Alpha, beta-unsaturated amide compound and application thereof

Abstract

The invention provides a compound with a structure as shown in a formula (I) or an enantiomer, a diastereoisomer, a racemate, a tautomer, a stereoisomer, a geometric isomer, a nitrogen oxide, a metabolite or pharmaceutically acceptable salt, a hydrate, an isotope labeled compound or a prodrug of the compound. The invention further discloses a pharmaceutical composition, a preparation method and application of the pharmaceutical composition.

Description

α,β-unsaturated amide compounds and their applications

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese patent applications No. 202310207938X filed on February 24, 2023 and No. 2023114617129 filed on November 3, 2023, and the entire contents of the above-mentioned Chinese patent applications are hereby cited as part of this application. Technical Field

[0003] The present invention relates to the field of medicine and relates to α,β-unsaturated amide compounds and their applications. Background Art

[0004] The Hippo pathway has emerged as a promising target for the treatment of hyperproliferative disorders and diseases, particularly cancer (SA Smith et al., J. Med. Chem. 2019, 62, 1291-1305; K C Lin et al., Annu. Rev. Cancer Biol. 2018, 2: 59-79; C.-L. Kim et al., Cells (2019), 8, 468; K F Harvey et al., Nature Reviews Cancer, Vol. 13, 246–257 (2013)). The Hippo signaling pathway regulates numerous biological processes, including cell proliferation, survival, differentiation, organ size, and tissue homeostasis. This pathway comprises a complex cascade of serine / threonine protein kinases, including serine threonine kinase 3 (STK3) and STK4. These kinases form a complex with the adaptor protein salvador homolog 1 (SAV1), which phosphorylates and activates the effector proteins LATS1 / 2. Upon activation, LATS1 / 2 binds to MOB kinase activator 1A / B (MOB1A / B) and inhibits the transcriptional cofactor yes-associated protein (YAP1) and the transcriptional coactivator with a PDZ binding motif (TAZ or WWTR1). When the Hippo pathway is "off," phosphorylated YAP / TAZ is retained in the cytoplasm and may undergo protein degradation. When the Hippo pathway is "on," unphosphorylated YAP / TAZ enters the nucleus and binds to the transcription factor TEA DNA-binding protein (TEAD1-4). Dysregulation of the Hippo pathway leads to increased YAP / TAZ activity, which is associated with tumorigenesis, hyperproliferation, cell invasion, metastasis, and chemoresistance.

[0005] The TEAD transcription factor family is the final effector of the Hippo pathway. It regulates the expression of target genes (Kras, Braf, Ctgf, Cyr6, Axl, Myc, etc.) by integrating and coordinating multiple signal transduction pathways (including Hippo, Wnt, TGFβ and EGFR), thereby mediating tumor growth, metastasis, and tissue homeostasis. Numerous clinical studies have found that TEAD is expressed at high levels in a variety of solid tumors, including prostate cancer, gastric cancer, breast cancer, germ cell tumors, head and neck squamous cell carcinoma, and renal cell carcinoma. Due to its high correlation with clinical pathological parameters of human malignancies, TEAD can be used as a prognostic biomarker for solid tumors. The Hippo pathway is an important anti-tumor target discovered in the past decade. Compared with targeting regulators upstream of the Hippo signaling pathway, inhibitors targeting TEAD-YAP may be more effective and direct in correcting the dysregulated Hippo signaling pathway, thereby achieving the goal of tumor treatment.

[0006] Therefore, cancers and other hyperproliferative disorders and diseases associated with Hippo pathway dysfunction can be prevented and / or treated by targeting YAP, TAZ or TEAD to inhibit the protein-protein interaction between YAP-TEAD, TAZ-TEAD or other functional proteins and TEAD, or the protein-protein interaction between other functional proteins and YAP / TAZ.

[0007] Summary of the Invention

[0008] To address one of the aforementioned technical problems in the prior art, the present application provides an α,β-unsaturated amide compound, composition thereof, preparation method, and application thereof. The compounds of the present application can prevent and / or treat cancers and other hyperproliferative conditions and diseases associated with Hippo pathway dysfunction by targeting YAP, TAZ, or TEAD, inhibiting protein-protein interactions between YAP-TEAD, TAZ-TEAD, or other functional proteins and TEAD, or protein-protein interactions between other functional proteins and YAP / TAZ.

[0009] In a first aspect of the present application, there is provided a compound having a structure as shown in Formula I, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof;

[0010] in,

[0011] Ring A is selected from the group consisting of: 5-6 membered heteroaryl, 5-6 membered heterocyclyl, 5-6 membered partially unsaturated heterocyclyl, and phenyl;

[0012] Ring B is selected from: 5-10 membered heteroaryl, C6-C 10 Aryl, C5-C6 cycloalkylphenyl, C5-C6 cycloalkyl 5-6 membered heteroaryl, 5-6 membered heterocyclylphenyl, 5-6 membered heterocyclyl 5-6 membered heteroaryl; preferably, ring B is selected from: 5 membered heteroarylphenyl, phenyl, 6 membered heteroaryl, C5-C6 cycloalkylphenyl;

[0013] Ring C is selected from the group consisting of: absence, C4-C6 cycloalkyl, 4-6 membered heterocyclyl, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclyl, 5-12 membered bridged cyclyl, 5-12 membered spirocyclyl, 5-12 membered fused cyclyl, 5-12 membered heterobridged cyclyl, 5-12 membered heterospirocyclyl, 5-12 membered heterofused cyclyl, 5-10 membered heteroaryl, C6-C 10 Aryl; when ring C is missing, L 2 With Y 2 Direct connection via key;

[0014] R 1 、R 2 、R 3 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxy, amino, C1-C6 alkyl, and C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally and independently substituted with 1-6 substituents selected from the group consisting of deuterium, halogen, amino, hydroxy, cyano, C1-C6 alkylamino, C1-C6 alkoxy, and O=;

[0015] Each R a R is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxy, amino, O=, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylamino; wherein the C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylamino are optionally substituted by 1-3 substituents independently selected from the group consisting of deuterium, halogen, amino, hydroxy, cyano, C1-C6 alkylamino, C1-C6 alkoxy, O=, -NHS(=O)2-C1-C4 alkyl, a 5-6-membered nitrogen- and / or oxygen-containing heterocyclic group (e.g., morpholinyl, piperazinyl, or N-methylpiperazinyl), wherein the 5-6-membered nitrogen- and / or oxygen-containing heterocyclic group is substituted by 1-5 substituents selected from the group consisting of deuterium, halogen, amino, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy; or two adjacent R aconnected to form a C4-C6 cycloalkyl, a 4-6 membered heterocyclyl, a C4-C6 partially unsaturated cycloalkyl, a 4-6 membered partially unsaturated heterocyclyl, a 5-6 membered heteroaryl, or a phenyl group; wherein the C4-C6 cycloalkyl, the 4-6 membered heterocyclyl, the C4-C6 partially unsaturated cycloalkyl, the 4-6 membered partially unsaturated heterocyclyl, the 5-6 membered heteroaryl, or the phenyl group are optionally and independently substituted with 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, or O=; preferably, each R a Independently selected from: hydrogen, deuterium, halogen, amino, cyano, O=, C1-C6 alkyl, C1-C6 alkoxy; wherein the C1-C6 alkyl, C1-C6 alkoxy is optionally substituted by 1-3 substituents selected from deuterium and halogen; or two adjacent R a connected to form a C4-C6 cycloalkyl, a 4-6 membered heterocyclic group, a C4-C6 partially unsaturated cycloalkyl, a 4-6 membered partially unsaturated heterocyclic group, a 5-6 membered heteroaryl, or a phenyl group;

[0016] Each R b Independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, SF5; wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino are optionally substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, O=; preferably, each R b Independently selected from: C1-C6 alkyl, C1-C6 alkoxy, SF5; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by 1-6 substituents selected from deuterium and halogen;

[0017] Each R c Independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, O=; preferably, each R c independently selected from: hydrogen, deuterium, halogen;

[0018] Y 1 Selected from: -C(=O)-, -S(=O)-, -S(=O)2-;

[0019] Y 2 Selected from: a bond, -N(R Y2 )-, -C1-C4 alkylene-; wherein R Y2 Selected from: hydrogen, C1-C4 alkyl;

[0020] L 1 Selected from: a bond, -N(R L1)-、-O-、-S-、-N(R L1 )-C1-C4 alkylene-, -C1-C4 alkylene-N(R L1 )-, -O-C1-C4 alkylene-, -C1-C4 alkylene-O-; wherein R L1 Selected from: hydrogen, C1-C4 alkyl;

[0021] L 2 Selected from: a bond, -N(R L2 )-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C1-C4 alkylene-, -C1-C4 alkylene-O-, -O-C1-C4 alkylene-, -C1-C4 alkylene-S-, -S-C1-C4 alkylene-, -C1-C4 alkylene-S(=O)-, -S(=O)-C1-C4 alkylene-, -C1-C4 alkylene-S(=O)2-, -S(=O)2-C1-C4 alkylene-; wherein R L2 Selected from: hydrogen, C1-C4 alkyl; preferably, L 2 Selected from: a bond, -C1-C4 alkylene-, -N(R L2 )-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-; where R L2 Selected from: hydrogen, C1-C4 alkyl;

[0022] On the A ring, L 2 In L 1 The ortho or meta position of

[0023] Indicates a triple bond or a double bond; when When it represents a triple bond, R 2 and R 3 does not exist;

[0024] n, m, and p are each independently selected from the group consisting of: 0, 1, 2, 3, 4, and 5.

[0025] According to some embodiments, L 1 Selected from: -N(R L1 )-、-O-、-S-、-N(R L1 )-C1-C4 alkylene-, -C1-C4 alkylene-N(R L1 )-, -O-C1-C4 alkylene-, -C1-C4 alkylene-O-; wherein R L1 Selected from: hydrogen, C1-C4 alkyl; and / or L 2 Selected from: -N(R L2)-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C1-C4 alkylene-, -C1-C4 alkylene-O-, -O-C1-C4 alkylene-, -C1-C4 alkylene-S-, -S-C1-C4 alkylene-, -C1-C4 alkylene-S(=O)-, -S(=O)-C1-C4 alkylene-, -C1-C4 alkylene-S(=O)2-, -S(=O)2-C1-C4 alkylene-, wherein R L2 Selected from: hydrogen, C1-C4 alkyl

[0026] According to some embodiments, L 1 Selected from: -N(R L1 )-、-O-;wherein R L1 Selected from: hydrogen, C1-C4 alkyl.

[0027] According to some embodiments, L 2 Selected from: -N(R L2 )-、-O-,where R L2 Selected from: hydrogen, C1-C4 alkyl.

[0028] According to some embodiments, L 1 and L 2 According to some embodiments, L 1 and L 2 Different from -N(R L1 )-or-O-.

[0029] According to some embodiments, Ring A has the following structure:

[0030] Among them, R a , p has the meaning given herein;

[0031] X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 are each independently selected from: CH, N;

[0032] E 1 、E 2 、E 3 、E 4 、E 5 、E 6 Each is independently selected from: CH2, NH, O, S.

[0033] According to some embodiments, Ring A has the following structure:

[0034] Among them, R a , p has the meaning given herein;

[0035] X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 are each independently selected from: CH, N;

[0036] E 1 、E 2 Each is independently selected from: CH2, NH, O, S.

[0037] According to some embodiments, Has the following structure:

[0038] Has the following structure:

[0039] Among them, R a , p has the meanings described herein.

[0040] According to some embodiments, Has the following structure:

[0041] Has the following structure:

[0042] Among them, R a , p has the meanings described herein.

[0043] According to some embodiments, Has the following structure: Among them, R a , p has the meanings described herein.

[0044] According to some embodiments, Has the following structure:

[0045] Has the following structure:

[0046] R aaEach is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0047] p1 is independently selected from the group consisting of: 0, 1, and 2.

[0048] According to some embodiments, Has the following structure:

[0049] R aa , p1 has the definition described herein;

[0050] According to some embodiments, yes R aa , p1 have the definitions described herein.

[0051] According to some embodiments, yes R aa , p1 have the definitions described herein.

[0052] According to some embodiments, yes R aa Has the definitions given herein.

[0053] According to some embodiments, R aa Each is independently selected from the group consisting of: hydrogen, deuterium, cyano, halogen, amino, O=, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkyl, halogenated C1-C4 alkoxy, C1-C4 alkylamino (preferably di-C1-C4 alkylamino), hydroxy-substituted C1-C4 alkoxy, and amino-substituted C1-C4 alkoxy.

[0054] According to some embodiments, R aa Each is independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, and dimethylamino.

[0055] According to some embodiments, R aaEach is independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, cyano, amino, O=, methyl, ethyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, and dimethylamino.

[0056] According to some embodiments, Has the following structure:

[0057] Missing (i.e. not present),

[0058] Among them, R c , n has the meaning given herein;

[0059] c1, c2 are each independently selected from: 0, 1;

[0060] c3, c4, c5, c6 are each independently selected from: 0, 1, 2;

[0061] c7, c8, c9, and c10 are each independently selected from: 1 and 2.

[0062] According to some embodiments, Has the following structure:

[0063] missing,

[0064] Among them, R c , n has the meaning given herein;

[0065] c1, c2 are each independently selected from: 0, 1;

[0066] c3, c4, c5, c6 are each independently selected from: 0, 1, 2;

[0067] c7, c8, c9, and c10 are each independently selected from: 1 and 2.

[0068] According to some embodiments, Has one of the following structures:

[0069] missing,

[0070] in,

[0071] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

[0072] n1 is independently selected from the group consisting of: 0, 1, and 2.

[0073] According to some embodiments, R cc are each independently selected from the group consisting of hydrogen, deuterium, fluorine, and methyl. cc According to some embodiments, R cc According to some embodiments, R cc According to some embodiments, R cc For fluorine.

[0074] According to some embodiments, R cc Each is independently selected from: hydrogen, deuterium, fluorine; n1 is independently selected from: 0, 1, 2.

[0075] According to some embodiments, Has one of the following structures:

[0076] Among them, R b , m have the definitions described herein.

[0077] According to some embodiments, Has the following structure: R b , m have the definitions described herein; preferably, each R b Independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl; preferably, m is 0, 1 or 2.

[0078] According to some embodiments, each R b Independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl.

[0079] According to some embodiments, m is 0, 1 or 2.

[0080] According to some embodiments, Has the following structure: R b , m have the definitions described herein; preferably, each R bIndependently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl; preferably, m is 0, 1 or 2.

[0081] According to some embodiments, Has the following structure: R b , m have the definitions described herein; preferably, each R b Independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl; preferably, m is 0, 1 or 2.

[0082] According to some embodiments, R 1 、R 2 、R 3 Each is independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy; wherein the C1-C4 alkyl and C1-C4 alkoxy are optionally and independently substituted by 1-6 deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkylamino, C1-C4 alkoxy, and O=.

[0083] According to some embodiments, each R a independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, amino, O=, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 alkylamino; wherein the C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 alkylamino are optionally and independently substituted with 1-3 deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkylamino, C1-C4 alkoxy, and O=; or two adjacent R a connected to form a C4-C6 cycloalkyl, a 4-6 membered heterocyclyl, a C4-C6 partially unsaturated cycloalkyl, a 4-6 membered partially unsaturated heterocyclyl, a 5-6 membered heteroaryl, or a phenyl group; wherein the C4-C6 cycloalkyl, the 4-6 membered heterocyclyl, the C4-C6 partially unsaturated cycloalkyl, the 4-6 membered partially unsaturated heterocyclyl, the 5-6 membered heteroaryl, or the phenyl group are optionally and independently substituted with 1-6 deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, or O=; preferably, each R a Independently selected from: hydrogen, deuterium, halogen, amino, O=, C1-C4 alkyl, C1-C4 alkoxy; wherein the C1-C4 alkyl, C1-C4 alkoxy is optionally substituted by 1-3 deuterium, halogen; or two adjacent R aThey are connected to form C4-C6 cycloalkyl, 4-6 membered heterocyclic group, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, 5-6 membered heteroaryl, and phenyl group.

[0084] According to some embodiments, R a It is a cyano group.

[0085] According to some embodiments, each R b Independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, SF5; wherein the C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino are optionally substituted by 1-6 deuterium, halogen, amino, hydroxyl, cyano, O=; preferably, each R b Independently selected from: C1-C4 alkyl, C1-C4 alkoxy, SF5; wherein the C1-C4 alkyl and C1-C4 alkoxy are optionally and independently substituted by 1-6 deuterium or halogen.

[0086] According to some embodiments, each R c Independently selected from the group consisting of: hydrogen, deuterium, halogen, C1-C4 alkyl; wherein the C1-C4 alkyl is optionally substituted by 1-6 deuterium, halogen, amino, hydroxyl, cyano, or O=.

[0087] According to some embodiments, Y 1 Selected from: -C(=O)-, -S(=O)-, -S(=O)2-.

[0088] According to some embodiments, Y 2 Selected from: a bond, -N(R Y2 )-, -C1-C2 alkylene-; wherein R Y2 Selected from: hydrogen, C1-C4 alkyl;

[0089] According to some embodiments, L 1 Selected from: a bond, -N(R L1 )-、-O-、-S-、-N(R L1 )-C1-C4 alkylene-, -C1-C4 alkylene-N(R L1 )-, -O-C1-C4 alkylene-, -C1-C4 alkylene-O-; wherein R L1 Selected from: hydrogen, C1-C4 alkyl.

[0090] According to some embodiments, L 2 Selected from: a bond, -N(R L2)-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C1-C4 alkylene-, -C1-C2 alkylene-O-, -O-C1-C2 alkylene-, -C1-C2 alkylene-S-, -S-C1-C2 alkylene-, -C1-C2 alkylene-S(=O)-, -S(=O)-C1-C2 alkylene-, -C1-C2 alkylene-S(=O)2-, -S(=O)2-C1-C2 alkylene-; wherein R L2 Selected from: hydrogen, C1-C4 alkyl.

[0091] According to some embodiments, R 1 、R 2 、R 3 Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxy, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, (CH3)2N-CH2-;

[0092] According to some embodiments, R a Independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, O=, methyl, ethyl, propyl, methoxy, ethoxy, propoxy; wherein the methyl, ethyl, propyl, methoxy, ethoxy, propoxy are optionally substituted by 1-3 deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=; or two adjacent R a connected to form a C4-C6 partially unsaturated cycloalkyl, a 4-6 membered partially unsaturated heterocyclic group, an imidazolyl, a furyl, a thiazolyl, a thienyl, a pyrazolyl, a pyridyl, a pyrimidinyl, or a phenyl group, wherein the C4-C6 partially unsaturated cycloalkyl, the 4-6 membered partially unsaturated heterocyclic group, an imidazolyl, a furyl, a thiazolyl, a thienyl, a pyrazolyl, a pyridyl, a pyrimidinyl, or a phenyl group are optionally and independently substituted with 1-6 deuterium, fluorine, chlorine, amino, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, or O=.

[0093] According to some embodiments, each R b Independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H.

[0094] According to some embodiments, R c Independently selected from: hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl; wherein the methyl, ethyl, propyl, isopropyl is optionally substituted by 1-6 deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=.

[0095] According to some embodiments, Y 1Selected from: -C(=O)-, -S(=O)-, -S(=O)2-.

[0096] According to some embodiments, Y 2 Selected from: a bond, -N(R Y2 )-, methylene, ethylene, propylene, isopropylene; wherein R Y2 Selected from: hydrogen, methyl, ethyl, propyl, isopropyl.

[0097] According to some embodiments, L 1 Selected from: a bond, -N(R L1 )-、-O-、-S-、-N(R L1 )-CH2-、-CH2-N(R L1 )-、-O-CH2-、-CH2-O-;wherein R L1 Selected from: hydrogen, methyl, ethyl, propyl, isopropyl.

[0098] According to some embodiments, L 2 Selected from: a bond, -N(R L2 )-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, methylene, ethylene, propylene, isopropylene, -CH2-O-, -O-CH2-, -CH2-S-, -S-CH2-, -CH2-S(=O)-, -S(=O)-CH2-, -CH2-S(=O)2-, -S(=O)2-CH2-, -CH2CH2-O-, -O-CH2CH2-, -CH2CH2-S-, -S-CH2CH2-, -CH2CH2-S(=O)-, -S(=O)-CH2CH2-, -CH2CH2-S(=O)2-, -S(=O)2-CH2CH2-; wherein R L2 Selected from: hydrogen, methyl, ethyl, propyl, isopropyl.

[0099] According to some embodiments, the compound of the present application has a structure represented by Formula II-1, II-2, II-3 or II-4, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof;

[0100] Among them, R 1 、R 2 、R 3 、Y 1 , L 2 , L 1 、R a ,p,ring B,R b ,m,RY2 has the definitions set out herein;

[0101] X 1 、X 2 、X 3 、X 4 、X 9 、X 10 are each independently selected from: CH, N;

[0102] E 1 Each independently selected from: CH2, NH, O, S;

[0103] M 1 are each independently selected from: CH, N;

[0104] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

[0105] n1 is independently selected from: 0, 1, 2;

[0106] c1, c2 are each independently selected from: 0, 1;

[0107] Preferably, R cc Each is independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, pentafluoroethyl;

[0108] Preferably, each R b Independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl;

[0109] Preferably, m is 0, 1 or 2.

[0110] According to some embodiments, the compounds of the present application have the structures shown in Formula III-1, III-2, III-3, or III-4, or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds, or prodrugs;

[0111] Among them, R 1 、R 2 、R 3 、Y 1 , L 2 , L 1 、R a ,p,R b , m has the meaning given herein;

[0112] X 1 、X 2 、X 3 、X 4 、X 9 、X 10 are each independently selected from: CH, N;

[0113] E 1 Each independently selected from: CH2, NH, O, S;

[0114] M 1 are each independently selected from: CH, N;

[0115] G 1 , G 2 are each independently selected from: CH, N;

[0116] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

[0117] n1 is independently selected from: 0, 1, 2;

[0118] c1, c2 are each independently selected from: 0, 1;

[0119] Preferably, p is 0 or 1;

[0120] Preferably, m is 0 or 1;

[0121] Preferably, each R b Independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl.

[0122] According to some embodiments, R cc Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, and pentafluoroethyl.

[0123] According to some embodiments, the compounds of the present application have the structures shown in Formula IV-1, IV-2, IV-3, IV-4, IV-5 or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs;

[0124] Among them, R 1 、R 2 、R 3 、R a 、R b、R cc 、X 1 、X 2 、X 3 、X 4 、X 9 、X 10 、E 1 , L 1 , L 2 ,p,m,n1,c1,c2,G 1 , G 2 As defined herein.

[0125] Preferably, G 1 and G 2 All are CH, or one of them is N;

[0126] Preferably, R cc Each is independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, pentafluoroethyl;

[0127] Preferably, each R b Independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl.

[0128] According to some embodiments, Selected from the following structures:

[0129] in,

[0130] R aa Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0131] p1 is independently selected from the group consisting of: 0, 1, and 2.

[0132] According to some embodiments, Selected from the following structures:

[0133] Among them, R aaEach is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0134] p1 is independently selected from the group consisting of: 0, 1, and 2.

[0135] According to some embodiments, Selected from the following structures:

[0136] According to some embodiments, Selected from the following structures:

[0137] Preferably, R aa Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, and dimethylamino;

[0138] Preferably, R aa Each is independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, amino, cyano, O=, methyl, ethyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; preferably, p1 is selected from the group consisting of: 0, 1, 2.

[0139] According to some embodiments, Selected from the following structures:

[0140] According to some embodiments, Selected from the following structures:

[0141] Among them, R aa , p1 have the definitions described herein.

[0142] According to some embodiments, R aaEach is independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, and dimethylamino.

[0143] According to some embodiments, R aa Each is independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, amino, cyano, O=, methyl, ethyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, and dimethylamino.

[0144] According to some embodiments, the compounds described herein have any of the following structural formulas:

[0145] Among them, R 1 、R 2 、R 3 、R b , L 1 , L 2 , p, m have the definitions given herein;

[0146] n1 is 0, 1, or 2;

[0147] R a Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0148] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

[0149] c1, c2 are each independently selected from: 0, 1;

[0150] Preferably, p is 0 or 1;

[0151] Preferably, m is 0 or 1;

[0152] Preferably, Ra Each is independently selected from the group consisting of hydrogen, deuterium, cyano, halogen, amino, O=, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkyl, halogenated C1-C4 alkoxy, hydroxy-substituted C1-C4 alkoxy, and amino-substituted C1-C4 alkoxy;

[0153] Preferably, wherein R a Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, and dimethylamino;

[0154] Preferably, R cc Each is independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, pentafluoroethyl;

[0155] Preferably, R b Each is independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl.

[0156] According to some embodiments, the compounds described herein have any of the following structural formulas:

[0157] In formulae (V-1) and (V-2), each symbol has the same meaning as described herein.

[0158] According to some embodiments, the compounds described herein have any of the following structural formulas:

[0159] Among them, R a 、R b , L 1 , L 2 , p have the definitions described herein.

[0160] According to some embodiments, the compounds described herein have any of the following structural formulas:

[0161] In structural formulas VI-1 to VI-39,

[0162] R 1 、R 2 、R 3 、R b , L 1 , L 2 , p, m have the definitions given herein;

[0163] n1 is 0, 1, or 2;

[0164] R a Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0165] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

[0166] c1, c2 are each independently selected from: 0, 1;

[0167] Preferably, m is 1;

[0168] Preferably, p is 0 or 1;

[0169] Preferably, R a Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino, more preferably, R a is selected from fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; more preferably, R a Selected from methyl, cyano;

[0170] Preferably, R cc Each is independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, pentafluoroethyl;

[0171] Preferably, R b trifluoromethyl, trifluoromethoxy, pentafluorinated sulfur, -CF2Cl, -OCF2Cl;

[0172] Preferably, R 1 is hydrogen;

[0173] Preferably, R 2 is hydrogen;

[0174] Preferably, R 3 is hydrogen or fluorine;

[0175] Preferably, c1 is 0, 1, c2 is 0, 1;

[0176] Preferably, L 1 is a single bond, NH or O;

[0177] Preferably, L 2 is a single bond, NH or O.

[0178] According to some embodiments, the compounds described herein have any of the following structural formulas:

[0179] In VI-40 and VI-41,

[0180] R 1 、R 2 、R 3 、R a 、R b , L 1 , L 2 , p has the meaning given herein;

[0181] n1 is 0, 1 or 2; R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

[0182] c1 and c2 are each independently selected from: 0, 1.

[0183] According to some embodiments, the compounds described herein have any of the following structural formulas:

[0184] In VI-42 to VI-48, R 1 、R 2 、R 3 、R a 、R b , L 1 , L 2 has the definitions set out herein;

[0185] n1 is 0, 1, or 2;

[0186] R a Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0187] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

[0188] c1 and c2 are each independently selected from: 0, 1.

[0189] Preferably, in VI-40 to VI-48, R a Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino, more preferably, R a is selected from fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; more preferably, R a Selected from methyl and cyano.

[0190] Preferably, in VI-40 to VI-48, R b It is trifluoromethyl, trifluoromethoxy, pentafluorinated sulfur, -CF2Cl, -OCF2Cl.

[0191] Preferably, in VI-40 to VI-48, R 1 For hydrogen.

[0192] Preferably, in VI-40 to VI-48, R 2 For hydrogen.

[0193] Preferably, in VI-40 to VI-48, R 3 is hydrogen or fluorine.

[0194] Preferably, in VI-40 to VI-48, c1 is 0 or 1, and c2 is 0 or 1.

[0195] Preferably, in VI-40 to VI-48, L 1 is a single bond, NH or O.

[0196] Preferably, in VI-40 to VI-48, L 2 is a single bond, NH or O.

[0197] According to some embodiments, the compound described herein has the following structural formula VII:

[0198] In Formula VII,

[0199] R 1 、R 2 、R 3 、R a 、R b , m, p1 have the definitions described herein;

[0200] Rcc are each independently selected from the group consisting of: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

[0201] n1 is 0, 1, or 2;

[0202] c1, c2 are each independently selected from: 0, 1;

[0203] Ring A is a 5-10 membered heteroaryl group; preferably pyridine or pyrazine;

[0204] Ring B is a 5-6 membered heteroaryl group; preferably benzene or pyridine;

[0205] L 1 Selected from: -N(R L1 )-、-O-、-S-、-N(R L1 )-C1-C4 alkylene-, -C1-C4 alkylene-N(R L1 )-, -O-C1-C4 alkylene-, -C1-C4 alkylene-O-; wherein R L1 Selected from: hydrogen, C1-C4 alkyl;

[0206] L 2 Selected from: -N(R L2)-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C1-C4 alkylene-, -C1-C4 alkylene-O-, -O-C1-C4 alkylene-, -C1-C4 alkylene-S-, -S-C1-C4 alkylene-, -C1-C4 alkylene-S(=O)-, -S(=O)-C1-C4 alkylene-, -C1-C4 alkylene-S(=O)2-, -S(=O)2-C1-C4 alkylene-; wherein R L2 Selected from: hydrogen, C1-C4 alkyl; preferably, L 2 Selected from: -N(R L2 )-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-; where R L2 Selected from: hydrogen, C1-C4 alkyl;

[0207] According to some embodiments, the compounds described herein are not

[0208] According to some embodiments, the compounds described herein are not

[0209] According to some embodiments, the compounds described herein are not

[0210] According to some embodiments, the compounds described herein are not:

[0211] According to some embodiments, the compounds described herein have the following structural formula:

[0212] R 1 、R 2 、R 3 、R b , L 1 , L 2 , m has the meaning given herein;

[0213] n1 is 0, 1, or 2;

[0214] R aa Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0215] R ccEach is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

[0216] c1 and c2 are each independently 0, 1 or 2;

[0217] Preferably, R aa Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino, more preferably, R aa is selected from fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; more preferably, R aa Selected from methyl, cyano;

[0218] Or two adjacent R aa connected to form a C4-C6 cycloalkyl, a 4-6 membered heterocyclic group, a C4-C6 partially unsaturated cycloalkyl, a 4-6 membered partially unsaturated heterocyclic group, a 5-6 membered heteroaryl, or a phenyl group;

[0219] Preferably, m is 1;

[0220] Preferably, R b trifluoromethyl, trifluoromethoxy, pentafluoride sulfur, CF2Cl;

[0221] Preferably, R 1 is hydrogen;

[0222] Preferably, R 2 is hydrogen;

[0223] Preferably, R 3 is hydrogen or fluorine;

[0224] Preferably, c1 is 0 or 1, c2 is 0, 1 or 2;

[0225] Preferably, L 1 is NH or O;

[0226] Preferably, L 2 is NH or O.

