Compound containing pyrazole ring and bicyclic heteroaryl group, pharmaceutical composition thereof and use thereof

Abstract

The present disclosure belongs to the field of pharmaceutical chemistry, and relates to a compound containing a pyrazole ring and a bicyclic heteroaryl group, with the structure as shown in formula (I). The present application also relates to a method for preparing the compound, a pharmaceutical composition containing the compound, and the use thereof in the treatment of related diseases (such as cancer or immune diseases).

Description

Compounds containing pyrazole rings and bicyclic heteroaryl groups, pharmaceutical compositions and uses thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This disclosure claims the benefit of and priority to the following three Chinese invention patent applications, the entire contents of which are hereby incorporated by reference in their entirety:

[0003] Chinese invention patent application No. CN202311716882.7 filed with the State Intellectual Property Office of China on December 13, 2023,

[0004] Chinese invention patent application No. CN202411548739.6 filed with the State Intellectual Property Office of China on November 1, 2024, and

[0005] Chinese invention patent application No. CN202411799022.9 submitted to the State Intellectual Property Office of China on December 9, 2024. Technical Field

[0006] The present disclosure belongs to the field of medicinal chemistry and relates to a compound containing a pyrazole ring and a bicyclic heteroaryl group, a preparation method thereof, a pharmaceutical composition containing the compound, and its use in treating related diseases (such as cancer or immune diseases). Background Art

[0007] Bruton's tyrosine kinase (BTK) is primarily expressed in B cells and distributed throughout the lymphatic, hematopoietic, and blood systems. It is a member of the Tec family of non-receptor tyrosine kinases, which also includes TEC, ITK / TSK / EMT, and BMX, sharing a high degree of structural homology. BTK plays a crucial role in the B cell signaling pathway, linking cell surface B-cell receptor stimulation to downstream intracellular responses. It is a key regulator of B cell development, activation, signaling, and survival. Recent studies on B cells, particularly in B cell non-Hodgkin's lymphoma and rheumatoid arthritis, have revealed that BTK is often abnormally expressed.

[0008] The development of small molecule targeted drugs based on the BTK signaling pathway offers a novel approach for the treatment of B-cell tumors such as leukemia, multiple myeloma, and B-cell immune diseases. Currently available irreversible inhibitors, such as ibrutinib, often mutate at their BTK binding sites, leading to decreased drug activity and the development of drug resistance. Therefore, more BTK inhibitors with high selectivity for BTK are clinically needed to avoid toxic side effects caused by off-target effects.

[0009] Detailed Description of the Invention

[0010] The present application relates to a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0011] in,

[0012] Y 1 and Y 2 are each independently selected from CH or N;

[0013] Ring A or Ring B is each independently selected from phenyl or 5-6 membered heteroaryl;

[0014] Ring C is selected from 6-12 membered aryl, 4-12 membered heterocyclyl or 5-12 membered heteroaryl;

[0015] Each R 1 are each independently selected from deuterium, hydroxyl, amino, cyano, nitro, halogen, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 haloalkylamino;

[0016] Each R 2 are independently selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, hydroxyl C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 haloalkylamino;

[0017] Each R 3 are independently selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C1-6 Alkylamino, C 2-8 Alkenyl, or C 2-8 Alkynyl, the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 2-8 Alkenyl, or C 2-8 Alkynyl is optionally substituted with one or more R 3a replace;

[0018] Each R 3a are each independently selected from deuterium, hydroxyl, halogen, amino, cyano, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, 3-6 membered cycloalkyl, or 4-6 membered heterocyclic group, the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, 3-6 membered cycloalkyl, or 4-6 membered heterocyclic group are optionally replaced by one or more R 3aa replace;

[0019] Each R 3aa are each independently selected from deuterium, hydroxyl, halogen, amino, cyano, =O, C 1-6 Alkyl, C 1-6 Alkoxy, -N(C 1-6 Alkyl)2, -NHC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl, or 4-6 membered heterocyclyl;

[0020] Each R is independently selected from 3-12 membered cycloalkyl, 4-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and the 3-12 membered cycloalkyl, 4-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl are optionally replaced by one or more R a replace;

[0021] Each R a are each independently selected from deuterium, hydroxyl, halogen, amino, cyano, =O, -N(C 1-6 Alkyl)2, -NHC 1-6 Alkyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, amino C 1-6Alkyl, C 1-6 Alkoxy C 1-6 Alkylene, deuterated C 1-6 Alkoxy C 1-6 Alkylene, halogenated C 1-6 Alkoxy C 1-6 Alkylene, C 1-6 Alkylamino C 1-6 Alkylene, di-C 1-6 Alkylamino C 1-6 Alkylene, C 1-6 Alkylthio C 1-6 Alkylene, 3-6 membered cycloalkyl, 4-6 membered heterocyclic group, 3-6 membered cycloalkyl C 1-6 Alkylene, or 4-6 membered heterocyclic group C 1-6 alkylene;

[0022] L1 is selected from a bond, -C 1-6 Alkylene-, -C(O)NHC 1-6 Alkylene-, -NHC(O)C 1-6 Alkylene-, or -NHC 1-6 Alkylene-, the-C 1-6 Alkylene-, -C(O)NHC 1-6 Alkylene-, -NHC(O)C 1-6 Alkylene-, or -NHC 1-6 Alkylene-optionally substituted with one or more radicals selected from deuterium, hydroxy, halogen, amino, cyano, =O, or C 1-6 Alkyl radical substitution;

[0023] L2 is selected from a bond, -NH-, -N(C 1-3 alkyl)-, -O-, or -S-;

[0024] m is selected from 0, 1, 2, 3, 4, 5 or 6;

[0025] n is selected from 0, 1, 2, 3, or 4;

[0026] p is selected from 0, 1, 2, 3, or 4;

[0027] q is selected from 0, 1, or 2;

[0028] The premise is that p+q≥1.

[0029] In some embodiments, the present application relates to a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0030] in,

[0031] Y 1 and Y 2 are each independently selected from CH or N;

[0032] Ring A or Ring B is each independently selected from phenyl or 5-6 membered heteroaryl;

[0033] Ring C is selected from 6-12 membered aryl, 4-12 membered heterocyclyl or 5-12 membered heteroaryl;

[0034] Each R 1 Each independently selected from hydroxy, amino, cyano, nitro, halogen, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 haloalkylamino;

[0035] Each R 2 Each independently selected from hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, hydroxyl C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 haloalkylamino;

[0036] Each R 3 Each independently selected from hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 The alkylamino group is optionally substituted with one or more R 3a replace;

[0037] Each R 3a Each independently selected from hydroxy, halogen, amino, cyano, =O, C1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, 3-6 membered cycloalkyl, or 4-6 membered heterocyclyl;

[0038] Each R is independently selected from 3-12 membered cycloalkyl, 4-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and the 3-12 membered cycloalkyl, 4-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl are optionally replaced by one or more R a replace;

[0039] Each R a Each independently selected from hydroxy, halogen, amino, cyano, =O, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkylene, C 1-6 Alkylamino C 1-6 Alkylene, di-C 1-6 Alkylamino C 1-6 Alkylene, C 1-6 Alkylthio C 1-6 Alkylene, 3-6 membered cycloalkyl, 4-6 membered heterocyclic group, 3-6 membered cycloalkyl C 1-6 Alkylene, or 4-6 membered heterocyclic group C 1-6 alkylene;

[0040] L1 is selected from a bond, -C 1-6 Alkylene-, -C(O)NHC 1-6 Alkylene-, -NHC(O)C 1-6 Alkylene-, or -NHC 1-6 Alkylene-, the-C 1-6 Alkylene-, -C(O)NHC 1-6 Alkylene-, -NHC(O)C 1-6 Alkylene-, or -NHC 1-6 Alkylene-optionally substituted by one or more groups selected from hydroxy, halogen, amino, cyano, =O, or C 1-6 Alkyl radical substitution;

[0041] L2 is selected from a bond, -NH-, -N(C 1-3 alkyl)-, -O-, or -S-;

[0042] m is selected from 0, 1, 2, 3, 4, 5 or 6;

[0043] n is selected from 0, 1, 2, 3, or 4;

[0044] p is selected from 0, 1, 2, 3, or 4;

[0045] q is selected from 0, 1, or 2;

[0046] The premise is that p+q≥1.

[0047] In some embodiments, Y 1 and Y 2 At least one is CH. In some embodiments, Y 1 CH, Y 2 is N. In some embodiments, Y 1 N, Y 2 In some embodiments, Y 1 and Y 2 All are CH.

[0048] In some embodiments, Ring A or Ring B is each independently selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyranyl, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, or isoxazolyl.

[0049] In some embodiments, Ring A or Ring B are each independently selected from phenyl, or 6-membered heteroaryl. In some embodiments, Ring A is selected from phenyl and Ring B is selected from 5-6-membered heteroaryl. In some embodiments, Ring A is selected from phenyl and Ring B is selected from 6-membered heteroaryl.

[0050] In some embodiments, Ring A is selected from phenyl, or pyridinyl. In some embodiments, Ring B is selected from phenyl, or pyridinyl.

[0051] In some embodiments, Ring A is selected from phenyl. In some embodiments, Ring B is selected from pyridinyl.

[0052] In some embodiments, Partially selected In some embodiments, Partially selected

[0053] In some embodiments, Partially selected In some embodiments, Partially selected In some embodiments, Partially selected

[0054] In some embodiments, ring C is selected from 6-10 membered aryl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl. In some embodiments, ring C is selected from phenyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl.

[0055] In some embodiments, ring C is selected from 6-12 membered aryl or 5-12 membered heteroaryl; in some embodiments, ring C is selected from 6-10 membered aryl or 5-6 membered heteroaryl. In some embodiments, ring C is selected from phenyl or 5-6 membered heteroaryl.

[0056] In some embodiments, Ring C is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or pyranyl.

[0057] In some embodiments, Ring C is selected from phenyl or pyridinyl. In some embodiments, Ring C is selected from pyridinyl.

[0058] In some embodiments, Partially selected In some embodiments, Partially selected In some embodiments, Partially selected In some embodiments, Partially selected

[0059] In some embodiments, Partially selected

[0060] In some embodiments, Partially selected

[0061] In some embodiments, Partially selected

[0062] In some embodiments, each R 1 Each independently selected from hydroxy, amino, cyano, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, or di-C 1-4 Alkylamino.

[0063] In some embodiments, each R 1 are each independently selected from halogen, C 1-6 Alkyl or C 1-6 In some embodiments, each R 1 are each independently selected from halogen, C 1-4 Alkyl or C 1-4 Alkoxy.

[0064] In some embodiments, each R1 Each is independently selected from hydroxy, amino, cyano, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoroethyl, dimethylamino, or diethylamino.

[0065] In other embodiments, each R 1 Each R is independently selected from fluoro, methyl or methoxy. 1 Each is independently selected from fluoro, or methoxy.

[0066] In some embodiments, each R 2 Each is independently selected from hydroxy, amino, cyano, halogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, or difluoromethyl.

[0067] In some embodiments, R 2 Selected from fluorine.

[0068] In some embodiments, each R 3 are independently selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, C 2-6 Alkenyl, or C 2-6 Alkynyl, the hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, C 2-6 Alkenyl, or C 2-6 Alkynyl is optionally substituted with one or more R 3a replace.

[0069] In some embodiments, each R 3 Each independently selected from amino, C 1-6 Alkyl or C 2-8 Alkenyl, the amino, C 1-6 Alkyl or C 2-8 The alkenyl group is optionally substituted with one or more R 3a In some embodiments, each R 3 Each independently selected from amino, C 1-4 Alkyl or C 2-6 Alkenyl, the amino, C 1-4 Alkyl or C 2-6 The alkenyl group is optionally substituted with one or more R 3a replace.

[0070] In some embodiments, each R 3 Each independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 The alkylamino group is optionally substituted with one or more R 3a In some embodiments, each R 3 Each independently selected from amino, C 2-6 Alkenyl, or C 2-6 Alkynyl, the amino, C 2-6 Alkenyl, or C 2-6 Alkynyl is optionally substituted with one or more R 3a replace.

[0071] In some embodiments, each R 3 are each independently selected from deuterium, cyano, fluorine, chlorine, bromine, or optionally substituted by one or more R 3a Substituted groups include: hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, tert-butyloxy, methylamino, ethylamino, dimethylamino, diethylamino, vinyl, propenyl, butenyl, pentenyl, propynyl, butynyl, and pentynyl.

[0072] In some embodiments, each R 3 Each independently selected from optionally one or more R 3a substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, tert-butyloxy, methylamino, ethylamino, dimethylamino, or diethylamino. 3 Each independently selected from optionally one or more R 3a Substituted groups include amino, or pentenyl.

[0073] In some embodiments, each R 3 are each independently selected from deuterium, cyano, fluorine, chlorine, or optionally substituted by one or more R 3aSubstituted: hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH=CH2, -CH2CH=CH2, -CH2CH2CH=CH2, -CH2CH=CHCH3, -CH2CH2CH2CH=CH2, -CH2CH2CH=CHCH3, or -CH2CH=CHCH2CH3.

[0074] In some embodiments, each R 3 Each independently selected from optionally one or more R 3a Substituted groups include amino, methyl, ethyl, n-propyl, or -CH2CH2CH2CH=CH2.

[0075] In some embodiments, each R 3a are independently selected from deuterium, halogen, cyano, =O, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, 3-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl, the hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, 3-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl are optionally substituted by one or more R 3aa replace.

[0076] In some embodiments, each R 3a Each independently selected from hydroxyl, halogen, C 1-6 Alkoxy, 3-6 membered cycloalkyl, or 4-6 membered heterocyclic group; the hydroxyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl, or 4-6 membered heterocyclic group are optionally substituted by one or more R 3aa replace.

[0077] In some embodiments, each R 3a Each independently selected from hydroxy, halogen, amino, cyano, =O, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, 3-6 membered cycloalkyl, or 4-6 membered heterocyclic group, the hydroxyl, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, 3-6 membered cycloalkyl, or 4-6 membered heterocyclic group are optionally replaced by one or more R 3aa replace.

[0078] In some embodiments, each R 3a Each independently selected from hydroxyl, halogen, C 1-4 Alkoxy, 3-6 membered cycloalkyl, or 4-6 membered heterocyclic group, the hydroxyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, or 4-6 membered heterocyclic group are optionally substituted by one or more R 3aa replace.

[0079] In some embodiments, each R 3a Each independently selected from hydroxy, halogen, amino, cyano, =O, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, 3-6 membered cycloalkyl, or 4-6 membered heterocyclic group.

[0080] In some embodiments, each R 3a each independently selected from hydroxy, halogen, amino, cyano, =0, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, piperidinyl, piperazinyl or morpholinyl, said hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, piperidinyl, piperazinyl or morpholinyl being optionally replaced by one or more R 3aa replace.

[0081] In some embodiments, each R 3a Each is independently selected from hydroxy, halogen, amino, cyano, =0, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, or morpholinyl.

[0082] In some embodiments, each R 3a are each independently selected from fluoro, hydroxy, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or piperidinyl, wherein the hydroxy, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or piperidinyl is optionally replaced by one or more R 3aa replace.

[0083] In some embodiments, each R 3aa are each independently selected from deuterium, hydroxyl, halogen, amino, cyano, =O, -N(C 1-3Alkyl)2, -NHC 1-3 Alkyl, C 1-3 alkyl, 3-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl.

[0084] In some embodiments, each R 3aa are each independently selected from deuterium, C 1-6 Alkyl, -N(C 1-6 alkyl) 2, or 3-6 membered cycloalkyl. In some embodiments, each R 3aa are each independently selected from deuterium, C 1-3 Alkyl, -N(C 1-3 alkyl) 2- or 3-6-membered cycloalkyl.

[0085] In some embodiments, each R 3aa are each independently selected from deuterium, halogen, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, or 3-5 membered cycloalkyl.

[0086] In some embodiments, each R 3aa Each is independently selected from deuterium, fluorine, -N(CH3)2, methyl, or cyclopropyl.

[0087] In some embodiments, each R 3a Each independently selected from hydroxy, fluoro, methoxy, ethoxy, -OCD3, cyclopropyl,

[0088] In some embodiments, each R is independently selected from optionally replaced by one or more R a substituted by: 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl. In some embodiments, each R is independently selected from optionally substituted by one or more R a Substituted groups include: 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl.

[0089] In some embodiments, each R is independently selected from a 4-12 membered heterocyclyl group, wherein the 4-12 membered heterocyclyl group is optionally replaced by one or more R a In some embodiments, each R is independently selected from a 4-8 membered heterocyclyl group, which is optionally replaced by one or more R a In some embodiments, each R is independently selected from a 4-6 membered heterocyclyl, which is optionally replaced by one or more R a replace.

[0090] In some embodiments, each R is independently selected from optionally replaced by one or more R a Substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, 1,4-dioxane, thiomorpholinyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or pyranyl.

[0091] In some embodiments, each R is independently selected from optionally replaced by one or more R a Substituted: 3-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl.

[0092] In some embodiments, each R is independently selected from optionally replaced by one or more R a Substituted 4-6 membered heterocycloalkyl.

[0093] In some embodiments, each R is independently selected from optionally replaced by one or more R a Substituted: piperidinyl or piperazinyl.

[0094] In some embodiments, each R a are each independently selected from deuterium, hydroxyl, halogen, amino, cyano, =O, -N(C 1-3 Alkyl)2, -NHC 1-3 Alkyl, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-3 Alkoxy C 1-3 Alkylene, deuterated C 1-3 Alkoxy C 1-3 Alkylene, halogenated C 1-3 Alkoxy C 1-3 Alkylene, C 1-3 Alkylamino C 1-3 Alkylene, di-C 1-3 Alkylamino C 1-3 Alkylene, C 1-3 Alkylthio C 1-3 Alkylene, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3-6 membered cycloalkyl C 1-3 Alkylene, or 4-6 membered heterocycloalkyl C 1-3 Alkylene.

[0095] In some embodiments, each R aEach independently selected from -N(C 1-6 Alkyl)2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkylene, deuterated C 1-6 Alkoxy C 1-6 In some embodiments, each R a Each independently selected from -N(C 1-3 Alkyl)2, C 1-3 Alkyl, deuterated C 1-4 Alkyl, C 1-3 Alkoxy C 1-3 Alkylene, deuterated C 1-3 Alkoxy C 1-3 In some embodiments, each R a Each independently selected from -N(C 1-3 Alkyl)2, C 1-3 Alkyl, deuterated C 1-4 Alkyl, C 1-3 Alkoxy C 1-3 Alkylene, deuterated C 1-3 Alkoxy C 1-3 alkylene, 3-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl.

[0096] In some embodiments, each R a Each independently selected from hydroxy, halogen, amino, -N(C 1-3 Alkyl)2, -NHC 1-3 Alkyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-3 Alkoxy C 1-3 Alkylene, deuterated C 1-3 Alkoxy C 1-3 Alkylene, halogenated C 1-3 Alkoxy C 1-3 alkylene, 3-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl.

[0097] In some embodiments, each R a Each independently selected from hydroxy, halogen, amino, cyano, =O, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, halogenated C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-3 Alkoxy C 1-3 Alkylene, C 1-3Alkylamino C 1-3 Alkylene, di-C 1-3 Alkylamino C 1-3 Alkylene, C 1-3 Alkylthio C 1-3 Alkylene, 3-6 membered cycloalkyl, 4-6 membered heterocyclic group, 3-6 membered cycloalkyl C 1-3 Alkylene, or 4-6 membered heterocyclic group C 1-3 Alkylene.

[0098] In some embodiments, each R a Each independently selected from C 1-3 Alkoxy C 1-3 Alkylene, C 1-3 Alkylamino C 1-3 Alkylene, di-C 1-3 Alkylamino C 1-3 alkylene, 3-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl.

[0099] In some embodiments, each R a Each is independently selected from 3-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl.

[0100] In some embodiments, each R a each independently selected from deuterium, hydroxyl, halogen, amino, cyano, =O, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxymethyl, hydroxyethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, pentafluoroethyl, trideuteriomethyl, dideuteriomethyl, monodeuteriomethyl, -CH2NH2, -CH2CH2NH2, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2OC D3, -CH2NHCH3, -CH2CH2NHCH3, -CH2N(CH3)2, -CH2CH2N(CH3)2, -CH2SCH3, -CH2CH2SCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, azetidinylmethyl, oxetanylmethyl, tetrahydrofuranylmethyl, tetrahydropyrrolylmethyl, tetrahydrothiophenylmethyl, piperidinylmethyl, piperazinylmethyl, or morpholinylmethyl.

[0101] In some embodiments, each R aeach independently selected from hydroxy, halogen, amino, cyano, =0, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxymethyl, hydroxyethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, pentafluoroethyl, aminomethyl, aminoethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methylaminomethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, methylthiomethyl , methylthioethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, azetidinylmethyl, oxetanylmethyl, tetrahydrofuranylmethyl, tetrahydropyrrolylmethyl, tetrahydrothiophenylmethyl, piperidinylmethyl, piperazinylmethyl, or morpholinylmethyl.

[0102] In some embodiments, each R a Each is independently selected from -N(CH3)2, methyl, trideuteromethyl, -CH2CH2OCH3, -CH2CH2OCD3, cyclopropyl, or oxetanyl.

[0103] In some embodiments, each R 3 Each independently selected from methyl,

[0104] In some embodiments, each R 3 Each independently selected from

[0105] In some embodiments, each R is independently selected from

[0106] In some embodiments, each R is independently selected from

[0107] In some embodiments, L1 is selected from a bond, -C 1-3 Alkylene-, -C(O)NHC 1-3 Alkylene-, -NHC(O)C 1-3 Alkylene-, or -NHC 1-3 Alkylene-, the-C 1-3 Alkylene-, -C(O)NHC 1-3 Alkylene-, -NHC(O)C 1-3 Alkylene-, or -NHC 1-3 Alkylene-optionally substituted by one or more groups selected from hydroxy, halogen, amino, cyano, =O, or C 1-3Alkyl groups are substituted.

[0108] In some embodiments, L1 is selected from -C(O)NHC 1-6 Alkylene-, or -NHC 1-6 Alkylene-.

[0109] In some embodiments, L1 is selected from a bond, -methylene-, -C(O)NHCH2-, -NHC(O)CH2-, or -NHCH2-.

[0110] In some embodiments, L1 is selected from -C(O)NHCH2- or -NHCH2-.

[0111] In some embodiments, L1 is selected from *-C(O)NHC 1-6 Alkylene-, *-NHC(O)C 1-6 Alkylene-, or *-NHC 1-6 Alkylene-, wherein * represents a In some embodiments, L1 is selected from *-C(O)NHC 1-6 Alkylene-, or *-NHC 1-6 Alkylene-, wherein * represents a Partially connected.

[0112] In some embodiments, L1 is selected from *-C(O)NHCH2-, or *-NHCH2-, wherein * represents a Partially connected.

[0113] In some embodiments, L2 is selected from -NH-.

[0114] In some embodiments, m is selected from 0, 1, 2, or 3.

[0115] In some embodiments, m is selected from 1 or 2.

[0116] In some embodiments, n is selected from 0, 1, or 2.

[0117] In some embodiments, n is 0.

[0118] In some embodiments, p is selected from 0, 1, 2, or 3.

[0119] In some embodiments, p is selected from 1 or 2.

[0120] In some embodiments, p is selected from 0 or 1.

[0121] In some embodiments, q is selected from 1 or 2.

[0122] In some embodiments, q is 1.

[0123] In some embodiments, the C 1-6 Alkyl or C 1-6 Alkylene is selected from C 1-4 Alkyl or C 1-4 In some embodiments, the C 1-4 Alkyl is selected from C 1-3 Alkyl or C 1-2 In some embodiments, the C 1-4 Alkylene is selected from C 1-3 Alkylene, C 1-2 Alkylene or methylene.

[0124] In some embodiments, the halo is selected from fluoro, chloro, bromo, or iodo. In some embodiments, the halo is selected from substituted with 1, 2, 3, 4, or 5 halogens.

[0125] In some embodiments, the deuterated substituent means that any number of H atoms present and replaceable on the substituent are replaced by deuterium atoms. For example, non-limiting examples of monodeuterated ethyl include but are not limited to: -CHD-CH3, -CH2-CH2D.

[0126] In some embodiments, the heteroaryl group contains 1, 2, 3, or 4 heteroatoms selected from N, O, or S. In some embodiments, the heteroaryl group contains 1, 2, 3, or 4 heteroatoms selected from N or O. In some embodiments, the heteroaryl group contains 1 N heteroatom.

[0127] In some embodiments, the heterocycloalkyl group contains 1, 2, 3, or 4 heteroatoms selected from N, O, or S. In some embodiments, the heterocycloalkyl group contains 1, 2, 3, or 4 heteroatoms selected from N or O. In some embodiments, the heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O. In some embodiments, the heterocycloalkyl group contains 2 heteroatoms selected from N.

[0128] In some embodiments, the heterocyclyl contains 1, 2, 3, 4, or 5 heteroatoms selected from N, O, or S. In some embodiments, the heterocyclyl contains 1, 2, 3, 4, or 5 heteroatoms selected from N or O. In some embodiments, the heterocyclyl contains 1, 2, 3, 4, or 5 heteroatoms selected from N or O. In some embodiments, the heterocyclyl contains 1, 2, or 3 heteroatoms selected from N or O. In some embodiments, the heterocyclyl contains 1 or 2 heteroatoms selected from N or O.

[0129] In some embodiments, the heterocyclyl is selected from heterocycloalkyl or unsaturated heterocyclyl.

[0130] In some embodiments, the heterocycloalkyl group includes a monocyclic, spirocyclic, or bridged ring.

[0131] In some embodiments, the cycloalkyl group includes a monocyclic, spirocyclic, or bridged ring.

[0132] In some embodiments, the heterocyclyl includes a monocyclic, spirocyclic, or bridged ring.

[0133] In some embodiments, the "one or more" is selected from one, two, three, four, five, or six. In some embodiments, the "one or more" is selected from one, two, three, or four. In some embodiments, the "one or more" is selected from one, two, or three. In some embodiments, the "one or more" is selected from one, or two.

[0134] In some embodiments, the "3-12 yuan" is selected from 4-12 yuan, 3-10 yuan, 5-10 yuan, 3-9 yuan, 3-8 yuan, 3-6 yuan, or 5-6 yuan. In some embodiments, the "4-12 yuan" is selected from 4-10 yuan, 5-10 yuan, 4-9 yuan, 4-8 yuan, 4-6 yuan, or 5-6 yuan. In some embodiments, the "6-10 yuan" is selected from 6-9 yuan, 6-8 yuan, and 6 yuan. In some embodiments, the "5-12 yuan" is selected from 5-10 yuan, 5-9 yuan, 5-8 yuan, or 5-6 yuan.

[0135] In some embodiments, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof is selected from the compound of formula (IA) or the compound of formula (II), the compound of formula (II-A), its stereoisomers or pharmaceutically acceptable salts thereof,

[0136] Among them, R 1 、m、L1、Y1、Y2、R 2 , n, L2, Ring A, Ring B, Ring C, R, q, R 3 , p are as defined herein, X1 and X2 are independently selected from CH or N. In some embodiments, X1 is selected from N, and X2 is selected from CH. In some embodiments, X1 is selected from CH, and X2 is selected from N.

[0137] In some embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is selected from the compound of formula (III-A) or the compound of formula (III-B), its stereoisomers, or pharmaceutically acceptable salts thereof,

[0138] Among them, R 1 ,m,R 2 ,n,L2,ring C,R,q,R 3, and p are defined as described in this disclosure.

[0139] It is to be understood that any of the embodiments of the compounds of the present disclosure as described above and the descriptions herein with respect to specific R in the compounds of the present disclosure as described above 1 、L1、Y1、Y2、R 2 , L2, Ring A, Ring B, Ring C, R and R 3 Any specific substituent described herein can be independently combined with other embodiments of the present disclosure and / or substituents of compounds to form embodiments of the present disclosure not specifically described above. 1 、L1、Y1、Y2、R 2 , L2, Ring A, Ring B, Ring C, R and R 3 Substituents Where a list of substituents is disclosed, it is understood that one or more substituents may be deleted from the list and the remaining list of substituents will be considered an embodiment of the disclosure.

[0140] The present application also relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof:

[0141] The present application also relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof:

[0142] In another aspect, the present application relates to a pharmaceutical composition comprising the compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient.

[0143] On the other hand, the present application relates to a method for treating a BTK-related disease in an individual (e.g., a mammal), comprising administering a therapeutically effective amount of a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to an individual (e.g., a mammal, preferably a human) in need of such treatment.

[0144] On the other hand, the present application relates to the use of the compound of the present application, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating BTK-related diseases.

[0145] On the other hand, the present application relates to the use of the compound of the present application, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in treating BTK-related diseases.

[0146] On the other hand, the present application relates to the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition for treating BTK-related diseases.

[0147] In some embodiments, the BTK-related disease is selected from cancer or immune disease. In some embodiments, the cancer is selected from lymphoma, for example, diffuse large B-cell lymphoma. The present application compounds include compounds of formula (I) (such as example compounds) that have good inhibitory activity against wild-type BTK kinase, C481S mutant BTK kinase, and tumor cells, and have good in vitro liver microsome stability, in vivo pharmacokinetic properties, and / or good in vivo anti-tumor activity.

[0148] definition

[0149] Unless otherwise indicated, the following terms used in this application have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0150] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0151] The term "optionally" or "optionally" means that the event or circumstance described subsequently may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0152] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C1-6 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0153] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition on each occurrence is independent. Thus, for example, if a group is substituted with two R's, each R has an independent alternative.

[0154] When one of the variables is selected from a covalent bond, it indicates that the two groups it connects are directly connected. For example, when L in ALZ represents a covalent bond, the structure is actually AZ. When L in the group ALZ is not a covalent bond, there is no restriction on the direction of its connection to A and Z. For example, when -L- is -C(O)-NH-methylene-, ALZ includes AC(O)-NH-methylene-Z and ZC(O)-NH-methylene-A.

[0155] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene. For example, the structural unit Partially represents R 1 Substitution can occur at any position on ring A or ring B, and L1 can also be connected to any position on ring A or ring B. For example, the structural unit Represents R 1 You can be at any position on this ring (for example, Y 1 or Y 2 ) is replaced.

[0156] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0157] The term "hydroxy" refers to an -OH group.

[0158] The term "cyano" refers to a -CN group.

[0159] The term "amino" refers to a -NH2 group.

[0160] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1-6The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.

[0161] Unless otherwise specified, the term “C 1-6 "Alkylene" by itself or as part of another substituent means a straight or branched divalent hydrocarbon radical consisting of 1 to 6 carbon atoms, including those having 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, the term "C 1-6 “Alkylene” refers to an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2- or -CH2CH(CH3)-), butylene (-CH2CH2CH2CH2-, -CH2CH(CH3)CH2- or -CH2CH2CH(CH3)-), and the like.

