Polycyclic fused ER degradation agent or inhibitor and application thereof in medicine

Abstract

The invention relates to a polycyclic fused ER degradation agent or inhibitor and application thereof in medicine, in particular to a compound shown in a general formula (I) or a stereoisomer, a racemate, a solvate, a prodrug, a metabolite, pharmaceutically acceptable salt or eutectic of the compound, an intermediate and a preparation method of the compound, and application of the compound or the stereoisomer, the racemate, the solvate, the prodrug, the metabolite, the pharmaceutically acceptable salt or the eutectic of the compound in ER related diseases such as tumors. And B-L-K (I).

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and provides a polycyclic fused-ring ER degrader or inhibitor and its pharmaceutical use. Specifically, it relates to a compound of general formula (I) or its stereoisomers, racemates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods thereof, and uses in ER-related diseases such as tumors. Background Art

[0002] Breast cancer is one of the most common malignant tumors in women. According to statistics, the incidence rate accounts for 7-10% of all kinds of malignant tumors in the body. Its incidence is often related to genetics, and the incidence rate is relatively high among women aged 40-60 and around menopause. It usually occurs in the breast glandular epithelial tissue. The incidence rate is higher in women, and male breast cancer accounts for 0.5% to 1% of all breast cancer patients. There are 1.35 million newly added breast cancers globally every year, among which 420,000 die, with an annual increase of 2%. In developed countries such as Western Europe and North America, the incidence rate of breast cancer ranks first among female cancers. The United States is the country with the highest incidence of breast cancer globally. Breast cancer has become the first among female tumors and the second leading cause of tumor death. Among newly diagnosed breast cancer cases, approximately 80% of the cases are estrogen receptor (ER)-positive breast cancer. Therefore, ER (Estrogen receptor, ER) is an important target in breast cancer drug research. So far, the primary intervention measure for treating ER (Estrogen receptor, ER)-positive breast cancer is still endocrine therapy by inhibiting estrogen levels related to breast cancer, mainly including selective estrogen receptor (ER) inhibitors, aromatase inhibitors, and selective ER (Estrogen receptor, ER) downregulators. Therefore, inhibiting the androgen receptor (Estrogen receptor, ER) is an effective means to directly block this pathway.

[0003] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. Such compounds can be recognized by the cell proteasome, causing the degradation of target proteins and effectively reducing the content of target proteins in cells. By introducing ligands that can bind different target proteins into PROTAC molecules, it becomes possible to apply PROTAC technology to the treatment of various diseases, and this technology has received extensive attention in recent years.

[0004] Therefore, it is necessary to develop novel PROTAC drugs targeting estrogen receptor (ER) inhibitors for treating tumor diseases related to estrogen receptors. Summary of the Invention

[0005] The object of the present invention is to provide a compound with a novel structure, good efficacy, high bioavailability, higher safety, and capable of inhibiting or degrading ER, for treating ER-related diseases such as tumors.

[0006] The compounds of the present invention have good pharmacokinetic properties and bioavailability, oral administration properties, and good safety.

[0007] The present invention provides a compound or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from the compounds represented by the general formula (I),

[0008] B-L-K (I);

[0009] In certain embodiments, the compounds represented by the general formula (I) are selected from the compounds represented by the general formula (II-1), (II-2), (II-3), (II-4), or (II-5),

[0010]

[0011]

[0012] In certain embodiments, B is selected from

[0013] In certain embodiments, is selected from an aromatic ring or a non-aromatic ring, which means the ring where it is located is an aromatic ring or a non-aromatic ring;

[0014] In certain embodiments, X 1 or X 5 is selected from CR X1 R X2 、NR X1 、O or S;

[0015] In certain embodiments, X 1 is selected from CR X1 R X2 or O;

[0016] In certain embodiments, X 5 is selected from NR X1 ;

[0017] In certain embodiments, X 2 is selected from CR X1, CR X1 R X2 , NR X1 , O or S;

[0018] In certain embodiments, X 2 is selected from CR X1 or S;

[0019] In certain embodiments, X 3 or X 4 is selected from CR X1 or N;

[0020] In certain embodiments, Y is selected from CR Y1 R Y2 , NR Y1 , O or S;

[0021] In certain embodiments, Y is selected from CR Y1 R Y2 or O;

[0022] In certain embodiments, B 1 is selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-7 carbocyclic group, 4-7 membered heterocyclic group, -O-C 3-12 carbocyclic group, -O-4-12 membered heterocyclic group, -CH 2 -C 3-12 carbocyclic group, -CH 2 -4-12 membered heterocyclic group, wherein the B 1 is optionally substituted by 1 to 4 substituents selected from deuterium, CF 3 , F, Cl, Br, I, OH, =O, NH 2 , CN, CONH 2 , COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 carbocyclic group, 4-6 membered heterocyclic group, fluorine-substituted phenyl;

[0023] In certain embodiments, B 1 is selected from C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 4-6 membered heterocyclic group, -O-C 3-6 carbocyclic group, -O-4-6 membered heterocyclic group, -CH 2 -C 3-6 carbocyclic group, -CH 2 -4-6 membered heterocyclic group, wherein the B 1 is optionally substituted by 1 to 4 substituents selected from deuterium, F, CF 3, Cl, Br, I, OH, =O, NH 2 , CN, CONH 2 , COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 carbocyclic group, 4-6 membered heterocyclic group, substituted by substituents of fluorine-substituted phenyl;

[0024] In certain embodiments, B 1 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxanyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, bicyclo[1.1.1]pentane, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 -piperazinyl, -CH 2 -morpholinyl, -CH 2 -oxetanyl, -CH 2 -tetrahydrofuranyl, -CH 2 -oxanyl, -CH 2 -phenyl, -CH 2 -pyridyl, -CH 2 -pyrazinyl, -CH 2 -pyridazinyl, -CH 2 -pyrazolyl, -CH 2 -imidazolyl, -CH 2 -pyrrolyl, -CH 2 -triazolyl, -CH 2 -bicyclo[1.1.1]pentane, and the B 1 is optionally substituted by 1 to 4 substituents selected from deuterium, F, CF 3 , Cl, Br, I, OH, =O, NH 2 , CN, CONH 2 , COOH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 4-6 membered heterocyclic group, substituted by substituents of fluorine-substituted phenyl;

[0025] In certain embodiments, B 1 is selected from

[0026] In certain embodiments, B 2 is selected from phenyl, 5- to 6-membered heteroaryl, 9- to 12-membered bicyclo-fused ring group, said B 2 optionally substituted with 1 to 4 Rs b2 ;

[0027] In certain embodiments, B 2 is selected from phenyl, 5- to 6-membered heteroaryl, benzofused 5-membered heterocyclic group, benzofused 6-membered heterocyclic group, benzofused 5-membered carbocyclic group, benzofused 6-membered carbocyclic group, benzofused 7-membered carbocyclic group, benzofused 8-membered carbocyclic group, pyridinofused 5-membered heterocyclic group, pyridinofused 6-membered heterocyclic group, said B 2 optionally substituted with 1 to 4 Rs b2 ;

[0028] In certain embodiments, B 2 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,

[0029] said B 2 optionally substituted with 1 to 2 Rs b2 ;

[0030] In certain embodiments, B 1a is selected from C 3-12 carbocyclic group or 4- to 12-membered heterocyclic group, said B 1a optionally substituted with 1 to 4 Rs b1a ;

[0031] In certain embodiments, B 1a is selected from phenyl or 5- to 6-membered heteroaryl, said B 1a optionally substituted with 1 to 4 Rs b1a ;

[0032] In certain embodiments, B 1a is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, said B 1a optionally substituted with 1 to 4 Rs b1a ;

[0033] In certain embodiments, L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0034] In certain embodiments, L is selected from -Ak1-, -Ak1-Ak2-, -Cy1-, -Cy1-Cy2-, -Cy1-Ak1-, -Ak1-Cy1-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak1-, -Ak1-Cy1-Cy2-, -Cy1-Ak1-Cy2-Ak2-, -Ak1-Cy1-Ak2-Cy2-;

[0035] In certain embodiments, each of Ak1, Ak2, Ak3, Ak4, Ak5 is independently selected from a bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, O, NR L 、NR L CO, CONR L 、CO, and the alkylene, alkenylene, alkynylene are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, COOH, CN, NH 2 、=O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 4- to 6-membered heterocyclic group;

[0036] In certain embodiments, each of Ak1, Ak2 is independently selected from C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, O, NR L 、NR L CO, CO, and the alkylene, alkenylene, alkynylene are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, COOH, CN, NH 2 、=O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 4- to 6-membered heterocyclic group;

[0037] In certain embodiments, each of Ak1, Ak2 is independently selected from methylene, ethylene, vinylene, ethynylene, and the methylene, ethylene, vinylene, ethynylene are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH 2 、COOH, CN, =O, C 1-4 alkyl, halogen-substituted C1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 substituted by substituents of a carbocyclic group, 4- to 6-membered heterocyclic group;

[0038] In certain embodiments, R L each independently selected from H or C 1-6 alkyl;

[0039] In certain embodiments, R L each independently H or C 1-4 alkyl;

[0040] In certain embodiments, R L each independently H, methyl, ethyl;

[0041] In certain embodiments, Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or one of the following groups optionally substituted by 1 to 4 R L2 substituted: 4- to 7-membered monocyclic heterocyclic group, 4- to 12-membered fused heterocyclic group, 5- to 13-membered spiro heterocyclic group, 7- to 12-membered bridged heterocyclic group, C 3-7 monocyclic carbocyclic group, C 4-12 fused carbocyclic group, C 5-13 spiro carbocyclic group, C 5-12 bridged carbocyclic group, 5- to 10-membered heteroaryl or C 6-10 aryl;

[0042] In certain embodiments, Cy1, Cy2 are each independently selected from one of the following groups optionally substituted by 1 to 4 R L2 substituted: 3- to 6-membered monocyclic heterocyclic group, 4- to 10-membered fused heterocyclic group, 5- to 11-membered spiro heterocyclic group, 5- to 10-membered bridged heterocyclic group, C 3-6 monocyclic carbocyclic group, C 4-10 fused carbocyclic group, C 5-11 spiro carbocyclic group, C 5-10 bridged carbocyclic group, 5- to 10-membered heteroaryl or C 6-10 aryl;

[0043] In certain embodiments, Cy1, Cy2 are each independently selected from one of the following groups optionally substituted by 1 to 4 R L2One of the following substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, phenyl, cyclopropyl-fused cyclopropyl, cyclopropyl-fused cyclobutyl, cyclopropyl-fused cyclopentyl, cyclopropyl-fused cyclohexyl, cyclobutyl-fused cyclobutyl, cyclobutyl-fused cyclopentyl, cyclobutyl-fused cyclohexyl, cyclopentyl-fused cyclopentyl, cyclopentyl-fused cyclohexyl, cyclohexyl-fused cyclohexyl, cyclopropyl-spiro cyclopropyl, cyclopropyl-spiro cyclobutyl, cyclopropyl-spiro cyclopentyl, cyclopropyl-spiro cyclohexyl, cyclobutyl-spiro cyclobutyl, cyclobutyl-spiro cyclopentyl, cyclobutyl-spiro cyclohexyl, cyclopentyl-spiro cyclopentyl, cyclopentyl-spiro cyclohexyl, cyclohexyl-spiro cyclohexyl, cyclopropyl-fused azetidinyl, cyclopropyl-fused pyrrolidinyl, cyclopropyl-fused piperidinyl, cyclobutyl-fused azetidinyl, cyclobutyl-fused pyrrolidinyl, cyclobutyl-fused piperidinyl, cyclopentyl-fused azetidinyl, cyclopentyl-fused pyrrolidinyl, cyclopentyl-fused piperidinyl, cyclohexyl-fused azetidinyl, cyclohexyl-fused pyrrolidinyl, cyclohexyl-fused piperidinyl, azetidinyl-fused azetidinyl, azetidinyl-fused pyrrolidinyl, azetidinyl-fused piperidinyl, pyrrolidinyl-fused azetidinyl, pyrrolidinyl-fused pyrrolidinyl, pyrrolidinyl-fused piperidinyl, piperidinyl-fused azetidinyl, piperidinyl-fused pyrrolidinyl, piperidinyl-fused piperidinyl, cyclobutyl-spiro azetidinyl, cyclobutyl-spiro pyrrolidinyl, cyclobutyl-spiro piperidinyl, cyclopentyl-spiro azetidinyl, cyclopentyl-spiro pyrrolidinyl, cyclopentyl-spiro piperidinyl, cyclohexyl-spiro azetidinyl, cyclohexyl-spiro pyrrolidinyl, cyclohexyl-spiro piperidinyl, azetidinyl-spiro azetidinyl, azetidinyl-spiro pyrrolidinyl, azetidinyl-spiro piperidinyl, pyrrolidinyl-spiro azetidinyl, pyrrolidinyl-spiro pyrrolidinyl, pyrrolidinyl-spiro piperidinyl, piperidinyl-spiro azetidinyl, piperidinyl-spiro pyrrolidinyl, piperidinyl-spiro piperidinyl

