Heterocyclic compound CCR4 inhibitor and its use

Abstract

The present invention discloses a heterocyclic compound represented by formula (I), its stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals, and pharmaceutical compositions thereof, and their use in the manufacture of pharmaceuticals for the treatment / prevention of CCR4-mediated diseases, wherein each group in formula (I) is as defined in the specification. [Chemical formula 1] TIFF2025518244000342.tif41156

Description

Technical Field

[0001] The present invention relates to CCR4 inhibitors, their stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterides, and their use in the manufacture of pharmaceuticals for treating CCR4-mediated related diseases.

Background Art

[0002] C-C chemokine receptor type 4 (CCR4), also called CD194, consists of a polypeptide chain containing a seven-transmembrane domain and belongs to the G protein-coupled receptor family. It contains 360 amino acids, has a molecular weight of about 41 kD, is mainly expressed in various lymphocytes and tissues, and its ligands include multiple chemokines. As an important chemokine receptor, CCR4 binds to other chemokine ligands and exerts its function, mainly involved in the control process of human autoimmune diseases including atopic dermatitis, asthma, and cutaneous T cell lymphoma. According to research, CCR4 is expressed by Th2 cells, regulatory T cells (Tregs), mast cells, and skin-homing lymphocyte Ag-positive T cells. By blocking the CCR4 receptor highly expressed on Th2 cells, it selectively inhibits the migration of Th2 cells to inflamed tissues, thereby acting on the upstream pathway of the pathogenesis of inflammation such as asthma and atopic dermatitis. Therefore, it plays an important role in inflammatory diseases often accompanied by massive infiltration of Th2-type CD4 + T cells, such as atopic dermatitis, asthma, allergic airway inflammation, etc.

Summary of the Invention

Means for Solving the Problems

[0003] The present invention provides 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), their stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals, which have the excellent effects of high activity, excellent physicochemical properties, easy formulation, excellent pharmacokinetic properties, high bioavailability, and low toxic side effects.

[0004] 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), their stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals, wherein

Chemical formula

Chemical formula

[0005] Examples of the C 4-6 cycloalkyl group include, but are not limited to, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, and examples of the 4- to 7-membered heterocycloalkyl group include, but are not limited to, oxocyclobutenyl group, azetidinyl group, oxocyclopentenyl group, azacyclopentenyl group, oxocyclohexenyl group, and azacyclohexenyl group.

[0006] Furthermore, a compound of the 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), its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or cocrystal, wherein

Chemical formula

Chemical formula

[0007] Said C 4-6Examples of cycloalkyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl groups. Examples of 4- to 7-membered heterocycloalkyl groups include, but are not limited to, oxocyclobutenyl, azetidinyl, oxocyclopentenyl, azacyclopentenyl, oxocyclohexenyl, and azacyclohexenyl groups.

[0008] The compound represented by formula (I) described in the present invention, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or cocrystal has a structure represented by formula (I-1), (I-1a), (I-1b), (I-1c), (I-1d), (I-1e), (I-1f), (I-1g),

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0009] The compound represented by formula (I) described in the present invention, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or cocrystal has a structure represented by formula (I-1a), (I-1b), (I-1c), (I-1d), (I-1e), (I-1f), (I-1g),

Chemical formula

Chemical formula

[0010] The compound represented by formula (I) described in the present invention, its stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals have the structures shown in formula (I-1a), (I-1b), (I-1c), (I-1d), (I-1e), (I-1f), (I-1g), (I-1h), [Chem.] The conditions are as follows (1) [Chem.] The ring [Chem.] is not (2) In formula (I-1h), [Chem.] The ring [Chem.] is not, and Cy2 is [Chem.] not (3) In formula (I-1d), [Chem.] The ring is [Chemical formula] not Here, [Chemical formula] represents being connected to the right side, [Chemical formula] represents being connected to the left side, In some embodiments, R 6 is, independently of each other, deuterium, halogen, cyano group, OH, amino group, SF 5 , N 3 , C 1-4 alkyl group, halogenated C 1-4 alkyl group, deuterated C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group, and as one option, two Rs 6 form a 5- to 6-membered cycloalkenyl group together with the atoms to which they are attached, and the cycloalkenyl group is optionally substituted with 1 to 5 selected Rs 6a . In some embodiments, R 6 is, independently of each other, deuterium, halogen, cyano group, OH, amino group, C 1-2 alkyl group, halogenated C 1-2 alkyl group, deuterated C 1-2 alkyl group, C 2-3 alkenyl group, C 2-3 alkynyl group, C 1-2 alkoxy group, and as one option, two Rs 6 form a 5- to 6-membered cycloalkenyl group together with the atoms to which they are attached, In some embodiments, R 6are each independently selected from F, Cl, Br, OH, an amino group, a methyl group, an ethyl group, a vinyl group, an ethynyl group, a methoxy group, an ethoxy group, a halogenated methyl group, and a halogenated ethyl group, In some embodiments, R 4 is deuterium, a halogen, a cyano group, OH, an amino group, C 1-4 alkyl group, halogenated C 1-4 alkyl group, deuterated C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group, deuterated C 1-4 alkoxy group, and as one option, two Rs on adjacent ring atoms 4 and the atoms to which they are attached together form a C 4-6 cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group is optionally further substituted with 1 to 3 groups selected from deuterium, a halogen, C 1-4 alkyl group, cyano group, OH, amino group, halogenated C 1-4 alkyl group, deuterated C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group, deuterated C 1-4 alkoxy group, In some embodiments, R 4 is deuterium, F, Cl, Br, cyano group, OH, amino group, C 1-2 alkyl group, halogenated C 1-2 alkyl group, deuterated C 1-2 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-2 alkoxy group, deuterated C 1-2 alkoxy group, and as one option, two Rs on adjacent ring atoms 4 and the atoms to which they are attached together form a C 4-6forms a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group is optionally deuterium, F, Cl, Br, C 1-2 alkyl group, cyano group, OH, amino group, halogenated C 1-2 alkyl group, deuterated C 1-2 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-2 alkoxy group, deuterated C 1-2 alkoxy group, and is further substituted with 1 to 3 groups selected from In some embodiments, R 4 is deuterium, F, Cl, Br, cyano group, OH, amino group, methyl group, ethyl group, fluoromethyl group, fluoroethyl group, vinyl group, propenyl group, ethynyl group, propynyl group, methoxy group, ethoxy group, and as one option, two Rs on adjacent ring atoms 4 and the atoms linked thereto together form a C 4-6 cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group is optionally deuterium, F, Cl, Br, cyano group, OH, amino group, methyl group, ethyl group, fluoromethyl group, fluoroethyl group, vinyl group, propenyl group, ethynyl group, propynyl group, methoxy group, ethoxy group, and is further substituted with 1 to 3 groups selected from Other groups are consistent with the above.

[0011] The compound represented by formula (I) described in the present invention, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or cocrystal has the structures shown in formula (I-1a), (I-1b), (I-1c), (I-1d), (I-1e), (I-1f), (I-1g), (I-1h),

Chemical formula

Chemical formula

[0012] Other groups are consistent with the above.

[0013] The compound shown in formula (I) described in the present invention, its stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals have the structure shown in formula (I-1d), [Chemical formula] [Chemical formula] The ring is [Chemical formula] selected from R 6 is, independently of one another, deuterium, halogen, cyano group, OH, amino group, SF 5 、N 3 、C 1-4 alkyl group, halogenated C 1-4 alkyl group, deuterated C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group, and as one option, two Rs 6 together with the atoms to which they are attached form a 5- to 6-membered cycloalkenyl group, and said cycloalkenyl group is optionally substituted with 1 to 5 selected Rs 6a and In some embodiments, R6 is, independently of one another, selected from F, Cl, Br, OH, amino group, methyl group, ethyl group, vinyl group, ethynyl group, methoxy group, ethoxy group, fluoromethyl group, fluoroethyl group, and the other groups are consistent with the above.

[0014] The compound represented by formula (I) described in the present invention, its stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals have the structure represented by formula (I-1h), [Chemical formula] Ring A is selected from a 6-membered heteroaryl group, a 9- to 10-membered bicyclic heteroaryl group, a 6- to 10-membered aryl group, a 9- to 10-membered bicyclic heterocycloalkyl group, R 4 is deuterium, halogen, cyano group, nitro group, OH, amino group, SF 5 、N 3 、C 1-6 alkyl group, halogenated C 1-6 alkyl group, deuterated C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, halogenated C1-6 an alkoxy group, deuterated C 1-6 an alkoxy group, -C(=O)R 4a selected from, In some embodiments, R 4 is deuterium, halogen, cyano group, nitro group, OH, amino group, C 1-4 alkyl group, halogenated C 1-4 alkyl group, deuterated C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group, halogenated C 1-4 alkoxy group, deuterated C 1-4 selected from alkoxy groups, In some embodiments,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0015] The compound (I), its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or cocrystal described in the present invention has the structures shown in formulas (I-2a), (I-2b), (I-2c), (I-2d), (I-2).

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0016] Furthermore, the compound (I), its stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals described in the present invention have the structures shown in formula (I-2a), (I-2b), (I-2c), or (I-2d),

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0017] The compound shown in formula (I) described in the present invention, its stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals have the structure shown in formula (I-3),

Chemical formula

Chem.

Chem.

[0018] The compound represented by formula (I) described in the present invention, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or cocrystal has the structures represented by formula (I-3) and (I-3a),

Chem.

Chem.

Chem.

[0019] The compound represented by formula (I) described in the present invention, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or cocrystal, wherein the compound has the structure of formula (I-4),

Chem.

[0020] A compound represented by formula (I) according to the present invention, a stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal thereof, wherein

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0021] Furthermore, a compound represented by formula (I) described in the present invention, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal, [Chemical formula] The ring is [Chemical formula] selected from, where [Chemical formula] represents being connected to the right side, [Chemical formula] represents being connected to the left side, As one option, R 4 , R 1 together with the atoms to which they are attached, together with ring A [Chemical formula] form to form The definitions of other groups are consistent with the above.

[0022] A compound represented by formula (I) described in the present invention, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal, [Chemical formula] The ring is [Chemical formula] selected from As one option, R 1 and R 6 together with the atoms to which they are attached, together with ring B [Chemistry] to form As one option, R 2a and R 6 together with the atoms connected to them, together with ring B [Chemistry] to form.

[0023] A compound represented by formula (I) described in the present invention, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal, [Chemistry] The ring is [Chemistry] selected from, or [Chemistry] The ring is [Chemistry] selected from, or [Chemistry] selected from, The definitions of other groups are consistent with the above.

[0024] Furthermore, a compound represented by formula (I) described in the present invention, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal, [Chemistry] The ring is [Chemistry] selected from, The definitions of other groups are consistent with the above.

[0025] A compound represented by formula (I) according to the present invention, a stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal thereof, wherein The Cy2 ring is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0026] A compound represented by formula (I) described in the present invention, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or cocrystal, The D ring is -Cy2-Cy3-#, -Cy2-L 1 -#, -L 1 -Cy2-#, Cy4, where # represents the connection site between the D ring and the A ring, In some embodiments, the D ring is -Cy2-Cy3-#, -Cy2-L 1 -#, -L 1 -Cy2-#, where # represents the connection site between the D ring and the A ring, In some embodiments, the D ring is selected from -Cy2-Cy3-#, where # represents the connection site between the D ring and the A ring, Cy2 is selected from a 4- to 7-membered monocyclic heteroalkyl group, a 7- to 10-membered bridged heteroalkyl group, a 7- to 10-membered spiroheteroalkyl group, an 8- to 10-membered fused heteroalkyl group, a 6- to 7-membered cycloalkyl group, a phenyl group, and the Cy2 is optionally substituted with 1 to 3 groups selected from =O, halogen, deuterium, CN, OH, C 1-4 alkyl group, halogenated C 1-4 alkyl group, deuterated C 1-4 alkyl group, C 1-4 alkoxy group, and NH 2 and is substituted with 1 to 3 groups selected therefrom, In some embodiments, Cy2 is selected from a 4- to 7-membered monocyclic heteroalkyl group, a 7- to 9-membered bridged heteroalkyl group, a 7- to 9-membered spiroheteroalkyl group, an 8- to 10-membered fused heteroalkyl group, a 6-membered cycloalkyl group, a phenyl group, and the Cy2 is optionally substituted with 1 to 3 groups selected from =O, F, Cl, Br, deuterium, CN, OH, C 1-2 alkyl group, halogenated C 1-2An alkyl group, deuterated C 1-2 An alkyl group, C 1-2 An alkoxy group and NH 2 Substituted with 1 to 3 groups selected from Cy3 is selected from a 4- to 7-membered monocyclic heteroalkyl group, a 5- to 6-membered heteroaryl group, a 6- to 10-membered fused heterocycloalkyl group, and a phenyl group, and said Cy3 is optionally =O, halogen, deuterium, CN, OH, C 1-2 An alkyl group and NH 2 Substituted with 1 to 3 groups selected from In some embodiments, Cy3 is selected from a 4- to 7-membered monocyclic heteroalkyl group, a 5- to 6-membered heteroaryl group, a 6- to 8-membered fused heterocycloalkyl group, and a phenyl group, and said Cy3 is optionally =O, F, Cl, Br, deuterium, CN, OH, a methyl group, an ethyl group, and NH 2 Substituted with 1 to 3 groups selected from L 1 Is selected from a methylene group, an ethylene group, a vinylene group, an ethynylene group, -C(=O)- A compound represented by formula (I) described in the present invention, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or cocrystal, The D ring is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

[0027] A compound represented by formula (I) described in the present invention, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal, The D ring is,

Chem.

Chem.

Chem.

[0028] A compound represented by formula (I) described in the present invention, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal, The D ring is,

Chem.

Chem.

Chem.

[0029] A compound represented by formula (I) according to the present invention, a stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal thereof, wherein Cy1 is selected from a 3- to 6-membered monocyclic cycloalkyl group, a 7- to 10-membered bicyclic cycloalkyl group, a 4- to 6-membered monocycloheteroalkyl group, and a 7- to 10-membered bicycloheteroalkyl group, and the cycloalkyl group and the cycloheteroalkyl group are optionally substituted with 1 to 3 groups selected from a C 1-4 alkyl group, halogen, deuterium, cyano group, nitro group, OH, halogenated C 1-4 alkyl group, deuterated C 1-4 alkyl group, and the definitions of the other groups are as defined above.

[0030] A compound represented by formula (I) according to the present invention, a stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal thereof, wherein R 3 is

Chemical formula

Chemical formula

Chemical formula

[0031] A compound represented by formula (I) according to the present invention, a stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal thereof, wherein R 3 is

Chemical formula

[0032] A compound represented by formula (I) according to the present invention, a stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal thereof, wherein R 3 is

Chemical formula

[0033] A compound represented by formula (I) according to the present invention, a stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is one selected from the structures in Table 1 below.

[0034]

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

[0035] A compound, stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or cocrystal as described in the present invention, wherein the compound is one selected from the structures in Table 2 below.

[0036]

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

Table 2-26

[0037] Next, the present invention further provides a pharmaceutical composition, which contains a compound, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt described in any one of the above technical solutions, and a pharmaceutically acceptable carrier and / or excipient.

[0038] Furthermore, the pharmaceutical composition or pharmaceutical preparation contains 1 to 1500 mg of the compound, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal described in any of the above technical aspects, and a pharmaceutically acceptable carrier and / or excipient.

[0039] Furthermore, the present invention further provides the use of the compound, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt or pharmaceutical composition described in any one of the above embodiments in the manufacture of a medicament for the treatment / prevention of CCR4-mediated diseases. Furthermore, CCR4-mediated diseases include, but are not limited to, tumors or inflammation.

[0040] The present invention further provides a method for treating a mammalian or human disease, the method comprising administering to a subject a therapeutically effective amount of the compound, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal described in any one of the above technical solutions, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is preferably a tumor or inflammation.

[0041] The present invention further provides a method for treating a mammalian or human disease, which comprises administering to the mammalian or human a therapeutically effective amount of the compound, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal or pharmaceutical composition described in the present invention. In some embodiments, the mammals described in the present invention do not include humans.

[0042] The "effective amount" or "therapeutically effective amount" described in this application includes administering a sufficient amount of the compounds disclosed in this application, which alleviates to some extent one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms or causes of the disease, or any other desirable change in the biological system. For example, the "effective amount" for therapeutic use is the amount of the composition comprising the compounds disclosed in this application necessary to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts are 1 to 1500 mg, 1 to 1400 mg, 1 to 1300 mg, 1 to 1200 mg, 1 to 1000 mg, 1 to 900 mg, 1 to 800 mg, 1 to 700 mg, 1 to 600 mg, 1 to 500 mg, 1 to 400 mg, 1 to 300 mg, 1 to 250 mg, 1 to 200 mg, 1 to 150 mg, 1 to 125 mg, 1 to 100 mg, 1 to 80 mg, 1 to 60 mg, 1 to 50 mg, 1 to 40 mg, 1 to 25 mg, 1 to 20 mg, 5 to 1500 mg, 5 to 1000 mg, 5 to 900 mg, 5 to 800 mg, 5 to 700 mg, 5 to 600 mg, 5 to 500 mg, 5 to 400 mg, 5 to 300 mg, 5 to 250 mg, 5 to 200 mg, 5 to 150 mg, 5 to 125 mg, 5 to 100 mg, 5 to 90 mg, 5 to 70 mg, 5 to 80 mg, 5 to 60 mg, 5 to 50 mg, 5 to 40 mg, 5 to 30 mg, 5 to 25 mg, 5 to 20 mg, 10 to 1500 mg, 10 to 1000 mg, 10 to 900 mg, 10 to 800 mg, 10 to 700 mg, 10 to 600 mg, 10 to 500 mg, 10 to 450 mg, 10 to 400 mg, 10 to 300 mg, 10 to 250 mg, 10 to 200 mg, 10 to 150 mg, 10 to 125 mg, 10 to 100 mg, 10 to 90 mg, 10 to 80 mg, 10 to 70 mg, 10 to 60 mg, 10 to 50 mg, 10 to 40 mg, 10 to 30 mg, 10 to 20 mg, 20 to 1500 mg, 20 to 1000 mg, 20 to 900 mg, 20 to 800 mg, 20 to 700 mg, 20 to 600 mg, 20 to 500 mg, 20 to 400 mg, 20 to 350 mg, 20 to 300 mg, 20 to 250 mg, 20 to 200 mg, 20 to 150 mg, 20 to 125 mg, 20 to 100 mg, 20 to 90 mg, 20 to 80 mg, 20 to 70 mg, 20 to 60 mg, 20 to 50 mg, 20 to 40 mg, 20 to 30 mg, 50 to 1500 mg, 50 to 1000 mg,including, but not limited to, 50 - 900 mg, 50 - 800 mg, 50 - 700 mg, 50 - 600 mg, 50 - 500 mg, 50 - 400 mg, 50 - 300 mg, 50 - 250 mg, 50 - 200 mg, 50 - 150 mg, 50 - 125 mg, 50 - 100 mg, 100 - 1500 mg, 100 - 1000 mg, 100 - 900 mg, 100 - 800 mg, 100 - 700 mg, 100 - 600 mg, 100 - 500 mg, 100 - 400 mg, 100 - 300 mg, 100 - 250 mg, 100 - 200 mg.

[0043] The present invention relates to a pharmaceutical composition or a pharmaceutical preparation, and the pharmaceutical composition or the pharmaceutical preparation comprises a therapeutically effective amount of the compound described in the present invention, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co - crystal, as well as a carrier and / or an excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in the unit dosage form is also called the "formulation specification"). In some embodiments, the pharmaceutical composition comprises, 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, 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 the compound of the present invention, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co - crystal.

[0044] A method for treating a mammalian or human disease, said method comprising administering to a subject a therapeutically effective amount of a compound of the present invention, its stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and said disease is preferably a tumor or inflammation.

[0045] A method for treating a mammalian or human disease, said method comprising administering to a subject a compound of the present invention which is a pharmaceutical, its stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals, and a pharmaceutically acceptable carrier and / or excipient, in a daily dose of 1 to 1500 mg / day, said daily dose may be a single dose or a divided dose, and in some embodiments, the daily dose includes, but is not limited to, 10 to 1500 mg / day, 20 to 1500 mg / day, 25 to 1500 mg / day, 50 to 1500 mg / day, 75 to 1500 mg / day, 100 to 1500 mg / day, 200 to 1500 mg / day, 10 to 1000 mg / day, 20 to 1000 mg / day, 25 to 1000 mg / day, 50 to 1000 mg / day, 75 to 1000 mg / day, 100 to 1000 mg / day, 200 to 1000 mg / day, 25 to 800 mg / day, 50 to 800 mg / day, 100 to 800 mg / day, 200 to 800 mg / day, 25 to 400 mg / day, 50 to 400 mg / day, 100 to 400 mg / day, 200 to 400 mg / day, and 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.

[0046] The present invention relates to a kit, which may contain a composition in the form of a single dose or multiple doses, and the kit contains a compound of the present invention, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or cocrystal, and the amount of the compound of the present invention, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or cocrystal is the same as its amount in the above pharmaceutical composition.

[0047] In the present invention, the amount of the compound of the present invention, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or cocrystal is, in each case, converted in the form of the free base.

[0048] "Formulation specification" refers to the weight of the active ingredient contained in one unit formulation, one tablet unit formulation, or each other unit formulation.

[0049] Synthetic route A person skilled in the art can combine known organic synthesis techniques to produce the compounds of the present invention, and the starting materials thereof are commercially available chemical products and / or compounds described in chemical literature. "Commercially available chemical products" are those obtained from regular commercial sources, and the suppliers include companies such as Titan Technology, Energy Chemical, Shanghai Derm, Chengdu Kelong Chemical Industry, Shaoyuan Chemical Technology, Nanjing Pharmatech, WuXi AppTec, and BLC Chemical Technology.

[0050] Specific and similar reactants can be selectively identified by the index of known chemical substances created by the Chemical Information Retrieval Service of the American Chemical Society, and these indexes are available in many public libraries, university libraries, and online. For chemical products that are known but not available in the catalog, they can optionally be requested from custom chemical synthesis contractors for production, and many of the standard chemical suppliers (for example, the companies listed above) provide custom synthesis services.

[0051] Terms Unless otherwise specified in the present invention, the terms of the present invention have the following meanings.

[0052] Carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen according to the groups and compounds described in the present invention includes any of their isotopes, and carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen according to the groups and compounds described in the present invention may optionally be further substituted by one or more corresponding isotopes thereof, where the isotopes of carbon are 12 C and 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called triple hydrogen), and the isotopes of oxygen are 16 O and 17 O and 18 O, the isotopes of sulfur are 32 S and 33 S and 34 S and 36 S, the isotopes of nitrogen are 14 N and 15 N, the isotope of fluorine is 19 F, the isotopes of chlorine are 35 Cl and 37 Cl, the isotopes of bromine are 79 Br and 81 Br.

[0053] As used herein, "halogen" refers to F, Cl, Br, I, or their isotopes.

[0054] "Halogenation" or "halogen substitution" refers to substitution by one or more selected from F, Cl, Br, I, or their isotopes, and the upper limit of the number of halogen substituents is equal to the sum of the replaceable hydrogens of the group to be substituted. Unless otherwise particularly limited, 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 substituted with the same or different halogens. Usually, cases of 1 to 5 halogen substitutions, 1 to 3 halogen substitutions, 1 to 2 halogen substitutions, and 1 halogen substitution are included.

[0055] "Deuterium" refers to deuterium, which is an isotope of hydrogen (H), and has the same meaning as "D".

[0056] "Deuteration" or "deuteride" refers to the case where at least one hydrogen atom in a group such as an alkyl group, cycloalkyl group, alkylene group, aryl group, heteroaryl group, mercapto group, heterocycloalkyl group, alkenyl group, or alkynyl group is substituted by at least one deuterium atom. The upper limit of the number of deuterations is equal to the sum of the replaceable hydrogens of the group to be substituted. Unless otherwise specifically limited, the number of deuterations is any integer between 1 and the upper limit. For example, it can be 1 to 20 deuterium atom substitutions, 1 to 10 deuterium atom substitutions, 1 to 6 deuterium atom substitutions, 1 to 3 deuterium atom substitutions, 1 to 2 deuterium atom substitutions, or 1 deuterium atom substitution.

[0057] "C x-y " group refers to a group containing x to y carbon atoms. For example, "C 1-6 alkyl group" refers to an alkyl group containing 1 to 6 carbon atoms.

[0058] "Alkyl group" refers to a monovalent straight-chain or branched-chain saturated aliphatic hydrocarbon group. Usually, 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 group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, neobutyl group, t-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, etc. The alkyl group may be further substituted with substituents.

[0059] "Alkylene group" refers to a divalent straight-chain and branched-chain saturated alkyl group. Examples of the alkylene group include, but are not limited to, methylene group, ethylene group, etc.

[0060] "Haloalkyl group" refers to the case where one or more hydrogens in an alkyl group are substituted by one or more halogen atoms (e.g., fluorine, chlorine, bromine, iodine, or their isotopes). The upper limit of the number of halogen substituents is equal to the sum of the replaceable hydrogens in the alkyl group. Unless otherwise specifically limited, the number of halogen substituents is any integer between 1 and the upper limit. Usually, the alkyl group is substituted with 1 to 5 halogens, or 1 to 3 halogens, or 1 to 2 halogens, or 1 halogen. When the number of halogen substituents is greater than 1, it may be substituted by the same or different halogens. Specific examples include, but are not limited to, -CF 3 、-CH 2 Cl、-CH 2 CF 3 、-CCl 2 、CF 3 etc.

[0061] "Alkoxy group" or "alkyloxy group" refers to an -O-alkyl group. For example, -O-C 1-8 alkyl group, -O-C 1-6 alkyl group, -O-C 1-4 alkyl group or -O-C 1-2 alkyl group. Specific non-limiting examples include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, t-butoxy group, n-pentyloxy group, n-hexyloxy group, cyclopropoxy group, and cyclobutoxy group, etc. The alkoxy group may optionally be substituted with a substituent.

[0062] "Haloalkoxy group" refers to an -O-haloalkyl group. For example, -O-halogenated C 1-8 alkyl group, -O-halogenated C 1-6 alkyl group, -O-halogenated C 1-4 alkyl group or -O-halogenated C 1-2It is an alkyl group. The upper limit of the number of halogen substituents is equal to the sum of the replaceable hydrogens of the group to be substituted. Unless otherwise particularly limited, the number of halogen substituents is any integer between 1 and the upper limit. Preferably, it is 1 to 5 halogen substitutions, 1 to 3 halogen substitutions, 1 to 2 halogen substitutions, or 1 halogen substitution. When the number of halogen substituents is greater than 1, it may be substituted by the same or different halogens. Non-limiting examples include monofluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, difluoroethyloxy group, etc.

[0063] "Hydroxy C 1-6 "alkyl group" refers to an alkyl group having 1 to 6 carbon atoms substituted with a hydroxy group.

[0064] "Alkenyl group" refers to a straight-chain hydrocarbon group or a branched-chain hydrocarbon group containing at least one carbon-carbon double bond (C=C). Usually, it contains 2 to 18 carbon atoms, for example, 2 to 8 carbon atoms, or for example, 2 to 6 carbon atoms, or further for example, 2 to 4 carbon atoms. Examples thereof include vinyl group, allyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-1-butenyl group, 2-methyl-1-butenyl group, 2-methyl-3-butenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 1-methyl-1-pentenyl group, 2-methyl-1-pentenyl group, 1-heptenyl group, 2-heptenyl group, 3-heptenyl group, 4-heptenyl group, 1-octenyl group, 3-octenyl group, 1-nonenyl group, 3-nonenyl group, 1-decenyl group, 4-decenyl group, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, etc., but are not limited thereto. The alkenyl group may optionally be further substituted with a substituent.

