Azepino pyrimidine derivatives and their medical use

Abstract

This invention relates to azaheptanidine derivatives and their pharmaceutical uses, with specific structures shown in formula (I). It also relates to methods for preparing said compounds, pharmaceutical compositions, and their use as KRas G12C inhibitors in the treatment of cancer.

Description

[0001] Cross-reference related citations

[0002] This application claims priority to Chinese Patent Application No. 201910843832.2, filed on September 6, 2019, entitled "Azacycloheptanopyrimidine Derivatives and Their Pharmaceutical Uses", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application relates to azaheptanidine derivatives, methods for their preparation, pharmaceutical compositions containing the compounds, and their use as KRas G12C inhibitors in the treatment of cancer. Background Technology

[0004] The Ras gene is an important proto-oncogene, named after its discovery in rat sarcoma virus. The Ras protein it encodes is located on the inner side of the cell membrane, can bind to GTP / GDP, and can hydrolyze GTP with the assistance of GTPase activator protein (GAP). By interconverting between its active (GTP-bound) and inactive (GDP-bound) conformations, the Ras protein controls the "on" and "off" of signal transduction processes such as growth factors and cytokines, playing an important role in life processes such as cell proliferation, differentiation, aging, and apoptosis (Bos JL et al., Cell, 2007, 129(5):865-877). The human Ras gene family has three members: Harvey rat sarcoma virus oncogene homolog (HRas), neuroblastoma rat sarcoma virus oncogene homolog (NRas), and Kersten rat sarcoma virus oncogene homolog (KRas). KRas is mainly expressed in the intestine, lung, and thymus (Rajalingam K et al., Biochim Biophys Acta, 2007, 1773(8):1177-1195).

[0005] Studies have shown that Ras gene mutations exist in more than 30% of human tumors, with KRas mutations accounting for approximately 86% (Riely GJ et al., Proc Am Thorac Soc, 2009, 6(2):201-205). For KRas mutations, mutations at glycine position 12 (G12) account for approximately 80%, while G12C mutations (where glycine at position 12 is replaced by cysteine) account for approximately 14% of all G12 mutations (Prior IA et al., Cancer Res, 2012, 72(10):2457-2467; Hobbs GA et al., Cancer Cell, 2016, 29(3):251-253). Mutations at G12 reduce the catalytic activity of GAP, ultimately leading to persistent Ras activation, which prevents Ras from effectively regulating cell signal transduction, thereby promoting tumor development and progression.

[0006] In recent years, researchers have made some progress in drug development using the allosteric sites of the KRas G12C mutant. Currently, there are KRas G12C inhibitors under development, including ARS-1620, MRTX-1257, AMG-510, and MRTX-849, among which AMG-510 and MRTX-849 have entered the clinical trial stage.

[0007] Invention Details

[0009] This application relates to compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0010]

[0011] in,

[0012] When q is 0, p is 2. Selected from single bonds;

[0013] Alternatively, when q is 1, p is 1. Selected from single or double bonds;

[0014] Alternatively, when q is 2, p is 0. Selected from single bonds;

[0015] when When selected from a double bond, R 4 and / or R 6 It does not exist;

[0016] Part A is selected from or Wherein, R is selected from H or C. 1-6 alkyl;

[0017] Or, AR 2 Some were jointly selected

[0018] It is a 4-10 membered heterocyclic alkyl group containing at least two nitrogen atoms; It is a 4-7 membered heterocyclic alkyl group containing at least one nitrogen atom;

[0019] Each R 1 The substitution is on the ring, and it is independently selected from halogen, oxo, -OH, -NH2, -CN, or optionally replaced by 1, 2 or 3 R. 0 The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamino, or di-C 1-6 Alkylamino;

[0020] Each R 0 Independently selected from halogens, -OH, -NH2, -CN, C 1-4 Alkoxy, C 1-4 alkylamino, or di-C 1-4 Alkylamino;

[0021] m is 0, 1, 2, 3, 4, 5, or 6;

[0022] Each R 2 Selected independently from C 1-6 Alkyl carbonyl, halogenated C 1-6 alkyl carbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylsulfonyl, -C(O)C≡CR b -SO2C≡CR b -C(O)C(R) a )=C(R b )2, or -SO2C(R a )=C(R b )2;

[0023] Each R a Independently selected from H, halogen, or C 1-4 alkyl;

[0024] Each R b Independently selected from H or optionally by 1, 2 or 3 Rs c The following groups are substituted: C 1-6 Alkyl, C 1-4 Alkoxy C 1-3 Alkyl, C 1-4 Alkylamino C 1-3 Alkyl, diC 1-4 Alkylamino C 1-3 Alkyl, 3-7 membered cycloalkyl C 1-3 Alkyl, or 4-7 membered heterocyclic alkyl C 1-3 alkyl;

[0025] Each R c Independently selected from halogens, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;

[0026] X is selected from single bonds, -S-, -O-, -NH-, or -N(C). 1-3 alkyl)-;

[0027] R 3 Selected from H or optionally by 1, 2, 3 or 4 Rs dThe following groups are substituted: C 1-6 Alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, benzo4-6 membered heterocycloyl, 4-7 membered heterocycloalkyl C 1-3 Alkyl, or 5-6 quinone heteroaryl C 1-3 alkyl;

[0028] Each R d Independently selected from halogens, -OH, oxo, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 4-7 membered heterocycloalkyl C 1-3 Alkyl, wherein the C 1-4 Alkylamino, diC 1-4 The alkylamino group is optionally substituted with a substituent selected from one or two cyano groups or 5-6 heteroaryl groups;

[0029] Y is selected from single bond, -CH2-, or carbonyl group;

[0030] B is selected from 1, 2, 3, 4, 5, or 6 R's. e Substituted phenyl, naphthyl, 5-6 membered heteroaryl, benzo5-6 membered cycloalkenyl, benzo5-6 membered heterocyclic, or benzo5-6 membered heteroaryl;

[0031] Each R e Independently selected from halogens, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, diC 1-6 Alkylamino, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkyl thiols, halogenated C 1-6 Alkylamino, di(halogenated C) 1-6 Alkyl)amino, or optionally surrounded by 1, 2 or 3 R e1 The following groups are substituted: 3-7 membered cycloalkyl, 3-7 membered cycloalkyl C 1-3 Alkyl, 4-7 membered heterocyclic alkyl, or 4-7 membered heterocyclic alkyl C 1-3 alkyl;

[0032] Each R e1 Independently selected from halogens, -CN, -OH, -NH2, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C1-4 alkylamino, or di-C 1-4 Alkylamino;

[0033] R 4 R 5 Independently selected from H, halogens, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl, or R 4 and R 5 Together they form carbonyl groups, 3-6 membered cycloalkyl groups, or 4-6 membered heterocycloalkyl groups;

[0034] R 6 R 7 Independently selected from H, halogens, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl, or R 6 and R 7 Together they form carbonyl groups, 3-6 membered cycloalkyl groups, or 4-6 membered heterocycloalkyl groups.

[0035] In some implementation schemes, It is a 4-10 or 4-9 membered heterocyclic alkyl group containing two nitrogen atoms; in some embodiments, It is a 4-7 or 4-6 heterocyclic alkyl group containing one nitrogen atom; in some embodiments, the heterocyclic alkyl group is a monocyclic heterocyclic or spirocyclic heterocyclic.

[0036] In some implementations, Part A is selected from Wherein, R is selected from H or C. 1-6 alkyl.

[0037] In some implementation schemes, AR 2 Some were jointly selected

[0038] In some implementations, Part A is selected from Wherein, R is selected from H or C. 1-6 Alkyl group. In some embodiments, part A is selected from...

[0039] In some implementation schemes, AR 2 Some were jointly selected Wherein, R is selected from H or C. 1-6 alkyl.

[0040] In some implementations, R is selected from H. In some implementations, R is selected from C.1-4 Alkyl group. In some embodiments, R is selected from methyl or ethyl.

[0041] In some implementation schemes, R 1 Independently selected from halogens, oxo groups, -OH, -NH2, -CN, or optionally surrounded by 1, 2, or 3 R groups. 0 The following groups are substituted: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 alkylamino, or di-C 1-4 Alkylamino. In some embodiments, R 1 Independently selected by 1, 2 or 3 Rs 0 Replacement C 1-4 alkyl.

[0042] In some implementation schemes, R 0 Independently selected from halogens, -OH, -NH2, -CN, C 1-3 Alkoxy, C 1-3 alkylamino, or di-C 1-3 Alkylamino. In some embodiments, R 0 Independently selected from -CN, or C 1-3 Alkyl group.

[0043] In some implementation schemes, R 1 Selected independently from C 1-4 Alkyl, cyano C 1-3 Alkyl, or C 1-3 Alkoxy C 1-3 Alkyl group. In some embodiments, R 1 Independently selected from methyl, cyanomethyl, or methoxymethyl. In some embodiments, R 1 It is independently selected from cyanomethyl.

[0044] In some implementations, m is 0, 1, 2, 3, or 4. In some implementations, m is 0, 1, or 2.

[0045] In some implementation schemes, AR 2 Some were jointly selected In some implementation schemes, AR 2 Some were jointly selected In some implementation schemes, AR 2 Some were jointly selected In some implementation schemes, AR 2 Some were jointly selected In some implementation schemes, AR 2 Some were jointly selected In some implementation schemes, AR 2 Some were jointly selected

[0046] In some implementation schemes, R 2 Selected independently from C 1-4 alkyl carbonyl, C 1-4 alkoxy carbonyl, or C 1-4 Alkyl sulfonyl group.

[0047] In some implementation schemes, R 2 Independently selected from halogenated C 1-4 Alkyl carbonyl. In some embodiments, R 2 Independently selected from fluorinated C 1-4 alkyl carbonyl or chlorinated C 1-4 Alkyl carbonyl group.

[0048] In some implementation schemes, R 2 Independently selected from -C(O)C≡CR b -SO2C≡CR b -C(O)C(R) a )=C(R b )2, or -SO2C(R a )=C(R b 2. In some implementation schemes, R 2 Independently selected from -C(O)C≡CR b -C(O)C(R) a )=CH(R b ), or -SO2CH=CH(R b In some implementations, R 2 Independently selected from -C(O)C(R) a )=CH(R b ).

[0049] In some implementation schemes, R a It is independently selected from H, fluorine, chlorine, methyl, or ethyl. In some embodiments, R a Selected independently from H.

[0050] In some implementation schemes, R b Independently selected from H or optionally by 1, 2 or 3 Rs c The following groups are substituted: C 1-4 Alkyl, diC 1-3 Alkylamino C 1-2 Alkyl, or 4-6 membered heterocyclic alkyl C 1-2 Alkyl group. In some embodiments, Rb Independently selected from H or optionally by 1, 2 or 3 Rs c The substituted groups include: methyl, dimethylaminomethyl, morpholinomethyl, piperidinylmethyl, tetrahydropyrrolylmethyl, or aziridinebutylmethyl. In some embodiments, R b Selected independently from H.

[0051] In some implementation schemes, R c Independently selected from fluorine, chlorine, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 alkoxy or fluorinated C 1-3 Alkyl group. In some embodiments, R c It is independently selected from fluorine, chlorine, methyl, ethyl or trifluoromethyl.

[0052] In some implementations, the R 2 Selected from the following groups: In some implementations, the R 2 Selected from the following groups: In some implementations, the R 2 Selected from the following groups: In some implementations, the R 2 Selected from the following groups:

[0053] In some embodiments, X is selected from a single bond, -O-, or -NH-. In some embodiments, X is selected from -O- or -NH-. In some embodiments, X is selected from -O-.

[0054] In some implementation schemes, R 3 Selected from H or optionally by 1, 2, 3 or 4 Rs d The following groups are substituted: C 1-4 Alkyl, 4-7 membered heterocyclic alkyl, 5-6 membered heteroaryl, phenyl, benzo5-6 membered heterocyclic, 4-7 membered heterocyclic alkyl C 1-3 Alkyl, or 5-6 quinone heteroaryl C 1-3 Alkyl group. In some embodiments, R 3 Selected from 1, 2, 3 or 4 Rs d The following groups are substituted: 4-7 membered heterocyclic alkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclic alkyl C 1-3 Alkyl, or 5-6 quinone heteroaryl C 1-3 Alkyl group. In some embodiments, R 3 Selected from 1, 2, 3 or 4 Rs d Substitution of the following groups: 4-7 membered heterocyclic alkyl C 1-3Alkyl group. In some embodiments, R 3 Selected from H or optionally by 1, 2, 3 or 4 Rs d The following groups are substituted: methyl, ethyl, propyl, 1,2,3,4-tetrahydroisoquinolinyl, aziridine, aziridinebutylethyl, aziridinebutylpropyl, tetrahydropyrrolemethyl, tetrahydropyrroleethyl, tetrahydropyrrolepropyl, morpholinyl, piperazinyl, piperidinyl, piperidinylethyl, piperidinylpropyl, morpholinylpropyl, pyrimidinyl, pyrimidinylmethyl, pyrimidinylethyl. In some implementation schemes, R 3 Selected from H or optionally by 1, 2, 3 or 4 Rs d The following groups are substituted: tetrahydropyrrolemethyl, tetrahydropyrroleethyl, tetrahydropyrrolepropyl, morpholino, piperazinyl, piperidinyl, piperidinylethyl, piperidinylpropyl, morpholinopropyl, pyrimidinyl, pyrimidinylmethyl, pyrimidinylethyl. In some implementation schemes, R 3 Selected from H or optionally by 1, 2, 3 or 4 Rs d The following groups are substituted: tetrahydropyrrolemethyl, tetrahydropyrroleethyl, tetrahydropyrrolepropyl, morpholinopropyl, In some implementation schemes, R 3 Selected from 1, 2, 3 or 4 Rs d Substituted tetrahydropyrrolemethyl.

[0055] In some implementation schemes, R d Independently selected from halogens, oxometalates, -OH, -NH2, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, 4-7 membered heterocyclic alkyl, or 4-7 membered heterocyclic alkyl C 1-3 Alkyl, wherein the C 1-4 Alkylamino, diC 1-4 The alkylamino group is optionally substituted with one or two substituents selected from cyano or 5-6-membered heteroaryl groups. In some embodiments, R d Independently selected from fluorine, oxo, -OH, -NH2, methyl, ethyl, isopropyl, tert-butyl, methoxy, dimethylamino, diethylamino, morpholino, tetrahydropyranyl, tetrahydropyrrolylmethyl, piperidinemethyl, In some implementation schemes, R d Independently selected from halogens, or C 1-4 Alkyl group. In some embodiments, R d It is independently selected from fluorine or methyl.

[0056] In some implementations, the R 3 Selected from H, In some implementations, the R 3 Selected from In some implementations, the R 3 Selected from

[0057] In some implementations, Y is selected from single bonds.

[0058] In some implementations, B is optionally selected from 1, 2, 3, 4, 5, or 6 Rs. e The following groups may be substituted: phenyl, indenyl, 2,3-dihydroindenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene, pyrroloyl, furanyl, thiophene, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinoxalinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiophene, benzoimidazolyl, benzopyrazolyl, indole, isoindole, indolinyl, or benzo[d][1,3]dioxane. In some embodiments, B is selected from those optionally replaced by 1, 2, 3, 4, 5, or 6 R groups. e The following groups may be substituted: phenyl, 2,3-dihydroindenyl, naphthyl, thienyl, thiazolyl, pyridyl, benzopyrazolyl, or benzo[d][1,3]dioxane. In some embodiments, B is selected from those optionally replaced by 1, 2, 3, or 4 R groups. e Substituted phenyl, naphthyl, benzopyrazolyl, or pyridyl groups. In some embodiments, B is selected from those optionally replaced by 1, 2, 3, or 4 R groups. e Substituted phenyl groups. In some embodiments, B is selected from those optionally replaced by 1, 2, 3, or 4 R groups. e Substituted naphthyl group. In some embodiments, B is selected from those optionally replaced by 1, 2, 3, or 4 R groups. e Substituted pyridinyl group.

[0059] In some implementation schemes, R e Independently selected from halogens, -CN, -OH, -NH2, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, or optionally surrounded by 1, 2 or 3 R e1 The following groups are substituted: 3-6 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 4-7 membered heterocycloalkyl C 1-3Alkyl group. In some embodiments, R e Independently selected from fluorine, chlorine, bromine, iodine, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, Difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, methoxy, ethoxy, methylamino, dimethylamino, or optionally surrounded by 1, 2, or 3 R's. e1 The following groups may be substituted: cyclopropane, cyclobutane, cyclopentane, cyclohexane, tetrahydropyrrolyl, piperidinyl, piperazine, tetrahydropyranyl, morpholinyl, tetrahydropyrrolidinemethyl, piperidinylmethyl, piperazinemethyl, tetrahydropyranmethyl, or morpholinylmethyl. In some embodiments, R e Independently selected from fluorine, chlorine, bromine, iodine, -CN, -OH, -NH2, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, Trifluoromethoxy, trifluoromethylthio, methoxy, methylamino, dimethylamino, or optionally marked with 1, 2, or 3 R's e1 The following groups may be substituted: cyclopropane, morpholino, piperazine methyl, or morpholinomethyl.

[0060] In some implementation schemes, R e1 Independently selected from fluorine, chlorine, bromine, iodine, -CN, -OH, -NH2, methyl, ethyl, trifluoromethyl, methoxy, methylamino, or dimethylamino. In some embodiments, R e1 It is independently selected from fluorine, -CN, -OH, -NH2, methyl, or ethyl.

[0061] In some implementation schemes, B is selected from

[0062] In some implementation schemes, B is selected from

[0063] In some implementation schemes, B is selected from In some implementation schemes, B is selected from

[0064] In some implementation schemes, B is selected from In some implementation schemes, B is selected from

[0065] In some implementation schemes, B is selected from

[0066] In some implementation schemes, B is selected from

[0067] In some implementation schemes, B is selected from

[0068] In some implementation schemes, B is selected from

[0069] In some implementations, when R 3 Not randomly selected by 1, 2, 3 or 4 Rs d Substituted tetrahydropyrrole C 1-3 Alkyl group, B is selected from In some implementations, when R 3 Not randomly selected by 1, 2, 3 or 4 Rs d Substituted tetrahydropyrrolemethyl, B is selected from

[0070] In some implementation schemes, R 4 R 5 Independently selected from H, halogens, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 Alkyl group. In some embodiments, R 4 R 5 Independently selected from H, halogen, -OH, -NH2, -CN, methyl, ethyl, methoxy, difluoromethyl, or trifluoromethyl. In some embodiments, R 4 R 5 Independently selected from H, halogen, or methyl. In some embodiments, R 4 R 5 All are methyl or R 4 R 5 All are fluorine. In some implementations, R 4 R 5 All are H.

[0071] In some implementation schemes, R 4 and R 5 Together they form a carbonyl group. In some embodiments, R 4 and R 5 Together they form 3- to 6-membered cycloalkyl groups. In some embodiments, R 4 and R 5 Together they form cyclopropane, cyclobutane, or cyclopentane. In some embodiments, R 4 and R 5 Together they form cyclopropane.

[0072] In some implementation schemes, R 6 R 7 Independently selected from H, halogens, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 Alkyl group. In some embodiments, R 6 R 7 Independently selected from H, halogen, -OH, -NH2, -CN, methyl, ethyl, methoxy, difluoromethyl, or trifluoromethyl. In some embodiments, R 6 R 7 Independently selected from H, halogen, or methyl. In some embodiments, R 6 R 7 All are H.

[0073] In some implementation schemes, R 6 and R 7 Together they form a carbonyl group. In some embodiments, R 6 and R 7 Together they form 3- to 6-membered cycloalkyl groups. In some embodiments, R 6 and R 7 Together they form cyclopropane, cyclobutane, or cyclopentane. In some embodiments, R 6 and R 7 Together they form cyclopropane.

[0074] In some implementations, the C 1-6 Alkyl groups are selected from C 1-4 Alkyl group. In some embodiments, the C... 1-4 Alkyl groups are selected from C 1-3 Alkyl or C 1-2 alkyl.

[0075] In some embodiments, the heterocyclic alkyl group contains one or two heteroatoms selected from N or O.

[0076] In some embodiments, the heterocyclic alkyl group contains one nitrogen atom.

[0077] In some embodiments, the heterocyclic alkyl group contains two nitrogen atoms.

[0078] In some embodiments, the heterocyclic alkyl group contains one oxygen atom.

[0079] In some embodiments, the heterocyclic alkyl group contains one N atom and one O atom.

[0080] In some embodiments, the heterocyclic group contains one or two heteroatoms selected from N or O.

[0081] In some embodiments, the heterocyclic group contains one N atom.

[0082] In some embodiments, the heterocyclic group contains two O atoms.

[0083] In some embodiments, the heteroaryl group contains one, two, or three heteroatoms selected from S, N, or O.

[0084] In some embodiments, the heteroaryl group contains one or two heteroatoms selected from S and N.

[0085] In some embodiments, the heteroaryl group contains one or two N atoms.

[0086] In some embodiments, the heterocyclic alkyl group comprises a monocyclic, spirocyclic, or bridged ring.

[0087] In some implementations, when q is 1 and p is 1, When selected from single or double bonds, the two bonds in the compound of formula (I) They are not selected from double bonds at the same time.

[0088] This application relates to compounds of formula (IIa), (IIb), or (IIc), or pharmaceutically acceptable salts thereof.

[0089]

[0090] Among them, R 2 R 3 R 4 R 5 R 6 R 7 X, Y, A, B, p, q and Some are as defined above.

[0091] This application relates to compounds of formula (Ia) or (Ib) or (Ic) or (Id) or (Ie) or (If) or pharmaceutically acceptable salts thereof.

[0092]

[0093] Among them, R 1 R 2 R 3 R 4 R 5 R 6 R 7 The parts X, m, A, and B are defined as above.

[0094] This application relates to compounds of formula (III), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe), or pharmaceutically acceptable salts thereof:

[0095]

[0096]

[0097] Among them, R 3 R a R b X, B, p, and q are defined as above.

[0098] This application also relates to the following compounds or pharmaceutically acceptable salts thereof:

[0099]

[0100]

[0101]

[0102] This application also relates to the following compounds or pharmaceutically acceptable salts thereof:

[0103]

[0104]

[0105] On the other hand, this application relates to pharmaceutical compositions comprising a compound of formula (I) of this application or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions of this application further include pharmaceutically acceptable excipients.

[0106] On the other hand, this application relates to a method for treating KRas G12C-related diseases in mammals, including administering to a mammal, preferably a human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0107] On the other hand, this application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating KRas G12C-related diseases.

[0108] On the other hand, this application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment of KRas G12C-related diseases.

[0109] On the other hand, this application relates to a compound of formula (I) for treating KRas G12C-related diseases, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0110] In some embodiments of this application, the KRas G12C-related disease is preferably cancer.

[0111] In some embodiments of this application, the cancer includes lung cancer and pancreatic cancer.

[0112] In some embodiments of this application, the cancer is lung cancer, preferably non-small cell lung cancer.

[0113] definition

[0114] Unless otherwise stated, the following terms as used in this application shall have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0115] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

[0116] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, the ethyl group “optionally” being halogenated means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0117] C in this article m-n This means that the part has an integer number of carbon atoms within a given range. For example, "C 1-6 "" 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.