[0227] According to some embodiments, the compounds described herein have a structure shown in Formula W1, W2, W3 or W4:

[0228] In formulas W1, W2, W3, and W4,

[0229] R 1 、R 2 、R 3 、R b , m has the meaning given herein;

[0230] R aa Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0231] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

[0232] n is 0, 1, or 2;

[0233] c1 and c2 are each independently 0, 1 or 2;

[0234] Preferably, R aa Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino, more preferably, R aa is selected from fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; more preferably, R aa Each independently selected from methyl, cyano;

[0235] Or two adjacent R aaconnected to form a C4-C6 cycloalkyl, a 4-6 membered heterocyclic group, a C4-C6 partially unsaturated cycloalkyl, a 4-6 membered partially unsaturated heterocyclic group, a 5-6 membered heteroaryl, or a phenyl group;

[0236] Preferably, R cc Each is independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, pentafluoroethyl;

[0237] Preferably, m is 1;

[0238] Preferably, R b trifluoromethyl, trifluoromethoxy, pentafluorinated sulfur, -CF2Cl, -OCF2Cl;

[0239] Preferably, R 1 is hydrogen;

[0240] Preferably, R 2 is hydrogen;

[0241] Preferably, R 3 is hydrogen or fluorine;

[0242] Preferably, c1 is 0 or 1, and c2 is 0, 1 or 2.

[0243] According to some embodiments, the compounds described herein have a structure represented by Formula W1.1, W1.2, W1.3 or W1.4.

[0244] In formula W1.1, R 1 、R 2 、R 3 、R b , m has the meaning given herein;

[0245] n1 is 0, 1, or 2;

[0246] R a1 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0247] R a2 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0248] Or, Ra1 and R a2 Connected to form 5-6 membered heteroaryl and phenyl groups;

[0249] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; preferably, R cc Each is independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, pentafluoroethyl;

[0250] c1 and c2 are each independently 0, 1 or 2;

[0251] Preferably, R a1 Independently selected from: deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino;

[0252] Preferably, R a2 are independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, and dimethylamino; preferably, R a2 independently selected from: hydrogen;

[0253] Preferably, m is 1;

[0254] Preferably, R b trifluoromethyl, trifluoromethoxy, pentafluorinated sulfur, -CF2Cl, -OCF2Cl;

[0255] Preferably, R b For para substitution;

[0256] Preferably, R 1 is hydrogen;

[0257] Preferably, R 2 is hydrogen;

[0258] Preferably, R 3 is hydrogen or fluorine;

[0259] Preferably, c1 is 0 or 1, and c2 is 0, 1 or 2.

[0260] In formula W1.2, R 1 、R 2 、R 3 、R b , m has the meaning given herein;

[0261] n1 is 0, 1, or 2;

[0262] R a1 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0263] R a2 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0264] Or, R a1 and R a2 Connected to form 5-6 membered heteroaryl and phenyl groups;

[0265] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; preferably, R cc Each is independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, pentafluoroethyl;

[0266] c1 and c2 are each independently 0, 1 or 2;

[0267] Preferably, R a1 are independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, and dimethylamino;

[0268] Preferably, R a2are independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, and dimethylamino; preferably, R a2 independently selected from: hydrogen;

[0269] Preferably, m is 1;

[0270] Preferably, R b trifluoromethyl, trifluoromethoxy, pentafluorinated sulfur, -CF2Cl, -OCF2Cl;

[0271] Preferably, R b For para substitution;

[0272] Preferably, R 1 is hydrogen;

[0273] Preferably, R 2 is hydrogen;

[0274] Preferably, R 3 is hydrogen or fluorine;

[0275] Preferably, c1 is 0 or 1, and c2 is 0, 1 or 2.

[0276] In formula W1.3, R 1 、R 2 、R 3 、R b , m has the meaning given herein;

[0277] n1 is 0, 1, or 2;

[0278] R aa Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0279] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; preferably, R cc Each is independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, pentafluoroethyl;

[0280] c1 and c2 are each independently 0, 1 or 2;

[0281] Preferably, R aa are independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, and dimethylamino;

[0282] Preferably, R b is trifluoromethyl, trifluoromethoxy, pentafluorinated sulfur, -CF2Cl;

[0283] Preferably, R b For para substitution;

[0284] Preferably, c1 is 0 or 1, c2 is 0, 1 or 2;

[0285] In formula W1.4, R 1 、R 2 、R 3 、R b , m has the meaning given herein;

[0286] n1 is 0, 1, or 2;

[0287] R aa Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0288] R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; preferably, R cc Each is independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, pentafluoroethyl;

[0289] c1 and c2 are each independently 0, 1 or 2;

[0290] Preferably, R aaare independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, and dimethylamino;

[0291] Preferably, R b is trifluoromethyl, trifluoromethoxy, pentafluorinated sulfur, -CF2Cl;

[0292] Preferably, R b For para substitution;

[0293] Preferably, c1 is 0 or 1, and c2 is 0, 1 or 2.

[0294] According to some embodiments, the compounds described herein have the following formula a, formula b, formula c, formula d, formula e, or formula f:

[0295] In formula a, formula b, formula c, formula d, formula e, formula f, and formula g, R a 、R b 、R c , L 1 , L 2 has the definitions set out herein;

[0296] Preferably, R a R is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxy, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, hydroxy-substituted methoxy, hydroxy-substituted ethoxy, hydroxy-substituted propoxy, amino-substituted ethoxy, amino-substituted propoxy, methylamino, dimethylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy; more preferably R a is selected from hydrogen, deuterium, fluorine, amino, cyano, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, -OCH2CH2-OH, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, and dimethylamino;

[0297] Preferably, R b trifluoromethyl, trifluoromethoxy, pentafluoride sulfur, -CF2Cl, -OCF2Cl;

[0298] Preferably, R cis hydrogen, deuterium, halogen, C1-C6 alkyl, or halogenated C1-C6 alkyl;

[0299] Preferably, L 1 and L 2 are not a bond, and are not O or NH at the same time; more preferably L 1 and L 2 One of them is O and the other is NH.

[0300] According to some embodiments, the compound of the present application has the following structural formula or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs; the compound has the following structural formula;

[0301] In the second aspect of the present application, a pharmaceutical composition is provided, which comprises the compound described in the present application or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug; and a pharmaceutically acceptable carrier or diluent.

[0302] In the third aspect of the present application, provided is the use of the compound described herein or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug or the pharmaceutical composition described herein for the preparation of a medicament for treating cancer; preferably, the cancer is associated with TEAD overexpression and / or the cancer is associated with increased TEAD activity.

[0303] In the fourth aspect of the present application, provided is the use of the compound described herein or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug or the pharmaceutical composition described herein for preparing a drug for inhibiting cancer progression.

[0304] In the fifth aspect of the present application, provided is the use of the compound described herein or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or the pharmaceutical composition described herein for the preparation of a medicament for treating a disease or condition associated with increased TEAD expression.

[0305] In a sixth aspect of the present application, provided is the use of the compound described herein or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or the pharmaceutical composition described herein for the preparation of a medicament for treating a disease or condition associated with TEAD activity; wherein, inhibiting TEAD activity will benefit the disease or condition.

[0306] In a seventh aspect of the present application, provided is a use of the compound described herein or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug, or the pharmaceutical composition described herein for preparing a medicament for treating a disease or condition associated with the Hippo pathway; wherein inhibition of the Hippo pathway is beneficial to the disease or condition.

[0307] In some embodiments, the disease or disorder is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.

[0308] In some embodiments, the cancer is one in which YAP is localized to the nucleus of the cancer cells.

[0309] In some embodiments, the TEAD overexpression, increased TEAD expression or increased TEAD activity is TEAD1 overexpression, increased TEAD1 expression or increased TEAD1 activity; and / or

[0310] The TEAD overexpression, increased TEAD expression or increased TEAD activity is TEAD2 overexpression, increased TEAD2 expression or increased TEAD2 activity; and / or

[0311] The TEAD overexpression, increased TEAD expression or increased TEAD activity is TEAD3 overexpression, increased TEAD3 expression or increased TEAD3 activity; and / or

[0312] The TEAD overexpression, increased TEAD expression or increased TEAD activity is TEAD4 overexpression, increased TEAD4 expression or increased TEAD4 activity.

[0313] In the eighth aspect of the present application, provided is the use of the compound described herein or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, hydrate, isotope-labeled compound or prodrug, or the pharmaceutical composition described herein for the preparation of a drug having the activity of binding to TEAD and blocking the interaction between YAP / TEAD.

[0314] In the ninth aspect of the present application, there is provided a use of the compound described herein or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug or the pharmaceutical composition described herein for preparing a medicament for treating a disease or condition; the disease or condition is a disease or condition associated with a protein that interacts with TEAD; preferably, the disease or condition associated with a protein that interacts with TEAD includes but is not limited to cancer, metabolic disease, inflammatory disease, or neurodegenerative disease; more preferably, the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelioma, melanoma Preferably, the cancer is selected from brain cancer, esophageal cancer, kidney cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, gastric cancer, breast cancer or prostate cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma and undifferentiated carcinoma; further preferably, the brain cancer includes but is not limited to glioma; head and neck cancer includes but is not limited to head and neck squamous cell carcinoma; lung cancer includes but is not limited to lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung cancer, large cell lung cancer, small cell lung cancer, papillary adenocarcinoma or non-small cell lung cancer; gastric cancer includes but is not limited to gastric adenocarcinoma; breast cancer includes but is not limited to ductal breast cancer, breast cancer or HR+ breast cancer; prostate cancer includes but is not limited to prostate adenocarcinoma, prostate squamous cell carcinoma or prostate adenosquamous carcinoma.

[0315] In the tenth aspect of the present application, there is provided a method for inhibiting the interaction between TEAD and YAP; or preventing and / or treating related diseases mediated by the nuclear transcription factor TEAD; or for non-therapeutic reversal of tumor cell resistance to anti-tumor drugs; or for reversing tumor cell resistance to anti-tumor drugs, comprising contacting the cell or administering to the subject the compound described herein or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug or the pharmaceutical composition described herein;

[0316] According to some embodiments, the subject is a mammal.

[0317] In other embodiments, the subject is human.

[0318] In the eleventh aspect of the present application, provided is a compound described herein or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug or the pharmaceutical composition described herein in inhibiting the interaction between TEAD and YAP; or preventing and / or treating related diseases mediated by the nuclear transcription factor TEAD; or for non-therapeutic reversal of tumor cell resistance to anti-tumor drugs; or for reversing tumor cell resistance to anti-tumor drugs.

[0319] In the twelfth aspect of the present application, there is provided a method for treating cancer in a patient, comprising administering to the patient a compound described herein or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug or a pharmaceutical composition described herein. Preferably, the cancer is associated with TEAD overexpression and / or the cancer is associated with increased TEAD activity.

[0320] In the thirteenth aspect of the present application, there is provided a method for inhibiting the progression of cancer in a patient, comprising administering to the patient a compound described herein or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug or a pharmaceutical composition described herein. Preferably, the cancer is associated with TEAD overexpression and / or the cancer is associated with increased TEAD activity.

[0321] In the thirteenth aspect of the present application, a method for treating a patient suffering from a disease or condition associated with increased TEAD expression is provided, comprising administering to the patient a compound described herein or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or a pharmaceutical composition described herein.

[0322] In the fourteenth aspect of the present application, a method for treating a patient suffering from a disease or condition associated with increased TEAD activity is provided, comprising utilizing the compound described herein or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or the pharmaceutical composition described herein.

[0323] In the fifteenth aspect of the present application, a method for treating a disease or condition is provided, comprising administering to the patient a compound described herein or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug or the pharmaceutical composition described herein.

[0324] In the sixteenth aspect of the present application, a method for treating a disease or condition is provided, wherein inhibition of the Hippo pathway will be beneficial to the disease or condition, comprising administering to the patient a compound described herein or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or the pharmaceutical composition described herein.

[0325] In the seventeenth aspect of the present application, a method for treating a disease or condition, wherein inhibition of the Hippo pathway will be beneficial to the disease or condition, is provided, comprising administering to the patient a compound described herein or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, or the pharmaceutical composition described herein.

[0326] According to some embodiments, the disease or disorder is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.

[0327] According to some embodiments, the cancer is one in which YAP is localized to the nucleus of the cancer cells.

[0328] According to some embodiments, the TEAD overexpression, increased TEAD expression or increased TEAD activity is TEAD1 overexpression, increased TEAD1 expression or increased TEAD1 activity; and / or

[0329] The TEAD overexpression, increased TEAD expression or increased TEAD activity is TEAD2 overexpression, increased TEAD2 expression or increased TEAD2 activity; and / or

[0330] The TEAD overexpression, increased TEAD expression or increased TEAD activity is TEAD3 overexpression, increased TEAD3 expression or increased TEAD3 activity; and / or

[0331] The TEAD overexpression, increased TEAD expression or increased TEAD activity is TEAD4 overexpression, increased TEAD4 expression or increased TEAD4 activity.

[0332] On the other hand, the present application relates to methods for preparing, separating and purifying compounds represented by formula (I), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3), and (IV-4).

[0333] Any embodiment of any aspect of the present application can be combined with other embodiments, as long as they do not conflict. In addition, in any embodiment of any aspect of the present application, any technical feature can be applied to the technical feature in other embodiments, as long as they do not conflict.

[0334] The foregoing description only summarizes certain aspects of the present application, but is not intended to be limiting. These and other aspects will be described in more detail and fully below. All references in this specification are incorporated herein by reference in their entirety. BRIEF DESCRIPTION OF THE DRAWINGS

[0335] FIG1 shows the inhibitory effect of compound 17 in Test Example 3 on YAP downstream target genes in H226 cells.

[0336] FIG2 shows the inhibitory effect of compound 47 in Test Example 3 on YAP downstream target genes in H226 cells.

[0337] FIG3 shows the inhibitory effect of compound 109 in Test Example 3 on YAP downstream target genes in H226 cells.

[0338] Figure 4 shows the inhibitory effects of compound 178 and control compound VT103 in Test Example 3 on YAP downstream target genes in H226 cells, wherein the inhibitory effect of compound 178 is significantly better than that of the control compound VT103.

[0339] Figure 5 shows the inhibitory effects of compound 183 and control compound VT103 in Test Example 3 on YAP downstream target genes in H226 cells, wherein the inhibitory effect of compound 183 is significantly better than that of the control compound VT103.

[0340] Figure 6 shows the inhibitory effects of Compound 200 and the control compound VT103 in Test Example 3 on YAP downstream target genes in H226 cells, wherein the inhibitory effect of Compound 200 is significantly better than that of the control compound VT103.

[0341] FIG7 shows the inhibitory effects of compound 207 and control compound VT103 in Test Example 3 on YAP downstream target genes in H226 cells, wherein the inhibitory effect of compound 207 is significantly better than that of the control compound VT103.

[0342] FIG8 shows the inhibitory effects of compound 209 and control compound VT103 in Test Example 3 on YAP downstream target genes in H226 cells, wherein the inhibitory effect of compound 209 is significantly better than that of the control compound VT103.

[0343] FIG9 shows the inhibitory effects of compound 203 and control compound VT103 in Test Example 3 on YAP downstream target genes in MSTO-211H cells. The inhibitory effect of compound 203 is better than that of the control compound VT103.

[0344] Figure 10 shows the inhibitory effect of compound 183 in Test Example 5 on YAP downstream target genes after short-term administration in mice with MSTO-211H cell subcutaneous transplantation tumor models.

[0345] FIG11 shows the inhibitory effect of compound 229 in Test Example 5 on YAP downstream target genes after short-term administration in mice with subcutaneous transplantation of MSTO-211H cells into tumor models.

[0346] FIG12 shows the inhibitory effect of compound 249 in Test Example 5 on YAP downstream target genes after short-term administration in mice with subcutaneous transplantation of MSTO-211H cells into tumor models.

[0347] FIG13 shows the tumor inhibition effect of Compound 121 in Test Example 6 at a dose of 30 mg / kg in mice during long-term efficacy testing, with no change in the body weight of the mice.

[0348] FIG14 shows the inhibitory effects of compound 122 and control compound VT103 in Test Example 7 on TEAD palmitoylation at the same dosage concentration. DETAILED DESCRIPTION

[0349] To make the purpose, technical solutions, and advantages of the present application more clearly understood, the present application is further described in detail below in conjunction with the embodiments. The specific embodiments described herein are intended only to explain the present application and are not intended to constitute any limitation thereto. In addition, in the following description, descriptions of known structures and technologies are omitted to avoid unnecessary confusion about the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0350] definition

[0351] Some embodiments of the present application are now described in detail, and examples thereof are illustrated by the accompanying structural formula and chemical formula. The application is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the present application as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present application. The application is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials are different from or contradictory to the present application (including but not limited to defined terms, term applications, described technology, etc.), the present application shall prevail.

[0352] It should be further appreciated that certain features of the present application, which for clarity are described in the context of multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present application, which for brevity are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0353] Unless otherwise specified, all technical terms used in this application have the same meaning as commonly understood by those skilled in the art to which this application belongs. All patents and publications involved in this application are incorporated herein by reference in their entirety.

[0354] Unless otherwise indicated, the following definitions used herein shall apply. For the purposes of this application, chemical elements are referred to in accordance with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry may be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0355] Unless otherwise specified or clearly contradicted by context, the articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more." Thus, as used herein, these articles refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., more than one component may be contemplated for use or use in implementing the described embodiments.

[0356] The term "subject" refers to an animal. Typically, the animal is a mammal. A subject also refers, for example, to a primate (e.g., human, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0357] The term "patient" refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0358] The term "comprising" is an open expression, that is, including the contents specified in the application, but not excluding other contents.

[0359] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0360] The term "enantiomers" refers to two non-superimposable isomers of a compound that are mirror images of each other.

[0361] The term "diastereoisomer" refers to stereoisomers that have two or more chiral neutrals and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0362] The terms "racemate," "racemate," or "racemic mixture" refer to an equimolar mixture of two enantiomers devoid of optical activity.

[0363] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions performed by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions performed by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present application are within the scope of the present application.

[0364] The term "stereoisomers" refers to compounds that have identical chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like.

[0365] The term "geometric isomers" is also called "cis-trans isomers", which are isomers caused by the inability of double bonds (including olefin double bonds, C=N double bonds and N=N double bonds) or single bonds of ring carbon atoms to rotate freely.

[0366] The stereochemical definitions and conventions used herein generally follow those of SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are the symbols used to designate the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0367] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[0368] Depending on the choice of starting materials and process, the compounds of the present invention may exist as one of the possible isomers or a mixture thereof, such as a racemate or a mixture of diastereomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0369] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0370] Any racemate of the resulting final product or intermediate can be resolved into its optical antipodes by methods familiar to those skilled in the art using known methods, such as by separation of its diastereomeric salts obtained. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0371] The term "nitrogen oxide" refers to when a compound contains several amine functional groups, where one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. Available oxidants such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) can be used to treat the corresponding amine to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), where, for example, an amine compound is reacted with meta-chloroperbenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0372] The term "metabolite" refers to a product resulting from the in vivo metabolism of a specific compound or salt thereof. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays such as those described herein. Such products can be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, this application encompasses metabolites of a compound, including metabolites produced by contacting a compound of this application with a mammal for a period of time.

[0373] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal to be treated therewith. Preferably, "pharmaceutically acceptable" as used herein means approved by federal regulatory agencies or national governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeia for use in animals, particularly humans.

[0374] The term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the compounds of the present application. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable salts include salts formed by compounds with acids, including but not limited to inorganic acid salts (such as hydrochlorides, hydrobromides, phosphates, sulfates, nitrates, perchlorates) and organic acid salts (such as acetates, glycolates, oxalates, maleates, tartrates, citrates, succinates, fumarates, mandelates, sulfosalicylate), or these salts can be obtained by other methods described in books and literature, such as ion exchange methods. Further pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts also include salts formed from compounds and bases, including but not limited to inorganic base salts (such as alkali metal salts, alkaline earth metal salts, ammonium salts and N+(C1-4 alkyl)4 salts), alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. The present application also contemplates quaternary ammonium salts formed by compounds of any group comprising N. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8 sulfonates and aromatic sulfonates. Organic base salts (e.g., primary, secondary, and tertiary amine salts, substituted amine salts (including naturally occurring substituted amines, cyclic amines, basic ion exchange resins)), certain organic amine salts include, for example, isopropylamine salts, benzathine salts, cholinate salts, diethanolamine salts, diethylamine salts, lysine salts, meglumine salts, piperazine salts, and tromethamine salts.

[0375] The term "solvate" refers to an association complex formed by one or more solvent molecules and the compound of the present application. The solvent can be water, acetic acid, ethyl ether, isopropyl ether, petroleum ether, ethyl formate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, methyl tert-butyl ether (MTBE), n-heptane, a mixed solvent of ethanol and water in a volume ratio of 10:90 to 90:10, acetone, methyl isobutyl ketone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, ethylene glycol, n-butanol, tert-butanol , sec-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, n-hexane, cyclohexane, n-heptane, a mixed solvent of n-heptane and ethyl acetate in a volume ratio of 1:5 to 5:1, isopropyl alcohol, methanol, butanone, l-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, n-propanol, isopropyl alcohol, 2-acetone, 4-methyl-2-pentanone, pyridine, tetrahydrofuran, methyl ethyl ketone, toluene, xylene, cumene or a mixture thereof, etc.

[0376] The term "hydrate" refers to an association formed by one or more water molecules and a compound of the present application.

[0377] The term "ester" is represented by the formula -OC(O)R or -C(O)OR, wherein R can be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein.

[0378] The term "isotopically labeled compound" means a compound of the present invention that is labeled with an isotope. It is identical to those compounds described herein except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Exemplary isotopes that may also be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0379] Compounds of the present invention that contain the aforementioned isotopes and / or other isotope-labeled compounds of the present invention and pharmaceutically acceptable salts of the compounds are all within the scope of the present invention. Isotope-labeled compounds of the present invention, such as radioisotopes, such as 3 H and 14C is incorporated into the compounds of the present invention for drug and / or substrate tissue distribution analysis. Due to ease of preparation and detection, tritiated, i.e., 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred. In addition, isotopes with larger mass numbers, such as deuterium, 2 H substitutions may offer therapeutic advantages of greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances.

[0380] The term "prodrug" as used in this application refers to a compound that is converted into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compound of this application can be an ester. In existing applications, esters that can be used as prodrugs include phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in this application contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds that are obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, please refer to the following literature: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series; Roche et al., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270, and Hecker et al., Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328-2345.

[0381] The term "comprising" is an open expression, that is, including the contents specified in the application, but not excluding other contents.

[0382] The term "partially unsaturated" is used as a prefix to a ring to indicate that it contains one or more degrees of unsaturation but is not aromatic.

[0383] The term "heteroatom" refers to O, S, N, P, and Si, including any oxidation state of S, N, and P; primary, secondary, and tertiary amines and quaternary ammonium salts; or the hydrogen on the nitrogen atom in the heterocyclic ring is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl), or NRT (such as NRT in N-substituted pyrrolidinyl, RT is a substituent on N). Among the compounds involved in this application, when containing multiple heteroatoms, the compounds composed thereof comply with the covalent rules and composition rules of organic compounds, that is, the compounds containing multiple heteroatoms should exclude compounds that do not comply with the covalent rules and composition rules of organic compounds.

[0384] The term "heterocyclyl" or "heterocycle" refers to a monovalent or multivalent saturated monocyclic ring system containing carbon atoms and heteroatoms as the ring atoms. The heteroatoms have the meanings as described herein. In one embodiment, a heterocyclyl group contains 3-6 ring atoms, such as a 3-6 membered heterocyclyl (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give groups such as SO, SO2, PO, PO2); in one embodiment, a heterocyclyl group contains 4-6 ring atoms, such as a 4-6 membered heterocyclyl; in one embodiment, a heterocyclyl group contains 5-6 ring atoms, such as a 5-6 membered heterocyclyl. Partially unsaturated heterocyclyl groups contain one or more degrees of unsaturation, but none of the aromatic rings are present.

[0385] The term "cycloalkyl" refers to a monovalent or multivalent saturated monocyclic ring in which the ring atoms are carbon atoms. In one embodiment, a cycloalkyl group contains 3-6 ring carbon atoms, such as a C3-C6 cycloalkyl group, which may also be represented as a 3-6 membered cycloalkyl group. In one embodiment, a cycloalkyl group contains 4-6 ring carbon atoms, such as a C4-C6 cycloalkyl group, which may also be represented as a 4-6 membered cycloalkyl group. Partially unsaturated cycloalkyl groups contain one or more degrees of unsaturation, but may not have any aromatic rings. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and the like.

[0386] The term "heteroaryl" refers to a monocyclic, bicyclic and tricyclic aromatic system containing 5 to 10 ring atoms. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5 to 10 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-10 membered heteroaryl group; the heteroaryl group is a heteroaryl group consisting of 5 to 8 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-8 membered heteroaryl group; in some embodiments, the heteroaryl group is a heteroaryl group consisting of 5 to 7 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-7 membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-6-atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-6-membered heteroaryl group; In some embodiments, the heteroaryl group is a 5-atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-membered heteroaryl group; In some embodiments, the heteroaryl group is a 6-atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 6-membered heteroaryl group.

[0387] The term "aryl" refers to a monocyclic or bicyclic aromatic carbon ring system containing 6 to 10 ring atoms, representing a 6-10 membered aromatic group. 10 Aryl refers to an aromatic group having 6 to 10 carbon atoms. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring". Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

[0388] The term "missing" means that the group in question is replaced by a bond. The term "hydrogen" means 1 H; "deuterium" refers to 2 H. The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). The term "amino" refers to -NH2. The term "hydroxy" refers to -OH. The term "cyano" refers to -CN. The term "nitro" refers to -NO2. The term "O=" refers to oxo, i.e., when the substituent is O=", the O is attached to the substituted group through a double bond.

[0389] The term "alkyl" or "alkyl group" refers to a saturated, straight-chain or branched, monovalent hydrocarbon group containing carbon atoms. In one embodiment, the alkyl group contains 1-6 carbon atoms, i.e., a C1-C6 alkyl group; in another embodiment, the alkyl group contains 1-4 carbon atoms, i.e., a C1-C4 alkyl group; in yet another embodiment, the alkyl group contains 1-3 carbon atoms, i.e., a C1-C3 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0390] The term "alkylene" refers to a saturated, straight-chain or branched, divalent hydrocarbon group containing carbon atoms. In one embodiment, the alkylene group contains 1-6 carbon atoms, i.e., C1-C6 alkylene; in another embodiment, the alkylene group contains 1-4 carbon atoms, i.e., C1-C4 alkylene; in yet another embodiment, the alkylene group contains 1-3 carbon atoms, i.e., C1-C3 alkylene. Examples of alkylene groups include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, and the like.

[0391] The term "alkoxy" refers to an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. In one embodiment, the alkoxy group contains 1-6 carbon atoms, i.e., C1-C6 alkoxy; in another embodiment, the alkoxy group contains 1-4 carbon atoms, i.e., C1-C4 alkoxy; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms, i.e., C1-C3 alkoxy.

[0392] The term "alkylamino" refers to an alkyl group attached to the remainder of a molecule via a nitrogen atom, wherein the alkyl group has the meaning as described herein. In one embodiment, one hydrogen atom on the amino group is replaced by an alkyl group. In one embodiment, both hydrogen atom on the amino group are replaced by alkyl groups. In one embodiment, the alkylamino group contains 1-6 carbon atoms, i.e., a C1-C6 alkylamino group; in another embodiment, the alkylamino group contains 1-4 carbon atoms, i.e., a C1-C4 alkylamino group; in yet another embodiment, the alkylamino group contains 1-3 carbon atoms, i.e., a C1-C3 alkylamino group.

[0393] The term "cycloalkylphenyl" refers to a cycloalkyl group and a phenyl group sharing two ring atoms to form a fused ring system. A C5-C6 cycloalkylphenyl group refers to a fused ring system formed by a C5-C6 cycloalkyl group and a phenyl group. The cycloalkyl group and the phenyl group have the definitions described herein.

[0394] The term "cycloalkylheteroaryl" means a cycloalkyl group and a heteroaryl group that share two ring atoms, forming a fused ring system. A C5-C6 cycloalkylheteroaryl group means that the fused ring system is formed by a C5-C6 cycloalkyl group and a 5-6-membered heteroaryl group. The cycloalkyl and heteroaryl groups have the definitions given herein.

[0395] The term "heterocyclylphenyl" refers to a heterocyclyl group and a phenyl group sharing two ring atoms to form a fused ring system. 5-6 membered heterocyclylphenyl refers to a fused ring system formed by a 5-6 membered heterocyclyl group and a phenyl group. The heterocyclyl group and the phenyl group have the definitions described herein.

[0396] The term "heterocyclyl and heteroaryl" means that a heterocyclyl and a heteroaryl group share two ring atoms, forming a fused ring system. A 5-6 membered heterocyclyl and 5-6 membered heteroaryl group means that the fused ring system is formed by a 5-6 membered heterocyclyl and a 5-6 membered heteroaryl group. The heterocyclyl and heteroaryl groups have the definitions given herein.

[0397] The term "spirocyclyl" refers to a saturated or unsaturated, non-aromatic bicyclic ring system containing carbon atoms, wherein the two rings share one ring atom. A 5-12 membered spirocyclyl group means that the spirocyclyl group has 5 to 12 ring atoms.

[0398] The terms "heterospirocyclyl" and "spiroheterocyclyl" are used interchangeably to indicate that the spirocyclyl group contains one or more heteroatoms in the ring atoms. A 5-12 membered heterospirocyclyl group indicates that the heterospirocyclyl group contains 5-12 ring atoms. An azaspirocyclyl group indicates that the heteroatom is a nitrogen atom. The heteroatoms have the meanings as described herein.

[0399] The term "fused cyclic group" refers to a saturated or unsaturated, non-aromatic bicyclic ring system containing carbon atoms, wherein the two rings in the system share two ring atoms. A 5-12 membered fused cyclic group means that the fused cyclic group has 5-12 ring atoms.

[0400] The terms "heterofused cyclyl" and "fused heterocyclyl" are used interchangeably to indicate that the fused cyclyl contains one or more heteroatoms in the ring atoms. A 5-12 membered heterofused cyclyl means that the heterofused cyclyl has 5-12 ring atoms. An aza-fused cyclyl means that the heteroatom is a nitrogen atom. The heteroatoms have the meanings as described herein.

