Heterocyclic compound CCR4 inhibitor and application thereof

Abstract

The invention discloses a heterocyclic compound shown in a formula (I) or a stereoisomer, a deuterated compound, a solvate, a pharmaceutically acceptable salt or a co-crystal of the heterocyclic compound and a pharmaceutical composition of the heterocyclic compound or the stereoisomer, the deuterated compound, the solvate, the pharmaceutically acceptable salt or the co-crystal, and application of the heterocyclic compound or the stereoisomer, the deuterated compound, the solvate and the pharmaceutically acceptable salt or the co-crystal in preparation of drugs for treating / preventing CCR4-mediated diseases. # imgabs0 #

Description

Heterocyclic compound CCR4 inhibitor and its use Technical Field

[0001] The present invention relates to a CCR4 inhibitor, its stereoisomers, pharmaceutically acceptable salts, solvates, cocrystals or deuterated substances, and use thereof in preparing drugs for treating CCR4-mediated related diseases. Background Art

[0002] CC chemokine receptor type 4 (CCR4), also known as CD194, is composed of a polypeptide chain containing 7 transmembrane domains and belongs to the G protein-coupled receptor family. It contains 360 amino acids and a molecular weight of approximately 41kD. It is mainly expressed in various lymphocytes and tissues, and its ligands include a variety of chemokines. As an important chemokine receptor, CCR4 binds to other chemokine ligands to exercise its functions and participate in the regulation of human autoimmune disease processes, mainly including atopic dermatitis, asthma, and cutaneous T-cell lymphoma. Studies have shown that CCR4 is expressed by Th2 cells, regulatory T cells (Tregs), mast cells, and skin-homing lymphocytes Ag-positive T cells. By blocking the CCR4 receptors highly expressed on Th2 cells, it selectively inhibits the migration of Th2 cells to inflamed tissues, thereby playing a role in the upstream pathway of the pathogenesis of inflammation such as asthma and atopic dermatitis. Therefore, it is often accompanied by Th2 type CD4 + T cells play an important role in inflammatory diseases with massive infiltration, such as atopic dermatitis, asthma, and allergic airway inflammation.

[0003] Summary of the Invention

[0004] The present invention provides a compound of formula (I), (I-1), (I-1a), (I-1b), (I-1c), (I-1d), (I-1e), (I-1f), (I-1g), (I-1h), (I-2), (I-2a), (I-2b), (I-2c), (I-2d), (I-3), (I-3a), (I-4), and a stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt or cocrystal thereof. The compound has the excellent effects of good activity, excellent physicochemical properties, ease of formulation, excellent pharmacokinetic properties, high bioavailability, and low toxic and side effects.

[0005] Compounds of formula (I), (I-1), (I-1a), (I-1b), (I-1c), (I-1d), (I-1e), (I-1f), (I-1g), (I-1h), (I-2), (I-2a), (I-2b), (I-2c), (I-2d), (I-3), (I-3a), (I-4), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts or cocrystals thereof,

[0006] in,

[0007] Ring A is selected from 6-membered heteroaryl, 9-10-membered bicyclic heteroaryl, aryl, 9-10-membered bicyclic heterocyclyl;

[0008] In some embodiments, Ring A is selected from 6-membered heteroaryl, 9-10 membered bicyclic heteroaryl, 6-10 membered aryl, 9-10 membered bicyclic heterocycloalkyl;

[0009] In some embodiments, Ring A is selected from 6-membered heteroaryl, 9-10 membered bicyclic heteroaryl, aryl;

[0010] Ring B is selected from phenyl, 8-10 membered aryl, 5-6 membered heteroaryl, 8-10 membered heteroaryl;

[0011] The D ring is selected from -Cy2-Cy3-#, -L1-Cy2-Cy3-#, -Cy2-L1-#, -L1-Cy2-#, -L1-Cy3-#, Cy4, -L1-Cy4-#, wherein # represents the connection site between the D ring and the A ring;

[0012] Cy2 is selected from 4-7 membered monoheterocycloalkyl, 7-10 membered bridged heterocycloalkyl, 7-10 membered spiroheterocycloalkyl, 8-10 membered heterocycloalkyl, 6-7 membered cycloalkyl, phenyl, wherein Cy2 is optionally substituted by 1-3 members selected from =O, halogen, deuterium, CN, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkoxy and NH2 group substitution;

[0013] In some embodiments, Cy2 is selected from 4-7 membered monoheterocycloalkyl, 7-10 membered bridged heterocycloalkyl, 7-10 membered spiroheterocycloalkyl, 8-10 membered heterocycloalkyl, 6-7 membered cycloalkyl, wherein Cy2 is optionally substituted by 1-3 members selected from =O, halogen, deuterium, CN, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C1-4 Alkoxy, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkoxy and NH2 group substitution;

[0014] Cy3 is selected from 4-7 membered monoheterocycloalkyl, 7-10 membered spiroheterocycloalkyl, 5-6 membered heteroaryl, 6-10 membered heterocycloalkyl or phenyl, wherein Cy3 is optionally substituted by 1-3 groups selected from =O, halogen, deuterium, CN, OH, C 1-4 Alkyl and NH2 group substitution;

[0015] In some embodiments, Cy3 is selected from 4-7 membered monoheterocycloalkyl, 7-10 membered spiroheterocycloalkyl, 5-6 membered heteroaryl, 6-10 membered spiroheterocycloalkyl, or phenyl;

[0016] Cy4 is selected from 7-10 membered bridged heterocycloalkyl, 7-10 membered spiroheterocycloalkyl, 8-10 membered heterocycloalkyl;

[0017] L1 is selected from a bond, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, -C(=O)-;

[0018] In some embodiments, L1 is selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(=O)-;

[0019] m, p, q, t are each independently selected from 0, 1, 2, 3, 4, 5;

[0020] R 1 、R 2a 、R 2b Each independently selected from H, deuterium, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 alkyl;

[0021] R 3 Selected from Cy1-R 3a 、R 3a ;

[0022] Cy1 is selected from 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, and the cycloalkyl and heterocycloalkyl groups are optionally further substituted by 1-3 groups selected from C 1-6 Alkyl, halogen, deuterium, cyano, nitro, OH, halo C 1-6 Alkyl, deuterated C 1-6 Alkyl radical substitution;

[0023] R 3a Selected from -COOH, COOC1-6 Alkyl, -P(O)(OH)OH, -P(O)(OH)H, hydroxyl C 1-6 Alkyl, -C 1-6 Alkyl-COOH, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, wherein the heteroaryl and heterocycloalkyl are optionally further substituted by 1-3 groups selected from =O, C 1-6 Alkyl, halogen, deuterium, cyano, nitro, OH, halo C 1-6 Alkyl, deuterated C 1-6 Alkyl radical substitution;

[0024] In some embodiments, R 3a Selected from -COOH, -COOC 1-6 Alkyl, -P(O)(OH)OH, -P(O)(OH)H, hydroxyl C 1-6 Alkyl, -C 1-6 Alkyl-COOH, -C 1-6 Alkyl-OH, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, wherein the heteroaryl and heterocycloalkyl are optionally further substituted by 1-3 groups selected from =O, methyl, ethyl, halogen, deuterium, cyano, nitro, OH, halo C 1-6 Alkyl radical substitution;

[0025] In some embodiments, R 3a Selected from -COOH, -COOC 1-6 Alkyl, -P(O)(OH)OH, -P(O)(OH)H, hydroxyl C 1-6 Alkyl, -C 1-6 Alkyl-COOH, -C 1-6 Alkyl-OH, 5-6 membered heteroaryl;

[0026] R 4 Selected from deuterium, halogen, cyano, nitro, OH, amino, SF5, N3, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -C(=O)R 4a ;

[0027] R 4a Selected from deuterium, halogen, OH, amino, C 1-6 alkyl;

[0028] R 6 、R 6aEach independently selected from deuterium, halogen, cyano, nitro, OH, amino, SF5, N3, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 alkoxy;

[0029] Alternatively, two R 6 Together with the atoms to which they are attached, they form a 5-6 membered cycloalkenyl group; the cycloalkenyl group is optionally selected from 1-5 R 6a replace;

[0030] Alternatively, R 4 With R 1 Together with the atoms to which they are attached, they form a 5-6 membered heteroaryl or a 5-6 membered heterocycloalkyl;

[0031] Alternatively, R 1 With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered heterocycloalkyl group;

[0032] Alternatively, R 2a With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered cycloalkyl group;

[0033] Alternatively, R 1 With R 2a Together with the atoms to which it is attached, it forms a 4-6 membered heterocycloalkyl group;

[0034] Alternatively, R on the same carbon atom or on different carbon atoms 2a With R 2b Together with the atoms to which it is attached, it forms a 3-membered cycloalkyl group or a 4-6-membered cycloalkyl group;

[0035] Alternatively, two R on adjacent ring atoms 4 and its connected atoms together form C 4-6 Cycloalkyl or 4-7 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl optionally further substituted by 1-3 groups selected from deuterium, halogen, C 1-6 Alkyl, cyano, OH, amino, SF5, N3, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy and COC 1-6Alkyl groups are substituted.

[0036] The C 4-6 Examples of cycloalkyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl; examples of 4-7 membered heterocycloalkyl groups include, but are not limited to, oxetanyl, azetidinyl, oxolanyl, azacyclopentenyl, oxinyl, and azacyclohexenyl.

[0037] Furthermore, the compounds of formula (I), (I-1a), (I-1b), (I-1c), (I-1d), (I-1e), (I-1f), (I-1g), (I-2a), (I-2b), (I-2c), (I-2d), (I-3), (I-3a), (I-2), their stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts or cocrystals,

[0038] in,

[0039] Ring A is selected from 6-membered heteroaryl, 9-10-membered bicyclic heteroaryl;

[0040] Ring B is selected from phenyl, 8-10 membered aryl, 5-6 membered heteroaryl, 8-10 membered heteroaryl;

[0041] The D ring is selected from -Cy2-Cy3-#, -L1-Cy2-Cy3-#, -Cy2-L1-#, -L1-Cy2-#, -L1-Cy3-#, Cy4, -L1-Cy4-#, wherein # represents the connection site between the D ring and the A ring;

[0042] Cy2 is selected from 4-7 membered monoheterocycloalkyl, 7-10 membered bridged heterocycloalkyl, 7-10 membered spiroheterocycloalkyl, 8-10 membered heterocycloalkyl, 6-7 membered cycloalkyl, wherein Cy2 is optionally substituted by 1-3 members selected from =O, halogen, deuterium, CN, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkoxy and NH2 group substitution;

[0043] Cy3 is selected from 4-7 membered monoheterocycloalkyl, 5-6 membered heteroaryl;

[0044] Cy4 is selected from 7-10 membered bridged heterocycloalkyl, 7-10 membered spiroheterocycloalkyl, 8-10 membered heterocycloalkyl;

[0045] L1 is selected from C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl;

[0046] m, p, q, t are each independently selected from 0, 1, 2, 3, 4, 5;

[0047] R 1 、R 2a 、R 2b Each independently selected from H, deuterium, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 alkyl;

[0048] R 3 Selected from Cy1-R 3a 、R 3a ;

[0049] Cy1 is selected from 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, and the cycloalkyl and heterocycloalkyl groups are optionally further substituted by 1-3 groups selected from C 1-6 Alkyl, halogen, deuterium, cyano, nitro, OH, halo C 1-6 Alkyl, deuterated C 1-6 Alkyl radical substitution;

[0050] R 3a Selected from -COOH, -COOC 1-6 Alkyl, -P(O)(OH)OH, -P(O)(OH)H, hydroxyl C 1-6 alkyl;

[0051] R 4 Selected from deuterium, halogen, cyano, nitro, OH, amino, SF5, N3, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -C(=O)R 4a ;

[0052] R 4a Selected from deuterium, halogen, OH, amino, C 1-6 alkyl;

[0053] R 6 Selected from deuterium, halogen, cyano, nitro, OH, amino, SF5, N3, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 alkoxy;

[0054] Alternatively, R 4 With R 1 Together with the atoms to which they are attached, they form a 5-6 membered heteroaryl or a 5-6 membered heterocycloalkyl;

[0055] Alternatively, R 1 With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered heterocycloalkyl group;

[0056] Alternatively, R 2a With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered cycloalkyl group;

[0057] Alternatively, R 1 With R 2a Together with the atoms to which it is attached, it forms a 4-6 membered heterocycloalkyl group;

[0058] Alternatively, R on the same carbon atom or on different carbon atoms 2a With R 2b Together with the atoms to which it is attached, it forms a 4-6 membered cycloalkyl group;

[0059] Alternatively, two R on adjacent ring atoms 4 and its connected atoms together form C 4-6 Cycloalkyl or 4-7 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl optionally further substituted by 1-3 groups selected from deuterium, halogen, C 1-6 Alkyl, cyano, OH, amino, SF5, N3, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy and COC 1-6 Alkyl groups are substituted.

[0060] The C 4-6 Examples of cycloalkyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl; examples of 4-7 membered heterocycloalkyl groups include, but are not limited to, oxetanyl, azetidinyl, oxolanyl, azacyclopentenyl, oxinyl, and azacyclohexenyl.

[0061] The compound of formula (I) of the present invention, its stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts or cocrystals, has the structure represented by formula (I-1), (I-1a), (I-1b), (I-1c), (I-1d), (I-1e), (I-1f), or (I-1g):

[0062] The condition is, Huan Buwei in Indicates connection with the right side, -------- indicates connection with the left side;

[0063] The remaining groups are the same as above.

[0064] The compound of formula (I) of the present invention, its stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts or cocrystals, has the structure represented by formula (I-1a), (I-1b), (I-1c), (I-1d), (I-1e), (I-1f), or (I-1g):

[0065] The condition is, Huan Buwei in Indicates connection with the right side, -------- indicates connection with the left side;

[0066] The remaining groups are the same as above.

[0067] The compound of formula (I) of the present invention, its stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts or cocrystals, has the structure represented by formula (I-1a), (I-1b), (I-1c), (I-1d), (I-1e), (I-1f), (I-1g), or (I-1h):

[0068] The condition is,

[0069] (1) Huan Buwei

[0070] (2) In formula (I-1h), Huan Buwei And Cy2 is not

[0071] (3) In formula (I-1d), Huan Buwei

[0072] in Indicates connection with the right side, -------- indicates connection with the left side;

[0073] In some embodiments, R 6 Each independently selected from deuterium, halogen, cyano, OH, amino, SF5, N3, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy; alternatively, two R 6 Together with the atoms to which they are attached, they form a 5-6 membered cycloalkenyl group; the cycloalkenyl group is optionally selected from 1-5 R 6a replace;

[0074] In some embodiments, R 6 Each independently selected from deuterium, halogen, cyano, OH, amino, C 1-2 Alkyl, halogenated C 1-2 Alkyl, deuterated C 1-2 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-2 Alkoxy; alternatively, two R 6 Together with the atoms to which they are attached, they form a 5-6 membered cycloalkenyl group;

[0075] In some embodiments, R 6 Each is independently selected from F, Cl, Br, OH, amino, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, halomethyl, haloethyl;

[0076] In some embodiments, R 4 Selected from deuterium, halogen, cyano, OH, amino, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, deuterated C 1-4 Alkoxy; alternatively, two R on adjacent ring atoms 4 and its connected atoms together form C 4-6 Cycloalkyl or 4-7 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl optionally further substituted by 1-3 groups selected from deuterium, halogen, C 1-4 Alkyl, cyano, OH, amino, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C1-4 Alkoxy, deuterated C 1-4 Alkoxy group substitution;

[0077] In some embodiments, R 4 Selected from deuterium, F, Cl, Br, cyano, OH, amino, C 1-2 Alkyl, halogenated C 1-2 Alkyl, deuterated C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-2 Alkoxy, deuterated C 1-2 Alkoxy; alternatively, two R on adjacent ring atoms 4 and its connected atoms together form C 4-6 Cycloalkyl or 4-7 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted by 1-3 atoms selected from deuterium, F, Cl, Br, C 1-2 Alkyl, cyano, OH, amino, halogenated C 1-2 Alkyl, deuterated C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-2 Alkoxy, deuterated C 1-2 Alkoxy group substitution;

[0078] In some embodiments, R 4 Selected from deuterium, F, Cl, Br, cyano, OH, amino, methyl, ethyl, fluoromethyl, fluoroethyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy; Alternatively, two R on adjacent ring atoms 4 and its connected atoms together form C 4-6 Cycloalkyl or 4-7 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-3 groups selected from deuterium, F, Cl, Br, cyano, OH, amino, methyl, ethyl, fluoromethyl, fluoroethyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy;

[0079] The remaining groups are the same as above.

[0080] The compound of formula (I) of the present invention, its stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts or cocrystals, has the structure represented by formula (I-1a), (I-1b), (I-1c), (I-1d), (I-1e), (I-1f), (I-1g), or (I-1h):

[0081] The condition is,

[0082] (1) Huan Buwei

[0083] (2) In formula (I-1h), Huan Buwei And Cy2 is not

[0084] (3) In formula (I-1d), The ring is selected from:

[0085] in Indicates connection to the right, and -------- indicates connection to the left.

[0086] The remaining groups are the same as above.

[0087] The compound of formula (I) of the present invention, its stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt or cocrystal has the structure shown in formula (I-1d):

[0088] The ring is selected from:

[0089] R 6 Each independently selected from deuterium, halogen, cyano, OH, amino, SF5, N3, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy; alternatively, two R 6 Together with the atoms to which they are attached, they form a 5-6 membered cycloalkenyl group; the cycloalkenyl group is optionally selected from 1-5 R 6a replace;

[0090] In some embodiments, R6 is each independently selected from F, Cl, Br, OH, amino, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, fluoromethyl, fluoroethyl;

[0091] The remaining groups are the same as above.

[0092] The compound of formula (I) of the present invention, its stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt or cocrystal has the structure shown in formula (I-1h):

[0093] Ring A is selected from 6-membered heteroaryl, 9-10-membered bicyclic heteroaryl, 6-10-membered aryl, 9-10-membered bicyclic heterocycloalkyl;

[0094] R 4 Selected from deuterium, halogen, cyano, nitro, OH, amino, SF5, N3, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -C(=O)R 4a ;

[0095] In some embodiments, R 4 Selected from deuterium, halogen, cyano, nitro, OH, amino, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, deuterated C 1-4 alkoxy;

[0096] In some embodiments, Ring selected from

[0097] Cy2 is selected from 4-7 membered monoheterocycloalkyl, 7-10 membered bridged heterocycloalkyl, 7-10 membered spiroheterocycloalkyl, 8-10 membered heterocycloalkyl, 6-7 membered cycloalkyl, phenyl, wherein Cy2 is optionally substituted by 1-3 members selected from =O, halogen, deuterium, CN, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, and NH2 group substitution;

[0098] In some embodiments, Cy2 is selected from 4-7 membered monoheterocycloalkyl, 7-9 membered bridged heterocycloalkyl, 7-9 membered spiroheterocycloalkyl, 8-10 membered heterocycloalkyl, 6 membered cycloalkyl, phenyl, wherein Cy2 is optionally substituted by 1-3 members selected from ═O, F, Cl, Br, deuterium, CN, OH, C 1-2 Alkyl, halogenated C 1-2 Alkyl, deuterated C 1-2 Alkyl, C 1-2 Alkoxy and NH2 group substitution;

[0099] Cy3 is selected from 4-7 membered monoheterocycloalkyl, 5-6 membered heteroaryl, 6-10 membered heterocycloalkyl, phenyl, and the Cy3 is optionally substituted by 1-3 groups selected from =O, halogen, deuterium, CN, OH, C 1-2 Alkyl and NH2 group substitution;

[0100] In some embodiments, Cy3 is selected from 4-7 membered monoheterocycloalkyl, 5-6 membered heteroaryl, 6-8 membered heterocycloalkyl, phenyl, and said Cy3 is optionally substituted with 1-3 groups selected from ═O, F, Cl, Br, deuterium, CN, OH, methyl, ethyl, and NH2;

[0101] The conditions are: Huan Buwei

[0102] The remaining groups are the same as above.

[0103] The compound (I) of the present invention, its stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts or cocrystals, has the structure represented by formula (I-2a), (I-2b), (I-2c), (I-2d), or (I-2):

[0104] In some embodiments, the D ring is selected from -Cy2-Cy3-#, -Cy2-L1-#, -L1-Cy2-#, Cy4, wherein # represents the connection site of the D ring to the A ring;

[0105] In some embodiments, the D ring is selected from -Cy2-Cy3-#, wherein # represents the site of attachment of the D ring to the A ring;

[0106] Provided that the D ring is not selected from in Indicates connection with the right side, -------- indicates connection with the left side;

[0107] The definitions of other groups are the same as above.

[0108] Furthermore, the compound (I) of the present invention, its stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt or cocrystal has the structure represented by formula (I-2a), (I-2b), (I-2c) or (I-2d):

[0109] Provided that the D ring is not selected from in Indicates connection with the right side, -------- indicates connection with the left side;

[0110] The definitions of other groups are the same as above.

[0111] The compound of formula (I) of the present invention, its stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts or cocrystals, has the structure shown in formula (I-3):

[0112] The condition is, Not selected

[0113] The definitions of other groups are the same as above.

[0114] The compound of formula (I) of the present invention, its stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts or cocrystals, has the structure shown in formula (I-3) or (I-3a):

[0115] The condition is, Not selected

[0116] The definitions of other groups are the same as above.

[0117] The compound of formula (I) of the present invention, its stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt or cocrystal, has the structure of formula (I-4):

[0118] In some embodiments, the D ring is selected from -Cy2-Cy3-#, -Cy2-L1-#, -L1-Cy2-#, wherein # represents the connection site of the D ring to the A ring;

[0119] In some embodiments, the D ring is selected from -Cy2-Cy3-#, wherein # represents the site of attachment of the D ring to the A ring;

[0120] The definitions of other groups are the same as above.

[0121] The compound of formula (I) of the present invention, its stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt or cocrystal, wherein

[0122] Ring selected from

[0123] or Ring selected from

[0124] or Ring selected from

[0125] or Ring selected from

[0126] in Indicates connection with the right side, -------- indicates connection with the left side;

[0127] Alternatively, R 4 、R 1 Together with the atoms to which they are attached, they form

[0128] The definitions of other groups are the same as above.

[0129] Furthermore, the compound of formula (I) of the present invention, its stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt or cocrystal, wherein

[0130] Ring selected from

[0131] in Indicates connection with the right side, -------- indicates connection with the left side;

[0132] Alternatively, R 4 、R 1 Together with the atoms to which they are attached, they form

[0133] The definitions of other groups are the same as above.

[0134] The compound of formula (I) of the present invention, its stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt or cocrystal,

[0135] Ring selected from

[0136] Alternatively, R 1 With R 6 Together with the atoms to which they are attached, they form ring B

[0137] Alternatively, R 2a With R 6 Together with the atoms to which they are attached, they form ring B

[0138] The compound of formula (I) of the present invention, its stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt or cocrystal,

[0139] Ring selected from or Ring selected from Or choose

[0140] The definitions of other groups are the same as above.

[0141] Furthermore, the compound of formula (I) of the present invention, its stereoisomers, deuterated substances, solvates, or pharmaceutically acceptable salts or cocrystals,

[0142] Ring selected from

[0143] The definitions of other groups are the same as above.

[0144] The compound of formula (I) of the present invention, its stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt or cocrystal, wherein

[0145] The Cy2 ring is selected from:

[0146] Or the Cy2 ring is selected from

[0147] The Cy3 ring is selected from Or the Cy3 ring is selected from Or the Cy3 ring is selected from Or the Cy3 ring is selected from Or the Cy3 ring is selected from

[0148] The Cy4 ring is selected from

[0149] L1 is selected from methylene, alkynylene, -C(=O)-; further, L1 is selected from methylene, alkynylene;

[0150] in Indicates connection with the right side, -------- indicates connection with the left side;

[0151] The definitions of other groups are the same as above.

[0152] The compound of formula (I) of the present invention, its stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt or cocrystal, wherein

[0153] The D ring is selected from -Cy2-Cy3-#, -Cy2-L1-#, -L1-Cy2-#, and Cy4, where # represents the connection site between the D ring and the A ring;

[0154] In some embodiments, the D ring is selected from -Cy2-Cy3-#, -Cy2-L1-#, -L1-Cy2-#, wherein # represents the connection site of the D ring to the A ring;

[0155] In some embodiments, the D ring is selected from -Cy2-Cy3-#, wherein # represents the site of attachment of the D ring to the A ring;

[0156] Cy2 is selected from 4-7 membered monoheterocycloalkyl, 7-10 membered bridged heterocycloalkyl, 7-10 membered spiroheterocycloalkyl, 8-10 membered heterocycloalkyl, 6-7 membered cycloalkyl, phenyl, wherein Cy2 is optionally substituted by 1-3 members selected from =O, halogen, deuterium, CN, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, and NH2 group substitution;

[0157] In some embodiments, Cy2 is selected from 4-7 membered monoheterocycloalkyl, 7-9 membered bridged heterocycloalkyl, 7-9 membered spiroheterocycloalkyl, 8-10 membered heterocycloalkyl, 6 membered cycloalkyl, phenyl, wherein Cy2 is optionally substituted by 1-3 members selected from ═O, F, Cl, Br, deuterium, CN, OH, C 1-2 Alkyl, halogenated C 1-2 Alkyl, deuterated C 1-2 Alkyl, C 1-2 Alkoxy and NH2 group substitution;

[0158] Cy3 is selected from 4-7 membered monoheterocycloalkyl, 5-6 membered heteroaryl, 6-10 membered heterocycloalkyl, phenyl, and the Cy3 is optionally substituted by 1-3 groups selected from =O, halogen, deuterium, CN, OH, C 1-2 Alkyl and NH2 group substitution;

[0159] In some embodiments, Cy3 is selected from 4-7 membered monoheterocycloalkyl, 5-6 membered heteroaryl, 6-8 membered heterocycloalkyl, phenyl, and said Cy3 is optionally substituted with 1-3 groups selected from ═O, F, Cl, Br, deuterium, CN, OH, methyl, ethyl, and NH2;

[0160] L1 is selected from methylene, ethylene, vinylene, ethynylene, -C(=O)-;

[0161] The compound of formula (I) of the present invention, its stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt or cocrystal, wherein

[0162] Ring D is selected from

[0163] Or the D ring is selected from Or the D ring is selected from Or the D ring is selected from

[0164] in Indicates connection with the right side, -------- indicates connection with the left side;

[0165] The other groups are the same as above.

[0166] The compound of formula (I) of the present invention, its stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt or cocrystal, wherein

[0167] Ring D is selected from

[0168] in Indicates connection with the right side, -------- indicates connection with the left side;

[0169] The other groups are the same as above.

[0170] The compound of formula (I) of the present invention, its stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt or cocrystal, wherein

[0171] Ring D is selected from

[0172] in Indicates connection with the right side, -------- indicates connection with the left side;

[0173] The other groups are the same as above.

[0174] The compound of formula (I) of the present invention, its stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt or cocrystal, wherein

[0175] Cy1 is selected from 3-6 membered monocyclic cycloalkyl, 7-10 membered bicyclic cycloalkyl, 4-6 membered monoheterocyclic alkyl, 7-10 membered bicyclic heterocyclic alkyl, and the cycloalkyl and heterocyclic alkyl groups are optionally further substituted by 1-3 groups selected from C 1-4 Alkyl, halogen, deuterium, cyano, nitro, OH, halo C 1-4 Alkyl, deuterated C 1-4 Alkyl radical substitution;

[0176] The definitions of other groups are the same as above.

[0177] The compound of formula (I) of the present invention, its stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt or cocrystal, wherein

[0178] R3 Selected from

[0179] or R 3 Selected from or R 3 Selected from

[0180] The definitions of other groups are the same as above.

[0181] The compound of formula (I) of the present invention, its stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt or cocrystal, wherein

[0182] R 3 Selected from

[0183] The definitions of other groups are the same as above.

[0184] The compound of formula (I) of the present invention, its stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt or cocrystal, wherein

[0185] R 3 Selected from

[0186] The definitions of other groups are the same as above.

[0187] The compound of the present invention, its stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt or cocrystal, is selected from one of the structures in Table 1 below:

[0188] Table 1

[0189] The compound of the present invention, its stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt or cocrystal, is selected from one of the structures in Table 2 below.

[0190] Table 2

[0191] Note: abs refers to absolute configuration.

[0192] Secondly, the present invention also provides a pharmaceutical composition, which contains the compound described in any one of the aforementioned technical solutions, its stereoisomers, solvates, deuterated substances, or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers and / or excipients.

[0193] Furthermore, the pharmaceutical composition or pharmaceutical preparation comprises 1-1500 mg of the compound described in any of the aforementioned technical solutions, its stereoisomers, deuterated substances, solvates, or pharmaceutically acceptable salts or cocrystals, and pharmaceutically acceptable carriers and / or excipients.

[0194] Furthermore, the present invention also provides the use of a compound according to any of the aforementioned embodiments, a stereoisomer, solvate, deuterated form, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof, in the preparation of a medicament for treating / preventing CCR4-mediated diseases. Furthermore, CCR4-mediated diseases include, but are not limited to, tumors or inflammation.

[0195] The present invention also provides a method for treating a disease in a mammal or a human, comprising administering to a subject a therapeutically effective amount of a compound according to any one of the aforementioned technical solutions, a stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably a tumor or inflammation.

[0196] The present invention also provides a method for treating a disease in a mammal or human, comprising administering to the mammal or human a therapeutically effective amount of a compound of the present invention, or a stereoisomer, deuterated form, solvate, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition thereof. In some embodiments, the mammal of the present invention does not include a human.

[0197] As used herein, an "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition being treated to some extent. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80mg, 1-60mg, 1-50mg, 1-40mg, 1-25mg, 1-20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5- 700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5-150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1 000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-200mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 1 0-50mg, 10-40mg, 10-30mg, 10-20mg; 20-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-250mg, 20-200mg, 20-150mg, 2 0-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg. ;

[0198] The present invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of a compound of the present invention, or a stereoisomer, deuterated form, solvate, pharmaceutically acceptable salt, or cocrystal thereof, and a carrier and / or excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as the "drug strength"). In some embodiments, the pharmaceutical composition includes but is not limited to 1-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 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 g, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of a compound of the present invention or a stereoisomer, deuterated form, solvate, pharmaceutically acceptable salt or cocrystal thereof.

[0199] A method for treating a disease in a mammal or human, comprising administering to a subject a therapeutically effective amount of a compound of the present invention, a stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably a tumor or inflammation.

[0200] A method for treating a disease in a mammal or a human, comprising administering a compound of the present invention, a stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier and / or excipient to a subject at a daily dose of 1-1500 mg / day, wherein 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, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, In some embodiments, the daily dose includes but is not limited to 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, 1500 mg / day.

[0201] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, deuterated form, solvate, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated form, solvate, pharmaceutically acceptable salt or cocrystal is the same as that in the above-mentioned pharmaceutical composition.

[0202] The amount of the compound of the invention or its stereoisomer, deuterated form, solvate, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.

[0203] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0204] Synthesis route

[0205] Those skilled in the art can prepare the compounds of the present invention by combining known organic synthesis techniques, using commercially available chemicals and / or compounds described in the chemical literature as starting materials. "Commercially available chemicals" are obtained from reputable commercial sources, including suppliers such as Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and J&K Technology.

[0206] Specific and similar reactants can be selectively identified by indexes of known chemical substances prepared by the American Chemical Society's Chemical Abstracts Service, which are available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis facilities, many of which standard chemical supply facilities (e.g., those listed above) offer custom synthesis services.

[0207] the term

[0208] Unless otherwise specified in the present invention, the terms of the present invention have the following meanings:

[0209] The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (deuterium, also known as heavy hydrogen), tritium (T, also known as super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, an isotope of fluorine 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0210] "Halogen" herein refers to F, Cl, Br, I, or isotopes thereof.

[0211] "Halo" or "halogen-substituted" refers to substitution with one or more halogens selected from F, Cl, Br, I, or isotopes thereof. The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be replaced by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, they may be the same or different halogens. Typical examples include 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, and 1 halogen substitution.

[0212] "Deuterium" refers to the isotope of hydrogen (H) and is synonymous with "D".

[0213] "Deuterated" or "deuterated compound" refers to a situation where a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, thiol, heterocycloalkyl, alkenyl, alkynyl or other group is replaced by at least one deuterium atom. The upper limit of the number of deuterated groups is equal to the sum of the number of replaceable hydrogen atoms in the substituted group. Unless otherwise specified, the number of deuterated groups is any integer between 1 and the upper limit, for example, 1-20 deuterium atoms, 1-10 deuterium atoms, 1-6 deuterium atoms, 1-3 deuterium atoms, 1-2 deuterium atoms or 1 deuterium atom.

[0214] “C x-y " group refers to a group containing x to y carbon atoms, such as "C 1-6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms.

[0215] "Alkyl" refers to a monovalent straight-chain or branched saturated aliphatic hydrocarbon group. Typically, it is an alkyl group having 1 to 20 carbon atoms, or an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 6 carbon atoms, or an alkyl group 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 the like. The alkyl group may be further substituted with a substituent.

[0216] "Alkylene" refers to a divalent straight-chain or branched saturated alkyl group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, and the like.

[0217] "Haloalkyl" refers to a situation where one or more hydrogen atoms in an alkyl group are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine, iodine, or their isotopes). The upper limit of the number of halogen substituents is equal to the sum of the number of replaceable hydrogen atoms in the alkyl group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. Typically, an alkyl group is substituted with 1-5 halogens, or 1-3 halogens, or 1-2 halogens, or 1 halogen. When the number of halogen substituents is greater than 1, they may be the same or different halogens. Specific examples include, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0218] "Alkoxy" or "alkyloxy" refers to an -O-alkyl group. For example, -OC 1-8 Alkyl, -OC 1-6 Alkyl, -OC 1-4 Alkyl or -OC 1-2 Specific non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy, and the like; the alkoxy groups may be optionally substituted with substituents.

[0219] "Haloalkoxy" refers to an -O-haloalkyl group. For example, -O-haloC 1-8 Alkyl, -O-halogenated C 1-6 Alkyl, -O-halogenated C 1-4 Alkyl or -O-halogenated C 1-2 Alkyl; the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be substituted by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit, preferably 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, or 1 halogen substitution; when the number of halogen substituents is greater than 1, they may be the same or different halogen substitutions; non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0220] "Hydroxy C 1-6 The term "alkyl" refers to an alkyl group of 1 to 6 carbon atoms substituted with a hydroxy group.

[0221] "Alkenyl" refers to a straight or branched chain hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and further such as 2 to 4 carbon atoms, examples of which include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-4-butenyl, 2-methyl-5-butenyl, 2-methyl-6-butenyl, 2-methyl-7-butenyl, 2-methyl-8-butenyl, 2-methyl-9-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3 ... -methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group may be optionally further substituted with a substituent.

[0222] "Alkenylene" refers to a straight or branched divalent unsaturated hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and further such as 2 to 4 carbon atoms. Non-limiting examples include ethynylene, and the alkenylene group may be optionally substituted with a substituent.

[0223] "Alkynyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), typically containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, and further containing 2 to 4 carbon atoms. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, and 4-decynyl. The alkynyl group may be optionally substituted with a substituent.

[0224] "Alkynylene" refers to a straight or branched divalent unsaturated hydrocarbon group containing a carbon-carbon triple bond (C≡C), typically containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, further containing 2-4 carbon atoms, non-limiting examples include ethynylene, propynylene, butynylene, and the alkynylene group may be optionally substituted with a substituent.

[0225] "Cycloalkyl" refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group containing no ring heteroatoms. Cycloalkyl can be monocyclic, bicyclic or polycyclic. Bicyclic or polycyclic rings can be cyclic, spirocyclic, bridged or a combination thereof. Bicyclic or polycyclic rings can include one or more aromatic rings, but the ring system as a whole does not have aromaticity. The attachment site can be on the aromatic ring or on the non-aromatic ring. Usually, the cycloalkyl group contains 3 to 20 carbon atoms, further contains 3-8 carbon atoms, and further contains 3-6 carbon atoms; when it is a monocyclic cycloalkyl group, it contains 3-15 carbon atoms, or 3-10 carbon atoms, or 3-8 carbon atoms, or 3-6 carbon atoms; when it is a bicyclic or polycyclic cycloalkyl group, it contains 5-12 carbon atoms, or 5-11 carbon atoms, or 6-10 carbon atoms; non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, butenyl, cyclopentenyl, cyclohexenyl, The cycloalkyl group may be optionally substituted with a substituent.

[0226] "Cycloalkylene" refers to a divalent radical of a cycloalkyl group.

[0227] "Aryl" refers to a carbon ring with aromaticity and no heteroatoms, including monocyclic aromatic groups and condensed aromatic groups. It usually contains 6 to 14 carbon atoms, and further contains 6 to 10 carbon atoms. Non-limiting examples include phenyl, naphthyl, anthracenyl, phenanthrenyl, aryl, It may be optionally substituted with a substituent.

[0228] "Carbocycle" or "carbocyclyl" refers to a saturated, partially unsaturated, or aromatic carbocycle, including aryl and cycloalkyl. Carbocycles can be monocyclic, bicyclic, or polycyclic, including bridged, fused, and spirocyclic rings and combinations thereof. Carbocycles typically have 3 to 12 carbon atoms, or 3-10 carbon atoms, or 3-6 carbon atoms. In non-limiting examples, monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, and bicyclic bridged rings include etc., double ring and ring include etc., bicyclic spiro ring includes The carbocyclic ring may be optionally substituted with a substituent.

[0229] "Heterocycloalkyl" refers to a saturated or partially unsaturated non-aromatic carbocyclic ring containing 1, 2, 3, or 4 heteroatoms selected from N, S, and O. Heterocycloalkyl can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic rings can be bridged, fused, spirocyclic, or a combination thereof. Bicyclic or polycyclic rings can include one or more aromatic or heteroaromatic rings, but the ring system as a whole is not aromatic. The attachment point can be on the aromatic ring or on the non-aromatic ring. Heterocycloalkyl groups are usually 3 to 20-membered rings. When they are monocyclic heterocycloalkyl groups, they are usually 3 to 15-membered rings, or 3-10-membered rings, or 3-8-membered rings, or 3-6-membered rings; when they are bicyclic or polycyclic heterocycloalkyl groups, they are usually 5-12-membered rings, or 5-11-membered rings, or 6-9-membered rings. The heteroatoms N and S include their oxidation states. Non-limiting examples of heterocycloalkyl groups include azetidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, oxetanyl, pyranyl, azolidinyl, azolinyl, oxolanyl, oxekinyl, and the like. Heterocycloalkyl groups may be optionally substituted with substituents.

[0230] "Heteroaromatic ring" or "heteroaryl" unless otherwise specified refers to a ring containing 1 to 4 heteroatoms selected from N, O or S and their oxidation states and having aromatic properties, which may be monocyclic, bicyclic or polycyclic, and the bicyclic or polycyclic rings may be bridged, parallel, spirocyclic or combinations thereof; when bicyclic or polycyclic, it may be a fusion of a heteroaryl and an aryl, or a fusion of a heteroaryl and a heteroaryl, wherein either the heteroaryl or the aryl may be a connection site. Non-limiting examples include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, purinyl, The heteroaryl group may be optionally substituted by a substituent.