[0118] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by two Rs, each R has an independent option.

[0119] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a covalent bond.

[0120] When one of the variables is selected as a covalent bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a covalent bond, it means that the structure is actually AZ.

[0121] When the linking group listed does not specify its linking direction, the linking direction is arbitrary. For example, in ALZ, the linking group L is -MW-, which means that the structure can be AMWZ or AWMZ.

[0122] When a substituent is cross-bonded to two atoms on a ring, it can bond to any atom on that ring. For example, structural units. This indicates that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0123] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0124] The term "hydroxyl group" refers to the -OH group.

[0125] The term "cyano" refers to the -CN group.

[0126] The term "thiol" refers to the -SH group.

[0127] The term "amino" refers to the -NH2 group.

[0128] The term "nitro" refers to the -NO2 group.

[0129] The term "alkyl" refers to a compound with the general formula C10. n H 2n+1 The alkyl group. This alkyl group can be straight-chain or branched. For example, the term "C 1-6 "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 groups has the same definition as above.

[0130] The term "alkoxy" refers to -O-alkyl.

[0131] The term "alkylamino" refers to -NH-alkyl.

[0132] The term "dialkylamino" refers to -N(alkyl)2.

[0133] The term "alkylsulfonyl" refers to -SO2-alkyl.

[0134] The term "alkylthio" refers to -S-alkyl.

[0135] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

[0136] The term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond. 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), and 1,3-butyrynyl (-C≡CC≡CH).

[0137] The term "cycloalkyl" refers to a fully saturated carbon ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-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.

[0138] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbon ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 5- to 8-membered ring. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, and cycloheptadienyl.

[0139] The term "heterocyclic group" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated) and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 7-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, and / or nitrogen (preferably 1 or 2 heteroatoms). Non-limiting examples of heterocyclic groups include, but are not limited to, ethylene oxide, tetrahydrofuranyl, dihydrofuranyl, pyrrolyl, N-methylpyrrolyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophene, etc.

[0140] The term "heterocyclic alkyl" refers to a fully saturated cyclic group that may exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 12-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen. Examples of 3-membered heterocyclic alkyl groups include, but are not limited to, ethylene oxide, cyclothioethylene, and cycloazoethylene; non-limiting examples of 4-membered heterocyclic alkyl groups include, but are not limited to, acridine, oxadiazolyl, and thiobutylcycloyl; examples of 5-membered heterocyclic alkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, and tetrahydropyrazolyl; examples of 6-membered heterocyclic alkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxane, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, and 1,4-dithiaalkyl; and examples of 7-membered heterocyclic alkyl groups include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl.

[0141] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic ring with a conjugated π-electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, and 1,2,3,4-tetrahydronaphthalene.

[0142] The term "heteroaryl" refers to a monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, and S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 4- to 8-membered ring, particularly a 5- to 8-membered ring, or multiple fused rings containing 6 to 14, particularly 6 to 10, ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiopheneyl, indoleyl, isoindoleyl, etc.

[0143] The term "treatment" means administering the compound or preparation described in this application to prevent, improve, or eliminate a disease or one or more symptoms related to said disease, and includes:

[0144] (i) To prevent the occurrence of disease or disease state in mammals, especially when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state;

[0145] (ii) To suppress the disease or disease state, that is, to curb its development;

[0146] (iii) Alleviate the disease or disease state, even if the disease or disease state subsides.

[0147] The term "therapeutic effective amount" means the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0148] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0149] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.

[0150] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or their salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

[0151] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0152] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0153] The compounds and intermediates of this application may also exist in different tautomer forms, and all such forms are included within the scope of this application. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via the recombination of some bonding electrons.

[0154] This application also includes compounds of this application that are identical to those described herein, but with one or more atoms replaced by isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this 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, etc.

[0155] Certain isotope-labeled compounds of this application (e.g., using...) 3 H and 14 Those labeled with C can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e. 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. The isotopically labeled compounds of this application can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0156] In addition, heavier isotopes (such as deuterium) are used. 2 H)) substitution can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in certain situations, where deuterium substitution can be partial or complete, with partial deuterium substitution referring to at least one hydrogen being replaced by at least one deuterium.

[0157] The compounds of this application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized using chiral starting materials or chiral reagents. Non-limiting examples of stereoisomers include, but are not limited to:

[0158]

[0159] The compounds of this application may have one or more transisomers, unless otherwise stated, where transisomers refer to photoactive isomers resulting from the restriction of free rotation between single bonds. The chiral axis compounds of this application can be isolated in racemic form. When the energy barrier for free rotation of the single bonds in the chiral axis compounds of this application is sufficiently high, their transisomers can be isolated in photoactive pure form. Non-limiting examples of transisomers include, but are not limited to:

[0160]

[0161] The pharmaceutical compositions of this application can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0162] Typical routes of administration for the compounds of this application or their pharmaceutically acceptable salts 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.

[0163] The pharmaceutical composition of this application can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0164] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of this application to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, gels, pastes, suspensions, etc., for oral administration to patients.

[0165] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0166] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0167] In all methods of administration of the compound of general formula I described herein, the daily dose is from 0.01 to 200 mg / kg body weight. The compound of this application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining it with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this application.

[0168] The chemical reactions in the specific embodiments of this application are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents and materials required in this application. In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction process based on existing embodiments.

[0169] In some embodiments, the compound of formula (Ia) can be prepared by a person skilled in the art of organic synthesis via route 1, wherein R 2 R 3 The X, A, and B parts are defined as above.

[0170]

[0171] Route 1

[0172] Under suitable conditions, starting material 1a-1 undergoes a substitution reaction to give intermediate 1a-2. Intermediate 1a-2 undergoes intramolecular ester condensation to give intermediate 1a-3, which then undergoes a condensation reaction to give intermediate 1a-4. Intermediate 1a-4 reacts to give intermediate 1a-5. Intermediate 1a-5 undergoes a substitution reaction with the corresponding cyclic A compound to give intermediate 1a-6. Subsequently, the nitrogen atom of cyclic A is protected to give intermediate 1a-7. Intermediate 1a-7 undergoes a substitution reaction to give intermediate 1a-8, which is then deprotected from the nitrogen protecting group on the seven-membered ring to give intermediate 1a-9. Intermediate 1a-9 undergoes a coupling reaction with the corresponding cyclic B compound to give intermediate 1a-10. Deprotection gives intermediate 1a-11, which is finally reacted with R... 2The corresponding acyl halide compounds react to give the compound of formula (Ia).

[0173] In some embodiments, the compound of formula (Ib) can be prepared by a person skilled in the art of organic synthesis via route 2, wherein R 2 R 3 The X, A, and B parts are defined as above.

[0174]

[0175] Route 2

[0176] Under suitable conditions, starting material 1b-1 undergoes a condensation reaction to give intermediate 1b-2, which then reacts to give intermediate 1b-3. Intermediate 1b-3 undergoes a substitution reaction with the corresponding cyclic A compound to give intermediate 1b-4. Subsequently, the nitrogen atom of cyclic A is protected to give intermediate 1b-5. Intermediate 1b-5 undergoes a substitution reaction to give intermediate 1b-6, which is then deprotected from the nitrogen protecting group on the seven-membered ring to give intermediate 1b-7. Intermediate 1b-7 undergoes a coupling reaction with the corresponding cyclic B compound to give intermediate 1b-8, which is then deprotected to give intermediate 1b-9. Finally, it reacts with R... 2 The corresponding acyl halide compounds react to give compounds of formula (Ib).

[0177] Each product obtained from the reactions described above can be obtained using conventional separation techniques, including but not limited to filtration, distillation, crystallization, and chromatographic separation. Starting materials can be synthesized in-house or purchased from commercial sources (e.g., but not limited to Adrich or Sigma). These materials can be characterized using conventional methods, such as physical constants and spectral data. The compounds described in this application can be synthesized to obtain single isomers or mixtures of isomers.

[0178] This application uses the following abbreviations:

[0179] aq represents aqueous solution; SEMCl represents (2-(chloromethoxy)ethyl)trimethylsilane; eq represents equivalent; 1,3-DPPP represents 1,3-bis(diphenylphosphine)propane; DCM represents dichloromethane; DMSO represents dimethyl sulfoxide; Tol represents toluene; PE represents petroleum ether; DMF represents N,N-dimethylformamide; NMP represents N-methylpyrrolidone; EtOAc represents ethyl acetate; i-PrOH represents isopropanol; EtOH represents ethanol; MeOH is methanol; MeONa is sodium methoxide; THF represents tetrahydrofuran; BPO represents benzoyl peroxide; Boc represents tert-butyloxycarbonyl; Bn represents benzyl; T3P is propylphosphonic anhydride; HOAc is acetic acid; NaCNBH3 is sodium cyanoborohydride; LAH is lithium aluminum hydride; 9-BBN is 9-boronibirane; MsC l is methanesulfonyl chloride; rt is room temperature; O / N is overnight; Boc2O is di-tert-butyl dicarbonate; TFA is trifluoroacetic acid; TFAA is trifluoroacetic anhydride; TEA is triethylamine; DIEA is N,N-diisopropylethylamine; DIBAL-H is diisobutylaluminum hydride; NBS is bromosuccinamide; DPPF is 1,1'-bis(diphenylphosphino)ferrocene; Ph3P is triphenylphosphine; Pd(OAc)2 is palladium acetate; Pd(PPh3P)2CL2 is palladium bis(triphenylphosphine)chloride; Pd2(dba)3 is tri(benzylacetone)dipalladium; XANTPHOS is 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene; n-BuLi is n-butyllithium; t-BuOK is potassium tert-butoxide; t-BuONa is sodium tert-butoxide; NaOt-Bu is sodium tert-butoxide; NaO t Bu is sodium tert-butoxide; RuPhos-Pd-G3 is (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonic acid; HATU is 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate; ACE-Cl is 1-chloroethyl chloroformate; DCE is 1,2-dichloroethane; ACN is acetonitrile; THP is 2-tetrahydropyranyl.

[0180] Compounds artificially or Software naming conventions are used; commercially available compounds use supplier catalog names.

[0181] For clarity, the present invention is further illustrated by embodiments, but these embodiments are not intended to limit the scope of this application. This application has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the embodiments of this application without departing from the spirit and scope of this application.

[0182] All reagents used in this application are commercially available and can be used without further purification. Example

[0183] Example 1

[0184]

[0185] Step 1

[0186] raw materials 1-1 10.0 g of methyl 5-bromobutyrate was dissolved in 100 mL of N,N-dimethylformamide, followed by the addition of 11.9 g of ethyl 5-bromobutyrate and 8.00 g of triethylamine. The resulting solution was stirred at 100 °C for 16 hours. After the reaction was complete, the solution was cooled to room temperature, diluted with 200 mL of water, and extracted with ethyl acetate (200 mL x 3). The combined organic phases were concentrated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10%-20%) to obtain the final product. 1-2 (11.4 grams).

[0187] LC-MS: m / z 322(M+H) +

[0188] Step 2

[0189] raw materials 1-2 11.4 g of the compound was dissolved in toluene (50 mL), and tert-butanol (3.70 g) and potassium tert-butoxide (5.97 g) were added at 0 °C. The resulting mixture was heated to 100 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature. It was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The crude organic compound was then concentrated to dryness. The product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10%-20%). 1-3 (6.14 grams).

[0190] LC-MS: m / z 276 (M+H) +

[0191] Step 3

[0192] raw materials 1-3 (14.3 g) was dissolved in anhydrous methanol (200 mL), and a 30% sodium methoxide methanol solution (36.0 g) and thiourea (15.2 g) were added at 0 °C. The resulting mixture was heated to 80 °C and stirred for 1 hour. After the reaction was complete, the reaction solution was cooled to room temperature. Dilute hydrochloric acid (1 mol / L) was added to adjust the pH to 7. The precipitated solid was collected by filtration and washed with water (50 mL). After drying the solid, the product was obtained. 1-4 (13.0 grams).

[0193] LC-MS: m / z 288 (M+H) +

[0194] Step 4

[0195] raw materials 1-4 (13.0 g) was suspended in phosphorus oxychloride (130 mL), and N,N-dimethylformamide (13.0 mL) was added. The resulting suspension was stirred at 100 °C for 5 hours. After the reaction was complete, the reaction solution was concentrated to dryness. The residue was added to water (100 mL) and the pH was adjusted to 8 with anhydrous sodium carbonate. The mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10%-50%) to obtain the final product. 1-5 (7.50 grams).

[0196] LC-MS: m / z 308 (M+H) +

[0197] Step 5

[0198] raw materials 1-5 (7.50 g) was dissolved in isopropanol (100 mL), and 2-cyanomethylpiperazine dihydrochloride (5.29 g) and diisopropylethylamine (12.6 g) were added sequentially. The resulting mixture was reacted at 80 °C for 12 hours. After the reaction was complete, water (200 mL) was added for dilution. The mixture was then extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the product. 1-6 (7.00 grams).

[0199] LC-MS: m / z 397 (M+H) +

[0200] Step 6

[0201] raw materials 1-6 (7.00 g) was dissolved in anhydrous tetrahydrofuran (100 mL), and di-tert-butyl dicarbonate (4.61 g) and diisopropylethylamine (2.72 g, 21.1 mmol) were added sequentially. The resulting solution was reacted at room temperature for 3 hours. After the reaction was complete, the solution was diluted with water (150 mL) and extracted with ethyl acetate (150 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 30%-60%) to obtain the final product. 1-7 (6.30 grams).

[0202] LC-MS: m / z 497 (M+H) +

[0203] Step 7

[0204] (S)-prolyl (2.18 g) was dissolved in anhydrous tetrahydrofuran (80 mL), and sodium hydride (60%) (0.760 g) was added at 0°C. After reacting at 0°C for 30 minutes, the starting material was added. 1-7 (6.30 g). The resulting solution was reacted at 70°C for 3 hours. After the reaction was complete, it was cooled to room temperature. The reaction was quenched with saturated ammonium chloride aqueous solution (150 mL) and extracted with ethyl acetate (150 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 5%-20%) to obtain the product. 1-8 (4.20 grams).

[0205] LC-MS: m / z 576 (M+H) +

[0206] Step 8

[0207] raw materials 1-8 4.20 g of palladium on carbon (10%) (0.42 g) and a methanol solution of ammonia (7 mol / L) (10 mL) were dissolved in anhydrous methanol (10 mL) under nitrogen protection. The resulting reaction solution was purged with hydrogen three times and reacted at 40°C for 16 hours. After the reaction was complete, the palladium on carbon was filtered off. The filtrate was concentrated to dryness to obtain the product. 1-9 (2.55 grams).

[0208] LC-MS: m / z 486 (M+H) +

[0209] Step 9

[0210] raw materials 1-9 50.0 mg was dissolved in toluene (2 mL), and 1-bromonaphthalene (25.5 mg), sodium tert-butoxide (49.4 mg), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg) were added sequentially. The resulting solution was stirred at 90 °C for 3 hours. After the reaction was complete, the solution was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10%-20%) to obtain the final product. 1-10 (25.0 mg).

[0211] LC-MS: m / z 612 (M+H) +

[0212] Step 10

[0213] To raw materials1-10 A solution of 1,4-dioxane hydrogen chloride (25.0 mg) in 2 mL was added. The resulting solution was stirred at room temperature for 10 minutes. After the reaction was complete, the solution was concentrated to dryness to obtain the product. 1-11 (15.0 mg). No purification required; can be used directly in the next reaction.

[0214] LC-MS: m / z 512 (M+H) +

[0215] Step 11

[0216] raw materials 1-11 (15.0 mg) was dissolved in dichloromethane (2 mL), cooled to -40°C, and then triethylamine (13.8 mg) and acryloyl chloride (2.47 mg) were added sequentially. The resulting solution was reacted at -40°C for 10 minutes. After the reaction was complete, water (5 mL) was added to quench the reaction and the solution was concentrated to dryness. The crude product was purified using a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 38-59%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 1 (10.8 mg).

[0217] LC-MS: m / z 566 (M+H) +

[0218] 1 H-NMR(CD3OD)δ:7.95(d,J=8.4Hz,1H),7.82(d,J=9.0Hz,1H),7.56(d,J=8.1Hz,1H),7.46-7.31(m,3H),7.22( d,J=7.8Hz,1H),7.00-6.75(m,1H),6.31(dd,J1=1.5Hz,J2=16.5Hz,1H),5.85(dd,J1=1.5Hz,J2=10.5Hz,1H),5 .12-4.60(m,1H),4.43-4.30(m,4H),4.21-4.08(m,1H),4.06-3.91(m,2H),3.82-3.63(m,1H),3.58-3.43(m,3H ),3.16-2.93(m,6H),2.83-2.67(m,1H),2.50(s,3H),2.40-2.31(m,1H),2.25-2.03(m,3H),1.87-1.65(m,3H).

[0219] Example 2

[0220]

[0221] Step 1

[0222] compound 2-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 8-chloro-1-bromonaphthalene (49.5 mg), sodium tert-butoxide (98.9 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 2-1 (25.0 mg).

[0223] LC-MS: m / z 646 (M+H) +

[0224] Step 2

[0225] compound 2-2 Synthetic reference compound 1-11 .raw material 2-1 (25.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 2 mL). Product obtained. 2-2 (20.0 mg).

[0226] LC-MS: m / z 546 (M+H) + .

[0227] Step 3

[0228] compound 2 Synthetic reference compound 1 .raw material 2-2 (20.0 mg), triethylamine (17.4 mg), acryloyl chloride (4.6 mg), dichloromethane (5 mL). Product obtained. 2 (4.1 mg).

[0229] LC-MS: m / z 600(M+H) +

[0230] 1H-NMR(DMSO)δ:7.90-7.83(m,1H),7.73-7.63(m,1H),7.55-7.22(m,4H),6.97-6. 77(m,1H),6.19(d,J=15.6Hz,1H),5.77(d,J=10.5Hz,1H),5.04-4.76(m,1H),4.5 3-4.10(m,4H),4.08-3.96(m,1H),3.74-3.41(m,5H),3.15-2.85(m,3H),2.83-2. 66(m,6H),2.30(s,3H),2.21-2.10(m,1H),2.02-1.76(m,2H),1.69-1.51(m,3H).

[0231] Example 3

[0232]

[0233] Step 1

[0234] compound 3-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 8-fluoro-1-bromonaphthalene (46.2 mg), sodium tert-butoxide (98.9 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 3-1 (25.0 mg).

[0235] LC-MS: m / z 630(M+H) +

[0236] Step 2

[0237] compound 3-2 Synthetic reference compound 1-11 .raw material 3-1 (25.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 2 mL). Product obtained. 3-2 (20.0 mg).

[0238] LC-MS: m / z 530 (M+H) + .

[0239] Step 3

[0240] compound 3 Synthetic reference compound 1 .raw material 3-2(20.0 mg), triethylamine (17.4 mg), acryloyl chloride (4.6 mg), dichloromethane (5 mL). Product obtained. 3 (4.1 mg).

[0241] LC-MS: m / z 584 (M+H) +

[0242] 1 H-NMR(DMSO)δ:7.90-7.83(m,1H),7.73-7.63(m,1H),7.55-7.22(m,4H),6.97-6. 77(m,1H),6.19(d,J=15.6Hz,1H),5.77(d,J=10.5Hz,1H),5.04-4.76(m,1H),4.5 3-4.10(m,4H),4.08-3.96(m,1H),3.74-3.41(m,5H),3.15-2.85(m,3H),2.83-2. 66(m,6H),2.30(s,3H),2.21-2.10(m,1H),2.02-1.76(m,2H),1.69-1.51(m,3H).

[0243] Example 5

[0244]

[0245] Step 1

[0246] compound 5-1 Synthetic reference compound 1 .raw material 4-2 (20.0 mg), 4-bromocrotonyl chloride (8.34 mg), dichloromethane (5 mL). Product obtained. 5-1 (18.3 mg).

[0247] LC-MS: m / z 672 (M+H) +

[0248] Step 2

[0249] raw materials 5-1(18.3 mg) was dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (7.02 mg) and morpholine (2.86 mg) were added sequentially. The resulting solution was reacted at room temperature for 16 hours. After the reaction was completed, water (5 mL) was added to quench the reaction and the solution was concentrated to dryness. The crude product was purified by preparative chromatography (column type: XBridge Shield RP18 OBDColumn, 5 μm, 19*150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 37-63%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 5 (2.00 mg).

[0250] LC-MS: m / z 679 (M+H) +

[0251] 1 H-NMR(CD3OD)δ:7.72-7.61(m,2H),7.44-7.11(m,4H),6.92-6.67(m,2H),5.17- 5.05(m,1H),4.70-4.56(m,1H),4.49-4.28(m,3H),4.25-4.07(m,2H),3.97-3.59 (m,7H),3.54-3.39(m,2H),3.27-3.22(m,2H),3.14-2.87(m,6H),2.86-2.70(m, 4H),2.60-2.44(m,5H),2.44-2.33(m,1H),2.19-1.94(m,4H),1.88-1.58(m,4H).

[0252] Example 6

[0253]

[0254] compound 6 Synthetic reference compound 5 .raw material 5-1 (15 mg), N,N-diisopropylethylamine (7.19 mg), 3-fluorobutylidine hydrochloride (2.00 mg), N,N-dimethylformamide (3 mL). Product obtained. 6 (0.30 mg).

[0255] LC-MS: m / z 667 (M+H) +

[0256] 1H-NMR(CD3OD)δ:7.81-7.53(m,2H),7.49-7.11(m,4H),6.89-6.54(m,2H),5 .35-5.20(m,1H),5.18-4.99(m,2H),4.67-4.60(m,2H),4.59-4.50(m,1H),4 .49-4.29(m,2H),4.26-4.06(m,2H),4.02-3.62(m,5H),3.59-3.35(m,6H), 3.30-2.88(m,7H),3.87-2.45(m,5H),2.44-2.16(m,2H),2.13-2.74(m,4H).

[0257] Examples 10, 11 and 12

[0258]

[0259] Step 1

[0260] compound 10-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 2-bromo-6-methyl-trifluorotoluene (49.0 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 10-1 (25.0 mg).

[0261] LC-MS: m / z 644 (M+H) +

[0262] Step 2

[0263] compound 10-2 Synthetic reference compound 1-11 .raw material 10-1 (25.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 10-2 (21.0 mg).

[0264] LC-MS: m / z 544 (M+H) + .

[0265] Step 3

[0266] compound 10 Synthetic reference compound 1 .raw material 10-2(21.0 mg), triethylamine (18.3 mg), acryloyl chloride (4.93 mg), dichloromethane (5 mL). Product obtained. 10 (13.5 mg).

[0267] LC-MS: m / z 598 (M+H) +

[0268] 1 H-NMR(CD3OD)δ:7.42(t,J=7.8Hz,1H),7.30(d,J=8.1Hz,1H),7.11(d,J=7.5Hz,1H),6.94-6.74(m,1H), 6.30(d,J=16.5Hz,1H),5.84(d,J=10.5Hz,1H),5.22-5.04(m,1H),4.71-4.47(m,1H),4.42-4.28(m,2H) ,4.27-4.06(m,3H),3.97-3.78(m,2H),3.57-3.37(m,1H),3.30-3.20(m,2H),3.16-2.93(m,4H),2.93-2 .70(m,3H),2.51(s,3H),2.47(q,J=3.6Hz,3H),2.42-2.31(m,1H),2.17-1.93(m,3H),1.90-1.63(m,3H).

