolved in methanol and acetonitrile and filtered through a 0.45 μm filter to prepare the sample solution.

[0433] 3. Preparative chromatographic conditions: a. The mobile phase consists of system A and B: mobile phase A: CO2; mobile phase B: isopropanol; b. Isocratic elution, with mobile phase B having a content of 25%; c. Flow rate of 120 mL / min.

[0434] The conditions for chiral analysis are as follows:

[0435] 1. Instrument: CAS-05-ANA-SFC-C; Column: OD column.

[0436] 2. Analytical chromatographic conditions: a. The mobile phase consists of system A and system B: Mobile phase A: carbon dioxide; Mobile phase B: isopropanol (containing 0.05% by volume 7 mol / L ammonia methanol solution); b. Gradient elution, with mobile phase B content of 5-40%; c. Flow rate of 3 mL / min.

[0437] Peak elution time: chiral isomer 1: 1.379 min, chiral isomer 2: 1.620 min.

[0438] One of the chiral isomers 1 and 2 of compound 1c is structure 1c-1, and the other is structure 1c-2.

[0439] Step 4: Preparation of 1 day

[0440] Chiral isomer 2 of 1c (1.07 g, 3.5 mmol) was dissolved in 10 mL of DMF, cooled to 0 °C under a nitrogen atmosphere, and 60% sodium hydride (212 mg) was slowly added in portions. After reacting at 0 °C for 1 h, chloroacetonitrile (533 mg, 7.06 mmol) was added dropwise, and the reaction was carried out at room temperature for 16 h. 30 mL of saturated ammonium chloride aqueous solution was added to the reaction system, and the mixture was extracted with ethyl acetate (50 mL × 4). The organic phase was washed with water (80 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 6:1) to give 1d (1.1 g, yield: 91%).

[0441] LCMS m / z = 345.3[M+1] +

[0442] Step 5: Preparation of 1e

[0443] 1d (1.1 g, 3.20 mmol) and 1B (1.32 g, 9.56 mmol) were dissolved in 40 mL of THF. Under nitrogen protection, a tetrahydrofuran solution of 1 mol / L LiHMDs (16.0 mL, 16.0 mmol) was slowly added dropwise at 0 °C, and the reaction was carried out at 0 °C for 2 h. 30 mL of saturated ammonium chloride aqueous solution was added to the reaction system, and the mixture was extracted with ethyl acetate (60 mL × 4). The organic phase was washed with water (80 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 6:1) to obtain a crude product (0.46 g). The crude product was then subjected to chiral resolution under the following conditions:

[0444] 1. Instrument: CAS-05-Prep-SFC-F; Column: IC column.

[0445] 2. The sample was dissolved in ethanol and acetonitrile and filtered through a 0.45 μm filter to prepare the sample solution.

[0446] 3. Preparative chromatographic conditions: a. The mobile phase consists of system A and B: mobile phase A: CO2; mobile phase B: isopropanol; b. Isocratic elution, with mobile phase B having a content of 18%; c. Flow rate of 130 mL / min.

[0447] The conditions for chiral analysis are as follows:

[0448] 1. Instrument: CAS-05-ANA-SFC-C; Column: IC column.

[0449] 2. Analytical chromatographic conditions: a. The mobile phase consists of system A and system B: Mobile phase A: carbon dioxide; Mobile phase B: isopropanol (containing 0.05% by volume 7 mol / L ammonia methanol solution); b. Gradient elution, with mobile phase B content of 5-40%; c. Flow rate of 3 mL / min.

[0450] Peak elution time of 1e: 1.458 min.

[0451] LCMS m / z = 385.3 [M+1] +

[0452] Compound 1e is one of the isomers of structure 1e-1 or 1e-2.

[0453] Step 6: Preparation of 1f

[0454] 1e (225 mg, 0.59 mmol) was dissolved in 3 mL of DMSO, and hydroxylamine hydrochloride (407 mg, 5.86 mmol) and sodium bicarbonate (492 mg, 5.86 mmol) were added separately. The mixture was reacted at 60 °C for 16 h. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 1f (260 mg).

[0455] LCMS m / z = 418.3[M+1] +

[0456] Step 7: Preparation of 1g

[0457] The crude product 1f (260 mg) was dissolved in 3 mL of DMSO, and CDI (191 mg, 1.18 mmol) and DBU (225 mg, 1.48 mmol) were added separately. The mixture was reacted at 35 °C for 2 h. 30 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 4:1) to give 1 g (80 mg, two-step yield from compound 1e: 31%).

[0458] LCMS m / z = 442.2 [M-1] -

[0459] Step 8: Preparation over 1 hour

[0460] 1 g (80 mg, 0.18 mmol) was dissolved in 2.5 mL of DMSO, and 0.27 mL of 2 mol / L sodium hydroxide aqueous solution was added. The reaction was carried out at 30 °C for 16 h. Water (30 mL) was added to the reaction system, and the pH was adjusted to 2-3 with 1 mol / L hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phase was washed with saturated brine (20 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 1 h (65 mg).

[0461] LCMS m / z = 428.2 [M-1] -

[0462] Step 9: Preparation of Compound 1

[0463] The crude product (32 mg) was dissolved in 2.5 mL of DMF, and intermediate 1-E (50 mg, 0.09 mmol), HATU (46 mg, 0.12 mmol), and N,N-diisopropylethylamine (29 mg, 0.22 mmol) were added. The reaction mixture was reacted at 30 °C for 48 h. The reaction system was then subjected to Pre-HPLC (instrument and preparative column: CAS-05-Semi-prep S preparative HPLC, column type C18, inner diameter × length = 19 mm × 250 mm). Preparation method: The acetonitrile solution of the crude product was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was used to elute 90% of the product with a 60% gradient (elution time 14 min), and the solution was lyophilized to obtain compound 1 (50 mg, yield: 57%).

[0464] LCMS m / z = 968.5 [M+1] +

[0465] Compound 1 is one of the isomers of compounds 1-1, 1-2, 1-3 or 1-4.

[0466] Example 2: Preparation of Compound 2

[0467] Step 1: Preparation of 2b

[0468] Compound 2b was obtained from chiral isomers 1 and 1B of 1c using the synthesis method described in Example 1.

[0469] Compound 2b was chirally resolved under the following conditions:

[0470] 1. Instrument: CAS-05-Prep-SFC-E; Column: AD column.

[0471] 2. The sample was dissolved in acetonitrile and methanol, and filtered through a 0.45 μm filter to prepare the sample solution.

[0472] 3. Preparative chromatographic conditions: a. The mobile phase consists of system A and system B: mobile phase A: CO2; mobile phase B: methanol (containing 0.1% NH3·H2O); b. Isocratic elution, mobile phase B content is 20%; c. Flow rate is 120 mL / min.

[0473] The conditions for chiral analysis are as follows:

[0474] 1. Instrument: CAS-05-ANA-SFC-D; Column: AD column.

[0475] 2. Analytical chromatographic conditions: a. The mobile phase consists of system A and system B: mobile phase A: carbon dioxide; mobile phase B: methanol (containing 0.05% by volume 7 mol / L ammonia methanol solution); b. Gradient elution, with mobile phase B content of 5-40%; c. Flow rate of 3 mL / min.

[0476] Peak elution time of 2b: 1.295 min.

[0477] LCMS m / z = 385.3 [M+1] +

[0478] Compound 2b is one of the isomers of structure 1e-1 or 1e-2.

[0479] Compound 2 was obtained from 2b using the synthesis method described in Example 1.

[0480] LCMS m / z = 968.5 [M+1] +

[0481] Compound 2 is one of the isomers of compounds 1-1, 1-2, 1-3 or 1-4.

[0482] Using compound 1h and intermediate 2-L as starting materials, the following compounds were synthesized under similar synthetic conditions as described in the above examples:

[0483] Using compound 2e and intermediate 2-L as starting materials, the following compounds were synthesized under similar synthetic conditions as described in the examples above:

[0484] Example 5: Preparation of Compound 5

[0485] Step 1: Preparation of 5-A

[0486] 1-B (5.9 g, 18.90 mmol) was dissolved in toluene (100 mL), and Lawesson's Reagent (7.64 g, 18.90 mmol) was added. The mixture was reacted at 100 °C for 18 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 4:1) to give 5-A (1.77 g, yield: 30%).

[0487] LCMS m / z = 312.0 [M+H] +

[0488] Step 2: Preparation of Compound 5

[0489] 5-B (150 mg, 0.2 mmol) (synthesis reference CN116003403), 5-A (78.06 mg, 0.25 mmol) were dissolved in N-methylpyrrolidone (3 mL). Cuprous iodide (48 mg, 0.25 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (36 mg, 0.25 mmol), and anhydrous potassium carbonate (69 mg, 0.5 mmol) were added to the system. The reaction was carried out at 130 °C for 2 h under a nitrogen atmosphere. Cool to room temperature, add 10 mL of water to the reaction solution, extract with ethyl acetate (10 mL × 3), wash with saturated sodium chloride aqueous solution (10 mL × 3), combine the organic layers and dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by Pre-HPLC (instrument and preparative column: CAS-05-Semi-prep S preparative HPLC, column type C18, inner diameter × length = 19 mm × 250 mm). Preparation method: Filter the crude product's acetonitrile solution through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: elute 90% of the acetonitrile by a 60% gradient (elution time 14 min), lyophilize to obtain compound 5.

[0490] LCMS m / z = 964.7 [MH] -

[0491] Example 6: Preparation of Compound 6

[0492] Step 1: Preparation of 6-B

[0493] 6-A (5.0 g, 20.5 mmol) was dissolved in 50 mL of dry DMF, and potassium carbonate (5.5 g, 41.0 mmol) was added. After stirring for 10 min, deuterated iodomethane (1.4 mL, 22.5 mmol) was added dropwise, and the mixture was heated to 50 °C and reacted for 5 h. After the reaction was complete as monitored by TLC, 250 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 3:1) to obtain 6-B (4.0 g, yield 76%).

[0494] LCMS m / z = 261.0 [M+H] +

[0495] Step 2: Preparation of 6-C

[0496] 6-B (4.0 g, 15.5 mmol) was placed in a 250 mL round-bottom flask, and 40 mL of anhydrous ethanol was added to dissolve it slightly. After adding 33 mL of 80% hydrazine hydrate solution and stirring, the system became clear. The temperature was raised to 125 °C and reacted for 6 h. The system became turbid and a solid precipitated. The mixture was filtered, and the filter cake was washed three times with purified water. After drying, 2.5 g of yellowish crude product was obtained, which was directly proceeded to the next step without further purification.

[0497] LCMS m / z = 247.1 [M+H] +

[0498] Step 3: Preparation of 6-D

[0499] 6-C (2.4 g, 10.0 mmol) was dissolved in 50 mL of dry DMF, and cesium carbonate (6.5 g, 20.0 mmol) and sodium iodide (3.0 g, 20.0 mmol) were added. After stirring for 10 min, 2,2'-dibromodiethyl ether (4.6 g, 20.0 mmol) was added dropwise, and the mixture was heated to 50 °C and reacted for 16 h. After the reaction was complete as monitored by TLC, 250 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to give 6-D (2.2 g, yield 71.7%).

[0500] Step 5: Preparation of 6-E

[0501] Following the synthetic method of intermediate 5-A, 6-E (0.2 g, 63% yield) was obtained from compound 6-D (0.3 g, 0.32 mmol).

[0502] LCMS m / z = 333.4 [M+H] +

[0503] Step 6: Preparation of Compound 6

[0504] Using 6-E (75 mg, 0.22 mmol) as the starting material, and following the synthetic method of compound 5, compound 6 (50 mg, yield 23%) was obtained by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; column: SunFire@Prep C18 (30 mm × 250 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% TFA). Acetonitrile gradient was increased from 50% to 95%, retention time 20 min).

[0505] 1H NMR(400MHz,CF3COOD)δ7.73-7.71(d,1H),7.68-7.56(m,2H),7.42-7.27(m,4 H),6.98-6.84(m,2H),6.17-6.02(m,1H),4.91-4.81(m,1H),4.76-4.61(m,2H ),4.32-4.09(m,4H),3.98-3.83(m,1H),3.61-3.32(m,2H),3.29-3.14(m,1H) ,2.50-2.33(m,8H),2.08-1.70(m,12H),1.55-1.49(m,7H),1.35-1.34(m,3H).

[0506] Example 7: Preparation of Compound 7

[0507] Step 1: Preparation of 7-A

[0508] Compound 7-A was obtained by using deuterated iodomethane as a substrate, following the synthetic method of 1-B.

[0509] LCMS m / z = 299.0 [M+H] +

[0510] Step 2: Preparation of Compound 7

[0511] Compound 7 (200 mg, yield: 33.6%) was obtained by following the synthetic method of compound 5 using 7-A as a substrate.

[0512] LCMS m / z = 969.7 [M+H] +

[0513] Example 8: Preparation of Compound 8

[0514] Step 1: Preparation of 8-A

[0515] 5-A (311 mg, 1.0 mmol) was dissolved in dichloromethane (15 mL) and placed in an ice bath. Methyl trifluoromethanesulfonate (328 mg, 2.0 mmol) was added, and the mixture was reacted at room temperature for 3 h. Then, the mixture was placed in an ice bath. DIPEA (258 mg, 2.0 mmol) and cyanamide (84 mg, 2.0 mmol) were dissolved in tetrahydrofuran (3 mL) and added to the reaction mixture. The mixture was reacted at room temperature for 1 h. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate. The mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 2:1) to obtain 8-A (110 mg, yield: 34.3%).