[0065] "Alkenylene group" refers to a linear or branched divalent unsaturated hydrocarbon group containing at least one carbon-carbon double bond (C=C), usually containing 2 to 18 carbon atoms, for example, 2 to 8 carbon atoms, further for example, 2 to 6 carbon atoms, still further for example, 2 to 4 carbon atoms, and non-limiting examples include an ethynylene group, and the alkenylene group may optionally be substituted with a substituent.

[0066] "Alkynyl group" refers to a linear hydrocarbon group or a branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), usually containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, still further containing 2 to 4 carbon atoms, and examples thereof include an ethynyl group, 1-propynyl group, 2-propynyl group, butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 4-pentynyl group, 3-pentynyl group, 1-methyl-2-butynyl group, 2-hexynyl group, 3-hexynyl group, 2-heptynyl group, 3-heptynyl group, 4-heptynyl group, 3-octynyl group, 3-nonynyl group, and 4-decynyl group, etc., but are not limited thereto, and the alkynyl group may optionally be substituted with a substituent.

[0067] "Alkynylene group" refers to a linear or branched divalent unsaturated hydrocarbon group containing a carbon-carbon triple bond (C≡C), usually containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, still further containing 2 to 4 carbon atoms, and non-limiting examples include an ethynylene group, propynylene group, and butynylene group, and the alkynylene group may optionally be substituted with a substituent.

[0068] "Cycloalkyl group" refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group that does not contain cycloheteroatoms. The cycloalkyl group may be monocyclic, bicyclic or polycyclic, and the bicyclic or polycyclic may be in the form of fused rings, spiro rings, bridged rings or combinations thereof. The bicyclic or polycyclic may contain one or more aromatic rings, but the entire ring system is not aromatic, and the linking site may be on an aromatic ring or a non-aromatic ring. Usually, the cycloalkyl group contains 3 to 20 carbon atoms, further contains 3 to 8 carbon atoms, and even further contains 3 to 6 carbon atoms. When it is a monocyclic cycloalkyl group, it contains 3 to 15 carbon atoms, or 3 to 10 carbon atoms, or 3 to 8 carbon atoms, or 3 to 6 carbon atoms. When it is a bicyclic or polycyclic cycloalkyl group, it contains 5 to 12 carbon atoms, or 5 to 11 carbon atoms, or 6 to 10 carbon atoms. Non-limiting examples include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, butenyl group, cyclopentenyl group, cyclohexenyl group,

Chemical formula

[0069] "Cycloalkylene group" is a divalent group of a cycloalkyl group.

[0070] "Aryl group" refers to an aromatic carbon ring that does not contain heteroatoms, and includes monocyclic aryl groups and fused-ring aryl groups. Usually, it contains 6 to 14 carbon atoms, and further contains 6 to 10 carbon atoms. Non-limiting examples include phenyl group, naphthyl group, anthryl group, phenanthryl group, aryl group,

Chemical formula

[0071] "Carbon ring" or "carbocyclic group" refers to a saturated, partially unsaturated, or aromatic carbocyclic ring, and its meaning includes aryl groups and cycloalkyl groups. The carbocyclic ring may be monocyclic, bicyclic or polycyclic, and the bicyclic or polycyclic rings include bridged rings, fused rings and spiro rings and combinations thereof. The carbocyclic ring usually has 3 to 12 carbon atoms, or 3 to 10 carbon atoms, or 3 to 6 carbon atoms. In non-limiting examples, monocyclic carbocyclic rings include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group or phenyl group, etc., and bicyclic bridged rings include

Chem.

Chem.

Chem.

[0072] "Heterocycloalkyl group" refers to a saturated or partially unsaturated non-aromatic carbocyclic ring containing 1, 2, 3, or 4 heteroatoms selected from N, S, and O. The heterocycloalkyl group may be monocyclic, bicyclic, or polycyclic, and the bicyclic or polycyclic ring may be in the form of a bridged ring, fused ring, spiro ring, or a combination thereof. The bicyclic or polycyclic ring may contain one or more aromatic or heteroaromatic rings, provided that the entire ring system is not aromatic, and the linking site may be on an aromatic or non-aromatic ring. Usually, the heterocycloalkyl group is a 3- to 20-membered ring. When it is a monocyclic heterocycloalkyl group, it is usually a 3- to 15-membered ring, or a 3- to 10-membered ring, or a 3- to 8-membered ring, or a 3- to 6-membered ring. When it is a bicyclic or polycyclic heterocycloalkyl group, it is usually a 5- to 12-membered ring, or a 5- to 11-membered ring, or a 6- to 9-membered ring. Here, the heteroatoms N and S include their oxidation states. Non-limiting examples of the heterocycloalkyl group include azetidinyl group, morpholinyl group, piperazinyl group, piperidinyl group, tetrahydropyranyl group, oxetanyl group, pyranyl group, azacyclopentenyl group, azacyclohexenyl group, oxolyl group, oxinyl group, etc. The heterocycloalkyl group may optionally be substituted with substituents.

[0073] "Heteroaromatic ring" or "heteroaryl group" refers to a ring having aromaticity and containing 1 to 4 heteroatoms selected from N, O, or S and their oxidation states, unless otherwise specified. It may be monocyclic, bicyclic, or polycyclic, and the bicyclic or polycyclic ring may be in the form of a bridged ring, fused ring, spiro ring, or a combination thereof. When it is bicyclic or polycyclic, it may be a condensation of a heteroaryl group and an aryl group, or a condensation of a heteroaryl group and a heteroaryl group. Here, both the heteroaryl group and the aryl group can be the linking sites. Non-limiting examples include furyl group, thienyl group, pyrrolyl group, oxazolyl group, thiazolyl group, imidazolyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, indolyl group, purinyl group,

Chemical Structure

[0074] "Heterocycle" or "heterocyclic group" 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, which includes heteroaryl groups and heterocycloalkyl groups. Heterocycles include monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles and bicyclic spiroheterocycles or combinations thereof. Usually, it is a 3- to 12-membered heterocycle or a 5- to 12-membered heterocycle, or a 5- to 7-membered heterocycle. The heterocyclic group may be linked on a heteroatom or a carbon atom, and non-limiting examples are oxiranyl group, azacyclopropyl group, oxetanyl group, azetidinyl group, 1,3-dioxolanyl group, 1,4-dioxolanyl group, 1,3-dioxanyl group, piperazinyl group, azacycloheptyl group, pyridyl group, furyl group, thienyl group, pyranyl group, N-alkylpyrrolyl group, pyrimidinyl group, pyrazinyl group, pyrazolyl group, pyridazinyl group, imidazolyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, 1,3-dithianyl group, dihydrofuryl group, dihydropyranyl group, dithiolanyl group, tetrahydrofuryl group, tetrahydropyrrolyl group, tetrahydroimidazolyl group, oxazolyl group, dihydrooxazolyl group, tetrahydrooxazolyl group, tetrahydrothiazolyl group, tetrahydropyranyl group, benzimidazolyl group, benzopyridyl group, pyrrolopyridyl group, benzodihydrofuryl group, azabicyclo[3.2.1]octyl group, azabicyclo[5.2.0]nonyl group, oxatricyclo[5.3.1.1]dodecyl group, azadamantyl group and oxaspiro[3.3]heptyl group,

Chemical formula

[0075] "Heterocyclylene group" refers to a divalent heterocyclic group which may be substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic. Non-limiting examples include [Chemical formula] and the like.

[0076] "Spiro ring" refers to a polycyclic group in which rings share one carbon atom (referred to as a spiro atom), which may contain 0 or one 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. Usually, the spiro ring is a 6- to 14-membered ring, or a 6- to 12-membered ring, or a 6- to 10-membered ring. Usually, the spiro ring is 3 spiro 3 (representing a 3-membered ring spiro 3-membered ring), 3 spiro 4, 3 spiro 5, 3 spiro 6, 4 spiro 4, 4 spiro 5, 4 spiro 6, 5 spiro 5 or 5 spiro 6. Non-limiting examples of the spiro ring include [Chemical formula] and the spiro ring may optionally be substituted with substituents.

[0077] "Fused ring" or "condensed ring" refers to a polycyclic group in which rings share two adjacent ring atoms and one chemical bond, which may contain one or more double bonds or triple bonds, and the fused ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidation states. Usually, the fused 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 fused ring is 3 fused 4 ring (representing a fused ring formed by a 3-membered ring and a 4-membered ring, based on the IUPC naming rules, a fused ring with a 3-membered ring as the basic ring is possible, and a fused ring with a 4-membered ring as the basic ring is also possible, and the same applies hereinafter), 3 fused 5 ring, 3 fused 6 ring, 4 fused 4 ring, 4 fused 5 ring, 4 fused 6 ring, 5 fused 5 ring, 5 fused 6 ring, 6 fused 6 ring. Non-limiting examples of the fused ring include purine, quinoline, isoquinoline, benzopyran, benzofuran, benzothiophene, [Chemical formula] including, wherein the parallel ring may be aromatic or non-aromatic and is optionally substituted with a substituent.

[0078] "Bridged ring" refers to a structure where two rings 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. Usually, the ring atoms of a bridged ring are 5 to 20, or 5 to 14, or 5 to 12, or 5 to 10. Non-limiting examples of bridged rings are adamantane,

Chemical formula

[0079] "Substituted" or "substituent" means that any substitution occurs at a chemically acceptable position and the number of substituents satisfies the laws of chemical bonding, unless otherwise specified. Exemplary substituents are C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 heteroalkyl group, C 5-12 aryl group, 5- to 12-membered heteroaryl group, hydroxy group, C 1-6 alkoxy group, C 5-12 aryloxy group, thiol group, C 1-6 alkylthio group, cyano group, halogen, C 1-6 alkylthiocarbonyl group, C 1-6 alkylcarbamoyl group, N-carbamoyl group, nitro group, silyl group, sulfinyl group, sulfonyl group, sulfoxide, halogenated C 1-6 alkyl group, halogenated C 1-6 alkoxy group, amino group, phosphonic acid, -CO 2 (C 1-6 alkyl group), -OC(=O)(C 1-6 alkyl group), -OCO 2 (C 1-6 alkyl group), -C(=O)NH 2 、-C(=O)N(C 1-6 alkyl group) 2 、-OC(=O)NH(C1-6 (alkyl group), -NHC(=O)(C 1-6 (alkyl group), -N(C 1-6 (alkyl group)C(=O)(C 1-6 (alkyl group), -NHCO 2 (C 1-6 (alkyl group), -NHC(=O)N(C 1-6 (alkyl group) 2 , -HC(=O)NH(C 1-6 (alkyl group), -NHC(=O)NH 2 , -NHSO 2 (C 1-6 (alkyl group), -SO 2 N(C 1-6 (alkyl group) 2 , -SO 2 NH(C 1-6 (alkyl group), -SO 2 NH 2 , -SO 2 C 1-6 including, but not limited to, an alkyl group, etc.

[0080] "Optional" or "optionally" means that the event or circumstance described thereafter may occur, but does not necessarily occur, and the description includes both the case where the event or circumstance occurs and the case where it does not occur. For example, "an alkyl group optionally substituted by F" means that the alkyl group may be substituted by F, but does not necessarily have to be substituted by F, indicating that it includes both the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

[0081] "Pharmaceutically acceptable salts" refer to salts obtained by reacting the compounds of the present invention with non-toxic inorganic bases or organic bases for free acids, or with non-toxic inorganic acids or organic acids for free bases, while maintaining the biological effectiveness and characteristics of the free acids or free bases.

[0082] "Pharmaceutical composition" refers to one or more of the compounds of the present specification, its stereoisomers, deuterated compounds, solvates, or pharmaceutically acceptable salts or cocrystals or cocrystals, mixtures with other components, where the other components include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0083] "Carrier" refers to a system that does not significantly stimulate the living body, does not eliminate the biological activity and properties of the given compound, and changes the administration form and in vivo distribution of the drug, controls the drug release rate, and can deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0084] "Excipient" refers to a substance that is not a therapeutic agent itself but is added to a pharmaceutical composition as a diluent, adjuvant, adhesive, and / or vehicle to improve its handling and storage properties or to permit or facilitate the compound or pharmaceutical composition to form a dosage form for administration. As is known to those skilled in the art, excipients can provide various functions and may be described as wetting agents, buffering agents, suspending aids, lubricants, emulsifying agents, disintegrating agents, absorbents, preservatives, surfactants, coloring agents, flavoring agents, and sweetening agents. Examples of excipients include, but are not limited to, the following: (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 carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and cross-linked carboxymethyl cellulose (e.g., sodium cross-linked carboxymethyl cellulose); (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, castor oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) water for endotoxin testing; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solutions; (21) polyesters, polycarbonates, and / or polyanhydrides; and (22) other non-toxic and compatible substances used in pharmaceutical formulations.

[0085] "Stereoisomer" refers to an isomer that results from different spatial arrangements of atoms in a molecule and includes cis-trans isomers, enantiomers, and conformational isomers.

[0086] The compounds of the present invention further include their tautomers. For example, when the left - hand compound in which the pyrimidine ring is substituted with OH is described in the present invention, the right - hand tautomeric compound is also included.

Chemical formula

[0087] "Solvate" refers to a substance formed by the intermolecular non - covalent bonding of a compound of the present invention or its salt with a stoichiometric or non - stoichiometric solvent. When the solvent is water, it becomes a hydrate.

[0088] "Co - crystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a co - crystal - forming substance (CCF) under the action of hydrogen bonding or other non - covalent bonds. Here, the pure states of API and CCF are both solids at room temperature, and there is a fixed stoichiometric ratio between the components. Co - crystals are multi - component crystals, including not only two - component co - crystals formed between two neutral solids, but also multi - component co - crystals formed between a neutral solid and a salt or a solvate.

Embodiments for Carrying out the Invention

[0089] Hereinafter, the technical solutions of the present invention will be described in detail in conjunction with examples. However, the protection scope of the present invention includes but is not limited to them.

[0090] Test Method The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR measurement is carried out using a nuclear magnetic resonance apparatus (Bruker Avance III 400 and Bruker Avance 300), and the measurement solvents are deuterated dimethyl sulfoxide (DMSO - d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD). The internal standard is tetramethylsilane (TMS). The MS measurement was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI)). The HPLC measurement was performed using an Agilent 1260 DAD high-pressure liquid chromatograph (Zorbax SB-C 18 100×4.6 mm, 3.5 μM). For thin-layer chromatography silica gel plates, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used. The silica gel plates used for thin-layer chromatography (TLC) adopted specifications of 0.15 mm to 0.20 mm, and the separation and purification of products by thin-layer chromatography adopted specifications of 0.4 mm to 0.5 mm. Column chromatography generally used silica gel of 200 - 300 mesh from Yantai Huanghai as the carrier. Example 1:

Chemical Structure

[0091] 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 react at room temperature for 16 hours after addition. Concentrate under reduced pressure, add water (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with a saturated aqueous sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate the residue by silica gel column chromatography (PE:EA (v / v) = 10:1) to obtain compound 1B (1.0 g, yield 57%).

[0092] LC-MS (ESI): m / z = 328.0 [M+H] + .

[0093] Step 2: 1B (0.2 g, 0.61 mmol), 1C (synthesized with reference to the method described in Patent WO 2019147862) (0.16 g, 0.61 mmol), triethylamine (0.12 g, 1.22 mmol), cesium fluoride (0.09 g, 0.61 mmol) were successively dissolved in dimethyl sulfoxide (20 mL), and reacted at 100 °C for 4 hours. After complete reaction, it was cooled to room temperature, water (20 mL) was added, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (DCM:MeOH(v / v)=10:1) to obtain the target compound 1D (0.12 g, yield 35%).

[0094] LC-MS (ESI): m / z = 558.3 [M+H] + 。

[0095] Step 3: Compound 1D (0.12 g, 0.22 mmol) was dissolved in a (THF:H 2 O (v / v)=1:1) solution (4 mL), lithium hydroxide (0.026 g, 1.1 mmol) was added, and stirred at room temperature for 4 hours to react. After complete reaction, the reaction solution was concentrated under reduced pressure, and the residue was separated by preparative HPLC to obtain compound 1 (0.07 g, yield 60%).

[0096] Preparative method: (Instrument name: Waters AutoP, chromatography column: Sunfire C18 (19×250 mm, 5 μm) Mobile phase: Phase A: acetonitrile, Phase B: water (containing 0.1% TFA), Gradient: A content 10% - 50%, 15 min.

[0097] 1 H NMR (400 MHz, CD 3CN; trifluoroacetate) δ 7.33 (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, 3H), 2.24 - 2.22 (m, 2H), 2.18 - 2.06 (m, 3H), 1.87 - 1.84 (m, 2H), 1.37 (s, 3H). LC-MS (ESI): m / z = 544.2 [M + H] + 。 Example 2:

Chemical Structure

[0098] Step 1: Dissolve raw material 2A (3 g, 13.27 mmol) in dichloroethane (100 mL), add 2B (2.55 g, 19.91 mmol), stir until the solution becomes clear, then add sodium borohydride acetate (5.62 g, 26.54 mmol), cool down to 0 °C, and dropwise add acetic acid (0.80 g, 13.27 mmol). Let it warm up to room temperature naturally and react overnight. Concentrate under reduced pressure, and purify the obtained crude product with a medium-pressure preparative apparatus Biotage Isolera One (80 g silica gel column, MeOH:DCM = 0% → 20%) to obtain product 2C (3.10 g, yield 68.92%).

[0099] LC-MS (ESI): m / z = 339.2 [M + H] + 。

[0100] Step 2: Compound 2C (1.4 g, 4.14 mmol) was dissolved in 1,4-dioxane (10 mL), and a 1,4-dioxane solution of hydrochloric acid (4 M, 10 mL) was added dropwise. The mixture was stirred at room temperature until the raw materials were consumed, and the reaction solution was concentrated to obtain Compound 2D, which was directly used in the next-step reaction without further purification.

[0101] LC-MS (ESI): m / z = 239.1 [M+H] + 。

[0102] Step 3: Compound 2D was dissolved in methanol (20 mL), and thionyl chloride (0.92 g, 7.72 mmol) was slowly added dropwise at room temperature. After the addition was complete, the temperature was raised, and the mixture was refluxed for 4 hours. After the reaction cooled to room temperature, it was concentrated to obtain 2E (1.21 g, two-step yield 89.4%).

[0103] LC-MS (ESI): m / z = 253.2 [M+H] + 。

[0104] Step 4: Compound 2E was dissolved in DMSO (10 mL), and Compound 2F (synthesized with reference to the method described in Patent WO 2019147862) (1.08 g, 3.07 mmol) was added. The mixture was stirred, and triethylamine (0.62 g, 6.14 mmol) and cesium fluoride (0.93 g, 6.14 mmol) were added sequentially. The reaction was carried out at 100 °C for 4 h under a nitrogen gas atmosphere. After the reaction cooled to room temperature, water (40 mL) and ethyl acetate (30 mL×3) were added for extraction. The combined organic phases were washed with saturated brine (40 mL×2), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by medium-pressure preparative apparatus Biotage Isolera One (24 g silica gel column, eluent: 0-30% EA / PE) to obtain the product 2G (0.48 g, yield 27.58%).

[0105] LC-MS (ESI): m / z = 568.1 [M+H] + 。

[0106] Step 5: Compound 2G (0.48 g, 0.85 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL), lithium hydroxide monohydrate (0.18 g, 4.25 mmol) was added, and the mixture was stirred overnight at room temperature. 6N hydrochloric acid was added dropwise to adjust the pH to 6 - 7, and the mixture was concentrated to obtain a crude product. The residue was separated and purified by high performance liquid chromatography to obtain Compound 2 Isomer 1 (0.13 g, yield 19.58%) and Compound 2 Isomer 2 (0.14 g, yield 21.09%).

[0107] HPLC preparative method: Instrument: Waters 2767 preparative liquid chromatograph, chromatography column: SunFire@ Prep C18 (19 mm×250 mm). The sample was dissolved in methanol and filtered through a 0.22 μm filter to prepare the sample solution. Preparative chromatography conditions: Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 1% TFA), gradient elution, the content of mobile phase A was 10% - 55%, the flow rate was 15 mL / min, and the elution time was 20 min.

[0108] HPLC analysis method: Instrument: Shimadzu LC-20AT, column: chromatography column model number: Xtimate C18 4.6*50 mm, 3 μm, mobile phase A was 0.05% TFA solution, mobile phase B was acetonitrile, gradient: A 95 - 5% B 5 - 95%, flow rate: 1 mL / min, column temperature: 35 °C, wavelength: 210 nm / 254 nm, collection time: 10 min.

[0109] Compound 2 Isomer 1 (retention time: 3.253 min): LC-MS (ESI): m / z = 554.2[M + H] + 。

[0110] 1 H NMR (400 MHz, CD 3CN, 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).

[0111] Compound 2 isomer 2 (retention time: 3.230 min): LC-MS (ESI): m / z = 554.2 [M + H] + .

[0112] 1 1H NMR (400 MHz, CD 3 CN, 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). Example 3:

Chemical Structure

[0113] Using compound 3A as the raw material and referring to the operations in steps 1, 2, 3, 4, and 5 of Example 2, compound 3 isomer 1 (0.15 g) and compound 3 isomer 2 (0.13 g) were obtained.

[0114] HPLC analysis method: Instrument: Shimadzu LC-20AT, Column: Chromatography column model number: Xtimate C18 4.6*50mm, 3μm, Mobile phase A is 0.05% TFA solution, Mobile phase B is acetonitrile, Gradient: A 95~5% B 5~95%, Flow rate: 1mL / min, Column temperature: 35°C, Wavelength: 210nm / 254nm, Collection time: 10min. Compound 3 isomer 1 (Retention time: 3.416min): LC-MS (ESI): m / z=554.2[M+H] + 。

[0115] 1 H NMR (400MHz,CD 3 CN) 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,6H),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).

[0116] Compound 3 isomer 2 (Retention time: 3.443min): LC-MS (ESI): m / z=554.2[M+H] + 。

[0117] 1 H NMR (400MHz,CD 3 CN) 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). Example 4:

Chemical Structure

[0118] Step 1: 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) were successively dissolved in methanol (10 mL) and stirred at room temperature overnight. The solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 30:1) to obtain the title compound 4B (1.2 g, 77%).

[0119] LCMS m / z = 443.9 [M+H] + 。

[0120] Step 2: Compound 4B (0.87 g, 1.97 mmol), trimethylsilylacetylene (0.39 g, 3.94 mmol), bis(triphenylphosphine)palladium dichloride (69.14 mg, 0.10 mmol), and cuprous iodide (18.76 mg, 0.10 mmol) were successively added to triethylamine (8 mL), and the mixture was stirred at 50 °C for 4 h under a nitrogen gas atmosphere. After the reaction cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with a saturated aqueous 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%).

[0121] LCMS m / z = 340.1 [M - 72+H] + 。

[0122] Step 3: Compound 4C (0.11 g, 0.27 mmol) and potassium carbonate (37.32 mg, 0.54 mmol) were sequentially added to methanol (4 mL), and the mixture was stirred at room temperature for 2 h. After completion of the reaction, water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3), washed with a saturated aqueous sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and 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%).

[0123] 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 sequentially added to dimethyl sulfoxide (3 mL), and the mixture was 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), washed with a saturated aqueous sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 9:1) to obtain the title compound 4E (47 mg, 54%).

[0124] Step 5: 4E (20.0 mg, 0.035 mmol) and lithium hydroxide (3.4 mg, 0.14 mmol) were sequentially added to a mixed solvent of methanol (2 mL), tetrahydrofuran (1 mL), and water (1 mL), and the mixture was stirred at room temperature for 2 h. The crude product was separated and purified by preparative HPLC.

[0125] Separation method: Instrument: Waters 2767 liquid fraction collector, chromatography column: SunFire@ Prep C18 (19mm×250mm), the sample was filtered through a 0.45μm filter to prepare a sample solution. Chromatography conditions for fractionation: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate) b. Gradient elution, the content of mobile phase A is 10% - 55% c. Flow rate is 12mL / min. Retention time 7.0min, the title compound 4 (12mg, 62%) was obtained.

[0126] 1 H NMR (400MHz, DMSO-d6) δ 9.86 (s, 1H), 9.52 (s, 1H), 7.57 (d, 1H), 7.46 - 7.30 (m, 2H), 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). LCMS m / z = 556.2[M + H] + 。 Example 5:

Chemical formula

[0127] 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), add a few drops of acetic acid, and continue stirring at room temperature for 2 hours to allow the reaction to proceed. Then add sodium cyanoborohydride (1.62 g, 25.60 mmol) and continue stirring for 18 hours to allow the reaction to proceed. Pour the reaction into water (30 mL), extract with dichloromethane (20 mL×3), dry the combined organic phases over anhydrous sodium sulfate, filter, concentrate, and separate and purify the residue 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%).

[0128] LC-MS (ESI): m / z = 390.2 [M+H] + 。

[0129] Step 2: Dissolve compound 5C (3.50 g, 8.97 mmol) in ethyl acetate (300 mL), add palladium carbon (951 mg, 8.97 mmol), and stir at room temperature for 5 h under a hydrogen gas atmosphere. Filter through diatomaceous earth to remove palladium carbon, concentrate the filtrate, and obtain the title compound 5D as a white oily liquid. It was used directly in the reaction of the next step without further purification.

[0130] LC-MS (ESI): m / z = 256.2 [M+H] + 。

[0131] Step 3: Dissolve Compound 5D in methanol (10 mL), add Compound 2B (1.21 g, 9.44 mmol), add a few drops of acetic acid, and continue stirring and reacting at room temperature for 5 hours after addition. Then add sodium cyanoborohydride (793.8 mg, 12.6 mmol) and continue stirring and reacting for 1 hour. Pour the reaction into water (30 mL), adjust the pH to 4 - 5 with aqueous citric acid solution, extract with dichloromethane (20 mL × 3), dry the combined organic phases over anhydrous sodium sulfate, filter, concentrate, and separate and purify the residue by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1 - 10:1) to obtain the title compound 5F (924.0 mg, 2-step yield 28%).

[0132] LC-MS (ESI): m / z = 368.3 [M+H] + 。

[0133] Step 4: Dissolve Compound 5F (924.0 mg, 2.50 mmol) in methanol (8 mL), add thionyl chloride (2 mL) under an ice bath, heat to 70 °C after addition, react for 1 hour, concentrate to obtain the hydrochloride salt of the title compound 5F. It was directly used in the reaction of the next step without further purification.

[0134] LC-MS (ESI): m / z = 282.2 [M+H] + 。

[0135] Step 5: Using the above hydrochloride salt of 5F and Compound 2F (876 mg, 2.52 mmol) as raw materials, referring to the operation in Step 4 of Example 2, the target compound 5G (449.1 mg, 2-step yield 31%) was obtained.

[0136] LC-MS (ESI): m / z = 595.3 [M+H] + 。

[0137] Step 6: Using Compound 5G (449.1 mg, 0.76 mmol) as a raw material, referring to the operation in Step 5 of Example 2, the title compound 5 (0.265 g, 61%) was obtained.

