Heteroaryl-substituted diaminocyclopentane derivatives, pharmaceutical compositions thereof and uses thereof

Abstract

The present application belongs to the field of medicine, and particularly relates to a heteroaryl-substituted diaminocyclopentane derivative, a pharmaceutical composition thereof and use thereof. Specifically, the present application relates to a compound of formula (I), or a stereoisomer, a tautomer, a nitroso compound, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound shown in formula (I), wherein each variable has the meaning described in the present application. The compound and the pharmaceutical composition thereof involved in the present application can be used for preparing a drug for preventing or treating a PCSK9-related disease.

Description

Technical Field

[0001] This invention pertains to the pharmaceutical field. Specifically, it relates to a heteroaryl-substituted diaminocyclopentane derivative, pharmaceutical compositions thereof, and the use of such compounds and pharmaceutical compositions thereof in the preparation of medicaments for the prevention or treatment of PCSK9-related diseases. Background Technology

[0002] The accumulation of low-density lipoprotein cholesterol (LDL-C) on the inner walls of arteries leads to atherosclerosis and may trigger an inflammatory response, resulting in cardiovascular events such as heart attacks and strokes. PCSK9 (Proprotein convertase subtilisin kexin type 9) is a serine protease that plays an important role in cholesterol metabolism. PCSK9 binds to the LDL receptor (LDLR) and guides it to lysosomes for degradation, thereby increasing plasma LDL-C levels. Loss-of-function mutations in the PCSK9 gene are associated with low LDL-C levels and reduced cardiovascular risk (Cohen, J.C., 2006), and it has been clinically validated as a therapeutic target for hyperlipidemia.

[0003] PCSK9 macromolecule inhibitors, such as monoclonal antibody-based drugs Alirocumab and Evolocumab, selectively bind to extracellular PCSK9 and prevent its interaction with LDLR. They have been approved by the FDA for lowering LDL-C levels and have shown good safety profiles. However, both drugs require injection, leading to poor patient adherence and high cost. Developing oral PCSK9 small molecule inhibitors holds promise for addressing patient adherence and reducing drug costs. Summary of the Invention

[0004] This invention provides a heteroaryl-substituted diaminocyclopentane derivative, or a pharmaceutical composition thereof, and relates to the use of said compound or pharmaceutical composition thereof in the preparation of a medicament for the prevention or treatment of PCSK9-related diseases or conditions. The diseases or conditions include those described in this invention.

[0005] On the one hand, the present invention provides compounds of formula (I), or stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of compounds of formula (I). (I), in, Z 1 Z 2 Z 3 Z 4 and Z 5 Each is independently N or CR4 ; L is -(CR) 5 R 6 ) r- R 5 and R 6 Each of the following is independently H, D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2; Ring A is C 3-7 Monocyclic cycloalkyl, C 5-12 Bridged cycloalkyl, C 5-12 Spirocyclic cycloalkyl, 3-7 membered monocyclic heterocyclic groups, 5-12 membered bridged heterocyclic groups, 5-12 membered spirocyclic heterocyclic groups, C 6-10 Aryl, 5-6 membered heteroaryl or 7-10 membered heteroaryl; Ring B is C 3-7 Monocyclic cycloalkyl, C 5-12 Bridged cycloalkyl, C 5-12 Spirocyclic cycloalkyl, 3-7 membered monocyclic heterocyclic groups, 5-12 membered bridged heterocyclic groups, 5-12 membered spirocyclic heterocyclic groups, C 6-10 Aryl, 5-6 membered heteroaryl or 7-10 membered heteroaryl; Each R 1 Independently, it is H, D, F, Cl, Br, I, CN, OH, NH2, COOH, oxo, -C(=O)NR 7 R 8 -S(=O)2C 1-6 Alkyl group, -S(=O)C 1-6 Alkyl group, -C(=O)C 1-6 Alkyl group, -NHC(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl group 2; or, two R atoms attached to the same carbon atom 1 Formed together with this carbon atom ; R a and R b Each of them independently is H, D, F, Cl, Br, I, CN, NH2, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2; R 7 and R 8 Each is independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups; Each R 2 Independently, H, D, F, Cl, Br, I, CN, OH, NR 7 R 8 COOH, oxo, -C(=O)NR 7 R 8 -S(=O)2C 1-6 Alkyl group, -S(=O)C 1-6 Alkyl group, -C(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 3-12Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally bounded by 1, 2, 3 or 4 R groups. c Replaced; Each R c Independently, they are D, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2; Each R 3 Independently, it is H, D, F, Cl, Br, I, CN, OH, NH2, COOH, oxo, -C(=O)NR 7 R 8 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2; Each R 4 Independently, H, D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2; m, n, q and r are each independently 0, 1, 2, 3 or 4; The condition is that the compound of formula (I) does not contain compound 6-(6-(((1) S ,3 S )-3-((5-(3-(difluoromethyl)cyclobutoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7 H -pyrrolo[3,4- b ]Pyridin-7-one and 6-(6-(((1) S ,3 S)-3-((5-(3,3-difluorocyclobutoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7 H -pyrrolo[3,4- b ]Pyridin-7-one.

[0006] In some implementations, ring A is C. 3-6 Monocyclic cycloalkyl, C 4-10 Bridged cycloalkyl, C 4-10 Spirocyclic cycloalkyl, 3-6 membered monocyclic heterocyclic group, 5-10 membered bridged heterocyclic group, 5-10 membered spirocyclic heterocyclic group, phenyl, naphthyl, 5-6 membered heteroaryl or 7-10 membered heteroaryl.

[0007] In some embodiments, ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethylene, 1,4-dioxanecyclo, oxacyclobutyl, aziranecyclobutyl, thiohexanecyclobutyl, pyrrolyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidinyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptyl, 2-oxo-spiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, 1,4-dioxaspiro[4.4]nonyl, 5,8-oxaspiro[3.4]octyl, 1,1-dioxothiabutyl, 7-azirane[3.5]nonyl, 3-azibicyclo[3.1.0]hexyl, octahydrofuran[2,3- c Pyridyl, dihydropyridyl, dihydropyrimidinyl, dihydropyridazinyl, 1,3-dihydro-2 H -imidazolyl, 1,3-dihydro-2 H -benzo[ d Imidazolyl, 1,3-dihydro-2 H -imidazo[ 4,5-b ]Pyridyl, 1,3-dihydro-2 H -imidazo[ 4,5-b ]Pyrazinyl, 5,6-dihydro-7 H -pyrrolo[3,4- b ]Pyridyl, 5,6-dihydro-7 H -pyrrolo[3,4- b [3.1.0]Pyridyl, dioxo-3-azabicyclo[3.1.0]hexyl, phenyl, naphthyl, pyrrolithyl, pyrazolyl, tetrazolyl, imidazolyl, furanyl, thiaranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridopyrimidinyl, benzopyridyl, pyridopyrrolithyl, benzopyrazolyl, pyrrolopyrazolyl or benzothiazolyl.

[0008] In some implementations, ring B is C. 3-6 Monocyclic cycloalkyl, C5-10 Bridged cycloalkyl, C 5-10 Spirocyclic cycloalkyl, 3-6 membered monocyclic heterocyclic group, 5-10 membered bridged heterocyclic group, 5-10 membered spirocyclic heterocyclic group, phenyl, naphthyl, 5-6 membered heteroaryl or 7-10 membered heteroaryl.

[0009] In some embodiments, ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethylene, 1,4-dioxanecyclo, oxacyclobutyl, aziranecyclobutyl, thiohexanecyclobutyl, pyrrolyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidinyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, 2-oxaspiro[3.3]heptyl, 1,4-dioxaspiro[4.4]nonyl, 5,8-oxaspiro[3.4]octyl, 1,1-dioxothiabutyl, 1,1-dioxo-isothiazolin-2-yl, 7-azirane[3.5]nonyl, 3-azibicyclo[3.1.0]hexyl, octahydrofuran[2,3- c Pyridyl, dihydropyridyl, dihydropyrimidinyl, dihydropyridazinyl, 1,3-dihydro-2 H -imidazolyl, 1,3-dihydro-2 H -benzo[ d Imidazolyl, 1,3-dihydro-2 H -imidazo[ 4,5-b ]Pyridyl, 1,3-dihydro-2 H -imidazo[ 4,5-b ]Pyrazinyl, 5,6-dihydro-7 H -pyrrolo[3,4- b ]Pyridyl, 5,6-dihydro-7 H -pyrrolo[3,4- b ]pyridyl, dioxo-3-azabicyclo[3.1.0]hexyl, oxooctahydrofuran[2,3- c Pyridyl, oxodihydropyridyl, oxodihydropyrimidinyl, oxodihydropyridazinyl, oxoimidazoalkyl, oxopyrrolidinyl, dioxopyrrolidinyl, dioxoimidazoalkyl, oxo-1,3-dihydro-2 H -imidazolyl, oxo-1,3-dihydro-2 H -benzo[ d Imidazolyl, oxo-1,3-dihydro-2 H -imidazo[ 4,5-b ]pyridyl, oxo-1,3-dihydro-2 H -imidazo[ 4,5-b ]Pyrazinyl, oxo-5,6-dihydro-7 H -pyrrolo[3,4- b ]Pyridyl, dioxo-5,6-dihydro-7H -pyrrolo[3,4- b ]pyridyl, oxo-1,2-dihydroquinolinyl, 2-oxo-3,4-dihydro-1,8-naphthidyl-1-yl, oxo-1,2,3,4-tetrahydroquinolinyl, 2-oxo-1,3-dihydro-2H-pyrrolo[2,3- b Pyridine, phenyl, naphthyl, pyrrolyl, pyrazolyl, tetrazolyl, imidazolyl, furanyl, thiaranyl, pyridyl, oxopyridyl, oxopyrimidinyl, oxopyridazinyl, pyrimidinyl, pyridinyl, pyridopyrimidinyl, benzopyrimidinyl, benzopyridyl, pyridopyrroleyl, benzopyrazolyl, pyrrolopyrazolyl, or benzothiazolyl.

[0010] In some implementations, ring B is phenyl, , , , , , , , , , , , , , , , , , , , , , or .

[0011] In some implementation schemes, each R 1 Independently, it is H, D, F, Cl, Br, I, CN, OH, NH2, COOH, oxo, -C(=O)NR 7 R 8 -S(=O)2C 1-4 Alkyl group, -S(=O)C 1-4 Alkyl group, -C(=O)C 1-4 Alkyl group, -NHC(=O)C 1-4 Alkyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Halogenated alkoxy C 1-4 Alkyl, -NH(C)1-4 alkyl) or -N(C) 1-4 Alkyl group 2; or, two R atoms attached to the same carbon atom 1 Formed together with this carbon atom ; R a and R b Each of them independently is H, D, F, Cl, Br, I, CN, NH2, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups, -NH(C 1-4 alkyl) or -N(C) 1-4 Alkyl)2; R 7 and R 8 Each is independently H, D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0012] In some implementation schemes, each R 1 Independently, it is H, D, F, Cl, Br, I, CN, OH, NH2, COOH, oxo, -C(=O)NR 7 R 8, -S(=O)2CH3, -S(=O)CH3, -C(=O)CH3, -NHC(=O)CH3, -NHC(=O)CH2CH3, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C( CH3)3, -CH≡CH, -CH≡CCH3, -CH2C≡CH, -(CH2)2C≡CH, -C=CH2, -(CH2)2C=CH2, -CH2=CHCH3, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -CH2OCH3, -(CH2)2OCH3, -CH2OCH2CH3, -(CH2)2OCH2CH3, -(CH2)3OCH3, -CH2OCF3, -(CH2)2OCF3, -CH2OCH2CF3, -(CH2)2OCH2CF3, -(CH2)3OCF3 or -CH2OCHFCF3; or, two R atoms attached to the same carbon atom. 1 Formed together with this carbon atom ; R a and R b Each can be independently H, D, F, Cl, Br, I, CN, NH2-CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3 or -N(CH3)2; R 7 and R 8Each can be independently H, D, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, phenyl, pyrrolyl, pyrazolyl, tetrazolyl, imidazolyl, furanyl, thiaranyl, pyridinyl, pyrimidinyl, or pyrazinyl.

[0013] In some implementation schemes, each R 2 Independently, H, D, F, Cl, Br, I, CN, OH, NR 7 R 8 COOH, oxo, -C(=O)NR 7 R 8 -S(=O)2C 1-4 Alkyl group, -S(=O)C 1-4 Alkyl group, -C(=O)C 1-4 Alkyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Halogenated alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Halogenated alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, phenyl, and 5-6-membered heteroaryl groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. c Replaced; Each R c Independently, they are D, F, Cl, Br, I, CN, OH, NH2, and C. 1-4 Alkyl group, -S(=O)2C 1-4 Alkyl, C1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups, -NH(C 1-4 alkyl) or -N(C) 1-4 Alkyl)2; In some implementation schemes, each R 2 Independently, H, D, F, Cl, Br, I, CN, OH, NR 7 R 8 COOH, oxo, -C(=O)NR 7 R 8, -S(=O)2CH3, -S(=O)CH3, -C(=O)CH3, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, - CH2CH(CH3)2, -CH2C(CH3)3, -C=CH2, -(CH2)2C=CH2, -CH2=CHCH3, -CH≡CH, -CH≡CCH3, -CH2C≡C H, -(CH2)2C≡CH, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -OCH3, -OCH2CH3, -O(CH2 )2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -OCF3, -OCH2F, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHFCHF2 , -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -CH2OCH3, -(CH2)2OCH3, - CH2OCH2CH3, -(CH2)2OCH2CH3, -(CH2)3OCH3, -CH2OCF3, -(CH2)2OCF3, -CH2OCH2CF3, -(CH2)2 OCH2CF3, -(CH2)3OCF3, -CH2OCHFCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethylene, 1,4-dioxanecycloyl, oxacyclobutyl, aziranecyclobutyl, thioheranecyclobutyl, pyrrolidinyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, phenyl, pyrazolyl, tetrazolyl, imidazolyl, furanyl, thiaranyl, pyridinyl, pyrimidinyl or pyrazinyl;The following are some of the following: -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -C=CH2, -(CH2)2C=CH2, -CH2=CHCH3, -CH≡CH, -CH≡CCH3, -CH2C≡CH, -(CH2)2C≡CH, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -OCH2F, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHFCHF2, -CH2OH, -(CH2)2OH, -(CH2)2CH 2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -CH2OCH3, -(CH2)2OCH3, -CH2OCH2CH3, -(CH2)2OCH2CH 3. -(CH2)3OCH3, -CH2OCF3, -(CH2)2OCF3, -CH2OCH2CF3, -(CH2)2OCH2CF3, -(CH2)3OCF3, -C H2OCHFCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethylene, 1,4-dioxanecyclo, oxacyclobutyl, azirhexacyclobutyl, thiohexacyclobutyl, pyrrolidinyl, pyrazolyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, phenyl, pyrazolyl, tetrazolyl, imidazolidinyl, furanyl, thiaranyl, pyridinyl, pyrimidinyl, and pyrazinyl are each independently and optionally marked with 1, 2, 3, or 4 Rs; c Replaced; Each R c Independently, it can be D, F, Cl, Br, I, CN, OH, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -S(=O)2CH3, -S(=O)2CH2CH3, -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3 or -N(CH3)2.

[0014] In some implementation schemes, each R 4 Independently, H, D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-4Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, -NH(C) 1-4 alkyl) or -N(C) 1-4 Alkyl)2; R 5 and R 6 Each of the following is independently H, D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, -NH(C) 1-4 alkyl) or -N(C) 1-4 Alkyl)2.

[0015] In some implementation schemes, each R 4 Independently, it can be H, D, F, Cl, Br, I, CN, OH, NH2, COOH, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3 or -N(CH3)2; R 5 and R 6 Each can be independently H, D, F, Cl, Br, I, CN, OH, NH2, COOH, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3 or -N(CH3)2.

[0016] In some embodiments, the compound of the present invention is the compound shown in (II), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the compound shown in (II). (II), Among them, Z 1 Z 2 Z 3 Z 4 Z 5 m, n, q, ring A, ring B, L, R 1 R 2 and R 3 Each has the definition as described in this invention.

[0017] On the other hand, the present invention provides a pharmaceutical composition comprising the compound described herein, or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

[0018] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient.

[0019] In some embodiments, the excipients described in this invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof. In some embodiments, the pharmaceutical composition may be a liquid, solid, semi-solid, gel, or spray formulation.

[0020] On the other hand, the present invention provides the use of the pharmaceutical composition described herein in the preparation of a medicament for the prevention, treatment or relief of PCSK9-related diseases.

[0021] The present invention further relates to any stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug of any of the compounds of general formula (I) shown, or the use of the pharmaceutical composition thereof in the preparation of an LDL-lowering drug; preferably, the LDL is LDL-C.

[0022] In some embodiments, the PCSK9-related diseases described in this invention are cardiovascular diseases, cerebrovascular diseases, and atherosclerosis-related diseases.

[0023] In some embodiments, the PCSK9-related diseases described in this invention are stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, vascular stenosis, chronic kidney disease, coronary heart disease, heart failure, atherosclerosis, hepatic steatosis, metabolic syndrome, and / or coronary artery disease.

[0024] In some embodiments, the compound of the present invention, or its stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs, constitute 0.01% to 99.9%, 0.1% to 99.5%, 0.1% to 95%, 0.5% to 85%, 1% to 60%, 10% to 50%, 15% to 40%, 20% to 30%, or 20% to 25% (based on the total weight of the pharmaceutical composition) in the composition.

[0025] On the other hand, the present invention also provides a method for preventing or treating PCSK9-related diseases, the method comprising administering to a patient a therapeutically effective amount of the compound or pharmaceutical composition thereof described in the present invention.

[0026] In some implementations, the patient has a gain-of-function mutation in the PCSK9 gene.

[0027] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds of formula (I) or (II).

[0028] Unless otherwise indicated, all stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds of this invention are within the scope of the compounds of this invention.

[0029] Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" includes the requirement that the substance or composition be chemically or toxically unsuitable. Physiology relates to the other components that make up the formulation and the mammals used for treatment.

[0030] The salts of the compounds of the present invention also include salts used for the preparation or purification of intermediates of the compounds of formula (I) or (II) or for the isolation of enantiomers of the compounds of formula (I) or (II), but are not necessarily pharmaceutically acceptable salts.

[0031] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below.

[0032] Detailed Description of the Invention Definitions and general terms Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0033] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0034] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0035] As used in this invention, the term "test subject" refers to an animal. Typically, the animal is a mammal. Test subjects also include, for example, primates (e.g., humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the test subject is a primate. In other embodiments, the test subject is a human.

[0036] As used in this invention, the term "patient" refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a person.

[0037] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0038] "Stereoisomers" refer to compounds that have the same chemical structure but differ in the spatial arrangement of their atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis / trans isomers), trans-blocking isomers, and so on. Unless otherwise stated, all stereoisomers or mixtures of stereoisomers of the structural formulas described in this invention are within the scope of this invention. Furthermore, unless otherwise stated, the structural formulas of the compounds described in this invention include enriched isotopes of one or more different atoms.

[0039] The stereochemical definitions and rules used in this invention generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994.

[0040] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0041] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is pyridine-4-ol and pyridine-4(1... H Tautomerism of keto tautomers. Unless otherwise indicated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0042] As described in this invention, the compounds of this invention can be independently and optionally substituted by one or more substituents, such as the general formula compounds above, or as the specific examples, subclasses, and classes of compounds included in this invention, as described in the embodiments. It should be understood that the terms "independently and optionally substituted" or "optionally substituted" are used interchangeably with the term "substituted or unsubstituted." Generally, the term "substituted" means that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions.

[0043] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0044] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, the invention includes every independent secondary combination of the various members of these group types and scopes. For example, the term "C..." 1-6 "Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0045] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0046] The term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be substituted by one or more substituents described in this invention. In one embodiment, the alkyl group contains 1 to 6 carbon atoms, denoted as C1. 1-6 Alkyl group; in yet another embodiment, the alkyl group contains 1-4 carbon atoms, denoted as C1 1-4 Alkyl group; in another embodiment, the alkyl group contains 1-3 carbon atoms, denoted as C1 1-3Alkyl groups. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (... n -Pr, -CH2CH2CH3), isopropyl ( i -Pr, -CH(CH3)2), n-butyl ( n -Bu、-CH2CH2CH2CH3), isobutyl ( i -Bu、-CH2CH(CH3)2), sec-butyl( s -Bu、-CH(CH3)CH2CH3), tert-butyl( t -Bu、-C(CH3)3), n-pentyl(-CH2CH2CH2CH2CH3), 2-pentyl(-CH(CH3)CH2CH2CH3), 3-pentyl(-CH(CH2CH3)2), 2-methyl-2-butyl(-C(CH3)2CH2CH3), 3-methyl-2-butyl(-CH(CH3)CH (CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl ( -CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc.