[0044]

[0045]

[0046] In certain embodiments, Cy1 and Cy2 are each independently selected from one of the following optionally substituted groups by 1 to 4 R L2 One of the following substituted groups:

[0047] In certain embodiments, K is selected from In certain embodiments, K is selected from In certain embodiments, K 1 Selected from phenyl, 5-6 membered heteroaryl, 9-12 membered bicyclo-fused ring group, Said K 1 Optionally substituted by 1 to 4 R k1 Substituted;

[0048] In certain embodiments, K 1Selected from phenyl, 5- or 6-membered heteroaryl, benzo-5-membered heterocyclic group, benzo-6-membered heterocyclic group, where K 1 is optionally substituted with 1 to 4 Rs k1 ; in certain embodiments, K 1 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,

[0049] where K 1 is optionally substituted with 1 to 2 Rs k1 ;

[0050] In certain embodiments, W is selected from 5- or 6-membered heterocyclic group;

[0051] In certain embodiments, Z 1 is selected from N or CR k2 ;

[0052] In certain embodiments, Z 2 is selected from CH or N;

[0053] In certain embodiments, Z 3 is selected from CH or N;

[0054] In certain embodiments, Q is selected from NR q CO, CONR q , CO, NR q or a bond;

[0055] In certain embodiments, R X1 , R X2 , R Y1 , R Y2 , R B , R b2 , R b3 , R b1a , R k1 , R k2 , R k3 , R q , R L2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, =S, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-7 carbocyclic group, 4- to 6-membered heterocyclic group, -O-C 3-7a carbocyclic group, -O-4-6-membered heterocyclic group, and the alkyl, alkoxy, heterocyclic group, and carbocyclic group are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, =O, NH 2 、CN、CONH 2 、COOH、C 1-6 alkyl, C 1-6 alkoxy, C 3-7 carbocyclic group, 4-6-membered heterocyclic group, and a fluorine-substituted phenyl group;

[0056] In certain embodiments, R X1 、R X2 、R Y1 、R Y2 、R B 、R b2 、R b3 、R b1a 、R k1 、R k2 、R k3 、R q 、R L2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, =S, NH 2 、CN、COOH、CONH 2 、C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 4-6-membered heterocyclic group, -O-C 3-6 carbocyclic group, -O-4-6-membered heterocyclic group, and the alkyl, alkoxy, heterocyclic group, and carbocyclic group are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, =O, NH 2 、CN、CONH 2 、COOH、C 1-4 alkyl, C 1-4 alkoxy, C 3-7 carbocyclic group, 4-6-membered heterocyclic group, and a fluorine-substituted phenyl group;

[0057] In certain embodiments, R X1 、R X2 、R Y1 、R Y2 、R B 、R b2 、R b3 、R b1a 、R k1 、R k2 、R k3 、R q 、R L2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, =S, NH2 , CN, COOH, CONH 2 , methyl, ethyl, propyl, isopropyl, butyl, tert - butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, tetrahydrofuranyl, oxanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridyl, - O - cyclopropyl, - O - cyclobutyl, - O - cyclopentyl, - O - cyclohexyl, - O - phenyl, said methyl, ethyl, propyl, isopropyl, butyl, tert - butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, tetrahydrofuranyl, oxanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, = O, NH 2 , CN, CONH 2 , COOH, C 1-4 alkyl, C 1-4 alkoxy, C 3-7 carbocyclic group, 4 - 6 - membered heterocyclic group, phenyl substituted by fluorine;

[0058] In certain embodiments, R X1 , R X2 , R Y1 or R Y2 are each independently selected from H, deuterium, F, CF 3 , methyl, ethyl, cyclopropyl;

[0059] In certain embodiments, R B is selected from H, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl;

[0060] In certain embodiments, R b2 , R b3 , R b1a , R k1 , R k2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, = O, NH 2 , CN, COOH, CONH 2 , CF 3 , CHF 2 , CH 2 F, methyl, ethyl, propyl, isopropyl, butyl, tert - butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, CH 2 OH;

[0061] In certain embodiments, R k3 are each independently selected from H, deuterium, methyl;

[0062] In certain embodiments, R L2 is independently selected from H, deuterium, F;

[0063] In certain embodiments, R q is independently selected from H, deuterium, methyl;

[0064] In certain embodiments, p2 is independently selected from 0, 1, 2, 3, or 4;

[0065] In certain embodiments, b3 is selected from 0, 1, 2, or 3;

[0066] In certain embodiments, L is selected from one of the fragments shown in Table A;

[0067] Table A

[0068]

[0069] In certain embodiments, B is selected from one of the structural fragments shown in Table B-1;

[0070] Table B-1

[0071]

[0072]

[0073] In certain embodiments, K is selected from one of the fragments shown in Table K-1;

[0074] Table K-1

[0075]

[0076]

[0077]

[0078] Optionally, in the compound, K 1 is required to be selected from the said K 1 is optionally substituted with 1 to 4 R k1 groups;

[0079] Or in the compound, B 2 is required to be selected from the said B 2 is optionally substituted with 1 to 4 R b2 groups.

[0080] Optionally, the compound satisfies the following conditions:

[0081] K 1 is selected from the said K 1Optionally substituted by 1 to 4 R k1 and the remaining definitions in the general formula (I) are as described above;

[0082] or B 2 is selected from said B 2 Optionally substituted by 1 to 4 R b2 and the remaining definitions in the general formula (I) are as described above.

[0083] As the first embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0084] B is selected from

[0085] selected from an aromatic ring or a non-aromatic ring;

[0086] X 1 or X 5 is selected from CR X1 R X2 、NR X1 、O or S;

[0087] X 2 is selected from CR X1 、CR X1 R X2 、NR X1 、O or S;

[0088] X 3 or X 4 is selected from CR X1 or N;

[0089] Y is selected from CR Y1 R Y2 、NR Y1 、O or S;

[0090] B 1 is selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-7 carbocyclic group, 4- to 7-membered heterocyclic group, -O-C 3-12 carbocyclic group, -O-4- to 12-membered heterocyclic group, -CH 2 -C 3-12 carbocyclic group, -CH 2 -4- to 12-membered heterocyclic group, and said B 1 Optionally substituted by 1 to 4 selected from deuterium, CF 3 、F、Cl、Br、I、OH、=O、NH 2 、CN、CONH2 、 COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 carbocyclic group, 4-6 membered heterocyclic group, substituted by substituents of fluorine-substituted phenyl;

[0091] B 2 selected from phenyl, 5-6 membered heteroaryl, 9-12 membered bicyclo fused ring group, said B 2 optionally substituted by 1 to 4 R b2 substituted;

[0092] B 1a selected from C 3-12 carbocyclic group or 4-12 membered heterocyclic group, said B 1a optionally substituted by 1 to 4 R b1a substituted;

[0093] b3 is selected from 0, 1, 2 or 3;

[0094] L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0095] Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from a bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, O, NR L 、NR L CO, CONR L 、CO, said alkylene, alkenylene, alkynylene optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, COOH, CN, NH 2 、=O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 4-6 membered heterocyclic group substituted by substituents;

[0096] R L are each independently selected from H or C 1-6 alkyl;

[0097] Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 substituted by one of the following groups: 4-7 membered monocyclic heterocyclic group, 4-12 membered fused heterocyclic group, 5-13 membered spiro heterocyclic group, 7-12 membered bridged heterocyclic group, C 3-7 monocyclic carbocyclic group, C 4-12 fused carbocyclic group, C5-13 Spirocyclic carbocyclic group, C 5-12 Bridged carbocyclic group, 5- to 10-membered heteroaryl group, or C 6-10 Aryl group;

[0098] K is selected from

[0099] K 1 Selected from phenyl, 5- to 6-membered heteroaryl group, 9- to 12-membered bicyclo-fused ring group, Said K 1 Optionally substituted by 1 to 4 R k1 Substituted;

[0100] W is selected from 5- to 6-membered heterocyclic groups;

[0101] Z 2 Selected from CH or N;

[0102] Z 3 Selected from CH or N;

[0103] Q is selected from NR q CO, CONR q , CO, NR q Or a bond;

[0104] Z 1 Selected from N or CR k2 ;

[0105] R X1 , R X2 , R Y1 , R Y2 , R B , R b2 , R b3 , R b1a , R k1 , R k2 , R k3 , R q , R L2 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, =S, NH 2 , CN, COOH, CONH 2 , C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-7 Carbocyclic group, 4- to 6-membered heterocyclic group, -O-C 3-7 Carbocyclic group, -O-4- to 6-membered heterocyclic group, and the alkyl group, alkoxy group, heterocyclic group, and carbocyclic group are optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, =O, NH 2 , CN, CONH 2 , COOH, C 1-6 Alkyl group, C1-6 Alkoxy, C 3-7 substituted by substituents of a carbocyclic group, a 4- to 6-membered heterocyclic group, or a fluorine-substituted phenyl group;

[0106] p2 are each independently selected from 0, 1, 2, 3, or 4;

[0107] provided that

[0108] in the compound, K 1 is selected from said K 1 optionally substituted by 1 to 4 R k1 substituents;

[0109] or in the compound, B 2 is selected from said B 2 optionally substituted by 1 to 4 R b2 substituents; the remaining definitions are the same as those in the first embodiment of the present invention.

[0110] As the second embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal,

[0111] L is selected from -Ak1-, -Ak1-Ak2-, -Cy1-, -Cy1-Cy2-, -Cy1-Ak1-, -Ak1-Cy1-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak1-, -Ak1-Cy1-Cy2-, -Cy1-Ak1-Cy2-Ak2-, -Ak1-Cy1-Ak2-Cy2-;

[0112] Ak1 and Ak2 are each independently selected from C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, O, NR L 、NR L CO, CO, and the alkylene, alkenylene, and alkynylene are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, COOH, CN, NH 2 、=O、C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, or substituents of a 4- to 6-membered heterocyclic group;

[0113] R L are each independently H or C 1-4 alkyl;

[0114] Cy1 and Cy2 are each independently selected from one of the following groups optionally substituted by 1 to 4 Rs L2 : monocyclic heterocyclic group having 3 to 6 members, fused heterocyclic group having 4 to 10 members, spiro heterocyclic group having 5 to 11 members, bridged heterocyclic group having 5 to 10 members, C 3-6 monocyclic carbocyclic group, C 4-10 fused carbocyclic group, C 5-11 spiro carbocyclic group, C 5-10 bridged carbocyclic group, heteroaryl having 5 to 10 members or C 6-10 aryl;

[0115] B 1 is selected from C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, heterocyclic group having 4 to 6 members, -O-C 3-6 carbocyclic group, -O-heterocyclic group having 4 to 6 members, -CH 2 -C 3-6 carbocyclic group, -CH 2 -heterocyclic group having 4 to 6 members, and the B 1 is optionally substituted by 1 to 4 substituents selected from deuterium, F, CF 3 , Cl, Br, I, OH, =O, NH 2 , CN, CONH 2 , COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 carbocyclic group, heterocyclic group having 4 to 6 members, and phenyl substituted with fluorine;

[0116] B 1a is selected from phenyl or heteroaryl having 5 to 6 members, and the B 1a is optionally substituted by 1 to 4 Rs b1a ;

[0117] B 2 is selected from phenyl, heteroaryl having 5 to 6 members, benzo-5-membered heterocyclic group, benzo-6-membered heterocyclic group, benzo-5-membered carbocyclic group, benzo-6-membered carbocyclic group, benzo-7-membered carbocyclic group, benzo-8-membered carbocyclic group, pyrido-5-membered heterocyclic group, pyrido-6-membered heterocyclic group, and the B 2 is optionally substituted by 1 to 4 Rs b2 ;

[0118] K 1 is selected from phenyl, heteroaryl having 5 to 6 members, benzo-5-membered heterocyclic group, benzo-6-membered heterocyclic group, and the K 1 is optionally substituted by 1 to 4 Rs k1 ;