[0516] LCMS m / z = 320.1 [M+H] + 322.1[M+H] +

[0517] Step 2: Preparation of Compound 8

[0518] 5-B (150 mg, 0.2 mmol) (synthetic reference CN116003403,2023,A), 8-A (80 mg, 0.25 mmol), and N-methylpyrrolidone (3 mL) were dissolved in the system. Cuprous iodide (48 mg, 0.25 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (36 mg, 0.25 mmol), and anhydrous potassium carbonate (69 mg, 0.5 mmol) were added to the system. The reaction was carried out at 130 °C for 3 h under a nitrogen atmosphere. Cool to room temperature, add 10 mL of water to the reaction solution, extract with ethyl acetate (10 mL × 3), wash with saturated sodium chloride aqueous solution (10 mL × 3), combine the organic layers and dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by column chromatography (eluent dichloromethane:methanol (v / v) = 30 / 1) to obtain compound 8 (40 mg, yield: 20.5%).

[0519] LCMS m / z = 972.7 [MH] -

[0520] Example 9: Preparation of Compound 9

[0521] Step 1: Preparation of compound 9-B

[0522] At 0°C, phosphorus oxychloride (0.58 g, 3.78 mmol) was added to DMF (2.5 mL, 32.43 mmol), and stirred for 20 minutes. Then, a DMF solution (10 mL) of 9-A (1.14 g, 3.15 mmol, CAS RN: 2212021-79-7, synthesis method referenced from patent: US2019 / 225604) was added. The reaction system was heated to 60°C and stirred for 12 hours. After the reaction was completed, the mixture was quenched in a saturated sodium bicarbonate solution (100 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by silica gel column chromatography to obtain 9-B (1.1 g, yield 86.3%).

[0523] LCMS m / z = 391.2[M+H] + ;

[0524] Step 2: Preparation of compound 9-C

[0525] 9-B (1.1 g, 2.71 mmol) was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.26 g, 10.84 mmol) was added under nitrogen protection. The reaction mixture was stirred at room temperature for 4 h. After the reaction was complete, the mixture was quenched in saturated sodium bicarbonate solution (50 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by silica gel column chromatography to give compound 9-C (850 mg, yield 83.2%).

[0526] LCMS m / z = 377.3 [M+H] + ;

[0527] Step 3: Preparation of compound 9-D

[0528] 9-C (850 mg, 2.26 mmol) was dissolved in DMF (9 mL) and cooled to 0 °C under nitrogen protection. Sodium hydride (135.6 mg, 3.39 mmol) was then added and the mixture was stirred for 30 minutes. Finally, chloroacetonitrile (341 mg, 4.52 mmol) was added. The reaction mixture was allowed to rise naturally to room temperature and stirred for 12 h. After the reaction was complete, the mixture was quenched with water (90 mL), extracted with ethyl acetate (15 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by silica gel column chromatography to obtain compound 9-D (920 mg, 98.1% yield).

[0529] LCMS m / z = 416.3 [M+H] + ;

[0530] Step 4: Preparation of compound 9-F

[0531] 9-D (920 mg, 2.21 mmol) and 9-E (915.8 mg, 6.63 mmol) were dissolved in tetrahydrofuran (10 mL). The solution was cooled to 0 °C, and then LiHMDS (4.4 mL, 2 M in THF) was added dropwise under nitrogen protection. The reaction system was stirred at 0 °C for 2 h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (15 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by silica gel column chromatography to give compound 9-F (340 mg, yield 33.7%).

[0532] LCMS m / z = 456.3 [M+H] + ;

[0533] Step 5: Preparation of compound 9-G

[0534] 9-F (340 mg, 0.75 mmol) was dissolved in DMSO (4 mL), followed by the addition of hydroxylamine hydrochloride (521.2 mg, 7.5 mmol) and sodium carbonate (794.9 mg, 7.5 mmol). The reaction mixture was heated to 60 °C and stirred for 12 h under nitrogen protection. After the reaction was complete, the mixture was diluted with water (50 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by silica gel column chromatography to obtain compound 9-G (355 mg, 97.4% yield).

[0535] Step 6: Preparation of compound 9-H

[0536] 9-G (355 mg, 0.73 mmol) was dissolved in DMSO (4 mL) and cooled to 0 °C. Then, CDI (236.7 mg, 1.46 mmol) and DBU (277.8 mg, 1.82 mmol) were added under a nitrogen atmosphere. The reaction system was stirred at room temperature for 2 h. After the reaction was complete, the system was diluted with water (50 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by silica gel column chromatography to give compound 9-H (310 mg, yield 82.9%).

[0537] LCMS m / z = 515.2 [M+H] + ;

[0538] Step 7: Preparation of compound 9-I

[0539] 9-H (180 mg, 0.35 mmol) was dissolved in n-propanol (1 mL), and then potassium hydroxide (196.4 mg, 3.5 mmol) was added. The reaction system was heated to 130 °C and stirred for 4 h. After the reaction was completed, the system was diluted with water (10 mL), extracted with ethyl acetate (5 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and then subjected to pre-HPLC to prepare compound 9-I (25 mg, yield 16.8%).

[0540] LCMS m / z = 424.1 [MH] - ;

[0541] Step 8: Preparation of Compound 9

[0542] 9-I (25 mg, 0.06 mmol) and 1-E (35 mg) were dissolved in DMF (0.5 mL), followed by the addition of HATU (33.7 mg, 0.09 mmol) and DIPEA (38.1 mg, 0.29 mmol). The reaction mixture was heated to 35 °C and stirred for 12 h. After the reaction was complete, the mixture was diluted with water (10 mL), extracted with ethyl acetate (5 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and then subjected to pre-HPLC to prepare compound 9 (6.9 mg, yield 12.1%).

[0543] LCMS m / z = 962.7 [MH]-;

[0544] HPLC Preparation Conditions: 1. Instruments: Waters 2767 preparative HPLC; Column: SUNFIRE@Prep C18 (19mm × 250mm) 2. The sample was dissolved in DMF and filtered through a 0.45μm filter to prepare the sample solution. 3. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 50mM ammonium bicarbonate) b. Gradient elution, with mobile phase A content ranging from 30% to 60% c. Flow rate: 12ml / min d. Elution time: 15min.

[0545] Example 10: Preparation of Compound 10

[0546] Step 1: Preparation of 10-B

[0547] 10-A (2.12 g, 10.0 mmol) was dissolved in dry tetrahydrofuran (80 mL) and placed at -70 °C. LDA (40 mL, 80 mmol, 2.0 M in THF / n-Hexane) was added dropwise, and the reaction was continued for 1 h. Then, 1,2-dibromoethane (11.28 g, 60 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched with a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 4:1) to obtain 10-B (902 mg, yield: 19%).

[0548] LCMS m / z = 238.0 [M+H] + 240.0 [M+H] +

[0549] Step 2: Preparation of compound 10-C

[0550] 10-B (902 mg, 3.8 mmol), methyl iodide (1.09 g, 7.67 mmol), and cesium carbonate (1.87 g, 5.73 mmol) were dissolved in DMF (15 mL) and reacted overnight at 70 °C. After cooling to room temperature, 60 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mL × 3), washed with saturated sodium chloride aqueous solution (50 mL × 2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 5 / 1) to give 10-C (880 mg, yield: 92.1%).

[0551] Step 3: Preparation of 10-D

[0552] 10-C (300 mg, 1.2 mmol) was dissolved in 1,2-dichloroethane (6 mL), and Lawesson's Reagent (283 mg, 0.7 mmol) was added. The mixture was reacted overnight at 70 °C. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 5:1) to give 10-D (100 mg, yield: 31.2%).

[0553] LCMS m / z = 268.0 [M+H] + 270.0 [M+H] +

[0554] Step 4: Preparation of Compound 10

[0555] 5-B (150 mg, 0.2 mmol) (synthetic reference CN116003403,2023,A), 10-D (67 mg, 0.25 mmol) were dissolved in N-methylpyrrolidone (4 mL). Cuprous iodide (57 mg, 0.3 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (43 mg, 0.3 mmol), and anhydrous potassium carbonate (69 mg, 0.5 mmol) were added to the system. The reaction was carried out at 130 °C for 3 h under a nitrogen atmosphere. Cool to room temperature, add 15 mL of water to the reaction solution, extract with ethyl acetate (50 mL × 3), wash with saturated sodium chloride aqueous solution (15 mL × 2), combine the organic layers and dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by column chromatography (eluent dichloromethane:methanol (v / v) = 30 / 1) to obtain compound 10 (110 mg, yield: 59.6%).

[0556] LCMS m / z = 920.6 [MH] -

[0557] Example 11: Preparation of Compound 11

[0558] Step 1: Preparation of 11-A

[0559] 5-A (155 mg, 0.5 mmol) was dissolved in dichloromethane (10 mL) and placed in an ice bath. Methyl trifluoromethanesulfonate (164 mg, 2.0 mmol) was added, and the mixture was reacted at room temperature for 3 h. Then, the mixture was placed in an ice bath. DIPEA (129 mg, 2.0 mmol) and methoxyamine hydrochloride (84 mg, 2.0 mmol) were dissolved in tetrahydrofuran (3 mL) and added to the reaction mixture. The mixture was reacted at room temperature for 1 h. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate. The mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 2:1) to obtain 11-A (62 mg, yield: 38.4%).

[0560] LCMS m / z = 325.0 [M+H] + 327.0 [M+H] +

[0561] Step 2: Preparation of Compound 11

[0562] 5-B (120 mg, 0.16 mmol) (synthetic reference CN116003403,2023,A), 11-A (62 mg, 0.19 mmol), and N-methylpyrrolidone (3 mL) were dissolved in the system. Cuprous iodide (46 mg, 0.24 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (34 mg, 0.24 mmol), and anhydrous potassium carbonate (66 mg, 0.48 mmol) were added to the system. The reaction was carried out at 130 °C for 3 h under a nitrogen atmosphere. Cool to room temperature, add 10 mL of water to the reaction solution, extract with ethyl acetate (10 mL × 3), wash with saturated sodium chloride aqueous solution (10 mL × 3), combine the organic layers and dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by column chromatography (eluent dichloromethane:methanol (v / v) = 30 / 1) to obtain compound 11 (131 mg, yield: 81.93%).

[0563] LCMS m / z = 490.2[M+2H] 2+

[0564] Example 12: Preparation of Compound 12

[0565] Step 1: Preparation of 12-A

[0566] 6A (5 g, 20.49 mmol) was dissolved in ultradry DMF (30 mL), and iodomethane (3.2 g, 22.54 mmol) and anhydrous potassium carbonate (5.5 g, 39.79 mmol) were added. The mixture was reacted at 60 °C for 2 h under a nitrogen atmosphere and then cooled to room temperature. 20 mL of saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The mixture was washed with saturated sodium chloride aqueous solution (20 mL × 3), and the organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain 12-A (4 g, yield 75.65%).

[0567] LCMS m / z = 258.0, 260.0 [M+H] +

[0568] Step 2: Preparation of compound 12-D

[0569] Using 12-A as a substrate, 12-D (300 mg, yield 75.5%) was obtained by referring to the synthesis method of intermediate 6-B.

[0570] LCMS m / z = 330.0 [M+H] +

[0571] Step 3: Preparation of Compound 12

[0572] Compound 12 (1.2 mg, yield 2.28%) was obtained by using 12-D as a substrate, following the synthetic method of compound 8.

[0573] LCMS m / z = 496.7 [M+2H] 2+

[0574] Example 13: Preparation of Compound 13

[0575] Using 7-B as a substrate, compound 13 (50 mg, yield: 41.32%) was obtained by following the synthetic method in steps one and two of Example 8.

[0576] LCMS m / z = 977.8 [M+H] +

[0577] LCMS m / z = 977.8 [M+H] +

[0578] 1H NMR(400MHz,CF3COOD)δ8.00(d,1H),7.68-7.56(m,2H),7.45-7.35(m,3H),7.32(d,2H),7.06(d,1H),6.95(s,1H),6.93(d,1H),6.18-6.03( m,1H),4.96-4.78(m,1H),4.56-4.42(m,2H),4.39-4.26(m,2H),4.22 -4.07(m,2H),3.96-3.84(m,1H),3.61-3.48(m,1H),3.41(d,1H),3.28 -3.15(m,1H),3.07-2.87(m,2H),2.38(s,6H),2.04(t,1H),1.99-1.77(m,8H),1.74(d,3H),1.55(s,3H)),1.49(s,3H),1.34(d,3H).

[0579] Example 14: Preparation of Compound 14

[0580] Step 1: Preparation of 14-B

[0581] 14-A (260 mg, 1.03 mmol) was dissolved in ultradry DMF (3 mL), and sodium hydride (49.6 mg, 1.24 mmol, 60% wt) was added under a nitrogen atmosphere at 0 °C. The mixture was stirred for 10 min, and iodomethane (219.3 mg, 1.54 mmol) was added. The mixture was then heated to room temperature and reacted for 12 h. 5 mL of saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3). The mixture was washed with saturated sodium chloride aqueous solution (5 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain 14-B (253 mg, yield 92.67%).

[0582] Step 2: Preparation of compound 14-C

[0583] 14-B (216 mg, 0.81 mmol) was dissolved in DCE (5 mL), and Lawesson's Reagent (242 mg, 0.6 mmol) was added. The mixture was reacted at 70 °C for 18 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 4:1) to give 14-C (198 mg, yield: 86.45%).