[0401] The term "bridged ring group" refers to a saturated or unsaturated, non-aromatic bicyclic ring system containing carbon atoms, wherein the two rings in the system share 3 or more ring atoms. A 5-12 membered bridged ring group means that the bridged ring group has 5-12 ring atoms.

[0402] The terms "heterobridged cyclyl" and "bridged heterocyclyl" are used interchangeably to indicate that the bridged cyclyl contains one or more heteroatoms. A 5-12 membered heterobridged cyclyl indicates that the heterobridged cyclyl has 5-12 ring atoms. An aza-bridged cyclyl indicates that the heteroatom is a nitrogen atom. The heteroatoms have the meanings as described herein.

[0403] As described herein, the ring system formed by the substituent R connected to the central ring by a bond (as shown below) represents the substituent R being substituted at any substitutable or any reasonable position on ring A or ring B. For example, formula f represents any possible substituted position on ring A or ring B, as shown in formulas f1-f8:

[0404] As described in this application, the substituents are connected to the central ring by a bond to form a ring system, such as (R x )n , representing n substituents R x Substitution can be made at any substitutable position on the ring. For example, formula a represents a benzene ring which can be substituted by n R x replace.

[0405] The term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is a substituent described above or a substituent appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position, i.e., each substitution is independent of each other. It will be understood by those skilled in the art that the combinations of substituents contemplated herein are those that are stable or chemically feasible.

[0406] Description of the compounds of the present application

[0407] The present application provides a compound for preparing an inhibitor of the interaction between TEAD and YAP; or for preparing a compound for preventing and / or treating diseases mediated by the nuclear transcription factor TEAD; or for non-therapeutic reversal of tumor cell resistance to anti-tumor drugs; or for preparing a drug for reversing tumor cell resistance to anti-tumor drugs. The preparation method of the compound described in the present application is simple and easy, the process is stable, and it is suitable for industrial production. Therefore, the compound provided in the present application has better drugability than currently available similar compounds.

[0408] Specifically, the present application provides a compound having the structure shown in Formula I or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs,

[0409] Among them, ring A, ring B, ring C, R 1 、R 2 、R 3 、R a 、R b 、R c 、Y 1 、Y 2 , L 1 , L 2 、 n, m, and p have the definitions given herein.

[0410] According to some embodiments, ring A is selected from the group consisting of: 5-6 membered heteroaryl, 5-6 membered heterocyclyl, 5-6 membered partially unsaturated heterocyclyl, and phenyl.

[0411] According to some embodiments, Ring A has the following structure:

[0412] Among them, R a ,p,X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、E 1 、E 2 、E 3 、E 4 、E 5 、E 6 Has the definitions given herein.

[0413] According to some embodiments, Ring A has the following structure:

[0414] Among them, R a ,p,X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、E 1 Has the definitions given herein.

[0415] According to some embodiments, X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 are each independently selected from: CH, N.

[0416] According to some embodiments, E 1 、E 2 、E 3 、E 4 、E 5 、E 6 Each is independently selected from: CH2, NH, O, S.

[0417] According to some embodiments, Has the following structure:

[0418] Among them, R a , p has the meanings described herein.

[0419] According to some embodiments, Has the following structure:

[0420] Among them, R a , p has the meanings described herein.

[0421] According to some embodiments, Has the following structure:

[0422] Among them, R aa , p1 have the definitions described herein.

[0423] According to some embodiments, R aa Each independently selected from: R aa Each is independently selected from the group consisting of: hydrogen, deuterium, halogen, amino, hydroxyl, cyano, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy.

[0424] According to some embodiments, R aa Each is independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, and dimethylamino.

[0425] According to some embodiments, p1 is independently selected from: 0, 1, 2.

[0426] According to some embodiments, ring B is selected from: 5-10 membered heteroaryl, C6-C 10 phenyl, C5-C6 cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl.

[0427] According to some embodiments, Has the following structure:

[0428] Among them, R b , m have the definitions described herein.

[0429] According to some embodiments, ring C is selected from the group consisting of: absence, C4-C6 cycloalkyl, 4-6 membered heterocyclyl, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclyl, 5-12 membered bridged cyclyl, 5-12 membered spirocyclyl, 5-12 membered fused cyclyl, 5-12 membered heterobridged cyclyl, 5-12 membered heterospirocyclyl, 5-12 membered heterofused cyclyl, 5-10 membered heteroaryl, C6-C 10 Aryl.

[0430] According to some embodiments, Has the following structure:

[0431] missing,

[0432] Among them, R c , n, c1, c2, c3, c4, c5, c6, c7, c8, c9, c10 have the definitions described herein.

[0433] According to some embodiments, Has the following structure:

[0434] missing,

[0435] Among them, R c , n, c1, c2, c3, c4, c5, c6, c7, c8, c9, c10 have the definitions described herein.

[0436] According to some embodiments, c1 and c2 are each independently selected from: 0, 1.

[0437] According to some embodiments, c3, c4, c5, and c6 are each independently selected from: 0, 1, and 2.

[0438] According to some embodiments, c7, c8, c9, and c10 are each independently selected from: 1, 2.

[0439] According to some embodiments, Has the following structure:

[0440] missing,

[0441] Among them, R cc , n1 have the definitions described herein.

[0442] According to some embodiments, R cc Each is independently selected from the group consisting of: hydrogen, deuterium, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl.

[0443] According to some embodiments, R cc Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, and pentafluoroethyl.

[0444] According to some embodiments, n1 is independently selected from: 0, 1, 2.

[0445] According to some embodiments, R 1 、R 2 、R 3 Each is independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally and independently substituted by 1-6 deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkylamino, C1-C6 alkoxy, and O=.

[0446] According to some embodiments, R 1 、R 2 、R 3 Each is independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy; wherein the C1-C4 alkyl and C1-C4 alkoxy are optionally and independently substituted by 1-6 deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkylamino, C1-C4 alkoxy, and O=.

[0447] According to some embodiments, R 1 、R 2 、R 3 Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxy, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, and (CH3)2N-CH2-.

[0448] According to some embodiments, each R a independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, amino, O=, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylamino; wherein the C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylamino are optionally and independently substituted with 1-3 deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkylamino, C1-C6 alkoxy, and O=; or two adjacent R aconnected to form a C4-C6 cycloalkyl, a 4-6 membered heterocyclyl, a C4-C6 partially unsaturated cycloalkyl, a 4-6 membered partially unsaturated heterocyclyl, a 5-6 membered heteroaryl, or a phenyl group; wherein the C4-C6 cycloalkyl, the 4-6 membered heterocyclyl, the C4-C6 partially unsaturated cycloalkyl, the 4-6 membered partially unsaturated heterocyclyl, the 5-6 membered heteroaryl, or the phenyl group are optionally and independently substituted with 1-6 deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkylamino, C1-C6 alkoxy, or O=.

[0449] According to some embodiments, each R a independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, amino, O=, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 alkylamino; wherein the C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 alkylamino are optionally and independently substituted with 1-3 deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkylamino, C1-C4 alkoxy, and O=; or two adjacent R a connected to form a C4-C6 cycloalkyl, a 4-6 membered heterocyclyl, a C4-C6 partially unsaturated cycloalkyl, a 4-6 membered partially unsaturated heterocyclyl, a 5-6 membered heteroaryl, or a phenyl group; wherein the C4-C6 cycloalkyl, the 4-6 membered heterocyclyl, the C4-C6 partially unsaturated cycloalkyl, the 4-6 membered partially unsaturated heterocyclyl, the 5-6 membered heteroaryl, or the phenyl group are optionally and independently substituted with 1-6 deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, or O=.

[0450] According to some embodiments, each R b Independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino; wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino are optionally and independently substituted by 1-6 deuterium, halogen, amino, hydroxyl, cyano, O=.

[0451] According to some embodiments, each R b Independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino; wherein the C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino are optionally and independently substituted by 1-6 deuterium, halogen, amino, hydroxyl, cyano, O=.

[0452] According to some embodiments, each R b Independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl.

[0453] According to some embodiments, each R c Independently selected from the group consisting of hydrogen, deuterium, halogen, and C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by 1-6 deuterium, halogen, amino, hydroxyl, cyano, and O=.

[0454] According to some embodiments, each R c Independently selected from the group consisting of hydrogen, deuterium, halogen, and C1-C4 alkyl; wherein the C1-C4 alkyl is optionally substituted by 1-6 deuterium, halogen, amino, hydroxyl, cyano, and O=.

[0455] According to some embodiments, R c Independently selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl; the methyl, ethyl, propyl, isopropyl mentioned above are optionally substituted by 1-6 deuterium, fluorine, chlorine, amino, hydroxyl, cyano, and O=.

[0456] According to some embodiments, Y 1 Selected from: -C(=O)-, -S(=O)-, -S(=O)2-.

[0457] According to some embodiments, Y 2 Selected from: a bond, -N(R Y2 )-, -C1-C4 alkylene-; wherein R Y2 Selected from: hydrogen, C1-C4 alkyl.

[0458] According to some embodiments, Y 2 Selected from: a bond, -N(R Y2 )-, methylene, ethylene, propylene, isopropylene; wherein R Y2 Selected from: hydrogen, methyl, ethyl, propyl, isopropyl.

[0459] According to some embodiments, L 1 Selected from: a bond, -N(R L1 )-、-O-、-S-;wherein R L1 Selected from: hydrogen, C1-C4 alkyl.

[0460] According to some embodiments, L 1 Selected from: a bond, -N(R L1 )-、-O-、-S-;wherein R L1 Selected from: hydrogen, methyl, ethyl, propyl, isopropyl.

[0461] According to some embodiments, L 2 Selected from: a bond, -N(R L2)-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C1-C4 alkylene-, -C1-C4 alkylene-O-, -O-C1-C4 alkylene-, -C1-C4 alkylene-S-, -S-C1-C4 alkylene-, -C1-C4 alkylene-S(=O)-, -S(=O)-C1-C4 alkylene-, -C1-C4 alkylene-S(=O)2-, -S(=O)2-C1-C4 alkylene-; wherein R L2 Selected from: hydrogen, C1-C4 alkyl.

[0462] According to some embodiments, L 2 Selected from: a bond, -N(R L2 )-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C1-C4 alkylene-, -C1-C2 alkylene-O-, -O-C1-C2 alkylene-, -C1-C2 alkylene-S-, -S-C1-C2 alkylene-, -C1-C2 alkylene-S(=O)-, -S(=O)-C1-C2 alkylene-, -C1-C2 alkylene-S(=O)2-, -S(=O)2-C1-C2 alkylene-; wherein R L2 Selected from: hydrogen, C1-C4 alkyl.

[0463] According to some embodiments, L 2 Selected from: a bond, -N(R L2 )-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, methylene, ethylene, propylene, isopropylene, -CH2-O-, -O-CH2-, -CH2-S-, -S-CH2-, -CH2-S(=O)-, -S(=O)-CH2-, -CH2-S(=O)2-, -S(=O)2-CH2-, -CH2CH2-O-, -O-CH2CH2-, -CH2CH2-S-, -S-CH2CH2-, -CH2CH2-S(=O)-, -S(=O)-CH2CH2-, -CH2CH2-S(=O)2-, -S(=O)2-CH2CH2-; wherein R L2 Selected from: hydrogen, methyl, ethyl, propyl, isopropyl.

[0464] On the A ring, L 2 In L 1 ortho or meta position.

[0465] According to some embodiments, Indicates a triple or double bond.

[0466] According to some embodiments, when When it represents a triple bond, R2 and R 3 Does not exist.

[0467] According to some embodiments, n, m, and p are each independently selected from: 0, 1, 2, 3, 4, and 5.

[0468] According to some embodiments, the compound of the present application has a structure represented by Formula II-1, II-2, II-3 or II-4, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof;

[0469] Among them, R 1 、R 2 、R 3 、Y 1 , L 2 , L 1 、R a ,p,ring B,R b ,m,R Y2 、X 1 、X 2 、X 3 、X 4 、X 9 、X 10 、E 1 、M 1 、R cc , n1, c1, c2 have the definitions described in this article.

[0470] According to some embodiments, X 1 、X 2 、X 3 、X 4 、X 9 、X 10 are each independently selected from: CH, N.

[0471] According to some embodiments, E 1 Each is independently selected from: CH2, NH, O, S.

[0472] According to some embodiments, M 1 are each independently selected from: CH, N.

[0473] According to some embodiments, R cc Each is independently selected from the group consisting of: hydrogen, deuterium, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl.

[0474] According to some embodiments, R ccEach is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, and pentafluoroethyl.

[0475] According to some embodiments, n1 is independently selected from: 0, 1, 2.

[0476] According to some embodiments, c1 and c2 are each independently selected from: 0, 1.

[0477] According to some embodiments, the compounds of the present application have the structures shown in Formula III-1, III-2, III-3, or III-4, or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds, or prodrugs;

[0478] Among them, R 1 、R 2 、R 3 、Y 1 , L 2 , L 1 、R a ,p,R b ,m,X 1 、X 2 、X 3 、X 4 、X 9 、X 10 、E 1 、M 1 , G 1 , G 2 、R cc , n1, c1, c2 have the definitions described in this article.

[0479] According to some embodiments, the compounds of the present application have the structures shown in Formula IV-1, IV-2, IV-3, IV-4 or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs;

[0480] Among them, R 1 、R 2 、R 3 , L 2 , L 1 、R a ,p,R b ,m,X 1 、X 2 、X 3 、X4 、X 9 、X 10 、E 1 、R cc , n1, c1, c2 have the definitions described herein; G 1 and G 2 All are CH, or one of them is N.

[0481] According to some embodiments, X 1 、X 2 、X 3 、X 4 、X 9 、X 10 are each independently selected from: CH, N.

[0482] According to some embodiments, E 1 Each is independently selected from: CH2, NH, O, S.

[0483] According to some embodiments, M 1 are each independently selected from: CH, N.

[0484] According to some embodiments, G 1 , G 2 are each independently selected from: CH, N.

[0485] According to some embodiments, R cc Each is independently selected from the group consisting of: hydrogen, deuterium, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl.

[0486] According to some embodiments, R cc Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, and pentafluoroethyl.

[0487] According to some embodiments, n1 is independently selected from: 0, 1, 2.

[0488] According to some embodiments, c1 and c2 are each independently selected from: 0, 1.

[0489] According to some embodiments, Selected from the following structures:

[0490] Among them, R aa 、p 1 Has the definitions given herein.

[0491] According to some embodiments, Selected from the following structures:

[0492] Among them, R aa 、p1 Has the definitions given herein.

[0493] According to some embodiments, R aa Each is independently selected from the group consisting of: hydrogen, deuterium, halogen, amino, hydroxyl, cyano, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, and halogenated C1-C6 alkylamino.

[0494] According to some embodiments, R aa Each is independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl.

[0495] According to some embodiments, p1 is independently selected from: 0, 1, 2.

[0496] Pharmaceutical compositions and methods of administration

[0497] The present application relates to a pharmaceutical composition comprising the compound described herein or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, hydrate, isotope-labeled compound or prodrug; and a pharmaceutically acceptable carrier or diluent.

[0498] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and diluents. Other components may also include excipients such as excipients, binders, and fillers, as well as additional therapeutic agents such as antidiabetic agents, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, or lipid-lowering agents. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0499] The term "carrier" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (e.g., antibacterial agent, antifungal agent), isotonic agent, salt, drug stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, colorant, or combination thereof, which are known to those skilled in the art (e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except in the case where any conventional carrier is incompatible with the active ingredient, its use in treatment or pharmaceutical composition is encompassed.

[0500] The application also relates to a pharmaceutical composition comprising a compound provided herein as an active ingredient or a pharmaceutically acceptable salt thereof, which can be particularly useful in treating neoplastic diseases, particularly cancer, as described herein. The composition can be formulated for non-parenteral administration, such as nasal, oral, rectal, pulmonary, vaginal, sublingual, topical, transdermal, eye, or particularly for oral administration, such as in the form of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules and soft capsules or hydroxypropylmethylcellulose (HPMC) capsules (applicably coated), orally disintegrating tablets, oral solutions, lipid emulsions or suspensions, or for parenteral administration, such as intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural administration to mammals, particularly humans, such as in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles. These compositions can include a single active ingredient, or preferably, together with a pharmaceutically acceptable carrier.

[0501] The compound provided herein or its pharmaceutically acceptable salt can be processed with pharmaceutically inert inorganic or organic excipients to produce oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules or HPMC capsules or orally disintegrating tablets. Fillers such as lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch or its derivatives, binders such as cellulose, starch, polyvinyl pyrrolidone or its derivatives, glidants such as talc, stearic acid or its salts, flow agents such as fumed silica, can be used as such excipients for the preparation and manufacture of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules or HPMC capsules or orally disintegrating tablets. Suitable excipients for soft capsules are such as vegetable oils, waxes, fats, semisolid and liquid polyols etc.

[0502] Suitable excipients for the production of oral solutions, lipid emulsions or suspensions are, for example, water, alcohols, polyols, sucrose, invert sugar, glucose and the like.

[0503] Suitable excipients for parenteral formulations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants and the like.

[0504] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical preparations may also contain other therapeutically valuable substances.

[0505] Dosage can vary within wide limits and, of course, will be determined in each particular case according to individual requirements. In general, in the case of oral administration, a daily dosage of about 1 to 1000 mg of a compound of formula (I) per person should be appropriate, although the above lower or upper limits may be exceeded where necessary.

[0506] The compounds provided herein can also be used in combination with one or more other pharmacologically active compounds that are also effective against the same disease, preferably using different modes of action, or reducing or preventing possible undesirable side effects of the compounds provided herein. The combination partners can be administered simultaneously in such treatments, for example, by incorporating them into a single pharmaceutical formulation, or sequentially by administering two or more different dosage forms (each containing one or more than one combination partner).

[0507] The compounds provided herein as described above, or pharmaceutically acceptable salts thereof, are particularly useful for treating neoplastic diseases, such as cancer, particularly cancer, sarcoma, leukemia, myeloma and lymphoma, and cancer of the brain and spinal cord, for example, when administered in a therapeutically effective amount. According to some embodiments, the cancer treated by the compounds of the present application is mediated by regulating the interaction between YAP / TAZ and TEAD. According to some embodiments, the compounds of the present application can treat cancer by regulating the interaction between YAP / TAZ and TEAD. According to some embodiments, the compounds of the present application can inhibit the interaction between YAP / TAZ and TEAD. According to some embodiments, the cancer is a solid tumor. According to some embodiments, the cancer is a hematological malignancy. In some cases, the solid tumor is a sarcoma or cancer. According to some embodiments, the solid tumor is a sarcoma. In some cases, the solid tumor is a cancer.

[0508] Examples of some proliferative disorders and diseases include, but are not limited to, epithelial tumors, squamous cell tumors, basal cell tumors, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, adnexal and skin appendage tumors, mucoepidermoid tumors, cystic tumors, mucinous and serous tumors, ductal, lobular and medullary tumors, acinar cell tumors, complex epithelial tumors, specialized glandular tumors, paragangliomas and glomus tumors, nevi and melanomas, soft tissue tumors and sarcomas, fibromatous tumors, myxomatous tumors, lipomatous tumors, myxomatous tumors, complex mixed stromal tumors, fibroepithelial tumors, synovial-like tumors, mesothelial tumors, germ cell tumors, trophoblastic tumors, mesonephromas, hemangiomas, lymphangiomas, bony and chondromatous tumors, giant cell tumors, miscellaneous bone tumors, odontogenic tumors, gliomas, neuroepitheliomatous and neuroendocrine tumors, meningiomas, schwannomas, granular cell tumors and alveolar soft tissue sarcomas, Hodgkin and non-Hodgkin lymphomas, B-cell lymphomas, T-cell lymphomas, hairy cell lymphomas, Burkitt's lymphoma and other lymphoreticular tumors, plasma cell tumors, mast cell tumors, immunoproliferative disorders, leukemias, miscellaneous myeloproliferative disorders, lymphoproliferative disorders, and myelodysplastic syndromes.

[0509] Examples of cancers of affected organs and parts of the body include, but are not limited to, breast, cervix, ovary, colon, rectum (including colon and rectum, i.e., colorectal cancer), lung (including small cell lung cancer, non-small cell lung cancer, large cell lung cancer, and mesothelioma), endocrine system, bone, adrenal gland, thymus, liver, stomach (gastric cancer), intestine, pancreas, bone marrow, hematological malignancies (such as lymphoma, leukemia, myeloma, or lymphoid malignancies), bladder, urinary tract, kidney, skin, thyroid, brain, head, neck, prostate, and testicle. Preferably, the cancer is selected from the group consisting of breast cancer, prostate cancer, cervical cancer, ovarian cancer, stomach cancer, colorectal cancer, pancreatic cancer, liver cancer, brain cancer, neuroendocrine cancer, lung cancer, kidney cancer, bladder cancer, mesothelioma, hematological malignancies, melanoma, and sarcoma.

[0510] The term "treatment" or "treating" as used herein in the context of treating a disease or disorder generally relates to treatment and therapy for humans or animals (e.g., in veterinary applications), wherein some desired therapeutic effects are obtained, e.g., suppressing the progression of a disease or disorder, and including reducing the rate of progression, stopping the rate of progression, alleviating the symptoms of a disease or disorder, improving a disease or disorder, and curing a disease or disorder. Also included are treatments (i.e., preventions) as preventive measures. For example, a patient who has not yet developed the disease or disorder but is at risk of developing the disease or disorder is covered by the term "treatment." For example, treatment includes prevention of cancer, reducing the incidence of cancer, alleviating cancer symptoms, etc.

[0511] As used herein, the term "therapeutically effective amount" relates to an amount of a compound, or a material, composition or dosage form containing a compound, that is effective, commensurate with a reasonable benefit / risk ratio, to produce some desired therapeutic effect when administered according to the desired treatment regimen.

[0512] Synthesis method

[0513] The compound provided herein can be synthesized by the method given below, by the method given in the experimental section below, or by similar methods. The schemes described herein are not intended to be an exhaustive list of methods for preparing the compound provided herein; On the contrary, other techniques known to skilled chemists can also be used for compound synthesis.

[0514] The structures of the compounds were determined by nuclear magnetic resonance ( 1 H-NMR, 13 C-NMR or / and 19 F-NMR). 1 H-NMR, 13 C-NMR, 19 F-NMR chemical shifts (δ) are given in parts per million (ppm). 1 H-NMR, 13 C-NMR, 19 F-NMR measurements were performed using a Bruker Ultrashield-400 NMR spectrometer and a Bruker Avance III HD 600 NMR spectrometer. The solvents used were deuterated chloroform (CDCl₃), deuterated methanol (CD₃OD or MeOH-d₄), or deuterated dimethyl sulfoxide (DMSO-d₆). TMS (0 ppm) or chloroform (7.25 ppm) was used as the reference standard. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), and brs (broadened singlet). Coupling constants, J, are expressed in Hertz (Hz).

[0515] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260 mass spectrometer. HPLC analysis was performed using an Agilent 1100 high pressure chromatograph (Microsorb 5micron C18 100 x 3.0 mm column).

[0516] TLC silica gel plates used were Qingdao GF254 silica gel plates, with a diameter of 0.15-0.20 mm for TLC and 0.4-0.5 mm for preparative thin layer chromatography. Column chromatography generally used Qingdao 200-300 mesh silica gel as a carrier.

[0517] The starting materials in the examples of this application are all known and commercially available, or can be synthesized using or according to literature data reported in the art.

[0518] Unless otherwise specified, all reactions in this application were carried out under the protection of dry inert gas (such as nitrogen or argon) with continuous magnetic stirring, and the reaction temperatures were all degrees Celsius.

[0519] It will be appreciated by those skilled in the art of organic synthesis that optimal reaction conditions may vary with the specific reactant or solvent used, but these conditions may be determined by conventional optimization procedures. In some cases, the order of the following reaction scheme and / or reaction steps may be changed to promote reaction or to avoid forming unwanted by-products. In addition, the functional groups present in each position of the molecule must be compatible with the proposed reagent and reaction. This limitation of substituents compatible with reaction conditions is apparent to those skilled in the art, and then alternative methods must be used. In addition, in some reactions mentioned herein, it may be necessary or desirable to protect any sensitive group in the compound, and it is assumed that such a blocking group (PG) is in the appropriate position if necessary. Conventional blocking groups can be used according to standard practices well known in the art (for explanation, see Greene TW, Wuts PGM, Protective Groups in Organic Synthesis [blocking group in organic synthesis], 5th edition, publisher: John Wiley & Sons (John Wiley & Sons), 2014). Blocking groups can be removed at any convenient stage in the synthesis using conventional techniques well known in the art, or blocking groups can be removed in subsequent reaction steps or aftertreatment.

[0520] The following abbreviations are used throughout this application:

[0521] Ir[dF(CF3)ppy]2(dtbbpy)PF6: Bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridinium][2-2'-bi(4-tert-butylpyridinium)]iridium bis(hexafluorophosphate)

[0522] tBuONa: sodium tert-butoxide; Na2SO4: sodium sulfate; KOAc: potassium acetate; K3PO4: potassium phosphate; CuI: cuprous iodide; Na2CO3: sodium carbonate; Cs2CO3: cesium carbonate; DMF: N,N-dimethylformamide; DIPEA, DIEA: N,N-diisopropylethylamine; THF: tetrahydrofuran; DCM: dichloromethane; EA: ethyl acetate; FA: formic acid; TFA: trifluoroacetic acid; 1,4-Dioxane / H2O: a mixed solution of 1,4-dioxane and water; Boc: tert-butyloxycarbonyl; HCl / 1,4-Dioxane: a solution of HCl in 1,4-dioxane; HCl / EA: a solution of HCl in ethyl acetate; MeCN: acetonitrile; DMSO: Dimethyl sulfoxide; DME: ethylene glycol dimethyl ether; H2O: water; μmol: micromole; μM: micromoles per liter; mg: milligram; μL: microliter; cm: centimeter; ℃: degrees Celsius; TLC: thin-layer chromatography; LCMS: liquid chromatography-mass spectrometry; HPLC: high-performance liquid chromatography; pre-HPLC: preparative liquid chromatography; W: watt; iPrMgCl: isopropylmagnesium chloride; DAST: diethylaminosulfur trifluoride; N2: nitrogen; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; Pd(dppf)Cl2: (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Brettphos Pd G3: methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II); BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; (Bpin)2: diboronic acid pinacol ester; PPh3: triphenylphosphine; Xantphos: 4,5-bisdiphenylphosphine-9,9-dimethylxanthene; DIAD: diisopropyl azodicarboxylate; m-CPBA: m-chloroperoxybenzoic acid

[0523] General synthetic methods

[0524] Typical synthetic steps for preparing the compounds disclosed in this application are shown in the following synthetic schemes.

[0525] Option 1:

[0526] Among them, c1, c2, R cc 、n1、R a ,p,X 1 、X 2 、X 3 、X 4 , G 1 , G 2 、R b,m,R 1 、R 2 、R 3 Has the definitions given herein.

[0527] W1-1 reacts with W1-2 under certain conditions to generate W1-3, such as in the presence of bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium bis(hexafluorophosphate), tris(trimethylsilyl)silane, [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridyl]dichloronickel(II), and sodium carbonate, under light conditions, in a certain solvent, such as ethylene glycol dimethyl ether, to generate W1-3; W1-3 reacts with W1-4 under certain conditions to generate W1-5, such as in the presence of sodium tert-butoxide, heating to a certain temperature, such as 120°C, in a certain solvent, such as DMF, to generate W1-5; W1-5 removes the Boc group under certain conditions to generate W1-6, such as in the presence of TFA or HCl, in a certain solvent, such as 1,4- Dioxane, acetonitrile, etc. react to generate W1-6; W1-6 and W1-7 react to generate W1-8 under certain conditions, such as in the presence of N,N-diisopropylethylamine, in a certain solvent, such as tetrahydrofuran, at a certain temperature, such as 0°C, to generate W1-8.

[0528] Option 2

[0529] Among them, c1, c2, R cc 、n1、R a ,p,X 1 、X 2 、X 3 、X 4 , G 1 , G 2 、R b ,m,R 1 、R 2 、R 3 Has the definitions given herein.

[0530] W2-1 reacts with W2-2 under certain conditions to generate W2-3, such as in the presence of NaH in a certain solvent, such as DMF, to obtain W2-3; W2-3 reacts with W2-4 under certain conditions to generate W2-5, such as in the presence of BrettPhos Pd G3 and sodium tert-butoxide, heated to a certain temperature, such as 100°C, in a certain solvent, such as toluene, to obtain W2-5; W2-5 removes the Boc group under certain conditions to generate W2-6, such as in the presence of TFA or HCl in a certain solvent, such as 1,4-dioxane, acetonitrile, etc., to obtain W2-6; W2-6 reacts with W2-7 under certain conditions to generate W2-8, such as in the presence of HATU and N,N-diisopropylethylamine in a certain solvent, such as DMF, at a certain temperature, such as 25°C, to obtain W2-8.

[0531] The following examples are provided to assist in understanding the present application. However, it should be understood that these examples are intended to illustrate the present application only and are not intended to limit the present application in any way. The actual scope of protection of the present application is set forth in the claims. It should be understood that any modifications and variations may be made without departing from the spirit of the present application.

[0532] Example 1 Synthesis of Compound 1

[0533] Step 1: Synthesis of Compound 1-3

[0534] The photocatalyst bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium bis(hexafluorophosphate) salt (6.4 mg, 5.7 μmol), compound 1-1 (201 mg, 0.85 mmol), 3-bromo-2-fluoropyridine (100 mg, 0.57 mmol), tris(trimethylsilyl)silane (180 μL, 0.57 mmol) and anhydrous sodium carbonate (120 mg, 1.14 mmol) were added to a reaction flask, the atmosphere was replaced with nitrogen, and then ethylene glycol dimethyl ether (4 mL) was added. To a separate vial, the catalyst nickel chloride dimethoxyethane (1.3 mg, 5.7 μmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (1.5 mg, 5.7 μmol) were added. The catalyst vial was sealed and purged with nitrogen, and then ethylene glycol dimethyl ether (2 mL) was added. The catalyst solution was stirred for 5 minutes, then 1 mL was injected into the reaction system. The reaction was stirred and illuminated with a 34W blue LED lamp (at a distance of 7 cm, maintaining the reaction temperature at 25°C) for 18 hours. After completion of the reaction as monitored by TLC, the reaction was quenched with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with water, dried, concentrated, and purified by column chromatography to yield compound 1-3.