[0138] 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.48 - 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). LC-MS (ESI): m / z = 581.2 [M + H] + . Example 6:

Chemical formula

[0139] Using 1A (100 mg, 0.51 mmol) and 6A (103 mg, 0.51 mmol) as raw materials, referring to the operation methods of Steps 1, 2, and 3 in Example 1, Compound 6 (117 mg) was obtained.

[0140] 1 H NMR (400 MHz, CDCl 3 ) δ 12.18 (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). LCMS m / z = 578.2 [M + H] + . Example 7:

Chemical formula

[0141] Step 1: 1-(2-Bromo-4-chlorophenyl)ethan-1-one (12.0 g, 51.37 mmol), trimethylsilylacetylene (7.57 g, 77.05 mmol), bis(triphenylphosphine)palladium dichloride (3.61 g, 5.14 mmol), and cuprous iodide (0.98 g, 5.14 mmol) were sequentially added to triethylamine (120 mL), purged with nitrogen gas three times, heated to 55 °C, and reacted for 1.5 hours. After complete reaction, it was cooled to room temperature, concentrated, and the residue was separated and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 100:1 to 20:1) to obtain product 7B (11.0 g, 85.38%).

[0142] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.75 (d, 1H), 7.62 (d, 1H), 7.58 - 7.57 (m, 1H), 2.62 (s, 3H), 0.24 (s, 9H).

[0143] 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, extracted, and separated. The aqueous phase was extracted with ethyl acetate (200 mL × 3), and the combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated 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%).

[0144] 11H NMR (400 MHz, DMSO-d6) δ 7.80 (d, 1H), 7.68 (d, 1H), 7.61 - 7.60 (m, 1H), 4.58 (s, 1H), 2.61 (s, 3H).

[0145] Step 3: 7C (2 g, 11.20 mmol) was dissolved in tetrahydrofuran (20 mL), and titanium tetraisopropoxide (6.37 g, 22.40 mmol) and (R)-(+)-t-butylsulfinamide (1.36 g, 11.20 mmol) were added sequentially. The temperature was raised to 60 °C and reacted for 16 hours. After complete reaction, it was cooled to room temperature, brine (30 mL) was added, a solid precipitated, filtered, the filter cake was washed with ethyl acetate (100 mL), the filtrate was extracted and separated, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (petroleum ether:ethyl acetate (v / v) = 20:1 - 5:1) was performed to obtain 7D (1.4 g, 44.36%).

[0146] LCMS (ESI): m / z = 282.0 [M+H] + .

[0147] Step 4: 7D (1.40 g, 4.97 mmol) was dissolved in a mixed solvent of tetrahydrofuran and water (v:v = 98:2) (15 mL), the temperature was lowered to -30 °C, and sodium borohydride (0.38 g, 9.94 mmol) was added little by little and reacted for 2 hours. After complete reaction, water (20 mL) and ethyl acetate (30 mL) were added, 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 - 3:1) to obtain 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%).

[0148] Isomer 7E:1 1H NMR (400 MHz, DMSO-d6) δ 7.56 - 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).

[0149] Isomer 7F: 1 1H NMR (400 MHz, DMSO-d6) δ 7.62 - 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).

[0150] Step 5: 7E (0.70 g, 2.47 mmol) was added to a 1,4-dioxane solution of hydrochloric acid (4 M, 10 mL), stirred at room temperature for 1 hour, concentrated, a mixed solvent of petroleum ether and ethyl acetate ((v / v) = 5:1, 10 mL) was added, stirred, filtered, and the filter cake was collected to obtain 7G (0.44 g, 75.32%).

[0151] LCMS (ESI): m / z = 180.1 [M + H] + .

[0152] Using 7F as the raw material, referring to the above synthesis method, 7H was obtained.

[0153] 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, referring to the operation method of Step 1 in Example 1, 7I (0.43 g, 65.34%) was obtained.

[0154] LCMS (ESI): m / z = 340.0 [M + H] + .

[0155] Using 7H as the raw material, referring to the above synthesis method, 7J was obtained.

[0156] Step 7: Using 1C (0.533 g, 1.76 mmol) and 7I (0.3 g, 0.88 mmol) as raw materials, referring to the operation method of Step 2 in Example 1, the product 7K (0.15 g, 29.88%) was obtained.

[0157] LCMS (ESI): m / z = 570.4 [M+H] + 。

[0158] Using 7J as a raw material and referring to the above synthesis method, 7L was obtained.

[0159] Step 8: Using 7K (150 mg, 0.26 mmol) as a raw material, referring to the operation method of Step 3 in Example 1, compound 7 isomer 1 (35 mg, 24.19%) was obtained.

[0160] 1 H NMR (400 MHz, DMSO-d6) δ 7.48 - 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 - 2.43 (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). LCMS m / z = 556.2 [M+H] + 。

[0161] Using 7L as a raw material and referring to the above synthesis method, compound 7 isomer 2 was obtained.

[0162] 11H NMR (400 MHz, DMSO-d6) δ 7.53 - 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). LCMS m / z = 556.4 [M + H] + . Example 8:

Chem.

[0163] Step 1: At room temperature, dissolve compound 8A (31 g, 0.32 mol) in tetrahydrofuran (1.5 L), add diethyl malonate (51.6 g, 0.32 mol) dropwise. After dropping for 5 minutes, start dropping a solution of t-butoxide (39.8 g, 0.35 mol) in tetrahydrofuran (0.5 L). After completion of dropping, react at room temperature for 1 hour. TLC indicates that the raw material has completely reacted. Dropwise add dilute hydrochloric acid (2N, 200 mL) to adjust the pH to 3, extract with EA (200 mL × 2), wash the combined organic phases with saturated aqueous sodium hydrogen carbonate solution (100 mL × 2), wash with saturated brine (100 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate to obtain 70 g (0.27 mol, 85% yield) of the crude product of compound 8B.

[0164] Step 2: At room temperature, the crude product of 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 sequentially dissolved in toluene (700 mL). A water separator and a reflux condenser were added and attached. The temperature was raised to 120 °C and reacted overnight. TLC indicated complete reaction. After cooling to room temperature and concentrating under reduced pressure, water (200 mL) was added for dilution, and extraction was performed with EA (200 mL × 2). The combined organic phases were washed with saturated aqueous sodium bicarbonate solution (100 mL × 2), washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (10% EA in PE) to obtain compound 8C (53 g, 65% yield).

[0165] Step 3: Under an ice bath, lithium aluminum hydride (8.34 g, 0.22 mol) was added little by little to ether (300 mL). A solution of compound 8C (44 g, 0.15 mol) in ether (300 mL) was added dropwise. After completion of the dropwise addition, the temperature was raised and refluxed for 1 hour. TLC indicated complete reaction. The temperature was lowered to room temperature. Under an ice bath, water (8.4 mL) and 15% aqueous NaOH solution (8.4 mL) were added dropwise in sequence. The reaction was quenched with water (25 mL), filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by column chromatography (7% MeOH in CH 2 Cl 2 ) to obtain compound 8D (26 g, 0.12 mol).

[0166] Step 4: At -20 °C, under a nitrogen gas atmosphere, to dry acetonitrile (250 mL), add compound 8D (10.8 g, 50 mmol) and diisopropylethylamine (16.1 g, 125 mmol). Slowly add trifluoromethanesulfonic anhydride (29.7 g, 105 mmol) dropwise. After stirring for 1 hour to allow the reaction to proceed, sequentially add diisopropylethylamine (16.1 g, 125 mmol) and benzylamine (8.1 g, 75 mmol). Then raise the temperature to 90 °C and react for 2 hours. TLC indicates that the reaction is complete. Cool to room temperature, add water (100 mL) and EA (100 mL) for dilution, extract, wash the organic phase with water (200 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the resulting crude product. Purify by silica gel column chromatography (5% MeOH in CH 2 Cl 2 ), and obtain compound 8E (10.81 g, 75% yield).

[0167] LC-MS (ESI): m / z = 288.3 [M+H] + 。

[0168] Step 5: At room temperature, add compound 8E (3.84 g, 13.4 mmol) to tetrahydrofuran (20 mL). Cool to 0 °C and add dropwise a 1,4-dioxane solution of hydrochloric acid (3 M, 22.3 mL). React to room temperature and stir for 1 hour. TLC / LCMS indicates that the reaction is complete. Add water (20 mL) and EA (30 mL) for dilution, extract, adjust the pH of the resulting aqueous phase to 9 with saturated aqueous sodium bicarbonate solution, extract with dichloromethane (30 mL × 2), dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate the resulting crude product. Purify by silica gel column chromatography (3% MeOH in CH 2 Cl 2 ), and obtain compound 8F (2.56 g, 79% yield).

[0169] LC-MS (ESI): m / z = 244.2 [M+H] + 。

[0170] Step 6: At room temperature, 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) were sequentially added to 1,2-dichloroethane (20 mL). The temperature was lowered to 0 °C, acetic acid (149 mg, 2.47 mmol) was added dropwise, and then the temperature was raised to room temperature and reacted overnight. TLC / LCMS indicated complete reaction. The crude product obtained by concentration under reduced pressure was separated and purified by silica gel column chromatography (70% MeOH in CH 2 Cl 2 ), and compound 8G (650 mg, 77% yield) was obtained.

[0171] LC-MS (ESI): m / z = 343.2 [M+H] + 。

[0172] Step 7: At room temperature, compound 8G (620 mg, 1.74 mmol) was added to methanol (50 mL). The temperature was lowered to 0 °C, thionyl chloride (2.07 g, 17.4 mmol) was added dropwise, and then the temperature was raised to room temperature and reacted for 1 hour. TLC / LCMS indicated complete reaction. The hydrochloride salt of compound 8H obtained by concentration under reduced pressure was directly used in the reaction of the next step without further purification.

[0173] LC-MS (ESI): m / z = 357.2 [M+H] + 。

[0174] Step 8: At room temperature, the hydrochloride salt of compound 8H was added to methanol (10 mL). After replacing with hydrogen gas three times, the temperature was raised to 50 °C and reacted overnight. TLC / LCMS indicated complete reaction. It was filtered, and the hydrochloride salt of compound 8I obtained by concentrating the filtrate under reduced pressure was directly used in the reaction of the next step without further purification.

[0175] LC-MS (ESI): m / z = 267.3 [M+H] + 。

[0176] Step 9: Using the hydrochloride of 8I and Compound 2F (537 mg, 1.53 mmol) as starting materials, referring to the operation method in Step 2 of Example 1, Compound 8J (240 mg, 0.413 mmol, 24% yield over 3 steps) was obtained.

[0177] LC-MS (ESI): m / z = 580.2 / 582.2 [M+H] + 。

[0178] Step 10: Using Compound 8J (240 mg, 0.413 mmol) as the starting material, referring to the operation method in Step 3 of Example 1, Compound 8 Isomer 1 (58.7 mg, 24.2%) and Compound 8 Isomer 2 (52.3 mg, 21.8%) were obtained.

[0179] HPLC analysis method: Instrument: SHIMADZU LC-30AD sf, Column: Chiralcel C2-3 50×4.6 mm I.D., 3 μm, Mobile phase: A for CO 2 , 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.

[0180] Compound 8 Isomer 1 (Retention time: 0.901 min): 1 1H NMR (400 MHz, Chloroform-d) δ 7.36 (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). LC-MS (ESI): m / z = 566.4 / 568.4 [M+H] + 。

[0181] Compound 8 Isomer 2 (Retention time: 1.243 min): 1 H NMR (400 MHz, Chloroform-d) δ 7.34 (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). LC-MS (ESI): m / z = 566.4 / 568.4 [M + H] + 。 Example 9:

Chemical Structure

[0182] Step 1: Dissolve Compound 9A (20.0 g, 108.0 mmol) in methanol (200 mL), sequentially add triethylamine (21.8 g, 218.0 mmol) and nitromethane (26.4 g, 432.0 mmol). After the addition, stir at room temperature for 17 hours. Concentrate to obtain a crude product of Compound 9B (26.5 g, 107.6 mmol), which was directly used in the reaction of the next step without further purification.

[0183] Step 2: Dissolve Compound 9B (26.5 g, 107.6 mmol) in methanol (250 mL), add Pd / C (5.2 g, Pd content 10%), and react under a hydrogen gas atmosphere for 15 hours. Filter, concentrate the filtrate to obtain a crude product of Compound 9C (21.1 g, 90.6%), which was directly used in the reaction of the next step without further purification.

[0184] M / Z (ESI): m / z = 217.1 [M + H] + 。

[0185] Step 3: Compound 9C (21.1 g, 91.6 mmol) was dissolved in a mixed solvent of tetrahydrofuran (200 mL) and water (100 mL), and sodium bicarbonate (24.6 g, 292.6 mmol) was added. The temperature was lowered to 5 °C, chloroacetyl chloride (22.1 g, 195.1 mmol) was added dropwise, and the temperature was controlled at 5 - 10 °C. After the addition was complete, the temperature was raised to room temperature and the reaction was carried out for 1 hour. After the reaction was complete, water (100 mL) was added, and the mixture was extracted with ethyl acetate (300 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2) to obtain the title compound 9D (17.2 g, 60.2%).

[0186] Step 4: Compound 9D (17.2 g, 58.8 mmol) was dissolved in t-butanol (170 mL), and t-butoxide (13.2 g, 117.5 mmol) was added little by little. After the addition was complete, the temperature was raised to 50 °C and the reaction was carried out for 2 hours. After the reaction was complete, it was cooled to room temperature, saturated ammonium chloride aqueous solution (200 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (150 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated and 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%).

[0187] M / Z (ESI): m / z = 201.1 [M + H - tBu] + 。

[0188] Step 5: Under a nitrogen gas atmosphere, Compound 9E (13.5 g, 52.7 mmol) was dissolved in tetrahydrofuran (150 mL), cooled to 0 °C, and sodium bis(2-methoxyethoxy)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, filtered through diatomaceous earth, and the filtrate was concentrated. 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%).

[0189] M / Z (ESI): m / z = 187.1 [M + H - tBu] + 。

[0190] Step 6: Compound 9F (7.6 g, 31.4 mmol) was dissolved in a mixed solvent of tetrahydrofuran (50 mL) and water (50 mL), and sodium hydrogen carbonate (7.9 g, 94.1 mmol) was added. The mixture was cooled to 0 - 5 °C, and benzyl chloroformate (6.4 g, 37.6 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 (100 mL) was added, and the mixture was extracted with ethyl acetate (150 mL × 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 and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v)=3:1) to obtain 9.2 g of a 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%).

[0191] Chiral HPLC analysis method: 1. Instrument: SHIMADZU LC-30AD sf; 2. Chromatography column: Chiralpak IC-3 50×4.6 mm I.D., 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. Compound 9G-1 (retention time 1.59 min) and compound 9G-2 (retention time 2.02 min).

[0192] Conditions for preparative chromatography separation: 1. Instrument: Waters 150 SFC; 2. Chromatography column: Chiralpak IC-Column (250×30 mm, I.D 30 mm, 10um particle size); 3. Mobile phase system: A for CO 2 and B for MeOH (0.1% NH 3 ·H 2 O); 4. Gradient: B 45%; 5. Flow rate: 180 mL / min.

[0193] Analysis method: 1. Instrument: SHIMADZU LC-30AD sf; 2. Chromatography column: Chiralpak IC-3 50×4.6 mm I.D., 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. Step 7: Compound 9G-1 (3.8 g, 10.1 mmol) was dissolved in methanol (40 mL), Pd / C (0.8 g, Pd content 10%) was added, and the reaction was carried out for 3 hours under a hydrogen gas atmosphere. After filtration, the filtrate was concentrated to obtain the title compound 9H-1 (2.3 g, 94.1%).

[0194] Referring to the above operation, using compound 9G-2 (3.4 g, 9.0 mmol) as the raw material, the title compound 9H-2 (2.1 g, 96.0%) was obtained.

[0195] Step 8: Compound 9H-1 (1.1 g, 4.5 mmol) and 3-oxo-1-methyl-cyclobutanecarboxylic acid (0.64 g, 5.0 mmol) were successively dissolved in 1,2-dichloroethane (15 mL), and glacial acetic acid (0.27 g, 4.5 mmol) was added. Sodium triacetoxyborohydride (1.4 g, 6.8 mmol) was added portionwise, and after the addition was complete, the reaction was carried out 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, filtered, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain the title compound 9I-1 (1.0 g, 62.1%).

[0196] Referring to the above operation, using compound 9H-2 (1.0 g, 4.1 mmol) as the raw material, the title compound 9I-2 (0.86 g, 58.7%) was obtained.

[0197] M / Z (ESI): m / z = 299.2 [M + H - tBu] + 。

[0198] Step 9: Compound 9I-1 (1.0 g, 2.8 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added, and the reaction was carried out at room temperature for 30 min. After the reaction was complete, it was directly concentrated to obtain the trifluoroacetate of compound 9J-1 (1.3 g, 95.6%).

[0199] Referring to the above operation, using compound 9I-2 (0.86 g, 2.4 mmol) as the raw material, the trifluoroacetate of the title compound 9J-2 (1.1 g, 93.8%) was obtained.

[0200] Step 10: Compound 2F (0.5 g, 1.4 mmol) and Compound 9J-1 (1.3 g, 2.7 mmol) were successively dissolved in dimethyl sulfoxide (5 mL). Cesium fluoride (0.43 g, 2.8 mmol) and N,N-diisopropylethylamine (0.55 g, 4.3 mmol) were added, and the temperature was raised to 100 °C and reacted for 5 hours. After complete reaction, it was cooled to room temperature, water (50 mL) was added, and it was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain 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%).

[0201] Compound 9 isomer 1: 1 H NMR (400 MHz, CDCl 3 ) δ 7.34 (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). M / Z (ESI): m / z = 568.2 [M + H] + .

[0202] Compound 9 isomer 2: 1 H NMR (400 MHz, CDCl 3) δ 7.35 (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). M / Z (ESI): m / z = 568.2 [M + H] + .

[0203] Referring to the above operation, using compound 9J - 2 (1.1 g, 2.4 mmol) as the raw material, 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%) were obtained.

[0204] Compound 9 isomer 3: 1 H NMR (400 MHz, CDCl 3 ) δ 7.34 (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). M / Z (ESI): m / z = 568.2 [M + H] + .

[0205] Compound 9 isomer 4: 1 H NMR (400 MHz, CDCl 3) δ 7.35 (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). M / Z (ESI): m / z = 568.2 [M + H] + . Example 10: [Chemical Formula]

[0206] Using 2,5 - dichloro - 3 - acetylthiophene (2 g, 10.26 mmol) as the raw material, referring to the operation methods of Steps 3, 4 (Compound 10C (Rf = 0.6 (petroleum ether:ethyl acetate = 5:1)) and Compound 10D Rf = 0.4 (petroleum ether:ethyl acetate = 5:1)), 5, 6, 7, 8 in Example 7, Compound 10 isomer 1 (70 mg) and Compound 10 isomer 2 (67 mg) were obtained.

[0207] Compound 10 isomer 1: 1 H NMR (400 MHz, CDCl 3 ) δ 6.69 (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, 2H), 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). LCMS m / z = 572.1 [M + H] + .

[0208] Compound 10 Isomer 2: 1 H NMR (400MHz, CDCl 3 ) δ 6.68 (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). LCMS m / z = 572.1 [M + H] + . Compound 11:

Chem.

[0209] Using 11A (15.0 g, 64.21 mmol) as the raw material, referring to the operation methods of Steps 1 - 8 in Example 7, Compound 11 Isomer 1 (47 mg) and Compound 11 Isomer 2 (45 mg) were obtained. Here, Isomers 11F (retention time 1.01 min) and 11G (retention time 1.12 min) (Chiral HPLC analysis method: 1. Instrument: SHIMADZU LC - 30AD sf, 2. Chromatography column: Chiralpak IC - 3 50×4.6 mm I.D., 3μm, 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.).

[0210] Compound 11 Isomer 1: 11H NMR (400 MHz, DMSO-d6) δ 7.48 - 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). LCMS m / z = 556.2 [M + H] + .

[0211] Compound 11 Isomer 2: 1 1H NMR (400 MHz, DMSO-d6) δ 7.49 - 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). LCMS m / z = 556.2 [M + H] + . Example 12: [Chemical Structure]

[0212] Step 1: At room temperature, compound 1C (636 mg, 1.87 mmol) and 2,4-dichloro-6-methylpyrimidine (457 mg, 2.81 mmol) were sequentially added to acetonitrile (10 mL). After uniform mixing, triethylamine (760 mg, 7.52 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. TLC / LCMS indicated complete reaction. Ethyl acetate (50 mL) was added for dilution, and the organic phase was washed with water (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by column chromatography on silica gel (5% MeOH in CH 2 Cl 2 ), and compound 12B (225 mg, 31% yield) was obtained.

[0213] LC-MS (ESI): m / z = 393.2 [M+H] + 。

[0214] Step 2: At room temperature, compound 12B (205 mg, 0.52 mmol) was dissolved in ethylene glycol dimethyl ether (5 mL) and t-butanol (5 mL). (R)-1-(2,4-dichlorophenyl)ethylamine (119 mg, 0.62 mmol), t-butoxide (88 mg, 0.78 mmol), BINAP (130 mg, 0.21 mmol), Pd 2 (dba) 3 (95 mg, 0.1 mmol) were sequentially added, and the mixture was stirred uniformly. Nitrogen gas was bubbled in, and the reaction was carried out at 100 °C for 1 hour in a sealed tube. After cooling to room temperature, dilute hydrochloric acid was added dropwise to adjust the pH to 5, and the mixture was concentrated under reduced pressure to obtain the crude product of 12C, which was directly used in the reaction of the next step without further purification.

[0215] Step 3: At room temperature, methanol (5 mL), water (5 mL), and lithium hydroxide (35 mg, 1.47 mmol) were sequentially added to compound 12C, and the mixture was stirred at room temperature for 1 hour. TLC / LCMS indicated complete reaction. The pH was adjusted to 5 with dilute hydrochloric acid, and the mixture was concentrated under reduced pressure. The obtained crude product was purified by preparative high-performance liquid chromatography to obtain compound 12 (22 mg, 0.041 mmol).

[0216] Separation method by preparative HPLC: Instrument: Waters 2767 preparative liquid chromatograph, chromatography column: XSelect@ Prep C18 (19 mm × 250 mm), preparative chromatography conditions: Dissolve the sample in DMF, filter with a 0.45 μm filter to prepare the sample solution, preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: Acetonitrile, Mobile phase B: Water (containing 0.05% aqueous ammonia). b. Gradient elution, the content of mobile phase A is 5% - 40%, the flow rate is 15 mL / min, and the elution time is 18 min.

[0217] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.49 (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). LC-MS (ESI): m / z = 532.2 [M + H] + 。 Example 13:

Chemical formula

[0218] Step 1: t-Butyl nitrite (2.31 g, 22.42 mmol) was added dropwise to a solution of copper(II) chloride (2.51 g, 18.68 mmol) in MeCN (40 mL). After stirring for 10 minutes, 4-bromobicyclo[4.2.0]octa-1,3,5-triene-3-amine 13A (3.7 g, 18.68 mmol) (prepared with reference to WO 2019183145A1) was added portionwise to the system. Stirring was continued for 1 hour. 1 N HCl solution (20 mL) was added dropwise to quench the reaction. After stirring for 10 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, the filtrate was concentrated under reduced pressure, and separated by silica gel column chromatography (PE) to obtain the target compound 13B (2.5 g, yield 61.54%).

[0219] 1 H NMR (400 MHz, CDCl 3 ) δ 7.29 (s, 1H), 7.15 (s, 1H), 3.18 - 3.10 (m, 4H).

[0220] Step 2: Compound 13B (2.5 g, 11.49 mmol), tributyl(1-ethoxyvinyl)tin (4.98 g, 13.79 mmol), Pd(PPh 3 ) 2 Cl 2 (0.81 g, 1.15 mmol) and potassium carbonate (2.38 g, 17.23 mmol) were sequentially added to anhydrous 1,4-dioxane (40 mL). Under nitrogen gas protection, the reaction was carried out at 85 °C for 3 hours. After cooling to room temperature, an aqueous potassium fluoride solution (10% wt, 30 mL) was added to the system and stirring was continued for 30 minutes. The mixture was filtered, the filter cake was washed twice with ethyl acetate, the filtrate was concentrated under reduced pressure, then hydrochloric acid (2N, 20 mL) and tetrahydrofuran (20 mL) were added, and stirring was continued for about 20 minutes. The mixture was extracted with dichloromethane (30 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE / EA (v / v) = 15:1) to obtain the target compound 13C (0.82 g, yield 39%).

[0221] 1 H NMR (400 MHz, CDCl 3 ) δ 7.16 (s, 1H), 7.09 (s, 1H), 3.22 - 3.15 (m, 4H), 2.61 (s, 3H).

[0222] 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 sequentially added to methanol (30 mL), the temperature was raised to 60 °C, and the reaction was carried out for 16 h. TLC detected that the reaction was complete. After cooling to room temperature, it was concentrated under reduced pressure, water (30 mL) was added, and it was extracted with dichloromethane (30 mL × 5). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by silica gel column chromatography (DCM:MeOH (v / v) = 10:1) to obtain the target compound 13D (0.62 g, yield 75%).

[0223] LC-MS (ESI): m / z = 182.1 [M + H] + .

[0224] 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, referring to the operation method of Step 1 of Example 1, compound 13E (0.68 g, yield 63.23%) was obtained LC-MS (ESI): m / z = 342.0 [M + H] + .

[0225] Step 5: Using 1C (0.68 g, 2.55 mmol) and compound 13E (0.88 g, 2.55 mmol) as raw materials, referring to the operation method of Step 2 of Example 1, the target compound 13F (0.57 g, yield 50%) was obtained.

[0226] LC-MS (ESI): m / z = 572.2 [M + H] + .

[0227] Step 6: Using compound 13F (0.57 g, 1 mmol) as the raw material, referring to the operation method of Step 3 in Example 1, the target compound 13 (0.49 g, yield 86%) was obtained.

[0228] 1 H NMR (400 MHz, CD 3 OD) δ 7.07 (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). LC-MS (ESI): m / z = 558.2 [M + H] + 。 Example 14:

Chemical Structure

[0229] Step 1: Dissolve 5,7-dichloropyrazolo[1,5-a]pyrimidine 14A (0.72 g, 3.83 mmol) and compound (R)-2,4-dichloro-α-methyl-benzylamine (0.73 g, 3.83 mmol) in isopropanol (20 mL), then dropwise add triethylamine (0.77 g, 7.66 mmol), react overnight at room temperature, then concentrate under reduced pressure, and purify the residue by silica gel column chromatography (PE / EA (v / v) = 4:1) to obtain compound 14B (1.12 g, yield 86%).

[0230] LC-MS (ESI): m / z = 341.0 [M+H] + 。

[0231] 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 DIPEA (0.26 g, 2.00 mmol) was added dropwise. After reacting at 90 °C for 40 hours, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 12:1) to obtain Compound 14C (32 mg, yield 5.6%).

[0232] LC-MS (ESI): m / z = 571.2 [M+H] + 。

[0233] Step 3: Compound 14C (32 mg, 0.056 mmol) was dissolved in tetrahydrofuran (5 mL), methanol (2 mL) and water (2 mL) were added, and after stirring uniformly, lithium hydroxide monohydrate (42 mg, 1 mmol) was added. The mixture was reacted at room temperature for 3 hours, the pH was adjusted to 5 with hydrochloric acid (1 N aqueous solution), and the system was concentrated under reduced pressure and then directly separated by silica gel column chromatography (DCM:MeOH (v / v) = 10:1) to obtain the crude product of the target compound 14. Further, preparative high-performance liquid chromatography (Preparative conditions 1. Instrument: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 250 mm). 2. The sample was dissolved in DMF, filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 1% TFA) b. Gradient elution, the content of mobile phase A is 10% - 80% c. Flow rate 15 ml / min. d. Elution time 18 min.) was performed to obtain the trifluoroacetate salt of Compound 14 (19 mg, yield 43%).