[0269] Step 4

[0270] compound 10 Chiral high-pressure separation (column type: CHIRAL ART Cellulose-SB2*25cm, 5µm; mobile phase A: n-hexane (0.1%, diethylamine), mobile phase: isopropanol; flow rate: 20 mL / min; gradient: 30%, time: 20 min; detector wavelength: 254 / 220 nm) yielded the product. 11 and 12 .

[0271] product 11 The retention time is 2.09 minutes.

[0272] 1H-NMR(CD3OD)δ:7.42(t,J=7.8Hz,1H),7.31(d,J=8.1Hz,1H),7.11(d,J=7.5Hz,1H),6.96-6.76(m, 1H),6.30(d,J=16.6Hz,1H),5.85(d,J=10.6Hz,1H),5.23-5.03(m,1H),4.68-4.58(m,1H),4.40-4. 28(m,2H),4.27-4.07(m,3H),3.97-3.80(m,2H),3.72-3.58(m,1H),3.29-3.22(m,2H),3.13-2.75( m,7H),2.51(s,3H),2.47(q,J=3.6Hz,3H),2.43-2.35(m,1H),2.14-1.96(m,3H),1.88-1.68(m,3H).

[0273] compound 12 The retention time is 3.20 minutes.

[0274] 1 H-NMR(CD3OD)δ:7.42-7.39(m,1H),7.31(d,J=8.1Hz,1H),7.12(d,J=7.5Hz,1H),6.96-6.76(m,1H),6 .30(d,J=16.6Hz,1H),5.87(d,J=10.6Hz,1H),5.26-5.05(m,1H),4.70-4.59(m,1H),4.40-4.32(m,2H) ,4.29-4.07(m,3H),3.97-3.81(m,2H),3.70-3.58(m,1H),3.33-3.22(m,3H),3.13-3.07(m,1H),3.06- 2.98(m,2H),2.92-2.80(m,3H),2.51(s,3H),2.47-2.40(m,4H),2.15-1.90(m,3H),1.88-1.68(m,3H).

[0275] Example 13

[0276]

[0277] Step 1

[0278] compound 13-1 Synthetic reference compound 1-10 .raw material 1-9(50.0 mg), 2-bromo-6-chlorotrifluorotoluene (53.1 mg), sodium tert-butoxide (98.9 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 13-1 (28.0 mg).

[0279] LC-MS: m / z 664 (M+H) +

[0280] Step 2

[0281] compound 13-2 Synthetic reference compound 1-11 .raw material 13-1 (28.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 13-2 (24.3 mg).

[0282] LC-MS: m / z 564 (M+H) + .

[0283] Step 3

[0284] compound 13 Synthetic reference compound 1 .raw material 13-2 (23.3 mg), triethylamine (19.6 mg), acryloyl chloride (5.28 mg), dichloromethane (5 mL). Product obtained. 13 (8.70 mg).

[0285] LC-MS: m / z 618 (M+H) +

[0286] 1H-NMR(CD3OD)δ:7.43(t,J=8.2Hz,1H),7.30-7.22(m,2H),6.94-6.75(m,1H),6.30(d,J=16. 5Hz,1H),5.84(d,J=10.5Hz,1H),5.19-5.01(m,1H),4.69-4.46(m,1H),4.41-4.20(m,4H),3 .99-3.75(m,3H),3.69-3.59(m,1H),3.47-3.36(m,1H),3.29-3.22(m,1H),3.19-2.89(m,4H ),2.88-2.73(m,3H),2.53(s,3H),2.45-2.33(m,1H),2.19-1.94(m,3H),1.91-1.67(m,3H).

[0287] Example 15

[0288]

[0289] Step 1

[0290] compound 15-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 1-bromo-7-methylnaphthalene (34.0 mg), sodium tert-butoxide (98.9 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 15-1 (25.0 mg).

[0291] LC-MS: m / z 626 (M+H) +

[0292] Step 2

[0293] compound 15-2 Synthetic reference compound 1-11 .raw material 15-1 (25.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 15-2 (21.5 mg).

[0294] LC-MS: m / z 526 (M+H) + .

[0295] Step 3

[0296] compound 15 Synthetic reference compound 1.raw material 15-2 (21.5 mg), triethylamine (19.4 mg), acryloyl chloride (5.20 mg), dichloromethane (5 mL). Product obtained. 15 (4.8 mg).

[0297] LC-MS: m / z 580 (M+H) +

[0298] 1 H-NMR(CD3OD)δ:7.78-7.65(m,2H),7.50(d,J=8.1Hz,1H),7.37-7.24(m,2H),7.17(d,J=7.4Hz,1H),6.93-6.7 9(m,1H),6.31(d,J=16.6Hz,1H),5.85(d,J=10.7Hz,1H),5.22-5.08(m,1H),4.69-4.53(m,1H),4.49-4.31(m,2 H),4.23-4.09(m,1H),4.05-3.88(m,2H),3.80-3.66(m,1H),3.61-3.41(m,3H),3.41-3.38(m,1H),3.22-2.91 (m,6H),2.84-2.74(m,1H),2.52(s,3H),2.42-2.37(m,1H),2.35(s,3H),2.25-2.01(m,3H),1.91-1.67(m,3H).

[0299] Example 16

[0300]

[0301] Step 1

[0302] compound 16-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 1-bromo-7-chloronaphthalene (49.4 mg), sodium tert-butoxide (98.9 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 16-1 (29.0 mg).

[0303] LC-MS: m / z 646 (M+H) +

[0304] Step 2

[0305] compound 16-2Synthetic reference compound 1-11 .raw material 16-1 (29.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 16-2 (24.5 mg).

[0306] LC-MS: m / z 546 (M+H) + .

[0307] Step 3

[0308] compound 16 Synthetic reference compound 1 .raw material 16-2 (24.5 mg), triethylamine (21.3 mg), acryloyl chloride (5.73 mg), dichloromethane (5 mL). Product obtained. 16 (5.0 mg).

[0309] LC-MS: m / z 600(M+H) +

[0310] 1 H-NMR(CD3OD)δ:7.93-7.78(m,2H),7.58(d,J=8.1Hz,1H),7.51-7.36(m,2H),7.29(d,J=7.8Hz,1H),6. 91-6.78(m,1H),6.31(d,J=16.5Hz,1H),5.85(d,J=10.7Hz,1H),5.21-5.07(m,1H),4.70-4.54(m,1H),4 .49-4.35(m,2H),4.28(d,J=4.2Hz,2H),4.08-3.90(m,2H),3.81-3.65(m,1H),3.61-3.52(m,1H),3.51 -3.37(m,2H),3.31-2.81(m,7H),2.55(s,3H),2.47-2.37(m,1H),2.28-2.02(m,3H),1.92-1.72(m,3H).

[0311] Example 17

[0312]

[0313] Step 1

[0314] compound 17-1 Synthetic reference compound 1-10 .raw material 1-9(50.0 mg), 2-bromo-6-methoxytrifluorotoluene (52.3 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 17-1 (32.0 mg).

[0315] LC-MS: m / z 660(M+H) +

[0316] Step 2

[0317] compound 17-2 Synthetic reference compound 1-11 .raw material 17-1 (32.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 17-2 (27.8 mg).

[0318] LC-MS: m / z 560 (M+H) + .

[0319] Step 3

[0320] compound 17 Synthetic reference compound 1 .raw material 17-2 (27.8 mg), triethylamine (23.6 mg), acryloyl chloride (6.34 mg), dichloromethane (5 mL). Product obtained. 17 (9.20 mg).

[0321] LC-MS: m / z 614 (M+H) +

[0322] 1H-NMR(CD3OD)δ:7.41(t,J=8.1Hz,1H),6.96-6.71(m,3H),6.30(d,J=16.8Hz,1H),5.84(d,J=1 0.8Hz,1H),5.21-5.05(m,1H),4.76-4.46(m,1H),4.43-4.33(m,2H),4.33-4.17(m,2H),4.16-4 .00(m,1H),3.98-3.88(m,1H),3.86(s,3H),3.83-3.74(m,1H),3.71-3.54(m,1H),3.49-3.35(m ,2H),3.24-2.77(m,7H),2.56(s,3H),2.49-2.36(m,1H),2.18-1.93(m,3H),1.91-1.68(m,3H).

[0323] Example 18

[0324]

[0325] Step 1

[0326] compound 18-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 3-bromo-4-trifluoromethylpyridine (46.4 mg), sodium tert-butoxide (98.9 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 18-1 (26.0 mg).

[0327] LC-MS: m / z 631(M+H) +

[0328] Step 2

[0329] compound 18-2 Synthetic reference compound 1-11 .raw material 18-1 (26.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 18-2 (22.5 mg).

[0330] LC-MS: m / z 531 (M+H) + .

[0331] Step 3

[0332] compound 18 Synthetic reference compound1 .raw material 18-2 (22.5 mg), triethylamine (20.1 mg), acryloyl chloride (5.40 mg), dichloromethane (5 mL). Product obtained. 18 (8.30 mg).

[0333] LC-MS: m / z 585 (M+H) +

[0334] 1 H-NMR(CD3OD)δ:8.69(s,1H),8.48(d,J=5.1Hz,1H),7.64(d,J=5.1Hz,1H),6.94-6.76(m,1 H),6.30(d,J=16.5Hz,1H),5.85(d,J=10.6Hz,1H),5.21-5.03(m,1H),4.81-4.51(m,1H),4. 44-4.25(m,4H),4.21-4.04(m,1H),3.96-3.78(m,2H),3.75-3.59(m,1H),3.56-3.41(m,2H ),3.16-2.69(m,7H),2.52(s,3H),2.44-2.32(m,1H),2.19-1.99(m,3H),1.89-1.65(m,3H).

[0335] Example 19

[0336]

[0337] Step 1

[0338] compound 19-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 2-bromo-6-fluorotrifluorotoluene (49.9 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 19-1 (27.0 mg).

[0339] LC-MS: m / z 648 (M+H) +

[0340] Step 2

[0341] compound 19-2 Synthetic reference compound 1-11 .raw material 19-1(27.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 19-2 (25.6 mg).

[0342] LC-MS: m / z 548 (M+H) + .

[0343] Step 3

[0344] compound 19 Synthetic reference compound 1 .raw material 19-2 (25.6 mg), triethylamine (22.2 mg), acryloyl chloride (5.96 mg), dichloromethane (5 mL). Product obtained. 19 (5.9 mg).

[0345] LC-MS: m / z 602(M+H) +

[0346] 1 H-NMR(CD3OD)δ:7.65-7.57(m,1H),7.45-7.35(m,2H),6.93-4.78(m,1H),6.30(d,J=1 6.5Hz,1H),5.85(d,J=10.6Hz,1H),5.22-5.07(m,1H),4.82-4.48(m,1H),4.40-4.27( m,2H),4.24-4.01(m,2H),4.00-3.79(m,2H),3.75-3.44(m,2H),3.28-3.17(m,2H),3. 13-2.70(m,7H),2.50(s,3H),2.42-2.32(m,1H),2.15-1.93(m,3H),1.88-1.67(m,3H).

[0347] Example 20

[0348]

[0349] Step 1

[0350] compound 20-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 2-fluorobromobenzene (35.8 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 20-1 (31.0 mg).

[0351] LC-MS: m / z 580 (M+H) +

[0352] Step 2

[0353] compound 20-2 Synthetic reference compound 1-11 .raw material 20-1 (31.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 20-2 (26.6 mg).

[0354] LC-MS: m / z 480(M+H) + .

[0355] Step 3

[0356] compound 20 Synthetic reference compound 1 .raw material 20-2 (26.6 mg), triethylamine (26.1 mg), acryloyl chloride (7.02 mg), dichloromethane (5 mL). Product obtained. 20 (6.8 mg).

[0357] LC-MS: m / z 534 (M+H) +

[0358] 1 H-NMR(CD3OD)δ:7.06-6.95(m,3H),6.93-6.73(m,5H),6.28(d,J=16.5Hz ,1H),5.83(d,J=10.5Hz,1H),5.18-5.02(m,1H),4.78-4.50(m,1H),4.47- 4.26(m,4H),3.96-3.95(m,2H),3.56(t,J=6.3Hz,2H),3.29-2.71(m,6H), 2.52(s,3H),2.38(q,J=9.0Hz,1H),2.17-1.99(m,3H),1.90-1.68(m,3H).

[0359] Example 21

[0360]

[0361] Step 1

[0362] compound 21-1 Synthetic reference compound 1-10 .raw material 1-9(50.0 mg), 1-bromo-4-fluoro-2,3-o-xylene (41.6 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 21-1 (32.0 mg).

[0363] LC-MS: m / z 608 (M+H) +

[0364] Step 2

[0365] compound 21-2 Synthetic reference compound 1-11 .raw material 21-1 (32.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 21-2 (27.8 mg).

[0366] LC-MS: m / z 508 (M+H) + .

[0367] Step 3

[0368] compound 21 Synthetic reference compound 1 .raw material 21-2 (27.8 mg), triethylamine (25.9 mg), acryloyl chloride (6.95 mg), dichloromethane (5 mL). Product obtained. 21 (8.8 mg).

[0369] LC-MS: m / z 562 (M+H) +

[0370] 1 H-NMR(CD3OD)δ:7.08-6.98(m,1H),6.94-6.78(m,2H),6.30(d,J=16.5Hz,1H),5 .85(d,J=10.5Hz,1H),5.20-5.07(m,1H),4.82-4.47(m,1H),4.44-4.31(m,2H),4 .19-3.81(m,5H),3.74-3.54(m,1H),3.29-2.82(m,9H),2.55(s,3H),2.49-2.37( m,1H),2.17(d,J=2.1Hz,3H),2.15(s,3H),2.13-1.94(m,3H),1.92-1.69(m,3H).

[0371] Example 23

[0372]

[0373] Step 1

[0374] compound 23-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 1-bromo-2-chloro-3-fluorobenzene (42.8 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 23-1 (31.0 mg).

[0375] LC-MS: m / z 614 (M+H) +

[0376] Step 2

[0377] compound 23-2 Synthetic reference compound 1-11 .raw material 23-1 (31.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 23-2 (27.2 mg).

[0378] LC-MS: m / z 514 (M+H) + .

[0379] Step 3

[0380] compound 23 Synthetic reference compound 1 .raw material 23-2 (27.2 mg), triethylamine (25.0 mg), acryloyl chloride (6.72 mg), dichloromethane (5 mL). Product obtained. 23 (6.8 mg).

[0381] LC-MS: m / z 568 (M+H) +

[0382] 1H-NMR(CD3OD)δ:7.27-7.18(m,1H),7.02-6.95(m,1H),6.93-6.74(m,2H),6.29(d,J=1 6.5Hz,1H),5.84(d,J=10.5Hz,1H),5.19-5.04(m,1H),4.69-4.51(m,1H),4.43-4.29( m,3H),4.14-3.82(m,3H),3.74-3.58(m,1H),3.51-3.38(m,2H),3.30-3.25(m,1H),3. 16-2.73(m,7H),2.53(s,3H),2.44-2.34(m,1H),2.22-2.01(m,3H),1.89-1.68(m,3H).

[0383] Example 24

[0384]

[0385] Step 1

[0386] compound 24-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 2-bromo-6-fluoroanisole (42.0 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 24-1 (26.0 mg).

[0387] LC-MS: m / z 610(M+H) +

[0388] Step 2

[0389] compound 24-2 Synthetic reference compound 1-11 .raw material 24-1 (26.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 24-2 (22.8 mg).

[0390] LC-MS: m / z 510 (M+H) + .

[0391] Step 3

[0392] compound 24 Synthetic reference compound 1 .raw material 24-2(22.8 mg), triethylamine (21.1 mg), acryloyl chloride (5.67 mg), dichloromethane (5 mL). Product obtained. 24 (7.2 mg).

[0393] LC-MS: m / z 564 (M+H) +

[0394] 1 H-NMR(CD3OD)δ:6.96-6.62(m,4H),6.29(d,J=16.5Hz,1H),5.83(d,J=10.5 Hz,1H),5.20-5.02(m,1H),4.79-4.52(m,1H),4.42-4.35(m,3H),4.13-3.7 9(m,3H),3.72-3.58(m,1H),3.54(s,3H),3.52-3.42(m,2H),3.30-2.74(m, 8H),2.54(s,3H),2.43-2.34(m,1H),2.19-1.98(m,3H),1.91-1.68(m,3H).

[0395] Example 25

[0396]

[0397] Step 1

[0398] compound 25-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 2-bromotrifluoromethoxybenzene (49.4 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 25-1 (32.0 mg).

[0399] LC-MS: m / z 646 (M+H) +

[0400] Step 2

[0401] compound 25-2 Synthetic reference compound 1-11 .raw material 25-1 (32.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 25-2 (27.9 mg).

[0402] LC-MS: m / z 546 (M+H) + .

[0403] Step 3

[0404] compound 25 Synthetic reference compound 1 .raw material 25-2 (27.9 mg), triethylamine (24.3 mg), acryloyl chloride (6.52 mg), dichloromethane (5 mL). Product obtained. 25 (7.7 mg).

[0405] LC-MS: m / z 600(M+H) +

[0406] 1 H-NMR(CD3OD)δ:7.29-7.16(m,2H),7.15-7.07(m,1H),7.00-6.73(m,2H),6.29(d ,J=16.5Hz,1H),5.83(d,J=10.5Hz,1H),5.20-5.01(m,1H),4.80-4.50(m,1H),4. 44-4.30(m,3H),4.15-3.75(m,3H),3.71-3.54(m,1H),3.51-3.37(m,2H),3.26-2 .74(m,8H),2.53(s,3H),2.43-2.33(m,1H),2.20-2.02(m,3H),1.89-1.68(m,3H).

[0407] Example 26

[0408]

[0409] Step 1

[0410] compound 26-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 4-bromo-3-trifluoromethyl-pyridine (46.3 mg), sodium tert-butoxide (98.9 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 26-1 (29.0 mg).

[0411] LC-MS: m / z 631(M+H) +

[0412] Step 2

[0413] compound 26-2 Synthetic reference compound 1-11 .raw material 26-1 (29.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 26-2 (25.5 mg).

[0414] LC-MS: m / z 531 (M+H) +

[0415] Step 3

[0416] compound 26 Synthetic reference compound 1 .raw material 26-2 (25.5 mg), triethylamine (22.7 mg), acryloyl chloride (6.12 mg), dichloromethane (5 mL). Product obtained. 26 (8.9 mg).

[0417] LC-MS: m / z 585 (M+H) +

[0418] 1 H-NMR(CD3OD)δ:8.39(d,J=4.2Hz,1H),7.93(d,J=8.4,1H),7.67-7.58(m,1H),7.96-7.76(m ,1H),6.30(d,J=16.5Hz,1H),5.85(d,J=10.5Hz,1H),5.22-5.03(m,1H),4.81-4.51(m,1H), 4.42-4.20(m,4H),4.14-3.81(m,3H),3.76-3.62(m,1H),3.47-3.39(m,1H),3.30-3.23(m,1 H),3.14-2.73(m,7H),2.51(s,3H),2.40-2.32(m,1H),2.15-1.95(m,3H),1.87-1.64(m,3H).

[0419] Example 27

[0420]

[0421] Step 1:

[0422] compound 27-1 Synthetic reference compound 1-10 .raw material 1-9(50.0 mg), 2-bromo-4-fluorotrifluorotoluene (49.8 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 27-1 (27.5 mg).

[0423] LC-MS: m / z 648 (M+H) +

[0424] Step 2:

[0425] compound 27-2 Synthetic reference compound 1-11 .raw material 27-1 (27.5 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 27-2 (24.3 mg).

[0426] LC-MS: m / z 548 (M+H) +

[0427] Step 3

[0428] compound 27 Synthetic reference compound 1 .raw material 27-2 (24.3 mg), triethylamine (0.0289 mL), acryloyl chloride (4.50 mg), dichloromethane (5 mL). Product obtained. 27 (7.5 mg).

[0429] LC-MS: m / z 602(M+H) +

[0430] 1 H-NMR(CD3OD)δ:7.74-7.61(m,1H),7.35-7.20(m,1H),7.10-6.98(m,1H),6.97-6.7 0(m,1H),6.29(d,J=16.5Hz,1H),5.84(d,J=10.5Hz,1H),5.19-4.98(m,1H),4.77-4 .41(m,3H),4.37-4.10(m,3H),3.98(d,J=15.0Hz,1H),3.85(d,J=12.0Hz,1H),3.74 -3.43(m,3H),3.19-2.89(m,7H),2.87(s,3H),2.37-2.25(m,1H),2.25-1.67(m,6H).

[0431] Example 28

[0432]

[0433] Step 1:

[0434] compound 28-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 3-bromo-2-methyltrifluorotoluene (49.0 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 28-1 (31.4 mg).

[0435] LC-MS: m / z 644 (M+H) +

[0436] Step 2:

[0437] compound 28-2 Synthetic reference compound 1-11 .raw material 28-1 (31.4 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 28-2 (27.3 mg).

[0438] LC-MS: m / z 544 (M+H) +

[0439] Step 3

[0440] compound 28 Synthetic reference compound 1 .raw material 28-2 (27.3 mg), triethylamine (0.0310 mL), acryloyl chloride (4.83 mg), dichloromethane (5 mL). Product obtained. 28 (8.2 mg).

[0441] LC-MS: m / z 598 (M+H) +

[0442] 1H-NMR(CD3OD)δ:7.47-7.25(m,3H),6.91-6.76(m,1H),6.29(d,J=16.5Hz,1H),5.34(d,J=10.5 Hz,1H),5.19-5.02(m,1H),4.66-4.51(m,1H),4.43-4.23(m,2H),4.21-4.03(m,3H),4.01-3.8 4(m,2H),3.76-3.60(m,1H),3.46-3.35(m,1H),3.29-3.22(m,1H),3.16-2.88(m,6H),2.83-2. 70(m,1H),2.52(s,3H),2.44-2.32(m,1H),2.27(s,3H),2.18-1.98(m,3H),1.89-1.66(m,3H).

[0443] Example 29

[0444]

[0445] Step 1:

[0446] compound 29-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 2-bromo-6-chlorotoluene (46.7 mg), sodium tert-butoxide (98.9 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 29-1 (29.3 mg).

[0447] LC-MS: m / z 610(M+H) +

[0448] Step 2:

[0449] compound 29-2 Synthetic reference compound 1-11 .raw material 29-1 (29.3 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 29-2 (25.8 mg).

[0450] LC-MS: m / z 510 (M+H) + .

[0451] Step 3

[0452] compound 29 Synthetic reference compound1 .raw material 29-2 (25.8 mg), triethylamine (0.0329 mL), acryloyl chloride (5.16 mg), dichloromethane (5 mL). Product obtained. 29 (7.9 mg).