[0535] Step 2: Synthesis of Compound 1-5

[0536] Compound 1-3 (87 mg, 0.34 mmol) and compound 1-4 (87 mg, 0.34 mmol) were added to N,N-dimethylformamide (2 mL), and sodium tert-butoxide (64 mg, 0.34 mmol) was added to the reaction system. The temperature was then raised to 120°C and the reaction was allowed to react for 2 h. After TLC monitoring, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with water, dried, concentrated, and purified by column chromatography to obtain compound 1-5.

[0537] Step 3: Synthesis of Compound 1-6

[0538] Compound 1-5 (65 mg, 0.16 mmol) was added to acetonitrile (2 mL). A solution of HCl in 1,4-dioxane (2 mL, 8 mmol) was added dropwise to the reaction system at 0°C and allowed to react for 1 h. After completion of the reaction as monitored by TLC, the mixture was dried and concentrated to yield compound 1-6.

[0539] Step 4: Synthesis of Compound 1

[0540] Compound 1-6 (100 mg, 0.32 mmol) and N,N-diisopropylethylamine (0.16 mL, 0.95 mmol) were added to tetrahydrofuran (8 mL). Acryloyl chloride (0.06 mL, 0.64 mmol) was added dropwise to the reaction system at 0°C and reacted at room temperature for 1 h. After the reaction was completed as monitored by TLC, the reaction was quenched with water (10 mL) and extracted with EA (20 mL×3). The organic phase was washed with water, dried, concentrated, and purified by HPLC to obtain compound 1.

[0541] 1 H NMR(CHLOROFORM-d)δ:8.62(dd,J=4.7,1.7Hz,1H),8.02-8.08(m,2H),7.54(dd,J=7.8,4.7Hz,1H),7.47(dd,J=8.6,1.5Hz,1H),7.38(d,J=3.3Hz,1H), 7.23(d,J=8.6Hz,1H),6.85(d,J=3.4Hz,1H),6.34(dd,J=17.0,1.8Hz,1H), 6.07-6.15(m,1H),5.68(dd,J=10.4,1.8Hz,1H),4.24-4.33(m,2H),4.07(br s,2H),3.83-3.91(m,1H).MS m / z(ESI):372.1[M+H] + .

[0542] Example 2: Synthesis of Compound 2

[0543] Step 1: Synthesis of compound 2

[0544] To a solution of crude compound 1-6 (323 mg, prepared according to the corresponding method in Example 1) in DMF (3 mL) were added 2-fluoroacrylic acid (68 mg, 0.76 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (433.95 mg, 1.14 mmol), 4-dimethylaminopyridine (9.30 mg, 0.08 mmol), and DIPEA (0.25 mL, 1.52 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. TLC (PE:EA = 1 / 1) indicated the formation of a major spot, and the desired mass was detected by LCMS. The mixture was quenched by the addition of purified water (5 mL) and extracted with EA (5 x 3 mL). The mixture was then washed three times with saturated brine (3 x 3 mL), and the combined organic layers were dried and concentrated to obtain a residue. The residue was purified by column chromatography (PE:EA = 1 / 1 to pure EA) and HPLC. Compound 2 was obtained after freeze-drying.

[0545] 1 H NMR(DMSO-d6)δ:8.58(br d,J=3.8Hz,1H),8.30(br d,J=7.5Hz,1H),8.10(s,1H),7.77(br d,J=2.9Hz,1H),7.66(brdd,J=7.5,4.8Hz,1H),7.48(br d,J=8.5Hz,1H),7.40(br d,J=8.6Hz,1H),6.90(br d,J=2.8Hz,1H),5.31-5.52(m,1H),5.23(br dd,J=16.5,3.1Hz,1H),4.27-4.47(m,2H),3.86-4.05(m,2H),3.82(br s,1H).MS m / z(ESI):390.1[M+H] + .

[0546] Example 3: Synthesis of Compound 3

[0547] Step 1: Compound 3-3

[0548] Compound 2-fluoro-3-iodopyridine (1.4 g, 6.2 mmol) was dissolved in THF (20 mL). After three replacements with N₂, the mixture was stirred at -20°C for 10 minutes, and then 8 mL of isopropylmagnesium chloride (1.5 mol / L) was slowly added. The reaction continued for 30 min, followed by the addition of 1-Boc-3-azetidinone (1.5 g, 12.4 mmol). The mixture was reacted at room temperature overnight, and then saturated ammonium chloride solution (20 mL) was added and extracted with EA (50 mL). After standing and separating the layers, the organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous Na₂SO₄, and then spin-dried to obtain a residue. The residue was purified by column chromatography (EA:PE=1 / 10) to obtain compound 3-3.

[0549] Step 2: Synthesis of compound 3-4

[0550] Compound 3-3 (1.4 g, 5.2 mmol) and 20 mL of DCM were added sequentially to a 100 mL flask. DAST (1.42 g, 8.84 mmol) was slowly added at -78°C, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was slowly added to 10 mL of NaHCO₃ solution and extracted with DCM (20 mL). After standing and separating the layers, the organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous Na₂SO₄, and spin-dried to obtain a residue. The residue was purified by column chromatography (EA:PE = 1 / 10) to obtain compound 3-4.

[0551] Step 3: Synthesis of Compound 3-6

[0552] Compound 3-4 (500 mg, 1.85 mmol), 5-trifluoromethylindole (342.5 mg, 1.85 mmol), potassium tert-butoxide (415.2 mg, 3.7 mmol), and 10 mL of DMF were added sequentially to a 50 mL flask, and the mixture was stirred at 120°C for 1 hour. After the reaction was complete, the reaction solution was slowly added to 30 mL of water and extracted with EA (20 mL). After standing and separating the layers, the organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous Na2SO4, and spin-dried to obtain a residue. The residue was purified by column chromatography (EA:PE = 1 / 10) to obtain compound 3-6.

[0553] Step 4: Synthesis of Compound 3-7

[0554] Compound 3-6 (350 mg, 0.8 mmol) was dissolved in 10 mL of HCl in 1,4-dioxane (1.5 mol / L), and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction solution was slowly added to 30 mL of NaHCO₃ and extracted with EA (20 mL). After standing and separating the layers, the organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous Na₂SO₄, and spin-dried to obtain compound 3-7.

[0555] Step 5: Synthesis of compound 3

[0556] Compound 3-7 (120 mg, 0.3 mmol) was dissolved in 10 mL of DCM solution, and acryloyl chloride (36 mg, 0.4 mmol) and DIPEA (77 mg, 0.6 mmol) were added sequentially. The mixture was then stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was slowly added to 30 mL of H2O and extracted with DCM (20 mL). After standing to separate the layers and separating the liquids, the organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous Na2SO4, and dried to dryness to a residue. The residue was purified by preparative chromatography to obtain compound 3.

[0557] 1 H NMR(DMSO-d6)δ:8.70-8.79(m,1H),8.33(dt,J=7.9,1.9Hz,1H),8.12(s,1H),7.74(ddd,J=7.8,4.8,0.8Hz,1H),7.62(d,J=3.4Hz,1H),7. 45-7.58(m,2H),6.93(d,J=3.3Hz,1H),6.08-6.20(m,1H),5.95-6.05(m,1H),5.57-5.70(m,1H),4.35-4.68(m,2H),3.79-4.17(m,2H).MS m / z(ESI):390[M+H] + .

[0558] Example 4: Synthesis of Compound 4

[0559] Step 1: Synthesis of compound 4-2

[0560] To a mixture of tert-butyl 3-bromoazetidine-1-carboxylate (1.50 g, 6.36 mmol) in DME (15 mL) were added 3-bromo-2-fluoropyrazine (750 mg, 4.24 mmol), bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium bis(hexafluorophosphate) (47.57 mg, 0.04 mmol), tris(trimethylsilyl)silane (1.05 g, 4.24 mmol), [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridyl]nickel(II) dichloride (16.88 mg, 0.04 mmol) and sodium carbonate (898.80 mg, 8.48 mmol), and the mixture was stirred at room temperature under nitrogen atmosphere and blue light irradiation for 16 hours. TLC (PE:EA=10 / 1) showed the formation of a major spot, and the desired mass was detected on LCMS. After cooling to 25°C, saturated ammonium chloride solution (5 mL) was added to quench the mixture and extracted with EA (50 mL). The mixture was then washed three times with saturated brine, and the combined organic layers were dried and concentrated to obtain a residue. The residue was purified by chromatography (PE:EA=20 / 1 to 10 / 1). Compound 4-2 was obtained.

[0561] Step 2: Synthesis of compound 4-4

[0562] To a solution of compound 4-2 (167 mg, 0.66 mmol) in DMF (2.5 mL) were added 5-trifluoromethylindole (122.08 mg, 0.66 mmol) and cesium carbonate (429.66 mg, 1.32 mmol) in sequence and stirred at 40°C for 14 hours. TLC (PE:EA=5 / 1) showed that a major spot was formed and the desired mass was detected on LCMS. After cooling to 25°C, the mixture was filtered, saturated ammonium chloride solution (2 mL) was added to the filtrate to quench the mixture and extracted with EA (10 mL). The mixture was then washed three times with saturated brine (2 mL×3), the combined organic layers were dried and concentrated to obtain a residue. The residue was purified by column chromatography (PE:EA=5 / 1 to 1 / 1). Compound 4-4 was obtained.

[0563] Step 3: Synthesis of compound 4-5

[0564] To a solution of compound 4-4 (113 mg) in dichloromethane (1 mL) was slowly added a solution of HCl in 1,4-dioxane (1 mL, 4 mol / L). The mixture was stirred at room temperature for 30 minutes. TLC (PE:EA = 5 / 1) indicated complete reaction of the starting material, and the molecular weight of the desired product was determined by LCMS. The mixture was concentrated under reduced pressure to yield the crude product of compound 4-5.

[0565] Step 4: Synthesis of compound 4

[0566] To a solution of the crude product of compound 4-5 (100 mg) in DMF (2 mL) were added 2-fluoroacrylic acid (23.58 mg, 0.26 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (147.34 mg, 0.39 mmol), and DIPEA (0.09 mL, 0.52 mmol), and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. TLC (PE:EA = 1 / 1) indicated the formation of a major spot, and the desired mass was detected on LCMS. The mixture was quenched by adding purified water (2 mL) and extracted with EA (3×3 mL). The mixture was then washed three times with saturated brine (3×3 mL), and the combined organic layers were dried and concentrated to obtain a residue. The residue was purified by column chromatography (PE:EA = 1 / 1 to pure EA) and HPLC. Compound 4 was obtained after lyophilization.

[0567] 1 H NMR(DMSO-d6)δ:8.90(d,J=2.3Hz,1H),8.69(d,J=2.3Hz,1H),8.12(s,1H),7.79(d,J=3.3Hz,1H), 7.47-7.58(m,2H),6.95(d,J=3.1Hz,1H),5.35-5.53(m,1H),5.26(dd,J=16.6,3.5Hz,1H),4.50(br s,2H),3.98-4.13(m,3H).MS m / z(ESI):391.1[M+H] + .

[0568] Example 7: Synthesis of Compound 7

[0569] Compound 3-7 (120 mg, 0.3 mmol) was dissolved in 10 mL of DCM solution, and 2-fluoroacrylic acid (40 mg, 0.4 mmol), HATU (228 mg, 0.6 mmol), and DIPEA (77 mg, 0.6 mmol) were added sequentially. The mixture was then stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was slowly added to 30 mL of H2O and extracted with EA (20 mL). After standing to separate the layers and separating the liquids, the organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous Na2SO4, and dried to a residue. The residue was purified by preparative chromatography to obtain compound 7.

[0570] 1H NMR(DMSO-d6)δ:8.65-8.85(m,1H),8.37(dt,J=7.9,1.9Hz,1H),8.12(s,1H), 7.74(ddd,J=7.8,4.8,0.8Hz,1H),7.61(d,J=3.4Hz,1H),7.46-7.58(m,2H),6 .93(d,J=3.4Hz,1H),5.46(d,J=3.6Hz,1H),5.33-5.55(m,1H),5.34(d,J=3.6 Hz,1H),5.23(dd,J=16.5,3.8Hz,1H),4.36-4.80(m,2H),3.87-4.25(m,2H).MS m / z(ESI):408[M+H] + .

[0571] Example 8: Synthesis of Compound 173

[0572] Step 1: Synthesis of compound 173-3

[0573] In a dry 50 mL single-necked bottle, 2-fluoro-3-bromopyridine (500 mg, 2.84 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1010 mg, 3.41 mmol), sodium carbonate (603 mg, 5.62 mmol), and Pd(dppf)Cl2 (213 mg, 0.28 mmol) were dissolved in 1,4-dioxane (10 mL) / water (2 mL) at room temperature, and the atmosphere was replaced with nitrogen. The reaction system was slowly heated to 105°C and stirred overnight. After completion of the reaction, the reaction solution was diluted with water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:5) to obtain compound 173-3.

[0574] Step 2: Synthesis of compound 173-4

[0575] In a dry 50 mL single-necked bottle, compound 173-3 (760 mg, 2.80 mmol) was dissolved in methanol (25 mL) at room temperature. Pd / C (10% 119 mg) was added to displace the H₂, and the reaction system was stirred at room temperature overnight. After the reaction was complete, the palladium-carbon solution was filtered using a Buchner funnel, and the filtrate was concentrated to obtain compound 173-4.

[0576] Step 3: Synthesis of compound 173-6

[0577] In a dry 25 mL single-necked vial, compound 173-4 (720 mg, 2.71 mmol), 5-(trifluoromethyl)-1H-indole (503 mg, 2.71 mmol), and sodium tert-butoxide (261 mg, 2.71 mmol) were dissolved in DMF (7 mL) at room temperature and the atmosphere was replaced with N2. The reaction system was slowly heated to 120°C and stirred for 1 hour. After the reaction was complete, the reaction system was diluted with water and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a preparative silica gel plate (ethyl acetate:petroleum ether = 1:5) to afford compound 173-6.

[0578] Step 4: Synthesis of compound 173-7

[0579] In a dry 25 mL single-necked vial, compound 173-6 (500 mg, 1.16 mmol) was dissolved in dichloromethane (5 mL) at room temperature and a solution of HCl in 1,4-dioxane (5 mL, 20 mmol) was added dropwise at 0°C. The reaction system was slowly warmed to room temperature and stirred for 1 hour. After the reaction was complete, the reaction mixture was concentrated to dryness to obtain compound 173-7 without purification.

[0580] Step 5: Synthesis of compound 173

[0581] In a dry 10 mL single-necked vial, compound 173-7 (500 mg, 1.51 mmol) was dissolved in DMF (5 mL) at room temperature and placed at 0°C. DIPEA (0.59 mL, 4.53 mmol) and acryloyl chloride (0.18 mL, 2.27 mmol) were added dropwise. The reaction system was slowly warmed to room temperature and stirred for 1 hour. After the reaction was complete, the reaction system was quenched with water and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a preparative silica gel plate (ethyl acetate:petroleum ether = 1:1) to afford compound 173.

[0582] 1H NMR(DMSO-d6)δ:8.54-8.60(m,1H),8.18(ddd,J=11.3,8.0,1.5Hz,1H),8.09(s,1H),7 .81-7.87(m,1H),7.56-7.71(m,1H),7.46(d,J=8.6Hz,1H),7.36(t,J=8.7Hz,1H),6.9 0(t,J=3.6Hz,1H),6.40-6.56(m,1H),6.05-6.13(m,1H),5.63(ddd,J=10.3,6.3,2.4H z,1H),3.67-3.82(m,1H),3.38-3.64(m,2H),3.09-3.30(m,2H),1.99-2.13(m,2H).MS m / z(ESI):386.2[M+H] + .

[0583] Compound 173 was separated on an Enantiopak@Y3 (silica gel coated with tris(3,5-dimethylphenylcarbamoyl) amylose) column with CO2:IPA=75:25 as the mobile phase to give compound 173 isomer-1 (retention time 2.563 min) and 173 isomer-2 (retention time 3.067 min).

[0584] Example 13: Synthesis of Compound 13

[0585] Step 1: Synthesis of compound 13-1

[0586] In a dry 25 mL single-necked vial, compound 173-3 (720 mg, 2.72 mmol), 5-(trifluoromethyl)-1H-indole (505.0 mg, 2.72 mmol), and sodium tert-butoxide (262.4 mg, 2.72 mmol) were dissolved in DMF (7 mL) at room temperature while displacing the nitrogen. The reaction system was slowly heated to 120°C and stirred for 1 hour. After the reaction was complete, the reaction system was diluted with water and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a preparative silica gel plate (ethyl acetate:petroleum ether = 1:5) to afford compound 13-1.

[0587] Step 2: Synthesis of compound 13-2

[0588] In a dry 25 mL single-necked vial, compound 13-1 (500 mg, 1.16 mmol) was dissolved in dichloromethane (5 mL) at room temperature and a solution of HCl in 1,4-dioxane (5 mL, 20 mmol) was added dropwise at 0°C. The reaction system was slowly warmed to room temperature and stirred for 1 hour. After the reaction was complete, the reaction mixture was directly concentrated to dryness to obtain compound 13-2 without purification.

[0589] Step 3: Synthesis of compound 13

[0590] In a dry 10 mL single-necked vial, compound 13-2 (500 mg, 1.51 mmol) was dissolved in DMF or DCM (5 mL) at room temperature and placed at 0°C. DIPEA (0.59 mL, 4.53 mmol) and acryloyl chloride (0.18 mL, 2.27 mmol) were added dropwise. The reaction system was slowly warmed to room temperature and stirred for 1 hour. After the reaction was complete, the reaction system was quenched with water and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a preparative silica gel plate (ethyl acetate:petroleum ether = 1:1) to provide compound 13.

[0591] 1 H NMR(DMSO-d6)δ:8.62(d,J=4.7Hz,1H),8.16(td,J=8.2,1.7Hz,1H),8.08( s,1H),7.71-7.74(m,1H),7.59-7.69(m,1H),7.47(s,2H),6.84-6.93(m,1H ),6.33-6.53(m,1H),6.05-6.17(m,1H),5.67(t,J=2.5Hz,0.5H),5.62-5.6 6(m,1H),5.42(t,J=2.0Hz,0.5H),4.30-4.38(m,2H),3.95-4.09(m,2H).MS m / z(ESI):384.12[M+H] + .

[0592] Example 16: Synthesis of Compound 16

[0593] Step 1: Synthesis of compound 16-2

[0594] To a solution of compound 31-2 (1.5 g, 3.86 mmol) in toluene (15 mL) were added compound 16-1 (0.72 g, 3.86 mmol), Pd(dba) (0.35 g, 0.39 mmol), BINAP (0.48 g, 0.77 mmol), and tBuONa (0.74 g, 7.73 mmol). The mixture was stirred at 105°C for 16 hours. The reaction mixture was poured into H2O (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude material was added to a silica gel column and eluted with 4:1 petroleum ether:ethyl acetate. The fractions were collected to obtain compound 16-2.

[0595] Step 2: Synthesis of compound 16-3

[0596] To a solution of compound 16-2 (90 mg, 0.20 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL, 2.68 mmol). The mixture was stirred at 25°C for 1 hour. The mixture was concentrated to dryness under reduced pressure to obtain compound 16-3 (60 mg).

[0597] Step 3: Synthesis of compound 16

[0598] To a solution of compound 16-3 (60 mg, 0.17 mmol) in dichloromethane (5 mL) was added DIEA (0.09 mL, 0.52 mmol). A solution of acryloyl chloride (0.02 mL, 0.21 mmol) in DCM (1.5 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for 0.5 hours. The mixture was poured into H2O (5 mL) and extracted with DCM (5 mL x 3). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The product was purified by high-performance liquid chromatography (neutral conditions) to yield compound 16.

[0599] 1 H NMR(DMSO-d6)δ:8.27(d,J=4.3Hz,1H),8.07(s,1H),8.04(d,J=3.3Hz,1H),7.70(m,2H),7.43-7.52(m,2H),6.89(d,J=3. 1Hz,1H),6.65-6.74(m,1H),6.03-6.10(m,1H),5.59-5.66(m,1H),3.34-3.42(m,4H),2.69(m,2H),2.52-2.61(m,2H).MS m / z(ESI):401.2[M+H] + .

[0600] Example 17: Synthesis of Compound 17

[0601] To a solution of 2-fluoroprop-2-enoic acid (32.76 mg, 0.36 mmol) in DMF (1 mL) were added HATU (115.27 mg, 0.30 mmol) and DIEA (0.13 mL, 0.81 mmol). The mixture was stirred at 25°C for 0.5 hours, and compound 16-3 (70 mg, 0.20 mmol) was added. The mixture was stirred at 25°C for 16 hours. The mixture was poured into H2O (2 mL) and extracted with DCM (5 mL x 3). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The product was purified by high-performance liquid chromatography (neutral conditions) to obtain compound 17.

[0602] 1 H NMR(DMSO-d6)δ:8.28(d,J=4.6Hz,1H),8.05-8.08(m,2H),7.69-7.74(m,2H),7.46-7.51( m,2H),6.89(d,J=3.1Hz,1H),5.04-5.29(m,2H),3.33-3.39(m,4H),2.62-2.75(m,4H).MS m / z(ESI):419.2[M+H] + .

[0603] Example 20: Synthesis of Compound 20

[0604] Step 1: Synthesis of compound 20-3

[0605] tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 3.24 mmol) and Pd(dppf)Cl2 (118 mg, 0.16 mmol) were dissolved in 1,4-dioxane (15 mL). 2-Fluoro-3-bromopyridine (855.31 mg, 4.86 mmol) and a 2M sodium carbonate solution (685 mg, 6.46 mmol) were added. The nitrogen atmosphere was replaced three times and protected with nitrogen. The reaction was stirred at 90°C overnight (12 h). After the reaction was completed, water and ethyl acetate were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 20-3.

[0606] Step 2: Synthesis of compound 20-4

[0607] Compound 20-3 (750 mg, 2.69 mmol) and palladium on carbon (10%) (150 mg) were dissolved in methanol (20 mL), and the hydrogen atmosphere was replaced three times under hydrogen protection. The mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was filtered with filter paper, and the filtrate was concentrated and dried to obtain compound 20-4.

[0608] Step 3: Synthesis of compound 20-6

[0609] Compound 20-4 (710 mg, 2.53 mmol) and 5-(trifluoromethyl)-1H-indole (468.92 mg, 2.53 mmol) were dissolved in DMF (10 mL), and sodium tert-butoxide (486.77 mg, 5.07 mmol) was added. The nitrogen atmosphere was replaced three times and protected with nitrogen. The mixture was stirred at 100°C for 12 hours. After the reaction was completed, saturated aqueous ammonium chloride was added to quench the reaction, and dichloromethane was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 20-6.

[0610] Step 4: Synthesis of compound 20-7

[0611] Compound 20-6 (670 mg, 1.50 mmol) was dissolved in dichloromethane (2 mL), and a 2M HCl solution in ethyl acetate (6 mL) was added in an ice bath. The mixture was stirred at room temperature overnight for 30 minutes. After the reaction was complete, the mixture was concentrated and dried to give compound 20-7.

[0612] Step 5: Synthesis of compound 20

[0613] Compound 20-7 (200 mg, 0.58 mmol) was dissolved in tetrahydrofuran (2 mL). DIEA (0.24 mL, 1.45 mmol) and prop-2-enoyl chloride (57.65 mg, 0.64 mmol) were added in an ice bath. The mixture was returned to room temperature and stirred for 30 minutes. After the reaction was complete, water and ethyl acetate were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 20.

[0614] 1H NMR(DMSO-d6)δ:8.52(dd,J=4.6,1.4Hz,1H),8.13(d,J=7.6Hz,1H),8.10(s,1H),7.82(d,J=3.3Hz,1H),7.58(dd,J=7.9,4.6Hz,1H),7.45(d,J=8.8Hz ,1H),7.32(d,J=8.6Hz,1H),6.89(d,J=3.3Hz,1H),6.77(dd,J=16.6,10.5H z,1H),6.08(dd,J=16.7,2.4Hz,1H),5.64(dd,J=10.5,2.4Hz,1H),4.48(br d,J=12.6Hz,1H),4.07(br d,J=13.5Hz,1H),2.81(br t,J=12.1Hz,1H),2.55-2.64(m,1H),2.30-2.45(m,1H),1.51-1.74(m,4H).MS m / z(ESI):400.2[M+H] + .

[0615] Example 22: Synthesis of Compound 22

[0616] Compound 20-7 (150 mg, 0.42 mmol) and 2-fluoroprop-2-enoic acid (39.11 mg, 0.43 mmol) were dissolved in DMF (2 mL), and DIEA (0.22 mL, 1.30 mmol) and HATU (330.29 mg, 0.87 mmol) were added. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, water and ethyl acetate were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 22.

[0617] 1 H NMR(DMSO-d6)δ:8.53(dd,J=4.6,1.6Hz,1H),8.18(dd,J=7.9,1.4Hz,1H),8.09( s,1H),7.81(d,J=3.3Hz,1H),7.60(dd,J=7.9,4.6Hz,1H),7.45(d,J=8.4Hz,1H), 7.32(d,J=8.6Hz,1H),6.89(d,J=3.3Hz,1H),5.04-5.27(m,2H),4.16-4.45(m,1H ),3.77-4.04(m,1H),2.80-3.08(m,1H),2.51-2.69(m,2H),1.60-1.78(m,4H).MS m / z(ESI):418.2[M+H] + .

[0618] Example 29: Synthesis of Compound 29

[0619] Step 1: Synthesis of compound 29-2

[0620] Compound 29-1 (1 g, 3.67 mmol), pinacol diboronate (1.03 g, 4.04 mmol), Pd(dppf)Cl2 (134.44 mg, 0.18 mmol), and potassium acetate (1.26 g, 12.86 mmol) were dissolved in 1,4-dioxane (50 mL). The nitrogen atmosphere was replaced three times and protected with nitrogen. The mixture was stirred at 100°C and reacted overnight (12 h). After the reaction was completed, water and ethyl acetate were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 29-2.

[0621] Step 2: Synthesis of compound 29-4

[0622] Compound 29-2 (788 mg, 2.47 mmol), 3-bromo-2-fluoropyridine (651.67 mg, 3.70 mmol), Pd(dppf)Cl2 (90.31 mg, 0.12 mmol), and a 2M sodium carbonate aqueous solution (523.29 mg, 4.94 mmol) were dissolved in 1,4-dioxane (10 mL). The nitrogen atmosphere was replaced three times and protected with nitrogen. The mixture was stirred at 90°C for 3 hours. After the reaction was completed, water and ethyl acetate were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 29-4.

[0623] Step 3: Synthesis of compound 29-6

[0624] Compound 29-4 (500 mg, 1.73 mmol) and 5-(trifluoromethyl)-1H-indole (321.08 mg, 1.73 mmol) were dissolved in DMF (3 mL), and sodium tert-butoxide (333.31 mg, 3.47 mmol) was added. The nitrogen atmosphere was replaced three times and protected with nitrogen. The mixture was stirred at 100°C for 12 hours. After the reaction was completed, saturated aqueous ammonium chloride was added to quench the reaction, and dichloromethane was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 29-6.

[0625] Step 4: Synthesis of compound 29-7

[0626] Compound 29-6 (90 mg, 0.20 mmol) was dissolved in dichloromethane (1 mL), and a 2M HCl solution in ethyl acetate (1 mL) was added in an ice bath. The mixture was stirred at room temperature overnight for 30 minutes. After the reaction was complete, the mixture was concentrated and dried to give compound 29-7.

[0627] Step 5: Synthesis of compound 29

[0628] Compound 29-7 (240 mg, 0.68 mmol) was dissolved in tetrahydrofuran (3 mL). DIEA (219.47 mg, 1.7 mmol) and prop-2-enoyl chloride (67.62 mg, 0.75 mmol) were added in an ice bath. The mixture was returned to room temperature and stirred for 30 minutes. After the reaction was complete, water and ethyl acetate were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 29.

[0629] 1 H NMR(DMSO-d6)δ:10.14(s,1H),8.68(dd,J=4.8,1.8Hz,1H),8.09(dd,J=7.7,1.8Hz,1H),7.97(s,1H),7.62-7.69(m,2H),7.58(t,J=8.3Hz,2H),7.40 (dd,J=8.8,1.5Hz,1H),7.30(d,J=3.4Hz,1H),7.17(t,J=7.9Hz,1H),6.64 -6.71(m,2H),6.32-6.43(m,1H),6.19-6.26(m,1H),5.70-5.77(m,1H).MS m / z(ESI):408.1[M+H] +

[0630] Example 30: Synthesis of Compound 30

[0631] Compound 29-7 (75 mg, 0.21 mmol) and 2-fluoroprop-2-enoic acid (19.11 mg, 0.21 mmol) were dissolved in DMF (2 mL), and DIEA (0.11 mL, 0.64 mmol) and HATU (161.42 mg, 0.42 mmol) were added. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, water and ethyl acetate were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 30.

[0632] 1H NMR(DMSO-d6)δ:10.30(br s,1H),8.68(dd,J=4.7,1.7Hz,1H),8.09(dd,J=7.7,1.7Hz,1H),7.97(s,1H),7.74(s,1H),7.56-7.69(m,3H),7.39(d,J=8.5Hz,1H),7.30 (d,J=3.4Hz,1H),7.18(t,J=7.9Hz,1H),6.72(d,J=7.8Hz,1H),6.67(d,J=3.4Hz,1H),5.59-5.75(m,1H),5.41(dd,J=15.6,3.6Hz,1H).MS m / z(ESI):426.1[M+H] +

[0633] Example 31

[0634] Step 1: Synthesis of compound 31-2

[0635] Compound 31-1 (2.5 g, 11.21 mmol) was added to a DMF (50 mL) solution of 5-trifluoromethylindole (2.18 g, 11.77 mmol) and cesium carbonate (5.48 g, 16.82 mmol) at 0°C and stirred at room temperature for 2 hours. The reaction was quenched by adding aqueous solution under an ice-water bath, extracted with EA, and the organic layer was washed with saturated saline solution, dried, and concentrated to obtain a residue. The residue was purified by column chromatography to obtain compound 31-2. MS m / z (ESI): 389.0 [M+H] + .

[0636] Step 2: Synthesis of compound 31-4

[0637] Under nitrogen, to a solution of compound 31-2 (500 mg, 1.29 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (306.50 mg, 1.55 mmol) in toluene (8 mL) were added Pd2(dba)3 (176.95 mg, 0.19 mmol), BINAP (240.65 mg, 0.39 mmol), and sodium tert-butoxide (247.60 mg, 2.58 mmol). The mixture was stirred at reflux at 100°C overnight. The mixture was filtered through Celite, dried, and the residue was purified by column chromatography to obtain compound 31-4. MS m / z (ESI): 459.2 [M+H] + .

