Pyrrolidine derivative and use thereof in drugs

Abstract

The present invention belongs to the field of medicinal chemistry, and relates to a pyrrolidine derivative and the use thereof in drugs. Specifically, disclosed in the present invention are a pyrrolidine derivative, a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the compound. Also disclosed in the present invention are a preparation method for the compound and the use thereof in the preparation of a drug for preventing and / or treating cardiovascular diseases.

Description

A pyrrolidine derivative and its use in pharmaceuticals Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry and relates to a pyrrolidine derivative and its preparation method, as well as the application of this type of compound in the preparation of drugs for the prevention and / or treatment of cardiovascular diseases. Background Technology

[0002] Lipoprotein(a) [Lp(a)] is considered a definitive independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic stenosis (CAVD). Its levels are primarily determined genetically and influenced by variations in the LPA gene locus, making lifestyle modifications ineffective. High serum Lp(a) levels (above 50 mg / dL or 125 nmol / L) are found to increase the risk of cardiovascular events in approximately 20% of the population, with the risk directly proportional to serum Lp(a) levels.

[0003] Lp(a) is composed of apolipoprotein B100 [apo B100] and apolipoprotein (a) [apo(a)], which are covalently linked by disulfide bonds. Elevated Lp(a) levels increase the residual risk of atherosclerotic cardiovascular disease (ASCVD), primarily due to Lp(a)-induced inflammation and oxidized phospholipids (OxPL). The most likely atherogenic components of Lp(a) are the low-density lipoprotein-like component containing apoB-100 molecules, apo(a) with antifibrinolytic properties, and OxPL, which exists in the lipid phase of Lp(a) and is covalently bound to apo(a). Among these, OxPL exhibits the strongest association, adversely affecting vascular inflammation, endothelial function, and thrombosis, thereby leading to atherosclerotic lesions.

[0004] Currently reported LP(a) inhibitors are mainly macromolecules or small nucleic acid drugs, such as the small interfering RNA Olpasiran and the antisense oligonucleotide Pelacarsen, which target the transcription of the LPA gene. These drugs are still in clinical development and all require injection. Therefore, there is an urgent need to develop a small molecule oral drug to reduce Lp(a) and provide patients with a more convenient and effective treatment method. Summary of the Invention

[0005] This invention provides a compound of formula (A), its stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof.

[0006] U is selected from oxygen atom, sulfur atom, NR2 or CR. 5h R 5i ;

[0007] Each X is independently selected from -O-, -S-, -NR2-, -C 1-6 Alkyl-, -C 1-6 Heteroalkyl- or -C 2-6 alkenyl-, wherein the alkyl, heteroalkyl, and alkenyl groups are optionally substituted with one or more R4 groups;

[0008] Y is selected from the following structure:

[0009] Wherein, W is selected from -NR 8c -、-O- or -S-;

[0010] A1 and A2 are either independently nonexistent or independently selected from -C. 1-6 Alkyl-, -C 1-6 Heteroalkyl-, -O-, -NR 8a -、-C(O)NR 8a -、-C(S)NR 8a -、-S(O)2NR 8a -、-S(O)NR 8a -、-NR 8a C(O)-、-NR 8a C(S)-、-NR 8a S(O)2- or -NR 8a S(O)-;

[0011] A3 and A4 are each independently selected from nitrogen atoms or CR atoms. 8b ;

[0012] L1, L2, L3, and L4 are each independently selected from chemical bonds, -O-, -S-, -NH-, and -C. 1-6 Alkyl-, -C 1-6 Heteroalkyl- or -C 2-6 Alkenyl-, wherein the alkyl, heteroalkyl, and alkenyl groups are optionally selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, oxo, thio, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cyclic alkyl group or one or more substituents of a 3-12 membered heterocyclic group are substituted.

[0013] R 7a R 7b R 7c R 7d Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, amide, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups, or R 7a and R 7b R 7c and R 7d Each of them, together with the carbon atoms they are attached to, forms C=O, C=C. 3-8 Cycloalkyl or 3-12 membered heterocyclic groups;

[0014] R 8a R 8b R 8c Each group is independently selected from hydrogen, deuterium, hydroxyl, cyano, amino, carboxyl, aldehyde, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), -C(O)-C1-6 Alkyl, -C(S)-C 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups;

[0015] Each ring A is independently selected from C. 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl or 3-12-membered heterocyclic groups, wherein the aryl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted by one or more R;

[0016] Each R is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, oxo, thio, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-8 cycloalkyl, C 6-10 The alkyl, 5-10-membered heteroaryl, or 3-12-membered heterocyclic group may be further selected from hydrogen, deuterium, halogen, alkoxy, haloalkoxy, deuteroalkoxy, alkylthio, alkenyl, deuteroalkenyl, alkynyl, deuteroalkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, optionally further selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, oxo, thio, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-8 cycloalkyl, C 6-10 The aryl group is substituted by one or more substituents from aryl, 5-10 heteroaryl, and 3-12 heterocyclic groups;

[0017] Each R1 is independently selected from hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 deuterated alkoxy group, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups;

[0018] Each R2 group is independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, aldehyde, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), -C(O)-C 1- 6-alkyl, -C(S)-C 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3- 8-cyclic alkyl or 3-12-membered heterocyclic groups;

[0019] Each R3, R4, R 5a R5b R 5c R 5d R 5e R 5f R 5g R 5h R 5i Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, amide, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups;

[0020] p and n are each independently selected from 0, 1, 2 or 3;

[0021] s is selected from 0, 1, 2, 3 or 4;

[0022] m is selected from 2, 3, or 4.

[0023] This invention provides a compound of formula (AI), its stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof.

[0024] Wherein, Y is selected from the following structure:

[0025] Wherein, W is selected from -NR 8c -、-O- or -S-;

[0026] A1 and A2 are either independently nonexistent or independently selected from -C. 1-6 Alkyl-, -C 1-6 Heteroalkyl-, -O-, -NR 8a -、-C(O)NR 8a -、-C(S)NR 8a -、-S(O)2NR 8a -、-S(O)NR 8a -、-NR 8a C(O)-、-NR8a C(S)-、-NR 8a S(O)2- or -NR 8a S(O)-;

[0027] A3 and A4 are each independently selected from nitrogen atoms or CR atoms. 8b ;

[0028] L1, L2, L3, and L4 are each independently selected from chemical bonds, -O-, -S-, -NH-, and -C. 1-6 Alkyl-, -C 1-6 Heteroalkyl- or -C 2-6 Alkenyl-, wherein the alkyl, heteroalkyl, and alkenyl groups are optionally selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, oxo, thio, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cyclic alkyl group or one or more substituents of a 3-12 membered heterocyclic group are substituted.

[0029] R 7a R 7b R 7c R 7d Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, amide, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups, or R 7a and R 7b R 7c and R 7d Each of them, together with the carbon atoms they are attached to, forms C=O, C=C. 3-8 Cycloalkyl or 3-12 membered heterocyclic groups;

[0030] R 8a R 8b R 8c Each group is independently selected from hydrogen, deuterium, hydroxyl, cyano, amino, carboxyl, aldehyde, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), -C(O)-C 1-6 Alkyl, -C(S)-C 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups;

[0031] Each ring A is independently selected from C. 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl or 3-12-membered heterocyclic groups, wherein the aryl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted by one or more R;

[0032] Each R is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, oxo, thio, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-8 cycloalkyl, C 6-10 The alkyl, 5-10-membered heteroaryl, or 3-12-membered heterocyclic group may be further selected from hydrogen, deuterium, halogen, alkoxy, haloalkoxy, deuteroalkoxy, alkylthio, alkenyl, deuteroalkenyl, alkynyl, deuteroalkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, optionally further selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, oxo, thio, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-8 cycloalkyl, C 6-10 The aryl group is substituted by one or more substituents from aryl, 5-10 heteroaryl, and 3-12 heterocyclic groups;

[0033] Each R1 is independently selected from hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 deuterated alkoxy group, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C3-8 Cycloalkyl or 3-12 membered heterocyclic groups;

[0034] Each R2 group is independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, aldehyde, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), -C(O)-C 1- 6-alkyl, -C(S)-C 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3- 8-cyclic alkyl or 3-12-membered heterocyclic groups;

[0035] For each R3, R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 5f R 5g Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, amide, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2- 6-acetylinyl, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups;

[0036] p and n are each independently selected from 0, 1, 2 or 3;

[0037] s is selected from 0, 1, 2, 3 or 4;

[0038] m is selected from 2, 3, or 4;

[0039] n1 is selected from 0, 1, 2, 3 or 4.

[0040] The compounds of formula (A) or formula (AI) described in this invention, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof,

[0041] Wherein, Y is selected from the following structure:

[0042] Wherein, W is selected from -NR 8c -、-O- or -S-;

[0043] L1, L2, L3, and L4 are each independently selected from chemical bonds, -O-, -S-, -NH-, and -C. 1-6 Alkyl-, -C 1-6 Heteroalkyl- or -C 2-6 Alkenyl-, wherein the alkyl, heteroalkyl, and alkenyl groups are optionally selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, oxo, thio, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cyclic alkyl group or one or more substituents of a 3-12 membered heterocyclic group are substituted.

[0044] R 7a R 7b R 7c R 7d Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, amide, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups, or R 7a and R 7b R 7c and R 7d Each of them, together with the carbon atoms they are attached to, forms C=O, C=C. 3-8 Cycloalkyl or 3-12 membered heterocyclic groups;

[0045] R 8a R 8b R 8c Each group is independently selected from hydrogen, deuterium, hydroxyl, cyano, amino, carboxyl, aldehyde, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), -C(O)-C 1-6 Alkyl, -C(S)-C 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups;

[0046] s is selected from 0, 1, 2, 3 or 4.

[0047] The compounds of formula (A) or formula (AI) described in this invention, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof,

[0048] Each ring A is independently selected from the following structures:

[0049] This invention provides the following compounds, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof.

[0050] This invention provides a compound of formula (A-II), its stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof.

[0051] Each of X1, X2, X3, and X4 is independently selected from either nitrogen atoms or CR atoms;

[0052] Y is selected from the following structure:

[0053] W is selected from -NR 8c -、-O- or -S-;

[0054] L1, L2, L3, and L4 are each independently selected from chemical bonds, -O-, -S-, -NH-, and -C. 1-6 Alkyl-, -C 1-6 Heteroalkyl- or -C 2-6 Alkenyl-, wherein the alkyl, heteroalkyl, and alkenyl groups are optionally selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, oxo, thio, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cyclic alkyl group or one or more substituents of a 3-12 membered heterocyclic group are substituted.

[0055] R 7a R 7b R 7c R7d Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, amide, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups, or R 7a and R 7b R 7c and R 7d Each of them, together with the carbon atoms they are attached to, forms C=O, C=C. 3-8 Cycloalkyl or 3-12 membered heterocyclic groups;

[0056] R 8a R 8b R 8c Each group is independently selected from hydrogen, deuterium, hydroxyl, cyano, amino, carboxyl, aldehyde, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), -C(O)-C 1-6 Alkyl, -C(S)-C 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic;

[0057] Each R is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1- 6-alkyl)2、-NH(C 1-6 Alkyl), C 3-8 cycloalkyl, C 6-10 The alkyl, 5-10-membered heteroaryl, or 3-12-membered heterocyclic group may be further selected from hydrogen, deuterium, halogen, alkoxy, haloalkoxy, deuteroalkoxy, alkylthio, alkenyl, deuteroalkenyl, alkynyl, deuteroalkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, optionally further selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, oxo, thio, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-8 cycloalkyl, C 6-10 The substituent is one or more of aryl, 5-10 heteroaryl, or 3-12 heterocyclic groups; or, two adjacent R groups are linked together to form an 8-12 fused heterocyclic group.