[0162] The term "alkoxy" refers to an -O-alkyl group.

[0163] The term "alkylamino" refers to an -NH-alkyl group.

[0164] The term "dialkylamino" refers to -N(alkyl)2.

[0165] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one double bond, including but not limited to 2 to 8, 2 to 6, 2 to 4, and 2 to 3 carbon atoms. Non-limiting examples of alkenyl include but are not limited to ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

[0166] The term "alkynyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond, including but not limited to 2 to 8, 2 to 6, 2 to 4, and 2 to 3 carbon atoms. Non-limiting examples of alkynyl groups include but are not limited to ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), 1,3-butadiynyl (-C≡C≡CH), and the like.

[0167] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 12-membered ring, a 3 to 10-membered ring, a 4 to 8-membered ring, a 5 to 8-membered ring, or a 5 to 6-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, etc.

[0168] The term "monocycloalkyl" refers to a cycloalkyl group existing as a single ring.

[0169] The term "bridged cycloalkyl" refers to a fully saturated, 5- to 14-membered carbon ring, preferably 6- to 10-membered, in which two rings share two or more atoms. Depending on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic or tricyclic, and more preferably bicyclic. Non-limiting examples of bridged cycloalkyl groups include: wait.

[0170] The term "spiroalkyl" refers to a fully saturated 5- to 20-membered carbon ring in which one carbon atom (called a spiro atom) is shared between the rings. Preferably, it is 6- to 14-membered, more preferably 6- to 10-membered. Spiroheterocycles are classified as monospiro, bispiro, or polyspiro depending on the number of spiro atoms shared between the rings, preferably monospiro or bispiro. Non-limiting examples of spirocycles include: wait.

[0171] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 4 to 12-membered ring (e.g., 5 to 10 members or 6 to 10 members) containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen. Non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl; examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl. Preferably, the heterocycloalkyl group is a monocyclic group having 5 or 6 ring atoms.

[0172] The term "spiroheterocycloalkyl" refers to a fully saturated 5 to 20 membered polycyclic ring that shares a carbon atom (called a spiral atom) between monocyclic rings, and one or more ring atoms in the polycyclic ring are selected from the heteroatoms (preferably 1 or 2 heteroatoms) of sulfur, oxygen and / or nitrogen, and the remaining ring atoms are carbon atoms. Preferably, it is 6 to 14 members, more preferably 6 to 10 members. According to the number of spiral atoms shared between the rings, the spiral heterocycle is divided into a single spiral heterocycle, a double spiral heterocycle or a multi-spiral heterocycle, preferably a single spiral heterocycle or a double spiral heterocycle, more preferably a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered single spiral heterocycle. Non-limiting examples of spiral heterocycles include: wait.

[0173] Term " heterocyclic radical " refers to fully saturated or partially undersaturated (but not fully unsaturated heteroaromatic) and can be with monocycle, bridged ring, and ring or spirocyclic non-aromatic ring.Unless otherwise indicated, the heterocycle is generally 3 to 12 yuan, 3 to 10 yuan, 8 to 10 yuan, 9 to 10 yuan, 4 to 8 yuan, 5 to 8 yuan, 5 to 6 yuan, 3 to 7 yuan or 4 to 6 yuan ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulphur, oxygen, nitrogen, phosphorus, silicon and / or boron.The limiting examples of heterocyclic radical include but are not limited to oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N- methylpyrrolidinyl, dihydropyrrolyl, piperidyl, piperazinyl, pyrazolidinyl, 4H- pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc.

[0174] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, 6-12, or 6-10 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene.

[0175] The term "heteroaryl" refers to an aromatic ring having at least one ring atom selected from N, O and / or S, and the remaining ring atoms being monocyclic or fused polycyclic rings of C atoms. Typically, it has 5 to 14, 5 to 12, 5 to 10, 5 to 8, 5 to 7 or 5 to 6 rings. Unless otherwise indicated, the heteroaryl can be a monocyclic, bicyclic or tricyclic ring. Unless otherwise indicated, the heteroaryl can have a single 5 to 8-membered ring, especially a 5 to 6-membered ring, or two or more fused rings containing 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, indolyl, quinazolinyl, quinoxalinyl, tetrazolyl, triazolyl, triazinyl, etc.

[0176] The "cycloalkyl", "heterocycloalkyl", "heterocyclyl", "aryl", and "heteroaryl" are each independently optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O) N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0177] The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0178] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0179] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0180] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats a specific disease, condition, or disorder, or (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0181] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0182] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0183] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0184] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0185] The term "subject" includes mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, and pigs; domestic animals, such as rabbits, dogs, and cats; and laboratory animals, including rodents, such as rats, mice, and guinea pigs. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0186] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0187] The compounds and intermediates of the present application can also exist in different tautomeric forms, and all such forms are included in the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. The specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0188] The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O.18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0189] Certain isotope-labeled compounds of the present application (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0190] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

[0191] The compounds of the present application may exist in specific geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which fall within the scope of the present application. The compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure form or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents. The cis and trans isomers of the present application are separated by using chiral starting materials or chiral reagents. Distinguish, when two Or two at the same time When a structure appears and a When denoting the trans form, non-limiting examples of cis and trans isomers include, but are not limited to and and and Etc. The (R)- and (S)-enantiomers of this application are used Non-limiting examples of enantiomers include, but are not limited to and and wait.

[0192] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0193] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0194] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0195] In all methods of administration described herein, the compounds of formula I are administered at a dosage of 0.01 to 200 mg / kg body weight per day in single or divided doses.

[0196] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0197] The chemical reactions described in the specific embodiments of the present application are carried out in a suitable solvent that is compatible with the chemical transformations described herein and the reagents and materials required. To obtain the compounds described herein, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0198] An important consideration in synthetic route planning in this field is the selection of an appropriate protecting group for a reactive functional group (such as an amino group in this application). For example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0199] In some embodiments, the compounds of the present application can be prepared by those skilled in the art of organic synthesis by referring to the following routes:

[0200] Among them, ring A, ring B, R 1 、m、L1、Y1、Y2、R 2 ,n,L2,ring C,R,q,R 3 The definitions of p are as described in the present disclosure, and X is selected from leaving groups including but not limited to F, Cl, Br, and I.

[0201] In some embodiments, the compounds of the present application can also be prepared by those skilled in the art of organic synthesis by referring to the following routes:

[0202] Among them, ring A, ring B, R 1 、m、L1、Y1、Y2、R 2 ,n,L2,ring C,R,q,R 3 The definitions of p are as described in the present disclosure, and X is selected from leaving groups including but not limited to F, Cl, Br, and I.

[0203] In some embodiments, the compounds of the present application can also be prepared by those skilled in the art of organic synthesis by referring to the following routes:

[0204] Among them, ring A, R 1 、m、Y1、Y2、R 2 ,n,L2,ring C,R,q,R 3 The definitions of p are as described in the present disclosure, and X is selected from leaving groups including but not limited to F, Cl, Br, and I.

[0205] Each product obtained by the reaction in the above-mentioned route can be obtained by traditional separation techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. The starting materials can be synthesized by themselves or purchased from commercial institutions (such as, but not limited to Adrich or Sigma). These raw materials can be characterized using conventional means, such as physical constants and spectral data. The compounds described in this application can be obtained as single isomers or mixtures of isomers using synthetic methods.

[0206] This application uses the following abbreviations:

[0207] DCM stands for dichloromethane; THF stands for tetrahydrofuran; DMSO stands for dimethyl sulfoxide; EA stands for ethyl acetate; CsF stands for cesium fluoride; TMSCF3 stands for (trifluoromethyl)trimethylsilane; and DPPF stands for 1,1′-bis(diphenylphosphino)ferrocene. DETAILED DESCRIPTION

[0208] For the sake of clarity, the present disclosure is further illustrated by examples, but the examples are not intended to limit the scope of this application. It will be apparent to those skilled in the art that various changes and modifications will be made to the specific embodiments of the present disclosure without departing from the spirit and scope of this disclosure. All reagents used in this application are commercially available and can be used without further purification.

[0209] Example 1: Preparation of Compounds 1 and 1-a, 1-b

[0210] Preparation of intermediate 1-1:

[0211] 2-Chloro-5-fluoropyridine-6-carbaldehyde (10 g) and 1-(2-methoxyethyl)piperazine (9.9 g) were added to N,N-dimethylformamide (100 mL), and potassium carbonate (22 g) was added. The mixture was stirred at 80°C for 2 h.

[0212] After the reaction was completed, purified water (300 mL) and DCM (300 mL) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 1-1 (19.2 g).

[0213] LC-MS: m / z 284.15 (M+H) + .

[0214] Preparation of intermediate 1-2:

[0215] Intermediate 1-1 (10 g) was added to THF (50 mL), the temperature was controlled at -20°C with stirring, and methylmagnesium bromide solution (3M, 17.8 mL) was slowly added; after the addition was completed, the temperature was slowly raised to 0°C and the reaction was stirred for 2 h.

[0216] After the reaction was complete, purified water (150 mL) was added to quench the mixture, stirred for 10 min, and DCM (200 mL) was added for extraction. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 1-2 (9.7 g).

[0217] LC-MS: m / z 300.25 (M+H) + .

[0218] Preparation of intermediate 1-3:

[0219] Intermediate 1-2 (9.7 g) was added to THF (100 mL), stirred at 0°C, and sodium hydroxide (60%, 1.4 g) was slowly added. After stirring for 20 min, iodomethane (5.1 g) was added, and the mixture was transferred to room temperature and stirred for 12 h.

[0220] After the reaction was complete, purified water (150 mL) was added to quench the mixture, stirred for 10 min, and ethyl acetate (200 mL) was added for extraction. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 1-3 (9 g).

[0221] LC-MS: m / z 314.31 (M+H) + .

[0222] Preparation of intermediate 1-4:

[0223] Ethyl pyruvate (19.5 g) and N,N-dimethylformamide diethyl acetal (24.7 g) were added to DCM (500 mL) and stirred at room temperature for 12 h;

[0224] After the reaction was completed, the mixture was concentrated under reduced pressure to obtain intermediate 1-4 (28.7 g).

[0225] Preparation of intermediate 1-5:

[0226] Intermediate 1-4 (28.7 g) was dissolved in N,N-dimethylformamide (100 mL), and concentrated hydrochloric acid (12 M, 9.8 mL) and p-cyanophenylhydrazine (15.6 g) were added, and the mixture was stirred at room temperature for 4 h.

[0227] After the reaction was completed, purified water (200 mL) was added to the reaction solution to precipitate a solid, which was filtered. The filter cake was intermediate 1-5 (18 g).

[0228] Preparation of intermediate 1-6:

[0229] Intermediate 1-5 (18 g) was dissolved in trifluoroacetic anhydride (200 mL), and concentrated nitric acid (65%, 17.6 g) was added at -15°C. The mixture was reacted at the same temperature for 30 min. The mixture was transferred to an ice bath and reacted at 0°C for 2 h.

[0230] After the reaction was completed, purified water (500 mL) was added at 0°C to precipitate a solid, which was filtered and the filter cake was washed with purified water and dried under reduced pressure at 50°C for 12 h to obtain intermediate 1-6 (16 g).

[0231] LC-MS: m / z 303.21 (M+H) + .

[0232] Preparation of intermediate 1-7:

[0233] Intermediate 1-6 (16 g) was added to borane-THF (1 M, 200 mL) and the reaction was stirred at room temperature for 12 h.

[0234] After the reaction was complete, ethanol (50 mL) was slowly added to quench the reaction and stirred for 1 h. The reaction solution was concentrated under reduced pressure, and dilute hydrochloric acid (1 M, 50 mL) was added to adjust the pH to 2-3. Purified water (200 mL) and DCM (300 mL) were added for extraction. The aqueous phase was adjusted to pH > 7 with saturated aqueous NaHCO₃ (200 mL); the aqueous phase was further extracted with DCM / methanol (6:1, 500 mL). The organic phase was stirred and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 1-7 (6.9 g).

[0235] LC-MS: m / z 291.28 (M+H) + .

[0236] Preparation of intermediate 1-8:

[0237] Intermediate 1-7 (4.6 g), 6-fluoroquinoline-8-carboxylic acid (3 g), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (8.9 g), and N,N-diisopropylethylamine (4.1 g) were added to N,N-dimethylformamide (50 mL), and the reaction was stirred at room temperature for 4 h.

[0238] After the reaction was completed, purified water (200 mL) and ethyl acetate (250 mL) were added for extraction, and the aqueous phase was extracted with ethyl acetate (150 mL × 2); the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1), and the eluate was concentrated under reduced pressure to obtain intermediate 1-8 (2 g).

[0239] LC-MS: m / z 464.46 (M+H) + .

[0240] Preparation of intermediate 1-9:

[0241] Intermediate 1-8 (2 g) was added to ammonia-methanol (7 M, 100 mL) and stirred at 60° C. After the reaction was complete, the product was concentrated under reduced pressure to give intermediate 1-9 (2 g), which was used directly in the next step without further purification.

[0242] LC-MS: m / z 435.11 (M+H) + .

[0243] Preparation of intermediate 1-10:

[0244] Intermediate 1-9 (2 g) was added to phosphorus oxychloride (3 mL) and the reaction was allowed to proceed at 70°C overnight. After the reaction was complete, purified water (50 mL) was added to quench the reaction and stirred for 30 min. Ethyl acetate (50 mL) was added for extraction, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 1-10 (1.5 g). This product was used directly in the next step without further purification.

[0245] LC-MS: m / z 417.23 (M+H) + .

[0246] Preparation of intermediate 1-11:

[0247] Intermediate 1-10 (1.5 g) was added to THF (25 mL), and palladium on carbon (10%, 500 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere overnight. After the reaction was complete, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give Intermediate 1-11 (1 g), which was used directly in the next step without further purification.

[0248] LC-MS: m / z 387.12 (M+H) + .

[0249] Preparation of intermediate 1-12:

[0250] Intermediate 1-11 (100 mg) and intermediate 1-3 (81 mg) were added to 1,4-dioxane (5 mL), and tris(dibenzylideneindeneacetone)dipalladium (47 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (59 mg) and cesium carbonate (169 mg) were added, and the mixture was reacted at 85°C for 12 h under nitrogen protection.

[0251] After the reaction was complete, ethyl acetate (100 mL) and purified water (100 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 1-12 (500 mg).

[0252] LC-MS: m / z 664.45 (M+H) + .

[0253] Preparation of compound 1:

[0254] Intermediate 1-12 (500 mg) was added to ethanol (2 mL), and sodium hydroxide solution (1 M, 2 mL) was added, and the temperature was controlled at 70° C. for 2 h.

[0255] After the reaction was complete, ethyl acetate (100 mL) and purified water (100 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and compound 1 was obtained by preparative liquid separation.

[0256] LC-MS: m / z 682.23 (M+H) + .

[0257] Preparation of compounds 1-a and 1-b:

[0258] Compound 1 was chiral resolved to give compounds 1-a and 1-b. The separation conditions were as follows: a CHIRALPAK AD-H (4.6×250 mm, 5.0 μm) preparative column; gradient elution with n-hexane as mobile phase A and ethanol as mobile phase B at a flow rate of 0.8 mL / min; detection at a wavelength of 254 nm; and peak elution times of 32.83 min (1-a) and 38.35 min (1-b), respectively.

[0259] Compound 1-a LC-MS: m / z 682.33 (M+H) + .

[0260] Compound 1-b LC-MS: m / z 682.23 (M+H) + .

[0261] The retention time of compound 1-a in the chiral chromatographic column is shorter than that of compound 1-b, and the retention time of compound 1-b in the chiral chromatographic column is longer than that of compound 1-a.

[0262] Example 2: Preparation of Compound 2

[0263] Preparation of intermediate 2-1:

[0264] Intermediate 1-1 (9 g) was added to methanol (150 mL), and sodium borohydride (1.8 g) was slowly added, and the reaction was stirred at room temperature for 12 h.

[0265] After the reaction was complete, purified water (500 mL) was added to quench the mixture, and the mixture was stirred for 10 min. DCM (600 mL) was added and the mixture was extracted. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 2-1 (9 g), which was used directly in the next step without further purification.

[0266] LC-MS: m / z 286.13 (M+H) + .

[0267] Preparation of intermediate 2-2:

[0268] Intermediate 2-1 (9 g) was added to THF (150 mL), stirred at 0°C, and sodium hydroxide (60%, 1.4 g) was slowly added. After stirring for 20 min, iodomethane (4.9 g) was added, and the mixture was transferred to room temperature and stirred for 4 h.

[0269] After the reaction was complete, purified water (150 mL) was added to quench the mixture, stirred for 10 min, and ethyl acetate (200 mL) was added for extraction. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 2-2 (8.4 g).

[0270] LC-MS: m / z 300.32 (M+H) + .

[0271] Preparation of intermediate 2-3:

[0272] Intermediate 1-11 (100 mg) and intermediate 2-2 (78 mg) were added to tert-butanol (5 mL), and palladium acetate (12 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (60 mg) and cesium carbonate (168 mg) were added, and the mixture was reacted at 85°C for 2 h under nitrogen protection.

[0273] After the reaction was complete, ethyl acetate (100 mL) and purified water (100 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 2-3 (200 mg).

[0274] LC-MS: m / z 650.42 (M+H) + .

[0275] Preparation of compound 2:

[0276] Intermediate 2-3 (200 mg) was added to ethanol (2 mL), and sodium hydroxide solution (1 M, 2 mL) was added, and the temperature was controlled at 70° C. for 2 h.

[0277] After the reaction was complete, ethyl acetate (100 mL) and purified water (100 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; compound 2 was obtained by preparative liquid separation.

[0278] LC-MS: m / z 668.32 (M+H) + .

[0279] 1H NMR (500MHz, DMSO-d6) δ11.25(s,1H),9.05(dd,J=4.2,1.8Hz,1H),8.57(dd,J=8.5,1.8Hz,1H),8.44–7.96(m,5H),7.59–7.36(m,6H ),6.78(d,J=8.8Hz,1H),4.76(d,J=6.0Hz,2H),4.45(s,2H),3.46(t,J=5.8Hz,7H),2.81(t,J=4.8Hz,4H),2.58(s,2H),2.07(s,3H).

[0280] Example 3: Preparation of Compounds 3, 3-a, and 3-b

[0281] Preparation of intermediate 3-1:

[0282] 5-Fluoro-2-methoxybenzaldehyde (5 g), aminoacetaldehyde dimethyl acetal (3.41 g), and 4A molecular sieves (3 g) were added to toluene (50 mL), a water separator was added, and the mixture was reacted at 120° C. for 7 h.

[0283] After the reaction was complete, the product was filtered and the filtrate was concentrated under reduced pressure. DCM (80 mL) was added to the concentrate and stirred to dissolve. Aluminum chloride (11 g) was added portionwise and stirred at room temperature for 6 h. After the reaction was complete, ice water was added and the mixture was stirred and separated. The aqueous phase was extracted with DCM, and the organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 3-1 (1.5 g).

[0284] LC-MS: m / z 178.10 (M+H) + .

[0285] Preparation of intermediate 3-2:

[0286] Intermediate 3-1 (1.5 g) was added to DCM (20 mL), and m-chloroperbenzoic acid (2.58 g) was added portionwise, and the reaction was stirred at room temperature overnight.

[0287] After the reaction was complete, 1 mol / L Na2S2O3 was added to quench the reaction. The organic phase was separated and saturated NaHCO3 solution was added. The aqueous phase was extracted three times with DCM. The organic phases were combined, washed with brine, dried, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 3-2 (1.6 g).

[0288] LC-MS: m / z 194.18 (M+H) + .

[0289] Preparation of intermediate 3-3:

[0290] Intermediate 1-7 (1 g), intermediate 3-2 (700 mg), tripyrrolidinylphosphonium bromide hexafluorophosphate (3.8 g), and N,N-diisopropylethylamine (1.9 g) were added to THF (20 mL), and the mixture was stirred at room temperature for 12 h.

[0291] After the reaction was completed, saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (100 mL) were added, stirred for 10 min, and allowed to stand for separation; the organic phase was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1), and the eluate was concentrated under reduced pressure to obtain intermediate 3-3 (300 mg).

[0292] LC-MS: m / z 466.26 (M+H) + .

[0293] Preparation of intermediate 3-4:

[0294] Intermediate 3-3 (300 mg) was added to ammonia-methanol (7 M, 10 mL) and stirred at 60° C. After the reaction was complete, the product was concentrated under reduced pressure to give intermediate 3-4 (400 mg), which was used directly in the next step without further purification.

[0295] LC-MS: m / z 437.25 (M+H) + .

[0296] Preparation of intermediate 3-5:

[0297] Intermediate 3-4 (400 mg) was added to THF (25 mL), and palladium on carbon (10%, 200 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere overnight. After the reaction was complete, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give Intermediate 3-5 (250 mg), which was used directly in the next step without further purification.

[0298] LC-MS: m / z 407.21 (M+H) + .

[0299] Preparation of compound 3:

[0300] Intermediate 3-5 (250 mg) and intermediate 1-3 (193 mg) were added to tert-butanol (5 mL), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (22 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (40 mg), and cesium carbonate (168 mg) were added, and the reaction was stirred at 85°C under nitrogen protection for 2 h.

[0301] After the reaction was complete, ethyl acetate (100 mL) and purified water (100 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; compound 3 was obtained by preparative liquid separation.

[0302] LC-MS: m / z 684.40 (M+H) + .

[0303] Preparation of compounds 3-a and 3-b:

[0304] Compound 3 was chiral resolved to give compounds 3-a and 3-b. The separation conditions were as follows: a CHIRALPAK AD-H (4.6×250 mm, 5.0 μm) preparative column; gradient elution with n-hexane as mobile phase A and ethanol as mobile phase B at a flow rate of 0.6 mL / min; detection at a wavelength of 254 nm; and peak elution times of 32.38 min (3-a) and 39.79 min (3-b), respectively.

[0305] Compound 3-a LC-MS: m / z 684.32 (M+H) + .

[0306] Compound 3-b LC-MS: m / z 684.41 (M+H) + .

[0307] The retention time of compound 3-a in the chiral chromatographic column is shorter than that of compound 3-b, while the retention time of compound 3-b in the chiral chromatographic column is longer than that of compound 3-a.

[0308] Example 4: Preparation of Compound 4

[0309] Preparation of compound 4-1:

[0310] Referring to the preparation steps of compound 3 in Example 3, intermediate 1-3 was replaced with tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate. After the reaction was completed, ethyl acetate was added to obtain intermediate 4-1 (300 mg).

[0311] LC-MS: m / z 667.34 (M+H) + .

[0312] Preparation of intermediate 4-2:

[0313] Intermediate 4-1 (300 mg) was added to DCM (5 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain intermediate 4-2 (600 mg), which was used directly in the next step without further purification.

[0314] LC-MS: m / z 567.21 (M+H) + .

[0315] Preparation of compound 4:

[0316] Intermediate 4-2 (300 mg) was added to DCM (10 mL), and 3-oxetanone (28 mg) and sodium triacetoxyborohydride (112 mg) were added, and the reaction was stirred at room temperature for 12 h.

[0317] After the reaction was complete, DCM (30 mL) and purified water (20 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with DCM (20 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; compound 4 was obtained by preparative liquid separation.

[0318] LC-MS: m / z 623.22 (M+H) + .

[0319] Example 5: Preparation of Compounds 5 and 5-a, 5-b

[0320] Preparation of intermediate 5-1:

[0321] 2-Chloro-5-fluoropyridine-6-carbaldehyde (5 g), N-methylpiperazine (3.77 g) and potassium carbonate (13 g) were added to N,N-dimethylformamide (50 mL), and the reaction was stirred at 80°C for 1 h.

[0322] After the reaction was complete, the mixture was filtered and the filtrate was extracted with purified water (100 mL) and ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate 5-1 (6.29 g).

[0323] LC-MS: m / z 240.14 (M+H) + .

[0324] Preparation of intermediate 5-2:

[0325] Intermediate 5-1 (2.5 g) was added to THF (20 mL), the temperature was controlled at -20°C with stirring, and cyclopropylmagnesium bromide solution (1 M, 20 mL) was slowly added dropwise. After the addition was completed, the temperature was slowly raised to 0°C and the reaction was stirred for 2 h.

[0326] After the reaction was complete, purified water (50 mL) was added to quench the mixture, stirred for 10 min, and ethyl acetate (50 mL) was added for extraction. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 5-2 (2.3 g).

[0327] LC-MS: m / z 282.18 (M+H) + .

[0328] Preparation of intermediate 5-3:

[0329] Referring to the preparation steps of compound 3 in Example 3, intermediate 3-5 was replaced by intermediate 1-11, and intermediate 1-3 was replaced by intermediate 5-2. After the reaction was completed, ethyl acetate was added to obtain intermediate 5-3 (232 mg).

[0330] LC-MS: m / z 632.39 (M+H) + .

[0331] Preparation of compound 5:

[0332] Intermediate 5-3 (232 mg) was added to a DMSO / ethanol (1:1) mixed solvent (15 mL) and stirred. Sodium hydroxide solution (5 M, 3 mL) and hydrogen peroxide (3 mL) were added, and the mixture was stirred at room temperature for 2.5 h.

[0333] After the reaction was complete, ethyl acetate (30 mL) and purified water (30 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (30 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; compound 5 was obtained by preparative liquid separation.

[0334] LC-MS: m / z 650.34 (M+H) + .

[0335] Preparation of compounds 5-a and 5-b:

[0336] Compound 5 was chiral resolved to give compounds 5-a and 5-b. The resolution conditions were as follows: a CHIRALPAK IC (4.6×250 mm, 5.0 μm) preparative column; isocratic elution with 0.1% ethanolamine in ethanol as the mobile phase at a flow rate of 0.8 mL / min; detection at a wavelength of 254 nm; and peak elution times of 22.970 min (5-a) and 30.947 min (5-b), respectively.

[0337] Compound 5-a LC-MS: m / z 650.38 (M+H) + .

[0338] Compound 5-b LC-MS: m / z 650.36 (M+H) + .

[0339] The retention time of compound 5-a in the chiral chromatographic column is shorter than that of compound 5-b, while the retention time of compound 5-b in the chiral chromatographic column is longer than that of compound 5-a.

[0340] Example 6: Preparation of Compound 6

[0341] Preparation of intermediate 6-1:

[0342] Intermediate 1-1 (3 g) was added to THF (20 mL), and the mixture was stirred at -20°C under nitrogen protection. Cyclopropylmagnesium bromide solution (1 M, 15 mL) was slowly added dropwise. After the addition, the temperature was slowly raised to 0°C and the mixture was stirred for 3 h.

[0343] After the reaction was complete, purified water (50 mL) was added to quench the mixture, stirred for 10 min, and ethyl acetate (50 mL) was added for extraction. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 6-1 (3.2 g).

[0344] LC-MS: m / z 326.19 (M+H) + .

[0345] Preparation of intermediate 6-2:

[0346] Referring to the preparation steps of compound 3 in Example 3, intermediate 3-5 was replaced by intermediate 1-11, and intermediate 1-3 was replaced by intermediate 6-1. After the reaction was completed, ethyl acetate was added to obtain intermediate 6-2 (279 mg).

[0347] LC-MS: m / z 676.36 (M+H) + .

[0348] Preparation of compound 6:

[0349] Intermediate 6-2 (279 mg) was added to a DMSO / ethanol (1:1) mixed solvent (15 mL) and stirred. Sodium hydroxide solution (5 M, 3 mL) and hydrogen peroxide (3 ml) were added, and the mixture was stirred at room temperature for 2.5 h.

[0350] After the reaction was complete, ethyl acetate (30 mL) and purified water (30 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (30 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; compound 6 was obtained by preparative liquid separation.

[0351] LC-MS: m / z 694.42 (M+H) + .

[0352] Example 7: Preparation of Compound 7

[0353] Preparation of intermediate 7-1:

[0354] Intermediate 5-1 (1.2 g) was added to THF (90 mL), and methylmagnesium bromide (3 M, 3 mL) was added dropwise under nitrogen protection at -20°C; after the addition, the temperature was controlled at 0°C and stirred for 3 h; after the reaction was complete, saturated ammonium chloride solution (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (60 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 7-1 (1.1 g).

[0355] LC-MS: m / z 256.15 (M+H) + .

[0356] Preparation of intermediate 7-2:

[0357] Referring to the preparation steps of compound 3 in Example 3, intermediate 3-5 was replaced by intermediate 1-11, and intermediate 1-3 was replaced by intermediate 7-1. After the reaction was completed, ethyl acetate was added to obtain intermediate 7-2 (310 mg).

[0358] LC-MS: m / z 606.32 (M+H) + .

[0359] Preparation of compound 7:

[0360] Intermediate 7-2 (310 mg) was added to DMSO (5 mL) and ethanol (5 mL), and sodium hydroxide solution (1 M, 5 mL) was added, and hydrogen peroxide (3 mL) was added dropwise. After the addition was completed, the mixture was stirred and reacted for 3 h.

[0361] After the reaction was complete, ethyl acetate (30 mL) and purified water (20 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; compound 7 was obtained by preparative liquid separation.

[0362] LC-MS: m / z 624.40 (M+H) + .

[0363] Example 8: Preparation of Compounds 8-a and 8-b

[0364] Preparation of intermediate 8-1:

[0365] 5-Fluoro-2-methoxybenzonitrile (20 g) was added to tetrahydrofuran (400 mL), placed in an ice bath, and lithium aluminum tetrahydride (20 g) was slowly added. After the addition, the ice bath was removed and the mixture was warmed to room temperature for 2 h.

[0366] After the reaction is complete, 5 mL of water is added to quench the reaction and stirred for 5 min; then 1 M aqueous sodium hydroxide solution (45 mL) is slowly added dropwise, ethyl acetate (150 mL) and water (200 mL) are added, and after extraction, the mixture is allowed to stand and separate. Anhydrous sodium sulfate is added to the organic phase for drying, filtration, and the filtrate is concentrated under reduced pressure to obtain intermediate 8-1 (20 g).

[0367] LC-MS: m / z 156.23 (M+H) + .

[0368] Preparation of intermediate 8-2:

[0369] Diisopropylamine (20 g) was added to dichloromethane (400 mL), and the mixture was placed in an ice bath. Triethylamine (21 g) and oxalyl chloride (37 g) were slowly added. After the addition, the ice bath was removed, and the mixture was heated to room temperature and reacted for 12 h.

[0370] After the reaction was completed, the reaction solution was concentrated under reduced pressure at 40°C to obtain intermediate 8-2 (18 g).

[0371] Preparation of intermediate 8-3:

[0372] 8-1 (20 g) was added to dichloromethane (300 mL), placed in an ice bath, and 8-2 (18 g) and triethylamine (15 g) were slowly added. After the addition, the ice bath was removed and the temperature was raised to room temperature for reaction for 3 h.