[0584] LCMS m / z = 282.0 [M+H] +

[0585] Step 3: Preparation of Compound 14

[0586] 5-B (100 mg, 0.14 mmol) and 14-C (39.11 mg, 0.14 mmol) were dissolved in N-methylpyrrolidone (2 mL). Cuprous iodide (40 mg, 0.21 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (30 mg, 0.21 mmol), and anhydrous potassium carbonate (58 mg, 0.42 mmol) were added to the system. The reaction was carried out at 130 °C for 2 h under a nitrogen atmosphere. After cooling to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The mixture was washed with saturated sodium chloride aqueous solution (10 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Pre-HPLC (instrument and preparative column: CAS-05-Semi-prep S preparative HPLC, column type C18, inner diameter × length = 19 mm × 250 mm). Preparation method: The crude product was filtered through an acetonitrile solution using a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was used to elute 90% by a 60% gradient (elution time 14 min), and the sample was lyophilized to obtain compound 14 (5 mg, yield: 3.92%).

[0587] Example 15: Preparation of Compound 15

[0588] Step 1: Preparation of 15-A

[0589] 6-E (114 mg, 0.34 mmol) was dissolved in dichloromethane (5 mL) and placed in an ice bath. Methyl trifluoromethanesulfonate (113 mg, 0.67 mmol) was added, and the mixture was reacted at room temperature for 3 h. Then, the mixture was placed in an ice bath. DIPEA (87 mg, 0.67 mmol) and cyanamide (29 mg, 0.67 mmol) were dissolved in tetrahydrofuran (1 mL) and added to the reaction mixture. The mixture was reacted at room temperature for 1 h. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate. The mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 2:1) to obtain 15-A (20 mg, yield: 17.1%).

[0590] LCMS m / z = 341.1 [M+H] +

[0591] Step 2: Preparation of Compound 15

[0592] Using 15-A (20 mg, 0.06 mmol) as the starting material, and following the synthetic method of compound 5, compound 15 was purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; column: SunFire@Prep C18 (19 mm × 250 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% TFA). Acetonitrile gradient was increased from 50% to 95%, flow rate was 15 mL / min, and retention time was 16.5 min) to obtain compound 15 (12 mg, yield 25.8%).

[0593] LCMS m / z = 995.2 [M+H] +

[0594] Example 16: Preparation of Compound 16

[0595] Step 1: Preparation of 16-B

[0596] 16-A (4.5 g, 21.2 mmol) was dissolved in 50 mL of dry DMF. 60% NaH (850 mg, 21.2 mmol) was added in portions under ice bath conditions. After stirring for 10 min, iodomethane (1.5 mL, 23.3 mmol) was added dropwise, and the mixture was transferred to room temperature and stirred overnight. After the reaction was complete as monitored by TLC, 250 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 4:1) to obtain 16-B (3.2 g, yield 67%).

[0597] Step 2: Preparation of 16-C

[0598] 16-B (1.5 g, 6.64 mmol) was dissolved in 35 mL of dry tetrahydrofuran and placed at -70 °C. Under a nitrogen atmosphere, LDA (10 mL, 20 mmol, 2.0 M in THF / n-Hexane) was slowly added dropwise while stirring for 1 h. Then, 2,2'-dibromodiethyl ether (3.1 g, 13.28 mmol) was added. After the addition was complete, the mixture was transferred to room temperature and reacted overnight. After the reaction was monitored by TLC until complete, the reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 2:1) to obtain 16-C (1.3 g, yield 66%).

[0599] LCMS m / z = 296.0 [M+H] +

[0600] Step 3: Preparation of 16-D

[0601] 16-C (600 mg, 2.03 mmol) was dissolved in 1,2-dichloroethane (10 mL), and Lawesson's Reagent (1.64 g, 4.06 mmol) was added. The mixture was reacted at 80 °C for 18 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane:methanol (v / v) = 20:1) to obtain 16-D (270 mg, yield 43%).

[0602] LCMS m / z = 312.0 [M+H] +

[0603] Step 4: Preparation of 16-E

[0604] 16-D (174 mg, 0.56 mmol) was dissolved in dichloromethane (10 mL) and placed in an ice bath. Methyl trifluoromethanesulfonate (184 mg, 1.12 mmol) was added, and the mixture was reacted at room temperature for 3 h. Then, the mixture was placed in an ice bath. DIPEA (145 mg, 1.12 mmol) and cyanamide (47 mg, 1.12 mmol) were dissolved in tetrahydrofuran (2 mL) and added to the reaction mixture. The mixture was reacted at room temperature for 1 h. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate. The mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 1:1) to obtain 16-E (150 mg, yield 84%).

[0605] LCMS m / z = 320.0 [M+H] +

[0606] Step 5: Preparation of Compound 16

[0607] Following the synthetic method of compound 5, compound 16 (95 mg, yield 22.3%) was obtained by preparative liquid chromatography (IPC) purification using 16-E (140 mg, 0.44 mmol) as the starting material (instrument: Waters 2767 preparative liquid chromatography; column: SunFire@Prep C18 (19 mm × 250 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% TFA). Acetonitrile gradient was increased from 50% to 95%, flow rate was 15 mL / min, and retention time was 16.4 min).

[0608] LCMS m / z = 974.5 [M+H] +

[0609] Example 17: Preparation of Compound 17

[0610] Step 1: Preparation of 17-A

[0611] 12-B (121 mg, 0.5 mmol) was dissolved in dry DMF (5 mL) and placed at 0 °C. Sodium hydride (50 mg, 1.25 mmol, 60% dispersion in mineral oil) was added, and the reaction was continued for 1 h. Then 3,3-bis(bromomethyl)oxetane (122 mg, 0.5 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched with saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 5:1) to obtain 17-A (51 mg, yield: 31.3%).

[0612] LCMS m / z = 326.0 [M+H] + 328.0 [M+H] +

[0613] Step 2: Preparation of Compound 17

[0614] 5-B (125 mg, 0.17 mmol) (synthetic reference CN116003403,2023,A) and 17-A (51 mg, 0.157 mmol) were dissolved in N-methylpyrrolidone (3 mL). Cuprous iodide (38 mg, 0.2 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (28 mg, 0.2 mmol), and anhydrous potassium carbonate (41 mg, 0.3 mmol) were added, and the mixture was reacted at 130 °C for 3 h under a nitrogen atmosphere. After cooling to room temperature, 15 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated sodium chloride aqueous solution (10 mL × 2), and the organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane:methanol (v / v) = 30 / 1) to give compound 9 (58 mg, yield: 37.7%).

[0615] LCMS m / z = 978.9 [MH] -

[0616] Example 18: Preparation of Compound 18

[0617] Step 1: Preparation of 18-B

[0618] 18-A (190 mg, 0.755 mmol), cesium carbonate (489 mg, 1.5 mmol), and iodomethane (213 mg, 1.5 mmol) were dissolved in acetonitrile (5 mL), reacted at 70 °C for 4 h, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 5:1) to obtain 18-B (188 mg, yield: 93.9%).

[0619] LCMS m / z = 266.1 [M+H] + 268.1 [M+H] +

[0620] Step 2: Preparation of 18-C

[0621] 18-B (150 mg, 0.566 mmol) was dissolved in 1,2-dichloroethane (6 mL), and Lawesson's Reagent (242 mg, 0.6 mmol) was added. The mixture was reacted at 70 °C for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 10:1) to give 18-C (123 mg, yield: 77.3%).

[0622] LCMS m / z = 282.0 [M+H] + 283.9 [M+H] +

[0623] Step 3: Preparation of Compound 18

[0624] 5-B (73 mg, 0.1 mmol) (synthetic reference CN116003403,2023,A), 18-C (28 mg, 0.1 mmol), were dissolved in N-methylpyrrolidone (2 mL), and cuprous iodide (28.6 mg, 0.15 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (21.3 mg, 0.15 mmol), and anhydrous potassium carbonate (41 mg, 0.3 mmol) were added. The mixture was reacted at 130 °C for 3 h under a nitrogen atmosphere. Cool to room temperature, add 15 mL of water to the reaction solution, extract with ethyl acetate (50 mL × 3), wash with saturated sodium chloride aqueous solution (10 mL × 2), combine the organic layers and dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by column chromatography (eluent dichloromethane:methanol (v / v) = 30 / 1) to obtain compound 18 (31 mg, yield: 32.1%).

[0625] LCMS m / z = 936.7 [M+H] +

[0626] Example 19: Preparation of Compound 19

[0627] Step 1: Preparation of Compound 19

[0628] 5-B (95.5 mg, 0.13 mmol) (synthesis reference CN116003403), 16-D (42 mg, 0.13 mmol) were dissolved in N-methylpyrrolidone (3 mL), and cuprous iodide (37.1 mg, 0.20 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (27.7 mg, 0.20 mmol) and anhydrous potassium carbonate (53.9 mg, 0.39 mmol) were added. The mixture was reacted at 110 °C for 3 h under a nitrogen atmosphere. Cool to room temperature, add 10 mL of water to the reaction solution, extract with ethyl acetate (10 mL × 3), wash with saturated sodium chloride aqueous solution (10 mL × 3), combine the organic layers and dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire C18 column, inner diameter × length = 19 mm × 250 mm). Preparation method: Filter the crude DMF solution through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: elute 95% acetonitrile with a 50% gradient (elution time 18 min), then maintain 95% acetonitrile elution for one minute, retention time 18.6 min. Lyophilization yields compound 19 (67 mg, yield: 51.6%).

[0629] LCMS m / z = 966.7 [MH] -

[0630] Example 20: Preparation of Compound 20

[0631] Step 1: Preparation of 20-A

[0632] 16-D (50 mg, 0.16 mmol) was dissolved in acetonitrile (2 mL) and placed in an ice bath. Methyl trifluoromethanesulfonate (52.5 mg, 0.32 mmol) was added. After reacting at room temperature for 3 h, DIPEA (62 mg, 0.48 mmol) and methoxyamine hydrochloride (26.7 mg, 0.32 mmol) were dissolved in acetonitrile (3 mL) and added to the reaction mixture. The reaction was carried out at 50 °C for 18 h. After cooling to room temperature, 10 mL of water was added to the reaction mixture. The mixture was extracted with ethyl acetate (10 mL × 3), washed with saturated sodium chloride aqueous solution (10 mL × 3), and the organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 2:1) to obtain 20-A (40 mg, yield: 76.8%).

[0633] LCMS m / z = 325.0 [MH] -

[0634] Step 2: Preparation of Compound 20

[0635] 5-B (88.2 mg, 0.12 mmol) (synthesis reference CN116003403) and 20-A (40 mg, 0.12 mmol) were dissolved in N-methylpyrrolidone (3 mL), and cuprous iodide (34.3 mg, 0.18 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (25.6 mg, 0.18 mmol) and anhydrous potassium carbonate (49.8 mg, 0.36 mmol) were added. The mixture was reacted at 110 °C for 3 h under a nitrogen atmosphere. Cool to room temperature, add 10 mL of water to the reaction solution, extract with ethyl acetate (10 mL × 3), wash with saturated sodium chloride aqueous solution (10 mL × 3), combine the organic layers and dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire C18 column, inner diameter × length = 19 mm × 250 mm). Preparation method: The crude product's DMF solution was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was used to elute 95% acetonitrile at a 50% gradient (elution time 18 min), then eluted at 95% acetonitrile for one minute, retention time 18.5 min. Lyophilization yielded compound 20 (35 mg, yield: 29.1%).

[0636] LCMS m / z = 979.7 [MH] -

[0637] Example 21: Preparation of compound 21

[0638] Step 1: Preparation of 21-A

[0639] Under an ice bath and nitrogen atmosphere, diisopropylamine (2.02 g, 20 mmol) was dissolved in tetrahydrofuran (5 mL), and n-butyllithium (7.96 mL, 20 mmol, 2.5 M in hexane) was added dropwise. The reaction was carried out in an ice bath for 0.5 h, and the resulting LDA solution was set aside for later use. 10-A (1.06 g, 5 mmol) was dissolved in tetrahydrofuran (5 mL), and under a nitrogen atmosphere, LDA was added dropwise to the system. The mixture was stirred for 0.5 h, and 1,1-bis-bromomethylcyclopropane (3.42 g, 15 mmol) was added dropwise. The mixture was then allowed to rise naturally to 30 °C and reacted for 18 h. The reaction was quenched by adding saturated ammonium chloride aqueous solution (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 21-A (218 mg, yield: 15.68%).

[0640] LCMS m / z = 278.0 [M+H] +

[0641] Step 2: Preparation of compound 21-B

[0642] 21-A (215 mg, 0.77 mmol) was dissolved in acetonitrile (5 mL), cesium carbonate (501.76 mg, 1.54 mmol) was added, and iodomethane (218.59 mg, 1.54 mmol) was added dropwise. The reaction was carried out at 60 °C for 18 h. The reaction was cooled to room temperature, the reaction was filtered, and the filter cake was washed with ethyl acetate (5 mL × 2). The filtrate was collected and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 21-B (194 mg, yield: 85.90%).

[0643] LCMS m / z = 292.0 [M+H] +

[0644] Step 3: Preparation of Compound 21

[0645] 5-B (102.87 mg, 0.14 mmol) was dissolved in NMP (3 mL), followed by the addition of 21-B (40.90 mg, 0.14 mmol), cuprous iodide (39.99 mg, 0.21 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (29.87 mg, 0.21 mmol), and potassium carbonate (58.05 mg, 0.42 mmol). The reaction was carried out under a nitrogen atmosphere at 130 °C for 3 h. After cooling to room temperature, the reaction was quenched by adding water (30 mL), extracted with ethyl acetate (15 mL × 3), and backwashed with saturated sodium chloride (45 mL × 2). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 21 (75 mg, yield: 56.6%).