[0638] Step 3: Synthesis of compound 31-5

[0639] To a solution of compound 31-4 (300 mg, 0.65 mmol) in DCM (10 mL) was added dropwise TFA (1.0 mL, 13.42 mmol) at 0°C and stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added under an ice-water bath to adjust the pH to 8. The mixture was extracted with DCM (16 mL). The organic layer was washed with saturated brine, dried, and concentrated to afford compound 31-5. MS m / z (ESI) 359.1 [M+H] + .

[0640] Step 4: Synthesis of compound 31

[0641] To a solution of compound 31-5 (143 mg, 0.40 mmol) and DIEA (198.36 μL, 1.20 mmol) in DCM (5 mL) was added acryloyl chloride (58.04 μL, 0.72 mmol) at 0°C and stirred at room temperature for 2 hours. The reaction was quenched by addition of water (12 mL) under an ice-water bath, followed by extraction with EA (16 mL). The organic layer was washed with saturated brine (12 mL x 3), dried, and concentrated to obtain a residue. The residue was purified by pre-HPLC to afford compound 31.

[0642] 1 H NMR (400MHz, DMSO-d6) δ=8.07(br s,1H),8.02(br d,J=3.5Hz,1H),7.71(br d,J=2.3Hz,1H),7.48(br d,J=8.5Hz,1H),7.43(br dd,J=4.6,7.4Hz,1H),7.34(br d,J=8.3Hz,1H),7.25(br d,J=7.8Hz,1H),6.87(br s,1H),6.21-6.09(m,1H),6.05-5.95(m,1H),5.58(br d,J=10.0Hz,1H),4.15(br s,2H),3.84(br s,2H),3.49(br s,4H).MS m / z(ESI):413.2[M+H] + .

[0643] Example 32: Synthesis of Compound 32

[0644] Compound 31-5 (170 mg, 0.47 mmol) was added to a solution of 2-fluoroacrylic acid (90 mg, 1.00 mmol), HATU (270.56 mg, 0.71 mmol), and DIEA (314.42 μL, 1.90 mmol) in DCM (5 mL). The mixture was stirred overnight at room temperature. The reaction was quenched by addition of water (12 mL) under an ice-water bath. Extraction was performed with EA (16 mL). The organic layer was washed with saturated brine (12 mL x 3), dried, and concentrated to obtain a residue. The residue was purified by pre-HPLC to yield compound 32.

[0645] 1 H NMR (400MHz, DMSO-d6) δ=8.07(br s,1H),8.04-7.98(m,1H),7.70(br d,J=3.1Hz,1H),7.48(br d,J=8.5Hz,1H),7.43(br dd,J=4.6,8.0Hz,1H),7.34(br d,J=8.6Hz,1H),7.24(br d,J=8.1Hz,1H),6.87(br d,J=2.9Hz,1H),5.47-5.26(m,1H),5.19(br dd,J=3.4,16.5Hz,1H),4.29(br s,2H),3.90(br s,2H),3.49(br s,4H).MS m / z(ESI):431.2[M+H] + .

[0646] Example 38: Synthesis of Compound 38

[0647] Step 1: Synthesis of compound 38-1

[0648] To a solution of compound 31-2 (654 mg, 1.69 mmol) in toluene (10 mL) were added 3-N-tert-butyloxycarbonylaminocyclobutylamine (348.25 mg, 2.02 mmol), tris(dibenzylideneacetone)dipalladium (154.30 mg, 0.17 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (209.85 mg, 0.34 mmol), and sodium tert-butoxide (323.86 mg, 3.37 mmol). The reaction was microwaved at 105°C for 5 hours. TLC (PE:EA = 10 / 1) indicated the formation of a new spot, and the desired mass was detected by LCMS. After cooling to 25°C, the mixture was filtered and quenched with saturated ammonium chloride solution (10 mL). The filtrate was then extracted with EA (10 x 3 mL). The mixture was then washed three times with saturated brine (5 x 3 mL). The combined organic layers were dried and concentrated to yield a residue. The residue was purified by column chromatography (PE:EA=10 / 1 to 5 / 1) to give compound 38-1.

[0649] Step 2: Synthesis of compound 38-2

[0650] To a solution of compound 38-1 (122 mg, 0.28 mmol) in dichloromethane (3 mL) was slowly added trifluoroacetic acid (1 mL) and stirred at room temperature for 3 hours. TLC (PE:EA = 5 / 1) indicated complete reaction of the starting material, and the molecular weight of the desired product was determined by LCMS. The mixture was concentrated under reduced pressure to afford crude compound 38-2.

[0651] Step 3: Synthesis of compound 38

[0652] To a solution of the crude product (113.1 mg) of compound 38-2 in THF (3 mL) was added DIPEA (0.14 mL, 0.85 mmol) and stirred for 15 min. Acryloyl chloride (34 μL, 0.37 mmol) was then added to the mixture at 0°C, and the mixture was allowed to warm to room temperature and stirred for 2 hours. TLC (PE:EA=2 / 1) showed the formation of a major spot, and the desired mass was detected on LCMS. Purified water (2 mL) was added to quench the mixture and extracted with EA (3×3 mL). The mixture was then washed three times with saturated brine (3×3 mL), and the combined organic layers were dried and concentrated to obtain a residue. The residue was purified by column chromatography (PE:EA=1 / 1 to pure EA) and HPLC. Compound 38 was obtained after freeze-drying.

[0653] 1H NMR(DMSO-d6)δ:8.51(d,J=6.4Hz,1H),8.07(s,1H),8.04(dd,J=4.6,1.5Hz,1H),7.72(d,J=3.3Hz,1H),7.49(dd,J=8.8,1.6Hz,1H),7.45 (dd,J=8.2,4.6Hz,1H),7.31(t,J=9.8Hz,2H),6.87(d,J=2.9Hz,1H),6.06(d,J=9.6Hz,1H),5.97-6.03(m,1H),5.53-5.59(m,1H),4.32(br d,J=6.5Hz,1H),3.53(t,J=7.8Hz,2H),3.22-3.28(m,2H).MS m / z(ESI):387.1[M+H] + .

[0654] Example 42: Synthesis of Compound 42

[0655] Step 1: Synthesis of compound 42-2

[0656] To a solution of compound 31-2 (1.0 g, 2.58 mmol) in toluene (15 mL) were added (S)-3-tert-butoxycarbonylaminopyrrolidine (527.85 mg, 2.83 mmol), methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (233.56 mg, 0.26 mmol), and sodium tert-butoxide (371.40 mg, 3.86 mmol). The reaction was microwaved at 105°C for 6 hours. TLC (PE:EA = 5 / 1) indicated the formation of a new spot, and the desired mass was detected by LCMS. After cooling to 25°C, the mixture was filtered, and the filtrate was quenched with saturated ammonium chloride solution (5 mL) and extracted with EA (20 × 3 mL). The mixture was then washed three times with saturated brine (5×3 mL), and the combined organic layers were dried and concentrated to obtain a residue. The residue was purified by chromatography (PE:EA=5 / 1 to 1 / 1) to obtain compound 42-2.

[0657] Step 2: Synthesis of compound 42-3

[0658] To a solution of compound 42-2 (96 mg, 0.22 mmol) in dichloromethane (3 mL) was slowly added trifluoroacetic acid (1 mL) and stirred at room temperature for 3 hours. TLC (PE:EA = 5 / 1) indicated complete reaction of the starting material, and the molecular weight of the desired product was determined by LCMS. The mixture was concentrated under reduced pressure to afford crude compound 42-3.

[0659] Step 3: Synthesis of compound 42

[0660] To a THF (3 mL) solution of the crude product (79.9 mg) of compound 42-3 was added DIPEA (0.10 mL, 0.58 mmol) and stirred for 15 min. Acryloyl chloride (20 μL, 0.25 mmol) was then added to the mixture at 0°C, warmed to room temperature and stirred for 2 hours. TLC (PE:EA=2 / 1) showed the formation of a major spot, and the desired mass was detected on LCMS. Purified water (2 mL) was added to quench the mixture and extracted with EA (3×3 mL). The mixture was then washed three times with saturated brine (3×3 mL), the combined organic layers were dried and concentrated to obtain a residue. The residue was purified by chromatography (PE:EA=1 / 1 to pure EA) and HPLC. Compound 42 was obtained after freeze-drying.

[0661] 1 H NMR(DMSO-d6)δ:8.09(br d,J=6.6Hz,1H),8.05(s,1H),8.00(dd,J=4.4,1.4Hz,1H),7.78(d,J=3.3Hz,1H),7.38-7.51(m,3H),7.33(d,J=8.6Hz,1H),6.85(d,J=3.3H z,1H),5.99-6.15(m,2H),5.52-5.57(m,1H),4.08-4.16(m,1H),3.36-3.38(m,1H),2.96(dd,J=9.8,6.3Hz,1H),2.84-2.91(m,1H),2.79(br d,J=6.0Hz,1H),2.59(dd,J=9.8,4.7Hz,1H),2.53-2.56(m,1H),1.90(dd,J=12.3,6.4Hz,1H),1.63-1.71(m,1H).MS m / z(ESI):401.3[M+H] + .

[0662] Example 43

[0663] Step 1: Synthesis of compound 43-2

[0664] To a solution of compound 31-2 (500 mg, 1.47 mmol) in toluene (13 mL) were added tert-butyl (R)-pyrrolidin-3-ylcarbamate (263.93 mg, 1.42 mmol), BrettPhos Pd G3 (116.78 mg, 0.13 mmol), and tBuONa (185.70 mg, 1.93 mmol). The mixture was stirred at 105°C in a microwave reactor for 4 hours. The reaction mixture was poured into H2O (10 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude material was added to a silica gel column and eluted with 4:1 PE:EA. Fractions were collected to provide compound 43-2.

[0665] Step 2: Synthesis of compound 43-3

[0666] To a solution of compound 43-2 (21 mg, 0.05 mmol) in DCM (1 mL) was added TFA (0.1 mL, 1.34 mmol) and the mixture was stirred at 25° C. for 1 hour. The mixture was concentrated to dryness under reduced pressure to obtain crude compound 43-3.

[0667] Step 3: Synthesis of compound 43

[0668] To a solution of compound 43-3 in DCM (1.5 mL) was added DIEA (0.02 mL, 0.10 mmol). Acryloyl chloride (3 uL, 0.04 mmol) in DCM (1.5 mL) was then added dropwise at 0°C. The mixture was stirred at 0°C for 0.5 h. The mixture was poured into H2O (2 mL) and extracted with DCM (5 mL x 3). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The product was purified by HPLC (neutral conditions) to afford compound 43.

[0669] 1H NMR(DMSO-d6)δ:8.09(br d,J=6.8Hz,1H),8.06(s,1H),8.01(dd,J=4.4,1.4Hz,1H),7.79(d,J=3.4Hz,1H),7.3 7-7.51(m,3H),7.34(d,J=8.6Hz,1H),6.85(d,J=3.1Hz,1H),6.00-6.16(m,2H),5.53 -5.57(m,1H),4.09-4.17(m,1H),2.97(dd,J=9.8,6.4Hz,1H),2.84-2.93(m,1H),2.7 6-2.84(m,1H),2.55-2.64(m,1H),1.91(dd,J=12.8,6.6Hz,1H),1.63-1.71(m,1H).MS m / z(ESI):401.2[M+H] +

[0670] Example 44

[0671] Step 1: Synthesis of compound 44-3

[0672] To a mixture of compound 44-1 (1.0 g, 5.75 mmol) in THF (10 mL) were added N-Boc-3-hydroxyazetidine (compound 44-2, 995 mg, 5.75 mmol) and triphenylphosphine (2.26 g, 8.62 mmol), and then diisopropyl azodicarboxylate (1.74 g, 8.62 mmol) was slowly added dropwise at 0°C. The mixture was stirred at 50°C under a nitrogen atmosphere for 6 hours. TLC (PE:EA=2 / 1) showed the formation of a major spot. After cooling to 25°C, the mixture was quenched by the addition of purified water (10 mL) and extracted with EA (50 mL). The mixture was then washed three times with saturated brine, and the combined organic layers were dried and concentrated to obtain a residue. The residue was purified by chromatography (PE:EA=5 / 1 to 1 / 1). The crude product of compound 44-3 was obtained.

[0673] Step 2: Synthesis of compound 44-5

[0674] To a solution of compound 44-3 (200 mg) in 1,4-dioxane (2 mL) were added 5-(trifluoromethyl)indole (134.99 mg, 0.73 mmol), tris(dibenzylideneacetone)dipalladium (55.64 mg, 0.06 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (70.31 mg, 0.12 mmol), and sodium tert-butoxide (70.06 mg, 0.73 mmol). The mixture was stirred at 100°C for 16 hours. TLC (PE:EA = 2 / 1) indicated the formation of a new spot, and the desired mass was detected by LCMS. After cooling to 25°C, the mixture was filtered, quenched with saturated ammonium chloride solution (2 mL), and extracted with EA (5 x 3 mL). The mixture was then washed three times with saturated brine (2 x 3 mL). The combined organic layers were dried and concentrated to yield a residue. The residue was purified by column chromatography (PE:EA=5 / 1 to 2 / 1) to give compound 44-5.

[0675] Step 3: Synthesis of compound 44-6

[0676] To a solution of compound 44-5 (107 mg, 0.25 mmol) in dichloromethane (2 mL) was slowly added a solution of HCl in 1,4-dioxane (2 mL). The mixture was stirred at room temperature for 1.5 hours. TLC (PE:EA = 5 / 1) indicated complete reaction of the starting material, and the molecular weight of the desired product was determined by LCMS. The mixture was concentrated under reduced pressure to yield crude compound 44-6.

[0677] Step 4: Synthesis of compound 44

[0678] To a solution of the crude product (104 mg) of compound 44-6 in THF (2 mL) was added DIPEA (0.13 mL, 0.78 mmol) and stirred for 15 min. Acryloyl chloride (34 μL, 0.37 mmol) was then added to the mixture at 0°C, and the mixture was allowed to rise to room temperature and stirred for 1.5 hours. TLC (PE:EA=1 / 1) showed the formation of a major spot, and the desired mass was detected on LCMS. Purified water (2 mL) was added to quench the mixture and extracted with EA (3×3 mL). The mixture was then washed three times with saturated brine (3×3 mL), and the combined organic layers were dried and concentrated to obtain a residue. The residue was purified by chromatography (PE:EA=1 / 1 to pure EA) and HPLC. Compound 44 was obtained after freeze-drying.

[0679] 1H NMR(CHLOROFORM-d)δ:8.30(d,J=4.6Hz,1H),7.96(s,1H),7.67-7.80(m,2H),7.46(br d,J=8.8Hz,1H),7.29-7.33(m,1H),7.15(br d,J=8.1Hz,1H),6.77(d,J=3.3Hz,1H),6.35(br d,J=17.0Hz,1H),6.13(dd,J=17.0,10.4Hz,1H),5.71(br d,J=10.4Hz,1H),4.91-5.07(m,1H),4.41-4.63(m,2H),4.07-4.25(m,2H)..MS m / z(ESI):386.1[MH] - .

[0680] Example 46

[0681] Step 1: Synthesis of compound 46-3

[0682] In a dry 25 mL single-necked bottle, 2,3-dibromopyrazine (364.07 mg, 2.10 mmol) was dissolved in N,N-dimethylformamide (10 mL) at room temperature. Sodium hydride (126.11 mg, 3.15 mmol) was added at 0°C and stirred for 15 minutes. Tert-butyl 3-hydroxyazetidine-1-carboxylate (364.07 mg, 2.10 mmol) was then added, and the atmosphere was replaced with nitrogen. The reaction system was slowly heated to 80°C and stirred for 1 hour. After completion of the reaction, the reaction system was diluted with water (10 mL) and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:5) to provide compound 46-3.

[0683] Step 2: Synthesis of compound 46-5

[0684] In a dry 25 mL single-necked flask, compound 46-3 (492 mg, 1.49 mmol) was dissolved in toluene (10 mL) at room temperature. 5-(Trifluoromethyl)-1H-indole (331.07 mg, 1.79 mmol), tris(dibenzylideneindeneacetone)dipalladium (136.45 mg, 0.15 mmol), sodium tert-butoxide (286.40 mg, 2.98 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (278.36 mg, 0.45 mmol) were added sequentially. The atmosphere was replaced with nitrogen, and the reaction system was slowly heated to 110°C and stirred for 10 hours. After the reaction was complete, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:3) to obtain compound 46-5.

[0685] Step 3: Synthesis of compound 46-6

[0686] In a dry 10 mL single-necked vial, compound 46-5 (226 mg, 0.52 mmol) was dissolved in dichloromethane (2 mL) at room temperature. Trifluoroacetic acid (1 mL, 13.42 mmol) was slowly added dropwise at 0°C. The reaction system was slowly warmed to 30°C and stirred for 1 hour. After the reaction was complete, the reaction system was quenched with a saturated sodium bicarbonate solution, diluted with water (5 mL), and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 46-6.

[0687] Step 4: Synthesis of compound 46

[0688] In a dry 25 mL single-necked vial, compound 46-6 (110 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (3 mL) at room temperature. N,N-diisopropylethylamine (136.31 μL, 0.82 mmol) and acryloyl chloride (29.25 μL, 0.36 mmol) were added sequentially at 0°C. The reaction system was slowly heated to 30°C and stirred for 1 hour. After completion of the reaction, the reaction solution was quenched with water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:1) to obtain compound 46.

[0689] 1H NMR(DMSO-d6)δ:8.32(d,J=2.6Hz,1H),8.27(d,J=2.8Hz,1H),8.16(d,J=3.4Hz, 1H),8.08(s,1H),8.04(d,J=8.8Hz,1H),7.53(d,J=8.8Hz,1H),6.91(d,J=3.4Hz ,1H),6.28-6.37(m,1H),6.11(dd,J=17.0,2.0Hz,1H),5.68(dd,J=10.3,2.1Hz, 1H),5.49-5.55(m,1H),4.64-4.72(m,1H),4.37(dd,J=11.3,6.6Hz,1H),4.31(br dd,J=10.0,3.5Hz,1H),4.01(dd,J=11.2,3.4Hz,1H).MS m / z(ESI):389.10[M+H] + .

[0690] Example 47

[0691] In a dry 25 mL single-necked flask, 2-fluoroacrylic acid (29.72 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (5 mL) at room temperature. 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (125.48 mg, 0.33 mmol) and N,N-diisopropylethylamine (136.31 μL, 0.82 mmol) were added sequentially. The mixture was stirred for 10 minutes, followed by the addition of compound 46-6 (110 mg, 0.33 mmol). The atmosphere was replaced with nitrogen, and the reaction system was stirred at 30°C for 3 hours. After completion of the reaction, the mixture was diluted with water (3 mL) and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:1) to provide compound 47.

[0692] 1H NMR(METHANOL-d4)δ:8.14(d,J=2.6Hz,1H),8.05(d,J=2.6Hz,1H),7.94(s,1H),7.93(d,J=3.1Hz,1H),7.86(s,1H),7.37(dd,J=8.8 ,1.1Hz,1H),6.74(d,J=3.5Hz,1H),5.37-5.53(m,2H),5.10(dd,J=16.0,3.4Hz,1H),4.79-4.84(m,1H),4.37-4.48(m,2H),4.05(br dd,J=11.7,2.8Hz,1H).MS m / z(ESI):407.10[M+H] +

[0693] Example 52: Synthesis of Compound 52

[0694] Step 1: Synthesis of compound 52-2

[0695] To a mixture of 2-bromopyridine-3-ol (170 mg, 0.98 mmol) in THF (3 mL) were added tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (200 mg, 0.98 mmol) and triphenylphosphine (394.39 mg, 1.47 mmol) in sequence, and then DIAD (0.29 mL, 1.47 mmol) was added dropwise at 0 ° C. The mixture was stirred at room temperature for 2.5 hours under a nitrogen atmosphere. TLC (PE: EA = 2 / 1) showed that a major spot was formed, and the desired mass was detected on LCMS. Purified water (3 mL) was added to quench the mixture and extracted with EA (5 × 3 mL). It was then washed three times with saturated brine (3 × 3 mL), the combined organic layers were dried and concentrated to obtain a residue. The residue was purified by chromatography (PE: EA = 5 / 1 to 1 / 1). Compound 52-2 crude product was obtained.

[0696] Step 2: Synthesis of compound 52-4

[0697] To a solution of crude compound 52-2 (537 mg, 1.48 mmol) in 1,4-dioxane (8 mL) were added 5-trifluoromethylindole (330.31 mg, 1.78 mmol), tris(dibenzylideneacetone)dipalladium (136.14 mg, 0.15 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (172.05 mg, 0.30 mmol), and sodium tert-butoxide (171.44 mg, 1.78 mmol). The mixture was stirred at 100°C for 16 hours. TLC (PE:EA = 2 / 1) indicated the formation of a major spot, and the desired mass was detected by LCMS. After cooling to 25°C, the mixture was filtered, quenched with saturated ammonium chloride solution (5 mL), and extracted with EA (10 x 3 mL). The mixture was then washed three times with saturated brine (5 x 3 mL). The combined organic layers were dried and concentrated to yield a residue. The residue was purified by chromatography (PE:EA=5 / 1 to 1 / 1) to give compound 52-4.

[0698] Step 3: Synthesis of compound 52-5

[0699] To a solution of compound 52-4 (287 mg, 0.62 mmol) in dichloromethane (5 mL) was slowly added trifluoroacetic acid (2 mL) and stirred at room temperature for 1.5 hours. TLC (PE:EA = 2 / 1) indicated complete reaction of the starting material, and the molecular weight of the desired product was determined by LCMS. The mixture was concentrated under reduced pressure to afford crude compound 52-5.

[0700] Step 4: Synthesis of compound 52

[0701] To a solution of the crude product of compound 52-5 (120 mg, 0.33 mmol) in THF (2 mL) was added DIPEA (0.14 mL, 0.82 mmol) and stirred for 15 min. Acryloyl chloride (32 μL, 0.36 mmol) was then added to the mixture at 0°C, and the mixture was allowed to warm to room temperature and stirred for 3 hours. TLC (PE:EA=2 / 1) showed the formation of a major spot, and the desired mass was detected on LCMS. The mixture was quenched by adding purified water (2 mL) and extracted with EA (3×3 mL). The mixture was then washed three times with saturated brine (3×3 mL), and the combined organic layers were dried and concentrated to obtain a residue. The residue was purified by column chromatography (PE:EA=1 / 1 to pure EA) and HPLC. Compound 52 was obtained after freeze-drying.

[0702] 1H NMR(DMSO-d6)δ:8.26(d,J=4.3Hz,1H),8.04(s,1H),7.81-7.90(m,2H),7.77(d,J=8.6Hz,1H),7.53(dd,J=8.2,4.7Hz,1H),7.47(br d,J=8.5Hz,1H),6.82(d,J=3.3Hz,1H),6.24(dd,J=16.9,10.2Hz,1H),6.10(dd ,J=16.9,1.9Hz,1H),5.68(dd,J=10.1,2.0Hz,1H),4.48-4.65(m,2H),4.39(br dd,J=18.6,10.4Hz,1H),4.20-4.32(m,1H),4.13(br dd,J=18.3,11.6Hz,1H),3.87-4.01(m,1H).MS m / z(ESI):420.1[M+H] + .

[0703] Example 53: Synthesis of Compound 53

[0704] To a solution of 2-fluoroacrylic acid (25 mg, 0.27 mmol) in DMF (2 mL) were added 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (156.12 mg, 0.41 mmol), crude compound 52-5 (120 mg, 0.33 mmol), and DIEA (0.18 mL, 1.09 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 15 hours. TLC (PE:EA = 1 / 2) indicated the formation of a major spot, and the desired mass was detected on LCMS. The mixture was quenched by the addition of purified water (5 mL) and extracted with EA (5 x 3 mL). The mixture was then washed three times with saturated brine (3 x 3 mL), and the combined organic layers were dried and concentrated to obtain a residue. The residue was purified by column chromatography (PE:EA = 1 / 2 to pure EA) and HPLC. Compound 53 was obtained after lyophilization.

[0705] 1H NMR(DMSO-d6)δ:8.26(d,J=4.4Hz,1H),8.04(s,1H),7.80-7.91(m,2H),7.75(br d,J=8.5Hz,1H),7.54(dd,J=8.2,4.7Hz,1H),7.45(br d,J=8.5Hz,1H),6.82(d,J=3.0Hz,1H),5.53(d,J=3.4Hz,1H),5.41(d,J=3.4Hz,1H) ,5.30(dd,J=16.4,3.6Hz,1H),4.59(s,1H),4.54(s,2H),4.28-4.44(m,1H),4.17(br dd,J=17.8,12.1Hz,1H),3.90-4.08(m,1H).MS m / z(ESI):438.1[M+H] + .

[0706] Example 54: Synthesis of Compound 54

[0707] Step 1: Synthesis of compound 54-1

[0708] To a solution of 5-trifluoromethylindole (131.53 mg, 0.71 mmol) and sodium tert-butoxide (68.27 mg, 0.71 mmol) in DMF (5 mL) was added compound 56-3 (200 mg, 0.70 mmol) at 0°C and stirred at room temperature for 2 hours. The reaction was quenched by adding water (12 mL) under an ice-water bath. Extraction was performed with EA (16 mL), and the organic layer was washed with saturated brine (12 mL x 3). The organic layer was dried and concentrated to obtain a residue. The residue was purified by column chromatography to obtain compound 54-1.

[0709] Step 2: Synthesis of compound 54-2

[0710] To a solution of compound 54-1 (115 mg, 0.26 mmol) in DCM (4 mL) was added dropwise TFA (765 mg, 6.71 mmol) at 0°C and stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added under ice-water bath to adjust the pH to 8. Extraction was performed with DCM (16 mL), and the organic layer was washed with saturated brine, dried, and concentrated to afford compound 54-2.

[0711] Step 3: Synthesis of compound 54

[0712] To a solution of compound 54-2 (50 mg, 0.14 mmol) and DIEA (59.29 μL, 0.36 mmol) in DCM (5 mL) was added acryloyl chloride (20.82 μL, 0.26 mmol) at 0°C and stirred at room temperature for 2 hours. The reaction was quenched by addition of water (12 mL) under an ice-water bath, followed by extraction with EA (16 mL). The organic layer was washed with saturated brine (12 mL x 3), dried, and concentrated to obtain a residue. The residue was purified by pre-HPLC to afford compound 54.

[0713] 1 H NMR(DMSO-d6)δ:8.49(dd,J=4.6,1.4Hz,1H),8.08(s,1H),7.89(dd,J=8.0,1.3Hz,1H),7.81(d,J=3.4Hz ,1H),7.60(dd,J=7.9,4.8Hz,1H),7.44-7.49(m,1H),7.38(d,J=8.6Hz,1H),6.88(d,J=3.3Hz,1H),6.21 (dd,J=17.0,10.3Hz,1H),6.06(dd,J=17.0,2.3Hz,1H),5.65(dd,J=10.2,2.2Hz,1H),4.67(t,J=8.5Hz, 1H),4.34-4.44(m,1H),4.22-4.34(m,1H),4.00(dd,J=9.3,4.9Hz,1H),3.67(dd,J=10.5,4.9Hz,1H).MS m / z(ESI):404.1[M+H] + .

[0714] Example 55: Synthesis of Compound 55

[0715] Compound 54-2 (50 mg, 0.14 mmol) was added to a solution of 2-fluoroacrylic acid (19.33 mg, 0.21 mmol), HATU (81.62 mg, 0.21 mmol), and DIEA (94.86 μL, 0.57 mmol) in DMF (5 mL). The mixture was stirred overnight at room temperature. The reaction was quenched by addition of water (12 mL) under an ice-water bath. Extraction was performed with EA (16 mL). The organic layer was washed with saturated brine (12 mL x 3), dried, and concentrated to obtain a residue. The residue was purified by pre-HPLC to yield compound 55.

[0716] 1H NMR(DMSO-d6)δ:8.49(br d,J=4.0Hz,1H),8.08(br s,1H),7.89(br d,J=7.8Hz,1H),7.81(br d,J=2.8Hz,1H),7.59(br dd,J=7.6,4.7Hz,1H),7.43-7.51(m,J=8.5Hz,1H),7.35-7.43(m,J=8.6Hz,1H),6.79-6.99(m,1H),5.49(br d,J=3.1Hz,1H),5.37(br d,J=3.3Hz,1H),5.27(br dd,J=16.4,3.1Hz,1H),4.81(br s,1H),4.44(br t,J=8.9Hz,1H),4.21-4.35(m,1H),4.04-4.20(m,1H),3.67-3.79(m,1H).MS m / z(ESI):444.1[M+Na] + .

[0717] Example 56: Synthesis of Compound 56

[0718] Step 1: Synthesis of compound 56-3

[0719] To a solution of 3-bromo-2-fluoropyridine (0.54 mL, 5.28 mmol) and tert-butyl 3-mercaptoazetidine-1-carboxylate (1000 mg, 5.28 mmol) in 1,4-dioxane (25 mL) was added Pd2(dba)3 (483.82 mg, 0.53 mmol), XantPhos (611.43 mg, 1.06 mmol), and DIEA (1.75 mL, 10.57 mmol) under nitrogen, and the mixture was refluxed at 100°C overnight. The mixture was filtered through Celite, dried, and the residue was purified by column chromatography to obtain compound 56-3.

[0720] Step 2: Synthesis of compound 56-4

[0721] To a solution of compound 56-3 (600 mg, 2.11 mmol) in DCM (8 mL) at 0°C, m-CPBA (1456.46 mg, 8.44 mmol) was added and stirred at room temperature for 2 hours. The reaction was quenched by the addition of 10% NaHSO₃ (10 mL) under an ice-water bath. The mixture was extracted with DCM (16 mL). The organic layer was washed with 10% NaHSO₃ (10 mL x 2) and monitored for residual m-CPBA using potassium iodide starch paper. The organic layer was dried and concentrated to obtain a residue. The residue was purified by column chromatography to obtain compound 56-4.

[0722] Step 3: Synthesis of compound 56-5

[0723] To a solution of 5-trifluoromethylindole (118.22 mg, 0.64 mmol) and sodium tert-butoxide (61.36 mg, 0.64 mmol) in DMF (4 mL) was added compound 56-4 (200 mg, 0.63 mmol) at 0°C and stirred at room temperature for 2 hours. The reaction was quenched by the addition of water (12 mL) under an ice-water bath. Extraction was performed with EA (16 mL), and the organic layer was washed with saturated brine (12 mL x 3). The organic layer was dried and concentrated to obtain a residue. The residue was purified by column chromatography to obtain compound 56-5.