[0373] After the reaction is complete, 45 mL of water is added to quench the reaction and stirred for 5 min; ethyl acetate (250 mL) and water (300 mL) are added, and after extraction, the mixture is allowed to stand and separate. Anhydrous sodium sulfate is added to the organic phase for drying, filtration, and the filtrate is concentrated under reduced pressure to obtain intermediate 8-3 (23 g).

[0374] LC-MS: m / z 311.25 (M+H) + .

[0375] Preparation of intermediate 8-4:

[0376] Compound 8-3 (23 g), allyl acetate (13.5 g), palladium acetate (1.5 g), silver carbonate (37.8 g) and dibutyl phosphate (4.3 g) were added to 1,2-dichloroethane (500 mL) and reacted in an oil bath at 100° C. for 12 h.

[0377] After monitoring the complete consumption of the starting materials, sodium hydroxide (35 g) was added, and the temperature was lowered to 80° C. and the reaction was continued for 6 h.

[0378] After the reaction is complete, ethyl acetate (600 mL) and water (500 mL) are added. After extraction, the mixture is allowed to stand and separate. Anhydrous sodium sulfate is added to the organic phase for drying, and the mixture is filtered. The filtrate is concentrated under reduced pressure. The mixture is purified and separated by column chromatography (ethyl acetate / petroleum ether = 1 / 5) to obtain intermediate 8-4 (16.5 g).

[0379] LC-MS: m / z 192.20 (M+H) + .

[0380] Preparation of intermediate 8-5:

[0381] 8-4 (16.5 g) was added to dichloromethane (150 mL), and m-chloroperbenzoic acid (60%, 34.5 g) was added, and the mixture was reacted at room temperature overnight.

[0382] After the reaction was completed, aqueous sodium bicarbonate solution (200 mL) was added, the aqueous phase was extracted with ethyl acetate (500 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 8-5 (10.3 g).

[0383] LC-MS: m / z 208.37 (M+H) + .

[0384] Preparation of intermediate 8-6:

[0385] Intermediate 1-7 (14 g), intermediate 8-5 (10.3 g), tripyrrolidinylphosphonium bromide hexafluorophosphate (90 g) and DIPEA (49 g) were added to THF (1 L) and reacted at room temperature for 12 h.

[0386] After the reaction was completed, saturated aqueous sodium bicarbonate solution (500 mL) was added and stirred for 10 min. Purified water (1.5 L) was added and extracted with ethyl acetate (1.2 L × 3). The organic phases were combined, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1), and the eluate was concentrated under reduced pressure to obtain intermediate 8-6 (8 g).

[0387] LC-MS: m / z 480.23 (M+H) + .

[0388] Preparation of intermediate 8-7:

[0389] Intermediate 8-6 (8 g) was added to ammonia-methanol (7 M, 800 mL) and stirred at 60° C. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain intermediate 8-7 (7.4 g).

[0390] LC-MS: m / z 451.25 (M+H) + .

[0391] Preparation of intermediate 8-8:

[0392] Intermediate 8-7 (7.4 g) was added to THF (500 mL), palladium carbon (10%, 3 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. After the reaction was complete, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain intermediate 8-8 (6.5 g).

[0393] LC-MS: m / z 421.21 (M+H) + .

[0394] Preparation of intermediate 8-9:

[0395] 2-Methyl-3-bromo-5-chloropyridine (718 mg), 3-dimethylaminocyclobutylamine hydrochloride (710 mg), tris(dibenzylideneacetone)dipalladium (510 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (630 mg), sodium tert-butoxide (1680 mg), and toluene (80 mL) were added, and the atmosphere was replaced with nitrogen three times, and the reaction was stirred at 100° C. for 5 hours.

[0396] After the reaction was complete, the mixture was cooled to room temperature, and ethyl acetate (50 mL) and purified water (30 mL) were added. The mixture was stirred for 10 min and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Intermediate 8-9 (569 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1).

[0397] LC-MS: m / z 240.15 (M+H) + .

[0398] Preparation of compounds 8-a and 8-b:

[0399] Intermediate 8-9 (138 mg) and intermediate 8-8 (290 mg) were added to tert-butanol (15 mL), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (72 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (95 mg), and lithium bistrimethylsilylamide (1 M, 7.5 mL) were added, and the reaction was stirred at 80°C under nitrogen protection for 2 h.

[0400] After the reaction was complete, ethyl acetate (100 mL) and purified water (100 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; compound 8-a and compound 8-b were obtained by preparative liquid separation under the following conditions: YMC SA (30 × 250 mm, 10 um) was used as a preparative column; n-hexane was used as mobile phase A and ethanol was used as mobile phase B, and gradient elution was performed at a flow rate of 30 mL per minute; the detection wavelength was 254 nm, and the peak times were 19 min (8-a) and 27 min (8-b), respectively.

[0401] Compound 8-a LC-MS: m / z 624.41 (M+H) + .

[0402] 1 H NMR (500MHz, DMSO-d6) δ8.34(t,J=5.9Hz,1H),7.80(s,1H),7.48(d,J=8.1Hz,2H),7.38(d,J=8.2Hz,2H),7 .31(t,J=9.3Hz,1H),6.82(dd,J=8.7,4.1Hz,1H),6.72(s,1H),6.66(d,J=8.5Hz,1H),6.56(d,J=8.5Hz,1H ),4.86–4.58(m,3H),3.97(s,3H),3.72(s,1H),2.83(p,J=6.8Hz,1H),2.34(s,3H),2.20(dt,J=12.7,7.2H z,2H),2.08(s,5H),1.97(ddd,J=12.0,7.5,3.9Hz,2H),1.24(d,J=5.1Hz,5H),0.85(tt,J=7.7,4.4Hz,2H).

[0403] Compound 8-b LC-MS: m / z 624.43 (M+H) + .

[0404] 1H NMR(500MHz,DMSO-d6)δ8.35(q,J=4.3Hz,1H),8.11(s,1H),7.79(s,1H),7.54–7.46(m,2H),7.43–7.36 (m,2H),7.31(dd,J=9.9,8.7Hz,1H),6.82(dd,J=8.7,3.8Hz,2H),6.72(s,1H),6.55(d,J=8.6Hz,1H),4. 80(d,J=5.9Hz,2H),4.55(d,J=7.7Hz,1H),3.97(s,4H),3.41(q,J=7.4Hz,2H),2.47(dp,J=6.8,2.1Hz, 2H),2.41–2.32(m,4H),2.26(s,3H),1.67(qd,J=8.6,2.6Hz,2H),1.33–1.20(m,4H),0.91–0.79(m,2H).

[0405] The retention time of compound 8-a in the chiral chromatographic column is shorter than that of compound 8-b, while the retention time of compound 8-b in the chiral chromatographic column is longer than that of compound 8-a.

[0406] Example 9: Preparation of Compound 9

[0407] Preparation of intermediate 9-1:

[0408] Intermediate 1-1 (320 mg), (trifluoromethyl)trimethylsilane (241 mg) and cesium fluoride (257 mg) were added to tetrahydrofuran (10 mL), and the reaction was stirred at room temperature for 12 h under nitrogen protection.

[0409] After the reaction was complete, saturated ammonium chloride solution (10 mL) was added to quench the reaction, stirred for 10 min, and ethyl acetate (20 mL x 2) was added for extraction. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 9-1 (240 mg).

[0410] LC-MS: m / z 354.16 (M+H) + .

[0411] Preparation of intermediate 9-2:

[0412] Intermediate 9-1 (460 mg) was added to THF (10 mL), stirred at 0°C, and sodium bicarbonate (60%, 100 mg) was slowly added. After stirring for 20 min, iodomethane (202 mg) was added, and the mixture was transferred to room temperature and stirred for 3 h.

[0413] After the reaction was complete, purified water (15 mL) was added to quench the mixture, stirred for 10 min, and ethyl acetate (20 mL) was added for extraction. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 9-2 (287 mg).

[0414] LC-MS: m / z 368.18 (M+H) + .

[0415] Preparation of compound 9:

[0416] Intermediate 8-8 (100 mg) and intermediate 9-2 (105 mg) were added to dioxane (3 mL), and (2-dicyclohexylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2-aminoethylphenyl)] palladium (II) chloride (39 mg), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (52 mg), and lithium bis(trimethylsilyl)amide (1 M, 0.24 mL) were added, and the reaction was stirred at 85 ° C under nitrogen protection for 2 h.

[0417] After the reaction was complete, ethyl acetate (100 mL) and purified water (100 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; compound 9 was obtained by preparative liquid separation.

[0418] LC-MS: m / z 752.39 (M+H) + .

[0419] 1 H NMR(500MHz,DMSO-d6)δ8.57(s,1H),8.35(d,J=6.1Hz,2H),7.72(d,J=9.0Hz,1H),7.51–7.4 8(m,2H),7.42–7.39(m,2H),7.31(dd,J=10.0,8.7Hz,1H),6.99(d,J=8.9Hz,1H),6.81(dd,J= 8.7,4.2Hz,1H),6.72(s,1H),5.60–5.56(m,1H),4.80(d,J=5.9Hz,2H),3.97(s,3H),3.46(t ,J=5.8Hz,2H),3.32(s,3H),3.25(s,3H),2.79–2.73(m,4H),2.59–2.52(m,6H),2.34(s,3H).

[0420] Example 10: Preparation of Compound 10

[0421] Preparation of intermediate 10-1:

[0422] 2-Bromo-5-fluoropyridine-6-carbaldehyde (9 g), 4-amino-N-methylpiperidine (5 g) and potassium carbonate (18.3 g) were added to N,N-dimethylformamide (100 mL) and stirred at 80°C for 3 h.

[0423] After the reaction was complete, the mixture was filtered and the filtrate was extracted with purified water (200 mL) and ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate 10-1 (11.2 g).

[0424] LC-MS: m / z 298.24 (M+H) + .

[0425] Preparation of intermediate 10-2:

[0426] Intermediate 10-1 (11.2 g) was added to THF (50 mL), and (trifluoromethyl)trimethylsilane (11 g) and tetrabutylammonium fluoride (1 M, 40 mL) were added. After the addition was complete, the reaction was stirred at room temperature for 2 h.

[0427] After the reaction was complete, purified water (50 mL) was added to quench the reaction, and the mixture was stirred for 10 min. Ethyl acetate (50 mL) was added and the mixture was extracted. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Intermediate 10-2 (500 mg) was obtained by preparative liquid phase separation.

[0428] LC-MS: m / z 368.22 (M+H) + .

[0429] Preparation of intermediate 10-3:

[0430] Intermediate 10-2 (200 mg) was added to THF (4 mL), cooled to 0°C, sodium hydride (43 mg) was added and stirred for 10 min, and then iodomethane (84 mg) was added dropwise. After the addition was complete, the temperature was raised to room temperature and stirred for 2 h.

[0431] After the reaction was complete, purified water (20 mL) was added to quench the reaction, and ethyl acetate (30 mL) was added for extraction. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 10-3 (254 mg).

[0432] LC-MS: m / z 382.42 (M+H) + .

[0433] Preparation of compound 10:

[0434] Intermediate 8-8 (70 mg) and intermediate 10-3 (61 mg) were added to tert-butanol (5 mL), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (26 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (21 mg), and lithium bistrimethylsilylamide (1 M, 0.3 mL) were added, and the reaction was stirred at 80 ° C under nitrogen protection for 2 h.

[0435] After the reaction was complete, ethyl acetate (100 mL) and purified water (100 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and compound 10 was obtained by preparative liquid separation.

[0436] LC-MS: m / z 708.41 (M+H) + .

[0437] 1 H NMR(500MHz DMSO-d6)δ8.35(t,J=6.0Hz,1H),8.23(s,1H),8.06(s,1H),7.49(d,J=8.5Hz,2H),7.39( d,J=8.5Hz,2H),7.32(m,1H),7.17(d,J=9.0Hz,1H),6.82(m,2H),6.77(d,J=6.6Hz,1H), 6.72(s,1H),5.27(m,1H),4.84(d,J=8.2Hz,1H),4.80(d,J=5.8Hz,2H),3.97(s,3H),3.1 7(m,1H),2.68(m,2H),2.34(s,3H),2.16(s,3H),2.00(m,2H),1.83(m,2H),1.38(m,2H).

[0438] Example 11: Preparation of Compounds 11 and 11-a, 11-b

[0439] Preparation of Intermediate 11-1

[0440] 2-Chloro-5-fluoropyridine-6-carbaldehyde (24 g) and 1-(3-oxetanyl)piperazine (22.2 g) were added to N,N-dimethylformamide (240 mL), and potassium carbonate (64.8 g) was added. The reaction was stirred at 80°C for 2 h.

[0441] After the reaction was complete, the mixture was filtered and the filtrate was poured into a saturated aqueous ammonium chloride solution (500 mL). Ethyl acetate (250 mL) was added for extraction. The layers were separated and the organic phase was washed with saturated brine. The layers were separated and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 11-1 (58 g).

[0442] LC-MS: m / z 282.11 (M+H) + .

[0443] Preparation of Intermediate 11-2

[0444] Intermediate 11-1 (6 g) was added to THF (60 mL), the temperature was controlled at 0°C with stirring, and a tetrahydrofuran solution of cyclopropylmagnesium bromide (1 M, 65 mL) was slowly added. After the addition was completed, the mixture was transferred to room temperature and stirred for reaction overnight.

[0445] After the reaction was complete, the mixture was transferred to a 0°C ice-water bath for cooling. Saturated ammonium chloride solution (150 mL) was slowly added dropwise to quench the reaction. The mixture was stirred for 10 min, and DCM (200 mL) was added. The mixture was extracted and allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. After column chromatography, intermediate 11-2 (2.5 g) was obtained.

[0446] LC-MS: m / z 324.18 (M+H) + .

[0447] Preparation of Intermediate 11-3

[0448] Intermediate 11-2 (200 mg) and intermediate 1-11 (200 mg) were added to a mixed solution of tert-butanol and tetrahydrofuran (1:1, 100 mL), and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (110 mg), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (206 mg) and cesium carbonate (506 mg) were added, and the reaction was carried out at 85°C under nitrogen protection for 2 h.

[0449] After the reaction was complete, the mixture was filtered and the filtrate was extracted with ethyl acetate (100 mL) and purified water (50 mL). The mixture was stirred for 10 min and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain intermediate 11-3 (1.2 g).

[0450] LC-MS: m / z 674.35 (M+H) + .

[0451] Preparation of compound 11:

[0452] Intermediate 11-3 (1.2 g) was added to ethanol (12 mL), and sodium hydroxide solution (1 M, 6 mL) was added, and the temperature was controlled at 70° C. for 2 h.

[0453] After the reaction was complete, ethyl acetate (100 mL) and purified water (50 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and compound 11 was obtained by preparative liquid separation.

[0454] LC-MS: m / z 692.23 (M+H) + .

[0455] 1 H NMR (500MHz, DMSO-d6) δ11.25(s,1H),9.04(dd,J=4.4,1.7Hz,1H),8.56(dd,J=8.4,1.8Hz,1H),8.38 -7.72(m,5H),7.57(d,J=8.7Hz,1H),7.52(d,J=8.2Hz,1H),7.45(d,J=8.1Hz,1H),6.76(d,J=8.7Hz,1H),5.06(d,J=6.8Hz,2H),4 .76(d,J=6.0Hz,2H),4.55(t,J=6.6Hz,2H),4.45(d,J=6.2,3.1Hz,2H),3.54-3.43(m,7H),2.98-2.86(m,4H),2.78-2.65(m,2H).

[0456] Preparation of compounds 11-a and 11-b:

[0457] Compound 11 was chirally resolved to give compounds 11-a and 11-b. Separation conditions were as follows: YMC Amylose-SA 10 μm 30*250 preparative column; gradient elution with methanol-dichloromethane (0%-30% / 0-60 min); peak elution times were 23.5 min (11-a) and 25.6 min (11-b), respectively.

[0458] Compound 11-a LC-MS: m / z 692.11 (M+H) + .

[0459] Compound 11-b LC-MS: m / z 692.15 (M+H) + .

[0460] The retention time of compound 11-a in the chiral chromatographic column is shorter than that of compound 11-b, and the retention time of compound 11-b in the chiral chromatographic column is longer than that of compound 11-a.

[0461] Example 12: Preparation of Compounds 12, 12-a, and 12-b

[0462] Preparation of intermediate 12-1:

[0463] Intermediate 1-9 (10 g) was added to tetrahydrofuran (800 mL), and palladium carbon (10%, 5 g) was added. The mixture was replaced with a hydrogen balloon three times, and the mixture was stirred at room temperature for 2 h.

[0464] After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure at 40°C to obtain intermediate 12-1 (6.3 g).

[0465] LC-MS: m / z 405.16 (M+H) + .

[0466] Preparation of intermediate 12-2:

[0467] 2-Chloro-5-fluoropyridine-6-carbaldehyde (2.97 g) and 1-(3-oxetanyl)piperazine (2.64 g) were added to N,N-dimethylformamide (50 mL), and potassium carbonate (7.6 g) was added. The reaction was stirred at 85°C for 1 h.

[0468] After the reaction was completed, purified water (100 mL) and EA (100 mL) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 12-2 (3.93 g).

[0469] LC-MS: m / z 282.10 (M+H) + .

[0470] Preparation of intermediate 12-3:

[0471] Intermediate 12-2 (990 mg) was added to THF (5 mL), and under nitrogen protection, (trifluoromethyl)trimethylsilane (750 mg) and tetrabutylammonium fluoride (1 M, 1 mL) were added dropwise in sequence. The reaction was stirred at room temperature for 3 h. After the reaction was complete, saturated ammonium chloride solution (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by column chromatography (dichloromethane / methanol = 50 / 1). The eluate was concentrated under reduced pressure to obtain Intermediate 12-3 (552 mg).

[0472] LC-MS: m / z 352.14 (M+H) + .

[0473] Preparation of compound 12:

[0474] Intermediate 12-1 (100 mg) and intermediate 12-3 (95 mg) were added to tert-butanol (8 mL), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (35 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (40 mg), and lithium bistrimethylsilylamide (1 M, 0.6 mL) were added, and the reaction was stirred at 80 ° C under nitrogen protection for 2 h.

[0475] After the reaction was complete, ethyl acetate (50 mL) and purified water (50 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; compound 12 was obtained by preparative liquid separation.

[0476] LC-MS: m / z 720.29 (M+H) + .

[0477] 1 H NMR (500MHz, DMSO-d6) δ11.24(t,J=6.0Hz,1H),9.05(dd,J=4.3,1.8Hz,1H),8.57(dd,J=8.4,1.8Hz,1H),8.51(s,1H) ,8.42–8.30(m,2H),8.07(dd,J=8.5,3.1Hz,1H),7.78–7.66(m,2H),7.53(d,J=8.5Hz,2H),7.48–7.41(m,2H),6.95(d, J=8.9Hz,1H),6.73(d,J=7.6Hz,1H),5.61(p,J=7.5Hz,1H),4.76(d,J=6.0Hz,2H),4.56(t,J=6.5Hz,2H),4.46(t,J=6. 1Hz, 2H), 3.48 (p, J = 6.3Hz, 1H), 3.34 (s, 4H), 2.89 (dt, J = 10.3, 4.3Hz, 2H), 2.74 (dt, J = 10.9, 4.5Hz, 2H), 2.41 (s, 2H).

[0478] Preparation method of compounds 12-a and 12-b:

[0479] Compound 12 was chiral resolved to give compounds 12-a and 12-b. The separation conditions were as follows: a Cellulose-SC preparative column (30×250 mm, 10 μm) with n-hexane as mobile phase A and ethanol as mobile phase B, using a gradient elution method at a flow rate of 0.8 mL / min. Detection was performed at a wavelength of 254 nm, with peak elution times of 53 min (12-a) and 60 min (12-b), respectively.

[0480] Compound 12-a LC-MS: m / z 720.29 (M+H) + .

[0481] 1 H NMR(500MHz DMSO-d6)δ11.24(t,J=5.5Hz,1H),9.05(d,J=3.0Hz,1H),8.57(d,J=8.0Hz,1H),8.51(s,1H), 8.36(m,2H),8.07(dd,J=8.5,2.5Hz,1H),7.72(m,2H),7.53(d,J=8.0Hz,2H),7.45(d,J=8.0H z,2H),6.95(d,J=9.0Hz,1H),6.72(d,J=7.5Hz,1H),5.61(m,1H),4.76(d,J=6.0Hz,2H),4.56 (t,J=6.0Hz,2H),4.46(t,J=6.0Hz,2H),3.48(m,1H),2.89(m,2H),2.74(m,2H),2.41(m,4H).

[0482] Compound 12-b LC-MS: m / z 720.31 (M+H) + .

[0483] 1H NMR(500MHz DMSO-d6) δ11.24(t,J=6.0Hz,1H),9.05(d,J=4.0,1.5Hz,1H),8.57(d,J=8.5,1.5Hz,1H),8.51( s,1H),8.36(m,2H),8.07(dd,J=8.5,2.5Hz,1H),7.72(m,2H),7.53(d,J=8.0Hz,2H),7.45(d,J= 8.0Hz,2H),6.95(d,J=9.0Hz,1H),6.72(d,J=7.5Hz,1H),5.61(m,1H),4.76(d,J=6.0Hz,2H),4. 56(t,J=6.0Hz,2H),4.46(t,J=6.0Hz,2H),3.48(m,1H),2.89(m,2H),2.74(m,2H),2.41(m,4H).

[0484] The retention time of compound 12-a in the chiral chromatographic column is shorter than that of compound 12-b, while the retention time of compound 12-b in the chiral chromatographic column is longer than that of compound 12-a.

[0485] Example 13: Preparation of Compounds 13 and 13-a, 13-b

[0486] Preparation of intermediate 13-1:

[0487] Refer to the preparation steps of Intermediate 5-2 in Example 5, replace Intermediate 5-1 with Intermediate 12-2, and replace cyclopropylmagnesium bromide with ethylmagnesium bromide. After the reaction is complete, ethyl acetate is added and the mixture is concentrated under reduced pressure to obtain Intermediate 13-1 (1 g).

[0488] LC-MS: m / z 312.17 (M+H) + .

[0489] Preparation of compound 13:

[0490] Referring to the preparation steps of compound 3 in Example 3, intermediate 3-5 was replaced by intermediate 12-1, intermediate 1-3 was replaced by intermediate 13-1, and cesium carbonate was replaced by potassium carbonate. The reaction was completed, filtered and concentrated to obtain a concentrate, which was separated by preparative liquid phase to obtain compound 13.

[0491] LC-MS: m / z 680.38 (M+H) + .

[0492] 1H NMR (500MHz, DMSO-d6) δ11.25(t,J=6.0Hz,1H),9.05(dd,J=4.2,1.8Hz,1H),8.57(dd,J=8.4,1.8Hz,1H),8.36(dd,J=9.6,3.1Hz,1H),8.3 2(s,1H),8.25(d,J=7.3Hz,2H),8.07(dd,J=8.5,3.1Hz,1H),7.73(dd,J=8.4,4.3Hz,1H),7.53(t,J=8.9Hz,3H),7.48–7.39(m,2H),6.74( d,J=8.7Hz,1H),4.82(dd,J=7.3,5.5Hz,1H),4.76(d,J=6.0Hz,2H),4.55(t,J=6.5Hz,2H),4.45(td,J=6.2,1.4Hz,2H),2.92(dt,J=10.2, 4.4Hz,2H),2.72(dt,J=10.5,4.2Hz,2H),2.39(s,3H),1.71(ddd,J=16.0,13.2,7.0Hz,2H),1.24(d,J=6.7Hz,1H),0.84(t,J=7.4Hz,3H).

[0493] Preparation method of compounds 13-a and 13-b:

[0494] Compound 13 was chirally resolved to give compounds 13-a and 13-b. The separation conditions were as follows: a Cellulose-SC preparative column (30×250 mm, 10 μm) was used; mobile phase A was n-hexane, and mobile phase B was ethanol; gradient elution was performed at a flow rate of 0.8 mL / min; the detection wavelength was 254 nm, and the peak elution times were 24 min (13-a) and 27 min (13-b), respectively.

[0495] Compound 13-a LC-MS: m / z 680.35 (M+H) + .

[0496] Compound 13-b LC-MS: m / z 680.31 (M+H) + .

[0497] The retention time of compound 13-a in the chiral chromatographic column is shorter than that of compound 13-b, while the retention time of compound 13-b in the chiral chromatographic column is longer than that of compound 13-a.

[0498] Example 14: Preparation of Compound 14

[0499] Preparation of intermediate 14-1:

[0500] 5-Bromo-2-chloropyridine (2.28 g), 1-cyclopropylpiperazine (1.49 g), tris(dibenzylideneacetone)dipalladium (542 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (675 mg), and cesium carbonate (5.4 g) were added to 1,4-dioxane (50 mL), stirred at 85° C. for 2 h under nitrogen protection, filtered, and purified by column chromatography (ethyl acetate: petroleum ether = 1:1). The fraction was concentrated under reduced pressure to obtain intermediate 14-1 (2 g).

[0501] LC-MS: m / z 238.16 (M+H) + .

[0502] Preparation of compound 14:

[0503] Referring to the preparation steps of compound 3 in Example 3, intermediate 3-5 was replaced by intermediate 12-1, intermediate 1-3 was replaced by intermediate 14-1, and cesium carbonate was replaced by lithium bis(trimethylsilylamide). The reaction was completed, filtered and concentrated to obtain a concentrate, which was separated by preparative liquid phase to obtain compound 14.

[0504] LC-MS: m / z 606.37 (M+H) + .

[0505] 1 H NMR (500MHz, DMSO-d6) δ11.24(t,J=6.0Hz,1H),9.05(dd,J=4.3,1.8Hz,1H),8.57(dd,J=8.4,1.8Hz,1H),8. 36(dd,J=9.6,3.2Hz,1H),8.16–7.99(m,3H),7.79(d,J=2.9Hz,1H),7.73(dd,J=8.4,4.2Hz,1H),7.52(d,J= 8.3Hz,2H),7.46–7.39(m,2H),7.32(dd,J=9.0,3.0Hz,1H),6.77(d,J=9.0Hz,1H),5.32(t,J=5.0Hz,1H),4. 76(d,J=6.0Hz,2H),2.97(t,J=5.0Hz,4H),2.66(t,J=4.9Hz,4H),0.47–0.40(m,2H),0.33(p,J=4.0Hz,2H).

[0506] Example 15: Preparation of Compound 15

[0507] Preparation of Intermediate 15-1

[0508] 5-Bromo-2-chloropyridine (2.2 g) and 1,3-dimethylpiperazine (1.5 g) were added to 1,4-dioxane (100 mL), followed by potassium tert-butoxide (2.5 g), palladium acetate (0.5 g) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.1 g), and the mixture was stirred at 85 °C for 4 h.

[0509] After the reaction was complete, the mixture was filtered and the filtrate was poured into purified water (250 mL). Ethyl acetate (150 mL) was added for extraction. The layers were separated and the organic phase was washed with saturated brine. The layers were separated and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and column chromatography was performed to obtain intermediate 15-1 (1.2 g).

[0510] LC-MS: m / z 226.12 (M+H) + .

[0511] Preparation of intermediate 15-2

[0512] Intermediate 1-9 (8 g) was added to tetrahydrofuran (160 mL), palladium carbon (10%, 500 mg) was added, and the mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. After the reaction was complete, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain Intermediate 15-2 (6 g).

[0513] LC-MS: m / z 405.12 (M+H) + .

[0514] Preparation of compound 15:

[0515] Intermediate 15-2 (150 mg) and intermediate 15-1 (150 mg) were added to tert-butanol (38 mL), and lithium bis(trimethylsilyl)amide (1 M, 375 μL), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (80 mg) and chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (60 mg) were added, and the reaction was carried out at 85°C under nitrogen protection for 1 h.

[0516] After the reaction was complete, the product was filtered and extracted with ethyl acetate (100 mL) and purified water (100 mL). The product was stirred for 10 min and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The product was filtered and the filtrate was concentrated under reduced pressure to obtain a concentrate. Compound 15 was obtained by preparative liquid separation.

[0517] LC-MS: m / z 594.45 (M+H) + .

[0518] 1 H NMR (500MHz, DMSO-d6) δ11.25(s,1H),9.04(d,J=4.2Hz,1H),8.55(d,J=8.5Hz,1H),8.35-7.72(m,5H),7.48(dd,J=43.9,8 .1Hz,2H),7.32(dd,J=9.0,2.8Hz,2H),6.79(d,J=9.0Hz,2H),4.76(d,J=6.0Hz,2H),3.05-2.85(m,6H),2.29-2.18(m,6H).

[0519] Example 16: Preparation of Compound 16

[0520] Preparation of intermediate 16-1:

[0521] 1,2-Dimethylpiperazine (1.37 g), 2-chloro-5-bromopyridine (1.92 g), tris(dibenzylideneacetone)palladium (229 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (579 mg), and cesium carbonate (6.52 g) were added to dioxane (100 mL) and stirred at 100-105°C under nitrogen protection for 15 h.

[0522] After the reaction was complete, the temperature was lowered to room temperature; purified water (300 mL) and ethyl acetate (300 mL) were added, stirred and extracted, and the mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 16-1 (2.26 g).

[0523] LC-MS: m / z 226.18 (M+H) + .

[0524] Preparation of compound 16:

[0525] Intermediate 16-1 (113 mg), intermediate 15-2 (100 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (40 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (54 mg), and potassium bis(trimethylsilyl)amide (1 M, 1 ml) were added to tert-butanol (20 mL), and the reaction was stirred at 100 ° C, 150 W under nitrogen protection in a microwave for 1.5 h;

[0526] After the reaction was complete, ethyl acetate (100 mL) was added to dilute the mixture, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a concentrate, which was then purified by preparative liquid chromatography to obtain compound 16.

[0527] LC-MS: m / z 594.39 (M+H) + .

[0528] 1 H NMR(500MHz,DMSO-d6)δ11.25(t,J=6.0Hz,1H),9.11–8.94(m,1H),8.57(dd,J=8.5,1.9Hz,1H),8.36(dd,J=9.6,3.1Hz,1H ),8.15–8.01(m,3H),7.80(d,J=2.9Hz,1H),7.73(dd,J=8.4,4.3Hz,1H),7.47(dd,J=45.7,8.1Hz,5H),7.32(dd,J=9.0,3. 0Hz,1H),6.78(d,J=8.9Hz,1H),4.76(d,J=6.0Hz,2H),2.79(dt,J=11.3,3.0Hz,1H),2.67(td,J=11.5,3.0Hz,1H),2.40–2 .24(m,2H),2.21(d,J=7.2Hz,3H),2.14(ddt,J=9.7,6.4,3.2Hz,1H),1.22(d,J=13.1Hz,1H),1.04(dd,J=17.6,6.2Hz,3H).