[0047] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon. In some embodiments, the alkylene group contains 1-6 carbon atoms, denoted as C1. 1-6 Alkylene; in other embodiments, the alkylene group contains 1-4 carbon atoms, denoted as C1. 1-4 Alkylene; in other embodiments, the alkylene group contains 1-3 carbon atoms, denoted as C1. 1-3 Alkylene; in other embodiments, the alkylene group contains 1-2 carbon atoms, denoted as C2. 1-2Alkylene groups. Examples of alkylene groups include, but are not limited to: -CH2-, -CH2CH2-, -CH(CH3)CH2-, etc.

[0048] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, with at least one unsaturated site, i.e., one carbon-carbon sp. 2 The double bond, wherein the alkenyl group may optionally be substituted by one or more substituents described in this invention, including the orientation of "cis" and "tans", or the orientation of "E" and "Z". In one embodiment, the alkenyl group comprises 2-10 carbon atoms; in another embodiment, the alkenyl group comprises 2-6 carbon atoms; in yet another embodiment, the alkenyl group comprises 2-4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), propenyl (-C=CHCH3), isopropenyl (-C(CH3)=CH2), etc.

[0049] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp triple bond, wherein the alkynyl group may optionally be substituted by one or more substituents described in this invention. In one embodiment, the alkynyl group contains 2-6 carbon atoms; in another embodiment, the alkynyl group contains 2-10 carbon atoms; the alkynyl group contains 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), etc.

[0050] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl and hydroxyl groups have the definitions described herein. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with 1, 2, 3, or 4 hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with one or two hydroxyl groups. In some embodiments, hydroxyalkyl refers to a C14-C ... 1-6 Hydroxyalkyl, i.e., C 1-6 Alkyl groups are substituted with one or more hydroxyl groups, preferably C 1-6 Hydroxyalkyl indicates C 1-6 An alkyl group is an alkyl group substituted with a hydroxyl group. In some embodiments, hydroxyalkyl represents C10. 1-4 Hydroxyalkyl. In some embodiments, hydroxyalkyl means C 1-3 Hydroxyalkyl groups. Examples of hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2CH2CH2OH, -CH2CH2OH, -CH2CH(OH)CH2CH2OH, -CH2CH(OH)CH2CH(CH3)OH, etc.

[0051] The term "haloalkyl" indicates that an alkyl group is replaced by one or more halogen atoms, wherein the alkyl group and the halogen atom have the definitions described herein. In some embodiments, the haloalkyl group is C10. 1-6 Haloalkyl, indicating C 1-6 The alkyl group is replaced by one or more halogen atoms; in other embodiments, the haloalkyl group is C10. 1-4 Haloalkyl, indicating C 1-4 The alkyl group is replaced by one or more halogen atoms; in other embodiments, the haloalkyl group is C10. 1-3 Haloalkyl, indicating C 1-3 The alkyl group is replaced by one or more halogen atoms. Examples of such groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and so on.

[0052] The term "alkoxy group" indicates that an alkyl group is attached to the remainder of the molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms, representing C0. 1-6 Alkoxy group; in another embodiment, the alkoxy group contains 1-4 carbon atoms, representing C 1-4 Alkoxy group; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms, representing C 1-3 Alkoxy group. The alkoxy group may optionally be replaced by one or more substituents described in this invention. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy ( n -PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy ( i -PrO、 i -propoxy, -OCH(CH3)2), 1-butoxy n -BuO、 n -Butoxy, -OCH2CH2CH2CH3), 2-Methyl-1-propoxy ( i -BuO、 i -butoxy, -OCH2CH(CH3)2), 2-butoxy ( s -BuO、 s-Butoxy, -OCH(CH3)CH2CH3), 2-Methyl-2-propoxy t -BuO、 t -Butoxy, -OC(CH3)3), 1-Pentoxy ( n -Pentoxy, -OCH2CH2CH2CH2CH3), 2-Pentoxy (-OCH(CH3)CH2CH2CH3), 3-Pentoxy (-OCH(CH2CH3)2), 2-Methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-Methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-Methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-Methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc.

[0053] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein the alkoxy and alkyl groups have the definitions as defined in this invention. In some embodiments, alkoxyalkyl refers to an alkyl group substituted with one alkoxy group. In some embodiments, alkoxyalkyl is an alkyl group substituted with one C 1-6 alkoxy-substituted C 1-6 Alkyl groups, represented by C 1-6 Alkoxy C 1-6 Alkyl; in some embodiments, the alkoxyalkyl group is formed by a C12C ... 1-4 alkoxy-substituted C 1-4 Alkyl groups, represented by C 1-4 Alkoxy C 1-4 Alkyl; in some embodiments, the alkoxyalkyl group is formed by a C12C ... 1-3 alkoxy-substituted C 1-3 Alkyl groups, represented by C 1-3 Alkoxy C 1-3 Alkyl groups. Examples of alkoxyalkyl groups include, but are not limited to, -CH2OCH3, -(CH2)2OCH3, -(CH2)3OCH3, -(CH2)2OCH2CH3 or -CH2OCH2CH3, etc.

[0054] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group and the halogen have the definitions as defined in this invention. In some embodiments, a haloalkoxy group refers to a haloalkoxy group containing 1-6 carbon atoms, i.e., C6. 1-6 Haloalkoxy group; in other embodiments, haloalkoxy group refers to a haloalkoxy group containing 1-4 carbon atoms, i.e., C646-C ... 1-4 Haloalkoxy group; in other embodiments, the haloalkoxy group refers to a haloalkoxy group containing 1-3 carbon atoms, i.e., C646-C ... 1-3Halogenated alkoxy groups. Examples of halogenated alkoxy groups include, but are not limited to, trifluoromethoxy (-OCF3), monofluoromethoxy (-OCH2F), 2-fluoroethoxy (-OCH2CH2F), etc.

[0055] The term "haloalkoxyalkyl" refers to an alkyl group substituted with one or more haloalkoxy groups, wherein the alkoxy and alkyl groups have the definitions as defined in this invention. In some embodiments, alkoxyalkyl refers to an alkyl group substituted with one alkoxy group. In some embodiments, haloalkoxyalkyl is an alkyl group substituted with one C 1-6 Halogenated alkoxy-substituted C 1-6 Alkyl groups, represented by C 1-6 Halogenated alkoxy C 1-6 Alkyl; in some embodiments, the haloalkoxyalkyl group is formed by a C12 group. 1-4 Halogenated alkoxy-substituted C 1-4 Alkyl groups, represented by C 1-4 Halogenated alkoxy C 1-4 Alkyl; in some embodiments, the haloalkoxyalkyl group is formed by a C12C ... 1-3 Halogenated alkoxy-substituted C 1-3 Alkyl groups, represented by C 1-3 Halogenated alkoxy C 1-3 Alkyl groups. Examples of haloalkoxyalkyl groups include, but are not limited to, -CH2OCF3, -(CH2)2OCF3, -CH2OCH2CF3, -(CH2)2OCH2CF3, -(CH2)3OCF3 or -CH2OCHFCF3, etc.

[0056] The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic carbocyclic system containing 3-12 ring carbon atoms, wherein the -CH2- group in the carbocyclic ring may optionally be replaced by -C(=O)- (or -(CO)-). Bicyclic carbocyclic systems include spirocyclic and bridged ring systems. In one embodiment, the cycloalkyl group comprises 3-10 ring carbon atoms, i.e., C2... 3-10 cycloalkyl; in another embodiment, the cycloalkyl group comprises 3-7 cyclic carbon atoms, i.e., C1 3-7 cycloalkyl; in another embodiment, the cycloalkyl group comprises 3-6 cyclic carbon atoms, i.e., C1 3-6 Cycloalkyl; in another embodiment, the cycloalkyl group comprises 3-5 cyclic carbon atoms, i.e., C1 3-5 Cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and octahydro-1-ylyl groups. H -Indenyl, octahydrocyclopentadienyl, etc. Examples of -CH2- groups in the carbide ring that can be replaced by -C(=O)- include, but are not limited to: cyclopentanone, cyclobutanone, etc.

[0057] The term "monocyclic cycloalkyl" refers to a monovalent saturated monocyclic carbocyclic system containing 3-12 ring carbon atoms, wherein the -CH2- group in the carbocyclic ring may optionally be replaced by -C(=O)- (in this invention, -C(=O)- is also represented as -(CO)-). In one embodiment, the monocyclic cycloalkyl group comprises 3-7 ring carbon atoms, i.e., C 3-7 Monocyclic cycloalkyl; in another embodiment, the monocyclic cycloalkyl group comprises 3-6 ring carbon atoms, i.e., C164-C264-C ... 3-6 Monocyclic cycloalkyl groups. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0058] The term "bridged cycloalkyl" refers to a saturated bicyclic or polycyclic system sharing two or more carbon atoms, wherein the ring atoms are carbon atoms. The -CH2- group in a bridged cycloalkyl group may optionally be replaced by -C(O)-. In some embodiments, the bridged cycloalkyl group contains 5-12 ring carbon atoms, i.e., representing C... 5-12 Bridged cycloalkyl group; in some other embodiments, the bridged cycloalkyl group contains 5-10 ring carbon atoms, i.e., representing C 5-10 Bridged cycloalkyl group; in some other embodiments, the bridged cycloalkyl group contains 6-12 ring carbon atoms, i.e., representing C 6-12 Bridged cycloalkyl group; in some other embodiments, the bridged cycloalkyl group contains 7-12 ring carbon atoms, i.e., representing C 7-12 Bridged cycloalkyl groups. Examples of bridged cycloalkyl groups include, but are not limited to: bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[2.2.0]hexyl, octahydro-1 H -Indene, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, etc.

[0059] The term "spirocycloalkyl" refers to a saturated ring system formed by two carbon rings sharing a single carbon atom, where the ring atom is a carbon atom. The -CH2- group in a spirocycloalkyl group may optionally be replaced by -C(O)-. In some embodiments, the spirocycloalkyl group contains 5-12 ring carbon atoms, i.e., C2. 5-12 Spirocycloalkyl; in some other embodiments, the spirocycloalkyl group contains 5-10 ring carbon atoms, i.e., representing C 5-10 Spirocycloalkyl; in some other embodiments, the spirocycloalkyl group contains 6-12 ring carbon atoms, i.e., representing C 6-12 Spirocycloalkyl; in some other embodiments, the spirocycloalkyl group contains 7-12 ring carbon atoms, i.e., representing C 7-12 Spirocycloalkyl. Examples of spirocycloalkyl include, but are not limited to: spiro[4.4]nonyl, spiro[3.4]octyl, spiro[4.5]decyl, 2-oxaspiro[3.3]heptyl, 1,4-dioxaspiro[4.4]nonyl, etc.

[0060] The terms "heterocycle" and "heterocyclic group" refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic system comprising 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms; wherein the heterocycle or heterocyclic group is non-aromatic and does not contain any aromatic ring. The bicyclic or tricyclic system includes spirocyclic or bridged ring systems. When a heterocycle is attached to other parts of a molecule via a linking site, the heterocycle is represented as a monovalent heterocyclic group. Unless otherwise stated, the heterocyclic group can be carbonyl or nitrogenyl, and the -CH2- group may optionally be replaced by -C(=O)-. The sulfur atom of the ring may optionally be oxidized to... S -Oxides. The nitrogen atom in the ring can optionally be oxidized to... N -Oxides. In some embodiments, the heterocycle or heterocyclic group consists of 3-10 atoms and is represented as a 3-10 membered heterocycle or a 3-10 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 3-9 atoms and is represented as a 3-9 membered heterocycle or a 3-9 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 5-9 atoms and is represented as a 5-9 membered heterocycle or a 5-9 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 3-6 atoms and is represented as a 3-6 membered heterocycle or a 3-6 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 5-6 atoms and is represented as a 5-6 membered heterocycle or a 5-6 membered heterocyclic group. Examples of the heterocycles include, but are not limited to, ethylene oxide, aziridine, aziridine, oxacyclobutane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazoline, pyrazolidine, pyrazolidine, pyrazoline, oxazolidine, imidazoline, piperidine, piperazine, morpholine, 3,8-diazabicyclo[3.2.1]octane, 3,6-diazabicyclo[3.1.1]heptane, and 2,5-diazabicyclo[2.2.2]octane. Examples of the heterocyclic groups include, but are not limited to, ethylene oxide, aziridine, aziridine, oxacyclobutane, pyrrolidine, tetrahydrofuranyl, tetrahydrothiophenyl, thiazoline, pyrazolidine, pyrazolidine, oxazolidine, imidazoline, piperidinyl, piperazinyl, or morpholinyl.

[0061] The term "monocyclic heterocyclic group" refers to a heterocyclic group in a monocyclic system. In some embodiments, the monocyclic heterocyclic group is a saturated monocyclic heterocyclic group. In some embodiments, the monocyclic heterocyclic group is a 3-7 member monocyclic heterocyclic group; in other embodiments, the monocyclic heterocyclic group is a 3-6 member monocyclic heterocyclic group; in still other embodiments, the monocyclic heterocyclic group is a 5-6 member monocyclic heterocyclic group. Examples of monocyclic heterocyclic groups include, but are not limited to: 1,2-epoxyethylene, 1,4-dioxane, oxohexacyclic, azacyclic, thiohexacyclic, pyrrolyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidinyl, oxodihydropyrimidinyl, oxodihydropyridazinyl, oxoimidazoalkyl, oxopyrrolyl, dioxopyrrolyl, etc.

[0062] The terms "bridged heterocyclic group," "bridged heterocyclic group," or "bridged heterocycle" refer to a non-aromatic, saturated or partially unsaturated bicyclic or polycyclic system sharing two or more carbon atoms, wherein the system contains at least one carbon atom and one, two, or three heteroatoms selected from O, N, and S. The -CH2- group in the bridged heterocycle may optionally be replaced by -C(O)-. The sulfur atom of the ring may optionally be oxidized to... S -Oxides, where the nitrogen atom of the ring can optionally be oxidized to N -Oxygen compounds. In some embodiments, the bridged heterocyclic group contains 5-12 ring atoms, i.e., represents a 5-12 membered bridged heterocyclic group; in some embodiments, the bridged heterocyclic group contains 5-10 ring atoms, i.e., represents a 5-10 membered bridged heterocyclic group; in some embodiments, the bridged heterocyclic group contains 6-12 ring atoms, i.e., represents a 6-12 membered bridged heterocyclic group; in other embodiments, the bridged heterocyclic group contains 6-10 ring atoms, i.e., represents a 6-10 membered bridged heterocyclic group. Examples of bridged heterocyclic groups include, but are not limited to: 3,6-diazabicyclo[3.1.1]heptyl, 3,8-diazabicyclo[3.2.1]octyl, 2-diazabicyclo[2.2.1]heptyl, octahydroimidazole[1,5- c Pyrimidinyl, 6-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 8-azabicyclo[3.2.1]octyl, 3-azabicyclo[3.2.1]octyl, 2-diazabicyclo[2.2.2]octyl, dioxo-3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hexyl, etc.

[0063] The terms "spirocyclic heterocyclic group" or "spiroheterocyclic group" or "spiroheterocycle" refer to a non-aromatic saturated or partially unsaturated ring system formed by two rings sharing a carbon atom, and the system contains one, two, or three heteroatoms selected from O, N, and S; the -CH2- group in the spiroheterocycle may optionally be replaced by -C(O)-, and the sulfur atom of the ring may optionally be oxidized to S -Oxides, where the nitrogen atom of the ring can optionally be oxidized to N -Oxygen compounds. In some embodiments, the spiroheterocycle contains 5-12 ring atoms, i.e., represents a 5-12 membered spiroheterocycle; in some embodiments, the spiroheterocycle contains 5-10 ring atoms, i.e., represents a 5-10 membered spiroheterocycle; in some embodiments, the spiroheterocycle contains 7-12 ring atoms, i.e., represents a 7-12 membered spiroheterocycle; in other embodiments, the spiroheterocycle contains 7-10 ring atoms, i.e., represents a 7-10 membered spiroheterocycle. Examples of spiroheterocycles include, but are not limited to: 4,7-diazaspiro[2.5]octane, 2,8-diazaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane, 2,7-diazaspiro[3.5]decane, 2,6-diazaspiro[3.3]heptane, 2,7-diazaspiro[4.4]nonane, 3-azaspiro[5.5]undecane, 2,7-diazaspiro[4.4]nonane-1-one, 7-azaspiro[3.5]nonyl, 5,8-oxaspiro[3.4]octane, etc.

[0064] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14, 6-12, or 6-10 ring atoms, wherein at least one ring system is aromatic, and each ring system comprises a ring of 3-7 atoms. In some embodiments, the aryl group contains 6-12 ring atoms, denoted as C 6-12 Aryl or 6-12-membered aryl. In some embodiments, the aryl group contains 6-10 ring atoms, denoted as C. 6-10 Aryl or 6-10 aryl groups. Examples of aryl groups may include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and anthracene. When the aryl group is a linking group, the term "aryl" is used to indicate an arylene, for example, A in general formula (I). 2 As a linking group, it can be C 6-10 Alpha-aryl.

[0065] The term "heteroaryl" or "heteroary ring" refers to a monovalent monocyclic, bicyclic, or tricyclic system containing 5-14, 5-12, 5-10, 5-6, or 7-10 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur. The heteroaryl group is typically, but not necessarily, linked to the parent molecule via its aromatic ring. When a -CH2- group is present in the heteroaryl group, the -CH2- group may optionally be replaced by -C(=O)-. Unless otherwise stated, the heteroaryl group may be linked to the remainder of the molecule (e.g., the main structure in the general formula) through any reasonable site (which may be C or N). The term "heteroaryl" may be used interchangeably with the terms "heteroary ring" or "heteroary aromatic compound." In some embodiments, the heteroaryl group is a heteroaryl group containing 5-12 ring atoms, denoted as a 5-12-membered heteroaryl group; in other embodiments, the heteroaryl group is a heteroaryl group containing 5-10 ring atoms, denoted as a 5-10-membered heteroaryl group; in other embodiments, the heteroaryl group is a heteroaryl group containing 5-6 ring atoms, denoted as a 5-6-membered heteroaryl group; in other embodiments, the heteroaryl group is a heteroaryl group containing 7-10 ring atoms, denoted as a 7-10-membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, thiophene, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrroleyl, benzopyrroleyl, benzopyrrolidinyl, oxo-1,3-dihydro-2 H -imidazolyl, oxo-1,3-dihydro-2 H -benzo[ d Imidazolyl, oxo-1,3-dihydro-2 H -imidazo[ 4,5-b ]pyridyl, oxo-1,3-dihydro-2 H -imidazo[ 4,5-b ]Pyrazinyl, oxo-5,6-dihydro-7 H -pyrrolo[3,4- b ]Pyridyl, dioxo-5,6-dihydro-7 H -pyrrolo[3,4- b ]pyridyl, 2-oxo-1,3-dihydro-2H-pyrrolo[2,3- b Pyridine, etc.

[0066] The term "halogen" refers to F (fluorine), Cl (chlorine), Br (bromine), or I (iodine).

[0067] The term "oxo" means =O.

[0068] The term "cyano" means -CN or -C≡N.

[0069] The term "hydroxyl group" represents -OH.

[0070] The term "carboxyl group" represents -C(=O)OH.

[0071] The term "amino" represents -NH2.

[0072] The term "composed of jk atoms" or "of jk elements" means that the cyclic group is composed of jk ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, P, etc.; j and k are each independently any non-zero natural number, and k > j; "jk" includes j, k, and any natural number between them. For example, "composed of 3-8 atoms" or "3-8-element", "composed of 3-6 atoms" or "3-6-element", "composed of 5-10 atoms" or "5-10-element", or "composed of 5-6 atoms" or "5-6-element" indicates that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7 or 8), 3-6 (i.e., 3, 4, 5 or 6), 5-10 (i.e., 5, 6, 7, 8, 9 or 10), or 5-6 (i.e., 5 or 6) ring atoms, wherein the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, P, etc.

[0073] As described in this invention, the substituent (R) 2 ) n A ring system formed by a single bond attached to a central ring represents n substituents R. 2 It can be substituted at any replaceable or reasonable position on the ring. For example, equation a represents that ring B can be replaced by n R. 2 Replace, n R 2 These represent substitutions performed at any replaceable or reasonable position on the ring, where n is greater than 1, and each R... 2 They can be independently selected from the same or different substituents.

[0074] Formula a As used in this invention, the term "prodrug" refers to the conversion of a compound into a compound represented by formula (I) or (I-1) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group.

[0075] "Metabolic products" refer to the products obtained from the metabolism of a specific compound or its salt in the body. The metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by subjecting the compound to oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0076] The term "pharmaceutically acceptable salt" as used in this invention refers to the organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in references such as SM Berge. et al. The invention describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed from non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobroms, phosphates, sulfates, and perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates, or obtained by other methods described in the literature, such as ion exchange. The invention also contemplates quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-C8 sulfonates, and aromatic sulfonates.