[0234] 1 H NMR (400 MHz, Methanol-d 4) δ 7.96 (d,1H),7.55 (d,1H),7.53 (d,1H),7.37 (dd,1H),6.17 (d,1H),5.25 (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). LC-MS (ESI):m / z=557.60[M+H] + . Example 15: [Chemical formula]

[0235] Using compound 15A (1.5 g, 10.13 mmol) and (R)-1-(2,4-dichlorophenyl)ethylamine (1.91 g, 10.13 mmol) as raw materials, referring to the operation methods of Steps 1 to 3 in Example 14, compound 15 (15 mg) was obtained.

[0236] 1 H NMR (400MHz,CD 3CN; trifluoroacetate) δ 8.06 (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). LC-MS (ESI): m / z = 518.2 [M + H] + . Example 16: [Chemical formula]

[0237] Step 1: Dissolve 3 - methylazetidine - 3 - carboxylic acid (2.00 g, 17.4 mmol) in dry 1,2 - dichloroethane (50 mL), sequentially add N - t - butoxycarbonyl - 3 - piperidone (4.15 g, 20.8 mmol) and acetic acid (1.04 g, 17.4 mmol), stir at room temperature for 5 hours, then add sodium triacetoxyborohydride (7.37 g, 34.7 mmol), and continue stirring at room temperature overnight. After monitoring the completion of the reaction by TLC, add water (2 mL) to quench the reaction, concentrate the resulting crude product, and separate and purify it by silica gel column chromatography (dichloromethane:methanol (v / v) = 4:1) to obtain 16C (4.51 g, 86.7%).

[0238] LC-MS (ESI): m / z = 299.2 [M + H] + .

[0239] 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 after the addition was complete, the reaction was continued for 1 hour. After monitoring the completion of the reaction by TLC, it was concentrated to obtain the trifluoroacetate of 16D, and the crude product was directly used in the reaction of the next step without further purification. LC-MS (ESI): m / z = 199.3 [M+H] + ;

[0240] Step 3: Methanol (70 mL) was added to the crude trifluoroacetate of compound 16D obtained in the previous step, stirred and dissolved, N-t-butoxycarbonyl-3-azetidinone (8.29 g, 48.4 mmol) and acetic acid (1.45 g, 24.2 mmol) were sequentially added, and after stirring at room temperature for 10 hours, sodium cyanoborohydride (2.95 g, 46.9 mmol) was added, and the stirring was continued at room temperature for 6 hours. After monitoring the completion of the reaction by TLC, water (2 mL) was added to quench the reaction, concentrated, and the obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 4:1) to obtain 16E (3.69 g, 2-step yield 69.1%). LC-MS (ESI): m / z = 354.2 [M+H] + ;

[0241] Step 4: Compound 16E (1.50 g, 4.25 mmol) was dissolved in methanol (40 mL), thionyl chloride (2.53 g, 21.25 mmol) was added dropwise at room temperature, and after the addition was complete, the reaction was continued for 3 hours. After monitoring the completion of the reaction by TLC, water (1 mL) was added to quench the reaction. It was concentrated, the obtained crude product was redissolved in methanol (10 mL), ethyl acetate (50 mL) was added, a solid precipitated, filtered, the solid was washed with ethyl acetate, and the filter cake was dried to obtain the hydrochloride of compound 16F (1.28 g, 80.1%). LC-MS (ESI): m / z = 268.2 [M+H] + ;

[0242] Step 5: 2F (500 mg, 1.43 mmol), hydrochloride of compound 16F (697 mg, 1.85 mmol), triethylamine (872 mg, 8.55 mmol) and cesium fluoride (433 mg, 2.85 mmol) were sequentially added to dimethyl sulfoxide (20 mL), stirred, heated to 100 °C, and reacted for about 4 hours. After complete reaction, it was cooled to room temperature, water (50 mL) and saturated aqueous sodium chloride solution (10 mL) were added, extracted with ethyl acetate (30 mL × 8), the combined organic phases were washed successively with saturated aqueous sodium chloride solution (50 mL) and water (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 9:1 - 5:1), and further separated and purified by chiral HPLC preparative separation to obtain two isomers, 16G (159 mg, 19.2%) and 16H (150 mg, 18.1%).

[0243] HPLC analysis method: 1. Instrument: SHIMADZU LC-30AD SFC, 2. Chromatography column: Chiralcel OX-3 50×4.6 mm I.D., 3 μm, 3. Mobile phase system: A for CO 2 , 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.

[0244] Separation and purification method by chiral HPLC preparative separation: Instrument: Waters 150 MGM, Chromatography column: Chiralcel OJ Column (250×30 mm, I.D 30 mm, 10um particle size), Mobile phase: A: carbon dioxide and B: methanol (0.1% aqueous ammonia), 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. LC-MS (ESI): m / z = 581.2[M + H] +;

[0245] Step 6: Compound 16G (150 mg, 0.258 mmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL), methanol (2 mL) and water (2 mL). After adding lithium hydroxide monohydrate (54.1 mg, 1.29 mmol) at room temperature, the mixture was stirred overnight to continue the reaction. After monitoring the disappearance of the raw material by TLC, it was concentrated, and the residue was separated and purified by preparative HPLC to obtain Compound 16 isomer 1 (112 mg, 76.5%).

[0246] Separation and purification method by preparative HPLC: 1. Instrument: waters 2767 preparative liquid chromatograph, chromatography column: SunFire@ Prep C18 (19 mm×250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.5% ammonium acetate), b. Gradient elution, the content of mobile phase A is 5% - 50%, c. Flow rate is 12 mL / min, d. Elution time is 10 min.

[0247] 1 H NMR (400 MHz, CD 3 OD): δ 7.43 (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). LC-MS (ESI): m / z = 567.2 [M + H] + ; Using 16H as the raw material and referring to the above synthesis method, Compound 16 isomer 2 was obtained.

[0248] 1 H NMR (400 MHz, CD 3 OD): δ 7.42 (d, 1H), 7.37 (d, 1H), 7.25 - 7.24 (m, 1H), 5.48 - 5.47 (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). LC - MS (ESI): m / z = 567.2 [M + H] + . Example 17: [Chemical formula]

[0249] Step 1: Dissolve 17A (3.7 g, 19.99 mmol) in DCM (20 mL), and dropwise add 1 M methylmagnesium bromide (8.3 g, 69.10 mmol) at -20°C. After the addition is complete, allow the temperature to rise to room temperature naturally and stir for 3 h. After the reaction is completed, add saturated ammonium chloride solution (20 mL) to quench the reaction, extract with ethyl acetate (50 mL × 3), wash the combined organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and then separate the residue by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 50:1) to obtain 17B (2.7 g, 82%).

[0250] Steps 2 - 4: Using 17B (2.0 g, 12.18 mmol) as the raw material, referring to the operation methods of Steps 1 - 3 of Example 14, the title compound 17 (67.0 mg) was obtained.

[0251] 11H NMR (400 MHz, CDCl 3 ) δ 7.34 (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). LCMS m / z = 533.2 [M + H] + . Example 18:

Chemical Structure

[0252] Step 1: Under nitrogen gas protection, add all of compound 2F (1.70 g, 4.84 mmol), compound 18A (3.02 g, 14.5 mmol), bis(triphenylphosphine)palladium dichloride (340 mg, 0.484 mmol), cuprous iodide (462 mg, 2.42 mmol), and triphenylphosphine (254 mg, 0.969 mmol) to a round-bottom flask. Add dry N,N-dimethylformamide (25 mL) and triethylamine (10 mL), heat to 100 °C, and react overnight. Monitor by TLC that the raw materials have completely reacted, cool to room temperature, concentrate under reduced pressure, and separate and purify the obtained residue by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 4:1) to obtain a mixture of 18B and 18C (2.36 g, 92.9%).

[0253] LC-MS (ESI): m / z = 523.2 [M + H] + .

[0254] The above mixture was separated and isolated by chiral HPLC to obtain Compound 18B (1.01 g, 39.8%) and Compound 18C (551 mg, 21.7%). Chiral separation method: Instrument: Waters 150 MGM, Chromatography column: Chiralpak Column, Mobile phase: A: carbon dioxide and B: methanol (0.1% aqueous ammonia), Isocratic elution: 35% Mobile phase B, Flow rate: 100 mL / min, Back pressure: 100 bar, Column temperature: 25 °C, Wavelength: 220 nm.

[0255] HPLC analysis method: 1. Instrument: SHIMADZU LC-30AD SFC, 2. Chromatography column: Chiralcel OX-3 50×4.6 mm I.D., 3 μm, 3. Mobile phase system: A for CO 2 , B for 0.05% DEA in MeOH, 4. Gradient: B 5 - 40%, 5. Flow rate: 3 mL / min. For Compound 18B, retention time 1.09 min, for Compound 18C, retention time 1.18 min.

[0256] 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 after addition, the reaction was continued for 1 hour. After monitoring the completion of the reaction by TLC, it was concentrated to obtain the trifluoroacetate salt of 18D, and the crude product was directly used in the reaction of the next step without further purification. LC-MS (ESI): m / z = 423.1 [M+H] + ;

[0257] Using 18C as the raw material, referring to the above synthetic method, Compound 18E was obtained.

[0258] Step 3: The crude trifluoroacetate of compound 18D obtained in the previous step was dissolved in 1,2-dichloroethane (30 mL), and compound 2B (157 mg, 1.23 mmol) and acetic acid (36.8 mg, 0.613 mmol) were sequentially added. 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 monitoring the completion of the reaction by TLC, water (1 mL) was added to quench the reaction, and it was directly concentrated under reduced pressure. The residue was separated and purified by preparative HPLC, and then the pH was adjusted to 7 - 8 with an aqueous sodium hydrogen carbonate solution to obtain compound 18 isomer 1 (64 mg, 2-step yield 20.9%) and compound 18 isomer 2 (78 mg, 2-step yield 25.4%).

[0259] HPLC analysis conditions: 1. Instrument: Shimadzu LC-20AT; 2. Chromatography column: Xtimate C18 4.6*50 mm, 3 μm; 3. Mobile phase system: 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.

[0260] Separation and purification method by preparative HPLC: 1. Instrument: waters 2767 preparative liquid chromatograph, chromatography column: SunFire@ Prep C18 (19 mm×250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% trifluoroacetic acid); b. Gradient elution, the content of mobile phase A is 5% - 50%; c. Flow rate is 12 mL / min; d. Elution time 30 min.

[0261] Compound 18 isomer 1: 11H NMR (400 MHz, Methanol-d4) δ 7.46 - 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). LC-MS (ESI): m / z = 535.2 [M+H] + ; Compound 18 Isomer 2: 1 1H NMR (400 MHz, Methanol-d4) δ 7.45 - 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). LC-MS (ESI): m / z = 535.2 [M+H] + ; Using 18E as the raw material and referring to the above synthetic method, Compound 18 Isomer 3 (53 mg, 2-step yield 17.3%) and Compound 18 Isomer 4 (111 mg, 2-step yield 36.2%) were obtained.

[0262] HPLC analysis conditions: 1. Instrument: Shimadzu LC-20AT, 2. Chromatography column: Xtimate C18 4.6 * 50 mm, 3 μm, 3. Mobile phase system: 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.

[0263] Compound 18 Isomer 3: 11H NMR (400 MHz, Methanol-d4) δ 7.45 - 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, 1H), 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). LC-MS (ESI): m / z = 535.2 [M + H] + ; Compound 18 Isomer 4: 1 1H NMR (400 MHz, Methanol-d4) δ 7.47 - 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). LC-MS (ESI): m / z = 535.2 [M + H] + . Example 19:

Chemical Structure

[0264] Step 1: Under a nitrogen gas atmosphere at room temperature, dissolve Compound 19A (140 mg, 0.83 mmol) in 1,2-dichloroethane (3 mL), add 9H-2 (where the carbon* represents a single stereoconfiguration R or S) (200 mg, 0.83 mmol), stir for 5 min, then add sodium triacetoxyborohydride (350 mg, 1.66 mmol) and react overnight. After completion of the reaction, add methanol (2 mL) to quench the reaction, concentrate, and separate and purify by column chromatography (eluent ratio: MeOH / DCM = 0% - 10%) to obtain Compound 19B (298 mg, 90%).

[0265] LC-MS (ESI): m / z = 401.6 [M+H] + 。

[0266] Step 2: At room temperature, compound 19B (298 mg, 0.74 mmol) was dissolved in dichloromethane (3 mL), and hydrogen chloride-dioxane solution (4 M, 2 mL) was added, followed by reaction for 1 h. After completion of the reaction, the reaction solution was concentrated to obtain the hydrochloride salt of compound 19C (200 mg), which was directly used in the next step reaction without further purification.

[0267] LC-MS (ESI): m / z = 187.1 [M+H] + 。

[0268] Step 3: Compound 19C (200 mg, 0.99 mmol) and 19D (350 mg, 0.99 mmol) (synthesized with reference to the method described in Patent WO 2018022992) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (260 mg, 2.01 mmol) was added at room temperature, followed by reaction overnight. The complete reaction was monitored by LCMS, and the crude product obtained by concentration under reduced pressure was separated by preparative HPLC to obtain compound 19 (150 mg, 31%). Separation method: 1. Instrument: waters 2767 preparative liquid chromatograph, chromatography column: SunFire@ Prep C18 (19 mm × 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate). b. Gradient elution, the content of mobile phase A is 10% - 55%. c. Flow rate is 12 mL / min.

[0269] 11H NMR (400 MHz, Chloroform-d) δ 7.83 (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). LC-MS (ESI): m / z = 502.5 [M + H] + . Example 20: [Chemical formula]

[0270] 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), heat up, and reflux for 24 hours. After completion of the reaction, cool to room temperature, concentrate under reduced pressure, dissolve the residue in dichloromethane (30 mL), wash the organic phase successively with water (20 mL × 3) and brine (20 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude title compound 20B (9.00 g, 75%). Without further purification, directly proceed to the reaction of the next step.

[0271] LC-MS (ESI): m / z = 216.2 [M + H] + .

[0272] Step 2: Compound 20B (9.00 g, 41.9 mmol) was dissolved in methanol (100 mL), and Raney nickel (4.47 g, 41.9 mmol) was added under an ice bath. The mixture was stirred for 3 h under a hydrogen gas atmosphere. TLC and LC-MS indicated that the reaction was complete, and the reaction was stopped. The reaction solution was filtered through diatomaceous earth and concentrated to obtain the title compound 20C (7.11 g, 85%) as an oily liquid. It was used directly in the reaction of the next step without further purification.

[0273] LC-MS (ESI): m / z = 200.2 [M+H] + 。

[0274] 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). t-Butoxide was slowly added under an ice bath, and the mixture was stirred for 1 h to continue the reaction. Then, the temperature was raised, and the mixture was refluxed overnight. After the reaction was completed, it was cooled to room temperature and concentrated. Water (30 mL) was added to the residue, and the pH was adjusted to 6 - 7 with an aqueous citric acid solution. The mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1 - 5:1) to obtain the title compound 20D (3.8 g, 51%).

[0275] LC-MS (ESI): m / z = 300.3 [M+H] + 。

[0276] Step 4: Compound 20D (3.8 g, 12.7 mmol) and (R)-1-(2,4-dichlorophenyl)ethan-1-amine (2.9 g, 15.2 mmol) were dissolved in N,N-dimethylformamide (18 mL), and BOP (9.0 g, 20.3 mmol) and DBU (5.8 g, 38.1 mmol) were added sequentially. The mixture was stirred at room temperature for 3 hours under a nitrogen gas atmosphere. After completion of the reaction, water (15 mL) was slowly added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v)=3:1~2:1) to obtain the title compound 20E (4.2 g, 70.2%).

[0277] LC-MS (ESI): m / z = 471.2 [M+H] + 。

[0278] Step 5: Compound 20E (4.2 g, 8.9 mmol) was dissolved in dichloromethane (8 mL), and hydrochloric acid-1,4-dioxane solution (8 mL) was added. The mixture was reacted at room temperature for 1 hour. After concentration, the hydrochloride salt of the title compound 20F (3.0 g, 92%) was obtained and used directly in the next step reaction without further purification.

[0279] LC-MS (ESI): m / z = 371.2 [M+H] + 。

[0280] Step 6: Dissolve compound 20F (3.0 g, 8.1 mmol) in 1,2-dichloroethane (10 mL), add N-t-butoxycarbonyl-3-piperidone (2.4 g, 12.1 mmol), add a few drops of acetic acid, and continue stirring and reacting for 3 hours after addition. Add sodium cyanoborohydride (1.52 g, 24.2 mmol) and continue stirring for 18 h. Pour the reaction into water (30 mL), add an aqueous sodium bicarbonate solution (5 mL), extract with ethyl acetate (20 mL × 3), dry the combined organic phases over anhydrous sodium sulfate, concentrate, and separate and purify the residue by silica gel column chromatography (dichloromethane:methanol (v / v) = 90:10) to obtain compound 20G (racemate) (3.0 g, 67%). Separate compound 20G 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%).

[0281] HPLC analysis method: 1. Instrument: SHIMADZU LC-30AD sf, 2. Chromatography column: Chiralcel OX-3 50×4.6 mm I.D., 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.

[0282] Conditions for preparative chromatography separation: 1. Instrument: Waters 150 SFC, 2. Chromatography column: Chiralpak IC -Column (250×30 mm, I.D 30 mm, 10um particle size), 3. Mobile phase system: A for CO 2 and B for MeOH (0.1% NH 3 ·H 2 O), 4. Gradient: B 45%, 5. Flow rate: 180 mL / min.

[0283] LC-MS (ESI): m / z = 554.2[M + H] + 。

[0284] Step 7: Compound 20G-1 (0.21 g, 0.38 mmol) was dissolved in dichloromethane (6 mL), hydrochloric acid - 1,4-dioxane solution (5 mL) was added, and after the addition was complete, the reaction was carried out at room temperature for 1 hour. It was concentrated to obtain the hydrochloride salt of the title compound 20H-1 (0.16 g, 95%). It was directly used in the reaction of the next step without further purification.

[0285] LC-MS (ESI): m / z = 454.2 [M + H] + 。

[0286] Referring to the above operation, using compound 20G-2 (0.25 g, 0.45 mmol) as the raw material, compound 20H-2 (0.197 g, 96.0%) was obtained.

[0287] LC-MS (ESI): m / z = 454.2 [M + H] + 。

[0288] Step 8: Compound 20H-1 (0.11 g, 0.23 mmol) was dissolved in methanol (10 mL), 3-oxo-1-methyl-cyclobutanecarboxylic acid (0.10 g, 0.28 mmol) and sodium triacetoxyborohydride (58 mg, 0.9 mmol) were added. Under a nitrogen gas atmosphere, glacial acetic acid (0.11 g, 0.23 mmol) was added under an ice bath, stirred for 5 min, warmed to room temperature, and stirring was continued for 18 h. It was concentrated to obtain a crude product, and the residue was separated and purified by high performance liquid chromatography to obtain 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%).

[0289] HPLC analysis method: 1. Instrument: Shimadzu LC-20AT, 2. Chromatography column: Xtimate C18 4.6 * 50 mm, 3 μm, 3. Mobile phase A is 0.05% TFA solution, mobile phase B is acetonitrile, 4. Gradient: A 95~5% B 5~95%, 5. Flow rate: 1 mL / min, column temperature: 35 °C, wavelength: 210 nm / 254 nm, collection time: 10 min.

[0290] Fractionation method: Instrument: Waters 2767 for liquid fractionation, Chromatography column: SunFire@ Prep C18 (19 mm×250 mm). The sample was dissolved in methanol and filtered through a 0.22 μm filter to prepare the sample solution. Chromatography conditions for fractionation: Composition of mobile phases A and B: Mobile phase A: Acetonitrile, Mobile phase B: Water (containing 1% ammonium acetate), gradient elution, the content of mobile phase A was 10% - 40%, and the flow rate was 12 mL / min. Elution time was 25 min.

[0291] Compound 20 Isomer 1: LC-MS (ESI): m / z = 566.2 [M+H] + 。

[0292] 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.39 (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).

[0293] Compound 20 Isomer 2: LC-MS (ESI): m / z = 566.2 [M+H] + 。

[0294] 1 H NMR (400 MHz, Methanol-d 4) δ 7.43 - 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).

[0295] Referring to the above operation, using compound 20H - 2 (3.4 g, 9.0 mmol) as the raw material, 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%) were obtained.

[0296] HPLC analysis method: 1. Instrument: Shimadzu LC - 20AT, 2. Chromatography column: Xtimate C18 4.6 * 50 mm, 3 μm, 3. Mobile phase A is 0.05% TFA solution, mobile phase B is acetonitrile, 4. Gradient: A 95~5% B 5~95%, 5. Flow rate: 1 mL / min, column temperature: 35 °C, wavelength: 210 nm / 254 nm, collection time: 10 min.

[0297] Compound 20 isomer 3: LC - MS (ESI): m / z = 566.2 [M + H] + .

[0298] 1 H NMR (400 MHz, Methanol - d 4 ) δ 7.39 (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).

[0299] Compound 20 Isomer 4: LC-MS (ESI): m / z = 566.2 [M+H] + .

[0300] 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.40 (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).

[0301] Compound 21:

Chem.

[0302] Using Compound 21A (0.5 g, 3.38 mmol) and Compound 1C (1.0 g, 3.38 mmol) as raw materials, referring to the operation methods of Steps 1 to 3 in Example 14, the title compound 21 (25 mg) was obtained.

[0303] 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.70 (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). LC-MS (ESI): m / z = 518.2 [M+H] + . Compound 22:

Chem.

[0304] Using 11F (526.0 mg, 2.94 mmol) and 5,7-dichloropyrazolo[1,5-a]pyrimidine (500.0 mg, 2.67 mmol) as raw materials, referring to the operation methods of Steps 1 to 3 in Example 14, the title compound 22 (20 mg) was obtained.

[0305] 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.72 (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). LCMS m / z = 556.2 [M + H] + . Compound 23:

Chemical Structure

[0306] Step 1: Dissolve Compound 15A (0.5 g, 3.40 mmol) in acetonitrile (15 mL), add Compound 11F (0.73 g, 4.10 mmol) and triethylamine (1.0 g, 10.1 mmol), heat to 70 °C and react for 16 hours. After completion of the reaction, cool to room temperature, concentrate, dissolve the concentrate in dichloromethane (30 mL), wash successively with water (20 mL × 3) and brine (20 mL × 3), dry the organic phase over anhydrous sodium sulfate, filter, and separate and purify the obtained crude product by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1 to 2:1) to obtain the title compound 23A (0.61 g, 62%).

[0307] LC-MS (ESI): m / z = 291.2 [M+H] + 。

[0308] Step 2: Dissolve Compound 23A (0.61 g, 2.1 mmol) in tetrahydrofuran (10 mL), add di-t-butyl dicarbonate (0.92 g, 4.2 mmol) and DMAP (45 mg, 0.4 mmol), and react under reflux for 12 hours. After completion of the reaction, cool to room temperature, concentrate, dissolve the concentrate in dichloromethane (30 mL), wash successively with water (20 mL × 3) and brine (20 mL × 3), dry the organic phase over anhydrous sodium sulfate, filter, and separate and purify the obtained crude product by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1 to 2:1) to obtain the title compound 23B (0.65 g, 83%).

[0309] LC-MS (ESI): m / z = 391.2 [M+H] + 。

[0310] Step 3: Compound 23B (0.32 g, 0.83 mmol) was dissolved in dimethyl sulfoxide (5 mL), 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 for 1 hour under microwave conditions. After completion of the reaction, it was cooled to room temperature, the reaction solution was dissolved in ethyl acetate (30 mL), washed successively with water (20 mL×3) and brine (20 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration 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%).

[0311] LC-MS (ESI): m / z = 622.2 [M+H] + 。

[0312] Step 4: 23C (0.32 g, 0.52 mmol) was dissolved in dichloromethane (8 mL), hydrochloric acid dioxane solution (8 mL) was added, and after the addition was completed, the reaction was carried out at room temperature for 1 hour. It was concentrated to obtain the hydrochloride of the title compound 23D (0.24 g, 90%). It was directly used in the reaction of the next step without further purification.

[0313] LC-MS (ESI): m / z = 522.2 [M+H] + 。

[0314] Step 5: Compound 23D (240 mg, 0.47 mmol) was dissolved in tetrahydrofuran (3 mL) and water (3 mL), lithium hydroxide hydrate (98.0 mg, 2.34 mmol) was added, and after stirring uniformly, the reaction was carried out at room temperature for 12 hours. After completion of the reaction, it was concentrated under reduced pressure, and the residue was separated and purified by high-speed preparative liquid to obtain the title compound 23 (0.17 g, 71%).

[0315] Fractionation method: 1. Instrument: Waters 2767 for fractionating liquids, chromatography column: SunFire@ Prep C18 (19mm×250mm). 2. The sample was filtered through a 0.45μm filter to prepare the sample solution. 3. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate). b. Gradient elution, the content of mobile phase A is 10% - 55%. c. Flow rate is 12mL / min.

[0316] 1 H NMR (400MHz, Methanol-d 4 ) δ 7.82 (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). LC-MS (ESI): m / z = 508.2 [M + H] + 。 Example 24:

Chemical Structure

[0317] 14B (0.34g, 1.0mmol), 24A (0.22g, 1.2mmol) (prepared with reference to CN 111732572 A), Pd 2 (dba) 3(91 mg, 0.10 mmol), BINAP (0.12 g, 0.20 mmol) and cesium carbonate (0.65 g, 2 mmol) were sequentially added to toluene (20 mL), and the temperature was raised to 95 °C and reacted for 6 hours. After completion of the reaction, it was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 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 a crude product of the target compound 24. The crude product was further fractionated by high performance liquid chromatography to obtain the trifluoroacetate salt of compound 24 (0.16 g, yield: 22%).

[0318] The production conditions are as follows. 1. Instrument: waters 2767 preparative liquid chromatograph, chromatography column: SunFire@ Prep C18 (19 mm × 250 mm). 2. The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. 3. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% TFA). b. Gradient elution was performed with the content of mobile phase A being 5% - 50%. c. The flow rate was 12 mL / min. d. Elution time was 18 min.

[0319] 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.97 (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, 2H), 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). LC-MS (ESI): m / z = 489.3 [M+H] + 。 Example 25:

Chem.

[0320] Using 14A (0.21 g, 1.11 mmol) and 1C (0.32 g, 1.20 mmol) as starting materials, referring to the operation methods of Steps 1 to 3 in Example 12, the trifluoroacetate salt (0.11 g) of Compound 25 was obtained.

[0321] 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.87 (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, 1H), 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). LC-MS (ESI): m / z = 557.3 [M+H] + 。 Example 26:

Chem.

[0322] Using 26A (2.0 g, 12.35 mmol) and (R)-1-(2,4-dichlorophenyl)ethylamine (2.33 g, 12.35 mmol) as starting materials, referring to the operation methods of Steps 1 to 3 in Example 14, Compound 26 (50 mg) was obtained.

[0323] 1 H NMR (400 MHz, CD 3 CN; 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). LC - MS (ESI): m / z = 532.2 [M + H] + . Example 27:

Chem.

