Oxo-tricyclic derivative and pharmaceutical use thereof

Abstract

The present invention relates to an oxo-tricyclic derivative and the pharmaceutical use thereof, in particular to a compound as shown in general formula (I), or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof, an intermediate thereof, a preparation method therefor, and the use thereof in the preparation of a drug for treating diseases associated with WRN activity or expression level.

Description

An oxo-tricyclic derivative and its application in medicine Technical Field

[0001] The present invention relates to a compound of general formula (I) or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods, and their use in preparing drugs for treating diseases related to WRN activity or expression. Background Art

[0002] DNA mismatch repair (MMR) is a conserved mechanism that helps maintain genomic stability by eliminating errors generated during DNA replication, long-pathway DNA repair synthesis, and recombination. Germline or somatic mutations and epigenetic changes in MMR component genes lead to a hypermutation phenotype characterized by cancer susceptibility and high genomic instability, particularly in genomic repetitive regions (called microsatellites). Microsatellites, or short tandem repeats, are short (1-6 base pairs) repetitive DNA sequences distributed in coding and non-coding regions, accounting for approximately 3% of the human genome. MMR defects lead to a phenotype called microsatellite instability (MSI), which is characterized by the accumulation of repeat length changes in microsatellite regions (Mol. Med Today 1997: 3, 61-68). A considerable proportion of MSI tumors do not respond to or develop resistance to immunotherapy and chemotherapy, suggesting that patients with MSI tumors are looking forward to the emergence of more and improved targeted and combination therapies (J. Immunother. Cancer, 2022: 10, 4001).

[0003] Numerous publications have reported a promising synthetic lethal relationship between RecQ-like family helicase proteins (WRN) and MSI tumors (iScience 2019:13, 488-497; Nature 2019:568, 551-556). WRN is a multifunctional enzyme with both helicase and exonuclease activities that plays a role in various cellular processes involved in maintaining genomic stability, including DNA replication, transcription, DNA repair, and telomere maintenance. Using CRISPR-Cas9 and RNAi screening, WRN was identified as essential in MSI but not microsatellite stability (MSS) cancer cell lines. Further analysis revealed that WRN depletion resulted in cell cycle arrest, DNA damage, mitotic defects, chromosome breakage, and apoptosis in MSI cells. Furthermore, WRN depletion reduced xenograft growth and tumor formation in mice transplanted with MSI cells (npj Precision Oncology 2022:85).

[0004] These findings suggest that the development of WRN inhibitors for the treatment of MSI tumors has potential applications. Currently, there are no reports of WRN inhibitors on the market or in clinical development, and the research and development of WRN inhibitors is urgently needed.

[0005] Summary of the Invention

[0006] The present invention aims to provide a class of heterocyclic compounds or pharmaceutically acceptable salts thereof for use as WRN inhibitors. The compounds of the present invention can effectively inhibit WRN and can be used to treat diseases such as tumors. The compounds of the present invention have good inhibitory activity against WRN helicase and have good cell proliferation inhibition effects on HCT-116 and SW48 cells, but poor cell proliferation inhibition activity against HT-29 cells. They have low toxicity and safety, such as weak inhibitory activity against CYP enzymes and hERG, and have good pharmacokinetic properties, such as good bioavailability and a suitable half-life.

[0007] The present invention provides a compound of general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals.

[0008] In some embodiments, represents a single bond or a double bond;

[0009] In some embodiments, Formula (I) is selected from Formula (Ia),

[0010] In some embodiments, Formula (I) is selected from Formula (Ib),

[0011] In some embodiments, Ring A is selected from C 3-15 carbocyclic or 4 to 15 membered heterocyclic ring, wherein the ring A is optionally substituted by 1 to 6 R a replace;

[0012] In some embodiments, ring A is selected from phenyl, 5- to 6-membered heteroaryl, C 3-6 Monocarbocyclic, 4 to 8 membered heteromonocyclic, wherein the ring A is optionally substituted by 1 to 5 R a replace;

[0013] In some embodiments, Ring A is selected from the group consisting of a substituted one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrrolyl, dihydropyridinyl, dihydrofuranyl, dihydropyranyl, phenyl, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl;

[0014] In some embodiments, Ring A is selected from the group consisting of a One of the following groups substituted:

[0015] In some embodiments, ring C is selected from C 3-15 carbocyclic or 4 to 15 membered heterocyclic ring, wherein the ring C is optionally substituted by 1 to 6 R c replace;

[0016] In some embodiments, ring C is selected from phenyl, naphthyl, benzo 4-6 carbocyclic, benzo 4 to 7 membered heterocyclic, 5 to 6 membered heteroaryl or 8-10 membered heteroaryl, wherein the ring C is optionally substituted by 1 to 5 R c replace;

[0017] In some embodiments, Ring C is selected from the group consisting of csubstituted one of the following groups: phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, benzopyrrolyl, benzothienyl, benzofuranyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzopyridazinyl, pyridopyrrolyl, pyridothiphenyl, pyridofuranyl, pyridopyrazolyl, pyridoimidazolyl, pyridothiazolyl, pyridisothiazolyl, pyridoxazolyl, pyridisoxazolyl, pyridopyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl,

[0018] In some embodiments, Ring C is selected from the group consisting of c One of the following groups substituted:

[0019] In some embodiments, Ring C is selected from the group consisting of c One of the following groups substituted:

[0020] In some embodiments, Ring C is selected from the group consisting of c One of the following groups substituted:

[0021] In some embodiments, Ring C is selected from In some embodiments, Ring C is selected from

[0022] In some embodiments, ring D is selected from C 3-15 carbocyclic or 4 to 15 membered heterocyclic ring, wherein the ring D is optionally substituted with 1 to 6 R d replace;

[0023] In some embodiments, ring D is selected from phenyl, naphthyl, benzo 4-6 carbocyclic, benzo 4 to 7 membered heterocyclic, 5 to 6 membered heteroaryl or 8-10 membered heteroaryl, wherein the ring D is optionally substituted by 1 to 5 R d replace;

[0024] In some embodiments, Ring D is selected from the group consisting of dsubstituted one of the following groups: phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, benzopyrrolyl, benzothienyl, benzofuranyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, pyridopyrrolyl, pyridothiphenyl, pyridofuranyl, pyridopyrazolyl, pyridoimidazolyl, pyridothiazolyl;

[0025] In some embodiments, Ring D is selected from the group consisting of d One of the following groups substituted:

[0026] In some embodiments, Selected from 1 to 3 R d One of the following groups substituted:

[0027] In some embodiments, Ring D is selected from y1 is selected from 0, 1, 2, preferably In some embodiments, Ring D is selected from

[0028] In some embodiments, Ring E is selected from C 4-10 carbocyclic or 4 to 10 membered heterocyclic ring, wherein the ring E is optionally substituted by 1 to 6 R e replace;

[0029] In some embodiments, Selected from It is directly connected to X2 above, s1 and s2 are independently selected from 0, 1, 2, 3; p1 is independently selected from 0, 1, 2, 3 or 4;

[0030] In some embodiments, each E1 is independently selected from NR e 、C(R e )2, O, S(=O)2 or S;

[0031] In some embodiments, each E1 is independently selected from NH, CH2, O, S(=O)2 or S;

[0032] In some embodiments, each of E1 is independently selected from NH, CH2, C(R e )2, O, S(=O)2 or S;

[0033] In some embodiments, Selected from It is directly connected to X2 directly above;

[0034] In some embodiments, Selected from Its left end is directly connected to ring A, s1 and s2 are each independently selected from 0, 1, and 2;

[0035] In some embodiments, Selected from Its left end is directly connected to ring A;

[0036] In some embodiments, Selected from Its left end is directly connected to ring A;

[0037] In some embodiments, X1, X2, X3, X4, X5, and X6 are each independently selected from N, CH, or C, at least two of X3, X4, X5, and X6 are selected from N, and at least one of X1 and X2 is selected from N;

[0038] In some embodiments, Selected from Its left end is directly connected to ring A;

[0039] In some embodiments, B is selected from B1 or B2;

[0040] In some embodiments, B1 is selected from

[0041] In some embodiments, B1 is selected from In some embodiments, B1 is selected from

[0042] In some embodiments, B2 is selected from

[0043] In some embodiments, B2 is selected from

[0044] In some embodiments, B2 is selected from m5 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0045] In some embodiments, B is selected from In some embodiments, B is selected from

[0046] In some embodiments, B is selected from B3 is selected from 5 to 7 membered heterocycloalkyl, 7 to 11 membered spiroheterocycloalkyl, 7 to 11 membered spiroheterocycloalkyl, 7 to 11 membered bridged heterocycloalkyl; B3 is preferably selected from

[0047] In some embodiments, B is selected from

[0048] In some embodiments, B is selected from In some embodiments, B is selected from In some embodiments, B is selected from

[0049] In some embodiments, n1, n2, n3, n4, n9, n10 are each independently selected from 1, 2, 3 or 4; in some embodiments, n1, n2, n3, n4 are each independently selected from 0, and the sum of n1, n2, n3, n4 is greater than 2;

[0050] In some embodiments, n5, n6, n7, n8, n11 are each independently selected from 0, 1, 2, 3 or 4;

[0051] In some embodiments, m1, m2, and m3 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, or 8; in some embodiments, m3 is selected from 0, 1, 2, 3, and 4; in some embodiments, m3 is selected from 0, 1, and 2; in some embodiments, m1 and m2 are each independently selected from 0, 1, 2, 3, and 4; in some embodiments, m1 is each independently selected from 0, 1;

[0052] In some embodiments, m5 is selected from 0, 1, 2, 3, 4;

[0053] In some embodiments, L is selected from -C(=O)-, -S(=O)-, -S(=O)(=NH)-, or -S(=O)2-;

[0054] In some embodiments, L is selected from -C(=O)-;

[0055] In some embodiments, R 1 Selected from H, deuterium, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, said alkyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0056] In some embodiments, R 1 Selected from H, deuterium, C 1-4 Alkyl, C 3-6 Carbocyclic ring, the alkyl group, the carbocyclic ring is optionally substituted by 1 to 4 R k replace;

[0057] In some embodiments, R 1 is selected from H, methyl, ethyl, cyclopropyl;

[0058] In some embodiments, R a 、R b 、R c 、R d 、R e Each independently selected from H, deuterium, halogen, OH, =O, CN, NH2, SF5, COOH, CONH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, -C(=O)NH-C 1-6 Alkyl, -C(=O)N(C 1-6 Alkyl)2, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbocyclic ring, -C 0-4 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k replace;

[0059] In some embodiments, R a 、R b 、R c 、R d 、R e Each independently selected from H, deuterium, halogen, OH, =O, CN, NH2, SF5, COOH, CONH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, -C(=O)NH-C 1-4 Alkyl, -C(=O)N(C 1-4 Alkyl)2, -OC3-6 Carbocycle, -O-3 to 6-membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 6-membered heterocyclic ring, -C 0-2 Alkylene-C 3-6 Carbocyclic ring, -C 0-2 Alkylene-3 to 6 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k replace;

[0060] In some embodiments, R a 、R b 、R c 、R d 、R e Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, CN, NH2, SF5, COOH, CONH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R k substituted one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl;

[0061] In some embodiments, R a 、R b 、R c 、R d Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, CN, NH2, SF5, COOH, CONH2, NHCH3, N(CH3)2, CD3, CHF2, CF3, CH2F, OCHF2, OCF3, SCF3, OCH2F, CH2CN, CHF2CH3, CHF2CF3, CH2OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl,

[0062] In some embodiments, R b Selected from -C 1-4 Alkylene-OC 3-6 Carbocyclic ring, -C 1-4 Alkylene-OC 1-6 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 1-6 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkylene-OC3-6 Carbocyclic ring, the alkyl, alkylene, carbocyclic ring is optionally 1 to 4 R k replace;

[0063] In some embodiments, R b Selected from -C 1-2 Alkylene-OC 3-6 Carbocyclic ring, -C 1-2 Alkylene-OC 1-4 Alkyl, -C 1-2 Alkylene-OC 1-2 Alkylene-OC 1-4 Alkyl, -C 1-2 Alkylene-OC 1-3 Alkylene-OC 3-6 Carbocyclic ring, the alkyl, alkylene, carbocyclic ring is optionally 1 to 4 R k replace;

[0064] In some embodiments, R b is selected from -methylene-O-cyclopropyl, -ethylene-O-methyl, -methylene-O-methyl, -methylene-O-ethyl, -methylene-O-ethylidene-O-methyl, -methylene-O-ethylidene-O-ethyl, -methylene-O-ethylidene-O-propyl, -methylene-O-ethylidene-O-cyclopropyl, -methylene-O-methylene-O-cyclopropyl, -methylene-O-ethylidene-O-cyclobutyl, wherein the methylene, ethylene, methyl, ethyl, propyl, cyclopropyl or cyclobutyl is optionally substituted by 1 to 4 R k replace;

[0065] In some embodiments, R b Selected from -CH2-O-cyclopropyl, -CH2-OCH3, -CH2-O-CH2CH2OCH3, -CH2OCH2CH2OCH2CH2OCH3, -CH2-O-CH2CH2O-cyclopropyl;

[0066] In some embodiments, R e Each is independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, SF5, COOH, CONH2, NHCH3, N(CH3)2, CD3, CHF2, CF3, CH2F, OCHF2, OCF3, SCF3, OCH2F, CH2CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl;

[0067] In some embodiments, the two R b Together with the atoms or ring skeletons to which it is connected, it forms a C3-6 Carbocyclic or 4- to 8-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0068] In some embodiments, the two R b Together with the atoms or ring skeletons to which it is connected, it forms a C 3-6 Cycloalkyl or 4 to 7 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl being optionally substituted by 1 to 4 R k replace;

[0069] In some embodiments, the two R b and the carbon atom directly connected thereto together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azopentyl, or azohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azopentyl, or azohexyl group is optionally substituted by 1 to 4 R k replace;

[0070] In some embodiments, both R b Together with the atoms or ring skeletons to which it is connected, it forms a C 3-6 Carbocyclic or 4- to 8-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0071] In some embodiments, both R b and the carbon atom directly connected thereto together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azopentyl, or azohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azopentyl, or azohexyl group is optionally substituted by 1 to 4 R k replace;

[0072] In some embodiments, both R e Together with the atoms it is connected to form C 3-6 Carbocyclic or 4- to 8-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0073] In some embodiments, both R e and the carbon atom directly connected thereto together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl are optionally substituted by 1 to 4 R k replace;

[0074] In some embodiments, R kEach independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 1-4 Alkylene-C 3-6 Carbocyclic ring, -C 1-4 Alkylene-3 to 7 membered heterocyclic ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0075] In some embodiments, R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocycle, -O-3 to 6-membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 6-membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 6 membered heterocyclic ring, C 3-6 Carbocyclic ring, 3 to 6 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0076] In some embodiments, R keach independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 groups selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0077] In some embodiments, R k Each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrole Alkyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy;

[0078] In some embodiments, R k Each is independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NH2, NO2, SF5, COOH, CONH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, CD3, OCD3, CF3, CH2F, CHF2, CH2OH, OCF3, OCHF2, OCH2F, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0079] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0080] Ring A is selected from C 3-15 carbocyclic or 4 to 15 membered heterocyclic ring, wherein the ring A is optionally substituted by 1 to 6 R a replace;

[0081] Ring C is selected from C 3-15 carbocyclic or 4 to 15 membered heterocyclic ring, wherein the ring C is optionally substituted by 1 to 6 R c replace;