[0119] R X1 、R X2 、R Y1 、R Y2 、R B 、R b2 、R b3 、R b1a 、R k1 、R k2 、R k3 、R q 、R L2 each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, =S, NH 2 、CN, COOH, CONH 2 、C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 4- to 6-membered heterocyclic group, -O-C 3-6 carbocyclic group, -O-4- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, heterocyclic group, and carbocyclic group are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, =O, NH 2 、CN, CONH 2 、COOH, C 1-4 alkyl, C 1-4 alkoxy, C 3-7 carbocyclic group, 4- to 6-membered heterocyclic group, and fluorine-substituted phenyl;

[0120] As a third embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0121] B 1 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxanyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, bicyclo[1.1.1]pentane, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 -piperazinyl, -CH 2 -morpholinyl, -CH 2-oxetanyl, -CH 2 -tetrahydrofuranyl, -CH 2 -oxanyl, -CH 2 -phenyl, -CH 2 -pyridyl, -CH 2 -pyrazinyl, -CH 2 -pyridazinyl, -CH 2 -pyrazolyl, -CH 2 -imidazolyl, -CH 2 -pyrrolyl, -CH 2 -triazolyl, -CH 2 -bicyclo[1.1.1]pentane, said B 1 optionally substituted by 1 to 4 substituents selected from deuterium, F, CF 3 , Cl, Br, I, OH, =O, NH 2 , CN, CONH 2 , COOH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 4- to 6-membered heterocyclic group, fluoro-substituted phenyl;

[0122] Ak1 and Ak2 are each independently selected from methylene, ethylene, vinylene, ethynylene, said methylene, ethylene, vinylene, ethynylene optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH 2 , COOH, CN, =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 4- to 6-membered heterocyclic group;

[0123] Cy1 and Cy2 are each independently selected from optionally substituted by 1 to 4 R L2One of the following substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, phenyl, cyclopropyl-fused cyclopropyl, cyclopropyl-fused cyclobutyl, cyclopropyl-fused cyclopentyl, cyclopropyl-fused cyclohexyl, cyclobutyl-fused cyclobutyl, cyclobutyl-fused cyclopentyl, cyclobutyl-fused cyclohexyl, cyclopentyl-fused cyclopentyl, cyclopentyl-fused cyclohexyl, cyclohexyl-fused cyclohexyl, cyclopropyl-spirocyclopropyl, cyclopropyl-spirocyclobutyl, cyclopropyl-spirocyclopentyl, cyclopropyl-spirocyclohexyl, cyclobutyl-spirocyclobutyl, cyclobutyl-spirocyclopentyl, cyclobutyl-spirocyclohexyl, cyclopentyl-spirocyclopentyl, cyclopentyl-spirocyclohexyl, cyclohexyl-spirocyclohexyl, cyclopropyl-fused azetidinyl, cyclopropyl-fused pyrrolidinyl, cyclopropyl-fused piperidinyl, cyclobutyl-fused azetidinyl, cyclobutyl-fused pyrrolidinyl, cyclobutyl-fused piperidinyl, cyclopentyl-fused azetidinyl, cyclopentyl-fused pyrrolidinyl, cyclopentyl-fused piperidinyl, cyclohexyl-fused azetidinyl, cyclohexyl-fused pyrrolidinyl, cyclohexyl-fused piperidinyl, azetidinyl-fused azetidinyl, azetidinyl-fused pyrrolidinyl, azetidinyl-fused piperidinyl, pyrrolidinyl-fused azetidinyl, pyrrolidinyl-fused pyrrolidinyl, pyrrolidinyl-fused piperidinyl, piperidinyl-fused azetidinyl, piperidinyl-fused pyrrolidinyl, piperidinyl-fused piperidinyl, cyclobutyl-spiroazetidinyl, cyclobutyl-spiropyrrolidinyl, cyclobutyl-spiropiperidinyl, cyclopentyl-spiroazetidinyl, cyclopentyl-spiropyrrolidinyl, cyclopentyl-spiropiperidinyl, cyclohexyl-spiroazetidinyl, cyclohexyl-spiropyrrolidinyl, cyclohexyl-spiropiperidinyl, azetidinyl-spiroazetidinyl, azetidinyl-spiropyrrolidinyl, azetidinyl-spiropiperidinyl, pyrrolidinyl-spiroazetidinyl, pyrrolidinyl-spiropyrrolidinyl, pyrrolidinyl-spiropiperidinyl, piperidinyl-spiroazetidinyl, piperidinyl-spiropyrrolidinyl, piperidinyl-spiropiperidinyl

[0124] The remaining definitions are the same as those in the first or second embodiment of the present invention.

[0125] As a fourth embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomers, racemates, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals

[0126] B 1 is selected from

[0127] B 2 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl

[0128]

[0129] The said B 2 Optionally substituted by 1 to 2 Rs b2 ;

[0130] B 1a Selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, and the said B 1a Optionally substituted by 1 to 4 Rs b1a ;

[0131] K 1 Selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,

[0132] The said K 1 Optionally substituted by 1 to 2 Rs k1 ;

[0133] Cy1 and Cy2 are each independently selected from the following groups optionally substituted by 1 to 4 Rs L2 One of the following:

[0134] R X1 、R X2 、R Y1 、R Y2 、R B 、R b2 、R b3 、R b1a 、R k1 、R k2 、R k3 、R q 、R L2 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, =S, NH 2 、CN、COOH、CONH 2, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, tetrahydrofuranyl, oxanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, and the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, tetrahydrofuranyl, oxanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, =O, NH 2 , CN, CONH 2 , COOH, C 1-4 alkyl, C 1-4 alkoxy, C 3-7 carbocyclic group, 4- to 6-membered heterocyclic group, and a substituent of a fluorine-substituted phenyl;

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

[0136] As the fifth embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0137] X 1 is selected from CR X1 R X2 or O;

[0138] X 5 is selected from NR X1 ;

[0139] X 2 is selected from CR X1 or S;

[0140] Y is selected from CR Y1 R Y2 or O;

[0141] Q is selected from CONR q , NR q CO, NR q or a bond;

[0142] R X1 , R X2 , R Y1 or R Y2 are each independently selected from H, deuterium, F, CF 3 , methyl, ethyl, cyclopropyl;

[0143] R B is independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl;

[0144] R b2 、R b3 、R b1a 、R k1 、R k2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 、CN, COOH, CONH 2 、CF 3 、CHF 2 、CH 2 F, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, CH 2 OH;

[0145] R k3 are each independently selected from H, deuterium, methyl;

[0146] R L2 are each independently selected from H, deuterium, F;

[0147] R q are each independently selected from H, deuterium, methyl.

[0148] The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

[0149] As the sixth embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0150] B is selected from one of the fragments shown in Table B-1;

[0151] L is selected from one of the fragments shown in Table A;

[0152] K is selected from one of the fragments shown in Table K-1.

[0153] The present invention relates to a compound or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures shown in Table E-1.

[0154] The present invention relates to a pharmaceutical composition comprising the above compound or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0155] The present invention relates to the use of the above-mentioned compound or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or the above-mentioned pharmaceutical composition for the preparation of a drug for inhibiting or degrading ER.

[0156] The present invention relates to the use of the above-mentioned compound or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or the above-mentioned pharmaceutical composition for the preparation of a drug for treating tumors.

[0157] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound described in the present invention or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal and a pharmaceutical excipient. The pharmaceutical composition can be in the form of a unit preparation (the amount of the active ingredient in the unit preparation is also referred to as the "preparation specification").

[0158] As used herein, the term "effective amount" or "therapeutically effective amount" means an amount of the compound disclosed in the present application that, when administered in sufficient quantity, will, to some extent, alleviate one or more symptoms of the disease or disorder being treated (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 alteration of a biological system. For example, for therapeutic use, an "effective amount" is the amount of the compound disclosed in the present application required to provide a clinically significant reduction in the symptoms of the disease. Examples of therapeutically effective amounts include, but are not limited to, 1 - 1500 mg, 1 - 1000 mg, 1 - 800 mg, 1 - 600 mg, 60 - 600 mg, 70 - 600 mg, 200 - 600 mg, 1 - 500 mg, 75 - 500 mg, 80 - 500 mg, 90 - 500 mg, 100 - 500 mg, 125 - 500 mg, 150 - 500 mg, 5 - 400 mg, 10 - 400 mg, 20 - 400 mg, 25 - 400 mg, 30 - 400 mg, 40 - 400 mg, 50 - 400 mg, 60 - 400 mg, 70 - 400 mg, 75 - 400 mg, 80 - 400 mg, 90 - 400 mg, 100 - 400 mg, 125 - 400 mg, 150 - 400 mg, 200 - 400 mg, 250 - 400 mg, 300 - 400 mg, 1 - 300 mg, 200 - 300 mg, 250 - 300 mg, 1 - 200 mg, 150 - 200 mg.

[0159] In some embodiments, the pharmaceutical composition includes, but is not limited to, 1 - 1500 mg, 1 - 1000 mg, 1 - 800 mg, 1 - 600 mg, 20 - 400 mg, 25 - 200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg of the compound of the present invention or its stereoisomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals.

[0160] A method for treating a disease in a mammal, the method comprising administering to a subject a daily dose of 1 - 1500 mg / day of the compound of the present invention or its stereoisomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, the daily dose can 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, 25 - 400 mg / day, 50 - 400 mg / day, 100 - 400 mg / day, 200 - 400 mg / day. In some embodiments, the daily dose includes, but is not limited to, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day.

[0161] The present invention relates to a kit, which may include the composition in single - dose or multi - dose form. The kit contains the compound of the present invention or its stereoisomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and the amount of the compound of the present invention or its stereoisomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals is the same as that in the above - mentioned pharmaceutical composition.

[0162] In the present invention, the amount of the compound of the present invention or its stereoisomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals is converted in the form of the free base in each case.

[0163] "Dosage form specification" refers to the weight of the active ingredient contained in each vial, tablet or other unit dosage form.

[0164] Unless otherwise stated, the terms used in the specification and claims of this application have the following meanings.

[0165] For the groups and compounds described in the present invention, carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved therein all include their isotope situations, that is, for the groups and compounds described in the present invention, carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved therein are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 11 C, 12 C, 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 15 O, 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S, 35 S and 36 S, the isotopes of nitrogen include 13 N, 14 N and 15 N, the isotopes of fluorine include 17 F, 18 F and 19 F, the isotopes of chlorine include 35 Cl, 36 Cl and 37 Cl, the isotopes of bromine include 79 Br and 81 Br, the isotopes of iodine include 123 I, 125 I, the isotopes of phosphorus include 31 P, 32 P.

[0166] "CN" refers to a cyano group.

[0167] "Halogen" refers to F, Cl, Br or I.

[0168] "Halogen-substituted" means substituted by F, Cl, Br or I, including but not limited to being substituted by 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 substituents selected from F, Cl, Br or I, 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is abbreviated as "halogenated".

[0169] "Alkyl" refers to a substituted or unsubstituted straight-chain or branched-chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups having 1 to 20 carbon atoms, alkyl groups having 1 to 8 carbon atoms, alkyl groups having 1 to 6 carbon atoms, and alkyl groups having 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and their various branched isomers; the alkyl group can be monovalent, divalent, trivalent or tetravalent.

[0170] "Alkylene" refers to a substituted or unsubstituted straight-chain and branched-chain divalent saturated hydrocarbon group, including -(CH 2 ) v -(where v is an integer from 1 to 10). Examples of alkylene include but are not limited to methylene, ethylene, propylene, and butylene.

[0171] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 12 carbon atoms. The cycloalkyl group can be monocyclic, fused-ring, bridged-ring, and spiro-ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-fused cyclobutyl, cyclobutyl-spiro cyclobutyl, adamantane, etc. The cycloalkyl group can be monovalent, divalent, trivalent or tetravalent.

[0172] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated ring hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, S or Se. The C, N, S on the ring of the heterocycloalkyl group can be oxidized to various oxidation states. The heterocycloalkyl group can be monocyclic, fused-ring, bridged-ring, and spiro-ring. The heterocycloalkyl group can be attached to a heteroatom or a carbon atom. Non-limiting examples include epoxyethyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl, The heterocycloalkyl group can be monovalent, divalent, trivalent or tetravalent.

[0173] "Alkenyl" refers to a substituted or unsubstituted straight-chain or branched-chain unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes but is not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 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.; alkenyl can be monovalent, divalent, trivalent or tetravalent.

[0174] "Alkynyl" refers to a substituted or unsubstituted straight-chain or branched-chain unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, and the main chain includes 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms in the main chain and having 2 to 4 carbon atoms in the main chain. Examples of alkynyl 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, 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, etc.; alkynyl can be monovalent, divalent, trivalent or tetravalent.