[0529] Example 17: Preparation of Compounds 17 and 17-a, 17-b

[0530] Preparation of compound 17:

[0531] Intermediate 1-2 (150 mg), intermediate 15-2 (100 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (40 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (54 mg), and potassium carbonate (138 mg) were added to tert-butanol (25 mL), and the reaction was stirred at 100 ° C, 150 W under nitrogen protection in a microwave for 1.5 h;

[0532] After the reaction was complete, ethyl acetate (100 mL) was added, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; the concentrate was purified by preparative liquid phase to obtain compound 17.

[0533] LC-MS: m / z 668.43 (M+H) + .

[0534] Preparation of compounds 17-a and 17-b:

[0535] Compound 17 was chiral resolved to give compounds 17-a and 17-b. The separation conditions were as follows: a YMC-Amylose-SA preparative column (30×150 mm, 10 μm); mobile phase A was n-hexane, and mobile phase B was 0.2% diethylamineethanol; gradient elution was performed at a flow rate of 40 mL / min; the detection wavelength was 254 nm, and the peak elution times were 18.0 min (17-a) and 24.0 min (17-b), respectively.

[0536] Compound 17-a LC-MS: m / z 668.41 (M+H) + .

[0537] Compound 17-b LC-MS: m / z 668.44 (M+H) + .

[0538] The retention time of compound 17-a in the chiral chromatographic column is shorter than that of compound 17-b, while the retention time of compound 17-b in the chiral chromatographic column is longer than that of compound 17-a.

[0539] Example 18: Preparation of Compound 18

[0540] Preparation of compound 18-1:

[0541] 2-Bromo-5-fluoropyridine-6-carbaldehyde (3 g) and N,N-dimethyl-1,4-cyclohexanediamine (3.2 g) were added to N,N-dimethylformamide (40 mL), and potassium carbonate (8.1 g) was added. The reaction was stirred at 120°C for 12 h.

[0542] After the reaction was complete, purified water (200 mL) and ethyl acetate (200 mL) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 18-1 (6.4 g).

[0543] LC-MS: m / z 326.14 (M+H) + .

[0544] Preparation of intermediate 18-2:

[0545] Refer to the preparation steps of Intermediate 10-2 in Example 10, replace Intermediate 10-1 with Intermediate 18-1, and the reaction is completed to obtain Intermediate 18-2 (384 mg).

[0546] LC-MS: m / z 396.21 (M+H) + .

[0547] Preparation of compound 18:

[0548] Referring to the preparation steps of compound 3 in Example 3, intermediate 1-3 was replaced by intermediate 18-2, and the reaction was completed to obtain compound 18.

[0549] LC-MS: m / z 722.14 (M+H) + .

[0550] 1 H NMR(500MHz DMSO-d6)δ8.46(t,J=6.0Hz,1H),8.23(m,2H),8.06(s,1H),7.90(d,J=5.8Hz,1H),7 .43(m,2H),7.38(m,3H),7.17(d,J=9.0Hz,1H),6.94(dd,J=9.0,4.0Hz,1H),6.87(d, J=5.7Hz,1H),6.84(d,J=9.0Hz,1H),5.27(m,1H),4.81(m,3H),4.00(s,3H),3.14(m ,1H),2.42(m,1H),2.31(m,6H),1.99(m,2H),1.86(m,2H),1.35(m,2H),1.16(m,2H).

[0551] Example 19: Preparation of Compound 19

[0552] Preparation of intermediate 19-1:

[0553] Intermediate 11-1 (281 mg) was added to THF (10 mL), and cyclopropanol (78 uL) was added dropwise under nitrogen protection; after the addition was completed, sodium hydride (48 mg) was added at 0°C; after stirring for 3 h, ethylmagnesium bromide (2 M; 1.0 mL) was directly added dropwise and stirred for 3 h. After the reaction was complete, saturated sodium chloride solution (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by column chromatography to obtain intermediate 19-1 (90 mg).

[0554] LC-MS: m / z 352.25 (M+H) + .

[0555] Preparation of compound 19:

[0556] Refer to the preparation steps of compound 3 in Example 3, replace Intermediate 1-3 with Intermediate 19-1, and replace Intermediate 3-5 with Intermediate 8-8.

[0557] The reaction was complete and compound 19 was obtained by preparative liquid separation.

[0558] LC-MS: m / z 736.42 (M+H) + .

[0559] 1 H NMR(500MHz,DMSO-d6)δ8.34(q,J=5.2Hz,1H),8.09(s,1H),8.04(s,1H),7.48(d,J=8.4Hz,2H),7.41–7.28(m ,4H),6.82(dd,J=8.8,4.2Hz,1H),6.75–6.58(m,3H),4.82–4.75(m,2H),4.55(t,J=6.5Hz,2H),4.45(t,J=6. 0Hz,2H),3.97(s,3H),3.90(s,1H),3.47(t,J=6.4Hz,1H),2.83(s,3H),2.48(q,J=1.9Hz,2H),2.39(s,3H),2 .34(s,2H),2.04–1.96(m,1H),1.93(d,J=1.3Hz,2H),1.56–1.44(m,2H),1.24(s,3H),0.83(q,J=8.4Hz,3H).

[0560] Example 20: Preparation of Compound 20

[0561] Preparation of intermediate 20-1:

[0562] (S)-4-N-tert-Butyloxycarbonyl-2-methylpiperazine (4.4 g), 2-chloro-5-fluoropyridine-6-aldehyde (3.19 g), and potassium carbonate (8.28 g) were added to N,N-dimethylformamide (40 mL) under nitrogen atmosphere and stirred at 80°C for 1.5 h. After the reaction was complete, purified water (400 mL) and ethyl acetate (400 mL) were added, and the mixture was stirred and extracted. The mixture was allowed to stand for separation. The organic phase was washed with aqueous citric acid, saturated brine, and dried over anhydrous sodium sulfate. Filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 20-1 (3.6 g).

[0563] LC-MS: m / z 284.0 (MC(CH3)3+2H) + .

[0564] Preparation of intermediate 20-2:

[0565] Intermediate 20-1 (1.8 g) was added to a solution of hydrogen chloride in ethyl acetate (4 M, 10 mL) and stirred at room temperature for 3 h. After the reaction was complete, the mixture was concentrated under reduced pressure to give Intermediate 20-2 (2.4 g).

[0566] LC-MS: m / z 240.1 (M+H) + .

[0567] Preparation of compound 20-3:

[0568] Intermediate 20-2 (2.4 g), 2-bromoethyl methyl ether (736 mg), and potassium carbonate (2.92 g) were added to N,N-dimethylformamide (10 mL) under nitrogen atmosphere and stirred at 80°C for 15 h. After the reaction was complete, purified water (200 mL) and ethyl acetate (200 mL) were added, stirred, and extracted. The mixture was allowed to stand for separation. The aqueous phase was adjusted to a pH of 8-9 with aqueous sodium carbonate solution, extracted with ethyl acetate (200 mL), allowed to stand for separation, and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure to yield Intermediate 20-3 (1.7 g).

[0569] LC-MS: m / z 298.1 (M+H) + .

[0570] Preparation of intermediate 20-4:

[0571] Intermediate 20-3 (1.7 g) was added to THF (50 mL), stirred at -20°C, and methylmagnesium bromide solution (3 M, 2.85 mL) was slowly added. After the addition was completed, the reaction was stirred at -20°C for 4 h.

[0572] After the reaction was complete, aqueous ammonium chloride (100 mL) was added to quench the reaction, and ethyl acetate (100 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 20-4 (0.47 g).

[0573] LC-MS: m / z 314.18 (M+H) + .

[0574] Preparation of compound 20:

[0575] Intermediate 20-4 (157 mg), intermediate 15-2 (100 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (40 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (54 mg), and potassium carbonate (138 mg) were added to tert-butanol (25 mL), and the reaction was stirred in a microwave at 100 ° C, 150 W under nitrogen protection;

[0576] After the reaction was complete, ethyl acetate (100 mL) was added to dilute the mixture, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a concentrate, which was then purified by preparative liquid phase to obtain compound 20.

[0577] LC-MS: m / z 682.36 (M+H) + .

[0578] 1 H NMR (500MHz, DMSO-d6) δ11.25(t,J=6.0Hz,1H),9.05(dd,J=4.2,1.8Hz,1H),8.57(dd,J=8.4,1.8Hz,1H),8.36(td,J=4.9,3 .1Hz,2H),8.29(s,1H),8.07(dd,J=8.5,3.1Hz,1H),7.73(dd,J=8.4,4.2Hz,2H),7.63–7.39(m,6H),6.76(d,J=8.8Hz,1H),5 .32(d,J=5.1Hz,1H),5.14(q,J=6.4Hz,1H),4.76(d,J=6.0Hz,2H),3.46(t,J=5.8Hz,3H),3.10–3.02(m,1H),2.97–2.77(m,3 H),2.76–2.65(m,1H),2.22(t,J=10.2Hz,1H),1.99–1.81(m,1H),1.35(d,J=6.3Hz,3H),1.24(s,2H),0.70(d,J=6.2Hz,3H).

[0579] Example 21: Preparation of Compound 21

[0580] Preparation of intermediate 21-1:

[0581] 2-Chloro-5-bromopyridine (3 g), N-methylpiperazine (1.88 g), tris(dibenzylideneacetone)dipalladium (0.72 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.91 g) and cesium carbonate (15.2 g) were added to dioxane (30 mL) and stirred at 85 ° C for 16 h under nitrogen protection;

[0582] After the reaction was complete, ethyl acetate (50 mL) and purified water (50 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure; and purified by column chromatography to obtain intermediate 21-1 (0.82 g).

[0583] LC-MS: m / z 212.16 (M+H) + .

[0584] Preparation of compound 21:

[0585] Intermediate 21-1 (95 mg), intermediate 15-2 (100 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (39.5 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (53.1 mg) and potassium bis(trimethylsilyl)amide (0.5 ml) were added to tert-butanol (10 mL), and the reaction was stirred at 100°C for 2 h under nitrogen protection;

[0586] After the reaction was complete, ethyl acetate (20 mL) and purified water (20 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and purified by preparative liquid phase to obtain compound 21.

[0587] LC-MS: m / z 580.33 (M+H) + .

[0588] 1 H NMR (500MHz, DMSO-d6) δ11.24(t,J=6.1Hz,1H),9.05(dd,J=4.3,1.8Hz,1H),8.57(dd,J=8.4,1.8H z,1H),8.36(dd,J=9.6,3.1Hz,1H),8.11(s,1H),8.09–8.04(m,2H),7.81(d,J=3.0Hz,1H),7.73(dd ,J=8.4,4.2Hz,1H),7.52(d,J=8.3Hz,2H),7.43(d,J=8.5Hz,2H),7.32(dd,J=9.0,3.0Hz,1H),6.78 (d,J=8.9Hz,1H),4.76(d,J=6.0Hz,2H),3.01(t,J=4.9Hz,4H),2.44(t,J=4.9Hz,4H),2.21(s,3H).

[0589] Example 22: Preparation of Compound 22

[0590] Preparation of intermediate 22-1:

[0591] Preparation of Intermediate 14-1 in Reference Example 14, 1-cyclopropylpiperazine was replaced with 4-tert-butyloxycarbonyl-2-methylpiperazine. After the reaction was complete, ethyl acetate (30 mL) and purified water (20 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 22-1 (1.1 g).

[0592] LC-MS: m / z 312.15 (M+H) + .

[0593] Preparation of intermediate 22-2:

[0594] Intermediate 22-1 (1.1 g) was added to ethyl acetate (10 mL), and hydrochloric acid ethyl acetate solution (5 mL, 4 M) was added. The mixture was stirred at room temperature overnight. After the reaction was complete, saturated NaHCO3 solution was added to adjust the pH to >7. n-Butanol (30 mL) and purified water (20 mL) were added, stirred for 10 min, and allowed to stand for separation. The aqueous phase was extracted with n-Butanol (30 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to obtain Intermediate 22-2 (564 mg).

[0595] LC-MS: m / z 212.14 (M+H) + .

[0596] Preparation of intermediate 22-3:

[0597] Referring to the preparation of compound 4 in Example 4, Intermediate 4-2 was replaced with Intermediate 22-2, and the reaction was stirred at room temperature for 12 h. After the reaction was complete, DCM (30 mL) and purified water (20 mL) were added, stirred for 10 min, and allowed to stand for separation. The aqueous phase was extracted with DCM (20 mL × 3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate. Preparative liquid separation was performed to obtain Intermediate 22-3 (326 mg).

[0598] LC-MS: m / z 268.14 (M+H) + .

[0599] Preparation of compound 22:

[0600] Referring to the preparation steps of compound 3 in Example 3, intermediate 3-5 was replaced by intermediate 15-2, intermediate 1-3 was replaced by intermediate 22-3, and cesium carbonate was replaced by lithium bis(trimethylsilylamide). The reaction was completed, filtered and concentrated to obtain a concentrate, which was separated by preparative liquid phase to obtain compound 22.

[0601] LC-MS: m / z 636.40 (M+H) + .

[0602] Example 23: Preparation of Compound 23

[0603] Preparation of intermediate 23-1:

[0604] Intermediate 1-1 (2 g), cesium fluoride (1.61 g) and (trifluoromethyl)trimethylsilane (1.51 g) were added to tetrahydrofuran (30 mL) and stirred at room temperature overnight;

[0605] After the reaction was complete, saturated ammonium chloride solution (50 mL) and dichloromethane (50 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with dichloromethane (50 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 23-1 (2.56 g).

[0606] LC-MS: m / z 354.15 (M+H) + .

[0607] Preparation of compound 23:

[0608] Intermediate 23-1 (183 mg), intermediate 15-2 (150 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (59.3 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (79.7 mg) and potassium bis(trimethylsilyl)amide (0.37 ml) were added to tert-butanol (80 mL), and the reaction was stirred at 85°C under nitrogen protection for 1 h.

[0609] After the reaction was complete, ethyl acetate (20 mL) and purified water (20 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and purified by preparative liquid phase to obtain compound 23.

[0610] LC-MS: m / z 722.34 (M+H) + .

[0611] 1H NMR (500MHz, DMSO-d6) δ11.24(t,J=6.0Hz,1H),9.05(dd,J=4.3,1.8Hz,1H),8.57(dd,J=8.5,1.8Hz,1H),8.50(s, 1H),8.36(d,J=9.7Hz,2H),8.07(dd,J=8.6,3.1Hz,1H),7.73(dd,J=8.4,4.3Hz,1H),7.69(d,J=8.9Hz,1H),7.53( d,J=8.4Hz,2H),7.45(d,J=8.5Hz,2H),6.94(d,J=8.9Hz,1H),6.81(d,J=7.5Hz,1H),5.60(p,J=7.6Hz,1H),4.76( d,J=6.0Hz,2H),3.46(t,J=5.8Hz,2H),3.25(s,3H),2.89–2.83(m,2H),2.74–2.68(m,2H),2.53(t,J=5.9Hz,5H).

[0612] Example 24: Preparation of Compounds 24, 24-a, and 24-b

[0613] Preparation of intermediate 24-1:

[0614] Intermediate 1-1 (917 mg) and (difluoromethyl)trimethylsilane (8.03 g) were added to tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (2 mL, 1 M) was slowly added dropwise. The reaction was allowed to proceed at room temperature for 1 h. After the reaction was complete, ethyl acetate (30 mL) and purified water (20 mL) were added, stirred for 10 min, and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to obtain intermediate 24-1 (700 mg).

[0615] LC-MS: m / z 336.15 (M+H) + .

[0616] Preparation of compound 24:

[0617] Referring to the preparation steps of compound 3 in Example 3, intermediate 3-5 was replaced by intermediate 15-2, intermediate 1-3 was replaced by intermediate 24-1, and cesium carbonate was replaced by lithium bis(trimethylsilylamide). The reaction was completed, filtered and concentrated to obtain a concentrate, which was separated by preparative liquid phase to obtain compound 24.

[0618] LC-MS: m / z 704.34 (M+H) + .

[0619] 1 H NMR (500MHz, DMSO-d6) δ11.24(t,J=6.0Hz,1H),9.05(dd,J=4.3,1.8Hz,1H),8.57(dd,J=8.4,1.8Hz,1H) ,8.42–8.33(m,2H),8.18(s,1H),8.07(dd,J=8.5,3.1Hz,1H),7.73(dd,J=8.4,4.2Hz,2H),7.61(d,J=8.9 Hz,1H),7.52(d,J=8.5Hz,2H),7.48–7.41(m,2H),6.84(d,J=8.9Hz,1H),6.23–6.04(m,2H),5.13(dd,J=1 2.8, 6.6Hz, 1H), 4.76 (d, J = 6.0Hz, 2H), 3.46 (s, 2H), 3.25 (s, 3H), 2.89 (s, 2H), 2.73 (s, 2H), 2.07 (s, 1H).

[0620] Preparation method of compound 24-a, 24-b:

[0621] Compound 24 was chiral resolved to give compounds 24-a and 24-b. The separation conditions were as follows: a Cellulose-SC preparative column (30×250 mm, 10 μm) with n-hexane as mobile phase A and ethanol as mobile phase B, using a gradient elution method at a flow rate of 0.8 mL / min. Detection was performed at a wavelength of 254 nm, with peak elution times of 36 min (24-a) and 45 min (24-b), respectively.

[0622] Compound 24-a LC-MS: m / z 704.25 (M+H) + .

[0623] Compound 24-b LC-MS: m / z 704.14 (M+H) + .

[0624] The retention time of compound 24-a in the chiral chromatographic column is shorter than that of compound 24-b, while the retention time of compound 24-b in the chiral chromatographic column is longer than that of compound 24-a.

[0625] Example 25: Preparation of Compound 25

[0626] Preparation of intermediate 25-1:

[0627] Intermediate 5-2 (0.8 g) was added to THF (20 mL), stirred at 0°C, and sodium hydrogen sulfide (60%, 0.17 g) was slowly added. After stirring at room temperature for 1 h, iodomethane (0.36 g) was added and the mixture was stirred at room temperature for 2 h.

[0628] After the reaction was complete, purified water (20 mL) was added to quench the mixture, stirred for 10 min, and extracted with ethyl acetate (20 mL). The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 25-1.

[0629] LC-MS: m / z 296.11 (M+H) + .

[0630] Preparation of compound 25:

[0631] Intermediate 25-1 (125 mg), intermediate 15-2 (120 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (47.2 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (63.5 mg) and potassium bis(trimethylsilyl)amide (0.3 mL) were added to tert-butanol (12 mL), and the reaction was stirred at 85°C under nitrogen protection for 0.5 h;

[0632] After the reaction was complete, ethyl acetate (20 mL) and purified water (20 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and purified by preparative liquid phase to obtain compound 25.

[0633] LC-MS: m / z 664.39 (M+H) + .

[0634] 1 H NMR (500MHz, DMSO-d6) δ11.14(s,1H),8.91(s,1H),8.42(d,J=8.3Hz,1H),8.34–8. 12(m,3H),7.93(d,J=8.5Hz,1H),7.59(s,2H),7.46–7.35(m,3H),7.30(d,J=8.2Hz, 2H),6.67(d,J=8.5Hz,1H),4.63(s,2H),4.01(d,J=8.7Hz,1H),3.01(s,3H),2.60( d,J=45.3Hz,4H),2.29(s,4H),2.08(s,3H),0.49(s,1H),0.34(s,1H),0.20(s,1H).

[0635] Example 26: Preparation of Compound 26

[0636] Preparation of intermediate 26-1:

[0637] 1-9 (8 g) was added to tetrahydrofuran (800 mL), and palladium carbon (10%, 4 g) was added. The mixture was replaced with a hydrogen balloon three times, and the reaction was stirred at room temperature for 2 h.

[0638] After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure at 40°C to obtain intermediate 26-1 (4.5 g).

[0639] LC-MS: m / z 405.16 (M+H) + .

[0640] Preparation of intermediate 26-2:

[0641] 2-Chloro-5-fluoropyridine-6-carbaldehyde (5 g) and 1-(3-oxetanyl)piperazine (4.5 g) were added to N,N-dimethylformamide (80 mL), and potassium carbonate (17.3 g) was added. The reaction was stirred at 80°C for 6 h.

[0642] After the reaction was complete, purified water (200 mL) and ethyl acetate (200 mL) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 26-2 (6.4 g).

[0643] LC-MS: m / z 282.34 (M+H) + .

[0644] Preparation of intermediate 26-3:

[0645] Refer to the preparation steps of Intermediate 10-2 in Example 10, replace Intermediate 10-1 with Intermediate 26-2, and the reaction is completed to obtain Intermediate 26-3 (1.1 g).

[0646] LC-MS: m / z 352.41 (M+H) + .

[0647] Preparation of intermediate 26-4:

[0648] Refer to the preparation steps of Intermediate 10-3 in Example 10, replace Intermediate 10-2 with Intermediate 26-3, and the reaction is completed to obtain Intermediate 26-4 (150 mg).

[0649] LC-MS: m / z 366.22 (M+H) + .

[0650] Preparation of compound 26:

[0651] Intermediate 26-4 (137 mg) and intermediate 26-1 (70 mg) were added to tert-butanol (5 mL) and 1,4-dioxane (5 mL), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (28 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (15 mg), and lithium bistrimethylsilylamide (1 M, 0.5 mL) were added, and the reaction was stirred at 80°C under nitrogen protection for 2 h.

[0652] After the reaction was complete, ethyl acetate (100 mL) and purified water (100 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; compound 26 was obtained by preparative liquid separation.

[0653] LC-MS: m / z 734.15 (M+H) + .

[0654] 1 H NMR(500MHz,DMSO-d6)δ11.25(s,1H),9.05(dd,J=4.3,1.8Hz,1H),8.64–8.52 (m,2H),8.36(d,J=9.0Hz,2H),8.07(dd,J=8.5,3.1Hz,1H),7.85–7.65(m,3H), 7.58–7.40(m,5H),7.01(d,J=8.9Hz,1H),5.57(q,J=7.3Hz,1H),4.77(d,J=6.0 Hz,2H),4.63–4.37(m,4H),3.59–3.43(m,1H),2.94–2.66(m,4H),2.43(s,3H).

[0655] Example 27: Preparation of Compound 27

[0656] Preparation of Intermediate 27-1

[0657] Intermediate 11-2 (2 g) was added to THF (30 mL), stirred at 0°C, and sodium hydroxide (60%, 296 mg) was slowly added. After stirring for 20 min, iodomethane (269 μL) was added, and the mixture was transferred to room temperature and stirred for 12 h.

[0658] After the reaction was complete, purified water (50 mL) was added to quench the mixture, stirred for 10 min, and ethyl acetate (100 mL) was added for extraction. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 27-1 (1.9 g).

[0659] LC-MS: m / z 338.15 (M+H) + .

[0660] Preparation of compound 27:

[0661] Intermediate 27-1 (150 mg) and intermediate 15-2 (150 mg) were added to tert-butanol (38 mL), and lithium bis(trimethylsilyl)amide (1 M, 375 μL), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (80 mg) and chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (60 mg) were added, and the mixture was reacted at 85°C under nitrogen protection for 1 h.

[0662] The reaction was complete and filtered. Ethyl acetate (100 mL) and purified water (100 mL) were added to the filtrate for extraction, stirred for 10 min, and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to obtain a concentrate. Compound 27 was obtained by preparative liquid separation.

[0663] LC-MS: m / z 706.12 (M+H) + .

[0664] Example 28: Preparation of Compound 28

[0665] Preparation of intermediate 28-1:

[0666] Intermediate 26-2 (1 g) was added to THF (20 mL), and ethylmagnesium bromide (3 M, 4 mL) was added dropwise under nitrogen protection at -20°C. After the addition, the mixture was stirred at 0°C for 3 h. After the reaction was complete, saturated ammonium chloride solution (20 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 28-1 (800 mg).

[0667] LC-MS: m / z 312.24 (M+H) + .

[0668] Preparation of intermediate 28-2:

[0669] Refer to the preparation steps of Intermediate 10-3 in Example 10, replace Intermediate 10-2 with Intermediate 28-1, and the reaction is completed to obtain Intermediate 28-2 (550 mg).

[0670] LC-MS: m / z 326.41 (M+H) + .

[0671] Preparation of compound 28:

[0672] Referring to the preparation steps of compound 26 in Example 26, intermediate 26-4 was replaced with intermediate 28-2, and the reaction was completed to obtain compound 28.

[0673] LC-MS: m / z 694.32 (M+H) + .

[0674] Example 29: Preparation of Compound 29

[0675] Preparation of intermediate 29-1:

[0676] Intermediate 6-1 (1.1 g) was added to THF (30 mL), stirred at 0°C, and sodium hydroxide (60%, 0.2 g) was slowly added. The mixture was stirred at room temperature for 1 h, and then iodomethane (0.38 g) was added. The mixture was stirred at room temperature for 2 h.

[0677] After the reaction was complete, purified water (20 mL) was added to quench the mixture, stirred for 10 min, and extracted with ethyl acetate (20 mL). The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 29-1.

[0678] LC-MS: m / z 340.18 (M+H) + .

[0679] Preparation of compound 29:

[0680] Intermediate 29-1 (150 mg), intermediate 15-2 (120 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (47.2 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (63.5 mg) and potassium bis(trimethylsilyl)amide (0.3 mL) were added to tert-butanol (12 mL), and the reaction was stirred at 85°C under nitrogen protection for 0.5 h;

[0681] After the reaction was complete, ethyl acetate (20 mL) and purified water (20 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and purified by preparative liquid phase to obtain compound 29.

[0682] LC-MS: m / z 708.44 (M+H) + .

[0683] 1 H NMR (500MHz, DMSO-d6) δ11.12(t,J=6.1Hz,1H),8.90(d,J=4.3Hz,1H),8.41(d,J=8.4Hz,1H),8.21(d,J=12.7Hz,3H),7.91(dd,J= 8.4,3.2Hz,1H),7.58(dd,J=8.4,4.3Hz,1H),7.42(s,1H),7.41–7.37(m,2H),7.31(d,J=8.1Hz,2H),6.66(d,J=8.7Hz,1H),4.63( d,J=6.0Hz,2H),4.01(d,J=8.8Hz,1H),3.30(t,J=5.8Hz,2H),3.10(s,3H),3.01(s,3H),2.64(q,J=5.3Hz,2H),2.59–2.51(m,2H) ,1.27–1.17(m,1H),1.10(d,J=17.2Hz,1H),0.48(dd,J=9.4,5.0Hz,1H),0.33(dd,J=9.6,4.9Hz,1H),0.19(dt,J=9.3,4.5Hz,1H).

[0684] Example 30: Preparation of Compound 30

[0685] Preparation of compound 30:

[0686] 1-(4-Bromophenyl)-4-methylpiperazine (63 mg), intermediate 15-2 (100 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (41 mg), cesium carbonate (160 mg), 1,4-dioxane (10 mL), reacted at 80 ° C for 3 h under nitrogen protection, the reaction was complete, filtered and concentrated to obtain a concentrate, which was separated by preparative liquid phase to obtain compound 30.

[0687] LC-MS: m / z 579.28 (M+H) + .

[0688] Example 31: Preparation of Compound 31

[0689] Preparation of intermediate 31-1:

[0690] 2-Chloro-5-fluoropyridine-6-carbaldehyde (1.6 g), 4-amino-1-methylpiperidine (1.14 g), and potassium carbonate (4.2 g) were added to DMF (40 mL) and stirred at 80°C for 2 hours. The mixture was cooled to room temperature, and ethyl acetate (40 mL) and purified water (30 mL) were added. The mixture was stirred for 10 minutes and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 31-1 (2.1 g).

[0691] LC-MS: m / z 254.21 (M+H) + .

[0692] Preparation of intermediate 31-2:

[0693] Intermediate 31-1 (2.1 g), hydrazine hydrate (85%, 1.8 g), KOH (1.9 g), and ethylene glycol (30 mL) were added to the reaction flask. After nitrogen replacement three times, the mixture was stirred at 140° C. for 2 hours.

[0694] After the reaction was complete, the temperature was lowered to room temperature, ethyl acetate (30 mL) and purified water (30 mL) were added, and the mixture was stirred for 10 min. The mixture was allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (30 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Intermediate 31-2 (1.3 g) was obtained by column chromatography (dichloromethane / methanol = 10 / 1).

[0695] LC-MS: m / z 240.27 (M+H) + .

[0696] Preparation of compound 31:

[0697] Intermediate 31-2 (86 mg) and intermediate 15-2 (100 mg) were added to tert-butanol (20 mL), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (69 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (79 mg), and potassium carbonate (150 mg) were added, and the reaction was stirred at 80°C under nitrogen protection for 3 h.

[0698] After the reaction was complete, ethyl acetate (30 mL) and purified water (30 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; compound 31 was obtained by preparative liquid separation.

[0699] LC-MS: m / z 608.37 (M+H) + .

[0700] Example 32: Preparation of Compound 32

[0701] Preparation of Intermediate 32-1

[0702] Intermediate 5-1 (1.2 g) was added to THF (24 mL), the temperature was controlled at 0°C with stirring, and a tetrahydrofuran solution of 3-butenylmagnesium bromide (1 M, 6 mL) was slowly added. After the addition was complete, the mixture was transferred to room temperature and stirred for reaction overnight.

[0703] After the reaction was complete, the mixture was transferred to a 0°C ice-water bath for cooling. Saturated ammonium chloride solution (50 mL) was slowly added dropwise to quench the reaction. The mixture was stirred for 10 min at this temperature. DCM (100 mL) was added, extracted, and allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Intermediate 32-1 (550 mg) was obtained after column chromatography.

[0704] LC-MS: m / z 296.21 (M+H) + .

[0705] Preparation of compound 32:

[0706] Intermediate 5-1 (120 mg) and intermediate 15-2 (120 mg) were added to tert-butanol (30 mL), and lithium bis(trimethylsilyl)amide (1 M, 300 μL), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (64 mg) and chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (48 mg) were added, and the reaction was carried out at 85°C under nitrogen protection for 1 h.

[0707] After the reaction was complete, the product was filtered and extracted with ethyl acetate (100 mL) and purified water (100 mL). The mixture was stirred for 10 min and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The product was filtered and the filtrate was concentrated under reduced pressure to obtain a concentrate. Compound 32 was obtained by preparative liquid separation.

[0708] LC-MS: m / z 664.17 (M+H) + .

[0709] 1 H NMR(500MHz,DMSO-d6)δ11.25(s,1H),9.10–8.88(m,2H),8.56(dd,J=8.4,1.8Hz,1H),8.40–8.20(m,5H),8.06(dd,J=8.5,3.1Hz,2H),7.72(dd,J =8.4,4.2Hz,2H),6.74(d,J=8.7Hz,2H),5.22–4.86(m,5H),4.76(d,J=6 .0Hz,4H),2.88-2.67(m,4H),2.43(s,3H),2.05(dd,J=15.1,7.8Hz,2H).