[0082] Ring D is selected from C 3-15 carbocyclic or 4 to 15 membered heterocyclic ring, wherein the ring D is optionally substituted with 1 to 6 R d replace;

[0083] Ring E is selected from C 4-10 carbocyclic or 4 to 10 membered heterocyclic ring, wherein the ring E is optionally substituted by 1 to 6 R e replace;

[0084] B is selected from B1 or B2;

[0085] B1 is selected from

[0086] B2 is selected from Indicates a single bond or a double bond;

[0087] n1, n2, n3, n4, n9, n10 are each independently selected from 1, 2, 3 or 4; or n1, n2, n3, n4 are each independently selected from 0, and the sum of n1, n2, n3, n4 is greater than 2;

[0088] n5, n6, n7, n8, n11 are each independently selected from 0, 1, 2, 3 or 4;

[0089] m1, m2, m3 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0090] L is selected from -C(=O)-, -S(=O)-, -S(=O)(=NH)- or -S(=O)2-;

[0091] X1, X2, X3, X4, X5, and X6 are each independently selected from N, CH, or C, at least two of X3, X4, X5, and X6 are selected from N, and at least one of X1 and X2 is selected from N;

[0092] R 1 Selected from H, deuterium, C 1-6 Alkyl, C 3-6Carbocyclic ring, 3 to 7 membered heterocyclic ring, said alkyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0093] R a 、R b 、R c 、R d 、R e Each independently selected from H, deuterium, halogen, OH, =O, CN, NH2, SF5, COOH, CONH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, -C(=O)NH-C 1-6 Alkyl, -C(=O)N(C 1-6 Alkyl)2, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbocyclic ring, -C 0-4 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k replace;

[0094] or R b Selected from -C 1-4 Alkylene-OC 3-6 Carbocyclic ring, -C 1-4 Alkylene-OC 1-6 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 1-6 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 3-6 Carbocyclic ring, the alkyl, alkylene, carbocyclic ring is optionally 1 to 4 R k replace;

[0095] Alternatively, the two R b Together with the atoms or ring skeletons to which it is connected, it forms a C 3-6 Carbocyclic or 4- to 8-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0096] Alternatively, two R e Together with the atoms it is connected to form C 3-6Carbocyclic or 4- to 8-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0097] R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7-membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 1-4 Alkylene-C 3-6 Carbocyclic ring, -C 1-4 Alkylene-3 to 7 membered heterocyclic ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent.

[0098] As a second embodiment of the present invention, the compound represented by the following general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0099] Ring A is selected from phenyl, 5- to 6-membered heteroaryl, C 3-6 Monocarbocyclic, 4 to 8 membered heteromonocyclic, wherein the ring A is optionally substituted by 1 to 5 R a replace;

[0100] Ring C is selected from phenyl, naphthyl, benzo 4-6 carbocyclic, benzo 4 to 7 membered heterocyclic, 5 to 6 membered heteroaryl or 8-10 membered heteroaryl, wherein the ring C is optionally substituted by 1 to 5 R c replace;

[0101] Ring D is selected from phenyl, naphthyl, benzo 4-6 carbocyclic, benzo 4 to 7 membered heterocyclic, 5 to 6 membered heteroaryl or 8-10 membered heteroaryl, wherein the ring D is optionally substituted by 1 to 5 R d replace;

[0102] Selected from Its left end is directly connected to ring A;

[0103] Selected from It is directly connected to X2 above, and s1 and s2 are independently selected from 0, 1, 2, and 3;

[0104] p1 is each independently selected from 0, 1, 2, 3 or 4;

[0105] E1 is each independently selected from NR e 、C(R e )2, O, S(=O)2 or S;

[0106] R 1 Selected from H, deuterium, C 1-4 Alkyl, C 3-6 Carbocyclic ring, the alkyl group, the carbocyclic ring is optionally substituted by 1 to 4 R k replace;

[0107] Alternatively, two R e Together with the atoms it is connected to form C 3-6 Carbocyclic or 4- to 8-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0108] The remaining definitions are the same as those of the first embodiment of the present invention.

[0109] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0110] B2 is selected from

[0111] R a 、R b 、R c 、R d 、R e Each independently selected from H, deuterium, halogen, OH, =O, CN, NH2, SF5, COOH, CONH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, -C(=O)NH-C 1-4 Alkyl, -C(=O)N(C 1-4 Alkyl)2, -OC 3-6 Carbocycle, -O-3 to 6-membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 6-membered heterocyclic ring, -C 0-2Alkylene-C 3-6 Carbocyclic ring, -C 0-2 Alkylene-3 to 6 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k replace;

[0112] or R b Selected from -C 1-2 Alkylene-OC 3-6 Carbocyclic ring, -C 1-2 Alkylene-OC 1-4 Alkyl, -C 1-2 Alkylene-OC 1-2 Alkylene-OC 1-4 Alkyl, -C 1-2 Alkylene-OC 1-3 Alkylene-OC 3-6 Carbocyclic ring, the alkyl, alkylene, carbocyclic ring is optionally 1 to 4 R k replace;

[0113] Alternatively, the two R b Together with the atoms or ring skeletons to which it is connected, it forms a C 3-6 Cycloalkyl or 4 to 7 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl being optionally substituted by 1 to 4 R k replace;

[0114] R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocycle, -O-3 to 6-membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 6-membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 6 membered heterocyclic ring, C 3-6 Carbocyclic ring, 3 to 6 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0115] The remaining definitions are the same as those of the first or second embodiment of the present invention.

[0116] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0117] Selected from Its left end is directly connected to ring A, s1 and s2 are each independently selected from 0, 1, and 2;

[0118] L is selected from -C(=O)-;

[0119] R 1 is selected from H, methyl, ethyl, cyclopropyl;

[0120] R a 、R b 、R c 、R d 、R e Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, CN, NH2, SF5, COOH, CONH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R k substituted one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl;

[0121] or R b is selected from -methylene-O-cyclopropyl, -ethylene-O-methyl, -methylene-O-methyl, -methylene-O-ethyl, -methylene-O-ethylidene-O-methyl, -methylene-O-ethylidene-O-ethyl, -methylene-O-ethylidene-O-propyl, -methylene-O-ethylidene-O-cyclopropyl, -methylene-O-methylene-O-cyclopropyl, -methylene-O-ethylidene-O-cyclobutyl, wherein the methylene, ethylene, methyl, ethyl, propyl, cyclopropyl or cyclobutyl is optionally substituted by 1 to 4 R k replace;

[0122] Alternatively, the two R b and the carbon atom directly connected thereto together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azopentyl, or azohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azopentyl, or azohexyl group is optionally substituted by 1 to 4 R k replace;

[0123] Alternatively, two R eand the carbon atom to which it is attached together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl is optionally substituted by 1 to 4 R k replace;

[0124] R k each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 groups selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0125] The remaining definitions are the same as those of the first, second or third embodiment of the present invention.

[0126] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0127] Ring A is selected from the group consisting of a substituted one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrrolyl, dihydropyridinyl, dihydrofuranyl, dihydropyranyl, phenyl, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl;

[0128] Ring C is selected from optionally 1 to 4 R csubstituted one of the following groups: phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, benzopyrrolyl, benzothienyl, benzofuranyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzopyridazinyl, pyridopyrrolyl, pyridothiphenyl, pyridofuranyl, pyridopyrazolyl, pyridoimidazolyl, pyridothiazolyl, pyridisothiazolyl, pyridoxazolyl, pyridisoxazolyl, pyridopyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl,

[0129] Ring D is selected from the group consisting of d substituted one of the following groups: phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, benzopyrrolyl, benzothienyl, benzofuranyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, pyridopyrrolyl, pyridothiphenyl, pyridofuranyl, pyridopyrazolyl, pyridoimidazolyl, pyridothiazolyl;

[0130] B2 is selected from

[0131] m5 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0132] B1 is selected from

[0133] Or B1 is selected from

[0134] R kEach independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, Ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, methoxy, and ethoxy;

[0135] The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

[0136] As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0137] Selected from Its left end is directly connected to ring A;

[0138] E1 is each independently selected from NH, CH2, O, S(=O)2 or S;

[0139] or E1 are each independently selected from C(R e )2;

[0140] Ring A is selected from the group consisting of a One of the following groups substituted:

[0141] Ring C is selected from optionally 1 to 4 R c One of the following groups substituted: or Ring C is selected from optionally 1 to 3 R c One of the following groups substituted: Selected from

[0142] Ring D is selected from the group consisting of d One of the following groups substituted: Selected from y1 is selected from 0, 1, 2;

[0143] B is selected from Selected from

[0144] m3 is selected from 0, 1, 2, 3, 4;

[0145] m5 is selected from 0, 1, 2, 3, 4; m1 and m2 are each independently selected from 0, 1, 2, 3, 4;

[0146] R a 、R b 、R c 、R d Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, CN, NH2, SF5, COOH, CONH2, NHCH3, N(CH3)2, CD3, CHF2, CF3, CH2F, OCHF2, OCF3, SCF3, OCH2F, CH2CN, CHF2CH3, CHF2CF3, CH2OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl,

[0147] or R b Selected from -CH2-O-cyclopropyl, -CH2-OCH3, -CH2-O-CH2CH2OCH3, -CH2OCH2CH2OCH2CH2OCH3, -CH2-O-CH2CH2O-cyclopropyl;

[0148] R e Each is independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, SF5, COOH, CONH2, NHCH3, N(CH3)2, CD3, CHF2, CF3, CH2F, OCHF2, OCF3, SCF3, OCH2F, CH2CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl;

[0149] The remaining definitions are the same as those of the first, second, third, fourth or fifth embodiment of the present invention.

[0150] As a seventh embodiment of the present invention, the compound represented by the aforementioned general formula (Ib) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0151] Ring A is selected from the group consisting of a substituted one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrrolyl, dihydropyridinyl, dihydrofuranyl, dihydropyranyl, phenyl, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl;

[0152] Ring C is selected from optionally 1 to 4 R c substituted one of the following groups: phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, benzopyrrolyl, benzothienyl, benzofuranyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzopyridazinyl, pyridopyrrolyl, pyridothiphenyl, pyridofuranyl, pyridopyrazolyl, pyridoimidazolyl, pyridothiazolyl, pyridisothiazolyl, pyridoxazolyl, pyridisoxazolyl, pyridopyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl,

[0153] Ring D is selected from the group consisting of d substituted one of the following groups: phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, benzopyrrolyl, benzothienyl, benzofuranyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, pyridopyrrolyl, pyridothiphenyl, pyridofuranyl, pyridopyrazolyl, pyridoimidazolyl, pyridothiazolyl;

[0154] B is selected from

[0155] Preferably, B is selected from

[0156] m5 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0157] m3 is each independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; preferably 0, 1, 2;

[0158] m1 and m2 are each independently selected from 0, 1, 2, 3, and 4; preferably 0 and 1;

[0159] R a 、R b 、R c 、R d Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, CN, NH2, SF5, COOH, CONH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R k substituted one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl;

[0160] Preferably, R b Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, SF5, NHCH3, N(CH3)2, CD3, CHF2, CF3, CH2F, CHF2CF3, CHF2CH3, OCHF2, OCF3, SCF3, OCH2F, CH2CN, CH2OH, -CH2-OCH3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy;

[0161] R k Each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrole Alkyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy.

[0162] As an eighth embodiment of the present invention, the compound represented by the aforementioned general formula (Ib) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0163] Ring A is selected from the group consisting of a One of the following groups substituted: Selected from

[0164] Ring C is selected from optionally 1 to 4 R c One of the following groups substituted:

[0165] Preferably selected from the group consisting of 1 to 2 R c One of the following groups substituted:

[0166] Ring D is selected from the group consisting of d One of the following groups substituted: Selected from y1 is selected from 0, 1, 2; further preferably

[0167] B is selected from Selected from

[0168] R a 、R c 、R d Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, CN, NH2, SF5, COOH, CONH2, NHCH3, N(CH3)2, CD3, CHF2, CF3, CH2F, CHF2CF3, CHF2CH3, OCHF2, OCF3, SCF3, OCH2F, CH2CN, CH2OH, -CH2-OCH3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl,

[0169] Preferably, R a 、R c 、R dEach is independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, SF5, NHCH3, N(CH3)2, CD3, CHF2, CF3, CH2F, CHF2CF3, CHF2CH3, OCHF2, OCF3, SCF3, OCH2F, CH2CN, CH2OH, -CH2-OCH3, methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy.

[0170] The present invention relates to the compounds shown below or their stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein the compound is selected from one of the structures shown in Table E-1.

[0171] Table E-1

[0172] The present invention relates to a pharmaceutical composition comprising any of the above compounds or their stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and a pharmaceutically acceptable carrier.

[0173] The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0174] In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as the "preparation strength").

[0175] As used herein, an "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated (e.g., a WRN abnormality-related disease such as cancer). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg , 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-40 0mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250- 400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg , 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.

[0176] In some embodiments, the pharmaceutical composition includes but is not limited to 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 1 70 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of a compound of the present invention or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0177] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, wherein the therapeutically effective amount is preferably 1-1500 mg. The disease is preferably a disease associated with WRN activity or expression (such as a tumor, preferably an MSI-H solid tumor or an MMRD solid tumor).

[0178] A method for treating a disease in a mammal, comprising administering to a subject a compound of the present invention or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof at a daily dose of 1-1000 mg / day, wherein the daily dose may be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, or the like. g / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, daily doses include but are not limited to 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, 1000 mg / day.

[0179] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as the amount in the above-mentioned pharmaceutical composition.

[0180] The present invention relates to the use of any of the above-mentioned compounds or their stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals for the preparation of drugs for treating diseases related to WRN activity or expression. Preferably, the disease is selected from tumors, and more preferably MSI-H solid tumors and MMRD solid tumors.

[0181] The present invention relates to the use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating a disease associated with WRN activity or expression. Preferably, the disease is selected from tumors, preferably MSI-H solid tumors and MMRD solid tumors.

[0182] The amount of the compound of the invention or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof is in each case calculated as the free base.

[0183] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0184] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include79 Br and 81 Br.

[0185] "CN" refers to cyano.

[0186] "Halogen" refers to F, Cl, Br or I.

[0187] "Halogen-substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is abbreviated as "halo".

[0188] "Alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0189] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0190] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, and adamantane. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0191] " Heterocycloalkyl " refers to a saturated cyclic hydrocarbon radical containing heteroatoms that is substituted or unsubstituted, including but not limited to 3 to 12 atoms, 3 to 8 atoms, comprising 1 to 3 heteroatoms selected from N, O, S or Se, and the C, N, S on the ring of heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocycle, a ring, a bridged ring and a spirocycle. Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazolidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl, The heterocycloalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0192] "Alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-4-butenyl, 2-methyl-5-butenyl, 2-methyl-6-butenyl, 2-methyl-7-butenyl, 2-methyl-8-butenyl, 2-methyl-9-butenyl, 2-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3 ... -methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent or tetravalent.

