Polycyclic compound, preparation method therefor, and use thereof

Abstract

Disclosed are a polycyclic compound, a preparation method therefor, and a use thereof. Specifically, disclosed are a compound represented by formula (I), and a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof. The compound of the present invention is a PCSK9 small-molecule inhibitor and can be used to prepare a medicament for treating and / or preventing PCSK9-related diseases.

Description

A polycyclic compound, its preparation method and application Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a polycyclic compound, its preparation method, and its applications. Background Technology

[0002] Cardiovascular disease (CVD) has a significant impact on human health. According to the World Heart Report 2023 published by the World Federation of Cardiology (WHF), more than 20 million people worldwide died from cardiovascular disease in 2021, of which approximately 3.8 million cases were attributable to risk factors related to elevated low-density lipoprotein cholesterol (LDL-C). Excessively high LDL-C levels in the blood can accumulate on the inner walls of arteries, leading to atherosclerosis and triggering a series of inflammatory responses, thereby causing cardiovascular events such as heart disease and stroke. Statins are currently the main lipid-lowering drugs commonly used in clinical practice, but their efficacy is limited. For patients who do not achieve the desired therapeutic effect or are intolerant to statin monotherapy, there is an urgent need for more effective treatment options.

[0003] Under normal physiological conditions, LDL-C in the blood is mainly transported into cells by forming a complex with the low-density lipoprotein receptor (LDLR) on the cell surface. Under the low pH conditions inside the cell, LDL-C is released from the LDLR and transported to lysosomes for degradation, while the LDLR returns to the cell membrane to participate in the next round of LDL-C transport. Proprotein convertase subtilisin / kexin type 9 (PCSK9) is a serine protease mainly expressed in hepatocytes. Studies have shown that it can bind to the LDLR, causing the LDLR and its transported LDL-C to be degraded together in lysosomes, thereby reducing the amount of circulating LDLR and inhibiting the clearance of LDL-C from the plasma. However, when the production or secretion of PCSK9 is inhibited, it can promote the clearance of LDL-C from the blood, thus achieving a cholesterol-lowering effect. PCSK9 has therefore become an important target in CVD drug development.

[0004] Currently, PCSK9 inhibitors are mainly large-molecule monoclonal antibodies and nucleic acid drugs. Several approved drugs, such as Alirocumab, Evolocumab, and Inclisiran, have shown good efficacy and activity. However, these drugs all require injection and have relatively high production costs and prices. In addition, there are some peptide-based PCSK9 inhibitors, such as Merck's MK-0616, which are in late-stage clinical development. Small-molecule drugs have advantages such as convenient administration, relatively easy production, and controllable quality, but no PCSK9 small-molecule inhibitors have been approved for marketing yet. The development of these drugs has become an important direction in PCSK9 inhibitor research and development. Summary of the Invention

[0005] The purpose of this application is to provide a novel polycyclic compound.

[0006] The purpose of this application is also to provide the use of the polycyclic compound described above as a PCSK9 inhibitor.

[0007] The purpose of this application is also to provide a pharmaceutical composition comprising the polycyclic compound as described above and a pharmaceutically acceptable carrier, excipient or excipient.

[0008] The purpose of this application is also to provide the use of the polycyclic compound described above in a medicament for treating PCSK9-related diseases.

[0009] The purpose of this application is also to provide a method for preventing or treating PCSK9-related diseases. These PCSK9-related diseases include cardiovascular diseases, cerebrovascular diseases, and / or related diseases.

[0010] In a first aspect of the invention, a compound of formula (I), its stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs are provided.

[0011] in, It can be a single bond or a double bond;

[0012] X is N or CR 1 Y is CR 2 Z represents CR 3 ;

[0013] Among them, R 1 Selected from the following groups: H, D, halogen, cyano, SF5, C 1-6 Alkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6Cycloalkyl, 4-8 membered heterocyclic groups, -C 0-4 Alkylene-OR 12 -C 0-4 Alkylene-SR 12 -C 0-4 Alkylene NR 10 R 11 Each of the groups may optionally be further coupled with one or more groups selected from D, halogen, cyano, hydroxyl, carboxyl, -C(O)OC 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-8 membered heterocyclic groups, C 1-6 Halogenated alkoxy groups, C 3-8 Halogenated cycloalkyl, C 3-8 Group substitution of halogenated cycloalkoxy groups;

[0014] R 2 R 3 Together with the atoms bonded to it, they form C 4-8 The carbon ring or a 4-8 membered heterocycle containing 1, 2, or 3 heteroatoms optionally selected from O, S, and N, wherein the C 4-8 The carbon ring or 4-8 membered heterocycle is further divided into one or more R 7 replace;

[0015] Each R 7 Independently selected from the following groups: D, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, -C 0-4 Alkylene-OR 12 -C 0-4 Alkylene-NR 10 R 11 -P(O)(R 14 )2、-C 0-4 Alkylene-OC(O)-C 0-4 Alkylene-R a -C 0-4 Alkylene-S(O)-C 0-4 Alkylene-R a -C 0-4 Alkylene-C(O)-C 0-4 Alkylene-R a -C 0-4 Alkylene-S(O)2-C 0-4 Alkylene-R a -C 0-4 Alkylene-S(O)(NR) 31 )-C 0-4 Alkylene-R a -C0-4 Alkylene-NHC(O)-R a -C 0-4 Alkylene-NHS(O)2-R a C 0-4 Alkylene-NHC(O)-C 1-4 Alkylene-R a -C 0-4 Alkylene-NHS(O)2-C 1-4 Alkylene-R a =O, =NR 31 =C(R) 13 2, 6-10 aryl, 5-10 heteroaryl, or two R atoms on the same or different atoms 7 All the atoms bonded to it together form C 3-8 The carbon ring or a 4-8 membered heterocycle containing 1, 2, or 3 heteroatoms selected from O, S, and N; each group may optionally be further surrounded by one or more atoms selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-8 membered heterocyclic groups, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Halogenated cycloalkyl, C 3-8 Group substitution of halogenated cycloalkoxy groups;

[0016] R a Selected from the following groups: H, D, hydroxyl, halogen, cyano, NR 10 R 11 OR 12 C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-8 membered heterocyclic groups, wherein each alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocyclic group may optionally be further substituted with one or more halogens;

[0017] m, n, and s are each independently 0, 1, 2, 3, 4, or 5;

[0018] Ring A is selected from the following group: C 6-10 Aromatic rings, 5-12 heterocyclic aromatic rings;

[0019] Cycle B is selected from the following group: 5-14 membered heterocycles, C 6-10 Aromatic rings, 5-14 quinary heterocyclic aromatic rings, 5-10 quinary heterocyclic cyclopentadienylene rings 6-10Aromatic rings, 5-10-membered heterocyclic rings and 5-10-membered heteroaromatic rings, preferably, the heterocyclic rings may optionally contain one or more intracyclic double bonds;

[0020] Each R 4 Independently selected from the following groups: H, D, halogens, -C 0-4 alkylene-cyano, -C 0-4 Alkylene-OR 12 C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, oxo groups (=O), =C(R) 13 )2, wherein each of the alkylene groups, alkyl groups, cycloalkyl groups, and heterocyclic groups may optionally be further substituted with one or more halogens;

[0021] Or, any two R 4 All the atoms bonded to it together form C 3-6 The carbon ring or a 4-6 membered heterocycle containing one or two heteroatoms optionally selected from O, S, and N, wherein each group may optionally be further surrounded by one or more atoms selected from D, halogen, hydroxyl, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Group substitution of halogenated alkoxy groups;

[0022] Each R 5 Independently selected from the following groups: H, D, halogens, -C 0-4 alkylene-cyano, -C 0-4 Alkylene-OR 12 -C 0-4 Alkylene-SR 12 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, NR 10 R 11 CONR 10 R 11 =O, =NR 31 =C(R) 13 )2, wherein each of the alkylene groups, alkyl groups, cycloalkyl groups, and heterocyclic groups may optionally be further substituted with one or more halogens;

[0023] Each R 6 Each is independently selected from the following groups: H, D, halogen, cyano, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, SF5, -C 0-4Alkylene-OR 12 -C 0-4 Alkylene-SR 12 -C 0-4 Alkylene-NR 10 R 11 -C 0-4 Alkylene-P(O)(R) 14 )2、-C 0-4 Alkylene C(O)-C 0-4 Alkylene-R a -C 0-4 Alkylene S(O)2-C 0-4 Alkylene-R a -C 0-4 Alkylene S(O)(NR) 31 )-C 0-4 Alkylene-R a =O, =NR 31 =C(R) 13 2. 6-10 aryl groups, 5-10 heteroaryl groups, wherein each group may optionally be further divided by one or more groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-8 membered heterocyclic groups, C 1-6 Halogenated alkoxy groups, C 3-8 Halogenated cycloalkyl, C 3-8 Group substitution of halogenated cycloalkoxy groups;

[0024] Each R 10 and each R 11 Each is independently selected from the following groups: H, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, -C(O)R b -S(O)2-R b -S(O)(NR) 31 )-R b Each of the groups may optionally be further surrounded by one or more elements selected from deuterium, halogen, =O, CN, hydroxyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3- 10 Cycloalkyl, 4-10 membered heterocyclic groups, C 3-10 Substituents of halocycloalkyl groups and 4-10 membered haloheterocyclic groups;

[0025] Or, R attached to the same nitrogen atom10 and R 11 The nitrogen atoms bonded to them together form 4-10 member nitrogen-containing heterocycles, which may optionally be further bonded by one or more elements selected from D, halogens, =O, CN, hydroxyl, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy group, -S(O)2-C 1-6 Alkyl, -C(O)-C 1-6 Substituents of alkyl groups;

[0026] Each R b Select independently from the following groups: H, D, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-8 membered heterocyclic group, 4-8 membered heterocyclic group, amino, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, wherein each group may optionally be further converted by one or more halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0027] Each R 12 Independently selected from the following groups: H, C 1-6 Alkyl, C 3-10 cycloalkyl, C 4-10 Heterocyclic groups, -C(O)-N(R) 31 )2, wherein the group may optionally be further selected by one or more elements selected from deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 3-10 Substituents of halocycloalkyl groups, 4-10 membered haloheterocyclic groups; optionally further substituted by one or more groups selected from the group consisting of cyano, C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups;

[0028] Each R 13 Independently selected from: H, D, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl, -C1-4 Alkylene-OR 12 ;

[0029] Alternatively, two R atoms attached to the same carbon atom 13 The carbon atoms bonded to them together form C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group may optionally be further selected from one or more elements selected from D, halogen, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy group, -S(O)2-C 1-6 Alkyl, -C(O)C 1-6 Substituents of alkyl groups;

[0030] Each R 14 Selected independently from: C 1-6 Alkyl, -C 1-4 Alkylene-OR 12 The alkyl and heterocyclic groups may optionally be further replaced by one or more substituents selected from D and halogens;

[0031] Each R 31 Independently selected from the following groups: H, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkoxy, 4-10 membered heterocyclic groups, said groups may optionally be further surrounded by one or more elements selected from deuterium, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1- 4-alkoxy group, C 1-4 Halogenated alkoxy groups, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 3-10 Substituents of halocycloalkyl groups and 4-10 membered haloheterocyclic groups;

[0032] The condition is that there is at least one R. 7 Not D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, oxo groups (=O), and phenyl groups.

[0033] In another preferred embodiment, the Selected from the following group: Wherein, ring C is C 3-8 Carbon ring or 4-8 membered heterocycle; q is 1, 2, 3, 4 or 5; X, R 7 The definition is as described above.

[0034] In another preferred embodiment, ring C is C 4-6Carbon ring or 4-6 membered heterocyclic ring. In another preferred embodiment, the ring C is C6. 4-6 Carbon rings, 4-6 membered N-containing heterocycles, 4-6 membered S-containing heterocycles, or 4-6 membered O-containing heterocycles.

[0035] In another preferred embodiment, the Selected from the following group:

[0036] Where each q is 1, 2, 3, 4, or 5; R 7 The definition is as described above.

[0037] In another preferred embodiment, the R 7 Selected from the following group: halogen, hydroxyl, C 1-4 Alkyl, -NR 10 R 11 -S(O)2-R a -CH2-S(O)2-NR 10 R 11 -S(O)-R a -OR a -(CH2)2-R a -CH2-OR 12 -C(O)-OR 12 -(CH2)2-OR a -(CH2)3-OR a -C(O)-R a -CH2-C(O)-R a -(CH2)2-C(O)-R a -(CH2)2-C(O)-OR a -CH2-S(O)2-R a -(CH2)2-S(O)2-R a -CH2-NH-C(O)-R a -CH2-NH-S(O)2-R a -NH-S(O)2-R a -NH-C(O)-R a -OC(O)NR 10 R 11 =O, =NR 31 =C(R) 13 2, 6-10 aryl, 5-10 heteroaryl, wherein two R atoms on the same atom or different atoms 7 The atoms connected to it optionally form C 3-6The carbon ring or a 4-6 membered heterocycle containing one or two heteroatoms optionally selected from O, S, and N; each group may optionally be further surrounded by one or more atoms selected from D, halogen, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Substitution of halocycloalkyl groups; the condition is that at least one R 7 Not halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, oxo groups (=O), phenyl groups;

[0038] R a Selected from the following groups: H, D, hydroxyl, halogen, cyano, NR 10 R 11 OR 12 C 1-6 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic groups, wherein each alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocyclic group may optionally be further substituted with one or more halogens;

[0039] Each R 10 and each R 11 Each is independently selected from the following groups: H, cyano, C. 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, -C(O)-R b -S(O)2-R b -S(O)(NR) 31 )-R b Each of the groups may optionally be further surrounded by one or more elements selected from deuterium, halogens, =O, hydroxyl, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Substituents of cycloalkyl groups;

[0040] Or, R attached to the same nitrogen atom 10 and R 11 The nitrogen atoms bonded to them together form a 4-8 membered nitrogen-containing heterocycle, which may optionally be further bonded by one or more elements selected from halogens, =O, hydroxyl groups, C, and O. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy group, -S(O)2-C 1-6Alkyl, -C(O)-C 1-6 Substituents of alkyl groups;

[0041] Each R b Select independently from the following groups: H, D, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, 4-6 membered heterocyclic group, amino, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl group 2, wherein each group may optionally be further converted by one or more halogens, hydroxyl groups, cyano groups, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Substituents of haloalkoxy groups;

[0042] Each R 12 Independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 cycloalkyl, C 4-6 Heterocyclic groups, -C(O)-N(R) 31 )2, wherein the group may optionally be further selected by one or more elements selected from deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 4-6 membered heterocyclic, C 3-6 The substituents are substituted with halocycloalkyl groups or 4-6 membered haloheterocyclic groups; the above substituents may optionally be further substituted with one or more groups selected from the group consisting of cyano, C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups;

[0043] Each R 13 Independently selected from: H, D, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl, -C 1-4 alkylene hydroxyl, -C 1-4 Alkylene-C 1-4 Alkoxy;

[0044] Alternatively, two R atoms attached to the same carbon atom 13 The carbon atoms bonded to them together form C 3-6Cycloalkyl or 4-6 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group may optionally be further selected from one or more elements selected from D, halogen, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy group, -S(O)2-C 1-4 Alkyl, -C(O)C 1-4 Substituents of alkyl groups;

[0045] Each R 31 Independently selected from the following groups: H, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, said group may optionally be further surrounded by one or more elements selected from deuterium, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1- 4-alkoxy group, C 1-4 The substituents of the haloalkoxy group are replaced.