[0710] Example 33: Preparation of Compound 33

[0711] Preparation of intermediate 33-1:

[0712] N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (7 g) and hydrochloric acid-ethyl acetate solution (50 ml) were added to ethyl acetate (15 ml) and stirred at room temperature for 1 h;

[0713] After the reaction is completed, the mixture is concentrated to dryness to obtain intermediate 33-1.

[0714] LC-MS: m / z 210.18 (M+H) + .

[0715] Preparation of intermediate 33-2:

[0716] Intermediate 33-1 (5.3 g), 1-iodo-2-methoxyethane (5 g) and triethylamine (6.9 g) were added to acetonitrile (70 ml) and stirred at room temperature overnight.

[0717] After the reaction was complete, ethyl acetate (50 mL) and purified water (50 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 33-2.

[0718] LC-MS: m / z 268.18 (M+H) + .

[0719] Preparation of intermediate 33-3:

[0720] Intermediate 33-2 (8.2 g), 3-bromo-6-chloropyridine-2-carboxaldehyde (4.5 g), DPPF palladium dichloride (1.5 g), and potassium carbonate (9.5 g) were added to dioxane (150 ml) and purified water (30 ml) and reacted at 80°C for 1 h;

[0721] After the reaction was complete, ethyl acetate (50 mL) and purified water (50 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 33-3.

[0722] LC-MS: m / z 281.10 (M+H) + .

[0723] Preparation of intermediate 33-4:

[0724] Refer to the preparation steps of compound 7-1 in Example 7, replace intermediate 5-1 with intermediate 33-3, and the reaction is completed to obtain intermediate 33-4.

[0725] LC-MS: m / z 297.14 (M+H) + .

[0726] Preparation of intermediate 33-5:

[0727] Intermediate 33-4 (5.14 g) and platinum dioxide (1.67 g) were added to methanol (100 ml), and the atmosphere was replaced with hydrogen three times. The reaction was allowed to proceed at room temperature overnight.

[0728] The reaction was completed, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 33-5.

[0729] LC-MS: m / z 299.14 (M+H) + .

[0730] Preparation of compound 33:

[0731] Intermediate 33-5 (114 mg), intermediate 15-2 (120 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (47.2 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (63.5 mg) and potassium bis(trimethylsilyl)amide (0.3 ml) were added to tert-butanol (15 mL), and the reaction was stirred at 85°C under nitrogen protection for 0.5 h.

[0732] After the reaction was complete, ethyl acetate (20 mL) and purified water (20 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and purified by preparative liquid phase to obtain compound 33.

[0733] LC-MS: m / z 667.40 (M+H) + .

[0734] 1 H NMR(500MHz,DMSO-d6)δ11.27(s,1H),9.05(s,1H),8.57(s,1H),8.37(s,1H),8 .27(d,J=25.0Hz,2H),8.07(s,1H),7.73(s,2H),7.51(d,J=32.2Hz,6H),6.73( s,1H),4.93(d,J=30.9Hz,2H),4.84–4.73(m,2H),3.45(s,3H),3.25(s,3H),2. 97(s,2H),2.79(s,1H),2.07(s,2H),1.60(d,J=27.0Hz,3H),1.44–1.33(m,3H).

[0735] Example 34: Preparation of Compound 34

[0736] Preparation of intermediate 34-1:

[0737] 5-Bromo-2-chloropyridine (2 g), 4-dimethylaminopiperidine (1.4 g), tris(dibenzylideneacetone)dipalladium (952 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (902 mg) and cesium carbonate (6.8 g) were added to 1,4-dioxane (50 mL), the atmosphere was replaced with nitrogen three times, and the reaction was stirred at 85°C for 4 h.

[0738] After the reaction was complete, ethyl acetate (100 mL) and purified water (100 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 34-1 (3.5 g).

[0739] LC-MS: m / z 240.23 (M+H) + .

[0740] Preparation of compound 34:

[0741] Refer to the preparation steps of compound 26 in Example 26, replace intermediate 26-4 with intermediate 34-1, and the reaction is completed to obtain compound 34.

[0742] LC-MS: m / z 608.41 (M+H) + .

[0743] Example 35: Preparation of Compound 35

[0744] Preparation of intermediate 35-1:

[0745] Refer to the preparation steps of intermediate 5-1 in Example 5, replace N-methylpiperazine with 1-cyclopropylpiperazine, the reaction is complete, filtered, and the filtrate is extracted with purified water (100 mL) and ethyl acetate (100 mL). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain intermediate 35-1 (4.37 g).

[0746] LC-MS: m / z 266.15 (M+H) + .

[0747] Preparation of intermediate 35-2:

[0748] Refer to the preparation steps of Intermediate 1-2 in Example 1, replacing Intermediate 1-1 with Intermediate 35-1, and replacing the methylmagnesium bromide solution with cyclopropylmagnesium bromide solution. After the reaction is complete, purified water (150 mL) is added to quench the reaction, stirring for 10 minutes, and ethyl acetate (200 mL) is added, followed by extraction. The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain Intermediate 35-2 (4 g).

[0749] LC-MS: m / z 308.18 (M+H) + .

[0750] Preparation of intermediate 35-3:

[0751] Refer to the preparation steps of Intermediate 1-3 in Example 1, replacing Intermediate 1-2 with Intermediate 35-2 and replacing iodomethane with deuterated iodomethane. After completion of the reaction, purified water (150 mL) was added to quench the reaction, stirred for 10 min, and ethyl acetate (200 mL) was added, extracted, and allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 35-3 (312 mg).

[0752] LC-MS: m / z 325.25 (M+H) + .

[0753] Preparation of compound 35:

[0754] Referring to the preparation steps of compound 3 in Example 3, intermediate 3-5 was replaced by intermediate 26-1, intermediate 1-3 was replaced by intermediate 35-3, and cesium carbonate was replaced by potassium carbonate. After the reaction was completed, the concentrate was filtered and concentrated to obtain a concentrate, which was separated by preparative liquid phase to obtain compound 35.

[0755] LC-MS: m / z 693.50 (M+H) + .

[0756] Example 36: Preparation of Compound 36

[0757] Preparation of intermediate 36-1:

[0758] N-tert-Butyloxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (500 mg), 2-chloro-5-bromopyridine-6-carbaldehyde (710 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (120 mg) and potassium carbonate (1.2 g) were added to 1,4-dioxane (10 mL) and purified water (2 mL), the atmosphere was replaced with nitrogen three times, and the reaction was stirred at 95 ° C for 4 h.

[0759] After the reaction was complete, ethyl acetate (100 mL) and purified water (100 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 36-1 (600 mg).

[0760] LC-MS: m / z 267.15 (MC(CH3)3+2H) + .

[0761] Preparation of intermediate 36-2:

[0762] Refer to the preparation steps of Intermediate 6-1 in Example 6, replace Intermediate 1-1 with Intermediate 36-1, and the reaction is completed to obtain Intermediate 36-2 (800 mg).

[0763] LC-MS: m / z 365.21 (M+H) + .

[0764] Preparation of intermediate 36-3:

[0765] Intermediate 36-2 (800 mg) was added to methanol (15 mL), and platinum dioxide (500 mg) was added. The atmosphere was replaced with hydrogen three times, and the mixture was stirred at room temperature for 12 h.

[0766] After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure at 40°C to obtain intermediate 36-3 (1 g).

[0767] LC-MS: m / z 367.17 (M+H) + .

[0768] Preparation of intermediate 36-4:

[0769] Intermediate 36-3 (1 g) was added to dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 2 h.

[0770] After the reaction was complete, the reaction solution was added to water, and sodium bicarbonate aqueous solution (1 M, 30 mL) was added to adjust the pH to about 7-8. Dichloromethane (40 mL) was added for extraction, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 36-4 (100 mg).

[0771] LC-MS: m / z 267.14 (M+H) + .

[0772] Preparation of intermediate 36-5:

[0773] Intermediate 36-4 (100 mg) and 3-oxetanone (34 mg) were dissolved in methanol (4 mL) and dichloromethane (4 mL), and sodium triacetoxyborohydride (159 mg) was added and reacted at room temperature for 12 h.

[0774] After the reaction was complete, ethyl acetate (50 mL) and purified water (50 mL) were added to the reaction solution, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 36-5.

[0775] LC-MS: m / z 323.13 (M+H) + .

[0776] Preparation of compound 36:

[0777] Refer to the preparation steps of compound 26 in Example 26, replace intermediate 26-4 with intermediate 36-5, and the reaction is completed to obtain compound 36.

[0778] LC-MS: m / z 691.25 (M+H) + .

[0779] Example 37: Preparation of Compounds 37-a and 37-b

[0780] Preparation of intermediate 37-1:

[0781] 2-Methyl-3-bromo-5-chloropyridine (2.27 g), 4-dimethylaminocyclohexylamine hydrochloride (2.52 g), tris(dibenzylideneacetone)dipalladium (850 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (1.18 g), sodium tert-butoxide (5.1 g), and toluene (180 mL) were added to the reaction flask. After nitrogen replacement three times, the reaction was stirred at 100 ° C for 2 hours.

[0782] After the reaction was complete, the temperature was lowered to room temperature, ethyl acetate (80 mL) and purified water (60 mL) were added, and the mixture was stirred for 10 min. The mixture was allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (580 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Intermediate 37-1 (1.4 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1).

[0783] LC-MS: m / z 268.29 (M+H) + .

[0784] Preparation of compounds 37-a and 37-b:

[0785] Intermediate 37-1 (170 mg) and intermediate 8-8 (260 mg) were added to tert-butanol (40 mL), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (160 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (220 mg), and lithium bistrimethylsilylamide (1 M, 770 uL) were added, and the reaction was stirred at 80 ° C under nitrogen protection for 3 h.

[0786] After the reaction was complete, ethyl acetate (30 mL) and purified water (30 mL) were added, stirred for 10 min, and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The product was filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate. Compounds 37-a and 37-b were obtained by preparative liquid phase separation. The preparation conditions were as follows: a Chiral AM-4 10 μm 20×250 mm column was used, with a gradient elution of 0.2% diethylamine-methanol-25% dichloromethane-n-hexane (5%-50% / 0-40 min) at a flow rate of 25 mL / min and detection at a wavelength of 254 nm. Compounds 37-a (retention time 15.2 min) and 37-b (retention time 17.1 min) were obtained, respectively.

[0787] Compound 37-a LC-MS: m / z 652.41 (M+H) + .

[0788] Compound 37-b LC-MS: m / z 652.39 (M+H) + .

[0789] Compound 37-b 1 H NMR(500MHz,DMSO-d6)δ8.02(s,1H),7.51(d,J=8.5Hz,3H),7.45(d,J=8.4 Hz,2H),7.24(s,2H),7.14(s,2H),7.04(s,2H),6.85(s,1H),6.75(d,J=9. 0Hz,1H),4.93(s,2H),2.76(d,J=4.7Hz,7H),2.40(d,J=6.2Hz,6H),1.90( d,J=13.6Hz,2H),1.78(t,J=11.8Hz,5H),1.67–1.53(m,3H),1.24(s,2H).

[0790] The retention time of compound 37-a in the chiral chromatographic column is shorter than that of compound 37-b, while the retention time of compound 37-b in the chiral chromatographic column is longer than that of compound 37-a.

[0791] Example 38: Preparation of Compound 38

[0792] Preparation of intermediate 38-1:

[0793] 2-Chloro-5-iodopyridine (1 g), N,N-dimethyl-1,4-cyclohexanediamine (1.4 g), tris(dibenzylideneacetone)dipalladium (193 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (243 mg) and sodium tert-butoxide solution (1 M, 21 mL) were added to dioxane (45 mL) and stirred at 85 ° C under nitrogen protection for 5 h.

[0794] After the reaction was complete, the product was filtered through celite. The filtrate was added with purified water (50 mL) and ethyl acetate (50 mL), stirred for 10 min, and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 38-1 (940 mg).

[0795] LC-MS: m / z 254.21 (M+H) + .

[0796] Preparation of compound 38:

[0797] Referring to the preparation steps of compound 9 in Example 9, intermediate 8-8 was replaced by intermediate 15-2, and intermediate 9-2 was replaced by intermediate 38-1. The reaction was completed and compound 38 was obtained by preparative liquid separation.

[0798] LC-MS: m / z 622.44 (M+H) + .

[0799] 1 H NMR (500MHz, DMSO-d6) δ11.24(t,J=6.0Hz,1H),9.04(dd,J=4.3,1.9Hz,1H),8.57(dd,J=8.4,1.9Hz,1H),8.36(dd,J=9 .6,3.1Hz,1H),8.23(s,1H),8.09–8.05(m,1H),7.83(d,J=12.7Hz,1H),7.73(dd,J=8.4,4.2Hz,1H),7.59–7.49(m,3H), 7.45–7.37(m,2H),6.96(dd,J=8.9,2.9Hz,1H),6.69(t,J=8.6Hz,1H),4.76(d,J=6.1Hz,2H),2.23(d,J=7.6Hz,6H),2. 04–1.96(m,2H),1.83(d,J=12.6Hz,2H),1.46(s,1H),1.34–1.27(m,2H),1.24(d,J=5.8Hz,2H),1.10(d,J=12.4Hz,1H).

[0800] Example 39: Preparation of Compound 39

[0801] Preparation of intermediate 39-1:

[0802] N-tert-Butyloxycarbonyl-piperazine (10 g) was added to THF (200 mL), and lithium aluminum hydride (4.5 g) was added under nitrogen protection and temperature controlled at 0°C; the reaction was stirred at room temperature overnight; after the reaction was completed under ice bath, sodium sulfate decahydrate (21 g) was added to quench the reaction, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 39-1 (3.58 g).

[0803] LC-MS: m / z 104.13 (M+H) + .

[0804] Preparation of intermediate 39-2:

[0805] 2-Chloro-5-fluoropyridine-6-carbaldehyde (5.54 g), 39-1 (3.58 g), and potassium carbonate (14.4 g) were added to N,N-dimethylformamide (55 mL), and the reaction was stirred at 80°C for 2 h.

[0806] After the reaction was complete, the mixture was filtered and the filtrate was extracted with purified water (100 mL) and ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate 39-2 (6 g).

[0807] LC-MS: m / z 243.14 (M+H) + .

[0808] Preparation of compound 39-3:

[0809] Intermediate 39-2 (6 g) was added to THF (40 mL), and the mixture was stirred at -20°C under nitrogen protection. Cyclopropylmagnesium bromide solution (1 M, 30 mL) was slowly added dropwise. After the addition, the temperature was slowly raised to 0°C and the mixture was stirred for 3 h.

[0810] After the reaction was complete, purified water (100 mL) was added to quench the mixture, stirred for 10 min, and ethyl acetate (100 mL) was added for extraction. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 39-3 (6.2 g).

[0811] LC-MS: m / z 285.18 (M+H) + .

[0812] Preparation of intermediate 39-4:

[0813] Intermediate 39-3 (6.2 g) was added to THF (100 mL), stirred at 0°C, and sodium hydroxide (60%, 980 mg) was slowly added. After stirring for 20 min, deuterated iodomethane (3.4 g) was added, and the mixture was transferred to room temperature and stirred for 4 h.

[0814] After the reaction was complete, purified water (100 mL) was added to quench the mixture, stirred for 10 min, and ethyl acetate (150 mL) was added for extraction. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 39-4 (5.8 g).

[0815] LC-MS: m / z 302.17 (M+H) + .

[0816] Preparation of compound 39:

[0817] Intermediate 39-4 (90 mg) and Intermediate 15-2 (92 mg) were added to tert-butanol (6 mL), followed by methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (39 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (51 mg), and lithium bis(trimethylsilylamide) (504 mg). The mixture was stirred at 85°C for 2 h under nitrogen. After the reaction was complete, ethyl acetate (100 mL) and purified water (1 M, 80 uL) were added, stirred for 10 min, and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (10 mL x 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered, and concentrated under reduced pressure to obtain the concentrate. Compound 39 was obtained by preparative liquid separation.

[0818] LC-MS: m / z 670.41 (M+H) + .

[0819] Example 40: Preparation of Compound 40

[0820] Preparation of intermediate 40-1:

[0821] Referring to the preparation steps of compound 1-3 in Example 1, iodomethane was replaced with iodoethane to obtain intermediate 40-1.

[0822] LC-MS: m / z 328.24 (M+H) + .

[0823] Preparation of compound 40:

[0824] Intermediate 40-1 (218 mg), intermediate 15-2 (150 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (59.3 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (63.5 mg) and potassium bis(trimethylsilyl)amide (0.3 ml) were added to tert-butanol (15 mL), and the reaction was stirred at 85°C under nitrogen protection for 0.5 h.

[0825] After the reaction was complete, ethyl acetate (20 mL) and purified water (20 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and purified by preparative liquid phase to obtain compound 40.

[0826] LC-MS: m / z 696.48 (M+H) + .

[0827] Example 41: Preparation of Compound 41

[0828] Preparation of intermediate 41-1:

[0829] 2-Chloro-5-fluoropyridine-6-carbaldehyde (1 g) and 4-dimethylaminopiperidine (844 mg) were added to N,N-dimethylformamide (30 mL), and potassium carbonate (2.6 g) was added. The mixture was stirred at 80°C for 2 h.

[0830] After the reaction was complete, purified water (200 mL) and ethyl acetate (200 mL) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 41-1 (1.5 g).

[0831] LC-MS: m / z 268.31 (M+H) + .

[0832] Preparation of intermediate 41-2:

[0833] Refer to the preparation steps of Intermediate 10-2 in Example 10, replace Intermediate 10-1 with Intermediate 41-1, and the reaction is completed to obtain Intermediate 41-2 (1.1 g).

[0834] LC-MS: m / z 338.22 (M+H) + .

[0835] Preparation of compound 41:

[0836] Referring to the preparation steps of compound 26 in Example 26, intermediate 26-4 was replaced with intermediate 41-2, and the reaction was completed to obtain compound 41.

[0837] LC-MS: m / z 706.35 (M+H) + .

[0838] 1H NMR(500MHz DMSO-d6) δ11.24(t,J=6.0Hz,1H),9.05(dd,J=4.0,2.0Hz,1H),8.57(dd,J=8.5,1.5Hz,1H),8.4 8(s,1H),8.36(m,2H),8.07(dd,J=8.5,3.0Hz,1H),7.73(dd,J=8.5,4.0Hz,1H),7.66(d,J=9.0Hz ,1H),7.53(d,J=8.5Hz,2H),7.44(d,J=8.5Hz,2H),6.92(m,2H),5.57(m,1H),4.76(d,J=6.0Hz, 2H),2.94(m,1H),2.79(m,2H),2.66(m,1H),2.21(s,6H),1.83(m,2H),1.50(m,2H),1.25(m,2H).

[0839] Example 42: Preparation of Compound 42

[0840] Preparation of intermediate 42-1:

[0841] Intermediate 41-1 (5.36 g) was added to THF (100 mL), the temperature was controlled at -20°C with stirring, and cyclopropylmagnesium bromide solution (1 M, 40 mL) was slowly added. After the addition was completed, the temperature was controlled at -20°C with stirring and the reaction was continued.

[0842] After the reaction was complete, aqueous ammonium chloride (100 mL) was added to quench the reaction, and ethyl acetate (200 mL) was added for extraction. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 42-1 (6.2 g).

[0843] LC-MS: m / z 310.18 (M+H) + .

[0844] Preparation of intermediate 42-2:

[0845] Intermediate 42-1 (0.93 g) was added to THF (30 mL), stirred in an ice bath, and sodium bicarbonate (60%, 0.18 g) was slowly added. After stirring evenly, iodomethane (213 mg) was added; the reaction mixture was transferred to room temperature and stirred.

[0846] After the reaction was complete, purified water (50 mL) was added to quench the reaction, and ethyl acetate (50 mL) was added for extraction. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain intermediate 42-2 (400 mg).

[0847] LC-MS: m / z 324.22 (M+H)+ .

[0848] Preparation of compound 42:

[0849] Intermediate 42-2 (81 mg), intermediate 15-2 (100 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (40 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (54 mg), and lithium bis(trimethylsilyl)amide (1 M, 250 uL) were added to tert-butanol (50 mL), and the reaction was stirred at 85°C under nitrogen protection for 0.5 h.

[0850] After the reaction was complete, ethyl acetate (100 mL) was added to dilute the mixture, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a concentrate, which was then purified by preparative liquid chromatography to obtain compound 42.

[0851] LC-MS: m / z 692.44 (M+H) + .

[0852] 1 H NMR(500MHz,DMSO-d6)δ11.25(t,J=6.1Hz,1H),9.05(dd,J=4.3,1.8Hz,1H),8.57 (dd,J=8.4,1.8Hz,1H),8.47–8.19(m,3H),8.07(dd,J=8.5,3.1Hz,1H),7.73(dd,J =8.4,4.3Hz,1H),7.52(dd,J=8.6,3.7Hz,3H),7.46–7.41(m,2H),6.78(d,J=8.7Hz ,1H),4.76(d,J=6.0Hz,2H),4.14(d,J=8.8Hz,1H),3.22–3.16(m,1H),3.15(s,2H) ,2.88(d,J=11.1Hz,1H),2.77(d,J=11.1Hz,1H),2.73–2.57(m,2H),2.20(s,5H),2 .18–2.10(m,1H),1.81(d,J=12.1Hz,2H),1.48(tq,J=12.6,5.8Hz,2H),1.35(ddt, J=13.2,8.5,4.2Hz,1H),1.28–1.21(m,2H),0.62(tt,J=9.0,4.3Hz,1H),0.49(dq, J=9.6,4.8Hz,1H),0.34(tdd,J=9.0,5.7,4.1Hz,1H),0.14(dq,J=9.6,4.7Hz,1H).

[0853] Example 43: Preparation of Compound 43

[0854] Preparation of intermediate 43-1:

[0855] Intermediate 41-2 (1 g) was added to THF (20 mL), and sodium bicarbonate (60%, 144 mg) was slowly added at room temperature. After stirring evenly, iodomethane (213 mg) was added and the mixture was stirred at room temperature to react.

[0856] After the reaction was complete, purified water was added to quench the reaction solution, and the reaction solution was concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain intermediate 43-1.

[0857] LC-MS: m / z 352.16 (M+H) + .

[0858] Preparation of compound 43:

[0859] Intermediate 43-1 (132 mg), intermediate 15-2 (150 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (60 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (81 mg), and lithium bis(trimethylsilyl)amide (1 M, 375 ul) were added to tert-butanol (75 mL) and the reaction was stirred at 85°C under nitrogen protection;

[0860] After the reaction was complete, ethyl acetate (100 mL) was added to dilute the mixture, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a concentrate, which was then purified by preparative liquid chromatography to obtain compound 43.

[0861] LC-MS: m / z 720.50 (M+H) + .

[0862] Example 44: Preparation of Compound 44

[0863] Preparation of intermediate 44-1:

[0864] Referring to the preparation steps of compound 1-3 in Example 1, iodomethane was replaced with deuterated iodomethane to obtain intermediate 44-1.

[0865] LC-MS: m / z 317.21 (M+H) + .

[0866] Preparation of compound 44:

[0867] Intermediate 44-1 (164 mg), intermediate 15-2 (150 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (59.3 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (63.5 mg) and potassium bis(trimethylsilyl)amide (0.3 ml) were added to tert-butanol (15 mL), and the reaction was stirred at 85°C under nitrogen protection for 0.5 h.

[0868] After the reaction was complete, ethyl acetate (20 mL) and purified water (20 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and purified by preparative liquid phase to obtain compound 44.

[0869] LC-MS: m / z 685.48 (M+H) + .

[0870] 1 H NMR (500MHz, DMSO-d6) δ11.24(t,J=6.1Hz,1H),9.05(dd,J=4.3,1.8Hz,1H),8.57(dd,J=8.4,1.8Hz,1H),8. 37(d,J=3.1Hz,1H),8.32(s,1H),8.31(s,1H),8.07(dd,J=8.5,3.1Hz,1H),7.73(dd,J=8.4,4.3Hz,1H),7.5 5–7.50(m,3H),7.45(s,1H),7.44(d,J=1.8Hz,1H),6.79(d,J=8.7Hz,1H),4.97(q,J=6.4Hz,1H),4.76(d,J= 6.0Hz,2H),3.46(t,J=5.8Hz,2H),3.25(s,3H),2.81–2.68(m,4H),1.36(d,J=6.4Hz,3H),1.31–1.13(m,4H).

[0871] Example 45: Preparation of Compound 45

[0872] Preparation of intermediate 45-1:

[0873] Intermediate 31-1 (2.7 g) was added to THF (150 mL), and cyclopropylmagnesium bromide (1 M, 30 mL) was added dropwise under nitrogen protection at a temperature of -10 to 0°C. After the addition, the mixture was stirred at the same temperature for 2 h. After the reaction was complete, saturated ammonium chloride solution (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by column chromatography (DCM: methanol = 12:1) to give intermediate 45-1 (0.46 g).

[0874] LC-MS: m / z 296.25 (M+H) + .

[0875] Preparation of compound 45:

[0876] Intermediate 45-1 (297 mg) and intermediate 15-2 (278 mg) were added to tert-butanol (50 mL), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (140 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (170 mg), and lithium bis(trimethylsilyl)amide (1 M, 740 uL) were added, and the reaction was stirred at 80 ° C under nitrogen protection for 2 h.

[0877] After the reaction was complete, ethyl acetate (30 mL) and purified water (30 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and compound 45 was obtained by preparative liquid separation.

[0878] LC-MS: m / z 664.37 (M+H) + .

[0879] 1H NMR (500MHz, DMSO-d6) δ11.24(t,J=6.0Hz,1H),9.04(dd,J=4.3,1.8Hz,1H),8.56(dd,J=8.4,1.8Hz,1H),8.36(dd,J=9.6,3.1Hz,1H),8. 24(s,1H),8.07(dd,J=8.5,3.1Hz,1H),7.91(s,1H),7.73(dd,J=8.4,4.3Hz,1H),7.55–7.49(m,2H),7.45–7.40(m,2H),7.04(d,J=8.8Hz ,1H),6.68(d,J=8.7Hz,1H),5.50(s,1H),5.05(s,1H),4.76(d,J=6.0Hz,2H),4.00(d,J=7.9Hz,1H),2.69(d,J=11.3Hz,2H),2.19(s,3H) ,2.14–2.03(m,2H),1.91(s,3H),1.46–1.33(m,3H),0.50(ddd,J=11.4,8.0,5.6Hz,1H),0.41(tq,J=6.0,2.5Hz,2H),0.33–0.22(m,1H).

[0880] Example 46: Preparation of Compound 46

[0881] Preparation of intermediate 46-1:

[0882] Intermediate 2-1 (700 mg) was added to THF (70 mL), stirred at 0°C, and sodium hydroxide (60%, 91 mg) was slowly added. After stirring for 20 min, deuterated iodomethane (357 mg) was added, and the mixture was transferred to room temperature and stirred for 4 h.

[0883] After the reaction was complete, purified water (50 mL) was added to quench the mixture, stirred for 10 min, and ethyl acetate (100 mL) was added for extraction. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 46-1 (208 mg).

[0884] LC-MS: m / z 303.14 (M+H) + .

[0885] Preparation of compound 46:

[0886] Referring to the preparation steps of compound 9 in Example 9, intermediate 8-8 was replaced by intermediate 15-2, and intermediate 9-2 was replaced by intermediate 46-1, and compound 46 was obtained by preparative liquid separation.

[0887] LC-MS: m / z 671.43 (M+H) + .

[0888] Example 47: Preparation of Compound 47

[0889] Preparation of intermediate 47-1:

[0890] Refer to the preparation steps of Intermediate 28-1 in Example 28, replace Intermediate 26-2 with Intermediate 41-1, and the reaction is completed to obtain Intermediate 47-1 (3.3 g).

[0891] LC-MS: m / z 298.25 (M+H) + .

[0892] Preparation of intermediate 47-2:

[0893] Refer to the preparation steps of Intermediate 10-3 in Example 10, replace Intermediate 10-2 with Intermediate 47-1, and the reaction is completed to obtain Intermediate 47-2 (400 mg).

[0894] LC-MS: m / z 312.25 (M+H) + .

[0895] Preparation of compound 47:

[0896] Referring to the preparation steps of compound 26 in Example 26, intermediate 26-4 was replaced with intermediate 47-2, and the reaction was completed to obtain compound 47.

[0897] LC-MS: m / z 680.34 (M+H) + .

[0898] 1H NMR(500MHz DMSO-d6) δ11.25(t,J=6.0Hz,1H),9.05(dd,J=4.2,1.5Hz,1H),8.57(dd,J=8.5,1.5Hz,1H),8.52(s,1H),8.48(s,1H),8. 36(dd,J=9.5,3.0Hz,1H),8.27(s,1H),8.08(dd,J=8.5,3.0Hz,1H),7.73(dd,J=8.5,4.0Hz,1H),7.65(brs,1H),7.52(d, J=8.5Hz,2H),7.48(d,J=9.0Hz,1H),7.44(d,J=8.5Hz,2H),6.77(d,J=8.5Hz,1H),4.85(t,J=6.5Hz,1H),4.76(d,J=6.0H z,2H),3.22(m,2H),3.07(s,9H),2.96(m,1H),2.79(m,1H),2.62(m,1H),2.18(m,2H),1.80(m,4H),0.85(t,J=7.0Hz,3H).

[0899] Example 48: Preparation of Compounds 48-a and 48-b

[0900] Preparation of intermediate 48-1:

[0901] 2-Chloro-5-fluoropyridine-6-carbaldehyde (3.6 g), (R)-4-Boc-2-methylpiperazine (5.10 g), and potassium carbonate (6.1 g) were added to DMF (100 mL) and stirred at 80°C for 3 hours. The mixture was cooled to room temperature, and ethyl acetate (50 mL) and purified water (30 mL) were added. The mixture was stirred for 10 minutes and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 48-1 (4.1 g).

[0902] LC-MS: m / z 340.21 (M+H) + .

[0903] Preparation of intermediate 48-2:

[0904] Intermediate 48-1 (1.52 g), THF (150 mL), and CsF (2.36 g) were added to the reaction flask, and TMSCF3 (2.40 g) was added under stirring. After nitrogen replacement three times, the reaction was stirred at room temperature for 3 hours.

[0905] After the reaction was complete, ethyl acetate (50 mL) and purified water (30 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 48-2 (1.32 g).

[0906] LC-MS: m / z 410.27 (M+H) + .

[0907] Preparation of intermediate 48-3:

[0908] Intermediate 48-2 (1.32 g) and ethyl acetate (30 mL) were added to the reaction flask, and hydrogen chloride / ethyl acetate (2 M, 30 mL) was added with stirring. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain Intermediate 48-3 (1.12 g).

[0909] LC-MS: m / z 310.12 (M+H) + .