[0077] In this invention, "solvent" refers to an association formed by one or more solvent molecules and a compound of this invention. Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0078] When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of the compound of the present invention may bind to one water molecule, such as a monohydrate; in another embodiment, a molecule of the compound of the present invention may bind to more than one water molecule, such as a dihydrate; and in yet another embodiment, a molecule of the compound of the present invention may bind to fewer than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the non-hydrated form of the compound.

[0079] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters), or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0080] The term “prevention” or “protection” refers to the reduction of the risk of acquiring a disease or disorder (i.e., stopping the development of at least one clinical symptom of the disease in a subject who may be facing or predisposed to facing the disease, but has not yet experienced or exhibited symptoms of the disease).

[0081] The term "therapeutic effective dose" refers to the amount of a compound that is sufficient to treat a disease when administered to a subject. The "therapeutic effective dose" can vary depending on the compound, the disease and its severity, and the condition, age, weight, and sex of the subject being treated.

[0082] Unless otherwise stated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of this invention are included within the scope of this invention.

[0083] In the structures disclosed in this invention, when the stereochemistry of any particular chiral atom is not specified, all stereoisomers of that structure are considered within the scope of this invention and are included in this invention as disclosed compounds. When the stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of that structure are thus clearly defined.

[0084] The nitrogen oxides of the compounds of this invention are also included within the scope of this invention. The nitrogen oxides of the compounds of this invention can be prepared by oxidizing the corresponding nitrogen-containing basic substances in the presence of an acid, such as acetic acid, using a common oxidizing agent (e.g., hydrogen peroxide) at elevated temperature, or by reacting with a peracid in a suitable solvent, such as with peracetic acid in dichloromethane, ethyl acetate, or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

[0085] The compounds shown in formula (I) or (II) can exist in the form of salts.

[0086] Any structural formulas provided in this invention are intended to represent both the unenriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures described by the general formulas provided in this invention, except that one or more atoms are replaced by atoms having a chosen atomic weight or mass number. Exemplary isotopes that may be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as... 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0087] Description of the compounds of the present invention This invention provides a heteroaryl-substituted diaminocyclopentane derivative, or a pharmaceutical composition thereof, which can act as a PCSK9 inhibitor. This invention further relates to the use of said compound or pharmaceutical composition thereof in the preparation of a medicament that treats related diseases and / or conditions by inhibiting PCSK9 activity. The diseases or conditions include those described in this invention.

[0088] The excellent properties of certain parameters of the compounds of this invention, such as half-life, clearance rate, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, and solubility, can promote the reduction of side effects, the expansion of the therapeutic index, or the improvement of tolerability.

[0089] On the one hand, the present invention provides compounds of formula (I), or stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of compounds of formula (I). (I), Among them, Z 1 Z 2 Z 3 Z 4 Z 5 m, n, q, ring A, ring B, L, R 1 R 2 and R 3 Each has the definition as described in this invention; provided that the compound of formula (I) does not contain compound 6-(6-(((1) S ,3 S )-3-((5-(3-(difluoromethyl)cyclobutoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7 H -pyrrolo[3,4- b ]Pyridin-7-one and 6-(6-(((1) S ,3 S )-3-((5-(3,3-difluorocyclobutoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7 H -pyrrolo[3,4- b ]Pyridin-7-one.

[0090] In some implementation schemes, Z 1 Z 2 Z 3 Z 4 and Z 5 Each is independently N or CR 4 , among which, each R 4 It has the definition as described in this invention.

[0091] In some implementation schemes, each R 4 Independently, H, D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2.

[0092] In some implementation schemes, each R 4 Independently, H, D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, -NH(C) 1-4 alkyl) or -N(C)1-4 Alkyl)2.

[0093] In some implementation schemes, each R 4 Independently, it can be H, D, F, Cl, Br, I, CN, OH, NH2, COOH, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3 or -N(CH3)2.

[0094] In some implementations, L is -(CR) 5 R 6 ) r- R 5 and R 6 Each of the following is independently H, D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2, wherein r has the definition as described in this invention.

[0095] In some implementation schemes, R 5 and R 6 Each of the following is independently H, D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, -NH(C) 1-4 alkyl) or -N(C) 1-4 Alkyl)2.

[0096] In some implementation schemes, R 5 and R 6Each can be independently H, D, F, Cl, Br, I, CN, OH, NH2, COOH, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3 or -N(CH3)2.

[0097] In some implementations, m, n, q, and r are each independently 0, 1, 2, 3, or 4.

[0098] In some implementations, ring A is C. 3-7 Monocyclic cycloalkyl, C 5-12 Bridged cycloalkyl, C 5-12 Spirocyclic cycloalkyl, 3-7 membered monocyclic heterocyclic groups, 5-12 membered bridged heterocyclic groups, 5-12 membered spirocyclic heterocyclic groups, C 6-10 Aryl, 5-6 heteroaryl or 7-10 heteroaryl.

[0099] In some implementations, ring A is C. 3-6 Monocyclic cycloalkyl, C 4-10 Bridged cycloalkyl, C 4-10 Spirocyclic cycloalkyl, 3-6 membered monocyclic heterocyclic group, 5-10 membered bridged heterocyclic group, 5-10 membered spirocyclic heterocyclic group, phenyl, naphthyl, 5-6 membered heteroaryl or 7-10 membered heteroaryl.

[0100] In some embodiments, ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethylene, 1,4-dioxanecyclo, oxacyclobutyl, aziranecyclobutyl, thiohexanecyclobutyl, pyrrolyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidinyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptyl, 2-oxo-spiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, 1,4-dioxaspiro[4.4]nonyl, 5,8-oxaspiro[3.4]octyl, 1,1-dioxothiabutyl, 7-azirane[3.5]nonyl, 3-azibicyclo[3.1.0]hexyl, octahydrofuran[2,3- cPyridyl, dihydropyridyl, dihydropyrimidinyl, dihydropyridazinyl, 1,3-dihydro-2 H -imidazolyl, 1,3-dihydro-2 H -benzo[ d Imidazolyl, 1,3-dihydro-2 H -imidazo[ 4,5-b ]Pyridyl, 1,3-dihydro-2 H -imidazo[ 4,5-b ]Pyrazinyl, 5,6-dihydro-7 H -pyrrolo[3,4- b ]Pyridyl, 5,6-dihydro-7 H -pyrrolo[3,4- b [3.1.0]Pyridyl, dioxo-3-azabicyclo[3.1.0]hexyl, phenyl, naphthyl, pyrrolithyl, pyrazolyl, tetrazolyl, imidazolyl, furanyl, thiaranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridopyrimidinyl, benzopyridyl, pyridopyrrolithyl, benzopyrazolyl, pyrrolopyrazolyl or benzothiazolyl.

[0101] In some implementations, ring B is C. 3-7 Monocyclic cycloalkyl, C 5-12 Bridged cycloalkyl, C 5-12 Spirocyclic cycloalkyl, 3-7 membered monocyclic heterocyclic groups, 5-12 membered bridged heterocyclic groups, 5-12 membered spirocyclic heterocyclic groups, C 6-10 Aryl, 5-6 heteroaryl or 7-10 heteroaryl.

[0102] In some implementations, ring B is C. 3-6 Monocyclic cycloalkyl, C 5-10 Bridged cycloalkyl, C 5-10 Spirocyclic cycloalkyl, 3-6 membered monocyclic heterocyclic group, 5-10 membered bridged heterocyclic group, 5-10 membered spirocyclic heterocyclic group, phenyl, naphthyl, 5-6 membered heteroaryl or 7-10 membered heteroaryl.

[0103] In some embodiments, ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethylene, 1,4-dioxanecyclo, oxacyclobutyl, aziranecyclobutyl, thiohexanecyclobutyl, pyrrolyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidinyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, 2-oxaspiro[3.3]heptyl, 1,4-dioxaspiro[4.4]nonyl, 5,8-oxaspiro[3.4]octyl, 1,1-dioxothiabutyl, 1,1-dioxo-isothiazolin-2-yl, 7-azirane[3.5]nonyl, 3-azibicyclo[3.1.0]hexyl, octahydrofuran[2,3- cPyridyl, dihydropyridyl, dihydropyrimidinyl, dihydropyridazinyl, 1,3-dihydro-2 H -imidazolyl, 1,3-dihydro-2 H -benzo[ d Imidazolyl, 1,3-dihydro-2 H -imidazo[ 4,5-b ]Pyridyl, 1,3-dihydro-2 H -imidazo[ 4,5-b ]Pyrazinyl, 5,6-dihydro-7 H -pyrrolo[3,4- b ]Pyridyl, 5,6-dihydro-7 H -pyrrolo[3,4- b ]pyridyl, dioxo-3-azabicyclo[3.1.0]hexyl, oxooctahydrofuran[2,3- c Pyridyl, oxodihydropyridyl, oxodihydropyrimidinyl, oxodihydropyridazinyl, oxoimidazoalkyl, oxopyrrolidinyl, dioxopyrrolidinyl, dioxoimidazoalkyl, oxo-1,3-dihydro-2 H -imidazolyl, oxo-1,3-dihydro-2 H -benzo[ d Imidazolyl, oxo-1,3-dihydro-2 H -imidazo[ 4,5-b ]pyridyl, oxo-1,3-dihydro-2 H -imidazo[ 4,5-b ]Pyrazinyl, oxo-5,6-dihydro-7 H -pyrrolo[3,4- b ]Pyridyl, dioxo-5,6-dihydro-7 H -pyrrolo[3,4- b ]pyridyl, oxo-1,2-dihydroquinolinyl, 2-oxo-3,4-dihydro-1,8-naphthidyl-1-yl, oxo-1,2,3,4-tetrahydroquinolinyl, 2-oxo-1,3-dihydro-2H-pyrrolo[2,3- b Pyridine, phenyl, naphthyl, pyrrolyl, pyrazolyl, tetrazolyl, imidazolyl, furanyl, thiaranyl, pyridyl, oxopyridyl, oxopyrimidinyl, oxopyridazinyl, pyrimidinyl, pyridinyl, pyridopyrimidinyl, benzopyrimidinyl, benzopyridyl, pyridopyrroleyl, benzopyrazolyl, pyrrolopyrazolyl, or benzothiazolyl.

[0104] In some implementations, ring B is phenyl, , , , , , , , , , , , , , , , , , , , , , or ; In some implementation schemes, each R 1 Independently, it is H, D, F, Cl, Br, I, CN, OH, NH2, COOH, oxo, -C(=O)NR 7 R 8 -S(=O)2C 1-6 Alkyl group, -S(=O)C 1-6 Alkyl group, -C(=O)C 1-6 Alkyl group, -NHC(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 alkyl)2; wherein, R 7 and R 8 Each has the definition as described in this invention.

[0105] In some implementation schemes, each R 1 Independently, it is H, D, F, Cl, Br, I, CN, OH, NH2, COOH, oxo, -C(=O)NR 7 R 8 -S(=O)2C 1-4 Alkyl group, -S(=O)C 1-4 Alkyl group, -C(=O)C 1-4 Alkyl group, -NHC(=O)C 1-4 Alkyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Halogenated alkoxy C 1-4 Alkyl, -NH(C) 1-4 alkyl) or -N(C) 1-4 alkyl)2; wherein, R 7 and R 8 Each has the definition as described in this invention.

[0106] In some implementation schemes, each R 1 Independently, it is H, D, F, Cl, Br, I, CN, OH, NH2, COOH, oxo, -C(=O)NR 7 R 8 , -S(=O)2CH3, -S(=O)CH3, -C(=O)CH3, -NHC(=O)CH3, -NHC(=O)CH2CH3, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH 2C(CH3)3, -CH≡CH, -CH≡CCH3, -CH2C≡CH, -(CH2)2C≡CH, -C=CH2, -(CH2)2C=CH2, -CH2=CHCH3, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, - OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -CH2OCH3, -(CH2) 2OCH3, -CH2OCH2CH3, -(CH2)2OCH2CH3, -(CH2)3OCH3, -CH2OCF3, -(CH2)2OCF3, -CH2OCH2CF3, -(CH2)2OCH2CF3, -(CH2)3OCF3 or -CH2OCHFCF3; where, R 7 and R 8 Each has the definition as described in this invention.

[0107] In some implementation schemes, R 7 and R 8 Each is independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0108] In some implementation schemes, R 7 and R 8 Each is independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0109] In some implementation schemes, R 7 and R 8 Each can be independently H, D, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, phenyl, pyrrolyl, pyrazolyl, tetrazolyl, imidazolyl, furanyl, thiaranyl, pyridinyl, pyrimidinyl, or pyrazinyl.

[0110] In some implementations, two R atoms bonded to the same carbon atom 1 Formed together with this carbon atom , where R a and R b Each has the definition as defined in this invention.

[0111] In some implementation schemes, R a and R b Each of them independently is H, D, F, Cl, Br, I, CN, NH2, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups, -NH(C 1-6 alkyl) or -N(C) 1-6 Alkyl)2.

[0112] In some implementation schemes, R a and R b Each of them independently is H, D, F, Cl, Br, I, CN, NH2, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups, -NH(C 1-4 alkyl) or -N(C) 1-4 Alkyl)2.

[0113] In some implementation schemes, R a and R bEach can be independently H, D, F, Cl, Br, I, CN, NH2-CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3 or -N(CH3)2.

[0114] In some implementation schemes, each R 2 Independently, H, D, F, Cl, Br, I, CN, OH, NR 7 R 8 COOH, oxo, -C(=O)NR 7 R 8 -S(=O)2C 1-6 Alkyl group, -S(=O)C 1-6 Alkyl group, -C(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally bounded by 1, 2, 3 or 4 R groups. c Replaced, of which R7 R 8 and R c Each has the definition as described in this invention.

[0115] In some implementation schemes, each R 2 Independently, H, D, F, Cl, Br, I, CN, OH, NR 7 R 8 COOH, oxo, -C(=O)NR 7 R 8 -S(=O)2C 1-4 Alkyl group, -S(=O)C 1-4 Alkyl group, -C(=O)C 1-4 Alkyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Halogenated alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Halogenated alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, phenyl, and 5-6-membered heteroaryl groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. c Replaced, of which R 7 R 8 and R c Each has the definition as described in this invention.

[0116] In some implementation schemes, each R 2 Independently, H, D, F, Cl, Br, I, CN, OH, NR 7 R 8 COOH, oxo, -C(=O)NR 7 R 8, -S(=O)2CH3, -S(=O)CH3, -C(=O)CH3, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, - CH2CH(CH3)2, -CH2C(CH3)3, -C=CH2, -(CH2)2C=CH2, -CH2=CHCH3, -CH≡CH, -CH≡CCH3, -CH2C≡C H, -(CH2)2C≡CH, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -OCH3, -OCH2CH3, -O(CH2 )2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -OCF3, -OCH2F, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHFCHF2 , -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -CH2OCH3, -(CH2)2OCH3, - CH2OCH2CH3, -(CH2)2OCH2CH3, -(CH2)3OCH3, -CH2OCF3, -(CH2)2OCF3, -CH2OCH2CF3, -(CH2)2 OCH2CF3, -(CH2)3OCF3, -CH2OCHFCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethylene, 1,4-dioxanecycloyl, oxacyclobutyl, aziranecyclobutyl, thioheranecyclobutyl, pyrrolidinyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, phenyl, pyrazolyl, tetrazolyl, imidazolyl, furanyl, thiaranyl, pyridinyl, pyrimidinyl or pyrazinyl;The following are some of the following: -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -C=CH2, -(CH2)2C=CH2, -CH2=CHCH3, -CH≡CH, -CH≡CCH3, -CH2C≡CH, -(CH2)2C≡CH, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -OCH2F, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHFCHF2, -CH2OH, -(CH2)2OH, -(CH2)2CH 2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -CH2OCH3, -(CH2)2OCH3, -CH2OCH2CH3, -(CH2)2OCH2CH 3. -(CH2)3OCH3, -CH2OCF3, -(CH2)2OCF3, -CH2OCH2CF3, -(CH2)2OCH2CF3, -(CH2)3OCF3, -C H2OCHFCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethylene, 1,4-dioxanecyclo, oxacyclobutyl, azirhexacyclobutyl, thiohexacyclobutyl, pyrrolidinyl, pyrazolyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, phenyl, pyrazolyl, tetrazolyl, imidazolidinyl, furanyl, thiaranyl, pyridinyl, pyrimidinyl, and pyrazinyl are each independently and optionally marked with 1, 2, 3, or 4 Rs; c Replaced, of which R 7 R 8 and R c Each has the definition as described in this invention.

[0117] In some implementation schemes, each R c Independently, they are D, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups, -NH(C 1-6 alkyl) or -N(C) 1-6 Alkyl)2.

[0118] In some implementation schemes, each R c Independently, they are D, F, Cl, Br, I, CN, OH, NH2, and C. 1-4 Alkyl group, -S(=O)2C 1-4 Alkyl, C1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups, -NH(C) 1-4 alkyl) or -N(C) 1-4 Alkyl)2.

[0119] In some implementation schemes, each R c Independently, it can be D, F, Cl, Br, I, CN, OH, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -S(=O)2CH3, -S(=O)2CH2CH3, -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3 or -N(CH3)2.

[0120] In some implementation schemes, each R 3 Independently, it is H, D, F, Cl, Br, I, CN, OH, NH2, COOH, oxo, -C(=O)NR 7 R 8 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 alkyl)2, wherein, R 7 and R 8 Each has the definition as described in this invention.

[0121] In some implementation schemes, each R 3 Independently, it is H, D, F, Cl, Br, I, CN, OH, NH2, COOH, oxo, -C(=O)NR 7 R 8 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Halogenated alkoxy C 1-4 Alkyl, -NH(C) 1-4 alkyl) or -N(C) 1-4 alkyl)2, wherein, R 7 and R 8 Each has the definition as described in this invention.

[0122] In some implementation schemes, each R 3 Independently, it can be H, D, F, Cl, Br, I, CN, OH, NH2, COOH, oxo, -C(=O)NH2, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CH≡CH, -CH≡CCH3, -CH2C≡CH, -(CH2)2C≡CH, -C=CH2, -(CH2)2C=CH2, -CH2=CHCH3, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3) 2. -OC(CH2)3CH3, -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -CH2OCH3, -(CH2)2OCH3, -CH2OCH2CH3, -(CH2) 2OCH2CH3, -(CH2)3OCH3, -CH2OCF3, -(CH2)2OCF3, -CH2OCH2CF3, -(CH2)2OCH2CF3, -(CH2)3OCF3 or -CH2OCHFCF3, -NHCH3 or -N(CH3)2.

[0123] In some embodiments, the compound of the present invention is the compound shown in (II), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the compound shown in (II). (II), Among them, Z 1 Z 2 Z 3 Z 4 Z 5 m, n, q, ring A, ring B, L, R 1 R 2 and R 3Each has the definition as described in this invention.

[0124] In some embodiments, the compound of the present invention is the compound shown in formula (IIa), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the compound shown in formula (IIa). (IIa), Among them, Z 1 Z 2 Z 3 Z 4 Z 5 m, n, q, ring A, ring B, R 1 R 2 and R 3 Each has the definition as described in this invention.

[0125] In some embodiments, the compound of the present invention is the compound shown in (IIb), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the compound shown in formula (IIb). (IIb), Among them, Z 1 Z 2 Z 3 Z 4 Z 5 m, n, q, ring B, R 1 R 2 and R 3 Each has the definition as described in this invention; Ring A 1 C 5-12 Bridged cycloalkyl, C 5-12 Spirocyclic cycloalkyl, 3-7 membered monocyclic heterocyclic group, 5-12 membered bridged heterocyclic group or 5-12 membered spirocyclic heterocyclic group.

[0126] In some implementation schemes, ring A 1 C 4-10 Bridged cycloalkyl, C 4-10 Spirocyclic cycloalkyl, 3-6 membered monocyclic heterocyclic group, 5-10 membered bridged heterocyclic group or 5-10 membered spirocyclic heterocyclic group.

[0127] In some implementation schemes, ring A 1The compounds are 1,2-epoxyethylene, 1,4-dioxane, oxetane, azirane, thiohexacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidinyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptyl, 2-oxo-spiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, 1,4-dioxaspiro[4.4]nonyl, 5,8-oxaspiro[3.4]octyl, 1,1-dioxothiabutyl, 7-azirane[3.5]nonyl, 3-azibicyclo[3.1.0]hexyl, octahydrofuran[2,3- c Pyridyl, dihydropyridyl, dihydropyrimidinyl, dihydropyridazinyl, 1,3-dihydro-2 H -imidazolyl, 1,3-dihydro-2 H -benzo[ d Imidazolyl, 1,3-dihydro-2 H -imidazo[ 4,5-b ]Pyridyl, 1,3-dihydro-2 H -imidazo[ 4,5-b ]Pyrazinyl, 5,6-dihydro-7 H -pyrrolo[3,4- b ]Pyridyl, 5,6-dihydro-7 H -pyrrolo[3,4- b ]pyridyl or dioxo-3-azabicyclo[3.1.0]hexyl.