[0231] "Heterocycle" or "heterocyclyl" refers to a saturated or unsaturated, aromatic or non-aromatic ring containing 1 to 4 heteroatoms selected from N, O, or S and their oxidation states, and includes heteroaryl and heterocycloalkyl. Heterocycles include monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic heterocycles, and bicyclic spiro heterocycles, or combinations thereof. Heterocycles are typically 3- to 12-membered heterocycles, 5- to 12-membered heterocycles, or 5- to 7-membered heterocycles. The heterocyclic group may be attached to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, piperazinyl, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dithio ... hydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl, The heterocyclic ring may be optionally substituted with a substituent.

[0232] "Heterocyclylene" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic divalent heterocyclic group. Non-limiting examples include wait.

[0233] "Spiro" refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the rings, which may contain 0 or more double bonds or triple bonds, and may contain 0 to 5 heteroatoms selected from N, O, S, P, Si and their oxidation states. Typically, the spiro ring is a 6- to 14-membered ring, or a 6- to 12-membered ring, or a 6- to 10-membered ring. Typically, the spiro ring is a trispirotri (representing a three-membered ring spirotricycle), a trispirotetra, a trispiropenta, a trispirohexa, a tetraspirotetra, a tetraspiropenta, a tetraspirohexa, a pentaspiropenta or a pentaspirohexa. Non-limiting examples of spiro rings include The spiro ring may be optionally substituted with a substituent.

[0234] "Parallel ring" or "condensed ring" refers to a polycyclic group in which the rings share two adjacent ring atoms and a chemical bond, and may contain one or more double bonds or triple bonds, and the rings may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidation states. Usually, the cyclic ring is a 5- to 20-membered ring, or a 5- to 14-membered ring, or a 5- to 12-membered ring, or a 5- to 10-membered ring. Usually, the cyclic ring is a three- to four-membered ring (representing a cyclic ring formed by a three-membered ring and a four-membered ring. According to the IUPC naming rules, it is possible to have a three-membered ring as the basic ring or a four-membered ring as the basic ring. The same applies below), a three- to five-ring ring, a three- to six-ring ring, a four- to four-ring ring, a four- to five-ring ring, a four- to six-ring ring, a five- to five-ring ring, a five- to six-ring ring, and a six- to six-ring ring. Non-limiting examples of cyclic rings include purine, quinoline, isoquinoline, benzopyran, benzofuran, benzothiophene, ; The ring may be aromatic or non-aromatic and optionally substituted by a substituent.

[0235] "Bridged ring" means two rings that share two non-adjacent ring atoms and may contain one or more double or triple bonds. A bridged ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidation states. Typically, the number of ring atoms in a bridged ring is 5 to 20, or 5 to 14, or 5 to 12, or 5 to 10. Non-limiting examples of bridged rings include adamantane,

[0236] "Substitution" or "substituent" unless otherwise specified refers to any substitution at a position permitted by chemical theory, and the number of substituents complies with the chemical bond rules. Exemplary substituents include but are not limited to: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Heteroalkyl, C 5-12 Aryl, 5-12 membered heteroaryl, hydroxyl, C 1-6 Alkoxy, C 5-12 Aryloxy, thiol, C 1-6 Alkylthio, cyano, halogen, C 1-6Alkylthiocarbonyl, C 1-6 Alkylcarbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, halo 1-6 Alkyl, halogenated C 1-6 Alkoxy, amino, phosphonic acid, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2,-OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2,-HC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 Alkyl)2,-SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, etc.

[0237] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0238] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that retain the biological effectiveness and properties of the free acids or free bases, and the free acids are reacted with non-toxic inorganic or organic bases, or the free bases are reacted with non-toxic inorganic or organic acids.

[0239] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or stereoisomers, deuterated forms, solvates, pharmaceutically acceptable salts, or cocrystals thereof, with other ingredients, wherein the other ingredients include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0240] "Carrier" refers to a system that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0241] An "excipient" is a substance that is not itself a therapeutic agent but serves as a diluent, adjuvant, binder, and / or vehicle that is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration. As known to those skilled in the art, excipients can serve a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of excipients include, but are not limited to: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, and cross-linked carboxymethylcellulose (e.g., cross-linked sodium carboxymethylcellulose); (4) tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, Sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other non-toxic compatible substances used in pharmaceutical preparations.

[0242] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0243] The compounds of the present invention also include their tautomers. For example, when the present invention describes a compound on the left side in which the pyrimidine ring is substituted with OH, it also includes the tautomer compound on the right side.

[0244] "Solvate" refers to a substance formed by a compound of the present invention or a salt thereof and a stoichiometric or non-stoichiometric amount of a solvent bound to the compound or salt thereof by non-covalent forces between the molecules. When the solvent is water, the solvate is a hydrate.

[0245] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate. DETAILED DESCRIPTION

[0246] The technical solutions of the present invention are described in detail below in conjunction with the embodiments, but the protection scope of the present invention includes but is not limited to them.

[0247] Test Method

[0248] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0249] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0250] HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C 18 100 × 4.6 mm, 3.5 μM);

[0251] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0252] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0253] Example 1:

[0254] Step 1: Dissolve 1A (1.0 g, 5.10 mmol) and (1R)-5-chloro-2,3-dihydro-1H-inden-1-amine (0.85 g, 5.10 mmol) in acetonitrile (20 mL). Add triethylamine (1.04 g, 10.20 mmol) and allow to react at room temperature for 16 hours. The mixture was concentrated under reduced pressure, added with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE:EA (v / v) = 10:1) to afford compound 1B (1.0 g, 57% yield).

[0255] LC-MS (ESI): m / z = 328.0 [M+H] + .

[0256] Step 2: 1B (0.2 g, 0.61 mmol), 1C (synthesized according to the method described in patent WO2019147862) (0.16 g, 0.61 mmol), triethylamine (0.12 g, 1.22 mmol), and cesium fluoride (0.09 g, 0.61 mmol) were dissolved in dimethyl sulfoxide (20 mL) and reacted at 100°C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (DCM:MeOH (v / v) = 10:1) to obtain the target compound 1D (0.12 g, 35% yield).

[0257] LC-MS (ESI): m / z = 558.3 ​​[M+H] + .

[0258] Step 3: Dissolve compound 1D (0.12 g, 0.22 mmol) in 4 mL of a 1:1 THF:H₂O (v / v) solution. Add lithium hydroxide (0.026 g, 1.1 mmol) and stir at room temperature for 4 hours. After completion of the reaction, concentrate the mixture under reduced pressure. The residue was purified by HPLC to yield compound 1 (0.07 g, 60% yield).

[0259] Preparation method: (Instrument name: Waters AutoP; Chromatographic column: Sunfire C18 (19×250 mm, 5 μm)) Mobile phase: Phase A: acetonitrile; Phase B: Water (containing 0.1% TFA); Gradient: Phase A content from 10% to 50%, 15 min.

[0260] 1H NMR (400MHz, CD3CN; trifluoroacetic acid salt)δ7.33(s,1H),7.29-7.22(m,2H),6.95-6.93(m,1H),4.25-4.22(m, 2H),4.02-3.99(m,2H),3.58-3.57(m,1H),3.44-3.40(m,1H),3.35-3.33( m,1H),3.13-3.06(m,2H),2.96-2.90(m,3H),2.65-2.54(m,6H),2.42(s,3 H),2.24-2.22(m,2H),2.18-2.06(m,3H),1.87-1.84(m,2H),1.37(s,3H).

[0261] LC-MS (ESI): m / z = 544.2 [M+H] + .

[0262] Example 2:

[0263] Step 1: Dissolve raw material 2A (3 g, 13.27 mmol) in dichloroethane (100 mL), add 2B (2.55 g, 19.91 mmol), and stir until dissolved. Then, add sodium acetate borohydride (5.62 g, 26.54 mmol). Cool the mixture to 0°C, and add acetic acid (0.80 g, 13.27 mmol) dropwise. Allow to warm to room temperature and react overnight. After concentration under reduced pressure, the crude product was purified using a Biotage Isolera One medium-pressure prep system (80 g silica gel column, MeOH:DCM = 0% → 20%) to afford product 2C (3.10 g, 68.92% yield).

[0264] LC-MS (ESI): m / z = 339.2 [M+H] + .

[0265] Step 2: Dissolve compound 2C (1.4 g, 4.14 mmol) in 1,4-dioxane (10 mL) and add 1,4-dioxane hydrochloride solution (4 M, 10 mL) dropwise. Stir at room temperature until the starting material disappears. Concentrate the reaction mixture to obtain compound 2D, which is used directly in the next step without further purification.

[0266] LC-MS (ESI): m / z = 239.1 [M+H] + .

[0267] Step 3: Dissolve compound 2D in methanol (20 mL) and slowly add thionyl chloride (0.92 g, 7.72 mmol) dropwise at room temperature. After the addition is complete, heat the mixture to reflux for 4 hours. Cool the reaction mixture to room temperature and concentrate to obtain 2E (1.21 g, 89.4% yield over two steps).

[0268] LC-MS (ESI): m / z = 253.2 [M+H] + .

[0269] Step 4: Dissolve compound 2E in DMSO (10 mL), add compound 2F (synthesized according to the method described in patent WO2019147862) (1.08 g, 3.07 mmol), and stir. Then, add triethylamine (0.62 g, 6.14 mmol) and cesium fluoride (0.93 g, 6.14 mmol) in that order. Under a nitrogen atmosphere, react at 100°C for 4 h. After the reaction is cooled to room temperature, water (40 mL) is added and extracted with ethyl acetate (30 mL x 3). The combined organic phases are washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, and concentrated. The crude product is purified using a medium-pressure preparation instrument Biotage Isolera One (24 g silica gel column, eluent: 0-30% EA / PE) to obtain product 2G (0.48 g, yield 27.58%).

[0270] LC-MS (ESI): m / z = 568.1 [M+H] + .

[0271] Step 5: Dissolve compound 2G (0.48 g, 0.85 mmol) in tetrahydrofuran (5 mL) and water (5 mL), add lithium hydroxide monohydrate (0.18 g, 4.25 mmol), and stir at room temperature overnight. Adjust the pH to 6-7 with 6N hydrochloric acid dropwise. Concentrate to obtain a crude product, which is then purified by HPLC to afford compound 2, isomer 1 (0.13 g, 19.58% yield) and compound 2, isomer 2 (0.14 g, 21.09% yield).

[0272] HPLC preparative method: Instrument: Waters 2767 preparative liquid chromatography; Column: SunFire@Prep C18 (19 mm × 250 mm). Dissolve the sample in methanol and filter through a 0.22 μm filter to prepare the sample solution. Preparative chromatography conditions: Mobile phase A, B composition: Mobile phase A: acetonitrile; Mobile phase B: water (containing 1% TFA), gradient elution, mobile phase A content from 10% to 55%, flow rate 15 mL / min, elution time 20 min.

[0273] HPLC analysis method: instrument: Shimadzu LC-20AT, column: chromatographic column model: Xtimate C18 4.6*50 mm, 3 μm, mobile phase A is 0.05% TFA solution, mobile phase B is acetonitrile, gradient: A 95-5% B 5-95%, flow rate: 1 mL / min, column temperature: 35°C, wavelength: 210 nm / 254 nm, acquisition time: 10 min.

[0274] Compound 2, isomer 1 (retention time: 3.253 min): LC-MS (ESI): m / z=554.2 [M+H] + .

[0275] 1 H NMR (400 MHz, CD3CN, trifluoroacetate) δ 10.66 (s, 1H), 7.52 (d, 1H), 7.45-7.37 (m, 2H), 7.35-7.34 (m, 1H), 5.64-5.57 (m, 1H), 4.05-3.82 (m, 2H), 3.76-3.40 (m, 4H), 3.35-3.12 (m, 2H), 2.87-2.60 (m, 3H), 2.47 (s, 3H), 2.26-2.11 (m, 5H), 1.61 (d, 3H), 1.42 (d, 3H).

[0276] Compound 2, isomer 2 (retention time: 3.230 min): LC-MS (ESI): m / z=554.2 [M+H] + .

[0277] 1 H NMR (400 MHz, CD3CN, trifluoroacetate) δ 10.60 (s, 1H), 7.52 (s, 1H), 7.45-7.34 (m, 3H), 5.62-5.59 (m, 1H), 4.07-3.63 (m, 5H), 3.59-3.35 (m, 2H), 2.88–2.75 (m, 3H), 2.50-2.34 (m, 4H), 2.26-2.09 (m, 4H), 1.61 (d, 3H), 1.41 (d, 3H).

[0278] Example 3:

[0279] Using compound 3A as starting material, the first, second, third, fourth and fifth steps of Example 2 were followed to obtain compound 3 isomer 1 (0.15 g) and compound 3 isomer 2 (0.13 g).

[0280] HPLC analysis method: Instrument: Shimadzu LC-20AT, Column: Xtimate C18 4.6*50mm, 3μm, Mobile phase A: 0.05% TFA solution, Mobile phase B: acetonitrile, Gradient: A 95-5% B 5-95%, Flow rate: 1 mL / min, Column temperature: 35°C, Wavelength: 210 nm / 254 nm, Acquisition time: 10 min. Compound 3 Isomer 1 (Retention time: 3.416 min): LC-MS (ESI): m / z = 554.2 [M+H] + .

[0281] 1 H NMR(400MHz,CD3CN)7.45(t,1H),7.38-7.37(m,1H),7.28-7.27(m,1H),5.45-5.41(m,1H),3.83-3.44(m,6 H),2.50-2.45(m,2H),2.25(s,3H),2.25-2.17(m,3H),1.70-1.66(m,5H),1.49(d,3H),1.32-1.30(m,4H).

[0282] Compound 3, isomer 2 (retention time: 3.443 min): LC-MS (ESI): m / z=554.2 [M+H] + .

[0283] 1 H NMR(400MHz,CD3CN)7.46(t,1H),7.39(d,1H),7.28-7.27(m,1H),5.48-5.43(m,1H),3.69-3.43(m,4H),2.95-2.87(m,1H) ,2.57-2.52(m,1H),2.45-2.35(m,4H),2.26(s,3H),1.95-1.90(m,2H),1.65-1.60(m,4H),1.51(d,3H),1.37-1.29(m,4H).

[0284] Example 4:

[0285] Step 1: Dissolve 4A (1.0 g, 3.50 mmol), (R)-1-(2,4-dichlorophenyl)ethan-1-amine (0.66 g, 3.50 mmol), and triethylamine (1.5 mL) in methanol (10 mL) and stir overnight at room temperature. Concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 30:1) to obtain the title compound 4B (1.2 g, 77%).

[0286] LCMS m / z=443.9[M+H] + .

[0287] Step 2: Compound 4B (0.87 g, 1.97 mmol), trimethylethynylsilane (0.39 g, 3.94 mmol), bistriphenylphosphine palladium dichloride (69.14 mg, 0.10 mmol), and cuprous iodide (18.76 mg, 0.10 mmol) were added sequentially to triethylamine (8 mL) under a nitrogen atmosphere and stirred at 50°C for 4 h. The reaction mixture was cooled to room temperature, added with water (10 mL), and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (3 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 30:1) to obtain the title compound 4C (310 mg, 38%).

[0288] LCMS m / z=340.1[M-72+H] + .

[0289] Step 3: Compound 4C (0.11 g, 0.27 mmol) and potassium carbonate (37.32 mg, 0.54 mmol) were added to methanol (4 mL) in sequence and stirred at room temperature for 2 h. After the reaction, water (5 mL) was added and the mixture was extracted with ethyl acetate (10 mL × 3). The mixture was washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 9:1) to obtain the title compound 4D (50.0 mg, 54%).

[0290] Step 4: 4D (50.0 mg, 0.15 mmol), 1C (42.0 mg, 0.15 mmol), triethylamine (0.1 mL, 0.75 mmol), and cesium fluoride (4.6 mg, 0.03 mmol) were added to dimethyl sulfoxide (3 mL) in sequence and stirred at 100°C for 2 h. After the reaction was cooled to room temperature, water (10 mL) was added and the mixture was extracted with ethyl acetate (10 mL × 3). The mixture was washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 9:1) to give the title compound 4E (47 mg, 54%).

[0291] Step 5: 4E (20.0 mg, 0.035 mmol) and lithium hydroxide (3.4 mg, 0.14 mmol) were added sequentially to a mixture of methanol (2 mL), tetrahydrofuran (1 mL), and water (1 mL) and stirred at room temperature for 2 h. The crude product was separated and purified by preparative HPLC.

[0292] Separation method: Instrument: Waters 2767 Preparative HPLC; Chromatographic column: SunFire@Prep C18 (19 mm × 250 mm); Samples were filtered through a 0.45 μm filter to prepare a sample solution. Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile; Mobile phase B: Water (containing 0.1% ammonium acetate); b. Gradient elution, mobile phase A content from 10% to 55%; c. Flow rate: 12 mL / min. Retention time: 7.0 min to yield the title compound 4 (12 mg, 62%).

[0293] 1 H NMR(400MHz,DMSO-d6)δ9.86(s,1H),9.52(s,1H),7.57(d,1H),7.46-7.30(m,2 H),5.51(s,1H),4.09(s,3H),3.85(s,3H),3.66-3.65(m,1H),3.34(d,1H),3.19 (s,1H),2.63(d,2H),2.52(s,2H),2.46(s,3H),2.33(s,1H),2.29-2.17(m,2H) ,1.90(d,1H),1.64(s,1H),1.50(d,1H),1.45(d,2H),1.31(s,3H),1.00(s,1H).

[0294] LCMS m / z=556.2[M+H] + .

[0295] Example 5:

[0296] Step 1: Dissolve compound 5A (3.00 g, 12.8 mmol) in methanol (15 mL), add 1-Boc-3-azetidinone 5B (3.29 g, 19.2 mmol) and a few drops of acetic acid. After the addition is complete, stir and react at room temperature for 2 hours. Then, add sodium cyanoborohydride (1.62 g, 25.60 mmol) and continue stirring and reacting for 18 hours. The reaction mixture is poured into water (30 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 20:1-10:1) to obtain the title compound 5C (3.50 g, 70%).

[0297] LC-MS (ESI): m / z = 390.2 [M+H] + .

[0298] Step 2: Dissolve compound 5C (3.50 g, 8.97 mmol) in ethyl acetate (300 mL) and add palladium on carbon (951 mg, 8.97 mmol). Stir at room temperature under a hydrogen atmosphere for 5 h. Filter through celite to remove the palladium on carbon, and concentrate the filtrate to obtain the title compound 5D as a white oil. This product was used directly in the next reaction without further purification.

[0299] LC-MS (ESI): m / z = 256.2 [M+H] + .

[0300] Step 3: Compound 5D was dissolved in methanol (10 mL), and compound 2B (1.21 g, 9.44 mmol) and a few drops of acetic acid were added. After the addition, the reaction was stirred at room temperature for 5 hours. Then, sodium cyanoborohydride (793.8 mg, 12.6 mmol) was added and the reaction was stirred for 1 hour. The reaction mixture was poured into water (30 mL), and the pH was adjusted to 4-5 with aqueous citric acid. The mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1-10:1) to obtain the title compound 5F (924.0 mg, 28% yield over two steps).

[0301] LC-MS (ESI): m / z = 368.3 [M+H] + .

[0302] Step 4: Dissolve compound 5F (924.0 mg, 2.50 mmol) in methanol (8 mL). Add thionyl chloride (2 mL) under ice-cooling. After addition, heat the temperature to 70°C, react for 1 hour, and concentrate to obtain the hydrochloride salt of the title compound 5F. Use directly in the next reaction without further purification.

[0303] LC-MS (ESI): m / z = 282.2 [M+H] + .

[0304] Step 5: Using the hydrochloride of 5F and compound 2F (876 mg, 2.52 mmol) as raw materials, refer to the fourth step of Example 2 to obtain the target compound 5G (449.1 mg, two-step yield 31%).

[0305] LC-MS (ESI): m / z = 595.3 [M+H] + .

[0306] Step 6: Using compound 5G (449.1 mg, 0.76 mmol) as starting material, refer to the fifth step of Example 2 to obtain the title compound 5 (0.265 g, 61%).

[0307] 1 H NMR(400MHz, Methanol-d4)δ7.48-7.46(m,1H),7.41-7.37(m,1H),7.34-7.29(m,1H),5.62-5.50(m,1H),4.34-3.98(m,3H),3.94-3.76(m,2H) ,3.75-3.61(m,1H),3.33-3.04(m,3H),2.94-2.58(m,7H),2.43(s,3H) ,2.36-2.18(m,2H),2.08(s,2H),1.62-1.51(m,3H),1.48-1.34(m,3H).

[0308] LC-MS (ESI): m / z = 581.2 [M+H] + .

[0309] Example 6:

[0310] Using 1A (100 mg, 0.51 mmol) and 6A (103 mg, 0.51 mmol) as starting materials, compound 6 (117 mg) was obtained by following the first, second and third steps of Example 1.

[0311] 1 H NMR (400MHz, CDCl3) δ12.18(s,1H),7.51(d,1H),7.39(d,1H),7.30(d,1H),6.97(s,1H),4.28-4.27(m,4H),3.61-3.38(m,3H),2.72(s,2H ),2.60(s,1H),2.57-2.49(m,2H),2.47(s,2H),2.42(s,3H),1.99(s,2H),1.84(s,1H),1.35-1.34(m,5H),1.26(s,3H),0.93-0.79(m,1H).

[0312] LCMS m / z=578.2[M+H] + .

[0313] Example 7:

[0314] Step 1: 1-(2-bromo-4-chlorophenyl)ethan-1-one (12.0 g, 51.37 mmol), trimethylethynylsilane (7.57 g, 77.05 mmol), bistriphenylphosphine palladium dichloride (3.61 g, 5.14 mmol), and cuprous iodide (0.98 g, 5.14 mmol) were added to triethylamine (120 mL) in sequence. The atmosphere was purged with nitrogen three times and the temperature was raised to 55°C for 1.5 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 100:1 to 20:1) to afford product 7B (11.0 g, 85.38%).

[0315] 1 H NMR (400MHz, DMSO-d6) δ7.75(d,1H),7.62(d,1H),7.58-7.57(m,1H),2.62(s,3H),0.24(s,9H).

[0316] Step 2: Potassium carbonate (1.65 g, 11.95 mmol) and methanol (10 mL) were sequentially added to a solution of 7B (6.0 g, 23.92 mmol) in tetrahydrofuran (60 mL) and stirred at room temperature for 4 hours. After completion of the reaction, water (120 mL) and ethyl acetate (200 mL) were added, and the mixture was extracted. The layers were separated, and the aqueous phase was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 100:1 to 10:1) to obtain product 7C (4.0 g, 93.62%).

[0317] 1 H NMR (400MHz, DMSO-d6) δ7.80(d,1H),7.68(d,1H),7.61-7.60(m,1H),4.58(s,1H),2.61(s,3H).

[0318] Step 3: Dissolve 7C (2 g, 11.20 mmol) in tetrahydrofuran (20 mL), add tetraisopropyl titanate (6.37 g, 22.40 mmol) and (R)-(+)-tert-butylsulfenamide (1.36 g, 11.20 mmol) in sequence, and heat to 60°C for 16 hours. After the reaction is complete, cool to room temperature and add brine (30 mL). The precipitated solid is filtered, and the filter cake is washed with ethyl acetate (100 mL). The filtrate is extracted and the organic phase is dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 20:1 to 5:1) to afford 7D (1.4 g, 44.36%).

[0319] LCMS (ESI): m / z = 282.0 [M+H] + .

[0320] Step 4: 7D (1.40 g, 4.97 mmol) was dissolved in a mixture of tetrahydrofuran and water (v:v = 98:2) (15 mL), cooled to -30°C, and sodium borohydride (0.38 g, 9.94 mmol) was added portionwise. The reaction was allowed to react for 2 hours. After the reaction was complete, water (20 mL) and ethyl acetate (30 mL) were added and extracted. The aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1 to 3:1) to afford 7E (Rf = 0.4 (petroleum ether:ethyl acetate (v / v) = 3:1), 0.7 g, 49.62%) and its isomer 7F (Rf = 0.3 (petroleum ether:ethyl acetate (v / v) = 3:1), 0.7 g, 49.62%).

[0321] Isomer 7E: 1 H NMR (400MHz, DMSO-d6) δ7.56-7.45(m,3H),5.47(d,1H),4.89-4.78(m,1H),4.58(s,1H),1.44(d,3H),1.10(s,9H).

[0322] Isomer 7F: 1 H NMR (400MHz, DMSO-d6) δ7.62-7.57(m,1H),7.53-7.47(m,2H),5.87(d,1H),4.81-4.80(m,1H),4.58(s,1H),1.35(d,3H),1.10(s,9H).

[0323] Step 5: 7E (0.70 g, 2.47 mmol) was added to a 1,4-dioxane hydrochloride solution (4 M, 10 mL), stirred at room temperature for 1 hour, concentrated, and a mixed solvent of petroleum ether and ethyl acetate ((v / v) = 5:1, 10 mL) was added. The mixture was stirred and filtered, and the filter cake was collected to obtain 7G (0.44 g, 75.32%).

[0324] LCMS (ESI): m / z = 180.1 [M+H] + .

[0325] 7H was obtained by using 7F as the starting material according to the above synthesis method.

[0326] Step 6: Using 2,4,5-trichloro-6-methylpyrimidine (0.39 g, 1.95 mmol) and 7G (0.35 g, 1.95 mmol) as raw materials, refer to the operation method of the first step of Example 1 to obtain 7I (0.43 g, 65.34%).

[0327] LCMS (ESI): m / z = 340.0 [M+H] + .

[0328] 7J was obtained by using 7H as the starting material according to the above synthesis method.

[0329] Step 7: Using 1C (0.533 g, 1.76 mmol) and 7I (0.3 g, 0.88 mmol) as starting materials, the product 7K (0.15 g, 29.88%) was obtained by following the procedure of Step 2 of Example 1.

[0330] LCMS (ESI): m / z = 570.4 [M+H] + .

[0331] 7L was obtained by using 7J as the starting material according to the above synthesis method.

[0332] Step 8: Using 7K (150 mg, 0.26 mmol) as starting material, the compound 7 isomer 1 (35 mg, 24.19%) was obtained by referring to the third step of Example 1.

[0333] 1 H NMR(400MHz,DMSO-d6)δ7.48-7.36(m,3H),7.20(d,1H),5.51-5.50(m,1H),4. 55(s,1H),3.84(t,1H),3.78(s,1H),3.59-3.48(m,2H),2.57(m,2H),2.44-2.4 3(m,2H),2.34-2.24(m,1H),2.17(s,3H),1.71-1.53(m,5H),1.44(d,4H),1.39 -1.32(m,1H),1.32-1.28(m,1H),1.27(s,3H),1.24(m,1H),0.82-0.69(m,1H).

[0334] LCMS m / z=556.2[M+H] + .

[0335] Compound 7 isomer 2 was obtained using 7L as raw material according to the above synthesis method.

[0336] 1H NMR(400MHz,DMSO-d6)δ7.53-7.33(m,3H),7.19(d,1H),5.50-5.49(m,1H),4.54(d,1H),3.84-3.83(m,1H),3.76 (s,1H),3.54-3.53(m,2H),2.65(d,2H),2.48-2.24(m,3H),2.17(s,3H),1.97-1.17(m,15H),0.89-0.72(m,1H).

[0337] LCMS m / z=556.4[M+H] + .

[0338] Example 8:

[0339] Step 1: Compound 8A (31 g, 0.32 mol) was dissolved in tetrahydrofuran (1.5 L) at room temperature, and diethyl malonate (51.6 g, 0.32 mol) was added dropwise. After stirring for 5 minutes, a solution of potassium tert-butoxide (39.8 g, 0.35 mol) in tetrahydrofuran (0.5 L) was added dropwise. After completion of the addition, the mixture was allowed to react at room temperature for 1 hour. TLC indicated complete reaction. Dilute hydrochloric acid (2N, 200 mL) was added dropwise to adjust the pH to 3. The mixture was extracted with EA (200 mL x 2). The combined organic phases were washed with saturated sodium bicarbonate (100 mL x 2) and saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 70 g (0.27 mol, 85% yield) of crude compound 8B.

[0340] Step 2: Crude compound 8B (70 g, 0.27 mol), ethylene glycol (50.3 g, 0.81 mol), and p-toluenesulfonic acid (4.7 g, 27 mmol) were dissolved in toluene (700 mL) at room temperature. A water separator and condenser were installed, and the temperature was raised to 120°C for overnight reaction. TLC indicated the reaction was complete. The mixture was cooled to room temperature, concentrated under reduced pressure, diluted with water (200 mL), and extracted with EA (200 mL x 2). The combined organic phases were washed with saturated sodium bicarbonate (100 mL x 2) and saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was then purified by column chromatography (10% EA in PE) to afford compound 8C (53 g, 65% yield).

[0341] Step 3: Under an ice bath, lithium aluminum tetrahydride (8.34 g, 0.22 mol) was added portionwise to diethyl ether (300 mL). A solution of compound 8C (44 g, 0.15 mol) in diethyl ether (300 mL) was then added dropwise. After the addition was complete, the mixture was refluxed for 1 hour. TLC indicated the reaction was complete. The mixture was cooled to room temperature and quenched by the dropwise addition of water (8.4 mL), 15% aqueous NaOH (8.4 mL), and water (25 mL) under an ice bath. The reaction was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (7% MeOH in CH2Cl2) to afford compound 8D (26 g, 0.12 mol).

[0342] Step 4: Compound 8D (10.8 g, 50 mmol) and diisopropylethylamine (16.1 g, 125 mmol) were added to dry acetonitrile (250 mL) at -20°C under a nitrogen atmosphere. Trifluoromethanesulfonic anhydride (29.7 g, 105 mmol) was then slowly added dropwise. After stirring for 1 hour, diisopropylethylamine (16.1 g, 125 mmol) and benzylamine (8.1 g, 75 mmol) were added sequentially. The temperature was then raised to 90°C for 2 hours. TLC indicated the reaction was complete. The mixture was cooled to room temperature, diluted with water (100 mL) and EA (100 mL), and extracted. The organic phase was washed with water (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product which was purified by silica gel column chromatography (5% MeOH in CH2Cl2) to afford compound 8E (10.81 g, 75% yield).

[0343] LC-MS (ESI): m / z = 288.3 [M+H] + .

[0344] Step 5: Compound 8E (3.84 g, 13.4 mmol) was added to tetrahydrofuran (20 mL) at room temperature. The temperature was lowered to 0°C, and a 3 M 1,4-dioxane hydrochloride solution (22.3 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 1 hour. TLC / LCMS indicated completion of the reaction. The mixture was diluted with water (20 mL) and EA (30 mL), extracted, and the resulting aqueous phase adjusted to pH 9 with saturated sodium bicarbonate aqueous solution. The mixture was then extracted with dichloromethane (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product, which was purified by silica gel column chromatography (3% MeOH in CH2Cl2) to afford compound 8F (2.56 g, 79% yield).

[0345] LC-MS (ESI): m / z = 244.2 [M+H] + .

[0346] Step 6: To 1,2-dichloroethane (20 mL) at room temperature were added compound 8F (600 mg, 2.47 mmol), 3-methyl-3-azetidinecarboxylic acid (285 mg, 2.47 mmol), and sodium triacetoxyborohydride (1.05 g, 4.94 mmol) in sequence. The temperature was lowered to 0°C, and acetic acid (149 mg, 2.47 mmol) was added dropwise. The mixture was then allowed to warm to room temperature and allowed to react overnight. TLC / LCMS indicated the reaction was complete. After concentration under reduced pressure, the crude product was purified by silica gel column chromatography (70% MeOH in CH2Cl2) to afford compound 8G (650 mg, 77% yield).

[0347] LC-MS (ESI): m / z = 343.2 [M+H] + .

[0348] Step 7: Compound 8G (620 mg, 1.74 mmol) was added to methanol (50 mL) at room temperature. The temperature was lowered to 0°C, and thionyl chloride (2.07 g, 17.4 mmol) was added dropwise. The mixture was allowed to warm to room temperature for 1 hour. TLC / LCMS indicated the reaction was complete. After concentration under reduced pressure, the hydrochloride salt of compound 8H was obtained, which was used directly in the next step without further purification.

[0349] LC-MS (ESI): m / z = 357.2 [M+H] + .

[0350] Step 8: Compound 8H hydrochloride was added to methanol (10 mL) at room temperature. The atmosphere was replaced with hydrogen three times, then the temperature was raised to 50°C and allowed to react overnight. TLC / LCMS indicated the reaction was complete. The filtrate was filtered and concentrated under reduced pressure to afford the hydrochloride salt of compound 8I, which was used directly in the next reaction without further purification.

[0351] LC-MS (ESI): m / z = 267.3 [M+H] + .

[0352] Step 9: Using the hydrochloride of 8I and compound 2F (537 mg, 1.53 mmol) as raw materials, the operation method of the second step of Example 1 was referred to obtain compound 8J (240 mg, 0.413 mmol, three-step yield 24%).

[0353] LC-MS(ESI):m / z=580.2 / 582.2[M+H] + .

[0354] Step 10: Using compound 8J (240 mg, 0.413 mmol) as starting material, refer to the third step of Example 1 to obtain compound 8 isomer 1 (58.7 mg, 24.2%) and compound 8 isomer 2 (52.3 mg, 21.8%).

[0355] HPLC analysis method: instrument: SHIMADZU LC-30AD sf, column: Chiralcel C2-3 50×4.6 mm ID, 3 μm, mobile phase: A for CO2, B for MeOH+ACN (0.05% DEA), gradient: B 50%, flow rate: 3 mL / min, back pressure: 100 bar, column temperature: 35°C, wavelength: 220 nm.

[0356] Compound 8 Isomer 1 (retention time: 0.901 min): 1 H NMR(400MHz,Chloroform-d)δ7.36(s,1H),7.23(d,1H),7.18(d,1H),5.52(m,1H),5.41-5.43(m,1H),3.85-3.98(m,2H) ,3.63(m,1H),3.23-3.42(m,2H),2.81(m,2H),2.51(m,2H),2.30(s,3H),2.01(m,2H),1.75(m,2H),1.51(m,3H),1.46(m, 3H),1.26(s,3H),1.23(m,2H),0.86(m,1H).

[0357] LC-MS(ESI):m / z=566.4 / 568.4[M+H] + .

[0358] Compound 8 Isomer 2 (retention time: 1.243 min): 1 H NMR(400MHz,Chloroform-d)δ7.34(s,1H),7.23(d,1H),7.18(d,1H),5.51(m,1H),5.41-5.43(m,1H),3.88-3.98(m,2H),3.63(m,1H),3.23-3.42(m, 2H),2.82(m,2H),2.49(m,2H),2.28(s,3H),2.01-2.03(m,2H),1.75(m,2H ),1.52(m,3H),1.46(m,3H),1.25(s,3H),1.21-1.22(m,2H),0.85(m,1H).

[0359] LC-MS(ESI):m / z=566.4 / 568.4[M+H] + .

[0360] Example 9:

[0361] Step 1: Compound 9A (20.0 g, 108.0 mmol) was dissolved in methanol (200 mL). Triethylamine (21.8 g, 218.0 mmol) and nitromethane (26.4 g, 432.0 mmol) were added sequentially. The mixture was stirred at room temperature for 17 hours. The crude product, compound 9B (26.5 g, 107.6 mmol), was concentrated and used directly in the next step without further purification.

[0362] Step 2: Compound 9B (26.5 g, 107.6 mmol) was dissolved in methanol (250 mL) and Pd / C (5.2 g, 10% Pd content) was added. The mixture was reacted under a hydrogen atmosphere for 15 hours. The filtrate was filtered and concentrated to afford crude compound 9C (21.1 g, 90.6%), which was used in the next step without further purification.

[0363] M / Z (ESI): m / z = 217.1 [M+H] + .

[0364] Step 3: Compound 9C (21.1 g, 91.6 mmol) was dissolved in a mixture of tetrahydrofuran (200 mL) and water (100 mL). Sodium bicarbonate (24.6 g, 292.6 mmol) was added. The temperature was cooled to 5°C, and chloroacetyl chloride (22.1 g, 195.1 mmol) was added dropwise. The temperature was maintained at 5-10°C. After the addition was complete, the mixture was warmed to room temperature and allowed to react for 1 hour. After the reaction was complete, water (100 mL) was added and extracted with ethyl acetate (300 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2) to yield the title compound 9D (17.2 g, 60.2%).

[0365] Step 4: Compound 9D (17.2 g, 58.8 mmol) was dissolved in tert-butanol (170 mL). Potassium tert-butoxide (13.2 g, 117.5 mmol) was added portionwise. The temperature was raised to 50°C and the reaction was allowed to react for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride (200 mL). The mixture was extracted with ethyl acetate (150 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2) to obtain the title compound 9E (13.5 g, 89.6%).

[0366] M / Z(ESI): m / z=201.1[M+H-tBu] + .

[0367] Step 5: Under a nitrogen atmosphere, compound 9E (13.5 g, 52.7 mmol) was dissolved in tetrahydrofuran (150 mL), cooled to 0°C, and sodium 2-hydrogen bis(dimethoxyethoxy)aluminate (45.1 mL, 3.5 mol / L toluene solution) was slowly added dropwise. After the addition was complete, the reaction was continued at 0-5°C for 3 hours. After the reaction was complete, 10% aqueous sodium hydroxide solution (45 mL) was slowly added dropwise to quench the reaction. After quenching, anhydrous magnesium sulfate was added, and the mixture was filtered through celite. The filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:3) to obtain the title compound 9F (7.6 g, 59.5%).

[0368] M / Z(ESI): m / z=187.1[M+H-tBu] + .

[0369] Step 6: Compound 9F (7.6 g, 31.4 mmol) was dissolved in a mixture of tetrahydrofuran (50 mL) and water (50 mL), and sodium bicarbonate (7.9 g, 94.1 mmol) was added. The temperature was lowered to 0-5°C, and benzyl chloroformate (6.4 g, 37.6 mmol) was slowly added dropwise. After the addition was complete, the mixture was allowed to react at 0-5°C for 1 hour. After the reaction was complete, water (100 mL) was added and extracted with ethyl acetate (150 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) to obtain 9.2 g of the racemate. The racemate was separated by chiral preparative HPLC to obtain two isomers, compound 9G-1 (3.8 g, 32.2%) and compound 9G-2 (3.4 g, 28.8%).

[0370] Chiral HPLC analysis method: 1. Instrument: SHIMADZU LC-30AD sf; 2. Column: Chiralpak IC-3 50×4.6 mm ID, 3 μm; 3. Mobile phases: A for CO2 and B for MeOH (0.05% DEA); 4. Gradient: B 5-40%; 5. Flow rate: 3 mL / min. Compound 9G-1 (retention time 1.59 min) and compound 9G-2 (retention time 2.02 min) were detected.

[0371] Preparative chromatography conditions: 1. Instrument: Waters 150 SFC; 2. Column: Chiralpak IC-Column (250×30 mm, ID 30 mm, 10 μm particle size); 3. Mobile phase system: A for CO2 and B for MeOH (0.1% NH3·H2O); 4. Gradient: B 45%; 5. Flow rate: 180 mL / min.