[0646] LCMS m / z = 944.5 [MH] -

[0647] Example 22: Preparation of compound 22

[0648] Step 1: Preparation of 22-A

[0649] 21-B (150.0 mg, 0.51 mmol) was dissolved in 1,2-dichloroethane (5 mL), and Lawson's reagent (210.0 mg, 0.51 mmol) was added. The reaction was carried out under nitrogen atmosphere at 70 °C for 1.5 h. The reaction system was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain the target product 22-A (144.0 mg, yield: 91.00%).

[0650] LCMS m / z = 308.0 [M+H] +

[0651] Step 2: Preparation of Compound 22

[0652] 5-B (102.87 mg, 0.14 mmol) was dissolved in NMP (3 mL), followed by the addition of 22-A (43.15 mg, 0.14 mmol), cuprous iodide (39.99 mg, 0.21 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (29.87 mg, 0.21 mmol), and potassium carbonate (58.05 mg, 0.42 mmol). The reaction was carried out at 130 °C for 3 h under a nitrogen atmosphere. After cooling to room temperature, the reaction was quenched by adding water (30 mL), extracted with ethyl acetate (15 mL × 3), and backwashed with saturated sodium chloride (45 mL × 2). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to Pre-HPLC (instrument and preparative column: CAS-05-Semi-prep S preparative HPLC, column type C18, inner diameter × length = 19 mm × 250 mm). Preparation method: The acetonitrile solution of the crude product was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was used to elute 90% of the product with a 60% gradient (elution time 14 min), and the product was lyophilized to obtain compound 22 (30 mg, yield: 22.27%).

[0653] LCMS m / z = 960.7 [MH] -

[0654] Example 23: Preparation of compound 23

[0655] Step 1: Preparation of 23-A

[0656] 14-C (160 mg, 0.57 mmol) was dissolved in dichloromethane (5 mL) and placed in an ice bath. Methyl trifluoromethanesulfonate (190 mg, 1.16 mmol) was added, and the mixture was reacted at room temperature for 3 h. Then, the mixture was placed in an ice bath. DIPEA (0.2 mL, 1.21 mmol) and cyanamide (48 mg, 1.14 mmol) were dissolved in tetrahydrofuran (1 mL) and added to the reaction mixture. The mixture was reacted at room temperature for 1 h. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 2:1) to obtain 23-A (43 mg, yield: 26.14%).

[0657] LCMS m / z = 290.0 [M+H] + 292.0 [M+H] +

[0658] Step 2: Preparation of Compound 23

[0659] 5-B (110 mg, 0.15 mmol) and 23-A (43 mg, 0.15 mmol) were dissolved in N-methylpyrrolidone (2 mL). Cuprous iodide (43 mg, 0.23 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (32 mg, 0.22 mmol), and anhydrous potassium carbonate (63 mg, 0.46 mmol) were added to the system. The reaction was carried out at 130 °C for 3 h under a nitrogen atmosphere. After cooling to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3), washed with saturated sodium chloride aqueous solution (10 mL × 3), and the organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by Pre-HPLC (instrument and preparative column: CAS-05-Semi-prep S preparative HPLC, column type C18, inner diameter × length = 19 mm × 250 mm). Preparation method: The crude product was filtered through an acetonitrile solution using a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was used to elute 90% of the product with a 60% gradient (elution time 14 min), and the solution was lyophilized to obtain compound 15 (16 mg, yield: 11.32%).

[0660] LCMS m / z = 944.5 [M+H] +

[0661] Example 24: Preparation of compound 24

[0662] Step 1: Preparation of Compound 24

[0663] 24-A (105 mg, 0.25 mmol, CAS: 2212021-48-0, synthetic method according to patent: CN 109790161) and 1-E (150 mg) were dissolved in DMF (2 mL), followed by the addition of HATU (142.6 mg, 0.28 mmol) and DIPEA (161.6 mg, 1.25 mmol). The mixture was stirred at 35 °C for 12 h. After the reaction was complete, the system was diluted with water (20 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and then subjected to pre-HPLC to prepare compound 24 (95.4 mg, yield 39.3%).

[0664] LCMS m / z = 960.0 [M+H] + ;

[0665] Prep-HPLC conditions: 1. Instrument: Waters 2767 preparative HPLC; Column: SUNFIRE@Prep C18 (19mm × 250mm) 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% TFA) b. Gradient elution, with mobile phase A content ranging from 40% to 75% c. Flow rate: 12 ml / min d. Elution time: 14 min.

[0666] Example 25: Preparation of Compound 25

[0667] Step 1: Preparation of 25-B

[0668] 25-A (20 g, 156.25 mmol) was dissolved in methanol (200 mL), and sodium borodeuteride (5.25 g, 125 mmol) was added in portions at 0 °C. The reaction was carried out at 0 °C for 2 h, and 5 M hydrochloric acid (50 mL) was added. After stirring for 10 min, the mixture was extracted with ethyl acetate (200 mL × 3), washed with saturated sodium chloride aqueous solution (100 mL × 2), and the organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 2 / 1) to obtain 25-B (16.77 g, yield: 81.9%).

[0669] Step 2: Preparation of 25-C

[0670] 25-B (16 g, 122 mmol) was dissolved in tetrahydrofuran (200 mL), and triphenylphosphine (38.35 g, 146.4 mmol) and imidazole (9.12 g, 134.2 mmol) were added. Under nitrogen protection, elemental iodine (34.08 g, 134.2 mmol) was added in portions in an ice bath, and the reaction was carried out overnight at 40 °C. After cooling the reaction to room temperature, water was added and stirred for 10 minutes. The mixture was extracted with ethyl acetate (300 mL × 3), washed with saturated sodium chloride aqueous solution (100 mL × 2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 97:3) to obtain 25-C (9.59 g, yield: 32.6%).

[0671] 1 H NMR (400MHz, CDCl3) δ83.73-3.54(m,2H),2.33-2.03(m,4H),1.21(s,3H),1.20(s,3H).

[0672] Step 4: Preparation of Compound 25

[0673] Compound 25 was synthesized in two steps using 25-C and 25-C-1 as starting materials, according to CN 109790161 A.

[0674] LCMS m / z = 951.6 [M+H] +

[0675] 1 H NMR(400MHz,CF3COOD)δ7.71-7.58(m,3H),7.40(d,1H),7.36-7.24(m,3H),7.21(s,1H),7.03(s,1H),6.99 -6.80(m,2H),6.19 -6.01(m,1H),4.95-4.81(m,1H),4.62-4.45(m,2H),4.31 -4.07(m,4H),3.90(t,1H),3.61-3.40(m,2H),3.39(s,3H),2.38(s,6H), 2.16-1.81(m,11H),1.75(d,3H),1.55(s,3H),1.49(s,3H),1.34(d,3H).

[0676] Example 26: Preparation of Compound 26

[0677] Step 1: Preparation of 26-B

[0678] Lithium aluminum deuterium (6.3 g, 150 mmol) was dissolved in THF (150 mL). Under a nitrogen atmosphere and at -40 °C, ethyl pyruvate (15 g, 129.3 mmol) dissolved in THF (50 mL) was slowly added dropwise to the system. After the addition was complete, the temperature was naturally raised to 0 °C and the reaction was carried out for 6 h. Under an ice bath, water (7.0 mL) was slowly added dropwise to the reaction system, and then the mixture was stirred in an ice bath until no more gas was produced. Then, 15% sodium hydroxide (7.0 mL) and water (21.0 mL) were added dropwise, and stirring was continued for 0.5 h. The reaction system was filtered through diatomaceous earth and the filter cake was washed with tetrahydrofuran (30 mL × 2). The filtrate was collected and concentrated (35 °C) to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 26-B (6.02 g, yield 59%).

[0679] 1 H NMR (400MHz, CDCl3) δ1.14 (s, 3H).

[0680] Step 2: Preparation of 26-C

[0681] Substrate 26-B (6.0 g, 76 mmol) was dissolved in carbon tetrachloride (100 mL). Thionyl chloride (12.66 g, 106.4 mmol) was added dropwise under an ice bath and nitrogen atmosphere. After the addition was complete, the mixture was heated to 60 °C and reacted for 0.5 h. Then, the mixture was cooled to room temperature, and acetonitrile (100 mL) and water (160 mL) were added. Finally, sodium periodate (25 g, 114 mmol) and ruthenium trichloride hydrate (30 mg, 0.13 mmol) were added, and the mixture was reacted at room temperature for 2 h. The reaction mixture was extracted with ethyl acetate (300 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 26-C (9.27 g, yield 80.3%).

[0682] 1 H NMR (400MHz, CDCl3) δ1.59 (s, 3H).

[0683] Step 3: Preparation of 26-D

[0684] Substrate 26-D-1 (3.0 g, 7.48 mmol, Ref: CN 109790161) and 26-C (2.11 g, 15 mmol) were dissolved in tetrahydrofuran (50 mL). Under ice bath and nitrogen atmosphere, a 1 M solution of bis(trimethylsilylamino)lithium in tetrahydrofuran (30 mL, 30 mmol) was slowly added dropwise. After the addition was complete, the reaction was continued for 1 h under ice bath. The reaction was quenched with saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (100 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The crude product was purified by silica gel column chromatography to obtain 26-D (1.1 mg, yield 33.1%).

[0685] LCMS m / z = 445.2[M+H] +

[0686] Step 4: Preparation of 26-E

[0687] Substrate 26-D (1.1 g, 2.47 mmol) was dissolved in DMSO (15 mL), and sodium carbonate (2.62 g, 24.7 mmol) and hydroxylamine hydrochloride (1.7 g, 24.7 mmol) were added sequentially. The reaction was carried out at 60 °C for 5 h under a nitrogen atmosphere. The reaction was quenched with water (50 mL), extracted with ethyl acetate (50 mL × 3), washed with saturated sodium chloride aqueous solution (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The crude product and N,N'-carbonyldiimidazole (800 mg, 4.94 mmol) were dissolved in DMSO (30 mL), and DBU (751 mg, 4.94 mmol) was added dropwise under an ice bath and a nitrogen atmosphere. After the addition was complete, the temperature was raised to 35 °C under a nitrogen atmosphere and the reaction was carried out for 4 h. The reaction was quenched with water (50 mL) under ice bath conditions, the pH was adjusted to 6-7 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (60 mL), collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a mixture of 26-E and its chiral isomers (982 mg, yield 79%). This mixture was then separated by chiral HPLC to prepare 26-E (402 mg, retention time: 1.980 min).

[0688] LCMS m / z = 504.3 [M+H] +

[0689] Chiral analysis methods:

[0690] Instrument: CAS-05-ANA-SFC-D; Column: IG column; Mobile phase: A for CO2; B for 0.05% MNH3 in ethanol; Flow rate: 3 mL / min; Column temperature: 35℃; Detection wavelength: 220 nm

[0691] Chiral HPLC preparation method:

[0692] Instrument: CAS-05-Prep-SFC-E; Column: IG column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in ethanol; Flow rate: 120 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm; Compound concentration: 30 mg / mL, dissolved in a mixture of methanol and acetonitrile.

[0693] Step 5: Preparation of 26-F

[0694] 26-E (402 mg, 0.8 mmol) was dissolved in ethylene glycol monomethyl ether (2 mL), and potassium hydroxide (448 mg, 8.0 mmol) was added. The mixture was reacted at 100 °C for 5 h. The solvent was removed by concentration under reduced pressure. The crude product was dissolved in water (30 mL), extracted with ethyl acetate (10 mL), and the aqueous phase was collected and the pH was adjusted to 2-3 with 1 M hydrochloric acid. The mixture was then extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 26-F (312 mg, 94% yield).

[0695] LCMS m / z = 413.0 [MH] -

[0696] Step 6: Preparation of Compound 26

[0697] 26-F (312 mg, 0.75 mmol) was dissolved in DMF (5 mL), and 1-E (445 mg, 0.8 mmol), HATU (334 mg, 0.88 mmol), and N,N-diisopropylethylamine (322 mg, 2.5 mmol) were added sequentially. The reaction was carried out under nitrogen atmosphere at 30 °C for 16 h. The reaction was quenched with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The organic phase was backwashed with saturated sodium chloride aqueous solution (100 mL), collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 26 (480 mg, yield 67.2%).

[0698] LCMS m / z = 953.5 [M+H] +

[0699] 1 H NMR(400MHz,CF3COOD)δ7.69-7.58(m,3H),7.40(d,1H),7.36-7.25(m,3H),7.20(s,1H),7.03(d,1H),6.95(s,1H),6.92(d,1H) ,6.21-6.04(m,1H),4.94-4.81(m,1H),4.63-4.48(m,2H),4.32-4.09(m,4H),3.90(t,1H),3.60-3.40(m,2H),3.39(s,3H),3.28 -3.17(m,1H),2.38(s,6H),2.19-2.04(m,4H),1.99-1.88(m,4H),1.75(d,3H),1.55(s,3H),1.49(s,3H),1.33(s,3H).

[0700] Example 27: Preparation of Compound 27

[0701] Step 1: Preparation of 27-B

[0702] Deuterated lithium aluminum hydride (7.5 g, 178.5 mmol) was dissolved in THF (200 mL). Under nitrogen atmosphere and ice bath, a THF solution of D-ethyl lactate (21.08 g, 178.5 mmol) was added dropwise. The mixture was allowed to naturally warm to room temperature for 18 h under nitrogen atmosphere. Under ice bath, water (7.5 mL) was slowly added dropwise to the reaction system. The mixture was stirred in the ice bath until no more gas was produced. Then, 15% sodium hydroxide (22 mL) and water (7.5 mL) were added dropwise, and stirring was continued for 0.5 h. The reaction system was filtered, and the filter cake was washed with tetrahydrofuran (30 mL × 2). The filtrate was collected and concentrated (35 °C) to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 27-B (8.3 g, yield 59.50%).

[0703] 1 H NMR (400MHz, CDCl3) δ3.92-3.83(m,1H),2.64(s,2H),1.15(d,3H).