[0128] In some embodiments, the compounds of this invention are compounds with the following structures, or stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs, or the following structures. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0129] On the other hand, the present invention provides a pharmaceutical composition comprising the compound described herein, or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

[0130] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient.

[0131] In some embodiments, the excipients described in this invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof. In some embodiments, the pharmaceutical composition may be a liquid, solid, semi-solid, gel, or spray formulation.

[0132] On the other hand, the present invention provides the use of the pharmaceutical composition described herein in the preparation of a medicament for the prevention, treatment or relief of PCSK9-related diseases.

[0133] The present invention further relates to any stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug of any of the compounds of general formula (I) shown, or the use of the pharmaceutical composition thereof in the preparation of an LDL-lowering drug; preferably, the LDL is LDL-C.

[0134] In some embodiments, the PCSK9-related diseases described in this invention are cardiovascular diseases, cerebrovascular diseases, and atherosclerosis-related diseases.

[0135] In some embodiments, the PCSK9-related diseases described in this invention are stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, vascular stenosis, chronic kidney disease, coronary heart disease, heart failure, atherosclerosis, hepatic steatosis, metabolic syndrome, and / or coronary artery disease.

[0136] In some embodiments, the compound of the present invention, or its stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs, constitute 0.01% to 99.9%, 0.1% to 99.5%, 0.1% to 95%, 0.5% to 85%, 1% to 60%, 10% to 50%, 15% to 40%, 20% to 30%, or 20% to 25% (based on the total weight of the pharmaceutical composition) in the composition.

[0137] On the other hand, the present invention also provides a method for preventing or treating PCSK9-related diseases, the method comprising administering to a patient a therapeutically effective amount of the compound or pharmaceutical composition thereof described in the present invention.

[0138] In some implementations, the patient has a gain-of-function mutation in the PCSK9 gene.

[0139] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds of formula (I), (II), (IIa) or (IIb).

[0140] Unless otherwise indicated, all stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds of this invention are within the scope of the compounds of this invention.

[0141] Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" includes the requirement that the substance or composition be chemically or toxically unsuitable. Physiology relates to the other components that make up the formulation and the mammals used for treatment.

[0142] The salts of the compounds of the present invention also include salts of intermediates used for the preparation or purification of compounds of formula (I), (II), (IIa) or (IIb) or enantiomers isolated from compounds of formula (I), (II), (IIa) or (IIb), but are not necessarily pharmaceutically acceptable salts.

[0143] Formulation, administration and use of pharmaceutical compositions of the compounds of the present invention The pharmaceutical compositions of the present invention are characterized by compounds represented by formulas (I), (II), (IIa), or (IIb), compounds listed in the present invention, or compounds of the examples, and pharmaceutically acceptable carriers. The amounts of compounds in the pharmaceutical compositions of the present invention are effective in treating or alleviating PCSK9 in patients.

[0144] The compounds of the present invention exist in free form or as suitable, pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be administered directly or indirectly as needed by a patient, compounds described in other aspects of the present invention, their metabolites, or their residues.

[0145] As described in this invention, pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable excipients, such as those used in this invention, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988-1999, Marcel Dekker, New York, the contents of which, taken together, show that various excipients can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. The use of any conventional excipients, except those incompatible with the compounds of the present invention, such as any adverse biological effects or harmful interactions with any other component of the pharmaceutically acceptable composition, is also within the scope of this invention.

[0146] Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. Sodium thiosulfate, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and spices, preservatives and antioxidants.

[0147] In preparing the pharmaceutical compositions provided by this invention, the active ingredient is typically mixed with an excipient, diluted by the excipient, or packaged in a carrier, such as a capsule, sachet, paper, or other container. If the excipient is used as a diluent, it can be a solid, semi-solid, or liquid material, serving as a carrier, container, or medium for the active ingredient. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, low-melting-point wax, cocoa butter, etc. Therefore, the composition can be in the form of tablets, pills, powders, lozenges, capsules, flat capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), such as ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterilely packaged powders. In one embodiment, the composition is formulated for oral administration. In one embodiment, the composition is formulated as a tablet or capsule.

[0148] The compounds or pharmaceutical compositions of this invention can be administered in oral dosage forms, such as tablets, capsules (each comprising a sustained-release or timed-release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsifiers. They can also be administered intravenously (in pills or infusions), intraperitoneally, subcutaneously, or intramuscularly, all dosage forms used being well known to those skilled in the art of pharmacy. They can be administered alone, but generally a pharmaceutical carrier will be selected for co-administration based on the chosen route of administration and standard pharmaceutical practice.

[0149] The compounds or pharmaceutical compositions of the present invention can be administered intranasally via a suitable intranasal carrier or transdermally via a transdermal patch. When administered via a transdermal delivery system, the dose is continuous rather than intermittent throughout the course of treatment.

[0150] The compounds or pharmaceutical compositions of the present invention can also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearamine, or phosphatidylcholine.

[0151] The compounds or pharmaceutical compositions of the present invention are also coupled with soluble polymers that act as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylate-phenol, polyhydroxyethyl asparagine, or polyvinyl oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention can be coupled with a class of biodegradable polymers for controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polycaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic blocking copolymers of hydrogels.

[0152] The dosing regimen of the compounds or pharmaceutical compositions of this invention will vary depending on a variety of known factors, such as the pharmacokinetic characteristics and patterns of administration of the specific agent; the recipient's race, age, sex, health status, medical condition, and weight; the nature and severity of symptoms; the types of concurrent treatments; the frequency of treatment; the route of administration; the patient's renal and hepatic function; and the desired effect. A physician or veterinarian can make a decision and prescribe an effective amount of the drug to prevent, counteract, or halt the development of cancer.

[0153] According to general guidelines, in order to achieve the specified effect, the dosage of each active ingredient used is in the range of approximately 0.001 to 1000 mg / kg body weight per day, preferably between approximately 0.01 and 100 mg / kg body weight. The compounds of the present invention can be administered once daily, or in two, three, or four divided doses per day.

[0154] Each unit dose of a suitable dosage form (pharmaceutical composition) may contain from about 1 mg to about 100 mg of the active ingredient. In these pharmaceutical compositions, the weight of the active ingredient will generally account for about 0.01% to 99.9%, 0.1% to 99.5%, or 0.1% to 95% of the total weight of the composition.

[0155] The compounds and compositions described in this invention can be administered alone or in combination with other compounds or other therapeutic agents. The compounds or compositions of this invention can be administered simultaneously or sequentially with other therapeutic agents via the same or different routes of administration. The compounds of this invention can be included in a single formulation along with other therapeutic agents or in a separate formulation.

[0156] When the compounds of the present invention are administered together with other therapeutic agents, the amount of each component in a typical daily dose and typical dosage form may generally be reduced relative to the usual dose when administered alone, taking into account the additional or synergistic effects of the therapeutic agents when administered in combination.

[0157] The compounds, pharmaceutical salts, hydrates, or pharmaceutical compositions thereof involved in this invention are effective in preventing, treating, or alleviating PCSK9-related diseases in patients.

[0158] In some implementations, PCSK9-related diseases include, but are not limited to, cardiovascular diseases, cerebrovascular diseases, and atherosclerosis-related diseases.

[0159] In some implementation schemes, PCSK9-related diseases include stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, vascular stenosis, chronic kidney disease, coronary heart disease, heart failure, atherosclerosis, hepatic steatosis, metabolic syndrome, and / or coronary artery disease.

[0160] General Synthesis Process To describe this invention, the following embodiments will be used to further illustrate the technical solution of this invention. These embodiments are only used to illustrate specific implementation methods of this invention so that those skilled in the art can understand it, but are not intended to limit the scope of protection of this invention. In the specific implementation methods of this invention, technical means or methods not specifically described are conventional technical means or methods in the art.

[0161] Unless otherwise specified, the substituents are defined as described in this invention. The following reaction schemes and examples are provided to further illustrate the content of this invention.

[0162] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0163] In the examples described below, unless otherwise specified, all temperatures are in degrees Celsius (°C). Room temperature in the examples represents 15 °C–30 °C; in some examples, room temperature is 20 °C–30 °C. Reagents were purchased from commodity suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company and were used without further purification. Unless otherwise specified, general reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Plant, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Plant.

[0164] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether are obtained by reflux drying with metallic sodium. Anhydrous dichloromethane and chloroform are obtained by reflux drying with calcium hydride. Ethyl acetate, petroleum ether, and n-hexane... N , N -dimethylacetamide and N , N - Dimethylformamide is used after being dried with anhydrous sodium sulfate.

[0165] The following reactions are generally carried out under positive pressure of nitrogen or argon or with a drying tube attached to an anhydrous solvent (unless otherwise specified). All reaction flasks are sealed with suitable rubber stoppers, and the substrate is injected using a syringe. All glassware is dried.

[0166] The chromatographic column used was a silica gel column. The silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0167] 1H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. 1 ¹H NMR spectra with CDCl₃ and DMSO- d 6. CD3OD or acetone - d 6 represents the solvent (in ppm), with TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When multiplets are observed, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), br s (broadened singlet), dd (doublet of doublets), dt (doublet of triplets). Coupling constant. J It is represented by Hertz (Hz).

[0168] The determination conditions for low-resolution mass spectrometry (MS) data were as follows: Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 μm, 6 min, flow rate: 0.6 mL / min; mobile phase: 5%–95% (CH3CN containing 0.1% formic acid) in (H2O containing 0.1% formic acid), electrospray ionization (ESI) at 210 nm / 254 nm, detection by UV.

[0169] Pure compounds were detected using UV at 210 nm / 254 nm using an Agilent 1260 pre-HPLC or a Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80 mm DAC).

[0170] The following English or abbreviation terms are used throughout this invention:

[0171] Synthesis scheme Synthesis of compound (II)

[0172] Compound (II) can be synthesized according to the above-described scheme, wherein Hal is a halogen, preferably Cl and Br, and Z 1 Z 2 Z 3Z 4 Z 5 m, n, q, ring A, ring B, L, R 1 R 2 and R 3 Each has the definition as described in this invention. Compound (II) is obtained by coupling reaction of compound (II-1) and compound (II-2) or the hydrochloride salt of compound (II-2) under suitable conditions (e.g., in a dioxane solvent under the action of t-BuOK and tBrettXPhos).

[0173] The following examples further illustrate the compounds, pharmaceutical compositions, and their applications provided by the present invention.

[0174] Example Example 1: 6'-(((1) S ,3 S )-3-((5-(3-(difluoromethylene)cyclobutoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2 H Synthesis of 1,3'-bipyridine]-2-one (compound 1) Compound 1

[0175] Step 1: ((1) S ,3 S Synthesis of tert-butyl 3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate ((1) S ,3 S 4.00 g (19.97 mmol) of tert-butyl 3-aminocyclopentylcarbamate was dissolved in DMSO (25 mL), followed by the addition of 2-fluoro-5-iodopyridine (5.34 g, 23.96 mmol) and DIPEA (5.16 g, 39.94 mmol). The mixture was heated to 120 °C and reacted for approximately 5 h. TLC analysis confirmed complete reaction of the starting material, and the reaction was stopped. The reaction solution was poured into 200 mL of water and extracted with ethyl acetate (200 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The solution was purified by column chromatography (PE:EA(v:v) = 20:3), and the eluents were combined and evaporated to dryness to obtain 6.05 g of a yellowish-white solid, yield 75.12%. MS (ESI, pos. ion) m / z: 404.1 [M+H] + . Step 2: ((1) S ,3 S )-3-((2-Oxo-2 HSynthesis of tert-butyl 1,3'-bipyridine]-6'-yl)amino)cyclopentyl)carbamate ((1) S ,3 S 3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate tert-butyl ester (6.00 g, 14.88 mmol), 1,2-dihydropyridin-2-one (3.11 g, 32.74 mmol), trans- N , N '-Dimethylcyclohexane-1,2-diamine (0.74 g, 5.21 mmol), cuprous iodide (0.85 g, 4.46 mmol), and potassium phosphate (4.74 g, 22.32 mmol) were dissolved in DMSO (50 mL), and the mixture was heated to 120 °C under nitrogen protection for approximately 5 h. TLC analysis showed complete reaction of the starting material, and the reaction was stopped. The mixture was extracted with 200 mL of water and 200 mL of ethyl acetate, washed with saturated brine, and the organic phases were combined and concentrated. The solution was purified by column chromatography (PE:EA(v:v) = 3:1), and the eluents were combined and evaporated to dryness to give 3.6 g of a yellow solid, with a yield of 65.31%. MS (ESI, pos. ion) m / z: 371.2 [M+H] + . Step 3: 6'-(((1) S ,3 S )-3-aminocyclopentyl)amino-2 H Synthesis of 1,3'-bipyridine]-2-one hydrochloride Add (1) to a 50 mL flask S ,3 S )-3-((2-Oxo-2 H 3.7 g (9.99 mmol) of tert-butyl [1,3'-bipyridine]-6'-yl)amino)cyclopentyl)carbamate, 5 mL of 1,4-dioxane, and a solution of 1,4-dioxane in hydrogen chloride (3.64 g, 99.9 mmol, 4 mol / L) were reacted at room temperature for 4 h. The solution was evaporated to dryness and slurried with EA (20 mL) to give 2.70 g of brown hydrochloride solid, yield 66.67%. MS (ESI, pos. ion) m / z: 271.2 [M+H] + . Step 4: Synthesis of 3-(benzyloxy)-1-(difluoro(pyridin-2-ylsulfonyl)methyl)cyclobutylcarboxylchloro-1-ol 3-(benzyloxy)cyclobutane-1-one (3 g, 17.03 mmol) and 2-[(difluoromethyl)sulfonyl]pyridine (2.30 g, 11.92 mmol) were dissolved in...N , N Dimethylformamide (20 mL) was added, cooled to -50 °C, and under nitrogen protection, potassium tert-butyrate (0.13 g, 1.14 mmol) was added, and the reaction was allowed to proceed for 1 h. TLC analysis showed complete reaction of the starting material, and the reaction was stopped. The mixture was quenched with dilute hydrochloric acid (20 mL, 2 mol / L). Water (200 mL) was added, and the mixture was extracted with EA (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography purification was performed (PE:EA = 3:2), and the eluents were combined and evaporated to dryness to give 1.9 g of a brownish-red liquid, yielding 30.29%. MS (ESI, pos. ion) m / z: 370.1 [M+H] + . Step 5: Synthesis of ((3-(difluoromethylene)cyclobutoxy)methyl)benzene Add 1.7 g (4.61 mmol) of 3-(benzyloxy)-1-(difluoro(pyridin-2-ylsulfonyl)methyl)cyclobutylcarboxychloro-1-ol to a 50 mL orbicular flask and N , N Dimethylformamide (15 mL) was added dropwise with concentrated hydrochloric acid (3.36 g, 92.2 mmol) under nitrogen protection at 130 °C for 3 h. TLC analysis showed complete reaction of the starting material and a distinct product spot. The reaction was stopped. 100 mL of water was added, and the mixture was extracted with EA (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography purification was performed (PE:EA(v:v) = 50:1). The eluents were combined, evaporated to dryness, and 300 mg of colorless liquid was obtained, yielding 30.92%. 1 H NMR (400MHz, CDCl3) δ 7.42 – 7.30 (m, 5H), 4.46 (d, J = 7.9 Hz, 2H), 4.19 (p, J = 6.5Hz, 1H), .99 – 2.86 (m, 2H), 2.71 (tt, J = 10.6, 5.2 Hz, 2H). Step 6: Synthesis of 3-(difluoromethylene)cyclobutane-1-ol In a 25 mL two-necked flask, ((3-(difluoromethylene)cyclobutoxy)methyl)benzene (0.6 g, 2.85 mmol) and DCM (3 mL) were added. The mixture was cooled to -78 °C and, under nitrogen protection, boron tribromide (1.43 g, 5.7 mmol) was added dropwise. The reaction was allowed to proceed for 30 min. TLC analysis showed that the starting material reacted completely and the product spot was clearly visible. The reaction was stopped. The mixture was quenched with saturated sodium bicarbonate solution (10 mL), extracted with DCM (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The solution was purified by column chromatography (PE:EA(v:v) = 3:1), and the eluents were combined and evaporated to dryness to give 160 mg of colorless liquid, with a yield of 46.68%.

[0176] Step 7: Synthesis of 3-(difluoromethylene)cyclobutyl 4-methylbenzenesulfonate 3-(difluoromethylene)cyclobutane-1-ol (0.20 g, 1.67 mmol) and dichloromethane (5 mL) were added to a 50 mL round-bottom flask. Sodium hydride (0.10 g, 2.50 mmol) was added at 0 °C, and the reaction was allowed to proceed for 30 min. Then, p-toluenesulfonyl chloride (0.38 g, 2.00 mmol) was added, and the reaction was allowed to proceed at room temperature. TLC analysis showed that the starting material reacted completely, and the product spot was clearly visible. The reaction was stopped. The mixture was quenched with water (10 mL), extracted with DCM (20 mL), washed with saturated sodium bicarbonate and saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The solution was purified by column chromatography (PE:EA(v:v) = 10:1), and the eluents were combined and evaporated to dryness to give 210 mg of colorless liquid, yield 52.54%. MS (ESI, pos. ion) m / z: 275.0 [M+H] + . Step 8: Synthesis of 2-chloro-5-(3-(difluoromethylene)cyclobutoxy)pyrimidine Add 3-(difluoromethylene)cyclobutyl 4-methylbenzene-1-sulfonate (0.32 g, 1.17 mmol), 2-chloropyrimidin-5-ol (0.18 g, 1.40 mmol), and cesium carbonate (0.57 g, 1.75 mmol) to a 50 mL round-bottom flask, and dissolve in... N , N - Dimethylformamide (5 mL) was reacted at 120 °C. TLC analysis showed complete reaction of the starting material and a distinct product spot. The reaction was stopped. 30 mL of water was added, and the mixture was extracted with EA (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography purification was performed (PE:EA (v:v) = 8:1). The eluates were combined and evaporated to dryness to give 150 mg of white solid, yield 55.27%. MS (ESI, pos. ion) m / z: 233.1 [M+H]+ . Step 9: 6'-(((1) S ,3 S )-3-((5-(3-(difluoromethylene)cyclobutoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2 H Synthesis of 1,3'-bipyridine]-2-one Add 2-chloro-5-(3-(difluoromethylene)cyclobutoxy)pyrimidine (0.12 g, 0.52 mmol) and 6'-(((1) to a 25 mL two-necked flask. S ,3 S )-3-aminocyclopentyl)amino-2 H -[1,3'-bipyridine]-2-one hydrochloride (0.21 g, 0.62 mmol), potassium tert-butoxide (0.18 g, 1.56 mmol), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.083 g, 0.10 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction was carried out under nitrogen protection at 110 °C. TLC analysis showed that the starting material reacted completely and the product spot was clear. The reaction was stopped. The mixture was filtered, the solvent was evaporated to dryness, water (20 mL) was added, and the mixture was extracted with DCM (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Thin-layer chromatography purification (DCM:MeOH (v:v) = 25:1), eluents combined, evaporated to dryness, yield 25 mg of yellow solid, 10.39% yield. MS (ESI, pos. ion) m / z: 467.0 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ8.02 (d, J = 24.1 Hz, 3H), 7.53 (d, J = 6.4 Hz, 1H), 7.41 (s, 1H), 7.29 (s,1H), 6.66 (d, J = 8.8 Hz, 1H), 6.46 (d, J = 7.6 Hz, 1H), 6.25 (s, 1H), 5.05(s, 1H), 4.93 (s, 1H), 4.67 (s, 1H), 4.39 (s, 1H), 4.26 (s, 1H), 3.11 (s,2H), 2.87 (s, 2H), 2.33 (s, 2H), 2.04 (s, 2H), 1.59 (s, 2H). Example 2: 6'-(((1S,3S)-3-((5-((1-(trifluoromethyl)cyclopropyl)methoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2 H Synthesis of -[1,3'-bipyridine]-2-one (compound 2) Compound 2

[0177] Step 1: Synthesis of 2-chloro-5-((1-(trifluoromethyl)cyclopropyl)methoxy)pyrimidine In a 50 mL round-bottom flask, 2-chloropyrimidin-5-ol (0.2 g, 1.53 mmol), 1-(bromomethyl)-1-(trifluoromethyl)cyclopropane (0.31 g, 1.53 mmol), and cesium carbonate (1.30 g, 3.97 mmol) were added to DMF (3 mL), and the reaction was carried out at 70 °C. TLC analysis showed that the starting material reacted completely, and the product spot was clearly visible. The reaction was stopped. Water (30 mL) was added, and the mixture was extracted with EA (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by column chromatography (PE:EA(v:v) = 9:1), and the eluents were combined and evaporated to dryness to give 220 mg of white solid, yield 56.84%.