[0724] Step 4: Synthesis of compound 56-6

[0725] To a solution of compound 56-5 (230 mg, 0.48 mmol) in DCM (4 mL) was added dropwise TFA (765 mg, 6.71 mmol) at 0°C and stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added under ice-water bath to adjust the pH to 8. The mixture was extracted with DCM (16 mL), and the organic layer was washed with saturated brine, dried, and concentrated to afford compound 56-6.

[0726] Step 5: Synthesis of compound 56

[0727] To a solution of compound 56-6 (110 mg, 0.29 mmol) and DIEA (120 μL, 0.72 mmol) in DCM (5 mL) was added acryloyl chloride (42 μL, 0.52 mmol) at 0°C and stirred at room temperature for 2 hours. The reaction was quenched by addition of water (12 mL) under an ice-water bath, followed by extraction with EA (16 mL). The organic layer was washed with saturated brine (12 mL x 3), dried, and concentrated to obtain a residue. The residue was purified by pre-HPLC to afford compound 56.

[0728] 1H NMR(DMSO-d6)δ:8.97(dd,J=4.8,1.5Hz,1H),8.72(dd,J=8.0,1.4Hz,1H),8. 09(s,1H),7.94(dd,J=8.0,4.8Hz,1H),7.83(d,J=3.3Hz,1H),7.47(d,J=8.6 Hz,1H),7.39(d,J=8.6Hz,1H),6.90(d,J=3.1Hz,1H),6.17(dd,J=16.9,10.2 Hz,1H),6.05(dd,J=17.0,2.0Hz,1H),5.66(dd,J=10.1,2.0Hz,1H),4.30(br d,J=9.0Hz,1H),4.17-4.25(m,1H),4.03-4.15(m,1H),3.86-3.97(m,1H),3.79(br dd,J=10.9,5.2Hz,1H).MS m / z(ESI):436.2[M+H] + .

[0729] Example 57: Synthesis of Compound 57

[0730] Compound 56-6 (110 mg, 0.29 mmol) was added to a solution of 2-fluoroacrylic acid (90 mg, 0.39 mmol), HATU (199 mg, 0.52 mmol), and DIEA (350 μL, 2.10 mmol) in DCM (5 mL). The mixture was stirred overnight at room temperature. The reaction was quenched by addition of water (12 mL) under an ice-water bath. Extraction was performed with EA (16 mL). The organic layer was washed with saturated brine (12 mL x 3), dried, and concentrated to obtain a residue. The residue was purified by pre-HPLC to afford compound 57.

[0731] 1H NMR(DMSO-d6)δ:8.97(dd,J=4.8,1.5Hz,1H),8.73(dd,J=8.0,1.6Hz,1H),8.09(s,1H),7.94(dd,J=8.0,4.9Hz,1H),7.83(d,J=3 .3Hz,1H),7.45-7.50(m,1H),7.37-7.44(m,1H),6.90(d,J=3.3Hz,1H),5.35-5.51(m,1H),5.28(dd,J=16.6,3.8Hz,1H),4.39(br d,J=7.6Hz,1H),4.07-4.23(m,2H),3.94-4.05(m,1H),3.86(br dd,J=11.1,4.7Hz,1H).MS m / z(ESI):436.2[M+H] + .

[0732] Example 59: Synthesis of Compound 59

[0733] Step 1: Synthesis of compound 59-1

[0734] The compound 3-bromo-2-fluoropyridine (800 mg, 4.5 mmol) was dissolved in 1,4-dioxane (20 mL), and (R)-3-mercapto-pyrrolidine-1-carboxylic acid tert-butyl ester (1.3 g, 6.7 mmol), Pd2(dba)3 (411 mg, 0.4 mmol), XantPhos (520 mg, 0.9 mmol), and cesium carbonate (2.9 g, 9 mmol) were added. After three replacements with N2, the mixture was stirred at 100°C overnight, saturated ammonium chloride solution (20 mL) was added, and the mixture was extracted with EA (50 mL). After standing and separating the layers, the organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous Na2SO4, and then spin-dried to obtain a residue. The residue was purified by chromatography (EA:PE = 1 / 4) to obtain compound 59-1.

[0735] Step 2: Synthesis of compound 59-2

[0736] To a 100 mL flask, compound 59-1 (500 mg, 3.2 mmol) and m-CPBA (1.1 g, 6.6 mmol) in 20 mL of DCM were added sequentially, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was slowly added to 20 mL of Na2S2O3 solution and extracted with DCM (20 mL). After standing and separating the layers, the organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous Na2SO4, and spin-dried to obtain a residue. The residue was purified by chromatography (EA:PE = 1 / 4) to obtain compound 59-2.

[0737] Step 3: Synthesis of compound 59-3

[0738] Compound 59-2 (440 mg, 1.3 mmol), cesium carbonate (945 mg, 2.6 mmol), and 10 mL of DMF were added sequentially to a 50 mL flask, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was slowly added to 30 mL of water and extracted with EA (20 mL). After standing and separating the layers, the organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous Na2SO4, and spin-dried to obtain a residue. The residue was purified by chromatography (EA:PE = 1 / 4) to obtain compound 59-3.

[0739] Step 4: Synthesis of compound 59-4

[0740] Compound 59-3 (445 mg, 0.9 mmol) was dissolved in 10 mL of HCl in 1,4-dioxane (1.5 mol / L), and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction solution was slowly added to 30 mL of NaHCO₃ and extracted with EA (20 mL). After standing and separating the layers, the organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous Na₂SO₄, and spin-dried to obtain compound 59-4.

[0741] Step 5: Synthesis of compound 59

[0742] Compound 59-4 (140 mg, 0.3 mmol) was dissolved in 10 mL of DCM solution, and acryloyl chloride (36 mg, 0.4 mmol) and DIPEA (77 mg, 0.6 mmol) were added sequentially. The mixture was then stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was slowly added to 30 mL of H2O and extracted with DCM (20 mL). After standing to separate the layers and separating the layers, the organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous Na2SO4, and dried to a residue. The residue was purified by preparative chromatography to obtain compound 59.

[0743] 1H NMR(DMSO-d6)δ:8.92-9.07(m,1H),8.63-8.80(m,1H),8.09(s,1H),7.96(dd,J=8.0,4.8Hz,1H),7.88(dd,J=5.2,3.4Hz,1H),7.35 -7.54(m,2H),6.86-6.99(m,1H),6.24-6.58(m,1H),6.00-6.18(m,1H),5.49-5.73(m,1H),3.38-3.78(m,5H),1.99-2.25(m,2H).MS m / z(ESI):450[M+H] + .

[0744] Example 60: Synthesis of Compound 60

[0745] Compound 59-4 (100 mg, 0.2 mmol) was dissolved in 10 mL of DCM solution, and 2-fluoroacrylic acid (40 mg, 0.4 mmol), HATU (228 mg, 0.6 mmol), and DIPEA (77 mg, 0.6 mmol) were added sequentially. The mixture was then stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was slowly added to 30 mL of H2O and extracted with EA (20 mL). After standing to separate the layers and separating the liquids, the organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous Na2SO4, and dried to dryness to a residue. The residue was purified by preparative chromatography to obtain compound 60.

[0746] 1 H NMR(DMSO-d6)δ:8.96-9.06(m,1H),8.65-8.78(m,1H),8.09(s,1H),7.96(dd,J=7.9,4.8Hz,1H),7.88(br d,J=3.3Hz,1H),7.37-7.52(m,2H),6.84-6.99(m,1H),5.18-5.49(m,2H),3.51-3.79(m,4H),3.38-3.88(m,5H),1.97-2.25(m,2H).MS m / z(ESI):468[M+H] + .

[0747] Example 61: Synthesis of Compound 61

[0748] DIPEA (0.12 mL, 0.75 mmol) was added to a THF (2 mL) solution of the crude product of compound 1-6 (95 mg) and stirred for 15 min. 2-Butynoyl chloride (28 μL, 0.33 mmol) was then added to the mixture at 0°C, and the mixture was allowed to warm to room temperature and stirred for 2 hours. TLC (PE:EA=1 / 1) showed the formation of a major spot, and the desired mass was detected on LCMS. Purified water (2 mL) was added to quench the mixture and extracted with EA (3×3 mL). The mixture was then washed three times with saturated brine (3×3 mL), and the combined organic layers were dried and concentrated to obtain a residue. The residue was purified by column chromatography (PE:EA=1 / 1 to pure EA) and HPLC. Compound 61 was obtained after freeze-drying.

[0749] 1 H NMR(DMSO-d6)δ:8.51-8.64(m,1H),8.25(br d,J=7.3Hz,1H),8.10(br s,1H),7.76(br s,1H),7.58-7.71(m,1H),7.47(br d,J=8.5Hz,1H),7.39(br d,J=8.4Hz,1H),6.90(br s,1H),4.14-4.27(m,1H),4.08(br s,1H),3.81-3.94(m,2H),3.73(br s,1H),1.94(s,3H).MS m / z(ESI):384.2[M+H] + .

[0750] Example 64: Synthesis of Compound 64

[0751] To a THF (2 mL) solution of the crude product (95 mg) of compound 1-6 was added DIPEA (0.12 mL, 0.75 mmol) and stirred for 15 min. Crotonoyl chloride (32 μL, 0.33 mmol) was then added to the mixture at 0°C, and the mixture was allowed to rise to room temperature and stirred for 2 hours. TLC (PE:EA=1 / 1) showed the formation of a major spot, and the desired mass was detected on LCMS. Purified water (2 mL) was added to quench the mixture and extracted with EA (3×3 mL). The mixture was then washed three times with saturated brine (3×3 mL), the combined organic layers were dried and concentrated to obtain a residue. The residue was purified by column chromatography (PE:EA=1 / 1 to pure EA) and HPLC. Compound 64 was obtained after freeze-drying.

[0752] 1H NMR(DMSO-d6)δ:8.58(br s,1H),8.24(br s,1H),8.11(br s,1H),7.77(br s,1H),7.65(br s,1H),7.47(br s,1H),7.41(br s,1H),6.91(br MS m / z(ESI):386.1[M+H] + .

[0753] Example 65: Synthesis of Compound 65

[0754] To a solution of crude compound 1-6 (65 mg) in DMF (3 mL) were added 2-cyano-4,4-dimethyl-2-pentenoic acid (26.15 mg, 0.17 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (95.06 mg, 0.25 mmol), and DIPEA (0.11 mL, 0.67 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. TLC (PE:EA = 2 / 1) indicated the formation of a major spot, and the desired mass was detected on LCMS. The mixture was quenched by the addition of purified water (5 mL) and extracted with EA (5 x 3 mL). The mixture was then washed three times with saturated brine (3 x 3 mL), and the combined organic layers were dried and concentrated to obtain a residue. The residue was purified by chromatography (PE:EA = 5 / 1 to 1 / 1) and HPLC. Compound 65 was obtained after lyophilization.

[0755] 1 H NMR(DMSO-d6)δ:8.59(br s,1H),8.20-8.40(m,1H),8.09(br s,1H),7.77(br s,1H),7.66(br s,1H), 7.46(br s,1H),7.40(br s,1H),7.09(br s,1H),6.90(br s,1H),4.18-4.45(m,2H),3.95(br s,2H),3.78-3.90(m,1H),1.15(br s,9H).MS m / z(ESI):453.2[M+H] + .

[0756] Example 66: Synthesis of Compound 66

[0757] To a solution of the crude product (65 mg) of compound 1-6 in DMF (3 mL) were added trans-4-dimethylaminocrotonic acid (22.05 mg, 0.17 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (97.36 mg, 0.26 mmol) and DIPEA (0.06 mL, 0.34 mmol), and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. TLC (DCM:MeOH=10 / 1) showed the formation of a major spot, and the desired mass was detected on LCMS. The mixture was quenched by adding purified water (5 mL) and extracted with EA (5×3 mL). The mixture was then washed three times with saturated brine (3×3 mL), and the combined organic layers were dried and concentrated to obtain a residue. The residue was purified by chromatography (DCM:MeOH=20 / 1 to 10 / 1) and HPLC. Compound 66 was obtained after lyophilization.

[0758] 1 H NMR(DMSO-d6)δ:8.64(dd,J=4.8,1.6Hz,1H),8.31(dd,J=7.9,1.6Hz,1H),8.17(s,1H),7.84(d,J =3.3Hz,1H),7.71(dd,J=7.9,4.8Hz,1H),7.54(dd,J=8.8,1.6Hz,1H),7.46(d,J=8.8Hz,1H),6.96 (d,J=3.3Hz,1H),6.58(dt,J=15.4,6.5Hz,1H),6.15(d,J=15.4Hz,1H),4.32-4.38(m,1H),4.21( dd,J=8.3,5.6Hz,1H),3.94-4.03(m,2H),3.80-3.88(m,1H),2.40(brs,6H),1.99-2.12(m,2H).MS m / z(ESI):429.6[M+H] + .

[0759] Example 109: Synthesis of Compound 109

[0760] Step 1: Synthesis of Compound 109-1

[0761] To a solution of compound 2-bromo-1H-imidazole (1 g, 6.80 mmol) in DMF (20 mL) were added tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (1.88 g, 7.48 mmol) and cesium carbonate (4.43 g, 13.61 mmol). The mixture was stirred at 100°C for 2 hours. The reaction mixture was poured into water (8 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (8 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was added to a silica gel column and eluted with 2:1 PE:EA. The fractions were collected to obtain compound 109-1.

[0762] Step 2: Synthesis of compound 109-2

[0763] To a solution of compound 109-1 (1 g, 3.31 mmol) in DMSO (15 mL) were added 5-(trifluoromethyl)-1H-indole (0.67 g, 3.64 mmol), cuprous iodide (0.13 g, 0.66 mmol), L-proline (0.15 g, 1.32 mmol), and potassium phosphate (1.40 g, 6.62 mmol). The mixture was stirred at 100°C for 18 hours. The reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was added to a silica gel column and eluted with 2:1 PE:EA. Fractions were collected to provide compound 109-2.

[0764] Step 3: Synthesis of compound 109-3

[0765] To a solution of compound 109-2 (325 mg, 0.80 mmol) in dichloromethane (3.5 mL) was added trifluoroacetic acid (0.77 mL). The mixture was stirred at 25°C for 1 hour. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate solution and extracted with dichloromethane (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 109-3.

[0766] Step 4: Synthesis of compound 109

[0767] To a solution of 2-fluoroprop-2-enoic acid (31.75 mg, 0.35 mmol) in DMF (1 mL) were added HATU (111.73 mg, 0.29 mmol) and DIEA (0.10 mL, 0.59 mmol), and the mixture was stirred at 25°C for 0.5 hours. Compound 109-3 (60 mg, 0.20 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was poured into water (1 mL) and extracted with dichloromethane (2 mL x 3). The combined organic phases were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The product was purified by high-performance liquid chromatography (neutral conditions) to yield compound 109.

[0768] 1 H NMR(DMSO-d6)δ:8.11(s,1H),7.94(d,J=1.3Hz,1H),7.76(d,J=3.3Hz,1H),7.52(d,J=8.7Hz,1H),7.39(d,J=8.8Hz,1H),7.18(d,J =1.3Hz,1H),6.92(d,J=3.3Hz,1H),5.38-5.55(m,1H),5.29(dd,J=16.6,3.6Hz,1H),4.74-4.83(m,1H),4.62-4.71(m,1H),4.59(br d,J=4.1Hz,1H),4.23-4.36(m,1H),4.17(br dd,J=10.7,5.3Hz,1H). MS(ESI): m / z=379.1[M+H] + .

[0769] Example 121: Synthesis of Compound 121

[0770] Step 1: Synthesis of compound 121-1

[0771] To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1.09 g, 6.31 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (0.38 g, 9.46 mmol). The mixture was stirred at 0°C for 0.5 hours. 2,3-Dibromopyrazine (1.5 g, 6.31 mmol) was then added. The mixture was stirred at 65°C for 2 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was added to a silica gel column and eluted with 4:1 PE:EA. The fractions were collected to obtain compound 121-1.

[0772] Step 2: Synthesis of compound 121-2

[0773] To a solution of compound 121-1 (500 mg, 1.51 mmol) in toluene (10 mL) were added 4-(trifluoromethyl)aniline (206.46 μL, 1.67 mmol), BrettPhos Pd G3 (137.43 mg, 0.15 mmol), and sodium tert-butoxide (28.83 mg, 0.30 mmol). The mixture was stirred at 100°C for 16 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was added to a silica gel column and eluted with 4:1 PE:EA. The fractions were collected to provide compound 121-2.

[0774] Step 3: Synthesis of compound 121-3

[0775] To a solution of compound 121-2 (300 mg, 0.73 mmol) in dichloromethane (6 mL) was added a 4M HCl solution in 1,4-dioxane (2 mL). The mixture was stirred at 25° C. for 1 hour. The mixture was concentrated to dryness under reduced pressure to obtain compound 121-3.

[0776] Step 4: Synthesis of compound 121

[0777] To a solution of 2-fluoroprop-2-enoic acid (118.06 mg, 1.31 mmol) in DMF (5 mL) were added HATU (415.44 mg, 1.09 mmol) and DIEA (0.8 mL, 4.83 mmol), and the mixture was stirred at 25°C for 0.5 hours. Compound 121-3 (226 mg, 0.73 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was poured into water (5 mL) and extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The product was purified by high-performance liquid chromatography (neutral conditions) to yield compound 121.

[0778] 1H NMR(DMSO-d6)δ:9.05(s,1H),8.11(d,J=8.6Hz,2H),7.83(d,J=3.0Hz,1H),7.68(d,J=8.8Hz,2H), 7.59(d,J=3.1Hz,1H),5.43-5.60(m,2H),5.33(dd,J=16.6,3.6Hz,1H),4.79-4.87(m,1H),4.54(br d, J=10.8Hz, 1H), 4.46 (br dd, J=11.0, 6.9Hz, 1H), 4.22 (br dd, J=11.6, 2.9Hz, 1H). MS(ESI): m / z=383.1[M+H] + .

[0779] Example 122 Synthesis of 2-fluoro-1-(3-(4-(trifluoromethyl)phenoxypyrazin-2-amino)azetidin-1-yl)prop-2-en-1-one (Compound 122)

[0780] Step 1: Synthesis of compound 122-b

[0781] To a solution of compound 122-a (1 g, 4.20 mmol) in DMF (10 mL) were added p-trifluoromethylphenol (0.75 g, 4.62 mmol) and potassium carbonate (0.87 g, 6.31 mmol). The reaction mixture was stirred at 100°C for 6 hours, quenched with water (10 mL), and extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated sodium chloride solution (10 mL x 3), dried, and concentrated. The resulting residue was purified by silica gel column chromatography to yield compound 122-b.

[0782] Step 2: Synthesis of compound 122-d

[0783] To a solution of compound 122-b (800 mg, 2.51 mmol) in toluene (10 mL) were added compound 124-c (57.72 mg, 0.43 mmol), BrettPhos Pd G3 (227.53 mg, 0.25 mmol), and sodium tert-butoxide (18.07 mg, 0.19 mmol). The reaction mixture was stirred at 100°C for 16 hours under nitrogen, then cooled to room temperature, quenched with water (10 mL), and extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated sodium chloride solution (10 mL x 3), dried, and concentrated. The resulting residue was purified by silica gel column chromatography to yield compound 122-d.

[0784] Step 3: Synthesis of compound 122-e

[0785] To a solution of compound 122-d (383 mg, 0.933 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at 25°C for 1 hour, then adjusted to pH 7 with saturated sodium bicarbonate solution, diluted with water (3 mL), and extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated sodium chloride solution (10 mL x 3), dried, and concentrated to yield compound 122-e.

[0786] Step 4: Synthesis of compound 122

[0787] To a solution of compound 122-e (279 mg, 0.899 mmol) in DMF (3 mL) were added 2-fluoroacrylic acid (145.75 mg, 1.619 mmol), EDCI (344.75 mg, 1.798 mmol), HOBt (243.00 mg, 1.798 mmol), and DIEA (0.594 mL, 3.597 mmol). The reaction mixture was stirred at room temperature for 18 hours, quenched with water (5 mL), and extracted with dichloromethane (5 mL*3). The organic phase was washed with saturated sodium chloride solution (2 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Purification by HPLC (neutral conditions) afforded compound 122 (200 mg, 0.523 mmol, 58.18% yield). MS m / z (ESI): 383.10 [M+H] + .

[0788] 1 H NMR(DMSO-d6)δ:7.78-7.84(m,3H),7.77(d,J=3.0Hz,1H),7.46(d,J=8.5Hz,2H),7.29(d,J=3.0Hz,1H),5.39- 5.55(m,1H),5.30(dd,J=16.6,3.5Hz,1H),4.65-4.78(m,2H),4.27-4.40(m,2H),4.05(dd,J=10.6,4.8Hz,1H).

[0789] Example 124 Synthesis of 1-(3-((5,6-dimethyl-3-(4-(trifluoromethylphenyl)amino)pyrazin-2-yl)oxy)azetidin-1-yl)-2-fluoroprop-2-en-1-one (Compound 124)

[0790] Step 1: Synthesis of compound 124-b

[0791] Compound 124-a (500 mg, 2.82 mmol) was dissolved in DMF (5 mL). Sodium tert-butoxide (271.42 mg, 2.82 mmol) and tert-butyl 3-hydroxyazetidine-1-carboxylate (489.21 mg, 2.82 mmol) were added and stirred at 0°C for 2 hours. The mixture was warmed to room temperature, quenched with water (20 mL), and extracted with EA (20 mL). The organic phase was washed with water (10 mL x 2), dried, and concentrated. The residue was purified by silica gel column chromatography using a 4 / 1 system (petroleum ether / ethyl acetate) as the eluent to afford the title compound 124-b.

[0792] Step 2: Synthesis of compound 124-c

[0793] Compound 124-b (408 mg, 1.30 mmol), 4-(trifluoromethyl)aniline (230.46 mg, 1.43 mmol), sodium tert-butoxide (187.43 mg, 1.95 mmol), and BrettPhos Pd G3 (236.0 mg, 0.26 mmol) were dissolved in 1,4-dioxane (5 ml). Under nitrogen, the reaction mixture was stirred at 100°C overnight, cooled to room temperature, quenched by the addition of water (20 mL), and extracted with EA (20 mL). The organic phase was washed with water (10 mL x 2), dried, and concentrated. The residue was purified by silica gel column chromatography using a 4 / 1 system (petroleum ether / ethyl acetate) as the eluent to obtain the title compound 124-c.

[0794] Step 3: Synthesis of compound 124-d

[0795] Compound 124-c (511 mg, 1.17 mmol) was dissolved in 5 mL of DCM, and 2 mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for one hour. The pH was adjusted to neutral with saturated sodium bicarbonate solution, quenched with water (20 mL), and extracted with EA (20 mL). The organic phase was washed with water (10 mL x 2), dried, and concentrated. The residue was purified by silica gel column chromatography using a 4 / 1 system (petroleum ether / ethyl acetate) to yield the title compound 124-d.

[0796] Step 4: Synthesis of compound 124

[0797] 2-Fluoroacrylic acid (78.30 mg, 0.0.87 mmol) was dissolved in 2 mL of DMF, and HOBT (234.98 mg, 1.74 mmol), EDCI (500.03 mg, 2.61 mmol), and DIEA (449.51 mg, 3.48 mmol) were added. The mixture was stirred at room temperature for half an hour, and then compound 124-d (353 mg, 1.04 mmol) was added. The mixture was allowed to react for another hour, quenched by the addition of water (20 mL), and extracted with EA (20 mL). The organic phase was washed with water (10 mL*2), dried, concentrated, and purified by high-performance liquid chromatography (instrument: LAIPU_LP3050_UV2000, column: LAIPU-SAC prep HPLC-C18-7um-30*250mm; mobile phase: A:A:10 mM NH4HCO3 / H2O B:ACN, gradient ratio: acetonitrile 45%-55%, flow rate: 30 mL / min) to obtain compound 124 (10 mg, 0.02 mmol, 2.80%).

[0798] MS m / z(ESI):411.0[M+H] + . 1 H NMR(DMSO-d6,400MHz)δ8.80(br s,1H),8.08(br d,2H,J=7.6Hz),7.63(br d,2H,J=8.0Hz),5.5-5.6(m,1H),5.5-5.5(m,1H),5.43(br d,1H,J=9.8Hz),5.4-5.7(m,1H),5.3-5.4(m,1H),4.7-4.9(m,1H),4.4-4.5(m,2H),4.1-4.2(m,1H),2.3-2.4(m,3H),2.29(br s,3H).

[0799] Example 125 Synthesis of 1-(3-(5-ethyl-6-methyl-3-(4-(trifluoromethyl)phenylamino)pyrazin-2-oxy)azetidin-1-yl)-2-fluoropropyl-2-en-1-one (Compound 125)

[0800] Step 1: Synthesis of compound 125-b

[0801] To a solution of compound 125-a (2 g, 18.16 mmol) in DMF (60 mL) was added compound NBS (3.88 g, 21.79 mmol). The reaction mixture was stirred at 25°C for 2 hours, quenched with water (15 mL), and extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (15 mL x 3), dried, and concentrated. The resulting residue was purified by silica gel column chromatography to yield compound 125-b.

[0802] Step 2: Synthesis of compound 125-d

[0803] To a solution of compound 125-b (2.47 g, 9.22 mmol) in isopropanol (20 mL) was added DIEA (27.75 μL, 0.17 mmol) and compound 125-c (1371.27 μL, 11.06 mmol). The reaction mixture was stirred at 80°C for 16 hours, quenched with water (10 mL), and extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (10 mL x 3), dried, and concentrated. The resulting residue was purified by silica gel column chromatography to yield compound 125-d.

[0804] Step 4: Synthesis of compound 125-e

[0805] To a solution of compound 125-d (1 g, 2.87 mmol) in 1,4-dioxane (18 mL) and water (4 mL) were added potassium vinyl fluoroborate (57.72 mg, 0.43 mmol), potassium carbonate (0.79 g, 5.75 mmol), and Pd(dppf)Cl2.CH2Cl2 (0.23 g, 0.29 mmol). The reaction mixture was stirred at 100°C for 16 hours under nitrogen, then cooled to room temperature, quenched with water (10 mL), and extracted with dichloromethane (10 mL*3). The organic phase was washed with saturated sodium chloride solution (10 mL*3), dried, and concentrated. The resulting residue was purified by silica gel column chromatography to yield compound 125-e.

[0806] Step 4: Synthesis of compound 125-f

[0807] To a solution of compound 125-e (300 mg, 1.02 mmol) in methanol (6 mL) and tetrahydrofuran (1 mL) was added 10% palladium on carbon (60 mg, 0.56 mmol). The system was filled with hydrogen and the reaction mixture was stirred at 25°C for 16 hours, filtered, and the filtrate was concentrated to obtain compound 125-f.

[0808] Step 5: Synthesis of compound 125-h

[0809] To a solution of compound 125-f (100 mg, 0.34 mmol) in NMP (2 mL) were added compound 125-g (58.43 μL, 0.34 mmol) and cesium carbonate (328.80 mg, 1.01 mmol). The reaction mixture was stirred at 50°C for 16 hours, quenched with water (3 mL), and extracted with dichloromethane (3 mL x 3). The organic phase was washed with saturated sodium chloride solution (3 mL x 3), dried, and concentrated. The resulting residue was purified by silica gel column chromatography to yield compound 125-h.

[0810] Step 6: Synthesis of compound 125-i

[0811] To a solution of compound 125-h (134 mg, 0.30 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at 25°C for 1 hour, then adjusted to pH 7 with saturated sodium bicarbonate solution, diluted with water (1 mL), and extracted with dichloromethane (2 mL x 3). The organic phase was washed with saturated sodium chloride solution (1 mL x 3), dried, and concentrated. The resulting residue was purified by silica gel column chromatography to yield compound 125-i.

[0812] Step 7: Synthesis of compound 125

[0813] To a solution of 2-fluoroacrylic acid (47.84 mg, 0.53 mmol) in DMF (2 mL) at 0°C were added HATU (168.34 mg, 0.44 mmol) and DIEA (0.15 mL, 0.89 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, followed by the addition of compound 125-i (104 mg, 0.30 mmol). The reaction mixture was stirred at room temperature for 16 hours, quenched with water (2 mL), and extracted with dichloromethane (2 mL*3). The organic phase was washed with saturated sodium chloride solution (2 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Purification by HPLC (neutral conditions) afforded compound 125 (56.2 mg, 0.13 mmol, yield: 44.67%). MS m / z (ESI): 425.2 [M+H] + .

[0814] 1H NMR(DMSO-d6)δ:8.83(s,1H),8.10(d,J=8.6Hz,2H),7.64(d,J=8.6Hz,2H),5.44-5.59(m,1H), 5.39-5.43(m,1H),5.32(dd,J=16.6,3.6Hz,1H),4.76-4.85(m,1H),4.40-4.51(m,2H),4.17(br dd,J=11.5,3.0Hz,1H),2.66(q,J=7.5Hz,2H),2.31(s,3H),1.23(t,J=7.5Hz,3H).

[0815] Example 128 Synthesis of 1-(3-((6-chloro-3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)oxy)azetidin-1-yl)-2-fluoroprop-2-en-1-one (Compound 128)

[0816] Step 1: Synthesis of compound 128-b

[0817] Compound Boc-3-hydroxyazetidine (1087.92 mg, 6.281 mmol) was dissolved in 20 mL of tetrahydrofuran. Under nitrogen, 60% sodium hydride (292.70 mg, 7.318 mmol) was slowly added portionwise at 0°C. The mixture was stirred at this temperature for 30 minutes. Compound 128-a (1000 mg, 6.098 mmol) was then slowly added portionwise at 0°C. The reaction mixture was slowly heated to 50°C and stirred overnight. After completion of the reaction, 20 mL of water was added to quench the mixture. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B (petroleum ether:ethyl acetate = 4:1) to obtain compound 128-b.

[0818] Step 2: Preparation of compound 128-c

[0819] Compound 128-b (200 mg, 0.665 mmol), p-iodobenzotrifluoride (117.273 μL, 0.798 mmol), XPhos Pd G4 (57.22 mg, 0.067 mmol) and sodium tert-butoxide (95.86 mg, 0.998 mmol) were dissolved in toluene (6.00 mL). The reaction solution was stirred at 80°C for 3 hours. After cooling to room temperature, the reaction solution was quenched by the addition of water (5 mL) and extracted with ethyl acetate (8 mL×3). The organic phases were combined and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate. The desiccant was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B (petroleum ether:ethyl acetate = 5:1) to obtain compound 128-c.