[0046] In another preferred embodiment, ring A is selected from the group consisting of: benzene ring, naphthalene ring, 5-9 membered heteroaryl ring, and 10 membered heteroaryl ring;

[0047] Preferably, ring A is selected from the group consisting of: benzene ring, naphthalene ring, quinoline, isoquinoline, and 5-6 membered heteroaromatic rings;

[0048] More preferably, ring A is selected from the group consisting of: benzene ring, furan, pyrrole, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyridazine, pyrimidine, and pyrazine.

[0049] In another preferred embodiment, Selected from: In another preferred embodiment, R 5 Selected from the following groups: hydrogen, deuterium, halogens, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -SC 1-6 Alkyl, -SC 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups.

[0050] In another preferred embodiment, ring B is selected from the group consisting of: 5-7 member heteromonocyclic rings, 8-12 heterospirocyclic rings, 8-12 member heterobridged rings, 5-7 member heterocyclic benzobenzene rings, 5-7 member heterocyclic benzo5-7 member heteroaromatic rings, benzene rings, naphthalene rings, and 5-12 member heteroaromatic rings.

[0051] Preferably, ring B is selected from the group consisting of: 5-7 saturated heteromonocyclic rings, 5-7 partially saturated heteromonocyclic rings, 8-11 heterospirocyclic rings, 8-11 heterobridged rings, 5-6 heterocyclic benzobenzene rings, 5-7 heterocyclic benzo5-6 heteroaromatic rings, and 5-9 heteroaromatic rings.

[0052] More preferably, the ring B is selected from the group consisting of: 5-7 saturated nitrogen-containing heteromonocycles, 5-7 partially saturated nitrogen-containing heteromonocycles, 8-11 nitrogen-containing heterospirocycles, 8-11 nitrogen-containing heterobridged rings, 5-6 nitrogen-containing heterocyclic benzobenzene rings, 5-7 heterocyclic benzo5-6 nitrogen-containing heteroaromatic rings, and 5-9 nitrogen-containing heteroaromatic rings;

[0053] More preferably, the ring B is selected from the group consisting of: 5-7 saturated nitrogen-containing heteromonocycles, 5-7 partially saturated nitrogen-containing heteromonocycles, 8-10 nitrogen-containing heterospirocycles, 8-10 nitrogen-containing heterobridged rings, 5-6 nitrogen-containing heterocyclic benzo[a]benzene rings, 5-7 nitrogen-containing heterocyclic benzo[a]5-6 nitrogen-containing heterocyclic aromatic rings, and 5-7 nitrogen-containing heterocyclic aromatic rings;

[0054] Most preferably, the ring B is selected from the group consisting of:

[0055] In another preferred embodiment, Selected from:

[0056] In another preferred embodiment, each R 4 Independently selected from the following groups: H, D, halogen, cyano, C 1-4 Alkyl, -C 0-4 Alkylene-C 1-4 Alkoxy, -OC 1-4 alkylene-hydroxyl, -OC 1-4 Alkylene-C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, oxo groups (=O), =C(R) 13 )2, wherein each of the alkylene groups, alkyl groups, cycloalkyl groups, and heterocyclic groups may optionally be further substituted with one or more halogens;

[0057] Or, any two R 4 All the atoms bonded to it together form C 3-6 The carbon ring or a 4-6 membered heterocycle containing one or two heteroatoms optionally selected from O, S, and N, wherein each group may optionally be further surrounded by one or more atoms selected from D, halogen, hydroxyl, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Group substitution of halogenated alkoxy groups;

[0058] Each R 5 Independently selected from the following groups: H, D, halogen, cyano, hydroxyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, SCF3, C 1-4 Alkoxy, -OC 1-4 alkylene-hydroxyl, -OC 1-4 Alkylene-C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, amino, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, wherein each group may optionally be further substituted with one or more halogens;

[0059] Each R 6 Each is independently selected from the following groups: H, D, halogen, cyano, C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, SF5, hydroxyl, -C 0-4 Alkylene-C 1-4 Alkoxy, -OC 1-4 alkylene-hydroxyl, -OC 1-4 Alkylene-C 1-4 Alkoxy, SCF3, -NR 10 R 11 -P(O)(C 1-4 Alkoxy group, carboxyl group, -C(O)C 1-4 Alkyl, -C(O)NR 10 R 11 -S(O)2-C 1-4 Alkyl group, -S(O)2NR 10 R 11 -S(O)(NR) 31 )-C 1-4 Alkyl, -S(O)(NR 31 )-NR 10 R 11 =O, =NR 31 =C(R) 13 2. Phenyl, 5-6-membered heteroaryl, wherein each group may optionally be further substituted by one or more groups selected from D, halogens;

[0060] R 10 R 11 R 13 R 31 The definition is as described above.

[0061] In another preferred embodiment, the compound has the structure shown in formula (II-1), (II-2), (II-3), or (II-4):

[0062] Where t1 is 0 or 1; t2 is 0, 1 or 2; t3 is 0 or 1; t4 is 0 or 1; q1 is 0, 1, 2, 3 or 4;

[0063] R 71 Selected from: hydroxyl group, -CH2-R a -NR 10 R 11 -S(O)2-R a -CH2-S(O)2-NR 10 R 11 -S(O)-R a -OR a -(CH2)2-R a -CH2-OR 12 -C(O)-OR 12 -(CH2)2-OR a -(CH2)3-OR a -C(O)-R a -CH2-C(O)-R a -(CH2)2-C(O)-R a -(CH2)2-C(O)-OR a -CH2-S(O)2-R a -(CH2)2-S(O)2-R a -CH2-NH-C(O)-R a -CH2-NH-S(O)2-R a -NH-S(O)2-R a -NH-C(O)-R a -OC(O)NR 10 R 11 =C(R) 13 2, 6-10 aryl, 5-8 heteroaryl, wherein two R atoms on the same atom or different atoms 7 The atoms connected to it optionally form C 3-6 The carbon ring or a 4-6 membered heterocycle containing one or two heteroatoms optionally selected from O, S, and N; each group may optionally be further surrounded by one or more atoms selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C3-6 Substitution of groups such as halocycloalkyl, 4-6 membered heterocyclic groups, and 4-6 membered haloheterocyclic groups;

[0064] Each R 72 Each is independently selected from: H, halogen, C 1-6 Alkyl, -NHSO2C1-C6 alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, where two R groups are... 72 Optional and connected atoms further form C 3-6 Cycloalkylene or 4-6 membered heterocyclic alkylene groups;

[0065] m, n, s, X, R a R 10 R 11 R 12 R 13 Ring A, Ring B, R 4 R 5 R 6 The definition is as described above.

[0066] In another preferred embodiment, R 1 Selected from the following groups: H, D, halogen, cyano, SF5, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, wherein each group may optionally be further surrounded by one or more groups selected from D, halogen, cyano, hydroxyl, carboxyl, -C(O)OC 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-8 membered heterocyclic groups, C 1-6 Halogenated alkoxy groups, C 3-8 Halogenated cycloalkyl, C 3-8 Group substitution of halogenated cycloalkoxy groups;

[0067] Preferably, R 1 Selected from the following groups: H, D, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, wherein each group may optionally be further substituted with one or more groups selected from D, halogens, or hydroxyl groups.

[0068] More preferably, R 1 Selected from the following groups: H, D, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C1- 4-Haloalkoxy group.

[0069] In another preferred embodiment, the compound is selected from the group consisting of:

[0070] A second aspect of the present invention provides a pharmaceutical composition comprising:

[0071] (i) the compounds described in the first aspect, their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs; and

[0072] (ii) Pharmaceutically acceptable carriers, excipients or excipients.

[0073] A third aspect of the invention provides the use of the compounds, stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs as described in the first aspect, or pharmaceutical compositions as described in the second aspect, for the preparation of medicaments for treating and / or preventing diseases associated with PCSK9.

[0074] Preferably, the PCSK9-related diseases are cardiovascular diseases, cerebrovascular diseases, and / or related diseases;

[0075] More preferably, the PCSK9-related diseases are selected from the group consisting of: dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, and congestive heart failure.

[0076] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0077] Through long-term and in-depth research and extensive screening, the inventors have developed a polycyclic compound, PCSK9, which exhibits strong inhibitory activity. Based on this, the inventors have completed this invention.

[0078] the term

[0079] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed-ended. In other words, the terms also include “consistently made of” or “made of”.

[0080] As used herein, the term "alkyl" refers to a monovalent, straight-chain or branched saturated hydrocarbon group consisting of carbon and hydrogen atoms, for example, "C 1-6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl. In this application, alkyl is also intended to include deuterated alkyl groups, examples of which include, but are not limited to, CD3, CD2CD3, and CD2CD2CD3.

[0081] As used herein, the term "alkylene" refers to the group obtained by removing a hydrogen atom from an alkyl group as described above, such as methylene (-CH2-), ethylene (-CH2CH2-), etc.

[0082] As used herein, the term "carbocyclic" or "carbocyclic group" refers to a saturated or partially saturated carbocyclic group composed of carbon and hydrogen atoms, such as a monocyclic, bicyclic, or tricyclic structure, wherein the ring structure as a whole is not aromatic but may contain one or more unsaturated structures. The ring may be further substituted by one or more substituents. When two or more rings are present in the carbocyclic group, the rings may further form fused rings, bridged rings, spirocyclic rings, or any combination thereof.

[0083] As used herein, the term "cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of carbon and hydrogen atoms, such as "C". 3-8 "Cycloalkyl" refers to a cycloalkyl group containing 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) carbon atoms, preferably C14. 3-6 Cycloalkyl groups. Cycloalkyl groups can be monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or similar groups, or bicyclic, such as fused rings, bridged rings or spirocyclic rings.

[0084] As used herein, the term "alkoxy" refers to -O-alkyl, and examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, tert-butoxy, etc.

[0085] As used herein, the term "hydroxyalkyl" refers to an alkyl group containing one or more hydroxyl groups, and the definition of an alkyl group is as described above. Examples of hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, etc.

[0086] As used herein, "halogen" refers to F, Cl, Br, I and their isotopes, including but not limited to F, 18 F, Cl,32 Cl, Br, I.

[0087] As used herein, the term "cyano" refers to -CN. As used herein, the term "amino" refers to -NH2.

[0088] As used herein, the term "carboxyl" refers to -COOH. As used herein, the term "oxo" refers to =O.

[0089] As used herein, the term "haloalkyl" refers to a group obtained by substituting one or more hydrogen atoms in an alkyl group as described above with the same or different halogens. Specifically, "haloC" refers to a group obtained by substituting one or more hydrogen atoms in an alkyl group with the same or different halogens. 1-6 "alkyl" is preferably a halogenated C 1-4 Alkyl groups, examples of which include, but are not limited to: -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl groups (e.g., -CF3-, -CF2CF3), etc.

[0090] As used herein, the term "halocycloalkyl" refers to a group obtained by substituting one or more hydrogens in a cycloalkyl group as described above with the same or different halogens.

[0091] As used herein, the term "haloalkoxy" refers to a group obtained by substituting one or more hydrogen atoms in an alkoxy group as described above with the same or different halogens. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, etc.

[0092] As used herein, the term "cycloalkoxy" refers to the formula -OR v Group, wherein R v Cycloalkyl groups are defined herein. Examples of cycloalkyloxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0093] As used herein, the term "heterocyclic" or "heterocyclic group" refers to a fully or partially saturated monocyclic, bicyclic, or polycyclic cyclic group on a ring backbone containing one or more heteroatoms selected from N, S, or O. For example, "4-7 membered heterocyclic group" refers to a group having 4-7 (e.g., 4, 5, 6, or 7) ring members. The nitrogen or sulfur atom may be oxidized, or the nitrogen atom may be quaternized. The heterocyclic group can be attached to any heteroatom or carbon residue in a ring or ring system molecule. Monocyclic heterocyclic groups include, but are not limited to: azacyclic butyl, pyrrolyl, oxacyclic butyl, pyrazolinyl, imidazolinyl, imidazoalkyl, oxazolinyl, isoxazolinyl, thiazoalkyl, isothiazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylyl, hexahydroachenginyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxane, and tetrahydro-1,1-dioxothiophene, etc. Polycyclic heterocyclic groups include, but are not limited to, spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0094] As used herein, the term "aromatic ring" or "aryl" refers to an aromatic cyclic hydrocarbon group (including monocyclic, bicyclic, or polycyclic groups), such as "C 6-12 "Aryl" refers to an aromatic cyclic hydrocarbon group having 6-12 (6, 7, 8, 9, 10, 11, or 12) ring carbon atoms. It contains two or more aromatic rings (such as bicyclic rings), and the aromatic rings of the aryl group can be linked by single bonds (such as biphenyl) or fused (such as naphthalene, anthracene, etc.). Examples of aryl groups (especially monocyclic and bicyclic groups) include, but are not limited to, phenyl, biphenyl, or naphthyl. Aryl groups can be fused with heterocyclic groups through single bonds or any two adjacent ring carbon atoms, for example: benzotetrahydrofuranyl, benzotetrahydropyranyl, benzodioxane, etc. wait.