[0175] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropoxy and cyclobutoxy.

[0176] "Carbocyclic group" or "carbocycle" refers to a substituted or unsubstituted aromatic ring or non-aromatic ring, which can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered tetracyclic system. The carbocyclic group can be attached to an aromatic ring or a non-aromatic ring, and the ring can be optionally a monocyclic ring, a fused ring, a bridged ring, or a spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclic group" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0177] "Heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted aromatic ring or non-aromatic ring, which can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered tetracyclic system, and contains one or more (including but not limited to 2, 3, 4, or 5) heteroatoms selected from N, O, S, or Se. The optionally substituted C, N, S, or Se in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and the heterocyclic group can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic ring, a bridged ring, a fused ring, or a spiro ring. Non-limiting examples include epoxyethyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiolyl, dihydrofuryl, dihydropyranyl, dithiolanyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azadamantyl, oxaspiro[3.3]heptyl,

[0178] "Heterocyclic group" or "heterocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0179] "Spirocycle" or "spirocyclic group" refers to a polycyclic group in which substituted or unsubstituted rings share one atom (called a spiro atom). The number of ring atoms in the spirocyclic system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, and one or more of the 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 heteroatoms selected from N, O, or S(=O) n (where n is 0, 1, or 2). Non-limiting examples include:

[0180] "Spirocycle" or "spirocyclic group" can be monovalent, divalent, trivalent, or tetravalent.

[0181] "Fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, where one or more of the rings may contain 0 or more (including but not limited to 1, 2, 3, or 4) double bonds, and may be substituted or unsubstituted. Each ring in the fused ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to selected from N, S(=O) n or O, where n is 0, 1, or 2). The number of ring atoms in the fused ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include: "Fused ring" or "fused ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0182] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two non-directly connected atoms, which may contain 0 or more double bonds. Any ring in the bridged ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, where n is 0, 1, 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:

[0183]

[0184] Cubane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0185] "Carbospirocycle", "spirocyclic carbocyclic group", "spirocarbocyclic group", or "carbospirocyclic group" refers to a "spirocycle" in which the ring system consists only of carbon atoms.

[0186] "Carbofused ring", "fused ring carbocyclic group", "carbo-fused ring group", or "carbofused ring group" refers to a "fused ring" in which the ring system consists only of carbon atoms.

[0187] "Carbocyclic bridged ring", "bridged carbocyclic group", "bridged carbocyclic radical" or "carbocyclic bridged group" refers to a "bridged ring" in which the ring system consists only of carbon atoms.

[0188] "Heteromonocyclic ring", "monocyclic heterocyclic group" or "heteromonocyclic group" refers to a "heterocyclic group" or "heterocyclic ring" of a monocyclic system.

[0189] "Fused heterocyclic ring", "fused heterocyclic group", "fused heterocyclic group of fused rings" or "fused heterocyclic group of fused rings" refers to a "fused ring" containing heteroatoms.

[0190] "Heterospiro ring", "heterospiro group", "spiro heterocyclic group" or "spiro heterocyclic group" refers to a "spiro ring" containing heteroatoms.

[0191] "Heterobridged ring", "heterobridged group", "bridged heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing heteroatoms.

[0192] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, and the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12 or 6 to 10 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbocyclic ring, and the ring connected to the parent structure is the aryl ring. Non-limiting examples include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the connection site is on the aryl ring.

[0193] "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, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes, but is not limited to, 5 to 15, 5 to 10 or 5 to 6. The atoms C, N, S on the ring are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, n is 1, 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, benzopyridyl, pyrrolopyridyl, pyridone group, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, and the ring connected to the parent structure is the aryl ring. Non-limiting examples include: The heteroaryl appearing in this article has the same definition as this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the connection site is on the aromatic ring.

[0194] "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-R a 、-O-(CH 2 ) m -C(=O)-R a 、-(CH 2 ) m -C(=O)-NR b R c 、-(CH 2 ) m S(=O) n R a 、-(CH 2 ) m -Alkenyl-R a 、OR d or -(CH 2 ) m -Alkynyl-R a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR b R c etc., where R b With R c Independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, as an option, R b With R c Can form a five- or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic, carbonyl, ester, bridged ring, spirocyclic or cyclized.

[0195] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from...", where X is selected from any integer between 1 and 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k Substitution. For example, "1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4 or 5 substituents selected from..." For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F. ​​​​​​

[0196] A ring of X-Y members (where X and Y are integers, and 3 ≤ X < Y, and X < Y ≤ 20, and X and Y are any integers selected from 4 to 20) includes rings of X, X+1, X+2, X+3, X+4…Y members. The ring includes a heterocyclic ring, a carbocyclic ring, an aromatic ring, an aryl group, a heteroaryl group, a cycloalkyl group, a heteromonocyclic ring, a hetero-fused ring, a heterospiro ring or a heterobridged ring. For example, a "4-7 membered heteromonocyclic ring" means a 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and a "5-10 membered hetero-fused ring" means a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered hetero-fused ring.

[0197] C x-y A carbocyclic ring (including an aryl group, a cycloalkyl group, a monocyclic carbocyclic ring, a spirocarbocyclic ring, a fused carbocyclic ring or a bridged carbocyclic ring) includes C x 、C x+1 、C x+2 、C x+3 、C x+4 …C y membered rings (x is an integer, and 3 ≤ x < y, and y is any integer selected from 4 to 20), for example. Such as C 3-6 A cycloalkyl group" means C 3 、C 4 、C 5 or C 6 cycloalkyl groups.

[0198] When a certain group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the connection mode of the chemical bond is non-specific and there are hydrogen atoms at the connectable sites, then when connecting the chemical bonds, the number of H atoms at the site will correspondingly decrease according to the number of connected chemical bonds to become a group with the corresponding valence. For example Indicates that any connectable site on the piperidyl group can be connected to other groups through 1 chemical bond, including at least these 4 connection modes, even if an H atom is drawn on the -N it also includes For example Indicates that the R group on the piperidyl group can be located on C or on N, including at least For example, the general formula fragment is When X is selected from CH 2 or NH, it indicates that the R group on the general formula fragment can be located on C or X. When X is selected from CH 2 the general formula fragment can be When X is selected from NH, the general formula fragment can be

[0199] When the listed linking groups do not specify their linking directions, the linking directions include those in the reading orders from left to right and from right to left. For example, for A-L-B, when L is selected from -M-W-, it includes A-M-W-B and A-W-M-B.

[0200] "Optional" or "optionally" means that the subsequently described event or circumstance may but does not have to occur, and this description includes the cases where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted by F" means that the alkyl may but does not have to be substituted by F, and the description includes the case where the alkyl is substituted by F and the case where the alkyl is not substituted by F.

[0201] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means a salt of the compound of the present invention that retains the biological effectiveness and characteristics of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0202] "Pharmaceutical composition" means a mixture formed by one or more compounds of the present invention, or their stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals and other chemical components, where "other chemical components" means pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0203] "Dosage form specification" means the weight of the active ingredient contained in each vial, tablet or other unit dosage form.

[0204] "Carrier" means a material that does not cause obvious irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound.

[0205] "Prodrug" means a compound of the present invention that can be metabolically converted in vivo into a biologically active compound. The prodrugs of the present invention are prepared by modifying the amino group or carboxyl group in the compound of the present invention, and this modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free amino group or carboxyl group.

[0206] "Cocrystal" means a crystal formed by the active pharmaceutical ingredient (API) and the cocrystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, where the pure states of API and CCF are both solids at room temperature, and there is a fixed stoichiometric ratio between the components. Cocrystals are multi-component crystals, including binary cocrystals formed between two neutral solids, as well as multi-component cocrystals formed between neutral solids and salts or solvates.

[0207] "Animal" means including mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.

[0208] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereoisomers, and conformational isomers.

[0209] "Tautomers" refer to functional group isomers produced by the rapid movement of a certain atom in a molecule between two positions, such as keto-enol tautomerism and amide-imidol tautomerism. Detailed implementation mode

[0210] 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 this.

[0211] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR measurement is performed using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometers, and the solvents for measurement are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is tetramethylsilane (TMS);

[0212] The MS measurement is performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0213] The HPLC measurement is performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5 μM);

[0214] The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF 254 or Qingdao GF 254 silica gel plate. The specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15 mm - 0.20 mm, and the specification of the silica gel plate used for thin-layer chromatography separation and purification of products is 0.4 mm - 0.5 mm;

[0215] Column chromatography generally uses Yantai Huanghai silica gel with 200 - 300 mesh as the carrier;

[0216] Boc: tert-Butyloxycarbonyl; Ts: p-Toluenesulfonyl; Cbz: Benzyloxycarbonyl; TMS: Trimethylsilyl.

[0217] Example 1: Preparation of Compound 1

[0218]

[0219] Step 1: Preparation of Compounds 1B-1 and 1B-2

[0220] Dissolve Compound 1A (2.8 g, 13.58 mmol) (the synthesis method refers to Bioorganic & Medicinal Chemistry Letters, 2016, 26, 5877-5882) in dichloromethane (50 mL), add Boc 2 O (5.93 g, 27.17 mmol), add DMAP (3.32 g, 27.18 mmol), and react at room temperature for 16 h. Wash the reaction system with 0.5 mol / L hydrochloric acid (50 mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 0:1 - 1:9) to obtain the racemate of Compound 1B (3.4 g, yield: 82%).

[0221] Perform chiral resolution on the racemate of 1B. The chiral resolution method is as follows:

[0222] 1. Instrument: SFC Prep 150AP; Chromatographic column: Daicel IC-H (19 mm × 250 mm).

[0223] 2. Dissolve the sample in methanol, filter it with a 0.45 μm filter head to prepare a sample solution.

[0224] 3. Preparation chromatographic conditions: a. The mobile phase consists of System A and System B: Mobile phase A: CO 2 ; Mobile phase B: methanol / isopropanol (v / v) = 1:1; b. Isocratic elution, the content of mobile phase B is 20%; c. Flow rate is 40 mL / min.

[0225] Elution time: Chiral isomer 1 (Compound 1B-1): 5.7 min, chiral isomer 2 (Compound 1B-2): 6.47 min.

[0226] According to the MicroED structure determination, Compound 1B-1 is in the R configuration and Compound 1B-2 is in the S configuration.

[0227] LCMS m / z = 307.3 [M+1] +

[0228] Step 2: Preparation of 1C

[0229] 1B-2 (1.145 g, 3.74 mmol) and NBS (0.73 g, 4.11 mmol) were added to acetonitrile (30 mL), and the reaction was carried out at room temperature for 1 h. The reaction solution was diluted with 200 mL of ethyl acetate and washed with water 3 times and with saturated aqueous sodium bicarbonate solution 1 time. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0 - 50%), to obtain 1C (1.30 g, yield: 90%).

[0230] LCMS m / z = 329.0 [M - 55] +

[0231] Step 3: Preparation of 1D

[0232] 1C (1.30 g, 3.37 mmol), 2,6 - bis(benzyloxy)-3-(4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)pyridine (2.11 g, 5.05 mmol), Pd(dppf)Cl 2 ·DCM (0.28 g, 0.34 mmol) and cesium carbonate (3.29 g, 10.12 mmol) were added to dioxane (50 mL) and water (5 mL). The reaction was carried out overnight at 80 °C under a nitrogen atmosphere. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0 - 60%), to obtain 1D (1.75 g, yield: 87%).

[0233] Step 4: Preparation of 1E

[0234] 1D (1.75 g, 2.94 mmol) and palladium - carbon (10%, 1.75 g) were added to THF (20 mL). The reaction was carried out overnight at 25 °C under a hydrogen atmosphere. The palladium - carbon was removed by filtration through diatomaceous earth, and the filter cake was washed with 200 mL of dichloromethane. The filtrate was concentrated under reduced pressure to obtain 1E (1.20 g, yield: 97%).

[0235] LCMS m / z = 362.1 [M - 55] +

[0236] Step 5: Preparation of 1F

[0237] Dissolve 1E (0.50 g, 1.20 mmol) in 15 mL of dichloromethane, add 15 mL of trifluoroacetic acid, and stir at room temperature for 30 min. Concentrate the reaction solution under reduced pressure, add a mixed solvent of dichloromethane / methanol (10:1) (30 mL×5) and saturated sodium bicarbonate aqueous solution (30 mL), stir and separate the layers, collect the organic phase, dry it with anhydrous sodium sulfate, filter, concentrate the filtrate, and obtain compound 1F (0.38 g, yield 99%).