[0193] "Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, and 2 to 4 carbon atoms in the backbone. Examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 6-pentynyl, 7-pentynyl, 8-pentynyl, 9-pentynyl, 10-pentynyl, 11-pentynyl, 12-pentynyl, 13-pentynyl, 14-pentynyl, 15-pentynyl, 16-pentynyl, 17-pentynyl, 18-pentynyl, 19-pentynyl, 20-pentynyl, 21-pentynyl, 22-pentynyl, 23-pentynyl, 24-pentynyl, 25-pentynyl, 26-pentynyl, 27-pentynyl, 28-pentynyl, 29-pentynyl, 30-pentynyl, 31-pentynyl, 32-pentynyl, 33-pentynyl, 34-pentynyl, 35-pentynyl, 36-pentynyl, 37-pentynyl, 38-pentynyl, 39-pentynyl, 40-pentynyl, 41-pentynyl, 42-pentynyl, 43-pentynyl, 44-pentynyl, 45-pentynyl, 46-pentynyl, 47-pentynyl, 48-pentyn Alkynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, and the like; an alkynyl group may be monovalent, divalent, trivalent, or tetravalent.

[0194] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0195] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocycle, a 4-12 membered bicycle, a 10-15 membered tricycle, or a 12-18 membered quaternary system. The carbocyclyl can be attached to the aromatic or non-aromatic ring, and the ring can be optionally a monocycle, a cyclic ring, a bridged ring, or a spirocycle. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, a benzene ring, a naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0196] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary ring, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se optionally substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused or spirocyclic ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxane, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiazyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.

[0197] "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom), and the number of ring atoms in the spirocycle system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 atoms selected from N, O or S (=O) n (n is 0, 1 or 2).

[0198] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0199] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted, and each ring in the parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0200] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in the bridged ring system may contain zero to five atoms selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, where n is 0, 1, or 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include "Bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

[0201] "Carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0202] "Carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" refers to a "carbocyclyl" ring system consisting of only carbon atoms.

[0203] "Carbobridged ring," "bridged carbocyclic group," "bridged carbocyclic group," or "carbon-bridged cyclic group" refers to a "bridged ring" in which the ring system consists of only carbon atoms.

[0204] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle",

[0205] "Heterocyclo", "heterocycloalkyl", "cycloheterocyclyl" or "cycloheterocyclyl" refers to a "cyclo" containing a heteroatom.

[0206] "Heterospirocycle," "heterospirocyclyl," "spiroheterocyclyl," or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom.

[0207] "Heterobridged ring", "heterobridged cyclic group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing a heteroatom.

[0208] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

[0209] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O, S(=O)n or Se(=O)n, where n is 0, 1 or 2). The number of ring atoms in the heteroaromatic ring is, but not limited to, 5 to 15, 5 to 10 or 5 to 6. The ring atoms C, N, and S are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1 or 2). Non-limiting examples of heteroaryl include but are not limited to pyridyl, furyl, thienyl, selenophenyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include When heteroaryl appears in this document, its definition is consistent with this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment point is located on the ring with aromaticity.

[0210] "Substituted" or "substituted" refers to substitution by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2), m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c R is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c Can form five or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or paracyclic group.

[0211] "1 to X substituents selected from..." means substituted by 1, 2, 3, ..., X substituents selected from ..., where X is any integer from 1 to 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k Substitution. For example, "substituted by 1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4, or 5 substituents selected from..." For example, "a heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3, or 4 substituents selected from H or F.

[0212] An XY-membered ring (X and Y are integers, and 3≤X<Y, X<Y≤20 is selected from any integer between 4 and 20) includes rings with X, X+1, X+2, X+3, X+4, ..., Y members. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heterocyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring.

[0213] C x-y Carbocycles (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, fused carbocycle or bridged carbocycle) include C x 、C x+1 、C x+2 、C x+3 、C x+4 ….C y A ring of 1-membered ring (x is an integer, and 3≤x<y, y is selected from any integer between 4 and 20), for example. 3-6 "Cycloalkyl" refers to C3, C4, C5 or C6 cycloalkyl;

[0214] When a group has one or more bondable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are hydrogen atoms at the bondable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of chemical bonds connected, and the group will become a group with the corresponding valence. For example Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes

[0215] When the listed linking groups do not specify their connection direction, their connection directions include connection from left to right and from right to left in the reading order, for example, when ALB, L is selected from -MW-, it includes AMWB and AWMB.

[0216] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0217] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0218] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0219] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0220] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0221] "Prodrugs" refer to compounds of the present invention that can be converted into biologically active compounds through in vivo metabolism. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups in compounds of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

[0222] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0223] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0224] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0225] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomers and amide-imino alcohol isomers.

[0226] “IC 50"It is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of the process such as an enzyme, receptor, cell, etc.) by half. DETAILED DESCRIPTION

[0227] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0228] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0229] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0230] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0231] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0232] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0233] In order to accomplish the purpose of the present invention, the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., Tokyo Chemical Industry Development Co., Ltd., Anage Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.

[0234] THF: tetrahydrofuran; DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine; Boc: tert-butoxycarbonyl.

[0235] Example 1: Preparation of Compound 1-A and Compound 1-B

[0236] Step 1: Preparation of 1b

[0237] Carbonyldiimidazole (15.36 g, 94.73 mmol) was added to a solution of 1a (15.00 g, 86.13 mmol) in anhydrous tetrahydrofuran (150 mL). The mixture was allowed to react at room temperature for 1 h. Then, potassium monomethyl malonate (16.14 g, 103.36 mmol) and anhydrous magnesium chloride (12.30 g, 129.19 mmol) were added and allowed to react at room temperature for 16 h. The pH was adjusted to 4-5 with aqueous hydrochloric acid (1.0 M) at 0°C. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 84:16) to obtain 1b (14.85 g, 75% yield).

[0238] LCMS m / z=231.3[M+H] +

[0239] Step 2: Preparation of 1c

[0240] Phosphoric acid (4.16 g, 42.43 mmol) was added to a 20 mL solution of 1b (9.77 g, 42.43 mmol) and 5-bromo-1H-1,2,4-triazol-3-amine (6.92 g, 42.43 mmol) in anhydrous ethanol. The mixture was reacted at 90°C for 48 h. The residue was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate was added to the residue to adjust the pH to 4-5. Water (100 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:tetrahydrofuran (v:v) = 87:13) to afford 1c (8.24 g, 57% yield).

[0241] LCMS m / z=343.1[M+H] +

[0242] Step 3: Preparation of 1d

[0243] Under nitrogen at -78°C, lithium bis(trimethylsilylamide) (46.6 mL, 1M in THF) was slowly added dropwise to a solution of 1c (4.00 g, 11.66 mmol) in anhydrous tetrahydrofuran (120 mL) at -78°C. The mixture was allowed to react for 1 h. Trimethylsilyl chloride (5.19 g, 47.78 mmol) was added at -78°C, and the reaction was continued for 30 min. A solution of N-bromosuccinimide (2.08 g, 11.66 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise at -78°C, and the reaction was continued for 16 h. At 0°C, the pH was adjusted to 4-5 with hydrochloric acid (1N). Saturated brine (150 mL) was added, and the mixture was extracted with ethyl acetate (80 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 1d (5.18 g, crude product).

[0244] LCMS m / z=423.3[M+H] +

[0245] Step 4: Preparation of 1e

[0246] N,N-Diisopropylethylenediamine (4.52 g, 34.98 mmol) was added to 1d (5.18 g, crude) in N,N-dimethylformamide (50 mL) and allowed to react at room temperature for 16 h. Water (100 mL) was added at 0°C, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 60:40) to afford 1e (773 mg, two-step yield: 19%).

[0247] LCMS m / z=341.2[M+H] +

[0248] Step 5: Preparation of 1f

[0249] [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (221 mg, 0.27 mmol) was added to a solution of 1e (1.85 g, 5.42 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.48 g, 7.05 mmol), and potassium phosphate (3.45 g, 16.26 mmol) in 1,4-dioxane (20 mL) and water (4 mL). The mixture was reacted at 80°C for 4 h under nitrogen. After cooling to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 30:70) to afford 1f (1.59 g, 85% yield).

[0250] LCMS m / z=345.3[M+H] +

[0251] Step 6: Preparation of 1g

[0252] N-Bromosuccinimide (1.07 g, 6.01 mmol) was added to a solution of 1f (1.73 g, 5.01 mmol) in N,N-dimethylformamide (15 mL) and allowed to react at room temperature for 2 h. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by column chromatography (dichloromethane:(dichloromethane / methanol = 10 / 1) (v:v) = 93:7) to yield 1g (1.82 g, 86% yield).

[0253] LCMS m / z=423.0[M+H] +

[0254] Step 7: 1h preparation

[0255] N-Boc-piperazine (3.57 g, 19.15 mmol) was added to a solution of 1 g (1.62 g, 3.83 mmol) of dimethyl sulfoxide (20 mL) and reacted at 120°C for 4 h. The mixture was cooled to room temperature, water (50 mL) was added, and extraction was performed with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane:(dichloromethane / methanol = 10 / 1) (v:v) = 80:20) to obtain 1h (1.60 g, 79% yield).

[0256] LCMS m / z=473.3[M-55] +

[0257] Step 8: Preparation of 1i

[0258] Lithium hydroxide monohydrate (159 mg, 3.80 mmol) was added to a solution of 1h (500 mmol, 0.95 mmol) in tetrahydrofuran (4 mL), water (1 mL), and methanol (2 mL) and allowed to react at room temperature for 1 h. The pH was adjusted to 5-6 with hydrochloric acid (1N) at 0°C. Saturated brine (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to yield 1i (480 mg, crude product).

[0259] LCMS m / z=445.2[M-55] +

[0260] Step 9: Preparation of 1j

[0261] At 0°C, oxalyl chloride (0.06 mL, 0.71 mmol) was slowly added to a solution of 1i (240 mg, 0.48 mmol) in anhydrous dichloromethane (5 mL). N,N-dimethylformamide (0.02 mL) was added, and the mixture was allowed to react at room temperature for 1 h under nitrogen. Triethylamine (143 mg, 1.41 mmol) and a solution of 2-chloro-4-(trifluoromethyl)aniline (119 mg, 0.61 mmol) in dichloromethane (2 mL) were then added, and the reaction was allowed to react at room temperature for 1 h. Silica gel was added, and the mixture was concentrated under reduced pressure to obtain a residue, which was then purified by column chromatography (dichloromethane:(dichloromethane / methanol = 10 / 1) (v:v) = 84:16) to afford 1j (197 mg, 61% yield).

[0262] LCMS m / z=622.2[M-55] +

[0263] Step 10: Preparation of 1k

[0264] A solution of hydrogen chloride in 1,4-dioxane (4N, 2.3 mL) was added dropwise to a solution of 1j (209 mg, 0.31 mmol) in dichloromethane (3 mL). The mixture was allowed to react at room temperature for 1 h. The mixture was concentrated under reduced pressure to obtain the hydrochloride salt of 1k (190 mg, crude product).

[0265] LCMS m / z=578.2[M+H] +

[0266] Step 11: Preparation of 1L

[0267] N,N-Diisopropylethylamine (80 mg, 0.62 mmol) was added to a solution of the hydrochloride salt of 1k (190 mg, crude), 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (83 mg, 0.34 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (141 mg, 0.37 mmol) in N,N-dimethylformamide (5 mL). The reaction was allowed to react at room temperature for 1 h. Water (20 mL) was added, and the product was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (dichloromethane:(dichloromethane / methanol = 10 / 1) (v:v) = 70:30) to afford 1l (244 mg, 98% yield over two steps).

[0268] LCMS m / z=804.2[M+H] +

[0269] Step 12: Preparation of Compound 1

[0270] Trifluoromethanesulfonic acid (0.08 mL) was added to a solution of 1 L (244 mg, 0.30 mmol) of trifluoroacetic acid (5 mL) and allowed to react at 50°C for 1 h. The residue was concentrated under reduced pressure and dissolved in 10 mL of dichloromethane. The pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate at 0°C, and extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product, which was purified by Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, XBridge@Prep C18 column, ID x length = 19 mm x 250 mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was acetonitrile / water (containing 0.05% NH3 / H2O). Gradient elution method: acetonitrile was eluted from 30% to 80% (flow rate: 12 mL / min; elution time: 15 min). After freeze-drying, compound 1 (150 mg, yield 70%) was obtained.

[0271] LCMS m / z=714.1[M+H] +

[0272] Step 13: Preparation of Compound 1-A and Compound 1-B

[0273] Compound 1 was purified by SFC on an AD column (instrument and preparative column: Waters 150Prep-SFC, preparative column model: Chiral IK column. Preparation method: Compound 1 was dissolved in acetonitrile and filtered through a 0.45μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2 and B for 0.1% NH3·H2O in ethanol and acetonitrile). Gradient elution method: 70% mobile phase B isocratic elution (flow rate: 100mL / min; elution time: 4.1min)), and lyophilized to obtain compounds 1-A and 1-B.

[0274] Analytical Method 1 (Instrument and Preparative Column: HPLC-Normal Phase Chromatography, Chiral IK Column, Mobile Phase System: A for CO2; B for 0.05% DEA in ethanol and acetonitrile, Column Temperature: 35°C, Flow Rate: 3.0 mL / min). Compound 1-A had a retention time of 0.606 min. Compound 1-B had a retention time of 1.397 min.

[0275] Analytical method 2 (instrument: SHIMADZU LC-20AT; preparative column model: CHIRALCEL OD-HOD-H, 4.6x250mm, 5μm; mobile phase system: n-hexane:ethanol = 60:40, wavelength: 210nm, column temperature: 35°C; flow rate: 1.0ml / min.) Retention time T = 8.803min for compound 1-A, retention time T = 16.026min for compound 1-B (compound 1-A and compound 1-B, one of which is compound 1-1 and the other is compound 1-2).

[0276] According to Example 30, compound 1-B was confirmed to be compound 1-2.

[0277] Compound 1-A:

[0278] LCMS m / z=714.1[M+H] + ;

[0279] 1H NMR(400MHz, CDCl3)δ11.80(s,1H),8.59(s,1H),8.51-8.37(m,2H),7.66(s,1H) ,7.54(d,1H),6.95-6.80(m,1H),5.76-5.53(m,1H),5.52-5.43(m,1H),4.89-4.6 3(m,1H),4.43-4.21(m,2H),3.97-3.68(m,4H),3.59-3.31(m,2H),3.18-2.97(m, 2H),2.92-2.64(m,4H),2.62-2.50(m,4H),2.40-2.11(m,2H),2.05-1.85(m,1H).

[0280] Compound 1-B:

[0281] LCMS m / z=714.1[M+H] + ;

[0282] 1 H NMR (400MHz, CDCl3) δ11.90(s,1H),8.60(s,1H),8.53-8.35(m,2H),7.66(s ,1H),7.54(d,1H),6.95-6.80(m,1H),5.72-5.54(m,1H),5.53-5.43(m,1H), 4.94-4.62(m,1H),4.44-4.19(m,2H),4.00-3.66(m,4H),3.60-3.28(m,2H), 3.21-2.97(m,2H),2.94-2.45(m,8H),2.37-2.12(m,2H),2.03-1.89(m,1H).

[0283] Example 2: Preparation of Compound 2-A and Compound 2-B

[0284] Step 1: Preparation of compound 2

[0285] Under ice bath, a solution of N,N-diisopropylethylamine (78 mg, 0.60 mmol), 3-hydroxy-2-pyridinecarboxylic acid (28 mg, 0.20 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38 mg, 0.20 mmol), and 1-hydroxybenzotriazole (27 mg, 0.20 mmol) in N,N-dimethylformamide (1 mL) was added to a solution of 1k hydrochloride (63 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL) and the mixture was reacted at room temperature for 2 h. A solution of 3-hydroxy-2-pyridinecarboxylic acid (12 mg, 0.86 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (37 mg, 0.97 mmol), and N,N-diisopropylethylamine (21 mg, 1.63 mmol) in N,N-dimethylformamide (1 mL) was added and allowed to react for 1 h. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in ethanol (10 mL), and hydrazine hydrate (1.2 mL, 80% aqueous solution) was added. The reaction was allowed to react at room temperature for 16 h. The mixture was concentrated under reduced pressure, water (20 mL) was added, and the pH was adjusted to 5-6 with hydrochloric acid (1 M). The mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (dichloromethane: (dichloromethane / methanol = 10 / 1) (v:v) = 70:30) to obtain compound 2 (58 mg, yield 79%).