[0095] As used herein, the term “heteroaromatic ring” or “heteroaryl” refers to an aromatic cyclic group (including monocyclic, bicyclic, or polycyclic groups) whose ring skeleton contains 1, 2, 3, or 4 heteroatoms selected from N, S, or O. For example, “5-12-membered heteroaryl” refers to a monocyclic, bicyclic, or tricyclic group having 5 to 12 (5, 6, 7, 8, 9, 10, 11, or 12) ring atoms. Examples of heteroaryl groups include, but are not limited to: imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thiophene, furanyl, pyranyl, pyridinyl, pyrroleyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophene, benzothiaranyl, benzimidazole, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzopyranyl, indoleyl, isoindoleyl, triazolyl, triazinyl, quinoxolinyl, purine, quinazolinyl, quinazinyl, naphthidyl, pteridinyl, carbazoleyl, and azazolyl. basalt, diazoxide acridine group, etc.

[0096] As used in this article, the term "multi-substitution" refers to a substance that includes two or more substitutions.

[0097] As used herein, “deuterated” means that one or more hydrogen atoms in a compound or group are replaced by deuterium. Deuteration can be monosubstituted, disubstituted, polysubstituted, or total substituted. The terms “one or more deuterated” and “one or more deuterated” are used interchangeably.

[0098] As used herein, the term "deuterated compound" refers to a compound in which one or more hydrogen atoms (H) are replaced by a deuterium atom (D).

[0099] When a group loses one hydrogen atom, it becomes a subunit of the corresponding group, and it is a divalent group. For example, an alkyl group loses one hydrogen atom to become an alkylene group (e.g., methylene, ethylene, propylene, isopropylene). ), butylide (such as) or ), pentylene (e.g.) ), hexyl (such as) ), subheptagen (such as ) etc.; cycloalkyl corresponds to cyclohexane (e.g.: (etc.); heterocyclic groups correspond to subheterocyclic groups (e.g.: Alkoxy groups correspond to alkoxy groups (e.g., -CH2O-, -CH2CH2O-, -OCH2CH2CH2-), and heteroalkyl groups correspond to heteroalkyl groups (e.g., -CH2-O-CH2CH2-, -CH2-O-(CH2)2CH2-, -CH2CH2-O-CH2CH2-, -CH2-O-CH2CH2CH2-, -CH2-S-CH2CH2-, -CH2-S-(CH2)2CH2-, -CH2CH2-S-CH2CH2-, -CH2-S-CH2CH2CH2-, -CH2-NH-CH2CH2-, -CH2-NH-(CH2)2CH2-, -CH2CH2-NH-CH2CH2-, -CH2-NH-CH2CH2CH2-, etc.).

[0100] In this invention, the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, unless otherwise specified, include substituted alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. The substituents include, but are not limited to, halogen, hydroxyl, cyano, acyl, sulfonyl, ester, sulfinyl, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, acyl, and ester groups.

[0101] As used herein, the term "substitution" refers to the replacement of one or more hydrogen atoms on a particular group by a particular substituent. The particular substituent is either the substituent described accordingly above or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a particular group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible.

[0102] Unless otherwise specified, the groups described in this invention may be substituted with substituents selected from the group consisting of: D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-12 membered heterocyclic groups, C3-C6 alkyl, ... 12 cycloalkyl, 5-10 heteroaryl and C6-C 10 Aryl.

[0103] In this document, “optionally” means that the event or condition described below may, but is not required to, occur, and the description includes both the possibility that the event or condition occurs and the possibility that the event or condition does not occur.

[0104] In this article, the term "multiple" refers to 2, 3, 4, 5, or a positive integer greater than 5.

[0105] Active ingredients

[0106] As used herein, “compound of the present invention” means a compound of formula (I), and also includes its stereoisomers, its optical isomers, its pharmaceutically acceptable salts, its crystal forms, its isotopic derivatives, its prodrugs, its metabolites, its solvates or hydrates thereof.

[0107] Unless otherwise specified, the structural formulas described in this invention are intended to include all stereoisomers (such as cis-trans isomers, enantiomers, diastereomers, and conformational isomers): R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, cis-trans isomers of cycloalkanes, etc. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, or conformational isomers, is within the scope of this invention.

[0108] The compounds of this invention may contain cis-trans isomers, one or more chiral carbon atoms, and thus can produce cis-trans isomers, chiral isomers, enantiomers, diastereomers, and other combinations of stereoisomers. Cis-trans isomerism refers to the diastereomeric phenomenon in which different functional groups in a compound molecule are arranged differently in space due to a restrictive factor that limits free rotation. This restrictive factor is generally caused by non-rotating functional groups in the structure of organic compounds, such as C=C double bonds, C=N double bonds, C=S double bonds, N=N double bonds, heterocycles, or cycloalkanes. Organic molecules containing such isomers, such as alkenes, azo compounds, and cycloalkanes, are considered cis-trans isomers. Cis refers to the same ligands being in adjacent positions, generally denoted by "cis" or "cis-"; trans refers to the same ligands being in diagonal positions, generally denoted by "trans" or "trans-". Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. This invention aims to include all possible isomers, their racemic and optically pure forms. The compounds of this invention can be prepared using racemic, cis-trans, chiral, diastereomer, or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0109] Conventional techniques for preparing / separating individual optical isomers (i.e., cis-trans isomers and chiral isomers) include chiral synthesis from suitable cis-trans precursors or optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography.

[0110] To design the synthesis of a specific stereoisomer of the compound of this invention, it can be prepared asymmetrically or derivatized with a chiral auxiliary. The resulting stereo mixture is then separated, and the chiral auxiliary is removed to obtain pure cis-trans monomers, chiral monomers, or mixed stereoisomers. If the molecule contains a cis-trans isomer center, it can be purified by column chromatography (normal-phase silica gel column or reverse-phase high-performance liquid chromatography) to obtain pure cis or trans products. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomeric salt, which is then separated by conventional methods such as separation crystallization or chromatography to obtain pure enantiomers.

[0111] This invention also includes isotopically labeled compounds (i.e., isotopic derivatives), equivalent to the original compounds disclosed herein. However, it is common practice to see one or more atoms replaced by atoms with different atomic weights or mass numbers. Examples of isotopes in the isotopic derivatives of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively as follows: 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Isotope derivatives of the compounds of this invention are all within the scope of protection of this invention. In this document, 3 H-labeled compounds and 14 C-labeled compounds are useful in tissue distribution experiments of drugs and substrates. Tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) Labeled compounds are relatively easy to prepare and detect, making them the preferred choice among isotopes. Furthermore, heavier isotope substitutions, such as deuterium, are also possible. 2 H, due to its excellent metabolic stability, offers advantages in certain therapies, such as increasing half-life or reducing dosage in vivo, and therefore may be preferred in some cases. Isotopically labeled compounds can be prepared using general methods, by replacing the non-isotopic reagent with an readily available isotopically labeled reagent, according to the scheme disclosed in the examples.

[0112] As used herein, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0113] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionates, hexanoates, octanoates, decanoates, undecenoates, glycolates, gluconates, lactates, sebates, adipates, glutarate, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbic acid salts, salicylates, 4-aminosalicylic acid salts, and naphthalene disulfonates. These salts can be prepared using methods known in this field.

[0114] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0115] Metabolites of the compound represented by formula (I) and its pharmaceutically acceptable salts, as well as prodrugs that can be converted in vivo into the compound represented by formula (I) and its pharmaceutically acceptable salts, are also included within the scope of protection of this invention.

[0116] As used herein, the term "solvent" refers to a complex of a compound of formula (I) coordinated with a solvent molecule in a specific ratio.

[0117] As used herein, the term "hydrate" refers to a complex of the compound represented by formula (I) coordinated with water molecules in a specific ratio.

[0118] As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to broaden their scope. Generally, the term "substitution" refers to replacing a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are substituted by multiple specific substituents, each position of the substituent can be the same or different. The term "substitution" as used herein includes all permissible organic group substitutions. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic groups. As described herein, heteroatomic nitrogen may be supplemented with a hydrogen substituent or any permissible organic group described above to complete its valence state. Furthermore, the present invention is not intended to limit permissible substituted organic groups in any way. The present invention considers the combination of substituents and variable groups to be beneficial in the treatment of diseases in the form of stable compounds. The term "stable" here means having a stable compound that, when tested over a sufficiently long period, maintains sufficient integrity of the compound structure, preferably remaining effective for a sufficiently long period, and is used herein for the purposes described above.

[0119] Pharmaceutical Compositions and Administration

[0120] Because the compounds of the present invention can inhibit PCSK9, and are used to treat diseases such as cardiovascular diseases, cerebrovascular diseases, and / or related diseases, the compounds of the present invention, their stereoisomers, their optical isomers, their pharmaceutically acceptable salts, their crystal forms, their isotopic derivatives, their prodrugs, their metabolites, their solvates or hydrates thereof, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to prevent and / or treat (stabilize, alleviate or cure) PCSK9-related diseases (cardiovascular diseases, cerebrovascular diseases, and / or related diseases).

[0121] The pharmaceutical compositions of the present invention comprise the compound of the present invention within a safe and effective range and a pharmaceutically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0122] "Pharmaceutically acceptable carriers" refer to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0123] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include, but are not limited to, oral administration and parenteral administration (intravenous, intramuscular, or subcutaneous).

[0124] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0125] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0126] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0127] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0128] In addition to the active ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0129] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0130] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as needed.

[0131] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0132] When administered in combination, the pharmaceutical composition further comprises one or more (two, three, four, or more) other pharmaceutically acceptable compounds. One or more (two, three, four, or more) of these other pharmaceutically acceptable compounds may be used simultaneously, separately, or sequentially with the compounds of the present invention for the prevention and / or treatment of PCSK9-related diseases.

[0133] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to the mammal (such as a human) requiring treatment. The dosage at the time of administration is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1-2000 mg, preferably 20-500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0134] The beneficial effects of this invention are: the compound of this invention has a very strong PCSK9 binding affinity and excellent metabolic properties, and has good development potential.

[0135] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, were generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0136] Preparation of intermediates

[0137] Preparation of Intermediate 1: 6'-Fluoro-2H-[1,3'-Bipyridine]-2-one

[0138] Pyridine-2(1H)-one (5.0 g, 52.6 mmol) and (6-fluoropyridin-3-yl)boronic acid (3.79 g, 26.9 mmol) were dissolved in dichloromethane (150 mL), and pyridine (2.65 g, 33.6 mmol) and copper acetate (4.068 g, 22.4 mmol) were added. The system was evacuated and purged with oxygen three times, then stirred overnight at room temperature. After the reaction was complete, the reaction solution was filtered, the filtrate was diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to give 6'-fluoro-2H-[1,3'-bipyridine]-2-one (2.2 g, yield: 43%). ESI-MS [M+H] + :found 191.1. 1 H NMR(400MHz, DMSO-d6)δ8.37-8.33(m,1H),8.14(ddd,J=8.7,7.2,2.8Hz,1H),7.76-7.69(m,1H),7.6 0-7.51(m,1H),7.37(dd,J=8.7,3.1Hz,1H),6.52(dd,J=9.3,0.4Hz,1H),6.36(td,J=6.8,1.2Hz,1H).

[0139] Intermediates 1a-1j can be prepared by selecting appropriate raw materials by referring to the synthesis method of intermediate 1, and their structures are shown in Table 1.

[0140] Table 1. Structural formulas and chemical names of intermediates 1a-1j

[0141] Preparation of Intermediate 2: 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0142] Step 1: 6'-fluoro-2H-[1,3'-bipyridine]-2-one (1.9 g, 10 mmol), (1S,3S)-3-aminocyclopentylcarbamate tert-butyl ester (2.0 g, 10 mmol), and diisopropylethylamine (3.87 g, 30 mmol) were dissolved in N-methylpyrrolidone (30 mL), and the mixture was heated to 140 °C and stirred for 60 hours. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain tert-butyl((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)carbamate (1.8 g, yield: 48.6%). ESI-MS [M+H] + :found 371.2. 1 H NMR(400MHz,DMSO-d6)δ7.92(d,J=2.6Hz,1H),7.60(dd,J=6.8,1.6Hz,1H),7.51-7.4 4(m,1H),7.39(dd,J=8.9,2.7Hz,1H),6.88(dd,J=18.7,7.0Hz,2H),6.50(d,J=8.9Hz ,1H),6.46-6.42(m,1H),6.27(td,J=6.7,1.3Hz,1H),4.29-4.18(m,1H),3.98-3.90( m,1H),2.13-2.02(m,1H),1.98-1.91(m,1H),1.82-1.69(m,2H),1.47-1.36(m,11H).

[0143] Step 2: 1.8 g (4.86 mmol) of tert-butyl((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)carbamate was dissolved in 1,4-dioxane (4.0 M, 10 mL) of hydrogen chloride solution and stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed by concentration to obtain 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (2.5 g, crude product, yield: 100%). The crude product can be used directly in subsequent reactions. ESI-MS [M+H] + :found 271.1.

[0144] Intermediates 2a-2i can be prepared by selecting appropriate raw materials by referring to the synthesis method of intermediate 2, and their structures are shown in Table 2.

[0145] Table 2. Structural formulas and chemical names of intermediates 2a-2i

[0146] Preparation of Intermediate 3: 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-3-methylimidazolidine-2,4-dione

[0147] The first step can refer to the first step in the preparation of intermediate 2 to select appropriate raw materials to obtain tert-butyl((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate.

[0148] Step 2: Dissolve tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate (710 mg, 2.641 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (760 mg, 6.667 mmol), 3-methylimidazoline-2,4-dione (229 mg, 1.613 mmol), cuprous iodide (306 mg, 1.613 mmol), and potassium phosphate (1.4 g, 6.452 mmol) in isopropanol (20 mL). Vacuum the system and purge with nitrogen three times. Then heat to 100 °C and stir for 16 hours. After the reaction was completed, the reaction solution was filtered, and the crude product was concentrated by normal phase column chromatography to obtain tert-butyl((1S,3S)-3-((5-(3-methyl-2,4-dioxoimidazolidine-1-yl)pyridin-2-yl)amino)cyclopentyl)carbamate (900 mg, yield: 81.82%).