[0058] Each R1 is independently selected from hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C2-6 Deuterated alkynyl group, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 deuterated alkoxy group, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic;

[0059] Each R2 group is independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, aldehyde, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), -C(O)-C 1- 6-alkyl, -C(S)-C 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3- 8-cyclic alkyl or 3-12-membered heterocyclic groups;

[0060] For each R3, R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 5f R 5g Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, amide, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6Deuterated alkenyl, C 2- 6-acetylinyl, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups, or R 4a and R 4b The carbon atoms connected to them bond together to form C. 3-8 Cycloalkyl or 3-12 membered heterocyclic groups;

[0061] p and n are each independently selected from 0, 1, 2 or 3;

[0062] s is selected from 0, 1, 2, 3 or 4;

[0063] n1 is selected from 0, 1, 2, 3 or 4;

[0064] m is selected from 2, 3, or 4.

[0065] This invention provides a compound of formula (I), its stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof.

[0066] Each of X1, X2, X3, and X4 is independently selected from either nitrogen atoms or CR atoms;

[0067] Y is selected from the following structure:

[0068] Each R1 is independently selected from hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 3- 8-cycloalkyl;

[0069] Each R2 is independently selected from hydrogen, deuterium, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3- 8-cyclic alkyl, 3-10-membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups;

[0070] Each R, R3, R4a R 4b R 5a R 5b R 5c R 5d R 5e R 5f R 5g Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups;

[0071] n is selected from 1, 2, or 3;

[0072] n1 is selected from 0, 1, 2 or 3;

[0073] m is selected from 2, 3, or 4.

[0074] This invention provides a compound of formula (II), its stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof.

[0075] Wherein, Y is selected from the following structure:

[0076] Each R1 is independently selected from hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 3- 8-cycloalkyl;

[0077] Each R2 is independently selected from hydrogen, deuterium, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3- 8-cyclic alkyl, 3-10-membered heterocyclic alkyl, C6-10 Aryl or 5-10 heteroaryl groups;

[0078] For each R3, R 6a R 6b R 6c R 6d Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups;

[0079] m is selected from 2, 3, or 4.

[0080] This invention provides a compound of formula (III), its stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof.

[0081] Wherein, Y is selected from the following structure:

[0082] R 1a R 1b R 1c Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups;

[0083] R 2a R 2b R 2c Each is independently selected from hydrogen, deuterium, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-8 cycloalkyl;

[0084] R 3a R 3b R3c Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-8 cycloalkyl;

[0085] R 4a R 4b R 4c R 4d R 5a R 5b R 5c R 5d R 6a R 6b R 6c R 6d Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-8 Cycloalkyl.

[0086] This invention provides a compound of formula (IV), its stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof.

[0087] Wherein, Y is selected from the following structure:

[0088] R 2a R 2b R 2c Each is independently selected from hydrogen, deuterium, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6Deuterated alkynyl or C 3-8 cycloalkyl;

[0089] R 3a R 3b R 3c Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-8 cycloalkyl;

[0090] R 4a R 4b R 4c R 4d R 5a R 5b R 5c R 5d R 6a R 6b R 6c R 6d Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-8 Cycloalkyl.

[0091] This invention provides a compound of formula (V), its stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof.

[0092] Wherein, Y is selected from the following structure:

[0093] Each R 6a R 6b R 6c R 6d Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, C 1-6 Alkyl, C1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl or 3-10 membered heterocyclic alkyl;

[0094] m is selected from 2, 3, or 4.

[0095] The compounds of formula (V) described in this invention, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof,

[0096] Wherein, Y is selected from the following structure:

[0097] This invention provides the following compounds, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof.

[0098] This invention provides the following compounds, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof.

[0099] This invention provides the following compounds, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof.

[0100] This invention provides the following compounds, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof.

[0101] This invention provides the following compounds, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof.

[0102] This invention provides the following compounds, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof.

[0103] This invention provides the following compounds, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof.

[0104] The present invention provides a pharmaceutical composition comprising a therapeutically effective dose of the compound of the present invention, its stereoisomers, tautomers, deuterated compounds or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0105] The compounds described in this invention, their stereoisomers, tautomers, deuterated compounds or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described in this invention are used as medicines (i.e. for therapeutic purposes).

[0106] The use of the compounds described in this invention, their stereoisomers, tautomers, deuterated compounds or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described in this invention in the preparation of medicaments for the prevention and / or treatment of diseases associated with elevated plasma LP(a) levels.

[0107] The use of the compounds described in this invention, their stereoisomers, tautomers, deuterated compounds or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described in this invention in the preparation of medicaments for the prevention and / or treatment of cardiovascular diseases.

[0108] The cardiovascular diseases described in this invention are selected from stroke, atherosclerosis, thrombosis, coronary heart disease, aortic stenosis, etc.

[0109] The present invention provides a method for preventing and / or treating diseases associated with elevated plasma LP(a) levels, which involves administering to the patient an effective amount of a compound of the present invention, its stereoisomers, tautomers, deuterated compounds or pharmaceutically acceptable salts thereof, or a pharmaceutical composition of the present invention.

[0110] The present invention provides a method for preventing and / or treating a patient with cardiovascular disease by administering to the patient an effective amount of a compound of the present invention, its stereoisomers, tautomers, deuterated compounds or pharmaceutically acceptable salts thereof, or a pharmaceutical composition of the present invention.

[0111] Invention Details

[0112] All technical and scientific terms used in this specification have the meanings commonly understood by those of ordinary skill in the art.

[0113] The term "hydrogen" refers to H herein.

[0114] The term "deuterium" refers to D herein.

[0115] The term "nitrogen atom" refers to N herein.

[0116] The term "cyano group" refers to -CN herein.

[0117] The term "hydroxyl group" refers to -OH herein.

[0118] The term "nitro group" refers to -NO2 herein.

[0119] The term "carboxyl group" refers to -COOH herein.

[0120] The term "aldehyde group" refers to -CHO herein.

[0121] The term "halogen" refers to -F, -Cl, -Br and -I in the text.

[0122] The term "oxo group" refers to =O in the text.

[0123] The term "thio group" refers to =S in the text.

[0124] The term "amino group" or "amine" can interchangeably refer to -NR2 group herein, where each R is, for example, H or a substituent. In some embodiments, the amino group is further substituted to form an ammonium ion, such as NR 3+ . The ammonium moiety is specifically included in the definition of "amino group" or "amine". The substituent can be, for example, an alkyl group, a deuterated alkyl group, an alkoxy group, an enyne, an alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an amide or a carboxylic acid ester. The R group can be further substituted by one or more (e.g., 1 to 4) groups selected from the following: halogen, cyano, alkenyl, alkynyl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, urea, carbonyl, carboxylic acid ester, amine and amide. Non-limiting examples of "amino group" or "amine" include -NH2, -NH(CH3) and -N(CH3)2, etc.

[0125] The term "alkyl" refers to a saturated aliphatic hydrocarbon group having one or more carbon atoms, preferably having 1 - 10 carbon atoms, more preferably having 1 - 6 carbon atoms, and this term includes straight-chain and branched-chain hydrocarbon groups. When a carbon atom number limit is present before the alkyl group, such as C 1-6Alkyl means that the alkyl group contains 1 to 6 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, etc. The alkyl groups described herein may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, acyloxy, oxo, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, heterocyclic, cycloalkenyl, heterocyclic alkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, heterocyclic alkyloxy, aryloxy, heteroaryloxy, aryl or heteroaryl.

[0126] The term "deuterated alkyl" as used herein refers to an alkyl group obtained by substituting a "alkyl" group by deuterium. Non-limiting examples of deuterated alkyl groups include deuterated methyl, deuterated ethyl, etc.

[0127] The term "haloalkyl" as used herein refers to an alkyl group obtained by substituting an alkyl group by a halogen, wherein the halogen includes fluorine, chlorine, bromine, iodine, etc. Non-limiting examples of haloalkyl groups include monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, etc.

[0128] The term "alkoxy" refers to the formula -OR a Group, wherein R a Alkyl groups as defined above. When the alkoxy group is preceded by a carbon number qualifier, such as C... 1-6 An alkoxy group is defined as an alkoxy group containing 1 to 6 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, tert-butoxy, and n-pentoxy.

[0129] The term "deuterated alkoxy" in this document refers to the alkoxy group obtained by substituting a "alkoxy" group as defined above with deuterium. Non-limiting examples of deuterated alkoxy groups include deuterated methoxy, deuterated ethoxy, etc.

[0130] The term "haloalkoxy" in this document refers to an alkoxy group obtained by substituting an alkoxy group (as defined above) with a halogen, including fluorine, chlorine, bromine, iodine, etc. Non-limiting examples of haloalkoxy groups include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, etc.

[0131] The term "alkylthio" refers to the formula -SR a Group, wherein R a Alkyl groups as defined above. When the alkylthio group is preceded by a carbon number qualifier, such as C... 1-6 An alkylthio group refers to an alkylthio group containing 1 to 6 carbon atoms. Examples of alkylthio groups include, but are not limited to, methylthio and ethylthio.

[0132] An alkenyl group is an unsaturated hydrocarbon group containing a carbon-carbon double bond. The term "alkenyl" herein refers to an alkyl group containing a carbon-carbon double bond in a molecule, wherein the alkyl group, as defined above, has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 2 to 6 carbon atoms. When the alkenyl group is preceded by a carbon atom number qualifier, such as C... 2-6 An alkenyl group is defined as having 2-6 carbon atoms. The alkenyl groups described herein may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, oxo, alkyl, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkyl mercapto, deuterated alkyl mercapto, sulfone, sulfoxide, silyl, phosphono, deuterated alkyl, heterocyclic, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl. Non-limiting examples of alkenyl groups include vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, etc.

[0133] The term "deuterated alkenyl" in this document refers to the alkenyl group obtained by substituting "alkenyl" as defined above with deuterium. Non-limiting examples of deuterated alkenyl groups include deuterated vinyl, deuterated propenyl, deuterated allyl, deuterated isopropenyl, deuterated butenyl, etc.

[0134] An alkynyl group is an unsaturated hydrocarbon group containing a carbon-carbon triple bond. The term "alkynyl" herein refers to an alkyl group containing a carbon-carbon triple bond in a molecule, wherein the alkyl group, as defined above, has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 2 to 6 carbon atoms. When the alkynyl group is preceded by a carbon number qualifier, such as C... 2-6 The alkynyl group refers to a group containing 2-6 carbon atoms. The alkynyl group may optionally be substituted by one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, oxo, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkyl mercapto, deuterated alkyl mercapto, sulfone, sulfoxide, silyl, phosphono, deuterated alkyl, heterocyclic, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, etc.

[0135] The term "deuterated alkynyl" in this document refers to the alkynyl group obtained by substituting "alkynyl" as defined above with deuterium. Non-limiting examples of deuterated alkynyl groups include deuterated ethynyl, deuterated 1-propynyl, deuterated 2-propynyl, deuterated 1-, 2- or 3-butynyl, etc.