[0372] Analytical Methods: 1. Instrument: SHIMADZU LC-30AD sf; 2. Column: Chiralpak IC-3 50×4.6mm ID, 3μm; 3. Mobile Phase: A for CO2 and B for MeOH (0.05% DEA); 4. Gradient: B 5-40%; 5. Flow Rate: 3mL / min. Step 7: Compound 9G-1 (3.8g, 10.1mmol) was dissolved in methanol (40mL), and Pd / C (0.8g, 10% Pd content) was added. The reaction was allowed to proceed under a hydrogen atmosphere for 3 hours. Filter and concentrate the filtrate to obtain the title compound 9H-1 (2.3g, 94.1%).

[0373] Referring to the above operation, compound 9G-2 (3.4 g, 9.0 mmol) was used as the starting material to obtain the title compound 9H-2 (2.1 g, 96.0%).

[0374] Step 8: Compound 9H-1 (1.1 g, 4.5 mmol) and 3-carbonyl-1-methyl-cyclobutanecarboxylic acid (0.64 g, 5.0 mmol) were sequentially dissolved in 1,2-dichloroethane (15 mL). Glacial acetic acid (0.27 g, 4.5 mmol) was added. Sodium triacetoxyborohydride (1.4 g, 6.8 mmol) was added portionwise and allowed to react for 15 hours. After completion of the reaction, the reaction was quenched with water (30 mL) and extracted with dichloromethane (50 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to yield the title compound 9I-1 (1.0 g, 62.1%).

[0375] Referring to the above operation, compound 9H-2 (1.0 g, 4.1 mmol) was used as the starting material to obtain the title compound 9I-2 (0.86 g, 58.7%).

[0376] M / Z(ESI): m / z=299.2[M+H-tBu] + .

[0377] Step 9: Dissolve compound 9I-1 (1.0 g, 2.8 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (3 mL), and react at room temperature for 30 min. After the reaction is complete, concentrate to obtain the trifluoroacetic acid salt of compound 9J-1 (1.3 g, 95.6%).

[0378] Referring to the above operation, compound 9I-2 (0.86 g, 2.4 mmol) was used as the starting material to obtain the trifluoroacetic acid salt of the title compound 9J-2 (1.1 g, 93.8%).

[0379] Step 10: Compound 2F (0.5 g, 1.4 mmol) and compound 9J-1 (1.3 g, 2.7 mmol) were dissolved in dimethyl sulfoxide (5 mL) in sequence, N,N-diisopropylethylamine (0.55 g, 4.3 mmol) and cesium fluoride (0.43 g, 2.8 mmol) were added, and the temperature was raised to 100°C for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 10:1) to give the title compound 9 isomer 1 (Rf = 0.6 (dichloromethane: methanol = 10:1), 160.0 mg, 19.8%) and the title compound 9 isomer 2 (Rf = 0.4 (dichloromethane: methanol = 10:1), 80.0 mg, 9.9%).

[0380] Compound 9 Isomer 1: 1 H NMR(400MHz, CDCl3)δ7.34(d,1H),7.21(d,1H),7.17-7.15(m,1H),5.55(d,1H),5.46-5.40(m,1H),3.99-3.95(m,1H) ,3.90-3.66(m,6H),2.88-2.55(m,6H),2.31(s,3H),2.01-1.93(m,3H),1.58-1.56(m,1H),1.51(d,3H),1.42(s,3H).

[0381] M / Z (ESI): m / z = 568.2 [M+H] + .

[0382] Compound 9 Isomer 2: 1H NMR (400MHz, CDCl3) δ7.35(d,1H),7.22(d,1H),7.19-7.16(m,1H),5.55(d,1H),5.47-5.41(m,1H),4.02-3.75(m,7H),3.03-2. 96(m,2H),2.88-2.85(m,1H),2.62-2.56(m,3H),2.32(s,3H),2.16-2.06(m,3H),1.76-1.70(m,1H),1.51(d,3H),1.42(s,3H).

[0383] M / Z (ESI): m / z = 568.2 [M+H] + .

[0384] Referring to the above operation, compound 9J-2 (1.1 g, 2.4 mmol) was used as the starting material to obtain the title compound 9 isomer 3 (Rf = 0.6 (dichloromethane: methanol = 10:1), 110.0 mg, 13.6%) and the title compound 9 isomer 4 (Rf = 0.4 (dichloromethane: methanol = 10:1), 70.0 mg, 8.7%).

[0385] Compound 9 Isomer 3: 1 H NMR(400MHz, CDCl3)δ7.34(d,1H),7.22(d,1H),7.18-7.16(m,1H),5.54(d,1H),5.46-5.40(m,1H),4.00-3.96(m,1H) ,3.90-3.60(m,6H),2.83-2.55(m,6H),2.30(s,3H),1.95-1.91(m,3H),1.58-1.56(m,1H),1.51(d,3H),1.40(s,3H).

[0386] M / Z (ESI): m / z = 568.2 [M+H] + .

[0387] Compound 9 Isomer 4: 1 H NMR (400MHz, CDCl3) δ7.35(d,1H),7.23(d,1H),7.18-7.16(m,1H),5.52(d,1H),5.46-5.40(m,1H),3.96-3.75(m,7H),3.00-2. 96(m,2H),2.88-2.85(m,1H),2.62-2.53(m,3H),2.31(s,3H),2.17-2.05(m,3H),1.73-1.68(m,1H),1.51(d,3H),1.41(s,3H).

[0388] M / Z (ESI): m / z = 568.2 [M+H] + .

[0389] Embodiment 10:

[0390] Using 2,5-dichloro-3-acetylthiophene (2 g, 10.26 mmol) as starting material, compound 10 isomer 1 (70 mg) and compound 10 isomer 2 (67 mg) were obtained by referring to the third and fourth steps of Example 7 (compound 10C (Rf = 0.6 (petroleum ether:ethyl acetate = 5:1)) and compound 10D Rf = 0.4 (petroleum ether:ethyl acetate = 5:1)), the fifth, sixth, seventh, and eighth steps.

[0391] Compound 10 Isomer 1: 1 H NMR(400MHz, CDCl3)δ6.69(s,1H),5.36(d,1H),5.20-5.19(m,1H),4.04- 4.03(m,1H),3.98-3.97(m,1H),3.80-3.79(m,1H),3.65(s,1H),3.11(s,2 H),3.02(d,1H),2.60-2.59(m,2H),2.30(s,3H),2.21(d,2H),1.94(s,2H ),1.86-1.70(m,3H),1.62(s,1H),1.49(d,3H),1.38(s,3H),0.87(d,1H).

[0392] LCMS m / z=572.1[M+H] + .

[0393] Compound 10 Isomer 2: 1 H NMR (400MHz, CDCl3) δ6.68(s,1H),5.35(d,1H),5.18-5.17(m,1H),4.03-4.02(m,1H),3.96-3.95(m,1H),3.75-3.74(m,2H),3.01( d,3H),2.59(d,2H),2.30(s,4H),2.11(s,2H),1.88(s,2H),1.82-1.66(m,3H),1.55(s,1H),1.49(d,3H),1.39(s,3H),0.88(s,1H).

[0394] LCMS m / z=572.1[M+H] + .

[0395] Compound 11:

[0396] Using 11A (15.0 g, 64.21 mmol) as the starting material, the first to eighth steps of Example 7 were used to obtain compound 11 isomer 1 (47 mg) and compound 11 isomer 2 (45 mg), wherein isomers 11F (retention time 1.01 min) and 11G (retention time 1.12 min) were obtained (chiral HPLC analysis method: 1. Instrument: SHIMADZU LC-30AD sf; 2. Chromatographic column: Chiralpak IC-3 50×4.6 mm ID, 3 μm; 3. Mobile phase system: A for CO2 and B for MeOH (0.05% DEA); 4. Gradient: B 5-40%; 5. Flow rate: 3 mL / min.).

[0397] Compound 11 Isomer 1: 1 H NMR (400MHz, DMSO-d6) δ7.48-7.44(m,2H),7.38-7.37(m,1H),7.28(d,1H),5.48-5. 36(m,1H),4.18(s,1H),3.84-3.83(m,1H),3.73(s,1H),3.55(s,2H),3.38(s,3H),2 .67-2.66(m,1H),2.59(s,1H),2.33(s,1H),2.17(s,3H),2.15-2.07(m,2H),1.89-1 .88(m,2H),1.70-1.69(m,1H),1.57(s,2H),1.44(d,3H),1.38(d,2H),1.30(s,3H).

[0398] LCMS m / z=556.2[M+H] + .

[0399] Compound 11 Isomer 2: 1 H NMR (400MHz, DMSO-d6) δ7.49-7.42(m,1H),7.38(d,1H),7.27(d,1H),5.48-5. 36(m,1H),4.22(s,1H),3.82-3.81(m,1H),3.74(s,1H),3.53(s,2H),3.38(s, 3H),2.65(d,1H),2.55(d,1H),2.31(d,1H),2.18(s,3H),2.15-2.07(m,2H),1 .87(d,2H),1.68(s,1H),1.57(s,1H),1.44(d,3H),1.36(d,2H),1.29(s,3H).

[0400] LCMS m / z=556.2[M+H] + .

[0401] Example 12:

[0402] Step 1: To acetonitrile (10 mL) at room temperature were added compound 1C (636 mg, 1.87 mmol) and 2,4-dichloro-6-methylpyrimidine (457 mg, 2.81 mmol) in sequence. After mixing, triethylamine (760 mg, 7.52 mmol) was added dropwise and stirred at room temperature overnight. TLC / LCMS indicated the reaction was complete. The mixture was diluted with EA (50 mL). The organic phase was washed with water (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (5% MeOH in CH2Cl2) to afford compound 12B (225 mg, 31% yield).

[0403] LC-MS (ESI): m / z = 393.2 [M+H] + .

[0404] Step 2: Compound 12B (205 mg, 0.52 mmol) was dissolved in ethylene glycol dimethyl ether (5 mL) and tert-butanol (5 mL) at room temperature. (R)-1-(2,4-dichlorophenyl)ethanamine (119 mg, 0.62 mmol), potassium tert-butoxide (88 mg, 0.78 mmol), BINAP (130 mg, 0.21 mmol), and Pd2(dba)3 (95 mg, 0.1 mmol) were added sequentially. The mixture was stirred uniformly, purged with nitrogen, and sealed in a tube at 100°C for 1 hour. The mixture was cooled to room temperature, and dilute hydrochloric acid was added dropwise to adjust the pH to 5. The mixture was concentrated under reduced pressure to obtain crude product 12C, which was used directly in the next step without further purification.

[0405] Step 3: Methanol (5 mL), water (5 mL), and lithium hydroxide (35 mg, 1.47 mmol) were added sequentially to compound 12C at room temperature and stirred at room temperature for 1 hour. TLC / LCMS indicated the reaction was complete. The pH was adjusted to 5 with dilute hydrochloric acid, and the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC to yield compound 12 (22 mg, 0.041 mmol).

[0406] Preparative HPLC separation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: XSelect@Prep C18 (19 mm × 250 mm). Preparative chromatography conditions: The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 0.05% ammonia water); b. Gradient elution, mobile phase A content from 5% to 40%, flow rate 15 mL / min, d. Elution time 18 min.

[0407] 1 H NMR(400MHz,DMSO-d6)δ7.49(m,2H),7.36(m,2H),5.43(m,1H),5.29(m,1H),3.85(m,2H),3.54(m,3H),2.58-2.60(m,4H),2.43(m,2H),2 .02(s,3H),1.61-1.69(m,5H),1.33(m,2H),1.26(m,3H),1.24(s,3H),1.51(d,3H),1.46(m,3H),1.26(s,3H),1.23(m,2H),0.84(m,1H).

[0408] LC-MS (ESI): m / z = 532.2 [M+H] + .

[0409] Example 13:

[0410] Step 1: To a solution of copper chloride (2.51 g, 18.68 mmol) in MeCN (40 mL) was added tert-butyl nitrite (2.31 g, 22.42 mmol) dropwise. After stirring for ten minutes, 4-bromobicyclo[4.2.0]octa-1,3,5-triene-3-amine 13A (3.7 g, 18.68 mmol) (prepared according to WO2019183145A1) was added portionwise. Stirring was continued for one hour. The reaction was quenched by the dropwise addition of 1N HCl solution (20 mL). After stirring for ten minutes, the mixture was extracted with ethyl acetate (40 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was separated by silica gel column chromatography (PE) to afford the target compound 13B (2.5 g, 61.54% yield).

[0411] 1 H NMR (400MHz, CDCl3) δ7.29(s,1H),7.15(s,1H),3.18-3.10(m,4H).

[0412] Step 2: Compound 13B (2.5 g, 11.49 mmol), tributyl(1-ethoxyethylene)tin (4.98 g, 13.79 mmol), Pd(PPh3)2Cl2 (0.81 g, 1.15 mmol), and potassium carbonate (2.38 g, 17.23 mmol) were added to anhydrous 1,4-dioxane (40 mL) in this order. The mixture was reacted at 85°C under nitrogen for 3 hours. After cooling to room temperature, potassium fluoride aqueous solution (10% wt, 30 mL) was added and stirring continued for 30 minutes. The mixture was filtered, and the filter cake was washed twice with ethyl acetate. The filtrate was concentrated under reduced pressure, and hydrochloric acid (2N, 20 mL) and tetrahydrofuran (20 mL) were added, followed by stirring for about 20 minutes. The mixture was extracted with dichloromethane (30 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 15:1) to obtain the target compound 13C (0.82 g, yield 39%).

[0413] 1 H NMR (400MHz, CDCl3) δ7.16(s,1H),7.09(s,1H),3.22-3.15(m,4H),2.61(s,3H).

[0414] Step 3: Compound 13C (0.82 g, 4.54 mmol), ammonium acetate (4.20 g, 54.5 mmol), and sodium cyanoborohydride (1.71 g, 27.2 mmol) were added sequentially to methanol (30 mL) and heated to 60°C for 16 hours. TLC confirmed the reaction was complete. The mixture was cooled to room temperature, concentrated under reduced pressure, and water (30 mL) was added. Extraction was performed with dichloromethane (30 mL x 5). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. Separation by silica gel column chromatography (DCM:MeOH (v / v) = 10:1) afforded the target compound 13D (0.62 g, 75% yield).

[0415] LC-MS (ESI): m / z = 182.1 [M+H] + .

[0416] Step 4: Using 2,4,5-trichloro-6-methylpyrimidine (0.62 g, 3.12 mmol) and compound 13D (0.57 g, 3.12 mmol) as raw materials, refer to the operation method of the first step of Example 1 to obtain compound 13E (0.68 g, yield 63.23%)

[0417] LC-MS (ESI): m / z = 342.0 [M+H] + .

[0418] Step 5: Using 1C (0.68 g, 2.55 mmol) and compound 13E (0.88 g, 2.55 mmol) as starting materials, the target compound 13F (0.57 g, yield 50%) was obtained by referring to the second step of Example 1.

[0419] LC-MS (ESI): m / z = 572.2 [M+H] + .

[0420] Step 6: Using compound 13F (0.57 g, 1 mmol) as starting material, the target compound 13 (0.49 g, yield 86%) was obtained by referring to the operation method of step 3 of Example 1.

[0421] 1 H NMR(400MHz,CD3OD)δ7.07(d,1H),7.01(s,1H),5.61-5.51(m,1H),4.04-3.97(m,1H),3.94-3 .88(m,1H),3.74-3.66(m,1H),3.61-3.50(m,1H),3.46-3.33(m,1H),3.15-3.07(m,4H),2.78 -2.66(m,2H),2.52-2.40(m,1H),2.40-2.30(m,1H),2.26(s,3H),2.23-2.12(m,1H),2.02-1. 87(m,5H),1.86-1.75(m,2H),1.74-1.59(m,1H),1.46(d,3H),1.37(d,3H),1.12-0.98(m,1H).

[0422] LC-MS (ESI): m / z = 558.2 [M+H] + .

[0423] Example 14:

[0424] Step 1: 5,7-Dichloropyrazolo[1,5-A]pyrimidine 14A (0.72 g, 3.83 mmol) and compound (R)-2,4-dichloro-ALPHA-methyl-benzylamine (0.73 g, 3.83 mmol) were dissolved in isopropanol (20 mL), and triethylamine (0.77 g, 7.66 mmol) was added dropwise. The mixture was reacted at room temperature overnight and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA (v / v) = 4:1) to give compound 14B (1.12 g, yield 86%).

[0425] LC-MS (ESI): m / z = 341.0 [M+H] + .

[0426] Step 2: Compound 14B (0.34 g, 1.00 mmol) and compound 1C (0.27 g, 1.01 mmol) were dissolved in DMF (20 mL), and then DIPEA (0.26 g, 2.00 mmol) was added dropwise. The mixture was reacted at 90°C for 40 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 12:1) to obtain compound 14C (32 mg, yield 5.6%).

[0427] LC-MS (ESI): m / z = 571.2 [M+H] + .

[0428] Step 3: Compound 14C (32 mg, 0.056 mmol) was dissolved in tetrahydrofuran (5 mL), and methanol (2 mL) and water (2 mL) were added. After stirring, lithium hydroxide monohydrate (42 mg, 1 mmol) was added and the mixture was reacted at room temperature for 3 hours. The pH was adjusted to 5 with hydrochloric acid (1N aqueous solution). The system was concentrated under reduced pressure and directly separated by silica gel column chromatography (DCM:MeOH (v / v) = 10:1) to obtain a crude product of the target compound 14. The product was further prepared by high performance liquid chromatography (HPLC) (preparative conditions: 1. Instrument: Waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm × 250 mm); 2. The sample was dissolved in DMF and filtered with a 0.45 μm filter to prepare a sample solution; 3. Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile Mobile phase B: water (containing 1% TFA); b. Gradient elution, mobile phase A content from 10% to 80%; c. Flow rate 15 ml / min; d. Elution time 18 min) to obtain the trifluoroacetate salt of compound 14 (19 mg, yield 43%).

[0429] 1H NMR(400MHz,Methanol-d4)δ7.96(d,1H),7.55(d,1H),7.53(d,1H),7.37(dd,1H),6.17(d,1H),5.2 5(q,1H),4.77(s,1H),4.31(t,1H),4.25-4.13(m,1H),4.10-4.03(m,1H),4.02-3.93(m,1H),3.80-3 .68(m,1H),3.54-3.45(m,1H),3.42-3.33(m,2H),2.88-2.78(m,2H),2.75-2.63(m,2H),2.48(t,1H ),2.30-2.18(m,2H),2.16-1.99(m,1H),1.98-1.88(m,1H),1.85-1.73(m,1H),1.70(d,3H),1.42(s, 3H),1.17(q,1H).

[0430] LC-MS (ESI): m / z = 557.60 [M+H] + .

[0431] Example 15:

[0432] Compound 15 (15 mg) was obtained by using compound 15A (1.5 g, 10.13 mmol) and (R)-1-(2,4-dichlorophenyl)ethanamine (1.91 g, 10.13 mmol) as starting materials and following the first to third steps of Example 14.

[0433] 1 H NMR (400MHz, CD3CN; trifluoroacetic acid salt)δ8.06(s,1H),7.54-7.53(m,1H),7.47-7.45(m,1H),7.39-7.37(m,1H), 5.03-5.00(m,1H),4.89(s,1H),4.21-4.14(m,1H),3.90-3.87(m,1H),3.61-3. 57(m,1H),3.43-3.32(m,3H),2.74-2.69(m,4H),2.52-2.46(m,4H),2.21-2.15 (m,3H),1.85-1.79(m,3H),1.56-1.54(d,3H),1.37(s,3H),1.11-1.05(m,1H).

[0434] LC-MS (ESI): m / z = 518.2 [M+H] + .

[0435] Example 16:

[0436] Step 1: Dissolve 3-methylazetidine-3-carboxylic acid (2.00 g, 17.4 mmol) in dry 1,2-dichloroethane (50 mL). Add N-tert-butyloxycarbonyl-3-piperidone (4.15 g, 20.8 mmol) and acetic acid (1.04 g, 17.4 mmol) sequentially. Stir at room temperature for 5 hours, then add sodium triacetoxyborohydride (7.37 g, 34.7 mmol). Continue stirring at room temperature overnight. After completion of the reaction, monitor the reaction by TLC. Quench the reaction with water (2 mL). Concentrate the resulting crude product and purify it by silica gel column chromatography (dichloromethane:methanol (v / v) = 4:1) to afford 16C (4.51 g, 86.7%).

[0437] LC-MS (ESI): m / z = 299.2 [M+H] + .

[0438] Step 2: Compound 16C (4.51 g, 15.1 mmol) was dissolved in dichloromethane (90 mL). Trifluoroacetic acid (30 mL) was added at room temperature and the reaction was continued for 1 hour. After completion of the reaction, the mixture was concentrated to afford the trifluoroacetate salt of 16D, which was used directly in the next reaction without further purification.

[0439] LC-MS (ESI): m / z = 199.3 [M+H] + ;

[0440] Step 3: Methanol (70 mL) was added to the crude trifluoroacetate salt of compound 16D obtained in the previous step, and the mixture was stirred to dissolve. N-tert-Butyloxycarbonyl-3-azetidinone (8.29 g, 48.4 mmol) and acetic acid (1.45 g, 24.2 mmol) were then added sequentially. After stirring at room temperature for 10 hours, sodium cyanoborohydride (2.95 g, 46.9 mmol) was added and stirring continued at room temperature for 6 hours. After completion of the reaction, the mixture was quenched by TLC, and water (2 mL) was added. The reaction was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 4:1) to afford 16E (3.69 g, 69.1% yield over two steps).

[0441] LC-MS (ESI): m / z = 354.2 [M+H] + ;

[0442] Step 4: Compound 16E (1.50 g, 4.25 mmol) was dissolved in methanol (40 mL), and thionyl chloride (2.53 g, 21.25 mmol) was added dropwise at room temperature. The reaction was continued for 3 hours. After completion of the reaction, water (1 mL) was added to quench the reaction. The crude product was concentrated and redissolved in methanol (10 mL). Ethyl acetate (50 mL) was added to precipitate a solid, which was filtered and washed with ethyl acetate. The filter cake was dried to afford the hydrochloride salt of compound 16F (1.28 g, 80.1%).

[0443] LC-MS (ESI): m / z = 268.2 [M+H] + ;

[0444] Step 5: 2F (500 mg, 1.43 mmol), compound 16F hydrochloride (697 mg, 1.85 mmol), triethylamine (872 mg, 8.55 mmol) and cesium fluoride (433 mg, 2.85 mmol) were added to dimethyl sulfoxide (20 mL) in sequence, stirred and heated to 100°C for about 4 hours. After the reaction was complete, the mixture was cooled to room temperature, and water (50 mL) and saturated aqueous sodium chloride solution (10 mL) were added. The mixture was extracted with ethyl acetate (30 mL × 8). The combined organic phases were washed sequentially with saturated aqueous sodium chloride solution (50 mL) and water (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 9:1 to 5:1), and further separated and purified by chiral HPLC to give two isomers 16G (159 mg, 19.2%) and 16H (150 mg, 18.1%).

[0445] HPLC analysis method: 1. Instrument: SHIMADZU LC-30AD SFC; 2. Column: Chiralcel OX-3 50×4.6 mm ID, 3 μm; 3. Mobile phase: A for CO2, B for 0.05% DEA in MeOH; 4. Gradient: B 5-40%; 5. Flow rate: 3 mL / min. Isomer 16G, retention time 1.16 min; 16H, retention time 1.76 min.

[0446] Chiral HPLC preparative separation and purification method: Instrument: Waters 150 MGM; Column: Chiralcel OJ Column (250×30 mm, ID 30 mm, 10 μm particle size); Mobile phases: A: carbon dioxide and B: methanol (0.1% ammonia in water); Isocratic elution: 35% mobile phase B; Flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: 25°C; Wavelength: 220 nm; Elution time: 2.9 min.

[0447] LC-MS (ESI): m / z = 581.2 [M+H] + ;

[0448] Step 6: Dissolve compound 16G (150 mg, 0.258 mmol) in a mixture of tetrahydrofuran (4 mL), methanol (2 mL), and water (2 mL). Add lithium hydroxide monohydrate (54.1 mg, 1.29 mmol) at room temperature and continue stirring overnight. After the disappearance of the starting material as monitored by TLC, concentrate the product. The residue is then purified by preparative HPLC to afford compound 16 isomer 1 (112 mg, 76.5%).

[0449] Preparative HPLC separation and purification method: 1. Apparatus: Waters 2767 preparative liquid chromatography; Column: SunFire@Prep C18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A and B composition: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.5% ammonium acetate); b. Gradient elution, mobile phase A content from 5% to 50%; c. Flow rate: 12 mL / min; d. Elution time: 10 min.

[0450] 1 H NMR (400MHz, CD3OD): δ7.43(d,1H),7.37(d,1H),7.25-7.24(m,1H),5.49-5.48(m, 1H),4.32-4.31(m,2H),4.04-3.97(m,1H),3.87-3.86(m,3H),3.79-3.78(m,1H),3 .50(s,1H),3.37-3.29(m,1H),3.26-3.16(m,1H),2.56(d,1H),2.42-2.25(m,3H), 2.27(s,3H),1.91-1.81(m,1H),1.74(d,1H),1.68-1.55(m,2H),1.55-1.46(m,6H).

[0451] LC-MS (ESI): m / z = 567.2 [M+H] + ;

[0452] Using 16H as the starting material, compound 16 isomer 2 was obtained by referring to the above synthesis method.

[0453] 1 H NMR (400MHz, CD3OD): δ7.42(d,1H),7.37(d,1H),7.25-7.24(m,1H),5.48-5.4 7(m,1H),4.31-4.30(m,2H),3.98-3.97(m,1H),3.94-3.81(m,3H),3.69-3.68 (m,1H),3.61-3.52(m,1H),3.39-3.32(m,1H),3.24-3.13(m,1H),2.52-2.38( m,3H),2.27(s,4H),1.86-1.74(m,1H),1.73-1.56(m,3H),1.56-1.46(m,6H).

[0454] LC-MS (ESI): m / z = 567.2 [M+H] + .

[0455] Example 17:

[0456] Step 1: Dissolve 17A (3.7 g, 19.99 mmol) in DCM (20 mL). Add 1 M methylmagnesium bromide (8.3 g, 69.10 mmol) dropwise at -20°C. After complete addition, warm the mixture to room temperature and stir for 3 h. After completion, quench the reaction with saturated ammonium chloride solution (20 mL). Extract the mixture with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 50:1) to afford 17B (2.7 g, 82%).

[0457] Step 2 to Step 4: Using 17B (2.0 g, 12.18 mmol) as starting material, follow the procedures of Steps 1 to 3 of Example 14 to obtain the title compound 17 (67.0 mg).

[0458] 1H NMR (400MHz, CDCl3) δ7.34(d,1H),7.31(d,1H),7.18(d,1H),5.40(s,1H),4.67(s,2H),4.06(s,2H),3.81(s,2H),3.46(s,1H),2. 88(s,2H),2.64(s,2H),2.38(s,1H),2.22(s,3H),2.08(s,1H),1.92(s,2H),1.70(s,4H),1.46(d,3H),1.41(s,3H),0.86(s,1H).

[0459] LCMS m / z=533.2[M+H] + .

[0460] Example 18:

[0461] Step 1: Under nitrogen, compound 2F (1.70 g, 4.84 mmol), compound 18A (3.02 g, 14.5 mmol), bistriphenylphosphine palladium dichloride (340 mg, 0.484 mmol), cuprous iodide (462 mg, 2.42 mmol), and triphenylphosphine (254 mg, 0.969 mmol) were added to a round-bottom flask. Dry N,N-dimethylformamide (25 mL) and triethylamine (10 mL) were added, and the mixture was heated to 100°C and reacted overnight. TLC confirmed the reaction was complete. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 4:1) to afford a mixture of compounds 18B and 18C (2.36 g, 92.9%).

[0462] LC-MS (ESI): m / z = 523.2 [M+H] + .

[0463] The above mixture was separated by chiral HPLC to produce compound 18B (1.01 g, 39.8%) and compound 18C (551 mg, 21.7%). Chiral preparation method: Instrument: Waters 150 MGM; Column: Chiralpak Column; Mobile phases: A: carbon dioxide and B: methanol (0.1% ammonia); Isocratic elution: 35% mobile phase B; Flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: 25°C; Wavelength: 220 nm.

[0464] HPLC analysis method: 1. Instrument: SHIMADZU LC-30AD SFC; 2. Column: Chiralcel OX-3 50×4.6 mm ID, 3 μm; 3. Mobile phase: A for CO2, B for 0.05% DEA in MeOH; 4. Gradient: B 5-40%; 5. Flow rate: 3 mL / min. Compound 18B, retention time 1.09 min; Compound 18C, retention time 1.18 min.

[0465] Step 2: Compound 18B (300 mg, 0.573 mmol) was dissolved in dichloromethane (9 mL). Trifluoroacetic acid (3 mL) was added at room temperature and the reaction was continued for 1 hour. After completion of the reaction, the mixture was concentrated to afford the trifluoroacetic acid salt of 18D, which was used directly in the next reaction without further purification.

[0466] LC-MS (ESI): m / z = 423.1 [M+H] + ;

[0467] Compound 18E was obtained using compound 18C as the starting material and referring to the above synthesis method.

[0468] Step 3: The crude trifluoroacetate salt of compound 18D obtained in the previous step was dissolved in 1,2-dichloroethane (30 mL). Compound 2B (157 mg, 1.23 mmol) and acetic acid (36.8 mg, 0.613 mmol) were added sequentially. After stirring at 60°C for 1 hour, sodium triacetoxyborohydride (390 mg, 1.84 mmol) was added and stirring was continued at 60°C for 5 hours. After completion of the reaction, monitored by TLC, water (1 mL) was added to quench the reaction and the mixture was directly concentrated under reduced pressure. The residue was separated and purified by preparative HPLC and the pH was adjusted to 7-8 with aqueous sodium bicarbonate to obtain compound 18 isomer 1 (64 mg, two-step yield 20.9%) and compound 18 isomer 2 (78 mg, two-step yield 25.4%).

[0469] HPLC analysis conditions: 1. Instrument: Shimadzu LC-20AT; 2. Column: Xtimate C18 4.6*50 mm, 3 μm; 3. Mobile phase: A for 0.05% TFA in H2O; B for ACN; 4. Gradient: B 5-95%; 5. Flow rate: 1.0 mL / min, Run time: 10 min. Retention time: Compound 18 Isomer 1: tR = retention time: 4.114 min; Compound 18 Isomer 2: tR retention time: = 4.162 min.

[0470] Preparative HPLC separation and purification method: 1. Apparatus: Waters 2767 preparative liquid phase; Column: SunFire@Prep C18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A and B composition: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% trifluoroacetic acid); b. Gradient elution, mobile phase A content from 5% to 50%; c. Flow rate: 12 mL / min; d. Elution time: 30 min.

[0471] Compound 18 Isomer 1: 1 H NMR(400MHz, Methanol-d4)δ7.46–7.38(m,2H),7.27(dd,1H),5.60(q,1H),3.50–3.42(m,1H),3.38(q,1H),3.27(d,1H),3.19–3 .07(m,1H),2.71–2.48(m,4H),2.38(s,3H),2.23–2.09(m,3H),1.98–1.82(m,2H),1.70–1.58(m,1H),1.55(d,3H),1.38(s,3H).

[0472] LC-MS (ESI): m / z = 535.2 [M+H] + ;

[0473] Compound 18 Isomer 2: 1 H NMR(400MHz, Methanol-d4)δ7.45–7.38(m,2H),7.27(dd,1H),5.60(q,1H),3.27–3.11(m,2H),3.02–2.85(m ,2H),2.73–2.62(m,2H),2.52–2.32(m,5H),2.08–1.83(m,4H),1.77–1.58(m,2H),1.55(d,3H),1.38(s,3H).

[0474] LC-MS (ESI): m / z = 535.2 [M+H] + ;

[0475] Using 18E as starting material, compound 18 isomer 3 (53 mg, two-step yield 17.3%) and compound 18 isomer 4 (111 mg, two-step yield 36.2%) were obtained referring to the above synthesis method.

[0476] HPLC analysis conditions: 1. Instrument: Shimadzu LC-20AT; 2. Column: Xtimate C18 4.6*50 mm, 3 μm; 3. Mobile phase: A for 0.05% TFA in H2O; B for ACN; 4. Gradient: B 5-95%; 5. Flow rate: 1.0 mL / min, Run time: 10 min. Retention time: Compound 18, Isomer 3, Retention time: 4.122 min; Compound 18, Isomer 4, Retention time: 4.147 min.

[0477] Compound 18 Isomer 3: 1 H NMR(400MHz, Methanol-d4)δ7.45–7.38(m,2H),7.27(dd,1H),5.60(q,1H),3.46–3.34(m,2H),3.23(d,1H),3.09(tt,1 H),2.69–2.48(m,4H),2.39(s,3H),2.25–2.07(m,3H),1.99–1.79(m,2H),1.72–1.58(m,1H),1.55(d,3H),1.38(s,3H).

[0478] LC-MS (ESI): m / z = 535.2 [M+H] + ;

[0479] Compound 18 Isomer 4: 1 H NMR(400MHz, Methanol-d4)δ7.47–7.37(m,2H),7.26(dd,1H),5.60(q,1H),3.26–3.11(m,2H),3.03–2.81(m ,2H),2.78–2.61(m,2H),2.51–2.32(m,5H),2.11–1.81(m,4H),1.76–1.56(m,2H),1.55(d,3H),1.37(s,3H).

[0480] LC-MS (ESI): m / z = 535.2 [M+H] + .

[0481] Example 19:

[0482] Step 1: Under nitrogen atmosphere, compound 19A (140 mg, 0.83 mmol) was dissolved in 1,2-dichloroethane (3 mL) at room temperature. 9H-2 (carbon * indicates a single configuration, R or S) (200 mg, 0.83 mmol) was added. After stirring for 5 minutes, sodium triacetoxyborohydride (350 mg, 1.66 mmol) was added and allowed to react overnight. After completion of the reaction, methanol (2 mL) was added to quench the reaction, which was then concentrated and purified by column chromatography (eluent ratio: MeOH / DCM = 0% to 10%) to afford compound 19B (298 mg, 90%).

[0483] LC-MS (ESI): m / z = 401.6 [M+H] + .

[0484] Step 2: Dissolve compound 19B (298 mg, 0.74 mmol) in dichloromethane (3 mL) at room temperature and add a 4M hydrogen chloride-dioxane solution (2 mL). Allow to react for 1 h. After completion of the reaction, concentrate the solution to obtain the hydrochloride salt of compound 19C (200 mg), which was used directly in the next step without further purification.

[0485] LC-MS (ESI): m / z = 187.1 [M+H] + .

[0486] Step 3: Compounds 19C (200 mg, 0.99 mmol) and 19D (350 mg, 0.99 mmol) (synthesized according to the method described in WO2018022992) were dissolved in N,N-dimethylformamide (5 mL). N,N-diisopropylethylamine (260 mg, 2.01 mmol) was added at room temperature and allowed to react overnight. The reaction was monitored for completion by LCMS. The crude product was concentrated under reduced pressure and separated by preparative HPLC to yield compound 19 (150 mg, 31%). Isolation method: 1. Apparatus: Waters 2767 Preparative HPLC; Column: SunFire@Prep C18 (19 mm × 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% ammonium acetate); b. Gradient elution, mobile phase A content from 10% to 55%; c. Flow rate: 12 mL / min.

[0487] 1H NMR(400MHz,Chloroform-d)δ7.83(s,1H),7.40-7.35(m,2H),7.20-7.19(m,1H), 6.47-6.46(m,1H),4.25-4.16(m,3H),4.10-4.09(m,1H),3.97-3.92(m,1H),3.79-3.66(m,4H), 2.91-2.81(m,3H),2.64-2.63(m,2H),2.33-2.31(m,1H),2.01-2.00(m,1H),1.91-1.90(m,3H).

[0488] LC-MS (ESI): m / z = 502.5 [M+H] + .

[0489] Example 20:

[0490] Step 1: Dissolve compound 20A (10.0 g, 54.9 mmol) in ethanol (25 mL), add hydroxylamine hydrochloride (4.58 g, 65.9 mmol) and triethylamine (6.66 g, 65.9 mmol), and reflux for 24 hours. After completion, cool the reaction to room temperature and concentrate under reduced pressure. The residue is dissolved in dichloromethane (30 mL). The organic phase is washed sequentially with water (20 mL × 3) and brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude title compound 20B (9.00 g, 75%). This product was directly processed into the next step without further purification.

[0491] LC-MS (ESI): m / z = 216.2 [M+H] + .

[0492] Step 2: Compound 20B (9.00 g, 41.9 mmol) was dissolved in methanol (100 mL). Raney nickel (4.47 g, 41.9 mmol) was added under an ice bath and stirred for 3 h under a hydrogen atmosphere. TLC and LC-MS showed the reaction was complete, and the reaction was stopped. The reaction solution was filtered through celite and concentrated to afford the title compound 20C (7.11 g, 85%) as an oily liquid. This was used directly in the next reaction without further purification.

[0493] LC-MS (ESI): m / z = 200.2 [M+H] + .

[0494] Step 3: Compound 20C (5.0 g, 25.1 mmol) and ethyl 2-chloroacetoacetate (4.1 g, 25.1 mmol) were dissolved in anhydrous methanol (10 mL). Potassium tert-butoxide was slowly added under ice-cooling and the reaction was continued with stirring for 1 hour. The mixture was then heated to reflux and allowed to react overnight. After completion of the reaction, the mixture was cooled to room temperature and concentrated. Water (30 mL) was added to the residue, and the pH was adjusted to 6-7 with aqueous citric acid. The mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1-5:1) to afford the title compound 20D (3.8 g, 51%).

[0495] LC-MS (ESI): m / z = 300.3 [M+H] + .

[0496] Step 4: Compound 20D (3.8 g, 12.7 mmol) and (R)-1-(2,4-dichlorophenyl)ethane-1-amine (2.9 g, 15.2 mmol) were dissolved in N,N-dimethylformamide (18 mL). BOP (9.0 g, 20.3 mmol) and DBU (5.8 g, 38.1 mmol) were then added sequentially. The mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After completion of the reaction, water (15 mL) was slowly added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1-2:1) to afford the title compound 20E (4.2 g, 70.2%).

[0497] LC-MS (ESI): m / z = 471.2 [M+H] + .

[0498] Step 5: Dissolve compound 20E (4.2 g, 8.9 mmol) in dichloromethane (8 mL) and add hydrochloric acid-1,4-dioxane solution (8 mL). React at room temperature for 1 hour. Concentrate to obtain the hydrochloride salt of title compound 20F (3.0 g, 92%). Use directly in the next reaction without further purification.

[0499] LC-MS (ESI): m / z = 371.2 [M+H] + .

[0500] Step 6: Dissolve compound 20F (3.0 g, 8.1 mmol) in 1,2-dichloroethane (10 mL). Add N-tert-butyloxycarbonyl-3-piperidone (2.4 g, 12.1 mmol) and a few drops of acetic acid. Stir the reaction for 3 hours. Add sodium cyanoborohydride (1.52 g, 24.2 mmol) and continue stirring for 18 hours. Pour the reaction mixture into water (30 mL). Add aqueous sodium bicarbonate (5 mL) and extract with ethyl acetate (20 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate and concentrated. The residue is purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 90:10) to yield compound 20G (racemate) (3.0 g, 67%). Compound 20G was separated by chiral preparative HPLC to obtain two isomers, compound 20G-1 (0.35 g, retention time 1.52 min, 23.3%) and compound 20G-2 (0.42 g, retention time 1.60 min, 28.0%).