[0910] Preparation of intermediate 48-4:

[0911] To a reaction flask, intermediate 48-3 (1.12 g), zinc chloride (120 mg), triethylamine (3.6 g), methanol (200 mL), and cyclobutanone (1.20 g) were added. After nitrogen substitution three times, the reaction was stirred at 65°C for 6 hours. The temperature was cooled to room temperature, and sodium cyanoborohydride (1.24 g) was added portionwise and stirred overnight. Ethyl acetate (80 mL) and purified water (60 mL) were added, stirred for 10 minutes, and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (60 mL x 2). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 48-4 (1.24 g).

[0912] LC-MS: m / z 366.06 (M+H) + .

[0913] Preparation of compounds 48-a and 48-b:

[0914] Intermediate 48-4 (150 mg) and intermediate 15-2 (158 mg) were added to tert-butanol (30 mL), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (70 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (90 mg), and lithium bis(trimethylsilyl)amide (1 M, 385 uL) were added, and the reaction was stirred at 80 ° C under nitrogen protection for 3 h.

[0915] After the reaction was complete, ethyl acetate (30 mL) and purified water (30 mL) were added, stirred for 10 min, and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The product was filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate. Compounds 48-a and 48-b were separated by preparative liquid phase separation. The preparation conditions were as follows: a YMCAQC18 (50 × 250 mm, 10 μm) preparative column was used; 0.5% formic acid-water was used as mobile phase A, and acetonitrile was used as mobile phase B. Gradient elution was performed at a flow rate of 50 mL / min. The detection wavelength was 254 nm, and the peak elution times were 45.23 min (48-a) and 49.52 min (48-b), respectively.

[0916] Compound 48-a LC-MS: m / z 734.27 (M+H) + .

[0917] 1 H NMR(500MHz,DMSO-d6)δ11.25(t,J=6.0Hz,1H),9.12–9.01(m,1H),8.62–8.53(m,2H),8.40(s,1H),8.36(dd,J=9.6,3.1Hz,1H),8.06(dd,J=8.5,3.2 Hz,1H),7.75–7.69(m,2H),7.53(d,J=8.5Hz,2H),7.48–7.43(m,2H),6.98 (d,J=8.9Hz,1H),6.36(d,J=7.4Hz,1H),5.83(p,J=7.0Hz,1H),4.77(d,J=6 .0Hz,2H),4.56(q,J=6.4Hz,2H),4.46(dt,J=9.2,6.1Hz,2H),3.46(t,J=6 .3Hz,1H),3.01(dqd,J=9.1,6.1,2.5Hz,1H),2.87(td,J=11.3,2.7Hz,1H) ,2.81–2.69(m,2H),2.60(dt,J=11.3,2.8Hz,1H),2.02(td,J=11.1,3.1Hz ,1H),1.73(t,J=10.2Hz,1H),1.24(d,J=4.7Hz,1H),0.70(d,J=6.3Hz,3H).

[0918] Compound 48-b LC-MS: m / z 734.26 (M+H) + .

[0919] 1H NMR(500MHz,DMSO-d6)δ11.25(q,J=5.0Hz,1H),9.13–9.00(m,1H),8.63–8.53(m,2H),8.45–8.33(m,2H),8.06(dd ,J=8.5,3.2Hz,1H),7.75–7.68(m,2H),7.53(d,J=8.3Hz,2H),7.45(d,J=8.3Hz,2H),6.98(d,J=8.9Hz,1H),5.67( q, J=7.7Hz, 1H), 4.77 (d, J=6.0Hz, 2H), 4.56 (td, J=6.5, 3.2Hz, 2H), 4.47 (dt, J=10.2, 6.1Hz, 2H), 3.15 (ddt, J=9. 5,6.3,3.4Hz,1H),2.89–2.68(m,4H),2.09(dt,J=10.9,6.2Hz,1H),1.74(t,J=10.3Hz,1H),0.70(d,J=6.2Hz,3H).

[0920] The retention time of compound 48-a in the chiral chromatographic column is shorter than that of compound 48-b, while the retention time of compound 48-b in the chiral chromatographic column is longer than that of compound 48-a.

[0921] Example 49: Preparation of Compounds 49-a and 49-b

[0922] Preparation of compounds 49-a and 49-b:

[0923] Refer to the preparation steps of compound 26 in Example 26, replacing intermediate 26-4 with intermediate 18-2.

[0924] The reaction was complete, yielding compounds 49-a and 49-b. The following conditions were used for the following: a YMC AQ C18 preparative column (30 × 250 mm, 10 μm) with 0.1% acetic acid as mobile phase A and acetonitrile as mobile phase B, with gradient elution at a flow rate of 30 mL / min; the detection wavelength was 254 nm, and the peak elution times were 33 min (49-a) and 35 min (49-b), respectively.

[0925] Compound 49-a LC-MS: m / z 720.23 (M+H) + .

[0926] Compound 49-b LC-MS: m / z 720.21 (M+H) + .

[0927] Compound 49-b 1H NMR(500MHz DMSO-d6) δ11.25(t,J=6.0Hz,1H),9.04(dd,J=4.2,1.5Hz,1H),8.57(dd,J=8.5,1.5Hz,1H),8.36(dd,J=9. 5,3.0Hz,1H),8.22(s,1H),8.07(dd,J=8.5,3.0Hz,1H),8.02(s,1H),7.73(dd,J=8.5,4.0Hz,1H),7.52(d, J=8.5Hz,2H),7.43(d,J=8.5Hz,2H),7.19(brs,1H),7.13(d,J=9.0Hz,1H),6.83(d,J=9.0Hz,1H),6.64(m, 1H), 5.32 (m, 1H), 5.24 (m, 1H), 4.76 (d, J = 6.0Hz, 2H), 3.45 (m, 1H), 2.17 (s, 6H), 2.01 (m, 2H), 1.58 (m, 8H).

[0928] The retention time of compound 49-a in the chiral chromatographic column is shorter than that of compound 49-b, while the retention time of compound 49-b in the chiral chromatographic column is longer than that of compound 49-a.

[0929] Example 50: Preparation of Compound 50

[0930] Preparation of intermediate 50-1:

[0931] 2-Bromo-5-fluoropyridine-6-carbaldehyde (18 g) and 4-amino-1-methylpiperidine (10.1 g) were added to N,N-dimethylformamide (200 mL), and potassium carbonate (36 g) was added. The mixture was stirred at 80°C for 2 h.

[0932] After the reaction was complete, purified water (400 mL) and ethyl acetate (400 mL) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 50-1 (22 g).

[0933] LC-MS: m / z 298.15 (M+H) + .

[0934] Preparation of intermediate 50-2:

[0935] Refer to the preparation steps of Intermediate 10-2 in Example 10, replace Intermediate 10-1 with Intermediate 50-1, and the reaction is completed to obtain Intermediate 50-2 (21 g).

[0936] LC-MS: m / z 368.42 (M+H) + .

[0937] Preparation of intermediate 50-3:

[0938] Refer to the preparation steps of Intermediate 10-3 in Example 10, replace Intermediate 10-2 with Intermediate 50-2, and the reaction is completed to obtain Intermediate 50-3 (510 mg).

[0939] LC-MS: m / z 382.16 (M+H) + .

[0940] Preparation of compound 50:

[0941] Referring to the preparation steps of compound 26 in Example 26, intermediate 26-4 was replaced with intermediate 50-3, and the reaction was completed to obtain compound 50.

[0942] LC-MS: m / z 706.11 (M+H) + .

[0943] 1 H NMR(500MHz DMSO-d6) δ11.24(t,J=6.0Hz,1H),9.04(dd,J=4.2,1.5Hz,1H),8.57(dd,J=8.5,1.5Hz,1H),8.36(dd,J=9.5,3. 0Hz,1H),8.32(s,1H),8.12(s,1H),8.07(dd,J=8.5,3.0Hz,1H),7.73(dd,J=8.5,4.0Hz,1H),7.52(d,J=8.5Hz, 2H),7.43(d,J=8.5Hz,2H),7.21(d,J=9.0Hz,1H),6.89(d,J=9.0Hz,1H),5.24(m,1H),4.76(d,J=6.0Hz,2H),4. 71(d,J=8.0Hz,1H),3.38(s,3H),3.23(m,1H),2.72(m,2H),2.19(s,3H),2.05(m,2H),1.85(m,2H),1.39(m,2H).

[0944] Example 51: Preparation of Compound 51

[0945] Preparation of intermediate 51-1:

[0946] Intermediate 45-1 (180 mg) and 2,6-lutidine (210 mg) were added to DCM (20 mL). The atmosphere was replaced with nitrogen three times, and trifluoromethanesulfonic anhydride (540 mg) was added dropwise at -78 to -70°C. The reaction was stirred at the same temperature for 2 h. Methanol (20 mL) was added, and the mixture was allowed to warm to room temperature and stirred overnight. Saturated ammonium chloride solution (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford Intermediate 51-1 (180 mg).

[0947] LC-MS: m / z 310.25 (M+H) + .

[0948] Preparation of compound 51:

[0949] Intermediate 51-1 (180 mg) and intermediate 15-2 (265 mg) were added to tert-butanol (40 mL), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (106 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (144 mg), and lithium bis(trimethylsilyl)amide (1 M, 670 uL) were added, and the reaction was stirred at 80°C under nitrogen protection for 2 h.

[0950] After the reaction was complete, ethyl acetate (30 mL) and purified water (30 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and compound 51 was obtained by preparative liquid separation.

[0951] LC-MS: m / z 678.40 (M+H) + .

[0952] 1H NMR (500MHz, DMSO-d6) δ11.24(t,J=6.1Hz,1H),9.04(dd,J=4.3,1.8Hz,1H),8.56(dd,J=8.4,1.8Hz,1H),8.36(dd,J=9.6,3.1Hz,1H) ,8.23(s,1H),8.07(dd,J=8.5,3.1Hz,1H),7.94(s,1H),7.73(dd,J=8.4,4.2Hz,1H),7.54–7.50(m,2H),7.45–7.41(m,2H),7.08(d,J= 8.9Hz,1H),6.73(d,J=8.7Hz,1H),4.77(t,J=7.7Hz,3H),3.68(d,J=8.6Hz,1H),3.20(s,3H),2.68(d,J=10.4Hz,2H),2.18(s,3H),2.1 0(d,J=8.3Hz,2H),1.95–1.85(m,2H),1.44–1.33(m,3H),1.27–1.22(m,1H),0.66–0.54(m,1H),0.51–0.34(m,2H),0.33–0.21(m,1H).

[0953] Example 52: Preparation of Compound 52

[0954] Preparation of intermediate 52-1:

[0955] 5-Chloro-2-fluorobenzonitrile (3 g), N,N-dimethyl-1,4-cyclohexanediamine (3.21 g) and potassium carbonate (6.21 g) were added to N,N-dimethylformamide (30 mL) and stirred at 85°C for 2 h.

[0956] After the reaction was complete, the mixture was filtered and the filtrate was extracted with purified water (50 mL) and ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate 52-1 (4.6 g).

[0957] LC-MS: m / z 279.22 (M+H) + .

[0958] Preparation of intermediate 52-2:

[0959] Intermediate 52-1 (1 g) was added to THF (10 mL), and ethylmagnesium bromide (3 M, 1.8 mL) was added dropwise under nitrogen protection at -20°C. After the addition, the reaction was stirred at 0°C for 3 h. After the reaction was complete, saturated ammonium chloride solution (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 52-2 (925 mg).

[0960] LC-MS: m / z 310.22 (M+H) + .

[0961] Preparation of intermediate 52-3:

[0962] Intermediate 52-2 (1 g) was added to methanol (10 mL), and sodium borohydride (244 mg) was slowly added, and the reaction was stirred at room temperature for 3 h.

[0963] After the reaction was complete, purified water (10 mL) was added to quench the mixture, stirred for 10 min, and DCM (30 mL) was added for extraction. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 52-3 (700 mg).

[0964] LC-MS: m / z 312.42 (M+H) + .

[0965] Preparation of intermediate 52-4:

[0966] Intermediate 52-3 (100 mg) was added to THF (5 mL), stirred at 0°C, and sodium hydroxide (60%, 50 mg) was slowly added. After stirring for 20 min, chloromethane solution (2 M, 2.5 mL) was added, and the mixture was transferred to room temperature and stirred for 12 h.

[0967] After the reaction was complete, purified water (10 mL) was added to quench the mixture, stirred for 10 min, and ethyl acetate (20 mL) was added for extraction. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 52-4 (94 mg).

[0968] LC-MS: m / z 326.36 (M+H) + .

[0969] Preparation of compound 52:

[0970] Referring to the preparation steps of compound 9 in Example 9, intermediate 8-8 was replaced by intermediate 15-2, and intermediate 9-2 was replaced by intermediate 52-4, and compound 52 was obtained by preparative liquid separation.

[0971] LC-MS: m / z 694.56 (M+H)+ .

[0972] 1 H NMR (500MHz, DMSO-d6) δ11.24(t,J=6.1Hz,1H),9.04(dd,J=4.3,1.8Hz,1H),8.56(dd,J=8.4,1.8Hz,1H),8.36(dd,J=9.6,3.1H z,1H),8.21(s,1H),8.07(dd,J=8.5,3.1Hz,1H),7.93(s,1H),7.73(dd,J=8.3,4.2Hz,1H),7.54–7.50(m,2H),7.44–7.41(m,2H) ,7.08(d,J=8.9Hz,1H),6.71(d,J=8.7Hz,1H),4.76(d,J=6.0Hz,2H),4.63(d,J=8.7Hz,1H),4.25(t,J=7.1Hz,1H),3.18(s,3H), 2.17(s,6H),2.01(td,J=11.5,3.4Hz,2H),1.31–1.27(m,2H),1.25(d,J=12.5Hz,4H),1.14–1.05(m,2H),0.87(t,J=7.4Hz,4H).

[0973] Example 53: Preparation of Compound 53

[0974] Preparation of intermediate 53-1:

[0975] Refer to the preparation steps of Intermediate 10-2 in Example 10, replace Intermediate 10-1 with Intermediate 41-1, and the reaction is completed to obtain Intermediate 53-1 (800 mg).

[0976] LC-MS: m / z 338.23 (M+H) + .

[0977] Preparation of compound 53:

[0978] Intermediate 53-1 (110 mg) and intermediate 3-5 (120 mg) were added to tert-butanol (5 mL) and 1,4-dioxane (5 mL), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (47 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (38 mg), and lithium bis(trimethylsilyl)amide (1 M, 0.3 mL) were added, and the reaction was stirred at 80°C under nitrogen protection for 2 h.

[0979] After the reaction was complete, ethyl acetate (50 mL) and purified water (60 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and compound 53 was obtained by preparative liquid separation.

[0980] LC-MS: m / z 708.31 (M+H) + .

[0981] Example 54: Preparation of Compounds 54, 54-a, and 54-b

[0982] Preparation of compound 54:

[0983] Referring to the preparation steps of compound 3 in Example 3, intermediate 1-3 was replaced by intermediate 12-2, and cesium carbonate was replaced by potassium carbonate. After the reaction was completed, the concentrate was filtered and concentrated to obtain a concentrate, which was separated by preparative liquid phase to obtain compound 54.

[0984] LC-MS: m / z 722.41 (M+H) + .

[0985] 1 H NMR(500MHz,DMSO-d6)δ8.51(s,1H),8.46(t,J=6.0Hz,1H),8.34(s,1H),8.15(s,2H),7.91(d,J=5 .8Hz,1H),7.71(d,J=8.9Hz,2H),7.52–7.32(m,6H),6.94(dd,J=8.8,4.0Hz,2H),6.87(d,J=5.8Hz, 1H),5.60(q,J=7.6Hz,1H),4.81(d,J=5.9Hz,2H),4.56(t,J=6.5Hz,2H),4.46(t,J=6.1Hz,2H),4. 00(s,3H),3.48(p,J=6.4Hz,1H),2.89(dt,J=9.9,4.5Hz,2H),2.74(d,J=13.3Hz,2H),2.40(s,3H).

[0986] Preparation method of compound 54-a, 54-b:

[0987] Compound 54 was chiral resolved to give compounds 54-a and 54-b. The separation conditions were as follows: a Cellulose-SC preparative column (30×250 mm, 10 μm) with n-hexane as mobile phase A and ethanol as mobile phase B, using a gradient elution method at a flow rate of 0.8 mL / min. Detection was performed at a wavelength of 254 nm, with peak elution times of 14 min (54-a) and 16 min (54-b), respectively.

[0988] Compound 54-a LC-MS: m / z 722.41 (M+H) + .

[0989] Compound 54-b LC-MS: m / z 722.43 (M+H) + .

[0990] The retention time of compound 54-a in the chiral chromatographic column is shorter than that of compound 54-b, while the retention time of compound 54-b in the chiral chromatographic column is longer than that of compound 54-a.

[0991] Example 55: Preparation of Compound 55

[0992] Preparation of compound 55:

[0993] Intermediate 6-1 (256 mg), intermediate 3-5 (200 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (78.7 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (105.8 mg) and potassium bis(trimethylsilyl)amide (0.5 ml) were added to tert-butanol (20 mL), and the reaction was stirred at 80°C under nitrogen protection for 0.5 h;

[0994] After the reaction was complete, ethyl acetate (20 mL) and purified water (20 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and purified by preparative liquid phase to obtain compound 55.

[0995] LC-MS: m / z 696.50 (M+H) + .

[0996] 1H NMR (500MHz, DMSO-d6) δ8.46(t,J=6.0Hz,1H),8.32(s,1H),8.27(s,1H),7.91(d,J=5.9Hz,1H),7.55(d,J=8.8 Hz,1H),7.44(d,J=8.5Hz,2H),7.40(dt,J=8.7,5.0Hz,3H),6.94(dd,J=8.8,4.2Hz,1H),6.87(d,J=5.7Hz,1H) ,6.74(d,J=8.8Hz,1H),4.81(d,J=5.9Hz,2H),4.39(d,J=7.2Hz,1H),4.00(s,3H),3.45(t,J=5.8Hz,2H),2.92 –2.84(m,2H),2.72–2.65(m,2H),2.58–2.51(m,4H),1.34–1.18(m,3H),0.49–0.37(m,2H),0.37–0.25(m,2H).

[0997] Example 56: Preparation of Compound 56

[0998] Preparation of compound 56:

[0999] Referring to the preparation steps of compound 3 in Example 3, intermediate 1-3 was replaced by intermediate 13-1, and cesium carbonate was replaced by potassium carbonate. After the reaction was completed, the concentrate was filtered and concentrated to obtain a concentrate, which was separated by preparative liquid phase to obtain compound 56.

[1000] LC-MS: m / z 682.37 (M+H) + .

[1001] 1H NMR (500MHz, DMSO-d6) δ8.46(t,J=5.9Hz,1H),8.31(s,1H),8.25(s,1H),8.17(s,1H),7.91(d,J=5.8Hz,1H),7.54( d,J=8.7Hz,1H),7.50–7.24(m,6H),6.94(dd,J=8.8,4.2Hz,1H),6.87(d,J=5.8Hz,1H),6.74(d,J=8.7Hz,1H),4.81( d,J=6.0Hz,3H),4.55(t,J=6.5Hz,2H),4.45(td,J=6.2,1.3Hz,2H),4.00(s,3H),3.47(p,J=6.3Hz,2H),2.92(dt,J= 10.2,4.3Hz,2H),2.71(dt,J=10.4,4.4Hz,2H),2.39(s,3H),1.81–1.65(m,2H),1.24(s,1H),0.84(t,J=7.4Hz,3H).

[1002] Example 57: Preparation of Compounds 57 and 57-a, 57-b

[1003] Preparation of compound 57:

[1004] Intermediate 11-2 (200 mg) and intermediate 3-5 (200 mg) were added to tert-butanol (50 mL), and lithium bis(trimethylsilyl)amide (1 M, 500 μL), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (106 mg) and chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (80 mg) were added, and the reaction was carried out at 85°C under nitrogen protection for 1 h.

[1005] The reaction was complete and filtered. Ethyl acetate (100 mL) and purified water (100 mL) were added to the filtrate for extraction, stirred for 10 min, and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to obtain a concentrate. Compound 57 was obtained after preparation.

[1006] 1H NMR(500MHz,DMSO-d6)δ8.45(t,J=6.0Hz,2H),8.33-8.27(m,2H),7.91(d,J=5.8Hz,1H),7.5 6(d,J=8.7Hz,1H),7.45(d,J=8.6Hz,2H),7.42-7.36(m,2H),6.93(dd,J=8.8,4.2Hz,1H),6.8 7(d,J=5.8Hz,1H),6.75(d,J=8.7Hz,1H),5.15-4.97(m,2H),4.81(d,J=5.9Hz,2H),4.55(t,J =6.5Hz,2H),4.45(dd,J=6.1,2.9Hz,2H),4.41(s,3H),4.34-4.00(m,8H),2.95-2.64(m,4H).

[1007] Preparation of compounds 57-a and 57-b:

[1008] Compound 57 was chiral resolved to give compounds 57-a and 57-b. The separation conditions were as follows: a YMC Cellulose SC (30 mm × 250 mm, 10 μm) preparative column; gradient elution with dichloromethane as mobile phase A and methanol as mobile phase B at a flow rate of 30 mL / min; detection at a wavelength of 254 nm; and peak elution times of 27 min (57-a) and 28 min (57-b), respectively.

[1009] Compound 57-a LC-MS: m / z 694.11 (M+H) + .

[1010] Compound 57-b LC-MS: m / z 694.15 (M+H) + .

[1011] The retention time of compound 57-a in the chiral chromatographic column is shorter than that of compound 57-b, while the retention time of compound 57-b in the chiral chromatographic column is longer than that of compound 57-a.

[1012] Example 58: Preparation of Compounds 58, 58-a, and 58-b

[1013] Preparation of intermediate 58-1:

[1014] Refer to the preparation steps of Intermediate 12-3 in Example 12, replace Intermediate 12-2 with Intermediate 5-1, and after the reaction is complete, add saturated ammonium chloride solution (5 mL) to quench the reaction, extract with ethyl acetate (60 mL×3), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter and concentrate to obtain Intermediate 58-1 (500 mg).

[1015] LC-MS: m / z 310.08 (M+H) + .

[1016] Preparation of compound 58:

[1017] Referring to the preparation steps of compound 3 in Example 3, intermediate 1-3 was replaced by intermediate 58-1, and cesium carbonate was replaced by potassium carbonate. After the reaction was completed, the concentrate was filtered and concentrated to obtain a concentrate, which was separated by preparative liquid phase to obtain compound 58.

[1018] LC-MS: m / z 680.35 (M+H) + .

[1019] 1 H NMR(500MHz,DMSO-d6)δ8.50(s,1H),8.46(t,J=6.0Hz,1H),8.34(s,1H),7.91(d,J =5.8Hz,1H),7.68(d,J=8.9Hz,2H),7.48–7.36(m,6H),6.94(dd,J=8.9,3.7Hz,2H), 6.86(d,J=5.7Hz,1H),6.78(d,J=7.5Hz,1H),5.60(s,1H),4.81(d,J=5.9Hz,2H),4 .00(s,3H),2.85(d,J=8.7Hz,2H),2.72(d,J=8.3Hz,2H),2.46(s,3H),2.23(s,3H).

[1020] Preparation method of compound 58-a, 58-b:

[1021] Compound 58 was chiral resolved to give compounds 58-a and 58-b. The separation conditions were as follows: a Daicel preparative column (20×250 mm, 10 μm); gradient elution with n-hexane as mobile phase A and ethanol as mobile phase B at a flow rate of 30 mL / min; detection at a wavelength of 254 nm; and peak elution times of 18.4 min (58-a) and 22.4 min (58-b), respectively.

[1022] Compound 58-a LC-MS: m / z 680.25 (M+H) + .

[1023] Compound 58-b LC-MS: m / z 680.27 (M+H) + .

[1024] The retention time of compound 58-a in the chiral chromatographic column is shorter than that of compound 58-b, while the retention time of compound 58-b in the chiral chromatographic column is longer than that of compound 58-a.

[1025] Example 59: Preparation of Compounds 59-a and 59-b

[1026] Preparation of compounds 59-a and 59-b:

[1027] Referring to the preparation steps of compound 9 in Example 9, intermediate 9-2 was replaced with intermediate 38-1, and compounds 59-a and 59-b were obtained by preparative liquid phase separation. The conditions were as follows: a YMC-AQ-C18 (50×250 mm, 10.0 μm) preparative column was used; methanol was used as mobile phase A and aqueous ammonium acetate solution was used as mobile phase B, with a gradient elution at a flow rate of 50 mL / min; the detection wavelength was 254 nm, and the peak elution times were 25.0 min (59-a) and 32.0 min (59-b), respectively.

[1028] Compound 59-a LC-MS: m / z 638.43 (M+H) + .

[1029] Compound 59-b LC-MS: m / z 638.43 (M+H) + .

[1030] The retention time of compound 59-a in the chiral chromatographic column is shorter than that of compound 59-b, while the retention time of compound 59-b in the chiral chromatographic column is longer than that of compound 59-a.

[1031] Example 60: Preparation of Compound 60

[1032] Preparation of intermediate 60-1:

[1033] Refer to the preparation steps of Intermediate 6-1 in Example 6, replace Intermediate 1-1 with Intermediate 26-2, and the reaction is completed to obtain Compound 60-1 (500 mg).

[1034] LC-MS: m / z 324.25 (M+H) + .

[1035] Preparation of compound 60:

[1036] Referring to the preparation steps of compound 10 in Example 10, intermediate 10-3 was replaced with intermediate 60-1, and the reaction was completed to obtain compound 60.

[1037] LC-MS: m / z 708.35 (M+H) + .

[1038] 1 H NMR(500MHz,DMSO-d6)δ8.40–8.31(m,2H),8.27(s,1H),7.57(d,J=8.7Hz,1H),7.52–7.46( m,2H),7.45–7.38(m,2H),7.32(dd,J=10.0,8.7Hz,1H),6.82(dd,J=8.8,4.2Hz,1H),6.77– 6.69(m,2H),5.07(d,J=6.7Hz,1H),4.80(d,J=5.9Hz,2H),3.97(s,3H),2.91(dt,J=10.1,4 .3Hz,2H),2.72(dt,J=10.3,4.4Hz,2H),2.34(s,8H),1.37–1.20(m,7H),0.52–0.19(m,4H).

[1039] Example 61: Preparation of Compounds 61 and 61-a, 61-b

[1040] Preparation of compound 61:

[1041] Referring to the preparation steps of compound 10 in Example 10, intermediate 10-3 was replaced with intermediate 26-3, and the reaction was completed to obtain compound 61.

[1042] LC-MS: m / z 736.41 (M+H) + .

[1043] Preparation of compounds 61-a and 61-b:

[1044] Compound 61 was chiral resolved to give compounds 61-a and 61-b. The separation conditions were as follows: a CHIRALPAK IC (4.6×250 mm, 5.0 μm) preparative column; gradient elution with n-hexane as mobile phase A and ethanol as mobile phase B at a flow rate of 0.5 mL / min; detection at a wavelength of 254 nm; and peak elution times of 34.010 min (61-a) and 46.978 min (61-b), respectively.

[1045] Compound 61-a LC-MS: m / z 736.45 (M+H) + .

[1046] 1H NMR(500MHz DMSO-d6)δ8.51(s,1H),8.35(m,2H),7.71(d,J=9.0Hz,1H),7.49(d,J=8.5Hz,2H),7.40(d ,J=8.5Hz,2H),7.32(dd,J=9.0,10.0Hz,1H),6.94(d,J=9.0Hz,1H),6.82(dd,J=9.0,4.0H z,1H),6.72(m,2H),5.60(m,1H),4.80(d,J=6.0Hz,2H),4.56(t,J=6.5Hz,2H),4.46(t,J= 6.0Hz,2H),3.97(s,3H),3.48(m,1H),2.89(m,2H),2.74(m,2H),2.40(m,4H),2.34(s,3H).

[1047] Compound 61-b LC-MS: m / z 736.41 (M+H) + .

[1048] 1 H NMR(500MHz DMSO-d6)δ8.51(s,1H),8.35(m,2H),7.71(d,J=9.0Hz,1H),7.49(d,J=8.5Hz,2H),7. 40(d,J=8.5Hz,2H),7.32(m,1H),6.94(d,J=9.0Hz,1H),6.82(dd,J=9.0,4.0Hz,1H),6 .72(m,2H),5.60(m,1H),4.80(d,J=6.0Hz,2H),4.56(t,J=6.5Hz,2H),4.46(t,J=6.0H z,2H),3.97(s,3H),3.48(m,1H),2.89(m,2H),2.74(m,2H),2.40(m,4H),2.34(s,3H).

[1049] The retention time of compound 61-a in the chiral chromatographic column is shorter than that of compound 61-b, while the retention time of compound 61-b in the chiral chromatographic column is longer than that of compound 61-a.

[1050] Example 62: Preparation of Compounds 62 and 62-a, 62-b

[1051] Preparation of compound 62:

[1052] Intermediate 23-1 (171 mg), intermediate 3-5 (150 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (59 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (79 mg) and potassium bis(trimethylsilyl)amide (0.4 ml) were added to tert-butanol (20 mL), and the reaction was stirred at 80°C under nitrogen protection for 0.5 h;

[1053] After the reaction was complete, ethyl acetate (20 mL) and purified water (20 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and purified by preparative liquid phase to obtain compound 62.

[1054] LC-MS: m / z 724.43 (M+H) + .

[1055] Preparation of compounds 62-a and 62-b:

[1056] Compound 62 was chiral resolved to give compounds 62-a and 62-b. Separation conditions were as follows: a Daicel ID (20*250 mm, 10 μm) preparative column; a gradient elution of ethanol-n-hexane:dichloromethane = 3:1 (5%-60% / 0-55 min) at a flow rate of 30 mL / min; detection at a wavelength of 254 nm; peak elution times were 23.2 min (62-a) and 27.0 min (62-b), respectively.

[1057] Compound 62-a LC-MS: m / z 724.39 (M+H) + .

[1058] Compound 62-b LC-MS: m / z 724.36 (M+H) + .

[1059] Compound 62-b 1H NMR(500MHz,DMSO-d6)δ8.53–8.43(m,2H),8.34(s,1H),7.91(d,J=5.8Hz,1H),7.6 9(d,J=8.8Hz,1H),7.51–7.34(m,6H),6.94(dd,J=8.9,4.8Hz,2H),6.87(d,J=5.8H z,1H),6.81(d,J=7.6Hz,1H),5.60(t,J=7.6Hz,1H),4.81(d,J=6.0Hz,2H),4.00(s ,3H),3.46(t,J=5.8Hz,2H),3.25(s,3H),2.85(d,J=9.5Hz,2H),2.75–2.68(m,2H).

[1060] The retention time of compound 62-a in the chiral chromatographic column is shorter than that of compound 62-b, while the retention time of compound 62-b in the chiral chromatographic column is longer than that of compound 62-a.