[0136] The term "cycloalkyl" refers to a stable, non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms. It can include fused ring systems, spirocyclic systems, or bridged ring systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and is either saturated or unsaturated and can be linked to the rest of the molecule via a single bond through any suitable carbon atom. When the cycloalkyl group is preceded by a carbon number limitation, such as C... 3-8 Cycloalkyl means that the cycloalkyl group contains 3-8 carbon atoms. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-dihydroindenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-hydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, and fluorenyl. Bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octahydro-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-cyclopentadienyl, etc. The cycloalkyl groups described herein may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, oxo, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, heterocyclic, cycloalkenyl, heterocyclic, alkenyl, alkynyl, cycloalkoxy, aryl, and heteroaryl.

[0137] The term "heterocyclic group" refers to a saturated or unsaturated aromatic or non-aromatic ring containing at least 1 to 5 heteroatoms selected from N, O, or S. The aromatic or non-aromatic ring can be a 3- to 10-membered monocyclic ring, a 4- to 20-membered spirocyclic ring, a fused ring, or a bridged ring. The selectively substituted N and S atoms in the heterocyclic group can be oxidized to various oxidation states (i.e., NO, O, and SO2), and the N atom can optionally be quaternized. 3- to 12-membered heterocyclic groups are preferred. Non-limiting embodiments include oxetyl propane, oxetyl butyl, oxetyl pentyl, oxetyl hexyl, oxetyl heptyl, oxetyl octyl, aziryl propane, aziryl butyl, aziryl pentyl, aziryl hexyl, aziryl propenyl, 1,3-dioxocyclopentyl, 1,4-dioxocyclopentyl, 1,3-dithiocyclopentyl, 1,3-dioxocyclohexyl, 1,3-dithiocyclohexyl, aziryl heptenyl, morpholinyl, piperazine, pyridinyl, furanyl, thiophene, pyrrole, pyranyl, N-alkylpyrrole, pyrimidinyl, pyrazine, pyridazine, imidazolyl, piperidinyl, thiomorpholinyl, dihydropyran, thiadiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, 1,4-dioxetylhexadienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. The heterocyclic groups described herein may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, heterocyclic, cycloalkenyl, heterocyclic, alkenyl, alkynyl, cycloalkoxy, aryl, and heteroaryl.

[0138] The term "heterocyclic alkyl" refers to a cyclic structure in which at least one carbon atom in the cycloalkyl ring is replaced by a heteroatom selected from N, O, or S. The N atom may optionally be quaternized, and the N and S atoms may optionally be oxidized (i.e., NO, O, and SO2). It includes monocyclic, bicyclic, and tricyclic heterocyclic systems, wherein bicyclic and tricyclic heterocyclic systems include spirocyclic, fused, and bridged heterocyclic systems. Heterocyclic alkyl groups can be unsubstituted or substituted, and when substituted, they can be substituted at any usable junction. The substituents are preferably one or more selected from halogens, hydroxyl groups, amino groups, cyano groups, oxo groups, alkyl groups, alkoxy groups, haloalkyl groups, cycloalkyl groups, heterocyclic alkyl groups, aryl groups, and heteroaryl groups. In this invention, the heterocyclic alkyl group is preferably 3-12 membered, 3-10 membered, and more preferably 3-8 membered. Non-limiting examples of heterocyclic alkyl groups include oxetane, oxetane, oxetane, oxetane, oxetane, oxetane, oxetane, oxetane, oxetane, oxetane, oxetane, oxetane, oxetane, 1,3-dioxocyclopentyl, 1,4-dioxocyclopentyl, 1,3-dithiocyclopentyl, 1,3-dioxocyclohexyl, 1,3-dithiocyclohexyl, pyrrole, morpholinyl, piperazine, piperidinyl, thiomorpholinyl, etc.

[0139] The term "aryl" herein refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent core structure is an aryl ring. The aryl group described herein may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, sulfonyl, sulfinyl, cycloalkyl, heterocyclic, cycloalkenyl, alkenyl, alkynyl, heterocyclic, cycloalkoxy, aryl, and heteroaryl.

[0140] The term "heteroaryl" herein refers to an aromatic group consisting of 5 to 10 atoms and containing at least one heteroatom selected from N, O, or S. The term may have a single ring (non-limiting examples include furan, thiophene, pyrrole, imidazole, triazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, pyrimidine, etc.) or multiple fused rings (non-limiting examples include benzothiophene, benzofuran, indole, isoindole, quinoline, isoquinoline, purine, etc.), wherein the fused ring may or may not be an aromatic group containing a heteroatom, assuming the connecting point is an atom of the aromatic heteroaryl group. The heteroaryl groups described herein may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, amino, oxo, alkyl, alkoxy, acyl, acyloxy, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, alkenyl, alkynyl, heterocyclic, cycloalkoxy, aryl, and heteroaryl.

[0141] This invention also includes isotopically labeled compounds of the invention, i.e., those with the same structure as disclosed above, but in which one or more atoms are replaced by atoms having the same number of protons but a different number of neutrons. Isotopic embodiments of the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine, respectively as follows: 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl and 131 I. The compounds of the present invention, their stereoisomers, tautomers, or pharmaceutically acceptable salts, as well as compounds in the above-described forms containing the aforementioned isotopes and / or other atomic isotopes, are all within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those labeled with… 3 H or 14The compounds labeled C can be used in drug tissue distribution assays, therefore, these 3 H or 14 C isotopes are particularly preferred due to their ease of preparation and detection. Heavier isotopes, such as... 2 H, 18 Some of the compounds of this invention replaced by O have certain therapeutic advantages due to their better metabolic stability, such as increased in vivo half-life and lower dosage, etc. 2 H, 18 O is also preferred in some cases.

[0142] The term “optional” or “optionally” means that the event or situation described below may, but not necessarily, occur, and the description includes both the cases in which the event or situation occurs and the cases in which it does not occur.

[0143] The term "compound of the present invention" (unless otherwise specifically stated) in this text refers to compounds of formulas (A), (A1), (A-II), (I), (II), (III), (IV), and (V), and all their pure and mixed stereoisomers, geometric isomers, tautomers, deuterated compounds, solvates, hydrates, prodrugs, and isotopically labeled compounds and any pharmaceutically acceptable salts. A solvate of the compounds of the present invention refers to a compound or its salts, such as hydrates, ethanolates, methanolates, etc., combined with stoichiometric and non-stoichiometric solvents. Compounds may also exist in one or more crystalline states, i.e., as eutectic, polymorphic, or as an amorphous solid. All such forms are covered by the claims.

[0144] The term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with the other components constituting the formulation and / or the mammals to which it is treated.

[0145] The term "optionally substituted from..." means that the structure is either unsubstituted or substituted by one or more substituents as described in this invention. The term "substituted" herein means any group that is monosubstituted or polysubstituted by a specified substituent to the extent that such monosubstituted or polysubstituted substitution (including multiple substitutions in the same part) is chemically permissible, each substituent may be located at any available position on the group and may be connected by any available atom on the substituent. "Any available position" means any position on the group that is chemically obtainable by methods known in the art or taught herein and does not produce an excessively unstable molecule. When there are two or more substituents on any group, each substituent is defined independently of any other substituent and therefore may be the same or different.

[0146] Throughout this specification, substituents of the compounds of the present invention are disclosed in the form of groups or ranges. This specifically means that the invention includes each member or subcombination of each individual member of such groups and ranges. As the term "C" indicates... 1-6 "alkyl" specifically means methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.

[0147] The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0148] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations.

[0149] The term "tautomer" in this document refers to structural isomers with different energies that can cross a low energy barrier and thus interconvert. Examples include proton tautomers, which interconvert via proton migration, such as enol-keto tautomers and imine-enamine tautomers, or tautomers containing heteroaryl groups attached to ring atoms of the -NH- and =N- moieties, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetraazoles. Valence tautomers include some interconversions due to bonding electron rearrangement.

[0150] The term “deuterated compound” in this paper refers to a compound formed by replacing one or more hydrogen atoms (1H) in a compound molecule with its stable isotope deuterium (2H, D).

[0151] The compounds of this invention can be used in the form of salts, such as "pharmaceutically acceptable salts" or "medically acceptable salts" derived from inorganic or organic acids. These include, but are not limited to, the following: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, butates, camphorates, camphor sulfonates, digluconate, cyclopentanepropionate, sodium dodecylbenzenesulfonate sulfate, ethanesulfonates, glucono-heptate, glycerophosphates, hemisulfates, heptanate, hexanoates, fumarates, hydrochlorides, hydrobromide, hydroiodates, 2-hydroxyethanesulfonate, lactates, maleates, methanesulfonates, hydrochlorides, 2-naphthalenesulfonate, oxalates, pectin esters, sulfates, 3-phenylpropionate, picrates, trimethylacetate, propionates, succinates, tartrates, thiocyanates, p-toluenesulfonates, and silicates, etc.

[0152] The term "effective amount" or "effective therapeutic amount" refers to an amount sufficient to provide therapeutic benefit or delay or minimize one or more symptoms associated with a disease or condition in the treatment or control of that disease or condition. For compound therapies, the "effective amount" refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in the treatment or control of a disease or condition. Detailed Implementation

[0153] The present invention is further illustrated below with examples, but is not limited thereto. Throughout this application, various embodiments of the compounds and methods of the present invention are mentioned. The present invention is not limited to these embodiments; the following embodiments are merely illustrative of methods for practicing the present invention and do not limit the scope of the invention in any way.

[0154] The compounds provided by this invention can be prepared using standard synthetic methods known in the art, and this specification provides a general method for preparing the compounds of this invention. Starting materials are generally commercially available, for example, via Alfa... It can be purchased from companies such as TCI, or prepared using methods known to those skilled in the art.

[0155] The following examples further explain and illustrate the compounds of the present invention and their corresponding preparation methods. It should be understood that although typical or preferred reaction conditions (such as reaction temperature, time, molar ratio of reactants, reaction solvent, etc.) are given in the specific examples, other reaction conditions may be used by those skilled in the art. Optimal reaction conditions may vary depending on the specific reaction substrate or solvent used, but these conditions can be determined by those skilled in the art through conventional optimization.

[0156] The structures of the compounds in the following examples were characterized by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). Using a Bruker Ascend 400MHz NMR spectrometer, the compounds were dissolved in a suitable deuterated reagent and analyzed at ambient temperature with TMS as an internal standard. 1 H-NMR analysis. NMR chemical shifts (δ) are expressed in ppm and are referred to as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; brs, broad singlet.

[0157] The reaction starting materials, intermediates, and compounds of the examples can be separated and purified by techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography (such as silica gel column chromatography, preparative chromatography, etc.).

[0158] The final step in the synthesis of each target compound involves deprotection under acidic conditions, and the purified compound is its hydrochloride salt. If the solution is adjusted to neutral using a base such as sodium hydroxide, and then purified by separation, the non-salt compound can be obtained.

[0159] intermediate preparation

[0160] Intermediate 1

[0161] Step 1

[0162] In a 2L reaction flask, 50.0 g of (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester, 29.5 g of potassium vinyltrifluoroborate, 45.6 g of potassium carbonate, 6.4 g of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, 200 mL of water, and 600 mL of 1,4-dioxane were added, and the system was purged under nitrogen atmosphere. The system was then heated to 95 °C and stirred for 3 h. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic phases were combined, dried, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give 42.0 g of a yellow oil. MS: [M+H] + =402.3.