[0453] LC-MS: m / z 564 (M+H) +

[0454] 1 H-NMR(CD3OD)δ:7.20-7.01(m,3H),6.98-6.75(m,1H),6.30(d,J=16.5Hz,1H),5.84(d,J=10.5Hz,1 H),5.20-5.03(m,1H),4.72-4.48(m,1H),4.43-4.27(m,2H),4.26-4.03(m,3H),4.03-3.81(m,2H), 3.78-3.61(m,1H),3.61-3.44(m,1H),3.44-3.35(m,1H),3.30-3.23(m,1H),3.19-2.85(m,5H),2.8 5-2.72(m,1H),2.52(s,3H),2.46-2.31(m,1H),2.21(s,3H),2.17-1.94(m,3H),1.93-1.65(m,3H).

[0455] Example 30

[0456]

[0457] Step 1:

[0458] compound 30-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 2,3-difluorobromobenzene (39.6 mg), sodium tert-butoxide (98.9 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 30-1 (29.1 mg).

[0459] LC-MS: m / z 598 (M+H) + .

[0460] Step 2:

[0461] compound 30-2 Synthetic reference compound 1-11 .raw material30-1 (29.1 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 30-2 (25.1 mg).

[0462] LC-MS: m / z 498 (M+H) + .

[0463] Step 3

[0464] compound 30 Synthetic reference compound 1 .raw material 30-2 (25.1 mg), triethylamine (0.0327 mL), acryloyl chloride (5.11 mg), dichloromethane (5 mL). Product obtained. 30 (5.7 mg).

[0465] LC-MS: m / z 552 (M+H) +

[0466] 1 H-NMR(CD3OD)δ:6.98-6.63(m,4H),6.23(d,J=16.5Hz,1H),5.83(d,J=10.5Hz ,1H),5.17-5.03(m,1H),4.67-4.57(m,1H),4.51-4.29(m,4H),4.16-4.00(m, 1H),3.98-3.85(m,1H),3.79(d,J=9.6Hz,1H),3.65-3.58(m,2H),3.27-2.74( m,8H),2.54(s,3H),2.46-2.36(m,1H),2.20-1.99(m,3H),1.92-1.68(m,3H).

[0467] Example 31

[0468]

[0469] Step 1:

[0470] compound 31-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 2,3-dimethylbromobenzene (37.9 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 31-1 (30.1 mg).

[0471] LC-MS: m / z 590 (M+H) + .

[0472] Step 2:

[0473] compound 31-2 Synthetic reference compound 1-11 .raw material 31-1 (30.1 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 31-2 (26.1 mg).

[0474] LC-MS: m / z 490 (M+H) + .

[0475] Step 3

[0476] compound 31 Synthetic reference compound 1 .raw material 31-2 (26.1 mg), triethylamine (0.0345 mL), acryloyl chloride (5.39 mg), dichloromethane (5 mL). Product obtained. 31 (7.3 mg).

[0477] LC-MS: m / z 544 (M+H) +

[0478] 1 H-NMR(CD3OD)δ:7.07-6.95(m,2H),6.94-6.76(m,2H),6.29(d,J=16.5Hz,1H),5.84(d,J=10.5Hz,1H) ,5.20-5.04(m,1H),4.70-4.50(m,1H),4.44-4.28(m,2H),4.21-3.80(m,5H),3.76-3.55(m,1H),3.30- 3.18(m,3H),3.15-3.07(m,1H),3.06-2.96(m,2H),2.95-2.85(m,2H),2.85-2.74(m,1H),2.53(s,3H), 2.44-2.33(m,1H),2.24(s,3H),2.16-2.11(m,1H),2.09(s,3H),2.07-1.92(m,2H),1.90-1.66(m,3H).

[0479] Example 32

[0480]

[0481] Step 1:

[0482] compound 32-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 3-bromo-2-methyl anisole (41.2 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 32-1 (31.4 mg).

[0483] LC-MS: m / z 606 (M+H) + .

[0484] Step 2:

[0485] compound 32-2 Synthetic reference compound 1-11 .raw material 32-1 (31.4 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 32-2 (27.1 mg).

[0486] LC-MS: m / z 506 (M+H) + .

[0487] Step 3

[0488] compound 32 Synthetic reference compound 1 .raw material 32-2 (27.1 mg), triethylamine (0.0348 mL), acryloyl chloride (5.42 mg), dichloromethane (5 mL). Product obtained. 32 (7.9 mg).

[0489] LC-MS: m / z 560 (M+H) +

[0490] 1H-NMR(CD3OD)δ:7.10(t,J=8.4Hz,1H),7.01-6.79(m,1H),6.76(d,J=8.1Hz,1H),6.66(d,J=8.1Hz, 1H),6.29(d,J=16.5Hz,1H),5.84(d,J=10.5Hz,1H),5.20-5.06(m,1H),4.64(m,1H),4.41-4.29(m,2 H),4.11(q,J=17.1Hz,3H),3.99-3.85(m,2H),3.80(s,3H),3.74-3.57(m,1H),3.29-3.18(m,2H),3. 13-2.71(m,7H),2.51(s,3H),2.43-2.31(m,1H),2.23-2.02(m,3H),2.00(s,3H),1.91-1.64(m,3H).

[0491] Example 33

[0492]

[0493] Step 1:

[0494] compound 33-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), m-trifluoromethylbromobenzene (46.1 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 33-1 (32.4 mg).

[0495] LC-MS: m / z 630(M+H) + .

[0496] Step 2:

[0497] compound 33-2 Synthetic reference compound 1-11 .raw material 33-1 (32.4 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 33-2 (28.4 mg).

[0498] LC-MS: m / z 530 (M+H) + .

[0499] Step 3

[0500] compound33 Synthetic reference compound 1 .raw material 33-2 (28.4 mg), triethylamine (0.0349 mL), acryloyl chloride (5.45 mg), dichloromethane (5 mL). Product obtained. 33 (8.8 mg).

[0501] LC-MS: m / z 584 (M+H) +

[0502] 1 H-NMR(CD3OD)δ:7.28(t,J=7.5Hz,1H),7.19-6.97(m,2H),6.95-6.68(m,2H),6.25(d,J=16.5Hz,1H),5.81(d,J=10.5Hz,1H),4.71-4.57 (m,3H),4.46-4.28(m,2H),4.18-3.49(m,6H),3.25-3.03(m,3H),3.03-2.75(m,5H),2.54(s,3H),2.46-2.31(m,1H),2.28-1.64(m,6H).

[0503] Compound 34

[0504]

[0505] Step 1:

[0506] compound 34-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 2,3-dichlorobromobenzene (46.4 mg), sodium tert-butoxide (98.9 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 34-1 (34.5 mg).

[0507] LC-MS: m / z 630(M+H) + .

[0508] Step 2:

[0509] compound 34-2 Synthetic reference compound 1-11 .raw material 34-1 (34.5 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 34-2 (30.1 mg).

[0510] LC-MS: m / z 530 (M+H) + .

[0511] Step 3

[0512] compound 34 Synthetic reference compound 1 .raw material 34-2 (30.1 mg), triethylamine (0.0370 mL), acryloyl chloride (5.77 mg), dichloromethane (5 mL). Product obtained. 34 (7.3 mg).

[0513] LC-MS: m / z 584 (M+H) +

[0514] 1 H-NMR(CD3OD)δ:7.26-7.10(m,3H),6.95-6.74(m,1H),6.29(d,J=16.8Hz,1H),5.84(d,J=10.8Hz,1H),5.19-5.07(m,1H ),4.76-4.63(m,1H),4.45-4.18(m,4H),4.15-3.74(m,3H),3.73-3.54(m,1H),3.50-3.36(m,2H),3.30-3.23(m,1H),3.1 4-2.72(m,6H),2.52(s,3H),2.44-2.32(m,1H),2.22-1.98(m,3H),1.90-1.65(m,3H).

[0515] Examples 35 and 36

[0516]

[0517] racemic compounds 34 Chiral high-pressure preparation and resolution into monomers 35 and 36 Column type: CHIRAL PAK IC 2*25cm, 5µm; Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase: ethanol; Flow rate: 20 mL / min; Gradient: 40%, time: 20 min; Detector wavelength: 254 / 220 nm.

[0518] compound 35 The retention time is 1.26 minutes.

[0519] 1H-NMR(CD3OD)δ:7.28-7.08(m,3H),6.93-6.72(m,1H),6.29(d,J=16.2Hz,1H),5. 84(d,J=10.7Hz,1H),5.19-5.00(m,1H),4.78-4.49(m,1H),4.43-4.32(m,2H),4. 30-4.19(m,2H),4.10-3.82(m,2H),3.75-3.37(m,3H),3.29-3.22(m,1H),3.19-2 .80(m,7H),2.57(s,3H),2.50-2.38(m,1H),2.25-2.00(m,3H),1.97-1.66(m,3H).

[0520] compound 36 The retention time is 1.68 minutes.

[0521] 1 H-NMR(CD3OD)δ:7.28-7.08(m,3H),6.93-6.72(m,1H),6.29(d,J=16.5Hz,1H),5.84 (d,J=10.7Hz,1H),5.19-5.00(m,1H),4.78-4.49(m,1H),4.43-4.32(m,2H),4.30-4 .19(m,2H),4.10-3.82(m,2H),3.75-3.37(m,3H),3.29-3.22(d,J=3.9Hz,1H),3.19 -2.80(m,7H),2.57(s,3H),2.50-2.38(m,1H),2.25-2.00(m,3H),1.97-1.66(m,3H).

[0522] Example 37

[0523]

[0524] Step 1:

[0525] compound 37-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 3-bromo-6-fluorotrifluorotoluene (49.8 mg), sodium tert-butoxide (98.9 mg), R-methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 37-1 (33.7 mg).

[0526] LC-MS: m / z 648 (M+H) +

[0527] Step 2:

[0528] compound 37-2 Synthetic reference compound 1-11 .raw material 37-1 (33.7 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 37-2 (29.7 mg).

[0529] LC-MS: m / z 548 (M+H) +

[0530] Step 3

[0531] compound 37 Synthetic reference compound 1 .raw material 37-2 (29.7 mg), triethylamine (0.0354 mL), diethylcarbamate (5.53 mg), dichloromethane (5 mL). Product obtained. 37 (9.3 mg).

[0532] LC-MS: m / z 602(M+H) +

[0533] 1 H-NMR(CD3OD)δ:7.13-6.99(m,3H),6.94-6.66(m,1H),6.26(d,J=16.2Hz,1H),5.81(d,J=10.8Hz,1H),5.15-4.99(m,1H),4. 69-4.53(m,3H),4.44-4.30(m,2H),4.11-3.54(m,5H),3.24-2.73(m,8H),2.53(s,3H),2.46-2.34(m,1H),2.20-1.66(m,6H).

[0534] Example 38

[0535]

[0536] Step 1:

[0537] compound 38-1 Synthetic reference compound 1-10 .raw material 1-9(50.0 mg), 3-bromo-2-chlorotoluene (42.0 mg), sodium tert-butoxide (98.9 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 38-1 (32.9 mg).

[0538] LC-MS: m / z 610(M+H) + .

[0539] Step 2:

[0540] compound 38-2 Synthetic reference compound 1-11 .raw material 38-1 (32.9 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 38-2 (29.0 mg).

[0541] LC-MS: m / z 510 (M+H) + .

[0542] Step 3

[0543] compound 38 Synthetic reference compound 1 .raw material 38-2 (29.0 mg), triethylamine (0.0369 mL), acryloyl chloride (5.75 mg), dichloromethane (5 mL). Product obtained. 38 (9.0 mg).

[0544] LC-MS: m / z 564 (M+H) +

[0545] 1H-NMR(CD3OD)δ:7.18-7.01(m,2H),6.96(d,J=7.5Hz,1H),6.92-6.72(m,1H),6.29(d,J=16.8Hz,1H),5.84(d,J=10.8 Hz,1H),5.21-5.08(m,1H),4.73-4.50(m,2H),4.44-4.27(m,2H),4.26-4.18(m,2H),4.01-3.81(m,2H),3.74-3.53(m, 1H),3.52-3.35(m,2H),3.28-3.20(m,1H),3.14-2.74(m,6H),2.53(s,3H ),2.46-2.37(m,1H),2.34(s,3H),2.25-1.94(m,3H),1.94-1.64(m,3H).

[0546] Example 39

[0547]

[0548] Step 1

[0549] compound 39-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 1-bromo-2-fluoro-3-methoxybenzene (40.0 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 39-1 (29.0 mg).

[0550] LC-MS: m / z 610(M+H) +

[0551] Step 2

[0552] compound 39-2 Synthetic reference compound 1-11 .raw material 39-1 (29.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 39-2 (25.3 mg).

[0553] LC-MS: m / z 510 (M+H) + .

[0554] Step 3

[0555] compound 39Synthetic reference compound 1 .raw material 39-2 (25.3 mg), triethylamine (23.4 mg), acryloyl chloride (6.30 mg), dichloromethane (5 mL). Product obtained. 39 (7.8 mg).

[0556] LC-MS: m / z 564 (M+H) +

[0557] 1 H-NMR(CD3OD)δ:6.96-6.71(m,2H),6.65-6.52(m,2H),6.28(d,J=16.8Hz,1H),5.83( d,J=10.5Hz,1H),5.18-5.00(m,1H),4.67-4.58(m,1H),4.46-4.31(m,4H),4.07-3.8 7(m,1H),3.82(s,3H),3.80-3.72(m,1H),3.61-3.49(m,2H),3.28-3.09(m,3H),3.06 -2.76(m,6H),2.54(s,3H),2.46-2.32(m,1H),2.17-1.99(m,3H),1.93-1.69(m,3H).

[0558] Example 40

[0559]

[0560] Step 1

[0561] compound 40-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 1-bromo-3-fluoro-2-difluorotoluene (46.1 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 40-1 (32.0 mg).

[0562] LC-MS: m / z 630(M+H) +

[0563] Step 2

[0564] compound 40-2 Synthetic reference compound 1-11 .raw material 40-1(32.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 40-2 (28.1 mg).

[0565] LC-MS: m / z 530 (M+H) + .

[0566] Step 3

[0567] compound 40 Synthetic reference compound 1 .raw material 40-2 (28.1 mg), triethylamine (25.1 mg), acryloyl chloride (6.75 mg), dichloromethane (5 mL). Product obtained. 40 (8.8 mg).

[0568] LC-MS: m / z 584 (M+H) +

[0569] 1 H-NMR(CD3OD)δ:7.46(q,J=7.2Hz,1H),7.10(d,J=9.0Hz,1H),6.98-6.66(m,3H ),6.30(d,J=16.9Hz,1H),5.85(d,J=10.5Hz,1H),5.19-5.01(m,1H),4.75-4.48 (m,1H),4.42(d,J=5.7Hz,2H),4.37-4.19(m,2H),4.16-3.82(m,3H),3.74-3.3 8(m,3H),3.27-2.84(m,7H),2.63(s,3H),2.58-2.48(m,1H),2.21-1.67(m,6H).

[0570] Example 41

[0571]

[0572] Step 1

[0573] compound 41-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 1-bromo-3-difluoromethyl-2-toluene (45.3 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 41-1 (35.0 mg).

[0574] LC-MS: m / z 626 (M+H) +

[0575] Step 2

[0576] compound 41-2 Synthetic reference compound 1-11 .raw material 41-1 (35.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 41-2 (30.9 mg).

[0577] LC-MS: m / z 526 (M+H) + .

[0578] Step 3

[0579] compound 41 Synthetic reference compound 1 .raw material 41-2 (30.9 mg), triethylamine (27.8 mg), acryloyl chloride (7.47 mg), dichloromethane (5 mL). Product obtained. 41 (9.8 mg).

[0580] LC-MS: m / z 580 (M+H) +

[0581] 1 H-NMR(CD3OD)δ:7.34-7.20(m,3H),7.07-6.66(m,2H),6.30(d,J=16.5Hz,1H),5.85(d,J=10 .5Hz,1H),5.24-5.04(m,1H),4.69-4.57(m,1H),4.42-4.30(m,2H),4.21-4.03(m,3H),4.01 -3.81(m,2H),3.73-3.45(m,1H),3.42-3.35(m,1H),3.31-3.24(m,1H),3.18-2.74(m,7H),2 .53(s,3H),2.45-2.34(m,1H),2.23(t,J=1.4Hz,3H),2.18-1.98(m,3H),1.93-1.67(m,3H).

[0582] Example 42

[0583]

[0584] Step 1:

[0585] At room temperature, the raw materials 1-7(3.60 g) was dissolved in 1,2-dichloroethane (100 mL). N,N-diisopropylethylamine (2.81 g) and 1-chloroethyl chloroformate (2.59 g) were added sequentially. The reaction was carried out at room temperature for 1 hour. After concentration under reduced pressure, methanol (100 mL) was added to dissolve the mixture, and the reaction solution was refluxed at 70°C for 1 hour. The reaction was quenched by slow addition of water (100 mL). Extraction was performed with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL). The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 5%-15%) to obtain the product. 42-1 (2.42 grams).

[0586] LC-MS: m / z 407 (M+H) + .

[0587] Step 2:

[0588] At room temperature, the raw materials 42-1 (2.42 g) was dissolved in toluene (50 mL), and 8-methyl-1-bromonaphthalene (2.62 g), sodium tert-butoxide (1.99 g), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.497 g) were added sequentially. The resulting mixture was purged with nitrogen three times and reacted at 90 °C for 3 hours. After the reaction was complete, water (100 mL) was added to quench the reaction. Extraction was performed with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL). The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15%-30%) to obtain the product. 42-2 (1.75 grams).

[0589] LC-MS: m / z 547 (M+H) + .

[0590] Step 3:

[0591] At room temperature, N-methyl-4,4-difluoro-L-prolyl (69.5 mg) was dissolved in tetrahydrofuran (5.0 mL), and sodium hydride (60%) (18.3 mg) was added at 0°C. After reacting at room temperature for 30 minutes, the starting material was added. 42-2 (50.0 mg). The reaction solution was reacted at 70°C for 2 hours. After the reaction was complete, water (20 mL) was added to quench the reaction. Extraction was performed with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL). The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 5%-20%) to obtain the product. 42-3(53.9 mg).

[0592] LC-MS: m / z 662 (M+H) + .

[0593] Step 4:

[0594] At room temperature, the raw materials 42-3 (53.9 mg) was dissolved in a 1,4-dioxane solution of hydrogen chloride (4 mol / L, 10 mL). The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain the crude product. 42-4 (44.9 mg). No purification required; can be used directly in the next reaction.

[0595] LC-MS: m / z 562 (M+H) + .

[0596] Step 5:

[0597] At room temperature, the raw materials 42-4 (44.9 mg) was suspended in dichloromethane (10 mL), and triethylamine (37.9 mg) and acryloyl chloride (8.1 mg) were added sequentially at -40 °C. The reaction mixture was reacted at -40 °C for 1 hour. After the reaction was complete, water (20 mL) was added to quench the reaction. Extraction was performed with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL). The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative reversed-phase chromatography (column type: SunFire Prep C18 OBD Column, 5 μm 10 nm, 19*150 mm; mobile phase A: water (0.05%, trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 35-70%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 42 (24.8 mg).

[0598] LC-MS: m / z 616 (M+H) + .

[0599] 1H-NMR(CD3OD)δ:7.69-7.66(m,2H),7.42-7.19(m,4H),7.00-6.80(m,1H),6.32 (d,J=16.8Hz,1H),5.86(d,J=10.5Hz,1H),5.15(s,1H),4.62-4.41(m,4H),4.17 (t,J=12.6Hz,2H),3.95-3.56(m,3H),3.47-3.39(m,3H),3.04-2.93(m,6H),2.8 3(s,3H),2.77-2.66(m,1H),2.59-2.50(m,1H),2.45(s,3H),2.22-2.04(m,3H).

[0600] Example 43

[0601]

[0602] Step 1:

[0603] raw materials 43-3 (2 g) was dissolved in a dry tetrahydrofuran (100 mL) solution, and the mixture was bubbled with nitrogen for 2 minutes. At 0°C, a tetrahydrofuran solution of lithium aluminum hydride (1 mol / L, 34.3 mL) was slowly added dropwise. The reaction mixture was allowed to react at 0°C for 1 hour, then continued at 70°C for 2 hours. After the reaction was complete, it was cooled to room temperature, quenched with sodium sulfate decahydrate (10 g), and extracted with ethyl acetate (150 mL x 3). The organic phase was washed with saturated brine and then concentrated to obtain the compound. 43-4 (844 mg).

[0604] LC-MS m / z 134(M+H) + .

[0605] Step 2:

[0606] compound 43-1 Synthetic reference compound 42-3 Among them, raw materials 42-2 (50.0 mg), (2S,4R) 43-4 (60.8 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 mL). Product obtained. 43-1 (47.4 mg).

[0607] LC-MS: m / z 644 (M+H) + .

[0608] Step 3:

[0609] compound43-2 Synthetic reference compound 42-4 Among them, raw materials 43-1 (47.4 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 10 mL). The product was obtained. 43-2 (40.7 mg). No purification required; can be used directly in the next reaction.

[0610] LC-MS: m / z 544 (M+H) + .

[0611] Step 4:

[0612] compound 43 Synthetic reference compound 42 Among them, raw materials 43-2 (40.7 mg), triethylamine (35.6 mg), acryloyl chloride (7.6 mg), dichloromethane (10 mL). The reaction product was purified by preparative reversed-phase chromatography (column type: XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 43-70%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 43 (24.9 mg).

[0613] LC-MS: m / z 598 (M+H) + .

[0614] 1 H-NMR(CD3OD)δ:7.74-7.67(m,2H),7.45-7.31(m,3H),7.21(d,J=4.8Hz,1H),7.00-6.80(m,1H),6.20( d,J=16.8Hz,1H),5.86(d,J=10.5Hz,1H),5.08-5.01(m,1H),4.39(t,J=17.1Hz,2H),4.28-4.23(m,1H), 4.17-3.96(m,3H),3.72-3.59(m,3H),3.46-3.39(m,2H),3.31-3.21(m,2H),3.17-3.14(m,1H),3.10-3. 05(m,1H),3.01-2.92(m,2H),2.85-2.82(m,2H),2.77(d,J=6.0Hz,4H),2.34(s,3H),2.12-1.79(m,4H).

[0615] Example 44

[0616]

[0617] Step 1:

[0618] raw materials 44-3 (2 g) was dissolved in a dry tetrahydrofuran (100 mL) solution, and the mixture was bubbled with nitrogen for 2 minutes. At 0°C, a tetrahydrofuran solution of lithium aluminum hydride (1 mol / L, 34.3 mL) was slowly added dropwise. The reaction mixture was allowed to react at 0°C for 1 hour, then continued at 70°C for 2 hours. After the reaction was complete, it was cooled to room temperature, quenched with sodium sulfate decahydrate (10 g), and extracted with ethyl acetate (150 mL x 3). The organic phase was washed with saturated brine and then concentrated to obtain the compound. 44-4 (844 mg).

[0619] LC-MS m / z 134(M+H) + .

[0620] Step 2:

[0621] compound 44-1 Synthetic reference compound 42-3 Among them, raw materials 42-2 (50.00 mg), 44-4 (61.2 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 mL). Product obtained. 44-1 (52.3 mg).