[0238] LCMS m / z=318.2[M+H] +

[0239] Step 6: Preparation of compound 1 trifluoroacetate

[0240] Dissolve 1G (80 mg, 0.19 mmol) (synthesis method refers to WO2022132652, CAS: 2229714-01-4) and 1F (60 mg, 0.19 mmol) in 1,2-dichloroethane (10 mL), dropwise add glacial acetic acid (11 mg, 0.19 mmol) at room temperature, stir and react overnight at room temperature after addition, add sodium triacetoxyborohydride (0.12 g, 0.57 mmol), and stir at room temperature for 5 h. Adjust to alkaline with sodium bicarbonate aqueous solution, extract with dichloromethane 3 times, combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V = 100 / 1 - 10 / 1)) to obtain 84 mg of the crude product. The obtained crude product is prepared (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30 mm×150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate of compound 1 (0.062 g).

[0241] LCMS m / z=713.2[M+H] +

[0242] Example 2: Preparation of compound 2

[0243]

[0244] Step 1: Preparation of 2A

[0245] Add 1B-1 (0.45 g, 1.47 mmol) and NBS (0.31 g, 1.74 mmol) to acetonitrile (10 mL), and react at room temperature for 1 h. Directly concentrate under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 0 - 50%) to obtain 2A (0.50 g, yield: 88%).

[0246] LCMS m / z = 329.1 [M - 55] +

[0247] Step 2: Preparation of 2B

[0248] 2A (0.5 g, 1.30 mmol), 2,6 - bis(benzyloxy)-3-(4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)pyridine (1.36 g, 3.26 mmol), Pd(dppf)Cl 2 ·DCM (0.11 g, 0.13 mmol) and cesium carbonate (1.27 g, 3.90 mmol) were added to dioxane (15 mL) and water (3 mL). Under a nitrogen atmosphere, the reaction was carried out at 100 °C overnight. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 0 - 60%), to obtain 2B (0.34 g, yield: 44%).

[0249] Step 3: Preparation of 2C

[0250] 2B (0.34 g, 0.57 mmol) and palladium on carbon (10%, 0.49 g) were added to THF (10 mL). Under a hydrogen atmosphere, the reaction was carried out at 35 °C overnight. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (V / V) = 0 - 10%) to obtain 2C (0.22 g, yield: 92%).

[0251] LCMS m / z = 418.2 [M + 1] +

[0252] Step 4: Preparation of 2D

[0253] 2C (0.22 g, 0.53 mmol) was dissolved in 3 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure, and a mixed solvent of dichloromethane / methanol (10:1) (30 mL × 5) and saturated sodium bicarbonate solution (30 mL) were added. The mixture was stirred and separated, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 2D (160 mg, yield 95%).

[0254] Step 5: Preparation of the trifluoroacetate salt of compound 2

[0255] 1G (80 mg, 0.19 mmol) and 2D (90 mg, 0.28 mmol) were dissolved in 1,2-dichloroethane (10 mL). Glacial acetic acid (11 mg, 0.19 mmol) was added dropwise at room temperature. After the addition, the reaction mixture was stirred at room temperature overnight. Sodium triacetoxyborohydride (0.12 g, 0.57 mmol) was added and the mixture was stirred at room temperature for 5 h. The mixture was adjusted to alkaline with aqueous sodium bicarbonate solution and extracted with dichloromethane three times. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V = 100 / 1 - 10 / 1)) to obtain the crude product. The obtained crude product was prepared (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30 mm × 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate salt of compound 2 (0.03 g).

[0256] LCMS m / z = 713.2 [M+H] +

[0257] Example 3: Preparation of Compound 3

[0258]

[0259] The trifluoroacetate salt of compound 3 (0.032 g) was obtained by referring to the synthesis of compound 1.

[0260] LCMS m / z = 753.5 [M+H] +

[0261] Example 4: Preparation of Compound 4

[0262]

[0263] First step: Preparation of Compound 4

[0264] 3F (55 mg, 0.12 mmol) and 2D (46 mg, 0.14 mmol) were dissolved in 1,2-dichloroethane (5 mL). Glacial acetic acid (14 mg, 0.24 mmol) was added dropwise at room temperature. After the addition, the reaction mixture was stirred at room temperature overnight. Sodium triacetoxyborohydride (0.13 g, 0.60 mmol) was added, and the mixture was stirred at room temperature for 5 h. The mixture was adjusted to alkaline with an aqueous sodium bicarbonate solution and extracted with dichloromethane three times. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V = 100 / 1 - 10 / 1)) to obtain the crude product. The obtained crude product was prepared (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30 mm × 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% formic acid)) to obtain compound 4 (0.013 g, yield: 14%).

[0265] LCMS m / z = 753.4 [M+H] +

[0266] Example 5: Preparation of compound 5

[0267]

[0268] First step: Preparation of 5B

[0269] 5A-1 (1.28 g, 3.49 mmol) (synthesis method refers to WO2023169391, CSA: 2047077-70-1), cesium carbonate (2.27 g, 6.97 mmol), palladium acetate (0.16 g, 0.71 mmol), XANT PHOS (0.20 g, 0.35 mmol), and 5A-2 (0.89 g, 4.91 mmol) were added to a dioxane solution (40 mL). The reaction was carried out at 105 °C for 3 h under a nitrogen atmosphere. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (80 × 3 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0 - 30%) to obtain 5B (1.30 g, yield: 80%).

[0270] LCMS m / z = 468.4 [M+1] +

[0271] Second step: Preparation of 5C

[0272] 5B (1.30 g, 2.78 mmol) was added to methanol (10 mL), and palladium on carbon (1.33 g, wt% = 10%), ammonium acetate (1.32 g, 17.13 mmol) were added. The reaction was carried out at room temperature in a hydrogen atmosphere for 12 h. It was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0 - 50%) to obtain 5C (0.76 g, yield: 90%).

[0273] LCMS m / z = 304.4 [M+1] +

[0274] Step 3: Preparation of 5E

[0275] 5C (0.76 g, 2.50 mmol), 5D (0.75 g, 7.50 mmol) and N,N-diisopropylethylamine (0.97 g, 7.50 mmol) were successively added to ethanol (50 mL), and the temperature was raised to 100 °C and reacted for 36 h. It was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (mobile phase: methanol / dichloromethane (V / V) = 0 - 6%) to obtain 5E (0.70 g, yield: 69%).

[0276] LCMS m / z = 404.2 [M+H] +

[0277] Step 4: Preparation of 5F

[0278] 5E (700 mg, 1.73 mmol) and N,N-diisopropylethylamine (671 mg, 5.19 mmol) were added to tetrahydrofuran (20 mL), and then triphosgene (565 mg, 1.90 mmol) was slowly added and reacted at room temperature for 1 h. Ammonia water (5 mL) was added, and the temperature was raised to 50 °C and reacted for another 2 h. Water (50 mL) was added, and it was extracted with ethyl acetate (50×2 mL). The organic phase was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (mobile phase: methanol / dichloromethane (V / V) = 0 - 10%) to obtain 5F (700 mg, yield: 90%).

[0279] Step 5: Preparation of 5G

[0280] 5F (0.70 g, 1.57 mmol) was added to acetonitrile (30 mL), and then 40% methanol solution of benzyltrimethylammonium hydroxide (2 mL) was added. The temperature was raised to 60 °C and reacted for 2 h. Silica gel was added, and it was concentrated under reduced pressure. The residue was separated and purified by column chromatography (mobile phase: methanol / dichloromethane (V / V) = 0 - 8%) to obtain 5G (530 mg, yield: 84%).

[0281] LCMS m / z = 401.4 [M+H] +

[0282] Step 6: Preparation of 5H

[0283] Dissolve 5G (50 mg, 0.12 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (2 mL), and stir at room temperature for 1 h. Concentrate the reaction solution under reduced pressure to remove trifluoroacetic acid, then add 5 mL of dichloromethane and 0.2 mL of triethylamine, and concentrate under reduced pressure to obtain the crude product of 5H.

[0284] LCMS m / z = 301.2 [M+H] +

[0285] Step 7: Preparation of Compound 5 Trifluoroacetate

[0286] Dissolve 3F (100 mg, 0.22 mmol) and 5H (77 mg, 0.24 mmol) in 1,2-dichloroethane (10 mL), dropwise add glacial acetic acid (13 mg, 0.22 mmol) at room temperature. After addition, stir the reaction mixture at room temperature overnight. Add sodium triacetoxyborohydride (140 mg, 0.66 mmol), stir at room temperature for 5 h, and then add another portion of sodium triacetoxyborohydride (140 mg, 0.66 mmol), stir at room temperature for 16 h. Adjust the reaction solution to alkaline with aqueous sodium bicarbonate solution, extract with dichloromethane three times, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V = 100 / 1 - 10 / 1)) to obtain the crude product. The obtained crude product is prepared (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30 mm × 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) to obtain compound 5 trifluoroacetate (0.04 g).

[0287] LCMS m / z = 736.3 [M+H] +

[0288] Example 6: Preparation of Compound 6

[0289]

[0290] Step 1: Preparation of Compound 6

[0291] Dissolve 1G (100 mg, 0.24 mmol) and 5H (110 mg, 0.36 mmol) in 1,2-dichloroethane (10 mL), add glacial acetic acid (29 mg, 0.48 mmol) dropwise at room temperature. After addition, stir the reaction mixture at room temperature overnight. Then add sodium triacetoxyborohydride (508 mg, 2.4 mmol) and stir at room temperature for 16 h. Adjust the reaction solution to alkaline with aqueous sodium bicarbonate solution, extract with dichloromethane three times, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V = 100 / 1 - 10 / 1)) to obtain the crude product. The obtained crude product was prepared (instrument: waters2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30 mm × 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate salt of compound 6 (35 mg).

[0292] LCMS m / z = 696.4 [M + H] +

[0293] Example 7: Preparation of Compound 7

[0294]

[0295] First step: Preparation of 7C

[0296] Add 1B-2 (6.50 g, 21.22 mmol) and NBS (4.53 g, 25.46 mmol) to acetonitrile (150 mL), and react at room temperature for 2 h. Dilute the reaction solution with 500 mL of ethyl acetate, wash it three times with water and once with saturated aqueous sodium bicarbonate solution, collect the organic phase, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: ethyl acetate: petroleum ether (v / v) = 0:1 - 1:6) to obtain 7C (6.29 g, yield: 77%).

[0297] LCMS m / z = 329.0 [M - 55] +

[0298] Second step: Preparation of 7D

[0299] 7C (6.29 g, 16.32 mmol), diphenylketimine (4.14 g, 22.85 mmol), cesium carbonate (10.63 g, 32.64 mmol), palladium acetate (0.73 g, 3.26 mmol), and XANT PHOS (0.94 g, 1.63 mmol) were added to dioxane solution (100 mL), and the reaction was carried out at 105 °C for 16 h under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered through diatomaceous earth to remove solids, the filter cake was washed with dichloromethane, the organic phase was collected, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 5) to obtain 7D (6.94 g, yield: 87%).

[0300] LCMS m / z = 486.2 [M+H] +

[0301] Step 3: Preparation of 7E

[0302] 7D (6.94 g, 14.29 mmol) was added to methanol (200 mL), palladium on carbon (6.92 g, wt% = 10%), and ammonium acetate (6.79 g, 88.03 mmol) were added, and the reaction was carried out at room temperature for 12 h under a hydrogen atmosphere (balloon pressure). The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain 7E (4.15 g, yield: 90%).

[0303] LCMS m / z = 322.2 [M+H] +

[0304] Step 4: Preparation of 7F

[0305] 7E (4.15 g, 12.91 mmol), ethyl acrylate (3.88 g, 38.73 mmol), and N,N - diisopropylethylamine (5.01 g, 38.73 mmol) were sequentially added to ethanol (60 mL), and the temperature was raised to 100 °C for 72 h. Concentrated under reduced pressure, the residue was separated and purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 20) to obtain 7F (3.91 g, yield: 71%).

[0306] LCMS m / z = 422.3 [M+H] +

[0307] Step 5: Preparation of 7G

[0308] 7F (0.50 g, 1.19 mmol) and N,N - diisopropylethylamine (0.46 g, 3.56 mmol) were added to tetrahydrofuran (20 mL), then triphosgene (0.39 g, 1.31 mmol) was slowly added and the reaction was carried out at room temperature for 1 h. Ammonia water (5 mL) was added, and the temperature was raised to 50 °C and the reaction was continued for 2 h. The reaction solution was diluted with 100 mL of ethyl acetate, the organic phase was washed with water 3 times, washed with saturated sodium chloride once, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain 7G (0.46 g, yield: 83%).