[0163] Step 2

[0164] The product from the previous step (42.0 g), potassium osmium tetroxide dihydrate (1.9 g), and tetrahydrofuran (100 mL) were added to a 500 mL reaction flask. After the addition was complete, the mixture was stirred at room temperature for 15 min. Subsequently, water (100 mL), 2,6-dimethylpyridine (11.0 g), and sodium periodate (65.5 g) were added to the system. After the addition was complete, the mixture was stirred at room temperature for another 18 h. The reaction solution was poured into an aqueous sodium sulfite solution, and the system was extracted with ethyl acetate. The organic phases were combined, dried, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give 40.0 g of a colorless oil. 1 H NMR (400MHz, DMSO-d6): δ10.00(s,1H),7.78-7.74(m,2H),7.57-7.50(m,2H),3.60-3.47(m,1H),3.40-3.30(m,1H),3.22-3.08(m,1H),3.02 (t,J=10.0Hz,1H),2.92-2.73(m,2H),2.62-2.49(m,1H),2.38-2.21(m ,1H),1.91-1.78(m,1H),1.67-1.50(m,1H),1.40(s,9H),1.19(s,9H).

[0165] Intermediate 2

[0166] Step 1

[0167] In a 250 mL single-necked flask, (R)-3-((S)-1-(tert-butoxy)-3-(3-formylphenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 1.3 g) and methanol (60 mL) were added. Sodium borohydride (140 mg) was added in portions while stirring at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was poured into an aqueous solution of ammonium chloride, extracted with ethyl acetate, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 2.7 g of a white solid. 1H NMR (400MHz, DMSO-d6): δ7.21(t,J=7.7Hz,1H),7.15-7.09(m,2H),7.03(d,J=7.3Hz ,1H),5.15(t,J=5.6Hz,1H),4.45(d,J=5.5Hz,2H),3.58-3.44(m,1H),3.39-3.28(m, 1H),3.21-3.06(m,1H),2.97(t,J=8.7Hz,1H),2.78-2.63(m,2H),2.53-2.39(m,1H) ,2.35-2.18(m,1H),1.89-1.76(m,1H),1.66-1.49(m,1H),1.40(s,9H),1.23(s,9H).

[0168] Step 2

[0169] Triphenylphosphine (5.8 g) and dichloromethane (80 mL) were added to a 250 mL single-necked flask. The reaction system was purged with nitrogen and then cooled in an ice bath. N-bromosuccinimide (4.0 g) was added in portions, and the reaction was continued in an ice bath for 30 minutes after the addition was complete. Then, the product from the previous step (3.0 g) was added in portions to the system, and the reaction was allowed to return to room temperature for 30 minutes after the addition was complete. The reaction solution was concentrated and purified by silica gel column chromatography to obtain 2.2 g of a pale yellow product. 1 H NMR (400MHz, CDCl3): δ7.28-7.16(m,3H),7.15-7.07(br s,1H),4.47(s,2H),3.78-3.39(m,2H),3.33-3.19(m,1H),3.12-2.93(m,1H),2.92-2.72(m,2H),2. 56-2.44(m,1H),2.44-2.30(m,1H),2.01-1.91(m,1H),1.71-1.60(m,1H),1.48(s,9H),1.29(s,9H).

[0170] Intermediate 3

[0171] Step 1

[0172] Sodium azide (1.3 g) and N,N-dimethylformamide (120 mL) were added to a reaction flask and stirred until dissolved at room temperature. Then, a solution of intermediate 2 (6.0 g) in N,N-dimethylformamide (20 mL) was added dropwise. After the addition was complete, the mixture was heated to 40 °C and stirred for 2 h. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated to give 5.0 g of a yellow oily substance.

[0173] Step 2

[0174] Add the product from the previous step (5.5 g), tetrahydrofuran (120 mL), and 10% palladium on carbon (2.0 g) to the reaction flask. After the addition is complete, replace the reaction system with hydrogen gas and stir at room temperature for 12 h. Filter the reaction solution through diatomaceous earth, collect the filtrate, and concentrate it to obtain 5.0 g of a brown oily substance. MS: [M+H] + =405.3.

[0175] Intermediate 4

[0176] Intermediate 1 (3.0 g), methanol (50 mL), a 1,4-dioxane solution of ammonia (92 mL, 0.4 M), and acetic acid (888 mg) were added to a reaction flask. After the addition was complete, the mixture was stirred at room temperature for 10 min. Subsequently, sodium cyanoborohydride (1.4 g) was added to the system, and the mixture was stirred at 45 °C for 2 h. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phases were combined, dried, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give 2.0 g of a white solid. MS: [M+H] + =792.5.

[0177] Intermediate 5

[0178] Intermediate 1 (5 g), methylamine hydrochloride (1.0 g), methanol (50 mL), and triethylamine (1.5 g) were added to a reaction flask, and the mixture was stirred at room temperature for 40 min after the addition was complete. Then, sodium borohydride (940 mg) was added to the system, and the mixture was stirred at room temperature for another 3 h after the addition was complete. The reaction mixture was poured into ice water, extracted with ethyl acetate, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give 3.9 g of a brown oily substance. MS: [M+H] + =419.3.

[0179] Intermediate 6

[0180] Step 1

[0181] Dimethyl 5-bromoisophthalate (1.0 g), cyclopropylboronic acid (440 mg), potassium phosphate (2.33 g), palladium acetate (16 mg), 2-dicyclohexylphospho-2′,4′,6′-triisopropylbiphenyl (70 mg), toluene (7 mL), and water (3 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was purged with nitrogen three times, and the system was heated to 80 °C and reacted for 3–5 h. Heating was stopped, and the system was allowed to cool to room temperature. The mixture was separated into aqueous and organic phases, extracted once with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 830 mg of an off-white solid. 1HNMR (400MHz, Chloroform-d) δ: 8.47 (t, J = 1.6, 1H), 7.94 (d, J = 1.6, 2H), 3.96 (s, 6H), 2.01 (s, 1H), 1.12–1.01 (m, 2H), 0.85–0.77 (m, 2H).

[0182] Step 2

[0183] Under ice-salt bath conditions, the product from the previous step (400 mg) and tetrahydrofuran (4 ml) were added sequentially to the reaction flask. The system was then purged under nitrogen atmosphere, and lithium aluminum hydride (195 mg) was added in portions. After the addition was complete, the system was allowed to continue reacting under ice-salt bath conditions for 30 min, then quenched in an aqueous sodium chloride solution. The mixture was separated, and the aqueous phase was extracted once with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue of 274 mg as a white solid. 1 HNMR(400MHz,Chloroform-d)δ:7.12(s,1H),6.99(s,2H),4.62(s,4H),2.28(m,2H),1.91(m,1H),1.04–0.92(m,2H),0.76–0.68(m,2H).

[0184] Step 3

[0185] Under ice-salt bath conditions, the product from the previous step (1.8 g), triphenylphosphine (13.6 g), and dichloromethane (36 mL) were added sequentially to the reaction flask. The system was then purged under nitrogen atmosphere, and the temperature was controlled at 5 ± 5 °C. N-bromosuccinimide (9.2 g) was added in portions. After the addition was complete, the system was slowly restored to room temperature and reacted for 2 h. The reaction was quenched with sodium bisulfite. The mixture was extracted with methyl ether, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1.88 g of an off-white solid. 1 HNMR (400MHz, Chloroform-d) δ: 7.22 (s, 1H), 7.04 (d, J = 1.6, 2H), 4.46 (s, 4H), 1.91 (m, 1H), 1.08–0.95 (m, 2H), 0.78–0.70 (m, 2H).

[0186] Step 4

[0187] In a three-necked flask, (R)-3-(2-((S)-4-benzyl-2-(benzimino)oxazolidine-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.1 g), a tetrahydrofuran solution (5 mL) of the product from the previous step (870 mg), and tetrahydrofuran (15 mL) were added sequentially. The system was purged with nitrogen and cooled to -25±5℃. Bistrimethylsilylaminolithium (1 M, 2.9 mL) was added dropwise at -15±5℃. After the addition was complete, the temperature was maintained for 1 h, followed by reaction at -5±5℃ for 16 h. After the reaction was complete, the reaction solution was quenched in an aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phases 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 silica gel column chromatography to give 840 mg of a white solid. MS: [M+H] + =686.3.

[0188] Step 5

[0189] At room temperature, the product from the previous step (0.5 g), potassium carbonate (0.21 g), phthalimide (0.14 g), and N,N-dimethylformamide (5 mL) were added sequentially to a reaction flask, and the mixture was stirred overnight at room temperature. After the reaction was complete, water was added to quench the reaction, and a white solid precipitated. The mixture was filtered, the filter cake was washed with water, and dried to obtain 0.5 g of a white solid, which was then directly proceeded to the next step. MS: [M+H] + =753.4.

[0190] Step 6

[0191] At room temperature, the product from the previous step (4.5 g), hydrogen peroxide (4 M, 4.5 mL), and tetrahydrofuran (45 mL) were added sequentially to a reaction flask. The mixture was cooled to 10 ± 5 °C, and an aqueous solution of lithium hydroxide monohydrate (753 mg) was added dropwise. The mixture was then warmed back to 25 °C and reacted for 16 h. After the reaction was complete, water was added, and the pH was adjusted to greater than 12 with sodium hydroxide. The mixture was washed with methyl tert-butyl ether, and the aqueous phase was adjusted to pH 2–3 with 6N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give 1.66 g of a white solid residue. MS: [M+H] + =519.3.

[0192] Step 7

[0193] At room temperature, the product from the previous step (1.89 g), THF (20 mL), and 2-tert-butyl-1,3-diisopropylisourea (1.6 g) were added sequentially to the reaction flask. After the addition was complete, the temperature was raised to 55 °C and the reaction was carried out for 2 h. Then, 2-tert-butyl-1,3-diisopropylisourea (1.6 g) was added, and the reaction was continued for another 2 h. Finally, 2-tert-butyl-1,3-diisopropylisourea (0.8 g) was added, and the reaction was continued for another 6 h. After the reaction was complete, the temperature was lowered to room temperature, and the mixture was filtered. The filter cake was washed with methyl tert-butyl ether, and the filtrate was concentrated under reduced pressure to obtain a residue of 1.8 g, which was used directly in the next step. MS: [M+H] + =575.3.

[0194] Step 8

[0195] The product from the previous step (1.8 g), ethanol (25 mL), and hydrazine hydrate (3 mL) were added sequentially to the reaction flask. After the addition was complete, the temperature was raised to 40 °C and the reaction was carried out for 4–6 h. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with ammonium chloride aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 600 mg of crude product. 1 H NMR(400MHz,DMSO-d6)δ:6.90–6.88(m,2H),6.73(s,1H),3.64(s,2H),3.58– 3.46(m,1H),3.37–3.32(m,1H),2.99–2.94(m,1H),2.69–2.66(m,2H),2.50– 2.41(m,1H),2.35–2.17(m,1H),1.87–1.81(m,2H),1.72–1.48(m,1H),1.40( s,9H),1.26(s,9H),1.20-1.16(m,1H),0.97–0.83(m,2H),0.66–0.57(m,2H).

[0196] Compound preparation

[0197] Example 1

[0198] Step 1

[0199] Intermediate 1 (1.1 g), 3-aminobenzoic acid (300 mg), methanol (20 mL), and acetic acid (658 mg) were added to a reaction flask. After the addition was complete, the mixture was cooled to below 10 °C and stirred. Then, sodium cyanoborohydride (413 mg) was added to the system, and the mixture was heated to 30 °C and stirred for 18 h. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 840 mg of a white solid. MS: [M+H] + =525.3.