[0286] LCMS m / z=699.2[M+H] +

[0287] Step 2: Preparation of Compound 2-A and Compound 2-B

[0288] Compound 2 was purified by SFC on an OX column (instrument and preparative column: Waters 150Prep-SFC, preparative column model: Chiral OX column. Preparation method: Compound 2 was dissolved in acetonitrile and methanol and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2 and B for 0.1% NH3·H2O in methanol and acetonitrile). Gradient elution method: 45% mobile phase B isocratic elution (flow rate: 110 mL / min; elution time 7.4 min)), and lyophilized to obtain compounds 2-A and 2-B.

[0289] Analytical method (instrument and preparative column: high performance liquid chromatography-normal phase chromatography, analytical column model: Chiral OX column, mobile phase system: A for CO2; B for 0.05% DEA in methanol and acetonitrile, column temperature: 35°C, flow rate: 3.0 mL / min. Retention time T = 0.860 min for compound 2-A. Retention time T = 1.343 min for compound 2-B (compounds 2-A and 2-B, one of which is compound 2-1 and the other is compound 2-2).

[0290] Compound 2-A: LCMS m / z=699.2 [M+H] + ;

[0291] 1 H NMR(400MHz, CDCl3)δ11.79(s,1H),8.51-8.36(m,2H),8.14(s,1H),7.66(s,1H) ,7.53(d,1H),7.44-7.32(m,1H),6.94-6.79(m,1H),5.61-5.43(m,1H),5.38-4.5 0(m,2H),4.49-4.19(m,2H),3.97-3.63(m,4H),3.61-3.30(m,2H),3.27-2.97(m, 2H),2.92-2.62(m,4H),2.61-2.47(m,1H),2.39-2.14(m,2H),2.01-1.90(m,1H).

[0292] Compound 2-B: LCMS m / z=699.2 [M+H] + ;

[0293] 1 H NMR(400MHz, CDCl3)δ11.47(s,1H),8.56-8.32(m,2H),8.20(s,1H),7.80(s,1H) ,7.66(s,1H),7.59-7.43(m,2H),6.95-6.84(m,1H),5.61-5.43(m,1H),4.92-4.5 1(m,2H),4.42-4.22(m,2H),3.97-3.81(m,2H),3.80-3.30(m,4H),3.29-2.96(m, 2H),2.92-2.62(m,4H),2.61-2.47(m,1H),2.42-2.14(m,2H),2.01-1.90(m,1H).

[0294] Example 3: Preparation of Compound 3-A and Compound 3-B

[0295] Compound 3 was obtained using 1i and 2-chloro-6-trifluoromethyl-3-aminopyridine as substrates, according to the synthetic method of Example 1. Compound 3 was purified by SFC on an OX column (instrument and preparative column: Waters 150Prep-SFC, preparative column model: Chiral OX column. Preparation method: Compound 3 was dissolved in acetonitrile and methanol and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2 and B for 0.1% NH3·H2O in methanol and acetonitrile). Gradient elution method: 45% mobile phase B isocratic elution (flow rate: 110 mL / min; elution time: 9.0 min)), and lyophilized to obtain compounds 3-A and 3-B.

[0296] Analytical method (instrument and preparative column: high performance liquid chromatography-normal phase chromatography, analytical column model: Chiral OX column, mobile phase system: A for CO2; B for 0.05% DEA in methanol and acetonitrile, column temperature: 35°C, flow rate: 3.0 mL / min. Retention time T = 1.009 min for compound 3-A. Retention time T = 1.537 min for compound 3-B (compounds 3-A and 3-B, one of which is compound 3-1 and the other is compound 3-2).

[0297] Compound 3-A: LCMS m / z=715.2 [M+H] + ;

[0298] 1 H NMR(400MHz, CDCl3)δ11.90(s,1H),8.83-8.76(m,1H),8.68-8.56(m,2H),7.64 (d,1H),6.91-6.81(m,1H),5.72-5.56(m,1H),5.55-5.47(m,1H),4.91-4.63(m ,1H),4.42-4.22(m,2H),3.97-3.63(m,4H),3.61-3.31(m,2H),3.20-2.97(m,2 H),2.96-2.62(m,4H),2.61-2.47(m,4H),2.40-2.11(m,2H),2.04-1.91(m,1H).

[0299] Compound 3-B: LCMS m / z=715.1[M+H] + ;

[0300] 1 H NMR (400MHz, CDCl3) δ11.88(s,1H),8.83-8.76(m,1H),8.68-8.56(m,2H),7.64 (d,1H),6.91-6.81(m,1H),5.72-5.56(m,1H),5.55-5.47(m,1H),4.91-4.63(m ,1H),4.42-4.22(m,2H),3.97-3.63(m,4H),3.61-3.31(m,2H),3.20-2.97(m,2 H),2.96-2.62(m,4H),2.61-2.47(m,4H),2.40-2.11(m,2H),2.04-1.91(m,1H).

[0301] Example 4: Preparation of Compound 4-A and Compound 4-B

[0302] Compound 4 was obtained using 1i and 2-methyl-6-trifluoromethyl-3-aminopyridine as substrates, following the synthetic method described in Example 1. Compound 4 was purified by SFC on an IK column (instrument and preparative column: Waters 150Prep-SFC, preparative column model: Chiral IK column). Preparation method: Compound 4 was dissolved in acetonitrile and methanol and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2 and B for 0.1% NH3·H2O in ethanol and acetonitrile. Gradient elution method: isocratic elution with 60% mobile phase B (flow rate: 90 mL / min; elution time: 3.2 min) was used, and lyophilized to obtain compounds 4-A and 4-B.

[0303] Analytical method (instrument and preparative column: high performance liquid chromatography-normal phase chromatography, analytical column model: Chiral IK column, mobile phase system: A for CO2; B for 0.05% DEA in methanol and acetonitrile, column temperature: 35°C, flow rate: 3.0 mL / min. Retention time T = 0.709 min for compound 4-A. Retention time T = 1.899 min for compound 4-B (compounds 4-A and 4-B, one of which is compound 4-1 and the other is compound 4-2).

[0304] Compound 4-A: LCMS m / z=695.4 [M+H] + ;

[0305] 1 H NMR(400MHz,DMSO-d6)δ10.45-10.29(m,1H),10.28-10.10(m,1H),8.57(s,1H),8.10-7.98(m ,1H),7.78-7.66(m,1H),6.86-6.74(m,1H),5.62-5.43(m,1H),4.60-4.43(m,1H),4.34-4.16 (m,2H),3.89-3.72(m,2H),3.59-3.46(m,2H),3.45-3.33(m,2H),3.30-3.20(m,3H),3.07-2. 76(m,3H),2.70-2.58(m,1H),2.54(s,3H),2.44(s,3H),2.41-2.27(m,2H),1.97-1.84(m,1H), 1.82-1.66(m,1H).

[0306] Compound 4-B: LCMS m / z=695.4 [M+H] + ;

[0307] 1 H NMR(400MHz,DMSO-d6)δ10.45-10.29(m,1H),10.28-10.10(m,1H),8.58(s,1H),8.10-7.98(m,1H) ,7.78-7.66(m,1H),6.86-6.74(m,1H),5.62-5.43(m,1H),4.60-4.43(m,1H),4.34-4.16(m,2H),3 .89-3.72(m,2H),3.59-3.46(m,2H),3.45-3.33(m,2H),3.30-3.20(m,3H),3.07-2.76(m,3H),2.7 0-2.58(m,1H),2.54(s,3H),2.45(s,3H),2.41-2.27(m,2H),1.97-1.84(m,1H),1.82-1.66(m,1H).

[0308] Example 5: Preparation of Compound 5-A and Compound 5-B

[0309] Compound 5 was obtained using 1i and 2-methyl-4-(trifluoromethyl)aniline as substrates, following the synthetic method described in Example 1. Compound 5 was purified by SFC on an AD column (instrument and preparative column: Waters 150Prep-SFC, preparative column model: Chiral IK column. Preparation method: Compound 5 was dissolved in acetonitrile and ethanol and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2 and B for 0.1% NH3·H2O in ethanol and acetonitrile). Gradient elution method: isocratic elution with 55% mobile phase B (flow rate: 100 mL / min; elution time: 5.5 min)), and lyophilized to obtain compounds 5-A and 5-B.

[0310] Analytical method (instrument and preparative column: high performance liquid chromatography-normal phase chromatography, analytical column model: Chiral IK column, mobile phase system: A for CO2; B for 0.05% DEA in ethanol and acetonitrile, column temperature: 35°C, flow rate: 3.0 mL / min. Retention time T = 0.505 min for compound 5-A. Retention time T = 0.894 min for compound 5-B (compounds 5-A and 5-B, one of which is compound 5-1 and the other is compound 5-2).

[0311] Compound 5-A: LCMS m / z=694.2[M+H] + ;

[0312] 1 H NMR (400MHz, DMSO-d6) δ10.30-10.15(m,1H),10.15-10.09(m,1H),8.57(s,1H),7.65-7.60(m, 1H),7.59-7.50(m,2H),6.84-6.78(m,1H),5.58-5.43(m,1H),4.57-4.44(m,1H),4.34-4.21(m, 2H),3.88-3.75(m,2H),3.60-3.46(m,2H),3.45-3.33(m,3H),3.30-3.20(m,2H),3.07-2.76(m ,3H),2.70-2.60(m,1H),2.45(s,3H),2.41-2.29(m,5H),1.96-1.85(m,1H),1.82-1.67(m,1H).

[0313] Compound 5-B: LCMS m / z=694.2[M+H]+ ;

[0314] 1 H NMR(400MHz,DMSO-d6)δ10.35-9.98(m,2H),8.58(s,1H),7.65-7.60(m,1H),7.59-7.50(m,2H), 6.84-6.78(m,1H),5.58-5.43(m,1H),4.57-4.44(m,1H),4.34-4.21(m,2H),3.88-3.74(m,2H), 3.60-3.46(m,2H),3.45-3.33(m,3H),3.30-3.20(m,2H),3.07-2.76(m,3H),2.70- 2.60(m,1H),2.45(s,3H),2.41-2.29(m,5H),1.96-1.85(m,1H),1.82-1.67(m,1H).

[0315] Example 6: Preparation of Compound 6-A and Compound 6-B

[0316] Compound 6 was obtained using 6a as a substrate, referring to the synthesis method of Example 1. Compound 6 was purified by SFC on an AD column (instrument and preparative column: Waters 150Prep-SFC, preparative column model: Chiral IK column. Preparation method: Compound 6 was dissolved in acetonitrile and ethanol and filtered through a 0.45μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2 and B for 0.1% NH3·H2O in ethanol and acetonitrile). Gradient elution method: 55% mobile phase B isocratic elution (flow rate: 100mL / min; elution time: 5.5min)), and lyophilized to obtain compounds 6-A and 6-B.

[0317] Analytical method (instrument and preparative column: high performance liquid chromatography-normal phase chromatography, analytical column model: Chiral IK column, mobile phase system: A for CO2; B for 0.05% DEA in ethanol and acetonitrile, column temperature: 35°C, flow rate: 3.0 mL / min. Retention time T = 0.578 min for compound 6-A. Retention time T = 1.129 min for compound 6-B (compounds 6-A and 6-B, one of which is compound 6-1 and the other is compound 6-2).

[0318] Compound 6-A:

[0319] LCMS m / z=700.2[M+H] + ;

[0320] 1 H NMR(400MHz,CF3COOD)δ9.11(s,1H),8.14(d,1H),7.93(s,1H),7.76(d,1H),7.22(s,1H),6.09(dd,1H),5.26-5.00(m,2H),4.75-4.70(m, 2H),4.69-4.59(m,2H),4.58-4.41(m,4H),4.39-4.26(m,2H),4.17-3 .97(m,2H),3.35-3.19(m,1H),3.18-3.05(m,4H),2.96-2.86(m,2H).

[0321] Compound 6-B:

[0322] LCMS m / z=700.1[M+H] + ;

[0323] 1 H NMR(400MHz,CF3COOD)δ9.08(s,1H),8.11(d,1H),7.90(s,1H),7.74(d,1H),7.20(s,1H), 6.07(dd,1H),5.28-4.95(m,2H),4.73-4.67(m,2H),4.66-4.57(m,2H),4.56-4.39(m,4H), 4.36-4.23(m,2H),4.14-3.95(m,2H),3.31-3.17(m,1H),3.16-3.01(m,4H),2.95-2.82(m,2H).

[0324] Example 7: Preparation of Compound 7-A and Compound 7-B

[0325] Compound 7 was prepared using 1 g of tert-butyl piperazine-1-carboxylate-2,2,3,3,5,5,6,6-d8 as substrates according to the synthetic method of Example 1.

[0326] LCMS m / z=722.2[M+1] +

[0327] Preparation of Compound 7-A and Compound 7-B

[0328] Compound 7 was purified by SFC on an IK column (instrument and preparative column: Waters 150Prep-SFC, preparative column model: Chiral IK column. Preparation method: Compound 7 was dissolved in acetonitrile and dichloromethane and filtered through a 0.45μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2 and B for 0.1% NH3·H2O in ethanol and acetonitrile). Gradient elution method: 60% mobile phase B isocratic elution (flow rate: 100mL / min; elution time: 6.2min)) and lyophilized to obtain compounds 7-A and 7-B.

[0329] Analytical method (instrument and preparative column: high performance liquid chromatography-normal phase chromatography, analytical column model: Chiral IK column, mobile phase system: A for CO2; B for 0.05% DEA in ethanol and acetonitrile, column temperature: 35°C, flow rate: 3.0 mL / min. Retention time T = 0.600 min is compound 7-A. Retention time T = 1.351 min is compound 7-B (compounds 7-A and 7-B, one of which is compound 7-1 and the other is compound 7-2).

[0330] Compound 7-A:

[0331] LCMS m / z=722.2[M+H]+;

[0332] 1 H NMR (400MHz, CDCl3) δ11.89(s,1H),8.60(s,1H),8.48(s,1H),8.41(d,1H),7. 66(d,1H),7.53(d,1H),6.89-6.82(m,1H),5.58-5.46(m,1H),4.42-4.20(m,2 H),4.00-3.80(m,2H),3.43-3.29(m,1H),3.16-3.00(m,1H),2.72-2.63(m,2H ),2.62-2.49(m,4H),2.36-2.24(m,1H),2.24-2.10(m,1H),1.99-1.91(m,1H).

[0333] Compound 7-B:

[0334] LCMS m / z=722.1[M+H]+;

[0335] 1H NMR (400MHz, CDCl3) δ11.90(s,1H),8.60(s,1H),8.48(s,1H),8.41(d,1H),7. 66(d,1H),7.53(d,1H),6.90-6.82(m,1H),5.56-5.46(m,1H),4.41-4.22(m,2 H),3.96-3.79(m,2H),3.46-3.31(m,1H),3.18-3.02(m,1H),2.73-2.62(m,2H ),2.62-2.50(m,4H),2.36-2.24(m,1H),2.24-2.10(m,1H),1.99-1.89(m,1H).