[0149] The third step can be prepared by referring to the second step in the preparation of intermediate 2 to obtain 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-3-methylimidazolidine-2,4-dione.

[0150] Intermediate 3a-3h can be prepared by selecting appropriate raw materials by referring to the synthesis method of intermediate 3, and its structure is shown in Table 3.

[0151] Table 3. Structural formulas and chemical names of intermediates 3a-3h

[0152] Preparation of Intermediate 4: 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5'-fluoro-2H-[1,3'-bipyridine]-2-one

[0153] Step 1: Dissolve 6'-chloro-5'-fluoro-2H-[1,3'-bipyridine]-2-one (0.73 g, 3.25 mmol) in 1,4-dioxane (10 mL), and add (1S,3S)-3-aminocyclopentylcarbamate tert-butyl ester (650 mg, 3.25 mmol), dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazolium-2-ylidene](3-chloropyridinyl)palladium (154 mg, 0.19 mmol) and cesium carbonate (1.58 g, 48.74 mmol) sequentially. After purging with nitrogen three times, heat to 110 °C and stir for 12 hours. After the reaction was completed, the system was cooled to room temperature. The crude product was concentrated and purified by normal phase column chromatography to obtain tert-butyl((1S,3S)-3-((5'-fluoro-2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)carbamate (1.10 g, yield: 87.13%).

[0154] Step 2: 1.37 g (3.52 mmol) of tert-butyl((1S,3S)-3-((5'-fluoro-2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)carbamate was dissolved in a 4 M, 20 mL solution of hydrogen chloride-dioxane and stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was directly concentrated to obtain 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5'-fluoro-2H-[1,3'-bipyridine]-2-one (1.37 g, yield: crude product). The crude product can be used directly in the next step of the reaction.

[0155] Preparation of intermediate 5: tert-butyl-2-chloro-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester

[0156] Step 1: Ethyl benzyl glycinate (30 g, 155.2 mmol), ethyl 4-carbonylvalerate (22.38 g, 155.2 mmol), and acetic acid (0.5 mL) were dissolved in methanol (250 mL). After stirring for half an hour, sodium borohydride acetate (48.8 g, 776.2 mmol) was slowly added. After the addition was complete, the reaction was continued for 16 hours. After the reaction was completed, the reaction solution was filtered, and the crude product was purified by normal phase column chromatography to obtain ethyl 4-(benzyl(2-ethoxy-2-carbonylethyl)amino)valerate (23.6 g, yield: 47.3%).

[0157] Step 2: Ethyl 4-(benzyl(2-ethoxy-2-carbonylethyl)amino)valerate (23.6 g, 73.520 mmol) was dissolved in toluene (250 mL), and sodium ethoxide (15 g, 220.501 mmol) was added. The mixture was heated to 110 °C and stirred for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography to obtain ethyl 1-benzyl-2-methyl-5-carbonylpiperidine-4-carboxylic acid ester (15.0 g, yield: 75.03%).

[0158] Step 3: Ethyl 1-benzyl-2-methyl-5-carbonylpiperidin-4-carboxylic acid ester (8 g, 29.091 mmol), urea (7 g, 116.367 mmol), and sodium ethoxide (5.1 g, 75.636 mmol) were dissolved in ethanol (100 mL), and the mixture was heated to 80 °C and stirred for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography to obtain 7-benzyl-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diol (5.0 g, yield: 63.45%).

[0159] Step 4: 4 g of 7-phenylmethyl-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diol was dissolved in phosphorus oxychloride (80 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated, the crude product was diluted with dichloromethane, and washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the crude product was purified by normal-phase column chromatography to obtain 1.5 g of 7-phenylmethyl-2,4-dichloro-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (yield: 33.33%).

[0160] Step 5: Dissolve 1 g of 7-benzyl-2,4-dichloro-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, 1.6 g of zinc powder, and 2.4 mL of ammonia in 20 mL of ethanol. Heat to 80 °C and stir for 2 hours. Filter the reaction mixture and concentrate the filtrate to obtain the crude product. Purify the crude product by normal-phase column chromatography to obtain 500 mg of 7-benzyl-2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (yield: 64.52%).

[0161] Step 6: Dissolve 500 mg of 7-benzyl-2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine in 1,2-dichloroethane (15 mL), add 1-chloroethyl chloroformate (15 mL), and heat to 70 °C with stirring for 16 hours. After the reaction is complete, concentrate the reaction solution, dilute with methanol, and then heat to 60 °C for 1 hour. After cooling to room temperature, concentrate the reaction solution to obtain 500 mg of crude 2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine.

[0162] Step 7: 2-Chloro-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (500 mg, 2.732 mmol), di-tert-butyl dicarbonate (61.2 g, 5.464 mmol), triethylamine (828 mg, 8.196 mmol), and 4-dimethylaminopyridine (67 mg, 0.546 mmol) were dissolved in dichloromethane (10 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was purified by normal-phase column chromatography to obtain tert-butyl-2-chloro-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (370 mg, yield: 47.87%).

[0163] Preparation of intermediate 6: tert-butyl-2-chloro-8-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester

[0164] Step 1: Ethyl alanine acid ester (50 g, 0.33 mol) was dissolved in dichloroethane (500 mL). Benzaldehyde (31 g, 0.29 mol), triethylamine (50 g, 0.49 mol), and sodium borohydride acetate (111 g, 0.52 mol) were added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, it was quenched with sodium bicarbonate solution (500 mL), extracted with dichloromethane (800 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was purified by silica gel column chromatography after concentration to obtain ethyl alanine acid ester (27.9 g, yield: 40.85%).

[0165] Step 2: Ethyl benzyl alanine (27.9 g, 0.13 mol) was dissolved in acetonitrile (560 mL) and water (56 mL). Ethyl 4-bromobutyrate (78.77 g, 0.39 mol), cesium carbonate (87.71 g, 0.26 mol), and potassium iodide (4.47 g, 0.026 mol) were added, and the mixture was stirred at room temperature for 48 hours. After the reaction was complete, the mixture was filtered. The filter cake was washed with dichloromethane (100 mL), and the filtrate was collected and concentrated. The residue was dissolved in dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the crude product was purified by silica gel column chromatography to obtain ethyl 4-(benzyl(1-ethoxy-1-carbonylpropane-2-yl)amino)butyrate (25.5 g, yield: 61.11%).

[0166] Steps three through eight can be performed by referring to steps two through seven in the synthesis of intermediate 5, selecting the appropriate reagents to finally obtain tert-butyl-2-chloro-8-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester.

[0167] Preparation of intermediate 7: tert-butyl-2-chloro-4-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester

[0168] At room temperature, methylboronic acid (592 mg, 9.87 mmol), potassium carbonate (2.7 g, 19.7 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (500 mg, 0.66 mmol) were added to a solution of tert-butyl-2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (2 g, 6.6 mmol) in dioxane (20 mL) and water (2 mL). The mixture was purged with nitrogen three times and then heated to 90 °C for 16 hours. After the reaction was complete, the system was cooled to room temperature, concentrated, and the crude product was purified by normal-phase column chromatography to give tert-butyl-2-chloro-4-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (670 mg, yield: 35.83%).

[0169] Intermediate 8: Preparation of tert-butyl-2-chloro-4-methoxy-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester

[0170] Sodium methoxide (933 mg, 17.3 mmol) was slowly added to a methanol (25 mL) solution of tert-butyl-2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (5 g, 16.4 mmol) at 0 °C. The mixture was stirred at 0 °C for 3 hours after the addition was complete. After the reaction was complete, the reaction was quenched with ice water, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered, and the crude product was purified by normal-phase column chromatography after concentration to give a yellow oily tert-butyl-2-chloro-4-methoxy-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (4.15 g, yield: 84.69%).

[0171] Preparation of Intermediate 9: 6'-(((1S,3S)-3-((5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0172] 230 mg (0.46 mmol) of tert-butyl 2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridinyl]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid ester was dissolved in a 1,4-dioxane solution of hydrogen chloride (4.0 M, 5 mL), and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed by concentration to obtain 6'-(((1S,3S)-3-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one (300 mg, crude product, yield: 100%). ESI-MS [M+H] + 504.4.

[0173] Intermediates 9a-9y can be prepared by selecting suitable raw materials by referring to the synthesis methods of Example 1 and Intermediate 3, and their structures are shown in Table 4. In the synthesis of some intermediates, the starting material (an analog of tert-butyl 2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester) can also be synthesized by referring to the method of Intermediate 4.

[0174] Table 4. Structural formulas and chemical names of intermediates 9a-9y

[0175] Preparation of Intermediate 10: 6'-(((1S,3S)-3-((5,5-difluoro-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0176] Step 1: Dissolve tert-butyl 3,5-dicarbonylpiperidine-1-carboxylic acid ester (16 g, 75.1 mmol) in toluene (110 mL), add N,N-dimethylformamide dimethyl acetal (13.44 g, 112.7 mmol), and stir overnight at 80 °C. After the reaction is complete, concentrate to obtain crude product tert-butyl 4-((dimethylamino)methylene)-3,5-dicarbonylpiperidine-1-carboxylic acid ester (30 g), which is directly used in the next step.

[0177] Step 2: 30 g of crude tert-butyl 4-((dimethylamino)methylene)-3,5-dicarbonylpiperidine-1-carboxylic acid ester was added to anhydrous N,N-dimethylformamide (100 mL), along with methyl carbamoylimide sulfate (6.76 g, 75.1 mmol). The mixture was stirred overnight at 100 °C. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain 2.3 g of crude tert-butyl 2-(methylthio)-5-carbonyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (yield: 10.4%).

[0178] Step 3: 2.3 g (7.8 mmol) of tert-butyl-2-(methylthio)-5-carbonyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester was dissolved in 60 mL of anhydrous dichloromethane. Diethylaminosulfur trifluoride (20 g, 124.8 mmol) was added, and the mixture was stirred at room temperature for 72 hours. After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain 1.0 g (yield: 40.5%) of tert-butyl-5,5-difluoro-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester.

[0179] Step 4: 500 mg (1.58 mmol) of tert-butyl 5,5-difluoro-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (dichloromethane) was dissolved in 20 mL of dichloromethane. 1.28 g (6.3 mmol) of m-chloroperoxybenzoic acid was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain 530 mg (yield: 96.4%) of tert-butyl 5,5-difluoro-2-(methanesulfonyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (dichloromethane).

[0180] Step 5: Dissolve tert-butyl 5,5-difluoro-2-(methanesulfonyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid ester (530 mg, 1.52 mmol) in dimethyl sulfoxide (10 mL), then add N,N-diisopropylethylamine (980 mg, 7.59 mmol) and 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (615 mg, 2.28 mmol) sequentially. Stir the mixture at 100 °C for 2 hours. After the reaction is complete, dilute with water and extract with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain tert-butyl-5,5-difluoro-2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (350 mg, yield: 42.7%).

[0181] Step 6: 200 mg (0.371 mmol) of tert-butyl 5,5-difluoro-2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridinyl]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid ester was dissolved in dichloromethane (2 mL), and 5 mL of hydrochloric acid-dioxane solution (4.0 M) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solution was concentrated to give 6'-(((1S,3S)-3-((5,5-difluoro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one (200 mg, yield: 100%).

[0182] Preparation of Intermediate 11: 2-Fluoroethyl 2-{[(1S,3S)-3-[(5-iodopyridin-2-yl)amino]cyclopentyl]amino}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carboxylic acid ester

[0183] Step 1: Dissolve (1S,3S)-N-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (20.00 g, 65.97 mmol) in N-methylpyrrolidone (200 mL), then add N,N-diisopropylethylamine (54.52 mL) and tert-butyl-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (19.57 g, 72.57 mmol) sequentially, and heat to 140 °C with stirring for 6 hours. After the reaction was completed, the system was cooled to room temperature and concentrated. The crude product was purified by normal phase column chromatography to obtain tert-butyl 2-(((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (7.60 g, yield: 21.48%).

[0184] Step 2: Dissolve 7.60 g (14.16 mmol) of tert-butyl-2-(((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester in a 60 mL solution of hydrogen chloride-dioxane and stir at room temperature for 1 hour. After the reaction is complete, the reaction solution is directly concentrated to obtain (1S,3S)-N 1 -(5-Iodopyridin-2-yl)-N 3 -(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)cyclopentane-1,3-diamine (7.60 g, yield: crude product).

[0185] Step 3: (1S,3S)-N 1 -(5-Iodopyridin-2-yl)-N 3 -(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)cyclopentane-1,3-diamine (2.50 g, 5.73 mmol) was dissolved in dichloromethane (3 mL), and triethylamine (2.38 mL) and compound B (0.72 g, 5.73 mmol) were added. The mixture was stirred at room temperature for half an hour. After the reaction was completed, the reaction solution was evaporated to dryness, and the crude product was purified by normal phase column chromatography to obtain 2-fluoroethyl 2-{[(1S,3S)-3-[(5-iodopyridin-2-yl)amino]cyclopentyl]amino}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7-carboxylic acid ester (320 mg, yield: 10.61%).

[0186] Preparation Examples

[0187] Example 1: Preparation of tert-butyl 2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester

[0188] Step 1: 26 g (85.8 mmol) of tert-butyl-2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester was dissolved in anhydrous ethanol (300 mL), and zinc powder (6.4 g, 102 mmol) and ammonia water (60 mL) were added. The mixture was heated to 85 °C and stirred overnight. After the reaction was complete, the reaction solution was filtered, the filtrate was diluted with water, and extracted with 10% methanol / dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain tert-butyl-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (10 g, yield: 43.3%). ESI-MS [M+Ht-Bu] + 214.0. 1 H NMR (400MHz, DMSO-d6) δ8.60(s,1H),4.54(s,2H),3.62(t,J=5.6Hz,2H),2.80(t,J=5.7Hz,2H),1.44(s,9H).