[0501] HPLC analysis method: 1. Instrument: SHIMADZU LC-30AD sf; 2. Chromatographic column: Chiralcel OX-3 50×4.6 mm ID, 3 μm; 3. Mobile phase system: A for CO2 and B for EtOH (0.05% DEA); 4. Gradient: B 5-40%; 5. Flow rate: 3 mL / min.

[0502] Preparative chromatography conditions: 1. Instrument: Waters 150 SFC; 2. Column: Chiralpak IC-Column (250×30 mm, ID 30 mm, 10 μm particle size); 3. Mobile phase system: A for CO2 and B for MeOH (0.1% NH3·H2O); 4. Gradient: B 45%; 5. Flow rate: 180 mL / min.

[0503] LC-MS (ESI): m / z = 554.2 [M+H] + .

[0504] Step 7: Dissolve compound 20G-1 (0.21 g, 0.38 mmol) in dichloromethane (6 mL) and add hydrochloric acid-1,4-dioxane solution (5 mL). After addition, react at room temperature for 1 hour. Concentrate to obtain the hydrochloride salt of the title compound 20H-1 (0.16 g, 95%). Use it directly in the next reaction without further purification.

[0505] LC-MS (ESI): m / z = 454.2 [M+H] + .

[0506] Referring to the above operation, compound 20H-2 (0.197 g, 96.0%) was obtained using compound 20G-2 (0.25 g, 0.45 mmol) as starting material.

[0507] LC-MS (ESI): m / z = 454.2 [M+H] + .

[0508] Step 8: Dissolve compound 20H-1 (0.11 g, 0.23 mmol) in methanol (10 mL), add 3-carbonyl-1-methyl-cyclobutanecarboxylic acid (0.10 g, 0.28 mmol) and sodium triacetoxyborohydride (58 mg, 0.9 mmol). Under a nitrogen atmosphere, add glacial acetic acid (0.11 g, 0.23 mmol) under an ice bath, stir for 5 minutes, warm to room temperature, and continue stirring for 18 hours. Concentrate to obtain a crude product, which is then purified by HPLC to give compound 20, isomer 1 (0.15 g, retention time 3.32 min, yield 28.56%) and compound 20, isomer 2 (0.13 g, retention time 3.30 min, yield 24.75%).

[0509] HPLC analysis method: 1. Instrument: Shimadzu LC-20AT; 2. Chromatographic column: Xtimate C18 4.6*50 mm, 3 μm; 3. Mobile phase A: 0.05% TFA solution, mobile phase B: acetonitrile; 4. Gradient: A 95-5% B 5-95%; 5. Flow rate: 1 mL / min, column temperature: 35°C, wavelength: 210 nm / 254 nm, acquisition time: 10 min.

[0510] Preparation Method: Apparatus: Waters 2767 Preparative Liquid Chromatography; Chromatographic Column: SunFire@Prep C18 (19 mm × 250 mm). Dissolve the sample in methanol and filter through a 0.22 μm filter to prepare the sample solution. Preparative Chromatography Conditions: Mobile Phase A, B Composition: Mobile Phase A: Acetonitrile; Mobile Phase B: Water (containing 1% ammonium acetate), Gradient Elution, Mobile Phase A from 10% to 40%, Flow Rate: 12 mL / min, Elution Time: 25 min.

[0511] Compound 20, isomer 1: LC-MS (ESI): m / z=566.2 [M+H] + .

[0512] 1H NMR(400MHz, Methanol-d4)δ7.39(d,1H),7.27(d,1H),7.17-7.14(m,1H),5.47-5.42(m,1H),3.77(d,1H),3.67-3.54(m,2H),3.47 -3.42(m,1H),3.23(d,1H),3.06-3.03(m,1H),2.73-2.46(m,5H),2.31(s,3H),1.93-1.52(m,7H),1.48(d,3H),1.27-1.13(m,4H).

[0513] Compound 20, isomer 2: LC-MS (ESI): m / z=566.2 [M+H] + .

[0514] 1 H NMR(400MHz,Methanol-d4)δ7.43-7.36(m,1H),7.26(d,1H),7.16-7.13(m,1H),5.46-5.43(m,1H),3.76(s,1H),3.58(d,2H),3 .45-3.42(m,1H),3.17(s,2H),2.65-2.62(m,3H),2.49-2.37(m,2H),2.31(s,3H),2.16-1.48(m,8H),1.47(d,3H),1.28(s,3H).

[0515] Referring to the above operation, compound 20H-2 (3.4 g, 9.0 mmol) was used as the starting material to obtain the title compound 20, isomer 3 (0.15 g, retention time 3.34 min, yield 28.56%) and compound 20, isomer 4 (0.13 g, retention time 3.31 min, yield 24.75%).

[0516] HPLC analysis method: 1. Instrument: Shimadzu LC-20AT; 2. Chromatographic column: Xtimate C18 4.6*50 mm, 3 μm; 3. Mobile phase A: 0.05% TFA solution, mobile phase B: acetonitrile; 4. Gradient: A 95-5% B 5-95%; 5. Flow rate: 1 mL / min, column temperature: 35°C, wavelength: 210 nm / 254 nm, acquisition time: 10 min.

[0517] Compound 20, isomer 3: LC-MS (ESI): m / z = 566.2 [M+H] + .

[0518] 1H NMR(400MHz,Methanol-d4)δ7.39(d,1H),7.27(d,1H),7.17-7.14(m,1H),5.45-5.42(m,1H),3.72-3.68(m,2H),3.60-3.57 (m,1H),3.46-3.42(m,1H),3.19-2.88(m,2H),2.67-2.41(m,5H),2.31(s,3H),1.96-1.53(m,8H),1.48(d,3H),1.26(s,3H).

[0519] Compound 20, isomer 4: LC-MS (ESI): m / z=566.2 [M+H] + .

[0520] 1 H NMR(400MHz, Methanol-d4)δ7.40(d,1H),7.27(d,1H),7.17-7.08(m,1H),5.44-5.41(m,1H),3.71-3.68(m,2H),3.59-3.55 (m,1H),3.42-3.38(m,1H),3.15-3.08(m,2H),2.79-2.36(m,5H),2.30(s,3H),2.10-1.57(m,8H),1.47(d,3H),1.27(s,3H).

[0521] Compound 21:

[0522] Using compound 21A (0.5 g, 3.38 mmol) and compound 1C (1.0 g, 3.38 mmol) as starting materials, the title compound 21 (25 mg) was obtained by following the first to third steps of Example 14.

[0523] 1 H NMR(400MHz,Methanol-d4)δ7.70(d,1H),7.45(d,1H),7.36(d,1H),7.28(m,1H),5.42(s, 1H),5.01-4.98(m,1H),4.35-3.78(m,4H),3.64(s,1H),3.47-3.25(m,2H),2.81-2 .52(m,4H),2.36(s,1H),2.15(s,2H),2.06-1.61(m,5H),1.51(d,3H),1.32(s,3H).

[0524] LC-MS (ESI): m / z = 518.2 [M+H]+ .

[0525] Compound 22:

[0526] Using 11F (526.0 mg, 2.94 mmol) and 5,7-dichloropyrazolo[1,5-A]pyrimidine (500.0 mg, 2.67 mmol) as starting materials, the title compound 22 (20 mg) was obtained by following the first to third steps of Example 14.

[0527] 1 H NMR(400MHz,Methanol-d4)δ7.72(d,1H),7.45(d,1H),7.39(d,1H),7.29-7.26(m ,1H),5.86(d,1H),5.05-4.98(m,1H),4.61(s,1H),3.91-3.88(m,2H),3.74-3.53 (m,2H),3.46-3.32(m,1H),3.29-3.22(m,1H),3.11(d,1H),2.68-2.56(m,2H),2. 41-2.38(m,2H),2.16-2.13(m,1H),1.99-1.69(m,8H),1.56(d,3H),1.28(s,3H).

[0528] LCMS m / z=556.2[M+H] + .

[0529] Compound 23:

[0530] Step 1: Compound 15A (0.5 g, 3.40 mmol) was dissolved in acetonitrile (15 mL), and compound 11F (0.73 g, 4.10 mmol) and triethylamine (1.0 g, 10.1 mmol) were added. The reaction mixture was heated to 70°C and reacted for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The concentrate was dissolved in dichloromethane (30 mL) and washed sequentially with water (20 mL × 3) and brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1-2:1) to obtain the title compound 23A (0.61 g, 62%).

[0531] LC-MS (ESI): m / z = 291.2 [M+H] + .

[0532] Step 2: Compound 23A (0.61 g, 2.1 mmol) was dissolved in tetrahydrofuran (10 mL), and di-tert-butyl dicarbonate (0.92 g, 4.2 mmol) and DMAP (45 mg, 0.4 mmol) were added. The mixture was refluxed for 12 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The concentrate was dissolved in dichloromethane (30 mL) and washed sequentially with water (20 mL × 3) and brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1-2:1) to give the title compound 23B (0.65 g, 83%).

[0533] LC-MS (ESI): m / z = 391.2 [M+H] + .

[0534] Step 3: Compound 23B (0.32 g, 0.83 mmol) was dissolved in dimethyl sulfoxide (5 mL), and compound 1C (0.22 g, 0.83 mmol) and triethylamine (0.25 g, 2.49 mmol) were added. The temperature was raised to 150°C and the reaction was carried out under microwave conditions for 1 hour. After completion of the reaction, the mixture was cooled to room temperature and dissolved in ethyl acetate (30 mL). The mixture was washed sequentially with water (20 mL × 3) and brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1-2:1) to obtain the title compound 23C (0.32 g, 62%).

[0535] LC-MS (ESI): m / z = 622.2 [M+H] + .

[0536] Step 4: Dissolve 23C (0.32 g, 0.52 mmol) in dichloromethane (8 mL) and add dioxane hydrochloride (8 mL). After addition, react at room temperature for 1 hour. Concentrate to obtain the hydrochloride salt of the title compound 23D (0.24 g, 90%). This was used directly in the next reaction without further purification.

[0537] LC-MS (ESI): m / z = 522.2 [M+H] + .

[0538] Step 5: Dissolve compound 23D (240 mg, 0.47 mmol) in tetrahydrofuran (3 mL) and water (3 mL). Add lithium hydroxide hydrate (98.0 mg, 2.34 mmol). Stir thoroughly and allow to react at room temperature for 12 hours. After completion of the reaction, concentrate under reduced pressure, and purify the residue by high-efficiency preparative liquid chromatography to yield the title compound 23 (0.17 g, 71%).

[0539] Preparation Method: 1. Apparatus: Waters 2767 Preparative Liquid Chromatography; Chromatographic Column: SunFire@Prep C18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare a sample solution. 3. Preparative Chromatography Conditions: a. Mobile Phase A and B Composition: Mobile Phase A: Acetonitrile; Mobile Phase B: Water (containing 0.1% ammonium acetate). b. Gradient elution, mobile phase A content ranging from 10% to 55%. c. Flow rate: 12 mL / min.

[0540] 1 H NMR(400MHz, Methanol-d4)δ7.82(d,1H),7.39(d,1H),7.34-7.18(m,2H),4.97(d,2H),3.88-3.85(m,2H),3.71-3.52(m,3H),3.40-3 .27(m,1H),3.13-2.98(m,1H),2.79-2.55(m,2H),2.53-2.29(m,2H),2.11-2.07(m,1H),1.94-1.47(m,8H),1.39(d,3H),1.27(s,3H).

[0541] LC-MS (ESI): m / z = 508.2 [M+H] + .

[0542] Example 24:

[0543] 14B (0.34 g, 1.0 mmol), 24A (0.22 g, 1.2 mmol) (prepared according to CN 111732572A), Pd2(dba)3 (91 mg, 0.10 mmol), BINAP (0.12 g, 0.20 mmol), and cesium carbonate (0.65 g, 2 mmol) were added sequentially to toluene (20 mL) and heated to 95°C for 6 hours. After the reaction, the mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (DCM:MeOH (v / v) = 8:1) to obtain the crude product of target compound 24. The crude product was further purified by high-performance liquid chromatography to obtain the trifluoroacetic acid salt of compound 24 (0.16 g, yield: 22%).

[0544] Preparative Conditions: 1. Apparatus: Waters 2767 Preparative Liquid Chromatography; Chromatographic Column: SunFire@Prep C18 (19 mm × 250 mm). 2. Dissolve the sample in DMF and filter through a 0.45 μm filter to prepare the sample solution. 3. Preparative Chromatographic Conditions: a. Mobile Phase A and B Composition: Mobile Phase A: Acetonitrile, Mobile Phase B: Water (containing 0.1% TFA). b. Gradient elution, mobile phase A content from 5% to 50%. c. Flow rate: 12 mL / min. d. Elution time: 18 min.

[0545] 1 H NMR(400MHz,Methanol-d4)δ7.97(d,1H),7.59-7.52(m,2H),7.39(dd,1H),6.20(d,1H ),5.28(q,1H),4.80(s,1H),4.34(t,1H),4.23(s,1H),4.08-3.95(m,2H),3.95-3.88(m ,2H),3.68(d,1H),3.58(d,1H),3.31-3.24(m,2H),3.00-2.90(m,1H),2.78-2.65(m,2 H),2.25-2.09(m,1H),2.06(d,1H),1.99-1.81(m,2H),1.72(d,3H),1.27-1.14(m,1H).

[0546] LC-MS (ESI): m / z = 489.3 [M+H] + .

[0547] Example 25:

[0548] Using 14A (0.21 g, 1.11 mmol) and 1C (0.32 g, 1.20 mmol) as starting materials, the trifluoroacetic acid salt of compound 25 (0.11 g) was prepared by following the first to third steps of Example 12.

[0549] 1H NMR(400MHz,Methanol-d4)δ7.87(d,1H),7.57(d,1H),7.50(d,1H),7.41(dd,1H),6.15( t,1H),5.19(q,1H),4.69(s,3H),4.45(s,2H),3.82-3.75(m,1H),3.53(d,1H),3.42(d,1 H),2.90-2.80(m,2H),2.80-2.65(m,2H),2.55-2.45(m,1H),2.27(d,2H),2.17(s,1H),2 .07(d,1H),1.98(d,1H),1.87-1.72(m,1H),1.64(d,3H),1.44(s,3H),1.26-1.12(m,1H).

[0550] LC-MS (ESI): m / z = 557.3 [M+H] + .

[0551] Example 26:

[0552] Using 26A (2.0 g, 12.35 mmol) and (R)-1-(2,4-dichlorophenyl)ethanamine (2.33 g, 12.35 mmol) as starting materials, the first to third steps of Example 14 were followed to obtain compound 26 (50 mg).

[0553] 1 H NMR (400MHz, CD3CN; trifluoroacetic acid salt)7.51-7.50(m,1H),7.44-7.42(m,1H),7.36-7.33(m,1H),4.96(s,1H), 4.73(s,1H),4.14-4.04(m,2H),3.90-3.85(m,2H),3.65-3.53(m,2H),3.39- 3.29(m,3H),2.69-2.66(m,3H),2.50-2.45(m,3H),2.33(s,3H),2.20-2.15( m,3H),1.85-1.75(m,2H),1.52-1.50(d,3H),1.34(s,3H),1.07-1.01(m,1H).

[0554] LC-MS (ESI): m / z = 532.2 [M+H] + .

[0555] Example 27:

[0556] 15B (0.4 g, 1.33 mmol), 24A (0.25 g, 1.33 mmol), Pd2(dba)3 (0.25 g, 0.27 mmol), XantPhos (0.31 g, 0.54 mmol), and cesium carbonate (1.29 g, 3.99 mmol) were dissolved in 1,4-dioxane (20 mL) and heated to 100°C for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, added with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (DCM:MeOH (v / v) = 5:1) to obtain the target compound 27 (0.05 g, 9% yield).

[0557] 1 H NMR(400MHz,CD3CN)δ8.03(s,1H),7.51-7.50(m,1H),7.45-7.41(m,1H),7.36- 7.34(m,1H),5.00-4.97(m,1H),4.85(s,1H),4.19-4.11(m,1H),3.85-3.81(m, 4H),3.59-3.47(m,3H),3.18-3.13(m,2H),2.79-2.75(m,2H),2.50-2.47(m,3H ),2.19-2.16(m,1H),1.89-1.82(m,3H),1.56-1.54(d,3H),1.07-1.04(m,1H).

[0558] LC-MS (ESI): m / z = 450.2 [M+H] + .

[0559] Example 28:

[0560] Compound 11H (200.0 mg, 0.59 mmol), intermediate 9J-2 (300.1 mg, 1.18 mmol), cesium fluoride (227.0 mg, 1.49 mmol), and N,N-diisopropylethylamine (0.3 mL) were added to dimethyl sulfoxide (5 mL) in sequence, stirred evenly, and then heated to 100°C for reaction for 16 h. After the reaction was complete, the mixture was cooled to room temperature, added with water (30 mL), and extracted with ethyl acetate (40 mL × 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:MeOH (v / v) = 7:1) to give compound 28, isomer 1 (Rf = 0.5, (EA:MeOH (v / v) = (7:1)) (30 mg, 10%) and isomer 2 (Rf = 0.4, (EA:MeOH (v / v) = 7:1)) (20 mg, 6%).

[0561] Compound 28, isomer 1: LC-MS (ESI): m / z=558.2 [M+H] + .

[0562] 1H NMR(400MHz,DMSO-d6)δ12.18(s,1H),7.48(d,1H),7.46(d,1H),7.39(dd,1H),7.27(d,1H),5.47-5.37(m,1H),4.22(d,1H),3.75(d,4H),3.50- 3.35(m,4H),2.77-2.61(m,1H),2.57(d,3H),2.41(d,1H),2.18(s,3H), 2.13(d,1H),1.92-1.65(m,3H),1.44(d,4H),1.32(s,1H),1.27(s,2H).

[0563] Compound 28, isomer 2: LC-MS (ESI): m / z=558.2 [M+H] + .

[0564] 1H NMR(400MHz,DMSO-d6)δ12.08(s,1H),7.48(s,1H),7.46(d,1H),7.39(d,1H),7.29(d,1H),5.49-5.35(m,1H),4.22(s,1H),3.75(d,4 H),3.50-3.36(m,2H),2.71-2.54(m,4H),2.41(d,2H),2.17(s,3H),1.74(d,3H),1.44(d,3H),1.36(d,1H),1.27(s,3H),1.23(s,1H).

[0565] Example 29:

[0566] Step 1: Dissolve compound 9I-2 (8.4 g, 23.72 mmol) in dichloromethane (500 mL) at room temperature. Add (trimethylsilyl)diazomethane (23.72 mL, 2 M) dropwise. Allow to react for 1 hour. Concentrate the mixture, and purify the residue by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to yield the title compound 29A (8.4 g, 96.3%).

[0567] LC-MS (ESI): m / z = 369.2 [M+H] + .

[0568] Step 2: Dissolve compound 29A (8.4 g, 22.82 mmol) in dichloromethane (500 mL), add dioxane hydrochloride solution (200 mL, 4 M), and react at room temperature for 30 min. After the reaction is complete, concentrate directly to obtain compound 29B (7.5 g, 100%).

[0569] M / Z (ESI): m / z = 269.2 [M+H] + .

[0570] Step 3: Compound 15B (95.3 mg, 0.32 mmol), 29B (170.0 mg, 0.63 mmol), cesium fluoride (63.0 mg, 0.63 mmol), and N,N-diisopropylethylamine (0.5 mL) were added to dimethyl sulfoxide (5 mL) in sequence and stirred at 130°C under microwave-assisted conditions for 1 h. After the reaction was complete, the mixture was cooled to room temperature, added with water (30 mL), and extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane:methanol (v / v) = 15:1) to afford 29C (100.0 mg, 30%).

[0571] Step 4: Compound 29C (100.0 mg, 0.19 mmol) was dissolved in a mixed solvent (6 mL) (tetrahydrofuran:methanol:water (v / v / v) = 1:1:1), and lithium hydroxide (18.0 mg, 0.76 mmol) was added. The mixture was stirred at room temperature for 2 h. After completion of the reaction, the mixture was concentrated, and the residue was separated by silica gel column chromatography (EA:MeOH (v / v) = 4:1) to give compound 29, isomer 1 (Rf = 0.6, (EA:MeOH (v / v) = 4:1)) (30 mg, 30%) and compound 29, isomer 2 (Rf = 0.5, (EA:MeOH (v / v) = 4:1)) (22 mg, 22%).

[0572] Compound 29, isomer 1: LC-MS (ESI): m / z=520.5 [M+H] + .

[0573] 1 H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.55(d,1H),7.45-7.37(m,3H),5.14(s,2H),3.82(d,3H),3.71-3.65(m,2H ),3.55-3.44(m,4H),2.75-2.68(m,3H),2.42(d,2H),1.83-1.68(m,3H),1.44(t,1H),1.36(d,3H),1.28(s,3H).

[0574] Compound 29, isomer 2: LC-MS (ESI): m / z=520.5 [M+H] + .

[0575] 1 H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.55(d,1H),7.46-7.37(m,3H),5.14(s,2H),3.82(d,3H),3.72-3.65(m,2H),3.5 3-3.44(m,4H),2.73(d,2H),2.60(d,2H),2.18-2.13(m,1H),1.93-1.76(m,3H),1.47(t,1H),1.36(d,3H),1.31(s,3H).

[0576] Example 30:

[0577] 7J (0.4 g, 1.18 mmol) was dissolved in dimethyl sulfoxide (5 mL), and 9J-2 (0.3 g, 1.18 mmol), N,N-diisopropylethylamine (0.46 g, 3.54 mmol), and cesium fluoride (0.36 g, 2.36 mmol) were added sequentially. The temperature was raised to 100°C and the reaction was allowed to react for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, and water (15 mL) and ethyl acetate (15 mL) were added for extraction. The aqueous phase was back-extracted with ethyl acetate (15 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:methanol (v / v) = 10:1) to give compound 30 isomer 1 (Rf = 0.4 (ethyl acetate:methanol = 10:1), 35.0 mg, 5.3%) and the title compound 30 isomer 2 (Rf = 0.2 (ethyl acetate:methanol = 10:1)).

[0578] Compound 30 Isomer 1: 1 H NMR(400MHz,DMSO-d6)δ12.20(s,1H),7.49-7.37(m,3H),7.18(d,1H),5.58-5.40(m,1H),4.55(s,1H),3.87-3.62(m,4H),3.49-3.37(m,2 H),2.68-2.54(m,4H),2.46-2.37(m,2H),2.17(s,3H),1.96-1.86(m,1H),1.81-1.66(m,3H),1.44(d,3H),1.41-1.33(m,1H),1.27(s,3H).

[0579] M / Z (ESI): m / z = 558.6 [M+H] + .

[0580] Example 31:

[0581] Compound 2F (0.15 g, 0.43 mmol) and compound 19C (0.26 g, 0.65 mmol) were dissolved in dimethyl sulfoxide (5 mL), and triethylamine (0.13 g, 1.3 mmol) and cesium fluoride (0.13 g, 0.86 mmol) were added. The reaction was heated to 100°C and stirred for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain the title compound 31 (90.0 mg, 41.8%).

[0582] 1 H NMR(400MHz, CDCl3)δ7.35(d,1H),7.23(d,1H),7.18-7.16(m,1H),5.50(d,1H),5.46-5.41(m,1H),3.99-3.96(m,1H) ,3.91-3.59(m,8H),2.75(d,2H),2.60-2.54(m,3H),2.30(s,3H),2.28-2.22(m,1H),1.92-1.87(m,1H),1.51(s,3H).

[0583] MS M / Z(ESI): m / z=500.2[M+H] + .

[0584] Example 32:

[0585] Using compounds 14B (160.6 mg, 0.47 mmol) and 29B (120.0 mg, 0.47 mmol) as raw materials, referring to the third and fourth steps of Example 29, compound 32, isomer 1 (Rf = 0.6, (ethyl acetate:methanol (v / v) = 5:1), 4 mg) and compound 32, isomer 2 (Rf = 0.5, (EA:MeOH (v / v) = 5:1), 5 mg) were obtained.

[0586] Compound 32, isomer 1: LC-MS (ESI): m / z=577.3 [M+H] + .

[0587] 1 H NMR(400MHz,DMSO-d6)δ7.99(d,1H),7.81(d,1H),7.66-7.60(m,2H),7.45-7.40(m,1H),5.90(d,1H),4.74(s,1H),3 .86-3.47(m,6H),3.49(d,2H),2.69-2.59(m,5H),2.12(s,1H),2.00(d,1H),1.81(d,3H),1.58(d,3H),1.24(s,3H).

[0588] Compound 32, isomer 2: LC-MS (ESI): m / z=577.3 [M+H] + .

[0589] 1 H NMR(400MHz,DMSO-d6)δ7.99(d,1H),7.81(d,1H),7.67-7.60(m,2H),7.43(dd,1H),5.90(d,1H),4.73(s,1H),3.90-3.67(m,6H),3.4 8(d,2H),2.71-2.57(m,5H),2.44-2.39(m,1H),2.16(s,1H),1.92-1.82(m,1H),1.79(d,1H),1.69(d,1H),1.59(d,3H),1.23(s,3H).

[0590] Example 33:

[0591] Using 33A (0.4 g, 1.96 mmol) and 1C (0.52 g, 1.96 mmol) as starting materials, the first to third steps of Example 12 were followed to obtain compound 33 (100 mg).

[0592] 1 H NMR (400MHz, CD3CN; trifluoroacetic acid salt)δ9.95(s,1H),8.00-7.99(m,1H),7.48-7.43(m,2H),7.31-7.29(m,1H),7.10-7. 08(m,1H),5.52-5.43(m,1H),4.56-4.51(m,1H),4.33-4.28(m,2H),4.08-4.00(m,1H) ,3.61-3.55(m,1H),3.41-3.31(m,3H),2.71-2.68(m,3H),2.48-2.33(m,4H),2.25-2. 12(m,2H),1.85-1.80(m,2H),1.51-1.49(d,3H),1.40-1.34(m,3H),1.09-1.01(m,1H).

[0593] LC-MS (ESI): m / z = 574.2 [M+H] + .

[0594] Example 34:

[0595] Using 34A (0.2 g, 1.06 mmol) and 1C (0.28 g, 1.06 mmol) as starting materials, the first to third steps of Example 12 were followed to obtain compound 34 (80 mg).

[0596] 1 H NMR (400MHz, CD3OD)7.42-7.40(m,2H),7.27-7.24(m,1H),5.37-5.32(m,1H),4.19-4.09 (m,2H),3.92-3.88(m,1H),3.71-3.66(m,1H),3.34-3.32(m,2H),3.27-3.24(m,1H),3.11-3.06(m,1H),2.80-2.64(m,6H),2. 48-2.42(m,2H),2.13-1.92(m,7H),1.83-1.80(m,2H),1.71-1.68(m,1H),1.47-1.45(d,3H),1.39(s,3H),1.09-1.00(m,1H).

[0597] LC-MS (ESI): m / z = 558.2 [M+H] + .

[0598] Example 35:

[0599] Step 1: Dissolve tert-butyl 3-(morpholin-2-yl)azetidine-1-carboxylate (1 g, 4.17 mmol) in acetonitrile (10 mL). Add ethyl 2-bromoacetate (1.04 g, 6.25 mmol) and diisopropylethylamine (1.61 g, 12.51 mmol) sequentially. Stir at room temperature for 3 hours. After completion of the reaction, concentrate to afford crude product 35B (1.31 g, 96%).

[0600] LC-MS (ESI): m / z = 329.5 [M+H] + .

[0601] Step 2: Under a nitrogen atmosphere, compound 35B (300 mg, 0.91 mmol) was dissolved in dry tetrahydrofuran (5 mL). Methylmagnesium bromide (2.73 mmol) was added dropwise at -78°C and allowed to react at room temperature for 2 h. After completion of the reaction, the mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 0-30%) to afford 35C (200 mg, 70%).

[0602] LC-MS (ESI): m / z = 315.5 [M+H] + .

[0603] Step 3: Compound 35C (200 mg, 0.64) was dissolved in 1,4-dioxane hydrochloride (2 mL), stirred at room temperature for 1 h, and directly dried to obtain the hydrochloride salt of compound 35D (150 mg).

[0604] LC-MS (ESI): m / z = 215.2 [M+H] + .

[0605] Step 4: Compound 35D (150 mg, 0.64 mmol) was dissolved in DMSO (5 mL), and (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidin-4-amine (225 mg, 0.64 mmol), DIEA (248 mg, 1.92 mmol), and cesium fluoride (97 mg, 0.64 mmol) were added sequentially. The reaction was heated to 100°C and stirred for 2 hours. After completion of the reaction, water (15 mL) and ethyl acetate (15 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (15 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (ethyl acetate:petroleum ether (v / v) = 0-50%) to afford compound 35 (80 mg, 24%).

[0606] LC-MS (ESI): m / z = 528.6 [M+H] + .

[0607] 1 H NMR (400MHz, CDCl3) δ7.35(d,1H),7.23(d,1H),7.18-7.17(m,1H),5.50(d,1H),5.44-5.43(m,1H),3.98(t,1H),3.89-3.80(m,2H),3.74-3. 73(m,2H),3.65-3.64(m,2H),2.73(s,2H),2.58-2.52(m,1H),2.46(t, 1H),2.33(d,2H),2.30(s,3H),2.09(t,1H),1.51(d,3H),1.17(s,6H).

[0608] Example 36:

[0609] Step 1: Compound 36A (2.8 g, 13.97 mmol) and platinum dioxide (0.16 g, 0.70 mmol) were dissolved in ethanol (20 mL) and ethyl acetate (30 mL). The mixture was reacted at room temperature under a hydrogen atmosphere for 4 h. The mixture was filtered through celite, and the filter cake was washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 3:1) to afford the target compound 36B (0.52 g, 18% yield).

[0610] LC-MS M / Z (ESI) = 204.30 [M+H] + .

[0611] Step 2: Compound 36B (0.52 g, 2.55 mmol) and di-tert-butyl dicarbonate (1.11 g, 5.07 mmol) were dissolved in acetonitrile (15 mL). DMAP (62 mg, 0.51 mmol) was added and allowed to react at room temperature for 4 h. After completion of the reaction, the mixture was concentrated under reduced pressure and directly separated by silica gel column chromatography (PE:EA (v / v) = 5:1) to afford the target compound 36C (0.58 g, 75% yield).

[0612] LC-MS M / Z (ESI) = 248.1 [M- t Bu+H] + .

[0613] Step 3: Compound 36C (0.58 g, 1.91 mmol) and ferric acetylacetonate (67 mg, 0.19 mmol) were dissolved in THF (10 mL), cooled to 0°C, and methylmagnesium chloride (1.2 mL, 3 M THF solution) was added dropwise. After complete addition, the reaction was continued under these conditions for 1 hour. The reaction was quenched with saturated ammonium chloride (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 4:1) to afford the target compound 36D (0.32 g, 59% yield).

[0614] 1 H NMR (400MHz, Chloroform-d) δ3.79-3.72(m,2H),2.65(t,2H),2.40(s,3H),2.03-1.94(m,2H),1.56(s,9H).

[0615] Step 4: Compound 36D (0.32 g, 1.13 mmol) was dissolved in DCM (10 mL), cooled to 0°C, and trifluoroacetic acid (3 mL) was added dropwise. After completion of the addition, the reaction was continued at room temperature for 1 h. After concentration under reduced pressure, ethyl acetate (30 mL) was added, and the mixture was washed with saturated sodium bicarbonate (30 mL). The aqueous phase was extracted again with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to provide the target compound 36E (0.14 g, yield: 67%).

[0616] Step 5: Compound 36E (0.14 g, 0.76 mmol) was dissolved in DMF (10 mL), cooled to 0°C, and sodium hydride (60 mg, 1.52 mmol, 60% wt) was added. After 20 minutes at room temperature, 1-(1-bromoethyl)-2,4-dichlorobenzene (0.39 g, 1.52 mmol) was added dropwise. After complete addition, the mixture was allowed to warm to room temperature for 30 minutes. The reaction was quenched with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 4:1) to afford the target compound 36F (0.19 g, 70% yield).

[0617] LC-MS M / Z (ESI) = 356.0 [M+H] + .

[0618] Step 6: 36F (0.19 g, 0.53 mmol) was dissolved in DMSO (10 mL). 1C (0.14 g, 0.53 mmol), triethylamine (0.27 g, 2.65 mmol), and cesium fluoride (0.16 g, 1.06 mmol) were added sequentially. The mixture was reacted at 100°C for 24 hours. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH (v / v) = 12:1) to obtain the target compound 36G (36 mg, 12% yield).

[0619] LC-MS M / Z (ESI) = 586.60 [M+H] + .

[0620] Step 7: Dissolve 36G (0.036 g, 0.061 mmol) in tetrahydrofuran (10 mL), add methanol (3 mL) and water (3 mL), stir thoroughly, then add lithium hydroxide (0.015 g, 0.63 mmol). React at room temperature for 3 hours. Add hydrochloric acid (1N aqueous solution) dropwise to adjust the pH to 5. The solution is concentrated under reduced pressure and directly separated by silica gel column chromatography (DCM:MeOH (v / v) = 10:1) to obtain the crude product of target compound 36. The product was further prepared by high performance liquid chromatography (HPLC) (preparative conditions: 1. Instrument: Waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm × 250 mm); 2. The sample was dissolved in DMF and filtered with a 0.45 μm filter to prepare a sample solution; 3. Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile Mobile phase B: water (containing 0.1% TFA); b. Gradient elution, mobile phase A content from 5% to 50%; c. Flow rate 15 ml / min; d. Elution time 18 min) to obtain the trifluoroacetate salt of compound 36 (15 mg, yield 30%).

[0621] LC-MS M / Z (ESI) = 572.2 [M+H] + .

[0622] 1H NMR(400MHz,Methanol-d4)δ7.61-7.51(m,2H),7.47-7.41(d,1H),6.33-6.21(m,1H),4 .38-4.25(m,2H),4.12-3.97(m,2H),3.82-3.69(m,1H),3.53(d,1H),3.42-3.35(d,2H) ,3.02-2.90(m,1H),2.89-2.78(m,2H),2.79-2.59(m,3H),2.59-2.42(m,2H),2.30(s,5 H),2.17-2.02(m,2H),1.99-1.75(m,4H),1.62(d,3H),1.44(s,3H),1.27-1.12(m,1H).

[0623] Example 37:

[0624] Step 1: Compound 37A (0.5 g, 2.22 mmol) was dissolved in acetonitrile (10 mL), and (R)-1-(2,4-dichlorophenyl)ethane-1-amine (0.46 g, 2.44 mmol) and triethylamine (672 mg, 6.66 mmol) were added. The mixture was allowed to react at room temperature for 16 hours. After the reaction was complete, water (20 mL) and ethyl acetate (30 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product which was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to afford compound 37B (0.5 g, 59%).

[0625] LCMS (ESI): m / z = 380.1 [M+H] + .

[0626] Step 2: Compound 37B (200 mg, 0.53 mmol), N,N-diisopropylethylamine (341 mg, 2.65 mmol) and cesium fluoride (8 mg, 0.05 mmol) were added to a solution of compound 9J-2 (135 mg, 0.53 mmol) in dimethyl sulfoxide (3 mL) in sequence, and the temperature was raised to 100°C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, and water (15 mL) and ethyl acetate (15 mL) were added. The liquids were separated and the aqueous phase was extracted with ethyl acetate (15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. After the filtrate was concentrated, the residue was separated and purified by silica gel column chromatography (ethyl acetate: methanol (v / v) = 5:1) to give the title compound 37 isomer 1 (Rf = 0.6 (ethyl acetate: methanol = 5:1), 30.0 mg, 9%) and the title compound 37 isomer 2 (Rf = 0.4 (ethyl acetate: methanol = 5:1), 20.0 mg, 6%).

[0627] Compound 37, isomer 1: LC-MS (ESI): m / z = 598.1 [M+H] + .

[0628] 1 H NMR(400MHz, CDCl3)δ7.98(s,1H),7.36(d,1H),7.22-7.17(m,2H),5.55-5.41(m,2H),3.99-3.77(m,5H) ,3.68-3.58(m,2H),2.82-2.77(m,1H),2.69-2.51(m,6H),1.92-1.84(m,2H),1.52(d,3H),1.40(s,3H).

[0629] Compound 37, isomer 2: LC-MS (ESI): m / z=598.1 [M+H] + .

[0630] 1 H NMR (400MHz, CDCl3) δ7.90(s,1H),7.36(d,1H),7.24-7.16(m,2H),5.49-5.41(m,2H),3.97-3.92(m,2H),3.87-3. 77(m,3H),3.02-2.86(m,3H),2.64-2.52(m,3H),2.18-2.00(m,4H),1.73-1.64(m,1H),1.52(d,3H),1.42(s,3H).

[0631] Example 38:

[0632] Using 24A (170 mg, 0.92 mmol) and 11H (313.4 mg, 0.92 mmol) as starting materials, the procedure of Example 24 was followed to obtain compound 38 (38 mg, 10%).

[0633] 1 H NMR(400MHz,DMSO-d6)δ7.49(d,1H),7.45(d,1H),7.40-7.39(m,1H),7.28(d,1H),5.41(d,1H),4.23(s,1H),3.84(t,1H),3.76(s ,1H),3.52(d,3H),2.67(s,2H),2.50(s,2H),2.45-2.25(m,3H),2.18(s,3H),1.93(s,1H),1.59(s,4H),1.42(t,4H),1.23(s,1H).

[0634] LC-MS (ESI): m / z = 488.6 [M+H] + .

[0635] Example 39:

[0636] Compound 39 (23 mg) was obtained by using compound 39A (359 mg, 1.74 mmol) and 1C (300 mg, 0.79 mmol) as starting materials and following the first to third steps of Example 12.

[0637] LC-MS (ESI): m / z = 531.2 [M+H] + .

[0638] 1 H NMR (400MHz, CD3OD) δ7.55(s,1H),7.47(d,J=8.5Hz,1H),7.38(d,J=8.5,1H),5.88(s,1H),5 .04-5.03(m,1H),5.00(m,1H),4.17(m,2H),3.91(m,2H),3.83-3.64(m,2H),3.51(m,1H),2. 88-2.80(m,2H),2.75-2.65(m,2H),2.48(m,1H),2.35(s,3H),2.25-2.20(m,2H),2.12-1.98 (m,2H),1.97-1.86(m,1H),1.83-1.72(m,1H),1.59(d,3H),1.44(s,3H),1.18-1.11(m,1H).

[0639] Example 40:

[0640] Compound 1C (275 mg, 0.93 mmol) and compound 40A (241 mg, 1.21 mmol) were used as starting materials and the first to third steps of Example 12 were followed to obtain compound 40 (40 mg).

[0641] LC-MS (ESI): m / z = 569.3 [M+H] + .

[0642] 1 H NMR(400MHz,CD3OD)δ7.89(m,1H),7.81(m,1H),7.53(m,1H),7.51-7.46(m,2H),7.4 2(m,1H),7.35(m,1H),5.64-5.52(m,1H),4.97(m,1H),4.76-4.47(m,2H),4.37-4.1 4(m,1H),3.79(m,1H),3.53(m,1H),3.41(m,1H),2.83(m,2H),2.72(m,2H),2.52(m, 1H),2.31(m,2H),2.12(m,2H),1.81(m,2H),1.60(m,3H),1.44(s,3H),1.21(m,1H).