[0622] LC-MS: m / z 644 (M+H) + .

[0623] Step 3:

[0624] compound 44-2 Synthetic reference compound 42-4 Among them, raw materials 44-1 (52.3 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 10 mL). The product was obtained. 44-2 (45.4 mg). No purification required; can be used directly in the next reaction.

[0625] LC-MS: m / z 544 (M+H) + .

[0626] Step 4:

[0627] compound 44 Synthetic reference compound 42 Among them, raw materials 44-2(45.4 mg), triethylamine (40.5 mg), acryloyl chloride (9.0 mg), dichloromethane (10 mL). The reaction product was purified by preparative reversed-phase chromatography (column type: XBridge Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 36-64%; time: 10 min; detector wavelength: 254 / 220 nm) to obtain the product. 44 (26.8 mg).

[0628] LC-MS: m / z 598 (M+H) + .

[0629] 1 H-NMR(CD3OD)δ:7.68-7.64(m,2H),7.43-7.19(m,4H),7.00-6.80(m,1H),6.31(d,J=12.6Hz, 1H),5.86(d,J=8.1Hz,1H),5.21-5.05(m,1H),4.61(s,1H),4.47-4.31(m,3H),4.17(t,J=12.3 Hz,2H),3.94-3.57(m,4H),3.51-3.37(m,2H),3.30-3.23(m,2H),3.15-3.00(m,3H),2.95-2. 89(m,1H),2.83(s,3H),2.80-2.77(m,1H),2.58-2.51(m,1H),2.47(s,3H),2.21-1.84(m,4H).

[0630] Example 45

[0631]

[0632] Step 1:

[0633] compound 45-1 Synthetic reference compound 42-3 Among them, raw materials 42-2 (50.0 mg), N-hydroxyethylpiperidine (58.9 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 mL). Product obtained. 45-1 (53.3 mg).

[0634] LC-MS: m / z 640(M+H) + .

[0635] Step 2:

[0636] compound 45-2Synthetic reference compound 42-4 Among them, raw materials 45-1 (53.3 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 10 mL). The product was obtained. 45-2 (45.7 mg). No purification required; can be used directly in the next reaction.

[0637] LC-MS: m / z 540 (M+H) + .

[0638] Step 3:

[0639] compound 45 Synthetic reference compound 42 Among them, raw materials 45-2 (45.7 mg), triethylamine (40.3 mg), acryloyl chloride (8.6 mg), dichloromethane (10 mL). The reaction product was purified by preparative reversed-phase chromatography (column type: XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 35-80%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 45 (24.3 mg).

[0640] LC-MS: m / z 594 (M+H) + .

[0641] 1 H-NMR(CD3OD)δ:7.69-7.63(m,2H),7.43-7.19(m,4H),7.00-6.80(m,1H),6.31(d,J=17. 1Hz,1H),5.86(d,J=10.8Hz,1H),5.15(s,1H),4.50-4.39(m,3H),4.16(t,J=12.6Hz,2H) ,3.92-3.67(m,3H),3.46-3.36(m,3H),3.30-3.24(m,1H),3.11-2.86(m,5H),2.84(s,3H ),2.76(t,J=2.4Hz,2H),2.55(s,3H),2.03(s,2H),1.64-1.57(m,4H),1.50-1.43(m,2H).

[0642] Example 46

[0643]

[0644]

[0645] Step 1:

[0646] At room temperature, the raw materials 46-3 (1.10 g) was dissolved in acetonitrile (50 mL), and potassium carbonate (965 mg) and bromoethanol (915 mg) were added sequentially. The resulting reaction solution was reacted at 90 °C for 12 hours. After the reaction was completed, water (150 mL) was added to quench the reaction. Extraction was performed with ethyl acetate (150 mL x 3). The combined organic phases were washed with saturated brine (150 mL). The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product. 46-4 (525.0 mg).

[0647] LC-MS: m / z 166 (M+H) + .

[0648] Step 2:

[0649] compound 46-1 Synthetic reference compound 42-3 Among them, raw materials 42-2 (50.0 mg), 46-4 (75.6 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 mL). Product obtained. 46-1 (54.0 mg).

[0650] LC-MS: m / z 676 (M+H) + .

[0651] Step 3:

[0652] compound 46-2 Synthetic reference compound 42-4 Among them, raw materials 46-1 (54.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 10 mL). The product was obtained. 46-2 (45.9 mg). No purification required; can be used directly in the next reaction.

[0653] LC-MS: m / z 576 (M+H) + .

[0654] Step 4:

[0655] compound 46 Synthetic reference compound 42 Among them, raw materials 46-2(45.9 mg), triethylamine (33.8 mg), acryloyl chloride (8.1 mg), dichloromethane (10 mL). The reaction product was purified by preparative reversed-phase chromatography (column type: XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 50-75%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 46 (26.9 mg).

[0656] LC-MS: m / z 630(M+H) + .

[0657] 1 H-NMR(CD3OD)δ:7.68-7.64(m,2H),7.43-7.18(m,4H),7.00-6.80(m,1H),6 .31(d,J=16.5Hz,1H),5.86(d,J=10.5Hz,1H),5.2(s,1H),4.49-4.39(m,3H) ,4.15(t,J=12.3Hz,2H),3.92-3.66(m,3H),3.45-3.36(m,2H),3.30-3.25(m ,1H),3.15-3.00(m,4H),2.94-2.83(m,6H),2.69(s,4H),2.04-1.91(m,6H).

[0658] Example 47

[0659]

[0660]

[0661] Step 1:

[0662] At room temperature, the raw materials 47-3 (1.10 g) was dissolved in acetonitrile (50 mL), and potassium carbonate (965 mg) and bromoethanol (915 mg) were added sequentially. The resulting reaction solution was reacted at 90 °C for 12 hours. After the reaction was completed, water (150 mL) was added to quench the reaction. Extraction was performed with ethyl acetate (150 mL x 3). The combined organic phases were washed with saturated brine (150 mL). The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product. 47-4 (586 mg).

[0663] LC-MS: m / z 166 (M+H) + .

[0664] Step 2:

[0665] compound 47-1 Synthetic reference compound 42-3 Among them, raw materials 42-2 (50.0 mg), 47-4 (75.6 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 mL). Product obtained. 47-1 (53.5 mg).

[0666] LC-MS: m / z 676 (M+H) + .

[0667] Step 3:

[0668] compound 47-2 Synthetic reference compound 42-4 Among them, raw materials 47-1 (53.5 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 10 mL). The product was obtained. 47-2 (45.8 mg). No purification required; can be used directly in the next reaction.

[0669] LC-MS: m / z 576 (M+H) + .

[0670] Step 4:

[0671] compound 47 Synthetic reference compound 42 Among them, raw materials 47-2 (45.8 mg), triethylamine (33.8 mg), acryloyl chloride (8.1 mg), dichloromethane (10 mL). The reaction product was purified by preparative reversed-phase chromatography (column type: XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 55-70%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 47 (26.1 mg).

[0672] LC-MS: m / z 630(M+H) + .

[0673] 1H-NMR(CD3OD)δ:7.69-7.64(m,2H),7.42-7.19(m,4H),7.00-6.80(m,1H),6.3 2(d,J=17.1Hz,1H),5.87(d,J=11.4Hz,1H),5.15-5.05(m,1H),4.50-4.40(m, 3H),4.17(t,J=12.0Hz,2H),3.94-3.67(m,3H),3.47-3.38(m,2H),3.30-3.26 (m,1H),3.11-3.00(m,4H),2.95-2.75(m,8H),2.58(s,2H),2.04-1.74(m,6H).

[0674] Example 48

[0675]

[0676]

[0677] Step 1:

[0678] At room temperature, the raw materials 48-3 (1.10 g) was dissolved in acetonitrile (50 mL), and potassium carbonate (3.47 g) and bromopropanol (1.91 g) were added sequentially. The resulting reaction solution was reacted at 90 °C for 12 hours. After the reaction was completed, water (150 mL) was added to quench the reaction. Extraction was performed with ethyl acetate (150 mL x 3). The combined organic phases were washed with saturated brine (150 mL). The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product. 48-4 (1.06 grams).

[0679] LC-MS: m / z 146 (M+H) + .

[0680] Step 2:

[0681] compound 48-1 Synthetic reference compound 42-3 Among them, raw materials 42-2 (50.0 mg), 48-4 (66.7 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 mL). Product obtained. 48-1 (50.1 mg).

[0682] LC-MS: m / z 656 (M+H) + .

[0683] Step 3:

[0684] compound 48-2 Synthetic reference compound42-4 Among them, raw materials 48-1 (50.1 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 10 mL). The product was obtained. 48-2 (40.5 mg). No purification required; can be used directly in the next reaction.

[0685] LC-MS: m / z 556 (M+H) + .

[0686] Step 4:

[0687] compound 48 Synthetic reference compound 42 Among them, raw materials 48-2 (40.5 mg), triethylamine (34.8 mg), acryloyl chloride (7.4 mg), dichloromethane (10 mL). The reaction product was purified by preparative reversed-phase chromatography (column type: XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 55-65%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 48 (22.0 mg).

[0688] LC-MS: m / z 610(M+H) + .

[0689] 1 H-NMR(CD3OD)δ:7.69-7.64(m,2H),7.42-7.20(m,4H),7.00-6.80(m,1H),6.32(d,J =17.1Hz,1H),5.87(d,J=9.9Hz,1H),4.64(s,1H),4.46-4.37(m,3H),4.16(t,J=12.6 Hz,2H),3.93-3.73(m,3H),3.67(s,5H),3.51-3.38(m,2H),3.29-3.25(m,1H),3.10 -3.01(m,3H),2.96-2.92(m,1H),2.84(s,3H),2.55-2.48(m,6H),2.09-1.94(m,4H).

[0690] Example 49

[0691]

[0692]

[0693] Step 1:

[0694] At room temperature, the raw materials 49-3 (1.10 g) was dissolved in acetonitrile (50 mL), and potassium carbonate (3.06 g) and bromopropanol (1.68 g) were added sequentially. The resulting reaction solution was reacted at 90 °C for 12 hours. After the reaction was completed, water (150 mL) was added to quench the reaction. Extraction was performed with ethyl acetate (150 mL x 3). The combined organic phases were washed with saturated brine (150 mL). The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product. 49-4 (841.0 mg).

[0695] LC-MS: m / z 158 (M+H) + .

[0696] Step 2:

[0697] compound 49-1 Synthetic reference compound 42-3 Among them, raw materials 42-2 (50.0 mg), 49-4 (71.9 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 mL). Product obtained. 49-1 (49.9 mg).

[0698] LC-MS: m / z 668 (M+H) + .

[0699] Step 3:

[0700] compound 49-2 Synthetic reference compound 42-4 Among them, raw materials 49-1 (49.9 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 10 mL). The product was obtained. 49-2 (39.4 mg). No purification required; can be used directly in the next reaction.

[0701] LC-MS: m / z 568 (M+H) + .

[0702] Step 4:

[0703] compound 49 Synthetic reference compound 42 Among them, raw materials 49-2(39.4 mg), triethylamine (33.8 mg), acryloyl chloride (7.2 mg), dichloromethane (10 mL). The reaction product was purified by preparative reversed-phase chromatography (column type: XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 40-58%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 49 (21.0 mg).

[0704] LC-MS: m / z 622(M+H) + .

[0705] 1 H-NMR(CD3OD)δ:7.68-7.64(m,2H),7.43-7.19(m,4H),7.00-6.80(m,1H),6.31(d,J=16.5Hz,1H),5.86(d ,J=10.5Hz,1H),5.15-5.05(m,1H),4.63(s,3H),4.45-4.37(m,4H),4.15(t,J=12.6Hz,2H),4.00(d,J=6. 30Hz,1H),3.92-3.77(m,2H),3.59-3.58(m,2H),3.46-3.36(m,2H),3.30-3.25(m,1H),3.10-2.99(m,3H) ,2.94-2.78(m,5H),2.76-2.69(m,1H),2.58(d,J=6.6Hz,1H),2.10-1.86(m,5H),1.731(d,J=7.8Hz,1H).

[0706] Example 50

[0707]

[0708]

[0709] Step 1:

[0710] At room temperature, the raw materials 50-3 (1.10 g) was dissolved in acetonitrile (5 mL), and potassium carbonate (3.06 g) and bromopropanol (1.68 g) were added sequentially. The resulting reaction solution was reacted at 90 °C for 12 hours. After the reaction was completed, water (150 mL) was added to quench the reaction. Extraction was performed with ethyl acetate (150 mL x 3). The combined organic phases were washed with saturated brine (150 mL). The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product. 50-4(799.2 mg).

[0711] LC-MS: m / z 158 (M+H) + .

[0712] Step 2:

[0713] compound 50-1 Synthetic reference compound 42-3 Among them, raw materials 42-2 (50.0 mg), 50-4 (71.9 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 mL). Product obtained. 50-1 (50.5 mg).

[0714] LC-MS: m / z 668 (M+H) + .

[0715] Step 3:

[0716] compound 50-2 Synthetic reference compound 42-4 Among them, raw materials 50-1 (50.5 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 10 mL). The product was obtained. 50-2 (41.4 mg). No purification required; can be used directly in the next reaction.

[0717] LC-MS: m / z 568 (M+H) + .

[0718] Step 4:

[0719] compound 50 Synthetic reference compound 42 Among them, raw materials 50-2 (41.4 mg), triethylamine (34.7 mg), acryloyl chloride (7.4 mg), dichloromethane (10 mL). The reaction product was purified by preparative reversed-phase chromatography (column type: XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 38-52%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 50 (22.8 mg).

[0720] LC-MS: m / z 622(M+H) + .

[0721] 1H-NMR(CD3OD)δ:7.68-7.64(m,2H),7.43-7.19(m,4H),7.00-6.80(m,1H),6.31(d,J=12.3Hz,1H),5.86(d,J=8 .1Hz,1H),5.15-5.05(m,1H),4.82-4.60(m,1H),4.44-4.37(m,4H),4.15(t,J=12.6Hz,2H),4.00(d,J=6.60Hz, 1H),3.92-3.67(m,3H),3.59-3.57(m,2H),3.45-3.35(m,2H),3.30-3.25(m,1H),3.15-2.97(m,4H),2.93-2.88 (m,1H),2.85-2.79(m,4H),2.76-2.69(m,1H),2.57(d,J=8.1Hz,1H),2.10-1.86(m,5H),1.72(d,J=7.5Hz,1H).

[0722] Example 51

[0723]

[0724] Step 1

[0725] raw materials 1-5 (1.50 g) was dissolved in isopropanol (30 mL), and N-Boc-piperazine (1.10 g) and diisopropylethylamine (1.26 g) were added sequentially. The resulting mixture was reacted at 80 °C for 12 hours. After the reaction was complete, it was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the product. 51-2 (1.34 grams).

[0726] LC-MS: m / z 458 (M+H) +

[0727] Step 2

[0728] (S)-prolyl (0.51 g) was dissolved in anhydrous tetrahydrofuran (15 mL), and sodium hydride (60%) (0.188 g) was added at 0°C. After reacting at 0°C for 30 minutes, the starting material was added. 51-2 (1.34 g). The resulting solution was reacted at 70°C for 3 hours. After the reaction was complete, it was cooled to room temperature. The reaction was quenched with saturated ammonium chloride aqueous solution (50 mL) and extracted with ethyl acetate (80 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 5%-20%) to obtain the product.51-3 (1.19 grams).

[0729] LC-MS: m / z 537 (M+H) +

[0730] Step 3

[0731] raw materials 51-3 1.19 g of palladium was dissolved in anhydrous methanol (30 mL), and 0.119 g of palladium on carbon (10%) was added sequentially under nitrogen protection. The resulting reaction solution was purged with hydrogen three times and reacted at room temperature for 16 hours. After the reaction was complete, the palladium on carbon was filtered off. The filtrate was concentrated to dryness to obtain the product. 51-4 (0.913 grams).

[0732] LC-MS: m / z 447 (M+H) +

[0733] Step 4

[0734] raw materials 51-4 50.0 mg was dissolved in toluene (2 mL), and 8-methyl-1-bromonaphthalene (37.0 mg), sodium tert-butoxide (108 mg), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (28.1 mg) were added sequentially. The resulting solution was stirred at 90 °C for 3 hours. After the reaction was complete, the solution was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10%-20%) to obtain the final product. 51-5 (40.0 mg).

[0735] LC-MS: m / z 587 (M+H) +

[0736] Step 5

[0737] To raw materials 51-5 A solution of 1,4-dioxane hydrogen chloride (5 mL) was added to (40.0 mg). The resulting solution was stirred at room temperature for 10 minutes. After the reaction was complete, the solution was concentrated to dryness to obtain the product. 51-6 (30 mg). No purification required; use directly in the next reaction.

[0738] LC-MS: m / z 487 (M+H) +

[0739] Step 6

[0740] raw materials 51-6(30.0 mg) was dissolved in dichloromethane (5 mL), cooled to -40°C, and then triethylamine (31.4 mg) and acryloyl chloride (8.44 mg) were added sequentially. The resulting solution was reacted at -40°C for 10 minutes. After the reaction was complete, water (5 mL) was added to quench the reaction and the solution was concentrated to dryness. The crude product was purified using a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 38-59%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 51 (11.2 mg).

[0741] LC-MS: m / z 541 (M+H) +

[0742] 1 H-NMR(CD3OD)δ:7.69-7.62(m,2H),7.42-7.36(m,2H),7.29(t,J=7.2Hz,1H),7.19(d,J=6.9Hz,1 H),6.89-6.78(m,1H),6.31-6.22(m,1H),5.84-5.78(m,1H),4.44-4.25(m,3H),4.14(d,J=15.3Hz ,1H),3.92-3.77(m,4H),3.54-3.31(m,6H),3.11-2.99(m,2H),2.94-2.85(m,1H),2.83(s,3H),2 .78-2.68(m,1H),2.47(d,J=2.7Hz,3H),2.41-2.28(m,1H),2.11-1.95(m,3H),1.87-1.65(m,3H).

[0743] Example 52

[0744]

[0745] Step 1:

[0746] compound 52-1 Synthetic reference compound 51-5 .raw material 51-4 (Prepared by mixing raw material 1 (50.0 mg), 8-chloro-1-bromonaphthalene (40.3 mg), sodium tert-butoxide (108 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (28.1 mg), and toluene (2 mL), the product was obtained.) 52-1(50.0 mg).

[0747] LC-MS: m / z 607 (M+H) + .

[0748] Step 2:

[0749] compound 52-2 Synthetic reference compound 51-6 .raw material 52-1 (50.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 52-2 (43.0 mg).

[0750] LC-MS: m / z 507 (M+H) + .

[0751] Step 3

[0752] compound 52 Synthetic reference compound 51 .raw material 52-2 (43.0 mg), triethylamine (40.1 mg), acryloyl chloride (10.8 mg), dichloromethane (5 mL). Product obtained. 52 (7.8 mg).

[0753] LC-MS: m / z 561 (M+H) +

[0754] 1 H-NMR(CD3OD)δ:7.79(d,J=8.4Hz,1H),7.64(d,J=8.1Hz,1H),7.48(d, J=7.8Hz,1H),7.45-7.31(m,3H),6.90-6.77(m,1H),6.25(d,J=16.5Hz,1H),5.80(d,J=10.5Hz,1H),4.41-4.23(m,4H),3.92-3. 72(m,4H),3.60-3.36(m,6H),3.12-2.98(m,2H),2.90-2.99(m,2H),4.48(d,J=1.2Hz,3H),2.40-2.30(m,1H),2.18-1.65(m,6H).

[0755] Example 53

[0756]

[0757] Step 1:

[0758] At room temperature, the raw materials 1-5(2.00 g) was dissolved in isopropanol (50 mL), and diisopropylethylamine (2.52 g) and (S)-4-N-tert-butyloxycarbonyl-2-methylpiperazine (1.43 g) were added sequentially. The resulting mixture was reacted at 80 °C for 12 hours. After the reaction was complete, it was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the product. 53-1 (1.04 grams).

[0759] LC-MS: m / z 472 (M+H) + .

[0760] Step 2:

[0761] (S)-prolyl (0.41 g) was dissolved in anhydrous tetrahydrofuran (20 mL), and sodium hydride (60%) (0.14 g) was added at 0°C. After reacting at 0°C for 30 minutes, the starting material was added. 53-1 (1.04 g). The resulting solution was reacted at 70°C for 3 hours. After the reaction was complete, it was cooled to room temperature. The reaction was quenched with saturated ammonium chloride aqueous solution (50 mL) and extracted with ethyl acetate (80 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 5%-20%) to obtain the product. 53-2 (716 mg).

[0762] LC-MS: m / z 551 (M+H) + .

[0763] Step 3:

[0764] At room temperature, the raw materials 53-2 (716 mg) was dissolved in anhydrous methanol (30 mL), and palladium on carbon (10%) (71.6 mg) was added under nitrogen protection. The resulting reaction solution was purged with hydrogen three times and reacted at room temperature for 2 hours. After the reaction was complete, the palladium on carbon was filtered off. The filtrate was concentrated to dryness to obtain the product. 53-3 (540 mg).

[0765] LC-MS: m / z 461(M+H) + .

[0766] Step 4:

[0767] At room temperature, the raw materials 53-3120 mg was dissolved in toluene (3 mL), and 1-bromo-8-methylnaphthalene (115 mg), sodium tert-butoxide (250 mg), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (65.3 mg) were added sequentially. The resulting solution was stirred at 90 °C for 3 hours. After the reaction was complete, the solution was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10%-20%) to obtain the final product. 53-4 (92.8 mg).

[0768] LC-MS: m / z 601(M+H) + .

[0769] Step 5:

[0770] At room temperature, to the raw material 53-4 A solution of 1,4-dioxane hydrogen chloride (10 mL) was added to (92.8 mg). The resulting solution was stirred at room temperature for 10 minutes. After the reaction was complete, the solution was concentrated to dryness to obtain the product. 53-5 (75.9 mg). No purification required; can be used directly in the next reaction.

[0771] LC-MS: m / z 501(M+H) + .

[0772] Step 6:

[0773] raw materials 53-5 (75.9 mg) was dissolved in dichloromethane (10 mL), cooled to -40°C, and then triethylamine (71.7 mg) and acryloyl chloride (15.3 mg) were added sequentially. The resulting solution was reacted at -40°C for 10 min. After the reaction was complete, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified using a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 35-80%; time: 12 min; detector wavelength: 254 / 220 nm) to obtain the product. 53 (57.1 mg).

[0774] LC-MS: m / z 555 (M+H) + .

[0775] 1H-NMR(CD3OD)δ:7.69-7.62(m,2H),7.43-7.18(m,4H),6.93-6.77(m,1H),6.29(d,J=16.2Hz,1H),5 .82(d,J=11.1Hz,1H),4.52-4.27(m,4H),4.19-3.93(m,3H),3.73-3.35(m,5H),3.29-3.15(m,1H),3 .10-2.99(m,2H),2.91-2.86(m,1H),2.83(d,J=5.7Hz,3H),2.80-2.68(m,1H),2.47(d,J=2.7Hz,3H) ,2.34(q,J=9.0Hz,1H),2.13-1.96(m,3H),1.85-1.76(m,2H),1.73-1.62(m,1H),1.31-1.18(m,3H).