[0336] Example 8: Preparation of Compound 8-A and Compound 8-B

[0337] Compound 8 was prepared by using 1 g of (R)-1-N-Boc-2-methylpiperazine as a substrate according to the synthetic method of Example 1.

[0338] LCMS m / z=728.2[M+1] +

[0339] Preparation of Compound 8-A and Compound 8-B

[0340] Compound 8 was purified by SFC on a Chiral IK column (instrument and preparative column: Waters 150Prep-SFC, preparative column model: Chiral IK column. Preparation method: Compound 8 was dissolved in acetonitrile and dichloromethane and filtered through a 0.45μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2 and B for 0.1% NH3·H2O in methanol and acetonitrile). Gradient elution method: 60% mobile phase B isocratic elution (flow rate: 100mL / min; elution time 6.2min)), and lyophilized to obtain compounds 8-A and 8-B.

[0341] Analytical method (instrument and preparative column: high performance liquid chromatography-normal phase chromatography, analytical column model: Chiral IK column, mobile phase system: A for CO2; B for 0.05% DEA in ethanol and acetonitrile, column temperature: 35°C, flow rate: 3.0 mL / min. Retention time T = 0.534 min for compound 8-A. Retention time T = 0.984 min for compound 8-B (compounds 8-A and 8-B, one of which is compound 8-1 and the other is compound 8-2).

[0342] Compound 8-A:

[0343] LCMS m / z=728.1[M+H]+;

[0344] 1 H NMR(400MHz,CF3COOD)δ9.62-9.42(m,1H),8.02-7.87(m,1H),7.81(s,1H),7.68-7.57(m,1H),7.24 -7.08(m,1H),6.05-5.89(m,1H),5.19-4.72(m,1H),4.71-4.54(m,2H),4.32-4.07(m,4H),4.06-3.87(m,1H),3.84 -3.52(m,2H),3.51-3.29(m,1H),3.24-3.13(m,1H),3.12-2.88(m,4H),2.85-2.58(m,4H),2.36-2.08(m,2H),1.92-1.54(m,3H).

[0345] Compound 8-B:

[0346] LCMS m / z=728.2[M+H]+;

[0347] 1 H NMR(400MHz,CF3COOD)δ9.12-8.97(m,1H),8.03-7.92(m,1H),7.85(s,1H), 7.74-7.62(m,1H),7.26-7.10(m,1H),6.03-5.92(m,1H),5.35-5.03(m,1H), 4.94-4.57(m,3H),4.33-4.04(m,5H),3.88-3.74(m,1H),3.50-3.20(m,2H), 3.17-2.91(m,4H),2.89-2.60(m,4H),2.35-2.18(m,2H),1.95-1.59(m,3H).

[0348] Example 9: Preparation of Compound 9

[0349] Compound 9 was prepared by using 1 g of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a substrate and referring to the synthesis method of Example 1.

[0350] LCMS m / z=726.1[M+H] + ;

[0351] 1 H NMR(400MHz,CF3COOD)δ9.61-8.86(m,1H),8.08-7.94(m,1H),7.92-7.85(m,1H),7.76-7.65(m,1H),7.25-7.11(m,1H),6.13-5.93(m,1H),5.66-5 .08(m,2H),5.07-4.82(m,1H),4.81-4.35(m,4H),4.34-3.99(m,3H),3.8 9-3.29(m,2H),3.28-2.95(m,4H),2.92-2.56(m,5H),2.48-2.23(m,2H).

[0352] Example 10: Preparation of Compound 10

[0353] Compound 10 was prepared by using 1 g of tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate as a substrate and referring to the synthesis method of Example 1.

[0354] LCMS m / z=740.1[M+H] + ;

[0355] 1 H NMR(400MHz,CF3COOD)δ9.65-9.48(m,1H),7.98(d,1H),7.90(s,1H),7.72(d,1H),7.25(s,1H), 6.19-5.96(m,1H),5.27-3.35(m,12H),3.15-2.65(m,7H),2.55-2.24(m,2H),1.98-1.18(m,4H).

[0356] Example 11: Preparation of Compound 11

[0357] Compound 11 was prepared using 1 g of cis-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2-carboxylate as a substrate by referring to the synthesis method of Example 1.

[0358] LCMS m / z=740.1[M+H] + ;

[0359] 1 H NMR(400MHz,CF3COOD)δ9.66-9.04(m,1H),8.06-7.98(m,1H),7.90(s,1H),7.76-7.68(m,1H),7.25-7.17(m,1H),6.03-5.94(m,1H),4.80-4 .47(m,7H),4.44-4.18(m,5H),4.03-3.77(m,2H),3.70-3.56(m,1H), 3.55-3.41(m,1H),3.04(s,3H),2.92-2.65(m,4H),2.42-2.27(m,2H).

[0360] Example 12: Preparation of Compound 12

[0361] Step 1: Preparation of 12b

[0362] 12a (500 mg, 2.49 mmol) and N-chlorosuccinimide (403 mg, 3.02 mmol) were added to acetonitrile (10 mL) and reacted at 90°C for 2 h. The mixture was cooled to room temperature, and water (10 mL) was added, followed by extraction with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 85:15) to afford 12b (570 mg, 97% yield).

[0363] LCMS m / z=236.0[M+1] +

[0364] Compound 12 was obtained using 1g and 12b as substrates according to the synthetic method of Example 1.

[0365] LCMS m / z=754.2[M+1] +

[0366] 1H NMR(400MHz,CF3COOD)δ9.08(s,1H),7.82-7.69(m,2H),7.59(d,1H),7.33-7.20(m,1H),6.10-5.95(m,1H),5.74-5.51(m,1H),5.28-5.05(m,1H ),5.01-4.62(m,4H),4.60-4.41(m,1H),4.40-3.89(m,5H),3.81-3.65( m,1H),3.62-3.43(m,1H),3.06(s,3H),2.97-2.68(m,4H),2.49-2.23(m, 2H),1.62-1.47(m,2H),1.20-1.10(m,2H).

[0367] Example 13: Preparation of Compound 13

[0368] Compound 13 was prepared by using 1 g of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a substrate and referring to the synthesis method of Example 1.

[0369] LCMS m / z=740.2[M+1] +

[0370] Preparation of Compound 13-A and Compound 13-B

[0371] Compound 13 was purified by SFC on an AD column (instrument and preparative column: Waters 150Prep-SFC, preparative column model: Chiral IK column. Preparation method: Compound 13 was dissolved in acetonitrile and dichloromethane and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2 and B for 0.1% NH3·H2O in methanol and acetonitrile). Gradient elution method: 70% mobile phase B isocratic elution (flow rate: 100 mL / min; elution time 5.3 min)), and lyophilized to obtain compounds 13-A and 13-B.

[0372] Analytical method (Instrument and preparative column: HPLC-normal phase chromatography, analytical column model: Chiral IK column, mobile phase system: A for CO2; B for 0.05% DEA in methanol and acetonitrile, column temperature: 35°C, flow rate: 3.0 mL / min. Retention time T = 0.753 min for compound 13-A. Retention time T = 1.364 min for compound 13-B (compounds 13-A and 13-B, one of which is compound 13-1 and the other is compound 13-2)

[0373] Compound 13-A:

[0374] LCMS m / z=740.2[M+H] + ;

[0375] 1 H NMR (400MHz, CDCl3) δ11.61-11.50(m,1H),8.61(s,1H),8.52-8.35(m,2H),7.69-7.64(m,1H),7.57 -7.50(m,1H),6.90-6.84(m,1H),5.54-5.45(m,1H),5.11-5.01(m,1H),4.58-4.49(m,1H),4.39-4.22(m,2H),3.96 -3.82(m,2H),3.82-3.70(m,2H),3.69-3.62(m,1H),3.39-3.26(m,2H),3.24-3.13(m,1H),2.73-2.63(m,2H),2.62 -2.50(m,4H),2.48-2.30(m,3H),2.28-2.13(m,1H),2.00-1.89(m,1H),1.88-1.76(m,2H).

[0376] Compound 13-B:

[0377] LCMS m / z=740.2[M+H] + ;

[0378] 1H NMR (400MHz, CDCl3) δ11.56-11.43(m,1H),8.61(s,1H),8.50-8.39(m,2H),7.69-7.64(m,1H),7.57 -7.50(m,1H),6.90-6.84(m,1H),5.54-5.43(m,1H),5.11 -5.01(m,1H),4.58-4.49(m,1H),4.40-4.23(m,2H),3.97-3.81(m,2H),3.81-3.71(m,2H),3.70-3.60(m,1H),3.39-3.26(m,2H),3. 26-3.12(m,1H),2.74-2.64(m,2H),2.61-2.48(m,4H),2.48-2.29(m,3H),2.28-2.13(m,1H),2.00-1.89(m,1H),1.88-1.76(m,2H).

[0379] Example 14: Preparation of Compound 14

[0380] Compound 14 was prepared by using 1 g of 2-tert-butyloxycarbonyl-2,7-diazaspiro[3.5]nonane as a substrate and referring to the synthesis method of Example 1.

[0381] LCMS m / z=754.3[M+1] +

[0382] Preparation of Compound 14-A and Compound 14-B

[0383] Compound 14 was purified by SFC on an AD column (instrument and preparative column: Waters 150Prep-SFC, preparative column model: Chiral AD column. Preparation method: Compound 14 was dissolved in acetonitrile and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2 and B for isopropanol). Gradient elution method: 55% mobile phase B isocratic elution (flow rate: 100 mL / min; elution time: 4.0 min)) and lyophilized to obtain compounds 14-A and 14-B.

[0384] Analytical method (instrument and preparative column: high performance liquid chromatography-normal phase chromatography, analytical column model: Chiral AD column, mobile phase system: A for CO2; B for 0.05% DEA in isopropanol, column temperature: 35°C, flow rate: 3.0 mL / min. Retention time T = 0.403 min for compound 14-A. Retention time T = 0.808 min for compound 14-B (compounds 14-A and 14-B, one of which is compound 14-1 and the other is compound 14-2).

[0385] Compound 14-A:

[0386] LCMS m / z=754.2[M+H] + ;

[0387] 1 H NMR(400MHz, CDCl3)δ12.69-12.46(m 1H),8.69-8.55(m,1H),8.47(s,1H),8.44-8.38(m,1H),7.67-7.63(m,1H),7.56-7.50(m,1H),6.94-6.79(m,1H),5.57-5.41(m,1H),4.74 -4.65(m,1H),4.57-4.47(m,1H),4.39-4.24(m,2H),4.14 -4.05(m,1H),3.96-3.83(m,3H),3.62-3.46(m,2H),3.39-3.24(m,1H),3.17-2.98(m,1H),2.85-2.72(m 1H),2.72-2.60(m,3H),2.60-2.48(m,4H), 2.36-2.11(m,2H),2.08-1.76(m,5H).

[0388] Compound 14-B:

[0389] LCMS m / z=754.2[M+H] + ;

[0390] 1H NMR (400MHz, CDCl3) δ12.56-12.32(m 1H),8.66-8.53(m,1H),8.46(s,1H),8.45-8.40(m,1H),7.67-7.62(m,1H),7.56-7.50( m,1H),6.90-6.82(m,1H),5.53-5.43(m,1H),4.75-4.65(m,1H),4.57-4.46(m,1H),4.42 -4.26(m,2H),4.14-4.04(m,1H),3.98-3.80(m,3H),3.63-3.45(m,2H),3.36-3.25(m,1H),3.14 -2.98(m,1H),2.83-2.73(m 1H),2.73-2.61(m,3H),2.61-2.49(m,4H),2.36-2.09(m,2H),2.05-1.74(m,5H).

[0391] Example 15: Preparation of Compound 15

[0392] Compound 15 was prepared using 1i and 2-fluoro-4-(trifluoromethyl)aniline as substrates according to the synthetic method of Example 1.

[0393] LCMS m / z=698.2[M+1] +

[0394] Preparation of Compound 15-A and Compound 15-B

[0395] Compound 15 was purified by SFC on an AD column (instrument and preparative column: Waters 150Prep-SFC, preparative column model: Chiral IK column. Preparation method: Compound 15 was dissolved in acetonitrile and dichloromethane and filtered through a 0.45μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2 and B for 0.1% NH3·H2O in ethanol and acetonitrile). Gradient elution method: 60% mobile phase B isocratic elution (flow rate: 100mL / min; elution time: 4.5min)), and lyophilized to obtain compounds 15-A and 15-B.

[0396] Analytical method (instrument and preparative column: high performance liquid chromatography-normal phase chromatography, analytical column model: Chiral IK column, mobile phase system: A for CO2; B for 0.05% DEA in ethanol and acetonitrile, column temperature: 35°C, flow rate: 3.0 mL / min. Retention time T = 0.478 min for compound 15-A. Retention time T = 0.997 min for compound 15-B (compounds 15-A and 15-B, one of which is compound 15-1 and the other is compound 15-2).

[0397] Compound 15-A:

[0398] 1 H NMR(400MHz, CDCl3)δ12.53(s,1H),8.72-8.62(m,2H),8.43-8.33(m,1H),7.45-7.35(m,2H), 6.97-6.89(m,1H),5.60-5.40(m,2H),4.87-4.72(m,1H),4.39-4.30(m,2H),3.98-3.86(m,2H ),3.83-3.68(m,2H),3.62-3.46(m,1H),3.46-3.31(m,1H),3.17-3.02(m,2H),2.99-2.79(m, 2H),2.76(s,3H),2.74-2.63(m,2H),2.62-2.49(m,1H),2.34-2.19(m,2H),1.99-1.86(m,1H).

[0399] Compound 15-B:

[0400] 1 H NMR(400MHz, CDCl3)δ11.91(s,1H),8.66-8.56(m,2H),8.43-8.36(m,1H),7.46-7.34(m,2H), 6.91-6.85(m,1H),5.68-5.42(m,2H),4.86-4.66(m,1H),4.39-4.28(m,2H),3.98-3.83(m,2H ),3.83-3.67(m,2H),3.68-3.41(m,1H),3.41-3.31(m,1H),3.18-2.98(m,2H),2.94-2.73(m, 2H),2.73-2.65(m,2H),2.59(s,3H),2.58-2.51(m,1H),2.36-2.16(m,2H),1.99-1.87(m,1H).

[0401] Example 16: Preparation of Compound 16

[0402] Step 1: Preparation of 16b

[0403] 16a (4.00 g, 15.68 mmol) was dissolved in tetrahydrofuran (50 mL). After nitrogen replacement, cyclopropylmagnesium bromide (24 mL, 24.00 mmol, 1 M solution in THF) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.28 g, 1.57 mmol) were added sequentially under an ice-water bath. The reaction was allowed to react at this temperature for 3 h. The reaction was quenched by the addition of 1 M hydrochloric acid solution (25 mL). The product was extracted with ethyl acetate (25 mL x 2) and washed with saturated brine (25 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 75:25) to afford 16b (2.94 g, yield: 72%).

[0404] LCMS m / z=261.3[M+H] +

[0405] Step 2: Preparation of 16c

[0406] 16b (2.94 g, 11.28 mmol) was dissolved in methanol (50 mL) and N,N-dimethylacetamide (10 mL). [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.92 g, 1.13 mmol) and triethylamine (3.42 g, 33.80 mmol) were added. The reaction mixture was heated to 75°C under a carbon monoxide atmosphere (0.3-0.5 MPa) for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 67:33) to afford 16c (0.62 g, 19% yield).