[0200] Step 2

[0201] The product from the previous step (231 mg), dichloromethane (7 mL), intermediate 4 (350 mg), and O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate (212 mg) were added to the reaction flask. After addition, the mixture was cooled to 10 °C and stirred for 5 min. Then, N,N-diisopropylethylamine (142 mg) was added to the system, and the mixture was stirred at room temperature for 17 h. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 320 mg of a white solid. MS: [M+H] + =1298.8.

[0202] Step 3

[0203] The product from the previous step (300 mg) and dioxane hydrochloride solution (4 M, 10 mL) were added to a reaction flask, and the mixture was stirred at room temperature for 18 h. The reaction solution was concentrated, slurry was added with an appropriate amount of ethyl acetate, filtered, and dried to obtain 150 mg of white solid. MS: [M+H] + =830.5.

[0204] Example 2

[0205] Step 1

[0206] In a reaction flask, intermediate 2 (1.0 g), m-hydroxybenzaldehyde (300 mg), potassium carbonate (600 mg), and N,N-dimethylformamide (25 mL) were added. After addition, the mixture was stirred at 50 °C for 3 h. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 800 mg of an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ9.98(s,1H),7.56-7.51(m,3H),7.36-7.30(m,4H),7 .18-7.15(m,1H),5.14(s,2H),3.56-3.48(m,1H),3.38-3.35(m,1H),3.20-3. 10(m,1H),3.00(t,J=10.0Hz,1H),2.81-2.67(m,2H),2.55-2.47(m,1H),2.33 -2.21(m,1H),1.86-1.82(m,1H),1.66-1.52(m,1H),1.40(s,9H),1.22(s,9H).

[0207] Step 2

[0208] The product from the previous step (620 mg), intermediate 4 (963 mg), methanol (15 mL), and acetic acid (366 mg) were added to the reaction flask. After the addition was complete, the mixture was cooled to 10 °C and stirred. Then, sodium cyanoborohydride (153 mg) was added to the system, and the mixture was stirred at 30 °C for 18 h. The reaction solution was poured into water and extracted with ethyl acetate. The organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 480 mg of a white solid. MS: [M+H] + =1285.8.

[0209] Step 3

[0210] In a reaction flask, the product from the previous step (400 mg) and dioxane hydrochloride solution (4 M, 10 mL) were added, and the mixture was stirred at room temperature for 18 h. The reaction solution was concentrated, and the concentrate was purified by preparative liquid chromatography to give 60 mg of a white solid. MS: [M+H] + =817.5.

[0211] Example 3

[0212] Step 1

[0213] Intermediate 3 (1.5 g), pyridine (439 mg), and dichloromethane (30 mL) were added to a 100 mL three-necked flask. After the addition was complete, the temperature was lowered to 0 °C, followed by the addition of oxaloyl chloride monomethyl ester (544 mg). The reaction mixture was then stirred at 0 °C for 1 h. The reaction solution was poured into saturated brine, extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated to give 1.6 g of a yellow oil. MS: [M+H] + =491.3.

[0214] Step 2

[0215] Add the product from the previous step (1.6 g) and tetrahydrofuran (20 mL) to the reaction flask. After the addition is complete, cool to 0 °C, then add a water solution (10 mL) containing lithium hydroxide monohydrate (274 mg). Continue stirring at 0 °C for 3 h after the addition is complete. Adjust the pH of the reaction solution to 5–6 with acetic acid, extract with ethyl acetate, combine the organic phases, dry and concentrate to obtain 1.5 g of colorless liquid.

[0216] Step 3

[0217] The product from the previous step (1.0 g), dichloromethane (30 mL), intermediate 4 (2.0 g), and O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate (1.3 g) were added to the reaction flask. After the addition was complete, the mixture was cooled to 10 °C and stirred for 5 min. Then, N,N-diisopropylethylamine (542 mg) and 4-dimethylaminopyridine (26 mg) were added. After the addition was complete, the system was stirred at room temperature for 15 h. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 800 mg of a white solid. MS: [M+H] + =1250.8.

[0218] Step 4

[0219] The product from the previous step (800 mg) and dioxane hydrochloride solution (4 M, 20 mL) were added to the reaction flask, and the mixture was stirred at room temperature for 15 h. The reaction solution was concentrated, and the concentrate was purified by preparative liquid chromatography to obtain 240 mg of white solid. 1 H NMR (400MHz, D2O): δ7.22-6.91(m,12H),4.46-4.24(m,6H),3.51-3.46(m,2H),3.43-3.27(m,4H),3.20-3. 10(m,3H),3.00-2.93(m,2H),2.89-2.53(m,10H),2.50-2.35(m,3H),2.13-2.01(m,3H),1.72-1.53(m,3H). MS:[M+H] + =782.4.

[0220] After neutralization with alkali and purification, a non-salt compound was obtained. 1 H NMR (400MHz, D2O): δ719-6.77(m,12H),4.43-4.10(m,6H),3.34-3.13(m,6H),3.12-2.98( m,3H),2.81-2.39(m,9H),2.36-2.15(m,6H),1.95(brs,3H),1.66-1.45(m,3H).MS:[M+H] + =782.4.

[0221] Example 4

[0222] Step 1

[0223] Intermediate 3 (600 mg), pyridine (141 mg), and tetrahydrofuran (10 mL) were added to a reaction flask. After the addition was complete, the mixture was cooled to 0 °C and stirred. Then, a solution of oxalyl chloride (94 mg) in dichloromethane (4 mL) was added. The reaction mixture was stirred at 0 °C for 4 h after the addition was complete. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and the organic phase was collected, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 100 mg of a white solid. MS: [M+H] + =863.5.

[0224] Step 2

[0225] In a 50 mL three-necked flask, add 100 mg of the product from the previous step and 5 mL of 4 M dioxane hydrochloride solution. After addition, stir the mixture at room temperature for 15 h. Concentrate the reaction solution, slurry with a small amount of ethyl acetate, filter, and dry to give 40 mg of a white solid. MS: [M+H] + =551.3.

[0226] Example 5

[0227] Step 1

[0228] Intermediate 4 (96.0 g), pyridine (14.4 g), and dichloromethane (1000 mL) were added to a 2000 mL single-necked flask. After the addition was complete, the mixture was stirred in an ice bath for 15 min. Then, a dichloromethane solution of oxaloyl chloride monomethyl ester (17.8 g dissolved in 100 mL of dichloromethane) was added dropwise. After the addition was complete, the mixture was stirred in an ice bath for 5 h. The reaction mixture was poured into water, separated, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give 86 g of white solid. MS: [M+H] + =878.5.

[0229] Step 2

[0230] Add the product from the previous step (86 g), tetrahydrofuran (500 mL), and water (1000 mL) to the reaction flask. After the addition is complete, stir for 10 min in an ice bath. Then add lithium hydroxide monohydrate (8.2 g) to the system. Continue stirring in an ice bath for 1.5 h after the addition is complete. Let the reaction solution stand, separate the liquids, collect the aqueous phase, adjust the pH of the aqueous phase to 5 with dilute hydrochloric acid, extract the aqueous phase with ethyl acetate, collect the organic phase, dry it with anhydrous sodium sulfate, filter and concentrate to obtain 83 g of yellow solid.

[0231] Step 3

[0232] The product from the previous step (2.0 g), intermediate 4 (1.5 g), N-methylimidazole (395 mg), and N,N-dimethylformamide (15 mL) were added to the reaction flask. After the addition was complete, the mixture was stirred at room temperature for 10 min. Then, N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (674 mg) was added to the system, and the reaction was continued to be stirred at room temperature for 4 h. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give 970 mg of white solid.

[0233] Step 4

[0234] In a 100 mL single-necked flask, the product from the previous step (970 mg) and dioxane hydrochloride solution (4 M, 30 mL) were added, and the mixture was stirred at 30 °C for 16 h. The reaction solution was concentrated to dryness, and the concentrate was purified by slurrying with ethyl acetate to give 660 mg of a pale yellow solid. 1 H NMR(400MHz,D2O): δ7.39-6.95(m,16H),4.71-4.24(m,8H),3.66-3.03(m,16 H),2.96-2.40(m,16H),2.27-2.04(m,4H),1.87-1.52(m,4H).ESI-MS:[M+H] + =1013.6.

[0235] Example 6

[0236] Step 1

[0237] Intermediate 5 (1.0 g), 2-(bis(3-((S)-3-(tert-butyloxy)-2-((R)-1-(tert-butyloxycarbonyl)pyrrolo-3-yl)-3-oxopropyl)benzyl)amino)-2-oxoacetic acid (2.5 g), N-methylimidazolium (476 mg), and N,N-dimethylformamide (10 mL) were added to the reaction flask, and the mixture was stirred at room temperature for 10 min after the addition was complete. Then, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (337 mg) was added to the system, and the reaction was continued to be stirred at room temperature for 5 h after the addition was complete. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give 960 mg of white solid. MS: [M+H] + =1264.8.

[0238] Step 2

[0239] In a 100 mL single-necked flask, the product from the previous step (960 mg) and dioxane hydrochloride solution (4 M, 30 mL) were added, and the mixture was stirred at 30 °C for 16 h. The reaction solution was concentrated to dryness, and the concentrate was purified by slurrying with ethyl acetate to give 650 mg of white solid. 1 H NMR (400MHz, D2O): δ7.40-6.93(m,12H),4.69-4.29(m,6H),3.65-3.33(m,6H),3.32-3.17(m ,3H),3.11-3.00(m,2H),2.99-2.40(m,16H),2.25-2.02(m,3H),1.87-1.54(m,3H).MS:[M+H] + =796.4.

[0240] Example 7

[0241] Step 1

[0242] (R)-3-((S)-1-(tert-butoxy)-3-(3-formylphenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 1, 5.0 g), cyclopropylamine (3.5 g), acetic acid (1.5 g), and methanol (100 mL) were added to a reaction flask. After the addition was complete, the mixture was stirred at room temperature for 30 min. Then, sodium cyanoborohydride (2.3 g) was added to the system, and the mixture was stirred at room temperature for another 3.5 h. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give 4.0 g of a colorless oil. 1 H NMR (400MHz, DMSO-d6): δ7.23-7.08(m,3H),7.02(d,J=7.2Hz,1H),3.67(s,2H),3.57 -3.44(m,1H),3.40-3.30(m,1H),3.21-3.08(m,1H),2.98(t,J=10.0Hz,1H),2.80-2. 64(m,2H),2.59-2.40(m,2H),2.35-2.18(m,1H),2.05-1.98(m,1H),1.89-1.77(m,1H ),1.68-1.50(m,1H),1.40(s,9H),1.23(s,9H),0.36-0.27(m,2H),0.27-0.19(m,2H). MS:[M+H] + =445.3.

[0243] Step 2

[0244] The product from the previous step (2.0 g), 2-(bis(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)amino)-2-oxoacetic acid (3.5 g), N-methylimidazolium (1.0 g), and N,N-dimethylformamide (35 mL) were added to the reaction flask. After the addition was complete, the mixture was stirred at room temperature for 10 min. Then, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (1.7 g) was added to the system, and the mixture was stirred at room temperature for another 4 h. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give 4.0 g of white solid. MS: [M+H] + =1290.9.