[0704] Step 2: Preparation of 27-C

[0705] 27-B (8.3 g, 106.26 mmol) was dissolved in carbon tetrachloride (85 mL). Thionyl chloride (17.70 g, 148.76 mmol) was added dropwise under an ice bath and nitrogen atmosphere. The reaction was carried out at 60 °C for 0.5 h. After cooling to room temperature, acetonitrile and water were added, followed by sodium periodate (34.09 g, 159.3 mmol) and ruthenium trichloride hydrate (0.24 g, 1.06 mmol). The reaction was carried out at room temperature for 1.5 h. The reaction was quenched by adding water (150 mL). The layers were separated and the organic layer was collected. The aqueous layer was extracted with ethyl acetate (100 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 27-C (11.0 g, yield 73.86%).

[0706] 1 H NMR (400MHz, CDCl3) δ5.16-5.08(m,1H),1.61(d,3H).

[0707] Step 3: Preparation of 27-D

[0708] 26-D-1 (1.45 g, 3.61 mmol, Ref: CN 109790161) and 27-C (1.52 g, 10.83 mmol) were dissolved in tetrahydrofuran (15 mL). Under an ice bath and nitrogen atmosphere, a 1 M solution of bis(trimethylsilylamino)lithium in tetrahydrofuran (14.4 mL, 14.44 mmol) was slowly added dropwise. The reaction was carried out for 1 h under an ice bath. The reaction was quenched by adding saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 27-D (945 mg, yield 58.99%).

[0709] LCMS m / z = 444.3[M+H] +

[0710] Step 4: Preparation of 27-E

[0711] 27-D (945 mg, 2.13 mmol) was dissolved in DMSO (10 mL), and sodium carbonate (2.26 g, 21.30 mmol) and hydroxylamine hydrochloride (1.48 g, 21.30 mmol) were added sequentially. The reaction was carried out at 60 °C for 18 h under a nitrogen atmosphere. The reaction was quenched with water (50 mL), extracted with ethyl acetate (20 mL × 3), backwashed with saturated sodium chloride aqueous solution (60 mL), and the organic phase was dried with anhydrous sodium sulfate. The mixture was filtered and concentrated to obtain the crude product. The crude product (973 mg, 2.04 mmol) and N,N'-carbonyldiimidazole (661.57 mg, 4.08 mmol) were dissolved in DMSO (10 mL), and DBU (776.42 mg, 5.1 mmol) was added dropwise under an ice bath and a nitrogen atmosphere. The reaction was carried out at 35 °C for 1 h under a nitrogen atmosphere. The reaction was quenched by adding water (50 mL) under ice bath conditions, the pH was adjusted to 6-7 with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, backwashed with saturated sodium chloride aqueous solution (60 mL), and the organic phase was collected. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 27-E (925.0 mg, yield 90.15%).

[0712] LCMS m / z = 503.2 [M+H] +

[0713] Step 5: Preparation of 27-F

[0714] 27-E (925 mg, 1.84 mmol) was dissolved in ethylene glycol monomethyl ether (4 mL), and potassium hydroxide (1.03 g, 18.40 mmol) was added. The mixture was reacted at 100 °C for 8 h. The solvent was removed by concentration under reduced pressure. The crude product was dissolved in water (20 mL), extracted with ethyl acetate (10 mL), and the aqueous phase was collected and the pH was adjusted to 2-3 with 1 N hydrochloric acid. The mixture was then extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 27-F (727.0 mg, yield 95.54%).

[0715] LCMS m / z = 412.2 [MH] -

[0716] Step 6: Preparation of Compound 27

[0717] 27-F (724 mg, 1.75 mmol) was dissolved in DMF (10 mL), and 1-E (1071.51 mg, 1.93 mmol), HATU (730 mg, 1.93 mmol), and N,N-diisopropylethylamine (680 mg, 5.25 mmol) were added sequentially. The reaction was carried out at 30 °C for 18 h under a nitrogen atmosphere. The reaction was quenched with water (50 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was backwashed with saturated sodium chloride aqueous solution (100 mL), collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 27 (1.02 g, yield 61.18%).

[0718] LCMS m / z = 952.6 [M+H] +

[0719] 1 H NMR(400MHz,CF3COOD)δ7.74-7.53(m,3H),7.40(d,1H),7.36-7.25(m,3H),7.24-7.17(m,1H),7.13-6.82(m,3H),6.19-5.8 7(m,1H),4.97-4.79(m,1H),4.64-4.47(m,2H),4.34-4.05(m,4H),3.99-3.82(m,1H),3.62-3.41(m,2H),3.39(s,3H),3.29 -3.16(m,1H),2.38(s,6H),2.19-2.04(m,4H),2.01-1.82(m,5H),1.75(d,3H),1.55(s,3H),1.49(s,3H),1.34(d,3H).

[0720] Example 28: Preparation of Compound 28

[0721] Step 1: Preparation of 28-B

[0722] 28-A (100 mg, 0.44 mmol) and 2-chloroethylchloromethyl ether (79 mg, 0.62 mmol) were dissolved in DMF (1 mL) and placed in an ice bath. The system was purged with nitrogen three times, followed by the addition of sodium hydride (39 mg, 0.96 mmol), and the reaction was carried out at room temperature for 1 h. The reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain 28-B (35 mg, yield: 28.1%).

[0723] LCMS m / z = 283.0 [M+H] +

[0724] Step 2: Preparation of Compound 28

[0725] 5-B (100 mg, 0.14 mmol) and 28-B (35 mg, 0.14 mmol) were dissolved in N-methylpyrrolidone (1.5 mL). Cuprous iodide (27 mg, 0.14 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.14 mmol), and anhydrous potassium carbonate (58 mg, 0.42 mmol) were added to the system. The reaction was carried out at 130 °C for 3 h under a nitrogen atmosphere. After cooling to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3), washed with saturated sodium chloride aqueous solution (10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by Pre-HPLC to give compound 28 (14 mg, yield: 11.1%).

[0726] LCMS m / z = 936.6 [M+H] +

[0727] HPLC Preparation Conditions: 1. Instrument: Waters 2767 preparative HPLC; Column: SUNFIRE@Prep C18 (19mm × 250mm) 2. The sample was dissolved in DMF and filtered through a 0.45μm filter to prepare the sample solution. 3. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% TFA) b. Gradient elution, with mobile phase A content ranging from 40% to 75% c. Flow rate: 12 ml / min d. Elution time: 14 min.

[0728] Example 29: Preparation of compound 29

[0729] Step 1: Preparation of 29-A

[0730] 28-B (520 mg, 1.84 mmol) was dissolved in 1,2-dichloroethane (6 mL), and Lawson's reagent (CAS: 19172-47-5, 409 mg, 1.01 mmol) was added. The mixture was reacted at 70 °C for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 29-A (290 mg, yield: 52.8%).

[0731] LCMS m / z = 300.0 [M+H] +

[0732] Step 2: Preparation of Compound 29

[0733] 5-B (100 mg, 0.14 mmol) and 29-A (42 mg, 0.14 mmol) were dissolved in N-methylpyrrolidone (1.5 mL), and cuprous iodide (27 mg, 0.14 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.14 mmol), and anhydrous potassium carbonate (58 mg, 0.42 mmol) were added. The reaction was carried out at 130 °C for 3 h under a nitrogen atmosphere. After cooling to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3), washed with saturated sodium chloride aqueous solution (10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by Pre-HPLC to give compound 29 (33 mg, yield: 25.2%).

[0734] LCMS m / z = 952.6 [M+H] +

[0735] HPLC Preparation Conditions: 1. Instrument: Waters 2767 preparative HPLC; Column: SUNFIRE@Prep C18 (19mm × 250mm) 2. The sample was dissolved in DMF and filtered through a 0.45μm filter to prepare the sample solution. 3. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% TFA) b. Gradient elution, with mobile phase A content ranging from 40% to 75% c. Flow rate: 12 ml / min d. Elution time: 14 min.

[0736] 1H NMR(400MHz,CF3COOD)δ7.70-7.55(m,3H),7.45-7.25(m,5H),7.05(s,1H),6.99-6.83(m,2H), 6.20-6.04(m,1H),4.95-4.78(m,1H),4.72-4.50(m,2H),4.39(d,1H),4.27-4.08(m,3H),3.96 -3.84(m,1H),3.74(s,3H),3.61-3.40(m,2H),3.27-3.18(m,1H),2.89-2.77(m,1H),2.46-2.3 4(m,7H),2.04(t,1H),1.99-1.81(m,6H),1.75(d,3H),1.55(s,3H),1.49(s,3H),1.34(d,3H).

[0737] Example 30: Preparation of compound 30

[0738] Step 1: Preparation of 30-B

[0739] 30-A (500 mg, 2.21 mmol) was dissolved in 1,2-dichloroethane (5 mL), and Lawson's reagent (492 mg, 1.22 mmol) was added. The mixture was reacted at 70 °C for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 30-B (250 mg, yield: 46.7%).

[0740] LCMS m / z = 244.0 [M+H] +

[0741] Step 2: Preparation of 30-C

[0742] 30-B (100 mg, 0.41 mmol) was dissolved in tetrahydrofuran (1 mL), and diisopropylaminolithium (0.15 mL, 2 M in THF) was added dropwise at -78 °C after three nitrogen purgings. The mixture was stirred for 30 minutes, followed by the addition of iodomethane (175 mg, 1.23 mmol). The system was slowly heated to room temperature and the reaction continued for 12 h. After the reaction was complete, a saturated ammonium chloride aqueous solution (5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 30-C (60 mg, yield: 53.8%).

[0743] LCMS m / z = 271.9 [M+H] +

[0744] Step 3: Preparation of Compound 30

[0745] 5-B (160 mg, 0.22 mmol) and 30-C (59 mg, 0.22 mmol) were dissolved in N-methylpyrrolidone (2 mL), and cuprous iodide (42 mg, 0.22 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (31 mg, 0.22 mmol), and anhydrous potassium carbonate (91 mg, 0.66 mmol) were added. The reaction mixture was reacted at 130 °C for 3 h under a nitrogen atmosphere. After cooling to room temperature, 10 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3), washed with saturated sodium chloride aqueous solution (10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by Pre-HPLC to give compound 30 (4 mg, yield: 1.8%).

[0746] LCMS m / z = 925.6 [M+H] +

[0747] HPLC Preparation Conditions: 1. Instrument: Waters 2767 preparative HPLC; Column: SUNFIRE@Prep C18 (19mm × 250mm) 2. The sample was dissolved in DMF and filtered through a 0.45μm filter to prepare the sample solution. 3. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% TFA) b. Gradient elution, with mobile phase A content ranging from 40% to 75% c. Flow rate: 12 ml / min d. Elution time: 14 min.

[0748] Example 31: Preparation of compounds 31-A-P1 and 31-A-P2

[0749] Step 1: Preparation of 29-Aa and 29-Ab

[0750] 29-A (240 mg, 0.80 mmol) was purified by chiral separation using SFC to obtain 29-A-P1 (71 mg) and 29-A-P2 (77 mg).

[0751] One of compounds 29-A-P1 and 29-A-P2 is 29-Aa, and the other is 29-Ab.

[0752] SFC chiral separation method: Instrument: CAS-05-Prep-SFC-e; Column: IG column. The sample was dissolved in acetonitrile and ethanol, filtered through a 0.45μm filter to prepare the sample solution. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: CO2; Mobile phase B: Ethanol (containing 0.1% NH3·H2O) b. Flow rate: 100mL / min.

[0753] Step 2: Preparation of compounds 31-Aa and 31-Ab

[0754] 5-B (100 mg, 0.14 mmol) and 29-A-P1 (42 mg, 0.14 mmol) were dissolved in N-methylpyrrolidone (1.5 mL). Cuprous iodide (27 mg, 0.14 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.14 mmol), and anhydrous potassium carbonate (58 mg, 0.42 mmol) were added to the system. The reaction was carried out at 130 °C for 3 h under a nitrogen atmosphere. After cooling to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3), washed with saturated sodium chloride aqueous solution (10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by Pre-HPLC to give compound 31-A-P1 (42 mg, yield: 32.4%).

[0755] LCMS m / z = 952.6 [M+H] +

[0756] 1 H NMR(400MHz,CF3COOD)δ7.69-7.57(m,3H),7.43-7.29(m,5H),7.05(d,1H),6.99-6.88(m,2H), 6.18-6.03(m,1H),4.92-4.79(m,1H),4.72-4.52(m,2H),4.39(d,1H),4.25-4.08(m,3H),3.97 -3.85(m,1H),3.74(s,3H),3.60-3.40(m,2H),3.26-3.17(m,1H),2.88-2.77(m,1H),2.46-2.3 6(m,7H),2.04(t,1H),2.00-1.85(m,6H),1.75(d,3H),1.55(s,3H),1.49(s,3H),1.34(d,3H).

[0757] HPLC Preparation Conditions: 1. Instrument: Waters 2767 preparative HPLC; Column: SUNFIRE@Prep C18 (19mm × 250mm) 2. The sample was dissolved in DMF and filtered through a 0.45μm filter to prepare the sample solution. 3. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% TFA) b. Gradient elution, with mobile phase A content ranging from 40% to 75% c. Flow rate: 12 ml / min d. Elution time: 14 min.

[0758] The preparation and purification methods of compound 31-A-P2 were the same as those of compound 31-A-P1, yielding compound 31-A-P2 (37 mg, yield: 28.2%).