[0820] Step 3: Preparation of compound 128-d

[0821] Compound 128-c (100 mg, 0.225 mmol) was dissolved in 4 mL of dichloromethane, and trifluoroacetic acid (600 μL, 7.835 mmol) was added at 0°C. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was slowly added at 0°C to adjust the pH to neutral. Dichloromethane (5 mL*3) was added, and the organic phases were combined and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the desiccant was filtered out. The filtrate was concentrated under reduced pressure to obtain compound 128-d.

[0822] Step 4: Preparation of compound 128

[0823] Compound 2-fluoroacrylic acid (40.23 mg, 0.447 mmol), HATU (127.40 mg, 0.335 mmol), N,N-diisopropylethylamine (118.972 μL, 0.670 mmol) and DMAP (2.73 mg, 0.022 mmol) were dissolved in dimethylformamide (3 mL). A solution of 128-d (75.79 mg, 1.009 mmol) in dimethylformamide (1 mL) was added and the mixture was reacted at room temperature overnight. After the reaction was completed, 5 mL of water was added to quench the reaction. The mixture was extracted with ethyl acetate (8 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B (petroleum ether:ethyl acetate = 3:1) to give compound 128 (50 mg, yield: 53.80%).

[0824] MS m / z(ESI):417.0[M+1] + . 1H NMR (400MHz, DMSO-d6): δ9.19 (s, 1H), 8.07-8.02 (m, J = 8.6Hz, 2H), 7.91 (s, 1H), 7. 73-7.64(m,J=8.6Hz,2H),5.59-5.42(m,2H),5.34(dd,J=3.6,16.6Hz,1H),4.82(br s,1H),4.56(br d,J=10.4Hz,1H),4.43(br d,J=6.8Hz,1H),4.31-4.19(m,1H).

[0825] Example 131 Synthesis of 2-fluoro-1-(3-(6-methoxy-3-(4-(trifluoromethylphenyl)amino)pyrazin-2-yl)oxy)azetidin-1-yl)prop-2-en-1-one (Compound 131)

[0826] Step 1: Preparation of compound 131-b

[0827] 60% NaH (1346.42 mg, 33.661 mmol) was dissolved in THF (100 mL) at 0°C. 2-Methylpropan-2-yl 3-hydroxyazetidine-1-carboxylate (5004.38 mg, 28.892 mmol) was slowly added and stirred for 30 min. Then, 131a (4600 mg, 28.050 mmol) was added. The reaction mixture was stirred at 50°C overnight, cooled to room temperature, quenched by the addition of water (30 mL), and extracted with EA (100 mL*2). The organic phase was washed with sodium chloride (20 mL) and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (petroleum ether / ethyl acetate: 4 / 1) to obtain the title compound 131-b.

[0828] Step 2: Preparation of compound 131-c

[0829] 131-b (5000 mg, 16.626 mmol), 4-(trifluoromethyl)aniline (2931.828 μL, 19.951 mmol), XPhos Pd G4 (57.22 mg, 0.067 mmol), and sodium tert-butoxide (2396.59 mg, 24.938 mmol) were dissolved in toluene (80 mL). Under nitrogen, the reaction mixture was stirred at 80°C for 3 hours, cooled to room temperature, quenched with water (20 mL), and extracted with EA (200 mL). The organic phase was washed with sodium chloride (20 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 4 / 1 system (petroleum ether / ethyl acetate) as the eluent to obtain the title compound 131-c.

[0830] Step 3: Preparation of compound 131-d

[0831] 131-c (1.5 g, 3.066 mmol) was dissolved in 1,4-dioxane (30 mL), and methanol (0.683 mL, 16.860 mmol), t-Bubrettphos (0.65 g, 1.349 mmol), Pd2(dba)3 (0.62 g, 0.674 mmol), and sodium tert-butoxide (0.45 g, 4.721 mmol) were added. Under nitrogen, the reaction mixture was stirred at 50°C for 8 hours, cooled to room temperature, quenched by the addition of water (8 mL), and extracted with EA (100 mL). The organic phase was washed with sodium chloride (8 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (petroleum ether / ethyl acetate: 5 / 1) to obtain the title compound 131-d.

[0832] Step 4: Preparation of compound 131-e

[0833] 131d (1.4 g, 3.179 mmol) was dissolved in dichloromethane (1 mL) at 0°C, and trifluoroacetic acid (1 mL, 13.059 mmol) was slowly added dropwise. The reaction mixture was stirred at 25°C for 1 hour, quenched with saturated sodium bicarbonate (5 mL), and extracted with EA (20 mL). The organic phase was washed with sodium chloride (5 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound 131-e.

[0834] Step 5: Preparation of compound 131

[0835] Difluoroacrylic acid (582.15 mg, 6.465 mmol), HATU (1843.60 mg, 4.849 mmol), DIEA (1721.624 μL, 9.697 mmol), and DMAP (39.49 mg, 0.323 mmol) were dissolved in DMF (20 mL) and stirred at room temperature for 10 minutes. Then, 131-e (1.1 g, 3.191 mmol) was added. The mixture was allowed to react overnight, quenched by the addition of water (10 mL), and extracted with EA (50 mL*2). The organic phase was washed with sodium chloride (10 mL), dried, and concentrated. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (petroleum ether / ethyl acetate: 1 / 1) to provide the title compound 131 (617.88 mg, yield: 45.70%).

[0836] MS m / z(ESI):413[M+H]+. 1 H NMR (400MHz, DMSO-d6) δ=8.74(s,1H),7.92(d,J=8.6Hz,2H),7.59(d,J=8.8Hz,2H),7.54(s,1H) ,5.58-5.43(m,2H),5.33(dd,J=3.6,16.6Hz,1H),4.93-4.76(m,1H),4.57-4.45(m,2H),4.21(br dd,J=2.9,11.3Hz,1H),3.83(s,3H).

[0837] Example 133 Synthesis of 1-(3-(6-difluoromethyl)-3-(4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)oxy)azetidin-1-yl)-2-fluoroprop-2-en-1-one (Compound 133)

[0838] Step 1: Synthesis of compound 133-c

[0839] To a solution of compound 133-b (2.51 g, 14.472 mmol) in tetrahydrofuran (10 mL) was added sodium hydroxide (0.63 g, 15.678 mmol). The reaction mixture was stirred at 0°C for 0.5 hours, followed by the addition of compound 133-a (3.05 g, 12.060 mmol). The reaction mixture was stirred at 50°C for 16 hours, quenched with water (10 mL), and extracted with dichloromethane (15 mL*3). The organic phase was washed with saturated sodium chloride solution (10 mL*3), dried, and concentrated. The resulting residue was purified by silica gel column chromatography to yield compound 133-c.

[0840] Step 2: Synthesis of compound 133-d

[0841] To a solution of compound 133-c (1 g, 2.87 mmol) in 1,4-dioxane (15 mL) and water (5 mL) were added potassium vinyl fluoroborate (0.45 g, 4.780 mmol), sodium carbonate (0.92 g, 8.691 mmol), and Pd(dppf)Cl2.CH2Cl2 (0.36 g, 0.435 mmol). The reaction mixture was stirred at 100°C for 18 hours under nitrogen, then cooled to room temperature, quenched with water (10 mL), and extracted with dichloromethane (10 mL*3). The organic phase was washed with saturated sodium chloride solution (5 mL*3), dried, and concentrated. The resulting residue was purified by silica gel column chromatography to yield compound 133-d.

[0842] Step 3: Synthesis of compound 133-e

[0843] To a solution of compound 133-d (1.03 g, 3.523 mmol) in toluene (15 mL) were added p-trifluoromethyliodobenzene (1.05 g, 3.876 mmol), XPhos Pd G2 (0.28 g, 0.352 mmol), and tBuONa (6.57 mg, 0.068 mmol). The reaction mixture was stirred at 100°C for 5 hours under nitrogen, cooled to room temperature, quenched with water (15 mL), and extracted with dichloromethane (15 mL x 3). The organic phase was washed with saturated sodium chloride solution (15 mL x 3), dried, and concentrated. The resulting residue was purified by silica gel column chromatography to yield compound 133-e.

[0844] Step 4: Synthesis of compound 133-f

[0845] To a solution of compound 133-e (400 mg, 0.917 mmol) in 1,4-dioxane (15 mL) and water (5 mL) were added sodium periodate (784.13 mg, 3.666 mmol) and potassium osmate monohydrate (10.13 mg, 0.027 mmol). The reaction mixture was stirred at 25°C for 1 hour, quenched with water (5 mL), and extracted with dichloromethane (15 mL*3). The organic phase was washed with saturated sodium chloride solution (5 mL*3), dried, and concentrated. The resulting residue was purified by silica gel column chromatography to obtain compound 133-f.

[0846] Step 5: Synthesis of compound 133-g

[0847] To a solution of compound 133-f (246 mg, 0.561 mmol) in dichloromethane (2 mL) at 0°C was added DAST (3 mL, 22.706 mmol). The reaction mixture was stirred at 25°C for 1 hour and then added dropwise to an ice-cold saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (5 mL x 3). The organic phase was washed with saturated sodium chloride solution (2 mL x 3), dried, and concentrated. The resulting residue was purified by silica gel column chromatography to obtain compound 133-g.

[0848] Step 6: Synthesis of compound 133-h

[0849] To a solution of compound 133-g (178 mg, 0.387 mmol) in dichloromethane (2 mL) at 0°C was added trifluoroacetic acid (0.5 mL, 0.022 mmol). The reaction mixture was stirred at 25°C for 1 hour, then adjusted to pH 7 with saturated sodium bicarbonate solution, diluted with water (3 mL), and extracted with dichloromethane (5 mL x 3). The organic phase was washed with saturated sodium chloride solution (2 mL x 3), dried, and concentrated to yield compound 133-h.

[0850] Step 7: Synthesis of compound 133

[0851] To a solution of compound 133-h (137 mg, 0.380 mmol) in DMF (2 mL) were added 2-fluoroacrylic acid (61.63 mg, 0.684 mmol), EDCI (145.79 mg, 0.760 mmol), HOBt (102.76 mg, 0.760 mmol), and DIEA (0.251 mL, 1.521 mmol). The reaction mixture was stirred at room temperature for 4 hours, quenched with water (5 mL), and extracted with dichloromethane (5 mL*3). The organic phase was washed with saturated sodium chloride solution (2 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Purification by HPLC (neutral conditions) afforded compound 133 (93.5 mg, 0.216 mmol, 56.81% yield). MS m / z (ESI): 433.10 [M+H] + .

[0852] 1H NMR(DMSO-d6)δ:9.39(s,1H),8.12(d,J=8.5Hz,2H),8.07(s,1H),7.72(d,J=8.8Hz,2H),6.89( t,J=54.5Hz,1H),5.42-5.59(m,2H),5.33(dd,J=16.6,3.6Hz,1H),4.77-4.87(m,1H),4.56(br d,J=10.6Hz,1H),4.45(br dd,J=11.2,6.9Hz,1H),4.20-4.29(m,1H).

[0853] Example 135 Synthesis of 1-(3-(6-amino-3-(4-(trifluoromethylphenyl)aminopyrazin-2-oxy)azetidin-1-yl)-2-fluoropropyl-2-en-1-one (Compound 135)

[0854] Step 1: Synthesis of compound 135-a

[0855] 131-b (2.5 g, 5.620 mmol) was dissolved in toluene (30 mL), and tert-butyl carbamate (0.79 g, 6.744 mmol), BrettPhos Pd G3 (0.51 g, 0.562 mmol), and sodium tert-butoxide (1.08 g, 11.240 mmol) were added. Under nitrogen, the reaction mixture was stirred at 100°C overnight, cooled to room temperature, quenched with water (10 mL), and extracted with EA (100 mL). The organic phase was washed with sodium chloride (10 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 5 / 1 system (petroleum ether / ethyl acetate) as the eluent to obtain the title compound 135-a.

[0856] Step 2: Synthesis of compound 135-b

[0857] 135-a (2.28 g, 4.338 mmol) was dissolved in dichloromethane (10 mL) at 0°C, and trifluoroacetic acid (4 mL, 52.236 mmol) was slowly added dropwise. The reaction mixture was stirred at 25°C for 1 hour, quenched with saturated sodium bicarbonate (8 mL), and extracted with EA (50 mL). The organic phase was washed with sodium chloride (5 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound 135-b.

[0858] Step 3: Preparation of compound 135

[0859] 2-Fluoroacrylic acid (582.15 mg, 6.465 mmol), HATU (1843.60 mg, 4.849 mmol), DIEA (1721.624 μL, 9.697 mmol) and DMAP (39.49 mg, 0.323 mmol) were dissolved in DMF (20 mL) and stirred at room temperature for 10 min. Then, 135--b (1.1 g, 3.191 mmol) was added. The mixture was allowed to react overnight, quenched by the addition of water (10 mL), and extracted with EA (50 mL*2). The organic phase was washed with sodium chloride (10 mL), dried, and concentrated. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (instrument: Gilson_306_1741, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm; mobile phase: A: 0.05% TFA / H2O). The mixture was purified by HPLC (B: ACN, gradient ratio: acetonitrile 5-95, flow rate: 35 mL / min) to afford 135 (269 mg, yield: 15.78%).

[0860] MS m / z(ESI):398[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 8.35 (s, 1H), 7.67 (d, J = 8.6Hz, 2H), 7.51 (d, J = 8.8Hz, 2H), 7.21 (s, 1H), 5.57-5.43 (m, 1H), 5.37-5.28 (m, 2H), 4.78 (br dd,J=4.6,10.3Hz,1H),4.42(br dd,J=7.5,10.5Hz,2H),4.10(br dd,J=3.1,11.4Hz,1H)).

[0861] Example 159 Synthesis of 2-fluoro-1-(4-(4-(trifluoromethylphenyl)amino)pyrimidin-5-yl)oxy)azetidin-1-yl)prop-2-en-1-one (Compound 159)

[0862] Step 1: Preparation of compound 159-b

[0863] 60% NaH (1518.40 mg, 37.96 mmol) was dissolved in DMF (20 mL) at 0°C. 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (4925.31 mg, 28.47 mmol) was slowly added and stirred for 30 min. Then, 163a (3000 mg, 18.98 mmol) was added. The reaction mixture was stirred at 80°C overnight, cooled to room temperature, quenched by the addition of water (30 mL), and extracted with EA (20 mL*2). The organic phase was washed with sodium chloride (20 mL) and dried over anhydrous sodium sulfate. The desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (petroleum ether / ethyl acetate: 4 / 1) to give the title compound 159-b.

[0864] Step 2: Preparation of compound 159-c

[0865] 159-b (2400 mg, 9.56 mmol) was dissolved in DCM (30 ml) and m-CPBA (2466.93 mg, 14.34 mmol) was slowly added under nitrogen. The reaction mixture was stirred at room temperature overnight, quenched with saturated sodium sulfite (20 mL), and extracted with DCM (50 mL). The organic phase was washed with sodium chloride (20 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound 159-c.

[0866] Step 3: Preparation of compound 159-d

[0867] 159-c (460 mg, 1.72 mmol) was dissolved in DCM (20 ml), and POCl (0.48 mL, 5.16 mmol) and DIPEA (0.92 mL, 5.16 mmol) were slowly added. The reaction mixture was stirred at 80°C for 3 hours, cooled to room temperature, quenched by the slow addition of ice water (20 mL), and extracted with DCM (20 mL). The organic phase was washed with sodium chloride (20 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 4 / 1 system (petroleum ether / ethyl acetate) as the eluent to afford the title compound 159-d.

[0868] Step 4: Preparation of compound 159-e

[0869] Compound 159-d (320 mg, 1.12 mmol) was dissolved in DMSO (10 ml), and p-trifluoromethylaniline (360.64 mg, 2.24 mmol) and potassium tert-butoxide (250.88 mg, 2.24 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, quenched by the addition of water (20 mL), and extracted with EA (10 mL). The organic phase was washed with sodium chloride (10 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 4 / 1 system (petroleum ether / ethyl acetate) as the eluent to afford the title compound 159-e.

[0870] Step 5: Preparation of compound 159-f

[0871] 159-e (310 mg, 0.75 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (1 mL, 13.059 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 1 hour, quenched with saturated sodium bicarbonate (5 mL), and extracted with EA (20 mL). The organic phase was washed with sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain the title compound 159-f.

[0872] Step 6: Preparation of compound 159

[0873] Difluoroacrylic acid (41.40 mg, 0.56 mmol), HATU (249.60 mg, 0.92 mmol) and DIEA (0.24 mL, 1.38 mmol) were dissolved in DMF (10 mL) and stirred at room temperature for 10 minutes. Then 159-f (145 mg, 0.46 mmol) was added. The mixture was allowed to react overnight, quenched by adding water (10 mL), and extracted with EA (10 mL*2). The organic phase was washed with sodium chloride (10 mL), dried and concentrated. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (instrument: Gilson_306_1741, column: Waters-CORTECS-C18-2.7μm-4.6*30mm; mobile phase: A: 0.05% TFA / H2O) Compound 159 (65 mg, yield: 12.33%) was obtained by purification using the HPLC-MS / ...

[0874] MS m / z(ESI):383.3[M+H] + . 1H NMR (400MHz, DMSO-d6) δ = 9.16 (s, 1H), 8.39 (s, 1H), 8.13-8.08 (m, 2H), 7.95 (s, 1H), 7.74-7.69 (m, 2H), 5.60 -5.44(m,1H),5.38-5.31(m,1H),5.27-5.20(m,1H),4.93-4.83(m,1H),4.60-4.46(m,2H),4.26-4.14(m,1H)

[0875] Example 160 Synthesis of 2-fluoro-1-(3-(2-(4-(trifluoromethylphenyl)amino)pyridin-3-yl)oxy)azetidin-1-yl)prop-2-en-1-one (Compound 160)

[0876] Step 1: Synthesis of compound 160-b

[0877] 160-a (1 g, 5.75 mmol) was dissolved in THF (10 mL) at 0°C, and 2-methylprop-2-yl 3-hydroxyazetidine-1-carboxylate (1.00 g, 5.75 mmol), triphenylphosphine (2.26 g, 8.62 mmol) and finally DIAD (1.74 g, 8.62 mmol) were added. The reaction mixture was stirred at 50°C for 6 hours, cooled to room temperature, quenched by the addition of water (10 mL), and extracted with EA (30 mL*2). The organic phase was washed with sodium chloride (10 mL) and dried over anhydrous sodium sulfate. The desiccant was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (petroleum ether / ethyl acetate: 2 / 1) to give the title compound 160-b.

[0878] Step 2: Synthesis of compound 160-c

[0879] 160-b (300 mg, 0.911 mmol) was dissolved in 1,4-dioxane (6 mL). 4-(Trifluoromethyl)aniline (0.126 mL, 1.002 mmol), Pd2(dba)3 (83.45 mg, 0.091 mmol), Xantphos (158.20 mg, 0.273 mmol), and sodium tert-butoxide (175.16 mg, 1.823 mmol) were added. Under nitrogen, the reaction mixture was stirred at 100°C overnight, cooled to room temperature, quenched with water (2 mL), and extracted with EA (20 mL x 2). The organic phase was washed with sodium chloride (2 mL) and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 3 / 1 system (petroleum ether / ethyl acetate) as the eluent to afford the title compound 160-c.

[0880] Step 3: Synthesis of compound 160-d

[0881] 160-c (265 mg, 0.647 mmol) was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (1 mL, 13.059 mmol) was slowly added dropwise. The reaction mixture was stirred at 25°C for 1 hour, quenched with saturated sodium bicarbonate (3 mL), and extracted with EA (20 mL x 2). The organic phase was washed with sodium chloride (3 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound 160-d.

[0882] Step 4: Synthesis of compound 160

[0883] 2-Fluoroacrylic acid (55.32 mg, 0.614 mmol) was dissolved in DMF (5 mL), and HATU (467.17 mg, 1.229 mmol) and DIEA (0.203 mL, 1.229 mmol) were added. The mixture was stirred at room temperature for 10 mins, and then 160d (190 mg, 0.614 mmol) was added. The mixture was stirred at 25 ° C for 3 hours, quenched by adding water (3 mL), and extracted with EA (25 mL * 2). The organic phase was washed with sodium chloride (3 mL), dried, and concentrated. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (instrument: Waters_2545_QDA / 2998, column: Waters-SunFire-C18-10μm-19*250mm; mobile phase: A:A:0.1% FA / H2O B:ACN, gradient ratio: acetonitrile 5-95, flow rate: 20 mL / min) to obtain 160 (121.52 mg, yield: 51.84%).

[0884] MS m / z(ESI):382[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 8.64 (s, 1H), 8.08 (d, J = 8.6Hz, 2H), 7.85 (dd, J = 1.1, 5.0Hz, 1H), 7.62 (d, J = 8.6Hz, 2H), 7.07 (d, J = 7.8Hz, 1H), 6.85 (dd, J=5.0,7.8Hz,1H),5.60-5.44(m,1H),5.34(dd,J=3.6,16.6Hz,1H),5.2 1-5.12(m,1H),4.93-4.79(m,1H),4.58-4.43(m,2H),4.23-4.11(m,1H).

[0885] Example 163 Synthesis of 2-fluoro-1-(3-((6-(trifluoromethyl)pyridin-3-amino)pyrazin-2-yl)oxy)azetidin-1-yl)prop-2-en-1-one (Compound 163)

[0886] Step 1: Synthesis of compound 163-b

[0887] 60% NaH (800 mg, 20.00 mmol) was dissolved in DMF (20 mL) at 0°C, tert-butyl 3-hydroxyazetidine-1-carboxylate (2595 mg, 15.00 mmol) was slowly added and stirred for 30 min. Compound 163-a (2370 mg, 10.00 mmol) was then added. The reaction mixture was stirred at 80°C overnight, cooled to room temperature, quenched with water (30 mL), and extracted with EA (20 mL*2). The organic phase was washed with sodium chloride (20 mL) and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (petroleum ether / ethyl acetate: 4 / 1) to give the title compound 163-b.

[0888] Step 2: Synthesis of compound 163-c

[0889] 163-b (200 mg, 0.60 mmol) was dissolved in dioxane (10 mL), and 6-(trifluoromethyl)pyridin-3-amine (162 mg, 1.00 mmol), BrettPhos Pd G3 (54.36 mg, 0.06 mmol), and sodium tert-butoxide (175.16 mg, 1.80 mmol) were added. Under nitrogen, the reaction mixture was stirred at 100°C overnight, cooled to room temperature, quenched with water (10 mL), and extracted with EA (20 mL x 2). The organic phase was washed with sodium chloride (5 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 3 / 1 system (petroleum ether / ethyl acetate) as the eluent to afford the title compound 163-c.

[0890] Step 3: Synthesis of compound 163-d

[0891] 163-c (110 mg, 0.26 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (1 mL, 13.059 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 1 hour, quenched with saturated sodium bicarbonate (5 mL), and extracted with EA (20 mL). The organic phase was washed with sodium chloride (5 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound 163-d.

[0892] Step 4: Synthesis of compound 163

[0893] Difluoroacrylic acid (25.20 mg, 0.28 mmol), HATU (144.10 mg, 0.38 mmol) and DIEA (0.09 mL, 0.54 mmol) were dissolved in DMF (5 mL) and stirred at room temperature for 10 minutes. Then 163-d (60 mg, 0.19 mmol) was added. The mixture was allowed to react overnight, quenched by adding water (10 mL), and extracted with EA (10 mL*2). The organic phase was washed with sodium chloride (10 mL), dried and concentrated. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (instrument: Gilson_306_1741, column: Waters-CORTECS-C18-2.7μm-4.6*30mm; mobile phase: A: 0.05% TFA / H2O) Compound 163 (8 mg, yield: 10.99%) was obtained by purification using the HPLC-MS / ...

[0894] MS m / z(ESI):384.1[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 9.31 (s, 1H), 9.15 (d, J = 2.5Hz, 1H), 8.62 (dd, J = 2.4, 8.6Hz, 1H), 7.88-7.83 (m, 2H), 7.6 5(d,J=3.1Hz,1H),5.58-5.31(m,2H),5.61-5.42(m,1H),4.90-4.78(m,1H),4.60-4.39(m,2H),4.28-4.16(m,1H)

[0895] Example 169 Synthesis of 2-fluoro-1-(3-(3-((4-(pentafluoro-6-sulfonylamino)phenyl)amino)pyrazin-2-yl)oxy)azetidin-1-yl)prop-2-en-1-one (Compound 169)

[0896] Step 1: Synthesis of compound 169-c

[0897] Compound 169-a (2 g, 8.4 mmol) and compound 169-b (1.46 g, 8.4 mmol) were dissolved in N,N-dimethylformamide (20 mL), and sodium tert-butoxide (806 mg, 8.4 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. 100 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (EA / PE) to obtain the title compound 169-c.

[0898] Step 2: Synthesis of compound 169-e

[0899] Compound 169-c (2.5 g, 7.58 mmol), compound 169-d (1.66 g, 7.58 mmol), BrettPhos Pd G3 (686.7 mg, 0.76 mmol), and sodium tert-butoxide (1.46 g, 15.2 mmol) were dissolved in dioxane (30 mL) and stirred at 100°C under a nitrogen atmosphere for 18 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (EA / PE) to obtain the title compound 169-e.

[0900] Step 3: Synthesis of compound 169-f

[0901] Compound 169-e (2.8 g, 6.0 mmol) was dissolved in dichloromethane (30 mL), trifluoroacetic acid (4.6 g, 60 mmol) was added in an ice bath, and the reaction was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered out, and the filtrate was concentrated under reduced pressure to obtain the title compound 169-f.

[0902] Step 4: Synthesis of compound 169

[0903] Compound 169-f (2 g, 5.4 mmol) was dissolved in N,N-dimethylformamide (20 mL), and compound 169-g (538 mg, 5.9 mmol), HATU (4.1 g, 10.8 mmol) and N,N-diisopropylethylamine (2 g, 16.2 mmol) were added. The mixture was stirred at room temperature for 12 hours. 100 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to give the title compound 169 (1 g, yield: 43%).

[0904] MS m / z(ESI):441.0[M+1] + . 1 H NMR (400MHz, DMSO-d6) δ = 8.02 (d, J = 9.1Hz, 2H), 7.78 (d, J = 3.0Hz, 1H), 7.75-7.70 (m, 2H), 7.54 (d, J = 3.1 Hz,1H),5.64-5.50(m,2H),5.23(dd,J=3.4,16.1Hz,1H),4.94-4.87(m,1H),4.63-4.52(m,2H),4.28(br dd,J=2.6,11.8Hz,1H).

[0905] Example 175 Synthesis of 2-fluoro-1-(3-((4-(trifluoromethoxy)phenyl)amino)pyrazin-2-yl)oxy)azetidin-1-yl)prop-2-en-1-one (Compound 175)

[0906] Step 1: Synthesis of compound 175-b

[0907] 60% NaH (800 mg, 20.00 mmol) was dissolved in DMF (20 mL) at 0°C, tert-butyl 3-hydroxyazetidine-1-carboxylate (2595 mg, 15.00 mmol) was slowly added, and the mixture was stirred for 30 min. Compound 175-a (2370 mg, 10.00 mmol) was then added. The reaction mixture was stirred at 80°C overnight, cooled to room temperature, quenched with water (30 mL), and extracted with EA (20 mL*2). The organic phase was washed with sodium chloride (20 mL) and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (petroleum ether / ethyl acetate: 4 / 1) to give the title compound 175b.

[0908] Step 2: Synthesis of compound 175-c

[0909] 175-b (200 mg, 0.60 mmol) was dissolved in dioxane (10 mL), and p-trifluoromethylaniline (0.126 mL, 1.00 mmol), BrettPhos Pd G3 (54.36 mg, 0.06 mmol), and sodium tert-butoxide (175.16 mg, 1.80 mmol) were added. Under nitrogen, the reaction mixture was stirred at 100°C overnight, cooled to room temperature, quenched with water (10 mL), and extracted with EA (20 mL x 2). The organic phase was washed with sodium chloride (5 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 3 / 1 system (petroleum ether / ethyl acetate) as the eluent to afford the title compound 175-c.

[0910] Step 3: Preparation of compound 175-d

[0911] 175-c (160 mg, 0.37 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (1 mL, 13.059 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 1 hour, quenched with saturated sodium bicarbonate (5 mL), and extracted with EA (20 mL). The organic phase was washed with sodium chloride (5 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound 175-d-.

[0912] Step 4: Preparation of compound 175

[0913] 2-Fluoroacrylic acid (49.69 mg, 0.55 mmol), HATU (205.20 mg, 0.54 mmol) and DIEA (0.14 mL, 0.81 mmol) were dissolved in DMF (5 mL) and stirred at room temperature for 10 minutes. Then 175-d (90 mg, 0.27 mmol) was added. The mixture was allowed to react overnight, quenched by adding water (10 mL), and extracted with EA (10 mL*2). The organic phase was washed with sodium chloride (10 mL), dried and concentrated. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (instrument: Gilson_306_1741, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm; mobile phase: A: 0.05% TFA / H2O) Compound 175 (22 mg, yield: 20.47%) was purified by HPLC (B: ACN, gradient ratio: acetonitrile 5-95, flow rate: 35 mL / min).

[0914] MS m / z(ESI):399.3[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 8.87 (s, 1H), 7.99-7.93 (m, 2H), 7.76 (d, J = 3.1Hz, 1H), 7.52 (d, J = 3.0Hz, 1H), 7.33 (d, J = 8. 5Hz,2H),5.65-5.43(m,2H),5.33(dd,J=3.6,16.6Hz,1H),4.88-4.76(m,1H),4.56-4.39(m,2H),4.25-4.16(m,1H).

[0915] Example 176 Synthesis of (E)-1-(3-((4-(pentafluoro-16-sulfanyl)phenylamino)pyrazin-2-yl)oxy)azetidin-1-yl)but-2-en-1-one (Compound 176)

[0916] Step 1: Preparation of compound 176

[0917] To a solution of compound 169-f (50 mg, 0.136 mmol) in DMF (1 mL) at 0°C were added triethylamine (56.711 μL, 0.408 mmol) and crotonyl chloride (15.6 μL, 0.163 mmol). The reaction mixture was stirred at room temperature for 1 hour, quenched by addition of aqueous solution (5 mL), and extracted with dichloromethane (5 mL*3). The organic phase was washed with saturated sodium chloride solution (2 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Purification by HPLC (neutral conditions) afforded compound 176 (15 mg, 0.034 mmol, yield: 25.32%). MS m / z (ESI): 437.1 [M+H] + . 1 H NMR(DMSO-d6)δ:9.15(s,1H),8.09(d,J=9.0Hz,2H),7.81-7.87(m,3H),7.61(d,J=3. 1Hz,1H),6.63-6.72(m,1H),6.05(dd,J=15.3,1.8Hz,1H),5.41-5.48(m,1H),4.65(br dd,J=9.4,6.8Hz,1H),4.28-4.38(m,2H),4.13(br dd,J=11.7,2.9Hz,1H),1.83(dd,J=6.9,1.6Hz,3H).