[0643] Example 41:

[0644] Step 1: Compound 41A (2.0 g, 9.60 mmol), (R)-1-(2,4-dichlorophenyl)ethane-1-amine (1.83 g, 9.60 mmol), and N,N-diisopropylethylamine (1.86 g, 14.39 mmol) were added sequentially to NMP (20 mL) and heated to 160°C for 48 hours. After cooling to room temperature, water (100 mL) and ethyl acetate (30 mL) were added and the mixture was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain the target compound 41B (2.2 g, 72.2%).

[0645] LC-MS (ESI): m / z = 317.0 [M+H] + .

[0646] Step 2: Dissolve 41B (2.0 g, 6.30 mmol) in acetic acid (18 mL), add dropwise a solution of sodium nitrite (434 mg, 6.30 mmol) in water (3 mL), and stir for 2 hours. After the reaction is complete, concentrate under reduced pressure to remove the solvent, add saturated sodium bicarbonate solution (30 mL), and extract with dichloromethane (20 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is separated by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) to afford 41C (1.2 g, 58.0%).

[0647] LC-MS (ESI): m / z = 328.3 [M+H] + .

[0648] Step 3: 41C (100 mg, 0.30 mmol), 9J-2 (82 mg, 0.30 mmol), and triethylamine (154 mg, 1.52 mmol) were dissolved in acetonitrile (5 mL) in this order and stirred at room temperature for 2 h. After the reaction was complete, water (30 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was separated on a silica gel preparative plate (ethyl acetate:methanol (v / v) = 10:1) to afford compound 41 isomer 1 (70 mg, Rf = 0.5, yield 42.1%) and compound 41 isomer 2 (50 mg, Rf = 0.3, yield 30.1%).

[0649] Compound 41 Isomer 1: LC-MS (ESI): m / z = 546.2 [M+H] + .

[0650] 1 H NMR(400MHz,DMSO-d6)δ12.17(s,1H),7.99(s,1H),7.67(d,1H),7.53-7.42 (m,2H),6.33-6.32(m,1H),4.27-3.94(m,4H),3.88-3.76(m,1H),3.65-3.4 4(m,2H),2.89-2.78(m,1H),2.70-2.55(m,3H),2.47-2.37(m,2H),1.97(d, 3H),1.86-1.77(m,1H),1.77-1.68(m,2H),1.54-1.44(m,1H),1.28(s,3H).

[0651] Compound 41 Isomer 2: LC-MS (ESI): m / z = 546.2 [M+H] + .

[0652] 1 H NMR(400MHz,DMSO-d6)δ12.18(s,1H),7.99(s,1H),7.66(d,1H),7.53-7.43 (m,2H),6.35-6.34(m,1H),4.27-3.91(m,4H),3.88-3.77(m,1H),3.66-3.4 6(m,2H),2.90-2.80(m,1H),2.80-2.70(m,1H),2.70-2.55(m,2H),2.24-2. 10(m,2H),1.97(d,3H),1.94-1.78(m,3H),1.57-1.45(m,1H),1.32(s,3H).

[0653] Example 42:

[0654] Using 42A (1 g, 5.46 mmol) and (R)-1-(3,5-dichlorophenyl)ethan-1-amine (1.04 g, 5.46 mmol) as raw materials, referring to the first and second steps of Example 37, compound 42 isomer 1 (Rf = 0.5, (EA:MeOH (v / v) = 7:1), 150 mg, 46%) and compound 42 isomer 2 (Rf = 0.4, (EA:MeOH (v / v) = 7:1), 20 mg, 6%) were obtained.

[0655] LC-MS (ESI): m / z = 554.2 [M+H] + .

[0656] Compound 42 Isomer 1: 1 H NMR (400MHz, CDCl3) δ = 7.92 (s, 1H), 7.37 (d, 1H), 7.22 (d, 1H), 7.19-7.18 (m, 1H), 5.54-5.53 (m, 1H), 5.45-5.44 (m, 1H), 4.05 -3.87(m,3H),3.84(s,2H),3.64(d,2H),2.83(s,1H),2.69(s,2H),2.64-2.52(m,3H),1.89(s,3H),1.52(d,4H),1.40(s,3H).

[0657] Compound 42 Isomer 2: 1H NMR(400MHz, CDCl3)δ=7.81(s,1H),7.36(s,1H),7.23(d,1H),7.18(d,1H),5.46(s,2H),3.96(d,2H),3.85(d,2H), 3.78(d,3H),3.00-2.99(m,2H),2.87(s,1H),2.63-2.52(m,3H),2.19-2.06(m,3H),1.52-1.51(m,3H),1.42(s,3H).

[0658] Example 43:

[0659] Step 1: Dissolve 43A (1.5 g, 8.0 mmol) in dry NN-dimethylformamide (30 mL). Cool to 0°C under nitrogen. Add sodium hydride (0.40 g, 10 mmol, 60% wt) portionwise. After addition, allow to react for 20 minutes. Add iodomethane (1.70 g, 12 mmol) dropwise. After addition, allow to react at room temperature for 30 minutes. Quench the reaction by adding water (100 mL). Extract with ethyl acetate (100 mL x 2). Combine the organic phases, wash with saturated brine (100 mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is then separated by silica gel column chromatography (PE:EA (v / v) = 5:1) to afford the target compound 43B (1.43 g, 89% yield).

[0660] LC-MS (ESI): m / z = 202.1 [M+H] + .

[0661] Step 2 to Step 4: Using 43B (0.20 g, 0.99 mmol) and 1C (0.26 g, 1 mmol) as starting materials, refer to the first to third steps of Example 12 to obtain the trifluoroacetic acid salt of compound 43 (80 mg).

[0662] LC-MS (ESI): m / z = 571.6 [M+H] + .

[0663] 1H NMR(400MHz,Methanol-d4)δ7.53-7.42(m,2H),7.31(d,1H),6.90(d,1H),6. 46(d,1H),5.52(q,1H),4.65-4.20(m,4H),3.86-3.70(m,1H),3.62(s,3H),3 .57-3.48(m,1H),3.42(d,1H),2.92-2.80(m,2H),2.75(d,2H),2.52(t,1H), 2.36-1.90(m,5H),1.81(d,1H),1.56(d,3H),1.44(s,3H),1.35-1.10(m,1H).

[0664] Example 44:

[0665] Step 1: Dissolve 44A (1.5 g, 8.0 mmol) in dry tetrahydrofuran (30 mL) and cool to 0°C under nitrogen. Add sodium hydride (0.40 g, 10 mmol, 60% wt) portionwise. After addition, allow to react for 20 minutes. Add iodomethane (1.70 g, 12 mmol) dropwise. After addition, allow to react at room temperature for 30 minutes. Quench the reaction by adding water (100 mL). Extract with ethyl acetate (100 mL x 2). Combine the organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is then separated by silica gel column chromatography (PE:EA (v / v) = 5:1) to afford the target compound 44B (1.38 g, 86% yield).

[0666] LC-MS (ESI): m / z = 202.1 [M+H] + .

[0667] Step 2 to Step 4: Using 44B (0.20 g, 0.99 mmol) and 1C (0.26 g, 1 mmol) as starting materials, refer to the first to third steps of Example 12 to obtain the trifluoroacetic acid salt of compound 44 (10 mg).

[0668] LC-MS (ESI): m / z = 571.2 [M+H] + .

[0669] 1H NMR(400MHz,Methanol-d4)δ7.40(d,1H),7.33(d,1H),7.26-7.18(m,2H),6.13(d,1H),5.31 (q,1H),4.45-4.27(m,2H),4.24-4.14(m,1H),3.80(s,4H),3.64(s,1H),3.45-3.31(m,1H), 2.77-2.67(m,2H),2.60(s,1H),2.46(s,1H),2.35(s,1H),2.21-2.05(m,2H), 2.02-1.80(m,3H),1.80-1.61(m,2H),1.52(d,1H),1.43(d,3H),1.32(s,3H).

[0670] Example 45:

[0671] Using 45A (0.19 g, 1.0 mmol) and 1C (0.26 g, 1.0 mmol) as starting materials, the trifluoroacetic acid salt of compound 45 (100 mg) was obtained by referring to the first to third steps of Example 12.

[0672] LC-MS M / Z (ESI) = 560.2 [M+H] + .

[0673] 1 H NMR(400MHz,Methanol-d4)δ7.50(d,1H),7.43(d,1H),7.34(dd,1H),5.46(s, 1H),5.03(s,2H),4.89(t,2H),4.36(s,2H),4.12(s,2H),3.76(t,1H),3.57-3 .45(m,1H),2.84(t,2H),2.72(t,1H),2.62(d,1H),2.47(t,1H),2.26(s,2H), 2.07(d,2H),1.98-1.70(m,3H),1.55(d,3H),1.44(s,3H),1.23-1.08(m,1H).

[0674] Example 46:

[0675] Step 1: At room temperature, compound 46A (synthesized according to the method described in patent WO2021129737) (1 g, 4.44 mmol), (R)-1-(2,4-dichlorophenyl)ethanamine (0.85 g, 4.44 mmol), triethylamine (0.90 g, 8.88 mmol), and dichloromethane (10 mL) were added sequentially to a 50 mL reaction flask. The mixture was stirred overnight at room temperature. After completion of the reaction, dichloromethane (20 mL) was added to the reaction solution, which was then washed with water (10 mL × 1) and saturated brine (10 mL × 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (DCM / MEOH = 0% to 5%) to obtain 46B (1.5 g, 89%).

[0676] LC-MS (ESI): m / z = 378.0 [M+H] + .

[0677] Step 2: Compound 46B (150 mg, 0.40 mmol), 9J-2 (84 mg, 0.33 mmol), sodium bicarbonate (55 mg, 0.66 mmol), and dimethyl sulfoxide (2 mL) were added sequentially to a 25 mL reaction flask at room temperature and stirred overnight at 100°C. After the reaction was completed, the mixture was cooled to room temperature and ethyl acetate (10 mL) was added. The mixture was then washed sequentially with water (5 mL × 1) and saturated brine (5 mL × 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (EA / MEOH = 0% to 10%) to give compound 46 isomer 1 (70 mg, 36%) and compound 46 isomer 2 (20 mg, 10%).

[0678] Compound 46 Isomer 1 (ethyl acetate:methanol (v / v)=9:1, Rf=0.32): 1 H NMR(400MHz,CD3OD)δ7.36 (d,1H),7.24(d,1H),7.18-7.17(d,1H),5.55-5.46(m,1H),5.01(s,1H),4.06-4.00(m,1H),3.92-3.81(m, 3H),3.71-3.57(m,2H),2.91-2.67(m,4H),2.66-2.43(m,8H),2.01-1.85(m,3H),1.53(d,3H),1.41(s,3H).

[0679] LC-MS (ESI): m / z = 596.3 [M+H] + .

[0680] Compound 46 Isomer 2 (ethyl acetate:methanol (v / v)=9:1, Rf=0.27): 1 H NMR(400MHz,CD3OD)δ7.36(d,1H),7.23(d,1H),7.18-7.16(m,1H),5.55-5.46(m,1H),4.85(d,1H),4.04-3.89(m,4H) ,3.84-3.75(m,2H),3.02(t,2H),2.94-2.85(m,2H),2.64-2.51(m,8H),2.19-2.08(m,3H),1.53(d,3H),1.42(s,3H).

[0681] LC-MS (ESI): m / z = 596.3 [M+H] + .

[0682] Example 47:

[0683] Step 1: Compound 9H-2 (0.5 g, 2.06 mmol) and methyl 3-carbonyl-cyclobutanecarboxylate (0.32 g, 2.48 mmol) were dissolved in 1,2-dichloroethane (10 mL) and glacial acetic acid (0.12 g, 2.06 mmol) was added. Sodium triacetoxyborohydride (1.09 g, 5.15 mmol) was added portionwise and allowed to react for 15 hours. After completion of the reaction, the mixture was quenched with water (30 mL) and extracted with dichloromethane (50 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to afford the title compound 47A (0.61 g, 82.2%).

[0684] M / Z (ESI): m / z = 299.2 [M+H- t Bu] + .

[0685] Step 2: Dissolve compound 47A (0.61 g, 1.72 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (1 mL), and react at room temperature for 0.5 hours. After the reaction is complete, concentrate directly to obtain the trifluoroacetic acid salt of compound 47B (0.81 g, 99.1%).

[0686] Step 3: Compound 2F (0.5 g, 1.4 mmol) and compound 47B (0.81 g, 1.71 mmol) were dissolved in dimethyl sulfoxide (5 mL) in sequence, and N,N-diisopropylethylamine (0.55 g, 4.3 mmol) and cesium fluoride (0.43 g, 2.8 mmol) were added. The temperature was raised to 100°C and the reaction was allowed to react for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain the title compound 47C (420.0 mg, 51.8%).

[0687] Step 4: Compound 47C (420.0 mg, 0.74 mmol) was added to a mixture of methanol (5 mL) and water (5 mL) at room temperature. After stirring, lithium hydroxide (151.7 mg, 3.7 mmol) was added and the mixture was allowed to react at room temperature for 1 h. TLC / LCMS indicated the reaction was complete. 1 M dilute hydrochloric acid was added dropwise to adjust the pH to 5. The crude product was concentrated under reduced pressure and purified by preparative HPLC to afford compound 47 isomer 1 (24.0 mg, 5.9%) and compound 47 isomer 2 (220.0 mg, 53.7%).

[0688] HPLC analysis method: 1. Instrument: Shimadzu LC-2020; 2. Column: Phenomenex C18; 3. Mobile phase: A for 0.1% TFA in H2O; B for ACN; 4. Gradient: B 10-80%; 5. Flow rate: 1.2 mL / min. Retention time: Compound 47 Isomer 1: tR = retention time: 3.05 min; Compound 47 Isomer 2: tR = retention time: 3.06 min.

[0689] Preparation Method: Apparatus: Waters 2767 Preparative Liquid Chromatography; Chromatographic Column: SunFire@Prep C18 (19 mm × 250 mm). Dissolve the sample in methanol and filter through a 0.22 μm filter to prepare the sample solution. Preparative Chromatography Conditions: Mobile Phase A, B Composition: Mobile Phase A: Acetonitrile; Mobile Phase B: Water (containing 0.1% ammonia), Gradient Elution, Mobile Phase A from 0% to 50%, Flow Rate: 18 mL / min, Elution Time: 30 min.

[0690] Compound 47 Isomer 1: 1H NMR(400MHz, CDCl3)δ7.35(d,1H),7.22(d,1H),7.18-7.16(m,1H),5.54(d,1H),5.46-5.41(m,1H),4.01-3.96(m,1H),3.91-3.57(m, 6H),3.04-2.98(m,2H),2.74-2.68(m,2H),2.59-2.54(m,1H),2.40-2.22(m,7H),1.96-1.94(m,1H),1.60-1.54(m,1H),1.51(d,3H).

[0691] M / Z (ESI): m / z = 554.2 [M+H] + .

[0692] Compound 47 Isomer 2: 1 H NMR(400MHz, CDCl3)δ7.34(d,1H),7.23(d,1H),7.18-7.16(m,1H),5.50(d,1H),5.45-5.39(m,1H),3.96-3.75 (m,7H),3.05-2.83(m,4H),2.61-2.48(m,5H),2.29(s,3H),2.12-2.07(m,1H),1.73-1.68(m,1H),1.50(d,3H).

[0693] M / Z (ESI): m / z = 554.2 [M+H] + .

[0694] Example 48:

[0695] Using 48A (0.2 g, 0.98 mmol) and 1C (0.26 g, 0.98 mmol) as starting materials, the first to third steps of Example 12 were followed to obtain compound 48 (100 mg).

[0696] 1H NMR(400MHz,CD3OD)7.44-7.40(m,2H),7.24-7.21(m,1H),7.10-7.09(m,1H),6.87 -6.86(m,1H),5.48(s,1H),5.41-5.36(m,1H),4.31-4.23(m,2H),4.05-4.01(m,1H) ,3.15-3.10(m,3H),3.03-3.00(m,1H),2.69-2.64(m,2H),2.55-2.51(m,2H),1.89- 1.80(m,7H),1.65-1.62(m,1H),1.46-1.44(d,3H),1.35(s,3H),1.02-0.99(m,1H).

[0697] LC-MS (ESI): m / z = 574.2 [M+H] + .

[0698] Example 49:

[0699] Using 49A (0.4 g, 1.73 mmol) and 1C (0.46 g, 1.73 mmol) as starting materials, the first to third steps of Example 12 were followed to obtain compound 49 (10 mg).

[0700] 1 H NMR(400MHz,CD3OD)7.46-7.42(m,3H),7.26-7.22(m,2H),5.35(s,1H),5.26- 5.21(m,1H),4.38-4.30(m,2H),4.05-3.98(m,2H),3.29-3.14(m,3H),2.76-2. 72(m,2H),2.61-2.59(m,1H),2.45-2.39(m,2H),2.23-2.16(m,2H),2.00-1.92 (m,5H),1.76-1.69(m,1H),1.48-1.47(m,3H),1.39(s,3H),1.17-1.11(m,1H).

[0701] LC-MS (ESI): m / z = 557.2 [M+H] + .

[0702] Example 50:

[0703] Using 50A (0.2 g, 1.21 mmol) and 1C (0.33 g, 1.21 mmol) as starting materials, the first to third steps of Example 12 were followed to obtain compound 50 (100 mg).

[0704] 1 H NMR (400MHz, CD3OD)7.71-7.70(m,1H),7.41-7.38(m,2H),7.26-7.24(m,1H),5. 52-5.46(m,1H),4.25-4.21(m,2H),3.95-3.92(m,2H),3.46-3.39(m,2H),3.21- 3.18(m,2H),2.75-2.70(m,2H),2.57-2.47(m,2H),2.28-2.22(m,1H),2.01-1.9 3(m,6H),1.71-1.68(m,1H),1.50-1.48(d,3H),1.38(s,3H),1.16-1.06(m,1H).

[0705] LC-MS (ESI): m / z = 536.2 [M+H] + .

[0706] Compound 51:

[0707] Using compound 1C (300.0 mg, 0.89 mmol) and compound 51A (168.0 mg, 0.89 mmol) as starting materials, the title compound 51 (25 mg) was obtained by following the first to third steps of Example 12.

[0708] 1 H NMR(400MHz,Methanol-d4)δ7.92(d,1H),7.44-7.30(m,2H),7.22(m,1H),6.70(d,1H),5.36(m,1H) ,4.57-4.09(m,3H),3.66-3.36(m,2H),2.85-1.63(m,13H),1.44(d,3H),1.33(s,3H),1.08(s,1H).

[0709] LCMS m / z=558.2[M+H] + .

[0710] Example 52:

[0711] Step 1: Compound 52A (0.5 g, 2.31 mmol) was dissolved in acetonitrile (15 mL), and (R)-1-(2,4-dichlorophenyl)ethane-1-amine (0.53 g, 2.78 mmol) and triethylamine (0.70 g, 6.93 mmol) were added. The reaction was heated to 70°C and allowed to react for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The concentrate was dissolved in dichloromethane (30 mL). The organic phase was washed sequentially with water (20 mL × 3) and brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1-2:1) to obtain the title compound 52B (0.51 g, 61%).

[0712] LC-MS (ESI): m / z = 370.2 [M+H] + .

[0713] Step 2: Compound 52B (0.51 g, 1.38 mmol) was dissolved in tetrahydrofuran (10 mL), and di-tert-butyl dicarbonate (0.45 g, 2.07 mmol) and DMAP (16 mg, 0.14 mmol) were added. The mixture was refluxed for 12 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The residue was dissolved in dichloromethane (30 mL). The organic phase was washed sequentially with water (20 mL × 3) and brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1-2:1) to obtain the title compound 52C (0.45 g, 70%).

[0714] LC-MS (ESI): m / z = 470.2 [M+H] + .

[0715] Step 3: Compound 52C (0.20 g, 0.43 mmol) was dissolved in dimethyl sulfoxide (5 mL), and compound 1C (0.16 g, 0.47 mmol) and triethylamine (0.13 g, 1.29 mmol) were added. The reaction mixture was heated to 150°C under microwave conditions for 1 hour. After completion of the reaction, the mixture was cooled to room temperature and dissolved in ethyl acetate (30 mL). The organic phase was washed sequentially with water (20 mL × 3) and brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1-2:1) to obtain the title compound 52D (0.19 g, 65%).

[0716] LC-MS (ESI): m / z = 700.2 [M+H] + .

[0717] Step 4: Dissolve 52D (0.19 g, 0.28 mmol) in dichloromethane (8 mL) and add dioxane hydrochloride (8 mL). After addition, react at room temperature for 1 hour. Concentrate to obtain the hydrochloride salt of the title compound 52E (0.15 g, 90%). This was used directly in the next reaction without further purification.

[0718] LC-MS (ESI): m / z = 600.2 [M+H] + .

[0719] Step 5: Dissolve compound 52E (150 mg, 0.25 mmol) in tetrahydrofuran (3 mL) and water (3 mL). Add lithium hydroxide hydrate (53.0 mg, 1.25 mmol). Stir thoroughly and allow to react at room temperature for 12 hours. After completion of the reaction, concentrate under reduced pressure, and purify the residue by high-efficiency preparative liquid chromatography to yield the title compound 52 (0.09 g, 65%).

[0720] Preparation Method: 1. Apparatus: Waters 2767 Preparative Liquid Chromatography; Chromatographic Column: SunFire@Prep C18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare a sample solution. 3. Preparative Chromatography Conditions: a. Mobile Phase A and B Composition: Mobile Phase A: Acetonitrile; Mobile Phase B: Water (containing 0.1% ammonium acetate). b. Gradient elution, mobile phase A content ranging from 10% to 55%. c. Flow rate: 12 mL / min.

[0721] 1 H NMR(400MHz, Methanol-d4)δ7.44(d,1H),7.39(d,1H),7.31-7.25(m,1H),5.21-4.94(m,2H),4.20-3.91(m,2H),3.82-3.65(m,2H),3.56-3.37 (m,1H),3.20(d,1H),2.88-2.67(m,2H),2.59-2.42(m,2H),2.25-2.20( m,1H),2.10-1.79(m,7H),1.78-1.61(m,1H),1.47(d,3H),1.37(s,3H).

[0722] LC-MS (ESI): m / z = 586.2 [M+H] + .

[0723] Example 53:

[0724] Step 1: Compound 48A (1.00 g, 4.88 mmol), (R)-1-(2,4-dichlorophenyl)ethan-1-amine (1.39 g, 7.32 mmol), and triethylamine (1.48 g, 14.6 mmol) were dissolved in dry acetonitrile (60 mL) and reacted at room temperature overnight. After the disappearance of the starting material by TLC, saturated aqueous ammonium chloride (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL x 5). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 80:20) to afford compound 53A (920 mg, 52.6%).

[0725] LC-MS (ESI): m / z = 358.1 [M+H] + .

[0726] Step 2: Compound 9J-2 (300 mg, 0.622 mmol) and 53A (245 mg, 0.685 mmol) were dissolved in dry dimethyl sulfoxide (6 mL). Triethylamine (378 mg, 3.73 mmol) and cesium fluoride (189 mg, 1.24 mmol) were added, and the mixture was heated to 100°C and reacted for approximately 4 hours. The starting material disappeared after TLC analysis. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:methanol (v / v) = 100:0 to 75:25) to give compound 53 isomer 1 (54 mg, 15.1%) and compound 53 isomer 2 (23 mg, 6.42%).

[0727] Compound 53 Isomer 1 (ethyl acetate:methanol (v / v) = 9:1, Rf = 0.45), 1 H NMR(400MHz, Methanol-d4)δ7.46-7.32(m,3H),7.22(d,1H),6.93(d,1H),5.60-5.59(m,1H),4.01-3.80(m,4H),3.78-3.52(m,3H) ,2.95-2.94(m,1H),2.80(d,2H),2.70-2.55(m,3H),2.09-2.08(m,1H),1.93-1.82(m,2H),1.71(t,1H),1.53(d,3H),1.37(s,3H).

[0728] LC-MS (ESI): m / z = 576.2 [M+H] + .

[0729] Compound 53 Isomer 2 (ethyl acetate:methanol (v / v) = 9:1, Rf = 0.42), 1H NMR(400MHz, Methanol-d4)δ7.47-7.34(m,3H),7.23(d,1H),6.94(d,1H),5.60-5.59(m,1H),4.02-3.92(m,2H),3.86(d,2H),3.80-3.59(m,3H) ,3.08-3.07(m,1H),2.94(d,2H),2.67(q,1H),2.50-2.37(m,2H),2.25- 2.24(m,1H),2.17-2.06(m,2H),1.89(t,1H),1.54(d,3H),1.40(s,3H).

[0730] LC-MS (ESI): m / z = 576.2 [M+H] + .

[0731] Example 54:

[0732] Compound 33A (500 mg, 2.44 mmol) and (R)-1-(2,4-dichlorophenyl)ethane-1-amine (695 mg, 3.66 mmol) were used as starting materials and the operation methods of steps 1 to 2 of Example 53 were used to obtain Compound 54 Isomer 1 (33 mg) and Compound 54 Isomer 2 (14 mg).

[0733] Compound 54 Isomer 1 (ethyl acetate:methanol (v / v) = 9:1, Rf = 0.55), 1 H NMR(400MHz,Methanol-d4)δ7.82(d,1H),7.43(d,1H),7.38(d,1H),7.24-7.23(m,1H ),7.07(d,1H),5.64(q,1H),4.00-3.99(m,1H),3.95-3.82(m,3H),3.79-3.71(m,1H) ,3.69-3.53(m,2H),2.89-2.88(p,1H),2.76(d,2H),2.71-2.63(m,1H),2.65-2.53(m ,2H),2.04-2.03(td,1H),1.88-1.78(m,2H),1.66(t,1H),1.54(d,3H),1.37(s,3H).

[0734] LC-MS (ESI): m / z = 576.2 [M+H] + .

[0735] Compound 54 Isomer 2 (ethyl acetate:methanol (v / v) = 9:1, Rf = 0.50), 1H NMR(400MHz, Methanol-d4)δ7.81(d,1H),7.43(d,1H),7.39(d,1H),7.24-7. 23(m,1H),7.07(d,1H),5.64-5.63(q,1H),4.04-3.84(m,4H),3.84-3.59(m, 3H),3.06-3.05(p,1H),2.94(d,2H),2.76-2.64(m,1H),2.42(t,2H),2.29-2 .20(m,1H),2.15-2.04(m,2H),1.88-1.87(t,1H),1.54(d,3H),1.40(s,3H).

[0736] LC-MS (ESI): m / z = 576.2 [M+H] + .

[0737] Example 55:

[0738] Compound 55A (227 mg, 1.18 mmol) and (R)-1-(2,4-dichlorophenyl)ethanamine (336 mg, 1.77 mmol) were used as starting materials and the trifluoroacetic acid salt of compound 55 (75 mg) was obtained by referring to the first to third steps of Example 14.

[0739] 1 H NMR(400MHz,CD3OD)δ7.96(m,1H),7.58(s,1H),7.54-7.46(m,2H),7.38(m,1H),5.88(s ,1H),5.18-5.17(m,1H),4.97(s,1H),4.21(m,1H),3.96(m,2H),3.75(m,1H),3.51(m,1 H),3.38(m,1H),2.83(m,2H),2.71(m,1H),2.61(m,1H),2.47(m,1H),2.25(m,2H),2.04 (m,2H),1.94(m,1H),1.81(m,1H),1.69(d,3H),1.44(s,3H),1.33(m,1H),1.17(m,1H).

[0740] LC-MS (ESI): m / z = 557.2 [M+H] + .

[0741] Example 56:

[0742] Using compound 56A (300 mg, 1.5 mmol) and compound 1C (565 mg, 1.5 mmol) as starting materials, the trifluoroacetic acid salt of compound 56 (191 mg) was obtained by referring to the first to third steps of Example 12.

[0743] LC-MS (ESI): m / z = 566.7 [M+H] + .

[0744] 1 H NMR(400MHz,CD3OD)δ7.48(s,1H),7.42(d,1H),7.32(d,1H),5.39(m,1H),4.41-3.90(m,2H ),3.74(m,1H),3.50(m,1H),3.33(m,2H),2.81(m,2H),2.70(m,1H),2.59-2.39(m,2H),2.36 (s,3H),2.29-2.20(m,2H),2.10-1.92(m,2H),1.86-1.68(m,2H),1.52(m,3H),1.42(s,3H),1.31(m,1H),1.13(m,1H).

[0745] Example 57:

[0746] Using compound 57A (227 mg, 1.08 mmol) and compound 1C (407 mg, 1.08 mmol) as starting materials, the trifluoroacetic acid salt of compound 57 (144 mg) was obtained by referring to the first to third steps of Example 12.

[0747] 1 H NMR(400MHz,CD3OD)δ7.46(s,1H),7.43(d,J=8.4Hz,1H),7.32(d,J=8.4Hz,1H), 5.65-5.64(m,1H),4.46(m,2H),4.23(m,2H),3.75(m,1H),3.51(m,1H),3.38(m,1 H),2.82(m,2H),2.72(m,2H),2.47(m,1H),2.37(s,3H),2.30(m,2H),2.18(m,1H ),2.05(m,1H),1.94(m,1H),1.83(m,1H),1.56(d,3H),1.43(s,3H),1.18(m,1H).

[0748] LC-MS (ESI): m / z = 550.2 [M+H] + .

[0749] Example 58:

[0750] Step 1: Dissolve compound 58A (456 mg, 2.10 mmol) in acetonitrile (10 mL), followed by triethylamine (638 mg, 6.30 mmol) and (R)-1-(2,4-dichlorophenyl)ethanamine (400 mg, 2.10 mmol), and stir at room temperature for 5 h. After completion, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to afford the title compound 58B (510 mg, 66%).

[0751] LC-MS (ESI): m / z = 371.5 [M+H] + .

[0752] Step 2: Compound 58B (200 mg, 0.54 mmol) was dissolved in acetonitrile (3 mL). 29B (140 mg, 0.54 mmol), N,N-diisopropylethylamine (210 mg, 1.62 mmol), and cesium fluoride (82 mg, 0.54 mmol) were added sequentially, and the mixture was stirred at 70°C overnight. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to afford the target compound 58C (143 mg, 44%).

[0753] LC-MS (ESI): m / z = 603.2 [M+H] + .

[0754] Step 3: Compound 58C (143 mg, 0.24 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL) and water (2 mL) were added, and the mixture was stirred thoroughly. Lithium hydroxide monohydrate (29 mg, 1.2 mmol) was added and the mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated, and the residue was separated by silica gel column chromatography (ethyl acetate:methanol (v / v) = 5:1) to afford compound 58, isomer 1 (Rf = 0.7, (ethyl acetate:methanol (v / v) = 5:1)) (27 mg, 19%) and isomer 2 (Rf = 0.6, (EA:MeOH (v / v) = 5:1)) (20 mg, 14%).

[0755] Compound 58, isomer 1: LC-MS (ESI): m / z=588.6 [M+H] + .

[0756] 1H NMR(400MHz,DMSO-d6)δ8.09(d,1H),8.06(s,1H),7.52(s,1H),7.45(d,1H),7.38(d,1H),5.27(s,1H),3.98-3.77(m ,5H),3.64(s,2H),3.47(s,2H),2.72-2.63(m,2H),2.59(d,2H),2.43(d,1H),1.76(d,3H),1.36(d,3H),1.31(s,3H).

[0757] Compound 58, isomer 2: LC-MS (ESI): m / z=588.6 [M+H] + .

[0758] 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),8.37(d,1H),8.14(s,1H),7.59(s,1H),7.47(d,1H),7.41(d,1H),5.33( d,1H),4.21-3.65(m,10H),2.92-2.73(m,2H),2.70-2.54(m,3H),2.27-2.08(m,2H),1.38(d,3H),1.34(d,3H).

[0759] Example 59:

[0760] Using 2,4-dichloro-6-(trifluoromethyl)pyrimidine (59A) (0.22 g, 1.00 mmol) and compound 1C (0.26 g, 1.00 mmol) as starting materials, the trifluoroacetic acid salt of compound 59 (0.19 g) was obtained by referring to the first to third steps of Example 12.

[0761] 1 H NMR(400MHz, Methanol-d4)δ7.45-7.38(m,2H),7.25-7.24(m,1H),5.96(d,1H),5.39(d,1H),4.22-3.96(m,2H),3.91-3.66(m,3H),3 .53-3.45(m,1H),2.82(t,2H),2.70(t,1H),2.63-2.36(m,2H),2.20(s,2H),2.10-1.67(m,4H),1.54-1.36(m,7H),1.23-1.08(m,1H).

[0762] LC-MS (ESI): m / z = 586.3 [M+H] +.

[0763] Example 60:

[0764] Using compounds 40A (358 mg, 1.8 mmol) and 29B (409 mg, 1.2 mmol) as starting materials, the first to third steps of Example 12 were used to obtain compound 60, isomer 1 (retention time 0.801 min, 16 mg, yield 19%), and isomer 2 (retention time 1.143 min, 8 mg, yield 9%).

[0765] Analytical method: Instrument: SHIMADZU LC-30AD sf, Column: Chiralcel C2-3 50×4.6 mm ID, 3 μm, Mobile phase: A for CO2, B for MeOH + ACN (0.05% DEA), Gradient: B 50%, Flow rate: 3 mL / min, Back pressure: 100 bar, Column temperature: 35°C, Wavelength: 220 nm. Compound 60, Isomer 1: LC-MS (ESI): m / z = 570.2 [M+H] + .

[0766] 1 H NMR (400MHz, CD3OD) δ7.80(d,J=8.4Hz,1H),7.65-7.64(m,1H),7.48(s,1H),7.46-7.45(m,1H),7.38(d,J=8 .4Hz,1H),7.30-7.29(m,1H),7.24-7.23(m,1H),5.51(m,1H),5.36(m,1H),4.88-4.87(m,2H),4.57-4.56(m ,2H),3.91-3.90(m,1H),3.67-3.66(m,2H),2.85-2.84(m,1H),2.76-2.75(m,2H),2.63-2.62(m,2H),2.21- 2.20(m,1H),2.04-2.03(m,1H),1.80-1.79(m,2H),1.54-1.53(m,3H),1.38-1.37(s,3H),0.91-0.90(m,1H).

[0767] Compound 60, Isomer 2: LC-MS (ESI): m / z = 570.1 [M+H] + .

[0768] 1H NMR (400MHz, CD3OD) δ7.82(d,J=8.4Hz,1H),7.69-7.68(m,1H),7.49(m,1H),7.47(d,J=8.4Hz,1H),7.40- 7.39(m,1H),7.32-7.31(m,1H),7.29-7.28(m,1H),5.52-5.51(m,1H),5.37-5.36(m,1H),4.57-4.55(m,4H ),3.92-3.91(m,1H),3.67-3.65(m,2H),3.52-3.51(m,1H),2.87-2.86(m,2H),2.80-2.79(m,2H),2.31-2. 30(m,1H),2.26-2.25(m,1H),2.06-2.05(m,2H),1.55-1.51(m,3H),1.43-1.40(s,3H),0.93-0.91(m,1H).

[0769] Example 61:

[0770] Using 61A (0.2 g, 1.11 mmol) and 1C (0.30 g, 1.11 mmol) as starting materials, the first to third steps of Example 12 were followed to obtain compound 61 (100 mg).

[0771] 1 H NMR(400MHz,CD3OD)7.42-7.40(m,2H),7.27-7.24(m,1H),5.29-5.24(m,1H),4.19-4 .11(m,2H),3.91-3.87(m,1H),3.71-3.69(m,1H),3.46-3.42(m,2H),3.17-3.14(m,2 H),2.77-2.72(m,2H),2.54-2.48(m,2H),2.26-2.21(m,1H),2.14-2.13(m,3H),2.03 -1.96(m,5H),1.86-1.82(m,2H),1.44-1.42(d,3H),1.40(s,3H),1.14-1.05(m,1H).

[0772] LC-MS (ESI): m / z = 550.2 [M+H] + .

[0773] Example 62:

[0774] Step 1: Dissolve the starting substrate 62A (6.3 g, 29.85 mmol) in THF (100 mL) at room temperature. Cool the mixture to 0°C under a nitrogen atmosphere and add sodium bis(trimethylsilyl)amide (17.9 mL, 35.82 mmol) dropwise. Stir for 1 hour after the addition is complete. Then, add a solution of N-phenylbis(trifluoromethanesulfonyl)imide (21.3 g, 59.7 mmol) in THF (100 mL) dropwise. After the addition is complete, warm the mixture to room temperature and react for 2 hours. The reaction is quenched by adding water (100 mL) and extracted with EA (500 mL x 3). The combined organic phases are washed with water (500 mL) and saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 50:1-20:1) to afford compound 62B (5.5 g, 61% yield).

[0775] LC-MS (ESI): m / z = 344.1 [M+H] + .

[0776] Step 2: Zinc powder (3.12 g, 48.11 mmol) was added to DMA (20 mL) at room temperature. 1,2-Dibromoethane (0.91 g, 4.81 mmol) and trimethylsilyl chloride (0.52 g, 4.81 mmol) were added dropwise under a nitrogen atmosphere. After the addition was complete, 1-CBZ-3-iodoacridine (4.52 g, 24.05 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was filtered and the filtrate was sequentially added with starting material 62B (5.5 g, 16.03 mmol), CuI (0.46 g, 2.4 mmol), and Pd(dppf)2Cl2 (1.74 g, 2.4 mmol). The temperature was raised to 85°C and the reaction was allowed to proceed for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, added with water (100 mL), and extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE:EA (v / v) = 1:1) to obtain the target compound 62C (2.9 g, yield 48%).

[0777] LC-MS (ESI): m / z = 385.2 [M+H] + .

[0778] Step 3: Compound 62C (2.9 g, 7.55 mmol) was dissolved in methanol (50 mL), and Pd / C (0.3 g, 10% Pd content) was added. The mixture was reacted under a hydrogen atmosphere for 15 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated to obtain crude compound 62D (1.9 g, 100%), which was used directly in the next reaction without further purification.

[0779] LC-MS (ESI): m / z = 253.2 [M+H] + .

[0780] Step 4: 62D (1.9 g, 7.55 mmol), 2F (2.65 g, 7.55 mmol), triethylamine (1.54 g, 15.1 mmol), and cesium fluoride (1.15 g, 7.55 mmol) were dissolved in dimethyl sulfoxide (100 mL) at room temperature, and then heated to 100°C for 4 h. After the reaction was complete, the mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (DCM:MeOH (v / v) = 10:1) to give 0.97 g of a racemate. The racemate was separated by chiral preparative HPLC to give two isomers, compound 62E-1 (0.25 g, retention time 1.63 min, 5.8%) and compound 62E-2 (0.28 g, retention time 1.77 min, 6.6%).

[0781] HPLC analysis method: 1. Instrument: SHIMADZU LC-30AD; 2. Chromatographic column: Chiralpak IC-3 50×4.6 mm ID; 3. Mobile phase system: A for CO2 and B for IPA (0.05% DEA); 4. Gradient: B 30%; 5. Flow rate: 3 mL / min.