[1061] Example 63: Preparation of Compounds 63 and 63-a, 63-b

[1062] Preparation of compound 63:

[1063] Referring to the preparation steps of compound 3 in Example 3, intermediate 1-3 was replaced by intermediate 24-1, and cesium carbonate was replaced by potassium carbonate. After the reaction was completed, the concentrate was filtered and concentrated to obtain a concentrate, which was separated by preparative liquid phase to obtain compound 63.

[1064] LC-MS: m / z 706.37 (M+H) + .

[1065] 1 H NMR(500MHz,DMSO-d6)δ8.46(t,J=6.0Hz,1H),8.40(s,1H),8.17(s,1H),7.91(d,J=5.8Hz,1H ),7.60(d,J=8.8Hz,1H),7.53–7.34(m,6H),6.94(dd,J=8.8,4.3Hz,1H),6.89–6.79(m,2H),6 .23–6.03(m,2H),5.11(dq,J=12.2,5.7Hz,1H),4.81(d,J=5.9Hz,2H),4.00(s,3H),3.47(d,J =6.3Hz,2H),3.25(s,3H),2.90(s,2H),2.74(s,2H),1.36–1.18(m,4H),0.91(t,J=7.3Hz,2H).

[1066] Preparation method of compound 63-a, 63-b:

[1067] Compound 63 was chiral resolved to give compounds 63-a and 63-b. The separation conditions were as follows: a Cellulose-SC preparative column (30×250 mm, 10 μm) with n-hexane as mobile phase A and ethanol as mobile phase B, using a gradient elution method at a flow rate of 0.8 mL / min. Detection was performed at a wavelength of 254 nm, with peak elution times of 23 min (63-a) and 29 min (63-b), respectively.

[1068] Compound 63-a LC-MS: m / z 706.35 (M+H) + .

[1069] Compound 63-b LC-MS: m / z 706.37 (M+H) + .

[1070] The retention time of compound 63-a in the chiral chromatographic column is shorter than that of compound 63-b, while the retention time of compound 63-b in the chiral chromatographic column is longer than that of compound 63-a.

[1071] Example 64: Preparation of Compound 64

[1072] Preparation of compound 64:

[1073] Refer to the preparation steps of compound 53 in Example 53, replace intermediate 53-1 with intermediate 28-2, and the reaction is completed. Compound 64 is obtained after purification by preparative liquid phase.

[1074] LC-MS: m / z 696.23 (M+H) + .

[1075] Example 65: Preparation of Compound 65

[1076] Preparation of compound 65:

[1077] Intermediate 25-1 (113 mg), intermediate 3-5 (120 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (47 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (63 mg) and potassium bis(trimethylsilyl)amide (0.3 ml) were added to tert-butanol (20 mL), and the reaction was stirred at 80°C under nitrogen protection for 0.5 h;

[1078] After the reaction was complete, ethyl acetate (20 mL) and purified water (20 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and purified by preparative liquid phase to obtain compound 65.

[1079] LC-MS: m / z 666.42 (M+H) + .

[1080] 1 H NMR (500MHz, DMSO-d6) δ8.46(t,J=6.0Hz,1H),8.36(s,1H),8.32(s,1H),7.91(d,J=5.8Hz,1H),7.54(d,J=8.7Hz,1H),7.45(s,1H),7 .44(s,1H),7.42–7.37(m,3H),6.94(dd,J=8.8,4.2Hz,1H),6.87(d,J=5.7Hz,1H),6.79(d,J=8.7Hz,1H),4.81(d,J=5.9Hz,2H),4.14 (d,J=8.7Hz,1H),4.00(s,3H),3.14(s,3H),2.82–2.75(m,2H),2.70(d,J=6.2Hz,2H),2.42(s,3H),2.21(s,3H),1.39–1.32(m,1H),1 .27–1.22(m,1H),0.62(qd,J=8.4,4.5Hz,1H),0.47(dq,J=9.6,4.9Hz,1H),0.33(dp,J=12.8,4.3Hz,1H),0.13(dq,J=9.6,4.8Hz,1H).

[1081] Example 66: Preparation of Compound 66

[1082] Preparation of compound 66:

[1083] Refer to the preparation steps of compound 53 in Example 53, replace intermediate 53-1 with intermediate 26-4, and the reaction is completed. Compound 66 is obtained after purification by preparative liquid phase.

[1084] LC-MS: m / z 736.15 (M+H) + .

[1085] Example 67: Preparation of Compound 67

[1086] Preparation of compound 67:

[1087] Intermediate 27-1 (150 mg) and intermediate 3-5 (150 mg) were added to tert-butanol (38 mL), and lithium bis(trimethylsilyl)amide (1 M, 375 μL), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (80 mg) and chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (60 mg) were added, and the reaction was carried out at 85°C under nitrogen protection for 1 h.

[1088] The reaction was complete and filtered. Ethyl acetate (100 mL) and purified water (100 mL) were added to the filtrate for extraction, and the mixture was stirred for 10 min and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a concentrate. Compound 67 was obtained by preparative liquid separation.

[1089] LC-MS: m / z 708.23 (M+H) + .

[1090] Example 68: Preparation of Compounds 68 and 68-a, 68-b

[1091] Preparation of compound 68:

[1092] Intermediate 29-1 (130 mg), intermediate 3-5 (120 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (47 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (63 mg) and potassium bis(trimethylsilyl)amide (0.3 mL) were added to tert-butanol (20 mL), and the reaction was stirred at 80°C under nitrogen protection for 0.5 h.

[1093] After the reaction was complete, ethyl acetate (20 mL) and purified water (20 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and purified by preparative liquid phase to obtain compound 68.

[1094] LC-MS: m / z 710.38 (M+H) + .

[1095] Preparation of compounds 68-a and 68-b:

[1096] Compound 68 was subjected to chiral resolution to afford compounds 68-a and 68-b. Separation conditions were as follows: a YMC Cellulose SC (30 mm x 250 mm, 10 μm) column; ethanol-n-hexane (10%-60% / 0-40 min gradient elution) at a flow rate of 40 mL / min; detection at a wavelength of 254 nm; and peak elution times of 23.5 min (68-a) and 29.5 min (68-b), respectively.

[1097] Compound 68-a LC-MS: m / z 710.40 (M+H) + .

[1098] Compound 68-b LC-MS: m / z 710.46 (M+H) + .

[1099] Compound 68-b 1 H NMR (500MHz, DMSO-d6) δ8.46(t,J=6.0Hz,1H),8.35(s,1H),8.32(s,1H),7.91(d,J=5.8Hz,1H),7.55(d,J=8.8Hz,1H),7.44(d,J=8. 4Hz,2H),7.42–7.38(m,3H),6.94(dd,J=8.8,4.2Hz,1H),6.87(d,J=5.7Hz,1H),6.79(d,J=8.8Hz,1H),4.81(d,J=5.9Hz,2H),4.15(d ,J=8.8Hz,1H),4.00(s,3H),3.45(t,J=5.8Hz,2H),3.32(s,5H),3.14(s,3H),2.82–2.75(m,2H),2.73–2.66(m,2H),1.36(td,J=8.4 ,4.0Hz,1H),1.25(d,J=12.9Hz,1H),0.66–0.59(m,1H),0.47(dq,J=9.6,4.8Hz,1H),0.37–0.29(m,1H),0.13(dq,J=9.5,5.0Hz,1H).

[1100] The retention time of compound 68-a in the chiral chromatographic column is shorter than that of compound 68-b, while the retention time of compound 68-b in the chiral chromatographic column is longer than that of compound 68-a.

[1101] Example 69: Preparation of Compound 69

[1102] Preparation of compound 69:

[1103] Intermediate 32-1 (120 mg) and intermediate 3-5 (120 mg) were added to tert-butanol (30 mL), and lithium bis(trimethylsilyl)amide (1 M, 300 μL), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (64 mg) and chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (48 mg) were added, and the reaction was carried out at 85°C under nitrogen protection for 1 h.

[1104] The reaction was complete and filtered. Ethyl acetate (100 mL) and purified water (100 mL) were added to the filtrate for extraction, stirred for 10 min, and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to obtain a concentrate. Compound 69 was obtained by preparative liquid separation.

[1105] LC-MS: m / z 666.13 (M+H) + .

[1106] Example 70: Preparation of Compound 70

[1107] Preparation of intermediate 70-1:

[1108] 1,2-Dimethylpiperazine (2.3 g) and 2-chloro-5-fluoropyridine-6-carbaldehyde (3.19 g) were added to N,N-dimethylformamide (20 mL), and potassium carbonate (11 g) was added. The mixture was stirred under nitrogen protection and the temperature was controlled at 80-90°C.

[1109] After the reaction was complete, purified water (200 mL) and dichloromethane (200 mL) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 70-1 (5.1 g).

[1110] LC-MS: m / z 254.16 (M+H) + .

[1111] Preparation of intermediate 70-2:

[1112] Intermediate 70-1 (5.1 g), cesium fluoride (4.56 g) and (trifluoromethyl)trimethylsilane (4.27 g) were added to tetrahydrofuran (100 mL) and stirred at 20-30°C under nitrogen protection;

[1113] After the reaction was complete, saturated ammonium chloride solution (100 mL) and dichloromethane (100 mL) were added, stirred and extracted, and allowed to stand for separation; the organic phase was dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 70-2 (6.4 g).

[1114] LC-MS: m / z 324.1 (M+H) + .

[1115] Preparation of compound 70:

[1116] Intermediate 70-2 (50 mg), intermediate 3-5 (50 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (20 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (26.6 mg), and potassium carbonate (34.2 mg) were added to tert-butanol (25 mL), and the reaction was completed under nitrogen protection in a microwave oven at 85°C and a power of 150 W.

[1117] Ethyl acetate (50 mL) was added to dilute the mixture, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a concentrate, which was then purified by preparative liquid phase to obtain compound 70.

[1118] LC-MS: m / z 694.36 (M+H) + .

[1119] Example 71: Preparation of Compounds 71-a and 71-b

[1120] Preparation of compounds 71-a and 71-b:

[1121] Intermediate 37-1 (98 mg) and intermediate 3-5 (106 mg) were added to tert-butanol (40 mL), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (48 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (74 mg), and potassium carbonate (120 mg) were added, and the reaction was stirred at 80°C under nitrogen protection for 6 h.

[1122] After the reaction was complete, ethyl acetate (30 mL) and purified water (30 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and preparative liquid separation was performed to obtain compounds 71-a and 71-b.

[1123] The preparation conditions are as follows: using a YMC TA C18 10μm 30*250 chromatographic column, acetonitrile-0.1% formic acid aqueous solution (5%-50% / 0-60min gradient elution), a flow rate of 40ml / min, and a detection wavelength of 254nm, compound 71-a (retention time 23.8min) and compound 71-b (retention time 32.5min) were obtained in turn.

[1124] Compound 71-a LC-MS: m / z 638.32 (M+H) + .

[1125] Compound 71-b LC-MS: m / z 638.30 (M+H) + .

[1126] Compound 71-b 1 H NMR(500MHz,DMSO-d6)δ8.46(t,J=6.0Hz,1H),8.12(s,1H),7.91(d,J=5.8Hz,1H),7.80(s,1 H),7.46–7.42(m,2H),7.42–7.36(m,3H),6.94(dd,J=8.7,5.0Hz,2H),6.87(d,J=5.7Hz,1H), 6.57(d,J=8.6Hz,1H),4.81(d,J=6.0Hz,2H),4.00(s,3H),3.04(tt,J=10.6,3.7Hz,1H),2.2 4(s,3H),2.18(s,6H),2.01–1.94(m,2H),1.90(s,3H),1.85–1.78(m,2H),1.33–1.15(m,4H).

[1127] The retention time of compound 71-a in the chiral chromatographic column is shorter than that of compound 71-b, while the retention time of compound 71-b in the chiral chromatographic column is longer than that of compound 71-a.

[1128] Example 72: Preparation of Compound 72

[1129] Preparation of compound 72:

[1130] Refer to the preparation steps of compound 53 in Example 53, replace intermediate 53-1 with intermediate 36-5, and the reaction is completed to obtain compound 72.

[1131] LC-MS: m / z 693.21 (M+H) + .

[1132] Example 73: Preparation of Compounds 73-a and 73-b

[1133] Preparation of intermediate 73-1:

[1134] Intermediate 18-1 (2.5 g) was added to THF (50 mL), and methylmagnesium bromide (3 M, 2.5 mL) was added dropwise at -20°C under nitrogen protection. After the addition, the reaction was stirred at 0°C for 3 h. After the reaction was complete, saturated ammonium chloride solution (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare and purify intermediate 73-1 (600 mg).

[1135] LC-MS: m / z 342.14 (M+H) + .

[1136] Preparation of compounds 73-a and 73-b:

[1137] Refer to the preparation procedure of compound 53 in Example 53, replacing intermediate 53-1 with intermediate 73-1.

[1138] The reaction was complete, yielding compounds 73-a and 73-b. The following conditions were used for the preparative column: a YMC AQ C18 column (30 × 250 mm, 10 μm) with 0.1% acetic acid as mobile phase A and acetonitrile as mobile phase B, using a gradient elution method at a flow rate of 30 mL / min. The detection wavelength was 254 nm, and the peak elution times were 29 min (73-a) and 32 min (73-b), respectively.

[1139] Compound 73-a LC-MS: m / z 668.25 (M+H) + .

[1140] 1 H NMR(500MHz DMSO-d6)δ8.46(t,J=6.0Hz,1H),8.18(s,1H),7.90(d,J=6.0Hz,1H),7.89(s,1H),7.4 3(m,2H),7.38(m,3H),7.03(d,J=9.0Hz,1H),6.94(dd,J=9.0,4.0Hz,1H),6.86(d,J=5. 5Hz,1H),6.66(d,J=8.5Hz,1H),5.40(m,1H),4.90(m,1H),4.78(m,3H),4.00(s,3H),3 .09(m,2H),2.17(m,8H),2.01(m,2H),1.79(m,2H),1.40(d,J=4.5Hz,3H),1.12(m,2H).

[1141] Compound 73-b LC-MS: m / z 668.21 (M+H) + .

[1142] 1 H NMR(500MHz DMSO-d6)δ8.46(t,J=6.0Hz,1H),8.18(s,1H),7.90(d,J=6.0Hz,1H),7.87(s,1H),7.4 3(m,2H),7.38(m,3H),6.99(d,J=9.0Hz,1H),6.94(dd,J=9.0,4.0Hz,1H),6.87(d,J=5. 5Hz,1H),6.66(d,J=8.5Hz,1H),5.60(m,1H),5.36(m,1H),4.81(m,3H),4.00(s,3H),3 .45(m,2H),2.16(m,8H),1.71(m,2H),1.57(m,2H),1.50(m,2H),1.45(d,J=6.5Hz,3H).

[1143] The retention time of compound 73-a in the chiral chromatographic column is shorter than that of compound 73-b, while the retention time of compound 73-b in the chiral chromatographic column is longer than that of compound 73-a.

[1144] Example 74: Preparation of Compounds 74, 74-a, and 74-b

[1145] Preparation of compound 74:

[1146] Intermediate 33-5 (131 mg), intermediate 3-5 (120 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (47 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (63 mg) and potassium bis(trimethylsilyl)amide (0.3 mL) were added to tert-butanol (20 mL), and the reaction was stirred at 80°C under nitrogen protection for 0.5 h;

[1147] After the reaction was complete, ethyl acetate (20 mL) and purified water (20 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and purified by preparative liquid phase to obtain compound 74.

[1148] LC-MS: m / z 669.36 (M+H) + .

[1149] Preparation of compounds 74-a and 74-b:

[1150] Compound 74 was chiral resolved to give compounds 74-a and 74-b. The separation conditions were as follows: AM-4 (20 mm × 250 mm, 10 μm) preparative column; gradient elution with n-hexane as mobile phase A and 0.2% diethylamine-ethanol as mobile phase B at a flow rate of 20 mL / min; detection at a wavelength of 254 nm; peak elution times were 27.52 min (74-a) and 30.15 min (74-b), respectively.

[1151] Compound 74-a LC-MS: m / z 669.42 (M+H) + .

[1152] Compound 74-b LC-MS: m / z 669.48 (M+H) + .

[1153] The retention time of compound 74-a in the chiral chromatographic column is shorter than that of compound 74-b, while the retention time of compound 74-b in the chiral chromatographic column is longer than that of compound 74-a.

[1154] Example 75: Preparation of Compounds 75 and 75-a, 75-b

[1155] Preparation of compound 75:

[1156] Intermediate 42-2 (120 mg), intermediate 3-5 (100 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (40 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (54 mg), and lithium bis(trimethylsilyl)amide (1 M, 250 ul) were added to tert-butanol (50 mL), and the reaction was stirred at 85°C under nitrogen protection for 0.5 h.

[1157] After the reaction was complete, ethyl acetate (100 mL) was added to dilute the mixture, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a concentrate, which was then purified by preparative liquid chromatography to obtain compound 75.

[1158] LC-MS: m / z 694.41 (M+H) + .

[1159] Preparation of compounds 75-a and 75-b:

[1160] Compound 75 was chiral resolved to give compounds 75-a and 75-b. Separation conditions: YMC Amylose-SA (30×250 mm, 10 μm) preparative column; gradient elution with n-hexane as mobile phase A and ethanol as mobile phase B at a flow rate of 30 mL / min; detection wavelength at 254 nm; peak elution times of 10 min (75-a) and 13 min (75-b), respectively.

[1161] Compound 75-a LC-MS: m / z 694.53 (M+H) + .

[1162] 1 H NMR (500MHz, DMSO-d6) δ8.46(t,J=5.7Hz,1H),8.34(d,J=8.3Hz,2H),7.91(d,J=5.9Hz,1H),7.51(dd,J=8.9,2.6Hz,1H),7.46(d,J=8.2Hz,2H) ,7.41(d,J=8.5Hz,3H),6.93(dd,J=8.9,4.3Hz,1H),6.87(d,J=5.7Hz,1H),6.79(d,J=8.6Hz,1H),4.82(d,J=5.9Hz,2H),4.15(d,J=8.6Hz,1H) ,4.00(d,J=2.5Hz,3H),2.88(d,J=11.1Hz,1H),2.77(d,J=10.9Hz,1H),2.73–2.58(m,2H),2.19(d,J=2.5Hz,6H),2.16–2.08(m,1H),1.86–1.7 4(m,2H),1.56–1.17(m,7H),0.62(tt,J=8.9,4.7Hz,1H),0.49(dq,J=9. 6,4.8Hz,1H),0.35(dq,J=9.8,4.7Hz,1H),0.15(dq,J=9.7,4.8Hz,1H).

[1163] Compound 75-b LC-MS: m / z 694.45 (M+H) + .

[1164] 1H NMR(500MHz,DMSO-d6)δ8.45(t,J=5.9Hz,1H),8.32(d,J=6.1Hz,2H),7.91( d,J=5.8Hz,1H),7.51(d,J=8.7Hz,1H),7.45(d,J=8.2Hz,2H),7.42–7.37(m, 3H),6.94(dd,J=8.8,4.2Hz,1H),6.87(d,J=5.8Hz,1H),6.78(d,J=8.7Hz,1H ),4.82(d,J=6.0Hz,2H),4.14(d,J=8.7Hz,1H),4.00(s,3H),3.15(s,2H),2. 88(d,J=11.2Hz,1H),2.81–2.73(m,1H),2.72–2.59(m,2H),2.19(s,5H),2.1 3(ddt,J=10.8,7.4,3.5Hz,1H),1.84–1.75(m,2H),1.47(qt,J=11.1,4.5Hz, 2H),1.40–1.29(m,2H),1.25(d,J=12.1Hz,3H),0.62(tt,J=8.1,4.5Hz,1H), 0.49(dq,J=9.6,4.9Hz,1H),0.39–0.29(m,1H),0.14(dq,J=9.6,4.8Hz,1H).

[1165] The retention time of compound 75-a in the chiral chromatographic column is shorter than that of compound 75-b, while the retention time of compound 75-b in the chiral chromatographic column is longer than that of compound 75-a.

[1166] Example 76: Preparation of Compound 76

[1167] Preparation of compound 76:

[1168] Referring to the preparation steps of compound 9 in Example 9, intermediate 8-8 was replaced by intermediate 3-5, and intermediate 9-2 was replaced by intermediate 38-1. The reaction was completed and compound 76 was obtained by preparative liquid separation.

[1169] LC-MS: m / z 624.35 (M+H) + .

[1170] 1H NMR (500MHz, DMSO-d6) δ8.45(t,J=5.9Hz,1H),8.07(s,1H),7.91(d,J=5.7Hz,1H),7.83(s,1H),7.5 7(d,J=2.9Hz,1H),7.44(d,J=8.2Hz,2H),7.38(t,J=7.3Hz,3H),6.95(ddd,J=12.8,8.8,3.6Hz,2H), 6.87(d,J=5.7Hz,1H),6.68(d,J=8.9Hz,1H),4.81(d,J=5.9Hz,2H),4.00(s,3H),2.21(s,6H),2.00 (dd,J=12.5,4.5Hz,2H),1.90(s,2H),1.81(d,J=11.6Hz,2H),1.32–1.25(m,2H),1.15–1.06(m,2H).

[1171] Example 77: Preparation of Compound 77

[1172] Preparation of compound 77:

[1173] Intermediate 44-1 (141 mg), intermediate 3-5 (120 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (47 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (63 mg) and potassium bis(trimethylsilyl)amide (0.3 mL) were added to tert-butanol (20 mL), and the reaction was stirred at 80°C under nitrogen protection for 0.5 h.

[1174] After the reaction was complete, ethyl acetate (20 mL) and purified water (20 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and purified by preparative liquid phase to obtain compound 77.

[1175] LC-MS: m / z 687.49 (M+H) + .

[1176] 1H NMR (500MHz, DMSO-d6) δ8.46(t,J=6.0Hz,1H),8.32(s,1H),8.30(s,1H),7.91(d,J=5.8Hz,1H),7. 52(d,J=8.8Hz,1H),7.45(s,1H),7.44(d,J=1.9Hz,1H),7.42–7.38(m,3H),6.94(dd,J=8.8,4.2Hz, 1H),6.87(d,J=5.8Hz,1H),6.78(d,J=8.8Hz,1H),4.96(q,J=6.4Hz,1H),4.81(d,J=6.0Hz,2H),4. 00(s,3H),3.46(t,J=5.8Hz,2H),3.25(s,3H),2.76(qd,J=10.7,5.0Hz,4H),1.36(d,J=6.3Hz,3H).

[1177] Example 78: Preparation of Compound 78

[1178] Preparation of compound 78:

[1179] Referring to the preparation steps of compound 10 in Example 10, intermediate 10-3 was replaced with intermediate 26-4, and the reaction was completed to obtain compound 78.

[1180] LC-MS: m / z 750.17 (M+H) + .

[1181] 1 H NMR(500MHz DMSO-d6)δ8.58(s,1H),8.36(s,2H),7.75(d,J=8.0Hz,1H),7.49(d,J=7.0Hz,2H),7.41(d,J=7.0Hz,2H),7.32(t,J=9.0Hz,1H),7.00(d,J=8.0 Hz,1H),6.82(m,1H),6.72(s,1H),5.57(m,1H),4.80(brs,2H),4.56(m, 2H),4.46(m,2H),3.97(s,3H),3.49(m,1H),2.79(m,4H),2.42(m,12H).

[1182] Example 79: Preparation of Compound 79

[1183] Preparation of compound 79:

[1184] Referring to the preparation steps of compound 10 in Example 10, intermediate 10-3 was replaced by intermediate 1-3, and the reaction was completed to obtain compound 79.

[1185] LC-MS: m / z 698.45 (M+H) + .

[1186] 1 H NMR(500MHz DMSO-d6)δ8.35(t,J=6.0Hz,1H),8.33(s,1H),8.30(s,1H),7.52(d,J=8.5Hz,1H),7.49(d, J=8.5Hz,2H),7.40(d,J=8.5Hz,2H),7.32(m,1H),6.82(dd,J=9.0,4.0Hz,1H),6.78(d,J=8. 5Hz,1H),6.72(s,1H),4.97(m,1H),4.80(d,J=6.0Hz,2H),3.97(s,3H),3.46(t,J=6.0Hz,2 H),3.25(s,3H),3.11(s,3H),2.76(m,4H),2.56(m,6H),2.34(s,3H),1.36(d,J=6.0Hz,3H).

[1187] Example 80: Preparation of Compounds 80-a and 80-b

[1188] Preparation of intermediate 80-1:

[1189] 5-Bromo-2-fluorobenzaldehyde (2 g), N,N-dimethyl-1,4-cyclohexanediamine (1.4 g) and potassium carbonate (4.1 g) were added to N,N-dimethylformamide (20 mL) and stirred at 85°C for 2 h.

[1190] After the reaction was complete, the mixture was filtered and the filtrate was extracted with purified water (20 mL) and ethyl acetate (40 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate 80-1 (2.4 g).

[1191] LC-MS: m / z 326.08 (M+H) + .

[1192] Preparation of intermediate 80-2:

[1193] Intermediate 80-2 (300 mg) was added to DCM (5 mL), stirred at 0°C, and (trifluoromethyl)trimethylsilane (200 mg) was slowly added. After stirring for 20 min, tetrabutylammonium fluoride (131 mg) was added, and the mixture was transferred to room temperature and stirred for 5 h.

[1194] After the reaction was complete, saturated ammonium chloride solution (10 mL) was added to quench the reaction, followed by stirring for 10 min. Ethyl acetate (20 mL x 2) was added for extraction and the mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to afford Intermediate 80-2 (120 mg).

[1195] LC-MS: m / z 396.11 (M+H) + .

[1196] Preparation of compounds 80-a and 80-b:

[1197] Referring to the preparation steps of compound 9 in Example 9, intermediate 9-2 was replaced with intermediate 80-2, and compounds 80-a and 80-b were obtained by preparative liquid phase separation. The conditions were as follows: a YMC-AQ-C18 (30×250 mm, 10.0 μm) preparative column was used; acetonitrile was used as mobile phase A, and 0.1% aqueous acetic acid was used as mobile phase B, with a gradient elution at a flow rate of 20 mL / min; the detection wavelength was 254 nm, and the peak elution times were 24.8 min (80-a) and 30.1 min (80-b), respectively.

[1198] Compound 80-a LC-MS: m / z 736.42 (M+H) + .

[1199] Compound 80-b LC-MS: m / z 736.42 (M+H) + .

[1200] Compound 80-b 1 H NMR(500MHz,DMSO-d6)δ8.34(t,J=5.9Hz,1H),8.21(s,1H),8.02(s,1H),7.49(d,J=8.3 Hz,2H),7.41–7.37(m,2H),7.31(dd,J=10.0,8.7Hz,1H),7.13(d,J=9.2Hz,1H),6.84–6. 80(m,2H),6.72(s,1H),5.23(q,J=7.9Hz,1H),5.10(s,1H),4.80(d,J=5.8Hz,2H),3.97( s,3H),2.34(s,3H),2.17(s,6H),1.69(q,J=5.9Hz,2H),1.61–1.49(m,6H),1.24(s,2H).

[1201] The retention time of compound 80-a in the chiral chromatographic column is shorter than that of compound 80-b, while the retention time of compound 80-b in the chiral chromatographic column is longer than that of compound 80-a.

[1202] Example 81: Preparation of Compound 81

[1203] Preparation of compound 81:

[1204] Referring to the preparation steps of compound 9 in Example 9, intermediate 8-8 was replaced by intermediate 3-5, and intermediate 9-2 was replaced by intermediate 52-3. The reaction was completed and the compound 81 was obtained by preparative liquid separation. Compound 81-a LC-MS: m / z 682.51 (M+H) + .

[1205] LC-MS: m / z 682.51 (M+H) + .

[1206] 1 H NMR(500MHz,DMSO-d6)δ8.45(t,J=6.0Hz,1H),8.17(s,1H),7.93–7.85(m,2H),7.46–7.36(m,5H),6.99 (d,J=8.8Hz,1H),6.94(dd,J=8.8,4.2Hz,1H),6.87(d,J=5.8Hz,1H),6.65(d,J=8.7Hz,1H),5.60(s,1H ),5.33(s,1H),4.81(d,J=6.0Hz,2H),4.53(t,J=6.7Hz,1H),4.00(s,3H),2.22(s,6H),1.83(dq,J=23. 4,6.7Hz,2H),1.74(d,J=11.3Hz,2H),1.54(dd,J=20.7,9.2Hz,6H),1.24(s,1H),0.90(t,J=7.4Hz,3H).

[1207] Example 82: Preparation of Compounds 82-a and 82-b

[1208] Preparation of intermediate 82-1:

[1209] 2-Bromo-5-fluoropyridine-6-carbaldehyde (2.0 g), 4-dimethylaminocyclohexylamine (2.38 g), and potassium carbonate (5.60 g) were added to DMF (180 mL) and stirred at 80°C for 3 hours. The mixture was cooled to room temperature, and ethyl acetate (80 mL) and purified water (50 mL) were added. The mixture was stirred for 10 minutes and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (60 mL x 2). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 82-1 (2.58 g).

[1210] LC-MS: m / z 326.14 (M+H) + .

[1211] Preparation of intermediate 82-2:

[1212] Intermediate 82-1 (1.0 g) was added to THF (100 mL), and cyclopropylmagnesium bromide (1 M, 8 mL) was added dropwise under nitrogen protection at a temperature of -10 to 0°C. After the addition, the mixture was stirred at the same temperature for 2 h. After the reaction was complete, saturated ammonium chloride solution (40 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 82-2 (1.14 g).

[1213] LC-MS: m / z 368.26 (M+H) + .

[1214] Preparation of compounds 82-a and 82-b:

[1215] Intermediate 82-2 (160 mg) and intermediate 3-5 (177 mg) were added to tert-butanol (30 mL), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (128 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (180 mg), and lithium bis(trimethylsilyl)amide (1 M, 480 uL) were added, and the reaction was stirred at 80 ° C under nitrogen protection for 2 h.

[1216] After the reaction was complete, ethyl acetate (30 mL) and purified water (30 mL) were added, stirred for 10 min, and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The product was filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate. Compounds 82-a and 82-b were obtained by preparative liquid phase separation. The preparation conditions were as follows: a YMC AQ C18 column (30*250 mm, 10 μm) was used, with mobile phases A: 0.1% acetic acid, B: acetonitrile; gradient: 5%-40% B 0-70 min, wavelength 254 nm, flow rate 30 ml / min, and peak elution times of 35 min (82-a) and 43 min (82-b), respectively.

[1217] Compound 82-a LC-MS: m / z 694.42 (M+H) + .

[1218] Compound 82-b LC-MS: m / z 694.40 (M+H) + .