[0776] Example 54

[0777]

[0778] Step 1:

[0779] compound 54-1 Synthetic reference compound 53-4 Among them, raw materials 53-3 (120 mg), 8-chloro-1-bromonaphthalene (125 mg), sodium tert-butoxide (250.5 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (65.5 mg), toluene (3 mL). Product obtained. 54-1 (107 mg).

[0780] LC-MS: m / z 621(M+H) + .

[0781] Step 2:

[0782] compound 54-2 Synthetic reference compound 53-5 Among them, raw materials 54-1 (107 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 10 mL). Product obtained. 54-2 (90.7 mg).

[0783] LC-MS: m / z 521(M+H) + .

[0784] Step 3:

[0785] compound54 Synthetic reference compound 53 .raw material 54-2 (90.7 mg), triethylamine (82.6 mg), acryloyl chloride (17.7 mg), dichloromethane (1 mL). Product obtained. 54 (61.7 mg).

[0786] LC-MS: m / z 575 (M+H) + .

[0787] 1 H-NMR(CD3OD)δ:7.79(d,J=8.1Hz,1H),7.64(t,J=7.5Hz,1H),7.50-7.29(m,4H),6.93-6.77(m,1H),6.29 (d,J=16.8Hz,1H),5.81(d,J=10.8Hz,1H),4.58-4.38(m,1H),4.33-4.27(m,4H),4.13-3.92(m,2H),3.73- 3.37(m,5H),3.29-3.16(m,1H),3.11-2.97(m,2H),2.87-2.70(m,2H),2.47(d,J=1.5Hz,3H),2.35(q,J=9 .0Hz,1H),2.19-2.02(m,2H),1.97-1.90(m,1H),1.86-1.77(m,2H),1.74-1.63(m,1H),1.28-1.16(m,3H).

[0788] Example 56

[0789]

[0790] Step 1:

[0791] compound 56-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 4-bromo-2-chloroanisole (45.3 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 56-1 (29.0 mg).

[0792] LC-MS: m / z 626 (M+H) + .

[0793] Step 2:

[0794] compound 56-2 Synthetic reference compound 1-11 .raw material 56-1 (30 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 56-2 (25.7 mg).

[0795] LC-MS: m / z 526 (M+H) + .

[0796] Step 3

[0797] compound 56 Synthetic reference compound 1 .raw material 56-2 (25.7 mg), triethylamine (0.0318 mL), diethylcarbamate (5.16 mg), dichloromethane (5 mL). Product obtained. 56 (7.0 mg).

[0798] LC-MS: m / z 580 (M+H) +

[0799] 1 H-NMR(CD3OD)δ:6.92-6.66(m,4H),6.25(d,J=16.8Hz,1H),5.81(d,J=10.5 Hz,1H),5.11-5.03(m,1H),4.67-4.59(m,1H),4.57-4.50(m,2H),4.50-4.3 0(m,2H),4.16-3.96(m,1H),3.95-3.78(m,2H),3.75(s,3H),3.72-3.50(m, 2H),3.26-2.73(m,8H),2.53(s,3H),2.46-2.29(m,1H),2.25-1.65(m,6H).

[0800] Example 57

[0801]

[0802] Step 1:

[0803] compound 57-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 3-bromo-5-chloro-4-methylpyridine (42.2 mg), sodium tert-butoxide (98.9 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained.57-1 (34.4 mg).

[0804] LC-MS: m / z 611(M+H) + .

[0805] Step 2:

[0806] compound 57-2 Synthetic reference compound 1-11 .raw material 57-1 (34.4 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 57-2 (30.0 mg).

[0807] LC-MS: m / z 511(M+H) + .

[0808] Step 3

[0809] compound 57 Synthetic reference compound 1 .raw material 57-2 (30.0 mg), triethylamine (0.0382 mL), acryloyl chloride (5.96 mg), dichloromethane (5 mL). Product obtained. 57 (8.8 mg).

[0810] LC-MS: m / z 565 (M+H) +

[0811] 1 H-NMR(CD3OD)δ:8.20(d,J=3.9Hz,2H),6.98-6.72(m,1H),6.29(d,J=16.8H z,1H),5.84(d,J=10.8Hz,1H),5.21-5.02(m,1H),4.68-4.54(m,1H),4.39-4 .14(m,4H),4.03-3.82(m,2H),3.79-3.36(m,4H),3.17-2.71(m,7H),2.51(s ,3H),2.45-2.31(m,1H),2.26(s,3H),2.21-1.99(m,3H),1.92-1.66(m,3H).

[0812] Example 58

[0813]

[0814] Step 1

[0815] raw materials 58-110.0 g of sodium methoxide was dissolved in anhydrous methanol (150 mL), and 26.2 g of a 30% sodium methoxide methanol solution and 11.0 g of thiourea were added at 0°C. The resulting mixture was heated to 80°C and stirred for 1 hour. After the reaction was complete, the reaction solution was cooled to room temperature. The pH was adjusted to 7 by adding dilute hydrochloric acid (1 mol / L). The precipitated solid was collected by filtration and washed with water (50 mL). After drying the solid, the product was obtained. 58-2 (8.10 g). No purification required; use directly in the next reaction.

[0816] LC-MS: m / z 288 (M+H) +

[0817] Step 2

[0818] raw materials 58-2 (8.10 g) was suspended in phosphorus oxychloride (100 mL), and N,N-dimethylformamide (10 mL) was added. The resulting suspension was stirred at 100 °C for 12 hours. After the reaction was complete, the reaction solution was concentrated to dryness. The residue was added to water (100 mL) and the pH was adjusted to 8 with anhydrous sodium carbonate solution. The mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10%-50%) to obtain the final product. 58-3 (6.50 grams).

[0819] LC-MS: m / z 308 (M+H) +

[0820] Step 3

[0821] raw materials 58-3 (6.50 g) was dissolved in isopropanol (100 mL), and 2-cyanomethylpiperazine dihydrochloride (4.59 g) and diisopropylethylamine (10.9 g) were added sequentially. The resulting mixture was reacted at 80 °C for 24 hours. After the reaction was completed, water (200 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the product. 58-4 (6.10 g). No purification required; use directly in the next reaction.

[0822] LC-MS: m / z 397 (M+H) +

[0823] Step 4

[0824] raw materials 58-4(6.10 g) was dissolved in anhydrous tetrahydrofuran (100 mL), and di-tert-butyl dicarbonate (4.03 g) and diisopropylethylamine (2.38 g) were added sequentially. The resulting solution was refluxed for 1 hour. After the reaction was complete, the solution was cooled to room temperature. The solution was diluted with water (150 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phases were concentrated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 30%-60%) to obtain the final product. 58-5 (5.50 grams).

[0825] LC-MS: m / z 497 (M+H) +

[0826] Step 5

[0827] (S)-prolyl (1.91 g) was dissolved in anhydrous tetrahydrofuran (100 mL), and sodium hydride (60%) (0.665 g) was added at 0°C. After reacting at 0°C for 30 minutes, the starting material was added. 58-5 (5.50 g). The resulting solution was refluxed for 3 hours. After the reaction was complete, it was cooled to room temperature. The reaction was quenched with saturated ammonium chloride aqueous solution (150 mL) and extracted with ethyl acetate (150 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 5%-20%) to obtain the product. 58-6 (4.20 grams).

[0828] LC-MS: m / z 576 (M+H) +

[0829] Step 6

[0830] raw materials 58-6 4.20 g of palladium on carbon (10%) (0.42 g) and a methanol solution of ammonia (7 mol / L) (10 mL) were dissolved in anhydrous methanol (10 mL) under nitrogen protection. The resulting reaction solution was purged with hydrogen three times and reacted at 40°C for 3 hours. After the reaction was complete, the palladium on carbon was filtered off. The filtrate was concentrated to dryness to obtain the product. 58-7 (2.50 grams).

[0831] LC-MS: m / z 486 (M+H) +

[0832] Step 7

[0833] raw materials 58-750.0 mg was dissolved in toluene (2 mL), and 1-bromonaphthalene (25.5 mg), sodium tert-butoxide (49.4 mg), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (8.6 mg) were added sequentially. The resulting solution was stirred at 90 °C for 3 hours. After the reaction was complete, the solution was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10%-20%) to obtain the final product. 58-8 (25.0 mg).

[0834] LC-MS: m / z 612 (M+H) +

[0835] Step 8

[0836] To raw materials 58-8 A solution of 1,4-dioxane in hydrogen chloride (25.0 mg) was added (2 mL). The resulting solution was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated to dryness to obtain the product. 58-9 (15.0 mg). No purification required; can be used directly in the next reaction.

[0837] LC-MS: m / z 512 (M+H) +

[0838] Step 9

[0839] raw materials 58-9 (15.0 mg) was dissolved in dichloromethane (2 mL), cooled to -40°C, and then triethylamine (13.8 mg) and acryloyl chloride (2.5 mg) were added sequentially. The resulting solution was reacted at -40°C for 1 hour. After the reaction was complete, water (5 mL) was added to quench the reaction and the solution was concentrated to dryness. The crude product was purified using a preparative chromatography column (column type: XBridge ShieldRP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient; 42-61%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 58 (7.8 mg).

[0840] LC-MS: m / z 566 (M+H) +

[0841] 1H-NMR(CD3OD)δ:8.37(d,J=8.1Hz,1H),7.85(d,J=6.6Hz,1H),7.60-7.46(m,3H),7.40(t,J=8.1Hz,1H),7.16( d,J=6.9Hz,1H),6.93-6.75(m,1H),6.29(dd,J1=1.5Hz,J2=16.5Hz,1H),5.84(dd,J1=1.5Hz,J2=10.5Hz,1H),5 .12-4.60(m,1H),4.45-4.35(m,2H),4.18-4.03(m,1H),3.93-3.77(m,2H),3.71-3.51(m,2H),3.30-3.23(m,6H ),3.22-3.01(m,6H),2.89-2.77(m,1H),2.56(s,3H),2.46-2.38(m,1H),2.18-2.07(m,1H),1.91-1.71(m,3H).

[0842] Example 59

[0843]

[0844] Step 1

[0845] compound 59-1 Synthetic reference compound 58-8 .raw material 58-7 (50.0 mg), 8-methyl-1-bromonaphthalene (45.3 mg), sodium tert-butoxide (98.9 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 59-1 (27.0 mg).

[0846] LC-MS: m / z 626 (M+H) +

[0847] Step 2

[0848] compound 59-2 Synthetic reference compound 58-9 .raw material 59-1 (27.0 mg), 1,4-dioxane (4 mol / L, 2 mL). Product obtained. 59-2 (22.0 mg).

[0849] LC-MS: m / z 526 (M+H) +

[0850] Step 3

[0851] compound 59 Synthetic reference compound 58 .raw material 59-2 (22.0 mg), triethylamine (19.8 mg), acryloyl chloride (5.3 mg), dichloromethane (5 mL). Product obtained. 59 (7.2 mg).

[0852] LC-MS: m / z 580 (M+H) +

[0853] 1 H-NMR(CD3OD)δ:7.70-7.63(m,2H),7.40-7.28(m,4H),6.94-6.70(m,1H),6.29(d,J =16.5Hz,1H),5.83(d,J=10.5Hz,1H),5.12-4.66(m,1H),4.46-4.36(m,2H),4.16-3 .99(m,1H),3.91-3.74(m,2H),3.55-3.36(m,5H),3.16(d,J=7.2Hz,3H),3.13-2.82 (m,10H),2.54(s,3H),2.47(q,J=3.6Hz,1H),2.21-2.09(m,1H),1.95-1.72(m,3H).

[0854] Example 60

[0855]

[0856] Step 1

[0857] compound 60-1 Synthetic reference compound 58-8 .raw material 58-7 (50.0 mg), 8-fluoro-1-bromonaphthalene (46.2 mg), sodium tert-butoxide (98.9 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 60-1 (24.0 mg).

[0858] LC-MS: m / z 630(M+H) +

[0859] Step 2

[0860] compound 60-2 Synthetic reference compound 58-9 .raw material 60-1(24.0 mg), 1,4-dioxane (4 mol / L, 2 mL). Product obtained. 60-2 (20.0 mg).

[0861] LC-MS: m / z 530 (M+H) +

[0862] Step 3

[0863] compound 60 Synthetic reference compound 58 .raw material 60-2 (20.0 mg), triethylamine (17.8 mg), acryloyl chloride (4.8 mg), dichloromethane (5 mL). Product obtained. 60 (8.0 mg).

[0864] LC-MS: m / z 584 (M+H) +

[0865] 1 H-NMR(CD3OD)δ:7.67(d,J=6.9Hz,1H),7.57(d,J=8.1Hz,1H),7.46-7.38(m,2H),7.21-7.12(m,2H ),6.97-6.74(m,1H),6.28(d,J=16.5Hz,1H),5.84(d,J=10.5Hz,1H),5.13-4.65(m,1H),4.40-4.17 (m,2H),4.21-4.04(m,1H),3.96-3.83(m,1H),3.81-3.55(m,4H),3.48-3.35(m,1H),3.29-3.18(m ,2H),3.16-2.90(m,9H),2.63(s,3H),2.53(q,J=3.6Hz,1H),2.25-2.10(m,1H),1.96-1.75(m,3H).

[0866] Example 61

[0867]

[0868] Step 1

[0869] compound 61-1 Synthetic reference compound 58-8 .raw material 58-7(50.0 mg), 8-chloro-1-bromonaphthalene (49.5 mg), sodium tert-butoxide (98.9 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 61-1 (25.0 mg).

[0870] LC-MS: m / z 646 (M+H) +

[0871] Step 2

[0872] compound 61-2 Synthetic reference compound 58-9 .raw material 61-1 (25.0 mg), 1,4-dioxane (4 mol / L, 2 mL). Product obtained. 61-2 (21.0 mg).

[0873] LC-MS: m / z 546 (M+H) +

[0874] Step 3

[0875] compound 61 Synthetic reference compound 58 .raw material 61-2 (21.0 mg), triethylamine (18.2 mg), acryloyl chloride (4.9 mg), dichloromethane (5 mL). Product obtained. 61 (8.5 mg).

[0876] LC-MS: m / z 600(M+H) +

[0877] 1H-NMR(CD3OD)δ:7.81(d,J=7.2Hz,1H),7.66(d,J=7.8Hz,1H),7.58(d,J=6.9Hz,1H),7.47-7.31(m,3H),6.94-6.71(m,1H),6.28(d,J=16.5Hz,1H), 5.84(d,J=10.5Hz,1H),5.13-4.65(m,1H),4.40-4.13(m,2H),4.18-4.03(m,1H),3.91-3.75(m,2H),3.67-3.50(m,4H),3.31- 3.20(m,2H),3.17-3.07(m,2H),3.03-2.79(m,7H),2.55(s,3H),2.41(q,J=3.6Hz,1H),2.17-2.06(m,1H),1.90-1.68(m,3H).

[0878] Example 62

[0879]

[0880] Step 1

[0881] raw materials 58-3 (3.00 g) was dissolved in isopropanol (80 mL), and (S)-2-cyanomethylpiperazine dihydrochloride (2.31 g) and diisopropylethylamine (5.04 g) were added sequentially. The resulting mixture was reacted at 80 °C for 24 hours. After the reaction was complete, it was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the product. 62-1 (2.80 grams).

[0882] LC-MS: m / z 397 (M+H) +

[0883] Step 2

[0884] raw materials 62-1 (2.80 g) was dissolved in anhydrous tetrahydrofuran (50 mL), and di-tert-butyl dicarbonate (1.85 g) and diisopropylethylamine (1.37 g) were added sequentially. The resulting solution was refluxed for 1 hour. After the reaction was complete, the solution was cooled to room temperature. The solution was diluted with water (150 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phases were concentrated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 30%-60%) to obtain the final product. 62-2 (2.70 grams).

[0885] LC-MS: m / z 497 (M+H) +

[0886] Step 3

[0887] (S)-prolyl (0.938 g) was dissolved in anhydrous tetrahydrofuran (100 mL), and sodium hydride (60%) (0.326 g) was added at 0°C. After reacting at 0°C for 30 minutes, the starting material was added. 62-2 (2.70 g). The resulting solution was reacted at 70°C for 3 hours. After the reaction was complete, it was cooled to room temperature. The reaction was quenched with saturated ammonium chloride aqueous solution (150 mL) and extracted with ethyl acetate (150 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 5%-20%) to obtain the product. 62-3 (2.20 grams).

[0888] LC-MS: m / z 576 (M+H) +

[0889] Step 4

[0890] raw materials 62-3 2.20 g of palladium on carbon (10%) (0.22 g) and a methanol solution of ammonia (7 mol / L) (8 mL) were dissolved in anhydrous methanol (8 mL) under nitrogen protection. The resulting reaction solution was purged with hydrogen three times and reacted at 40°C for 3 hours. After the reaction was complete, the palladium on carbon was filtered off. The filtrate was concentrated to dryness to obtain the product. 62-4 (1.50 grams).

[0891] LC-MS: m / z 486 (M+H) +

[0892] Step 5

[0893] raw materials 62-4 50.0 mg was dissolved in toluene (2 mL), and 8-methyl-1-bromonaphthalene (27.2 mg), sodium tert-butoxide (49.4 mg), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (8.6 mg) were added sequentially. The resulting solution was reacted at 90°C for 3 hours. After the reaction was completed, the solution was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10%-20%) to obtain the final product. 62-5 (24.0 mg).

[0894] LC-MS: m / z 626 (M+H) +

[0895] Step 6

[0896] To raw materials 62-5 A solution (2 mL) of 1,4-dioxane hydrogen chloride was added to (24.0 mg). The resulting solution was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated to dryness to obtain the product. 62-6 (15.0 mg). No purification required; can be used directly in the next reaction.

[0897] LC-MS: m / z 526 (M+H) +

[0898] Step 7

[0899] raw materials 62-6 (15.0 mg) was dissolved in dichloromethane (2 mL), cooled to -40°C, and then triethylamine (13.4 mg) and acryloyl chloride (2.4 mg) were added sequentially. The resulting solution was reacted at -40°C for 1 hour. After the reaction was complete, water (5 mL) was added to quench the reaction and the solution was concentrated to dryness. The crude product was purified using a preparative chromatography column (column type: XBridge ShieldRP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 25 mL / min; gradient: 42-61%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 62 (7.8 mg).

[0900] LC-MS: m / z 580 (M+H) +

[0901] 1 H-NMR(CD3OD)δ:7.74-7.62(m,2H),7.45-7.28(m,4H),6.95-6.77(m,1H),6.29(dd,J1=1.5Hz,J2= 16.5Hz,1H),5.84(dd,J1=1.5Hz,J2=10.5Hz,1H),5.12-4.60(m,1H),4.45-4.35(m,2H),4.18-4.03 (m,1H),3.93-3.77(m,2H),3.71-3.51(m,2H),3.50-3.36(m,3H),3.35-3.28(m,2H),3.19(d,J=7. 2Hz,3H),3.16-3.09(m,4H),3.07-2.82(m,5H),2.72(s,3H),2.30-2.15(m,1H),2.00-1.80(m,3H).

[0902] Example 63

[0903]

[0904] raw materials 62-6 (15.5 mg) was dissolved in dichloromethane (2 mL), cooled to -40°C, and then triethylamine (13.8 mg) and vinylsulfonyl chloride (3.5 mg) were added sequentially. The resulting solution was reacted at -40°C for 10 min. After the reaction was complete, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (150 mL). The organic phases were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crude product was purified using a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5 μm, 19 x 150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 40-75%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 63 (10.8 mg).

[0905] LC-MS: m / z 616 (M+H) +

[0906] 1 H-NMR(CD3OD)δ:7.66(dd,J1=7.2Hz,J2=5.4Hz,2H),7.39-7.27(m,4H),6.78(dd,J1=9.9Hz ,J2=6.6Hz,1H),6.27(d,J=16.2Hz,1H),6.06(d,J=9.6Hz,1H),4.54(q,J1=11.7Hz,J2=13.2 Hz,2H),4.43-4.39(m,1H),3.88(d,J=13.8Hz,1H),3.73-3.67(m,2H),3.56-3.37(m,7H),3 .15(d,J=9.6Hz,4H),3.10-2.88(m,8H),2.83(s,3H),2.36-2.21(m,1H),2.10-1.85(m,3H).

[0907] Example 64

[0908]

[0909] raw materials 62-6(15.5 mg) was dissolved in dichloromethane (2 mL), cooled to -40°C, and then triethylamine (13.8 mg) and 3-(N,N-dimethylamino)methacryloyl chloride (4.0 mg) were added sequentially. The resulting solution was reacted at -40°C for 10 min. After the reaction was complete, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL). The organic phases were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crude product was purified using a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 35-72%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 64 (10.5 mg).

[0910] LC-MS: m / z 637(M+H) +

[0911] 1 H-NMR(CD3OD)δ:7.72-7-64(m,2H),7.40-7.27(m,4H),6.91-6.63(m,2H),5. 09(s,1H),4.46(d,J=5.4Hz,2H),3.60-3.40(m,4H),3.29-3.22(m,4H),3.16 (d,J=6.3Hz,3H),3.12-2.87(m,8H),2.67(s,3H),2.62-2.54(m,1H),2.33(s ,6H),2.26-2.10(m,2H),1.98-1.90(m,3H),1.88-1.75(m,2H),1.61(s,1H).

[0912] Example 65

[0913]

[0914] raw materials 62-615.5 mg was dissolved in dichloromethane (2 mL), cooled to -40°C, and then N,N-diisopropylethylamine (7.1 mg), propylphosphonic anhydride (50% ethyl acetate solution) (35.1 mg), and 2-butynedic acid (4.6 mg) were added sequentially. The resulting solution was reacted at 0°C for 1 hour. After the reaction was complete, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (150 mL). The organic phases were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crude product was purified using a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5µm, 19*150mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 32-70%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 65 (8.1 mg).

[0915] LC-MS: m / z 592 (M+H) +

[0916] 1 H-NMR(CD3OD)δ:7.66(dd,J1=7.5Hz,J2=5.4Hz,2H),7.39-7.27(m,4H),5.0 2(s,1H),4.48-4.45(m,2H),3.53-3.40(m,4H),3.29-2.26(m,1H),3.23-3.2 0(m,1H),3.17-3.08(m,7H),3.05-2.86(m,6H),2.70(d,J=3.3Hz,3H),2.65 -2.60(m,1H),2.25-2.16(m,2H),2.09(d,J=11.1Hz,3H),2.00-1.80(m,4H).

[0917] Example 66

[0918]

[0919] Step 1

[0920] raw materials 58-3 (3.00 g) was dissolved in isopropanol (80 mL), and (R)-2-cyanomethylpiperazine dihydrochloride (2.31 g) and diisopropylethylamine (5.04 g) were added sequentially. The resulting mixture was reacted at 80 °C for 24 hours. After the reaction was complete, it was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the product. 66-1(2.70 grams).