[0178] Step 2: 6'-(((1S,3S)-3-((5-((1-(trifluoromethyl)cyclopropyl)methoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2 H Synthesis of 1,3'-bipyridine]-2-one Add 0.12 g (0.48 mmol) of 2-chloro-5-((1-(trifluoromethyl)cyclopropyl)methoxy)pyrimidine and 6'-(((1)-(trifluoromethyl)cyclopropyl)methoxy)pyrimidine to a 25 mL two-necked flask. S ,3 S )-3-aminocyclopentyl)amino-2 H-[1,3'-bipyridine]-2-one hydrochloride (0.20 g, 0.58 mmol, Example 1, step 3), potassium tert-butoxide (0.16 g, 1.44 mmol), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.076 g, 0.096 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction was carried out under nitrogen protection at 110 °C for 8 h. TLC analysis showed that the starting material reacted completely and the product spot was distinct. The reaction was stopped. The mixture was filtered, the solvent was evaporated, and the product was extracted with DCM (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was purified by column chromatography (DCM:MeOH = 25:1) to give 20 mg of a yellowish-white solid, yield 8.65%. MS(ESI, pos. ion) m / z: 487.0 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.08 (s, 3H), 7.54 (d, J = 7.8 Hz, 1H), 7.46 – 7.37 (m, 1H), 7.32 (d, J = 6.4 Hz, 1H), 6.67 (d,J = 9.0 Hz, 1H), 6.47 (d, J = 8.3 Hz, 1H), 6.26 (t, J = 6.4 Hz, 1H), 5.06 (s,1H), 4.93 (s, 1H), 4.40 (d, J = 6.2 Hz, 1H), 4.26 (d, J = 5.6 Hz, 1H), 4.04(s, 2H), 2.34 (d, J = 4.6 Hz, 2H), 2.05 (d, J = 6.5 Hz, 2H), 1.59 (s, 2H), 1.17 (s, 2H), 0.91 (s, 2H). Example 3: 6'-(((1) S ,3 S )-3-((5-((1-methylcyclopropyl)methoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2 H Synthesis of -[1,3'-bipyrimidine]-2-one (compound 3) Compound 3

[0179] Step 1: Synthesis of (1-methylcyclopropyl)methylmethanesulfonate In a 50 mL round-bottom flask, 0.5 g (1-methylcyclopropyl)methanol (5.81 mmol) was added and dissolved in 5 mL dichloromethane. Triethylamine (0.88 g, 8.71 mmol) was added at 0 °C, followed by dropwise addition of methanesulfonyl chloride (0.67 g, 5.81 mmol). After the addition was complete, the reaction was allowed to proceed at room temperature for 3 h. TLC analysis showed that the starting material had reacted completely, and the reaction was stopped. 20 mL of water was added, and the mixture was extracted with DCM (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. 860 mg of a colorless liquid was obtained, with a yield of 90.21%.

[0180] Step 2: Synthesis of 2-chloro-5-((1-methylcyclopropyl)methoxy)pyrimidine In a 50 mL round-bottom flask, 2-chloropyrimidin-5-ol (1.3 g, 9.96 mmol), (1-methylcyclopropyl)methylmethanesulfonate (0.82 g, 4.98 mmol), and cesium carbonate (4.87 g, 14.94 mmol) were added and dissolved in DMF (10 mL). The reaction was carried out at 110 °C. TLC analysis showed that the starting material reacted completely, and the product spot was clearly visible. The reaction was stopped. Water (40 mL) was added, and the mixture was extracted with EA (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by column chromatography (PE:EA = 6:1), and the eluents were combined and evaporated to dryness to give 400 mg of white solid, with a yield of 20.22%. MS (ESI, pos. ion) m / z: 199.1 [M+H] + . Step 3: 6'-(((1) S ,3 S )-3-((5-((1-methylcyclopropyl)methoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2 H Synthesis of 1,3'-bipyrimidine]-2-one Add 2-chloro-5-((1-methylcyclopropyl)methoxy)pyrimidine (0.20 g, 1.01 mmol) and 6'-(((1)-methylcyclopropyl)methoxy)pyrimidine to a 25 mL two-necked flask. S ,3 S )-3-aminocyclopentyl)amino-2 H-[1,3'-bipyridine]-2-one hydrochloride (0.42 g, 1.21 mmol, Example 1, step 3), potassium tert-butoxide (0.34 g, 3.03 mmol), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.16 g, 0.20 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction was carried out under nitrogen protection at 110 °C for 8 h. TLC analysis showed that the starting material had reacted completely, and the reaction was stopped. The mixture was filtered, the solvent was evaporated, 20 mL of water was added, and the mixture was extracted with DCM (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by column chromatography (DCM:MeOH = 25:1) to give 50 mg of a yellowish-white solid, with a yield of 11.48%. MS (ESI,pos. ion) m / z: 433.1[M+H] + ; 1 H NMR (599 MHz, CDCl3) δ 8.10 – 8.02 (m, 3H), 7.53 (dd, J = 8.8, 2.6 Hz, 1H), 7.41 (ddd, J = 8.9, 6.6, 2.0 Hz, 1H), 7.31 (dd, J= 6.8, 1.6 Hz, 1H), 6.66 (d, J = 9.2 Hz, 1H), 6.46 (d, J = 8.9 Hz, 1H), 6.25(td, J = 6.7, 0.9 Hz, 1H), 4.94 (d, J = 6.8 Hz, 1H), 4.86 (d, J = 6.3 Hz,1H), 4.40 (dq, J = 13.3, 6.7 Hz, 1H), 4.26 (dq, J = 12.8, 6.3 Hz, 1H), 3.71(s, 2H), 2.34 (dq, J = 12.1, 7.4 Hz, 2H), 2.08 – 2.00 (m, 2H), 1.62 – 1.54(m, 2H), 1.25 (s, 3H), 0.56 – 0.50 (m, 2H), 0.48 – 0.42 (m, 2H). Example 4: N -Methyl-3-(((2-(((1) S ,3 S )-3-((2-Oxo-2 HSynthesis of -[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)pyrimidin-5-yl)oxy)methyl)bicyclo[1.1.1]pentane-1-aminocarboxamide (compound 4) Compound 4

[0181] Step 1: Synthesis of methyl 3-((4-methoxybenzyl)(methyl)carbamoyl)bicyclo[1.1.1]pentane-1-carboxylate 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (3 g, 17.63 mmol) was added to a 100 mL single-necked flask, dissolved in acetonitrile (30 mL), and cooled to -5 °C. Then, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (13.41 g, 35.26 mmol) and DIPEA (11.39 g, 88.15 mmol) were added. After stirring for 5 minutes, 4-methoxy-N-methylbenzylamine (2.93 g, 19.39 mmol) was added, and the mixture was kept at this temperature for 10 minutes. The mixture was then transferred to room temperature and reacted for 4 hours. TLC monitoring showed that the starting material had reacted completely, and the reaction was stopped. Water (30 mL) was added, and EA (50 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA(v:v) = 10:1-2:1). 2.4 g of a green liquid was obtained, with a yield of 44.87%. MS (ESI, pos. ion) m / z: 304.1 [M+H] + . Step 2: 3-(hydroxymethyl)- N -(4-Methoxybenzyl)- N Synthesis of 1-methylbicyclo[1.1.1]pentane-1-carboxamide 1.3 g (4.29 mmol) of 3-((4-methoxybenzyl)(methyl)carbamoyl)bicyclo[1.1.1]pentane-1-carboxylate was added to a 100 mL single-necked flask, dissolved in methanol (10 mL), and cooled at 0 °C. Then, NaBH4 (0.49 g, 12.87 mmol) and sodium methoxide (0.023 g, 0.43 mmol) were added sequentially. The mixture was kept at this temperature for 10 min and then transferred to room temperature for 5 h. TLC monitoring (DCM:CH3OH(v:v)=50:1) showed that the starting material had reacted completely, and the reaction was stopped. Saturated ammonium chloride (10 mL) was added, followed by extraction with DCM (20 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:CH3OH(v:v)=1:0-50:1) to obtain 800 mg of green liquid, with a yield of 85.23%. MS (ESI, pos. ion) m / z: 276.1 [M+H] + . Step 3: Synthesis of (3-((4-methoxybenzyl)(methyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)methyl 4-methylbenzenesulfonate Add 3-(hydroxymethyl)- to a 50 mL flask N -(4-Methoxybenzyl)- N 530 mg of methylbicyclo[1.1.1]pentane-1-carboxamide (10 mL) was dissolved in THF. NaH (0.12 g, 2.88 mmol) was added at 0 °C and stirred for half an hour. TsCl (0.55 g, 2.88 mmol) was added, and the mixture was transferred to room temperature and reacted for 3 h. The reaction was detected by TLC and the starting material was completely reacted. The reaction was stopped, 20 mL of water was added, and the mixture was extracted with DCM (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE:EA(v:v) = 10:1-4:1) to obtain 530 mg of pale yellow liquid. The liquid was then slurried with EA (20 mL) to obtain 2.70 g of brown solid, with a yield of 64.10%.

[0182] Step 4: 3-(((2-chloropyrimidin-5-yl)oxy)methyl)- N -(4-Methoxybenzyl)- N Synthesis of 1-methylbicyclo[1.1.1]pentane-1-carboxamide 2-Chloropremine-5-ol (50 mg, 0.38 mmol), 3-((4-methoxybenzyl)(methyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)methyl 4-methylbenzenesulfonate (80 mg, 0.19 mmol), and cesium carbonate (0.19 g, 0.57 mmol) were added to a 50 mL single-necked flask and dissolved in DMF (5 mL). The reaction was carried out at 130 °C for 2 h. TLC analysis showed that the starting material had reacted completely, and the reaction was stopped. Water (20 mL) was added, and the mixture was extracted with EA (12 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by column chromatography (PE:EA(v:v) = 2:1), and the eluents were combined and evaporated to dryness to give 40 mg of a colorless, transparent liquid, with a yield of 26.92%. MS (ESI, pos. ion) m / z: 388.1 [M+H] + . Step 5: Synthesis of 3-(((2-chloropyrimidin-5-yl)oxy)methyl)-N-methylbicyclo[1.1.1]pentane-1-carboxamide Add 3-(((2-chloropyrimidin-5-yl)oxy)methyl)- N -(4-Methoxybenzyl)- N 1-Methylbicyclo[1.1.1]pentane-1-carboxamide (300 mg, 1.09 mmol) was dissolved in DCM (6 mL), and trifluoroacetic acid (7.64 g, 65.4 mmol) was added. The reaction was carried out at 70°C for 13 h. TLC analysis showed that the starting material had reacted completely, and the reaction was stopped. Anhydrous potassium phosphate aqueous solution was added to adjust the pH to approximately 7, and the mixture was extracted with DCM (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography purification (PE:EA(v:v) = 100:1) yielded 100 mg of a pale yellow solid, with a yield of 59.14%. 1 H NMR (400 MHz, CDCl3) δ 8.29 (s, 2H), 5.63 – 5.52 (m, 1H), 4.11 (s, 2H), 2.84 (d, J = 4.9Hz, 3H), 2.10 (s, 6H). Step 6: N -Methyl-3-(((2-(((1) S ,3 S )-3-((2-Oxo-2 H Synthesis of -[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)pyrimidin-5-yl)oxy)methyl)bicyclo[1.1.1]pentane-1-aminocarboxamide Add 3-(((2-chloropyrimidin-5-yl)oxy)methyl)-N -Methylbicyclo[1.1.1]pentyl-1-carboxamide (0.08 g, 0.3 mmol), 6'-(((1 S ,3 S )-3-aminocyclopentyl)amino-2 H -[1,3'-bipyridine]-2-one hydrochloride (0.12 g, 0.36 mmol), potassium tert-butoxide (0.34 g, 3.03 mmol, step 3 of Example 1), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.10 g, 0.90 mmol), and 1,4-dioxane (8 mL) were added. The mixture was stirred at 110 °C for 15 h under nitrogen protection, and then the reaction was stopped. The mixture was filtered, the solvent was evaporated, 20 mL of water was added, and the mixture was extracted with DCM (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by column chromatography (DCM:MeOH (v:v) = 30:1) to give 35 mg of a yellowish-brown solid, with a yield of 23.35%. MS(ESI, pos. ion) m / z: 502.1[M+H]+; 1 H NMR (400 MHz, DMSO- d 6) δ 8.54 (s, 1H), 8.11 (d, J = 15.8 Hz, 4H), 7.83 (d, J = 9.5 Hz, 1H), 7.73 (d, J = 4.3 Hz, 1H), 7.66 (d, J = 6.7 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.01 (d, J = 9.7 Hz, 1H), 6.49 (d, J = 9.2 Hz, 1H), 6.34 (t, J = 6.6 Hz, 1H), 4.43 – 4.37 (m, 1H), 4.21 (s, 2H), 3.71 (s, 1H), 2.55 (d, J = 4.5 Hz, 3H), 2.29 – 2.17 (m, 2H), 2.17 – 2.06 (m, 2H), 2.05 – 1.97 (m, 2H), 1.92 (s, 6H). Example 5: Synthesis of 6'-(((1S,3S)-3-((5-((2-oxaspiro[3.3]heptane-6-yl)oxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Compound 5

[0183] Step 1: Synthesis of 2-oxaspiro[3.3]heptane-6-ol 2-oxaspiro[3.3]heptan-6-one (880 mg, 7.85 mmol) and methanol (10 mL) were added to a 100 mL single-necked flask. NaBH4 (0.45 g, 11.77 mmol) was added at 0 °C, and the reaction was maintained at this temperature for 1 h. The mixture was then transferred to room temperature and reacted overnight. TLC analysis showed that the starting material had reacted completely. The reaction was stopped, and 20 mL of water was added to quench the reaction. Dichloromethane (20 mL × 3) was added for extraction. The organic phase was dried, concentrated, and purified by column chromatography (DCM:EA(v:v)=6:1) to obtain 376 mg of a pale yellow oily liquid, with a yield of 41.97%. 1 H NMR (400 MHz, Chloroform- d ) δ 4.68 (s, 2H), 4.65 (s, 2H), 4.13 (q,J = 7.1 Hz, 1H), 2.64 (ddd, J = 9.9, 7.0, 3.1 Hz, 2H), 2.09 (ddd, J = 10.1,7.3, 3.0 Hz, 2H). Step 2: 2-oxaspiro[3.3]heptane-6-yl-4-methylbenzenesulfonate 2-oxaspiro[3.3]heptan-6-ol (375 mg, 3.29 mmol) was added to a 100 mL single-necked flask, followed by THF (6 mL). The mixture was stirred at 0 °C, and sodium hydride (0.20 g, 4.94 mmol) was added. The mixture was kept at this temperature for 30 min, and then TsCl (0.10 g, 0.53 mmol) was added. The mixture was then transferred to room temperature and reacted for 4 h. TLC analysis showed that the starting material had reacted completely. The reaction was stopped, and 15 mL of water was added to quench the reaction. Ethyl acetate (10 mL × 3) was added for extraction. The organic phase was dried, concentrated, and purified by column chromatography (PE:EA(v:v) = 6:1) to obtain 400 mg of a yellow oily liquid, with a yield of 45.37%. MS (ESI, pos. ion) m / z: 269.1 [M+H] + . Step 3: Synthesis of 5-((2-oxaspiro[3.3]heptane-6-yl)oxy)-2-chloropyrimidine Following the synthesis method in step 8 of Example 1, 5-((2-oxaspiro[3.3]heptane-6-yl-4-methylbenzenesulfonate)-2-chloropyrimidine (80 mg, yellow solid) was synthesized from 2-oxaspiro[3.3]heptane-6-yl)oxy)-2-chloropyrimidine as the starting material, with a yield of 63.14%.1 H NMR (400 MHz, Chloroform- d ) δ 8.18 (s, 2H), 4.77 (s, 2H), 4.72(s, 2H), 4.60 (p, J = 6.6 Hz, 1H), 2.89 – 2.82 (m, 2H), 2.45 – 2.38 (m, 2H). Step 4: Synthesis of 6'-((1S,3S)-3-(((5-((2-oxaspiro[3.3]heptane-6-yl)oxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Following the synthetic method in step 9 of Example 1, using 5-((2-oxaspiro[3.3]heptane-6-yl)oxy)-2-chloropyrimidine as the starting material, target compound 5 (80 mg, yellow solid) was synthesized in 4.92% yield. MS (ESI, pos.ion) m / z: 461.1 [M+H] + ; 1 H NMR (400 MHz, Chloroform- d ) δ 8.07 – 8.03 (m, 1H),7.96 (s, 1H), 7.54 (dd, J = 8.0, 3.5 Hz, 1H), 7.40 (dd, J = 8.7, 2.6 Hz, 1H),7.31 (d, J = 6.2 Hz, 2H), 6.67 (d, J = 9.3 Hz, 1H), 6.49 – 6.44 (m, 1H), 6.25(t, J = 6.9 Hz, 1H), 5.39 – 5.35 (m, 1H), 4.99 (d, J = 7.7 Hz, 1H), 4.87 (d,J = 6.2 Hz, 1H), 4.73 (d, J = 12.8 Hz, 4H), 4.28 – 4.23 (m, 1H), 2.80 – 2.73(m, 2H), 2.40 – 2.30 (m, 4H), 2.26 – 2.22 (m, 1H), 2.08 – 1.98 (m, 4H). Example 6: Synthesis of 6'-(((1S,3S)-3-((5-(cyclopropylmethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Compound 6

[0184] Step 1: Synthesis of 2-chloro-5-(cyclopropylmethoxy)pyrimidine Following the synthetic method described in step 8 of Example 1, 2-chloro-5-(cyclopropylmethoxy)pyrimidine (330 mg, white solid) was synthesized from (bromomethyl)cyclopropane as the starting material, with a yield of 46.66%. MS (ESI, pos. ion) m / z: 185.0 [M+H] + ; Step 2: Synthesis of 6'-(((1S,3S)-3-((5-(cyclopropylmethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Following the synthetic method described in step 9 of Example 1, using 2-chloro-5-(cyclopropylmethoxy)pyrimidine as the starting material, target compound 6 (60 mg, yellowish-white solid) was synthesized in 17.65% yield. MS (ESI, pos. ion) m / z: 419.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.12 – 8.01 (m, 3H), 7.53 (dd, J = 8.8, 2.6 Hz, 1H), 7.41 (ddd, J = 8.9, 6.6, 1.9 Hz, 1H), 7.31 (dd, J = 6.8, 1.6 Hz, 1H), 6.66 (d, J = 9.2 Hz, 1H), 6.45 (d, J = 8.9 Hz, 1H), 6.25 (t, J = 6.4 Hz, 1H), 4.97 (d, J = 6.8 Hz, 1H), 4.88 (d, J = 6.6 Hz, 1H), 4.39 (dd, J = 13.4, 6.7Hz, 1H), 4.26 (dd, J = 12.6, 6.3 Hz, 1H), 3.78 (d, J = 7.0 Hz, 2H), 2.33 (qd,J = 11.3, 6.8 Hz, 2H), 2.07 – 2.00 (m, 2H), 1.58 (td, J = 12.6, 7.5 Hz, 2H), 1.23 (dd, J = 7.4, 4.7 Hz, 1H), 0.66 (q, J = 5.6 Hz, 2H), 0.35 (q, J = 5.0Hz, 2H). Example 7: Synthesis of 6'-(((1S,3S)-3-((5-(1-(methoxymethyl)cyclopropoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Compound 7

[0185] Step 1: Synthesis of methyl 1-((2-chloropyrimidin-5-yl)oxy)cyclopropane-1-carboxylic acid In a 100 mL round-bottom flask, 2-chloropyrimidin-5-ol (1 g, 7.66 mmol) and cesium carbonate (9.98 g, 30.64 mmol) were added and dissolved in 30 mL of acetonitrile. Then, methyl 2,4-dibromobutyrate (2.99 g, 11.49 mmol) was added, and the mixture was heated to 70 °C and reacted for approximately 12 h. TLC analysis showed complete reaction of the starting material, and the reaction was stopped. The reaction solution was poured into 50 mL of water, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The solution was purified by column chromatography (PE:EA(v:v) = 8:1), and the eluents were combined and concentrated to give 900 mg of a yellow liquid, with a yield of 51.38%.