[0245] Step 3

[0246] In a 100 mL single-necked flask, 2 g of the product from the previous step and 4 M dioxane hydrochloride solution (4 mL) were added. The mixture was stirred at 45 °C for 16 h. After cooling to room temperature, the liquid was decanted, and the solid was purified by slurry extraction with ethyl acetate to give 120 mg of a white solid. MS: [M+H] + =822.5.

[0247] Example 8

[0248] Step 1

[0249] (R)-3-((S)-1-(tert-butoxy)-3-(3-formylphenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 1, 5.0 g), propargylamine (4.1 g), acetic acid (1.5 g), and methanol (100 mL) were added to a reaction flask. After the addition was complete, the mixture was stirred at room temperature for 30 min. Then, sodium cyanoborohydride (2.3 g) was added to the system, and the mixture was stirred at room temperature for another 3.5 h. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give 3.8 g of a colorless oil. MS: [M+H] + =443.3.

[0250] Step 2

[0251] The product from the previous step (2.0 g), 2-(bis(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)amino)-2-oxoacetic acid (4.7 g), N-methylimidazolium (0.9 g), and N,N-dimethylformamide (20 mL) were added to the reaction flask. After the addition was complete, the mixture was stirred at room temperature for 10 min. Then, N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (1.5 g) was added to the system, and the mixture was stirred at room temperature for another 4 h. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give 3.6 g of a colorless viscous substance. MS: [M+H] + =1288.8.

[0252] Step 3

[0253] In a 100 mL single-necked flask, 200 mg of the product from the previous step and 5 mL of 4 M dioxane hydrochloride solution were added. The mixture was stirred at 40 °C for 16 h. After cooling to room temperature, the mixture was filtered, the solid was collected, and purified by slurry extraction with ethyl acetate to give 100 mg of an off-white solid. MS: [M+H] + =820.5.

[0254] Example 9

[0255] Step 1

[0256] Add dimethylmalonic acid (0.1 g), dichloromethane (5 mL), and 1 drop of N,N-dimethylformamide to a reaction flask. Cool to 0 °C and add oxaloyl chloride (0.4 g) dropwise. After the addition is complete, stir the reaction at room temperature for 30 minutes and concentrate to obtain a pale yellow liquid.

[0257] Step 2

[0258] Intermediate 4 (1.3 g), dichloromethane (10 mL), and triethylamine (0.3 g) were added to a reaction flask. The mixture was cooled to 0 °C, and a dichloromethane solution of the first-step product was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1 h. The solution was concentrated to obtain a pale yellow liquid. The concentrate was purified by silica gel column chromatography to give 0.6 g of a white solid.

[0259] Step 3

[0260] Add the product from the previous step (0.4 g) and 10 mL of ethyl acetate solution of 4 M hydrochloric acid to the reaction flask. After the addition is complete, react at 40 °C for 18 hours. Concentrate to obtain a white solid. Add 2 mL of purified water and extract impurities with ethyl acetate. Concentrate the aqueous phase to obtain 0.1 g of white solid. 1H NMR (400MHz, D2O): δ7.27-7.02(m,8H),6.86-6.65(m,8H),4.31-3.98(m,4H),3.73-3.0 6(m,16H),3.06-2.38(m,20H),2.12-2.03(m,4H),1.71-1.60(m,4H),1.37-1.29(m,6H). MS:[M+H] + =1055.6.

[0261] Example 10

[0262] Step 1

[0263] Add 0.1 g of 1,1-cyclopropyl dicarboxylic acid, 5 mL of dichloromethane, and 1 drop of N,N-dimethylformamide to a reaction flask. Cool the mixture to 0 °C and add 0.4 g of oxaloyl chloride. After the addition is complete, stir the mixture at room temperature for 30 minutes and concentrate it to obtain a pale yellow liquid.

[0264] Step 2

[0265] Intermediate 4 (1.3 g), dichloromethane (10 mL), and triethylamine (0.3 g) were added to a reaction flask. The mixture was cooled to 0 °C, and a dichloromethane solution of the first-step product was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1 h. The solution was concentrated to obtain a pale yellow liquid. The concentrate was purified by silica gel column chromatography to give 0.7 g of a white solid.

[0266] Step 3

[0267] Add the product from the previous step (0.5 g) and ethyl acetate solution of 4 M hydrochloric acid (10 mL) to the reaction flask. After the addition is complete, react at 40 °C for 18 hours. Concentrate to obtain a white solid. Add 2 mL of purified water and extract impurities with ethyl acetate (3 mL). Concentrate the aqueous phase to obtain 0.2 g of white solid. 1 H NMR (400MHz, D2O): δ7.34-7.16(m,8H),6.98-6.84(m,8H),4.54(s,4H),4.24(s,4H),3.59-3.48(m,4H),3.45-3.37(m,4H),3.29-3 .18(m,4H),3.10-2.96(m,4H),2.89-2.64(m,12H),2.59-2.46(m,4H),2.20-2.10(m,4H),1.80-1.70(m,4H),1.44(d,J=9.7Hz,4H). MS:[M+H] + =1053.6.

[0268] Example 11

[0269] The preparation was carried out using a similar method to Example 3, except that in step 1, intermediate 3 was replaced with (R)-3-((S)-3-(3-(aminomethyl)-5-cyclopropylphenyl)-1-(tert-butyloxy)-1-oxopropyl-2-yl)pyrrole-1-carboxylic acid tert-butyl ester (intermediate 6). The specific procedures are as follows:

[0270] Step 1

[0271] Intermediate 6 (3.0 g), dichloromethane (60 mL), and triethylamine (0.96 g) were added sequentially to a reaction flask. The mixture was purged with nitrogen, and the temperature was lowered to -20 to -10 °C. Monoethyl chlorooxalate (1.12 g) was slowly added dropwise. After the addition was complete, the mixture was stirred at -20 to -10 °C for 2 hours. After the reaction was complete, purified water was added to quench the reaction, followed by extraction with dichloromethane. The organic phase was collected and washed once with sodium chloride solution. The organic phase was concentrated under reduced pressure to obtain a pale yellow oil. The concentrate was purified by silica gel column chromatography to obtain 3.1 g of a white solid.

[0272] Step 2

[0273] Add the product from the previous step (2.0 g) and tetrahydrofuran (12 mL) to the reaction flask, purge with nitrogen, cool to 0–10 °C, and slowly add an aqueous solution of lithium hydroxide (0.31 g). After the addition is complete, continue the reaction for 3 hours. Once the reaction is complete, adjust the pH to 4–5 with 6 M hydrochloric acid and stir for another 15 minutes. Extract twice with ethyl acetate, combine the organic phases, wash with an aqueous sodium chloride solution, and reduce the pressure to obtain 1.7 g of a white solid.

[0274] Step 3

[0275] Acetonitrile (30 mL), the product from the previous step (1.5 g), intermediate 4 (2.7 g), and N-methylimidazole (0.7 g) were added sequentially to the reaction flask. The mixture was purged with nitrogen, and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (1.2 g) was added in portions. After the addition was complete, the reaction mixture was reacted at 20–30 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography to give 2.9 g of a white solid. 1H NMR (400MHz, DMSO-d6): δ9.46(t,J=5.8Hz,1H),7.26(t,J=7.4Hz,2H),7.19-6.99(m,6H),6.83( s,2H),6.74(s,1H),4.44-4.18(m,6H),3.52-3.43(m,3H),3.38-3.30(m,4H),3.17-3.08(m,3H) ,3.00-2.84(m,3H),2.73-2.68(m,4H),2.57-2.53(m,3H),2.39-2.17(m,4H),1.86-1.73(m,4H) ,1.63-1.49(m,3H),1.39(d,J=3.2Hz,27H),1.20(s,27H),0.88-0.83(m,2H),0.57-0.53(m,2H).

[0276] Step 4

[0277] The product from the previous step (2.0 g) and 1,4-dioxane (10 mL) were added sequentially to the reaction flask. The mixture was purged with nitrogen, and concentrated hydrochloric acid (10 mL) was added dropwise while maintaining the temperature at 10–20 °C. After the addition was complete, the mixture was reacted at 10–20 °C for 4 hours. After the reaction was complete, the mixture was concentrated to dryness under reduced pressure at room temperature to obtain 1.4 g of a white solid. 1 H NMR (400MHz, D2O): δ7.21-7.07(m,4H),6.94(d,J=7.6Hz,1H),6.89(d,J=7.6Hz,3H) ,6.77(s,1H),6.75(s,1H),6.70(s,1H),4.43-4.24(m,6H),3.51-3.44(m,2H),3.41 -3.26(m,4H),3.20-3.09(m,3H),2.98-2.91(m,2H),2.87-2.69(m,5H),2.66-2.32( m,8H),2.12-2.04(m,3H),1.71-1.55(m,4H),0.79-0.77(m,2H),0.46-0.42(m,2H). MS:[M+H] + =822.4.

[0278] After neutralization with alkali and purification, a non-salt compound was obtained. 1H NMR (400MHz, D2O): δ7.14-7.07(m,2H),7.01(d,J=7.6Hz,2H),6.88(s,3H),6.80( d,J=7.5Hz,1H),6.73(s,1H),6.62(s,1H),6.59(s,1H),4.41-4.06(m,6H),3.32- 3.11(m,6H),3.11-2.96(m,3H),2.79-2.34(m,9H),2.33-2.12(m,6H),2.02-1.84 (m,3H),1.65-1.44(m,4H),0.70(d,J=7.9Hz,2H),0.39(d,J=4.0Hz,2H).MS:[M+H] + =822.5.

[0279] Preparation of comparative compounds

[0280] The comparative compound Ref-1 was prepared according to the method of Example 1 in patent WO2020247429A1.

[0281] Biological testing

[0282] 1. In vitro Lp(a) assembly detection test

[0283] The in vitro Lp(a) assembly was detected by a double-antibody sandwich ELISA. The specific procedure was as follows: The test compound was added to the supernatant of HEK293-Lp(a) cell culture, followed by the supernatant of HEPG2 cell culture medium. The mixture was incubated at 37°C. The reaction was terminated by adding 6-EACA stop solution. The sample was added to an ELISA plate pre-coated with capture antibody, sealed, and incubated at room temperature. After washing 5 times, the detection antibody was added, and the plate was incubated at room temperature. After washing 5 times, TMB was added to each well for color development. The reaction was then terminated with dilute sulfuric acid. The absorbance at OD450 nm was measured using a microplate reader. The data were fitted using Graphpad Prism software to calculate the IC50 of the test compound. 50 value.

[0284] The experimental results are shown in the table below, where "A" indicates the inhibitory activity IC50. 50 <50 nM, "B" indicates inhibitory activity 50 nM ≤ IC 50 <100nM, "C" indicates inhibitory activity IC50 50 ≥100nM.

[0285] In vitro Lp(a) assembly assay results show that the compound of the present invention has a significant inhibitory effect on Lp(a) assembly.

[0286] 2. In vitro Lp(a) assembly detection test

[0287] Following the method described in Biological Assay 1, in vitro Lp(a) assembly was detected by a double-antibody sandwich ELISA. The experimental results are shown in the table below, where "A" indicates inhibitory activity IC50. 50 <20 nM, "B" indicates inhibitory activity 20 nM ≤ IC 50 <50 nM, where "C" indicates inhibitory activity IC50 50 ≥50nM.

[0288] Experimental results show that the compounds of this invention have a significant inhibitory effect on Lp(a) assembly.

[0289] 3. In vitro Lp(a) assembly detection test

[0290] In vitro Lp(a) assembly was detected by double-antibody sandwich ELISA, following the procedure outlined in Bioassay 1. The results are shown in the table below.