[0782] Preparative chromatography conditions: 1. Instrument: Waters 150 SFC; 2. Column: Chiralpak IC-Column (250×30 mm, ID 30 mm, 10 μm particle size); 3. Mobile phase system: A for CO2 and B for IPA; 4. Gradient: B 30%; 5. Flow rate: 110 mL / min.

[0783] LC-MS (ESI): m / z = 566.3 [M+H] + .

[0784] Step 5: Dissolve compound 62E-1 (0.25 g, 0.44 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (3 mL), and react at room temperature for 30 min. After the reaction is complete, concentrate directly to obtain the trifluoroacetic acid salt of compound 62F-1 (0.2 g, 98%).

[0785] Referring to the above operation, compound 62E-2 (0.86 g, 2.4 mmol) was used as the starting material to obtain the trifluoroacetic acid salt of the title compound 62F-2 (0.22 g, 98%).

[0786] LC-MS (ESI): m / z = 466.3 [M+H] + .

[0787] Step 6: Compound 62F-1 (0.2 g, 0.43 mmol) and 3-carbonyl-1-methyl-cyclobutanecarboxylic acid (55 mg, 0.43 mmol) were dissolved in 1,2-dichloroethane (15 mL) in sequence, and glacial acetic acid (26 mg, 0.43 mmol) was added. Sodium triacetoxyborohydride (0.18 g, 0.86 mmol) was added in batches and the mixture was allowed to react for 15 hours. After the reaction was complete, water (30 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL×2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 10:1) to give the title compound 62 isomer 1 (Rf = 0.4 (dichloromethane: methanol = 10:1), 30 mg, 12%) and the title compound 62 isomer 2 (Rf = 0.6 (dichloromethane: methanol = 10:1), 20 mg, 8%).

[0788] Compound 62 Isomer 1: 1 H NMR(400MHz,CD3CN)δ7.51-7.50(m,1H),7.41-7.39(m,1H),7.34-7.31(m, 1H),6.10-6.08(m,1H),5.52-5.45(m,1H),4.17-4.05(m,1H),3.92-3.87( m,1H),3.58-3.55(m,1H),3.24-3.14(m,5H),2.73-2.68(m,6H),2.24(s,3 H),1.93-1.85(m,5H),1.73-1.67(m,1H),1.54-1.52(d,3H),1.33(s,3H).

[0789] M / Z (ESI): m / z = 578.2 [M+H] + .

[0790] Compound 62 Isomer 2: 1H NMR (400MHz, CD3CN) δ7.52-7.51(m,1H),7.41-7.39(m,1H),7.34-7.31(m,1H),6.10-6.08(m,1H),5.49-5.43(m,1H),4.46-4.37(m,1H),3. 99-3.89(m,2H),3.57-3.54(m,1H),3.25-3.11(m,5H),2.78-2.67(m, 6H),2.24(s,3H),1.89-1.86(m,5H),1.54-1.52(d,3H),1.33(s,3H).

[0791] M / Z (ESI): m / z = 578.2 [M+H] + .

[0792] Referring to the above operation, compound 62F-2 (0.22 g, 0.47 mmol) was used as the starting material to obtain the title compound 62 isomer 3 (Rf = 0.4 (dichloromethane: methanol = 10:1), 30 mg, 11%) and the title compound 62 isomer 4 (Rf = 0.6 (dichloromethane: methanol = 10:1), 20 mg, 7.5%).

[0793] Compound 62 Isomer 3: 1 H NMR(400MHz,CD3CN)δ7.51-7.50(m,1H),7.42-7.39(m,1H),7.33-7.30(m, 1H),6.13-6.11(m,1H),5.52-5.45(m,1H),4.17-4.11(m,1H),4.02-3.88( m,2H),3.57-3.49(m,1H),3.29-3.24(m,4H),2.82-2.60(m,6H),2.24(s,3 H),1.93-1.75(m,5H),1.61-1.60(m,1H),1.54-1.52(d,3H),1.33(s,3H).

[0794] M / Z (ESI): m / z = 578.2 [M+H] + .

[0795] Compound 62 Isomer 4: 1H NMR (400MHz, CD3CN) δ7.52-7.51(m,1H),7.41-7.39(m,1H),7.34-7.31(m,1H),6.10-6.08(m,1H),5.49-5.43(m,1H),4.41-4.38(m,1H),3. 99-3.89(m,2H),3.57-3.54(m,1H),3.25-3.11(m,5H),2.78-2.67(m, 6H),2.24(s,3H),1.89-1.86(m,5H),1.54-1.52(d,3H),1.33(s,3H).

[0796] M / Z (ESI): m / z = 578.2 [M+H] + .

[0797] Example 63:

[0798] Using compound 63A (1.0 g, 4.93 mmol) and (R)-1-(2,4-dichlorophenyl)ethane-1-amine (936 mg, 4.93 mmol) as raw materials, referring to the first and second steps of Example 37, compound 63 isomer 1 (70 mg, Rf = 0.5 (ethyl acetate: methanol (v / v) = 8:1)) and compound 63 isomer 2 (30 mg, Rf = 0.3 (ethyl acetate: methanol (v / v) = 8:1)) were obtained.

[0799] Compound 63, Isomer 1: LC-MS (ESI): m / z = 574.2 [M+H] + .

[0800] 1 H NMR (400MHz, DMSO-d6) δ12.16(s,1H),8.37(d,1H),7.92(s,1H),7.59-7.49(m,1H),7.45-7.30(m,2H),5.52(s,1H),3.90-3.70( m,4H),3.67(s,3H),3.52-3.33(m,3H),2.71-2.53(m,4H),2.47-2.36(m,2H),1.84-1.65(m,3H),1.51-1.37(m,4H),1.28(s,3H).

[0801] Compound 63, Isomer 2: LC-MS (ESI): m / z = 574.2 [M+H] + .

[0802] 1H NMR(400MHz,DMSO-d6)δ8.38(d,1H),7.92(s,1H),7.56-7.53(m,1H),7.46-7.32(m,2H),5.59-5.47(m,1H),3.89-3.70(m,4H),3.66(s,3H),3.5 3-3.39(m,3H),2.80-2.69(m,1H),2.68-2.53(m,3H),2.21-2.09(m,2H) ,1.95-1.84(m,2H),1.84-1.74(m,1H),1.52-1.40(m,4H),1.32(s,3H).

[0803] Example 64:

[0804] Step 1: Compound 64A (10.00 g, 45.66 mmol) was dissolved in acetonitrile (50 mL). Dimethylhydroxylamine hydrochloride (5.34 g, 54.79 mmol), N-methylmorpholine (18.45 g, 182.64 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (13.13 g, 68.49 mmol) were added sequentially. The mixture was allowed to react at room temperature for 3 hours. After completion, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford the title compound 64B (11.72 g, 98.0%), which was used directly in the next step without further purification.

[0805] Step 2: Under a nitrogen atmosphere, compound 64B (11.2 g, 42.7 mmol) was dissolved in anhydrous tetrahydrofuran (110 mL), cooled to -78°C, and diisobutylaluminum hydride (64 mL, 64.05 mmol, 1.0 mol / L toluene solution) was slowly added dropwise. After the addition was complete, the reaction was continued at -78°C for 1 hour. After completion, a 10% aqueous solution of potassium sodium tartrate (50 mL) was added dropwise to quench the reaction. The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound 64C (8.6 g, 99.1%), which was used directly in the next step without further purification.

[0806] Step 3: Dissolve compound 64C (8.0 g, 39.37 mmol) in methanol (80 mL), add triethylamine (7.97 g, 78.74 mmol) and nitromethane (9.61 g, 157.48 mmol) sequentially, and stir at room temperature for 17 hours. After completion of the reaction, concentrate the product, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 4:1) to obtain the title compound 64D (9.3 g, 89.39%).

[0807] Step 4: Dissolve compound 64D (9.3 g, 35.19 mmol) in methanol (100 mL) and add Raney nickel (0.41 g, 7.04 mmol). React under a hydrogen atmosphere for 15 hours. After completion, filter the mixture and concentrate the filtrate to obtain crude compound 64E (7.6 g, 92.2%), which was used directly in the next step without further purification.

[0808] M / Z (ESI): m / z = 187.1 [M+H- t Bu] + .

[0809] Step 5: Compound 64E (7.6 g, 32.44 mmol) was dissolved in a mixture of tetrahydrofuran (70 mL) and water (40 mL). Sodium bicarbonate (8.18 g, 97.32 mmol) was added dropwise at 5-10°C. After the addition was complete, the mixture was allowed to warm to room temperature and allowed to react for 1 hour. After the reaction was complete, water (50 mL) was added and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:3) to afford the title compound 64F (9.2 g, 91.2%).

[0810] Step 6: Potassium tert-butoxide (6.65 g, 59.22 mmol) was dissolved in tert-butanol (170 mL). Compound 64F (9.2 g, 29.61 mmol) was added portionwise. After addition, the temperature was raised to 40°C and the reaction mixture was allowed to react for 1 hour. After completion of the reaction, the mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride (100 mL). The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:3) to obtain the title compound 64G (7.2 g, 88.65%).

[0811] Step 7: Under a nitrogen atmosphere, compound 64G (7.2 g, 26.25 mmol) was dissolved in tetrahydrofuran (75 mL), cooled to 0°C, and sodium 2-hydrogen bis(dimethoxyethoxy)aluminate (22.5 mL, 3.5 mol / L toluene solution) was added dropwise. After the addition was complete, the reaction was continued at 0-5°C for 3 hours. After the reaction was complete, the temperature was controlled at 0-5°C, and a 10% aqueous sodium hydroxide solution (20 mL) was added dropwise to quench the reaction. After quenching, the mixture was dried over anhydrous magnesium sulfate and filtered through celite. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 5:1) to obtain the title compound 64H (5.3 g, 77.5%).

[0812] M / Z (ESI): m / z = 205.2 [M+H- t Bu] + .

[0813] Step 8: Dissolve compound 64H (5.3 g, 20.36 mmol) in a mixture of tetrahydrofuran (30 mL) and water (30 mL), add sodium bicarbonate (5.13 g, 61.08 mmol), cool to 0-5°C, and slowly add benzyl chloroformate (4.17 g, 24.43 mmol) dropwise. After the addition is complete, continue the reaction at 0-5°C for 1 hour. After completion of the reaction, water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 5:1) to give 4.8 g of a racemate. The racemate was separated by chiral preparative HPLC to give two isomers, compound 64I-1 (1.6 g, retention time 1.33 min, 19.9%) and compound 64I-2 (2.0 g, retention time 1.48 min, 24.9%).

[0814] HPLC analysis method: 1. Instrument: SHIMADZU LC-30AD SFC; 2. Chromatographic column: Chiralcel OX-3 50×4.6mm ID, 3μm; 3. Mobile phase system: A for CO2, B for 0.05% DEA in IPA; 4. Gradient: B 5-40%; 5. Flow rate: 3mL / min.

[0815] Preparative chromatography conditions: 1. Instrument: Waters 150 SFC; 2. Column: Chiralpak OX–Column (250×30 mm, ID 30 mm, 10 μm particle size); 3. Mobile phase system: A for CO2 and B for IPA; 4. Gradient: B 20%; 5. Flow rate: 100 mL / min; 6. Elution time: 3.3 min.

[0816] Step 9: Dissolve compound 64I-1 (1.6 g, 4.06 mmol) in methanol (20 mL) and add Pd / C (0.4 g, 10% Pd content). React under a hydrogen atmosphere for 3 hours. After completion of the reaction, filter and concentrate the filtrate to obtain the title compound 64J-1 (1.00 g, 94.6%).

[0817] Referring to the above operation, compound 64I-2 (2.00 g, 5.31 mmol) was used as the starting material to obtain the title compound 64J-2 (1.21 g, 94.0%).

[0818] Step 10: Compound 64J-1 (1.00 g, 3.84 mmol) and 3-carbonyl-1-methyl-cyclobutanecarboxylic acid (0.74 g, 5.76 mmol) were sequentially dissolved in methanol (15 mL). Glacial acetic acid (0.46 g, 7.46 mmol) was added. Sodium cyanoborohydride (0.72 g, 11.44 mmol) was added portionwise and allowed to react for 1 hour. After completion of the reaction, the mixture was quenched with water (30 mL) and extracted with dichloromethane (50 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to afford the title compound 64K-1 (1.20 g, 83.9%).

[0819] Referring to the above operation, compound 64J-2 (1.21 g, 4.1 mmol) was used as the starting material to obtain the title compound 64K-2 (1.51 g, 87.1%).

[0820] M / Z (ESI): m / z = 373.3 [M+H] + .

[0821] Step 11: Dissolve compound 64K-1 (1.20 g, 3.22 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (3 mL), and react at room temperature for 30 min. After the reaction is complete, concentrate to obtain the trifluoroacetate salt of compound 64L-1 (1.6 g, 99.3%).

[0822] Referring to the above operation, compound 64K-2 (1.51 g, 4.26 mmol) was used as the starting material to obtain the trifluoroacetic acid salt of the title compound 64L-2 (2.00 g, 97.3%).

[0823] Step 12: Compound 2F (0.15 g, 1.4 mmol) and compound 64L-1 (0.43 g, 0.86 mmol) were dissolved in dimethyl sulfoxide (3 mL) in sequence, N,N-diisopropylethylamine (0.17 g, 1.29 mmol) and cesium fluoride (0.13 g, 0.86 mmol) were added, and the temperature was raised to 100°C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, and water (20 mL) was added, followed by extraction with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 1:10) to give the title compound 64 isomer 1 (Rf = 0.5 (ethyl acetate: methanol = 20:1), 95.0 mg, 37.6%) and the title compound 64 isomer 2 (Rf = 0.3 (ethyl acetate: methanol = 20:1), 50.0 mg, 19.8%).

[0824] Compound 64 Isomer 1: 1 H NMR (400MHz, CDCl3) δ7.35(d,1H),7.21(d,1H),7.18-7.15(m,1H),5.54(d,1H),5.46-5.40(m,1H),4.23-4.16(m,1H),4.04-3. 83(m,4H),3.72-3.63(m,2H),2.84-2.77(m,2H),2.68-3.55(m,3H),2.30(s,3H),1.96-1.71(m,4H),1.51(d,3H),1.39(s,3H).

[0825] M / Z (ESI): m / z = 586.2 [M+H] + .

[0826] Compound 64 Isomer 2: 1H NMR(400MHz, CDCl3)δ7.36(d,1H),7.21(d,1H),7.18-7.16(m,1H),5.54(d,1H),5.46-5.42(m,1H),4.24-4.16(m,1H),4.04-3.74(m, 6H),2.98(d,1H),2.91(d,1H),2.84-2.81(m,1H),2.52-2.47(m,2H),2.30(s,3H),2.10-2.00(m,3H),1.87-1.82(m,1H),1.51(d,3H), 1.41(s,3H).

[0827] M / Z (ESI): m / z = 586.2 [M+H] + .

[0828] Referring to the above operation, compound 64L-2 (0.43 g, 0.86 mmol) was used as the starting material to obtain the title compound 64 isomer 3 (Rf = 0.5 (ethyl acetate: methanol = 20:1), 110.0 mg, 13.6%) and the title compound 64 isomer 4 (Rf = 0.3 (ethyl acetate: methanol = 20:1), 70.0 mg, 8.7%).

[0829] Compound 64 Isomer 3: 1 H NMR (400MHz, CDCl3) δ7.36(d,1H),7.22(d,1H),7.18-7.16(m,1H),5.56(d,1H),5.44-5.41(m,1H),4.19-4.11(m,1H),4.04-3. 86(m,4H),3.74-3.65(m,2H),2.91-2.81(m,2H),2.74-3.59(m,3H),2.31(s,3H),2.00-1.74(m,4H),1.51(d,3H),1.41(s,3H).

[0830] M / Z (ESI): m / z = 586.2 [M+H] + .

[0831] Compound 64 Isomer 4: 1H NMR (400MHz, CDCl3) δ7.36(d,1H),7.23(d,1H),7.19-7.16(m,1H),5.54(d,1H),5.46-5.42(m,1H),4.19-4.12(m,1H),4.04-3.78(m,6H),3. 08(d,1H),2.98(d,1H),2.89-2.84(m,1H),2.62-2.57(m,2H),2.30(s ,3H),2.13-2.03(m,3H),1.90-1.85(m,1H),1.51(d,3H),1.42(s,3H).

[0832] M / Z (ESI): m / z = 586.2 [M+H] + .

[0833] Example 65:

[0834] Step 1: Compound 65A (0.50 g, 1.99 mmol) was dissolved in dichloromethane (10 mL). (R)-1-(2,4-dichlorophenyl)ethanamine (0.45 g, 2.39 mmol) and triethylamine (0.60 g, 5.97 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to afford the title compound 65B (0.68 g, 84.5%).

[0835] Step 2: Compound 65B (0.15 g, 0.37 mmol) and compound 64L-1 (0.37 g, 0.74 mmol) were dissolved in dimethyl sulfoxide (3 mL) in sequence, N,N-diisopropylethylamine (0.14 g, 1.11 mmol) and cesium fluoride (0.11 g, 0.74 mmol) were added, and the temperature was raised to 100°C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, and water (20 mL) was added, followed by extraction with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 1:5) to give the title compound 65 isomer 1 (Rf = 0.4 (ethyl acetate: petroleum ether = 10:1), 110.0 mg, 46.4%) and the title compound 65 isomer 2 (Rf = 0.2 (ethyl acetate: petroleum ether = 10:1), 55.0 mg, 23.2%).

[0836] Compound 65 Isomer 1: 1H NMR(400MHz, CDCl3)δ7.38(d,1H),7.23-7.18(m,2H),5.89(d,1H), 5.49-5.43(m,1H),4.29-4.21(m,1H),4.09-3.92(m,4H),3.73-3.65(m,2H),2.89-2.80(m ,2H),2.71-3.59(m,3H),1.99-1.87(m,3H),1.78-1.72(m,1H),1.55(d,3H),1.43(s,3H).

[0837] M / Z (ESI): m / z = 640.2 [M+H] + .

[0838] Compound 65 Isomer 2: 1 H NMR (400MHz, CDCl3) δ7.39(d,1H),7.23-7.19(m,1H),5.89(d,1H),5.48-5.45(m,1H),4.30-4.23(m,1H),4.10-3.81(m,6H),3. 10(d,1H),3.01(d,1H),2.91-2.88(m,1H),2.61-2.56(m,2H),2.15-2.07(m,3H),1.92-1.87(m,1H),1.55(d,3H),1.43(s,3H).

[0839] M / Z (ESI): m / z = 640.2 [M+H] + .

[0840] Referring to the above operation, compound 65B (0.15 g, 0.37 mmol) and compound 64L-2 (0.37 g, 0.74 mmol) were used as raw materials to obtain the title compound 65 isomer 3 (Rf = 0.4 (ethyl acetate: petroleum ether = 10:1), 100.0 mg, 42.1%) and the title compound 65 isomer 4 (Rf = 0.2 (ethyl acetate: petroleum ether = 10:1), 50.0 mg, 21.1%).

[0841] Compound 65 Isomer 3: 1H NMR(400MHz, CDCl3)δ7.39(d,1H),7.23-7.18(m,2H),5.88(d,1H),5.47-5.43(m,1H),4.23-4.16(m,1H),4.06-3.91(m,4H) ,3.71-3.62(m,2H),2.89-2.79(m,2H),2.69-3.60(m,3H),1.96-1.86(m,3H),1.75-1.70(m,1H),1.55(d,3H),1.43(s,3H).

[0842] M / Z (ESI): m / z = 640.2 [M+H] + .

[0843] Compound 65 Isomer 4: 1 H NMR(400MHz, CDCl3)δ7.38(d,1H),7.23-7.19(m,1H),5.89(d,1H),5.48-5.44(m,1H),4.25-4.18(m,1H),4.08-3.80(m,6H),3. 09(d,1H),2.99(d,1H),2.90-2.85(m,1H),2.62-2.58(m,2H),2.17-2.04(m,3H),1.89-1.84(m,1H),1.55(d,3H),1.42(s,3H).

[0844] M / Z (ESI): m / z = 640.2 [M+H] + .

[0845] Example 66:

[0846] Step 1: Compound 66A (5.00 g, 29.40 mmol) was dissolved in glacial acetic acid / acetic anhydride (v / v = 20 / 1, 100 mL). A catalytic amount of ferric chloride was added, and the mixture was heated to 95°C. Sulfonyl chloride (7.93 g, 58.78 mmol) was added dropwise. After the addition, the mixture was heated to reflux and reacted for 15 hours. After the reaction was complete, the solution was cooled to 10°C and filtered. The filter cake was washed with acetic acid and water, and dried in vacuo to obtain the title compound 66B (3.6 g, 60%).

[0847] Step 2: Compound 66B (3.0 g, 14.70 mmol) was dissolved in phosphorus oxychloride (30 mL), cooled to 0°C, and N,N-diethylaniline (4.39 g, 29.42 mmol) was added dropwise. After addition, the temperature was raised to 100°C and the mixture was reacted for 15 hours. After completion of the reaction, the phosphorus oxychloride was removed by concentration, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain the title compound 66C (2.7 g, 76.1%).

[0848] Step 3: Compound 66C (2.70 g, 11.16 mmol) was dissolved in dichloromethane (30 mL). (R)-1-(2,4-dichlorophenyl)ethanamine (2.55 g, 13.39 mmol) and triethylamine (3.39 g, 33.48 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain the title compound 66D (4.20 g, 95.2%).

[0849] Step 4: Compound 66D (4.20 g, 10.63 mmol) was dissolved in ethanol (50 mL), and iodine (5.40 g, 21.28 mmol) was added. Sodium borohydride (2.01 g, 53.15 mmol) was added in batches. The mixture was allowed to react at room temperature for 3 hours. After the reaction was complete, the ethanol was removed by concentration. Water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) to obtain the title compound 66E (2.60 g, 66.6%).

[0850] Step 5: Compound 66E (2.60 g, 7.08 mmol) was dissolved in 1,2-dichloroethane (30 mL). Activated manganese dioxide (3.08 g, 35.53 mmol) was added and the temperature was raised to 80°C for 5 hours. After completion of the reaction, the mixture was filtered through Celite and the filtrate was concentrated to afford crude compound 66F (2.10 g, 81.2%), which was used in the next step without further purification.

[0851] Step 6: Compound 66F (1.50 g, 4.11 mmol) was dissolved in dichloromethane (20 mL). Diethylaminosulfur trifluoride (1.99 g, 12.33 mmol) was added at room temperature and stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to afford the title compound 66G (0.61 g, 38.3%).

[0852] Step 7: Compound 66G (0.15 g, 0.39 mmol) and compound 64L-1 (0.39 g, 0.78 mmol) were dissolved in dimethyl sulfoxide (3 mL) in sequence. N,N-diisopropylethylamine (0.15 g, 1.17 mmol) and cesium fluoride (0.12 g, 0.78 mmol) were added, and the temperature was raised to 100°C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, and water (20 mL) was added, followed by extraction with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 1:5) to give the title compound 66 isomer 1 (Rf = 0.4 (ethyl acetate: petroleum ether = 10:1), 56.0 mg, 23.1%) and the title compound 66 isomer 2 (Rf = 0.2 (ethyl acetate: petroleum ether = 10:1), 70.0 mg, 28.8%).

[0853] Compound 66 Isomer 1: 1 H NMR (400MHz, CDCl3) δ7.37(d,1H),7.23-7.18(m,2H),6.65-6.39(m,1H),5.76(d,1H),5.49-5.42(m,1H),4.26-4.20(m,1H),4.06-3. 91(m,4H),3.74-3.65(m,2H),2.89-2.79(m,2H),2.71-2.60(m,3H),1.99-1.87(m,3H),1.78-1.73(m,1H),1.54(d,3H),1.41(s,3H).

[0854] M / Z (ESI): m / z = 622.2 [M+H] + .

[0855] Compound 66 Isomer 2: 1 H NMR(400MHz, CDCl3)δ7.38(d,1H),7.23-7.18(m,2H),6.65-6.39(m,1H),5.77(d,1H),5.48-5.44(m,1H),4.29-4.20(m,1H),4.09-3.81( m,6H),3.09(d,1H),3.00(d,1H),2.91-2.87(m,1H),2.62-2.57(m,2H),2.16-2.06(m,3H),1.92-1.86(m,1H),1.54(d,3H),1.43(s,3H).

[0856] M / Z (ESI): m / z = 622.2 [M+H]+ .

[0857] Referring to the above operation, compound 66G (0.15 g, 0.39 mmol) and compound 64L-2 (0.39 g, 0.78 mmol) were used as raw materials to obtain the title compound 66 isomer 3 (Rf = 0.4 (ethyl acetate: petroleum ether = 10:1), 55.0 mg, 22.6%) and the title compound 66 isomer 4 (Rf = 0.2 (ethyl acetate: petroleum ether = 10:1), 65.0 mg, 26.7%).

[0858] Compound 66 Isomer 3: 1 H NMR (400MHz, CDCl3) δ7.37(d,1H),7.23-7.18(m,2H),6.65-6.39(m,1H),5.76(d,1H),5.49-5.42(m,1H),4.28-4.20(m,1H),4.06-3. 91(m,4H),3.74-3.65(m,2H),2.87-2.79(m,2H),2.71-2.60(m,3H),1.99-1.87(m,3H),1.78-1.73(m,1H),1.54(d,3H),1.41(s,3H).

[0859] M / Z (ESI): m / z = 622.2 [M+H] + .

[0860] Compound 66 Isomer 4: 1 H NMR (400MHz, CDCl3) δ7.38(d,1H),7.24-7.18(m,2H),6.65-6.38(m,1H),5.77(d,1H),5.47-5.44(m,1H),4.24-4.17(m,1H),4.07-3.79( m,6H),3.09(d,1H),3.00(d,1H),2.91-2.87(m,1H),2.61-2.57(m,2H),2.17-2.06(m,3H),1.90-1.84(m,1H),1.54(d,3H),1.42(s,3H).

[0861] M / Z (ESI): m / z = 622.2 [M+H] + .

[0862] Example 67:

[0863] Step 1: Compound 40A (1.00 g, 5.02 mmol), (R)-1-(2,4-dichlorophenyl)ethanamine (1.05 g, 5.53 mmol), and triethylamine (1.53 g, 15.1 mmol) were dissolved in dry acetonitrile (50 mL) and reacted at room temperature overnight. After the disappearance of the starting material by TLC, the reaction was quenched with saturated aqueous ammonium chloride (50 mL). The product was extracted with ethyl acetate (20 mL x 5). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 80:20 to 0:100) to afford compound 67A (1.48 g, 83.5%).

[0864] LC-MS (ESI): m / z = 352.1 [M+H] + .

[0865] Step 2: Dissolve the hydrochloride salt of compound 29B (300 mg, 0.879 mmol) and 67A (341 mg, 0.967 mmol) in dry dimethyl sulfoxide (6 mL). Add triethylamine (534 mg, 5.27 mmol) and cesium fluoride (267 mg, 1.76 mmol). After addition, heat to 100°C and react for approximately 5 hours. TLC analysis indicated the disappearance of the starting material. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 90:10) to afford compound 67B (460 mg, 89.5%).

[0866] LC-MS (ESI): m / z = 584.2 [M+H] + .

[0867] Step 3: Compound 67B (460 mg, 0.787 mmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL), methanol (4 mL), and water (4 mL). Lithium hydroxide monohydrate (132 mg, 3.15 mmol) was added at room temperature and allowed to react for 4 hours. After TLC monitoring of the disappearance of the starting material, the pH was adjusted to neutral with dilute hydrochloric acid. The mixture was concentrated under reduced pressure and directly purified by silica gel column chromatography (ethyl acetate:methanol (v / v) = 80:20 to 50:50) to obtain Compound 67, Isomer 1 (172 mg, 38.3%) and Compound 67, Isomer 2 (105 mg, 23.4%).

[0868] Compound 67, Isomer 1 (Rf = 0.25 (ethyl acetate:methanol (v / v) = 5:1): 1H NMR(400MHz,CD3OD)δ8.28-8.27(m,1H),7.23-7.22(m,1H),7.49-7.41(m,2H), 7.42-7.33(m,2H),7.27-7.26(m,1H),5.70-5.69(m,1H),4.21-4.01(m,3H),4. 00-3.83(m,2H),3.70-3.58(m,2H),2.87-2.68(m,4H),2.61-2.60(m,2H),1.98 -1.97(m,1H),1.80-1.79(m,2H),1.67(d,3H),1.61-1.60(m,1H),1.36(s,3H);

[0869] LC-MS (ESI): m / z = 570.2 [M+H] + .

[0870] Compound 67, Isomer 2 (Rf = 0.15 (ethyl acetate:methanol (v / v) = 5:1): 1 H NMR(400MHz,CD3OD)δ8.26-8.25(m,1H),7.71-7.70(m,1H),7.50-7.34(m,4 H),7.27-7.26(m,1H),5.70-5.69(m,1H),4.17-4.16(m,1H),4.13-4.00(m, 2H),3.99-3.87(m,2H),3.67-3.66(m,2H),2.98-2.70(m,4H),2.40-2.27(m ,2H),2.17-1.98(m,3H),1.80-1.68(m,1H),1.63-1.62(m,3H),1.40(s,3H).

[0871] LC-MS (ESI): m / z = 570.2 [M+H] + .

[0872] Example 68:

[0873] Step 1: Dissolve 29B (0.5 g, 1.47 mmol) and 68A (0.43 g, 1.47 mmol) in acetonitrile (20 mL). Add triethylamine (0.75 g, 7.35 mmol) and allow to react at room temperature for 16 hours. The mixture was concentrated under reduced pressure, added with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE:EA (v / v) = 10:1) to afford compound 68B (0.6 g, 78% yield).

[0874] LC-MS (ESI): m / z = 522.3 [M+H] + .

[0875] Step 2: 68B (0.55 g, 1.06 mmol), (R)-1-(2,4-dichlorophenyl)ethanamine (0.2 g, 1.06 mmol), Pd2(dba)3 (0.19 g, 0.21 mmol), BINAP (0.26 g, 0.42 mmol), and cesium carbonate (1.03 g, 3.18 mmol) were dissolved in 1,4-dioxane (40 mL) and reacted at 100°C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, added with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (DCM:MeOH (v / v) = 10:1) to obtain the target compound 68C (330 mg, 46% yield).

[0876] LC-MS (ESI): m / z = 675.3 [M+H] + .

[0877] Step 3: Compound 68C (0.33 g, 0.49 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride solution (2 mL, 4 M) was added. The mixture was allowed to react at room temperature for 30 min. After the reaction was complete, saturated sodium bicarbonate solution was added to adjust the pH to 8, followed by extraction with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound 68D, which was used directly in the next reaction without purification (0.28 g, 100%).

[0878] LC-MS (ESI): m / z = 575.3 [M+H] + .

[0879] Step 4: Compound 68D (180 mg, 0.31 mmol) and formaldehyde (24 mg, 40% formaldehyde solution) were dissolved in 1,2-dichloroethane (15 mL) and glacial acetic acid (19 mg, 0.31 mmol) was added. Sodium triacetoxyborohydride (131 mg, 0.62 mmol) was added in batches and allowed to react for 15 hours. After completion of the reaction, the mixture was quenched with water (20 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to afford the title compound 68E (180 mg, 97%).

[0880] LC-MS (ESI): m / z = 589.3 [M+H] + .

[0881] Step 5: Compound 68E (180 mg, 0.31 mmol) was dissolved in 4 mL of a (THF:H₂O (v / v) = 1:1) solution, and lithium hydroxide (82 mg, 3.1 mmol) was added. The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to afford the title compound 68, isomer 1 (Rf = 0.6 (dichloromethane:methanol = 10:1), 35 mg, 19.8%) and the title compound 68, isomer 2 (Rf = 0.4 (dichloromethane:methanol = 10:1), 15 mg, 8.5%).

[0882] Compound 68 Isomer 1: 1 H NMR (400MHz, CD3OD) δ7.41-7.39(m,2H),7.25-7.22(m,1H),5.37-5.31(m,1H),4.07-3.90(m,6H),3.78-3.77(m,2H),3.69-3.57(m,2H),2. 90-2.74(m,4H),2.66(s,3H),2.61-2.58(m,2H),2.06-1.96(m,4H),1 .86-1.81(m,2H),1.66-1.61(m,1H),1.45-1.44(d,3H),1.38(s,3H).

[0883] M / Z (ESI): m / z = 575.2 [M+H] + .

[0884] Compound 68 Isomer 2: 1H NMR (400MHz, CD3OD) δ7.41-7.39(m,2H),7.25-7.22(m,1H),5.37-5.31(m,1H),4.07-3.90(m,6H),3.71-3.59(m,4H),2. 91-2.70(m,4H),2.61(s,3H),2.35-2.30(m,2H),2.13-2.02(m,6H),1.78-1.68(m,1H),1.45-1.43(d,3H),1.38(s,3H).

[0885] M / Z (ESI): m / z = 575.2 [M+H] + .

[0886] Example 69:

[0887] Step 1: Compound 69A (3.8 g, 20.2 mmol) and ferric acetylacetonate (0.71 g, 2.0 mmol) were dissolved in THF (50 mL). The mixture was cooled to 0°C and methylmagnesium chloride (20 mL, 3 M in THF) was added dropwise. The reaction was continued for 1 hour after the addition was complete. The reaction was quenched by the addition of saturated ammonium chloride (100 mL). The mixture was extracted with ethyl acetate (120 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 3:1) to afford the target compound 69B (1.9 g, 56% yield).

[0888] LC-MS (ESI): m / z = 168.2 [M+H] + .

[0889] Step 2: Compound 69B (1.9 g, 11.3 mmol) was dissolved in DMF (30 mL) and cooled to 0°C. Sodium hydride (0.55 g, 13.6 mmol, 60% wt) was added. After 20 minutes at room temperature, 1-(1-bromoethyl)-2,4-dichlorobenzene (4.32 g, 17.0 mmol) was added dropwise. After complete addition, the mixture was allowed to warm to room temperature for 30 minutes. The reaction was quenched with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (80 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 4:1) to afford the target compound 69C (2.5 g, 65% yield). Chiral SFC was then used to separate the two isomers of compound 69C.

[0890] Separation method: Instrument: Waters 150 SFC, Column: Chiralcel OJ Column (250*30 mm, ID 30 mm, 10 μm particle size), Mobile phase: A for CO2 and B for IPA, Gradient: 15% phase B isocratic elution, Flow rate: 100 mL / min, Back pressure: 100 bar, Column temperature: 25°C, Wavelength: 220 nm, Cycle time: 2.9 min

[0891] Analytical Method: Instrument: Shimadzu LC-30AD SFC, Column: Chiralcel OJ-3 50×4.6 mm ID, 3 μm, Mobile Phase: A for CO2, B for 0.05% DEA in IPA, Gradient: B 5-40%, Flow Rate: 3 mL / min, Back Pressure: 100 bar, Column Temperature: 35°C, Wavelength: 220 nm. Retention Time: Compound 69C Isomer 1: 1.15 min, Compound 69C Isomer 2: 1.40 min.

[0892] Compound 69C Isomer 1: LC-MS M / Z (ESI) = 340.2 [M+H] + .

[0893] Compound 69C Isomer 2: LC-MS M / Z (ESI) = 340.2 [M+H] + .

[0894] Step 3: Compound 69C (Isomer 1) (0.34 g, 1.0 mmol) was dissolved in DMSO (20 mL), and compound 29B (0.34 g, 1.0 mmol) was added. After stirring, triethylamine (0.40 g, 4.0 mmol) and cesium fluoride (0.30 g, 2.0 mmol) were added sequentially. After completion of the addition, the temperature was raised to 100°C and the reaction was allowed to react for 36 hours. The reaction solution was cooled to room temperature, water (40 mL) was added, and extraction was performed with ethyl acetate (40 mL x 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH (v / v) = 12:1) to obtain the target compound 69D (Isomer 1) (0.16 g, 28% yield).

[0895] LC-MS M / Z (ESI) = 572.2 [M+H] + .

[0896] 69C (isomer 2) (0.34 g, 1.0 mmol) was dissolved in DMSO (20 mL), and 29B (0.34 g, 1.0 mmol) was added. After stirring, triethylamine (0.40 g, 4.0 mmol) and cesium fluoride (0.30 g, 2.0 mmol) were added sequentially. After completion of the addition, the mixture was reacted at 100°C for 36 hours. The reaction solution was cooled to room temperature, and water (40 mL) was added. The mixture was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH (v / v) = 12:1) to obtain the target compound 69D (isomer 2) (0.14 g, 24% yield).

[0897] LC-MS M / Z (ESI) = 572.2 [M+H] + .

[0898] Step 4: Compound 69D (isomer 1) (0.16 g, 0.28 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (3 mL) and water (3 mL) were added, and the mixture was stirred evenly. Lithium hydroxide monohydrate (0.12 g, 3 mmol) was added and reacted at room temperature for 3 hours. The pH was adjusted to 5 with hydrochloric acid (1N aqueous solution). The system was concentrated under reduced pressure and directly separated by silica gel column chromatography (EA:MeOH (v / v) = 10:1) to obtain two isomers of the target compound 69 (isomer 1: Rf = 0.48 (EA:MeOH (v / v) = 10:1); isomer 2: Rf = 0.32 (EA:MeOH (v / v) = 10:1)).

[0899] Compound 69 Isomer 1: 1 H NMR(400MHz,Methanol-d4)δ7.35(d,1H),7.20-7.11(m,2H),7.03(d,1H),6.3 6(d,1H),6.06(q,1H),4.04-3.86(m,3H),3.85-3.72(m,2H),3.61-3.50(m,2H ),2.88-2.76(m,1H),2.76-2.66(m,2H),2.65-2.54(m,1H),2.53-2.45(m,2H) ,2.41(s,3H),2.02-1.92(m,1H),1.81-1.70(m,5H),1.65(t,1H),1.26(s,3H).

[0900] LC-MS (ESI): m / z = 558.2 [M+H] + .

[0901] Compound 69 Isomer 2:1 H NMR(400MHz,Methanol-d4)δ7.35(d,1H),7.21-7.12(m,2H),7.04(d,1H),6.37 (d,1H),6.08(q,1H),4.06-3.85(m,4H),3.83-3.76(m,1H),3.69-3.58(m,2H),3 .07-2.96(m,1H),2.90(t,2H),2.70-2.58(m,1H),2.42(s,3H),2.38-2.30(m,2H ),2.25-2.15(m,1H),2.05-1.97(m,2H),1.89(t,1H),1.73(d,3H),1.30(s,3H).

[0902] LC-MS (ESI): m / z = 558.2 [M+H] + .

[0903] Compound 69D (isomer 2) (0.14 g, 0.24 mmol) was dissolved in tetrahydrofuran (10 mL), and methanol (3 mL) and water (3 mL) were added. After stirring, lithium hydroxide monohydrate (0.12 g, 3 mmol) was added and the mixture was reacted at room temperature for 3 hours. The pH was adjusted to 5 with hydrochloric acid (1N aqueous solution). The system was concentrated under reduced pressure and directly separated by silica gel column chromatography (EA:MeOH (v / v) = 10:1) to obtain the other two isomers of the target compound 69 (isomer 3: Rf = 0.49 (EA:MeOH (v / v) = 10:1); isomer 4: Rf = 0.31 (EA:MeOH (v / v) = 10:1)).