[0186] Step 2: Synthesis of (1-((2-chloropyrimidin-5-yl)oxy)cyclopropyl)methanol Methyl 1-((2-chloropyrimidin-5-yl)oxy)cyclopropane-1-carboxylate (600 mg, 2.62 mmol) was added to a 25 mL two-necked flask, purged with nitrogen three times, and then 8 mL of tetrahydrofuran was added. Lithium aluminum hydride (0.099 g, 2.62 mmol) was slowly added at -10 °C. After 0.5 h, TLC showed complete reaction of the starting material, and the reaction was stopped. The reaction was quenched with 1N HCl (2 mL), 20 mL of water was added, and the mixture was extracted with 15 mL of ethyl acetate. The organic phase was dried and purified by column chromatography (PE:EA(v:v) = 3:1) to give 190 mg of a yellow oily liquid, with a yield of 36.09%. MS (ESI, pos. ion) m / z: 201.0 [M+H] + . Step 3: Synthesis of 2-chloro-5-(1-(methoxymethyl)cyclopropoxy)pyrimidine In a 50 mL single-necked flask, 185 mg (0.92 mmol) of (1-((2-chloropyrimidin-5-yl)oxy)cyclopropyl)methanol and 4 mL of DMF were added. Sodium hydride (0.055 g, 1.38 mmol) was added at 0 °C. After 0.5 h, 0.20 g (1.38 mmol) of iodomethane was added. After the addition was complete, the mixture was transferred to 30 °C for reaction. After 3 h, TLC analysis showed that the starting material had reacted completely. 30 mL of water was added, and the mixture was extracted with ethyl acetate (12 mL × 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by column chromatography (PE:EA(v:v) = 4:1). The eluents were combined and evaporated to dryness to give 100 mg of a yellow solid, with a yield of 50.52%.

[0187] Step 4: Synthesis of 6'-(((1S,3S)-3-((5-(1-(methoxymethyl)cyclopropoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one In a 25 mL two-necked flask, 2-chloro-5-(1-(methoxymethyl)cyclopropoxy)pyrimidine (0.08 g, 0.37 mmol), 1-(6-{[(1S,3S)-3-aminocyclopentyl]amino}pyridin-3-yl)-1,2-dihydropyridin-2-one (0.13 g, 0.48 mmol), cesium carbonate (0.24 g, 0.74 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (0.047 g, 0.056 mmol) were dissolved in DMF (1 mL). The mixture was reacted at 100 °C under nitrogen protection. After 5 h, TLC analysis showed complete reaction of the starting material and a clearly visible product spot. The reaction was stopped. The mixture was filtered, the solvent was evaporated to dryness, 20 mL of water was added, and the mixture was extracted with EA (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Thin-layer chromatography purification (DCM:MeOH (v:v) = 20:1), combined eluents, evaporated to dryness, yielding 80 mg of yellow solid, 47.86% yield. MS (ESI, pos. ion) m / z: 449.1 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 2H), 8.04 (d, J = 2.4 Hz, 1H), 7.52 (dd, J = 8.9, 2.6 Hz, 1H), 7.40 (ddd, J = 8.9, 6.6, 2.0 Hz, 1H), 7.31 (dd, J = 6.8, 1.5 Hz,1H), 6.66 (d, J = 9.2 Hz, 1H), 6.45 (d, J = 8.9 Hz, 1H), 6.24 (t, J = 6.2 Hz,1H), 5.01 (d, J = 7.0 Hz, 1H), 4.90 (d, J = 6.7Hz, 1H), 4.39 (dd, J = 13.4,6.7 Hz, 1H), 4.25 (dd, J = 12.6, 6.4 Hz, 1H), 4.03 (s, 2H), 3.41 (s,3H), 2.33(qd, J = 11.5, 6.9 Hz, 2H), 2.11 – 1.98 (m, 2H), 1.62 – 1.51 (m, 2H), 0.97(t, J = 6.3Hz, 2H), 0.70 (q, J = 5.7 Hz, 2H). Example 8: Synthesis of 1-(6-{[(1S,3S)-3-[(5-(oxecyclobutane-3-oxy)pyrimidin-2-yl)amino]cyclopentyl]amino}pyridin-3-yl)-1,2-dihydropyridin-2-one) Compound 8

[0188] Step 1: Synthesis of 2-chloro-5-(oxakan-3-yloxy)pyrimidine Following the synthetic method described in step 8 of Example 1, 2-chloro-5-(oxacan-3-yloxy)pyrimidine (520 mg, white solid) was synthesized from 3-iodooxetane as the starting material, with a yield of 45.47%. MS (ESI, pos. ion) m / z: 187.1 [M+H] + . Step 2: Synthesis of 1-(6-{[(1S,3S)-3-[(5-(oxecyclobutane-3-oxy)pyrimidin-2-yl)amino]cyclopentyl]amino}pyridin-3-yl)-1,2-dihydropyridin-2-one) Following the synthetic method described in step 4 of Example 7, using 2-chloro-5-(oxacan-3-yloxy)pyrimidine as the starting material, target compound 8 (170 mg, yellowish-white solid) was synthesized in 50.30% yield. MS (ESI, pos. ion) m / z: 421.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 2.3 Hz, 1H), 7.90 (s, 2H), 7.52 (dd, J = 8.9, 2.5 Hz, 1H), 7.45 – 7.36 (m, 1H), 7.33 – 7.29 (m, 1H), 6.66 (d, J = 9.2 Hz, 1H), 6.44 (d, J = 8.9 Hz, 1H), 6.25 (t, J = 6.7 Hz, 1H), 5.11 (dd, J = 11.1, 5.5 Hz, 1H), 5.05 (d, J = 6.8 Hz, 1H), 4.93 (t, J = 6.7Hz, 2H), 4.87 (d, J = 6.6 Hz, 1H), 4.79–4.72 (m, 2H), 4.37 (dd, J = 13.4, 6.7Hz, 1H), 4.25 (dd, J = 12.7, 6.3 Hz, 1H), 2.32 (qd, J = 11.6, 6.8 Hz, 2H), 2.08–1.97 (m, 2H), 1.63–1.52 (m, 2H). Example 9: Synthesis of 6'-(((1S,3S)-3-((5-cyclobutoxypyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Compound 9

[0189] Step 1: Synthesis of 2-chloro-5-cyclobutoxypyrimidine Following the synthetic method described in step 8 of Example 1, 2-chloro-5-cyclobutoxypyrimidine (390 mg, white solid) was synthesized from cyclobutyl bromide as the starting material, with a yield of 57.04%. MS (ESI, pos. ion) m / z: 185.0 [M+H] + . Step 2: Synthesis of 6'-(((1S,3S)-3-((5-cyclobutoxypyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Following the synthetic method described in step 4 of Example 7, using 2-chloro-5-cyclobutoxypyrimidine as the starting material, target compound 9 (70 mg, yellowish-white solid) was synthesized in 50.30% yield. MS (ESI, pos. ion) m / z: 419.1 [M+H] + ; 1 HNMR (400 MHz, CDCl3) δ 8.04 (d, J = 2.2 Hz, 1H), 7.98 (s, 2H), 7.53 (dd, J =8.9, 2.5 Hz, 1H), 7.43 – 7.36 (m, 1H), 7.30 (dd, J = 6.8, 1.4 Hz, 1H), 6.66(d, J = 9.2 Hz, 1H), 6.45 (d, J = 8.8 Hz, 1H), 6.24 (t, J = 6.2 Hz, 1H), 4.98(d, J = 6.7 Hz, 1H), 4.92 (d, J = 6.1 Hz, 1H), 4.52 (p, J = 6.9 Hz, 1H), 4.38(dd, J = 13.2, 6.6 Hz, 1H), 4.25 (dd, J = 12.5, 6.2 Hz, 1H), 2.39 (dt, J =9.4, 6.1 Hz, 2H), 2.32 (dt, J = 10.0, 5.0 Hz, 2H), 2.20 – 2.12 (m, 2H), 2.04 (dd, J = 11.6, 6.2 Hz, 2H), 1.84 (s, 2H), 1.58 (dd, J = 7.8, 5.3 Hz, 2H). Example 10: Synthesis of 6'-((1S,3S)-3-((5-(bicyclo[3.1.0]hex-3-yloxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Compound 10

[0190] Step 1: Synthesis of bicyclo[3.1.0]hexane-3-yl-4-methylbenzenesulfonate Bicyclo[3.1.0]hexyl-3-ol (0.8 g, 8.15 mmol) was added to a single-necked flask and dissolved in tetrahydrofuran (5 mL). Sodium hydride (0.29 g, 12.23 mmol) was added at 0 °C, and the mixture was stirred for 30 min. Then, p-toluenesulfonyl chloride (1.71 g, 8.97 mmol) was added, and the mixture was stirred at 40 °C for 5 h. The starting material reacted completely, and the product spot was clearly visible. The product was quenched with 20 mL of water, extracted with 50 mL of EA, dried, and concentrated. The organic phase was purified by column chromatography (PE:EA(v:v) = 100:1). The eluent was collected and evaporated to dryness to give 0.9 g of yellow liquid, with a yield of 43.76%. 1 H NMR (400 MHz, CDCl3) δ 7.77 (t, J = 6.8 Hz, 2H), 7.34 (d, J= 8.1 Hz, 2H), 4.68 – 4.24 (m, 1H), 2.46 (s, 3H), 2.10 (dd, J = 13.0, 7.4 Hz,2H), 1.91 (ddd, J = 14.0, 12.2, 9.3 Hz, 2H), 1.29 – 1.25 (m, 2H), 0.46 – 0.34(m, 1H), 0.11 – 0.12 (m, 1H). Step 2: Synthesis of 5-(bicyclo[3.1.0]hex-3-yloxy)-2-chloropyrimidine Following the synthesis method in step 8 of Example 1, 5-(bicyclo[3.1.0]hexane-3-yl-4-methylbenzenesulfonate)-2-chloropyrimidine (110 mg, white solid) was synthesized from bicyclo[3.1.0]hex-3-yloxy)-2-chloropyrimidine as the starting material, with a yield of 32.94%.

[0191] Step 3: Synthesis of 6'-(((1S,3S)-3-((5-cyclobutoxypyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Following the synthetic method described in step 9 of Example 1, using 5-(bicyclo[3.1.0]hex-3-yloxy)-2-chloropyrimidine as the starting material, target compound 10 (110 mg, yellowish-white solid) was synthesized in 57.92% yield. MS (ESI, pos. ion) m / z: 445.1 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.95 (s, 2H), 7.56 –7.48 (m, 1H), 7.39 (t, J = 7.0 Hz, 1H), 7.32 – 7.28 (m, 1H), 6.65 (d, J = 9.2Hz, 1H), 6.44 (d, J = 8.8 Hz, 1H), 6.24 (t, J = 6.4 Hz, 1H), 4.94 (dd, J =12.3, 6.7 Hz, 2H), 4.64 (t, J = 6.3 Hz, 1H), 4.37 (dd, J = 12.8, 6.4 Hz, 1H),4.28 – 4.17 (m, 1H), 2.32 (dd, J = 16.5, 11.3 Hz, 2H), 2.15 (d, J = 8.5 Hz, 2H), 2.00 (s, 1H), 1.92 (s, 2H), 1.57 (dd, J = 17.2, 11.6 Hz, 2H), 1.41 (d, J= 18.1 Hz, 1H), 1.37 – 1.31 (m, 2H), 0.56 (m, 2H). Example 11: Synthesis of 6'-(((1S,3S)-3-((5-((3-methyloxetane-3-yl)methoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Compound 11

[0192] Step 1: Synthesis of methyl (3-methyloxetane-3-yl)methanesulfonate In a 100 mL single-necked flask, 1 g of (3-methyloxetane-3-yl)methanol (9.79 mmol) and 8 mL of DCM were added. TEA (1.49 g, 14.68 mmol) was added at 0 °C, followed by dropwise addition of methanesulfonyl chloride (1.12 g, 9.79 mmol). After the addition was complete, the mixture was transferred to room temperature and reacted for approximately 1 h. TLC analysis showed that the starting material had essentially reacted completely. The reaction was stopped, 20 mL of water was added, and the mixture was extracted with DCM (15 mL × 2). The organic phase was dried and concentrated to yield 1.68 g of a yellow oily liquid, with a yield of 95.20%.

[0193] Step 2: Synthesis of 2-chloro-5-((3-methyloxetane-3-yl)methoxy)pyrimidine Following the synthetic method described in step 8 of Example 1, methyl (3-methyloxetane-3-yl)methanesulfonate was used as the starting material to synthesize 2-chloro-5-((3-methyloxetane-3-yl)methoxy)pyrimidine (690 mg, white solid), with a yield of 35.54%. MS (ESI, pos. ion) m / z: 215.0 [M+H] + ; 1 H NMR (400 MHz, Chloroform-d) δ8.36 (s, 2H), 4.61 (d, J = 6.1 Hz, 2H), 4.51 (d, J = 6.1 Hz, 2H), 4.16 (s,2H), 1.47 (s, 3H). Step 3: Synthesis of 6'-(((1S,3S)-3-((5-((3-methyloxetane-3-yl)methoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Following the synthetic method described in step 4 of Example 7, starting with 2-chloro-5-((3-methyloxetane-3-yl)methoxy)pyrimidine, target compound 11 (85 mg, brown solid) was synthesized in 29.77% yield. MS (ESI, pos.ion) m / z: 449.1 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 2H), 8.04 (d, J = 2.4Hz, 1H), 7.53 (dd, J = 8.9, 2.5 Hz, 1H), 7.40 (td, J = 6.7, 3.3 Hz, 1H), 7.32– 7.29 (m, 1H), 6.66 (d, J = 9.2 Hz, 1H), 6.45 (d, J = 8.9 Hz, 1H), 6.27 –6.23 (m, 1H), 5.01 (d, J = 6.9 Hz, 1H), 4.90 (d, J = 6.5 Hz, 1H), 4.62 (d, J= 6.0 Hz, 2H), 4.47 (d, J = 6.0 Hz, 2H), 4.40 (q, J = 6.8 Hz, 1H), 4.26 (q, J= 6.2 Hz, 1H), 4.01 (s, 2H), 2.34 (dt, J = 10.2, 5.0 Hz, 2H), 2.07 – 2.01 (m,2H), 1.62 – 1.56 (m, 2H), 1.44 (s, 3H). Example 12: Synthesis of 6'-(((1S,3S)-3-((5-(oxecyclobutane-3-ylmethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Compound 12

[0194] Step 1: Synthesis of 2-chloro-5-(oxetane-3-ylmethoxy)pyrimidine Following the synthetic method described in step 8 of Example 1, 2-chloro-5-(oxetane-3-ylmethoxy)pyrimidine (500 mg, white solid) was synthesized from 3-(iodomethyl)oxetane as the starting material, with a yield of 61.19%. MS (ESI, pos.ion) m / z: 201.0 [M+H] + . Step 2: Synthesis of 6'-(((1S,3S)-3-((5-(oxecyclobutane-3-ylmethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Following the synthetic method described in step 4 of Example 7, using 2-chloro-5-(oxetane-3-ylmethoxy)pyrimidine as the starting material, target compound 12 (110 mg, white solid) was synthesized in 50.30% yield. MS (ESI, pos. ion) m / z: 435.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 2.2 Hz, 1H), 7.98 (s,2H), 7.53 (dd, J = 8.9, 2.5 Hz, 1H), 7.43 – 7.36 (m, 1H), 7.30 (dd, J = 6.8,1.4 Hz, 1H), 6.66 (d, J = 9.2 Hz, 1H), 6.45 (d, J = 8.8 Hz, 1H), 6.24 (t, J =6.2 Hz, 1H), 4.98 (d, J = 6.7 Hz, 1H), 4.92 (d, J = 6.1 Hz, 1H), 4.52 (p, J =6.9 Hz, 1H), 4.38 (dd, J = 13.2, 6.6 Hz, 1H), 4.25 (dd, J = 12.5, 6.2 Hz, 1H), 2.39 (dt, J = 9.4, 6.1 Hz, 2H), 2.32 (dt, J = 10.0, 5.0 Hz, 2H), 2.20 –2.12 (m, 2H), 2.04 (dd, J = 11.6, 6.2 Hz, 2H), 1.84 (s, 2H), 1.58 (dd, J =7.8, 5.3 Hz, 2H). Example 13: Synthesis of 1-(6-{[(1S,3S)-3-[(5-[(1-fluorocyclopropyl)methoxy]pyrimidin-2-yl)amino]cyclopentyl]amino}pyridin-3-yl)-1,2-dihydropyridin-2-one) Compound 13

[0195] Step 1: Synthesis of methyl (1-fluorocyclopropyl)chlorosulfonate Following the synthesis method in step 1 of Example 11, methyl chlorosulfonate (1.02 g, colorless liquid) was synthesized from (1-fluorocyclopropyl)methanol as the starting material, with a yield of 97.45%.

[0196] Step 2: Synthesis of 2-chloro-5-[(1-fluorocyclopropyl)methoxy]pyrimidine Following the synthetic method described in step 8 of Example 1, 2-chloro-5-[(1-fluorocyclopropyl)methoxy]pyrimidine (520 mg, white solid) was synthesized from methyl (1-fluorocyclopropyl)chlorosulfonate as the starting material, with a yield of 55.34%. MS (ESI, pos.ion) m / z: 203.1 [M+H] + . Step 3: Synthesis of 1-(6-{[(1S,3S)-3-[(5-[(1-fluorocyclopropyl)methoxy]pyrimidin-2-yl)amino]cyclopentyl]amino}pyridin-3-yl)-1,2-dihydropyridin-2-one) Following the synthetic method described in step 4 of Example 7, using 2-chloro-5-[(1-fluorocyclopropyl)methoxy]pyrimidine as the starting material, target compound 13 (120 mg, white solid) was synthesized in 46.42% yield. MS (ESI, pos. ion) m / z: 437.0 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.13 (s, 2H), 8.04 (d, J = 2.4 Hz, 1H), 7.52 (dd, J = 8.9, 2.6 Hz, 1H), 7.40 (ddd, J = 9.0, 6.6, 1.9 Hz, 1H), 7.31(dd, J = 6.8, 1.6 Hz, 1H), 6.66 (d, J = 9.2 Hz, 1H), 6.45 (d, J = 8.9 Hz,1H), 6.25 (t, J = 6.7 Hz, 1H), 5.04 (d, J = 6.9 Hz, 1H), 4.88 (d, J = 6.7 Hz,1H), 4.40 (dd, J = 13.6, 6.8 Hz, 1H), 4.26 (dd, J = 12.6, 6.4 Hz, 1H), 4.17(t, J = 17.2 Hz, 2H), 2.33 (qd, J = 11.4, 6.8 Hz, 2H), 2.10 – 1.95 (m, 2H), 1.63 – 1.53 (m, 2H), 1.25 – 1.17 (m, 2H), 0.80 (t, J = 7.6 Hz, 2H). Example 14: Synthesis of N-(3-(((2-(((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)pyrimidin-5-yl)oxy)methyl)bicyclo[1.1.1]pentyl)acetamide Compound 14

[0197] Step 1: Synthesis of methyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (5 g, 31.6 mmol) was added to a 25 mL single-necked flask and dissolved in tert-butanol (20 mL). Then, triethylamine (12.7 g, 125.6 mmol) and diphenyl azidophosphate (18.2 g, 47.1 mmol) were added. The mixture was reacted at room temperature for 1 h, and then heated to 83 °C to start the reaction. After 10 h, the reaction was monitored by TLC and the starting material was found to be basically complete. Heating was stopped, the mixture was evaporated to dryness, and 20 mL of EA and saturated sodium chloride solution (10 mL × 2) were added for extraction. The organic phases were combined, evaporated to dryness, mixed, and subjected to column chromatography (PE:EA(v:v) = 15-10:1) to obtain 3.5 g of white solid product, with a yield of 46.14%. 1 H NMR (400 MHz, CDCl3) δ 4.96 (s, 1H), 3.70 (s, 3H), 2.30 (s, 6H), 1.46 (s, 9H). Step 2: Synthesis of tert-butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentyl)carbamate Methyl 3-((tert-Butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (3.5 g, 9.21 mmol) was added to a 25 mL two-necked flask, dissolved in 10 mL THF, and purged with nitrogen three times. The flask was then placed at -20 °C, and lithium aluminum hydride (0.45 g, 9.21 mmol) was slowly added dropwise. After 1 h, TLC monitoring showed that the starting material had completely reacted, and the reaction was stopped. The reaction was quenched with 1 M HCl (2 mL), extracted with 10 mL water and 20 mL EA, evaporated to dryness, stirred, and subjected to column chromatography (PE:EA(v:v) = 4:1-3:1) to give 1.6 g of white solid product. The yield was 62.22%. 1 H NMR (400 MHz, CDCl3) δ 4.97 (s, 1H), 3.72 (s, 2H), 1.96 (s, 6H), 1.46 (s, 9H). Step 3: Synthesis of (3-((tert-Butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-yl)methylsulfonate Following the synthesis method in step 1 of Example 11, tert-butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentyl)carbamate was used as the starting material to synthesize (3-((tert-butyloxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methanesulfonate (1.96 g, white solid), with a yield of 89.96%.