[1219] The retention time of compound 82-a in the chiral chromatographic column is shorter than that of compound 82-b, while the retention time of compound 82-b in the chiral chromatographic column is longer than that of compound 82-a.

[1220] Example 83: Preparation of Compound 83

[1221] Preparation of intermediate 83-1:

[1222] Tert-butyl-4-(2-hydroxyethyl)piperazine-1-carboxylate (2.3 g) was added to THF (50 mL), and sodium hydroxide (60%, 0.6 g) was slowly added at room temperature. After stirring evenly, deuterated iodomethane (1.45 g) was added and the mixture was stirred at room temperature overnight; deuterated iodomethane (0.29 g) was further added and the mixture was stirred at room temperature.

[1223] After the reaction was completed, purified water was added to quench the reaction solution, and the reaction solution was concentrated under reduced pressure to obtain intermediate 83-1 (3.1 g).

[1224] Preparation of intermediate 83-2:

[1225] Intermediate 83-1 (3.1 g) was added to a solution of hydrogen chloride in dioxane (4 M, 5 ml) and the mixture was stirred at room temperature.

[1226] After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain intermediate 83-2 (2.8 g).

[1227] Preparation of intermediate 83-3:

[1228] Intermediate 83-2 (2.8 g) and 2-chloro-5-fluoropyridine-6-carbaldehyde (1.6 g) were added to N,N-dimethylformamide (40 mL), and potassium carbonate (8.28 g) was added. The reaction was stirred under nitrogen protection and the temperature was controlled at 80-90°C.

[1229] After the reaction was completed, purified water (200 mL) and dichloromethane (200 mL) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 83-3 (2.8 g).

[1230] LC-MS: m / z 287.11 (M+H) + .

[1231] Preparation of intermediate 83-4:

[1232] Intermediate 83-3 (2 g) was added to THF (50 mL), the temperature was controlled at -20°C with stirring, and methylmagnesium bromide solution (3 M, 4.7 mL) was slowly added. After the addition was completed, the temperature was controlled at -20°C with stirring and the reaction was continued.

[1233] After the reaction was complete, aqueous ammonium chloride (100 mL) was added to quench the reaction, and ethyl acetate (100 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 83-4 (2.12 g).

[1234] LC-MS: m / z 303.17 (M+H) + .

[1235] Preparation of intermediate 83-5:

[1236] Intermediate 83-4 (1.06 g) was added to THF (50 mL), and sodium bicarbonate (60%, 210 mg) was slowly added under ice-bath. After stirring evenly, iodomethane (250 mg) was added; the reaction was stirred under ice-bath.

[1237] After the reaction was complete, purified water was added to quench the reaction solution, and the reaction solution was concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain intermediate 83-5.

[1238] LC-MS: m / z 317.18 (M+H) + .

[1239] Preparation of compound 83:

[1240] Intermediate 83-5 (158 mg), intermediate 3-5 (100 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (40 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (54 mg), and lithium bis(trimethylsilyl)amide (1 M, 250 ul) were added to tert-butanol (50 mL), and the reaction was stirred at 85°C under nitrogen protection for 0.5 h;

[1241] After the reaction was complete, ethyl acetate (100 mL) was added to dilute the mixture, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a concentrate, which was then purified by preparative liquid chromatography to obtain compound 83.

[1242] LC-MS: m / z 687.41 (M+H) + .

[1243] 1H NMR (500MHz, DMSO-d6) δ8.46(t,J=6.0Hz,1H),8.31(d,J=10.5Hz,2H),7.91(d,J=5.8Hz,1H),7.75–7.6(b r,1H),7.52(d,J=8.6Hz,1H),7.45(d,J=8.1Hz,2H),7.39(d,J=8.0Hz,3H),6.94(dd,J=8.7,4.4Hz,1H),6 .87(d,J=5.8Hz,1H),6.78(d,J=8.7Hz,1H),4.97(q,J=6.4Hz,1H),4.81(d,J=6.0Hz,2H),4.00(s,3H),3. 45(t,J=5.8Hz,2H),3.11(s,3H),2.77(tt,J=12.5,4.7Hz,4H),2.58–2.51(m,6H),1.36(d,J=6.4Hz,3H).

[1244] Example 84: Preparation of Compound 84

[1245] Preparation of intermediate 84-1:

[1246] Intermediate 83-4 (1.06 g) was added to THF (50 mL), and sodium bicarbonate (60%, 210 mg) was slowly added under ice-bath. After stirring evenly, deuterated iodomethane (250 mg) was added; the reaction was stirred under ice-bath.

[1247] After the reaction was complete, purified water was added to quench the reaction solution, and the reaction solution was concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain intermediate 84-1.

[1248] LC-MS: m / z 320.20 (M+H) + .

[1249] Preparation of compound 84:

[1250] Intermediate 84-1 (160 mg), intermediate 3-5 (100 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (40 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (54 mg), and lithium bis(trimethylsilyl)amide (1 M, 250 ul) were added to tert-butanol (50 mL), and the reaction was stirred at 85°C under nitrogen protection for 0.5 h;

[1251] After the reaction was complete, ethyl acetate (100 mL) was added to dilute the mixture, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a concentrate, which was then purified by preparative liquid chromatography to obtain compound 84.

[1252] LC-MS: m / z 690.45 (M+H) + .

[1253] 1 H NMR (500MHz, DMSO-d6) δ8.46(t,J=6.0Hz,1H),8.31(d,J=10.6Hz,2H),7.91(d,J=5.8Hz,1H),7.75–7. 6(br,1H),7.52(d,J=8.8Hz,1H),7.45(d,J=8.2Hz,2H),7.39(d,J=8.0Hz,3H),6.94(dd,J=8.8,4.2Hz ,1H),6.87(d,J=5.8Hz,1H),6.78(d,J=8.7Hz,1H),4.96(q,J=6.4Hz,1H),4.81(d,J=6.0Hz,2H),4.00 (s,3H),3.46(t,J=5.8Hz,2H),2.75(dt,J=12.4,5.1Hz,4H),2.59–2.51(m,6H),1.36(d,J=6.4Hz,3H).

[1254] Example 85: Preparation of Compound 85

[1255] Preparation of intermediate 85-1:

[1256] Intermediate 39-3 (6.2 g) was added to THF (100 mL), stirred at 0°C, and sodium hydroxide (60%, 980 mg) was slowly added. After stirring for 20 min, iodomethane (3.4 g) was added, and the mixture was transferred to room temperature and stirred for 4 h.

[1257] After the reaction was complete, purified water (100 mL) was added to quench the mixture, stirred for 10 min, and ethyl acetate (150 mL) was added for extraction. The mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 85-1 (5.8 g).

[1258] LC-MS: m / z 299.12 (M+H) + .

[1259] Preparation of compound 85:

[1260] Referring to the preparation steps of compound 3 in Example 3, intermediate 1-3 was replaced by intermediate 85-1, and compound 85 (5 mg) was obtained after purification.

[1261] LC-MS: m / z 669.40 (M+H) + .

[1262] Example 86: Preparation of Compound 86

[1263] Preparation of intermediate 86-1:

[1264] Intermediate 1-1 (0.60 g) was added to THF (50 mL), and cyclopropylmagnesium bromide (1 M, 4.4 mL) was added dropwise at -10 to 0°C under nitrogen protection. After the addition, the mixture was stirred at the same temperature for 2 h. After the reaction was complete, saturated ammonium chloride solution (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 86-1 (0.54 g).

[1265] LC-MS: m / z 326.26 (M+H) + .

[1266] Preparation of intermediate 86:

[1267] Intermediate 86-1 (70 mg) and intermediate 8-8 (122 mg) were added to tert-butanol (24 mL), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (50 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (72 mg), and lithium bis(trimethylsilyl)amide (1 M, 36 uL) were added, and the reaction was stirred at 80 ° C under nitrogen protection for 2 h.

[1268] After the reaction was complete, ethyl acetate (30 mL) and purified water (30 mL) were added, stirred for 10 min, and allowed to stand for separation; the aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to obtain a concentrate; and compound 86 was obtained by preparative liquid separation.

[1269] LC-MS: m / z 710.42 (M+H) + .

[1270] Example 87: Preparation of Compound 87

[1271] Preparation of compound 87:

[1272] Intermediate 23-1 (177 mg), intermediate 8-8 (100 mg), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (40 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (54 mg), and lithium bis(trimethylsilyl)amide (1 M, 250 μL) were added to tert-butanol (50 mL) and the reaction was stirred at 85°C under nitrogen for 0.5 h.

[1273] After the reaction was complete, ethyl acetate (100 mL) was added to dilute the mixture, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a concentrate, which was then purified by preparative liquid chromatography to obtain compound 87.

[1274] LC-MS: m / z 738.39 (M+H) + .

[1275] Example 88: Preparation of Compounds 88 and 88-a, 88-b

[1276] Preparation of compound 88:

[1277] Referring to the preparation steps of compound 3 in Example 3, intermediate 3-5 was replaced by intermediate 8-8, intermediate 1-3 was replaced by intermediate 43-1, and cesium carbonate was replaced by potassium carbonate. After the reaction was completed, the concentrate was filtered and concentrated to obtain a concentrate, which was separated by preparative liquid phase to obtain compound 88.

[1278] LC-MS: m / z 736.55 (M+H) + .

[1279] 1H NMR (500MHz, DMSO-d6) δ8.58(s,1H),8.35(d,J=5.3Hz,2H),8.21(s,2H),7.69(d,J=8.9Hz,1H),7.49(d,J=8.5Hz, 2H),7.44–7.37(m,2H),7.32(dd,J=10.0,8.7Hz,2H),6.99(d,J=8.9Hz,1H),6.82(dd,J=8.8,4.2Hz,1H),6.72(s,1 H),5.57(q,J=7.2Hz,1H),4.80(d,J=5.9Hz,2H),3.97(s,3H),3.17(s,1H),2.87(d,J=11.6Hz,1H),2.83–2.69(m,3 H),2.63(d,J=11.8Hz,1H),2.45(s,5H),2.34(s,3H),1.93(d,J=12.1Hz,2H),1.68(ddt,J=15.9,11.4,6.2Hz,2H).

[1280] Preparation method of compound 88-a and 88-b:

[1281] Compound 88 was chiral resolved to give compounds 88-a and 88-b. The separation conditions were as follows: a YMC Amylose-SA (30×250 mm, 10 μm) preparative column; gradient elution with n-hexane as mobile phase A and ethanol as mobile phase B at a flow rate of 0.8 mL / min; detection at a wavelength of 254 nm; and peak elution times of 15.5 min (88-a) and 16.3 min (88-b), respectively.

[1282] Compound 88-a LC-MS: m / z 736.45 (M+H) + .

[1283] Compound 88-b LC-MS: m / z 736.42 (M+H) + .

[1284] The retention time of compound 88-a in the chiral chromatographic column is shorter than that of 88-b, while the retention time of compound 88-b in the chiral chromatographic column is longer than that of 88-a.

[1285] Test Example 1: In vitro cell proliferation inhibitory activity

[1286] 1.1 OCI-LY10 cell proliferation inhibitory activity assay

[1287] Take OCI-LY10 cells in good growth state, collect them into centrifuge tubes, and adjust the cell density to 9×104 The cells were incubated in a 96-well plate at 100 μL / well for 72 hours. After overnight culture in a cell culture incubator, the compound was added using a nanoliter pipette to a final concentration of 1000 nM to 1.64 nM. Two replicate wells were used, and a control was also set up. After 72 hours of incubation in a cell culture incubator, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added. After incubation in a cell culture incubator for 4 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and the dose-effect curve was fitted to calculate the IC. 50 The test results are shown in Table 1.

[1288] Table 1. OCI-LY10 cell proliferation inhibitory activity

[1289] Test Example 2: In vitro liver microstructure stability evaluation

[1290] The final 300μL incubation system contains 30μL of liver microsomes (protein concentration: 0.15 mg / mL), 30μL of NADPH + MgCl2, 3μL of the test compound (prepared in acetonitrile), and 237μL of PBS buffer (pH 7.4). The organic solvent (acetonitrile) ratio is 1%. Two 0.3mL aliquots are prepared for each species. Prepare a 270μL substrate and enzyme mixture in each tube. Pre-incubate with NADPH at 37°C for 5 minutes, then add 30μL of NADPH + MgCl2. Remove 50μL of the mixture at 0, 15, 30, and 60 minutes and terminate the reaction with 300μL of glacial acetonitrile containing an internal standard.

[1291] 50 μL of the incubated sample was precipitated by adding 300 μL of glacial acetonitrile containing the internal standard (diazepam 20 ng / mL). After vortexing for 5 minutes, the sample was centrifuged (12,000 rpm, 4°C) for 10 minutes. 75 μL of the supernatant was aspirated, diluted and mixed with 75 μL of ultrapure water, and 0.5 μL was injected for analysis.

[1292] The compounds of the present application have good in vitro liver microsome stability. The test results are shown in Table 2.

[1293] Table 2

[1294] Test Example 3: In vitro kinase inhibitory activity

[1295] 3.1 BTK (WT) kinase inhibitory activity assay

[1296] BTK kinase solution (concentration 0.003 ng / μL) was added to the detection wells at 6 μL per well. Different compounds dissolved in DMSO were added to the detection wells using a nanoliter pipette to make the final concentration of the compound 1000nM-0.244nM. Two replicate wells were used, and a control was set up at the same time. The above system was incubated for 30 minutes. ATP (concentration 50μM) and ULight-poly GT substrate (manufacturer: PerkinElmer, concentration 0.5μM) were mixed at a ratio of 1:1 and added to the detection wells at 4μL per well. After reacting at room temperature for 2 hours, 5μL EDTA was added to terminate the reaction. Then, 5μL detection antibody (manufacturer: PerkinElmer, concentration 8nM) was added and incubated at room temperature for 1 hour. The detection was performed using a PerkinElmer Envision multi-function microplate reader (excitation 320nm, emission 615nm / 665nm). The IC was calculated using a four-parameter fit. 50 The test results are shown in Table 3.

[1297] 3.2 BTK (C481S) kinase inhibitory activity assay

[1298] BTK (C481S) kinase solution (concentration 0.006 ng / μL) was added to the detection wells at 6 μL per well. Different compounds dissolved in DMSO were added to the detection wells using a nanoliter pipette to make the final concentration of the compound 1000 nM-0.244 nM. Two replicate wells were used, and a control was set up at the same time. The above system was incubated for 30 minutes. ATP (concentration 50 μM) and ULight-poly GT substrate (manufacturer: PerkinElmer, concentration 0.5 μM) were mixed at a ratio of 1:1 and added to the detection wells at 4 μL per well. After reacting at room temperature for 2 hours, 5 μL of EDTA was added to terminate the reaction. Then, 5 μL of detection antibody (manufacturer: PerkinElmer, concentration 8 nM) was added and incubated at room temperature for 1 hour. The detection was performed using a PerkinElmer Envision multi-function microplate reader (excitation 320 nm, emission 615 nm / 665 nm). The IC was calculated using a four-parameter fit. 50 The test results are shown in Table 3, where A represents: IC 50 Value ≤10nM.

[1299] Table 3

[1300] Experimental Example 4: Pharmacokinetic Study in Mice

[1301] ICR mice weighing 20-25 g were randomly divided into 6 intravenous injection groups and 3 oral gavage groups after 3-5 days of adaptation. All mice were gavaged (IG) and intravenously (IV) with a solution of the compound of the application at a dose of 5 mg / kg.

[1302] Blood samples were collected from the eye socket at 30 minutes, 2 hours, 8 hours, and 24 hours after oral gavage, and at 0.083 hours (5 minutes), 0.25 hours (15 minutes), 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after intravenous injection. 30 μL of the plasma sample and the standard curve were aspirated and protein precipitated with acetonitrile containing the internal standard. The supernatant was diluted and used for LC / MS / MS analysis. A non-compartmental model was used for fitting. Pharmacokinetic parameters are shown in Table 4.

[1303] Table 4

[1304] Experimental Example 5: In vivo pharmacodynamic study

[1305] 5.1 Pharmacodynamic evaluation of OCI-LY10 cells in a mouse subcutaneous transplant tumor model

[1306] OCI-LY10 cells were subcutaneously inoculated in the right axilla of SPF female NOD-SCID mice (source: Shanghai Lingchang Biotechnology Co., Ltd.) at a rate of 1×10 7 When the average tumor volume reaches 180mm 3 When about 30 seconds, divide the animals into groups.

[1307] The day of grouping was designated Day 0. Starting from Day 1, mice were gavaged once daily at a dose of 20 or 40 mpk. Tumor volume was measured twice weekly, and mice were weighed and recorded. General performance of the mice was observed and recorded daily. At the end of the experiment, tumors were removed, weighed, and photographed.

[1308] The detection indicators and calculation formulas are as follows:

[1309] Tumor volume, TV (mm 3 )=1 / 2×(a×b 2 ), where a is the long diameter of the tumor and b is the short diameter of the tumor.

[1310] Relative tumor volume, RTV = TV t / TV0; TV0 is the tumor volume on day 0, TV t is the tumor volume at each measurement.

[1311] Relative tumor growth rate, T / C (%) = T RTV / C RTV ×100%; where T RTV RTV for the treatment group; C RTV The vehicle control group was RTV.

[1312] Tumor volume inhibition rate, TGI(TV) (%), TGI(%) = [1-(T-T0) / (C-C0)] × 100%; where T is the mean tumor volume of the treatment group; T0 is the mean tumor volume of the treatment group on day 0; C is the mean tumor volume of the control group; C0 is the mean tumor volume of the control group on day 0.

[1313] Tumor weight inhibition rate, TGI(TW)(%), TGI(%)=(1-TWt / TWc)×100%; wherein, TWt is the tumor weight of the treatment group; TWc is the tumor weight of the control group.

[1314] Body weight change rate, WCR (%) = (Wt t -Wt0) / Wt0×100%; where Wt0 is the weight of mice on day 0, Wt t is the weight of the mice at each measurement.

[1315] The compounds of the present application, including the exemplified compounds, exhibited high in vivo tumor-suppressing effects. For example, Compound 3-b, Compound 12-a, Compound 54-a, and Compound 14 demonstrated tumor volume inhibition rates exceeding 95% and tumor weight inhibition rates exceeding 92% on day 23 of administration.

Claims

1. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, Y 1 and Y 2 are each independently selected from CH or N; Ring A or Ring B is each independently selected from phenyl or 5-6 membered heteroaryl; Ring C is selected from 6-12 membered aryl, 4-12 membered heterocyclyl or 5-12 membered heteroaryl; Each R 1 are each independently selected from deuterium, hydroxyl, amino, cyano, nitro, halogen, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 Haloalkylamino; Each R 2 are each independently selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 Haloalkylamino; Each R 3 are each independently selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 2-8 Alkenyl, or C 2-8 Alkynyl, the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 2-8 Alkenyl, or C 2-8 The alkynyl group is optionally substituted with one or more R 3a replace; Each R 3a are each independently selected from deuterium, hydroxyl, halogen, amino, cyano, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 alkylamino, 3-6 membered cycloalkyl, or 4-6 membered heterocyclic group, the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, 3-6 membered cycloalkyl, or 4-6 membered heterocyclic group are optionally substituted by one or more R 3aa replace; Each R 3aa are each independently selected from deuterium, hydroxyl, halogen, amino, cyano, =O, C 1-6 Alkyl, C 1-6 Alkoxy, -N(C 1-6 Alkyl)2, -NHC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl, or 4-6 membered heterocyclyl; Each R is independently selected from 3-12 membered cycloalkyl, 4-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, wherein the 3-12 membered cycloalkyl, 4-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl is optionally substituted by one or more R a replace; Each R a are each independently selected from deuterium, hydroxyl, halogen, amino, cyano, =O, -N(C 1-6 Alkyl)2, -NHC 1-6 Alkyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkylene, deuterated C 1-6 Alkoxy C 1-6 Alkylene, halogenated C 1-6 Alkoxy C 1-6 Alkylene, C 1-6 Alkylamino C 1-6 Alkylene, di-C 1-6 Alkylamino C 1-6 Alkylene, C 1-6 Alkylthio C 1-6 Alkylene, 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, 3-6 membered cycloalkyl 1-6 Alkylene, or 4-6 membered heterocyclic group C 1-6 Alkylene; L1 is selected from a bond, -C 1-6 Alkylene-, -C(O)NHC 1-6 Alkylene-, -NHC(O)C 1-6 Alkylene-, or -NHC 1-6 Alkylene-, the-C 1-6 Alkylene-, -C(O)NHC 1-6 Alkylene-, -NHC(O)C 1-6 Alkylene-, or -NHC 1-6 Alkylene-optionally substituted with one or more selected from deuterium, hydroxy, halogen, amino, cyano, =O, or C 1-6 Alkyl radical substitution; L2 is selected from a bond, -NH-, -N(C 1-3 alkyl)-, -O-, or -S-; m is selected from 0, 1, 2, 3, 4, 5 or 6; n is selected from 0, 1, 2, 3, or 4; p is selected from 0, 1, 2, 3, or 4; q is selected from 0, 1, or 2; The premise is that p+q≥1.

2. The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Y 1 and Y 2 At least one is CH; or, Y 1 CH, Y 2 N; or, Y 1 N, Y 2 is CH; or, Y 1 and Y 2 All are CH.

3. The compound of formula (I) according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein Ring A or Ring B is each independently selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyranyl, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, or isoxazolyl; Alternatively, ring A or ring B is each independently selected from phenyl or 6-membered heteroaryl; alternatively, ring A is selected from phenyl and ring B is selected from 5-6-membered heteroaryl; alternatively, ring A is selected from phenyl and ring B is selected from 6-membered heteroaryl; Alternatively, ring A is selected from phenyl or pyridyl; or, ring B is selected from phenyl or pyridyl; or, Partially selected or, Partially selected or, Partially selected 4. The compound of formula (I) according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein ring C is selected from a 6-10 membered aryl group, a 5-10 membered heterocyclyl group or a 5-10 membered heteroaryl group; or, ring C is selected from a phenyl group, a 5-6 membered heterocyclyl group or a 5-6 membered heteroaryl group; Alternatively, ring C is selected from 6-10 membered aryl or 5-6 membered heteroaryl; Alternatively, ring C is selected from phenyl or 5-6 membered heteroaryl; Alternatively, ring C is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or pyranyl; Alternatively, ring C is selected from phenyl or pyridyl; Alternatively, Ring C is selected from pyridyl; or, Partially selected or, Partially selected or, Partially selected or, Partially selected 5. The compound of formula (I) according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R 1 Each independently selected from hydroxyl, amino, cyano, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Alkylamino, or di-C 1-4 Alkylamino; Or, each R 1 are each independently selected from halogen, C 1-6 Alkyl or C 1-6 Alkoxy; Or, each R 1 Each is independently selected from hydroxy, amino, cyano, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoroethyl, dimethylamino, or diethylamino; Or, each R 1 Each is independently selected from fluoro, methyl or methoxy.

6. A compound of formula (I) as claimed in any one of claims 1 to 5, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein each R 2 Each is independently selected from hydroxy, amino, cyano, halogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, or difluoromethyl; Or, R 2 Selected from fluorine.

7. A compound of formula (I) as claimed in any one of claims 1 to 6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein each R 3 are each independently selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, C 2-6 Alkenyl, or C 2-6 Alkynyl, the hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, C 2-6 Alkenyl, or C 2-6 The alkynyl group is optionally substituted with one or more R 3a replace; Or, each R 3 Each independently selected from amino, C 1-6 Alkyl or C 2-8 alkenyl, the amino, C 1-6 Alkyl or C 2-8 The alkenyl group is optionally substituted with one or more R 3a replace; Or, each R 3 are each independently selected from deuterium, cyano, fluorine, chlorine, or optionally substituted by one or more R 3a Substituted with the following groups: hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH=CH2, -CH2CH=CH2, -CH2CH2CH=CH2, -CH2CH=CHCH3, -CH2CH2CH2CH=CH2, -CH2CH2CH=CHCH3, or -CH2CH=CHCH2CH3; Or, each R 3 Each independently selected from optionally one or more R 3a Substituted with the following groups: amino, methyl, ethyl, n-propyl, or -CH2CH2CH2CH=CH2; Or, each R 3 Each independently selected from methyl, Optionally, each R 3a are each independently selected from deuterium, halogen, cyano, =O, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 alkylamino, 3-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl, the hydroxyl, amino, C 1-6 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, 3-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl are optionally substituted with one or more R 3aa replace; Or, each R 3a Each independently selected from hydroxyl, halogen, C 1-6 alkoxy, 3-6 membered cycloalkyl, or 4-6 membered heterocyclic group; the hydroxyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl, or 4-6 membered heterocyclic group is optionally substituted by one or more R 3aa replace; Or, each R 3a each independently selected from hydroxy, halogen, amino, cyano, =0, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothienyl, piperidinyl, piperazinyl or morpholinyl, wherein the hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothienyl, piperidinyl, piperazinyl or morpholinyl is optionally replaced by one or more R 3aa replace; Or, each R 3a are each independently selected from fluoro, hydroxy, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or piperidinyl, wherein the hydroxy, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or piperidinyl is optionally replaced by one or more R 3aa replace; Or, each R 3a Each independently selected from hydroxy, fluoro, methoxy, ethoxy, -OCD3, cyclopropyl, Optionally, each R 3aa are each independently selected from deuterium, hydroxyl, halogen, amino, cyano, =O, -N(C 1-3 Alkyl)2, -NHC 1-3 Alkyl, C 1-3 Alkyl, 3-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl; Or, each R 3aa are each independently selected from deuterium, C 1-6 Alkyl, -N(C 1-6 Alkyl) 2, or 3-6 membered cycloalkyl; Or, each R 3aa Each is independently selected from deuterium, fluorine, -N(CH3)2, methyl, or cyclopropyl.

8. A compound of formula (I) as claimed in any one of claims 1 to 7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from the group consisting of a The following groups substituted: 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; or, each R is independently selected from optionally substituted with one or more R a Substituted groups: 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; Alternatively, each R is independently selected from a 4-12 membered heterocyclic group, wherein the 4-12 membered heterocyclic group is optionally substituted by one or more R a replace; Alternatively, each R is independently selected from optionally one or more R a Substituted as follows: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, 1,4-dioxane, thiomorpholinyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or pyranyl; Alternatively, each R is independently selected from optionally one or more R a Substituted as follows: piperidinyl or piperazinyl; Alternatively, each R is independently selected from Optionally, each R a are each independently selected from deuterium, hydroxyl, halogen, amino, cyano, =O, -N(C 1-3 Alkyl)2, -NHC 1-3 Alkyl, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-3 Alkoxy C 1-3 Alkylene, deuterated C 1-3 Alkoxy C 1-3 Alkylene, halogenated C 1-3 Alkoxy C 1-3 Alkylene, C 1-3 Alkylamino C 1-3 Alkylene, di-C 1-3 Alkylamino C 1-3 Alkylene, C 1-3 Alkylthio C 1-3 Alkylene, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3-6 membered cycloalkylC 1-3 Alkylene, or 4-6 membered heterocycloalkyl C 1-3 Alkylene; Or, each R a Each independently selected from -N(C 1-6 Alkyl)2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkylene, deuterated C 1-6 Alkoxy C 1-6 Alkylene, 3-6 membered cycloalkyl, or 4-6 membered heterocyclyl; Or, each R a Each independently selected from C 1-3 Alkoxy C 1-3 Alkylene, C 1-3 Alkylamino C 1-3 Alkylene, di-C 1-3 Alkylamino C 1-3 Alkylene, 3-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl; Or, each R a Each is independently selected from deuterium, hydroxyl, halogen, amino, cyano, =O, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxymethyl, hydroxyethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, pentafluoroethyl, trideuteriomethyl, dideuteriomethyl, monodeuteriomethyl, -CH2NH2, -CH2CH2NH2, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2OC D3, -CH2NHCH3, -CH2CH2NHCH3, -CH2N(CH3)2, -CH2CH2N(CH3)2, -CH2SCH3, -CH2CH2SCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, azetidinylmethyl, oxetanylmethyl, tetrahydrofuranylmethyl, tetrahydropyrrolylmethyl, tetrahydrothiophenylmethyl, piperidinylmethyl, piperazinylmethyl, or morpholinylmethyl; Or, each R a Each is independently selected from -N(CH3)2, methyl, trideuterated methyl, -CH2CH2OCH3, -CH2CH2OCD3, cyclopropyl, or oxetanyl.

9. A compound of formula (I) as claimed in any one of claims 1 to 8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein L1 is selected from a bond, -C 1-3 Alkylene-, -C(O)NHC 1-3 Alkylene-, -NHC(O)C 1-3 Alkylene-, or -NHC 1-3 Alkylene-, the-C 1-3 Alkylene-, -C(O)NHC 1-3 Alkylene-, -NHC(O)C 1-3 Alkylene-, or -NHC 1-3 Alkylene-optionally substituted by one or more selected from hydroxy, halogen, amino, cyano, =O, or C 1-3 Alkyl radical substitution; or L1 is selected from -C(O)NHC 1-6 Alkylene-, or -NHC 1-6 Alkylene-; Alternatively, L1 is selected from a bond, -methylene-, -C(O)NHCH2-, -NHC(O)CH2-, or -NHCH2-; Alternatively, L1 is selected from -C(O)NHCH2- or -NHCH2-; Optionally, L2 is selected from -NH-.

10. The compound of formula (I) according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein m is selected from 0, 1, 2 or 3; or, m is selected from 1 or 2; Optionally, n is selected from 0, 1 or 2; or, n is 0; Optionally, p is selected from 0, 1, 2 or 3; Alternatively, p is selected from 1 or 2; Alternatively, p is selected from 0 or 1; Optionally, q is selected from 1 or 2; alternatively, q is 1.

11. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from a compound of formula (IA), a compound of formula (II), or a compound of formula (II-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, R 1 、m、L1、Y1、Y2、R 2 , n, L2, ring A, ring B, ring C, R, q, R 3 , p is defined as in any one of claims 1-10, X1 and X2 are independently selected from CH or N; or, X1 is selected from N, X2 is selected from CH; or, X1 is selected from CH, X2 is selected from N.

12. The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compound of formula (III-A) or the compound of formula (III-B), its stereoisomer or a pharmaceutically acceptable salt thereof, in, R 1 ,m,R 2 ,n,L2,ringC,R,q,R 3 , p is defined as in any one of claims 1-11.

13. The following compound, its stereoisomer or its pharmaceutically acceptable salt: Alternatively, the following compound, its stereoisomer or a pharmaceutically acceptable salt thereof:

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, its stereoisomer or a pharmaceutically acceptable salt thereof.

15. Use of the compound according to any one of claims 1 to 13, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14 in the preparation of a medicament for treating a BTK-related disease; optionally, the BTK-related disease is selected from cancer or immune disease; or, the BTK-related disease is selected from lymphoma; optionally, the lymphoma is selected from diffuse large B-cell lymphoma.