[0759] LCMS m / z = 952.6 [M+H] +

[0760] 1 H NMR(400MHz,CF3COOD)δ7.68-7.57(m,3H),7.42-7.28(m,5H),7.05(d,1H),7.00-6.90(m,2H), 6.17-6.06(m,1H),4.92-4.81(m,1H),4.70-4.51(m,2H),4.39(d,1H),4.25-4.09(m,3H),3.96 -3.85(m,1H),3.74(s,3H),3.59-3.40(m,2H),3.26-3.18(m,1H),2.89-2.76(m,1H),2.45-2.3 7(m,7H),2.04(t,1H),1.99-1.85(m,6H),1.75(d,3H),1.55(s,3H),1.49(s,3H),1.34(d,3H).

[0761] One of compounds 31-A-P1 and 31-A-P2 is 31-Aa, and the other is 31-Ab.

[0762] Example 32: Preparation of compound 32

[0763] Step 1: Preparation of 32-B

[0764] 32-A (16.77 g, 226.38 mmol) was dissolved in methanol (600 mL). Sodium borodeuteride (9.5 g, 226.95 mmol) was added in portions under a nitrogen atmosphere and in an ice bath. The reaction mixture was then brought to room temperature and reacted for 16 hours. Under ice bath conditions, 3N hydrochloric acid was slowly added dropwise to adjust the pH to weakly acidic. The mixture was concentrated to obtain the crude product, which was then purified by silica gel column chromatography to obtain 32-B (6.322 g, yield 36.22%).

[0765] 1 H NMR(400MHz, CDCl3)δ4.18-3.14(m,2H),3.16(s,2H),1.20(s,3H),

[0766] Step 2: Preparation of Compound 32

[0767] Using 32-B as a substrate, compound 32 was obtained by following the synthetic methods of steps two through six of compound 26 (106 mg, yield 41.8%).

[0768] LCMS m / z = 951.5 [M+H] +

[0769] 1 H NMR(400MHz,CF3COOD)δ7.70-7.57(m,3H),7.39(d,1H),7.35-7.26(m,3H),7.21(s,1H),7.03(d,1H),6.96(s,1H),6.93(d,1H),6. 16-6.05(m,1H),4.95-4.77(m,1H),4.64-4.46(m,2H),4.33-4.06(m,4H),3.98-3.83(m,1H),3.60-3.40(m,2H),3.39(s,3H),3.27 -3.16(m,1H),2.38(s,6H),2.17-1.90(m,9H),1.79(d,1H),1.75(d,3H),1.55(s,3H),1.49(s,3H),1.33(s,3H).

[0770] Example 33: Preparation of compounds 33-E-1 and 33-E-2

[0771] Step 1: Preparation of 33-B

[0772] 33-A (25 g, 117.90 mmol) was dissolved in acetonitrile (250 mL), and the system was purged three times with nitrogen. Deuterated iodomethane (34 g, 235.80 mmol) and potassium carbonate (48 g, 353.70 mmol) were then added. The reaction was carried out under nitrogen atmosphere at 70 °C for 12 h. After the reaction was complete, the mixture was filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 33-B (16 g, yield: 59.2%).

[0773] LCMS m / z = 231.0 [M+H] +

[0774] Step 2: Preparation of 33-C

[0775] Sodium hydride (3.8 g, 95.59 mmol) was added to a drying flask, which was then purged three times with nitrogen. DMF (50 mL) was added, and the mixture was cooled to -10 °C. A DMF (50 mL) solution of 33-B (10 g, 43.65 mmol) was then added, and the mixture was stirred for 30 minutes. 2-Chloroethylchloromethyl ether (8.5 g, 65.47 mmol) was added dropwise. The mixture was slowly heated to room temperature and stirred for 2 hours. After the reaction was complete, the mixture was quenched by adding dropwise to a saturated ammonium chloride solution (1 L). The mixture was extracted with ethyl acetate (100 mL × 3), and the organic phase was washed with saturated sodium chloride (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give 33-C (6.8 g, yield: 54.6%).

[0776] Step 3: Preparation of 33-D

[0777] 33-C (7.9 g, 27.70 mmol) was dissolved in 1,2-dichloroethane (80 mL), followed by the addition of Lawson's reagent (6.2 g, 15.24 mmol). The mixture was stirred at 70 °C for 4 h. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give 33-D (4.5 g, yield: 53.9%).

[0778] LCMS m / z = 304.0 [M+H] +

[0779] Step 4: Preparation of 33-Da and 33-Db

[0780] 33-D (2.1 g, 6.97 mmol) was purified by chiral separation using stoichiometry (SFC) to yield 33-D-P1 (850 mg, SFC retention time T = 1.661 min) and 33-D-P2 (920 mg, SFC retention time T = 2.176 min). Compounds 33-D-P1 and 33-D-P2 are, respectively, compounds 33-Da and 33-Db.

[0781] SFC chiral separation method: Instrument: CAS-05-Prep-SFC-e; Column: IG column. The sample was dissolved in acetonitrile and ethanol, filtered through a 0.45μm filter to prepare the sample solution. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: CO2; Mobile phase B: Ethanol (containing 0.1% NH3·H2O) b. Flow rate: 100mL / min.

[0782] Step 5: Preparation of compounds 33-Ea and 33-Eb

[0783] 5-B (100 mg, 0.14 mmol) and 33-D-P1 (42 mg, 0.14 mmol) were dissolved in N-methylpyrrolidone (1.5 mL), and cuprous iodide (27 mg, 0.14 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.14 mmol) and anhydrous potassium carbonate (58 mg, 0.42 mmol) were added. The reaction mixture was reacted at 130 °C for 3 h under a nitrogen atmosphere. After cooling to room temperature, 10 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3), washed with saturated sodium chloride aqueous solution (10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by Pre-HPLC to give compound 33-E-1 (43 mg, yield: 33.1%).

[0784] LCMS m / z = 955.6 [M+H] +

[0785] 1 H NMR(400MHz,CF3COOD)δ7.68-7.59(m,3H),7.43-7.29(m,5H),7.04(d,1H),6.98-6.91(m,2 H),6.15-6.07(m,1H),4.92-4.81(m,1H),4.71-4.54(m,2H),4.39(d,1H),4.26-4.06(m,3H ),3.98-3.84(m,1H),3.59-3.39(m,2H),3.26-3.18(m,1H),2.87-2.78(m,1H),2.46-2.36( m,7H),2.04(t,1H),1.99-1.84(m,6H),1.75(d,3H),1.55(s,3H),1.49(s,3H),1.34(d,3H).

[0786] Pre-HPLC preparation conditions: 1. Instrument: Waters 2767 preparative HPLC; Column: SUNFIRE@Prep C18 (19mm × 250mm) 2. The sample was dissolved in DMF and filtered through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% TFA) b. Gradient elution, with mobile phase A content ranging from 40% to 75% c. Flow rate: 12 ml / min d. Elution time: 14 min.

[0787] The preparation and purification methods of compound 33-E-2 were the same as those of compound 33-E-1, yielding compound 33-E-2 (44 mg, yield: 33.6%).

[0788] LCMS m / z = 955.6 [M+H] +

[0789] 1 H NMR(400MHz,CF3COOD)δ7.72-7.52(m,3H),7.46-7.19(m,5H),7.11-6.86(m,3H), 6.22-5.87(m,1H),4.95-4.81(m,1H),4.74-4.49(m,2H),4.39(d,1H),4.28-4.06( m,3H),3.97-3.83(m,1H),3.62-3.35(m,2H),3.30-3.15(m,1H),2.92-2.74(m,1H ),2.48-2.31(m,7H),2.08-1.71(m,10H),1.55(s,3H),1.49(s,3H),1.34(d,3H)..

[0790] Compounds 33-E-1 and 33-E-2, one of which is compound 33-Ea and the other is compound 33-Eb.

[0791] Example 34: Preparation of compounds 34-C-1 and 33-C-2

[0792] Step 1: Preparation of 34-B

[0793] 34-A (500 mg, 1.21 mmol, CAS: 2212021-63-9) was dissolved in DMF (10 mL), and 27-F (503 mg, 1.33 mmol), HATU (552 mg, 1.45 mmol), and N,N-diisopropylethylamine (782 mg, 6.05 mmol) were added sequentially. The reaction was carried out at 30 °C for 12 h. After the reaction was completed, water (50 mL) was added to quench the reaction, and the organic phase was extracted with ethyl acetate (30 mL × 3). The organic phase was backwashed with saturated brine (100 mL), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 34-B (650 mg, yield: 72.9%).

[0794] LCMS m / z = 231.0 [M+H] +

[0795] Step 2: Preparation of compounds 34-Ca and 34-Cb

[0796] 34-B (50 mg, 0.07 mmol) and 33-D-P1 (20 mg, 0.07 mmol) were dissolved in N-methylpyrrolidone (1 mL). Cuprous iodide (13 mg, 0.07 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (10 mg, 0.07 mmol), and anhydrous potassium carbonate (28 mg, 0.20 mmol) were added to the system. The reaction was carried out at 130 °C for 3 h under a nitrogen atmosphere. After cooling to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3), washed with saturated sodium chloride aqueous solution (10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by Pre-HPLC to give compound 34-C-1 (23 mg, yield: 34.9%).

[0797] LCMS m / z = 957.6 [M+H] +

[0798] 1 H NMR(400MHz,CF3COOD)δ7.71-7.56(m,3H),7.44-7.26(m,5H),7.05(s,1H),7.00-6.79(m ,2H),6.22-6.01(m,1H),4.95-4.78(m,1H),4.74-4.49(m,2H),4.39(d,1H),4.27-4.06(m ,3H),4.01-3.78(m,1H),3.60-3.34(m,2H),3.26-3.15(m,1H),2.96-2.76(m,1H),2.45-2 .36(m,7H),1.99-1.84(m,5H),1.81-1.67(m,3H),1.55(s,3H),1.49(s,3H),1.33(d,3H).

[0799] Pre-HPLC preparation conditions: 1. Instrument: Waters 2767 preparative HPLC; Column: SUNFIRE@Prep C18 (19mm × 250mm) 2. The sample was dissolved in DMF and filtered through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% TFA) b. Gradient elution, with mobile phase A content ranging from 40% to 75% c. Flow rate: 12 ml / min d. Elution time: 14 min.

[0800] The preparation and purification methods of compound 34-C-2 were the same as those of compound 34-C-1, yielding compound 34-C-2 (23 mg, yield: 35.2%).

[0801] Of compounds 34-C-1 and 34-C-2, one is compound 34-Ca and the other is compound 34-Cb.

[0802] Example 35: Preparation of compound 35G and its stereoisomers

[0803] Step 1: Preparation of 35-C

[0804] 35-A (CAS: 2212022-56-3, 3.89 g, 7.94 mmol) was dissolved in DMF (75 mL), and 35-B (CAS: 2212021-78-6, 2.17 g, 7.94 mmol), HATU (3.02 g, 7.94 mmol), and N,N-diisopropylethylamine (4.2 mL, 25.41 mmol) were added sequentially. After the addition was complete, the reaction was carried out at 30 °C for 16 h under a nitrogen atmosphere. The reaction was quenched with water (300 mL), extracted with ethyl acetate (100 mL × 3), and the organic phases were combined. The organic phase was backwashed with saturated sodium chloride aqueous solution (100 mL), collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 35-C (5.45 g, yield 92.08%).

[0805] LCMS m / z = 745.4 [M+H] +

[0806] Step 2: Preparation of 35-D

[0807] 35-C (5.45 g, 7.32 mmol) was dissolved in 1,2-dichloroethane (50 mL), and Lawesson's Reagent (2.96 g, 7.32 mmol) was added. The mixture was reacted at 70 °C for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to give 35-D (5.12 g, yield: 91.96%).

[0808] LCMS m / z = 761.4 [M+H] +

[0809] Step 3: Preparation of 35-E

[0810] 35-D (5.12 g, 6.73 mmol) was dissolved in DMF (60 mL), and sodium hydride (297 mg, 7.42 mmol) was added under ice bath conditions. After stirring at 0 °C for 1 h, chloroacetonitrile (610 mg, 8.08 mmol) was added, and the reaction was carried out at room temperature for 16 h. The reaction was quenched with saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic phases were combined. The organic phase was backwashed with saturated sodium chloride aqueous solution (100 mL), collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 35-E (3.5 g, yield 65.02%).

[0811] Step 4: Preparation of 35-F

[0812] 35-E (1.5 g, 1.88 mmol) and (4R)-4-methyl-1,3,2-dioxathiapentane (778 mg, 5.63 mmol) were dissolved in tetrahydrofuran (20 mL). A 1 M solution of bis(trimethylsilylamino)lithium in tetrahydrofuran (7.5 mL, 7.5 mmol) was slowly added dropwise under an ice bath and nitrogen atmosphere. The reaction was carried out for 16 h under ice bath conditions. The reaction was quenched with saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 35-F (1.1 g, yield 69.84%).

[0813] LCMS m / z = 840.5 [M+H] +

[0814] Step 5: Preparation of 35-G

[0815] 35-F (45 mg, 0.054 mmol) was dissolved in DMSO (3 mL), and sodium carbonate (57 mg, 0.54 mmol) and hydroxylamine hydrochloride (37 mg, 0.54 mmol) were added sequentially. The reaction was carried out at 60 °C for 5 h under a nitrogen atmosphere. The reaction was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 3), washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product.