[0189] Step 2: 1.0 g (3.7 mmol) of tert-butyl-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid ester, 1.9 g (3.7 mmol) of 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (1.9 g (3.7 mmol)), 2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (466 mg (0.56 mmol) and cesium carbonate (3.64 g (11.1 mmol) were dissolved in 1,4-dioxane (30 mL). The system was evacuated and purged with nitrogen three times, then stirred overnight at 100 °C. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by normal-phase column chromatography to obtain tert-butyl 2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridinyl]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (230 mg, yield: 12%). ESI-MS [M+H] + 504.4. 1H NMR (400MHz, DMSO-d6) δ8.09(s,1H),7.91(d,J=2.6Hz,1H),7.60(dd,J=6.8,2.0Hz,1H),7.47(ddd, J=8.9,6.6,2.1Hz,1H),7.43-7.36(m,1H),7.09(s,1H),6.91(d,J=6.9Hz,1H),6.52(d,J=8.8Hz,1H) ,6.44(d,J=9.0Hz,1H),6.27(t,J=6.7Hz,1H),4.37-4.23(m,4H),3.54(s,2H),2.56(t,J=5.7Hz,2H ), 2.12(ddd,J=17.1,10.5,5.0Hz,2H),1.95-1.79(m,2H),1.49(dd,J=9.2,5.1Hz,2H),1.42(s,9H).

[0190] Example 2: Preparation of 6'-(((1S,3S)-3-((7-acetyl-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0191] 6'-(((1S,3S)-3-((5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (60 mg, 0.09 mmol) was dissolved in 10 mL of anhydrous dichloromethane. The solution was cooled to 0 °C, and triethylamine (0.5 mL) and acetyl chloride (8 mg, 0.1 mmol) were added. The mixture was stirred at room temperature for 20 minutes. After the reaction was completed, the crude product was concentrated and purified by reverse-phase chromatography to obtain 6'-(((1S,3S)-3-((7-acetyl-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (10.38 mg, yield: 25.9%, purity: 97.056%). ESI-MS [M+H] + 446.2. 1H NMR (400MHz, DMSO-d6) δ8.10(s,1H),7.91(d,J=2.4Hz,1H),7.60(d,J=6.6Hz,1H),7.47(t,J=7.1Hz ,1H),7.39(dd,J=8.9,2.1Hz,1H),7.09(t,J=7.6Hz,1H),6.91(d,J=6.8Hz,1H),6.52(d,J=8.9Hz,1 H),6.44(d,J=9.1Hz,1H),6.27(t,J=6.6Hz,1H),(d,J=13.2Hz,1H),4.37-4.25(m,2H),3.64(s,2H) ,2.64(t,J=5.4Hz,1H),2.56-2.50(m,1H),2.19-2.04(m,5H),1.96-1.78(m,2H),1.56-1.42(m,2H).

[0192] Examples 3-45 can be prepared by selecting suitable raw materials according to the synthesis method of Example 2, and their structures are shown in Table 5.

[0193] Table 5. Structural formulas, chemical names, and mass spectrometry data of Examples 3-45

[0194] The NMR data of some of the compounds in the examples are as follows:

[0195] Example 46: Preparation of 2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-formamide

[0196] 6'-(((1S,3S)-3-((5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (60 mg, 0.09 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (0.5 mL) and trimethylisocyanate (11 mg, 0.1 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by reverse-phase synthesis to obtain 2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-formamide (11.71 mg, yield: 29.2%, purity: 97.834%). ESI-MS [M+H] + :found 447.1. 1 H NMR (400MHz, DMSO-d6) δ8.07(s,1H),7.91(d,J=2.6Hz,1H),7.60(dd,J=6.8,1.6Hz,1H),7.47(ddd,J =8.9,6.6,2.0Hz,1H),7.39(dd,J=8.9,2.7Hz,1H),7.04(d,J=7.3Hz,1H),6.90(d,J=6.9Hz,1H),6.5 2(d,J=8.9Hz,1H),6.44(d,J=8.8Hz,1H),6.27(td,J=6.7,1.3Hz,1H),6.10(s,2H),4.37-4.25(m,4H ),3.51(t,J=5.7Hz,2H),2.57-2.50(m,2H),2.20-2.06(m,2H),1.96-1.80(m,2H),1.57-1.42(m,2H).

[0197] Example 47 can be prepared by selecting suitable raw materials according to the synthesis method of Example 46, and its structure is shown in Table 6.

[0198] Table 6. Structural formulas, chemical names, and mass spectrometry data of Example 47

[0199] The NMR data of some of the compounds in the examples are as follows:

[0200] Example 48: Preparation of N-ethyl-2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridinyl]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-formamide

[0201] 6'-(((1S,3S)-3-((5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (150 mg, 0.37 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (149.48 mg, 1.48 mmol) and isocyanate ethane (47.79 mg, 0.45 mmol) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by reverse-phase synthesis to obtain N-ethyl-2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridinyl]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-formamide (17.96 mg, yield: 10.24%, purity: 96.861%). ESI-MS [M+H] + :found 475.4. 1 H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.92(d,J=2.6Hz,1H),7.60(dd,J=6.8,1.9Hz,1H),7.51-7.44(m,1H) ,7.39(dd,J=8.9,2.7Hz,1H),7.03(d,J=7.3Hz,1H),6.90(d,J=6.8Hz,1H),6.63(t,J=5.3Hz,1H),6.52(d,J =8.9Hz,1H),6.44(d,J=9.1Hz,1H),6.31-6.23(m,1H),4.36-4.25(m,4H),3.52(t,J=5.7Hz,2H),3.10-3.02 (m,2H),2.57-2.50(m,2H),2.19-2.05(m,2H),1.96-1.79(m,2H),1.57-1.44(m,2H),1.01(t,J=7.1Hz,3H).

[0202] Example 49: Preparation of 2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-sulfonamide

[0203] Step 1: Dissolve tert-butanol (38 mg, 0.5 mmol) in anhydrous dichloromethane (5 mL), cool to 0 °C, add chlorosulfonyl isocyanate (73 mg, 0.5 mmol) dropwise, stir at 0 °C for 1.5 hours, then add a solution of 6'-(((1S,3S)-3-((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (200 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol) in dichloromethane (2 mL), stir at 0 °C for 1 hour. After the reaction was completed, the crude product was concentrated and purified by normal phase column chromatography to obtain tert-butyl((2-(((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)sulfonyl)carbamate (150 mg, yield: 64%).

[0204] Step 2: Dissolve tert-butyl((2-(((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)sulfonyl)carbamate (150 mg, 0.26 mmol) in dioxane solution (2 mL), and add hydrogen chloride-dioxane solution (5 mL). Stir the reaction at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by reverse-phase synthesis to obtain 2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-sulfonamide (40.31 mg, yield: 33%, purity: 98.160%). ESI-MS [M+H] + :found 469.1. 1 H NMR(400MHz, DMSO-d6)δ8.25(s,1H),7.92(d,J=2.6Hz,1H),7.60(dd,J=6.8,1.8Hz,1H),7.51-7.44(m,1H),7.42-7.35(m,2H),7.00-6.86(m,3H ),6.52(d,J=8.9Hz,1H),6.44(d,J=9.0Hz,1H),6.30-6.24(m,1H),4.40 -4.25(m,6H),2.20-2.06(m,2H),1.96-1.80(m,2H),1.58-1.43(m,2H).

[0205] Example 50: Preparation of 2-(2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)acetamide

[0206] 6'-(((1S,3S)-3-((5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (75 mg, HCl salt, 0.1 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of 2-iodoacetamide (15 mg, 0.11 mmol), potassium carbonate (69 mg, 0.5 mmol), and potassium iodide (18 mg, 0.11 mmol). The mixture was stirred at 50 °C for 2 hours. After the reaction was complete, the reaction solution was filtered, and the crude product was concentrated and purified by reverse-phase chromatography to obtain 2-(2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridinyl]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)acetamide (10.23 mg, yield: 22.2%, purity: 99.359%). ESI-MS [M+H] + :found 461.3. 1 H NMR (400MHz, DMSO-d6) δ8.06(s,1H),7.91(d,J=2.6Hz,1H),7.60(dd,J=6.8,1.8Hz,1H),7.47(ddd,J=8.8,6. 6,2.0Hz,1H),7.39(dd,J=8.9,2.7Hz,1H),7.26(s,1H),7.12(s,1H),6.97(d,J=7.3Hz,1H),6.90(d,J=6.9Hz, 1H),6.52(d,J=8.9Hz,1H),6.44(d,J=9.1Hz,1H),6.27(td,J=6.8,1.2Hz,1H),4.39-4.23(m,2H),3.45(s,2H) ,3.05(s,2H),2.72-2.66(m,2H),2.65-2.59(m,2H),2.17-2.03(m,2H),1.94-1.79(m,2H),1.55-1.41(m,2H).

[0207] Example 51 can be prepared by selecting suitable raw materials according to the synthesis method of Example 50, and its structure is shown in Table 7.

[0208] Table 7. Structural formulas, chemical names, and mass spectrometry data of Example 51

[0209] The NMR data of some of the compounds in the examples are as follows:

[0210] Example 52: Preparation of cyclopropylmethyl 2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester

[0211] At room temperature, triethylamine (31.3 mg, 0.31 mmol) and cyclopropylmethanol (22 mg, 0.31 mmol) were added sequentially to a 3 mL solution of bis(2,5-dioxopyrrolidone-1-yl) carbonate (64 mg, 0.25 mmol) in acetonitrile. The mixture was stirred at room temperature for 16 hours after the addition was complete. Then, triethylamine (31.3 mg, 0.31 mmol) and 6'-((1S,3S)-3-((5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (20 mg, 0.05 mmol) were added sequentially, and the mixture was stirred for another 4 hours. After the reaction, the system was directly concentrated, and a small amount of acetonitrile was added. After filtration, the crude product was concentrated and purified by reverse-phase chromatography to obtain cyclopropylmethyl 2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridinyl]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (27.88 mg, yield: 111.30%, purity: 95.93%). ESI-MS [M+H] + :found 502.3. 1H NMR (400MHz, DMSO-d6) δ8.44(s,0.25H,FA),8.10(s,1H),7.91(d,J=2.6Hz,1H),7.60(d,J=5.1Hz,1H),7.52-7. 43(m,1H),7.39(dd,J=8.8,2.6Hz,1H),7.10(d,J=6.0Hz,1H),6.91(d,J=6.9Hz,1H),6.52(d,J=8.9Hz,1H),6.44 (d,J=9.1Hz,1H),6.31-6.23(m,1H),4.41-4.25(m,4H),3.88(d,J=7.1Hz,2H),3.60(s,2H),2.63-2.55(m,2H),2 .17-2.07(m,2H),1.94-1.80(m,2H),1.57-1.42(m,2H),1.15-1.05(m,1H),0.55-0.47(m,2H),0.31-0.23(m,2H)

[0212] Examples 53-100 were prepared by selecting suitable raw materials according to the synthesis method of Example 52, and their structures are shown in Table 8.

[0213] Table 8. Structural formulas, chemical names, and mass spectrometry data of Examples 53-100

[0214] The NMR data of some of the compounds in the examples are as follows:

[0215] Example 101: Preparation of N-(2-methoxyethyl)-2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridinyl]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-sulfonamide

[0216] Step 1: Dissolve 2-methoxyethane-1-amine (1 g, 13.3 mmol) in dichloromethane (20 mL), add triethylamine (2.8 mL) and sulfonyl chloride (1.6 mL) at 0 °C, and stir the mixture at room temperature for 2 hours after the addition is complete. Quench the reaction with water (20 mL), and extract with dichloromethane. Wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain (2-methoxyethyl)aminosulfonyl chloride (1.2 g). The crude product is used directly in the next step of the reaction.

[0217] Step 2: 6'-((1S,3S)-3-((5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (100 mg, 0.248 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (75.18 mg, 0.248 mmol) and the crude (2-methoxyethyl)aminosulfonyl chloride product prepared in the previous step (1.2 g) were added at 0 °C. The mixture was stirred at room temperature for 2 hours after the addition was complete. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by reverse-phase synthesis to obtain N-(2-methoxyethyl)-2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridinyl]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-sulfonamide (4.12 mg, yield: 3.07%, purity: 99.620%). ESI-MS [M+H] + :found 541.3. 1 H NMR (400MHz, DMSO-d6) δ8.13 (s, 0.06H, FA), 8.11 (s, 1H), 7.92 (d, J = 2.6Hz, 1H), 7.60 (dd, J = 6.8, 1.8Hz, 1H),7.56-7.44(m,2H),7.40(d,J=6.6Hz,1H),7.12(d,J=7.2Hz,1H),6.93(brs,1H),6.53(d,J=8.9Hz,1 H),6.44(d,J=9.1Hz,1H),6.30-6.23(m,1H),4.38-4.25(m,2H),4.05(s,2H),3.39-3.34(m,4H),3.21(s ,3H),3.03(q,J=5.8Hz,2H),2.69-2.62(m,2H),2.20-2.06(m,2H),1.97-1.81(m,2H),1.57-1.43(m,2H).

[0218] Example 102: Preparation of 2-hydroxyethyl 2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridinyl]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester

[0219] Step 1: The synthesis of ethyl 2-((tert-butyldimethylsilyl)oxy)2-(((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate can be carried out by referring to the operation in Example 52 and selecting the appropriate reagents.

[0220] Step 2: At room temperature, add tetrabutylammonium fluoride (1M tetrahydrofuran solution, 0.1mL) to a tetrahydrofuran (1.5mL) solution of ethyl 2-((tert-butyldimethylsilyl)oxy)2-(((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridinyl]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (86mg, 0.14mmol), and stir the reaction for 20 minutes. The reaction solution was concentrated, and the crude product was directly purified by reverse-phase synthesis to obtain 2-hydroxyethyl 2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridinyl]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (15.17 mg, yield: 21.73%, purity: 96.73%). ESI-MS [M+H] + :found 492.3. 1 H NMR(400MHz, DMSO-d6)δ8.10(s,1H),7.91(d,J=2.5Hz,1H),7.60(d,J=5.3Hz,1H),7.53-7.43(m,1H), 7.39(dd,J=8.9,2.6Hz,1H),7.09(s,1H),6.91(d,J=6.8Hz,1H),6.52(d,J=8.9Hz,1H),6.44(d,J=9.1 Hz,1H),6.27(t,J=6.7Hz,1H),4.81(s,1H),4.43-4.26(m,4H),4.04(t,J=4.9Hz,2H),3.65-3.54(m,4 H),2.58(s,2H),2.12(ddd,J=18.1,11.5,6.8Hz,2H),1.88(qd,J=12.9,5.9Hz,2H),1.56-1.44(m,2H).