[0407] LCMS m / z=285.2[M+H] +

[0408] Step 3: Preparation of 16d

[0409] 16c (0.62 g, 2.18 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2M aqueous sodium hydroxide solution (5 mL) was added and the mixture was allowed to react at room temperature for 10 min. The solvent was removed by concentration under reduced pressure, and the pH was adjusted to 2-3 with 2M hydrochloric acid solution. The precipitated solid was filtered and dried to afford 16d (0.58 g, 98% yield).

[0410] LCMS m / z=271.2[M+H]+

[0411] Preparation of compound 16

[0412] Compound 16 was prepared using 16d and 1k as substrates according to the synthetic method of Example 1.

[0413] LCMS m / z=740.2[M+H] +

[0414] Example 17: Preparation of Compound 17

[0415] Compound 17 was obtained using methyl-D3-magnesium iodide as a substrate and the synthetic method of Example 16 was used as a reference.

[0416] LCMS m / z=717.2[M+H] +

[0417] Example 18: Synthesis of Compound 18

[0418] Compound 18 was prepared by using 1 g of (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a substrate and referring to the synthesis method of Example 1.

[0419] LCMS m / z=726.2[M+1] +

[0420] 1 H NMR(400MHz,CF3COOD)δ9.68-8.86(m,1H),8.08-7.94(m,1H),7.92-7.85(m,1H),7.76-7.65(m,1H),7.25-7.11(m,1H),6.13-5.93(m,1H),5.66-5 .08(m,2H),5.07-4.82(m,1H),4.81-4.35(m,4H),4.34-3.99(m,3H),3.8 9-3.29(m,2H),3.28-2.95(m,4H),2.92-2.56(m,5H),2.48-2.23(m,2H).

[0421] Example 19: Synthesis of Compound 19

[0422] Compound 19 was prepared by using 1 g of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a substrate and referring to the synthesis method of Example 1.

[0423] LCMS m / z=740.2[M+1] +

[0424] 1 H NMR(400MHz,CF3COOD)δ9.09-8.99(m,1H),8.12-8.00(m,1H),7.91(s,1H), 7.78-7.69(m,1H),7.26-7.15(m,1H),6.19-6.07(m,1H),6.06-5.93(m,1H), 5.32-5.17(m,1H),4.80-4.60(m,2H),4.39-4.03(m,4H),3.91-3.73(m,1H), 3.53-3.31(m,1H),3.20-2.96(m,5H),2.94-2.67(m,4H),2.58-2.14(m,6H).

[0425] Example 20: Synthesis of Compound 20-A and Compound 20-B

[0426] Crude compound 20 was prepared using 1 g of tert-butyl (2S,6S)-2,6-dimethylpiperazine-1-carboxylate as a substrate, following the synthesis method described in Example 1. Compound 20 (200 mg) was purified by Pre-HPLC (instrument and preparative column: Waters 2767 Preparative Liquid Phase, Xbridge Prep C18 (19 mm × 250 mm), 5 μm, inner diameter × length = 19 mm × 150 mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. The mobile phase system was acetonitrile / water (containing 0.05% ammonium bicarbonate). Gradient elution method: acetonitrile was gradient eluted from 10% to 55% (flow rate: 15 mL / min; elution time: 20 min). After lyophilization, compound 20-A (18 mg, retention time T = 17.85 min) and compound 20-B (13 mg, retention time T = 19.15 min) were obtained.

[0427] Analytical method (instrument: SHIMADZU LC-20AT; preparative column model: CHIRALPAKAS-H, 4.6 x 150 mm, 5 μm; mobile phase system: n-hexane: ethanol = 70:30, wavelength: 210 nm, column temperature: 35°C; flow rate: 1.0 ml / min.) Retention time T = 6.573 min for compound 20-A; retention time T = 4.488 min for compound 20-B (compound 20-A and compound 20-B, one of which is compound 20-1 and the other is compound 20-2).

[0428] According to Example 32, compound 20-A was confirmed to be compound 20-2.

[0429] Compound 20-A

[0430] LCMS m / z=742.0[M+1] +

[0431] 1 H NMR(400MHz,CF3COOD)δ9.12(s,1H),8.06(d,1H),7.93(s,1H),7.76(d,1 H),7.33-7.20(m,1H),6.20-6.00(m,1H),5.25-4.86(m,2H),4.82-4.65(m ,2H),4.60-4.42(m,1H),4.41-4.24(m,2H),4.16-3.57(m,4H),3.50-3.3 1(m,1H),3.07(s,3H),2.99-2.70(m,4H),2.42-2.23(m,2H),1.91(s,6H).

[0432] Compound 20-B

[0433] LCMS m / z=742.0[M+1] +

[0434] 1 H NMR(400MHz,CF3COOD)δ9.11(s,1H),8.06(d,1H),7.93(s,1H),7.76(d,1H),7 .33-7.20(m,1H),6.14-5.94(m,1H),5.16-4.83(m,2H),4.82-4.63(m,2H),4.4 8-4.23(m,3H),4.17-4.05(m,1H),3.96-3.80(m,1H),3.79-3.32(m,3H),3.07 (s,3H),2.97-2.88(m,2H),2.87-2.73(m,2H),2.44-2.24(m,2H),1.90(s,6H).

[0435] Example 21: Synthesis of Compound 21

[0436] Compound 21 was prepared using 1 g of tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate as a substrate by referring to the synthesis method of Example 1.

[0437] LCMS m / z=742.3[M+1] +

[0438] 1H NMR(400MHz,CF3COOD)δ9.17-9.08(m,1H),8.08-8.00(m,1H),7.93(s,1H),7.8 0-7.71(m,1H),7.33-7.22(m,1H),6.17-5.99(m,1H),5.68-5.21(m,1H),5.10-4 .90(m,1H),4.87-4.65(m,3H),4.62-4.40(m,1H),4.39-4.03(m,3H),4.02-3.2 7(m,3H),3.08(s,3H),2.98-2.69(m,4H),2.49-2.24(m,2H),1.90-1.59(m,6H).

[0439] Example 22: Synthesis of Compound 22

[0440] Compound 22 was prepared by using 1 g of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate as a substrate and referring to the synthesis method of Example 1.

[0441] LCMS m / z=754.1[M+1] +

[0442] 1 H NMR(400MHz,CF3COOD)δ9.13(s,1H),8.04(d,1H),7.93(s,1H),7.75(d,1H ),7.31-7.22(m,1H),6.08-5.99(m,1H),5.48-5.01(m,4H),4.81-4.62(m,2 H),4.43-4.21(m,4H),4.18-4.01(m,2H),3.64-3.50(m,1H),3.49-3.34(m, 1H),3.06(s,3H),2.98-2.88(m,2H),2.87-2.55(m,6H),2.41-2.25(m,2H).

[0443] Example 23: Synthesis of Compound 23

[0444] Compound 23 was prepared using 1 g of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate as a substrate and the synthetic method of Example 1 was used as a reference.

[0445] LCMS m / z=754.3[M+1] +

[0446] Example 24: Synthesis of Compound 24

[0447] Compound 24 was prepared using 1 g of tert-butyl (2S)-2-(methoxymethyl)-1-piperazinecarboxylate as a substrate and the synthetic method of Example 1.

[0448] LCMS m / z=758.2[M+1] +

[0449] 1 H NMR(400MHz,CF3COOD)δ9.26-9.04(m,1H),8.10-7.89(m,2H),7.86-7.71(m ,1H),7.38-7.20(m,1H),6.21-6.08(m,1H),6.07-5.76(m,1H),5.71-5.36(m ,1H),5.35-4.92(m,2H),4.87-4.52(m,4H),4.48-4.05(m,5H),3.96-3.83(m ,3H),3.73-3.42(m,2H),3.10(s,3H),2.99-2.76(m,4H),2.57-2.38(m,2H).

[0450] Example 25: Synthesis of Compound 25

[0451] Compound 25 was obtained by using 1 g of 2-BOC-2,8-diaza-spiro[4.5]decane as a substrate and referring to the synthesis method of Example 1.

[0452] LCMS m / z=768.2[M+1] +

[0453] 1 H NMR (400MHz, CDCl3) δ13.08-12.53(m,1H),8.74-8.57(m,1H),8.51-8.39(m,2 H),7.68-7.62(m,1H),7.57-7.48(m,1H),6.91-6.83(m,1H),5.52-5.45(m,1H ),4.42-4.21(m,3H),4.09-3.49(m,6H),3.39-3.23(m,1H),3.16-2.97(m,1H) ,2.80-2.50(m,7H),2.39-2.08(m,3H),2.07-2.00(m,1H),1.99-1.60(m,7H).

[0454] Example 26: Synthesis of Compound 26-A and Compound 26-B

[0455] Crude compound 26 was obtained using 1 g of (S)-4-N-tert-butyloxycarbonyl-2-methylpiperazine as the substrate, following the synthesis method of Example 1. Compound 26 was purified by Pre-HPLC (instrument and preparative column: Waters 2767 Preparative Liquid Phase, Xbridge Prep C18 (19 mm × 250 mm), 5 μm, inner diameter × length = 19 mm × 150 mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. The mobile phase system was acetonitrile / water (containing 0.05% ammonium bicarbonate). Gradient elution method: acetonitrile was gradient eluted from 20% to 55% (flow rate: 15 mL / min; elution time: 14 min). After lyophilization, compound 26-A (retention time T = 12.25 min) and compound 26-B (retention time T = 13.51 min) were obtained. One of compound 26-A and compound 26-B was compound 26-1 and the other was compound 26-2.

[0456] Compound 26-A

[0457] LCMS m / z=728.0[M+1] +

[0458] 1 H NMR(400MHz,CF3COOD)δ9.17-9.05(m,1H),8.10-7.96(m,1H),7.94(s,1H),7.82-7.70(m,1H),7.38 -7.20(m,1H),6.15-6.01(m,1H),5.91-5.68(m,1H),5.42-5.13(m,2H),5.05-4.62(m,3H),4.59-4.10(m,4H),4.09 -3.67(m,2H),3.55-3.34(m,1H),3.09(s,3H),2.98-2.74(m,4H),2.51-2.29(m,2H),1.76-1.54(m,3H).

[0459] Compound 26-B

[0460] LCMS m / z=727.9[M+1] +

[0461] 1H NMR(400MHz,CF3COOD)δ9.16-9.05(m,1H),8.10-7.98(m,1H),7.94(s,1H),7.82-7.70(m,1H),7.38 -7.20(m,1H),6.15-6.01(m,1H),5.91-5.68(m,1H),5.39-5.09(m,2H),5.02-4.62(m,3H),4.59-4.13(m,3H),4.12 -3.74(m,2H),3.73-3.47(m,2H),3.09(s,3H),2.98-2.72(m,4H),2.56-2.29(m,2H),1.78-1.55(m,3H).

[0462] Example 27: Synthesis of Compound 27

[0463] Compound 27 was prepared by using 1 g of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate as a substrate and referring to the synthesis method of Example 1.

[0464] LCMS m / z=726.0[M+1] +

[0465] 1 H NMR (400MHz, CDCl3) δ12.34(s,1H),8.58(s,1H),8.45-8.32(m,2H),7.70-7.62(m,1 H),7.57-7.50(m,1H),6.92-6.85(m,1H),5.55-5.43(m,1H),5.20-5.05(m,2H),4.5 3-4.24(m,8H),3.96-3.83(m,2H),3.48-3.31(m,1H),3.20-3.05(m,1H),2.78-2.64 (m,2H),2.60-2.46(m,4H),2.33-2.23(m,1H),2.22-2.08(m,1H),2.00-1.90(m,1H).

[0466] Example 28: Preparation of Compound 28

[0467] Step 1: Preparation of 28b

[0468] N-Iodosuccinimide (3.90 g, 17.34 mmol) was added to a solution of 28a (2.31 g, 17.34 mmol) in N,N-dimethylformamide (15 mL) and allowed to react at room temperature for 16 h. Water (50 mL) was added at 0°C, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 92:8) to afford 28b (4.15 g, 92% yield).

[0469] LCMS m / z=260.0[M+H] +

[0470] Step 2: Preparation of 28c

[0471] A solution of benzyl chloroformate (3.01 g, 17.62 mmol) in tetrahydrofuran (10 mL) was added dropwise to a solution of 28b (4.15 g, 16.02 mmol) and sodium bicarbonate (2.96 g, 35.24 mmol) in tetrahydrofuran (40 mL) at 0°C. The mixture was allowed to react at room temperature for 16 h. Water (100 mL) was added at 0°C, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 95:5) to afford 28c (5.47 g, 87% yield).

[0472] LCMS m / z=394.0[M+H] +

[0473] Step 3: Preparation of 28d

[0474] Cuprous iodide (2.58 g, 13.57 mmol), methyl fluorosulfonyldifluoroacetate (10.43 g, 54.28 mmol), and hexamethylphosphoric triamide (9.73 g, 54.28 mmol) were added to a solution of 28c (5.34 g, 13.58 mmol) in N,N-dimethylformamide (100 mL) and reacted at 75°C for 16 h under a nitrogen atmosphere. The mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate. The filtrate was added to water (500 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated sodium chloride (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 95:5) to afford 28d (4.23 g, 93% yield).

[0475] LCMS m / z=336.1[M+H] +

[0476] Step 4: Preparation of 28e

[0477] Palladium hydroxide on carbon (1.2 g, 10%) was added to 28d (3.96 g, 11.81 mmol) in anhydrous methanol (100 mL) and reacted at 45°C for 16 h. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give 28e (2.26 g, crude product).

[0478] LCMS m / z=202.1[M+H] +

[0479] Compound 28 was obtained using 1i and 28e as substrates according to the synthetic method of Example 1.

[0480] LCMS m / z=720.3[M+1] +

[0481] 1 H NMR (400MHz, CDCl3) δ11.85(s,1H),8.59(s,1H),8.12(s,1H),7.88(d,1H) ,7.42(d,1H),6.93-6.80(m,1H),5.72-5.45(m,2H),4.90-4.62(m,1H),4.4 5-4.18(m,2H),3.99-3.84(m,2H),3.83-3.65(m,2H),3.59-3.25(m,2H),3. 24-2.97(m,4H),2.93-2.52(m,10H),2.36-2.08(m,4H),1.97-1.87(m,1H).

[0482] Example 29: Preparation of Compound 29

[0483] Compound 29 was prepared by referring to the synthesis method of Example 1 using 1 g of (R)-tert-butyl 3-(methoxymethyl)-1-piperazinecarboxylate as a substrate.

[0484] LCMS m / z=758.2[M+1] +

[0485] 1H NMR(400MHz,CF3COOD)δ9.18-9.06(m,1H),8.11-7.87(m,2H),7.81-7.69(m,1H), 7.36-7.22(m,1H),6.23-5.96(m,1H),5.91-5.60(m,1H),5.42-5.08(m,2H),4.96 -4.19(m,6H),4.13-3.35(m,9H),3.09(s,3H),2.99-2.70(m,4H),2.54-2.28(m,2H).