[0816] LCMS m / z = 873.3 [M+H] +

[0817] Step 6: Preparation of compounds 35-Ha and 35-Hb

[0818] The crude product obtained in step 5 and N,N'-carbonyldiimidazole (24 mg, 0.15 mmol) were dissolved in DMSO (3 mL). DBU (30 mg, 0.2 mmol) was added dropwise under an ice bath and nitrogen atmosphere, and the reaction was carried out at 35 °C for 4 h under a nitrogen atmosphere. The reaction was quenched with water (10 mL) under an ice bath, the pH was adjusted to 6-7 with 1 M hydrochloric acid, and the product was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (10 mL), and the organic phase was collected. The product was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by Pre-HPLC: 1. Instrument: Waters 2767; Column: Waters SunFire C8 19*250 5 μm. 2. The sample was dissolved in DMF to prepare a sample solution. 3. Preparative chromatographic conditions: Mobile phase A: acetonitrile; Mobile phase B: water (containing 5 mmol / L ammonium acetate), A phase ratio 30 to 77.5, gradient elution for 19 min. The flow rate was 12 ml / min. The eluent was collected and lyophilized to obtain compounds 35-H-P1 (5 mg, Pre-HPLC retention time 15.50 min) and 35-H-P2 (10 mg, Pre-HPLC retention time 17.45 min).

[0819] Compound 35-H-P1: LCMS m / z = 899.5 [M+H] +

[0820] Compound 35-H-P2: LCMS m / z = 899.5 [M+H] +

[0821] One of the compounds 35-H-P1 and 35-H-P2 is 35-Ha, and the other is 35-Hb.

[0822] Biological test example 1:

[0823] In vitro activity assay

[0824] HEK293-CRE-luc-GLP-1R cells were added to 384-well cell culture plates (Greiner#781946) at a specific cell density (5 μL / well); 5 μL / well of 2× working solution was added to each well, and the plates were sealed with sealing film. The plates were incubated at 37°C in a 5% CO2 incubator (Thermo) for 1 h. Subsequently, the cAMP-GS HIRANGE KIT (PerkinElmer, 62AM6PEB) was used for detection, and the assay reagents were prepared according to the kit instructions. After incubation, the assay reagents were added to the 384-well plates and incubated at room temperature in the dark for 1 h. The HTRF signals at 665 nm and 620 nm were then detected using a multi-mode microplate reader, and the data were exported in Excel format from the microplate reader. Open Prism GraphPad, take the logarithm of the sample concentration, and then perform a four-parameter fitting with the logarithm on the x-axis and the ratio of 665nm / 620nm on the y-axis to obtain the EC50 value of the curve.

[0825] Biological test results:

[0826] Table 1 EC of compounds 50 value

[0827] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a good agonistic effect on the GLP-1 receptor.

[0828] Biological test example 2:

[0829] Oral glucose tolerance test (OGTT)

[0830] The hypoglycemic effect of GLP-1 receptor agonists was evaluated in male C57BL / 6-G1p1rem2(hGLP1R)Smoc mice using an oral glucose tolerance test (OGTT). Animals were fasted for more than 16 hours and then randomly divided into groups. Basal fasting blood glucose (FBG) values ​​were measured using a glucometer. Mice with FBG in the range of 3.5–6.5 mmol / L were selected for oral administration, while the control group received the solvent. Fifteen minutes after administration, each group of animals was administered 25% glucose solution by gavage. Blood glucose levels were measured at 15 min, 30 min, 45 min, 1 h, and 2 h after glucose administration. The AUC of the 0-2 h blood glucose was calculated using Graphpad Prism software. 0-2h Calculate the inhibition rate.

[0831] Calculation formula: Glucose inhibition rate = (AUC of solvent group) 0-2h -AUC in the treatment group 0-2h ) / Solvent group AUC 0-2h ×100%

[0832] Conclusion: The compounds of the present invention, such as those in the examples, have good oral hypoglycemic effects on GLP-1 receptors.

[0833] Biological Test Example 3: Mouse Pharmacokinetic Test

[0834] Experimental animals: male C57 mice, 22-25g, 6 mice / compound.

[0835] Experimental design: On the day of the experiment, C57 mice were randomly divided into groups according to body weight. They were fasted for 12-14 hours before administration but allowed free access to water, and were fed 4 hours after administration.

[0836] Table 2. Dosage Information

[0837] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Gavage administration solvent: 5% DMSO + 5% Solutol + 10% PEG400 + 80% (20% SBE-β-CD);

[0838] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; DMSO: dimethyl sulfoxide; PEG400: polyethylene glycol 400; SBE-β-CD: sulfobutyl betacyclodextrin)

[0839] Blood samples of 0.06 mL were collected via the orbital cavity before and after isoflurane anesthesia, placed in EDTAK2 centrifuge tubes, and centrifuged at 5000 rpm for 10 min at 4°C to collect plasma. Blood collection time points for both the intravenous and gavage groups were 0, 5, 15, 30 min, 1, 2, 4, 7, and 24 h. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0840] Table 2-1 Pharmacokinetic results of the test compounds in mice (IV-2.5 mg / kg)

[0841] Table 2-2 Pharmacokinetic results of the test compounds in mice (PO₄ - 10 mg / kg)

[0842] Conclusion: The compounds of the present invention, such as those in the examples, have good mouse metabolic kinetic properties.

[0843] Biological Test Example 4: Monkey Pharmacokinetic Test

[0844] Experimental animals: Male cynomolgus monkeys, 3–5 kg, 3–6 years old, 5 animals / compound. Purchased from Hainan Xinzhengyuan Biotechnology Co., Ltd.

[0845] Experimental method: On the day of the experiment, 5 monkeys were randomly divided into two groups according to their body weight: 2 monkeys were given intravenous administration and 3 monkeys were given oral administration. The monkeys were fasted for 14-18 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[0846] Table 3. Dosage Information

[0847] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Gavage administration solvent: 5% DMSO + 5% Solutol + 90% (0.5% MC);

[0848] Blood samples of 1.0 mL were collected from venous sites in the extremities before and after drug administration and placed in OEDTAK2 centrifuge tubes. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min. Blood collection time points for both the intravenous and gavage groups were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, and 48 h. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0849] Table 3-1 Pharmacokinetic results of the test compounds in monkeys (IV-1 mg / kg)

[0850] Table 3-2 Pharmacokinetic results of the test compounds in monkeys (PO₄⁻ 5 mg / kg)

[0851] Conclusion: The compounds of the present invention, such as those in the examples, exhibit good monkey metabolic kinetic properties.

[0852] Biological Test Example 5: CYP450 Enzyme Inhibition Test

[0853] The aim of this study was to evaluate the effects of test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro assay system. Specific probe substrates for CYP450 isoenzymes were co-incubated with human liver microsomes and different concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS) after sample processing, and the changes in CYP enzyme activity were measured. The IC50 values ​​were calculated. 50 The value is used to evaluate the inhibitory potential of the test substance against each CYP enzyme subtype.

[0854] Table 4: IC50 of the test substance on CYP enzyme inhibition

[0855] Conclusion: The compounds of the present invention, such as those in the examples, exhibit weak inhibition of CYP.

[0856] Biological Test Example 6: Rat Pharmacokinetic Test

[0857] Experimental animals: Male SD rats, approximately 220g, 6-8 weeks old, 6 rats / compound.

[0858] Experimental design: On the day of the experiment, SD rats were randomly divided into groups according to their body weight. They were fasted for 12-14 hours before drug administration but allowed free access to water, and were fed 4 hours after drug administration.

[0859] Table 5. Dosage Information

[0860] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Gavage administration solvent: 5% DMSO + 5% Kolliphor Hs-15 + 90% (0.5%) MC

[0861] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; MC: methylcellulose)

[0862] Table 5-1: Pharmacokinetic results of the test compounds in rats (PO₄⁻ 5 mg / kg)

[0863] Conclusion: The compounds of the present invention, such as those in the examples, have good oral performance in rats.

[0864] Biological Test Example 7: Pharmacokinetic Test in Beagle Dogs

[0865] Experimental animals: Male beagles, weighing approximately 8–11 kg, 6 per compound, purchased from Beijing Mars Biotechnology Co., Ltd.

[0866] Experimental Methods: On the day of the experiment, 12 beagle dogs were randomly divided into groups according to their body weight. They were fasted for 12–14 hours prior to administration but allowed free access to water. Food was given 4 hours after administration. Administration was performed according to Table 4.

[0867] Table 6. Dosage Information

[0868] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Gavage administration solvent: 0.5% MC

[0869] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; MC: methylcellulose solution;)

[0870] Blood samples (1 ml) were collected via jugular or limb veins before and after drug administration and placed in EDTAK2 centrifuge tubes. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min. Blood collection time points for both the intravenous and gavage groups were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0871] Conclusion: The compounds of the present invention, such as those in the examples, have good oral performance in beagle dogs.

[0872] Biological Test Example 8: SLC Transporter Inhibition

[0873] HEK293-OATP1B1 and OATP1B3 cells were incubated for appropriate times with and without the analyte (0–30 μM), and samples were collected. The substrate content in the samples was detected using liquid chromatography-tandem mass spectrometry (LC-MS / MS). The transport activity of transporters was calculated with and without the analyte, yielding the percentage of transporter activity (%VC, Vehicle Control, solvent control) at different analyte concentrations. The half-maximal inhibitory concentration (IC50) was then calculated from this result. 50 ).

[0874] Conclusion: The compounds of the present invention, such as those in the examples, have weak inhibitory effects on OATP1B1 and OATP1B3.

[0875] Biological Test Example 9: UGT1A1 Inhibitory Activity Test

[0876] This experiment evaluated the inhibitory potential of test substances against UGT1A1 using recombinant human UGT1A1 enzyme. Bilirubin, a probe substrate for UGT1A1 enzyme, was co-incubated with recombinant human UGT1A1 enzyme and different concentrations (0–10 μM) of test substances. Uridine diphosphate glucuronide (UDPGA) was added to initiate the reaction. After the reaction, the samples were processed, and specific metabolites produced by bilirubin were quantitatively detected using liquid chromatography-tandem mass spectrometry (LC-MS / MS). Changes in UGT1A1 enzyme activity were measured, and the inhibition rates and IC50 values ​​at different concentrations were calculated to evaluate the inhibitory potential of the test substances against each UGT1A1 enzyme.

[0877] Table 7: UGT1A1 inhibition of the test compounds

[0878] Conclusion: The compounds of the present invention, such as the compounds in the examples, have weaker UGT1A1 inhibition and lower risk of hepatotoxicity compared to the control compounds.

[0879] Biological Test Example 10: An Exploratory Experiment on Oral Gavage Dosage in Crab-Eating Mammals

[0880] Animal information: 3-5 years old; weight range 2-5 kg; number of animals: a certain number of males and females in each dosage group; dosage group: 1 solvent control group + 3 compound dosage groups; administration method: oral gavage; administration frequency: once a day.

[0881] Main detection indicators:

[0882] 1. Clinical observation: 1-2 times daily;

[0883] 2. Weight: 1-2 times per week;

[0884] 3. Food intake: Once a day;

[0885] 4. Ophthalmological examination: once during the adaptation period and once before the last dose;

[0886] 5. Body temperature: Once during the adaptation period, and 3-4 times during the administration period;

[0887] 6. Electrocardiogram and blood pressure: once during the adaptation period, and 3-4 times during the medication period;

[0888] 7. Hematology: One dose during the adaptation period, and 2-3 doses during the administration period;

[0889] 8. Blood biochemistry: once during the adaptation period, and 2-3 times during the drug administration period;

[0890] 9. Blood coagulation: Once during the adaptation period, and 2-3 times during the administration period;

[0891] 10. Urine test: once during the adaptation period and once during the medication period;

[0892] 11. Gross observation: Dissection at the end of drug administration;

[0893] 12. Organ weight and coefficient: Weigh the major organs and calculate the organ-body / organ-brain coefficient;

[0894] 13. Bone marrow smear: At the last dissection after drug administration, take a sternal smear, prepare it, and review the slide;

[0895] 14: Histopathological examination: all organs;

[0896] 15: Accompanying TK: Blood samples were collected at 8-10 time points before the first and last administration and after administration, plasma was prepared, and blood drug concentration was detected by LC-MS / MS and toxicokinetic parameters (AUC, Cmax, T1 / 2, etc.) were calculated.

[0897] Conclusion: The compounds of the present invention, such as those in the examples, have good safety.

[0898] Biological Test Example 11: CaCO2 Permeability Test

[0899] The experiment used monolayers of Caco-2 cells, incubated in triple parallel in 96-well Transwell plates. A transport buffer solution (HBSS, 10 mM HEPES, pH 7.4±0.05) containing either the compound of the present invention (2 μM) or the control compounds digoxin (10 μM), naldolol (2 μM), and metoprolol (2 μM) was added to the dosing well on the apical or basal side. A transport buffer solution containing DMSO was added to the corresponding receiving well. After incubation at 37±1 °C for 2 hours, the cell plate was removed, and appropriate amounts of sample were transferred from both the apical and basal sides to new 96-well plates. Acetonitrile containing an internal standard was then added to precipitate the protein. The samples were analyzed using LC MS / MS to determine the concentrations of the compound of the present invention and the control compounds. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to the basal side of the monolayer cells, and from the basal side to the apical side, thereby calculating the efflux rate. Leakage of fluorescein was used to evaluate the integrity of the monolayer cells after 2 hours of incubation.

[0900] Conclusion: The compounds of the present invention, such as those in the examples, have good permeability.

[0901] Biological Test Example 12: CYP3A4 Induction Activity Assay

[0902] 1. Cell inoculation

[0903] 1) DPX2 cells were cultured in growth medium containing 10% fetal bovine serum.

[0904] 2) DPX2 cells were cultured in T-75 culture flasks in an incubator at 37°C, 5% CO2 and 95% relative humidity. The cells were digested when they reached 80-90% confluence with the bottom of the culture flask.

[0905] 3) Wash the surface of T-75 cultured cells with 10mL PBS, remove the PBS, add 3-5mL trypsin, digest at 37℃ for 5 minutes or until the cells are digested and suspended, and add excess culture medium containing fetal bovine serum to stop the trypsin digestion.