[0921] LC-MS: m / z 397 (M+H) +

[0922] Step 2

[0923] raw materials 66-1 (2.70 g) was dissolved in anhydrous tetrahydrofuran (50 mL), and di-tert-butyl dicarbonate (1.78 g) and diisopropylethylamine (1.32 g) were added sequentially. The resulting solution was refluxed for 1 hour. After the reaction was complete, the solution was cooled to room temperature. The solution was diluted with water (150 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phases were concentrated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 30%-60%) to obtain the final product. 66-2 (2.70 grams).

[0924] LC-MS: m / z 497 (M+H) +

[0925] Step 3

[0926] (S)-prolyl (0.938 g) was dissolved in anhydrous tetrahydrofuran (100 mL), and sodium hydride (60%) (0.326 g) was added at 0°C. After reacting at 0°C for 30 minutes, the starting material was added. 66-2 (2.70 g). The resulting solution was reacted at 70°C for 3 hours. After the reaction was complete, it was cooled to room temperature. The reaction was quenched with saturated ammonium chloride aqueous solution (150 mL) and extracted with ethyl acetate (150 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 5%-20%) to obtain the product. 66-3 (2.25 grams).

[0927] LC-MS: m / z 576 (M+H) +

[0928] Step 4

[0929] raw materials 66-3 2.25 g of palladium on carbon (10%) (0.22 g) and a methanol solution of ammonia (7 mol / L) (8 mL) were dissolved in anhydrous methanol (8 mL) under nitrogen protection. The resulting reaction solution was purged with hydrogen three times and reacted at 40°C for 3 hours. After the reaction was complete, the palladium on carbon was filtered off. The filtrate was concentrated to dryness to obtain the product. 66-4 (1.60 grams).

[0930] LC-MS: m / z 486 (M+H) +

[0931] Step 5

[0932] raw materials 66-4 50.0 mg was dissolved in toluene (2 mL), and 8-methyl-1-bromonaphthalene (27.2 mg), sodium tert-butoxide (49.4 mg), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (8.6 mg) were added sequentially. The resulting solution was stirred at 90 °C for 3 hours. After the reaction was complete, the solution was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10%-20%) to obtain the final product. 66-5 (24.0 mg).

[0933] LC-MS: m / z 626 (M+H) +

[0934] Step 6

[0935] To raw materials 66-5 A solution (2 mL) of 1,4-dioxane hydrogen chloride was added to (24.0 mg). The resulting solution was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated to dryness to obtain the product. 66-6 (15.0 mg). No purification required; can be used directly in the next reaction.

[0936] LC-MS: m / z 526 (M+H) +

[0937] Step 7

[0938] raw materials 66-6 (15.0 mg) was dissolved in dichloromethane (2 mL), cooled to -40°C, and then triethylamine (13.4 mg) and acryloyl chloride (2.4 mg) were added sequentially. The resulting solution was reacted at -40°C for 1 hour. After the reaction was complete, water (5 mL) was added to quench the reaction and the solution was concentrated to dryness. The crude product was purified using a preparative chromatography column (column type: XBridge ShieldRP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 42-61%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 66 (7.8 mg).

[0939] LC-MS: m / z 580 (M+H) +

[0940] 1H-NMR(CD3OD)δ:7.70-7.63(m,2H),7.39-7.27(m,4H),6.92-6.75(m,1H),6.28(d,J=1 6.5Hz,1H),5.83(d,J=10.5Hz,1H),5.12-4.60(m,1H),4.50-4.22(m,2H),4.18-4.01( m,1H),3.93-3.77(m,2H),3.71-3.62(m,1H),3.55-3.39(m,4H),3.30-3.23(m,2H),3. 19-3.06(m,7H),3.04-2.83(m,5H),2.72(s,3H),2.27-2.17(m,1H),2.01-1.79(m,3H).

[0941] Example 67

[0942]

[0943] Step 1:

[0944] compound 67-1 Synthetic reference compound 66-5 .raw material 66-4 (50.0 mg), 1-bromonaphthalene (42.4 mg), sodium tert-butoxide (98.9 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 67-1 (30.0 mg).

[0945] LC-MS: m / z 612 (M+H) +

[0946] Step 2:

[0947] compound 67-2 Synthetic reference compound 66-6 .raw material 67-1 (30.0 mg), 1,4-dioxane (4 mol / L, 5 mL). Product obtained. 67-2 (26.0 mg).

[0948] LC-MS: m / z 512 (M+H) +

[0949] Step 3:

[0950] compound 67 Synthetic reference compound 66 .raw material 67-2(26.0 mg), triethylamine (24.0 mg), acryloyl chloride (6.45 mg), dichloromethane (5 mL). Product obtained. 67 (3.7 mg).

[0951] LC-MS: m / z 566 (M+H) +

[0952] 1 H-NMR(CD3OD)δ:8.36(d,J=8.4Hz,1H),7.89-7.82(m,1H),7.63-7.36(m,4H),7.16(d,J =7.5Hz,1H),6.94-6.73(m,1H),6.29(d,J=16.7Hz,1H),5.84(d,J=10.6Hz,1H),5.17-5. 05(m,1H),4.81-4.52(m,1H),4.54-4.43(m,2H),4.17-4.01(m,1H),3.99-3.52(m,4H),3 .31-2.88(m,11H),2.69(s,3H),2.67-2.52(m,1H),2.3-2.14(m,1H),2.06-1.71(m,4H).

[0953] Example 68

[0954]

[0955] Step 1:

[0956] compound 68-1 Synthetic reference compound 66-5 .raw material 66-4 (50.0 mg), 8-chloro-1-bromonaphthalene (49.4 mg), sodium tert-butoxide (98.9 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 68-1 (48.0 mg).

[0957] LC-MS: m / z 646 (M+H) +

[0958] Step 2:

[0959] compound 68-2 Synthetic reference compound 66-6 .raw material 68-1 (48.0 mg), 1,4-dioxane (4 mol / L, 5 mL). Product obtained. 68-2 (42.0 mg).

[0960] LC-MS: m / z 546 (M+H) +

[0961] Step 3:

[0962] compound 68 Synthetic reference compound 66 .raw material 68-2 (42.0 mg), triethylamine (36.5 mg), acryloyl chloride (9.81 mg), dichloromethane (5 mL). Product obtained. 68 (6.0 mg).

[0963] LC-MS: m / z 600(M+H) +

[0964] 1 H-NMR(CD3OD)δ:7.82(d,J=7.7Hz,1H),7.67(d,J=8.0Hz,1H),7.58(d,J=7.5Hz,1H),7.49-7.3 1(m,3H),6.95-6.72(m,1H),6.29(d,J=16.5Hz,1H),5.83(d,J=10.6Hz,1H),5.18-5.04(m,1H) ,4.81-4.55(m,1H),4.34(d,J=5.7Hz,2H),4.17-3.71(m,4H),3.70-3.48(m,4H),3.33-3.16(m ,2H),3.13-2.83(m,7H),2.63(s,3H),2.59-2.45(m,1H),2.25-2.06(m,1H),2.01-1.71(m,3H).

[0965] Example 69

[0966]

[0967] Step 1:

[0968] compound 69-1 Synthetic reference compound 66-5 .raw material 66-4 (50.0 mg), 8-ethyl-1-bromonaphthalene (48.2 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 69-1 (36.0 mg).

[0969] LC-MS: m / z 640(M+H) +

[0970] Step 2:

[0971] compound 69-2 Synthetic reference compound 66-6 .raw material 69-1 (36.0 mg), 1,4-dioxane (4 mol / L, 5 mL). Product obtained. 69-2 (31.4 mg).

[0972] LC-MS: m / z 540 (M+H) +

[0973] Step 3:

[0974] compound 69 Synthetic reference compound 66 .raw material 69-2 (31.4 mg), triethylamine (27.6 mg), acryloyl chloride (7.4 mg), dichloromethane (5 mL). Product obtained. 69 (7.4 mg).

[0975] LC-MS: m / z 594 (M+H) +

[0976] 1 H-NMR(CD3OD)δ:7.72-7.64(m,2H),7.40-7.30(m,4H),6.89-6.72(m,1H) ,6.28(d,J=4.8Hz,1H),5.83(d,J=10.5Hz,1H),5.18-4.97(m,1H),4.79- 4.38(m,3H),4.21-3.37(m,12H),3.21-2.90(m,7H),2.89-2.83(m,1H),2 .81(s,3H),2.34-2.20(m,1H),2.10-1.81(m,3H),1.28(q,J=7.5Hz,3H).

[0977] Example 70

[0978]

[0979] Step 1

[0980] raw materials 58-3(2.00 g) was dissolved in isopropanol (80 mL), and tert-butyl piperazine carboxylate (1.45 g) and diisopropylethylamine (1.68 g) were added sequentially. The resulting mixture was reacted at 80 °C for 24 hours. After the reaction was complete, it was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the product. 70-1 (1.30 grams).

[0981] LC-MS: m / z 458 (M+H) +

[0982] Step 2

[0983] (S)-prolyl (0.528 g) was dissolved in anhydrous tetrahydrofuran (100 mL), and sodium hydride (60%) (0.183 g) was added at 0°C. After reacting at 0°C for 30 minutes, the starting material was added. 70-1 (1.30 g). The resulting solution was reacted at 70°C for 3 hours. After the reaction was complete, it was cooled to room temperature. The reaction was quenched with saturated ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 5%-20%) to obtain the product. 70-2 (1.10 grams).

[0984] LC-MS: m / z 537 (M+H) +

[0985] Step 3

[0986] raw materials 70-2 1.10 g of palladium on carbon (0.11 g) was dissolved in anhydrous methanol (40 mL). Under nitrogen protection, palladium on carbon (10%) and a methanol solution of ammonia (7 mol / L) (4 mL) were added sequentially. The resulting reaction solution was purged with hydrogen three times and reacted at 40°C for 3 hours. After the reaction was complete, the palladium on carbon was filtered off. The filtrate was concentrated to dryness to obtain the product. 70-3 (0.80 grams).

[0987] LC-MS: m / z 447 (M+H) +

[0988] Step 4

[0989] raw materials 70-350.0 mg was dissolved in toluene (2 mL), and 8-methyl-1-bromonaphthalene (49.2 mg), sodium tert-butoxide (53.7 mg), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (9.4 mg) were added sequentially. The resulting solution was stirred at 90 °C for 3 hours. After the reaction was complete, the solution was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10%-20%) to obtain the final product. 70-4 (21.0 mg).

[0990] LC-MS: m / z 587 (M+H) +

[0991] Step 5

[0992] To raw materials 70-4 A solution of 1,4-dioxane in hydrogen chloride (21.0 mg) (2 mL) was added. The resulting solution was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated to dryness to obtain the product. 70-5 (15.0 mg). No purification required; can be used directly in the next reaction.

[0993] LC-MS: m / z 487 (M+H) +

[0994] Step 6

[0995] raw materials 70-5 (15.0 mg) was dissolved in dichloromethane (2 mL), cooled to -40°C, and then triethylamine (14.5 mg) and acryloyl chloride (2.6 mg) were added sequentially. The resulting solution was reacted at -40°C for 1 hour. After the reaction was complete, water (5 mL) was added to quench the reaction and the solution was concentrated to dryness. The crude product was purified using a preparative chromatography column (column type: XBridge ShieldRP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 30-65%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 70 (7.8 mg).

[0996] LC-MS: m / z 541 (M+H) +

[0997] 1H-NMR(CD3OD)δ:7.70-7.63(m,2H),7.39-7.27(m,4H),6.85-6.76(m,1H),6. 29(dd,J1=2.1Hz,J2=16.8Hz,1H),5.79(dd,J1=2.1Hz,J2=10.8Hz,1H),4.61- 4.45(m,2H),3.84-3.77(m,4H),3.52-3.37(m,9H),3.16(s,3H),3.13-2.95( m,4H),2.90-2.85(m,2H),2.84(s,3H),2.33-2.22(m,1H),2.09-1.88(m,3H).

[0998] Example 71

[0999]

[1000] Step 1

[1001] raw materials 58-3 (2.00 g) was dissolved in isopropanol (80 mL), and (S)-3-methylpiperazine carboxylate tert-butyl ester (1.56 g) and diisopropylethylamine (1.68 g) were added sequentially. The resulting mixture was reacted at 80 °C for 24 hours. After the reaction was complete, it was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the product. 71-1 (1.00 g).

[1002] LC-MS: m / z 472 (M+H) +

[1003] Step 2

[1004] (S)-prolyl (0.365 g) was dissolved in anhydrous tetrahydrofuran (100 mL), and sodium hydride (60%) (0.127 g) was added at 0°C. After reacting at 0°C for 30 minutes, the starting material was added. 71-1 (1.00 g). The resulting solution was reacted at 70°C for 3 hours. After the reaction was complete, it was cooled to room temperature. The reaction was quenched with saturated ammonium chloride aqueous solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 5%-20%) to obtain the product. 71-2 (0.850 grams).

[1005] LC-MS: m / z 551 (M+H) +

[1006] Step 3

[1007] raw materials 71-2 0.850 g of palladium on carbon (10%) (0.085 g) and a methanol solution of ammonia (7 mol / L) (2.5 mL) were added sequentially under nitrogen protection. The resulting reaction solution was purged with hydrogen three times and reacted at 40°C for 3 hours. After the reaction was complete, the palladium on carbon was filtered off. The filtrate was concentrated to dryness to obtain the product. 71-3 (0.550 grams).

[1008] LC-MS: m / z 461(M+H) +

[1009] Step 4

[1010] raw materials 71-3 50.0 mg was dissolved in toluene (2 mL), and 8-methyl-1-bromonaphthalene (47.7 mg), sodium tert-butoxide (51.8 mg), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (9.0 mg) were added sequentially. The resulting solution was stirred at 90 °C for 3 hours. After the reaction was complete, the solution was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10%-20%) to obtain the final product. 71-4 (23.0 mg).

[1011] LC-MS: m / z 601(M+H) +

[1012] Step 5

[1013] To raw materials 71-4 A solution (2 mL) of 1,4-dioxane hydrogen chloride was added to (23.0 mg). The resulting solution was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated to dryness to obtain the product. 71-5 (15.0 mg). No purification required; can be used directly in the next reaction.

[1014] LC-MS: m / z 501(M+H) +

[1015] Step 6

[1016] raw materials 71-5(15.0 mg) was dissolved in dichloromethane (2 mL), cooled to -40°C, and then triethylamine (14.5 mg) and acryloyl chloride (2.5 mg) were added sequentially. The resulting solution was reacted at -40°C for 1 hour. After the reaction was complete, water (5 mL) was added to quench the reaction and the solution was concentrated to dryness. The crude product was purified using a preparative chromatography column (column type: XBridge ShieldRP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 42-62%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 71 (7.8 mg).

[1017] LC-MS: m / z 555 (M+H) +

[1018] 1 H-NMR(CD3OD)δ:7.70-7.63(m,2H),7.39-7.27(m,4H),6.88-6.73(m,1H),6.27(dd,J1=2.1Hz ,J2=16.8Hz,1H),5.80(dd,J1=2.1Hz,J2=10.8Hz,1H),4.56-4.38(m,3H),4.23-4.02(m,3H), 3.95-3.82(m,1H),3.69-3.37(m,6H),3.30-3.21(m,2H),3.16(d,J=4.8Hz,3H),3.12-2.93(m ,4H),2.89-2.80(m,1H),2.77(s,3H),2.28-2.18(m,1H),2.02-1.82(m,3H),1.24-1.19(m,3H)

[1019] Example 72

[1020]

[1021] Step 1

[1022] compound 72-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 3-(1,1-difluoroethyl)-bromobenzene (45.3 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 72-1 (32.0 mg).

[1023] LC-MS: m / z 626 (M+H) +

[1024] Step 2

[1025] compound 72-2 Synthetic reference compound 1-11 .raw material 72-1 (32.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 72-2 (28.4 mg).

[1026] LC-MS: m / z 526 (M+H) + .

[1027] Step 3

[1028] compound 72 Synthetic reference compound 1 .raw material 72-2 (28.4 mg), triethylamine (25.6 mg), acryloyl chloride (6.88 mg), dichloromethane (5 mL). Product obtained. 72 (8.9 mg).

[1029] LC-MS: m / z 580 (M+H) +

[1030] 1 H-NMR(CD3OD)δ:7.19(t,J=8.0Hz,1H),6.97(s,1H),6.90(d,J=8.7Hz,1H), 6.85-6.68(m,J=7.5Hz,2H),6.26(d,J=16.7Hz,1H),5.81(d,J=10.5Hz,1H) ,4.63(d,J=2.3Hz,2H),4.46-4.32(m,2H),4.12-3.46(m,6H),3.24-3.06(m ,3H),3.02-2.73(m,6H),2.56(s,3H),2.47-2.37(m,1H),2.17-1.75(m,9H).

[1031] Example 73

[1032]

[1033]

[1034] Step 1:

[1035] At room temperature, the raw materials 73-3(1.00 g) was dissolved in THF (5 mL), and triethylamine (0.734 g) and bromomethyl methyl ether (0.722 g) were added sequentially. The resulting reaction solution was allowed to react at room temperature for 2 hours. After the reaction was complete, water (50 mL) was added to quench the reaction. Extraction was performed with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL). The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product. 73-4 (1.10 grams).

[1036] LC-MS: m / z 251 (M+H) +

[1037] Step 2:

[1038] compound 73-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 73-4 (51.5 mg), sodium tert-butoxide (98.9 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 73-1 (35.0 mg).

[1039] LC-MS: m / z 656 (M+H) +

[1040] Step 3:

[1041] compound 73-2 Synthetic reference compound 1-11 .raw material 73-1 (35.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 73-2 (28.9 mg).

[1042] LC-MS: m / z 512 (M+H) + .

[1043] Step 4:

[1044] compound 73 Synthetic reference compound 1 .raw material 73-2(28.9 mg), triethylamine (26.7 mg), acryloyl chloride (5.27 mg), dichloromethane (5 mL). The crude product was purified using a preparative chromatographic column (column type: XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (0.5% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 27%-47%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 73 (5.3 mg).

[1045] LC-MS: m / z 566 (M+H) +

[1046] 1 H-NMR(CD3OD)δ:8.58(s,1H),7.05(t,J=8.1Hz,1H),6.91-6.74(m,1H),6.70(d,J=8.3Hz,1 H),6.63(d,J=8.1Hz,1H),6.30(d,J=16.8Hz,1H),5.85(d,J=10.5Hz,1H),5.18-5.08(m,1H ),4.70-4.48(m,2H),4.26(s,2H),4.17-3.84(m,3H),3.75-3.54(m,3H),3.53-3.35(m,3H) ,3.30-2.99(m,5H),2.97(s,3H),2.92-2.86(m,1H),2.40-2.28(m,1H),2.19-1.96(m,5H).

[1047] Example 74

[1048]

[1049] Step 1:

[1050] compound 74-1 Synthetic reference compound 1-10 .raw material 1-9 (50.0 mg), 3,4-dichlorobromobenzene (46.1 mg), sodium tert-butoxide (98.9 mg), mesylate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product obtained. 74-1 (31.9 mg).

[1051] LC-MS: m / z 630(M+H) +

[1052] Step 2:

[1053] compound 74-2 Synthetic reference compound 1-10 .raw material 74-1 (31.9 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). Product obtained. 74-2 (28.5 mg).

[1054] LC-MS: m / z 530 (M+H) +

[1055] Step 3

[1056] compound 74 Synthetic reference compound 1 .raw material 74-2 (28.5 mg), triethylamine (25.4 mg), acryloyl chloride (5.77 mg), dichloromethane (5 mL). Product obtained. 74 (7.0 mg).

[1057] LC-MS: m / z 584 (M+H) +

[1058] 1 H-NMR(CD3OD)δ:7.19(d,J=9.0Hz,1H),6.96(d,J=3.0Hz,1H),6.91-6.67(m,2H),6.26(d ,J=16.8Hz,1H),5.81(d,J=10.5Hz,1H),5.15-4.97(m,1H),4.64-4.51(m,2H),4.41(d,J= 5.7Hz,2H),4.13-3.96(m,1H),3.95-3.71(m,3H),3.69-3.44(m,2H),3.27-3.07(m,3H), 3.02-2.80(m,5H),2.58(s,3H),2.53-2.41(m,1H),2.24-2.06(m,1H),2.04-1.67(m,5H).

[1059] Example 75

[1060]

[1061] Step 1:

[1062] compound 75-1 Synthetic reference compound 42-2 Among them, raw materials 42-1(1.00 g), 2,3-dichloro-1-bromobenzene (1.10 g), sodium tert-butoxide (1.18 g), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.206 g), toluene (20 mL). Product obtained. 75-1 (400 mg).

[1063] LC-MS: m / z 551 (M+H) +

[1064] Step 2:

[1065] At room temperature, the raw materials 75-1 50.0 mg of 3-amino-N,N-dimethylpropionamide (21.1 mg) and N,N-diisopropylethylamine (35.2 mg) were dissolved in dimethyl sulfoxide (2.0 mL), and N,N-diisopropylethylamine (35.2 mg) was added. The reaction mixture was placed at 120 °C and reacted overnight. After the reaction was complete, water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL). The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 5%-20%) to obtain the product. 75-2 (25.0 mg).

[1066] LC-MS: m / z 631(M+H) +

[1067] Step 3:

[1068] compound 75-3 Synthetic reference compound 42-4 Among them, raw materials 75-2 (25.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). The product was obtained. 75-3 (22.3 mg). No purification required; can be used directly in the next reaction.

[1069] LC-MS: m / z 531 (M+H) +

[1070] Step 4:

[1071] compound 75 Synthetic reference compound 42 Among them, raw materials 75-3 (22.3 mg), triethylamine (19.9 mg), acryloyl chloride (5.35 mg), dichloromethane (5 mL). Product obtained. 75 (4.0 mg).

[1072] LC-MS: m / z 585 (M+H) +

[1073] 1 H-NMR(CD3OD)δ:7.25-7.10(m,3H),6.94-6.78(m,1H),6.29(d,J=16.8Hz,1H),5. 84(d,J=10.5Hz,1H),5.25-5.11(m,1H),4.22-4.04(m,3H),3.88-3.74(m,2H),3.7 0-3.58(m,3H),3.50-3.35(m,3H),3.21-3.14(m,1H),3.05(s,3H),3.04-2.95(m, 2H),2.93(s,3H),2.81(t,J=5.2Hz,2H),2.70(t,J=6.6Hz,2H),2.17-1.95(m,2H).

[1074] Example 76

[1075]

[1076] Step 1:

[1077] compound 76-1 Synthetic reference compound 42-2 Among them, raw materials 42-1 (1.00 g), 1-bromo-3-methyl-2-trifluorotoluene (1.17 g), sodium tert-butoxide (1.18 g), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.206 g), toluene (20 mL). Product obtained. 76-1 (350 mg).

[1078] LC-MS: m / z 565 (M+H) +

[1079] Step 2:

[1080] compound 76-2 Synthetic reference compound 42-3 Among them, raw materials 76-1 (50.0 mg) and 5-hydroxypyrimidine (12.8 mg), sodium hydride (60%) (5.32 mg), tetrahydrofuran (5.0 mL). Product obtained. 76-2 (27.0 mg).