[0486] Example 30: Preparation of Compound 1-2

[0487] Step 1: Preparation of 30a

[0488] Lithium hydroxide monohydrate (3.86 g, 92.04 mmol) was added to a solution of 1f (7.92 g, 23.01 mmol) in tetrahydrofuran (80 mL), water (20 mL), and methanol (40 mL) and allowed to react at room temperature for 1 h. The pH was adjusted to 2-3 with 1N hydrochloric acid at 0°C. Saturated brine (20 mL) was added, and sodium chloride was added to saturate the aqueous phase. The mixture was extracted with ethyl acetate (30 mL x 15). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 30a (6.70 g, crude product).

[0489] LCMS m / z=317.2[M+H] +

[0490] Step 2: Preparation of 30b

[0491] At 0°C, oxalyl chloride (3.48 mL, 41.12 mmol) was slowly added to a solution of 30a (6.50 g, crude product) in anhydrous dichloromethane (160 mL). N,N-dimethylformamide (0.47 mL) was added, and the mixture was allowed to react at room temperature for 1 h under nitrogen. Triethylamine (10.40 g, 102.75 mmol) and a solution of 2-chloro-4-(trifluoromethyl)aniline (12.06 g, 61.65 mmol) in dichloromethane (32 mL) were then added, and the reaction was allowed to react at room temperature for 1 h. Silica gel was added, and the mixture was concentrated under reduced pressure to obtain a residue, which was then purified by column chromatography (dichloromethane:(dichloromethane / methanol = 10 / 1) (v:v) = 84:16) to afford 30b (8.47 g).

[0492] LCMS m / z=494.1[M+H] +

[0493] Step 3: Preparation of 30c

[0494] N-Bromosuccinimide (3.36 g, 18.86 mmol) was added to 30b (8.47 g, 17.15 mmol) in N,N-dimethylformamide (150 mL) and the mixture was allowed to react at 50°C for 2 h. Ice water (1 L) was added, stirred for 30 min, and the crude product was filtered to obtain the product. The crude product was then slurried in ethyl acetate (100 mL) to obtain 30c (7.90 g, 80% yield).

[0495] LCMS m / z=572.0[M+H] +

[0496] Compound 30c was purified by SFC on an IC column (Waters 150Prep-SFC, Chiral IC column). Preparation method: Compound 1 was dissolved in acetonitrile and methanol and filtered through a 0.45 μm filter to a 50 mg / ml sample solution. Mobile phases: A for CO2 and B for isopropanol and acetonitrile. Gradient elution: 60% mobile phase B (flow rate: 100 mL / min; elution time: 6 min). After lyophilization, 30d and 30e were obtained.

[0497] Analytical method: (Instrument and preparative column: SHIMADZU LC-20AT; analytical column model: Chiralcel AD-H, 4.6x250mm 5μm; system: n-hexane:ethanol = 80:20; wavelength: 210nm, column temperature: 35℃; flow rate: 1.0mL / min.) Retention time T = 17.481min is 30d, retention time T = 24.569min is 30e.

[0498] 30d: LCMS m / z = 572.0 [M+H] + ;

[0499] 30e: LCMS m / z = 572.1 [M+H] + ;

[0500] Step 5: Preparation of 30f

[0501] N-Boc-piperazine (326 mg, 1.75 mmol) was added to a solution of 30d (200 mg, 0.35 mmol) in dimethyl sulfoxide (4 mL) and the reaction was allowed to proceed at 110°C for 1 h. The mixture was cooled to room temperature, and water (30 mL) was added, followed by extraction with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by column chromatography (dichloromethane:(dichloromethane / methanol = 10 / 1) (v:v) = 80:20) to afford 30f (394 mg, crude product).

[0502] LCMS m / z=622.1[M-55] +

[0503] Compound 1-2 was obtained using 30f as a substrate according to the synthetic method of Example 1.

[0504] LCMS m / z=714.2[M+H] + ;

[0505] 1 H NMR(400MHz, CDCl3)δ11.86(s,1H),8.60(s,1H),8.53-8.35(m,2H),7.66(s ,1H),7.54(d,1H),6.95-6.80(m,1H),5.72-5.54(m,1H),5.53-5.43(m,1H), 4.94-4.62(m,1H),4.44-4.19(m,2H),4.00-3.66(m,4H),3.60-3.28(m,2H), 3.21-2.97(m,2H),2.94-2.45(m,8H),2.37-2.12(m,2H),2.03-1.89(m,1H).

[0506] Analytical method (instrument: SHIMADZU LC-20AT; preparative column model: CHIRALCEL OD-HOD-H, 4.6 x 250 mm, 5 μm; mobile phase system: n-hexane:ethanol = 60:40, wavelength: 210 nm, column temperature: 35°C; flow rate: 1.0 ml / min.) Retention time T = 16.026 min.

[0507] Chiral HPLC confirmed that compound 1-B obtained in Example 1 was compound 1-2.

[0508] Example 31: Preparation of Compound 31

[0509] Anhydrous lithium chloride (70 mg, 1.64 mmol) was added to a solution of 31c (340 mg, 0.41 mmol; 31c was obtained using 30d and tert-butyl 2-ethynylpiperazine-1-carboxylate as starting materials, according to the synthesis method of Example 30) in N,N-dimethylformamide (4 mL). The reaction was microwaved at 150°C for 2 h. Water (40 mL) was added, and the mixture was extracted with dichloromethane (15 mL x 3). The crude product was purified by Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, XBridge@Prep C18 column, ID x L = 19 mm x 250 mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. The mobile phase system was acetonitrile / water (containing 5 mmol / L NH4HCO3). Gradient elution method: acetonitrile was eluted in a gradient from 20% to 59% (flow rate: 15 mL / min; elution time: 13 min). Compound 31 was obtained after freeze-drying.

[0510] LCMS m / z=738.1[M+H] + ;

[0511] Compound 31 was purified by SFC on Chiral IK column (instrument and preparative column: Waters 150Prep-SFC, preparative column model: Chiral IK column. Preparation method: Compound 31 was dissolved in acetonitrile and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A is CO2 and B is ethanol and acetonitrile). Gradient elution method: 50% mobile phase B isocratic elution (flow rate: 100 mL / min; elution time 9.0 min)), and after lyophilization, compounds 31-A and 31-B were obtained. Analytical method (instrument and preparative column: SHIMADZU LC-20AD, analytical column model: Chiral IK column mobile phase system: A is CO 2； B was a 0.05% DEA solution in ethanol and acetonitrile. Column temperature: 35°C, flow rate: 3.0 mL / min. Retention time T = 0.816 min for compound 31-A, retention time T = 1.251 min for compound 31-B (compounds 31-A and 31-B, one of which is compound 31-1, the other is compound 31-2).

[0512] Compound 31-A:

[0513] LCMS m / z=738.2[M+H] + ;

[0514] Compound 31-B:

[0515] LCMS m / z=738.2[M+H] + ;

[0516] Example 32: Preparation of Compound 20-2

[0517] Compound 20-2 was obtained using 30d and (2S,6S)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester as substrates by referring to the synthetic method of Example 30.

[0518] Compound 20-2

[0519] LCMS m / z=742.0[M+1] +

[0520] Analytical method (instrument: SHIMADZU LC-20AT; preparative column model: CHIRALPAKAS-H, 4.6 x 150 mm, 5 μm; mobile phase system: n-hexane:ethanol = 70:30, wavelength: 210 nm, column temperature: 35°C; flow rate: 1.0 ml / min.) Retention time T = 6.573 min;

[0521] Chiral HPLC confirmed that compound 20-A obtained in Example 20 was compound 20-2.

[0522] Biological test cases

[0523] 1: WRN helicase ATPase activity test

[0524] Assay buffer working solution: 30mM Tris PH7.5+0.02% BSA+2mM MgCl2+50mM NaCl+ WRN protein (AA N517-P1238, ICE) was expressed and purified in vitro using F127 cells supplemented with 1 mM DTT. A single-stranded DNA substrate (TTTTTTTTTTTTTTTTTTTTTTTTCCAAGTAAAACGACGGCCAGTGC) was synthesized in vitro. 1 μL of compound, WRN protein, and DNA substrate at varying concentrations, along with 2 μL of ATP, were added to a 384-well plate to achieve working concentrations of 0.3 nM, 0.2 nM, and 10 μM, respectively. The cells were incubated at room temperature for 20 minutes. After incubation, chemiluminescence was measured using the ADP-Glo ​​assay kit (Promega).

[0525] The inhibition rate was calculated according to Formula 1, where RLUsample is the compound well reading, RLUmax is the DMSO control well reading, and RLUmin is the WRN protein-free control well reading. GraphPad Prism software was used to perform curve fitting using four parameters (log (inhibitor) vs. response--Variable slope) and calculate the IC50 value.

[0526] Inhibition%=(1-(RLUsample-RLUmin) / (RLUmax-RLUmin))×100% (Formula 1)

[0527] Table 1 Inhibitory activity of test compounds on WRN helicase ATPase activity Note: A<0.02μM, 0.02μM≤B<0.1μM, 0.1μM≤C<0.5μM, 0.5μM≤D<1μM

[0528] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a good inhibitory effect on WRN helicase ATPase.

[0529] 2: WRN helicase activity test experiment

[0530] Assay buffer was prepared in RNAase-free water: 25 mM Tris (pH 7.5), 2 mM MgCl2, 50 mM NaCl, 0.02% BSA, 0.01% Tween, and 1 mM DTT. WRN protein (AA N517-P1238, ICE, Cat. S2212T-H56HZ) was expressed and purified in vitro. Two single-stranded DNAs were synthesized: TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCGTACCCGATGTGTTCGTTC-BHQ2 (quencher) and TAMRA-GAACGAACACATCGGGTACGTTTTTTTTTTTTTTTTTTTTTTTTTTTT (fluorophore). These two single-stranded DNAs were annealed to generate dsDNA (FORKF). Binding of WRN to FORKF unwinds the dsDNA, exposing the fluorophore and generating fluorescence. 2 μL of compound at various concentrations and 4 μL of WRN protein were added to a 384-well black plate (Greiner, Cat# 784075) and preincubated at room temperature for 20 minutes. ATP and FORKF substrate (2 μL each) were then added to achieve working concentrations of 10 nM for WRN protein, 10 nM for FORKF, and 2 mM for ATP, respectively. The incubation was continued at room temperature for 20 minutes. After incubation, fluorescence at Ex 540 nm and Em 590 nm was measured using a BMG microplate reader (PHERAstar FSX).

[0531] The inhibition rate was calculated according to Formula 2, where RLU sample Read the compound wells, RLU max Read the value for the DMSO control well, RLU min The values ​​of the control wells without WRN protein were read and the IC concentration of the compound at which the inhibition rate was 50% was calculated using a four-parameter curve fitting using GraphPad Prism software. 50 Inhibition% = (1-(RLU sample -RLU min ) / (RLU max -RLU min ))×100%(Formula 2)

[0532] Table 2 Inhibitory activity of test compounds on WRN helicase activity Note: A<0.02μM, 0.02μM≤B<0.1μM

[0533] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a good inhibitory effect on WRN helicase.

[0534] 3. Cell proliferation inhibition experiment

[0535] 3.1 HCT-116 cell proliferation inhibition experiment:

[0536] HCT-116 cell culture conditions: RPMI-1640 + 10% FBS + 1% double antibody, cultured in a 37 ° C, 5% CO2 incubator. On the first day, HCT-116 cells in the exponential growth phase were collected and plated on a 96-well culture plate, 180 μL per well, with a plating density of 800 cells / well, and cultured in a 37 ° C, 5% CO2 incubator overnight. The T0 well was plated at the same time. On the second day, 20 μL of different concentrations of compounds were added to each well (9 compound gradients, 1 DMSO well and 1 Blank well; 3 replicates were plated for each compound concentration) to make the final DMSO concentration in each well 0.1%, and cultured in a 37 ° C, 5% CO2 incubator for 4 days. The T0 plate was detected using the CellTiter-Glo kit at the same time as the drug addition on the second day, and recorded as RLU0. After the incubation period, 100 μL of detection solution (Cell Viability Assay, Promega) was added to each well and incubated at room temperature with slow shaking for 10 minutes. The chemiluminescence readings were detected using a BMG microplate reader (PHERAstar FSX). The results were processed according to formula (3) to calculate the proliferation inhibition rate of each concentration of the compound. GraphPad Prism software was used to fit the curve using four parameters to calculate the concentration GI of the compound when the proliferation inhibition rate was 50%. 50 Value. RLU compoundThe readings for the drug-treated groups, RLU control is the average value of the compound solvent control group, RLU Blank The value is the average value of the blank control group. Inhibition % = (1-(RLU compound -RLU0-RLU Blank ) / (RLU control - RLU0-RLU Blank ))×100% Formula (3)

[0537] 3.2 HT-29 cell proliferation inhibition experiment:

[0538] HT-29 cell culture conditions: DMEM + 10% FBS + 1% double antibody, cultured in a 37°C, 5% CO2 incubator. On the first day, HT-29 cells in the exponential growth phase were collected and plated on a 96-well culture plate, 180 μL per well, with a plating density of 1000 cells / well, and cultured overnight in a 37°C, 5% CO2 incubator. T0 wells were also plated at the same time. On the second day, 20 μL of different concentrations of compounds (9 compound gradients, 1 DMSO well and 1 Blank well; 3 replicates for each compound concentration) were added to each well, so that the final DMSO concentration in each well was 0.1%, and cultured in a 37°C, 5% CO2 incubator for 4 days. The T0 plate was detected using the CellTiter-Glo kit at the same time as the drug addition on the second day, and recorded as RLU0. After the incubation period, 100 μL of detection solution (Cell Viability Assay, Promega) was added to each well and incubated at room temperature with slow shaking for 10 minutes. The chemiluminescence readings were detected using a BMG microplate reader (PHERAstar FSX). The results were processed according to formula (4) to calculate the proliferation inhibition rate of each concentration of the compound. GraphPad Prism software was used to fit the curve using four parameters to calculate the concentration GI of the compound when the proliferation inhibition rate was 50%. 50 Value. RLU compound The readings for the drug-treated groups, RLU control is the average value of the compound solvent control group, RLU Blank The value is the average value of the blank control group. Inhibition % = (1-(RLU compound -RLU0-RLU Blank ) / (RLU control - RLU0-RLU Blank ))×100% Formula (4)

[0539] 3.3 SW48 cell proliferation inhibition experiment:

[0540] SW48 cell culture conditions: Leibovitz L15 + 10% FBS + 1% double antibody, cultured at 37 ° C, in a CO2-free incubator. On the first day, SW48 cells in the exponential growth phase were collected and plated on a 96-well culture plate, 180 μL per well, with a plating density of 1000 cells / well, and cultured overnight in a 37 ° C, CO2-free incubator. T0 wells were also plated at the same time. On the second day, 20 μL of different concentrations of compounds were added to each well (9 compound gradients, 1 DMSO well and 1 Blank well; 3 replicates were plated for each compound concentration) to make the final DMSO concentration in each well 0.1%. Cultured at 37 ° C, in a CO2-free incubator for 4 days. The T0 plate was detected using the CellTiter-Glo kit at the same time as the drug addition on the second day, and recorded as RLU0. After the incubation period, 100 μL of detection solution (Cell Viability Assay, Promega) was added to each well and incubated at room temperature with slow shaking for 10 minutes. The chemiluminescence readings were detected using a BMG microplate reader (PHERAstar FSX). The results were processed according to formula (5) to calculate the proliferation inhibition rate of each concentration of the compound. GraphPad Prism software was used to fit the curve using four parameters to calculate the concentration GI of the compound when the proliferation inhibition rate was 50%. 50 Value. RLU compound The readings for the drug-treated groups, RLU control is the average value of the compound solvent control group, RLU Blank The average value of the blank control group. Inhibition% = (1-(RLU compound -RLU0-RLU Blank ) / (RLU control -RLU0-RLU Blank ))×100% Formula:5)

[0541] Table 3 Results of the cell proliferation inhibition activity of the test compounds Note: A<0.1μM, 0.1μM≤B<0.5μM, 0.5μM≤C<1μM, 1μM≤D<10μM, 10μM≤E

[0542] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good cell proliferation inhibitory effects on HCT-116 cells and SW48 cells, but have poor cell proliferation inhibitory activity on HT-29 cells.