[0906] 4) Transfer the cell suspension to a conical-bottom centrifuge tube and centrifuge at 150g for 5 minutes at room temperature. Carefully aspirate the supernatant, resuspend the cells in treatment medium, and adjust the concentration to 3.2 × 10⁵ cells / mL (incubation time: 24 hours, seeding density: 4.0 × 10⁵ cells / mL). Add 25 μL of cell suspension to each well of a 384-well cell culture plate. Incubate the cell culture plate at 37°C, 5% CO₂, and 95% relative humidity for 24 hours.

[0907] 2. Compound preparation

[0908] 1) Prepare stock solutions of the test compound, positive control (rifampin), and negative control (propranolol) at a concentration of 1000× using DMSO. The final concentrations of the positive control (rifampin) are 1 μM and 10 μM, and the final concentration of the negative control (propranolol) is 10 μM. The final concentrations of the test compound are 10, 1, 0.1 μM or 30, 10, 3, 1, 0.3, 0.1 μM. The final concentration of DMSO is 0.1%.

[0909] 2) Remove the cell culture plate from the incubator and add 25 nL of positive and negative control drugs or test compound stock solutions directly using Echo, setting up three replicates for each concentration. Place the cell culture plate back into the incubator and continue incubation for 48 hours.

[0910] 3) Before starting experiments using the substrate, check cell morphology and monolayer integrity to ensure that the monolayer has acceptable research quality.

[0911] 3. Quantitative detection of PXR activation

[0912] 1) After 48 hours of drug treatment, the culture can be used for quantitative detection of PXR activation.

[0913] 2) CellTiter-Fluor TM Cell viability assay kit and One-Glo Luciferase reagent were equilibrated to room temperature. GF-AFC substrate (10 μL) was added to Assay Buffer (10 mL) to form a 2X reagent, which was then diluted with 10 mL PBS to form a 1X reagent. ONE-Glo Luciferase substrate was added to ONE-Glo Luciferase Assay Buffer.

[0914] 3) Remove the culture plate from the incubator, discard the culture medium, and add 1X CellTiter-Fluor TM Pour the reagent into the sample loading tank, add 25 μL of reagent to each well of the culture plate using a pipette, and then incubate in an incubator for 30 minutes.

[0915] 4) Remove the cell culture plate from the incubator, let it cool slightly to room temperature, and measure the fluorescence value using a fully automated quantitative microplate reader. The excitation light is 400nm and the emission light is 505nm.

[0916] 5) Pour ONE-Glo reagent into the sample loading tank, add 25 μL to each well, gently mix the plate, incubate at room temperature for 5 minutes, and measure the luminescence value.

[0917] 4. Data Analysis

[0918] All data was calculated using Microsoft Excel.

[0919] 1) The activity of luciferase is represented by RFU / RLU, where RLU is the average luminescence intensity value of three parallels for each concentration of each compound, and RFU is the average fluorescence intensity value of three parallels for each concentration of each compound.

[0920] The activation fold of mRNA is calculated using the following formula: Fold activation = (RLU test / RFU test) / (RLUvehicle / RFUvehicle)

[0921] 2) The cell viability percentage of the compound is calculated using the following formula:

[0922] Cell Viability%=(RFUtest / RFUvehicle)×100

[0923] 3) The percentage relative to the positive control is calculated using the following formula: Percent of positive control (%) = (Fold activation test / Fold activation Positive control) × 100

[0924] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no or weak CYP3A4 induction activity, and therefore have a lower risk of drug-drug interactions.

Claims

1. A compound or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein the compound is selected from compounds represented by general formula (I), wherein, Indicates a double bond; Y is selected from C, Z is selected from N, and J is selected from N; Ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, said ring A is optionally substituted with 1 to 5 R a substituents; Ring B is selected from C 6-10 aryl, 5- to 6-membered heteroaryl, 5 and 5-membered heteroaryl, 5 and 6-membered heteroaryl, 6 and 6-membered heteroaryl, C 3-10 carbocyclyl, 4- to 10-membered heterocyclyl, said Ring B is optionally substituted with 1 to 4 R b substituents; Ring D is selected from benzo 4- to 6-membered heterocyclyl, 11- to 12-membered tricyclic heterocyclyl, 13- to 16-membered tricyclic or tetracyclic heterocyclyl, 17- to 30-membered tricyclic or tetracyclic heterocyclyl, said ring D is optionally substituted with 1 to 6 R d substituents; L1 is selected from -C(=O)- and -C(=S)-; L2is selected from -(CR L1 R L2 ) m -; X is selected from O; Q is selected from key; m is selected from 1; R 4 selected from R 4d selected from H; R 6 selected from 4 to 10 membered heterocyclyl, said R 6 optionally substituted with 1 to 10 R 6a substituents; R a , R b , R 6a each independently is selected from H, deuterium, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -O-C 3-6 carbocyclyl, said alkyl, carbocyclyl being optionally substituted with 1 to 4 R 3-6 carbocyclyl, said alkyl, carbocyclyl being optionally substituted with 1 to 4 R k substituents; R d each independently selected from H, deuterium, halogen, =0, =S, CN, OH, C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -O-C 3-6 carbocyclyl, =N-R 5d , -NH-R 5d , C 3-6 carbocyclyl, said alkyl, alkylene, carbocyclyl being optionally substituted with 1 to 4 R k substituents; R 5d selected from CN, OH, -OC 1-6 alkyl, said alkyl being optionally substituted with 1 to 4 R k substituents; R 1 , R 2 is selected from H; R 3 selected from C 1-6 alkyl, said alkyl being optionally substituted with one to four R k substituents; R L1 R L2 and the atoms to which they are attached collectively form a C 3-8 carbocyclyl group optionally substituted with 1 to 4 R k substituents; R k Each is independently selected from deuterium, halogens, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic groups, -O-3 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-3 to 7-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 alkylene-3 to 7-membered heterocyclic groups, C 3-6 Carbocyclic groups, 3- to 7-membered heterocyclic groups, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic groups are optionally selected from one to four groups chosen from deuterium, halogen, CN, OH, NH2, CH2CN, C 1-6 Alkyl, C 1-6 The alkoxy group is replaced by a substituent.

2. The compound according to claim 1, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt. Ring B is selected from a 5- and 5-membered heteroaryl or a 5- and 6-membered heteroaryl, said ring B being optionally substituted with 1 to 4 R b substituents; Preferably, ring B is selected from pyrrolothienyl, pyrrolopyrazolyl, pyrrolopyrrolyl, pyrroloimidazolyl, pyrazolothienyl, imidazothienyl, imidazoiimidazolyl, pyrazolopyrazolyl, pyrrolothiazolyl, pyrrolofuranyl, indolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, pyrrolotriazinyl, pyrazolophenyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazophenyl, imidazopyridinyl, imidazopyrimidinyl, thienopyridinyl, thienophenyl, furanopyridinyl, furanophenyl, said ring B being optionally substituted with 1 to 4 R b substituents; Ring D is selected from said ring D is optionally substituted with 1 to 4 R d substituted; or Ring D is selected from said ring D is optionally substituted with 1 to 4 R d substituted; and L1is selected from -C(=S)-; ring A is selected from phenyl, 5- to 6- membered heteroaryl, said ring A is optionally substituted with 1 to 5 R a substituted; and L1is selected from -C(=S)-; ring A is selected from phenyl, 5- to 6- membered heteroaryl, said ring A is optionally substituted with 1 to 5 R R 6 selected from 4 to 8 membered single heterocyclyl, said R 6 optionally substituted with 1 to 10 R 6a substituents; R a , R b , R 6a are each independently selected from the group consisting of H, deuterium, halogen, C 1-4 alkyl-OC 1-4 alkyl, -SC 1-4 alkyl, -O-C 3-6 carbocyclyl C 3-6 carbocyclyl, said alkyl, carbocyclyl being optionally substituted with one to four R k substituents; R d each independently selected from H, deuterium, halogen, =0, =S, CN, OH, C 1-4 alkyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -O-C 3-6 carbocyclyl, =N-R 5d , -NH-R 5d , C 3-6 carbocyclyl, said alkyl, alkylene, carbocyclyl being optionally substituted with 1 to 4 R k substituents; R 5d selected from CN, OH, -OC 1-4 alkyl, said alkyl being optionally substituted with 1 to 4 R k substituents; R 3 selected from C 1-4 alkyl, said alkyl being optionally substituted with 1 to 4 R k substituents; R L1 R L2 and the carbon atoms to which they are attached join to form a C 3-6 carbocyclyl, which is optionally substituted with 1 to 4 R k substituents; R k each independently selected from deuterium, halogen, =0, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl)2, -O-C 3-6 carbocyclyl, -O-3- to 6-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 6-membered heterocyclyl, -C 1-2 alkylene-C 3-6 carbocyclyl, -C 1-2 alkylene-3- to 6-membered heterocyclyl, C 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic groups are optionally selected from one to four groups chosen from deuterium, halogen, CN, OH, NH2, CH2CN, C 1-4 Alkyl, C 1-4 The alkoxy group is replaced by a substituent.

3. The compound according to claim 2, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein, Ring B is selected from one of the following groups optionally substituted with 1 to 4 R b substituted with one of the following groups: Its right side is connected to Q; R 6 selected from oxetanyl, oxolanyl, oxanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, said R 6 optionally substituted with 1 to 10 R 6a substituents; R a R b R 6a Each element is independently selected from H, deuterium, F, Cl, Br, or arbitrarily selected from 1 to 3 R. k The substitution may be made with one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, or cyclopropyl; R d each independently selected from H, deuterium, F, Cl, Br, or one of the following groups optionally substituted with 1 to 3 R k methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl; R 5d selected from CN, OH, methoxy or ethoxy; R 3 selected from methyl, ethyl; R L1 R L2 and the carbon atoms to which they are attached together form a group which is optionally substituted by 1 to 4 R k cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; R k each independently selected from deuterium, F, CI, Br, I, =0, CN, OH, SH, N02, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy.

4. The compound according to claim 3, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein... R 4 selected from Ring A is selected from 1 to 5 R's. a Substituted phenyl; L2is selected from one of the following groups optionally substituted with 1 to 4 R k substituted as follows: Preferably, L2is selected from R k2 selected from H or deuterium; R k3 selected from H or deuterium; R k4 selected from H or deuterium; R k each independently selected from the group consisting of deuterium, F, Cl, Br, methyl, ethyl, said methyl, ethyl being optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, F, Cl, Br, I, CN, OH, NH2, CH2CN, methyl, ethyl, methoxy, ethoxy.

5. The compound according to claim 1, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt. L2is selected from Ring A is selected from phenyl, said ring A is optionally substituted with 1 to 5 R a substituents; Ring B is selected from said ring B is optionally substituted with 1 to 4 R b substituted, right side is connected with Q; -Q-R 6 selected from optionally substituted When substituted, it is replaced by 1 to 10 substituents selected from deuterium, F, Cl, Br, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy, or ethoxy. R a each independently selected from deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, methoxy, cyclopropyl, R b each independently selected from deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl; R d each independently selected from deuterium, F, Cl, Br, I, CN, OH, CHF2, CH2F, CF3, CD3, methyl, ethyl, methoxy, ethoxy, cyclopropyl.

6. The compound according to claim 5, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt. Ring A is selected from selected from the group consisting of k is selected from 0, 1, 2, 3, and 4; R k1 each independently is selected from deuterium, F, Cl, methyl, ethyl, CD3; Ring D is selected from or Ring D is selected from L1 is selected from -C(=S)-; R d1 selected from H, CD3, methyl, cyclopropyl; R d2 selected from H, deuterium, F, Cl, Br, CHF2, CF3, CD3, methyl, ethyl, cyclopropyl.

7. The compound according to claim 5 or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, the compound of general formula (I) is selected from general formula (Ig) or (Ih) ###00011### (Ig) (Ih) R k1 each independently is selected from deuterium, F, Cl, methyl, ethyl, CD3; R k2 selected from H or deuterium; R k3 selected from H or deuterium; R k4 selected from H or deuterium; Ring D1 is selected from Preferably, ring D is selected from said ring D is optionally substituted with 1 to 4 R d substituted; R d each independently selected from H, deuterium, halogen, =0, =S, CN, OH, C 1-4 alkyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -O-C 3-6 carbocyclyl, C 3-6 carbocyclyl, said alkyl, alkylene, carbocyclyl optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, C 1-4 alkyl or C 1-4 alkoxy; Preferably, ring D is selected from Preferably, ring D1 is selected from R 5d selected from CN, OH, methoxy or ethoxy; R d1 selected from H, CD3, methyl, cyclopropyl; R d2 selected from H, deuterium, F, Cl, Br, CHF2, CF3, CD3, methyl, ethyl, cyclopropyl; p1 is selected from 0, 1, 2, 3, 4 or 5; k is selected from 0, 1, 2, 3, and 4; R a each independently selected from deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, methoxy, cyclopropyl, 8. The compound according to claim 1, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein the compound is selected from one of the structures in Table E-1.

9. A pharmaceutical composition comprising the compound of any one of claims 1-8 or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, preferably, the pharmaceutical composition containing 1-1500 mg of the compound of any one of claims 1-8 or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt.

10. The use of the compound of any one of claims 1-8, or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, or pharmaceutical composition of claim 8, in the preparation of a medicament for treating diseases related to GLP-1R activity or expression levels, preferably, the diseases being selected from diabetes or obesity.

11. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1-8 or its racemate, stereoisomer, pharmaceutically acceptable salt, or pharmaceutical composition of claim 9, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably a disease related to GLP-1R activity or expression.

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