[1081] LC-MS: m / z 625 (M+H) +

[1082] Step 3:

[1083] compound 76-3 Synthetic reference compound 42-4 Among them, raw materials 76-2 (27.0 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). The product was obtained. 76-3 (23.5 mg). No purification required; can be used directly in the next reaction.

[1084] LC-MS: m / z 525 (M+H) +

[1085] Step 4:

[1086] compound 76 Synthetic reference compound 42 Among them, raw materials 76-3 (23.5 mg), triethylamine (21.1 mg), acryloyl chloride (5.66 mg), dichloromethane (5 mL). Product obtained. 76 (8.2 mg).

[1087] LC-MS: m / z 579 (M+H) +

[1088] 1 H-NMR(CDCl3)δ:9.06(s,1H),8.72(s,2H),7.36(d,J=8.0Hz,1H),7.19(d,J= 8.1Hz,1H),7.06(d,J=7.8Hz,1H),6.65-6.52(m,1H),6.40(d,J=16.5Hz,1H) ,5.84(d,J=10.2Hz,1H),5.24-4.97(m,1H),4.28-4.04(m,2H),3.91-3.52(m ,3H),3.38-3.11(m,3H),3.07-3.65(m,5H),2.49(s,3H),2.19-1.89(m,3H).

[1089] Example 77

[1090]

[1091] Step 1:

[1092] compound 77-1 Synthetic reference compound 42-3 Among them, raw materials 76-1 (50.0 mg) and pyrimidine-2-methanol (14.6 mg), sodium hydride (60%) (5.32 mg), tetrahydrofuran (5.0 mL). Product obtained. 77-1(27.8 mg).

[1093] LC-MS: m / z 639 (M+H) +

[1094] Step 2:

[1095] compound 77-2 Synthetic reference compound 42-4 Among them, raw materials 77-1 (27.8 mg), a solution of 1,4-dioxane hydrogen chloride (4 mol / L, 5 mL). The product was obtained. 77-2 (24.5 mg). No purification required; can be used directly in the next reaction.

[1096] LC-MS: m / z 539 (M+H) +

[1097] Step 3:

[1098] compound 77 Synthetic reference compound 42 Among them, raw materials 77-2 (24.5 mg), triethylamine (21.6 mg), acryloyl chloride (5.80 mg), dichloromethane (5 mL). Product obtained. 77 (4.0 mg).

[1099] LC-MS: m / z 593 (M+H) +

[1100] 1 H-NMR(CDCl3)δ:8.74(d,J=4.9Hz,2H),7.33(t,J=7.9Hz,1H),7.22(t,J=4.9Hz,1H),7.14 (d,J=8.1Hz,1H),7.02(d,J=7.6Hz,1H),6.67-6.50(m,1H),6.38(d,J=16.7Hz,1H),5.82(d ,J=10.0Hz,1H),5.56(s,2H),5.23-4.91(m,1H),4.73-4.43(m,1H),4.19(q,J=17.4Hz,2H) ,3.91-3.51(m,3H),3.32-3.11(m,3H),3.00-2.65(m,5H),2.48(s,3H),2.09-1.91(m,2H).

[1101] Example 78

[1102]

[1103] Step 1

[1104] raw materials 78-1 (22.0 g) was dissolved in N,N-dimethylformamide (250 mL), and ethyl 5-bromopentanoate (26.3 g) and N,N-diisopropylethylamine (17.9 g) were added sequentially. The resulting solution was stirred at 80 °C for 24 hours. After the reaction was complete, the solution was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (200 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10%-20%) to obtain the final product. 78-2 (13.1 grams).

[1105] LC-MS: m / z 304 (M+H) +

[1106] Step 2

[1107] raw materials 78-2 (13.1 g) was dissolved in N,N-dimethylformamide (150 mL), and N,N-diisopropylethylamine (6.65 g) and oxaloyl chloride monoethyl ester (6.42 g) were added sequentially. The resulting solution was stirred at room temperature for 16 hours. After the reaction was complete, water (150 mL) was added for dilution, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10%-20%) to obtain the final product. 78-3 (8.00 grams).

[1108] LC-MS: m / z 404 (M+H) +

[1109] Step 3

[1110] raw materials 78-3 (8.00 g) was dissolved in N,N-dimethylformamide (100 mL), and sodium hydride (1.20 g) was added. The resulting solution was stirred at 110 °C for 16 hours. After the reaction was complete, the solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (200 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 20%-30%) to obtain the final product. 78-4 (4.00 grams).

[1111] LC-MS: m / z 358 (M+H) +

[1112] Step 4

[1113] raw materials 78-4(4.00 g) was dissolved in ethanol (100 mL), and a sodium ethoxide ethanol solution (1.20 g) was added sequentially. The resulting solution was stirred at 80 °C for 16 hours. After the reaction was complete, the solution was cooled to room temperature, the pH was adjusted to weakly acidic with dilute hydrochloric acid, diluted with water (100 mL), and extracted with ethyl acetate (200 mL x 3). The combined organic phases were concentrated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 20%-30%) to obtain the final product. 78-5 (400 mg).

[1114] LC-MS: m / z 370 (M+H) +

[1115] Step 5

[1116] raw materials 78-5 (400 mg) was suspended in phosphorus oxychloride (100 mL), and N,N-dimethylformamide (1 mL) was added. The resulting solution was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated to dryness. The residue was added to water (100 mL) and the pH was adjusted to 8 with anhydrous sodium carbonate. It was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 20%-30%) to obtain the product. 78-6 (326 mg).

[1117] LC-MS: m / z 390(M+H) +

[1118] Step 6

[1119] raw materials 78-6 (326 mg) was dissolved in isopropanol (100 mL), and 2-cyanomethylpiperazine dihydrochloride (182 mg) and N,N-diisopropylethylamine (377 mg) were added sequentially. The resulting solution was stirred at room temperature for 1 hour. After the reaction was complete, water (100 mL) was added for dilution, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined and concentrated to dryness to obtain the product. 78-7 (294 mg).

[1120] LC-MS: m / z 479 (M+H) +

[1121] Step 7

[1122] raw materials 78-7(294 mg) was dissolved in anhydrous tetrahydrofuran (50 mL), and di-tert-butyl dicarbonate (160 mg) and N,N-diisopropylethylamine (119 mg) were added sequentially. The resulting solution was reacted at 50 °C for 2 hours. After the reaction was complete, the solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 30%-60%) to obtain the final product. 78-8 (254 mg).

[1123] LC-MS: m / z 579 (M+H) +

[1124] Step 8

[1125] (S)-prolyl (75.7 mg) was dissolved in anhydrous tetrahydrofuran (50 mL), and sodium hydride (60%) (26.3 mg) was added at 0°C. After reacting at 0°C for 30 minutes, the starting material was added. 78-8 (254 mg). The resulting solution was reacted at 70°C for 3 hours. After the reaction was complete, it was cooled to room temperature. The reaction was quenched with saturated ammonium chloride aqueous solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 5%-20%) to obtain the product. 78-9 (98.0 mg).

[1126] LC-MS: m / z 658 (M+H) +

[1127] Step 9

[1128] To raw materials 78-9 A solution of 1,4-dioxane hydrogen chloride (5 mL) was added to (98.0 mg). The resulting solution was stirred at room temperature for 10 minutes. After the reaction was complete, the solution was concentrated to dryness to obtain the product. 78-10 (53.0 mg). No purification required; can be used directly in the next reaction.

[1129] LC-MS: m / z 558 (M+H) +

[1130] Step 10

[1131] raw materials 78-10(53.0 mg) was dissolved in dichloromethane (5 mL), cooled to -40°C, and then triethylamine (28.8 mg) and acryloyl chloride (12.8 mg) were added sequentially. The resulting solution was reacted at -40°C for 10 minutes. After the reaction was complete, water (5 mL) was added to quench the reaction and the solution was concentrated to dryness. The crude product was purified using a preparative chromatography column (column type: XBridge ShieldRP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (0.5% formic acid); mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 40-70%; time: 8 min; detector wavelength: 254 / 220 nm) to obtain the product. 78 (10.0 mg).

[1132] LC-MS: m / z 612 (M+H) +

[1133] 1 H-NMR(CD3OD)δ:8.52(s,1H),7.77(d,J=6.8Hz,1H),7.65-7.45(m,2H),6.84(s,1H),6.32(d,J=16.0Hz,1H),5.86(d,J=12.0Hz,1H),5.31-5 .06(m,1H),4.43-4.02(m,3H),4.00-3.75(m,2H),3.75-3.50(m,4H), 3.22-2.87(m,9H),2.42(s,3H),2.40-2.20(m,3H),2.18-1.89(m,5H).

[1134] Example 79

[1135]

[1136] Step 1:

[1137] At room temperature, the raw materials 1-9 126.4 mg was dissolved in toluene (3 mL), and 2-bromo-3-fluoroanisole (106.4 mg), sodium tert-butoxide (250 mg), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (65.3 mg) were added sequentially. The resulting solution was stirred at 90 °C for 3 hours. After the reaction was complete, the solution was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10%-20%) to obtain the final product. 79-1 (96.7 mg).

[1138] LC-MS: m / z 610(M+H) + .

[1139] Step 2:

[1140] At room temperature, to the raw material 79-1 A solution of 1,4-dioxane in hydrogen chloride (10 mL) was added to (96.7 mg). The resulting solution was stirred at room temperature for 10 minutes. After the reaction was complete, the solution was concentrated to dryness to obtain the product. 79-2 (79.6 mg). No purification required; can be used directly in the next reaction.

[1141] LC-MS: m / z 510 (M+H) + .

[1142] Step 3:

[1143] raw materials 79-2 (79.6 mg) was dissolved in dichloromethane (10 mL), cooled to -40°C, and then triethylamine (71.7 mg) and acryloyl chloride (15.3 mg) were added sequentially. The resulting solution was reacted at -40°C for 10 min. After the reaction was complete, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined and concentrated to dryness. The crude product was purified using a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (10 mmol / L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 35-80%; time: 12 min; detector wavelength: 254 / 220 nm) to obtain the product. 79 (59.6 mg).

[1144] LC-MS: m / z 564 (M+H) +

[1145] 1H-NMR(CD3OD)δ:7.05-7.04(m,1H),7.03-6.77(m,2H),6.67-6.66(m,1H),6.30(d,J=12.3Hz,1H),5. 85(dd,J=7.8Hz,1H),5.12-5.03(m,1H),4.56-4.40(m,2H),4.43-4.40(m,2H),4.39-4.20(m,2H),3. 98-3.80(m,2H),3.77(s,3H),3.75-3.62(m,1H),3.52-3.47(m,1H),3.35-3.25(m,3H),3.11-2.97(m ,3H),2.95-2.91(m,2H),2.70-2.60(m,4H),2.20-2.10(m,1H),2.05-1.89(m,4H),1.85-1.75(m,1H).

[1146] Experimental Example 1: Detection of Protein Covalent Addition Reaction Products

[1147] 3 μM of the analyte compound and 2 μM of the GDP-His-KRAS-G12C protein complex were incubated in reaction buffer (12.5 mM HEPES, pH 7.5, 75 mM NaCl, 1 mM MgCl2) at room temperature for 5 and 30 minutes, respectively. The reaction was then terminated with 5% formic acid. After centrifugation at 15,000 rpm for 10 minutes, the supernatant was analyzed using a Waters Acquity I Class instrument to determine the relative amounts of His-KRAS-G12C and the His-KRAS-G12C complex covalently bound to the compound.

[1148] Calculate the amount of the compound binding to the KRAS-G12C protein (POC value, percent of control) after 5 and 30 minutes of incubation using the following formula:

[1149] POC, % = Peak value of the complex after the protein-compound addition reaction / (Peak value of the complex after the protein-compound addition reaction + Peak value of the protein) × 100

[1150] The test results of the compounds in the examples are shown in Table 1.

[1151] Table 1: Binding amount of the compound to KRAS-G12C protein

[1152]

[1153]

[1154] Note: + indicates 30% ≤ POC value < 50%;

[1155] ++ indicates that 50% ≤ POC value < 80%;

[1156] +++ indicates a POC value ≥ 80%.

[1157] Experimental Example 2: KRAS-G12C Inhibitory Activity

[1158] 1. ERK protein phosphorylation detection

[1159] H358 cells (ATCC, CRL-5807) or MIA expressing KRAS-G12C protein PaCa-2 (ATCC, CRL-1420) cells were seeded at 6000 cells per well in 384-well poly-L-lysine-coated cell culture plates (Corning, BD356663). The culture medium consisted of RPMI 1640 (Gibco, A10491-01), 10% FBS (Gibco, 10099141C), and 1% Pen / Strep (Gibco, 15140-122). The cells were cultured in a 5% CO2 incubator for 16 hours. Serially diluted compounds were added to the cell culture medium using an Echo 550, with a final DMSO concentration of 0.5%, and the cells were cultured for another 3 hours. Then, 40 μL / well of 8% paraformaldehyde (Solarbio, P1112) was added, and the cells were incubated at room temperature for 20 minutes. After washing once with PBS, 40 μL / well of cold 100% methanol was added, and the cells were incubated at room temperature for 10 minutes. After washing once with PBS, 20 μL of... Block cells with blocking buffer (LI-COR, 927-40000) at room temperature for 1 hour; then dilute rabbit anti-phospho-p44 / 42MAPK (T202 / Y204) antibody (CST, 4370S) 1:1000 with blocking buffer, dilute mouse anti-GAPDH (D4C6R) antibody (CST, 97166S) 1:2000 with blocking buffer, add 20 μL / well to cells, and block overnight at 4°C; wash with PBST. Three incubations were performed, each lasting 2 minutes. Then, goat anti-rabbit 800CW antibody (LI-COR, 926-32211) and goat anti-mouse 680RD antibody (LI-COR, 926-68070) were diluted 1:1000 with blocking buffer and added to the cells at 20 μL / well. The cells were incubated at room temperature for 45 minutes. After washing three times with PBST, each incubation lasting 2 minutes, the cell culture plates were inverted and centrifuged at 1000 rpm for 1 minute. The fluorescence signal was then read using an Odyssey CLx.

[1160] The data was fitted using XLFit 5.0 according to the 4-parameter formula Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)) to calculate IC.50 value.

[1161] The test results of the compounds in the examples are shown in Table 2.

[1162] Table 2: Detection results of ERK protein phosphorylation of compound ERK

[1163]

[1164]

[1165] Note: A represents IC. 50 ≤50nM;

[1166] B represents 50nM < IC 50 ≤150nM;

[1167] C represents 150nM < IC 50 ≤500nM;

[1168] D represents 500 nm < IC 50 ≤999nM;

[1169] —Represents IC 50 Value not detected.

[1170] 2. Cell proliferation inhibition detection

[1171] The serially diluted compound was added to a low-adsorption round-bottom 384-well cell culture plate (Corning, CLS3830-50EA) using an Echo 550. 40 μL of suspension containing 400 H358 or MIA PaCa-2 cells was added to each well, and the cells were cultured for 3 days at 37°C in a 5% CO2 incubator. One day in advance, the 3D CellTiter-Glo reagent (Promega, G9683) was thawed at 4°C. Before use, the plate was allowed to equilibrate at room temperature for 30 minutes, and 20 μL was added to each well. The plate was incubated at 100 rpm for 30 minutes, then allowed to stand at room temperature for 2 hours. The luminescence signal value was read using an Envision 2104.

[1172] The data was fitted using XLFit 5.0 according to the 4-parameter formula Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)) to calculate IC. 50 value.

[1173] The test results of the compounds in the examples are shown in Table 3.

[1174] Table 3: Results of the cell proliferation inhibition assay using compounds

[1175]

[1176] Note: A represents IC. 50 ≤50nM;

[1177] B represents 50nM < IC 50 ≤150nM;

[1178] C represents 150nM < IC 50 ≤500nM;

[1179] D represents 500 nm < IC 50 ≤999nM.

[1180] Pharmacokinetic Experiment Example 3

[1181] 1. Liver microsomal metabolic stability experiment

[1182] 1) Prepare the reaction system according to the table below.

[1183]

[1184] 2) Incubate the reaction system in a 37°C water bath for 10 minutes. Add 40 μL of 10 mM NADPH solution to the reaction system, resulting in a final NADPH concentration of 1 mM. Use 40 μL of ultrapure water instead of NADPH solution as a negative control. The negative control is used to eliminate the influence of the compound's own chemical stability.

[1185] 3) Add 4 μL of 200 μM of the test compound to the reaction system to start the reaction. The final drug concentration is 2 μM.

[1186] 4) At 0, 15, 30, 45, and 60 minutes, 50 μL of the reaction sample was collected and quenched with 4 times the volume of cold acetonitrile containing internal standards (200 nM alprazolam, 200 nM labetalol, 2 μM ketoprofen, and 200 nM caffeine). The sample was centrifuged at 3,220 g for 45 minutes. After centrifugation, 90 μL of the supernatant was mixed with 90 μL of ultrapure water for LC-MS / MS analysis.

[1187] The test results of the compound in Example 66 are shown in Table 4.

[1188] Table 4: Results of the liver microsomal stability experiment of the compound

[1189]

[1190] 2. Plasma stability test

[1191] The test results of the compounds in the representative examples are shown in Table 5.

[1192] Table 5: Results of mouse plasma stability test of the compound

[1193]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, q is 1, p is 1, and Selected from single or double bonds; Alternatively, q is 2, p is 0, and Selected from single bonds; when When selected from a double bond, R 4 and / or R 6 It does not exist; Part A is selected from Each R 1 The replacement on the ring is independently selected from 1, 2, or 3 R's. 0 Replacement C 1-4 alkyl; Each R 0 Independently selected from -CN, or C 1-3 Alkoxy; m is 0, 1, or 2; Each R 2 Independently selected from -C(O)C≡CR b -C(O)C(R) a )=C(R b )2, or -SO2C(R a )=C(R b )2; Each R a Independently selected from H, halogen, or C 1-4 alkyl; Each R b Independently selected from H or optionally by 1, 2 or 3 Rs c The following groups are substituted: methyl, dimethylaminomethyl, morpholinomethyl, piperidinylmethyl, tetrahydropyrrolylmethyl, or aziridinebutylmethyl; Each R c Independently selected from fluorine, chlorine, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 alkoxy or fluorinated C 1-3 alkyl; X is selected from single bonds, -O-, or -NH-; R 3 Selected from H or optionally by 1, 2, 3 or 4 Rs d The following groups are substituted: C 1-4 Alkyl, 4-7 membered heterocyclic alkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclic alkyl C 1-3 Alkyl, or 5-6 quinone heteroaryl C 1-3 alkyl; Each R d Independently selected from halogens, oxidants, and carbon atoms. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 alkylamino, or di-C 1-4 Alkylamino; Y is selected from a single bond; B is selected from 1, 2, 3, 4, 5, or 6 R's. e Substituted phenyl, naphthyl, 5-6 heteroaryl, or benzo5-6 heteroaryl; Each R e Independently selected from halogens, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, diC 1-6 Alkylamino, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkyl thiols, halogenated C 1-6 Alkylamino, or di(halogenated C) 1-6 alkyl)amino; R 4 R 5 Independently selected from H; R 6 R 7 Independently selected from H, or R 6 and R 7 Together they form a carbonyl group; The condition is that the compound of formula (I) is not 2. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R 1 It is independently selected from methyl, cyanomethyl, or methoxymethyl.

3. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, AR 2 Some were jointly selected 4. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R a It is independently selected from H, fluorine, chlorine, methyl or ethyl.

5. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R c It is independently selected from fluorine, chlorine, methyl, ethyl or trifluoromethyl.

6. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The R 2 Selected from the following groups:

7. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The R 2 Selected from the following groups:

8. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, X is selected from -O-.

9. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The R 3 Selected from 1, 2, 3 or 4 Rs d The following groups are substituted: 4-7 membered heterocyclic alkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclic alkyl C 1-3 Alkyl, or 5-6 quinone heteroaryl C 1-3 alkyl.

10. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R 3 Selected from H or optionally by 1, 2, 3 or 4 Rs d The following groups are substituted: methyl, ethyl, propyl, 1,2,3,4-tetrahydroisoquinolinyl, aziridine, aziridinebutylethyl, aziridinebutylpropyl, tetrahydropyrrolemethyl, tetrahydropyrroleethyl, tetrahydropyrrolepropyl, morpholinyl, piperazinyl, piperidinyl, piperidinylethyl, piperidinylpropyl, morpholinylpropyl, pyrimidinyl, pyrimidinylmethyl, pyrimidinylethyl.

11. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R 3 Selected from H or optionally by 1, 2, 3 or 4 Rs d The following groups are substituted: tetrahydropyrrolemethyl, tetrahydropyrroleethyl, tetrahydropyrrolepropyl, morpholinopropyl, 12. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R 3 Selected from 1, 2, 3 or 4 Rs d Substituted tetrahydropyrrolemethyl.

13. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R d It is independently selected from fluorine, oxo, methyl, ethyl, isopropyl, tert-butyl, methoxy, dimethylamino, or diethylamino.

14. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R d It is independently selected from fluorine or methyl.

15. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The R 3 Selected from H, 16. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, B is selected from 1, 2, 3, 4, 5, or 6 R's. e The following groups may be substituted: phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzopyrazolyl, indoleyl, or isoindoleyl.

17. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, B is selected from 1, 2, 3, 4, 5, or 6 R's. e The following groups may be substituted: phenyl, naphthyl, pyridyl, or benzopyrazole.

18. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, B is selected from 1, 2, 3, or 4 Rs. e The following groups may be substituted: phenyl, naphthyl, or pyridyl.

19. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R e Independently selected from halogens, -CN, -OH, -NH2, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, C 1-4 Alkoxy, C 1-4 alkylamino, or di-C 1-4 Alkylamino.

20. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R e Independently selected from fluorine, chlorine, bromine, iodine, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, Difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, methoxy, ethoxy, methylamino, or dimethylamino.

21. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R e Independently selected from fluorine, chlorine, bromine, iodine, -CN, -OH, -NH2, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, Trifluoromethoxy, trifluoromethylthio, methoxy, methylamino, or dimethylamino.

22. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, B is selected from 23. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, B is selected from 24. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R 6 R 7 Selected independently from H.

25. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R 6 and R 7 Together they form a carbonyl group.

26. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from compounds represented by the following general formula or pharmaceutically acceptable salts thereof. in, R 1 R 2 R 3 R 4 R 5 R 6 R 7 ,X,Y,m,A,B,p,q and Part of it is as defined in claim 1.

27. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of compounds or pharmaceutically acceptable salts thereof.

28. A pharmaceutical composition comprising a compound as claimed in any one of claims 1-27 or a pharmaceutically acceptable salt thereof.

29. Use of the compound of any one of claims 1-27 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 28, in the preparation of a medicament for treating KRas G12C-related diseases.

30. The use as described in claim 29, characterized in that, The KRas G12C-related diseases mentioned are cancer.

31. The use as described in claim 30, characterized in that, The cancers mentioned include lung cancer and pancreatic cancer.

32. The use as described in claim 30, characterized in that, The cancer in question is lung cancer.

33. The use as described in claim 32, characterized in that, The lung cancer in question is non-small cell lung cancer.

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