[0221] Examples 103-104 can be prepared by selecting suitable raw materials according to the synthesis method of Example 102, and their structures are shown in Table 9.

[0222] Table 9. Structural formulas, chemical names, and mass spectrometry data of Examples 103-104

[0223] The NMR data of some of the compounds in the examples are as follows:

[0224] Example 105: Preparation of 6'-(((1S,3S)-3-((7-(((3-hydroxyacetidin-1-yl)sulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0225] The first and second steps can be performed with appropriate reagents as described in Example 101 to obtain 6'-(((1S,3S)-3-((7-((3-((tert-butyldiphenylsilyl)oxo)acetidin-1-yl)sulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one. The third step can be performed with appropriate reagents as described in the second step of the preparation in Example 102 to obtain 6'-(((1S,3S)-3-((7-((3-hydroxyacetidin-1-yl)sulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one. ESI-MS [M+H] + :found 539.1. 1HNMR(400MHz,DMSO-d6)δ8.12(s,1H),7.91(d,J=2.6Hz,1H),7.60(dd,J=6.8,1.7Hz,1H),7.52-7.44(m,1H),7 .39(dd,J=8.9,2.7Hz,1H),7.14(d,J=7.3Hz,1H),6.90(d,J=6.9Hz,1H),6.52(d,J=8.9Hz,1H),6.44(d,J=9.1H z,1H),6.30-6.23(m,1H),5.80(d,J=6.4Hz,1H),4.41-4.27(m,3H),4.13(s,2H),3.93-3.84(m,2H),3.66-3.58 (m,2H),3.45(t,J=5.7Hz,2H),2.65(t,J=5.8Hz,2H),2.18-2.04(m,2H),1.96-1.80(m,2H),1.56-1.43(m,2H).

[0226] Example 106 can be prepared by selecting appropriate raw materials according to the synthesis method of Example 105, and its structure is shown in Table 10.

[0227] Table 10. Structural formulas, chemical names, and mass spectrometry data of Example 106

[0228] The NMR data of some of the compounds in the examples are as follows:

[0229] Example 107: Preparation of (1-hydroxycyclopropyl)methyl 2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester

[0230] The first step can be performed by selecting the appropriate reagents as described in the first step of Example 52 to prepare methyl 1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)-2-((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid.

[0231] Step 2: At room temperature, add 0.5 mL of trifluoroacetic acid to a solution of methyl 1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)-2-((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid (70 mg, 0.12 mmol) in 2 mL of dichloromethane. After the addition is complete, react for 1 hour. After concentrating the reaction solution, the crude product was purified by reverse-phase reaction to obtain (1-hydroxycyclopropyl)methyl 2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (6.35 mg, yield: 10.00%, purity: 99.05%). ESI-MS [M+H] + :found 518.4. 1 H NMR(400MHz,MeOD-d4)δ8.07(s,1H),7.94(d,J=2.5Hz,1H),7.65-7.56(m,2H),7.44(d d,J=9.0,2.6Hz,1H),6.61(d,J=8.9Hz,2H),6.49-6.43(m,1H),4.56(s,1H),4.49-4.38 (m,2H),4.37-4.29(m,1H),4.17(s,2H),3.84-3.64(m,2H),2.73-2.65(m,2H),2.32-2 .20(m,2H),2.03-1.95(m,2H),1.67-1.55(m,2H),0.80-0.75(m,2H),0.72-0.64(m,2H)

[0232] Example 108: Preparation of (1-methoxycyclopropyl)methyl 2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester

[0233] (1-Methoxycyclopropyl)methanol (76 mg, 0.744 mmol) was dissolved in dichloromethane (10 mL). Pyridine (120 mg, 0.744 mmol) and triphosgene (74 mg, 0.248 mmol) were added sequentially at 0 °C, and the mixture was stirred at room temperature for 1 hour after the addition was complete. Then, pyridine (120 mg, 0.744 mmol) and 6'-(((1S,3S)-3-((5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (100 mg, 0.248 mmol) were added sequentially, and the mixture was stirred overnight. After the reaction, the system was directly concentrated, and the crude product was purified by reverse-phase reaction to obtain (1-methoxycyclopropyl)methyl 2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (10.85 mg, yield: 8.24%, purity: 96.362%). ESI-MS [M+H] + :found 532.2. 1 H NMR(400MHz,MeOD-d4)δ8.07(s,1H),7.94(d,J=2.5Hz,1H),7.64-7.54(m,2H),7.44(dd ,J=9.0,2.7Hz,1H),6.61(d,J=9.0Hz,2H),6.49-6.43(m,1H),4.55-4.38(m,3H),4.36-4 .32(m,1H),4.28(s,2H),3.80-3.66(m,2H),3.36(s,3H),2.68(t,J=5.7Hz,2H),2.32-2 .20(m,2H),2.04-1.96(m,2H),1.67-1.52(m,2H),0.90-0.82(m,2H),0.74-0.66(m,2H).

[0234] Example 109 can be prepared by selecting suitable raw materials according to the synthesis method of Example 108, and its structure is shown in Table 11.

[0235] Table 11. Structural formulas, chemical names, and mass spectrometry data of Example 109

[0236] The NMR data of some of the compounds in the examples are as follows:

[0237] Example 110: Preparation of N-(cyclopropylmethyl)-N-methyl-2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-formamide

[0238] Triphosgene (293 mg, 0.98 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (0.5 mL) and 1-cyclopropyl-N-methylmethylamine (160 mg, 1.88 mmol) in dichloromethane (5 mL) were added sequentially at 0 °C. After the addition was complete, the mixture was stirred for 2 hours. Then, 6'-(((1S,3S)-3-((5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (200 mg, 0.49 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction solution was concentrated, and the crude product was purified by reverse-phase chromatography to obtain N-(cyclopropylmethyl)-N-methyl-2-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-formamide (8.24 mg, yield: 3.23%, purity: 99.864%). ESI-MS [M+H] + :found 515.2. 1 H NMR (400MHz, DMSO-d6) δ8.07(s,1H),7.91(d,J=2.6Hz,1H),7.59(d,J=6.9Hz,1H),7.51-7.43(m,1H),7.39(dd,J=8 .9,2.6Hz,1H),7.04(d,J=7.3Hz,1H),6.90(d,J=6.9Hz,1H),6.52(d,J=8.8Hz,1H),6.44(d,J=8.8Hz,1H),6.30-6.2 3(m,1H),4.41-4.23(m,2H),4.08(s,2H),3.42-3.33(m,2H),3.01(d,J=6.7Hz,2H),2.86(s,3H),2.64-2.55(m,2H) ,2.19-2.05(m,2H),1.95-1.78(m,2H),1.55-1.43(m,2H),1.02-0.88(m,1H),0.50-0.42(m,2H),0.21-0.13(m,2H).

[0239] Example 111 can be prepared by selecting suitable raw materials according to the synthesis method of Example 110, and its structure is shown in Table 12.

[0240] Table 12. Structural formula, chemical name, and mass spectrometry data of Example 111

[0241] The NMR data of some of the compounds in the examples are as follows:

[0242] Example 112: Preparation of 2-fluoroethyl 2-(((1S,3S)-3-((3-hydroxy-2-carbonyl-2H-[1,3'-bipyridinyl]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester

[0243] Step 1: 2-Fluoroethyl 2-{[(1S,3S)-3-[(5-iodopyridin-2-yl)amino]cyclopentyl]amino}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carboxylic acid ester (0.10 g, 0.19 mmol) was dissolved in dimethyl sulfoxide (2 mL), and 3-((4-methoxybenzyl)oxo)pyridin-2(1H)-one (65 mg, 0.28 mmol) was added. 1 N 2 Dimethylcyclohexane-1,2-diamine (2.7 mg, 0.01 mmol), cuprous iodide (3 mg, 0.01 mmol), and potassium phosphate (80 mg, 0.38 mmol) were added, and the mixture was heated to 120°C and stirred for 12 hours. After the reaction was complete, the system was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain 2-fluoroethyl 2-(((1S,3S)-3-((3-((4-methoxybenzyl)oxo)-2-carbonyl-2H-[1,3'-bipyridinyl]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (39 mg, yield: 5.85%).

[0244] Step 2: Dissolve 2-fluoroethyl 2-(((1S,3S)-3-((3-(((4-methoxybenzyl)oxo)-2-carbonyl-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (39 mg, 0.06 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (0.5 mL), and stir at room temperature for half an hour. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by reverse-phase chromatography to obtain 2-fluoroethyl 2-(((1S,3S)-3-((3-hydroxy-2-carbonyl-2H-[1,3'-bipyridinyl]-6'-yl)amino)cyclopentyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (0.70 mg, yield: 2.22%, purity: 96.084%). ESI-MS [M+H] + :found 510.1. 1 H NMR (400MHz, MeOD-d4) δ8.10(s,1H),8.03(d,J=1.9Hz,1H),7.80(d,J=9.4Hz,1H),7.08(d,J= 6.9Hz,1H),6.95(d,J=9.4Hz,1H),6.91(dd,J=7.4,1.4Hz,1H),6.35(t,J=7.2Hz,1H),4.69-4 .65(m,1H),4.57-4.54(m,1H),4.52-4.42(m,3H),4.41-4.38(m,1H),4.34-4.25(m,2H),3.78 -3.67(m,2H),2.70(t,J=5.6Hz,2H),2.42-2.25(m,2H),2.12-2.06(m,2H),1.75-1.65(m,2H).

[0245] Examples 113-117 can be prepared using the same synthesis method as in Example 112, selecting suitable raw materials. Their structures are shown in Table 13. In some examples, the final acidic deprotection step is not required to obtain the target product during synthesis.

[0246] Table 13. Structural formulas, chemical names, and mass spectrometry data of Examples 113-117

[0247] The NMR data of some of the compounds in the examples are as follows:

[0248] Example 118: Preparation of 6'-(((1S,3S)-3-((7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0249] 6'-(((1S,3S)-3-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (120 mg, 0.29 mmol) was dissolved in dimethyl sulfoxide (2 mL), and 2-chloropyrimidine (34 mg, 0.29 mmol) and cesium fluoride (225 mg, 1.48 mmol) were added. The mixture was heated to 120 °C and stirred for 12 hours. After the reaction was completed, the system was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The product was filtered, concentrated, and purified by reversed-phase column chromatography to obtain 6'-(((1S,3S)-3-((7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (35.06 mg, yield: 24.48%, purity: 98.382%). ESI-MS [M+H] + :found 482.1. 1 H NMR (400MHz, DMSO-d6) δ8.40(d,J=4.7Hz,2H),8.11(s,1H),7.92(d,J=2.6Hz,1H),7.60(dd,J=6.8,1.7Hz, 1H),7.52-7.44(m,1H),7.39(dd,J=8.9,2.7Hz,1H),7.08(d,J=7.3Hz,1H),6.91(d,J=6.9Hz,1H),6.67(t, J=4.7Hz,1H),6.53(d,J=8.9Hz,1H),6.44(d,J=9.0Hz,1H),6.30-6.23(m,1H),4.67(s,2H),4.41-4.25(m, 2H), 4.01 (t, J = 5.7Hz, 2H), 2.64 (t, J = 5.6Hz, 2H), 2.20-2.06 (m, 2H), 1.97-1.82 (m, 2H), 1.60-1.44 (m, 2H).

[0250] Example 119: Preparation of 6'-(((1S,3S)-3-((7-phenyl-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0251] Dissolve 6'-(((1S,3S)-3-((5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (120 mg, 0.29 mmol) (300 mg, 0.74 mmol) in 1,4-dioxane solution (5 mL), then add iodobenzene (151 mg, 0.74 mmol) and methanesulfonic acid (2- Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (62 mg, 0.07 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (69 mg, 0.14 mmol) and cesium carbonate (484 mg, 1.48 mmol) were heated to 100 °C and stirred for 12 hours under nitrogen protection. After the reaction was complete, the system was cooled to room temperature and directly concentrated. The crude product was purified by reversed-phase column chromatography to obtain 6'-(((1S,3S)-3-((7-phenyl-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (3.23 mg, yield: 0.91%, purity: 97.820%). ESI-MS [M+H] + :found 480.1. 1 H NMR(400MHz,MeOD-d4)δ8.07(s,1H),7.94(d,J=2.5Hz,1H),7.64-7.55(m,2H),7.44( dd,J=9.0,2.7Hz,1H),7.29-7.21(m,2H),7.02(d,J=8.0Hz,2H),6.88-6.80(m,1H),6. 64-6.60(m,2H),6.49-6.42(m,1H),4.48-4.30(m,2H),4.17(s,2H),3.54(t,J=5.8Hz ,2H),2.78(t,J=5.8Hz,2H),2.35-2.21(m,2H),2.05-1.98(m,2H),1.66-1.55(m,2H).

[0252] Example 120 can be prepared by selecting suitable raw materials according to the synthesis method of Example 119, and its structure is shown in Table 14.

[0253] Table 14. Structural formulas, chemical names, and mass spectrometry data of Example 120

[0254] The NMR data of some of the compounds in the examples are as follows:

[0255] Example 121: Preparation of 6'-(((1S,3S)-3-((7-(5-fluoropyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0256] 6'-(((1S,3S)-3-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (120 mg, 0.29 mmol) (100 mg, 0.248 mmol) was dissolved in dimethyl sulfoxide (2 mL), and 2-chloro-5-fluoropyrimidine (39.41 mg, 0.297 mmol) and N,N-diisopropylethylamine (96.10 mg, 0.744 mmol) were added. The mixture was stirred at 100 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by reverse-phase chromatography to obtain 6'-(((1S,3S)-3-((7-(5-fluoropyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (14.16 mg, yield: 11.18%, purity: 97.795%). ESI-MS [M+H] + :500.5.1H NMR (400MHz, CD3OD) δ8.32(s,2H),8.08(s,1H),7.94(d,J=2.8Hz,1H),7.64-7.56(m,2H),7.53-7.40(m,1H),6.62(d,J=8.8Hz,2H),6.46(t,J=6.8 Hz,1H),4.70(s,2H),4.49-4.29(m,2H),4.04(t,J=5.8Hz,2H),2.72(t,J =5.8Hz,2H),2.36-2.22(m,2H),2.01(t,J=6.8Hz,2H),1.69-1.56(m,2H).