[0543] 4. Pharmacokinetic Testing in Mice

[0544] 4.1 Experimental Animals: Male Balb / c mice, approximately 22 g, 6 to 8 weeks old, 6 mice per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0545] 4.2 Experimental Design: On the day of the experiment, Balb / c mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before dosing and fed 4 hours after dosing.

[0546] Table 4. Dosing Information

[0547] Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 5% DMSO + 95% (20% SBE-β-CD in Saline)

[0548] Before and after drug administration, 0.03 ml of blood was collected from the eye sockets under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from the intravenous and oral gavage groups at 0, 2, 5, 15, 30 minutes, and 1, 2, 4, and 7 hours. All samples were stored at -80°C until analysis.

[0549] Table 5. Pharmacokinetic parameters of test compounds in mouse plasma

[0550] Conclusion: The compounds of the present invention, such as compound 1-B, compound 8-B, and compound 20-A, have good pharmacokinetic properties, especially compound 20-A, which has a higher exposure in mice and good bioavailability.

[0551] 5.CYP450 enzyme inhibition test

[0552] The purpose of this study was to evaluate the effects of test substances on the activities of five cytochrome P450 (CYP) isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) in human liver microsomes using an in vitro assay system. Specific probe substrates for each CYP450 isoform were incubated with human liver microsomes and varying concentrations of the test substances. The reaction was initiated by the addition of reduced nicotinamide adenine dinucleotide phosphate (NADPH). After the reaction, the samples were processed and metabolites generated from the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Changes in CYP enzyme activity were measured, and IC50 values ​​were calculated to evaluate the inhibitory potential of the test substances against each CYP enzyme isoform.

[0553] Conclusion: The inhibitory activities of the compounds of the present invention, such as compound 1-B, compound 8-B, and compound 20-A, against CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 are all greater than 30 μM.

[0554] 6. hERG potassium channel effect test

[0555] Experimental platform: electrophysiology manual patch clamp system

[0556] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

[0557] Experimental methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. The tip resistance after perfusing the electrode liquid was about 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV to induce the hERG potassium current (I hERG ) was administered with a 2-second depolarization step from -80 mV to +20 mV, followed by repolarization to -50 mV for 1 second before returning to -80 mV. This voltage stimulus was administered every 10 seconds, and administration began after confirming that the hERG potassium current was stable (for at least 1 minute). Compounds were administered for at least 1 minute at each test concentration, and at least two cells (n ≥ 2) were tested for each concentration.

[0558] Data processing: Data analysis was performed using pClamp 10, GraphPad Prism 5, and Excel. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula: Inhibition% = [1-(I / Io)] × 100%

[0559] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitudes of hERG potassium current before and after drug addition, respectively.

[0560] Compound IC 50 Calculated using GraphPad Prism 5 software by fitting the following equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope))

[0561] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0562] Conclusion: The hERG inhibitory activity of the compounds of the present invention, such as compound 1-B and compound 8-B, is >40 μM.

[0563] 7. Beagle Dog Pharmacokinetic Test

[0564] 7.1 Test Animals: Male beagle dogs, weighing approximately 8-13 kg, 6 per compound.

[0565] 7.2 Experimental Methods: On the day of the experiment, beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 14–18 hours prior to dosing. Food was resumed 4 hours after dosing. Dosing was performed according to Table 6.

[0566] Table 6. Dosing Information

[0567] *Dosage is based on the free base.

[0568] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 5% DMSO + 95% (20% SBE-β-CD in Saline) (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; MC: methylcellulose)

[0569] Before and after dosing, 1 ml of blood was collected from the jugular vein or limb vein into an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected at the following time points for both the intravenous and oral administration groups: 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, and 48 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0570] Table 7. Pharmacokinetic parameters of test compounds in beagle dog plasma

[0571] Conclusion: Compounds of the present invention, such as the Example compounds, have higher exposure in dogs.

[0572] 8. In vivo efficacy study of SW48 transplanted tumor in BALB / c nude mice

[0573] SW48 cell culture conditions: Leibovitz L15 + 10% FBS + 1% double antibody, cultured at 37 ° C in a CO2-free incubator. When the cell saturation reached 80%-90% and the number reached the required level, the cells were harvested and counted. 0.1 mL (5 × 10 6 SW48 cells were subcutaneously inoculated into the right back of female BALB / c nude mice when the average tumor volume reached 100-150 mm. 3The animals were divided into groups according to tumor volume, with 10 animals per group. Each group was gavaged with different doses of the test compound once a day. The day of grouping was designated as D0. The body weight and tumor diameter of the animals were measured three times a week during the experiment, and the values ​​were calculated according to the formula V = 0.5 × a × b. 2 The tumor diameter was calculated, and a and b represent the long diameter and short diameter of the tumor, respectively. The anti-tumor efficacy of the test compound was evaluated by the tumor growth inhibition rate (TGI%).

[0574] TGI%=[1-(average tumor volume of a treatment group at the end of drug administration / average tumor volume of the treatment group at the beginning of drug administration) / (average tumor volume of the vehicle control group at the end of treatment / average tumor volume of the vehicle control group at the beginning of treatment)]×100%.

[0575] Conclusion: After 14 days of administration, the test compound, such as compound 1-B, can significantly inhibit the growth of SW48 tumors, and tumor shrinkage can be seen in the 15 mg / kg and 50 mg / kg dose groups.

Claims

1. A compound or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the compound being selected from the compounds represented by general formula (I), wherein: Ring A is selected from C 3-15 carbocyclic or 4 to 15 membered heterocyclic ring, wherein the ring A is optionally substituted by 1 to 6 R a replace; Ring C is selected from C 3-15 carbocyclic or 4 to 15 membered heterocyclic ring, wherein the ring C is optionally substituted by 1 to 6 R c replace; Ring D is selected from C 3-15 carbocyclic or 4 to 15 membered heterocyclic ring, wherein the ring D is optionally substituted with 1 to 6 R d replace; Ring E is selected from C 4-10 carbocyclic or 4 to 10 membered heterocyclic ring, wherein the ring E is optionally substituted by 1 to 6 R e replace; B is selected from B1 or B2; B1 is selected from B2 is selected from represents a single bond or a double bond; n1, n2, n3, n4, n9, n10 are each independently selected from 1, 2, 3 or 4; Or n1, n2, n3, n4 are each independently selected from 0, and the sum of n1, n2, n3, n4 is greater than 2; n5, n6, n7, n8, n11 are each independently selected from 0, 1, 2, 3 or 4; m1, m2, m3 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; L is selected from -C(=O)-, -S(=O)-, -S(=O)(=NH)- or -S(=O)2-; X1, X2, X3, X4, X5, and X6 are each independently selected from N, CH or C, at least two of X3, X4, X5, and X6 are selected from N, and at least one of X1 and X2 is selected from N; R 1 Selected from H, deuterium, C 1-6 Alkyl, C 3-6 carbocyclic ring, 3 to 7 membered heterocyclic ring, the alkyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; R a , R b , R c , R d , R e Each independently selected from H, deuterium, halogen, OH, =O, CN, NH2, SF5, COOH, CONH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -C(=O)NH-C 1-6 Alkyl, -C(=O)N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbon ring, -C 0-4 Alkylene-3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; or R b Selected from -C 1-4 Alkylene-OC 3-6 Carbon ring, -C 1-4 Alkylene-OC 1-6 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkylene -OC 1-6 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 3-6 The alkyl, alkylene, or carbocyclic ring is optionally substituted by 1 to 4 R k replace; Alternatively, the two R b Together with the atoms or ring skeletons to which they are connected, they form C 3-6 A carbocyclic ring or a 4- to 8-membered heterocyclic ring, wherein the carbocyclic ring or the heterocyclic ring is optionally substituted by 1 to 4 R k replace; Alternatively, two R e Together with the atoms it is connected to, it forms C 3-6 A carbocyclic ring or a 4- to 8-membered heterocyclic ring, wherein the carbocyclic ring or the heterocyclic ring is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -C 1-4 Alkylene-C 3-6 Carbon ring, -C 1-4 Alkylene-3 to 7 membered heterocyclic ring, C 3-6 carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with an alkoxy substituent.

2. The compound according to claim 1 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: Ring A is selected from phenyl, 5- to 6-membered heteroaryl, C 3-6 monocarbocyclic ring, 4 to 8 membered heteromonocyclic ring, wherein the ring A is optionally substituted by 1 to 5 R a replace; Ring C is selected from phenyl, naphthyl, benzo 4-6 carbocyclic ring, benzo 4 to 7 membered heterocyclic ring, 5 to 6 membered heteroaryl or 8-10 membered heteroaryl ring, wherein the ring C is optionally substituted by 1 to 5 R c replace; Ring D is selected from phenyl, naphthyl, benzo 4-6 carbocyclic ring, benzo 4 to 7 membered heterocyclic ring, 5 to 6 membered heteroaryl or 8-10 membered heteroaryl ring, wherein the ring D is optionally substituted by 1 to 5 R d replace; Selected from Its left end is directly connected to ring A; Selected from It is directly connected to X2 above, and s1 and s2 are independently selected from 0, 1, 2, and 3; p1 is each independently selected from 0, 1, 2, 3 or 4; E1 is each independently selected from NR e , C(R e )2, O, S(=O)2 or S; R 1 Selected from H, deuterium, C 1-4 Alkyl, C 3-6 The alkyl group or the carbocyclic ring is optionally substituted by 1 to 4 R k replace; Alternatively, two R e Together with the atoms it is connected to, it forms C 3-6 A carbocyclic ring or a 4- to 8-membered heterocyclic ring, wherein the carbocyclic ring or the heterocyclic ring is optionally substituted by 1 to 4 R k replace.

3. The compound according to claim 2 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B2 is selected from R a , R b , R c , R d , R e Each independently selected from H, deuterium, halogen, OH, =O, CN, NH2, SF5, COOH, CONH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -C(=O)NH-C 1-4 Alkyl, -C(=O)N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-3 to 6-membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 6-membered heterocyclic ring, -C 0-2 Alkylene-C 3-6 Carbon ring, -C 0-2 Alkylene-3 to 6 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; or R b Selected from -C 1-2 Alkylene-OC 3-6 Carbon ring, -C 1-2 Alkylene-OC 1-4 Alkyl, -C 1-2 Alkylene-OC 1-2 Alkylene-OC 1-4 Alkyl, -C 1-2 Alkylene-OC 1-3 Alkylene-OC 3-6 The alkyl, alkylene, or carbocyclic ring is optionally substituted by 1 to 4 R k replace; Alternatively, the two R b Together with the atoms or ring skeletons to which they are connected, they form C 3-6 Cycloalkyl or 4 to 7 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-3 to 6-membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 6-membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbon ring, -C 1-2 Alkylene-3 to 6 membered heterocyclic ring, C 3-6 carbocyclic ring, 3 to 6 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with an alkoxy substituent.

4. The compound according to claim 3 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: Selected from Its left end is directly connected to ring A, and s1 and s2 are each independently selected from 0, 1, and 2; L is selected from -C(=O)-; R 1 is selected from H, methyl, ethyl, cyclopropyl; R a , R b , R c , R d , R e Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, CN, NH2, SF5, COOH, CONH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R k substituted by one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl; or R b is selected from -methylene-O-cyclopropyl, -ethylene-O-methyl, -methylene-O-methyl, -methylene-O-ethyl, -methylene-O-ethylidene-O-methyl, -methylene-O-ethylidene-O-ethyl, -methylene-O-ethylidene-O-propyl, -methylene-O-ethylidene-O-cyclopropyl, -methylene-O-methylene-O-cyclopropyl, -methylene-O-ethylidene-O-cyclobutyl, wherein the methylene, ethylene, methyl, ethyl, propyl, cyclopropyl or cyclobutyl is optionally substituted by 1 to 4 R k replace; Alternatively, the two R b and the carbon atom directly connected thereto together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azolopentyl, or azolohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azolopentyl, or azolohexyl group is optionally substituted by 1 to 4 R k replace; Alternatively, two R e and the carbon atom to which it is attached together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl is optionally substituted by 1 to 4 R k replace; R k each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted with an alkoxy substituent.

5. The compound according to claim 4 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: Ring A is selected from a substituted by one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrrolyl, dihydropyridinyl, dihydrofuranyl, dihydropyranyl, phenyl, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl; Ring C is selected from optionally 1 to 4 R c substituted by one of the following groups: phenyl, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, benzopyrrolyl, benzothiophenyl, benzofuranyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzopyridazinyl, pyridopyrrolyl, pyridothiphenyl, pyridofuranyl, pyridopyrazolyl, pyridoimidazolyl, pyridothiazolyl, pyridoisothiazolyl, pyridoxazolyl, pyridisoxazolyl, pyridopyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, Ring D is selected from d substituted by one of the following groups: phenyl, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, benzopyrrolyl, benzothienyl, benzofuranyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, pyridopyrrolyl, pyridothiphenyl, pyridofuranyl, pyridopyrazolyl, pyridoimidazolyl, pyridothiazolyl; B2 is selected from m5 is selected from 0, 1, 2, 3, 4, 5 or 6; B1 is selected from Or B1 is selected from R k Each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrole Alkyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy.

6. The compound according to claim 5 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: Selected from Its left end is directly connected to ring A; E1 is each independently selected from NH, CH2, C(R e )2, O, S(=O)2 or S; Ring A is selected from a One of the following groups substituted: Ring C is selected from optionally 1 to 4 R c One of the following groups substituted: or Ring C is selected from optionally 1 to 3 R c One of the following groups substituted: Ring D is selected from d One of the following groups substituted: B is selected from m3 is selected from 0, 1, 2, 3, 4; m5 is selected from 0, 1, 2, 3, 4; m1 and m2 are each independently selected from 0, 1, 2, 3, and 4; R e Each is independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, SF5, COOH, CONH2, NHCH3, N(CH3)2, CD3, CHF2, CF3, CH2F, OCHF2, OCF3, SCF3, OCH2F, CH2CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl; R a , R b , R c , R d Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, CN, NH2, SF5, COOH, CONH2, NHCH3, N(CH3)2, CD3, CHF2, CF3, CH2F, CHF2CF3, CHF2CH3, OCHF2, OCF3, SCF3, OCH2F, CH2CN, CH2OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, or R b Selected from -CH2-O-cyclopropyl, -CH2-OCH3, -CH2-O-CH2CH2OCH3, -CH2OCH2CH2OCH2CH2CH2OCH3, -CH2-O-CH2CH2O-cyclopropyl.

7. The compound according to claim 1, or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from one of the structures in Table E-1.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1 to 1500 mg of a compound according to any one of claims 1 to 5 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

9. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating a disease associated with WRN.

10. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating tumors (preferably MSI-H solid tumors, MMRD solid tumors).

11. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 7 or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount is preferably 1-1500 mg, the disease is preferably a tumor, and more preferably an MSI-H solid tumor or an MMRD solid tumor.

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