[0309] LCMS m / z = 465.3 [M + H] +

[0310] Step 6: Preparation of 7H

[0311] 7G (0.46 g, 1.00 mmol) was added to acetonitrile (10 mL), then benzyltrimethylammonium hydroxide 40% methanol solution (1.2 mL) was added, and the temperature was raised to 60 °C and the reaction was carried out for 2 h. Silica gel was added, concentrated under reduced pressure, and the residue was separated and purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain 7H (0.21 g, yield: 50%).

[0312] Step 7: Preparation of 7I

[0313] 7H (0.21 g, 0.50 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to remove trifluoroacetic acid, then 10 mL of dichloromethane and 1 mL of isopropanol were added to dissolve the residue, adjusted to alkaline with aqueous sodium bicarbonate solution, and extracted 3 times with dichloromethane / isopropanol (v / v) = 1 / 10. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 7I (0.158 g).

[0314] LCMS m / z = 319.2 [M + H] +

[0315] Step 8: Preparation of Compound 7

[0316] Dissolve 1G (0.07 g, 0.17 mmol) and 7I (0.054 g, 0.17 mmol) in 10 mL of chloroform, add dropwise acetic acid (0.02 g, 0.34 mmol) and sodium sulfate (0.048 g, 0.34 mmol). After addition, heat to 60 °C and stir for 30 min, then add sodium triacetoxyborohydride (0.36 g, 1.70 mmol) in batches and continue stirring at 60 °C overnight. Add 10 mL of saturated sodium bicarbonate solution and 30 mL of dichloromethane, extract, concentrate the organic phase under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain compound 7 (0.07 g, yield: 57%).

[0317] LCMS m / z = 714.3 [M+H] +

[0318] Example 8: Preparation of compound 8

[0319]

[0320] First step: Preparation of 8A

[0321] Add 1B-1 (6.50 g, 21.22 mmol) and NBS (4.53 g, 25.46 mmol) to acetonitrile (150 mL), and react at room temperature for 2 h. Dilute with 500 mL of ethyl acetate and wash with water 3 times. Collect the organic phase, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether (v / v) = 0:1 - 1:6) to obtain 8A (6.29 g, yield: 77%).

[0322] LCMS m / z = 329.0 [M-55] +

[0323] Second step: Preparation of 8B

[0324] Add 8A (5.0 g, 12.98 mmol), diphenylketimine (3.05 mL, 3.29 g, 18.17 mmol), cesium carbonate (9.30 g, 28.56 mmol), palladium acetate (583 mg, 2.6 mmol), and XANT PHOS (751 mg, 1.3 mmol) to a dioxane solution (100 mL), and react at 100 °C for 16 h under a nitrogen atmosphere. Cool the reaction solution to room temperature, filter through diatomaceous earth to remove solids, wash the filter cake with dichloromethane, collect the organic phase, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 5) to obtain 8B (5.6 g, yield: 89%).

[0325] LCMS m / z = 486.3 [M+H] +

[0326] Step 3: Preparation of 8C

[0327] 8B (5.6 g, 11.53 mmol) was added to methanol (200 mL), and palladium on carbon (3.0 g, wt% = 10%), ammonium acetate (5.6 g, 72.6 mmol) were added. The reaction was carried out at room temperature for 16 h under a hydrogen atmosphere (balloon pressure). The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain 8C (3.6 g, yield: 97%).

[0328] LCMS m / z = 322.3 [M+H] +

[0329] Step 4: Preparation of 8D

[0330] 8C (3.6 g, 11.2 mmol), ethyl acrylate (3.36 g, 33.60 mmol) and N,N - diisopropylethylamine (4.34 g, 33.60 mmol) were successively added to ethanol (100 mL). The temperature was raised to 100 °C and the reaction was carried out for 72 h. The mixture was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 20) to obtain 8D (3.0 g, yield: 64%).

[0331] LCMS m / z = 422.3 [M+H] +

[0332] Step 5: Preparation of 8E

[0333] 8D (1.0 g, 2.37 mmol) and N,N - diisopropylethylamine (0.92 g, 7.11 mmol) were added to tetrahydrofuran (30 mL), and then triphosgene (0.77 g, 2.61 mmol) was slowly added and the reaction was carried out at room temperature for 1 h. Ammonia water (9 mL) was added, and the temperature was raised to 50 °C and the reaction was continued for 2 h. The reaction solution was diluted with 100 mL of ethyl acetate, and the organic phase was washed 3 times with water, once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain 8E (1.0 g, yield: 91%).

[0334] LCMS m / z = 465.3 [M+H] +

[0335] Step 6: Preparation of 8F

[0336] 8E (1.0 g, 2.15 mmol) was added to acetonitrile (20 mL), and then benzyltrimethylammonium hydroxide 40% methanol solution (2.5 mL, 6.45 mmol) was added. The temperature was raised to 60 °C and the reaction was carried out for 2 h. Silica gel was added, and the mixture was concentrated under reduced pressure. The residue was separated and purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain 8F (0.69 g, yield: 77%).

[0337] LCMS m / z=363.2[M-55] +

[0338] Step 7: Preparation of 8G

[0339] 8F (0.5 g, 1.19 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to remove trifluoroacetic acid, and then 10 mL of dichloromethane and 1 mL of isopropanol were added to dissolve the residue. The solution was adjusted to alkaline with aqueous sodium carbonate solution, and extracted 3 times with dichloromethane / isopropanol (v / v) = 1 / 10. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 8G (0.37 g, yield: 97%).

[0340] LCMS m / z=319.2[M+H] +

[0341] Step 8: Preparation of Compound 8

[0342] 1G (0.07 g, 0.17 mmol) and 8G (0.054 g, 0.17 mmol) were dissolved in 10 mL of chloroform. Acetic acid (0.02 g, 0.34 mmol) and anhydrous sodium sulfate (0.048 g, 0.34 mmol) were added dropwise. After addition, the temperature was raised to 60 °C and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (0.36 g, 1.70 mmol) was added in batches, and the mixture was stirred at 60 °C overnight. 10 mL of saturated aqueous sodium bicarbonate solution and 30 mL of dichloromethane were added and stirred to separate the layers. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain Compound 8 (0.08 g, yield: 66%).

[0343] LCMS m / z=714.5[M+H] +

[0344] Example 9: Preparation of Compound 9

[0345]

[0346] Compound 9 (0.076 g, yield: 63%) was obtained by referring to the synthesis of Compound 1 and Compound 2.

[0347] LCMS m / z = 739.4 [M+H] +

[0348] Example 10: Preparation of Compound 10

[0349]

[0350] Dissolve 9D (0.07 g, 0.16 mmol) and 1F (0.051 g, 0.16 mmol) in chloroform (5 mL). Dropwise add glacial acetic acid (0.02 g, 0.32 mmol) at room temperature. After addition, heat to 60 °C and stir for 30 min. Then add sodium triacetoxyborohydride (0.36 g, 1.70 mmol) in batches and continue stirring at 60 °C overnight. Add 10 mL of saturated sodium bicarbonate aqueous solution and 30 mL of dichloromethane, extract, and concentrate the organic phase under reduced pressure. The residue is purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V = 100 / 1 - 10 / 1)) to obtain the crude product. The obtained crude product is prepared (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30 mm × 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate of Compound 10 (0.05 g).

[0351] LCMS m / z = 739.4 [M+H] +

[0352] Example 11: Preparation of Compound 11

[0353]

[0354] First step: Preparation of Compound 11

[0355] Dissolve 3F (0.06 g, 0.13 mmol) and 7I (0.041 g, 0.13 mmol) in 10 mL of chloroform. Dropwise add acetic acid (0.016 g, 0.26 mmol) and sodium sulfate (0.037 g, 0.26 mmol). After addition, heat to 60 °C and stir for 30 min. Then add sodium triacetoxyborohydride (0.28 g, 1.30 mmol) in batches and continue stirring at 60 °C for 4 h. Add 10 mL of saturated sodium bicarbonate aqueous solution and 30 mL of dichloromethane, extract, and concentrate the organic phase under reduced pressure. The residue is purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain Compound 11 (0.07 g, yield: 71%).

[0356] LCMS m / z = 754.3 [M+H] +

[0357] Example 12: Preparation of Compound 12

[0358]

[0359] Dissolve 3F (60 mg, 0.13 mmol) and 8G (52 mg, 0.13 mmol) in chloroform (5 mL), add glacial acetic acid (8 mg, 0.13 mmol) dropwise. After addition, stir the reaction mixture at 60 °C for 2 hours. Then add sodium triacetoxyborohydride (83 mg, 0.39 mmol) and continue stirring at 60 °C for 2 h. Adjust the mixture to alkaline with aqueous sodium bicarbonate solution, extract with dichloromethane three times, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V = 100 / 1 - 10 / 1)) to obtain Compound 12 (80 mg, yield: 82%).

[0360] LCMS m / z = 754.3 [M+H] +

[0361] Example 13: Preparation of Compound 13

[0362]

[0363] First step: Preparation of 13A

[0364] Dissolve 3D (300 mg, 0.46 mmol) and 4-piperidone ethylene acetal (99 mg, 0.69 mmol) in toluene (6 mL), add 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (44 mg, 0.092 mmol), palladium acetate (1 mg, 0.069 mmol) and sodium tert-butoxide (130 mg, 1.38 mmol). After addition, react at 90 °C for 16 hours under nitrogen protection. Cool the reaction mixture to room temperature, dilute with ethyl acetate, filter through diatomaceous earth, concentrate the filtrate under reduced pressure, and purify the concentrate by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0 - 10%) to obtain 13A (245 mg).

[0365] Second step: Preparation of 13B

[0366] Dissolve 13A (243 mg, 0.49 mmol) in 3 mL of tetrahydrofuran, add 2.8 mL of 2 M sulfuric acid, and stir at 70 °C for 1 h. Cool the reaction mixture to room temperature, adjust the pH to 7 - 8 with saturated aqueous sodium bicarbonate solution, extract with ethyl acetate three times, dry, and concentrate to obtain Compound 13B (211 mg).

[0367] Third step: Preparation of Compound 13

[0368] Dissolve 13B (50 mg, 0.13 mmol) and 7I (41 mg, 0.13 mmol) in chloroform (6 mL), add glacial acetic acid (8 mg, 0.13 mmol) dropwise at room temperature. After addition, heat to 60 °C and stir for 30 min. Then add sodium triacetoxyborohydride (83 mg, 0.39 mmol) in batches and stir at the same temperature for 5 h. Adjust to alkaline with aqueous sodium bicarbonate solution, extract with dichloromethane three times, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V = 100 / 1 - 10 / 1)) to obtain compound 13 (29 mg, yield: 32%).

[0369] LCMS m / z = 700.3 [M+H] +

[0370] Example 14: Preparation of Compound 14

[0371]

[0372] Dissolve 13B (70 mg, 0.18 mmol) and 8G (57 mg, 0.18 mmol) in chloroform (5 mL), add glacial acetic acid (11 mg, 0.18 mmol) dropwise. After addition, stir at 60 °C overnight. Add sodium triacetoxyborohydride (0.11 g, 0.54 mmol) in batches and continue to stir at 60 °C for 5 h. Adjust to alkaline with aqueous sodium bicarbonate solution, extract with dichloromethane three times, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V = 100 / 1 - 10 / 1)) to obtain compound 14 (50 mg, yield: 40%).

[0373] LCMS m / z = 700.5 [M+H] +

[0374] Example 15: Preparation of Compound 15

[0375]

[0376] 9D (70 mg, 0.16 mmol) and 8G (51 mg, 0.16 mmol) were dissolved in chloroform (5 mL), glacial acetic acid (10 mg, 0.16 mmol) was added dropwise. After addition, the mixture was stirred at 60 °C overnight. Sodium triacetoxyborohydride (0.10 g, 0.48 mmol) was added in portions, and stirring was continued at 60 °C for 5 h. The mixture was adjusted to alkaline with aqueous sodium bicarbonate solution, extracted with dichloromethane three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V = 100 / 1 - 10 / 1)) to obtain compound 15 (60 mg, yield: 51%).