[0198] Step 4: Synthesis of tert-butyl(3-(((2-chloropyrimidin-5-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate Following the synthetic method in step 8 of Example 1, tert-butyl(3-(((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methylsulfonate was used as the starting material to synthesize tert-butyl(3-((((2-chloropyrimidin-5-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate (1.50 g, white solid), with a yield of 68.44%. MS (ESI, pos. ion) m / z: 326.1 [M+H] + . Step 5: Synthesis of 3-(((2-chloropyrimidin-5-yl)oxy)methyl)bicyclo[1.1.1]pentane-1-amine 1.5 g (4.60 mmol) of tert-butyl(3-(((2-chloropyrimidin-5-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate, 1,4-dioxane (5 mL), and methanol (3 mL) were added to a 50 mL single-necked flask and dissolved. Then, a solution of 1,4-dioxane in hydrogen chloride (2.18 g, 59.8 mmol, 4 M) was added. The reaction was carried out at room temperature for 2 h. TLC monitoring showed that the starting material had reacted completely. The reaction was stopped, and the solution was evaporated to dryness to give 1.2 g of a white solid product, yielding 99.86%. MS (ESI, pos. ion) m / z: 226.1 [M+H] + . Step 6: Synthesis of N-(3-(((2-chloropyrimidin-5-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)acetamide 3-((2-chloropyrimidin-5-yl)oxy)methyl)bicyclo[1.1.1]pentane-1-amine (0.6 g, 2.66 mmol) was added to a 50 mL single-necked flask, dissolved in 6 mL of tetrahydrofuran, followed by the addition of triethylamine (1.35 g, 13.3 mmol). The flask was placed at 0 °C, and acetyl chloride (0.31 g, 3.99 mmol) was slowly added. After the addition was complete, the flask was transferred to room temperature. After 1 h, TLC monitoring showed that the starting material had completely reacted, and the reaction was stopped. The reaction was quenched with 2 mL of methanol. The solution was evaporated to dryness, and the concentrate was purified by column chromatography (PE:EA(v:v) = 2:1) to give 0.46 g of white solid, with a yield of 64.63%. MS (ESI, pos. ion) m / z: 268.0 [M+H] + . Step 7: Synthesis of N-(3-(((2-(((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)pyrimidin-5-yl)oxy)methyl)bicyclo[1.1.1]pentyl)acetamide Following the synthetic method described in step 4 of Example 7, using N-(3-((((2-chloropyrimidin-5-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)acetamide as the starting material, target compound 14 (55 mg, white solid) was synthesized in 24.21% yield. MS (ESI, pos. ion) m / z: 502.2 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ 8.05 (s,2H), 7.53 (dd, J = 8.9, 2.5 Hz, 1H), 7.44 – 7.38 (m, 1H), 7.33 –7.29 (m, 1H), 6.66 (d, J = 9.2 Hz, 1H), 6.46 (d, J = 8.9 Hz, 1H), 6.25 (t, J = 6.3 Hz, 1H), 5.89 (s, 1H), 5.37– 5.29 (m, 1H), 4.96 (d, J = 6.9 Hz, 1H), 4.88 (d, J = 6.4Hz, 1H), 4.39 (dd, J = 13.5, 6.8 Hz, 1H), 4.26 (dd, J = 12.7, 6.5 Hz, 1H), 4.04 (s, 2H), 2.33 (qd, J = 11.2, 6.7 Hz, 2H), 2.11 (d, J = 12.5 Hz, 6H), 2.04 (dd, J = 12.9, 6.2 Hz, 2H), 1.97 (d, J = 11.0 Hz, 3H), 1.58 (dd, J = 8.9,5.2 Hz, 2H). Example 15: Synthesis of 1-(((2-(((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)pyrimidin-5-yl)oxy)methyl)cyclopropane-1-nitrile) Compound 15

[0199] Step 1: Synthesis of methyl methanesulfonate (1-cyanocyclopropyl) Following the synthesis method in step 1 of Example 11, methyl methanesulfonate (1-cyanocyclopropyl) ester (275 mg, colorless liquid) was synthesized from 1-(hydroxymethyl)cyclopropane-1-nitrile as the starting material, with a yield of 30.49%.

[0200] Step 2: Synthesis of 1-(((2-chloropyrimidin-5-yl)oxy)methyl)cyclopropane-1-nitrile Following the synthetic method described in step 8 of Example 1, 1-(((2-chloropyrimidin-5-yl)oxy)methyl)cyclopropane-1-onitrile (110 mg, white solid) was synthesized from methyl methanesulfonate (1-cyanocyclopropyl) as the starting material, with a yield of 34.05%. MS (ESI, pos. ion) m / z: 210.1 [M+H]+ . Step 3: Synthesis of 1-(((2-(((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)pyrimidin-2-yl)oxy)methyl)cyclopropane-1-nitrile) Following the synthetic method described in step 4 of Example 7, starting with 1-((((2-chloropyrimidin-5-yl)oxy)methyl)cyclopropane-1-nitrile), the target compound 15 (70 mg, yellow solid) was synthesized in 39.69% yield. MS (ESI, pos.ion) m / z: 444.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.09 (s, 2H), 8.05 – 8.03 (m,1H), 7.52 (dd, J = 8.8, 2.4 Hz, 1H), 7.42 – 7.39 (m, 1H), 7.32 – 7.30 (m,1H), 6.66 (d, J = 9.3 Hz, 1H), 6.45 (d, J = 8.9 Hz, 1H), 6.25 (t, J = 6.4 Hz,1H), 5.15 (d, J = 6.7 Hz, 1H), 4.96 (d, J = 6.3 Hz, 1H), 4.39 (q, J = 6.7 Hz,1H), 4.25 (q, J = 6.2 Hz, 1H), 3.92 (s, 2H), 2.32 (td, J = 11.3, 4.9 Hz, 2H), 2.04 (dd, J = 13.7, 7.0 Hz, 2H), 1.60 – 1.55 (m, 2H), 1.43 – 1.41 (m, 2H),1.12 – 1.08 (m, 2H). Example 16: Synthesis of 6'-(((1S,3S)-3-((5-((2,2-difluorocyclopropyl)methoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Compound 16

[0201] Step 1: Synthesis of 2-chloro-5-(2,2-difluorocyclopropyl)methoxy)pyrimidine Following the synthetic method described in step 8 of Example 1, 2-chloro-5-(2,2-difluorocyclopropyl)methoxypyrimidine (200 mg, colorless liquid) was synthesized from 2-(bromomethyl)-1,1-difluorocyclopropane as the starting material, with a yield of 51.57%. MS (ESI, pos. ion) m / z: 221.1 [M+H] + . Step 2: Synthesis of 6'-((1S,3S)-3-((5-(2,2-difluorocyclopropyl)methoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Following the synthetic method described in step 4 of Example 7, using 2-chloro-5-(2,2-difluorocyclopropyl)methoxy)pyrimidine as the starting material, target compound 16 (50 mg, pink solid) was synthesized in 24.27% yield. MS (ESI, pos. ion) m / z: 455.2 [M+H] + ; 1 H NMR (599 MHz, CDCl3) δ 8.08 (s, 2H), 8.04 (s, 1H), 7.52 (dd, J= 8.8, 1.6 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 6.7 Hz, 1H), 6.66(d, J = 9.2 Hz, 1H), 6.45 (d, J = 8.9 Hz, 1H), 6.25 (t, J = 6.7 Hz, 1H), 5.07(d, J = 6.7 Hz, 1H), 4.92 (d, J = 6.5 Hz, 1H), 4.40 (dd, J = 13.4, 6.7 Hz,1H), 4.26 (dd, J = 12.6, 6.3 Hz, 1H), 4.01 (t, J = 7.1 Hz, 2H), 2.33 (td, J =11.4, 5.0 Hz, 2H), 2.06 – 2.03 (m, 2H), 1.61 – 1.57 (m, 2H), 1.32 – 1.28 (m,2H), 0.89 (dd, J = 14.0, 6.7 Hz, 1H). Example 17: Synthesis of 1-(6-{[(1S,3S)-3-[(5-[(6-oxaspiro[3.3]heptane-2-yl)oxy]pyrimidin-2-yl)amino]cyclopentyl]amino}pyridin-3-yl)-1,2-dihydropyridin-2-one Compound 17

[0202] Step 1: Synthesis of 6-oxaspiro[3.3]heptane-2-yl-4-methylbenzenesulfonate Following the synthesis method in step 1 of Example 10, 6-oxaspiro[3.3]heptane-2-one was used as the starting material to synthesize 6-oxaspiro[3.3]heptane-2-yl 4-methylbenzenesulfonate (48 mg, colorless liquid) with a yield of 98.82%.

[0203] Step 2: Synthesis of 6-[(2-chloropyrimidin-5-yl)oxy]spiro[3.3]heptane-2-one Following the synthetic method in step 8 of Example 1, 6-oxaspiro[3.3]heptane-2-yl 4-methylbenzenesulfonate was used as the starting material to synthesize 6-[(2-chloropyrimidin-5-yl)oxy]spiro[3.3]heptane-2-one (80 mg, white solid), with a yield of 32.60%. MS (ESI, pos. ion) m / z: 239.1 [M+H] + ; Step 3: Synthesis of 1-(6-{[(1S,3S)-3-[(5-[(6-oxaspiro[3.3]heptane-2-yl)oxy]pyrimidin-2-yl)amino]cyclopentyl]amino}pyridin-3-yl)-1,2-dihydropyridin-2-one Following the synthetic method described in step 9 of Example 1, using 6-[(2-chloropyrimidin-5-yl)oxy]spiro[3.3]heptane-2-one as the starting material, target compound 17 (71 mg, yellow solid) was synthesized in 44.83% yield. MS (ESI, pos.ion) m / z: 473.2 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 2.3 Hz, 1H), 7.99 (s, 2H), 7.53 (dd, J = 8.8, 2.4 Hz, 1H), 7.40 (dd, J = 11.4, 4.4 Hz, 1H), 7.31 (d, J = 5.4 Hz, 1H), 6.66 (d, J = 9.2 Hz, 1H), 6.46 (d, J = 8.9 Hz, 1H), 6.25 (t, J = 6.3 Hz, 1H), 5.00 (d, J = 6.9 Hz, 1H), 4.87 (d, J = 6.4 Hz, 1H),4.64 – 4.56 (m, 1H), 4.38 (dd, J = 13.4, 6.6 Hz, 1H), 4.26 (d, J = 6.5 Hz, 1H), 3.18 (d, J = 6.3 Hz, 4H), 2.73 – 2.64 (m, 2H), 2.53 – 2.44 (m, 2H), 2.33(td, J = 17.6, 11.7 Hz, 2H), 2.04 (dd, J = 13.5, 6.8 Hz, 2H), 1.62 – 1.54 (m,2H). Example 18: Synthesis of 6'-(((1S,3S)-3-((5-((((1S,5S)-3-oxabicyclo[3.1.0]hexane-6-yl)methoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Compound 18

[0204] Step 1: Synthesis of (1S,5S)-3-oxabicyclo[3.1.0]hexane-6-ol (1S,5S)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid (600 mg, 4.68 mmol) was added to a 50 mL double-necked flask under nitrogen protection. THF (8 mL) was added, and LiAlH4 (0.21 g, 5.62 mmol) was added at -6 °C. The reaction was maintained at this temperature for 3.5 h. TLC analysis showed that the starting material had reacted completely. The reaction was stopped, and 8 mL of water was added to quench the reaction. Ethyl acetate (5 mL × 3) was added for extraction. The organic phase was dried, concentrated, and purified by column chromatography (DCM / MeOH = 50 / 1) to obtain 100 mg of yellow oily liquid, with a yield of 18.71%. 1H NMR (400 MHz, Chloroform-d) δ 3.89 (d, J = 8.3 Hz, 2H), 3.71 (d, J= 8.2 Hz, 2H), 3.54 (d, J = 7.0 Hz, 2H), 1.56 (s, 2H), 1.10 (tt, J = 7.0, 3.5Hz, 1H). Step 2: Synthesis of ((1S,5S)-3-oxabicyclo[3.1.0]hexane-6-yl)methylmethanesulfonate Following the synthetic method described in step 1 of Example 11, (1S,5S)-3-oxabicyclo[3.1.0]hexane-6-ol was used as the starting material to synthesize ((1S,5S)-3-oxabicyclo[3.1.0]hexane-6-yl)methyl methanesulfonate (160 mg, yellow liquid), with a yield of 95.00%. MS (ESI, pos. ion) m / z: 193.1 [M+H] + . Step 3: Synthesis of 5-((1S,5S)-3-oxabicyclo[3.1.0]hexane-6-yl)methoxy)-2-chloropyrimidine Following the synthetic method described in step 8 of Example 1, 5-(((1S,5S)-3-oxabicyclo[3.1.0]hexane-6-yl)methylmethanesulfonate was synthesized as the starting material to obtain 5-(((1S,5S)-3-oxabicyclo[3.1.0]hexane-6-yl)methoxy)-2-chloropyrimidine (100 mg, white solid), yield 53.01%. MS (ESI, pos. ion) m / z: 227.1 [M+H] + . Step 4: Synthesis of 6'-(((1S,3S)-3-((5-((((1S,5S)-3-oxabicyclo[3.1.0]hexane-6-yl)methoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Following the synthetic method described in step 4 of Example 7, starting with 5-(((1S,5S)-3-oxabicyclo[3.1.0]hexane-6-yl)methoxy)-2-chloropyrimidine, target compound 18 (50 mg, brown solid) was synthesized in 31.76% yield. MS (ESI, pos. ion) m / z: 461.2 [M+H] + ; 1H NMR (400 MHz, CDCl3)δ 8.03 (d, J = 6.9Hz, 3H), 7.50 (d, J = 8.7 Hz, 1H), 7.42 – 7.36 (m, 1H), 7.29 (s, 1H), 6.64(d, J = 9.0 Hz, 1H), 6.43 (d, J = 8.6 Hz, 1H), 6.26 – 6.19 (m, 1H), 5.02 (d,J = 6.3 Hz, 1H), 4.94 – 4.89 (m, 1H), 4.37 (d, J = 7.3 Hz, 1H), 4.23 (d, J =6.1 Hz, 1H), 3.91 (d, J = 8.0 Hz, 2H), 3.82 (d, J = 6.5 Hz, 2H), 3.71 (d, J =7.6 Hz, 2H), 2.31 (d, J = 4.7 Hz, 2H), 2.04 – 2.00 (m, 2H), 1.64 (s, 2H), 1.58 – 1.55 (m, 1H), 1.42 (s, 2H). Example 19: Synthesis of 6'-(((1S,3S)-3-((5-((6,6-difluorospiro[3.3]heptane-2-yl)oxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Compound 19

[0205] Step 1: Synthesis of 6,6-difluorospiro[3.3]hepta-2-ol 6,6-Difluorospiro[3.3]heptane-2-one (600 mg, 4.11 mmol) and methanol (5 mL) were added to a 50 mL single-necked flask. Sodium borohydride (0.23 g, 6.17 mmol) was added at 0 °C, and the reaction was maintained at this temperature for 0.5 h. The mixture was then transferred to room temperature and reacted for about 2 h. TLC analysis showed that the starting material had reacted completely. The reaction was stopped, and 15 mL of water was added to quench the reaction. The mixture was extracted with DCM (8 mL × 3), the organic phase was dried, concentrated, and purified by column chromatography (PE:EA(v:v)=5:1) to obtain 500 mg of a colorless, transparent oily liquid, with a yield of 82.20%. 1 H NMR (400 MHz, Chloroform- d) δ 4.30 – 4.23 (m, 1H), 2.56 (t, J = 12.2 Hz, 4H), 2.48 (td, J = 6.8, 3.5 Hz, 2H), 2.08 (ddd, J = 10.1, 7.5, 3.0 Hz, 2H). Step 2: Synthesis of 6,6-difluorospiro[3.3]heptane-2-ylmethanesulfonate Following the synthesis method in step 2 of Example 11, 6,6-difluorospiro[3.3]heptan-2-ol was used as the starting material to synthesize 6,6-difluorospiro[3.3]heptan-2-yl methanesulfonate (730 mg, pale yellow liquid) with a yield of 95.61%.

[0206] Step 3: Synthesis of 2-chloro-5-((6,6-difluorospiro[3.3]heptane-2-yl)oxy)pyrimidine Following the synthetic method described in step 8 of Example 1, 2-chloro-5-((6,6-difluorospiro[3.3]heptane-2-yl)oxy)pyrimidine (500 mg, white solid) was synthesized from 6,6-difluorospiro[3.3]heptane-2-yl)oxy)methanesulfonate as the starting material, with a yield of 59.45%. MS (ESI, pos. ion) m / z: 261.1 [M+H] + . Step 4: Synthesis of 6'-(((1S,3S)-3-((5-((6,6-difluorospiro[3.3]heptane-2-yl)oxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Following the synthetic method described in step 4 of Example 7, using 2-chloro-5-((6,6-difluorospiro[3.3]heptane-2-yl)oxy)pyrimidine as the starting material, target compound 19 (20 mg, yellow solid) was synthesized in 6.59% yield. MS (ESI, pos.ion) m / z: 495.2 [M+H] + ; 1H NMR (400 MHz, CDCl3)δ 8.04 – 8.01 (m, 1H), 7.94 (s,2H), 7.53 – 7.49 (m, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.30 (s, 1H), 6.64 (d, J= 9.4 Hz, 1H), 6.43 (d, J = 9.0 Hz, 1H), 6.24 (d, J = 7.1 Hz, 1H), 4.95 (d, J= 7.2 Hz, 1H), 4.82 (d, J = 6.7 Hz, 1H), 4.52 – 4.47 (m, 1H), 4.37 (d, J =10.4 Hz, 1H), 4.24 (s, 1H), 2.65 – 2.57 (m, 6H), 2.34 – 2.27 (m, 4H), 2.07 –1.96 (m, 4H). Example 20: Synthesis of 3-(methylamino)-6'-(((1S,3S)-3-((5-((1-(trifluoromethyl)cyclopropyl)methoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Compound 20

[0207] Step 1: Synthesis of 3-amino-1-(6-chloropyridin-3-yl)-1,2-dihydropyridin-2-one Following the synthesis method in step 2 of Example 1, 3-amino-1-(6-chloropyridin-3-yl)-1,2-dihydropyridin-2-one (860 mg, yellowish-white solid) was synthesized from 2-chloro-5-iodopyridine as the starting material, with a yield of 72.34%.

[0208] Step 2: Synthesis of 1-(6-chloropyridin-3-yl)-3-(methylamino)-1,2-dihydropyridin-2-one 3-Amino-1-(6-chloropyridin-3-yl)-1,2-dihydropyridin-2-one (0.5 g, 2.26 mmol) was added to a 50 mL single-necked flask and dissolved in 15 mL of methanol. Acetic acid (0.014 g, 0.23 mmol) was then added, followed by formaldehyde (0.37 g, 4.29 mmol, 37% by mass). The reaction was carried out at room temperature for 2 h. Sodium cyanoborohydride (0.43 g, 6.78 mmol) was then added. After 4 h, TLC monitoring showed that the reactants had essentially reacted completely, and the reaction was stopped. The sample was evaporated to dryness, extracted with DCM (20 mL × 2) and water (10 mL), and the organic phase was collected. The sample was evaporated to dryness with anhydrous sodium sulfate, mixed, and subjected to column chromatography (PE:EA(v:v) = 10:1–5:1) to give 160 mg of a white solid. The yield was 30.09%. MS (ESI, pos. ion) m / z: 236.1 [M+H] + . Step 3: Synthesis of (1S,3S)-3-((3-(methylamino)-2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)tert-butyl carbamate Following the synthesis method in step 4 of Example 7, using 1-(6-chloropyridin-3-yl)-3-(methylamino)-1,2-dihydropyridin-2-one as the starting material, tert-butyl carbamate (110 mg, yellowish-white solid) was synthesized with a yield of 75.08%. Step 4: Synthesis of 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-(methylamino)-2H-[1,3'-bipyridine]-2-one Following the synthetic method in step 3 of Example 1, 6'-(((1S,3S)-3-((3-(methylamino)-2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)carbamate tert-butyl ester was synthesized as the starting material to obtain 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-(methylamino)-2H-[1,3'-bipyridine]-2-one (100 mg, yellow solid), with a yield of 99.62%. Step 5: Synthesis of 3-(methylamino)-6'-(((1S,3S)-3-((5-((1-(trifluoromethyl)cyclopropyl)methoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Following the synthetic method described in step 4 of Example 7, starting with 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-(methylamino)-2H-[1,3'-bipyridine]-2-one, the target compound 20 (27 mg, yellow solid) was synthesized in 20.67% yield. MS (ESI, pos. ion) m / z: 516.2 [M+H] + ; 1 H NMR (599 MHz, CDCl3) δ 8.10 –8.02 (m, 2H), 7.58 (dd, J = 8.9, 2.2 Hz, 1H), 7.35 – 7.30 (m, 1H), 7.12 –7.06 (m, 1H), 6.67 (d, J = 5.5 Hz, 1H), 6.51 (d, J = 8.9 Hz, 1H), 6.27 – 6.23(m, 1H), 6.22 (d, J = 6.3 Hz, 1H), 5.40 (s, 1H), 5.19 (s, 1H), 4.41 (dd, J =13.1, 6.6 Hz, 1H), 4.23 (s, 1H), 4.05 (s, 2H), 2.88 (s, 3H), 2.38 – 2.32 (m,2H), 2.04 (dd, J = 5.7, 3.2 Hz, 2H), 1.65 (d, J = 4.9 Hz, 2H), 1.44 (d, J =7.2 Hz, 4H). Activity test examples I. Determination of the concentration of PCSK9 and LDLR level secreted by HepG2 cells by the compounds of this invention HepG2 cells in good growth condition were digested with trypsin (Gibco, 25200072), resuspended in DMEM medium (Hyclone, SH30243.01B) containing 10% FBS (Gibco, 10099141C), counted, and seeded at a density of 25,000 cells / well in 96-well plates, 200 μL per well. The cells were cultured overnight at 37°C and 5% CO2 to allow adherence. The next day, the medium was discarded, and 200 μL of blank medium containing the compound or a blank control (0.5% DMSO) was added. The cells were then cultured at 37°C and 5% CO2 for another 48 h before the following analysis was performed.