[0291] The results show that the compounds of this invention have a strong inhibitory effect on Lp(a) assembly.

[0292] 4. Selectivity evaluation test: Affinity test for human plasminogen

[0293] The selectivity of a compound to plasminogen is evaluated by measuring plasminogen (PLG) activity.

[0294] The binding affinity of the compound of this invention to human plasminogen was tested using the SPR (surface plasmon resonance) method. The test was performed using a Biacore instrument. The Series S Sensor Chip CM5 chip was equilibrated to room temperature, and the chip surface was activated with EDC (1-ethyl-(3-dimethylaminopropyl)carbodiimide) and NHS (N-hydroxysuccinimide). Human plasminogen protein diluted with sodium acetate coupling buffer was coupled to the Series S Sensor Chip CM5 chip, with a protein immobilization amount of ~3000 RU. The CM5 chip surface was blocked with ethanolamine. The diluted test compound was sequentially flowed through the immobilized protein surface from low to high concentration, with a binding time of 90 seconds and a dissociation time of 150 seconds, at a flow rate of 30 μL / min. Data analysis was performed using Biacore Instrument Evaluation Software. After subtracting the reference channel and buffer control, the binding-dissociation curves of the compound were obtained, and the affinity data with human plasminogen was obtained by bivalent binding mode kinetic fitting.

[0295] The experimental results are shown in the table below, where "A" indicates KD < 40 nM, "B" indicates 40 nM ≤ KD < 75 nM, and "C" indicates KD ≥ 75 nM.

[0296] The results showed that the compounds of the present invention had a low affinity for plasminogen, which was significantly better than that of the comparative compound Ref-1. This indicates that compounds 4, 13, and 19 of the present invention have high selectivity for human plasminogen, a lower risk of thrombosis than Ref-1, and higher safety.

[0297] In addition, the compounds of the present invention, such as 4, 13, and 19, also have better selectivity for the KIV2 domain.

[0298] 5. Lp(a) inhibition assay in transgenic mice

[0299] Test samples: Compound 13 and Compound 19;

[0300] Animal species and number: 10 B6-RCL-hLPA / Alb-cre / TG(APOB) mice, half male and half female;

[0301] Test groups and dosages: Compound 13 group (3 mg / kg, QD×10), Compound 19 group (3 mg / kg, QD×10);

[0302] Administration route and frequency: Oral gavage, once daily for 10 consecutive days;

[0303] At the end of the experiment, the serum Lp(a) level of all animals in each group was measured, and the serum Lp(a) inhibition rate was calculated.

[0304] Lp(a) inhibition rate calculation: serum Lp(a) inhibition rate (%) on day n of the dosing period = (baseline serum Lp(a) level - serum Lp(a) level on day n of the dosing period) / baseline serum Lp(a) level × 100.

[0305] The inhibition rates of serum Lp(a) at D10 in each group of animals are shown in the table below, where “+” indicates inhibition rate ≤30%; “++” indicates inhibition rate 30%–50%; “+++” indicates inhibition rate 50%–70%; and “++++” indicates inhibition rate ≥70%.

[0306] Experimental results: After continuous administration at a dose of 3 mg / kg for 10 days, compounds 13 and 19 of the present invention significantly reduced the level of serum Lp(a) in mice.

[0307] 6. Lp(a) inhibition assay in transgenic mice

[0308] Test samples: Compound 13 and Ref-1;

[0309] Animal species and number: 10 B6-RCL-hLPA / Alb-cre / TG(APOB) mice, half male and half female;

[0310] Test groups and dosages: Compound 13 (3 mg / kg, QD×12), Ref-1 (3 mg / kg, QD×12);

[0311] Administration route and frequency: Oral gavage, once daily for 12 consecutive days;

[0312] At the end of the experiment, the serum Lp(a) level of all animals in each group was measured, and the serum Lp(a) inhibition rate was calculated.

[0313] Lp(a) inhibition rate calculation: serum Lp(a) inhibition rate (%) on day n of the dosing period = (baseline serum Lp(a) level - serum Lp(a) level on day n of the dosing period) / baseline serum Lp(a) level × 100.

[0314] The inhibition rates of serum Lp(a) in each group of animals at D12 are shown in the table below, where “+” indicates inhibition rate ≤30%; “++” indicates inhibition rate 30%–50%; “+++” indicates inhibition rate 50%–70%; and “++++” indicates inhibition rate ≥70%.

[0315] Experimental results: After continuous administration at a dose of 3 mg / kg for 12 days, compound 13 of the present invention significantly reduced the level of serum Lp(a) in mice, and the reduction effect was significantly better than that of the comparative compound Ref-1.

[0316] 7. Lp(a) inhibition test in cynomolgus monkeys 1

[0317] Test samples: Compound 4 and Ref-1;

[0318] Animal species and numbers: 4 crab-eating macaques per group, half male and half female;

[0319] Experimental groups and dosages: solvent control group, compound 4 group (0.2 mg / kg, QD×14), Ref-1 group (0.2 mg / kg, QD×14);

[0320] Administration route and frequency: Oral gavage, once daily for 14 consecutive days;

[0321] General condition observation: During the experiment, the general condition of each group of animals was observed at least once a day, including but not limited to the local administration site, mental state, feeding, drinking, fur, excrement, death and other abnormal manifestations in the cynomolgus monkeys.

[0322] Lp(a) inhibition rate calculation: serum Lp(a) inhibition rate (%) on day n of the dosing period = (baseline serum Lp(a) level - serum Lp(a) level on day n of the dosing period) / baseline serum Lp(a) level × 100.

[0323] The inhibition rates of serum Lp(a) in each group of animals on D14 are shown in the table below, where “+” indicates inhibition rate ≤10%; “++” indicates inhibition rate 10%–25%; “+++” indicates inhibition rate 25%–45%; and “++++” indicates inhibition rate ≥45%.

[0324] Experimental results: After continuous administration at a dose of 0.2 mg / kg for 14 days, compound 4 of the present invention significantly reduced the serum Lp(a) level in cynomolgus monkeys, while the control compound Ref-1 showed almost no inhibitory effect.

[0325] 8. Lp(a) inhibition test in cynomolgus monkeys 2

[0326] Test samples: Compound 13, Compound 19 and Ref-1;

[0327] Animal species and numbers: 4 crab-eating macaques per group, half male and half female;

[0328] Test groups and dosages: Compound 13 group (1 mg / kg, QD×10), Compound 19 group (1 mg / kg, QD×10), Ref-1 group (1 mg / kg, QD×10);

[0329] Administration route and frequency: Oral gavage, once daily for 10 consecutive days;

[0330] General condition observation: During the experiment, the general condition of each group of animals was observed at least once a day, including but not limited to the local administration site, mental state, feeding, drinking, fur, excrement, death and other abnormal manifestations in the cynomolgus monkeys.

[0331] Lp(a) inhibition rate calculation: serum Lp(a) inhibition rate (%) on day n of the dosing period = (baseline serum Lp(a) level - serum Lp(a) level on day n of the dosing period) / baseline serum Lp(a) level × 100.

[0332] The inhibition rates of serum Lp(a) at D10 in each group of animals are shown in the table below, where “+” indicates inhibition rate ≤20%; “++” indicates inhibition rate 20%–40%; “+++” indicates inhibition rate 40%–60%; and “++++” indicates inhibition rate ≥60%.

[0333] Experimental results: After continuous administration at a dose of 1 mg / kg for 10 days, compounds 13 and 19 of the present invention significantly reduced the serum Lp(a) level in cynomolgus monkeys, and the reduction effect was significantly better than that of the comparative compound Ref-1.

[0334] 9. Safety study of rats with repeated administration over 14 days 1

[0335] Test sample: Compound 4;

[0336] Animal species and number: 12 normal SD rats, half male and half female;

[0337] Animal groups and dosages: solvent control group, compound group 4 (1000 mg / kg);

[0338] Dosage frequency: once daily for 14 consecutive days;

[0339] Experimental Procedure: SD rats were randomly divided into a solvent control group and four compound groups according to body weight, with six rats in each group (half male and half female). Compound groups were administered compound 1000 mg / kg via gavage once daily for 14 consecutive days. The day of the first administration was defined as day 1 of the administration period (D1). During the experiment, the rats' physical appearance, behavior, food intake, and body weight were observed daily. On day 15, the rats were euthanized, and a full gross necropsy was performed to observe the condition of major organs and weigh them.

[0340] Experimental Results: During the experiment, the weight changes of SD rats in the drug-treated group showed a consistent trend with those in the solvent-treated group, and no abnormalities were observed in their appearance, physical signs, or behavior. At the end of the experiment, no abnormalities were observed in the major organs of the SD rats. This indicates that compound 4 of the present invention has excellent safety.

[0341] 10. Safety study of rats with repeated administration over 14 days 2

[0342] Test sample: Compound 27;

[0343] Animal species and number: 12 normal SD rats, half male and half female;

[0344] Animal groups and dosages: solvent control group, compound 27 group (300 mg / kg);

[0345] Dosage frequency: once daily for 14 consecutive days;

[0346] Experimental Procedure: SD rats were randomly divided into a solvent control group and a compound 27 group, with 6 rats in each group (half male and half female). The compound 27 group was administered compound 27 by gavage at a dose of 300 mg / kg once daily for 14 consecutive days. The day of the first administration was defined as day 1 of the administration period (D1). During the experiment, the rats' physical appearance, behavior, food intake, and body weight were observed daily. On day 15, the rats were euthanized, and a full gross necropsy was performed to observe the condition of major organs and weigh them.

[0347] Experimental Results: During the experiment, the weight changes of SD rats in the drug-treated group showed a consistent trend with those in the solvent-treated group, and no abnormalities were observed in their appearance, physical signs, or behavior. At the end of the experiment, no abnormalities were observed in the major organs of the SD rats. This indicates that compound 27 of the present invention has excellent safety.

Claims

1. A compound of formula (A), its stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof. in, U is selected from an oxygen atom, a sulfur atom, NR2or CR 5h R 5i ; each X is independently selected from -0-, -S-, -NR2-, -C 1-6 alkyl-, -C 1-6 heteroalkyl-, or -C 2-6 alkenyl-, wherein the alkyl, heteroalkyl, and alkenyl groups are optionally substituted with one or more R4; Y is selected from the following structure: wherein W is selected from -NR 8c -0- or -S-; A1, A2are each independently absent or each independently selected from -C 1-6 alkyl-, -C 1-6 heteroalkyl-, -O- 8a -, -C(O)NR 8a -, -C(S)NR 8a -, -S(O)2NR 8a -, -S(O)NR 8a -, -NR 8a C(O)-, -NR 8a C(S)-, -NR 8a S(O)2- or -NR 8a S(O)-; A3, A4are each independently selected from a nitrogen atom or CR 8b ; L1, L2, L3, and L4 are each independently selected from chemical bonds, -O-, -S-, -NH-, and -C. 1-6 Alkyl-, -C 1-6 Heteroalkyl- or -C 2-6 Alkenyl-, wherein the alkyl, heteroalkyl, and alkenyl groups are optionally selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, oxo, thio, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cyclic alkyl group or one or more substituents of a 3-12 membered heterocyclic group are substituted. R 7a R 7b R 7c R 7d Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, amide, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups, or R 7a and R 7b R 7c and R 7d Each of them, together with the carbon atoms they are attached to, forms C=O, C=C. 3-8 Cycloalkyl or 3-12 membered heterocyclic groups; R 8a R 8b R 8c Each group is independently selected from hydrogen, deuterium, hydroxyl, cyano, amino, carboxyl, aldehyde, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), -C(O)-C 1-6 Alkyl, -C(S)-C 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups; Each ring A is independently selected from C. 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl or 3-12-membered heterocyclic groups, wherein the aryl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted by one or more R; Each R is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, oxo, thio, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-8 cycloalkyl, C 6-10 The alkyl, 5-10-membered heteroaryl, or 3-12-membered heterocyclic group may be further selected from hydrogen, deuterium, halogen, alkoxy, haloalkoxy, deuteroalkoxy, alkylthio, alkenyl, deuteroalkenyl, alkynyl, deuteroalkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, optionally further selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, oxo, thio, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-8 cycloalkyl, C 6-10 The aryl group is substituted by one or more substituents from aryl, 5-10 heteroaryl, and 3-12 heterocyclic groups; Each R1 is independently selected from hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy group, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups; Each R2 group is independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, aldehyde, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), -C(O)-C 1- 6-alkyl, -C(S)-C 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3- 8-cyclic alkyl or 3-12-membered heterocyclic groups; Each R3, R4, R 5a R 5b R 5c R 5d R 5e R 5f R 5g R 5h R 5i Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, amide, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups; p and n are each independently selected from 0, 1, 2 or 3; s is selected from 0, 1, 2, 3 or 4; m is selected from 2, 3, or 4.