[0377] LCMS m / z = 740.5 [M+H] +

[0378] Example 16: Preparation of Compound 16

[0379]

[0380] First step: Preparation of Compound 16

[0381] 9D (0.044 g, 0.10 mmol) and 7I (0.032 g, 0.10 mmol) were dissolved in 10 mL of chloroform, acetic acid (0.012 g, 0.20 mmol) and sodium sulfate (0.028 g, 0.20 mmol) were added dropwise. After addition, the temperature was raised to 60 °C and stirred for 30 min. Sodium triacetoxyborohydride (0.21 g, 1.00 mmol) was added in portions, and stirring was continued at 60 °C overnight. 10 mL of saturated sodium bicarbonate solution and 30 mL of dichloromethane were added, extracted, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain compound 16 (0.047 g, yield: 60%).

[0382] LCMS m / z = 740.3 [M+H] +

[0383] Example 17: Preparation of Compound 17

[0384]

[0385] Dissolve 9D (0.07 g, 0.16 mmol) and 5H (0.048 g, 0.16 mmol) in 5 mL of chloroform, add acetic acid (0.02 g, 0.32 mmol) dropwise. After addition, heat the mixture to 60 °C and stir for 30 min. Then add sodium triacetoxyborohydride (0.36 g, 1.70 mmol) in batches and continue to stir at 60 °C overnight. Add 10 mL of saturated aqueous sodium bicarbonate solution and 30 mL of dichloromethane, extract, and concentrate the organic phase under reduced pressure. The residue is purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain compound 17 (0.06 g, yield: 52%).

[0386] LCMS m / z = 722.5 [M+H] +

[0387] Example 18: Preparation of Compound 18

[0388]

[0389] Step 1: Preparation of 18A

[0390] Under a nitrogen atmosphere, add 1C (7.00 g, 18.17 mmol) and 70 mL of tetrahydrofuran to a reaction flask. Then cool the mixture to -78 °C and slowly add 2.5 M n-butyllithium in hexane solution (14.50 mL, 36.34 mmol). Stir the system at -78 °C for 1.5 h, then displace carbon dioxide three times, control the system temperature below -40 °C, and place it under a carbon dioxide balloon atmosphere to react for 0.5 h. Then restore the system to room temperature, add 20 mL of ethyl acetate to the system, adjust the pH to 2 with 1 M dilute hydrochloric acid, extract with ethyl acetate (30 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1 to 2:1) to obtain compound 18A (2.4 g, reaction yield 37%).

[0391] Step 2: Preparation of 18B

[0392] Dissolve 18A (110 mg, 0.31 mmol) in dichloromethane (6 mL), add trifluoroacetic acid (2 mL). After addition, react at room temperature for 1 h. Concentrate the reaction solution under reduced pressure, and use the residue as it is.

[0393] Compound 1G (100 mg, 0.24 mmol), glacial acetic acid (14 mg, 0.24 mmol) and N,N-dimethylacetamide (4 mL) were added to the aforementioned residue to be used. After addition, the reaction was stirred at room temperature overnight. Sodium triacetoxyborohydride (153 mg, 0.72 mmol) was added and the mixture was stirred at room temperature for 5 h. Water (40 mL) was added to the reaction solution, and a solid was precipitated. The solid was filtered by suction, and the filter cake was washed with water (10 mL×3) and then dried in vacuo to obtain compound 18B, which was directly used for the next reaction.

[0394] Step 3: Preparation of compound 18

[0395] Compound 18B (150 mg, 0.23 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (113 mg, 0.69 mmol), 4-methylmorpholine (140 mg, 1.38 mmol), 1-hydroxybenzotriazole (HOBT) (62 mg, 0.46 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (110 mg, 0.58 mmol) were dissolved in N,N-dimethylformamide (4 mL). After addition, the reaction was carried out at room temperature overnight. Water (40 mL) was added to the reaction solution, and a solid was precipitated. The solid was filtered by suction, and the filter cake was washed with water (10 mL×3). After concentration under reduced pressure to dryness, a crude product was obtained. The obtained crude product was prepared (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30 mm×150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate of compound 18 (56 mg).

[0396] LCMS m / z = 756.4 [M+H] +

[0397] Example 19: Preparation of compound 19

[0398]

[0399] Step 1: Preparation of compound 19A

[0400] Compound 19A was obtained by using 2A as the raw material and referring to the synthesis method of 18A.

[0401] Step 2: Preparation of compound 19B

[0402] 19A (100 mg, 0.29 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.6 mL) was added. After addition, the reaction was carried out at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was used for further use.

[0403] Compound 1G (100 mg, 0.24 mmol), glacial acetic acid (29 mg, 0.48 mmol) and N,N-dimethylacetamide (4 mL) were added to the aforementioned residue to be used. After the addition, the reaction was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (153 mg, 0.72 mmol) was added and the mixture was stirred at room temperature for 16 h. Water (40 mL) was added to the reaction solution, and a solid was precipitated. The solid was filtered by suction, and the filter cake was washed with water (10 mL×3) and then dried under vacuum to obtain compound 19B, which was directly used for the next reaction step.

[0404] Step 3: Preparation of compound 19

[0405] Compound 19B (130 mg, 0.20 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (99 mg, 0.60 mmol), 1-hydroxybenzotriazole (HOBT) (54 mg, 0.40 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (96 mg, 0.50 mmol) were dissolved in N,N-dimethylformamide (4 mL), and then 4-methylmorpholine (121 mg, 1.20 mmol) was added. After the addition, the reaction was carried out at room temperature overnight. Water (40 mL) was added to the reaction solution, and a solid was precipitated. The solid was filtered by suction, and the filter cake was washed with water (10 mL×3). After concentration under reduced pressure to dryness, a crude product was obtained. The obtained crude product was purified (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30 mm×150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate of compound 19 (0.06 g).

[0406] LCMS m / z = 756.4 [M+H] +

[0407] Example 20: Preparation of compound 20

[0408]

[0409] Compound 20 (50 mg, yield: 62%) was obtained by referring to the synthesis of compound 1 and compound 2.

[0410] LCMS m / z = 739.4 [M+H] +

[0411] Example 21: Preparation of compound 21

[0412]

[0413] Step 1: Preparation of compound 21

[0414] 20D (48 mg, 0.11 mmol) and 1F (35 mg, 0.11 mmol) were dissolved in 10 mL of chloroform. Acetic acid (13 mg, 0.22 mmol) was added dropwise. After addition, the temperature was raised to 60 °C and stirred for 1 h. Sodium triacetoxyborohydride (70 mg, 0.33 mmol) was added in batches, and stirring was continued at 60 °C overnight. 10 mL of saturated aqueous sodium bicarbonate solution and 30 mL of dichloromethane were added. After phase separation, the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15), and the crude product was purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: XBridge@Prep C18 (30 mm × 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate salt of compound 21 (14 mg).

[0415] LCMS m / z = 370.3 [M+2H / 2] +

[0416] Example 22: Preparation of Compound 22

[0417]

[0418] Compound 22 (90 mg, yield: 61%) was obtained by referring to the synthesis of Compound 1 and Compound 2.

[0419] LCMS m / z = 767.3 [M+H] +

[0420] Example 23: Preparation of Compound 23

[0421]

[0422] First step: Preparation of Compound 23

[0423] 22E (90 mg, 0.19 mmol) and 1F (60 mg, 0.19 mmol) were dissolved in 10 mL of chloroform. Acetic acid (23 mg, 0.38 mmol) was added dropwise. After addition, the temperature was raised to 60 °C and stirred for 1 h. Sodium triacetoxyborohydride (120 mg, 0.57 mmol) was added in batches, and stirring was continued at 60 °C overnight. 10 mL of saturated aqueous sodium bicarbonate solution and 30 mL of dichloromethane were added for extraction. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15), and the crude product was purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: XBridge@Prep C18 (30 mm × 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate salt of compound 23 (29 mg).

[0424] LCMS m / z=384.4[(M+2H) / 2] +

[0425] Example 24: Preparation of Compound 24

[0426]

[0427] Compound 24 (90 mg, yield: 79%) was obtained by referring to the synthesis of compound 1 and compound 2.

[0428] LCMS m / z=781.3[M+H] +

[0429] Example 25: Preparation of Compound 25

[0430]

[0431] 24D (100 mg, 0.21 mmol) and 1F (67 mg, 0.21 mmol) were dissolved in chloroform (10 mL), and glacial acetic acid (25 mg, 0.42 mmol) and sodium sulfate (60 mg, 0.42 mmol) were added dropwise at room temperature. After the addition, the temperature was raised to 60°C and stirred for 1 hour. Then sodium triacetoxyborohydride (445 mg, 2.10 mmol) was added in batches, and the reaction was continued at 60°C with stirring overnight. Sodium bicarbonate aqueous solution was added to adjust to alkalinity, and dichloromethane was extracted 3 times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V=100 / 1-10 / 1)) to obtain compound 25 (109 mg, 66%).

[0432] LCMS m / z=391.5[(M+2H) / 2] +

[0433] Example 26: Preparation of Compound 26

[0434]

[0435] Step 1: Preparation of Compound 26A

[0436] 19A (120 mg, 0.34 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.6 mL) was added. After addition, the mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was used for later use.

[0437] Compound 9D (100 mg, 0.23 mmol), glacial acetic acid (28 mg, 0.46 mmol) and N,N-dimethylacetamide (4 mL) were added to the aforementioned residue to be used. After addition, the reaction was stirred at room temperature for 1 h, and sodium triacetoxyborohydride (146 mg, 0.69 mmol) was added, and the mixture was stirred at room temperature for 16 h. Water (40 mL) was added to the reaction solution, and a solid was precipitated. The solid was filtered by suction, and the filter cake was washed with water (10 mL×3) and then dried under vacuum to obtain compound 26A, which was directly used for the next reaction step.

[0438] Step 3: Preparation of Compound 26

[0439] Compound 26A (134 mg, 0.20 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (99 mg, 0.60 mmol), 1-hydroxybenzotriazole (HOBT) (54 mg, 0.40 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (96 mg, 0.50 mmol) were dissolved in N,N-dimethylformamide (4 mL), and then 4-methylmorpholine (121 mg, 1.20 mmol) was added. After addition, the reaction was carried out at room temperature overnight. Water (40 mL) was added to the reaction solution, and a solid was precipitated. The solid was filtered by suction, and the filter cake was washed with water (10 mL×3). After concentration under reduced pressure to dryness, a crude product was obtained. The obtained crude product was prepared (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30 mm×150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate of compound 26 (0.05 g).

[0440] LCMS m / z = 782.3 [M+H] +

[0441] Example 27: Preparation of Compound 27

[0442]

[0443] Step 1: Preparation of 27A

[0444] 18A (105 mg, 0.3 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. After addition, the reaction was carried out at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was used for the next step.

[0445] Dissolve 9D (100 mg, 0.23 mmol) and the residue obtained in the previous step in 10 mL of N,N-dimethylacetamide, add dropwise acetic acid (0.014 g, 0.23 mmol) and sodium sulfate (0.048 g, 0.34 mmol). After addition, heat to 60 °C and stir for 30 min, then add sodium triacetoxyborohydride (146 mg, 0.69 mmol) in batches and continue to stir at 60 °C overnight. Cool the reaction mixture to room temperature, add 10 mL of water, precipitate a solid, filter by suction, wash the filter cake with water, and concentrate under reduced pressure to dryness to obtain compound 27A (125 mg, yield: 83%).

[0446] LCMS m / z=672.3[M+H] +

[0447] Step 2: Preparation of compound 27

[0448] Dissolve 27A (120 mg, 0.18 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (89 mg, 0.54 mmol), 4-methylmorpholine (109 mg, 1.08 mmol), 1-hydroxybenzotriazole (HOBT) (49 mg, 0.36 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol) in N,N-dimethylformamide (4 mL). After addition, react at room temperature overnight. Add water (40 mL) to the reaction mixture, precipitate a solid, filter by suction, wash the filter cake with water (10 mL×3), concentrate under reduced pressure to dryness to obtain a crude product, and subject the obtained crude product to preparation (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30 mm×150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate salt of compound 27 (56 mg).

[0449] LCMS m / z=391.9[(M+2H) / 2] +

[0450] Example 28: Preparation of compound 28

[0451]

[0452] Compound 28 was obtained by referring to the synthesis of compound 1.

[0453] LCMS m / z=749.4[(M+H] +

[0454] Example 29: Preparation of compound 29

[0455]

[0456] Compound 29 was obtained by referring to the synthesis of compound 3.