[0209] Collect 100 μL of cell culture supernatant and use a human PCSK9 ELISA kit (Elite, E-EL-H6182) to detect PCSK9 levels. Set up standard wells, blank wells, and sample wells. Add 100 μL of serially diluted standard to the standard wells, 100 μL of standard and sample diluent to the blank wells, and 100 μL of sample to the remaining wells. Cover the plate and incubate at 37°C for 90 min. Discard the liquid from the wells, add 100 μL of biotinylated antibody working solution to each well, cover the plate, and incubate at 37°C for 1 h. Wash the plate three times with 350 μL of washing buffer per well, add 100 μL of HRP enzyme conjugate working solution to each well, cover the plate, and incubate at 37°C for 30 min. Wash the plate five times with 350 μL of washing buffer per well, add 90 μL of substrate solution to each well, and incubate at room temperature in the dark for 10 min. Add 50 μL of stop solution to each well to terminate the reaction, and immediately measure the absorbance (OD value) of each well at 450 nm using a microplate reader. Subtract the OD value of the blank well from the OD value of each well as the correction value. Calculate the standard curve based on the readings of the standard wells and determine the PCSK9 concentration in each sample well. Calculate the relative expression level of PCSK9 using the following formula: PCSK9 relative expression level % = Sample PCSK9 concentration / Average PCSK9 concentration in blank control * 100%.

[0210] Cell viability in 96-well plates with 100 μL of cell culture supernatant removed was assessed using CCK8 (Tongren Chemical, CK04). 10 μL of CCK8 reagent was added to each well, with 100 μL of cell-free blank culture medium in each well serving as a background control. The 96-well plates were incubated at 37°C and 5% CO2 for 10 min in the dark, and the OD value of each well was measured at 450 nm using a microplate reader. Relative cell viability was calculated using the following formula: Relative cell viability % = ((Test well value - Average background well value) / (Average blank control well value - Average background well value)) * 100%.

[0211] Following the same steps described above, plate another 96-well plate and administer the drug. Incubate at 37°C and 5% CO2 for 48 h. Discard the culture medium. Wash cells twice with phosphate-buffered saline (Ginobio, GMN20015-2). Add 50 μL of cell lysis buffer (Beyotime, P0013B) containing 1% PMSF to each well and lyse on ice for 10 min. Detect LDLR levels in the lysis buffer using a human LDLR ELISA kit (E-EL-H1211). Set up standard wells, blank wells, and sample wells. Add 100 μL of serially diluted standard to the standard wells, 100 μL of standard and sample diluent to the blank wells, and 100 μL of sample to the remaining wells. Cover the plate with a membrane and incubate at 37°C for 90 min. Discard the liquid from the wells, add 100 μL of biotinylated antibody working solution to each well, cover the plate with a membrane, and incubate at 37°C for 1 h. Wash the plate three times with 350 μL of washing buffer per well using a plate washer. Add 100 μL of HRP enzyme conjugate working solution to each well, cover the plate, and incubate at 37°C for 30 min. Wash the plate five times with 350 μL of washing buffer per well using a plate washer. Add 90 μL of substrate solution to each well and incubate at room temperature in the dark for 10 min. Stop the reaction by adding 50 μL of stop solution to each well. Immediately measure the absorbance (OD value) of each well at 450 nm using a microplate reader. Subtract the OD value of the blank well from the OD value of each well as the correction value. Calculate the standard curve based on the readings of the standard wells and determine the LDLR concentration of each sample well. Calculate the relative expression level of LDLR using the following formula: LDLR relative expression level % = Sample LDLR concentration / Average concentration of blank control PCSK9 * 100%.

[0212] The effects of the compounds of this invention at concentrations of 100 μM and 50 μM on the concentration of PCSK9 secreted by HepG2 cells and on the expression level of LDLR in HepG2 cells at a concentration of 50 μM are shown in Table 1 below.

[0213] Table 1

[0214] Note: "-" indicates that it has not been tested.

[0215] As shown in Table 1, the compounds of this invention have a good inhibitory effect on PCSK9 secreted by HepG2 cells and can upregulate LDLR levels.

[0216] II. Binding affinity test of the compounds of this invention to PCSK9 protein Surface plasmon resonance (SPR) analysis was performed using a Biacore 8K system to determine the binding affinity of the compounds to PCSK9. The CM5 sensor chip was activated with a mixture of 400 mM EDC and 100 mM NHS at a flow rate of 10 μL / min for 600 s. Subsequently, the PCSK9 protein was diluted to 50 μg / mL with 10 mM sodium acetate buffer and coupled at a flow rate of 5 μL / min for 600 s. Unbound sites were blocked with 1 M ethanolamine at a flow rate of 10 μL / min for 600 s. During the analysis phase, the analyte was diluted to an appropriate concentration with running buffer (10 mM PBS, pH 7.4, 137 mM NaCl, 2.7 mM KCl, 0.05% P2O, and 1% DMSO) and injected into the system at a flow rate of 30 μL / min. Binding and dissociation phases each lasted 180 s. Finally, all experimental results were fitted using a 1:1 kinetic model to determine the binding affinity of the compound to PCSK9.

[0217] Experiments show that the compounds of this invention have a good binding effect on PCSK9 protein. The binding affinity (Kd) of some compounds of this invention to PCSK9 protein at a concentration of 500 nM is shown in Table 2 below.

[0218] Table 2

[0219] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "some implementations," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments, implementations, or examples described in this specification, as well as the features of different embodiments, implementations, or examples.

[0220] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention without departing from the principles and spirit of the present invention, the scope of which is defined by the claims and their equivalents.

Claims

1. A compound, which is a compound of formula (I), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (I), (I)， in, Z 1 Z 2 Z 3 Z 4 and Z 5 Each is independently N or CR 4 ; L is -(CR) 5 R 6 ) r- R 5 and R 6 Each of the following is independently H, D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2; Ring A is C 3-7 Monocyclic cycloalkyl, C 5-12 Bridged cycloalkyl, C 5-12 Spirocyclic cycloalkyl, 3-7 membered monocyclic heterocyclic groups, 5-12 membered bridged heterocyclic groups, 5-12 membered spirocyclic heterocyclic groups, C 6-10 Aryl, 5-6 membered heteroaryl or 7-10 membered heteroaryl; Ring B is C 3-7 Monocyclic cycloalkyl, C 5-12 Bridged cycloalkyl, C 5-12 Spirocyclic cycloalkyl, 3-7 membered monocyclic heterocyclic groups, 5-12 membered bridged heterocyclic groups, 5-12 membered spirocyclic heterocyclic groups, C 6-10 Aryl, 5-6 membered heteroaryl or 7-10 membered heteroaryl; Each R 1 Independently, it is H, D, F, Cl, Br, I, CN, OH, NH2, COOH, oxo, -C(=O)NR 7 R 8 -S(=O)2C 1-6 Alkyl group, -S(=O)C 1-6 Alkyl group, -C(=O)C 1-6 Alkyl group, -NHC(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl group 2; or, two R atoms attached to the same carbon atom 1 Formed together with this carbon atom ; R a and R b Each of them independently is H, D, F, Cl, Br, I, CN, NH2, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups, -NH(C 1-6 alkyl) or -N(C) 1-6 Alkyl)2; R 7 and R 8 Each is independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups; Each R 2 Independently, H, D, F, Cl, Br, I, CN, OH, NR 7 R 8 COOH, oxo, -C(=O)NR 7 R 8 -S(=O)2C 1-6 Alkyl group, -S(=O)C 1-6 Alkyl group, -C(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally bounded by 1, 2, 3 or 4 R groups. c Replaced; Each R c Independently, they are D, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2; Each R 3 Independently, it is H, D, F, Cl, Br, I, CN, OH, NH2, COOH, oxo, -C(=O)NR 7 R 8 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2; Each R 4 Independently, H, D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2; m, n, q and r are each independently 0, 1, 2, 3 or 4; The condition is that the compound of formula (I) does not contain compound 6-(6-(((1) S ,3 S )-3-((5-(3-(difluoromethyl)cyclobutoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7 H -pyrrolo[3,4- b ]Pyridin-7-one and 6-(6-(((1) S ,3 S )-3-((5-(3,3-difluorocyclobutoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7 H -pyrrolo[3,4- b ]Pyridin-7-one.

2. The compound according to claim 1, wherein, Ring A is C 3-6 Monocyclic cycloalkyl, C 4-10 Bridged cycloalkyl, C 4-10 Spirocyclic cycloalkyl, 3-6 membered monocyclic heterocyclic group, 5-10 membered bridged ring heterocyclic group, 5-10 membered spirocyclic heterocyclic group, phenyl, naphthyl, 5-6 membered heteroaryl or 7-10 membered heteroaryl; Alternatively, ring A may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethylene, 1,4-dioxanecyclo, oxacyclobutyl, aziranecyclobutyl, thiohexanecyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidinyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptyl, 2-oxo-spiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, 1,4-dioxaspiro[4.4]nonyl, 5,8-oxaspiro[3.4]octyl, 1,1-dioxothiabutyl, 7-azirane[3.5]nonyl, 3-azibicyclo[3.1.0]hexyl, octahydrofuran[2,3- c Pyridyl, dihydropyridyl, dihydropyrimidinyl, dihydropyridazinyl, 1,3-dihydro-2 H -imidazolyl, 1,3-dihydro-2 H -benzo[ d Imidazolyl, 1,3-dihydro-2 H -imidazo[ 4,5-b ]Pyridyl, 1,3-dihydro-2 H -imidazo[ 4,5-b ]Pyrazinyl, 5,6-dihydro-7 H -pyrrolo[3,4- b ]Pyridyl, 5,6-dihydro-7 H -pyrrolo[3,4- b [3.1.0]Pyridyl, dioxo-3-azabicyclo[3.1.0]hexyl, phenyl, naphthyl, pyrrolithyl, pyrazolyl, tetrazolyl, imidazolyl, furanyl, thiaranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridopyrimidinyl, benzopyridyl, pyridopyrrolithyl, benzopyrazolyl, pyrrolopyrazolyl or benzothiazolyl.

3. The compound according to claim 1 or 2, wherein, Ring B is C 3-6 Monocyclic cycloalkyl, C 5-10 Bridged cycloalkyl, C 5-10 Spirocyclic cycloalkyl, 3-6 membered monocyclic heterocyclic group, 5-10 membered bridged ring heterocyclic group, 5-10 membered spirocyclic heterocyclic group, phenyl, naphthyl, 5-6 membered heteroaryl or 7-10 membered heteroaryl; Alternatively, ring B can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethylene, 1,4-dioxanecyclo, oxacyclobutyl, aziranecyclobutyl, thiohexanecyclobutyl, pyrrolyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidinyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, 2-oxaspiro[3.3]heptyl, 1,4-dioxaspiro[4.4]nonyl, 5,8-oxaspiro[3.4]octyl, 1,1-dioxothiabutyl, 1,1-dioxo-isothiazolin-2-yl, 7-azirane[3.5]nonyl, 3-azibicyclo[3.1.0]hexyl, octahydrofuran[2,3- c Pyridyl, dihydropyridyl, dihydropyrimidinyl, dihydropyridazinyl, 1,3-dihydro-2 H -imidazolyl, 1,3-dihydro-2 H -benzo[ d Imidazolyl, 1,3-dihydro-2 H -imidazo[ 4,5-b ]Pyridyl, 1,3-dihydro-2 H -imidazo[ 4,5-b ]Pyrazinyl, 5,6-dihydro-7 H -pyrrolo[3,4- b ]Pyridyl, 5,6-dihydro-7 H -pyrrolo[3,4- b ]pyridyl, dioxo-3-azabicyclo[3.1.0]hexyl, oxooctahydrofuran[2,3- c Pyridyl, oxodihydropyridyl, oxodihydropyrimidinyl, oxodihydropyridazinyl, oxoimidazoalkyl, oxopyrrolidinyl, dioxopyrrolidinyl, dioxoimidazoalkyl, oxo-1,3-dihydro-2 H -imidazolyl, oxo-1,3-dihydro-2 H -benzo[ d Imidazolyl, oxo-1,3-dihydro-2 H -imidazo[ 4,5-b ]pyridyl, oxo-1,3-dihydro-2 H -imidazo[ 4,5-b ]Pyrazinyl, oxo-5,6-dihydro-7 H -pyrrolo[3,4- b ]Pyridyl, dioxo-5,6-dihydro-7 H -pyrrolo[3,4- b ]pyridyl, oxo-1,2-dihydroquinolinyl, 2-oxo-3,4-dihydro-1,8-naphthidyl-1-yl, oxo-1,2,3,4-tetrahydroquinolinyl, 2-oxo-1,3-dihydro-2H-pyrrolo[2,3- b Pyridine, phenyl, naphthyl, pyrrolyl, pyrazolyl, tetrazolyl, imidazolyl, furanyl, thiaranyl, pyridyl, oxopyridyl, oxopyrimidinyl, oxopyridazinyl, pyrimidinyl, pyridinyl, pyridopyrimidinyl, benzopyrimidinyl, benzopyridyl, pyridopyrroleyl, benzopyrazolyl, pyrrolopyrazolyl, or benzothiazolyl.

4. The compound according to any one of claims 1-3, wherein, Ring B is phenyl, , , , , , , , , , , , , , , , , , , , , , or .

5. The compound according to any one of claims 1-4, wherein, Each R 1 Independently, it is H, D, F, Cl, Br, I, CN, OH, NH2, COOH, oxo, -C(=O)NR 7 R 8 -S(=O)2C 1-4 Alkyl group, -S(=O)C 1-4 Alkyl group, -C(=O)C 1-4 Alkyl group, -NHC(=O)C 1-4 Alkyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Halogenated alkoxy C 1-4 Alkyl, -NH(C) 1-4 alkyl) or -N(C) 1-4 Alkyl group 2; or, two R atoms attached to the same carbon atom 1 Formed together with this carbon atom ; R a and R b Each of them independently is H, D, F, Cl, Br, I, CN, NH2, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups, -NH(C) 1-4 alkyl) or -N(C) 1-4 Alkyl)2; R 7 and R 8 Each is independently H, D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl compounds.

6. The compound according to any one of claims 1-5, wherein, Each R 1 Independently, it is H, D, F, Cl, Br, I, CN, OH, NH2, COOH, oxo, -C(=O)NR 7 R 8 , -S(=O)2CH3, -S(=O)CH3, -C(=O)CH3, -NHC(=O)CH3, -NHC(=O)CH2CH3, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C( CH3)3, -CH≡CH, -CH≡CCH3, -CH2C≡CH, -(CH2)2C≡CH, -C=CH2, -(CH2)2C=CH2, -CH2=CHCH3, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -CH2OCH3, -(CH2)2OCH3, -CH2OCH2CH3, -(CH2)2OCH2CH3, -(CH2)3OCH3, -CH2OCF3, -(CH2)2OCF3, -CH2OCH2CF3, -(CH2)2OCH2CF3, -(CH2)3OCF3 or -CH2OCHFCF3; or, two R atoms attached to the same carbon atom. 1 Formed together with this carbon atom ; R a and R b Each can be independently H, D, F, Cl, Br, I, CN, NH2-CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3 or -N(CH3)2; R 7 and R 8 Each can be independently H, D, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, phenyl, pyrrolyl, pyrazolyl, tetrazolyl, imidazolyl, furanyl, thiaranyl, pyridinyl, pyrimidinyl, or pyrazinyl.

7. The compound according to any one of claims 1-6, wherein, Each R 2 Independently, H, D, F, Cl, Br, I, CN, OH, NR 7 R 8 COOH, oxo, -C(=O)NR 7 R 8 -S(=O)2C 1-4 Alkyl group, -S(=O)C 1-4 Alkyl group, -C(=O)C 1-4 Alkyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Halogenated alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Halogenated alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, phenyl, and 5-6-membered heteroaryl groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. c Replaced; Each R c Independently, they are D, F, Cl, Br, I, CN, OH, NH2, and C. 1-4 Alkyl group, -S(=O)2C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups, -NH(C) 1-4 alkyl) or -N(C) 1-4 alkyl) 2。 8. The compound according to any one of claims 1-7, wherein, Each R 2 Independently, H, D, F, Cl, Br, I, CN, OH, NR 7 R 8 COOH, oxo, -C(=O)NR 7 R 8 , -S(=O)2CH3, -S(=O)CH3, -C(=O)CH3, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, - CH2CH(CH3)2, -CH2C(CH3)3, -C=CH2, -(CH2)2C=CH2, -CH2=CHCH3, -CH≡CH, -CH≡CCH3, -CH2C≡C H, -(CH2)2C≡CH, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -OCH3, -OCH2CH3, -O(CH2 )2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -OCF3, -OCH2F, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHFCHF2 , -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -CH2OCH3, -(CH2)2OCH3, - CH2OCH2CH3, -(CH2)2OCH2CH3, -(CH2)3OCH3, -CH2OCF3, -(CH2)2OCF3, -CH2OCH2CF3, -(CH2)2 OCH2CF3, -(CH2)3OCF3, -CH2OCHFCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethylene, 1,4-dioxanecycloyl, oxacyclobutyl, aziranecyclobutyl, thioheranecyclobutyl, pyrrolidinyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, phenyl, pyrazolyl, tetrazolyl, imidazolyl, furanyl, thiaranyl, pyridinyl, pyrimidinyl or pyrazinyl;The following are some of the following: -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -C=CH2, -(CH2)2C=CH2, -CH2=CHCH3, -CH≡CH, -CH≡CCH3, -CH2C≡CH, -(CH2)2C≡CH, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -OCH2F, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHFCHF2, -CH2OH, -(CH2)2OH, -(CH2)2CH 2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -CH2OCH3, -(CH2)2OCH3, -CH2OCH2CH3, -(CH2)2OCH2CH 3. -(CH2)3OCH3, -CH2OCF3, -(CH2)2OCF3, -CH2OCH2CF3, -(CH2)2OCH2CF3, -(CH2)3OCF3, -C H2OCHFCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethylene, 1,4-dioxanecyclo, oxacyclobutyl, aziroxybutyl, thiohexacyclobutyl, pyrrolidinyl, pyrazolyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, phenyl, pyrazolyl, tetrazolyl, imidazolidinyl, furanyl, thiaranyl, pyridinyl, pyrimidinyl, and pyrazinyl are each independently and optionally marked with 1, 2, 3, or 4 Rs; c Replaced; Each R c Independently, it can be D, F, Cl, Br, I, CN, OH, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -S(=O)2CH3, -S(=O)2CH2CH3, -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3 or -N(CH3)2.

9. The compound according to any one of claims 1-8, wherein, Each R 4 Independently, H, D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, -NH(C) 1-4 alkyl) or -N(C) 1-4 Alkyl)2; R 5 and R 6 Each of the following is independently H, D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, -NH(C) 1-4 alkyl) or -N(C) 1-4 Alkyl)2.

10. The compound according to any one of claims 1-9, wherein, Each R 4 Independently, it can be H, D, F, Cl, Br, I, CN, OH, NH2, COOH, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3 or -N(CH3)2; R 5 and R 6 Each can be independently H, D, F, Cl, Br, I, CN, OH, NH2, COOH, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -CHFCHF2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -CH2OH, -(CH2)2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3 or -N(CH3)2.

11. The compound according to any one of claims 1-10, wherein it is a compound with the following structure, or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug, 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

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15.

16.

17.

18.

19.

20. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or 。 12. A pharmaceutical composition comprising the compound of any one of claims 1-11; optionally, the pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

13. Use of the compound of any one of claims 1-11 or the pharmaceutical composition of claim 12 in the preparation of a medicament for the prevention, treatment or relief of PCSK9-related diseases.

14. The use according to claim 13, wherein, The PCSK9-related diseases are cardiovascular diseases, cerebrovascular diseases, and atherosclerosis-related diseases; or, the PCSK9-related diseases are stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, vascular stenosis, chronic kidney disease, coronary heart disease, heart failure, atherosclerosis, hepatic steatosis, metabolic syndrome, and / or coronary artery disease.

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