2. A compound of formula (AI), its stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof. in, Y is selected from the following structure: Wherein, W is selected from -NR 8c -、-O- or -S-; A1 and A2 are either independently nonexistent or independently selected from -C. 1-6 Alkyl-, -C 1-6 heteroalkyl-, -O-, -NR 8a -、-C(O)NR 8a -、-C(S)NR 8a -、-S(O)2NR 8a -、-S(O)NR 8a -、-NR 8a C(O)-、-NR 8a C(S)-、-NR 8a S(O)2- or -NR 8a S(O)-; A3 and A4 are each independently selected from nitrogen atoms or CR atoms. 8b ; L1, L2, L3, and L4 are each independently selected from chemical bonds, -O-, -S-, -NH-, and -C. 1-6 Alkyl-, -C 1-6 Heteroalkyl- or -C 2-6 Alkenyl-, wherein the alkyl, heteroalkyl, and alkenyl groups are optionally selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, oxo, thio, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cyclic alkyl group or one or more substituents of a 3-12 membered heterocyclic group are substituted. R 7a R 7b R 7c R 7d Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, amide, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups, or R 7a and R 7b R 7c and R 7d Each of them, together with the carbon atoms they are attached to, forms C=O, C=C. 3-8 Cycloalkyl or 3-12 membered heterocyclic groups; R 8a R 8b R 8c Each group is independently selected from hydrogen, deuterium, hydroxyl, cyano, amino, carboxyl, aldehyde, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), -C(O)-C 1-6 Alkyl, -C(S)-C 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups; Each ring A is independently selected from C. 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl or 3-12-membered heterocyclic groups, wherein the aryl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted by one or more R; Each R is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, oxo, thio, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-8 cycloalkyl, C 6-10 The alkyl, 5-10-membered heteroaryl, or 3-12-membered heterocyclic group may be further selected from hydrogen, deuterium, halogen, alkoxy, haloalkoxy, deuteroalkoxy, alkylthio, alkenyl, deuteroalkenyl, alkynyl, deuteroalkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, optionally further selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, oxo, thio, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-8 cycloalkyl, C 6-10 The aryl group is substituted by one or more substituents from aryl, 5-10 heteroaryl, and 3-12 heterocyclic groups; Each R1 is independently selected from hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy group, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups; Each R2 group is independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, aldehyde, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), -C(O)-C 1- 6-alkyl, -C(S)-C 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3- 8-cyclic alkyl or 3-12-membered heterocyclic groups; For each R3, R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 5f R 5g Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, amide, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2- 6-acetylinyl, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups; p and n are each independently selected from 0, 1, 2 or 3; s is selected from 0, 1, 2, 3 or 4; m is selected from 2, 3, or 4; n1 is selected from 0, 1, 2, 3 or 4.

3. The compound according to claim 1 or 2, its stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof. in, Y is selected from the following structure: Wherein, W is selected from -NR 8c -、-O- or -S-; L1, L2, L3, and L4 are each independently selected from chemical bonds, -O-, -S-, -NH-, and -C. 1-6 Alkyl-, -C 1-6 Heteroalkyl- or -C 2-6 Alkenyl-, wherein the alkyl, heteroalkyl, and alkenyl groups are optionally selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, oxo, thio, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cyclic alkyl group or one or more substituents of a 3-12 membered heterocyclic group are substituted. R 7a R 7b R 7c R 7d Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, amide, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups, or R 7a and R 7b R 7c and R 7d Each of them, together with the carbon atoms they are attached to, forms C=O, C=C. 3-8 Cycloalkyl or 3-12 membered heterocyclic groups; R 8a R 8b R 8c Each group is independently selected from hydrogen, deuterium, hydroxyl, cyano, amino, carboxyl, aldehyde, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), -C(O)-C 1-6 Alkyl, -C(S)-C 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups; s is selected from 0, 1, 2, 3 or 4.

4. The compound according to claim 1 or 2, its stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof. in, Each ring A is independently selected from the following structures:

5. The following compounds, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof, 6. A compound of formula (A-II), its stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof. in, Each X1, X2, X3, and X4 is independently selected from either nitrogen atoms or CR atoms; Y is selected from the following structure: W is selected from -NR 8c -、-O- or -S-; L1, L2, L3, and L4 are each independently selected from chemical bonds, -O-, -S-, -NH-, and -C. 1-6 Alkyl-, -C 1-6 Heteroalkyl- or -C 2-6 Alkenyl-, wherein the alkyl, heteroalkyl, and alkenyl groups are optionally selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, oxo, thio, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cyclic alkyl group or one or more substituents of a 3-12 membered heterocyclic group are substituted. R 7a R 7b R 7c R 7d Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, amide, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups, or R 7a and R 7b R 7c and R 7d Each of them, together with the carbon atoms they are attached to, forms C=O, C=C. 3-8 Cycloalkyl or 3-12 membered heterocyclic groups; R 8a R 8b R 8c Each group is independently selected from hydrogen, deuterium, hydroxyl, cyano, amino, carboxyl, aldehyde, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), -C(O)-C 1-6 Alkyl, -C(S)-C 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic; Each R is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1- 6-alkyl)2、-NH(C 1-6 Alkyl), C 3-8 cycloalkyl, C 6-10 The alkyl, 5-10-membered heteroaryl, or 3-12-membered heterocyclic group may be further selected from hydrogen, deuterium, halogen, alkoxy, haloalkoxy, deuteroalkoxy, alkylthio, alkenyl, deuteroalkenyl, alkynyl, deuteroalkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, optionally further selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, oxo, thio, amide, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-8 cycloalkyl, C 6-10 The substituent is one or more of aryl, 5-10 heteroaryl, or 3-12 heterocyclic groups; or, two adjacent R groups are linked together to form an 8-12 fused heterocyclic group. Each R1 is independently selected from hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy group, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic; Each R2 group is independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, aldehyde, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), -C(O)-C 1- 6-alkyl, -C(S)-C 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3- 8-cyclic alkyl or 3-12-membered heterocyclic groups; For each R3, R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 5f R 5g Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, amide, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2- 6-acetylinyl, C 2-6 Deuterated alkynyl group, -N(C 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups, or R 4a and R 4b The carbon atoms connected to them bond together to form C. 3-8 Cycloalkyl or 3-12 membered heterocyclic groups; p and n are each independently selected from 0, 1, 2 or 3; s is selected from 0, 1, 2, 3 or 4; n1 is selected from 0, 1, 2, 3 or 4; m is selected from 2, 3, or 4.

7. A compound of formula (I), its stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof. in, Each X1, X2, X3, and X4 is independently selected from either nitrogen atoms or CR atoms; Y is selected from the following structure: Each R1 is independently selected from hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 3- 8-cycloalkyl; Each R2 is independently selected from hydrogen, deuterium, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3- 8-cyclic alkyl, 3-10-membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups; Each R, R3, R 4a R 4b R 5a R 5b R 5c R 5d R 5e R 5f R 5g Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups; n is selected from 1, 2, or 3; n1 is selected from 0, 1, 2 or 3; m is selected from 2, 3, or 4.

8. A compound of formula (II), its stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof, in, Y is selected from the following structure: Each R1 is independently selected from hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 3- 8-cycloalkyl; Each R2 is independently selected from hydrogen, deuterium, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3- 8-cyclic alkyl, 3-10-membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups; For each R3, R 6a R 6b R 6c R 6d Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups; m is selected from 2, 3, or 4.

9. A compound of formula (III), its stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof. in, Y is selected from the following structure: R 1a R 1b R 1c Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups; R 2a R 2b R 2c Each is independently selected from hydrogen, deuterium, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-8 cycloalkyl; R 3a R 3b R 3c Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-8 cycloalkyl; R 4a R 4b R 4c R 4d R 5a R 5b R 5c R 5d R 6a R 6b R 6c R 6d Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-8 Cycloalkyl.

10. A compound of formula (IV), its stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof. in, Y is selected from the following structure: R 2a R 2b R 2c Each is independently selected from hydrogen, deuterium, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-8 cycloalkyl; R 3a R 3b R 3c Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-8 cycloalkyl; R 4a R 4b R 4c R 4d R 5a R 5b R 5c R 5d R 6a R 6b R 6c R 6d Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl or C 3-8 Cycloalkyl.

11. A compound of formula (V), its stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof, in, Y is selected from the following structure: Each R 6a R 6b R 6c R 6d Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, aldehyde, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Deuterated alkenyl, C 2-6 alkynyl group, C 2-6 Deuterated alkynyl group, C 3-8 Cycloalkyl or 3-10 membered heterocyclic alkyl; m is selected from 2, 3, or 4.

12. The compound of formula (V) according to claim 11, its stereoisomers, tautomers, deuterated compounds or pharmaceutically acceptable salts thereof, in, Y is selected from the following structure:

13. The following compounds, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts, 14. The following compounds, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof, 15. The following compounds, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof, 16. The following compounds, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof, 17. The following compounds, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts, 18. The following compounds, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof, 19. The following compounds, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof, 20. A pharmaceutical composition comprising a therapeutically effective dose of the compound of any one of claims 1 to 19, its stereoisomer, tautomer, deuterated compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. The use of the compound, stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20 in the preparation of a medicament for the prevention and / or treatment of diseases associated with elevated plasma LP(a) levels.

22. The use of the compound, stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20 in the preparation of a medicament for the prevention and / or treatment of cardiovascular diseases.

23. The use according to claim 22, wherein the cardiovascular disease is selected from stroke, atherosclerosis, thrombosis, coronary heart disease, aortic stenosis, etc.

24. A method for preventing and / or treating a disease associated with elevated plasma LP(a) levels, comprising administering to the patient an effective amount of a compound as claimed in any one of claims 1-19, its stereoisomers, tautomers, deuterated compounds or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 20.

25. A method for preventing and / or treating a patient with cardiovascular disease, comprising administering to the patient an effective amount of a compound as claimed in any one of claims 1-19, its stereoisomers, tautomers, deuterated compounds or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 20.

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