[0324] 15B (0.4 g, 1.33 mmol), 24A (0.25 g, 1.33 mmol), Pd 2 (dba) 3 (0.25 g, 0.27 mmol), XantPhos (0.31 g, 0.54 mmol), cesium carbonate (1.29 g, 3.99 mmol) were successively dissolved in 1,4 - dioxane (20 mL), heated to 100 °C, and reacted for 4 hours. After complete reaction, it was cooled to room temperature, water (20 mL) was added, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (DCM:MeOH (v / v) = 5:1) to obtain the target compound 27 (0.05 g, yield 9%).

[0325] 1 H NMR (400 MHz, CD 3(CN) δ 8.03 (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). LC-MS (ESI): m / z = 450.2 [M + H] + . Example 28: [Chemical Structure]

[0326] 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 sequentially added to dimethyl sulfoxide (5 mL). After uniformly stirring, the temperature was raised to 100 °C and the reaction was carried out for 16 h. After complete reaction, it was cooled to room temperature, water (30 mL) was added, and the mixture was 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 obtain 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%).

[0327] Compound 28 Isomer 1: LC-MS (ESI): m / z = 558.2 [M + H] + .

[0328] 1H NMR (400 MHz, DMSO-d6) δ 12.18 (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).

[0329] Compound 28 Isomer 2: LC-MS (ESI): m / z = 558.2 [M + H] + .

[0330] 1H NMR (400 MHz, DMSO-d6) δ 12.08 (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, 4H), 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). Example 29: [Chemical formula]

[0331] Step 1: At room temperature, dissolve compound 9I-2 (8.4 g, 23.72 mmol) in dichloromethane (500 mL), add (trimethylsilyl)diazomethane (23.72 mL, 2 M) dropwise. After the addition is complete, react for 1 hour. Concentrate and separate and purify the residue by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain the title compound 29A (8.4 g, 96.3%).

[0332] LC-MS (ESI): m / z = 369.2 [M+H] + 。

[0333] Step 2: Compound 29A (8.4 g, 22.82 mmol) was dissolved in dichloromethane (500 mL), and a dioxane hydrochloride solution (200 mL, 4 M) was added. The mixture was reacted at room temperature for 30 min. After complete reaction, it was directly concentrated to obtain Compound 29B (7.5 g, 100%).

[0334] M / Z (ESI): m / z = 269.2 [M+H] + 。

[0335] 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 sequentially added to dimethyl sulfoxide (5 mL). The mixture was stirred at 130 °C for 1 h under microwave irradiation. After complete reaction, it was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 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 obtain 29C (100.0 mg, 30%).

[0336] 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, it was concentrated, and the residue was separated by silica gel column chromatography (EA:MeOH (v / v) = 4:1) to obtain 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%).

[0337] Compound 29 isomer 1: LC-MS (ESI): m / z=520.5[M+H] + .

[0338] 1 H NMR (400MHz, DMSO-d6) δ 7.88 (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).

[0339] Compound 29 isomer 2: LC-MS (ESI): m / z=520.5[M+H] + .

[0340] 1 H NMR (400MHz, DMSO-d6) δ 7.88 (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),3.53-3.44 (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). Example 30:

change

[0341] 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 sequentially added. The temperature was raised to 100 °C and the reaction was carried out for 4 hours. After complete reaction, it was cooled to room temperature, water (15 mL) and ethyl acetate (15 mL) were added, and extraction was performed. 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, concentrated, and the residue was purified by a silica gel chromatography column (ethyl acetate:methanol (v / v) = 10:1) to obtain 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)).

[0342] Compound 30 isomer 1: 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.20 (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, 2H), 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). M / Z (ESI): m / z = 558.6 [M + H] + 。 Example 31:

Chemical formula

[0343] Compound 2F (0.15 g, 0.43 mmol) and compound 19C (0.26 g, 0.65 mmol) were dissolved in dimethyl sulfoxide (5 mL), 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, it was cooled to room temperature, water (20 mL) was added, extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, 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%).

[0344] 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 (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). MS M / Z(ESI): m / z = 500.2[M + H] + 。 Example 32:

Chemical Structure

[0345] Using compound 14B (160.6 mg, 0.47 mmol) and 29B (120.0 mg, 0.47 mmol) as raw materials, referring to the operation methods of Steps 3 and 4 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.

[0346] Compound 32 Isomer 1: LC-MS (ESI): m / z = 577.3 [M+H] + .

[0347] 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (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).

[0348] Compound 32 Isomer 2: LC-MS (ESI): m / z = 577.3 [M+H] + .

[0349] 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (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), 3.48 (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). Example 33:

Chemical Structure

[0350] Using 33A (0.4 g, 1.96 mmol) and 1C (0.52 g, 1.96 mmol) as raw materials, referring to the operation methods of Steps 1 to 3 in Example 12, Compound 33 (100 mg) was obtained.

[0351] 1 H NMR (400 MHz, CD 3CN; trifluoroacetate) δ 9.95 (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). LC-MS (ESI): m / z = 574.2 [M + H] + . Example 34: [Chemical formula]

[0352] Using 34A (0.2 g, 1.06 mmol) and 1C (0.28 g, 1.06 mmol) as raw materials, referring to the operation methods of Steps 1 to 3 in Example 12, compound 34 (80 mg) was obtained.

[0353] 1 H NMR (400 MHz, CD 3 OD) 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). LC-MS (ESI): m / z = 558.2 [M+H] + 。 Example 35:

Chemical Structure

[0354] Step 1: Dissolve tert-butyl 3-(morpholin-2-yl)azetidine-1-carboxylate (1 g, 4.17 mmol) in acetonitrile (10 mL), sequentially add ethyl 2-bromoacetate (1.04 g, 6.25 mmol) and diisopropylethylamine (1.61 g, 12.51 mmol), and stir at room temperature for 3 hours. After completion of the reaction, concentrate directly to obtain the crude product of 35B (1.31 g, 96%).

[0355] LC-MS (ESI): m / z = 329.5 [M+H] + 。

[0356] Step 2: Under a nitrogen gas atmosphere, dissolve compound 35B (300 mg, 0.91 mmol) in dry tetrahydrofuran (5 mL), add methylmagnesium bromide (2.73 mmol) dropwise at -78 °C, and react at room temperature for 2 h after completion of the dropwise addition. After completion of the reaction, add saturated aqueous ammonium chloride solution (10 mL) to quench, extract with ethyl acetate (15 mL × 2), wash the combined organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and then perform column chromatography (petroleum ether:ethyl acetate (v / v) = 0 - 30%) to obtain 35C (200 mg, 70%).

[0357] LC-MS (ESI): m / z = 315.5 [M+H] + 。

[0358] Step 3: Dissolve compound 35C (200 mg, 0.64) in 1,4-dioxane hydrochloride (2 mL), stir at room temperature for 1 h, and directly spin-dry to obtain the hydrochloride compound of 35D (150 mg).

[0359] LC-MS (ESI): m / z = 215.2 [M+H] + 。

[0360] Step 4: Dissolve compound 35D (150 mg, 0.64 mmol) in DMSO (5 mL), and sequentially add (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). Heat the reaction to 100 °C and stir for 2 hours. After completion of the reaction, add water (15 mL) and ethyl acetate (15 mL), extract and separate the layers. Extract the aqueous phase with ethyl acetate (15 mL × 2). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (ethyl acetate: petroleum ether (v / v) = 0 - 50%) on the obtained residue to obtain compound 35 (80 mg, 24%).

[0361] LC-MS (ESI): m / z = 528.6 [M+H] + 。 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 (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). Example 36:

Chemical Structure

[0362] Step 1: Compound 36A (2.8 g, 13.97 mmol) and platinum dioxide (0.16 g, 0.70 mmol) were dissolved by mixing in a solution of ethanol (20 mL) and ethyl acetate (30 mL), and reacted at room temperature for 4 h under a hydrogen gas atmosphere. It was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (30 mL), and after the filtrate was concentrated under reduced pressure, it was separated by silica gel column chromatography (PE:EA (v / v) = 3:1) to obtain the target compound 36B (0.52 g, yield 18%).

[0363] LC-MS M / Z (ESI)=204.30[M+H] + 。

[0364] Step 2: Compound 36B (0.52 g, 2.55 mmol) and di-t-butyl dicarbonate (1.11 g, 5.07 mmol) were dissolved by mixing in acetonitrile (15 mL), DMAP (62 mg, 0.51 mmol) was added, and the mixture was reacted at room temperature for 4 h. After completion of the reaction, it was concentrated under reduced pressure and directly separated by silica gel column chromatography (PE:EA (v / v) = 5:1) to obtain the target compound 36C (0.58 g, yield 75%).

[0365] LC-MS M / Z (ESI)=248.1[M- t Bu+H] + 。

[0366] Step 3: Compound 36C (0.58 g, 1.91 mmol) and acetylacetonato (67 mg, 0.19 mmol) were dissolved by mixing in THF (10 mL), cooled to 0 °C, methylmagnesium chloride (1.2 mL, 3 M THF solution) was added dropwise, and after completion of the dropwise addition, the reaction was continued under these conditions for 1 h. The reaction was quenched with saturated ammonium chloride (30 mL), extracted with ethyl acetate (30 mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and after the filtrate was concentrated under reduced pressure, it was separated by silica gel column chromatography (PE:EA (v / v) = 4:1) to obtain the target compound 36D (0.32 g, yield 59%).

[0367] 1 1H NMR (400 MHz, Chloroform-d) δ 3.79 - 3.72 (m, 2H), 2.65 (t, 2H), 2.40 (s, 3H), 2.03 - 1.94 (m, 2H), 1.56 (s, 9H).

[0368] Step 4: Compound 36D (0.32 g, 1.13 mmol) was dissolved in DCM (10 mL), cooled to 0 °C, trifluoroacetic acid (3 mL) was added dropwise, and after the addition was complete, the reaction was continued at room temperature for 1 h. After concentration under reduced pressure, ethyl acetate (30 mL) was added, washed with saturated sodium bicarbonate (30 mL), the aqueous phase was re-extracted with ethyl acetate (30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound 36E (0.14 g, yield: 67%).

[0369] Step 5: Compound 36E (0.14 g, 0.76 mmol) was dissolved in DMF (10 mL), cooled to 0 °C, sodium hydride (60 mg, 1.52 mmol, 60% wt) was added, and after reacting at room temperature for 20 min, 1-(1-bromoethyl)-2,4-dichlorobenzene (0.39 g, 1.52 mmol) was added dropwise. After the addition was complete, the temperature was raised to room temperature and the reaction was carried out for 30 min. The reaction was quenched with saturated aqueous sodium bicarbonate solution (30 mL), extracted with ethyl acetate (30 mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated by silica gel column chromatography (PE:EA (v / v) = 4:1) to obtain the target compound 36F (0.19 g, yield 70%).

[0370] LC-MS M / Z (ESI) = 356.0 [M + H] + .

[0371] Step 6: Dissolve 36F (0.19 g, 0.53 mmol) in DMSO (10 mL), and sequentially add 1C (0.14 g, 0.53 mmol), triethylamine (0.27 g, 2.65 mmol), and cesium fluoride (0.16 g, 1.06 mmol). After the addition, react at 100 °C for 24 hours. When the reaction mixture is cooled to room temperature, add water (20 mL), extract with ethyl acetate (30 mL × 3), wash the combined organic phases with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and then separate and purify by silica gel column chromatography (DCM:MeOH (v / v) = 12:1) to obtain the target compound 36G (36 mg, yield 12%).

[0372] LC-MS M / Z (ESI)=586.60[M+H] + 。

[0373] Step 7: Dissolve 36G (0.036 g, 0.061 mmol) in tetrahydrofuran (10 mL), add methanol (3 mL) and water (3 mL), stir uniformly, then add lithium hydroxide (0.015 g, 0.63 mmol), and react at room temperature for 3 hours. Adjust the pH to 5 by dropping hydrochloric acid (1N aqueous solution), concentrate the system under reduced pressure, and then directly separate by silica gel column chromatography (DCM:MeOH (v / v) = 10:1) to obtain the crude product of the target compound 36. Further, perform high-speed liquid fractionation (fractionation conditions: 1. Instrument: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 250 mm). 2. Dissolve the sample in DMF, filter with a 0.45 μm filter to prepare the sample solution. 3. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% TFA). b. Gradient elution, the content of mobile phase A is 5% - 50%. c. Flow rate is 15 ml / min. d. Elution time is 18 min.) to obtain the trifluoroacetate salt of compound 36 (15 mg, yield 30%).

[0374] LC-MS M / Z (ESI)=572.2[M+H]+ . 1 H NMR (400MHz, Methanol-d 4 ) δ 7.61 - 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, 5H), 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). Example 37:

Chem.

[0375] Step 1: Dissolve compound 37A (0.5 g, 2.22 mmol) in acetonitrile (10 mL), add (R)-1-(2,4-dichlorophenyl)ethan-1-amine (0.46 g, 2.44 mmol) and triethylamine (672 mg, 6.66 mmol), and react at room temperature for 16 hours. After complete reaction, add water (20 mL) and ethyl acetate (30 mL), extract and separate the layers. Extract the aqueous phase with ethyl acetate (30 mL). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the resulting crude product. Separate and purify it by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain compound 37B (0.5 g, 59%).

[0376] LCMS (ESI): m / z = 380.1 [M + H] + .

[0377] 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 sequentially added to a solution of compound 9J - 2 (135 mg, 0.53 mmol) in dimethyl sulfoxide (3 mL). The temperature was raised to 100 °C and the reaction was carried out for 16 hours. After complete reaction, it was cooled to room temperature, water (15 mL) and ethyl acetate (15 mL) were added, and extraction and liquid separation were performed. 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, concentrated, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (ethyl acetate:methanol (v / v) = 5:1) to obtain 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%).

[0378] Compound 37 isomer 1: LC - MS (ESI): m / z = 598.1 [M + H] + 。

[0379] 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (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).

[0380] Compound 37 isomer 2: LC - MS (ESI): m / z = 598.1 [M + H] + 。

[0381] 1 H NMR (400 MHz, CDCl 3) δ 7.90 (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). Example 38:

Chem.

[0382] Using 24A (170 mg, 0.92 mmol) and 11H (313.4 mg, 0.92 mmol) as raw materials, referring to the operation method of Example 24, compound 38 (38 mg, 10%) was obtained.

[0383] 1 H NMR (400 MHz, DMSO-d6) δ 7.49 (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). LC-MS (ESI): m / z = 488.6 [M + H] + . Example 39:

Chem.

[0384] Using compound 39A (359 mg, 1.74 mmol) and 1C (300 mg, 0.79 mmol) as raw materials, referring to the operation methods of Steps 1 to 3 of Example 12, compound 39 (23 mg) was obtained.

[0385] LC-MS (ESI): m / z = 531.2 [M+H] + 。

[0386] 1 H NMR (400 MHz, CD 3 OD) δ 7.55 (s, 1H), 7.47 (d, J = 8.5 Hz, 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). Example 40:

Chemical formula

[0387] Using compound 1C (275 mg, 0.93 mmol) and compound 40A (241 mg, 1.21 mmol) as raw materials, referring to the operation methods of steps 1 to 3 in Example 12, compound 40 (40 mg) was obtained.

[0388] LC-MS (ESI): m / z = 569.3 [M+H] + 。 1 H NMR (400 MHz, CD 3OD) δ 7.89 (m, 1H), 7.81 (m, 1H), 7.53 (m, 1H), 7.51 - 7.46 (m, 2H), 7.42 (m, 1H), 7.35 (m, 1H), 5.64 - 5.52 (m, 1H), 4.97 (m, 1H), 4.76 - 4.47 (m, 2H), 4.37 - 4.14 (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). Example 41:

Chemical Structure

[0389] Step 1: Compound 41A (2.0 g, 9.60 mmol), (R)-1-(2,4-dichlorophenyl)ethan-1-amine (1.83 g, 9.60 mmol), and N,N-diisopropylethylamine (1.86 g, 14.39 mmol) were sequentially added to NMP (20 mL). The temperature was raised to 160 °C and the reaction was carried out for 48 hours. After cooling to room temperature, water (100 mL) and ethyl acetate (30 mL) were added, and the mixture was extracted and separated. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue after concentration of the filtrate was separated and 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%).

[0390] LC-MS(ESI): m / z = 317.0 [M + H] + .

[0391] Step 2: 41B (2.0 g, 6.30 mmol) was dissolved in acetic acid (18 mL), and a solution of sodium nitrite (434 mg, 6.30 mmol) in water (3 mL) was added dropwise. The mixture was stirred for 2 hours. After complete reaction, it was concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate solution (30 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) to obtain 41C (1.2 g, 58.0%).

[0392] LC-MS(ESI): m / z = 328.3[M + H] + 。

[0393] Step 3: 41C (100 mg, 0.30 mmol), 9J-2 (82 mg, 0.30 mmol), and triethylamine (154 mg, 1.52 mmol) were successively dissolved in acetonitrile (5 mL), and the mixture was stirred at room temperature for 2 h. After complete reaction, water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL × 3). 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 preparative silica gel plate (ethyl acetate:methanol (v / v) = 10:1) to obtain 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%).

[0394] Compound 41 Isomer 1: LC-MS(ESI): m / z = 546.2[M + H] + 。

[0395] 1 H NMR (400 MHz, DMSO-d 6) δ 12.17 (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 - 3.44 (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).

[0396] Compound 41 Isomer 2: LC-MS (ESI): m / z = 546.2 [M + H] + .

[0397] 1 H NMR (400MHz, DMSO-d 6 ) δ 12.18 (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 - 3.46 (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). Example 42:

Chemical Structure

[0398] Using 42A (1g, 5.46mmol) and (R)-1-(3,5-dichlorophenyl)ethan-1-amine (1.04g, 5.46mmol) as raw materials, referring to the operation methods of Steps 1 and 2 in Example 37, Compound 42 Isomer 1 (Rf = 0.5, (EA:MeOH (v / v) = 7:1), 150mg, 46%) and Compound 42 Isomer 2 (Rf = 0.4, (EA:MeOH (v / v) = 7:1), 20mg, 6%) were obtained.

[0399] LC-MS (ESI): m / z=554.2[M+H] + .

[0400] Compound 42 isomer 1: 1 H NMR (400MHz, CDCl 3 ) 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).

[0401] Compound 42 Isomer 2: 1 H NMR (400MHz, CDCl 3 ) 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). Example 43:

change

[0402] Step 1: 43A (1.5 g, 8.0 mmol) was dissolved in dry N,N-dimethylformamide (30 mL). Under the protection of nitrogen gas, it was cooled to 0 °C, and sodium hydride (0.40 g, 10 mmol, 60% wt) was added little by little. After the addition was completed, the reaction was carried out under this condition for 20 minutes. Iodomethane (1.70 g, 12 mmol) was added dropwise. After the dropwise addition was completed, the reaction was carried out at room temperature for 30 minutes. Water (100 mL) was added to quench the reaction, and it was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Then the residue was separated by silica gel column chromatography (PE:EA (v / v) = 5:1) to obtain the target compound 43B (1.43 g, yield 89%).

[0403] LC-MS (ESI): m / z = 202.1 [M+H] + 。

[0404] Steps 2 to 4: Using 43B (0.20 g, 0.99 mmol) and 1C (0.26 g, 1 mmol) as raw materials, referring to the operation methods of Steps 1 to 3 in Example 12, the trifluoroacetate of compound 43 (80 mg) was obtained.

[0405] LC-MS (ESI): m / z = 571.6 [M+H] + 。 1 1H NMR (400 MHz, Methanol-d 4 ) δ 7.53 - 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). Example 44: [Chemistry]

[0406] Step 1: Dissolve 44A (1.5 g, 8.0 mmol) in tetrahydrofuran (30 mL), cool it to 0 °C under nitrogen gas protection, add sodium hydride (0.40 g, 10 mmol, 60% wt) little by little. After the addition is complete, react for 20 minutes under this condition. Dropwise add iodomethane (1.70 g, 12 mmol). After the addition is complete, react at room temperature for 30 minutes. Add water (100 mL) to quench the reaction, extract with ethyl acetate (100 mL × 2), combine the organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and then separate the residue by silica gel column chromatography (PE:EA (v / v) = 5:1) to obtain the target compound 44B (1.38 g, yield 86%).

[0407] LC-MS (ESI): m / z = 202.1 [M + H] + .

[0408] Steps 2 - 4: Using 44B (0.20 g, 0.99 mmol) and 1C (0.26 g, 1 mmol) as raw materials, referring to the operation method of Steps 1 - 3 in Example 12, the trifluoroacetate salt of compound 44 (10 mg) was obtained.

[0409] LC-MS (ESI): m / z = 571.2 [M + H] + . 1 H NMR (400 MHz, Methanol-d 4) δ 7.40 (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). Example 45:

Chemical formula

[0410] Using 45A (0.19 g, 1.0 mmol) and 1C (0.26 g, 1.0 mmol) as raw materials, referring to the operation methods of Steps 1 to 3 in Example 12, the trifluoroacetate salt (100 mg) of Compound 45 was obtained.

[0411] LC-MS M / Z (ESI) = 560.2 [M + H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.50 (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). Example 46:

Chemical formula

[0412] Step 1: At room temperature, in a 50 mL reaction flask, compound 46A (synthesized with reference to the method described in Patent WO 2021129737) (1 g, 4.44 mmol), (R)-1-(2,4-dichlorophenyl)ethylamine (0.85 g, 4.44 mmol), triethylamine (0.90 g, 8.88 mmol) and dichloromethane (10 mL) were added sequentially. After the addition was completed, the mixture was stirred at room temperature overnight. After the reaction was completed, dichloromethane (20 mL) was added to the reaction solution, and it was washed sequentially with water (10 mL×1) and saturated brine (10 mL×1). The organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (DCM / MEOH = 0% - 5%) to obtain 46B (1.5 g, 89%).

[0413] LC-MS (ESI): m / z = 378.0[M+H] + 。

[0414] Step 2: At room temperature, in a 25 mL reaction flask, compound 46B (150 mg, 0.40 mmol), 9J-2 (84 mg, 0.33 mmol), sodium hydrogen carbonate (55 mg, 0.66 mmol) and dimethyl sulfoxide (2 mL) were added sequentially. After the addition was completed, the mixture was stirred at 100 °C overnight. After the reaction was completed, it was cooled to room temperature, ethyl acetate (10 mL) was added to the reaction solution, and it was washed sequentially with water (5 mL×1) and saturated brine (5 mL×1). The organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (EA / MEOH = 0% - 10%) to obtain compound 46 isomer 1 (70 mg, 36%) and compound 46 isomer 2 (20 mg, 10%).

[0415] Compound 46 isomer 1 (ethyl acetate:methanol (v / v) = 9:1, Rf = 0.32): 1 H NMR (400MHz,CD 3OD) δ 7.36 (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). LC-MS (ESI): m / z = 596.3 [M + H] + .

[0416] Compound 46 Isomer 2 (Ethyl Acetate:Methanol (v / v) = 9:1, Rf = 0.27): 1 H NMR (400 MHz, CD 3 OD) δ 7.36 (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). LC-MS (ESI): m / z = 596.3 [M + H] + . Example 47: [Chemical Structure]

[0417] Step 1: 9H-2 (0.5 g, 2.06 mmol) and 3-carbonyl-cyclobutanecarboxylate (0.32 g, 2.48 mmol) were successively 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 little by little, and after the addition was complete, the reaction was carried out 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, filtered, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain the title compound 47A (0.61 g, 82.2%).

[0418] M / Z (ESI): m / z = 299.2[M+H- t Bu] + 。

[0419] Step 2: Compound 47A (0.61 g, 1.72 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the reaction was carried out at room temperature for 0.5 hour. After the reaction was complete, it was directly concentrated to obtain the trifluoroacetate of compound 47B (0.81 g, 99.1%).

[0420] Step 3: Dissolve compound 2F (0.5 g, 1.4 mmol) and compound 47B (0.81 g, 1.71 mmol) in dimethyl sulfoxide (5 mL), add N,N - diisopropylethylamine (0.55 g, 4.3 mmol) and cesium fluoride (0.43 g, 2.8 mmol), heat to 100 °C, and react for 5 hours. After complete reaction, cool to room temperature, add water (50 mL), extract with ethyl acetate (50 mL × 3), wash the combined organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and separate and purify the residue by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain the title compound 47C (420.0 mg, 51.8%).

[0421] Step 4: At room temperature, add compound 47C (420.0 mg, 0.74 mmol) to a mixed solvent of methanol (5 mL) and water (5 mL), stir uniformly, then add lithium hydroxide (151.7 mg, 3.7 mmol), and react at room temperature for 1 h. TLC / LCMS indicated complete reaction. Add 1 M dilute hydrochloric acid dropwise to adjust the pH to 5, concentrate under reduced pressure, and separate and purify the obtained crude product by preparative HPLC to obtain compound 47 isomer 1 (24.0 mg, 5.9%) and compound 47 isomer 2 (220.0 mg, 53.7%).

[0422] HPLC analysis method: 1. Instrument: Shimadzu LC - 2020; 2. Chromatography column: Phenomenex C18; 3. Mobile phase system: 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.

[0423] Fractionation method: Instrument: Waters 2767 for fractionating liquids, Chromatography column: SunFire@ Prep C18 (19 mm×250 mm). The sample was dissolved in methanol and filtered through a 0.22 μm filter to prepare the sample solution. Chromatography conditions for fractionation: Composition of mobile phases A and B: Mobile phase A: Acetonitrile, Mobile phase B: Water (containing 0.1% aqueous ammonia), gradient elution, the content of mobile phase A was 0% - 50%, and the flow rate was 18 mL / min. Elution time was 30 min.

[0424] Compound 47 Isomer 1: 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 (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). M / Z (ESI): m / z = 554.2 [M + H] + .

[0425] Compound 47 Isomer 2: 1 H NMR (400 MHz, CDCl 3 ) δ 7.34 (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). M / Z (ESI): m / z = 554.2 [M + H] + . Example 48:

Chemical Structure

[0426] Using 48A (0.2 g, 0.98 mmol) and 1C (0.26 g, 0.98 mmol) as raw materials, referring to the operation methods of Steps 1 to 3 in Example 12, compound 48 (100 mg) was obtained.

[0427] 1 H NMR (400 MHz, CD 3 OD) 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). LC-MS (ESI): m / z = 574.2 [M + H] + . Example 49:

Chemical formula

[0428] Using 49A (0.4 g, 1.73 mmol) and 1C (0.46 g, 1.73 mmol) as raw materials, referring to the operation methods of Steps 1 to 3 in Example 12, compound 49 (10 mg) was obtained.

[0429] 1 H NMR (400 MHz, CD 3OD) 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). LC - MS (ESI): m / z = 557.2 [M + H] + 。 Example 50:

Chem.

[0430] Using 50A (0.2 g, 1.21 mmol) and 1C (0.33 g, 1.21 mmol) as raw materials, referring to the operation methods of Steps 1 to 3 in Example 12, compound 50 (100 mg) was obtained.

[0431] 1 H NMR (400 MHz, CD 3 OD) 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 - 1.93 (m, 6H), 1.71 - 1.68 (m, 1H), 1.50 - 1.48 (d, 3H), 1.38(s, 3H), 1.16 - 1.06 (m, 1H). LC - MS (ESI): m / z = 536.2 [M + H] + 。 Compound 51:

Chem.