[0257] Example 122: Preparation of 2-fluoroethyl 3-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)-7,8-dihydropyrido[3,4-e][1,2,4]triazine-6(5H)-carboxylic acid ester

[0258] Step 1: 6.3 g (29.03 mmol) of benzyl 3,6-dihydropyridine-1(2H)-carboxylic acid ester was dissolved in acetonitrile (35 mL) and pure water (20 mL). N-methylmorpholine oxide (3.74 g, 31.9 mmol) and potassium osmium tetroxide (111 mg, 0.3 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was quenched with saturated sodium sulfite, concentrated to remove acetonitrile, and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain benzyl 3,4-dihydroxypiperidine-1-carboxylic acid ester (6.6 g, yield: 90.4%).

[0259] Step 2: At -60°C, dissolve dimethyl sulfoxide (7.07 g, 90.63 mmol) in anhydrous dichloromethane (250 mL), add trifluoroacetic anhydride (17.3 g, 82.39 mmol), and stir at -60°C for 20 minutes. Add dropwise a solution of benzyl 3,4-dihydroxypiperidine-1-carboxylic acid ester (5.17 g, 20.6 mmol) in dichloromethane (86 mL), and stir at -60°C for 1.5 hours. Then add triethylamine (18.93 g, 187.44 mmol), and continue stirring at -60°C for another 1.5 hours. After the reaction is complete, heat to room temperature, adjust the pH to 5-6 with 1 M HCl, and extract with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated by reversed-phase column chromatography to obtain benzyl 5-hydroxy-4-carbonyl-3,4-dihydropyridine-1(2H)-carboxylic acid ester (3g, yield: 59%).

[0260] Step 3: Benzyl 5-hydroxy-4-carbonyl-3,4-dihydropyridine-1(2H)-carboxylic acid ester (1 g, 4.05 mmol) and hydrazine thioamide (479 mg, 5.26 mmol) were dissolved in anhydrous ethanol (100 mL). After stirring at 80 °C for 0.5 hours, potassium carbonate (727 mg, 5.26 mmol) was added, and the reaction was continued at 80 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and the system was directly concentrated. The crude product was purified by normal-phase column chromatography to obtain benzyl 3-mercapto-7,8-dihydropyrido[3,4-e][1,2,4]triazine-6(5H)-carboxylic acid ester (600 mg).

[0261] Step 4: 500 mg (1.65 mmol) of benzyl 3-mercapto-7,8-dihydropyrido[3,4-e][1,2,4]triazine-6(5H)-carboxylic acid ester was dissolved in tetrahydrofuran (20 mL), and triethylamine (1.33 g, 13.2 mmol) and iodomethane (1.88 g, 13.2 mmol) were added. The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered, and the crude product was purified by normal-phase column chromatography to obtain 110 mg of benzyl 3-(methylthio)-7,8-dihydropyrido[3,4-e][1,2,4]triazine-6(5H)-carboxylic acid ester.

[0262] Step 5: Dissolve 700 mg of benzyl 3-(methylthio)-7,8-dihydropyrido[3,4-e][1,2,4]triazine-6(5H)-carboxylic acid ester (2.213 mmol) in acetic acid and hydrobromic acid (5 mL), stir at room temperature for 2 hours. After the reaction is complete, slowly add diethyl ether to the reaction solution to precipitate the solid. Filter and dry the filter cake to obtain 3-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-e][1,2,4]triazine (400 mg, crude product).

[0263] Step 6: Dissolve 3-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-e][1,2,4]triazine (400 mg, 2.195 mmol) in dichloromethane (8 mL), add triethylamine ethyl (888.39 mg, 8.779 mmol) and 2-fluoroethyl chloride ester (400 mg, 2.195 mmol), and stir for 2 hours. After the reaction is complete, concentrate the reaction solution, and purify the crude product by reversed-phase column chromatography to obtain 2-fluoroethyl 3-(methylthio)-7,8-dihydropyrido[3,4-e][1,2,4]triazine-6(5H)-carboxylic acid ester (338 mg, yield: 56.55%).

[0264] Step 7: Dissolve m-chloroperoxybenzoic acid (63.37 mg, 0.367 mmol) in dichloromethane (2 mL) and add anhydrous magnesium sulfate (132.60 mg, 1.102 mmol). Stir at room temperature for 2 hours. Then, dissolve 2-fluoroethyl 3-(methylthio)-7,8-dihydropyrido[3,4-e][1,2,4]triazine-6(5H)-carboxylic acid ester (100 mg, 0.367 mmol) in dichloromethane (1 mL) and add it to the reaction solution. Continue stirring for 2 hours. After the reaction is complete, quench the reaction with saturated sodium sulfite solution and extract with dichloromethane. Wash the organic phase with saturated brine and dry with anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude product was purified by reverse-phase column chromatography to obtain 2-fluoroethyl 3-(methylthionyl<sulfinyl>)-7,8-dihydropyrido[3,4-e][1,2,4]triazine-6(5H)-carboxylic acid ester (75 mg, yield: 70.84%).

[0265] Step 8: Dissolve 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (79.96 mg, 0.296 mmol) in ultra-dry N-methylpyrrolidone (2 mL), add N,N-diisopropylethylamine (127.43 mg, 986 mmol) and 2-fluoroethyl 3-(methylthionyl<sulfinyl>)-7,8-dihydropyrido[3,4-e][1,2,4]triazine-6(5H)-carboxylic acid ester. (75 mg, 0.246 mmol), stirred at room temperature for 12 hours. After the reaction was completed, the crude product was concentrated and purified by reverse-phase reaction to obtain compound 2-fluoroethyl 3-(((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)-7,8-dihydropyrido[3,4-e][1,2,4]triazine-6(5H)-carboxylic acid ester (1.1 mg, purity: 90.563%, yield: 0.90%). ESI-MS [M+H] + :found 495.1. 1H NMR(400MHz,MeOD-d4)δ7.94(d,J=2.5Hz,1H),7.64-7.54(m,2H),7.44(dd,J=9 .0,2.7Hz,1H),6.61(d,J=9.0Hz,2H),6.49-6.43(m,1H),4.74(s,2H),4.69-4.6 6(m,1H),4.58-4.55(m,1H),4.51–4.44(m,1H),4.42-4.31(m,3H),3.82(s,2H), 2.85(t,J=6.0Hz,2H),2.34-2.21(m,2H),2.16-1.95(m,2H),1.76-1.50(m,2H).

[0266] Biological testing evaluation

[0267] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0268] Assay A. PCSK9 protein binding assay

[0269] This experiment used the plasma resonance (SPR) method to detect the effect of the compound on the binding of PCSK9 protein.

[0270] The binding effect of the compounds of this invention on PCSK9 protein can be detected using a Biacore instrument (BIAcore S200, GE Healthcare). First, 100 to 150 μg / mL of PCSK9 protein (Acro) was immobilized on a SAChip flow cell to a level of 8000 RU (resonance units) in 10 mM acetate buffer (pH 5.0). A stock solution (30 mM) of the test compound was prepared by dissolving it in DMSO and then serially diluted 3-fold in 10 mM Hepes (pH 7.4) + 150 mM NaCl buffer to a final DMSO concentration of 1%. Binding / kinetic studies were then performed by passing different concentrations of working solution over a blank and a surface immobilized with PCSK9 protein. Data were analyzed using BIAcore S200 evaluation software. All curves were subtracted from the reference. The baselines of all curves were adjusted to zero 5 seconds before the end of sample injection, and the data were expressed as binding RU (average over a 5-second window). For the determination of KD (equilibrium dissociation constant), the analyte curves were subtracted from the buffer blank, and a simple 1:1 interaction was assumed to model the kinetic data. The test results are shown in Table 15. "A" represents KD. D ≤100nM, where “B” indicates 100nM <K D≤400nM, where "C" indicates 400nM <K D .

[0271] Assay B. Determination of the effect of a compound on the concentration of PCSK9 secreted by HepG2 cells

[0272] This study used a human PCSK9 ELISA kit (Bepsys CEA-C202) to detect the inhibitory effect of compounds on PCSK9. HepG2 human cell line (ATCC: HB-8065) ​​was purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences and cultured in DMEM medium (Bio-channel, BC-M-020) and low-fat fetal bovine serum (Lonsera, U412-002) in a cell culture incubator (Thermo Scientific, BB150) at 37°C and 5% CO2. In this experiment, the compound was dissolved in DMSO and serially diluted to 2 mM or 1.5 mM working concentrations using dilution buffers (DMEM, 10% low-fat FBS, 1% NEAA, 1% P / S, and 2% DMSO) (final concentrations of the test compound were 100 μM and 75 μM, respectively). HepG2 cells were seeded in 96-well plates, with 190 μL of cell suspension per well, containing 25,000 HepG2 cells. Cell culture plates were incubated in a CO2 incubator for 24 hours. Then, 10 μL of DMSO solution was added to each well of a 96-well plate, and the plates were incubated for 48 hours. An additional well containing 0.5% DMSO was prepared as the Vehicle group for subsequent data analysis. After 48 hours of incubation, 100 μL of supernatant culture medium was taken from each well for subsequent ELISA assays. The specific steps are as follows: 1. Prepare the standard curve solution by serial dilution according to the instructions; 2. Add 50 μL of the corresponding sample to each well (replicas) according to the standard curve and sample wells set in the plate map, followed by 50 μL of Biotin Antibody solution, seal the plate, and incubate at room temperature for 2 hours; 3. Wash 5 times with Washing Buffer, then add 100 μL of Streptavidin-HRP solution, seal the plate, and incubate at room temperature in the dark for 30 minutes; 4. Wash 5 times with Washing Buffer, then add 100 μL of Substrate solution to each well, seal the plate, and incubate at room temperature in the dark for 15 minutes; 5. Add 50 μL of STOP solution to each well, mix well, and measure the absorbance response at 450 nm and 630 nm using a microplate reader (Perkin Elmer, Ensight) within 10 minutes. Calculate the PCSK9 concentration in the sample by substituting the values ​​into the standard curve. Convert the raw data into the PCSK9 secretion rate using the equation (sample well concentration / vehicle well concentration) * 100%. The test results are shown in Table 15.

[0273] Assay C. Determination of the effect of compound on LDLR levels in HepG2 cells

[0274] This study used the Human LDL R Quantikine ELISA Kit (R&D: DLDLR0) to detect the effect of compounds on LDLR protein levels. HepG2 human cell line (ATCC: HB-8065) ​​was purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences and cultured in DMEM medium (Bio-channel, BC-M-020) and low-fat fetal bovine serum (Lonsera, U412-002) in a cell culture incubator (Thermo Scientific, BB150) at 37°C and 5% CO2. In this experiment, the compound was dissolved in DMSO and serially diluted to a working concentration of 0.67 mM using dilution buffers (DMEM, 10% low-fat FBS, 1% NEAA, 1% P / S, and 2% DMSO) (final concentration of the test compound was 33.3 μM). HepG2 cells were seeded in 96-well plates, with 180 μL of cell suspension per well, containing 25,000 HepG2 cells. Cell culture plates were incubated in a CO2 incubator for 24 h. Then, 10 μL of DMSO solution and 10 μL of PCSK9 protein solution (final concentration 0.1 μg / mL) were added to each well of a 96-well plate, and the plates were incubated for 48 h. An additional well containing 0.5% DMSO was prepared as the Vehicle group for subsequent data analysis. After 48 h of incubation, the culture medium was removed, and appropriate amounts of cell lysis buffer (Absin, abs9225), General Protease Inhibitor Cocktail (Absin, abs9161), and 2 mM PMSF (Absin, abs812852) were added to each well. The plates were incubated at 4°C for 15 min to extract LDLR protein. The lysis buffer was centrifuged, and 100 μL of the supernatant was used for subsequent ELISA assays. The specific steps are as follows: 1. Prepare the standard curve solution by serial dilution according to the instructions; 2. Add 100 μL of the corresponding sample to each well (replicas) according to the standard curve wells and sample wells set in the plate map, seal the plate, and incubate at room temperature for 1 hour; 3. Wash 3 times with Washing Buffer, then add 100 μL of Enzyme-Binding Working Solution, seal the plate, and incubate at room temperature for 1 hour; 4. Wash 5 times with Washing Buffer, then add 90 μL of Substrate Solution to each well, seal the plate, and incubate at room temperature in the dark for 15 minutes; 5. Add 50 μL of LTOP Solution to each well, mix well, and immediately measure the absorbance response at 450 nm using a microplate reader (Perkin Elmer, Ensight). Calculate the LDLR concentration in the sample by substituting the values ​​into the standard curve. Convert the raw data into the percentage increase in LDLR concentration using the equation (sample well concentration / Vehicle well concentration - 1) * 100%. The test results are shown in Table 15.

[0275] Table 15. Test results of compounds in some examples

[0276] The positive compound is Example 458B from PCT patent WO2020150473, and its structure is as follows:

[0277] Experimental conclusion: The compounds in the embodiments of this invention have a good binding effect on PCSK9 protein, can significantly inhibit the secretion of PCSK9 in HepG2 cells, increase the expression of LDLR, thereby reducing LDL-C and achieving the therapeutic effect on related diseases.