[0904] Compound 69 Isomer 3: 1 H NMR(400MHz,Methanol-d4)δ7.50-7.46(m,1H),7.33-7.23(m,2H),7.16(d,1H) ,6.49(d,1H),6.19(q,1H),4.12-4.05(m,2H),3.99-3.86(m,3H),3.73-3.63(m, 2H),2.99-2.90(m,1H),2.89-2.78(m,2H),2.77-2.68(m,1H),2.66-2.59(m,2H ),2.54(s,3H),2.14-2.05(m,1H),1.94-1.82(m,5H),1.77(t,1H),1.39(s,3H).

[0905] LC-MS (ESI): m / z = 558.2 [M+H] + .

[0906] Compound 69 Isomer 4: 1 H NMR(400MHz,Methanol-d4)δ7.48(d,1H),7.33-7.23(m,2H),7.16(d,1H),6.49(d,1H) ,6.20(q,1H),4.13-4.04(m,2H),4.02-3.89(m,3H),3.80-3.70(m,2H),3.16-3.07(m, 1H),3.07-2.96(m,2H),2.80-2.70(m,1H),2.54(s,3H),2.50-2.40(m,2H),2 .35-2.25(m,1H),2.17-2.08(m,2H),2.00(t,1H),1.86(d,3H),1.42(s,3H).

[0907] LC-MS (ESI): m / z = 558.2 [M+H] + .

[0908] Example 70:

[0909] Step 1: 3-Oxocyclobutane-1-carbonitrile (3.00 g, 31.49 mmol), p-toluenesulfonic acid monohydrate (0.27 g, 1.57 mmol), and ethylene glycol (2.1 g, 34.64 mmol) were added to toluene (60 mL) in sequence and refluxed for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 20:1 to 2:1) to afford product 70B (3.25 g, 74.17%).

[0910] 1 H NMR (400MHz, Chloroform-d) δ3.91 (s, 4H), 2.93-2.82 (m, 1H), 2.79-2.66 (m, 4H).

[0911] Step 2: Dissolve 70B (3.25 g, 23.36 mmol) in anhydrous tetrahydrofuran (32 mL), cool to -78°C, and add a solution of lithium diisopropylamide in tetrahydrofuran (7.01 mL, 28.03 mmol) dropwise. After stirring for 1 hour, add iodomethane (4.31 g, 30.31 mmol) dropwise. After complete addition, warm to room temperature and react for 16 hours. Add water (120 mL) and ethyl acetate (100 mL), extract, separate, and extract the aqueous phase with ethyl acetate (100 mL x 3). The combined organic phases are washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 20:1 to 1:1) to obtain product 70C (2.33 g, 65.11%).

[0912] 1 H NMR (400MHz, Chloroform-d) δ3.93-3.88(m,4H),2.97-2.93(m,1H),2.93-2.89(m,1H),2.44-2.40(m,1H),2.40-2.34(m,1H),1.59(s,3H).

[0913] Step 3: Dissolve 70C (2.33 g, 15.21 mmol) in acetone (46 mL), add 6N hydrochloric acid (4.6 mL, 27.53 mmol), and stir at room temperature for 16 hours. Stop the reaction and concentrate to remove the solvent to obtain crude product 70D (1.72 g).

[0914] 1 H NMR (400MHz, Chloroform-d) δ3.77-3.73(m,1H),3.73-3.68(m,1H),3.20-3.15(m,1H),3.15-3.09(m,1H),1.73(s,3H).

[0915] Step 4: Dissolve 9J-2 (2.25 g, 9.29 mmol) and 70D (1.72 g, 11.06 mmol) in DCE (40 mL). Add acetic acid (0.26 g, 9.29 mmol). After stirring at room temperature for 1 hour, sodium cyanoborohydride (1.17 g, 18.58 mmol) was added portionwise. After complete addition, the mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, water (50 mL) was added, and the mixture was extracted. The layers were separated, and the aqueous phase was extracted with dichloromethane (50 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was isolated and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1 to 1:1) to afford 70E (0.79 g, 25.35%).

[0916] LCMS (ESI): m / z = 336.3 [M+H] + .

[0917] Step 5: Dissolve 70E (0.10 g, 0.30 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL) dropwise, and stir at room temperature for 2 hours. After completion of the reaction, monitor by LCMS, concentrate to remove most of the trifluoroacetic acid, and dissolve the residue in anhydrous DMSO (3 mL). Add 2F (0.13 g, 0.37 mmol), DIEA (0.20 g, 1.51 mmol), and cesium fluoride (91 mg, 0.60 mmol) in that order. Heat to 102°C and react for 2 hours. After completion of the reaction, cool to room temperature, add water (15 mL) and ethyl acetate (15 mL), extract, and separate. The aqueous phase is extracted with ethyl acetate (15 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. The residue is purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1 to 1:4) to afford compound 70 (61 mg, 36.98%).

[0918] 1 H NMR(400MHz,Chloroform-d)δ7.38-7.32(m,1H),7.25-7.20(m,1H),7.20-7.14(m,1H ),5.58-5.46(m,1H),5.46-5.37(m,1H),4.02-3.93(m,1H),3.91-3.81(m,2H),3.81-3 .66(m,2H),3.65-3.51(m,2H),2.90-2.80(m,1H),2.64-2.50(m,3H),2.50-2.40(m,2H ),2.30(s,3H),2.23-2.15(m,2H),1.98-1.88(m,1H),1.55(s,3H),1.53-1.49(m,3H).

[0919] LCMS m / z=549.2[M+H] + .

[0920] Example 71:

[0921] Step 1: Dissolve 70E (0.67 g, 2.00 mmol) in DMF (12 mL), add sodium azide (0.78 g, 12 mmol) and ammonium chloride (0.64 g, 12 mmol), replace the atmosphere with nitrogen, and heat at 140°C for 5 hours. Stop the reaction, cool to room temperature, and perform reverse phase purification to obtain a crude product. The crude product was concentrated to dryness and purified by column chromatography (dichloromethane:methanol (v / v) = 100:1 to 4:1) to afford 71A (0.12, 15.85%).

[0922] LCMS m / z=579.1[M+H] + .

[0923] Step 2: Dissolve 71A (0.12 g, 0.32 mmol) in dichloromethane (4 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 2 hours. After completion of the reaction as monitored by LCMS, concentrate to remove most of the trifluoroacetic acid. The resulting residue is dissolved in anhydrous DMSO (3 mL), and 2F (0.13 g, 0.38 mmol), DIEA (0.21 g, 1.60 mmol), and cesium fluoride (97 mg, 0.64 mmol) are added. The temperature is raised to 102°C and the reaction is allowed to react for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and water (15 mL) and ethyl acetate (15 mL) were added. The liquid phase was separated, and the aqueous phase was extracted with ethyl acetate (15 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (dichloromethane: methanol (v / v) = 100:1 to 1:4) to obtain a crude product. The crude product was further purified by thin layer chromatography (dichloromethane: methanol (v / v) = 10:1) to obtain compound 71 isomer 1 (Rf = 0.35 (dichloromethane: methanol = 10:1), 12 mg, 6.32%) and compound 71 isomer 2 (Rf = 0.40 (dichloromethane: methanol = 10:1), 30 mg, 15.81%).

[0924] Compound 71 Isomer 1: 1 H NMR(400MHz,Chloroform-d)δ7.38-7.34(m,1H),7.24-7.20(m,1H),7.20-7.15( m,1H),5.66-5.60(m,1H),5.48-5.39(m,1H),4.01-3.93(m,1H),3.93-3.78(m,3H ),3.78-3.58(m,3H),3.02-2.93(m,1H),2.83-2.64(m,4H),2.63-2.51(m,1H),2. 23(s,3H),2.24-2.12(m,2H),2.05-1.95(m,1H),1.61(s,3H),1.55-1.46(m,3H).

[0925] LCMS m / z=592.1[M+H] + .

[0926] Compound 71 Isomer 2: 1H NMR(400MHz, Methanol-d4)δ7.43-7.39(m,1H),7.37-7.33(m,1H),7.27-7.21(m,1H),5.51-5.42(m ,1H),3.94-3.86(m,2H),3.86-3.80(m,1H),3.80-3.74(m,1H),3.73-3.66(m,1H),3.66-3.57(m,1H) ,3.57-3.51(m,1H),3.18-3.09(m,1H),2.80-2.78(m,2H),2.65-2.57(m,1H),2.50-2.42(m,2H),2. 38-2.30(m,2H),2.26(s,3H),2.16-2.08(m,1H),1.78-1.70(m,1H),1.59(s,3H),1.52-1.46(m,3H).

[0927] LCMS m / z=592.3[M+H] + .

[0928] Example 72:

[0929] Step 1: Potassium carbonate (14.33 g, 103.71 mmol) and 1,2-dibromoethane (12.99 g, 69.14 mmol) were added to a solution of 72A (5 g, 34.57 mmol) in ethylene glycol (50 mL). The mixture was then heated to 100°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, and water (50 mL) and ethyl acetate (60 mL) were added. The mixture was separated and the aqueous phase was extracted with ethyl acetate (60 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to afford 72B (3.47 g, 59%).

[0930] LC-MS (ESI): m / z = 171.1 [M+H] + .

[0931] Step 2: Acetyl chloride (3.19 g, 40.68 mmol) was added to a solution of 72B (3.47 g, 20.34 mmol) in dichloromethane (40 mL). Aluminum chloride (5.42 g, 40.68 mmol) was added portionwise and the mixture was allowed to react at 45°C for 3 h. After completion of the reaction, the mixture was cooled to room temperature and poured into ice water. The layers were separated and the aqueous phase was extracted with dichloromethane (50 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) to afford 72C (3.9 g, 90%).

[0932] LC-MS (ESI): m / z = 213.1 [M+H] + .

[0933] Step 3 to Step 6: Using (R)-(+)-tert-butylsulfenamide (2.67 g, 22.01 mmol) and 72C (3.9 g, 18.34 mmol) as raw materials, refer to the third to sixth steps of Example 7 to obtain compound 72G-1 and compound 72G-2.

[0934] LCMS (ESI): m / z = 374.1 [M+H] + .

[0935] Step 7: Add 9J-2 (130 mg, 0.53 mmol), DIEA (210 mg, 1.59 mmol) and cesium fluoride (240 mg, 1.59 mmol) to a DMSO (4 mL) solution of compound 72G-1 (200 mg, 0.53 mmol), and heat to 100 °C for 2 hours. After completion of the reaction, water (15 mL) and ethyl acetate (15 mL) were added, and the liquids were separated. The aqueous phase was extracted with ethyl acetate (15 mL×2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (EA:MeOH (v / v) = 5:1) to give compound 72 isomer 1 (Rf = 0.5, (EA:MeOH (v / v) = 3:1), 200 mg, 64%) and compound 72 isomer 2 (Rf = 0.4, (EA:MeOH (v / v) = 3:1), 50 mg, 16%).

[0936] Compound 72 Isomer 1: 1 H NMR (400MHz, CDCl3) δ = 6.85 (s, 1H), 6.78 (s, 1H), 5.56-5.55 (m, 1H), 5.44-5.36 (m, 1H), 4.22 (s, 4H), 4.02-4.01 (m, 1H), 3.91-3.83 (m, 4H) ,3.76-3.64(m,2H),2.97-2.88(m,1H),2.80-2.73(m,2H),2.62-2.49(m,3H),2.30(s,3H),2.08-2.04(m,3H),1.91(m,1H),1.48-1.47(m, 3H),1.40(s,3H).

[0937] LCMS (ESI): m / z = 592.2 [M+H] + .

[0938] Compound 72 Isomer 2: 1 H NMR(400MHz, CDCl3)δ=6.84(s,1H),6.78(s,1H),5.48-5.47(m,1H),5.41-5.32(m,1H),4.21(s,4H),4.04-3.85(m,5H),3.84-3.68(m,2H),3 .03-2.94(m,1H),2.88-2.82(m,2H),2.60-2.52(m,3H),2.29(s,3H), 2.17-2.05(m,3H),1.77-1.72(m,1H),1.48-1.47(m,3H),1.42(s,3H).

[0939] LCMS (ESI): m / z = 592.2 [M+H] + .

[0940] By referring to the above operation, compound 72G-2 was used as the starting material (0.1 g, 0.27 mmol) to obtain the title compound 72 isomer 3 (Rf = 0.4, (EA:MeOH (v / v) = 3:1), 50 mg, 31%) and compound 72 isomer 4 (Rf = 0.3, (EA:MeOH (v / v) = 3:1), 20 mg, 13%).

[0941] Compound 72 Isomer 3: 1 H NMR (400MHz, CDCl3) δ = 6.86 (s, 1H), 6.78 (s, 1H), 5.52-5.51 (m, 1H), 5.41- 5.39(m,1H),4.21(s,4H),4.03-4.02(m,1H),3.98-3.78(m,4H),3.69-3.61 (m,2H),2.88-2.80(m,1H),2.75-2.71(m,2H),2.60-2.56(m,3H),2.30(s, 3H),2.02-1.83(m,3H),1.58-1.57(m,1H),1.48-1.46(m,3H),1.39(s,3H).

[0942] LCMS (ESI): m / z = 592.2 [M+H] + .

[0943] Compound 72 Isomer 4: 1H NMR(400MHz, CDCl3)δ6.85(s,1H),6.78(s,1H),5.49-5.48(m,1H),5.41-5.39(m,1H),4.21(s,4H),3.99-3.98(m,1H),3.96-3.76(m,6H),3 .01-3.00(m,2H),2.89-2.82(m,1H),2.66-2.56(m,3H),2.28(s,3H), 2.13-2.05(m,3H),1.74-1.73(m,1H),1.48-1.47(m,3H),1.42(s,3H).

[0944] LCMS (ESI): m / z = 592.2 [M+H] + .

[0945] Example 73:

[0946] Step 1: Compound 73A (40.0 g, 187.5 mmol) was dissolved in methanol (400 mL). Nitromethane (45.8 g, 750.2 mmol) and triethylamine (37.9 g, 375.1 mmol) were added sequentially. The mixture was stirred at room temperature for 17 hours. The crude product 73B (55.0 g) was obtained by concentration and used directly in the next step without further purification.

[0947] LCMS m / z=219.1[M+H- t Bu] + .

[0948] Step 2: Compound 73B (55.0 g, 200.5 mmol) was dissolved in methanol (550 mL) and Pd / C (11.0 g, 10% Pd content) was added. The mixture was reacted under a hydrogen atmosphere at room temperature for 24 hours. The filtrate was filtered and concentrated to afford crude compound 73C (40.0 g, 82%), which was used directly in the next step without further purification.

[0949] LCMS m / z=189.2[M+H- t Bu] + .

[0950] Step 3: Compound 73C (40.0 g, 163.7 mmol) was dissolved in a mixture of ethyl acetate (200 mL) and water (200 mL). Sodium bicarbonate (41.2 g, 491.1 mmol) was added. The temperature was cooled to 5°C, and chloroacetyl chloride (27.7 g, 245.6 mmol) was added dropwise. The temperature was maintained at 5-10°C. After the addition was complete, the mixture was warmed to room temperature and allowed to react for 1 hour. After the reaction was complete, water (100 mL) was added and extracted with ethyl acetate (300 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2) to afford the title compound 73D (30.0 g, 57%).

[0951] LCMS m / z=221.1[M+H-Boc] + .

[0952] Step 4: Potassium tert-butoxide (20.9 g, 187.0 mmol) was added to tert-butanol (200 mL), followed by a solution of compound 73D (30.0 g, 93.5 mmol) in tert-butanol (100 mL). The mixture was stirred at 30-40°C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride (200 mL). The mixture was extracted with ethyl acetate (300 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2) to afford the title compound 73E (23.6 g, 89%).

[0953] LCMS m / z=185.2[M+H-Boc] + .

[0954] Step 5: Under a nitrogen atmosphere, compound 73E (23.6 g, 83.0 mmol) was dissolved in toluene (230 mL), cooled to -10°C, and sodium 2-hydrogen bis(dimethoxyethoxy)aluminate (71.1 mL, 3.5 mol / L toluene solution) was slowly added dropwise. After the addition was complete, the reaction was continued at -10°C for 3 hours. After the reaction was complete, 10% aqueous sodium hydroxide solution (50 mL) was slowly added dropwise to quench the reaction. After quenching, ethyl acetate (100 mL) was added to the reaction solution and extracted. The organic phase was washed with water (50 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 73F (20.3 g, 90%).

[0955] LCMS m / z=215.2[M+H- t Bu] + .

[0956] Step 6: Compound 73F (8.0 g, 29.6 mmol) was dissolved in a mixture of tetrahydrofuran (50 mL) and water (50 mL), and sodium bicarbonate (7.4 g, 88.8 mmol) was added. The temperature was lowered to 0-5°C, and benzyl chloroformate (6.0 g, 35.6 mmol) was slowly added dropwise. After the addition was complete, the reaction was continued at 0-5°C for 1 hour. After completion of the reaction, water (100 mL) and ethyl acetate (150 mL x 2) were added for extraction. The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) to afford 10.0 g of the racemate. The racemate was separated by chiral preparative HPLC to yield two isomers, compound 73G-1 (3.8 g, 32%) and compound 73G-2 (3.5 g, 29%).

[0957] LCMS m / z=305.2[M+H-Boc] + .

[0958] Preparative chromatography conditions: 1. Instrument: Waters 150 SFC; 2. Column: Chiralcel OX Column (250×30 mm, ID 30 mm, 10 μm particle size); 3. Mobile phase system: A for CO2 and B for IPA (0.1% NH3·H2O); 4. Gradient: B 25%; 5. Flow rate: 100 mL / min.

[0959] HPLC Analysis Method: 1. Instrument: SHIMADZU LC-30AD; 2. Column: Whelk-O1 column; 3. Mobile phase: A for CO2; B for 0.05% DEA in MEOH; 4. Gradient: B 5-40%; 5. Flow rate: 3 mL / min. Compound 73G-1 (retention time 1.46 min) and compound 73G-2 (retention time 1.55 min) were detected.

[0960] Step 7: Compound 73G-1 (3.8 g, 9.4 mmol) was dissolved in ethyl acetate (40 mL), and Pd / C (0.8 g, 10% Pd content) was added. The mixture was reacted under a hydrogen atmosphere at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated to obtain the title compound 73H-1 (2.3 g, 91%).

[0961] Referring to the above operation, compound 73G-2 (3.5 g, 9.0 mmol) was used as the starting material to obtain the title compound 73H-2 (2.1 g, 90%).

[0962] LCMS m / z=215.3[M+H- t Bu] + .

[0963] Step 8: Compound 73H-1 (200 mg, 0.74 mmol) and 3-carbonyl-1-methyl-cyclobutanecarboxylic acid (113.7 mg, 0.89 mmol) were sequentially dissolved in methanol (5 mL). Glacial acetic acid (44.4 mg, 0.74 mmol) was added, followed by sodium cyanoborohydride (93.2 mg, 1.48 mmol). The mixture was allowed to react at room temperature for 30 minutes. After completion of the reaction, water (2 mL) was added to quench the reaction, followed by extraction with dichloromethane (5 mL × 2). The combined organic phases were washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to afford the title compound 73I-1 (200 mg, 71%).

[0964] By referring to the above operation, compound 73H-2 (200 mg, 0.74 mmol) was used as the starting material to obtain the title compound 73I-2 (200 mg, 71%).

[0965] LCMS m / z=383.6[M+H] + .

[0966] Step 9: Dissolve compound 73I-1 (200 mg, 0.52 mmol) in dichloromethane (4 mL), add trifluoroacetic acid (1 mL), and react at room temperature for 2 h. After the reaction is complete, concentrate to obtain the trifluoroacetic acid salt of compound 73J-1 (146 mg, 99%).

[0967] Referring to the above operation, compound 73I-2 (200 mg, 0.52 mmol) was used as the starting material to obtain the trifluoroacetic acid salt of the title compound 73J-2 (142 mg, 96%).

[0968] LCMS m / z=283.4[M+H] + .

[0969] Step 10: Compound 2F (90.5 mg, 0.26 mmol) and compound 73J-1 (146 mg, 0.52 mmol) were dissolved in dimethyl sulfoxide (2 mL) in sequence, N,N-diisopropylethylamine (199.7 mg, 1.56 mmol) and cesium fluoride (160.2 mg, 1.04 mmol) were added, and the temperature was raised to 100°C for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, water (2 mL) was added, and the mixture was extracted with ethyl acetate (5 mL×3). The combined organic phases were washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was separated and purified by silica gel column chromatography (ethyl acetate: methanol (v / v) = 9:1) to give the title compound 73 isomer 1 (Rf = 0.3 (ethyl acetate: methanol (v / v) = 9:1), 30.0 mg, 10%) and the title compound 73 isomer 2 (Rf = 0.2 (ethyl acetate: methanol (v / v) = 9:1), 10.0 mg, 3%).

[0970] Compound 73 Isomer 1: 1 H NMR (400MHz, CDCl3) δ7.35-7.32(m,1H),7.24-7.21(m,1H),7.17-7.13(m,1H), 5.43-5.34(m,2H),4.58-4.47(m,2H),3.94-3.87(m,1H),3.72-3.62(m,1H),3. 35-3.28(m,1H),2.98-2.89(m,2H),2.85-2.78(m,1H),2.63-2.38(m,7H),2.27 (s,3H),2.06-1.98(m,4H),1.76-1.70(m,1H),1.51-1.48(m,3H),1.37(s,3H).

[0971] LCMS m / z=596.2[M+H] + .

[0972] Compound 73 Isomer 2: 1H NMR (400MHz, CDCl3) δ7.35-7.32(m,1H),7.24-7.21(m,1H),7.17-7.13(m,1H), 5.43-5.34(m,2H),4.58-4.47(m,2H),3.94-3.88(m,1H),3.71-3.62(m,1H),3. 35-3.21(m,1H),2.98-2.88(m,2H),2.85-2.78(m,1H),2.63-2.38(m,7H),2.27 (s,3H),2.06-1.98(m,4H),1.76-1.71(m,1H),1.51-1.48(m,3H),1.37(s,3H).

[0973] LCMS m / z=596.2[M+H] + .

[0974] Referring to the above operation, compound 73J-2 (142 mg, 0.50 mmol) was used as the starting material to obtain the title compound 73 isomer 3 (Rf = 0.3 (ethyl acetate:methanol (v / v) = 9:1), 50.0 mg, 17%) and the title compound 73 isomer 4 (Rf = 0.2 (ethyl acetate:methanol (v / v) = 9:1), 8.0 mg, 3%). Compound 73 isomer 3: 1 H NMR (400MHz, CDCl3) δ7.35-7.33(m,1H),7.23-7.20(m,1H),7.16-7.13(m, 1H),5.44-5.36(m,2H),4.58-4.46(m,2H),3.90-3.83(m,1H),3.64-3.57( m,1H),3.23-3.16(m,1H),2.87-2.49(m,8H),2.27(s,3H),1.98-1.84(m,3 H),1.77-1.63(m,2H),1.58-1.51(m,2H),1.50-1.48(m,3H),1.40(s,3H).

[0975] LCMS m / z=596.2[M+H] + .

[0976] Compound 73 Isomer 4: 1H NMR (400MHz, CDCl3) δ7.36-7.33(m,1H),7.23-7.20(m,1H),7.17-7.14(m,1H), 5.46-5.35(m,2H),4.60-4.45(m,2H),3.97-3.90(m,1H),3.80-3.69(m,1H),3. 40-3.31(m,1H),3.10-3.01(m,2H),2.63-2.50(m,6H),2.28(s,3H),2.19-2.08 (m,4H),1.90-1.83(m,1H),1.70-1.59(m,2H),1.52-1.49(m,3H),1.40(s,3H).

[0977] LCMS m / z=596.2[M+H] + .

[0978] Example 74:

[0979] Step 1: Compound 74A (50.0 g, 253.46 mmol) was dissolved in dichloromethane (1000 mL), and selenium oxide (14.06 g, 126.73 mmol) was added. The temperature was lowered to 0-5°C, and tert-butyl hydroperoxide (81.58 g, 633.65 mmol, 70% aqueous solution) was slowly added dropwise. The temperature was maintained at 0-5°C for 15 hours. After completion of the reaction, saturated aqueous sodium bisulfite solution (300 mL) was slowly added dropwise. After quenching, the layers were separated, and the aqueous phase was extracted with dichloromethane (150 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to obtain compound 74B (25.0 g, 46.2%).

[0980] Step 2: Under a nitrogen atmosphere, compound 74B (25.0 g, 117.24 mmol) was dissolved in toluene (250 mL). The temperature was controlled at 25-30°C, and diethylzinc (235 mL, 235.0 mmol, 1.0 mol / L n-hexane solution) was added dropwise. After the addition was complete, the mixture was stirred for 0.5 hours. Diiodomethane (94.20 g, 351.72 mmol) was slowly added dropwise. After the addition was complete, the reaction was continued at 25-30°C for 1 hour. After the reaction was complete, the temperature was lowered to 0-5°C, and saturated aqueous ammonium chloride (100 mL) was slowly added dropwise to quench the reaction. After quenching, the filtrate was filtered and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to obtain compound 74C (23.0 g, 86.3%).

[0981] Step 3: Compound 74C (23.00 g, 101.19 mmol) was dissolved in dichloromethane (250 mL), cooled to 0°C, and Dess-Martin periodinane (85.84 g, 202.38 mmol) was added portionwise. After complete addition, the mixture was allowed to warm to room temperature and allowed to react for 2 hours. After completion, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate (200 mL). After quenching, the filtrate was filtered through celite and separated. The aqueous phase was extracted with dichloromethane (100 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 74D (22.00 g, 96.5%).

[0982] Step 4: Under a nitrogen atmosphere, triethyl phosphoacetate (43.79 g, 195.32 mmol) was dissolved in tetrahydrofuran (200 mL). The temperature was maintained at 0-5°C. Sodium hydride (5.86 g, 146.5 mmol, 60% content) was added portionwise. Stirring was continued for 0.5 hour after the addition. A solution of compound 74D (22.00 g, 97.66 mmol) in tetrahydrofuran (100 mL) was added dropwise. After the addition was complete, the temperature was naturally warmed to room temperature and allowed to react for 1 hour. After completion of the reaction, saturated aqueous ammonium chloride (100 mL) was added to quench the reaction. After quenching, the mixture was extracted with ethyl acetate (150 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 4:1) to obtain compound 74E (25.0 g, 86.7%).

[0983] Step 5: Compound 74E (25.0 g, 84.64 mmol) was dissolved in methanol (250 mL) and Lindela's catalyst (9.01 g, 5% Pd content) was added. The reaction was allowed to proceed under a hydrogen atmosphere for 3 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated to afford crude compound 74F (23.0 g, 91.3%), which was used directly in the next step without further purification.

[0984] Step 6: Under a nitrogen atmosphere, compound 74F (23.0 g, 77.34 mmol) was dissolved in tetrahydrofuran (250 mL), cooled to -78°C, and lithium diisopropylamide (135 mL, 270.68 mmol, 2 mol / L) was slowly added dropwise. After the addition was complete, the temperature was maintained below -70°C and the reaction continued for 0.5 hour. Paraformaldehyde (23.22 g, 773.33 mmol) was added portionwise. After the addition was complete, the temperature was slowly warmed to room temperature and the reaction continued for 15 hours. After completion, the reaction was quenched by the addition of saturated aqueous ammonium chloride (300 mL) and extracted with ethyl acetate (150 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to obtain compound 74G (17.0 g, 67.1%).

[0985] Step 7: Under a nitrogen atmosphere, compound 74G (17.0 g, 51.92 mmol) was dissolved in tetrahydrofuran (200 mL). The temperature was lowered to 0-5°C, and lithium aluminum hydride (3.94 g, 103.84 mmol) was added in batches. After the addition was complete, the temperature was maintained at 0-5°C and the reaction was allowed to proceed for 2 hours. After the reaction was complete, water (4.0 mL) was slowly added dropwise while the temperature was maintained at 0°C. After the addition was complete, the mixture was stirred for 10 minutes. A 15% aqueous sodium hydroxide solution (4.0 mL) was then added dropwise. After the addition was complete and the mixture was stirred for 10 minutes, water (12.0 mL) was added dropwise again. After the addition was complete, anhydrous magnesium sulfate was added and stirred for 1 hour. The mixture was filtered and the filtrate was concentrated. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain compound 74H (11.0 g, 74.2%).

[0986] Step 8: Compound 74H (11.0 g, 38.55 mmol) was dissolved in dichloromethane (200 mL), and 4-dimethylaminopyridine (18.84 g, 154.2 mmol) was added. The temperature was lowered to 0-5°C, and p-toluenesulfonyl chloride (22.05 g, 115.66 mol) was added portionwise. After the addition was complete, the mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, water was added to quench the reaction, followed by extraction with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to afford compound 74I (19.1 g, 83.5%).

[0987] Step 9: Compound 74I (19.1 g, 32.17 mmol) was dissolved in acetonitrile (200 mL), and benzylamine (10.34 g, 96.51 mmol) was added. The mixture was then heated to 80°C and reacted for 15 hours. After completion of the reaction, the mixture was concentrated, and the residue was separated by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to afford the racemate of compound 74J. The racemate was then separated by chiral preparative HPLC to yield two isomers: compound 74J-1 (1.0 g, retention time 1.70 min, 8.72%) and compound 74J-2 (1.1 g, retention time 1.85 min, 9.6%).

[0988] HPLC analysis method: 1. Instrument: SHIMADZU LC-30AD SFC; 2. Chromatographic column: Chiralcel OX-3 50×4.6 mm ID, 3 μm; 3. Mobile phase system: A for CO2, B for 0.05% DEA in MeOH; 4. Gradient: B 5-40%; 5. Flow rate: 3 mL / min.

[0989] Preparative chromatography conditions: 1. Instrument: Waters 150 SFC; 2. Column: Chiralpak OX–Column (250×30 mm, ID 30 mm, 10 μm particle size); 3. Mobile phase system: A for CO2 and B for MeOH+ACN (0.1% NH3·H2O); 4. Gradient: B 20%; 5. Flow rate: 100 mL / min; 6. Elution time: 5.2 min.

[0990] Step 10: Compound 74J-1 (1.0 g, 2.81 mmol) was dissolved in a mixed solvent of dichloromethane (10 mL) and trifluoroacetic acid (3 mL) and stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated and the residue was dissolved in dichloromethane (50 mL). Saturated aqueous sodium bicarbonate was added to adjust the pH to 7-8. The mixture was extracted and separated. The aqueous phase was extracted with dichloromethane (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude compound 74K-1 (0.68 g, 94.3%), which was used directly in the next reaction without further purification.

[0991] Referring to the above operation, compound 74J-2 (1.0 g, 3.09 mmol) was used as the starting material to obtain the title compound 74K-2 (0.73 g, 92.1%).

[0992] Step 11: Compound 74K-1 (0.68 g, 2.65 mmol) and 3-carbonyl-1-methyl-cyclobutanecarboxylic acid (0.41 g, 3.21 mmol) were dissolved in methanol (10 mL) and glacial acetic acid (0.32 g, 5.33 mmol) was added. Sodium cyanoborohydride (0.33 g, 5.25 mmol) was added in batches and allowed to react for 1 hour. After completion of the reaction, the mixture was concentrated and the residue was purified using a reverse-phase column (0.2% aqueous trifluoroacetic acid:acetonitrile (v / v) = 5:95 to 95:5) to afford the trifluoroacetate salt of the title compound 74L-1 (1.0 g, 63.26%).

[0993] Referring to the above operation, compound 74K-2 (0.73 g, 2.85 mmol) was used as the starting material to obtain the trifluoroacetic acid salt of the title compound 74L-2 (1.1 g, 64.7%).

[0994] M / Z (ESI): m / z = 369.2 [M+H] + .

[0995] Step 12: Compound 74L-1 (1.0 g, 1.68 mmol) was dissolved in methanol (10 mL), and Pd / C (0.18 g, 10% Pd content) was added. The mixture was reacted under a hydrogen atmosphere for 15 hours. The filtrate was filtered and concentrated to afford crude compound 74M-1 (0.80 g, 94.0%), which was used in the next step without further purification.

[0996] Referring to the above operation, compound 74L-2 (11 g, 1.84 mmol) was used as the starting material to obtain the trifluoroacetic acid salt of the title compound 74M-2 (0.85 g, 91.2%).

[0997] M / Z (ESI): m / z = 279.2 [M+H] + .

[0998] Step 13: Compound 66G (90.0 mg, 0.23 mmol) and compound 74M-1 (233.0 mg, 0.46 mmol) were dissolved in dimethyl sulfoxide (5 mL) in sequence. N,N-diisopropylethylamine (0.12 g, 0.93 mmol) and cesium fluoride (70 mg, 0.46 mmol) were added. After the addition, the temperature was raised to 100°C and the reaction was carried out for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was separated and purified by silica gel column chromatography (ethyl acetate: methanol (v / v) = 10:1) to give the title compound 74 isomer 1 (Rf = 0.5 (ethyl acetate: methanol = 10:1), 20.0 mg, 13.8%) and the title compound 74 isomer 2 (Rf = 0.3 (dichloromethane: methanol = 10:1), 10.0 mg, 6.9%).

[0999] Compound 74 Isomer 1: 1 H NMR(400MHz,CD3OD)δ7.32(d,1H),7.28(d,1H),7.18-7.15(m,1H),6.71-6.44(m,1H) ,5.41-5.39(m,1H),3.97-3.93(m,1H),3.85-3.78(m,1H),3.65-3.62(m,1H),3.42-3. 34(m,1H),2.75-2.45(m,7H),1.97-1.92(m,1H),1.87-1.82(m,1H),1.55-1.46(m,2H ),1.42(d,3H),1.30(s,3H),1.23-1.19(m,2H),0.49-0.47(m,1H),0.28-0.23(m,3H).

[1000] M / Z (ESI): m / z = 630.0 [M+H] + .

[1001] Compound 74 Isomer 2: 1H NMR(400MHz,CD3OD)δ7.32(d,1H),7.27(d,1H),7.17-7.14(m,1H),6.68-6.41(m,1H) ,5.43-5.37(m,1H),4.01-3.97(m,1H),3.84-3.80(m,1H),3.50-3.46(m,1H),3.32-3. 25(m,1H),3.03-2.59(m,5H),2.48-2.40(m,2H),2.16-2.09(m,2H),1.84-1.50(m,2H ),1.40(d,3H),1.27(s,3H),1.23-1.17(m,2H),0.56-0.54(m,1H),0.32-0.28(m,3H).

[1002] M / Z (ESI): m / z = 630.0 [M+H] + .

[1003] Referring to the above operation, compound 66G (90.0 mg 0.23 mmol) and compound 74M-2 (233.0 mg, 0.46 mmol) were used as raw materials to obtain the title compound 74 isomer 3 (Rf = 0.5 (ethyl acetate: methanol = 10:1), 11.0 mg, 7.6%) and the title compound 74 isomer 4 (Rf = 0.3 (ethyl acetate: methanol = 10:1), 8.0 mg, 5.5%).

[1004] Compound 74 Isomer 3: 1 H NMR(400MHz,CD3OD)δ7.32(d,1H),7.27(d,1H),7.18-7.15(m,1H),6.71-6.44(m,1H) ,5.39-5.35(m,1H),3.95-3.90(m,1H),3.88-3.80(m,1H),3.61-3.57(m,1H),3.38-3. 30(m,1H),2.78-2.59(m,7H),1.93-1.88(m,1H),1.81-1.76(m,1H),1.58-1.48(m,2H ),1.42(d,3H),1.29(s,3H),1.23-1.19(m,2H),0.47-0.45(m,1H),0.30-0.25(m,3H).

[1005] M / Z (ESI): m / z = 630.0 [M+H] + .

[1006] Compound 74 Isomer 4: 1H NMR(400MHz,CD3OD)δ7.32(d,1H),7.25(d,1H),7.16-7.14(m,1H),6.69-6.42(m ,1H),5.40-5.38(m,1H),3.96-3.92(m,2H),3.68-3.63(m,1H),3.38-3.29(m,2H) ,3.03-2.59(m,5H),2.46-2.40(m,2H),2.13-2.11(m,2H),1.84-1.51(m,2H),1. 41(d,3H),1.27(s,3H),1.24-1.17(m,2H),0.53-0.51(m,1H),0.31-0.27(m,3H).

[1007] M / Z (ESI): m / z = 630.0 [M+H] + .

[1008] Example 75:

[1009] Step 1: Compound 75A (10.0 g, 48.2 mmol) was dissolved in dichloromethane (200 mL). Imidazole (4.59 g, 67.5 mmol) and tert-butyldimethylsilyl chloride (9.45 g, 62.7 mmol) were added sequentially at 0°C. Stirring was continued at 0°C for 30 minutes, then the mixture was warmed to room temperature and stirred overnight. After TLC monitoring of the disappearance of the starting material, the mixture was quenched with water (200 mL). The aqueous phase was extracted with dichloromethane (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 100:0 to 90:10) to afford compound 75B (15.1 g, 97.4%).

[1010] Step 2: Under nitrogen, compound 75B (8.00 g, 24.9 mmol), (R)-1-(2,4-dichlorophenyl)ethane-1-amine (5.20 g, 27.4 mmol), palladium acetate (558 mg, 2.49 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (2.32 g, 3.73 mmol), and sodium tert-butoxide (3.58 g, 37.3 mmol) were added sequentially to dry toluene (150 mL). The temperature was raised to 110°C and the reaction was allowed to react for 3 hours. After the disappearance of the starting material as monitored by TLC, the mixture was cooled to room temperature, filtered through celite, and washed with ethyl acetate (100 mL x 5). The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 85:15) to obtain compound 75C (8.48 g, 79.1%).

[1011] LC-MS (ESI): m / z = 430.1 [M+H] + .

[1012] Step 3: Compound 75C (8.48 g, 19.7 mmol) was dissolved in dry tetrahydrofuran (100 mL). Tetrabutylammonium fluoride (29.5 mL, 29.5 mmol, 1 mol in THF) was added at 0°C. After complete addition, the mixture was warmed to room temperature and stirred for 30 minutes. After the disappearance of the starting material as monitored by TLC, the reaction was quenched by addition of saturated aqueous ammonium chloride (100 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 80:20) to afford compound 75D (6.10 g, 97.9%).

[1013] LC-MS (ESI): m / z = 316.1 [M+H] + .

[1014] Step 4: Compound 75D (3.50 g, 11.1 mmol) was dissolved in dry dichloromethane (100 mL). Triethylamine (1.79 g, 17.7 mmol) and trifluoromethanesulfonic anhydride (3.43 g, 12.2 mmol) were added sequentially at 0°C. Stirring was continued at 0°C for 2 hours. After the disappearance of the starting material as monitored by TLC, the reaction was quenched by addition of water (200 mL). The aqueous phase was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 90:10) to afford compound 75E (4.27 g, 86.1%).

[1015] LC-MS (ESI): m / z = 448.0 [M+H] + .