[0432] Using Compound 1C (300.0 mg, 0.89 mmol) and Compound 51A (168.0 mg, 0.89 mmol) as starting materials, referring to the operation methods of Steps 1 to 3 of Example 12, the title compound 51 (25 mg) was obtained.

[0433] 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.92 (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). LCMS m / z = 558.2[M + H] + 。 Example 52:

Chemical formula

[0434] Step 1: Dissolve Compound 52A (0.5 g, 2.31 mmol) in acetonitrile (15 mL), add (R)-1-(2,4-dichlorophenyl)ethan-1-amine (0.53 g, 2.78 mmol) and triethylamine (0.70 g, 6.93 mmol), heat to 70 °C and react for 16 hours. After completion of the reaction, cool to room temperature, concentrate, dissolve the concentrate in dichloromethane (30 mL), wash the organic phase successively with water (20 mL × 3) and brine (20 mL × 3), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify the obtained crude product by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1 to 2:1) to obtain the title compound 52B (0.51 g, 61%).

[0435] LC-MS (ESI): m / z = 370.2[M + H] +。

[0436] Step 2: Dissolve compound 52B (0.51 g, 1.38 mmol) in tetrahydrofuran (10 mL), add di-t-butyl dicarbonate (0.45 g, 2.07 mmol) and DMAP (16 mg, 0.14 mmol), and reflux for 12 hours. After completion of the reaction, cool to room temperature, concentrate, dissolve the residue in dichloromethane (30 mL), wash the organic phase successively with water (20 mL × 3) and brine (20 mL × 3), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify the obtained crude product by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1 to 2:1) to obtain the title compound 52C (0.45 g, 70%).

[0437] LC-MS (ESI): m / z = 470.2 [M+H] + 。

[0438] Step 3: Dissolve compound 52C (0.20 g, 0.43 mmol) in dimethyl sulfoxide (5 mL), add compound 1C (0.16 g, 0.47 mmol) and triethylamine (0.13 g, 1.29 mmol), heat to 150 °C under microwave conditions, and react for 1 hour. After completion of the reaction, cool to room temperature, dissolve the reaction solution in ethyl acetate (30 mL), wash the organic phase successively with water (20 mL × 3) and brine (20 mL × 3), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify the obtained crude product by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1 to 2:1) to obtain the title compound 52D (0.19 g, 65%).

[0439] LC-MS (ESI): m / z = 700.2 [M+H] + 。

[0440] Step 4: 52D (0.19 g, 0.28 mmol) was dissolved in dichloromethane (8 mL), and a dioxane hydrochloride solution (8 mL) was added. After the addition was complete, the reaction was carried out at room temperature for 1 hour. It was concentrated to obtain the hydrochloride salt of the title compound 52E (0.15 g, 90%). It was directly used in the reaction of the next step without further purification.

[0441] LC-MS (ESI): m / z = 600.2 [M+H] + 。

[0442] Step 5: Compound 52E (150 mg, 0.25 mmol) was dissolved in tetrahydrofuran (3 mL) and water (3 mL), lithium hydroxide hydrate (53.0 mg, 1.25 mmol) was added, and after stirring uniformly, the reaction was carried out at room temperature for 12 hours. After the reaction was completed, it was concentrated under reduced pressure, and the residue was separated and purified by high-speed preparative liquid chromatography to obtain the title compound 52 (0.09 g, 65%).

[0443] Preparative method: 1. Instrument: waters 2767 preparative liquid chromatograph, chromatography 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. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate) b. Gradient elution, the content of mobile phase A is 10% - 55% c. Flow rate is 12 mL / min.

[0444] 1 H NMR (400 MHz, Methanol-d 4) δ 7.44 (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). LC-MS (ESI): m / z = 586.2 [M + H] + . Example 53:

Chemical Structure

[0445] Step 1: Dissolve 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) in dry acetonitrile (60 mL) and react overnight at room temperature. After detecting the disappearance of the raw materials by TLC, add saturated ammonium chloride aqueous solution (50 mL) to quench, extract with ethyl acetate (20 mL × 5), combine the organic phases, dry over anhydrous Na 2 SO 4 and filter and concentrate. Purify the obtained residue by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 80:20) to obtain compound 53A (920 mg, 52.6%).

[0446] LC-MS (ESI): m / z = 358.1 [M + H] + .

[0447] 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, the temperature was raised to 100 °C, and the reaction was carried out for about 4 hours. The disappearance of the raw materials was detected by TLC, and after cooling to room temperature, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol (v / v) = 100:0 - 75:25), and compound 53 isomer 1 (54 mg, 15.1%) and compound 53 isomer 2 (23 mg, 6.42%) were obtained successively.

[0448] Compound 53 isomer 1 (ethyl acetate:methanol (v / v) = 9:1, Rf = 0.45), 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.46 - 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). LC-MS (ESI): m / z = 576.2 [M+H] + .

[0449] Compound 53 isomer 2 (ethyl acetate:methanol (v / v) = 9:1, Rf = 0.42), 1 H NMR (400 MHz, Methanol-d 4) δ 7.47 - 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). LC-MS (ESI): m / z = 576.2 [M + H] + . Example 54: [Chemical formula]

[0450] Using compound 33A (500 mg, 2.44 mmol) and (R)-1-(2,4-dichlorophenyl)ethan-1-amine (695 mg, 3.66 mmol) as raw materials, referring to the operation methods of steps 1 to 2 in Example 53, compound 54 isomer 1 (33 mg) and compound 54 isomer 2 (14 mg) were obtained.

[0451] Compound 54 isomer 1 (ethyl acetate:methanol (v / v) = 9:1, Rf = 0.55), 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.82 (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). LC-MS (ESI): m / z = 576.2 [M+H] + 。

[0452] Compound 54 Isomer 2 (ethyl acetate:methanol (v / v) = 9:1, Rf = 0.50), 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.81 (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). LC-MS (ESI): m / z = 576.2 [M+H] + 。 Example 55:

Chem.

[0453] Using Compound 55A (227 mg, 1.18 mmol) and (R)-1-(2,4-dichlorophenyl)ethylamine (336 mg, 1.77 mmol) as raw materials, referring to the operation methods of Steps 1 to 3 of Example 14, the trifluoroacetate salt of Compound 55 (75 mg) was obtained.

[0454] 1 H NMR (400 MHz, CD 3OD) δ 7.96 (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, 1H), 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). LC-MS (ESI): m / z = 557.2 [M + H] + . Example 56:

Chemical Structure

[0455] Using compound 56A (300 mg, 1.5 mmol) and compound 1C (565 mg, 1.5 mmol) as starting materials, referring to the operation methods of steps 1 to 3 in Example 12, the trifluoroacetate salt of compound 56 (191 mg) was obtained.

[0456] LC-MS (ESI): m / z = 566.7 [M + H] + . 1 1H NMR (400 MHz, CD 3 OD) δ 7.48 (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). Example 57:

Chem.

[0457] Using compound 57A (227 mg, 1.08 mmol) and compound 1C (407 mg, 1.08 mmol) as starting materials, referring to the operation methods of steps 1 to 3 in Example 12, the trifluoroacetate salt of compound 57 (144 mg) was obtained.

[0458] 1 H NMR (400 MHz, CD 3 OD) δ 7.46 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 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, 1H), 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). LC-MS (ESI): m / z = 550.2 [M + H] + . Example 58:

Chem.

[0459] Step 1: Dissolve compound 58A (456 mg, 2.10 mmol) in acetonitrile (10 mL), and sequentially stir triethylamine (638 mg, 6.30 mmol) and (R)-1-(2,4-dichlorophenyl)ethylamine (400 mg, 2.10 mmol) at room temperature for 5 h. After the reaction was completed, it was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain the target compound 58B (510 mg, 66%).

[0460] LC-MS (ESI): m / z = 371.5 [M+H] + 。

[0461] Step 2: Compound 58B (200 mg, 0.54 mmol) was dissolved in acetonitrile (3 mL), and 29B (140 mg, 0.54 mmol), N,N-diisopropylethylamine (210 mg, 1.62 mmol), and cesium fluoride (82 mg, 0.54 mmol) were sequentially added. The mixture was stirred at 70 °C overnight. After completion of the reaction, it was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain the target compound 58C (143 mg, 44%).

[0462] LC-MS (ESI): m / z = 603.2 [M+H] + 。

[0463] 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 after stirring uniformly, lithium hydroxide monohydrate (29 mg, 1.2 mmol) was added. The reaction was carried out at room temperature for 2 hours. After completion of the reaction, it was concentrated, and the residue was separated by silica gel column chromatography (ethyl acetate:methanol (v / v) = 5:1) to obtain 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%).

[0464] Compound 58 isomer 1: LC-MS (ESI): m / z = 588.6 [M+H] + 。

[0465] 11H NMR (400 MHz, DMSO-d6) δ 8.09 (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).

[0466] Compound 58 Isomer 2: LC-MS (ESI): m / z = 588.6 [M+H] + 。

[0467] 1 1H NMR (400 MHz, DMSO-d6) δ 10.22 (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). Example 59:

Chem.

[0468] 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, referring to the operating methods of Steps 1 to 3 in Example 12, the trifluoroacetate salt of Compound 59 (0.19 g) was obtained.

[0469] 1 1H NMR (400 MHz, Methanol-d 4) δ 7.45 - 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). LC-MS (ESI): m / z = 586.3 [M + H] + . Example 60:

Chemical Structure

[0470] Using compound 40A (358 mg, 1.8 mmol) and 29B (409 mg, 1.2 mmol) as starting materials, referring to the operation methods of steps 1 to 3 in Example 12, 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%) were obtained.

[0471] Analysis method: Instrument: SHIMADZU LC - 30AD sf, Column: Chiralcel C2 - 3 50×4.6 mm I.D., 3μm, Mobile phase: A for CO 2 , 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] + .

[0472] 1 1H NMR (400 MHz, CD 3OD) δ 7.80 (d, J = 8.4 Hz, 1H), 7.65 - 7.64 (m, 1H), 7.48 (s, 1H), 7.46 - 7.45 (m, 1H), 7.38 (d, J = 8.4 Hz, 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).

[0473] Compound 60 Isomer 2: LC-MS (ESI): m / z = 570.1 [M + H] + 。

[0474] 1 H NMR (400 MHz, CD 3 OD) δ 7.82 (d, J = 8.4 Hz, 1H), 7.69 - 7.68 (m, 1H), 7.49 (m, 1H), 7.47 (d, J = 8.4 Hz, 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). Example 61:

Chem.

[0475] Using 61A (0.2 g, 1.11 mmol) and 1C (0.30 g, 1.11 mmol) as raw materials, referring to the operation methods of Steps 1 to 3 in Example 12, compound 61 (100 mg) was obtained.

[0476] 1 H NMR (400 MHz, CD 3 OD) 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, 2H), 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). LC-MS (ESI): m / z = 550.2 [M + H] + . Example 62: [Chemical formula]

[0477] Step 1: At room temperature, the raw material substrate 62A (6.3 g, 29.85 mmol) was dissolved in THF (100 mL). Under a nitrogen gas atmosphere, the temperature was lowered to 0 °C, and sodium bis(trimethylsilyl)amide (17.9 mL, 35.82 mmol) was added dropwise. After the addition was complete, stirring was continued for 1 hour, and then a solution of N-phenylbis(trifluoromethanesulfonyl)imide (21.3 g, 59.7 mmol) in THF (100 mL) was added dropwise. After the addition was complete, the temperature was allowed to rise naturally to room temperature, and the reaction was carried out for 2 hours. Water (100 mL) was added to quench the reaction, and the mixture was extracted with EA (500 mL × 3). The combined organic phases were washed with water (500 mL), washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then subjected to column chromatography (PE:EA = 50:1~20:1) to obtain compound 62B (5.5 g, yield 61%).

[0478] LC-MS (ESI): m / z = 344.1 [M+H] + 。

[0479] Step 2: At room temperature, zinc powder (3.12 g, 48.11 mmol) was added to DMA (20 mL). Under a nitrogen gas atmosphere, 1,2-dibromoethane (0.91 g, 4.81 mmol) and trimethylchlorosilane (0.52 g, 4.81 mmol) were added dropwise to the reaction. After the addition was complete, 1-CBZ-3-iodoacridine (4.52 g, 24.05 mmol) was added thereto, and stirring was continued at room temperature for 1 hour. The mixture was filtered, and to the filtrate were sequentially added the raw material 62B (5.5 g, 16.03 mmol), CuI (0.46 g, 2.4 mmol), and Pd(dppf) 2 Cl 2 (1.74 g, 2.4 mmol). The temperature was raised to 85 °C, and the reaction was carried out for 16 hours. After the reaction was complete, it 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 (PE:EA(v / v) = 1:1) to obtain the target compound 62C (2.9 g, yield 48%).

[0480] LC-MS (ESI): m / z = 385.2 [M+H] + 。

[0481] Step 3: Compound 62C (2.9 g, 7.55 mmol) was dissolved in methanol (50 mL), Pd / C (0.3 g, Pd content 10%) was added, and the reaction was carried out for 15 hours under a hydrogen gas atmosphere. After completion of the reaction, filtration was performed, and after concentration of the filtrate, crude compound 62D (1.9 g, 100%) was obtained and used directly in the reaction of the next step without further purification.

[0482] LC-MS(ESI): m / z = 253.2 [M+H] + 。

[0483] Step 4: At room temperature, 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 successively dissolved in dimethyl sulfoxide (100 mL), then the temperature was raised to 100 °C and the reaction was carried out for 4 hours. After complete reaction, it was cooled to room temperature, water (100 mL) was added, and extraction was performed with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (DCM:MeOH (v / v) = 10:1) to obtain 0.97 g of the racemate. The racemate was separated by chiral preparative HPLC to obtain 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%).

[0484] HPLC analysis method Analysis method: 1. Instrument: SHIMADZU LC-30AD, 2. Chromatography column: Chiralpak IC-3 50×4.6 mm I.D., 3. Mobile phase system: A for CO2 and B for IPA (0.05% DEA), 4. Gradient: B 30%, 5. Flow rate: 3 mL / min.

[0485] Conditions for preparative chromatography separation: 1. Instrument: Waters 150 SFC; 2. Chromatography column: Chiralpak IC - Column (250×30 mm, I.D 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.

[0486] LC-MS (ESI): m / z = 566.3 [M+H] + 。

[0487] Step 5: Compound 62E-1 (0.25 g, 0.44 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added, and the mixture was reacted at room temperature for 30 min. After complete reaction, it was directly concentrated to obtain the trifluoroacetate salt of compound 62F-1 (0.2 g, 98%).

[0488] Referring to the above operation, using compound 62E-2 (0.86 g, 2.4 mmol) as the raw material, the trifluoroacetate salt of the title compound 62F-2 (0.22 g, 98%) was obtained.

[0489] LC-MS (ESI): m / z = 466.3 [M+H] + 。

[0490] Step 6: Compound 62F-1 (0.2 g, 0.43 mmol) and 3-oxo-1-methyl-cyclobutanecarboxylic acid (55 mg, 0.43 mmol) were successively dissolved in 1,2-dichloroethane (15 mL), and glacial acetic acid (26 mg, 0.43 mmol) was added. Sodium triacetoxyborohydride (0.18 g, 0.86 mmol) was added little by little, and after the addition was complete, the reaction was carried out 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, filtered, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=10:1) to obtain 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%).

[0491] Compound 62 isomer 1: 1 H NMR (400 MHz, CD 3 CN) δ 7.51 - 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, 3H), 1.93 - 1.85 (m, 5H), 1.73 - 1.67 (m, 1H), 1.54 - 1.52 (d, 3H), 1.33 (s, 3H). M / Z (ESI): m / z = 578.2 [M + H] + 。

[0492] Compound 62 isomer 2: 1 H NMR (400 MHz, CD 3CN) δ 7.52 - 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). M / Z (ESI): m / z = 578.2 [M + H] + 。

[0493] Referring to the above operations, using compound 62F - 2 (0.22 g, 0.47 mmol) as the raw material, 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%) were obtained. Compound 62 isomer 3: 1 H NMR (400 MHz, CD 3 CN) δ 7.51 - 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, 3H), 1.93 - 1.75 (m, 5H), 1.61 - 1.60 (m, 1H), 1.54 - 1.52 (d, 3H), 1.33 (s, 3H). M / Z (ESI): m / z = 578.2 [M + H] + 。

[0494] Compound 62 isomer 4: 1 H NMR (400 MHz, CD 3CN) δ 7.52 - 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). M / Z (ESI): m / z = 578.2 [M + H] + . Example 63:

Chemical Structure

[0495] Using compound 63A (1.0 g, 4.93 mmol) and (R)-1-(2,4-dichlorophenyl)ethan-1-amine (936 mg, 4.93 mmol) as raw materials, referring to the operation methods of Step 1 and Step 2 in 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.

[0496] Compound 63 isomer 1: LC-MS (ESI): m / z = 574.2 [M + H] + .

[0497] 1 1H NMR (400 MHz, DMSO-d6) δ 12.16 (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).

[0498] Compound 63 Isomer 2: LC-MS (ESI): m / z = 574.2 [M+H] + 。

[0499] 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (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), 3.53 - 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). Example 64:

Chem.

[0500] Step 1: Dissolve compound 64A (10.00 g, 45.66 mmol) in acetonitrile (50 mL), and sequentially add dimethylhydroxylamine hydrochloride (5.34 g, 54.79 mmol), N-methylmorpholine (18.45 g, 182.64 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (13.13 g, 68.49 mmol). After the addition, react at room temperature for 3 hours. After the reaction is completed, add water (50 mL) to quench the reaction, extract with ethyl acetate (100 mL × 2), wash the combined organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 64B (11.72 g, 98.0%), which was directly used in the reaction of the next step without further purification.

[0501] Step 2: Under a nitrogen gas 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 the reaction was complete, 10% aqueous sodium potassium tartrate solution (50 mL) was added dropwise to quench the reaction, 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, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 64C (8.6 g, 99.1%). Without further purification, it was directly used in the next step reaction.

[0502] Step 3: Compound 64C (8.0 g, 39.37 mmol) was dissolved in methanol (80 mL), triethylamine (7.97 g, 78.74 mmol) and nitromethane (9.61 g, 157.48 mmol) were added sequentially. After the addition was complete, the mixture was stirred at room temperature for 17 hours. After the reaction was complete, it was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 4:1) to obtain the title compound 64D (9.3 g, 89.39%).

[0503] Step 4: Compound 64D (9.3 g, 35.19 mmol) was dissolved in methanol (100 mL), Raney nickel (0.41 g, 7.04 mmol) was added, and the reaction was carried out under a hydrogen gas atmosphere for 15 hours. After the reaction was complete, it was filtered, and the filtrate was concentrated to obtain a crude product of compound 64E (7.6 g, 92.2%). Without further purification, it was directly used in the next step reaction.

[0504] M / Z (ESI): m / z = 187.1[M+H- t Bu] + 。

[0505] Step 5: Compound 64E (7.6 g, 32.44 mmol) was dissolved in a mixed solvent of tetrahydrofuran (70 mL) and water (40 mL), and sodium bicarbonate (8.18 g, 97.32 mmol) was added. The temperature was controlled at 5 - 10 °C, and chloroacetyl chloride (7.33 g, 64.88 mmol) was added dropwise. After the addition was complete, the temperature was raised to room temperature and the reaction was carried out for 1 hour. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:3) to obtain the title compound 64F (9.2 g, 91.2%).

[0506] Step 6: t-Butoxide (6.65 g, 59.22 mmol) was dissolved in t-butanol (170 mL), and compound 64F (9.2 g, 29.61 mmol) was added little by little. After the addition was complete, the temperature was raised to 40 °C and the reaction was carried out for 1 hour. After the reaction was complete, it was cooled to room temperature, saturated aqueous ammonium chloride solution (100 mL) was added to quench the reaction, 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, filtered, and the filtrate was concentrated. Then the residue was separated and 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%).

[0507] Step 7: Under a nitrogen gas atmosphere, compound 64G (7.2 g, 26.25 mmol) was dissolved in tetrahydrofuran (75 mL), and the temperature was lowered to 0 °C. Sodium dihydrobis(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 complete reaction, the temperature was controlled at 0 - 5 °C, and 10% aqueous sodium hydroxide solution (20 mL) was added dropwise to quench the reaction. After quenching was complete, anhydrous magnesium sulfate was added for drying, and the mixture was filtered through diatomaceous earth. After concentrating the filtrate, the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 5:1) to obtain the title compound 64H (5.3 g, 77.5%).

[0508] M / Z (ESI): m / z = 205.2[M+H- t Bu] + 。

[0509] Step 8: Compound 64H (5.3 g, 20.36 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 mL) and water (30 mL), and sodium hydrogen carbonate (5.13 g, 61.08 mmol) was added. The temperature was lowered to 0 - 5 °C, and benzyl chloroformate (4.17 g, 24.43 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 (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, filtered, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain 4.8 g of the racemate. The racemate was separated by chiral preparative HPLC to obtain 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%).

[0510] HPLC analysis method: 1. Instrument: SHIMADZU LC-30AD SFC; 2. Chromatography column: Chiralcel OX-3 50×4.6mm I.D., 3μm; 3. Mobile phase system: A for CO2, B for 0.05% DEA in IPA; 4. Gradient: B 5 - 40%; 5. Flow rate: 3 mL / min.

[0511] Conditions for preparative chromatography separation: 1. Instrument: Waters 150 SFC; 2. Chromatography column: Chiralpak OX - Column (250×30mm, I.D 30mm, 10um particle size); 3. Mobile phase system: A for CO 2 and B for IPA; 4. Gradient: B 20%; 5. Flow rate: 100 mL / min; 6. Elution time: 3.3 min.

[0512] Step 9: Compound 64I-1 (1.6 g, 4.06 mmol) was dissolved in methanol (20 mL), Pd / C (0.4 g, Pd content 10%) was added, and the reaction was carried out for 3 hours under a hydrogen gas atmosphere. After completion of the reaction, filtration was performed, and the filtrate was concentrated to obtain the title compound 64J-1 (1.00 g, 94.6%).

[0513] Referring to the above operation, using compound 64I-2 (2.00 g, 5.31 mmol) as the raw material, the title compound 64J-2 (1.21 g, 94.0%) was obtained.

[0514] Step 10: Compound 64J-1 (1.00 g, 3.84 mmol) and 3-oxo-1-methyl-cyclobutanecarboxylic acid (0.74 g, 5.76 mmol) were successively dissolved in methanol (15 mL), and glacial acetic acid (0.46 g, 7.46 mmol) was added. Sodium cyanoborohydride (0.72 g, 11.44 mmol) was added portionwise, and after the addition was complete, the reaction was carried out for 1 hour. After complete reaction, 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, filtered, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain the title compound 64K-1 (1.20 g, 83.9%).

[0515] Referring to the above operation, using compound 64J-2 (1.21 g, 4.1 mmol) as the raw material, the title compound 64K-2 (1.51 g, 87.1%) was obtained.

[0516] M / Z (ESI): m / z = 373.3 [M+H] + 。

[0517] Step 11: Compound 64K-1 (1.20 g, 3.22 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added, and the reaction was carried out at room temperature for 30 min. After complete reaction, it was directly concentrated to obtain the trifluoroacetate of compound 64L-1 (1.6 g, 99.3%).

[0518] Referring to the above operation, using compound 64K-2 (1.51 g, 4.26 mmol) as the raw material, the trifluoroacetate of the title compound 64L-2 (2.00 g, 97.3%) was obtained.

[0519] Step 12: Compound 2F (0.15 g, 1.4 mmol) and Compound 64L-1 (0.43 g, 0.86 mmol) were successively dissolved in dimethyl sulfoxide (3 mL), N,N-diisopropylethylamine (0.17 g, 1.29 mmol) and cesium fluoride (0.13 g, 0.86 mmol) were added, the temperature was raised to 100 °C, and the reaction was carried out for 3 hours. After the reaction was completed, it was cooled to room temperature, water (20 mL) was added, extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, 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 obtain 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%).

[0520] Compound 64 isomer 1: 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 (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). M / Z (ESI): m / z = 586.2 [M + H] + 。

[0521] Compound 64 isomer 2: 1 H NMR (400 MHz, CDCl 3) δ 7.36 (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). M / Z (ESI): m / z = 586.2 [M + H] + .

[0522] Referring to the above operation, using compound 64L - 2 (0.43 g, 0.86 mmol) as the raw material, 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%) were obtained.

[0523] Compound 64 isomer 3: 1 H NMR (400 MHz, CDCl 3 ) δ 7.36 (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). M / Z (ESI): m / z = 586.2 [M + H] + .

[0524] Compound 64 isomer 4: 1 H NMR (400 MHz, CDCl 3) δ 7.36 (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). M / Z (ESI): m / z = 586.2 [M + H] + . Example 65:

Chemical Structure

[0525] Step 1: Dissolve compound 65A (0.50 g, 1.99 mmol) in dichloromethane (10 mL), sequentially add (R)-1-(2,4-dichlorophenyl)ethylamine (0.45 g, 2.39 mmol) and triethylamine (0.60 g, 5.97 mmol). After addition, stir at room temperature for 1 hour. After completion of the reaction, concentrate the mixture. Separate and purify the concentrated residue by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain the title compound 65B (0.68 g, 84.5%).

[0526] Step 2: Compound 65B (0.15 g, 0.37 mmol) and Compound 64L-1 (0.37 g, 0.74 mmol) were successively dissolved in dimethyl sulfoxide (3 mL). 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 and reacted for 3 hours. After complete reaction, it was cooled to room temperature, water (20 mL) was added, and it was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:5) to obtain 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%).

[0527] Compound 65 isomer 1: 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 (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). M / Z (ESI): m / z = 640.2 [M + H] + .

[0528] Compound 65 isomer 2: 1 H NMR (400 MHz, CDCl 3) δ 7.39 (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). M / Z (ESI): m / z = 640.2 [M + H] + .

[0529] Referring to the above operations, using compound 65B (0.15 g, 0.37 mmol) and compound 64L - 2 (0.37 g, 0.74 mmol) as raw materials, 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%) were obtained.

[0530] Compound 65 isomer 3: 1 H NMR (400 MHz, CDCl 3 ) δ 7.39 (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). M / Z (ESI): m / z = 640.2 [M + H] + .

[0531] Compound 65 isomer 4: 1 H NMR (400 MHz, CDCl 3) δ 7.38 (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). M / Z (ESI): m / z = 640.2 [M + H] + . Example 66:

Chemical formula

[0532] Step 1: Dissolve compound 66A (5.00 g, 29.40 mmol) in glacial acetic acid / acetic anhydride (v / v = 20 / 1, 100 mL). After adding a catalytic amount of ferric chloride, heat the mixture to 95 °C. Then, dropwise add sulfonyl chloride (7.93 g, 58.78 mmol). After the addition is complete, raise the temperature and react under reflux for 15 hours. After the reaction is complete, cool the solution to 10 °C, filter, wash the filter cake successively with acetic acid and water, and dry it under vacuum to obtain the title compound 66B (3.6 g, 60%).

[0533] Step 2: Dissolve compound 66B (3.0 g, 14.70 mmol) in phosphorus oxychloride (30 mL). Cool the solution to 0 °C, and dropwise add N,N - diethylaniline (4.39 g, 29.42 mmol). After the addition is complete, raise the temperature to 100 °C and react for 15 hours. After the reaction is complete, concentrate the solution to remove phosphorus oxychloride. Separate and purify the concentrated residue by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain the title compound 66C (2.7 g, 76.1%).