[0278] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of formula (I), its stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, in, It can be a single bond or a double bond; X is N or CR 1 Y is CR 2 Z represents CR 3 ; Among them, R 1 Selected from the following groups: H, D, halogen, cyano, SF5, C 1-6 Alkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, -C 0-4 Alkylene-OR 12 -C 0-4 Alkylene-SR 12 -C 0-4 Alkylene NR 10 R 11 Each of the groups may optionally be further coupled with one or more groups selected from D, halogen, cyano, hydroxyl, carboxyl, -C(O)OC 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-8 membered heterocyclic groups, C 1-6 Halogenated alkoxy groups, C 3-8 Halogenated cycloalkyl, C 3-8 Group substitution of halogenated cycloalkoxy groups; R 2 R 3 Together with the atoms bonded to it, they form C 4-8 The carbon ring or a 4-8 membered heterocycle containing 1, 2, or 3 heteroatoms optionally selected from O, S, and N, wherein the C 4-8 The carbon ring or 4-8 membered heterocycle is further divided into one or more R 7 replace; Each R 7 Independently selected from the following groups: D, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, -C 0-4 Alkylene-OR 12 -C 0-4 Alkylene-NR 10 R 11 -P(O)(R 14 )2、-C 0-4 Alkylene-OC(O)-C 0-4 Alkylene-R a -C 0-4 Alkylene-S(O)-C 0-4 Alkylene-R a -C 0-4 Alkylene-C(O)-C 0-4 Alkylene-R a -C 0-4 Alkylene-S(O)2-C 0-4 Alkylene-R a -C 0-4 Alkylene-S(O)(NR) 31 )-C 0-4 Alkylene-R a -C 0-4 Alkylene-NHC(O)-R a -C 0-4 Alkylene-NHS(O)2-R a C 0-4 Alkylene-NHC(O)-C 1-4 Alkylene-R a -C 0-4 Alkylene-NHS(O)2-C 1-4 Alkylene-R a =O, =NR 31 =C(R) 13 2, 6-10 aryl, 5-10 heteroaryl, or two R atoms on the same or different atoms 7 All the atoms bonded to it together form C 3-8 The carbon ring or a 4-8 membered heterocycle containing 1, 2, or 3 heteroatoms optionally selected from O, S, or N; each group may optionally be further surrounded by one or more atoms selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-8 membered heterocyclic groups, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Halogenated cycloalkyl, C 3-8 Group substitution of halogenated cycloalkoxy groups; R a Selected from the following groups: H, D, hydroxyl, halogen, cyano, NR 10 R 11 OR 12 C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-8 membered heterocyclic groups, wherein each alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocyclic group may optionally be further substituted with one or more halogens; m, n, and s are each independently 0, 1, 2, 3, 4, or 5; Ring A is selected from the following group: C 6-10 Aromatic rings, 5-12 heterocyclic aromatic rings; Cycle B is selected from the following group: 5-14 membered heterocycles, C 6-10 Aromatic rings, 5-14 quinary heterocyclic aromatic rings, 5-10 quinary heterocyclic cyclopentadienylene rings 6-10 Aromatic rings, 5-10-membered heterocyclic rings and 5-10-membered heteroaromatic rings, preferably, the heterocyclic rings may optionally contain one or more intracyclic double bonds; Each R 4 Independently selected from the following groups: H, D, halogens, -C 0-4 alkylene-cyano, -C 0-4 Alkylene-OR 12 C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, oxo groups (=O), =C(R) 13 )2, wherein each of the alkylene groups, alkyl groups, cycloalkyl groups, and heterocyclic groups may optionally be further substituted with one or more halogens; Or, any two R 4 All the atoms bonded to it together form C 3-6 The carbon ring or a 4-6 membered heterocycle containing one or two heteroatoms optionally selected from O, S, and N, wherein each group may optionally be further surrounded by one or more atoms selected from D, halogen, hydroxyl, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Group substitution of halogenated alkoxy groups; Each R 5 Independently selected from the following groups: H, D, halogens, -C 0-4 alkylene-cyano, -C 0-4 Alkylene-OR 12 -C 0-4 Alkylene-SR 12 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, NR 10 R 11 CONR 10 R 11 =O, =NR 31 =C(R) 13 )2, wherein each of the alkylene groups, alkyl groups, cycloalkyl groups, and heterocyclic groups may optionally be further substituted with one or more halogens; Each R 6 Each is independently selected from the following groups: H, D, halogen, cyano, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, SF5, -C 0-4 Alkylene-OR 12 -C 0-4 Alkylene-SR 12 -C 0-4 Alkylene-NR 10 R 11 -C 0-4 Alkylene-P(O)(R) 14 )2、-C 0-4 Alkylene C(O)-C 0-4 Alkylene-R a -C 0-4 Alkylene S(O)2-C 0-4 Alkylene-R a -C 0-4 Alkylene S(O)(NR) 31 )-C 0-4 Alkylene-R a =O, =NR 31 =C(R) 13 2. 6-10 aryl groups, 5-10 heteroaryl groups, wherein each group may optionally be further surrounded by one or more groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-8 membered heterocyclic groups, C 1-6 Halogenated alkoxy groups, C 3-8 Halogenated cycloalkyl, C 3-8 Group substitution of halogenated cycloalkoxy groups; Each R 10 and each R 11 Each is independently selected from the following groups: H, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, -C(O)R b -S(O)2-R b -S(O)(NR) 31 )-R b Each of the groups may optionally be further surrounded by one or more elements selected from deuterium, halogen, =O, CN, hydroxyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3- 10 Cycloalkyl, 4-10 membered heterocyclic groups, C 3-10 Substituents of halocycloalkyl groups and 4-10 membered haloheterocyclic groups; Or, R attached to the same nitrogen atom 10 and R 11 The nitrogen atoms bonded to them together form 4-10 member nitrogen-containing heterocycles, which may optionally be further bonded by one or more elements selected from D, halogens, =O, CN, hydroxyl, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy group, -S(O)2-C 1-6 Alkyl, -C(O)-C 1-6 Substituents of alkyl groups; Each R b Select independently from the following groups: H, D, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-8 membered heterocyclic group, 4-8 membered heterocyclic group, amino, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, wherein each group may optionally be further converted by one or more halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups; Each R 12 Independently selected from the following groups: H, C 1-6 Alkyl, C 3-10 cycloalkyl, C 4-10 Heterocyclic groups, -C(O)-N(R) 31 )2, wherein the group may optionally be further selected by one or more elements selected from deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 3-10 Substituents of halocycloalkyl groups, 4-10 membered haloheterocyclic groups; optionally further substituted by one or more groups selected from the group consisting of cyano, C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups; Each R 13 Independently selected from: H, D, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl, -C 1-4 Alkylene-OR 12 ; Alternatively, two R atoms attached to the same carbon atom 13 The carbon atoms bonded to them together form C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group may optionally be further selected from one or more elements selected from D, halogen, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy group, -S(O)2-C 1-6 Alkyl, -C(O)C 1-6 Substituents of alkyl groups; Each R 14 Selected independently from: C 1-6 Alkyl, -C 1-4 Alkylene-OR 12 The alkyl and heterocyclic groups may optionally be further replaced by one or more substituents selected from D and halogens; Each R 31 Independently selected from the following groups: H, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkoxy, 4-10 membered heterocyclic groups, said groups may optionally be further surrounded by one or more elements selected from deuterium, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1- 4-alkoxy group, C 1-4 Halogenated alkoxy groups, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 3-10 Substituents of halocycloalkyl groups and 4-10 membered haloheterocyclic groups; Ideally, there should be at least one R. 7 Not D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, oxo groups (=O).

2. The compound, its stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as claimed in claim 1, characterized in that, The Selected from the following group: Wherein, ring C is C 3-8 Carbon rings or 4-8 membered heterocycles; q is 1, 2, 3, 4, or 5; X, R 7 The definition is as described in claim 1.

3. The compound, its stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as described in claim 1, characterized in that, The Selected from the following group: Where each q is 1, 2, 3, 4 or 5; R 7 The definition is as described in claim 1.

4. The compound of claim 1, its stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, characterized in that, The ring A is selected from the following group: benzene ring, naphthalene ring, 5-9 membered heteroary ring, 10 membered heteroary ring; Preferably, ring A is selected from the group consisting of: benzene ring, naphthalene ring, quinoline, isoquinoline, and 5-6 membered heteroaromatic rings; More preferably, ring A is selected from the group consisting of: benzene ring, furan, pyrrole, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyridazine, pyrimidine, and pyrazine.

5. The compound of claim 1, its stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, characterized in that, The ring B is selected from the following group: 5-7 member heteromonocyclic rings, 8-12 heterospirocyclic rings, 8-12 member heterobridged rings, 5-7 member heterocyclic benzobenzene rings, 5-7 member heterocyclic benzo5-7 member heteroaromatic rings, benzene rings, naphthalene rings, and 5-12 member heteroaromatic rings; Preferably, ring B is selected from the group consisting of: 5-7 saturated heteromonocyclic rings, 5-7 partially saturated heteromonocyclic rings, 8-11 heterospirocyclic rings, 8-11 heterobridged rings, 5-6 heterocyclic benzobenzene rings, 5-7 heterocyclic benzo5-6 heteroaromatic rings, and 5-9 heteroaromatic rings. More preferably, the ring B is selected from the group consisting of: 5-7 saturated nitrogen-containing heteromonocycles, 5-7 partially saturated nitrogen-containing heteromonocycles, 8-11 nitrogen-containing heterospirocycles, 8-11 nitrogen-containing heterobridged rings, 5-6 nitrogen-containing heterocyclic benzobenzene rings, 5-7 heterocyclic benzo5-6 nitrogen-containing heteroaromatic rings, and 5-9 nitrogen-containing heteroaromatic rings; More preferably, the ring B is selected from the group consisting of: 5-7 saturated nitrogen-containing heteromonocycles, 5-7 partially saturated nitrogen-containing heteromonocycles, 8-10 nitrogen-containing heterospirocycles, 8-10 nitrogen-containing heterobridged rings, 5-6 nitrogen-containing heterocyclic benzo[a]benzene rings, 5-7 nitrogen-containing heterocyclic benzo[a]5-6 nitrogen-containing heterocyclic aromatic rings, and 5-7 nitrogen-containing heterocyclic aromatic rings; Most preferably, the ring B is selected from the group consisting of:

6. The compound, its stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as claimed in claim 1, characterized in that, Each R 4 Independently selected from the following groups: H, D, halogen, cyano, C 1-4 Alkyl, -C 0-4 Alkylene-C 1-4 Alkoxy, -OC 1-4 alkylene-hydroxyl, -OC 1-4 Alkylene-C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, oxo groups (=O), =C(R) 13 )2, wherein each of the alkylene groups, alkyl groups, cycloalkyl groups, and heterocyclic groups may optionally be further substituted with one or more halogens; Or, any two R 4 All the atoms bonded to it together form C 3-6 The carbon ring or a 4-6 membered heterocycle containing one or two heteroatoms optionally selected from O, S, and N, wherein each group may optionally be further surrounded by one or more atoms selected from D, halogen, hydroxyl, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Group substitution of halogenated alkoxy groups; Each R 5 Independently selected from the following groups: H, D, halogen, cyano, hydroxyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, SCF3, C 1-4 Alkoxy, -OC 1-4 alkylene-hydroxyl, -OC 1-4 Alkylene-C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, amino, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, wherein each group may optionally be further substituted with one or more halogens; Each R 6 Each is independently selected from the following groups: H, D, halogen, cyano, C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, SF5, hydroxyl, -C 0-4 Alkylene-C 1-4 Alkoxy, -OC 1-4 alkylene-hydroxyl, -OC 1-4 Alkylene-C 1-4 Alkoxy, SCF3, -NR 10 R 11 -P(O)(C 1-4 Alkoxy group, carboxyl group, -C(O)C 1-4 Alkyl, -C(O)NR 10 R 11 -S(O)2-C 1-4 Alkyl group, -S(O)2NR 10 R 11 -S(O)(NR) 31 )-C 1-4 Alkyl, -S(O)(NR 31 )-NR 10 R 11 =O, =NR 31 =C(R) 13 2. Phenyl, 5-6-membered heteroaryl, wherein each group may optionally be further substituted by one or more groups selected from D, halogens; R 10 R 11 R 13 R 31 The definition is as described in claim 1.

7. The compound of claim 1, its stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, characterized in that, The compound has the structure shown in formula (II-1), (II-2), (II-3), or (II-4): Where t1 is 0 or 1; t2 is 0, 1 or 2; t3 is 0 or 1; t4 is 0 or 1; q1 is 0, 1, 2, 3 or 4; R 71 Selected from: hydroxyl group, -CH2-R a -NR 10 R 11 -S(O)2-R a -CH2-S(O)2-NR 10 R 11 -S(O)-R a -OR a -(CH2)2-R a -CH2-OR 12 -C(O)-OR 12 -(CH2)2-OR a -(CH2)3-OR a -C(O)-R a -CH2-C(O)-R a -(CH2)2-C(O)-R a -(CH2)2-C(O)-OR a -CH2-S(O)2-R a -(CH2)2-S(O)2-R a -CH2-NH-C(O)-R a -CH2-NH-S(O)2-R a -NH-S(O)2-R a -NH-C(O)-R a -OC(O)NR 10 R 11 =C(R) 13 2, 6-10 aryl, 5-8 heteroaryl, wherein two R atoms on the same atom or different atoms 7 The atoms connected to it optionally form C 3-6 The carbon ring or a 4-6 membered heterocycle containing one or two heteroatoms optionally selected from O, S, and N; each group may optionally be further surrounded by one or more atoms selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-6 Substitution of groups such as halocycloalkyl, 4-6 membered heterocyclic groups, and 4-6 membered haloheterocyclic groups; Each R 72 Each is independently selected from: H, halogen, C 1-6 Alkyl, -NHSO2C1-C6 alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, where two R groups are... 72 Optional and connected atoms further form C 3-6 Cycloalkylene or 4-6 membered heterocyclic alkylene groups; m, n, s, X, R a R 10 R 11 R 12 R 13 Ring A, Ring B, R 4 R 5 R 6 The definition is as described in claim 1.

8. The compound of claim 1, its stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, characterized in that, The compounds are selected from the group consisting of:

9. A pharmaceutical composition, characterized in that, The composition comprises: (i) The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug as described in any one of claims 1-8; and (ii) Pharmaceutically acceptable carriers, excipients or excipients.

10. The use of the compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug as claimed in any one of claims 1-8, or the pharmaceutical composition as claimed in claim 9, characterized in that, Used in the preparation of drugs for the treatment and / or prevention of PCSK9-related diseases; Preferably, the PCSK9-related diseases are cardiovascular diseases, cerebrovascular diseases, and / or related diseases; More preferably, the PCSK9-related diseases are selected from the group consisting of: dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, and congestive heart failure.

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