[1016] Step 5: Under nitrogen, compound 75E (1.50 g, 3.34 mmol), tert-butyl 3-ethynylpiperidine-1-carboxylate (1.06 g, 5.01 mmol), bistriphenylphosphine palladium dichloride (235 mg, 0.334 mmol), cuprous iodide (318 mg, 1.67 mmol), and triphenylphosphine (175 mg, 0.669 mmol) were added sequentially to a mixture of dry N,N-dimethylformamide (20 mL) and triethylamine (8 mL). The mixture was then heated to 100°C and reacted overnight. TLC confirmed the complete disappearance of the starting material. After cooling to room temperature, the mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 90:10) to afford a mixture of 75F and 75G (1.55 g, 91.2%). The above mixture was separated by chiral HPLC to prepare compound 75F (624 mg, 36.7%) and compound 75G (694 mg, 40.8%).

[1017] HPLC analysis conditions: 1. Instrument: SHIMADZU LC-30AD SFC; 2. Column: Chiralcel OX-3 50×4.6mm ID, 3μm; 3. Mobile phase: A for CO2, B for 0.05% DEA in MeOH; 4. Gradient: B 5-40%; 5. Flow rate: 3mL / min. Compound 75F, retention time 2.11min; Compound 75G, retention time 2.24min.

[1018] Chiral preparation method: Instrument: Waters 150 MGM; Column: Chiralpak Column; Mobile phase: A: carbon dioxide and B: methanol (0.1% ammonia); Isocratic elution: 35% mobile phase B; Flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: 25°C; Wavelength: 220 nm.

[1019] LC-MS (ESI): m / z = 507.1 [M+H] + ;

[1020] Step 6: Compound 75F (200 mg, 0.394 mmol) was dissolved in dichloromethane (9 mL). Trifluoroacetic acid (3 mL) was added at room temperature and the reaction was continued for 1 hour. After completion of the reaction, the mixture was concentrated to afford the crude trifluoroacetate salt of 75H, which was used directly in the next reaction without purification.

[1021] LC-MS (ESI): m / z = 407.1 [M+H] + ;

[1022] Compound 75I was obtained using 75G as the starting material and referring to the above synthesis method.

[1023] Step 7: The crude trifluoroacetate salt of compound 75H obtained in the previous step was dissolved in methanol (30 mL). Compound 2B (101 mg, 0.788 mmol) and acetic acid (23.7 mg, 0.394 mmol) were added sequentially. After stirring at room temperature for 1 hour, sodium cyanoborohydride (74.2 mg, 1.18 mmol) was added and stirring continued for 1 hour. After completion of the reaction, monitored by TLC, the reaction was quenched by the addition of water (1 mL) and concentrated under reduced pressure. The residue was purified on preparative silica gel (ethyl acetate:methanol (v / v) = 90:10) to obtain compound 75 isomer 1 (70 mg, two-step yield 34.2%) and isomer 2 (88 mg, two-step yield 43.0%), respectively.

[1024] Compound 75 Isomer 1: R f =0.60 (ethyl acetate:methanol (v / v)=90:10), 1 H NMR(400MHz,DMSO-d6)δ12.15(s,1H),7.62-7.61(m,1H),7.50-7.49(m,1H),7.43 -7.38(m,1H),7.22-7.21(m,1H),6.61-6.53(m,1H),6.21-6.20(d,1H),5.88-5.8 7(d,1H),4.88-4.76(m,1H),2.76-2.52(m,4H),2.47-2.37(m,2H),1.89-1.73(m, 3H),1.72-1.55(m,3H),1.50-1.49(d,3H),1.46-1.35(m,1H),1.35-1.20(m,4H).

[1025] LC-MS (ESI): m / z = 519.1 [M+H] + ;

[1026] Compound 75 Isomer 2: R f =0.40 (ethyl acetate:methanol (v / v)=90:10), 1H NMR(400MHz,DMSO-d6)δ7.63-7.62(d,1H),7.50-7.49(d,1H),7.43-7.37(m,1H),7 .22-7.21(d,1H),6.60-6.55(m,1H),6.22-6.21(d,1H),5.87-5.86(d,-1H),4.88- 4.77(m,1H),2.79-2.68(m,2H),2.65-2.53(m,2H),2.18-2.05(m,2H),1.94-1.72( m,5H),1.66-1.55(m,1H),1.51-1.50(d,3H),1.47-1.36(m,1H),1.34-1.20(m,4H).

[1027] LC-MS (ESI): m / z = 519.1 [M+H] + ;

[1028] Using 75I as the starting material, compound 75 isomer 3 (75 mg, two-step yield 36.6%) and compound 75 isomer 4 (85 mg, two-step yield 41.5%) were obtained according to the above synthesis method.

[1029] Compound 75 Isomer 3: R f =0.65 (ethyl acetate:methanol (v / v)=90:10), 1 H NMR(400MHz,DMSO-d6)δ12.14(s,1H),7.61-7.60(d,1H),7.51-7.50(d,1H), 7.44-7.37(m,1H),7.23-7.22(d,1H),6.61-6.54(m,1H),6.21-6.20(d,1H), 5.88-5.87(d,1H),4.87-4.77(m,1H),2.76-2.52(m,4H),2.47-2.39(m,2H), 1.88-1.55(m,6H),1.51-1.50(d,3H),1.47-1.35(m,1H),1.34-1.21(m,4H).

[1030] LC-MS (ESI): m / z = 519.1 [M+H] + ;

[1031] Compound 75 Isomer 4: R f =0.50 (ethyl acetate:methanol (v / v)=90:10), 1H NMR(400MHz,DMSO-d6)δ7.62-7.61(d,1H),7.50-7.49(d,1H),7.43-7.37(m,1H), 7.23-7.22(d,1H),6.636.51(m,1H),6.23-6.22(d,1H),5.87-5.86(d,1H),4.89-4 .76(m,1H),2.82-2.68(m,2H),2.66-2.54(m,2H),2.19-2.06(m,2H),1.96-1.73(m ,5H),1.68-1.56(m,1H),1.50-1.49(d,3H),1.46-1.35(m,1H),1.34-1.25(m,4H).

[1032] LC-MS (ESI): m / z = 519.1 [M+H] + .

[1033] Example 76:

[1034] Step 1: Dissolve compound 76A (135.9 mg, 0.81 mmol) and compound 73H-1 (200 mg, 0.74 mmol) in acetonitrile (3.0 mL) at room temperature. Add triethylamine (149.7 mg, 1.48 mmol) and stir at room temperature for 12 hours. After the reaction is complete, concentrate the mixture and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to obtain the title compound 76B-1 (180 mg, 68%).

[1035] By referring to the above operation, compound 76A (135.9 mg, 0.81 mmol) and compound 73H-2 (200 mg, 0.74 mmol) were used as starting materials to obtain the title compound 76B-2 (175 mg, 66%).

[1036] LCMS m / z=357.3[M+H] + .

[1037] Step 2: Dissolve compound 76B-1 (180 mg, 0.50 mmol) in dichloromethane (4.0 mL), add trifluoroacetic acid (1.0 mL), and react at room temperature for 2 h. After the reaction is complete, concentrate directly to obtain the trifluoroacetic acid salt of compound 76C-1 (120 mg, 93%).

[1038] Referring to the above operation, compound 76B-2 (175 mg, 0.49 mmol) was used as the starting material to obtain the trifluoroacetic acid salt of the title compound 76C-2 (115 mg, 91%).

[1039] LCMS m / z=257.3[M+H] + .

[1040] Step 3: Compound 2F (82.2 mg, 0.23 mmol) and compound 76C-1 (120 mg, 0.47 mmol) were dissolved in dimethyl sulfoxide (2.0 mL) in sequence, and N,N-diisopropylethylamine (180.5 mg, 1.41 mmol) and cesium fluoride (144.8 mg, 0.94 mmol) were added. The temperature was raised to 100°C and the reaction was allowed to react for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, and water (2.0 mL) was added. The mixture was extracted with ethyl acetate (5.0 mL × 3). The combined organic phases were washed with saturated brine (2.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain the title compound 76D-1 (150 mg, 56%).

[1041] Referring to the above operation, compound 76C-2 (115 mg, 0.45 mmol) was used as the starting material to obtain the title compound 76D-2 (136 mg, 53%).

[1042] LCMS m / z=570.0[M+H] + .

[1043] Step 4: Compound 76D-1 (150 mg, 0.26 mmol) was dissolved in methanol (4 mL) and water (1 mL) at room temperature, and lithium hydroxide (32.8 mg, 0.78 mmol) was added. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the solvent was dried, water (2.0 mL) was added, and 1 M HCl was added dropwise to adjust the pH to 6-7. The mixture was extracted with dichloromethane (5.0 mL × 3). The combined organic phases were washed with saturated brine (2.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 9:1) to obtain the title compound 76 Isomer 1 (Rf = 0.3 (dichloromethane:methanol (v / v) = 9:1), 100 mg, 68%).

[1044] By referring to the above operation, compound 76D-2 (136 mg, 0.24 mmol) was used as the starting material to obtain the title compound 76 Isomer 2 (Rf = 0.3 (dichloromethane:methanol (v / v) = 9:1), 90 mg, 68%).

[1045] Compound 76 Isomer 1: 1H NMR(400MHz,Methanol-d4)δ7.43-7.40(m,1H),7.35-7.32(m,1H),7.25-7.22(m,1H),5.43-5.3 7(m,1H),4.54-4.45(m,2H),4.03-3.98(m,1H),3.72-3.64(m,1H),3.37-3.32(m,1H),3.26-3.20 (m,2H),3.14-3.07(m,2H),2.75-2.66(m,1H),2.65-2.59(m,1H),2.59-2.49(m,4H),2.25(s,3H) ,1.74-1.62(m,2H),1.52-1.48(m,3H),1.44-1.37(m,1H),1.19-1.08(m,1H),0.93-0.81(m,1H).

[1046] LCMS m / z=556.4[M+H] + .

[1047] Compound 76 Isomer 2: 1 H NMR(400MHz,Methanol-d4)δ7.43-7.40(m,1H),7.35-7.32(m,1H),7.25-7.22(m,1H),5.45-5.3 9(m,1H),4.57-4.48(m,2H),4.02-3.97(m,1H),3.71-3.64(m,1H),3.31-3.26(m,1H),3.20-3.12 (m,2H),3.07-3.00(m,2H),2.66-2.58(m,3H),2.55-2.51(m,2H),2.46-2.38(m,1H),2.27(s,3H) ,1.69-1.60(m,2H),1.57-1.54(m,1H),1.53-1.50(m,3H),1.24-1.14(m,1H),0.87-0.74(m,1H).

[1048] LCMS m / z=556.4[M+H] + .

[1049] Example 77:

[1050] Compound 9J-2 (61 mg, 0.24 mmol), DIEA (210 mg, 1.59 mmol) and cesium fluoride (72 mg, 0.48 mmol) were added sequentially to a DMSO (4 mL) solution of compound 66G (100 mg, 0.24 mmol) and heated at 100°C for 2 hours. After completion of the reaction, water (15 mL) and ethyl acetate (15 mL) were added, extracted, and the layers were separated. The aqueous phase was extracted with ethyl acetate (15 mL × 2). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (EA:MeOH (v / v) = 5:1) to give compound 77 isomer 1 (Rf = 0.5, (EA:MeOH (v / v) = 3:1), 56 mg, 39%) and compound 77 isomer 2 (Rf = 0.4, (EA:MeOH (v / v) = 3:1), 23 mg, 16%).

[1051] Compound 77 Isomer 1: 1 H NMR(400MHz, CDCl3)δ7.36(d,1H),7.22(d,1H),7.21-7.18(m,1H),6.50(t,1H),5.71(d,1H),5.48-5.41(m,1H),3.98(t,1H),3.87-3 .81(m,3H),3.78-3.73(m,3H),3.04-2.95(m,2H),2.90-2.84(m,1H),2.64-2.55(m,3H),2.19-2.03(m,3H),1.53(d,3H),1.42(s,3H).

[1052] LCMS (ESI): m / z = 604.9 [M+H] + .

[1053] Compound 77 Isomer 2: 1 H NMR(400MHz, CDCl3)δ7.37(d,1H),7.22(d,1H),7.20-7.17(m,1H),6.51(t,1H),5.71(d,1H),5.48-5.41(m,1H),4.00(t,1H),3.94-3 .77(m,4H),3.67-3.58(m,2H),2.89-2.79(m,1H),2.69-2.67(m,2H),2.63-2.56(m,3H),2.01-1.82(m,3H),1.53(d,3H),1.42(s,3H).

[1054] LCMS (ESI): m / z = 604.9 [M+H] +.

[1055] Example 78:

[1056] Step 1: Compound 78A (30.0 g, 147.6 mmol) was dissolved in methanol (300 mL). Di-tert-butyl dicarbonate (38.6 g, 177.1 mmol) and Pd / C (3.0 g, 10% Pd content) were added sequentially. After the addition, the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to obtain the title compound 78B (15.0 g, 48%).

[1057] LCMS m / z=158.2[M+H-tBu] + .

[1058] Step 2: Compound 78B (15.0 g, 70.3 mmol) was dissolved in ethyl acetate (200 mL), and 2-iodoacylbenzoic acid (41.3 g, 147.6 mmol) was added. The mixture was stirred at 80°C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 78C (13.0 g, 87%).

[1059] LCMS m / z=156.1[M+H-tBu] + .

[1060] Step 3: Compound 78C (13.0 g, 61.5 mmol) was dissolved in a mixture of methanol (130 mL) and nitromethane (130 mL). Triethylamine (12.4 g, 123 mmol) was added and stirred at room temperature for 17 hours. After the reaction, the residue was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to yield the title compound 78D (7.0 g, 42%).

[1061] LCMS m / z=217.1[M+H-tBu] + .

[1062] Step 4: Compound 78D (7.0 g, 25.7 mmol) was dissolved in a mixture of methanol (70 mL) and water (10 mL). Ammonium chloride (16.3 g, 308.4 mmol) was added, followed by the slow addition of zinc powder (16.7 g, 257 mmol) at 0°C. The mixture was allowed to warm to room temperature and react for 2 h. After completion of the reaction, the mixture was filtered and the filtrate was concentrated to afford crude compound 78E (6.0 g, 96%), which was used in the next step without further purification.

[1063] LCMS m / z=187.2[M+H-tBu] + .

[1064] Step 5: Compound 78E (6.0 g, 24.8 mmol) was dissolved in a mixture of ethyl acetate (60 mL) and water (60 mL). Sodium bicarbonate (6.2 g, 74.4 mmol) was added. The temperature was cooled to 5°C, and chloroacetyl chloride (4.2 g, 37.2 mmol) was added dropwise. The temperature was maintained at 5-10°C. After the addition was complete, the mixture was allowed to warm to room temperature and allowed to react for 1 hour. After the reaction was complete, water (30 mL) was added and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2) to afford the title compound 78F (5.5 g, 70%).

[1065] LCMS m / z=245.2[M+H-Boc-H2O] + .

[1066] Step 6: Potassium tert-butoxide (3.5 g, 31.4 mmol) was dissolved in tert-butanol (50 mL). A solution of compound 78F (5.5 g, 15.7 mmol) in tert-butanol (50 mL) was added. After the addition was complete, the temperature was maintained at 30-40°C and the reaction was allowed to react for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2) to obtain the title compound 78G (4.5 g, 92%).

[1067] LCMS m / z=227.2[M+H-Boc] + .

[1068] Step 7: Under a nitrogen atmosphere, compound 78G (4.5 g, 15.9 mmol) was dissolved in toluene (45 mL), cooled to -10°C, and sodium 2-hydrogen bis(dimethoxyethoxy)aluminate (13.6 mL, 3.5 mol / L toluene solution) was slowly added dropwise. After the addition was complete, the reaction was continued at -10°C for 3 hours. After the reaction was complete, 10% aqueous sodium hydroxide solution (10 mL) was slowly added dropwise to quench the reaction. After quenching, ethyl acetate (30 mL) was added to the reaction solution and extracted. The organic phase was washed with water (20 mL), saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 78H (3.8 g, 89%).

[1069] LCMS m / z=213.4[M+H-tBu]+ .

[1070] Step 8: Compound 78H (3.8 g, 14.2 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 mL) and water (30 mL), and sodium bicarbonate (3.6 g, 42.6 mmol) was added. The temperature was lowered to 0-5°C, and benzyl chloroformate (2.9 g, 17.0 mmol) was slowly added dropwise. After the addition was complete, the reaction was continued at 0-5°C for 1 hour. After the reaction was complete, water (10 mL) was added and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 3:1) to give 4.2 g of a racemate. The racemate was separated by chiral preparative HPLC to give two isomers, compound 78I-1 (1.9 g, retention time 4.02 min, 33%) and compound 78I-2 (1.9 g, retention time 4.53 min, 33%).

[1071] HPLC analysis method: 1. Instrument: Waters UPC2 analytical SFC (SFC-H); 2. Chromatographic column: ChiralPak IC, 100×4.6 mm ID, 3 μm; 3. Mobile phase system: A for CO2 and B for Ethanol (0.05% DEA); 4. Gradient: B 40%; 5. Flow rate: 3 mL / min.

[1072] LCMS m / z=303.2[M+H-Boc] + .

[1073] Preparative chromatography conditions: 1. Instrument: Waters 150 SFC; 2. Column: ChiralPak IC, 250×30 mm ID, 10 μm; 3. Mobile phase: A for CO2 and B for Ethanol; 4. Gradient: B 25%; 5. Flow rate: 80 mL / min.

[1074] Step 9: Dissolve compound 78I-1 (1.0 g, 2.48 mmol) in ethyl acetate (10 mL) and add Pd / C (0.2 g, 10% Pd content). React under a hydrogen atmosphere for 3 hours. After completion of the reaction, filter and concentrate the filtrate to obtain the title compound 78J-1 (0.63 g, 94.7%).

[1075] Referring to the above operation, compound 78I-2 (1 g, 2.48 mmol) was used as the starting material to obtain the title compound 78J-2 (0.61 g, 91.7%).

[1076] LC-MS (ESI): m / z = 213.2 [M+H] + .

[1077] Step 10: Compound 78J-1 (0.63 g, 2.35 mmol) and 3-carbonyl-1-methyl-cyclobutanecarboxylic acid (0.45 g, 3.50 mmol) were dissolved in methanol (15 mL) in sequence. Glacial acetic acid (0.14 g, 2.35 mmol) was added, followed by sodium cyanoborohydride (0.73 g, 11.69 mmol) added in batches. The mixture was allowed to react for 1 hour. After completion of the reaction, water (30 mL) was added to quench the reaction, followed by extraction with dichloromethane (50 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to afford the title compound 78K-1 (0.75 g, 83.9%).

[1078] By referring to the above operation, compound 78J-2 (0.61 g, 2.27 mmol) was used as the starting material to obtain the title compound 78K-2 (0.73 g, 84.5%).

[1079] LC-MS (ESI): m / z = 325.2 [M+H] + .

[1080] Step 11: Dissolve compound 78K-1 (0.3 g, 0.79 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and react at room temperature for 30 min. After the reaction is complete, concentrate directly to obtain the trifluoroacetic acid salt of compound 78L-1 (0.3 g, 100%).

[1081] Referring to the above operation, compound 78K-2 (0.3 g, 0.79 mmol) was used as the starting material to obtain the trifluoroacetic acid salt of the title compound 78L-2 (0.31 g, 100%).

[1082] LC-MS (ESI): m / z = 281.2 [M+H] + .

[1083] Step 12: Compound 2F (0.27 g, 0.79 mmol), DIEA (0.3 g, 2.23 mmol) and cesium fluoride (0.25 g, 0.79 mmol) were added to a DMSO (4 mL) solution of compound 78L-1 (0.3 g, 0.79 mmol) in sequence, and the temperature was raised to 100°C for reaction for 2 hours. After completion of the reaction, water (15 mL) and ethyl acetate (15 mL) were added, extracted, and the liquids were separated. The aqueous phase was extracted with ethyl acetate (15 mL×2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (EA:MeOH (v / v) = 5:1) to give compound 78 isomer 1 (Rf = 0.5, (EA:MeOH (v / v) = 3:1), 102 mg, 22.12%) and compound 78 isomer 2 (Rf = 0.4, (EA:MeOH (v / v) = 3:1), 50 mg, 11.06%).

[1084] Compound 78 Isomer 1: 1 H NMR(400MHz, CDCl3)δ7.36(d,1H),7.22(d,1H),7.17-7.15(m,1H),5.47-5.41(m,2H),3.87(d,1H),3.72(d,1H),3.59(t,2H),3.37-3.34(m,1H) ,2.99(t,1H),2.86-2.81(m,2H),2.70-2.55(m,4H),2.27(s,3H),2.04- 1.84(m,4H),1.78(t,1H),1.65-1.61(m,1H),1.49(d,3H),1.41(s,3H).

[1085] LCMS (ESI): m / z = 594.2 [M+H] + .

[1086] Compound 78 Isomer 2: 1H NMR(400MHz, CDCl3)δ=7.37(d,1H),7.22(d,1H),7.18-7.15(m,1H),5.47-5.41 (m,2H),3.99-3.90(m,1H),3.73(d,2H),3.37-3.34(m,1H),3.16-3.11(m,3H),3 .00(d,1H),2.91-2.87(m,1H),2.52-2.50(m,2H),2.28(s,3H),2.21-2.09(m,4H ),1.91(t,2H),1.69-1.64(m,2H),1.57-1.53(m,1H),1.50(d,3H),1.40(s,3H).

[1087] LCMS (ESI): m / z = 594.2 [M+H] + .

[1088] Referring to the above operation, compound 78L-2 was used as the starting material (0.1 g, 0.27 mmol) to obtain the title compound 78 isomer 3 (Rf = 0.4, (EA:MeOH (v / v) = 3:1), 98 mg, 21.67%) and compound 78 isomer 4 (Rf = 0.3, (EA:MeOH (v / v) = 3:1), 33 mg, 7.3%).

[1089] Compound 78 Isomer 3: 1 H NMR(400MHz, CDCl3)δ7.35(d,1H),7.21(d,1H),7.16-7.14(m,1H),5.43-5.41(m,2H),3.87(d,1H),3.79(d,1H),3.59(t,2H),3.34-3.30 (m,1H),2.97(t,1H),2.86-2.77(m,2H),2.65-2.58(m,4H),2.27(s,3H),2.02-1.86(m,4H),1.77(t,1H),1.64-1.60(m,1H),1.49(d,3H), 1.42(s,3H).

[1090] LCMS (ESI): m / z = 594.2 [M+H] + .

[1091] Compound 78 Isomer 4: 1H NMR(400MHz, CDCl3)δ7.35(d,1H),7.21(d,1H),7.17-7.15(m,1H),5.44-5.40(m,2 H),3.95(d,1H),3.80(d,1H),3.72(t,1H),3.36-3.32(m,1H),3.16-3.10(m,3H),3 .02(d,1H),2.93-2.88(m,1H),2.55-2.50(m,2H),2.29(s,3H),2.20-2.11(m,4H), 1.92-1.91(t,2H),1.68-1.64(m,1H),1.56-1.53(m,2H),1.50(d,3H),1.41(s,3H).

[1092] LCMS (ESI): m / z = 594.2 [M+H] + .

[1093] Example 79:

[1094] Step 1: Compound 9H-2 (1.50 g, 6.19 mmol) was dissolved in dry methanol (40 mL). 3-Oxocyclobutanecarbonitrile (706 mg, 7.43 mmol) and acetic acid (372 mg, 6.19 mmol) were added sequentially. After stirring at room temperature for 1 hour, sodium cyanoborohydride (778 mg, 12.4 mmol) was added and stirring continued for 3 hours. After completion of the reaction, as monitored by TLC, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 8). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 75:25) to afford compound 79A (1.38 g, 69.3%).

[1095] LC-MS (ESI): m / z = 322.2 [M+H] + .

[1096] Step 2: Compound 79A (1.38 g, 4.29 mmol), ammonium chloride (1.15 g, 21.5 mmol), and sodium azide (1.40 g, 21.5 mmol) were added sequentially to dry N,N-dimethylformamide (30 mL). The temperature was raised to 140°C and the reaction was allowed to react for approximately 5 hours. After the disappearance of the starting material as monitored by TLC, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 80:20 to 60:40) to afford crude product 79B (1.35 g).

[1097] LC-MS (ESI): m / z = 365.2 [M+H] + .

[1098] Step 3: Dissolve 79B (1.35 g) in dry dichloromethane (30 mL) and add trifluoroacetic acid (10 mL) at room temperature. Continue the reaction for 1 hour. After completion of the reaction, monitor the reaction by LCMS and concentrate to afford the crude trifluoroacetate salt of 79C (1.45 g), which is used directly in the next reaction without purification.

[1099] LC-MS (ESI): m / z = 265.2 [M+H] + .

[1100] Step 4: The crude trifluoroacetate salt of 79C (1.45 g), compound 2F (350 mg, 0.997 mmol), N,N-diisopropylethylamine (772 mg, 5.98 mmol), and cesium fluoride (303 mg, 1.99 mmol) were added sequentially to dry dimethyl sulfoxide (20 mL). The temperature was raised to 100°C and the reaction was allowed to proceed for approximately 2 hours. TLC confirmed the complete disappearance of the starting material. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 90:10) to afford a mixture of isomers 1 and 2 of compound 79 (310 mg, 12.4% yield over three steps).

[1101] After further separation and purification by preparative HPLC, compound 79 isomer 1 (26 mg, three-step yield 1.05%) and compound 79 isomer 2 (23 mg, three-step yield 0.924%) were obtained.

[1102] Preparative HPLC separation and purification method: 1. Apparatus: Waters 2767 preparative liquid phase; Column: SunFire@Prep C18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A and B composition: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% ammonium acetate); b. Gradient elution, mobile phase A content from 5% to 50%; c. Flow rate: 12 mL / min; d. Elution time: 30 min.

[1103] HPLC analysis conditions: 1. Instrument: Shimadzu LC-20AT; 2. Column: Xtimate C18 4.6 x 50 mm, 3 μm; 3. Mobile phase: A for 0.05% TFA in H2O; B for ACN; 4. Gradient: B 5-95%; 5. Flow rate: 1.0 mL / min, Run time: 10 min. Retention time: Compound 79 Isomer 1: tR = retention time: 3.226 min; Compound 79 Isomer 2: tR = retention time: 3.201 min.

[1104] Compound 79 Isomer 1:1 H NMR(400MHz, Methanol-d4)δ7.43-7.42(d,1H),7.36-7.35(d,1H),7.27-7.26(d,1H),5.50-5.49(t,1H),4.60(s,1H),4.06-3.79(m,4H),3.79-3 .58(m,4H),3.44-3.43(d,1H),2.98-2.97(t,2H),2.74-2.56(m,3H),2.5 7-2.42(m,2H),2.37-2.43(m,4H),1.96-1.95(t,1H),1.51-1.49(d,3H);

[1105] LC-MS (ESI): m / z = 578.2 [M+H] + ;

[1106] Compound 79 Isomer 2: 1 H NMR(400MHz, Methanol-d4)δ7.42-7.41(d,1H),7.36-7.35(d,1H),7.25-7.24(d,1H),5.49-5.48(q,1H),4.07-3.79(m,4H),3.80 -3.49(m,4H),3.26-3.25(d,1H),3.09-2.97(m,2H),2.78-2.65(m,3H),2.48-2.22(m,6H),2.05-2.04(t,1H),1.51-1.50(d,3H).

[1107] LC-MS (ESI): m / z = 578.2 [M+H] + .

[1108] Example 80:

[1109] Step 1: Dissolve compound 9A (65 g, 350.92 mmol) in 30% methylamine ethanol solution (30%, 300 mL). Stir at room temperature for 0.5 hours, cool to 0°C, and add trimethylsilyl cyanide (34.8 g, 350.92 mmol) dropwise. After completion of the addition, react at room temperature for 16 hours. After completion of the reaction, concentrate the mixture, add water (300 mL), and extract with dichloromethane (200 mL x 2). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield crude compound 80A (80 g, 100%).

[1110] LCMS(ESI):m / z=170.2[M+H-tBu] + .

[1111] Step 2: Compound 80A (80 g, 350.93 mmol) was dissolved in dichloromethane (400 mL), and triethylamine (106.5 g, 1052.76 mmol) was added dropwise. Trifluoroacetic anhydride (73.7 g, 350.93 mmol) was added dropwise at room temperature. The reaction was continued for 1 hour after the addition was complete. Water (300 mL) was added and the mixture was extracted. The aqueous phase was extracted with dichloromethane (200 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 80B (100 g, 88.6%).

[1112] LCMS(ESI):m / z=266.1[M+H-tBu] + .

[1113] Step 3: Dissolve compound 80B (100 g, 311.24 mmol) in methanol (1000 mL), add Raney nickel (20 g), and react at room temperature under a hydrogen atmosphere for 16 hours. After completion of the reaction, filter and concentrate to obtain crude compound 80C (90 g, 88.9%).

[1114] LCMS(ESI):m / z=270.4[M+H-tBu] + .

[1115] Step 4: Dissolve compound 80C (90 g, 276.64 mmol) in a mixture of methanol (500 mL) and water (500 mL). Add sodium hydroxide (33.2 g, 830.17 mmol) and allow to react at room temperature for 2 hours. After completion of the reaction, extract with dichloromethane (500 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to yield crude compound 80D (60 g, 94.5%).

[1116] LCMS (ESI): m / z = 230.3 [M+H] + .

[1117] Step 5: Dissolve compound 80D (60 g, 261.64 mmol) in ethanol (500 mL), add dimethyl oxalate (30.9 g, 261.64 mmol), and reflux for 16 hours. After completion of the reaction, cool to room temperature, concentrate, add water (500 mL), and extract with dichloromethane (500 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated to yield crude compound 80E (40 g, 53.9%).

[1118] LCMS(ESI):m / z=228.2[M+H-tBu] + .

[1119] Step 6: Dissolve compound 80E (40 g, 141.18 mmol) in tetrahydrofuran (800 mL) and add lithium aluminum hydride (13.4 g, 352.98 mmol) portionwise at 0°C. Continue the reaction at 0°C for 1 hour. After completion of the reaction, water (13.4 mL), 10% aqueous sodium hydroxide solution (13.4 mL), and water (40.2 mL) were added dropwise. After complete addition, anhydrous magnesium sulfate was added and stirred for 0.5 hour. After quenching, the mixture was filtered and the filtrate was concentrated to obtain crude compound 80F (32 g, 88.7%).

[1120] LCMS (ESI): m / z = 256.3 [M+H] + .

[1121] Step 7: Compound 80F (32 g, 125.31 mmol) was dissolved in tetrahydrofuran (300 mL). Water (13.4 mL) and sodium bicarbonate (31.6 g, 375.93 mmol) were added. Benzyl chloroformate (21.38 g, 125.31 mmol) was added dropwise at 0°C. After completion of the addition, the mixture was allowed to react at room temperature for 1 hour. Water (500 mL) was added and the mixture was extracted with dichloromethane (500 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain 4 g of the racemate of 80F. The racemate was separated by chiral preparative HPLC to yield two isomers, compound...

Claims

1. A compound represented by formula (I), its stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt or cocrystal, in, Ring A is selected from 6-membered heteroaryl, 9-10-membered bicyclic heteroaryl, 6-10-membered aryl, 9-10-membered bicyclic heterocycloalkyl; Ring B is selected from phenyl, 8-10 membered aryl, 5-6 membered heteroaryl, 8-10 membered heteroaryl; The D ring is selected from -Cy2-Cy3-#, -L1-Cy2-Cy3-#, -Cy2-L1-#, -L1-Cy2-#, -L1-Cy3-#, Cy4, -L1-Cy4-#, wherein # represents the connection site between the D ring and the A ring; Cy2 is selected from 4-7 membered monoheterocycloalkyl, 7-10 membered bridged heterocycloalkyl, 7-10 membered spiroheterocycloalkyl, 8-10 membered heterocycloalkyl, 6-7 membered cycloalkyl, phenyl, wherein Cy2 is optionally substituted by 1-3 members selected from =O, halogen, deuterium, CN, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkoxy and NH2 group substitution; Cy3 is selected from 4-7 membered monoheterocycloalkyl, 7-10 membered spiroheterocycloalkyl, 5-6 membered heteroaryl, 6-10 membered heterocycloalkyl, phenyl, and the Cy3 is optionally substituted by 1-3 groups selected from =O, halogen, deuterium, CN, OH, C 1-4 Alkyl and NH2 group substitution; Cy4 is selected from 7-10 membered bridged heterocycloalkyl, 7-10 membered spiroheterocycloalkyl, 8-10 membered heterocycloalkyl; L1 is selected from a bond, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, -C(=O)-; m, p, q, t are each independently selected from 0, 1, 2, 3, 4, 5; R 1 、R 2a 、R 2b Each independently selected from H, deuterium, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 alkyl; R 3 Selected from -Cy1-R 3a 、R 3a ; Cy1 is selected from 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, and the cycloalkyl and heterocycloalkyl groups are optionally further substituted by 1-3 groups selected from C 1-6 Alkyl, halogen, deuterium, cyano, nitro, OH, halo C 1-6 Alkyl, deuterated C 1-6 Alkyl radical substitution; R 3a Selected from -COOH, COOC 1-6 Alkyl, -P(O)(OH)OH, -P(O)(OH)H, hydroxyl C 1-6 Alkyl, -C 1-6 Alkyl-COOH, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, wherein the heteroaryl and heterocycloalkyl are optionally further substituted by 1-3 groups selected from =O, C 1-6 Alkyl, halogen, deuterium, cyano, nitro, OH, halo C 1-6 Alkyl, deuterated C 1-6 Alkyl radical substitution; R 4 Selected from deuterium, halogen, cyano, nitro, OH, amino, SF5, N3, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -C(=O)R 4a ; R 4a Selected from deuterium, halogen, OH, amino, C 1-6 alkyl; R 6 、R 6a Each independently selected from deuterium, halogen, cyano, nitro, OH, amino, SF5, N3, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 alkoxy; Alternatively, two R 6 Together with the atoms to which they are attached, they form a 5-6 membered cycloalkenyl group; the cycloalkenyl group is optionally selected from 1-5 R 6a replace; Alternatively, R 4 With R 1 Together with the atoms to which they are attached, they form a 5-6 membered heteroaryl or a 5-6 membered heterocycloalkyl; Alternatively, R 1 With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered heterocycloalkyl group; Alternatively, R 2a With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered cycloalkyl group; Alternatively, R 1 With R 2a Together with the atoms to which it is attached, it forms a 4-6 membered heterocycloalkyl group; Alternatively, R on the same carbon atom or on different carbon atoms 2a With R 2b Together with the atoms to which it is attached, it forms a 3-membered cycloalkyl group or a 4-6-membered cycloalkyl group; Alternatively, two R on adjacent ring atoms 4 and its connected atoms together form C 4-6 Cycloalkyl or 4-7 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl optionally further substituted by 1-3 groups selected from deuterium, halogen, C 1-6 Alkyl, cyano, OH, amino, SF5, N3, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy and COC 1-6 Alkyl groups are substituted.

2. The compound of formula (I) according to claim 1, its stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt or cocrystal, wherein the compound has the structure represented by formula (I-1), (I-1a), (I-1b), (I-1c), (I-1d), (I-1e), (I-1f), or (I-1g): The condition is, (1)、 Huan Buwei (2) In formula (I-1h), Huan Buwei And Cy2 is not (3) In formula (I-1d), Ring selected from in Indicates connection with the right side, Indicates connection to the left.

3. The compound of formula (I) according to claim 1, its stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt or cocrystal, wherein the compound has the structure shown in formula (I-2a), (I-2b), (I-2c), (I-2d), or (I-2): Provided that the D ring is not selected from in Indicates connection with the right side, Indicates connection to the left.

4. The compound of formula (I) according to claim 1, its stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt or cocrystal, wherein the compound has the structure shown in formula (I-3) or (I-3a): The condition is, Not selected 5. The compound of formula (I) according to claim 1, its stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt or cocrystal, wherein the compound has the structure of formula (I-4):

6. The compound of formula (I) according to claim 1, its stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt or cocrystal, wherein Ring selected from in Indicates connection with the right side, Indicates connection with the left side; Alternatively, R 4 、R 1 Together with the atoms to which they are attached, they form 7. The compound of formula (I) according to claim 1, its stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt or cocrystal, Ring selected from Alternatively, R 1 、R 6 Together with the atoms to which they are attached, they form ring B Alternatively, R 2a 、R 6 Together with the atoms to which they are attached, they form ring B 8. The compound of formula (I) according to claim 1, its stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt or cocrystal, wherein The D ring is selected from -Cy2-Cy3-#, -Cy2-L1-#, -L1-Cy2-#, and Cy4, where # represents the connection site between the D ring and the A ring; Cy2 is selected from 4-7 membered monoheterocycloalkyl, 7-10 membered bridged heterocycloalkyl, 7-10 membered spiroheterocycloalkyl, 8-10 membered heterocycloalkyl, 6-7 membered cycloalkyl, phenyl, wherein Cy2 is optionally substituted by 1-3 members selected from =O, halogen, deuterium, CN, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, and NH2 group substitution; Cy3 is selected from 4-7 membered monoheterocycloalkyl, 5-6 membered heteroaryl, 6-10 membered heterocycloalkyl, phenyl, and the Cy3 is optionally substituted by 1-3 groups selected from =O, halogen, deuterium, CN, OH, C 1-2 Alkyl and NH2 group substitution; L1 is selected from methylene, ethylene, vinylene, ethynylene, and -C(=O)-.

9. The compound of formula (I) according to claim 1, its stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt or cocrystal, wherein The Cy2 ring is selected from: The Cy3 ring is selected from The Cy4 ring is selected from L1 is selected from methylene, alkynylene, -C(=O)-; in Indicates connection with the right side, Indicates connection to the left.

10. The compound of formula (I) according to claim 1, its stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt or cocrystal, wherein Ring D is selected from: in Indicates connection with the right side, Indicates connection to the left.

11. The compound of formula (I) according to claim 1, its stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt or cocrystal, wherein Cy1 is selected from 3-6 membered monocyclic cycloalkyl, 7-10 membered bicyclic cycloalkyl, 4-6 membered monoheterocyclic alkyl, 7-10 membered bicyclic heterocyclic alkyl, and the cycloalkyl and heterocyclic alkyl groups are optionally further substituted by 1-3 groups selected from C 1-4 Alkyl, halogen, deuterium, cyano, nitro, OH, halo C 1-4 Alkyl, deuterated C 1-4 Alkyl radical substitution; R 3 Selected from 12. The compound according to claim 1, its stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table 1.

13. The compound according to claim 1, its stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table 2.

14. A pharmaceutical composition or pharmaceutical formulation comprising the compound according to any one of claims 1 to 13, or a stereoisomer, deuterated form, solvate, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier and / or excipient.

15. The pharmaceutical composition or pharmaceutical formulation according to claim 1, comprising 1-1500 mg of the compound according to any one of claims 1-13 or its stereoisomer, deuterated form, solvate, pharmaceutically acceptable salt or cocrystal and a carrier and / or excipient.

16. Use of the compound according to any one of claims 1 to 13, its stereoisomer, deuterated form, solvate, pharmaceutically acceptable salt or cocrystal, or the composition according to claim 14 or 15 in the preparation of a medicament for treating / preventing a CCR4-mediated disease. The use according to claim 16 , wherein the CCR4-mediated disease is selected from tumors or inflammation.

18. A method for treating a disease in a mammal or a human, comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 13 or a stereoisomer, deuterated form, solvate, pharmaceutically acceptable salt or cocrystal thereof, preferably 1 to 1500 mg, wherein the disease is preferably a tumor or inflammation.

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