[0534] Step 3: Dissolve compound 66C (2.70 g, 11.16 mmol) in dichloromethane (30 mL), sequentially add (R)-1-(2,4-dichlorophenyl)ethylamine (2.55 g, 13.39 mmol) and triethylamine (3.39 g, 33.48 mmol). After addition, stir at room temperature for 1 hour. After completion of the reaction, concentrate the mixture, and separate and purify the concentrated residue by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain the title compound 66D (4.20 g, 95.2%).

[0535] Step 4: Dissolve compound 66D (4.20 g, 10.63 mmol) in ethanol (50 mL), add iodine (5.40 g, 21.28 mmol), and add sodium borohydride (2.01 g, 53.15 mmol) portionwise. After addition, react at room temperature for 3 hours. After complete reaction, concentrate to remove ethanol, add water (50 mL) to the residue, extract with ethyl acetate (50 mL × 2), wash the combined organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and then separate and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) to obtain the title compound 66E (2.60 g, 66.6%).

[0536] Step 5: Dissolve compound 66E (2.60 g, 7.08 mmol) in 1,2-dichloroethane (30 mL), add activated manganese dioxide (3.08 g, 35.53 mmol). After addition, heat to 80 °C and react for 5 hours. After completion of the reaction, filter by laying diatomaceous earth, concentrate the filtrate to obtain a crude product of compound 66F (2.10 g, 81.2%), and directly use it in the reaction of the next step without further purification.

[0537] Step 6: Compound 66F (1.50 g, 4.11 mmol) was dissolved in dichloromethane (20 mL), and diethylaminotrifluoride (1.99 g, 12.33 mmol) was added at room temperature. After the addition was complete, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, it was concentrated, and the concentrated residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain the title compound 66G (0.61 g, 38.3%).

[0538] Step 7: Compound 66G (0.15 g, 0.39 mmol) and compound 64L-1 (0.39 g, 0.78 mmol) were successively dissolved in dimethyl sulfoxide (3 mL), N,N-diisopropylethylamine (0.15 g, 1.17 mmol) and cesium fluoride (0.12 g, 0.78 mmol) were added, the temperature was raised to 100 °C, and the reaction was carried out for 3 hours. After complete reaction, it was cooled to room temperature, water (20 mL) was added, and it was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, 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 obtain 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%).

[0539] Compound 66 isomer 1: 1 H NMR (400 MHz, CDCl 3 ) δ 7.37 (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). M / Z (ESI): m / z = 622.2 [M+H] + 。

[0540] Compound 66 Isomer 2: 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 (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). M / Z (ESI): m / z = 622.2 [M+H] + 。

[0541] Referring to the above operation, using Compound 66G (0.15 g, 0.39 mmol) and Compound 64L-2 (0.39 g, 0.78 mmol) as raw materials, 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%) were obtained.

[0542] Compound 66 Isomer 3: 1 H NMR (400 MHz, CDCl 3 ) δ 7.37 (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). M / Z (ESI): m / z = 622.2 [M+H]+ .

[0543] Compound 66 Isomer 4: 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 (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). M / Z (ESI): m / z = 622.2 [M + H] + . Example 67: [Chemical Structure]

[0544] Step 1: Dissolve compound 40A (1.00 g, 5.02 mmol), (R)-1-(2,4-dichlorophenyl)ethylamine (1.05 g, 5.53 mmol) and triethylamine (1.53 g, 15.1 mmol) in dry acetonitrile (50 mL) and react overnight at room temperature. After detecting the disappearance of the raw materials by TLC, add saturated aqueous ammonium chloride solution (50 mL) to quench, extract with ethyl acetate (20 mL × 5), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. Purify the obtained residue by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 80:20~0:100) to obtain compound 67A (1.48 g, 83.5%).

[0545] LC-MS (ESI): m / z = 352.1 [M + H] + .

[0546] Step 2: Hydrochloride of compound 29B (300 mg, 0.879 mmol), 67A (341 mg, 0.967 mmol) were dissolved in dry dimethyl sulfoxide (6 mL), triethylamine (534 mg, 5.27 mmol) and cesium fluoride (267 mg, 1.76 mmol) were added. After addition, the temperature was raised to 100 °C and reacted for about 5 hours. The disappearance of the raw materials was detected by TLC. After cooling to room temperature, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v)=90:10) to obtain compound 67B (460 mg, 89.5%).

[0547] LC-MS (ESI): m / z = 584.2 [M+H] + 。

[0548] 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 reacted for 4 hours. After monitoring the disappearance of the raw materials by TLC, the pH was adjusted to neutral with dilute hydrochloric acid. After concentration under reduced pressure, it was directly purified by silica gel column chromatography (ethyl acetate:methanol (v / v)=80:20~50:50) to obtain compound 67 isomer 1 (172 mg, 38.3%) and compound 67 isomer 2 (105 mg, 23.4%) sequentially.

[0549] Compound 67 isomer 1 (Rf = 0.25 (ethyl acetate:methanol (v / v)=5:1): 1 H NMR (400 MHz, CD 3OD) δ 8.28 - 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); LC - MS (ESI): m / z = 570.2 [M + H] + 。

[0550] Compound 67 Isomer 2 (Rf = 0.15 (ethyl acetate:methanol (v / v) = 5:1): 1 H NMR (400MHz, CD 3 OD) δ 8.26 - 8.25 (m, 1H), 7.71 - 7.70 (m, 1H), 7.50 - 7.34 (m, 4H), 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). LC - MS (ESI): m / z = 570.2 [M + H] + 。 Example 68:

Chemical Structure

[0551] Step 1: 29B (0.5 g, 1.47 mmol) and 68A (0.43 g, 1.47 mmol) were dissolved in acetonitrile (20 mL), triethylamine (0.75 g, 7.35 mmol) was added, and after the addition was complete, the reaction was carried out at room temperature for 16 hours. It was concentrated under reduced pressure, water (20 mL) was added, extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, 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 obtain compound 68B (0.6 g, yield 78%).

[0552] LC-MS (ESI): m / z = 522.3[M+H] + 。

[0553] Step 2: 68B (0.55 g, 1.06 mmol), (R)-1-(2,4-dichlorophenyl)ethylamine (0.2 g, 1.06 mmol), Pd 2 (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 successively dissolved in 1,4-dioxane (40 mL), and the reaction was carried out at 100 °C for 4 hours. After the reaction was complete, it was cooled to room temperature, water (20 mL) was added, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (DCM:MeOH(v / v)=10:1) to obtain the target compound 68C (330 mg, yield 46%).

[0554] LC-MS (ESI): m / z = 675.3[M+H] + 。

[0555] Step 3: Compound 68C (0.33 g, 0.49 mmol) was dissolved in dichloromethane (10 mL), hydrochloric acid dioxane solution (2 mL, 4 M) was added, and the mixture was reacted at room temperature for 30 min. After complete reaction, saturated sodium bicarbonate solution was added thereto, and after adjusting the pH of the reaction solution to 8, extraction was performed with dichloromethane (20 mL × 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 to obtain compound 68D, which could be directly used in the reaction of the next step without purification. (0.28 g, 100%).

[0556] LC-MS (ESI): m / z = 575.3 [M + H] + 。

[0557] Step 4: Compound 68D (180 mg, 0.31 mmol) and formaldehyde (24 mg, 40% aqueous formaldehyde solution) were successively 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 portionwise, and after completion of the addition, the mixture was reacted for 15 h. After complete reaction, water (20 mL) was added to quench the reaction, and extraction was performed with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and after concentrating the filtrate, the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain the title compound 68E (180 mg, 97%).

[0558] LC-MS (ESI): m / z = 589.3 [M + H] + 。

[0559] Step 5: Compound 68E (180 mg, 0.31 mmol) was dissolved in (THF:H 2Dissolve it in a solution (4 mL) of O (v / v) = 1:1), add lithium hydroxide (82 mg, 3.1 mmol), and stir at room temperature for 4 hours to react. After complete reaction, concentrate the reaction solution under reduced pressure, and separate and purify the residue by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain 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%).

[0560] Compound 68 isomer 1: 1 H NMR (400 MHz, CD 3 OD) δ 7.41 - 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). M / Z (ESI): m / z = 575.2 [M + H] + 。

[0561] Compound 68 isomer 2: 1 H NMR (400 MHz, CD 3 OD) δ 7.41 - 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). M / Z (ESI): m / z = 575.2 [M + H] + 。 Example 69: [Chemical formula]

[0562] Step 1: Compound 69A (3.8 g, 20.2 mmol) and acetylacetonate (0.71 g, 2.0 mmol) were mixed and dissolved in THF (50 mL), cooled to 0 °C, and methylmagnesium chloride (20 mL, 3 M THF solution) was added dropwise. After the addition was complete, the reaction was continued for 1 h. Saturated ammonium chloride (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (120 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Then, separation was carried out by silica gel column chromatography (PE:EA (v / v) = 3:1) to obtain the target compound 69B (1.9 g, yield 56%).

[0563] LC-MS (ESI): m / z = 168.2 [M+H] + .

[0564] Step 2: Compound 69B (1.9 g, 11.3 mmol) was dissolved in DMF (30 mL), cooled to 0 °C, and sodium hydride (0.55 g, 13.6 mmol, 60% wt) was added. After stirring at room temperature for 20 min, 1-(1-bromoethyl)-2,4-dichlorobenzene (4.32 g, 17.0 mmol) was added dropwise. After the addition was complete, the temperature was raised to room temperature and the reaction was carried out for 30 min. Saturated aqueous sodium bicarbonate solution (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (80 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Then, separation was carried out by silica gel column chromatography (PE:EA (v / v) = 4:1) to obtain the target compound 69C (2.5 g, yield 65%). Further separation by chiral SFC gave two isomers of compound 69C.

[0565] Separation method: Instrument: Waters 150 SFC, Column: Chiralcel OJ Column (250*30mm, I.D 30mm, 10um particle size), Mobile phase: A for CO 2 and B for IPA, Gradient: 15% phase B isocratic elution, Flow rate: 100mL / min, Back pressure: 100 bar, Column temperature: 25℃, Wavelength: 220nm, Cycle time: 2.9min

[0566] Analysis method: Instrument: SHIMADZU LC-30AD SFC, Column: Chiralcel OJ-3 50×4.6mm I.D., 3μm, Mobile phase: A for CO 2 , B for 0.05% DEA in IPA, Gradient: B 5~40%, Flow rate: 3mL / min, Back pressure: 100bar, Column temperature: 35℃, Wavelength: 220nm. Retention time: Compound 69C isomer 1: 1.15min, Compound 69C isomer 2: 1.40min.

[0567] Compound 69C isomer 1: LC-MS M / Z (ESI)=340.2[M+H] + .

[0568] Compound 69C isomer 2: LC-MS M / Z (ESI)=340.2[M+H] + .

[0569] Step 3: Dissolve compound 69C (isomer 1) (0.34 g, 1.0 mmol) in DMSO (20 mL), add compound 29B (0.34 g, 1.0 mmol), stir uniformly, then sequentially add triethylamine (0.40 g, 4.0 mmol) and cesium fluoride (0.30 g, 2.0 mmol). After addition, heat the mixture to 100 °C and react for 36 hours. Cool the reaction solution to room temperature, add water (40 mL), extract with ethyl acetate (40 mL × 3), combine the organic phases, wash with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and then separate and purify by silica gel column chromatography (DCM:MeOH (v / v) = 12:1) to obtain the target compound 69D (isomer 1) (0.16 g, yield 28%).

[0570] LC-MS M / Z (ESI)=572.2[M+H] + 。

[0571] Dissolve 69C (isomer 2) (0.34 g, 1.0 mmol) in DMSO (20 mL), add 29B (0.34 g, 1.0 mmol), stir uniformly, then sequentially add triethylamine (0.40 g, 4.0 mmol) and cesium fluoride (0.30 g, 2.0 mmol). After addition, react at 100 °C for 36 hours. Cool the reaction solution to room temperature, add water (40 mL), extract with ethyl acetate (40 mL × 3), combine the organic phases, wash with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and then separate and purify by silica gel column chromatography (DCM:MeOH (v / v) = 12:1) to obtain the target compound 69D (isomer 2) (0.14 g, yield 24%).

[0572] LC-MS M / Z (ESI)=572.2[M+H] + 。

[0573] Step 4: Dissolve compound 69D (isomer 1) (0.16 g, 0.28 mmol) in tetrahydrofuran (10 mL), add methanol (3 mL) and water (3 mL), stir uniformly, then add lithium hydroxide monohydrate (0.12 g, 3 mmol), react at room temperature for 3 hours, adjust the pH to 5 with hydrochloric acid (1N aqueous solution), concentrate the system under reduced pressure, and directly separate 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)).

[0574] Compound 69 isomer 1: 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.35 (d, 1H), 7.20 - 7.11 (m, 2H), 7.03 (d, 1H), 6.36 (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). LC-MS (ESI): m / z = 558.2[M + H] + .

[0575] Compound 69 isomer 2: 1 H NMR (400 MHz, Methanol-d 4) δ 7.35 (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). LC - MS (ESI): m / z = 558.2[M + H] + .

[0576] Compound 69D (isomer 2) (0.14 g, 0.24 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (3 mL) and water (3 mL) were added. After stirring uniformly, lithium hydroxide monohydrate (0.12 g, 3 mmol) was added and the reaction was carried out at room temperature for 3 hours. The pH was adjusted to 5 with hydrochloric acid (1N aqueous solution), and the system was concentrated under reduced pressure and then separated directly by silica gel column chromatography (EA:MeOH (v / v) = 10:1) to obtain two other 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)).

[0577] Compound 69 isomer 3: 1 H NMR (400 MHz, Methanol - d 4) δ 7.50 - 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). LC - MS (ESI): m / z = 558.2 [M + H] + .

[0578] Compound 69 Isomer 4: 1 H NMR (400 MHz, Methanol - d 4 ) δ 7.48 (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). LC - MS (ESI): m / z = 558.2 [M + H] + . Example 70:

Chemical Structure

[0579] 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 sequentially added to toluene (60 mL). Under reflux, water was separated and the mixture was reacted for 16 hours. After complete reaction, it was cooled to room temperature, concentrated, and the residue was separated and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 20:1 to 2:1) to obtain product 70B (3.25 g, 74.17%).

[0580] 1 H NMR (400 MHz, Chloroform-d) δ 3.91 (s, 4H), 2.93 - 2.82 (m, 1H), 2.79 - 2.66 (m, 4H).

[0581] Step 2: 70B (3.25 g, 23.36 mmol) was dissolved in anhydrous tetrahydrofuran (32 mL), cooled to -78 °C, and a solution of lithium diisopropylamide in tetrahydrofuran (7.01 mL, 28.03 mmol) was added dropwise. After stirring for 1 hour, iodomethane (4.31 g, 30.31 mmol) was added dropwise. After complete addition, the temperature was raised to room temperature and the mixture was reacted for 16 hours. Water (120 mL) and ethyl acetate (100 mL) were added, and the mixture was extracted and separated. The aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated 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%).

[0582] 1 H NMR (400 MHz, Chloroform-d) δ 3.93 - 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).

[0583] Step 3: 70C (2.33 g, 15.21 mmol) was dissolved in acetone (46 mL), 6N hydrochloric acid (4.6 mL, 27.53 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction was stopped and concentrated to remove the solvent, and the crude product 70D (1.72 g) was obtained.

[0584] 1 H NMR (400 MHz, Chloroform-d) δ 3.77 - 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).

[0585] Step 4: 9J-2 (2.25 g, 9.29 mmol), 70D (1.72 g, 11.06 mmol) were dissolved in DCE (40 mL), acetic acid (0.26 g, 9.29 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, sodium cyanoborohydride (1.17 g, 18.58 mmol) was added little by little. After the addition was complete, the reaction was carried out at room temperature for 16 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted and separated. The aqueous phase was extracted with dichloromethane (50 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1 - 1:1) to obtain 70E (0.79 g, 25.35%).

[0586] LCMS (ESI): m / z = 336.3[M + H] + 。

[0587] Step 5: 70E (0.10 g, 0.30 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. After monitoring by LCMS to confirm complete reaction, it was concentrated to remove most of the trifluoroacetic acid. The residue was dissolved in anhydrous DMSO (3 mL), and 2F (0.13 g, 0.37 mmol), DIEA (0.20 g, 1.51 mmol), and cesium fluoride (91 mg, 0.60 mmol) were sequentially added. The temperature was raised to 102 °C and the reaction was carried out for 2 hours. After completion of the reaction, it was cooled to room temperature, water (15 mL) and ethyl acetate (15 mL) were added, and extraction, liquid separation were performed. The aqueous phase was extracted with ethyl acetate (15 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1 - 1:4) was performed on the residue to obtain compound 70 (61 mg, 36.98%).

[0588] 1 H NMR (400 MHz, Chloroform-d) δ 7.38 - 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). LCMS m / z = 549.2 [M + H] + 。 Example 71:

Chemical Structure

[0589] 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), displace with nitrogen gas, heat to 140 °C and react for 5 hours. Stop the reaction, cool to room temperature, purify by reverse phase to obtain a crude product, concentrate the crude product to dryness, and perform column chromatography (dichloromethane:methanol (v / v) = 100:1 to 4:1) to obtain 71A (0.12 g, 15.85%).

[0590] LCMS m / z = 579.1 [M+H] + 。

[0591] 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 monitoring by LCMS that the reaction was complete, concentrate to remove most of the trifluoroacetic acid, dissolve the resulting residue in anhydrous DMSO (3 mL), add 2F (0.13 g, 0.38 mmol), DIEA (0.21 g, 1.60 mmol), and cesium fluoride (97 mg, 0.64 mmol), 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 layers, extract the aqueous phase with ethyl acetate (15 mL × 2), dry the combined organic phases over anhydrous sodium sulfate, filter, concentrate, and separate the residue by column chromatography (dichloromethane:methanol (v / v) = 100:1 to 1:4) to obtain a crude product. Further perform thin layer chromatography (dichloromethane:methanol (v / v) = 10:1) on the crude product 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%).

[0592] Compound 71 Isomer 1: 11H NMR (400 MHz, Chloroform-d) δ 7.38 - 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). LCMS m / z = 592.1 [M + H] + .

[0593] Compound 71 Isomer 2: 1 1H NMR (400 MHz, Methanol-d4) δ 7.43 - 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). LCMS m / z = 592.3 [M + H] + . Example 72:

Chemical Structure

[0594] 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), and the temperature was raised to 100 °C and stirred for 16 h. After completion of the reaction, it was cooled to room temperature, water (50 mL) and ethyl acetate (60 mL) were added, extracted and separated, 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 column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) was performed to obtain 72B (3.47 g, 59%).

[0595] LC-MS (ESI): m / z = 171.1 [M+H] + 。

[0596] 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 trichloride (5.42 g, 40.68 mmol) was added little by little, and the reaction was carried out at 45 °C for 3 h. After completion of the reaction, it was cooled to room temperature, the reaction solution was poured into ice water, separated, the aqueous phase was extracted with dichloromethane (50 mL×2), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) was performed to obtain 72C (3.9 g, 90%).

[0597] LC-MS (ESI): m / z = 213.1 [M+H] + 。

[0598] Steps 3 to 6: Using (R)-(+)-t-butylsulfinamide (2.67 g, 22.01 mmol) and 72C (3.9 g, 18.34 mmol) as raw materials, referring to the operation methods of Steps 3 to 6 of Example 7, Compound 72G-1 and Compound 72G-2 were obtained.

[0599] LCMS (ESI): m / z = 374.1 [M+H] + 。

[0600] Step 7: 9J-2 (130 mg, 0.53 mmol), DIEA (210 mg, 1.59 mmol) and cesium fluoride (240 mg, 1.59 mmol) were added to a DMSO (4 mL) solution of compound 72G-1 (200 mg, 0.53 mmol), and the temperature was raised to 100 °C and reacted for 2 hours. After completion of the reaction, water (15 mL) and ethyl acetate (15 mL) were added, extracted and 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, concentrated, and the residue was purified by silica gel chromatography column (EA:MeOH (v / v) = 5:1), and then 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%) were obtained.

[0601] Compound 72 isomer 1: 1 H NMR (400 MHz, CDCl 3 ) 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). LCMS (ESI): m / z = 592.2 [M+H] + 。

[0602] Compound 72 isomer 2: 1 H NMR (400 MHz, CDCl 3) 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). LCMS (ESI): m / z = 592.2 [M+H] + .

[0603] With reference to the above operations, using compound 72G-2 as the raw material (0.1 g, 0.27 mmol), 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%) were obtained.

[0604] Compound 72 isomer 3: 1 H NMR (400 MHz, CDCl 3 ) 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). LCMS (ESI): m / z = 592.2 [M+H] + .

[0605] Compound 72 isomer 4: 1 H NMR (400 MHz, CDCl 3) δ 6.85 (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). LCMS (ESI): m / z = 592.2 [M + H] + . Example 73: [Chemical formula]

[0606] Step 1: Dissolve compound 73A (40.0 g, 187.5 mmol) in methanol (400 mL), sequentially add nitromethane (45.8 g, 750.2 mmol) and triethylamine (37.9 g, 375.1 mmol). After addition, stir at room temperature for 17 hours. Concentrate to obtain the crude product of compound 73B (55.0 g), and use it directly in the reaction of the next step without further purification.

[0607] LCMS m / z = 219.1 [M + H - t Bu] + .

[0608] Step 2: Dissolve compound 73B (55.0 g, 200.5 mmol) in methanol (550 mL), add Pd / C (11.0 g, Pd content 10%), and react at room temperature for 24 hours under a hydrogen gas atmosphere. Filter, concentrate the filtrate to obtain the crude product of compound 73C (40.0 g, 82%), and use it directly in the reaction of the next step without further purification.

[0609] LCMS m / z = 189.2 [M + H - t Bu] + .

[0610] Step 3: Compound 73C (40.0 g, 163.7 mmol) was dissolved in a mixed solvent of ethyl acetate (200 mL) and water (200 mL), and sodium bicarbonate (41.2 g, 491.1 mmol) was added. The temperature was lowered to 5 °C, chloroacetyl chloride (27.7 g, 245.6 mmol) was added dropwise, and the temperature was controlled at 5 - 10 °C. After the addition was complete, the temperature was raised to room temperature and the reaction was carried out for 1 hour. After the reaction was complete, water (100 mL) was added, and the mixture was extracted with ethyl acetate (300 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2) to obtain the title compound 73D (30.0 g, 57%).

[0611] LCMS m / z = 221.1 [M + H - Boc] + 。

[0612] Step 4: t-Butoxide (20.9 g, 187.0 mmol) was added to t-butanol (200 mL), and a solution of compound 73D (30.0 g, 93.5 mmol) in t-butanol (100 mL) was added. The temperature was controlled at 30 - 40 °C and stirred for 2 hours. After the reaction was complete, it was cooled to room temperature, saturated aqueous ammonium chloride solution (200 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (300 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2) to obtain the title compound 73E (23.6 g, 89%).

[0613] LCMS m / z = 185.2 [M + H - Boc] + 。

[0614] Step 5: Under a nitrogen gas atmosphere, compound 73E (23.6 g, 83.0 mmol) was dissolved in toluene (230 mL), the temperature was lowered to -10°C, and sodium bis(2-methoxyethoxy)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 the quenching was complete, ethyl acetate (100 mL) was added to the reaction solution, and extraction was performed. The organic phase was washed with water (50 mL), washed with 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%).

[0615] LCMS m / z=215.2[M+H- t Bu] + 。

[0616] Step 6: Compound 73F (8.0 g, 29.6 mmol) was dissolved in a mixed solvent 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 the reaction was complete, water (100 mL) was added, and extraction was performed with ethyl acetate (150 mL×2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was then separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v)=3:1) to obtain 10.0 g of the racemate. The racemate was separated by chiral preparative HPLC to obtain two isomers, compound 73G-1 (3.8 g, 32%) and compound 73G-2 (3.5 g, 29%).

[0617] LCMS m / z=305.2[M+H-Boc] + 。

[0618] Conditions for preparative chromatography separation: 1. Instrument: Waters 150 SFC; 2. Chromatography column: Chiralcel OX Column (250×30 mm, I.D 30 mm, 10 μm particle size); 3. Mobile phase system: A for CO 2 and B for IPA (0.1% NH 3 ·H 2 O); 4. Gradient: B 25%; 5. Flow rate: 100 mL / min.

[0619] HPLC analysis method: 1. Instrument: SHIMADZU LC-30AD; 2. Chromatography column: Whelk-O1 column; 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. Compound 73G-1 (retention time 1.46 min) and compound 73G-2 (retention time 1.55 min).

[0620] Step 7: Compound 73G-1 (3.8 g, 9.4 mmol) was dissolved in ethyl acetate (40 mL), Pd / C (0.8 g, Pd content 10%) was added, and the reaction was carried out at room temperature for 3 hours under a hydrogen gas atmosphere. After filtration, the filtrate was concentrated to obtain the title compound 73H-1 (2.3 g, 91%).

[0621] Referring to the above operation, using compound 73G-2 (3.5 g, 9.0 mmol) as the raw material, the title compound 73H-2 (2.1 g, 90%) was obtained.

[0622] LCMS m / z = 215.3[M + H - t Bu] + .

[0623] Step 8: Compound 73H-1 (200 mg, 0.74 mmol) and 3-oxo-1-methyl-cyclobutanecarboxylic acid (113.7 mg, 0.89 mmol) were successively dissolved in methanol (5 mL), glacial acetic acid (44.4 mg, 0.74 mmol) was added, and finally sodium cyanoborohydride (93.2 mg, 1.48 mmol) was added. After the addition was complete, the reaction was carried out at room temperature for 30 minutes. After the reaction was complete, water (2 mL) was added to quench the reaction, and the mixture was extracted 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 separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain the title compound 73I-1 (200 mg, 71%).

[0624] Referring to the above operation, using compound 73H-2 (200 mg, 0.74 mmol) as the raw material, the title compound 73I-2 (200 mg, 71%) was obtained.

[0625] LCMS m / z = 383.6[M+H] + 。

[0626] Step 9: Compound 73I-1 (200 mg, 0.52 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added, and the reaction was carried out at room temperature for 2 h. After the reaction was complete, it was directly concentrated to obtain the trifluoroacetate of compound 73J-1 (146 mg, 99%).

[0627] Referring to the above operation, using compound 73I-2 (200 mg, 0.52 mmol) as the raw material, the trifluoroacetate of the title compound 73J-2 (142 mg, 96%) was obtained.

[0628] LCMS m / z = 283.4[M+H] + 。

[0629] Step 10: Compound 2F (90.5 mg, 0.26 mmol) and compound 73J-1 (146 mg, 0.52 mmol) were successively dissolved in dimethyl sulfoxide (2 mL). 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 and reacted for 5 hours. After complete reaction, it was cooled to room temperature, water (2 mL) was added, and it was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (ethyl acetate:methanol (v / v) = 9:1) to obtain 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%).

[0630] Compound 73 isomer 1: 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 - 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). LCMS m / z = 596.2[M + H] + .

[0631] Compound 73 isomer 2: 1 H NMR (400 MHz, CDCl 3) δ 7.35 - 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). LCMS m / z = 596.2 [M + H] + .

[0632] Referring to the above operations, using compound 73J - 2 (142 mg, 0.50 mmol) as the raw material, 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%) were obtained. Compound 73 isomer 3: 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 - 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, 3H), 1.77 - 1.63 (m, 2H), 1.58 - 1.51 (m, 2H), 1.50 - 1.48 (m, 3H), 1.40 (s, 3H). LCMS m / z = 596.2 [M + H] + .