[0457] LCMS m / z = 789.5 [(M+H] +

[0458] Biological test examples

[0459] Test example 1: Detection of ER degradation in MCF7 cells

[0460] MCF7 is a human breast cancer cell line, purchased from ATCC. Culture conditions: EMEM + 10% FBS + 1% double antibody + 0.01 mg / ml human insulin, cultured at 37 °C, 5% CO 2 in an incubator. Cells were seeded in 6-well plates at 5×10 5 cells / well. After seeding, different concentrations of the compound were added and cultured at 37 °C, 5% CO 2 in an incubator for 24 hours. After the culture, the cells were collected, RIPA lysis buffer (beyotime, Cat. P0013B) was added and lysed on ice for 15 minutes, then centrifuged at 12000 rpm at 4 °C for 10 minutes. The supernatant protein samples were collected, quantified using a BCA kit (Beyotime, Cat. P0009), and the protein was diluted to 0.25 mg / mL. The expression of ER (CST, Cat. 13258S) and the internal reference β-actin (CST, Cat. 3700S) was detected using an automated western blot quantification analyzer (Proteinsimple). Using the "Compass for SW" software, when the internal reference area was 10000, the relative peak area of ER was calculated. According to formula (1), the percentage of ER relative to the vehicle control group at different drug concentrations was calculated, where ER treat was the relative peak area of the drug-treated group, and ER solvent was the relative peak area of the vehicle control group. The data processed according to formula (1) was analyzed using GraphPad Prism 8.3.0 software, and the DC 50 value was calculated using a four-parameter nonlinear regression model.

[0461] ER% = ER streat / ER solvent ×100% Formula 1

[0462] Table 1: Degradation activity of test compounds on ER protein in MCF7 cells

[0463] Compound number <![CDATA[DC 50 (nM)]]> Trifluoroacetate salt of compound 9 A Trifluoroacetate salt of compound 26 A Trifluoroacetate salt of compound 27 A Compound 28 A Compound 29 A

[0464] Note: In Table 1, A < 50 nM, 50 nM ≤ B < 100 nM, 100 nM ≤ C

[0465] Conclusion: The compounds of the present invention, such as the compounds of the examples, have good ER degradation activity.

Claims

1. A compound or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the compound being selected from the compounds represented by general formula (I), wherein: BLK(I); B is selected from Selected from aromatic rings or non-aromatic rings; X1 or X5 selected from CR X1 R X2 NR X1 , O or S; X2 Selected from CR X1 , CR X1 R X2 NR X1 , O or S; X3 or X4 selected from CR X1 or N; Y is selected from CR Y1 R Y2 NR Y1 , O or S; B1 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Carbocyclic group, 4-7 membered heterocyclic group, -OC 3-12 Carbocyclic group, -O-4-12 membered heterocyclic group, -CH2-C 3-12 carbocyclic group, -CH2-4-12 membered heterocyclic group, wherein B1 is optionally substituted by 1 to 4 selected from deuterium, CF3, F, Cl, Br, I, OH, =O, NH2, CN, CONH2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Substituted by a substituent of a carbocyclic group, a 4-6 membered heterocyclic group, or a fluorine-substituted phenyl group; B2 is selected from phenyl, 5-6 membered heteroaryl, 9-12 membered bicyclic ring radical, The B2 is optionally replaced by 1 to 4 R b2 replace; B 1a Selected from C 3-12 A carbocyclic group or a 4-12 membered heterocyclic group, wherein B 1a Optional 1 to 4 R b1a replace; b3 is selected from 0, 1, 2 or 3; L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-; Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from a bond, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, O, NR L NR L CO、CONR L , CO, wherein the alkylene, alkenylene, alkynylene is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, COOH, CN, NH2, =O, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted by a substituent of a carbocyclic group or a 4-6-membered heterocyclic group; R L Each independently selected from H or C 1-6 alkyl; Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following groups substituted: 4-7 membered monocyclic heterocyclic group, 4-12 membered cyclic heterocyclic group, 5-13 membered spirocyclic heterocyclic group, 7-12 membered bridged heterocyclic group, C 3-7 Monocyclic carbocyclic group, C 4-12 Cyclic carbocyclic group, C 5-13 Spirocarbocyclic group, C 5-12 A bridged carbocyclic group, a 5-10 membered heteroaryl group or a C 6-10 Aryl; K is selected from K1 is selected from phenyl, 5-6 membered heteroaryl, 9-12 membered bicyclic ring group, The K1 is optionally replaced by 1 to 4 R k1 replace; W is selected from a 5-6 membered heterocyclic group; Z2 is selected from CH or N; Z3 is selected from CH or N; Q is selected from NR q CO、CONR q 、CO、NR q or key; Z1 is selected from N or CR k2 ; R X1 , R X2 , R Y1 , R Y2 , R B , R b2 , R b3 , R b1a , R k1 , R k2 , R k3 , R q , R L2 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, =S, NH2, CN, COOH, CONH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Carbocyclic group, 4-6 membered heterocyclic group, -OC 3-7 carbocyclic group, -O-4-6 membered heterocyclic group, wherein the alkyl, alkoxy, heterocyclic group, and carbocyclic group are optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, =O, NH2, CN, CONH2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Substituted by a substituent of a carbocyclic group, a 4-6 membered heterocyclic group, or a fluorine-substituted phenyl group; p2 is each independently selected from 0, 1, 2, 3 or 4; The condition is, In the compound, K1 should be selected from The K1 is optionally replaced by 1 to 4 R k1 replace; Or the compound B2 needs to be selected from The B2 is optionally replaced by 1 to 4 R b2 replace.

2. The compound according to claim 1 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: L is selected from -Ak1-, -Ak1-Ak2-, -Cy1-, -Cy1-Cy2-, -Cy1-Ak1-, -Ak1-Cy1-, -Cy1-Ak1-Cy 2-, -Cy1-Cy2-Ak1-, -Ak1-Cy1-Cy2-, -Cy1-Ak1-Cy2-Ak2-, -Ak1-Cy1-Ak2-Cy2-; Ak1 and Ak2 are each independently selected from C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, O, NR L NR L CO, CO, wherein the alkylene, alkenylene, alkynylene is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, COOH, CN, NH2, =O, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted by a substituent of a carbocyclic group or a 4-6-membered heterocyclic group; R L Each independently H or C 1-4 alkyl; Cy1 and Cy2 are each independently selected from L2 One of the following groups substituted: 3-6 membered monocyclic heterocyclic group, 4-10 membered cyclic heterocyclic group, 5-11 membered spirocyclic heterocyclic group, 5-10 membered bridged heterocyclic group, C 3-6 Monocyclic carbocyclic group, C 4-10 Cyclic carbocyclic group, C 5-11 Spirocarbocyclic group, C 5-10 A bridged carbocyclic group, a 5-10 membered heteroaryl group or a C 6-10 Aryl; B1 is selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocyclic group, 4-6 membered heterocyclic group, -OC 3-6 Carbocyclic group, -O-4-6 membered heterocyclic group, -CH2-C 3-6 carbocyclic group, -CH2-4-6 membered heterocyclic group, wherein B1 is optionally substituted by 1 to 4 selected from deuterium, F, CF3, Cl, Br, I, OH, =O, NH2, CN, CONH2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Substituted by a substituent of a carbocyclic group, a 4-6 membered heterocyclic group, or a fluorine-substituted phenyl group; B 1a is selected from phenyl or 5-6 membered heteroaryl, wherein B 1a Optional 1 to 4 R b1a replace; B2 is selected from phenyl, 5-6 membered heteroaryl, benzo 5-membered heterocyclic group, benzo 6-membered heterocyclic group, benzo 5-membered carbocyclic group, benzo 6-membered carbocyclic group, benzo 7-membered carbocyclic group, benzo 8-membered carbocyclic group, pyrido 5-membered heterocyclic group, pyrido 6-membered heterocyclic group, wherein B2 is optionally substituted by 1 to 4 R b2 replace; K1 is selected from phenyl, 5-6 membered heteroaryl, Benzo 5-membered heterocyclic group, benzo 6-membered heterocyclic group, wherein K1 is optionally substituted by 1 to 4 R k1 replace; R X1 , R X2 , R Y1 , R Y2 , R B , R b2 , R b3 , R b1a , R k1 , R k2 , R k3 , R q , R L2 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, =S, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocyclic group, 4-6 membered heterocyclic group, -OC 3-6 carbocyclic group, -O-4-6 membered heterocyclic group, wherein the alkyl, alkoxy, heterocyclic group, and carbocyclic group are optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, =O, NH2, CN, CONH2, COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 The phenyl group may be substituted by a substituent such as a carbocyclic group, a 4- to 6-membered heterocyclic group, or a fluorine-substituted phenyl group.

3. The compound according to claim 2 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B1 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxacyclohexyl, phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, bicyclo[1.1.1]pentane, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -C H2-piperazinyl, -CH2-morpholinyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-oxacyclohexyl, -CH2-phenyl, -CH2-pyridyl, -CH2-pyrazinyl, -CH2-pyridazinyl, -CH2-pyrazolyl, -CH2-imidazolyl, -CH2-pyrrolyl, -CH2-triazolyl, -CH2-bicyclo[1.1.1]pentane, wherein B1 is optionally replaced by 1 to 4 deuterium, F, CF3, Cl, Br, I, OH, =O, NH2, CN, CONH2, COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted by a substituent of a carbocyclic group, a 4-6 membered heterocyclic group, or a fluorine-substituted phenyl group; Ak1 and Ak2 are each independently selected from methylene, ethylene, vinylene, and ethynylene, wherein the methylene, ethylene, vinylene, and ethynylene are optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, NH2, COOH, CN, =O, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted by a substituent of a carbocyclic group or a 4-6-membered heterocyclic group; Cy1 and Cy2 are each independently selected from a group optionally replaced by 1 to 4 R L2 Substituted with one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclo butyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl pyridinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinazetidinyl, azetidinpyrrolidinyl, azetidinpiperidinyl, pyrrolidinazetidinyl, pyrrolidinpyrrolidinyl, pyrrolidinpiperidinyl, piperidinylazetidinyl, piperidinylpyrrolidinyl, piperidinylpiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidinyl, cyclobutylspiropiperidine yl, cyclopentyl spiroazetidinyl, cyclopentyl spiropyrrolidinyl, cyclopentyl spiropiperidinyl, cyclohexyl spiroazetidinyl, cyclohexyl spiropyrrolidinyl, cyclohexyl spiropiperidinyl, azetidinyl spiroazetidinyl, azetidinyl spiropyrrolidinyl, azetidinyl spiropiperidinyl, pyrrolidinyl spiroazetidinyl, pyrrolidinyl spiropyrrolidinyl, pyrrolidinyl spiropiperidinyl, piperidinyl spiroazetidinyl, piperidinyl spiropyrrolidinyl, piperidinyl spiropiperidinyl, 4. The compound according to claim 3 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B1 is selected from B2 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furanyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, The B2 is optionally replaced by 1 to 2 R b2 replace; B 1a is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, wherein B 1a Optional 1 to 4 R b1a replace; K1 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furanyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, The K1 is optionally replaced by 1 to 2 R k1 replace; Cy1 and Cy2 are each independently selected from a group optionally replaced by 1 to 4 R L2 One of the following groups substituted: R X1 , R X2 , R Y1 , R Y2 , R B , R b2 , R b3 , R b1a , R k1 , R k2 , R k3 , R q , R L2 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, =S, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, tetrahydrofuranyl, oxacyclohexyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridinyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridyl are optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, =O, NH2, CN, CONH2, COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 The phenyl group may be substituted by a substituent such as a carbocyclic group, a 4- to 6-membered heterocyclic group, or a fluorine-substituted phenyl group.

5. The compound according to claim 4 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: X1 from CR X1 R X2 or O; X5 Selected from NR X1 ; X2 Selected from CR X1 or S; Y is selected from CR Y1 R Y2 or O; Q is selected from CONR q NR q CO、NR q or key; R X1 , R X2 , R Y1 or R Y2 Each is independently selected from H, deuterium, F, CF3, methyl, ethyl, cyclopropyl; R B Selected from H, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl; R b2 , R b3 , R b1a , R k1 , R k2 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, CF3, CHF2, CH2F, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, CH2OH; R k3 Each is independently selected from H, deuterium, and methyl; R L2 Each independently selected from H, deuterium, and F; R q Each is independently selected from H, deuterium, and methyl.

6. The compound according to claim 5 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B is selected from one of the fragments shown in Table B-1; L is selected from one of the fragments shown in Table A; K is selected from one of the fragments shown in Table K-1.

7. The compound according to claim 1 or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, 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, racemate, 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 7 or a stereoisomer, racemate, 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, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 8 in the preparation of drugs related to the inhibition or degradation of ER.

10. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, racemate, 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 tumors.

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