[0633] Compound 73 isomer 4: 1 H NMR (400 MHz, CDCl 3) δ 7.36 - 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). LCMS m / z = 596.2 [M + H] + . Example 74: [Chemical formula]

[0634] Step 1: Dissolve compound 74A (50.0 g, 253.46 mmol) in dichloromethane (1000 mL), add selenium oxide (14.06 g, 126.73 mmol), cool the temperature to 0 - 5 °C after addition, slowly dropwise add t-butyl hydroperoxide (81.58 g, 633.65 mmol, 70% aqueous solution), control the temperature at 0 - 5 °C after the addition is complete, and react for 15 hours. After the reaction is complete, slowly dropwise add saturated aqueous sodium bisulfite solution (300 mL), after quenching, separate the layers, extract the aqueous phase with dichloromethane (150 mL × 2), wash the combined organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and then separate the residue by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to obtain compound 74B (25.0 g, 46.2%).

[0635] Step 2: Under a nitrogen gas atmosphere, compound 74B (25.0 g, 117.24 mmol) was dissolved in toluene (250 mL), the temperature was controlled at 25 - 30 °C, 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 h, and 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 h. After the reaction was complete, the temperature was lowered to 0 - 5 °C, and saturated ammonium chloride aqueous solution (100 mL) was slowly added dropwise to quench the reaction. After quenching, filtration was carried out, and the filtrate was extracted with ethyl acetate (100 mL × 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%).

[0636] Step 3: Compound 74C (23.00 g, 101.19 mmol) was dissolved in dichloromethane (250 mL), the temperature was lowered to 0 °C, Dess - Martin periodinane (85.84 g, 202.38 mmol) was added little by little. After the addition was complete, the temperature was raised to room temperature and the reaction was carried out for 2 h. After the reaction was complete, saturated sodium bicarbonate aqueous solution (200 mL) was added to quench the reaction. After quenching, filtration was carried out through diatomaceous earth, the filtrate was extracted and separated, the aqueous phase was extracted with dichloromethane (100 mL × 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%).

[0637] Step 4: Under a nitrogen gas atmosphere, dissolve triethylphosphorylacetate (43.79 g, 195.32 mmol) in tetrahydrofuran (200 mL), control the temperature to 0 - 5 °C, add sodium hydride (5.86 g, 146.5 mmol, 60% content) portionwise, and continue stirring for 0.5 h after addition. Then, dropwise add a solution of compound 74D (22.00 g, 97.66 mmol) in tetrahydrofuran (100 mL). After the addition is complete, allow the temperature to rise to room temperature naturally and react for 1 h. After the reaction is complete, add saturated aqueous ammonium chloride solution (100 mL) to quench the reaction. After quenching, extract with ethyl acetate (150 mL × 2). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and separate the residue by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 4:1) to obtain compound 74E (25.0 g, 86.7%).

[0638] Step 5: Dissolve compound 74E (25.0 g, 84.64 mmol) in methanol (250 mL), add Lindlar catalyst (9.01 g, 5% Pd content), and react under a hydrogen gas atmosphere for 3 h. After the reaction is complete, filter, concentrate the filtrate to obtain a crude product of compound 74F (23.0 g, 91.3%), and use it directly in the next step reaction without further purification.

[0639] Step 6: Under a nitrogen gas 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 controlled below -70 °C and the reaction was continued for 0.5 h. Paraformaldehyde (23.22 g, 773.33 mmol) was added little by little. After the addition was complete, the temperature was slowly raised to room temperature and the reaction was continued for 15 h. After the reaction was complete, saturated ammonium chloride aqueous solution (300 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (150 mL × 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%).

[0640] Step 7: Under a nitrogen gas atmosphere, compound 74G (17.0 g, 51.92 mmol) was dissolved in tetrahydrofuran (200 mL), cooled to 0 - 5 °C, and lithium aluminum hydride (3.94 g, 103.84 mmol) was added little by little. After the addition was complete, the temperature was controlled at 0 - 5 °C and the reaction was carried out for 2 h. After the reaction was complete, the temperature was controlled at 0 °C, and water (4.0 mL) was slowly added dropwise. After the addition was complete, stirring was carried out for 10 min, and 15% aqueous sodium hydroxide solution (4.0 mL) was continuously added dropwise. After the addition was complete, stirring was carried out for 10 min, then water (12.0 mL) was added dropwise again. After the addition was complete, anhydrous magnesium sulfate was added, and stirring was carried out for 1 h. 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%).

[0641] Step 8: Dissolve compound 74H (11.0 g, 38.55 mmol) in dichloromethane (200 mL), add 4-dimethylaminopyridine (18.84 g, 154.2 mmol), cool the temperature to 0 - 5 °C, add p-toluenesulfonyl chloride (22.05 g, 115.66 mmol) little by little. After the addition is complete, cool the temperature to room temperature and react for 1 hour. After the reaction is completed, add water to quench the reaction. After quenching, extract with ethyl acetate (100 mL × 2). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate the residue by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain compound 74I (19.1 g, 83.5%).

[0642] Step 9: Dissolve compound 74I (19.1 g, 32.17 mmol) in acetonitrile (200 mL), add benzylamine (10.34 g, 96.51 mmol), and heat the temperature to 80 °C and react for 15 hours. After the reaction is completed, concentrate, and separate the residue by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain the racemate of compound 74J. Separate the racemate by chiral preparative HPLC to obtain 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%).

[0643] HPLC analysis method: 1. Instrument: SHIMADZU LC-30AD SFC; 2. Chromatography column: Chiralcel OX-3 50×4.6 mm I.D., 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.

[0644] Conditions for preparative chromatography separation: 1. Instrument: Waters 150 SFC; 2. Chromatography column: Chiralpak OX - Column (250×30 mm, I.D 30 mm, 10 μm particle size); 3. Mobile phase system: A for CO 2 and B for MeOH + ACN (0.1% NH 3 ·H 2 O); 4. Gradient: B 20%; 5. Flow rate: 100 mL / min; 6. Elution time: 5.2 min.

[0645] 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, it was concentrated, and the residue was dissolved in dichloromethane (50 mL). An aqueous solution of saturated sodium bicarbonate was added to adjust the pH to 7 - 8, followed by extraction, liquid separation. The aqueous phase was extracted with dichloromethane (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product of compound 74K-1 (0.68 g, 94.3%), which was directly used in the reaction of the next step without further purification.

[0646] Referring to the above operation, using compound 74J-2 (1.0 g, 3.09 mmol) as the raw material, the title compound 74K-2 (0.73 g, 92.1%) was obtained.

[0647] Step 11: Compound 74K-1 (0.68 g, 2.65 mmol) and 3-oxo-1-methyl-cyclobutanecarboxylic acid (0.41 g, 3.21 mmol) were successively 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 little by little, and after completion of the addition, the reaction was carried out for 1 hour. After completion of the reaction, it was concentrated, and the residue was separated and purified by a reverse-phase column (0.2% aqueous trifluoroacetic acid: acetonitrile (v / v) = 5:95 - 95:5) to obtain the trifluoroacetate of the title compound 74L-1 (1.0 g, 63.26%).

[0648] With reference to the above operation, using compound 74K-2 (0.73 g, 2.85 mmol) as the raw material, the trifluoroacetate of the title compound 74L-2 (1.1 g, 64.7%) was obtained.

[0649] M / Z (ESI): m / z = 369.2 [M+H] + 。

[0650] Step 12: Compound 74L-1 (1.0 g, 1.68 mmol) was dissolved in methanol (10 mL), Pd / C (0.18 g, Pd content 10%) was added, and the reaction was carried out for 15 hours under a hydrogen gas atmosphere. After filtration and concentration of the filtrate, the crude product of compound 74M-1 (0.80 g, 94.0%) was obtained and used directly in the reaction of the next step without further purification.

[0651] With reference to the above operation, using compound 74L-2 (11 g, 1.84 mmol) as the raw material, the trifluoroacetate of the title compound 74M-2 (0.85 g, 91.2%) was obtained.

[0652] M / Z (ESI): m / z = 279.2 [M+H] + 。

[0653] Step 13: Compound 66G (90.0 mg, 0.23 mmol) and compound 74M-1 (233.0 mg, 0.46 mmol) were successively dissolved in dimethyl sulfoxide (5 mL). N,N-Diisopropylethylamine (0.12 g, 0.93 mmol) and cesium fluoride (70 mg, 0.46 mmol) were added. After addition, the temperature was raised to 100 °C and the reaction was carried out for 5 hours. After completion of the reaction, it 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, filtered, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (ethyl acetate:methanol (v / v) = 10:1) to obtain 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%).

[0654] Compound 74 isomer 1: 1 H NMR (400 MHz, CD 3 OD) δ 7.32 (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). M / Z (ESI): m / z = 630.0 [M + H] + 。

[0655] Compound 74 isomer 2: 1 H NMR (400 MHz, CD 3OD) δ 7.32 (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). M / Z (ESI): m / z = 630.0 [M + H] + .

[0656] Referring to the above operations, using Compound 66G (90.0 mg, 0.23 mmol) and Compound 74M-2 (233.0 mg, 0.46 mmol) as raw materials, 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%) were obtained.

[0657] Compound 74 isomer 3: 1 H NMR (400 MHz, CD 3 OD) δ 7.32 (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). M / Z (ESI): m / z = 630.0 [M + H] + .

[0658] Compound 74 Isomer 4: 1 H NMR (400 MHz, CD 3 OD) δ 7.32 (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). M / Z (ESI): m / z = 630.0 [M + H] + . Example 75: [Chemical formula]

[0659] Step 1: Dissolve compound 75A (10.0 g, 48.2 mmol) in dichloromethane (200 mL). Add imidazole (4.59 g, 67.5 mmol) and t-butyldimethylchlorosilane (9.45 g, 62.7 mmol) sequentially at 0 °C. After addition, stir continuously at 0 °C for 30 minutes, then warm to room temperature and stir overnight to allow the reaction to proceed. After monitoring the disappearance of the starting material by TLC, add water (200 mL) to quench the reaction. Extract the aqueous phase with dichloromethane (50 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate. Then purify the resulting crude product by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 100:0 - 90:10) to obtain compound 75B (15.1 g, 97.4%).

[0660] Step 2: Under nitrogen gas protection, compound 75B (8.00 g, 24.9 mmol), (R)-1-(2,4-dichlorophenyl)ethan-1-amine (5.20 g, 27.4 mmol), palladium acetate (558 mg, 2.49 mmol), 1,1'-binaphthyl-2,2'-diphenylphosphino (2.32 g, 3.73 mmol), and sodium t-butoxide (3.58 g, 37.3 mmol) were successively added to dry toluene (150 mL). The temperature was raised to 110 °C and the reaction was carried out for 3 hours. After monitoring the disappearance of the starting materials by TLC, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate (100 mL × 5), and the filtrate was concentrated. Then, it was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 85:15) to obtain compound 75C (8.48 g, 79.1%).

[0661] LC-MS (ESI): m / z = 430.1 [M + H] + 。

[0662] Step 3: Compound 75C (8.48 g, 19.7 mmol) was dissolved in dry tetrahydrofuran (100 mL), and tetrabutylammonium fluoride (29.5 mL, 29.5 mmol, 1 moL in THF) was added at 0 °C. After the addition was complete, the temperature was raised to room temperature and stirring was continued for 30 minutes. After monitoring the disappearance of the starting materials by TLC, saturated aqueous ammonium chloride solution (100 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (50 mL × 4), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Then, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 80:20) to obtain compound 75D (6.10 g, 97.9%).

[0663] LC-MS (ESI): m / z = 316.1 [M + H] + 。

[0664] 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 sequentially added at 0 °C. After the addition was complete, stirring was continued at 0 °C for 2 hours. After monitoring the disappearance of the starting material by TLC, water (200 mL) was added to quench the reaction. The aqueous phase was extracted with dichloromethane (50 mL × 3). 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) = 90:10) to obtain Compound 75E (4.27 g, 86.1%).

[0665] LC-MS (ESI): m / z = 448.0 [M + H] + 。

[0666] Step 5: Under nitrogen gas protection, Compound 75E (1.50 g, 3.34 mmol), tert-butyl 3-ethynylpiperidine-1-carboxylate (1.06 g, 5.01 mmol), bis(triphenylphosphine)palladium(II) dichloride (235 mg, 0.334 mmol), cuprous iodide (318 mg, 1.67 mmol), and triphenylphosphine (175 mg, 0.669 mmol) were sequentially added to a mixed solvent of dry N,N-dimethylformamide (20 mL) and triethylamine (8 mL). The temperature was raised to 100 °C and the reaction was carried out overnight. After monitoring by TLC that the starting material had completely disappeared and cooling to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 90:10) to obtain a mixture of 75F and 75G (1.55 g, 91.2%). The above mixture was separated by preparative chiral HPLC to obtain Compound 75F (624 mg, 36.7%) and Compound 75G (694 mg, 40.8%).

[0667] HPLC analysis conditions: 1. Instrument: SHIMADZU LC-30AD SFC; 2. Chromatography column: Chiralcel OX-3 50×4.6 mm I.D., 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. For compound 75F, retention time 2.11 min; for compound 75G, retention time 2.24 min.

[0668] Chiral separation method: Instrument: Waters 150 MGM; Chromatography column: Chiralpak Column; Mobile phase: A: carbon dioxide and B: methanol (0.1% aqueous ammonia); Isocratic elution: 35% mobile phase B; Flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: 25 °C; Wavelength: 220 nm.

[0669] LC-MS (ESI): m / z = 507.1 [M+H] + ; Step 6: Dissolve compound 75F (200 mg, 0.394 mmol) in dichloromethane (9 mL), add trifluoroacetic acid (3 mL) at room temperature, and continue to react for 1 hour after addition. After monitoring the completion of the reaction by TLC, concentrate to obtain the crude trifluoroacetate of 75H and directly proceed to the next step of the reaction without purification.

[0670] LC-MS (ESI): m / z = 407.1 [M+H] + ; Using 75G as the raw material, referring to the above synthesis method, compound 75I was obtained.

[0671] Step 7: The crude trifluoroacetate of compound 75H obtained in the previous step was dissolved in methanol (30 mL), and compound 2B (101 mg, 0.788 mmol) and acetic acid (23.7 mg, 0.394 mmol) were sequentially added. After stirring at room temperature for 1 hour, sodium cyanoborohydride (74.2 mg, 1.18 mmol) was added, and stirring was continued for 1 hour. After monitoring the completion of the reaction by TLC, water (1 mL) was added to quench the reaction, and it was directly concentrated under reduced pressure. The residue was purified by preparative silica gel plate (ethyl acetate:methanol (v / v) = 90:10) to obtain compound 75 isomer 1 (70 mg, 2-step yield 34.2%) and compound 75 isomer 2 (88 mg, 2-step yield 43.0%) respectively.

[0672] Compound 75 isomer 1: R f = 0.60 (ethyl acetate:methanol (v / v) = 90:10), 1 1H NMR (400 MHz, DMSO-d 6 ) δ 12.15 (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 - 5.87 (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). LC-MS (ESI): m / z = 519.1 [M + H] + Compound 75 isomer 2: R f = 0.40 (ethyl acetate:methanol (v / v) = 90:10), 1 1H NMR (400 MHz, DMSO-d 6) δ 7.63 - 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). LC-MS (ESI): m / z = 519.1 [M + H] + ; Using 75I as the raw material and referring to the above synthetic method, 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.

[0673] Compound 75 isomer 3: R f = 0.65 (ethyl acetate: methanol (v / v) = 90:10), 1 1H NMR (400 MHz, DMSO-d 6 ) δ 12.14 (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). LC-MS (ESI): m / z = 519.1 [M + H] + ; Compound 75 isomer 4: R f = 0.50 (ethyl acetate: methanol (v / v) = 90:10), 1 1H NMR (400 MHz, DMSO-d 6) δ 7.62-7.61 (d, 1H), 7.50-7.49 (d, 1H), 7.43-7.37 (m, 1H), 7.23-7.22 (d, 1H), 6.63 - 6.51 (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...

Claims

1. A compound represented by formula (I), a stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal thereof, wherein 【Chemical 1】 wherein Ring A is selected from a 6-membered heteroaryl group, a 9- to 10-membered bicyclic heteroaryl group, a 6- to 10-membered aryl group, and a 9- to 10-membered bicyclic heterocycloalkyl group; Ring B is selected from a phenyl group, an 8- to 10-membered aryl group, a 5- to 6-membered heteroaryl group, and an 8- to 10-membered heteroaryl group; The D ring is -Cy2-Cy3-#, -L １ -Cy2-Cy3-#, -Cy2-L １ -#, -L １ -Cy2-#, -L １ -Cy3-#, Cy4, -L １ selected from -Cy4-#, where # represents the connecting site between the D ring and the A ring Cy2 is selected from a 4- to 7-membered monocyclic heteroalkyl group, a 7- to 10-membered bridged heteroalkyl group, a 7- to 10-membered spiroheteroalkyl group, an 8- to 10-membered fused heteroalkyl group, a 6- to 7-membered cycloalkyl group, and a phenyl group, and said Cy2 is optionally substituted with 1 to 3 groups selected from =O, halogen, deuterium, CN, OH, C １－４ alkyl group, halogenated C １－４ alkyl group, deuterated C １－４ alkyl group, C １－４ alkoxy group, halogenated C １－４ alkoxy group, deuterated C １－４ alkoxy group, and NH ２ and is substituted with 1 to 3 groups selected therefrom. Cy3 is selected from a 4- to 7-membered monocyclic heteroalkyl group, a 7- to 10-membered spiroheterocycloalkyl group, a 5- to 6-membered heteroaryl group, a 6- to 10-membered fused heterocycloalkyl group, and a phenyl group, and the Cy3 is optionally substituted with 1 to 3 groups selected from =O, halogen, deuterium, CN, OH, C １－４ alkyl group and NH ２ and is substituted with 1 to 3 groups selected therefrom, Cy4 is selected from a 7- to 10-membered bridged heterocycloalkyl group, a 7- to 10-membered spiroheterocycloalkyl group, and an 8- to 10-membered fused heterocycloalkyl group; L １ is selected from a bond, C １－６ alkylene group, C ２－６ alkenylene group, C ２－６ alkynylene group, -C(=O)-, m, p, q, and t are each independently selected from 0, 1, 2, 3, 4, and 5; R １ 、R ２ａ 、R ２ｂ are each independently selected from H, deuterium, C １－４ alkyl group, halogenated C １－４ alkyl group, deuterated C １－４ alkyl group, R ３ is -Cy1-R ３ａ R ３ａ is selected from Cy1 is selected from a 3- to 10-membered cycloalkyl group and a 4- to 10-membered heterocycloalkyl group, and the cycloalkyl group and the heterocycloalkyl group are optionally C １－６ alkyl group, halogen, deuterium, cyano group, nitro group, OH, halogenated C １－６ alkyl group, deuterated C １－６ alkyl group and are further substituted with 1 to 3 groups selected therefrom, R ３ａ is selected from -COOH, COOC １－６ alkyl group, -P(O)(OH)OH, -P(O)(OH)H, hydroxy C １－６ alkyl group, -C １－６ alkyl group -COOH, 5- to 6-membered heteroaryl group, 5- to 6-membered heterocycloalkyl group, and the heteroaryl group and heterocycloalkyl group are optionally further substituted with 1 to 3 groups selected from =O, C １－６ alkyl group, halogen, deuterium, cyano group, nitro group, OH, halogenated C １－６ alkyl group, deuterated C １－６ alkyl group, and R ４ is selected from deuterium, halogen, cyano group, nitro group, OH, amino group, SF ５ , N ３ , C １－６ alkyl group, halogenated C １－６ alkyl group, deuterated C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ alkoxy group, halogenated C １－６ alkoxy group, deuterated C １－６ alkoxy group, -C(=O)R ４ａ and is selected from R ４ａ is selected from deuterium, halogen, OH, amino group, C １－６ alkyl group, and R ６ 、R ６ａ are each independently deuterium, a halogen, a cyano group, a nitro group, OH, an amino group, SF ５ 、N ３ 、C １－６ alkyl group, halogenated C １－６ alkyl group, deuterated C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ alkoxy group, halogenated C １－６ alkoxy group, deuterated C １－６ alkoxy group, and are selected from As one option, two Rs ６ together with the atoms connecting thereto form a 5- to 6-membered cycloalkenyl group, and said cycloalkenyl group is optionally substituted with 1 to 5 Rs ６ａ selected, As one option, R ４ and R １ together with the atoms connecting thereto form a 5- to 6-membered heteroaryl group or a 5- to 6-membered heterocycloalkyl group, As one option, R １ and R ６ together with the atoms connecting thereto form a 5- to 6-membered heterocycloalkyl group, As one option, R ２ａ and R ６ together with the atoms connecting to them form a 5- to 6-membered cycloalkyl group, As an option, R １ and R ２ａ together with the atoms connecting thereto form a 4- to 6-membered heterocycloalkyl group, As one option, R on the same carbon atom or different carbon atoms ２ａ and R ２ｂ together with the atoms to which they are attached form a 3-membered cycloalkyl group or a 4- to 6-membered cycloalkyl group, As an alternative, two Rs on adjacent ring atoms ４ and the atoms attached thereto together form a C ４－６ cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group is optionally deuterium, halogen, C １－６ alkyl group, cyano group, OH, amino group, SF ５ , N ３ , halogenated C １－６ alkyl group, deuterated C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ alkoxy group, halogenated C １－６ alkoxy group, deuterated C １－６ alkoxy group and COC １－６ alkyl group, and the compound represented by formula (I), its stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals, which are further substituted with 1 to 3 groups selected from

2. The compound has a structure represented by formula (I-1), (I-1a), (I-1b), (I-1c), (I-1d), (I-1e), (I-1f), (I-1g), provided that 【Chemical Formula 2】 the ring is （１） 【Chemical Formula 3】 not 【Chemical 4】 and in formula (I-1h), 【Chemical Formula 5】 the ring is 【Chemical Formula 6】 not 【Chemical Formula 7】 and Cy2 is not 【Chemical 8】 and 【Chemical Formula 9】 in formula (I-1d), the ring is selected from wherein 【Chemical Formula 10】 represents being linked to the right side, 【Chemical 11】 represents being linked to the left side. The compound represented by formula (I) according to claim 1, a stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal thereof.

3. The compound has a structure represented by formula (I-2a), (I-2b), (I-2c), (I-2d), (I-2), provided that ring D is not selected from 【Chemical 12】 wherein 【Chemical 13】 represents being linked to the right side, 【Chemical 14】 represents being linked to the left side. The compound represented by formula (I) according to claim 1, a stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal thereof. 【Chemical Formula 15】

4. The compound has a structure represented by formula (I-3), (I-3a): wherein 【Chemical 16】 is not selected from wherein 【Chemical 17】 is 【Chemical Formula 18】 The compound represented by formula (I) according to claim 1, a stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal thereof.

5. The compound has a structure of formula (I-4): 【Chemical 19】 The compound represented by formula (I) according to claim 1, a stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt or co-crystal thereof. The ring is selected from

6. 【Fig. 20】 wherein 【Chemical 21】 represents being linked to the right side, represents being linked to the left side, 【Chemical 22】 wherein 【Chemical 23】 ​ As one option, R ４ , R １ , together with the atoms linked thereto, together with ring A 【Chemical Formula 24】 The compound represented by formula (I) according to claim 1, its stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals, which form

7. 【Fig. 25】 The ring is 【Chemical 26】 selected from As one option, R １ , R ６ , together with the atoms connected to them, together with ring B 【Chemical 27】 forms As one option, R ２ａ , R ６ , together with the atoms connecting to them, together with ring B 【Chemical Formula 28】 The compound represented by formula (I) according to claim 1, its stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals, which form

8. The D ring is selected from -Cy2-Cy3-#, -Cy2-L １ -#, -L １ -Cy2-#, Cy4, where # represents the linking site between the D ring and the A ring Cy2 is selected from a 4- to 7-membered monocyclic heteroalkyl group, a 7- to 10-membered bridged heteroalkyl group, a 7- to 10-membered spiroheteroalkyl group, an 8- to 10-membered fused heteroalkyl group, a 6- to 7-membered cycloalkyl group, and a phenyl group, and the Cy2 is optionally substituted with one to three groups selected from =O, halogen, deuterium, CN, OH, C １－４ alkyl group, halogenated C １－４ alkyl group, deuterated C １－４ alkyl group, C １－４ alkoxy group, and NH ２ and is substituted with one to three groups selected therefrom, Cy3 is selected from a 4- to 7-membered monocycloheteroalkyl group, a 5- to 6-membered heteroaryl group, a 6- to 10-membered fused cycloheteroalkyl group, and a phenyl group, and the Cy3 is optionally substituted with 1 to 3 groups selected from =O, halogen, deuterium, CN, OH, C １－２ alkyl group, and NH ２ and is substituted with 1 to 3 groups selected therefrom, L １ is a compound represented by formula (I) according to claim 1, a stereoisomer thereof, a deuteride, a solvate, or a pharmaceutically acceptable salt or co-crystal, selected from a methylene group, an ethylene group, a vinylene group, an ethynylene group, and -C(=O)-.

9. The Cy2 ring is 【Chemical formula 29】 selected from The Cy3 ring is 【Chemical Formula 30】 selected from The Cy4 ring is 【Chemical 31】 selected from L １ is selected from a methylene group, an alkynylene group, and -C(=O)-, where 【Chemical Formula 32】 represents being connected to the right side, 【Chemical 33】 represents being connected to the left side, the compound represented by formula (I) according to claim 1, its stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals

10. The D ring is 【Chemical 34】 selected from where 【Chemical 35】 represents being connected to the right side, 【Chemical 36】 represents being connected to the left side, the compound represented by formula (I) according to claim 1, its stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals

11. Cy1 is selected from a 3- to 6-membered monocyclic cycloalkyl group, a 7- to 10-membered bicyclic cycloalkyl group, a 4- to 6-membered monocycloheteroalkyl group, and a 7- to 10-membered bicyclic cycloheteroalkyl group, and the cycloalkyl group and the cycloheteroalkyl group are optionally １－４ substituted with 1 to 3 groups selected from a C １－４ alkyl group, a halogen, deuterium, a cyano group, a nitro group, OH, a C １－４ haloalkyl group, and a C R ３ is 【Chemical 37】 selected from, the compound represented by formula (I) according to claim 1, its stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals

12. The compound is one selected from the structures in Table 1, the compound according to claim 1, its stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals

13. The compound is one selected from the structures in Table 2, the compound according to claim 1, its stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals

14. A pharmaceutical composition or pharmaceutical preparation containing the compound according to any one of claims 1 to 13, its stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals, and a pharmaceutically acceptable carrier and / or excipient

15. The pharmaceutical composition or pharmaceutical preparation according to claim 1, containing 1 to 1500 mg of the compound according to any one of claims 1 to 13, its stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals and a carrier and / or excipient

16. Use of the compound according to any one of claims 1 to 13, its stereoisomers, deuterides, solvates, or pharmaceutically acceptable salts or co-crystals, or the composition according to claim 14 or 15, in the manufacture of a medicament for the treatment / prevention of CCR4-mediated diseases

17. The use according to claim 16, wherein the CCR4-mediated disease is selected from tumors or inflammation.

18. A method for treating a mammalian or human disease, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 13, a stereoisomer thereof, a deuteride, a solvate, or a pharmaceutically acceptable salt or cocrystal, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is preferably a tumor or inflammation.

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