[0918] Example 177 Synthesis of 3-((1-(2-fluoroacryloyl)azetidin-3-yl)oxy)-2-((4-(trifluoromethyl)phenyl)amino)isonicotinonitrile (Compound 177)

[0919] Step 1: Synthesis of compound 177-c

[0920] Compound 177-b (0.8 g, 5.0 mmol, Bidex) and cesium carbonate (4.1 g, 12.4 mmol, Anaiji) were dissolved in 20 mL of N,N-dimethylformamide, and compound 177-a (1 g, 4.15 mmol, Bidex) was added. The mixture was stirred and reacted at 60°C overnight. 200 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (200 mL × 3). The organic phases were dried over anhydrous sodium sulfate, the desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 177-c.

[0921] Step 2: Synthesis of compound 177-d

[0922] Compound 177-c (250 mg, 0.65 mmol) was dissolved in N-methylpyrrolidone (10 mL), and cuprous cyanide (117 mg, 1.31 mmol, Anaiji) was added. The reaction was stirred at 140°C overnight under nitrogen. 200 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed with saturated brine (200 mL × 3). The organic phases were dried over anhydrous sodium sulfate, the desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to obtain the title compound 177-d.

[0923] Step 3: Synthesis of compound 177-f

[0924] Compound 177-e (81 mg, 0.47 mmol, Bidex) and potassium carbonate (162 mg, 1.17 mmol, Anaiji) were dissolved in 10 mL of N,N-dimethylformamide, and compound 177-d (110 mg, 0.39 mmol) was added, and the mixture was stirred at room temperature for 18 hours. 100 mL of water was added to the reaction solution, and the organic phases were combined and washed with saturated brine (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 177-f.

[0925] Step 4: Preparation of compound 177-g

[0926] Compound 177-f (110 mg, 0.25 mmol) was dissolved in dichloromethane (10 mL), and a 2M hydrochloric acid ethyl acetate solution (2 mL, 4 mmol, Anaiji) was added. The mixture was allowed to react at room temperature for 0.5 h. The reaction solution was quenched with 20 mL of saturated sodium carbonate solution and then separated by adding 20 mL of ethyl acetate. The organic phase was collected and concentrated under reduced pressure to obtain crude compound 177 g.

[0927] Step 5: Preparation of Compound 177

[0928] Compound 177-h (27 mg, 0.30 mmol, Bidex) and N,N-diisopropylethylamine (77 mg, 0.60 mmol, Anaiji) were dissolved in 2 mL of N,N-dimethylformamide and stirred at room temperature for 0.5 hours. Compound 177-g (100 mg, 0.30 mmol) was added to the reaction solution, and the reaction was continued for 2 hours. 20 mL of water was added to the reaction solution, and the organic phases were extracted with ethyl acetate. The combined organic phases were washed with saturated saline solution (40 mL × 3). The organic phase was dried over anhydrous sodium sulfate, and the desiccant was filtered out. The filtrate was concentrated under reduced pressure. The residue was concentrated under reduced pressure and purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 0%-95%, flow rate: 30 mL / min) to give the title compound 177 (1.1 mg, yield: 26%).

[0929] MS m / z(ESI):407.1[M+1] + . 1 H NMR (400MHz, METHANOL-d4) δ=8.07-8.03(m,1H),7.94(d,J=8.6Hz,2H),7.60(d,J=8.6Hz,2H),7.58-7.57(m,1H),7.04(d,J=5.1Hz,1H) ,5.68-5.52(m,1H),5.45-5.36(m,1H),5.40(dt,J=3.3,6.8Hz,1H),5.26(dd,J=3.5,16.0Hz,1H),4.89-4.88(m,4H),4.58-4.45(m,1H)

[0930] Example 178 Synthesis of 3-((1-(2-fluoroacryloyl)azetidin-3-yl)amino)-2-(4-(trifluoromethyl)phenoxy)isonicotinonitrile (Compound 178)

[0931] Step 1: Synthesis of compound 178-c

[0932] Compound 178-b (15.14 g, 93.4 mmol, Bidex Pharmaceuticals) and potassium carbonate (17.2 g, 124.5 mmol) were dissolved in 50 mL of N,N-dimethylformamide, and compound 178-a (15 g, 62.246 mmol, Bidex Pharmaceuticals) was added. The mixture was stirred and reacted at 75°C overnight. 500 mL of water was added to the reaction solution, and extraction with ethyl acetate (200 mL × 3) was performed. The organic phases were combined and washed with saturated brine (500 mL × 3). The organic phases were dried over anhydrous sodium sulfate, the desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to obtain the title compound 178-c.

[0933] Step 2: Synthesis of compound 178-d

[0934] Compound 178-c (15.0 g, 33.3 mmol) was dissolved in N-methylpyrrolidone (50 mL), and cuprous cyanide (6.0 g, 66.6 mmol, Anaiji) was added. The reaction was stirred at 140°C under nitrogen for 48 hours. 500 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed with saturated brine (500 mL × 3). The organic phases were dried over anhydrous sodium sulfate, the desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to obtain the title compound 178-d.

[0935] Step 3: Synthesis of compound 178-f

[0936] Compound 178-e (3.52 g, 20.4 mmol, Bid) and N,N-diisopropylethylamine (6.60 g, 20.4 mmol, Anaiji) were dissolved in 40 mL of N,N-dimethylformamide, and compound 178-d (4.8 g, 17.0 mmol) was added, and the mixture was stirred at room temperature for 24 hours. 400 mL of water was added to the reaction solution, and the organic phases were combined and washed with saturated brine (400 mL × 3). The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 178-f.

[0937] Step 4: Synthesis of compound 178-g

[0938] Compound 178-f (2 g, 4.6 mmol) was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (4 mL, 52.2 mmol, Anaiji) was added. The mixture was allowed to react at room temperature for 0.5 h. The reaction solution was quenched with 50 mL of saturated sodium carbonate solution, and then 50 mL of ethyl acetate was added for phase separation. The organic phase was collected and concentrated under reduced pressure to obtain crude compound 178-g.

[0939] Step 5: Synthesis of Compound 178

[0940] Compound 178-h (0.37 g, 4.06 mmol, Bidex) and N,N-diisopropylethylamine (1.05 g, 8.12 mmol, Anaiji) and HATU (2.32 g, 6.09 mmol, Bidex) were dissolved in 20 mL of N,N-dimethylformamide and stirred at room temperature for 0.5 hours. Compound 178-g (1.92 g, 4.06 mmol) was added to the reaction solution and the reaction was continued for 2 hours. 200 mL of water was added to the reaction solution, and after extraction with ethyl acetate, the organic phases were combined and washed with saturated brine (400 mL × 3). The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 178 (430 mg, yield: 26%).

[0941] MS m / z(ESI):407.1[M+1] + . 1 H NMR (400MHz, DMSO-d6) δ = 7.81 (d, J = 8.6Hz, 2H), 7.45-7.34 (m, 4H), 7.24 (d, J = 5.4Hz, 1H), 5.60-5.39 (m, 1H), 5.31 (dd, J = 3.5, 16.6Hz, 1H), 4.84 (br s,1H),4.90-4.77(m,1H),4.69(br s,1H),4.63-4.47(m,1H),4.39-4.28(m,1H),4.16(dd,J=4.8,10.6Hz,1H).

[0942] Synthesis of Example 181 Synthesis of 2-fluoro-1-(3-(6-methoxy-3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one (Compound 181)

[0943] Step 1: Synthesis of compound 181-b

[0944] 181-a (2.8 g, 10.282 mmol) was dissolved in DMF (30 mL) at 0°C, and 2-methylprop-2-yl 3-aminoazetidine-1-carboxylate (1.77 g, 10.282 mmol) and DIEA (3.399 mL, 20.564 mmol) were added. The reaction mixture was stirred at 120°C for one hour, cooled to room temperature, quenched by the addition of water (30 mL), and extracted with EA (100 mL*2). The organic phase was washed with sodium chloride (30 mL) and dried over anhydrous sodium sulfate. The desiccant was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (petroleum ether / ethyl acetate: 10 / 1) to give the title compound 181-b.

[0945] 2) Step 2: Synthesis of Compound 181-c

[0946] 181-b (500 mg, 1.375 mmol), 4-(trifluoromethyl)phenol (222.90 mg, 1.375 mmol), and sodium tert-butoxide (198.20 mg, 2.062 mmol) were dissolved in DMF (2.5 mL). Under nitrogen, the reaction mixture was stirred in a microwave oven at 140°C for 2 hours. The mixture was cooled to room temperature, quenched with water (10 mL), and extracted with EA (50 mL x 2). The organic phase was washed with sodium chloride (5 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 10 / 1 system (petroleum ether / ethyl acetate) as the eluent to obtain the title compound 181-c.

[0947] Step 3: Synthesis of compound 181-d

[0948] Compound 181-c (100 mg, 0.204 mmol) was dissolved in 1,4-dioxane (0.5 mL). Methanol (0.041 mL, 1.022 mmol), t-Bubrettphos (39.62 mg, 0.082 mmol), Pd2(dba)3 (37.43 mg, 0.041 mmol), and sodium tert-butoxide (27.50 mg, 0.286 mmol) were added. The reaction mixture was stirred at 50°C overnight under nitrogen, cooled to room temperature, quenched with water (2 mL), and extracted with EA (20 mL x 2). The organic phase was washed with sodium chloride (5 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 5 / 1 system (petroleum ether / ethyl acetate) as the eluent to afford the title compound 181-d.

[0949] Step 4: Synthesis of compound 181-e

[0950] At 0°C, 181-d (100 mg, 0.227 mmol) was dissolved in dichloromethane (1 mL). 4 mol / L hydrochloric acid (0.5 mL, 2.000 mmol) was slowly added dropwise. The reaction mixture was stirred at 25°C for 1 hour before being quenched with saturated sodium bicarbonate (3 mL). The mixture was then extracted with EA (20 mL x 2). The organic phase was washed with sodium chloride (3 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to yield the title compound 181-e.

[0951] Step 5: Synthesis of compound 181

[0952] 2-Fluoroacrylic acid (7.94 mg, 0.088 mmol), EDCI (33.80 mg, 0.176 mmol), HOBt (23.82 mg, 0.176 mmol), and DIEA (0.058 mL, 0.353 mmol) were dissolved in THF (2 mL) and stirred at room temperature for 10 minutes. Compound 181-e (30 mg, 0.088 mmol) was then added. The mixture was allowed to react overnight, quenched with water (5 mL), and extracted with EA (25 mL x 2). The organic phase was washed with sodium chloride (5 mL), dried, and concentrated. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 3 / 1 system (petroleum ether / ethyl acetate) to afford the title compound 181 (12.4 mg, 32.69% yield).

[0953] MS m / z(ESI):413[M+H] + . 1 HNMR(400MHz,DMSO-d6)δ=7.74-7.69(m,2H),7.68(s,1H),7.23-7.16(m,3H),5 .45(d,J=3.5Hz,1H),5.23(dd,J=3.4,16.6Hz,1H),4.45-4.33(m,2H),4.26(br d,J=4.3Hz,1H),4.14-4.02(m,1H),3.97(br d,J=3.8Hz,1H),3.94(s,3H).

[0954] Example 183 2-Fluoro-1-(3-((4-methyl-2-(4-(trifluoromethyl)phenoxy)pyridin-3-yl)amino)azetidin-1-yl)prop-2-en-1-one (183)

[0955] 1) Preparation of compound 183-b

[0956] Compound 183-a (1000 mg, 5.31 mmol) was dissolved in DMF (10 mL). p-Trifluoromethylphenol (1292 mg, 7.97 mmol) and cesium carbonate (3430 mg, 10.62 mmol) were added. The reaction mixture was stirred at 100°C overnight, cooled to room temperature, quenched with water (30 mL), and extracted with ethyl acetate (20 mL x 2). The organic phase was washed with sodium chloride (20 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 10 / 1 system (petroleum ether / ethyl acetate) to afford the title compound 189-b (420 mg, 20.36% yield).

[0957] 2) Preparation of the second step compound 183-c

[0958] 183-b (420 mg, 1.27 mmol) was dissolved in toluene (10 mL), and tert-butyl 3-aminoazetidine-1-carboxylate (262 mg, 1.52 mmol), XantPhos Pd G4 (194 mg, 0.12 mmol), and Cs2CO3 (822 mg, 2.54 mmol) were added. Under nitrogen, the reaction mixture was stirred at 100°C overnight, cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (20 mL x 2). The organic phase was washed with sodium chloride (5 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 4 / 1 system (petroleum ether / ethyl acetate) to afford the title compound 183-c (240 mg, 44.67% yield).

[0959] 3) Preparation of the third step compound 183-d

[0960] 183-c (240 mg, 0.56 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (0.08 mL, 1.06 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 1 hour, then quenched with saturated sodium bicarbonate (5 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with sodium chloride (5 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound 183-d (130 mg, yield: 71.64%).

[0961] 4) Preparation of the fourth step compound 183

[0962] 2-Fluoroacrylic acid (40 mg, 0.44 mmol), HATU (210 mg, 0.55 mmol) and DIEA (0.13 mL, 0.74 mmol) were dissolved in DMF (5 mL) and stirred at room temperature for 10 minutes. Then 183-d (120 mg, 0.37 mmol) was added. The mixture was allowed to react overnight and quenched with water (10 mL). The mixture was extracted with ethyl acetate (10 mL*2). The organic phase was washed with sodium chloride (10 mL), dried and concentrated. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (instrument: Gilson_306_1741, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm; mobile phase: A: 0.05% TFA / H2O). Compound 183 (97 mg, yield: 66.37%) was obtained by purification using the HPLC-MS / ...

[0963] MS (ESI): m / z = 396.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ=7.75(d,J=8.6Hz,2H),7.52(d,J=4.9Hz,1H),7.24(d,J=8.5Hz,2H),6.98(d,J=4.9Hz,1 H),5.52-5.35(m,1H),5.33-5.21(m,2H),5.31-5.17(m,2H),4.62-4.39(m,2H),3.98-3.87(m,1H),2.28(s,3H).

[0964] Example 185 1-(3-((4-chloro-2-(4-(trifluoromethyl)phenoxy)pyridin-3-yl)amino)azetidin-1-yl)-2-fluoropropan-2-yl-1-one (185)

[0965] 1) Preparation of compound 185-b

[0966] 3-Bromo-4-chloro-2-fluoropyridine (350 mg, 1.66 mmol, Bidex Pharmaceuticals) was dissolved in 5 mL of DMF, and p-trifluoromethylphenol (270 mg, 1.66 mmol, Shaoyuan Chemical) and cesium carbonate (1084 mg, 3.33 mmol, Anaiji) were added. The reaction solution was stirred at 80°C for 3 hours. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B (pure petroleum ether) to obtain compound 185-b (434 mg).

[0967] 2) Preparation of the second step compound 185-d

[0968] Compound 185-b (434 mg, 1.23 mmol) was dissolved in toluene (5 mL), and tert-butyl 3-aminoazetidine-1-carboxylate (254 mg, 1.48 mmol, Bidex Pharmaceuticals), XantPhos Pd G4 (199 mg, 0.12 mmol, Bidex Pharmaceuticals), and cesium carbonate (802 mg, 2.46 mmol, Anaiji) were added. The reaction solution was stirred at 100°C for 18 hours. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B (petroleum ether:ethyl acetate = 5:1) to obtain compound 185-d (142 mg).

[0969] 3) Preparation of the third step compound 185-e

[0970] Compound 185-d (71 mg, 0.16 mmol) was dissolved in 1 mL of dichloromethane, and trifluoroacetic acid (0.2 mL, Anaiji) was slowly added dropwise. The mixture was stirred at 25°C for 1 hour. After the reaction, it was slowly added dropwise to 5 mL of saturated sodium bicarbonate solution to quench the reaction. The mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue containing compound 185-e (53 mg).

[0971] 4) Preparation of the fourth step compound 185

[0972] The residue (53 mg) containing compound 185-e was dissolved in DMF (1 mL), and HATU (73 mg, 0.19 mmol), DIEA (42 μL, 0.26 mmol), and 2-fluoroacrylic acid (11.6 mg, 0.13 mmol) were added. The mixture was allowed to react at room temperature for 16 hours. 5 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B (petroleum ether:ethyl acetate = 1:1) to obtain the title compound 185 (20.97 mg, yield: 39.25%).

[0973] MS m / z(ESI):416.1[M+1]. 1 H NMR (400MHz, DMSO-d6) δ = 7.81-7.75 (m, J = 8.6Hz, 2H), 7.52 (d, J = 5.3Hz, 1H), 7.37-7.32 (m, J = 8.5Hz, 2H), 7.24 (d, J = 5.3Hz, 1H), 5.83-5. 75(m,1H),5.52-5.37(m,1H),5.27(dd,J=3.5,16.5Hz,1H),4.67-4.53(m,2H),4.42-4.34(m,1H),4.24-4.17(m,1H),4.05-3.97(m,1H).

[0974] Example 187 3-((1-(2-Fluoroacryloyl)azetidin-3-yl)oxy)-2-((4-(trifluoromethyl)phenyl)amino)isonicotinonitrile (187)

[0975] 1) Preparation of Compound 187-b

[0976] Compound 187-a (2.8 g, 19.0 mmol, Bidex) and potassium carbonate (5.25 g, 38.0 mmol, Anaiji) were dissolved in 10 mL of acetone, and iodomethane (2.4 mL, 38.0 mmol, Anaiji) was added. The reaction was stirred at room temperature overnight. 50 mL of water was added to the reaction solution, and the organic phases were combined and washed with saturated brine (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to obtain compound 187-b (1 g, yield: 33%).

[0977] 2) Preparation of the second step compound 187-c

[0978] Compound 187-b (1 g, 6.2 mmol) was dissolved in tetrahydrofuran (30 mL), purged with nitrogen three times, and then cooled to -78°C. n-Butyl lithium (5.0 mL, 2.5 M, 12.4 mmol, Anaiji) was added under nitrogen protection and stirred for one hour. An iodine solution in tetrahydrofuran (2.4 g, 9.3 mmol, 20 mL, Bidex) was added to the system and stirred at -78°C for half an hour before slowly warming to room temperature and stirring continued overnight. The reaction solution was quenched by adding 50 mL of water, separated and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (50 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 187-c (1.4 g, yield: 78%).

[0979] 3) Preparation of the third step compound 187-d

[0980] Compound 187-c (1.4 g, 4.9 mmol) was dissolved in N-methylpyrrolidone (10 mL), and cuprous cyanide (0.9 g, 9.7 mmol, Anaiji) was added. The reaction was stirred at 140°C overnight under nitrogen. 200 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed with saturated brine (200 mL × 3). The organic phases were dried over anhydrous sodium sulfate, the desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to obtain the title compound 187-d (0.7 g, 80% yield).

[0981] 4) Preparation of the fourth step compound 187-f

[0982] Compound p-trifluoromethylphenol (334 mg, 2.1 mmol, Bidex) and cesium carbonate (1.5 g, 4.7 mmol, Anaiji) were dissolved in 15 mL of DMF, and compound 187-d (350 mg, 1.9 mmol) was added, and the mixture was stirred at 60°C overnight. 150 mL of water was added to the reaction solution, and the organic phases were combined and washed with saturated brine (150 mL × 3). The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 187-f (120 mg, yield: 19%).

[0983] 5) Preparation of the fifth step compound 187-h

[0984] Compound 187-f (145 mg, 0.4 mmol) was dissolved in 1,4-dioxane (1 mL), and tert-butyl 3-aminoazetidine-1-carboxylate (91 mg, 0.5 mmol, Bidex), cesium carbonate (287 mg, 0.9 mmol, Anaiji), BINAP (55 mg, 0.1 mmol, Anaiji), and tetrakistriphenylphosphine palladium (51 mg, 0.04 mmol, Bidex) were added. The atmosphere was purged with nitrogen and the reaction was allowed to proceed overnight at 110°C. The reaction mixture was separated by adding ethyl acetate (10 mL) and saturated brine (10 mL), and then extracted with ethyl acetate (10 mL × 3). The mixture was washed with saturated brine (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The desiccant was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to obtain the title compound 187-h (50 mg, yield: 24%).

[0985] 6) Preparation of the sixth step compound 187-i

[0986] Compound 187-h (45 mg, 0.1 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.25 mL, 3.3 mmol, Anaiji) was added. The mixture was allowed to react at room temperature for 0.5 h. The reaction solution was quenched with 20 mL of saturated sodium carbonate solution, and 20 mL of ethyl acetate was added for phase separation. The organic phase was collected and concentrated under reduced pressure to obtain crude compound 187-i (45 mg, 127% yield).

[0987] 7) Step 7 Preparation of Compound 187

[0988] Compound 187-i (11 mg, 0.1 mmol), DIEA (32 mg, 0.2 mmol, Anaiji), and HATU (70 mg, 0.2 mmol, Bidex) were dissolved in 2 mL of DMF and stirred at room temperature for 0.5 hours. 2-Fluoroacrylic acid (45 mg, 0.1 mmol) was added to the reaction solution, and the reaction was continued for 2 hours. 10 mL of water was added to the reaction solution, and the organic phases were combined and washed with saturated saline solution (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was concentrated under reduced pressure and purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 0%-95%, flow rate: 30 mL / min) to obtain the title compound 187 (4.5 mg, yield: 8%).

[0989] MS m / z(ESI):437.1[M+1] + . 1H NMR (400MHz, DMSO-d6) δ = 7.77 (d, J = 8.8Hz, 2H), 7.38-7.27 (m, 3H), 7.22 (s, 1H), 5.56-5.38 (m, 1H), 5.30 (d d,J=3.5,16.5Hz,1H),4.88-4.75(m,1H),4.71-4.62(m,1H),4.52-4.44(m,1H),4.36-4.25(m,1H),4.13(br dd,J=4.6,10.7Hz,1H),3.87(s,3H).

[0990] Example 189 2-Fluoro-1-(3-((4-methyl-2-((4-(trifluoromethyl)phenyl)amino)pyridin-3-yl)oxy)azetidin-1-yl)prop-2-en-1-one (189)

[0991] 1) Preparation of Compound 189-b

[0992] Compound 189-a (500 mg, 3.49 mmol) was dissolved in DMF (10 mL), and tert-butyl 3-iodoazetidine-1-carboxylate (1187 mg, 4.19 mmol) and cesium carbonate (2268 mg, 6.98 mmol) were added. The reaction mixture was stirred at 100°C overnight, cooled to room temperature, quenched with water (30 mL), and extracted with ethyl acetate (20 mL x 2). The organic phase was washed with sodium chloride (20 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 10 / 1 system (petroleum ether / ethyl acetate) to afford the title compound 189-b (320 mg, 30.76% yield).

[0993] 2) Preparation of the second step compound 189-c

[0994] 189-b (320 mg, 1.07 mmol) was dissolved in dioxane (10 mL), and p-trifluoromethylaniline (207 mg, 1.28 mmol), Pd2(dba)3 (91 mg, 0.10 mmol), BINAP (91 mg, 0.20 mmol), and sodium tert-butoxide (183 mg, 1.80 mmol) were added. Under nitrogen, the reaction mixture was stirred at 100°C overnight, cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (20 mL x 2). The organic phase was washed with sodium chloride (5 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 4 / 1 system (petroleum ether / ethyl acetate) to afford the title compound 189-c (150 mg, 33.14% yield).

[0995] 3) Preparation of the third step compound 189-d

[0996] 189-c (150 mg, 0.35 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (0.08 mL, 1.06 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 1 hour, quenched with saturated sodium bicarbonate (5 mL), and extracted with ethyl acetate (20 mL). The organic phase was washed with sodium chloride (5 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound 189-d (90 mg, yield: 79.36%).

[0997] 4) Preparation of the fourth step compound 189

[0998] 2-Fluoroacrylic acid (41.40 mg, 0.56 mmol), HATU (249.60 mg, 0.92 mmol) and DIEA (0.24 mL, 1.38 mmol) were dissolved in DMF (10 mL) and stirred at room temperature for 10 minutes. Then 189-d (90 mg, 0.27 mmol) was added. The mixture was allowed to react overnight and quenched with water (10 mL). The mixture was extracted with ethyl acetate (10 mL*2). The organic phase was washed with sodium chloride (10 mL), dried and concentrated. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (instrument: Gilson_306_1741, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm; mobile phase: A: 0.05% TFA / H2O). Compound 189 (19 mg, yield: 17.77%) was obtained by purification using the HPLC-MS / ...

[0999] MS (ESI): m / z=396.1[M+H]+. 1 H NMR (400MHz, DMSO-d6) δ=8.73(s,1H),7.98-7.91(m,2H),7.90-7.86(m,1H),7.62-7.55(m,2H),6.81(d,J=5.1Hz,1H ),5.56-5.41(m,1H),5.34-5.26(m,1H),4.87-4.76(m,1H),4.68-4.56(m,2H),4.32-4.19(m,2H),2.29-2.22(m,3H).

[1000] Example 191 1-(3-((4-chloro-2-((4-(trifluoromethyl)phenyl)amino)pyridin-3-yl)oxy)azetidin-1-yl)-2-fluoropropan-2-en-1-one (191)

[1001] 1) Preparation of Compound 191-c

[1002] 2,4-Dichloropyridin-3-ol (500 mg, 3.05 mmol, Bidex Pharmaceuticals) was dissolved in 5 mL of DMF, and tert-butyl 3-iodoazetidine-1-carboxylate (0.53 mL, 3.05 mmol, Bidex Pharmaceuticals) and cesium carbonate (1987 mg, 6.10 mmol, Anaiji) were added. The reaction solution was stirred at 100°C for 4 hours. After the reaction was completed, 10 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B (petroleum ether:ethyl acetate = 5:1) to obtain compound 191-c (996 mg).

[1003] 2) Preparation of the second step compound 191-d

[1004] Compound 191-c (996 mg, 3.12 mmol) was dissolved in toluene (15 mL), and p-trifluoromethylaniline (0.47 mL, 3.74 mmol, Bidex Pharmaceuticals), Pd2(dba)3 (286 mg, 0.31 mmol, Anaiji), XantPhos (181 mg, 0.62 mmol, Bidex Pharmaceuticals), and sodium tert-butoxide (600 mg, 6.24 mmol, Anaiji) were added. The reaction solution was stirred at 100°C for 18 hours. After the reaction was completed, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B (petroleum ether:ethyl acetate = 5:1) to obtain compound 191-d (451 mg).

[1005] 3) Preparation of the third step compound 191-e

[1006] Compound 191-d (71 mg, 0.16 mmol) was dissolved in 1 mL of dichloromethane, and trifluoroacetic acid (0.2 mL, Anaiji) was slowly added dropwise. The mixture was stirred at 25°C for 3 hours. After completion of the reaction, it was slowly added dropwise to 5 mL of saturated sodium bicarbonate solution to quench the reaction. The mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue containing compound 191-e (80 mg).

[1007] 4) Preparation of the fourth step compound 191

[1008] The residue (80 mg) containing compound 191-e was dissolved in DMF (1 mL), and HATU (111 mg, 0.29 mmol), DIEA (64 μL, 0.39 mmol), and 2-fluoroacrylic acid (17.5 mg, 0.19 mmol) were added. The mixture was allowed to react at room temperature for 16 hours. 5 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System B (petroleum ether:ethyl acetate = 2:1) to obtain the title compound 191 (28.14 mg, yield: 34.90%).

[1009] MS m / z(ESI):415.9[M+1]. 1H NMR (400MHz, DMSO-d6) δ = 9.00 (s, 1H), 8.01-7.92 (m, 3H), 7.63 (br d,J=8.5Hz,2H),7.06(d,J=5.4Hz,1H),5.58-5.42(m,1H),5.32(dd,J=3.5,16.5Hz,1H),5.00(quin,J=5.3Hz,1H),4.68(br s,2H),4.37-4.27(m,2H).

[1010] Example 196 2-Fluoro-1-(3-((2-methyl-6-(4-(trifluoromethyl)phenoxy)-2H-pyrazolo[4,3-c]pyridin-7-yl)amino)azetidin-1-yl)prop-2-en-1-one (196)

[1011] 1) Preparation of Compound 196-b

[1012] 196-a (2 g, 12.536 mmol) was dissolved in tetrahydrofuran (50 mL) at 25°C. 1,3-Propanediol (0.904 mL, 12.536 mmol) and N-[dioxo(trifluoromethyl)-λ6-thio]-1,1,1-trifluoromethanesulfonamide (2.11 g, 7.522 mmol) were slowly added. The reaction mixture was stirred at 70°C overnight, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 50 / 1 solvent system (petroleum ether / ethyl acetate) to afford the title compound 196-b (1004 mg, 36.80% yield).

[1013] 2) Preparation of the second step compound 196-c

[1014] Under nitrogen protection, 196-b (1000 mg, 4.595 mmol) was dissolved in tetrahydrofuran (20 mL) and placed at -78 ° C. n-Butyl lithium (1.838 mL, 4.595 mmol) and N,N,N',N'-tetramethylethylenediamine (0.689 mL, 4.595 mmol) were slowly added and stirred for 30 minutes. Then 1,2-dibromo-1,1,2,2-tetrafluoroethane (1193.92 mg, 4.595 mmol) was added and stirred for 30 minutes. Saturated ammonium chloride solution (10 mL) was added to quench the mixture, and the temperature was returned to room temperature and extracted with ethyl acetate (100 mL). The organic phase was washed with sodium chloride (10 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (petroleum ether / ethyl acetate: 10 / 1) to give the title compound 196-c (1309 mg, yield: 96.07%).

[1015] 3) Preparation of the third step compound 196-d

[1016] Compound 196-c (1.309 g, 4.415 mmol) was dissolved in DMF (20 mL), and p-trifluoromethylphenol (0.79 g, 4.856 mmol) and cesium carbonate (1.44 g, 4.415 mmol) were added. Under nitrogen, the reaction mixture was stirred at 25°C for 18 hours, quenched by the addition of water (10 mL), and extracted with ethyl acetate (100 mL x 2). The organic phase was washed with sodium chloride (10 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 10 / 1 system (petroleum ether / ethyl acetate) to afford the title compound 196-d (1904 mg, 98.33% yield).

[1017] 4) Preparation of the fourth step compound 196-e

[1018] At 0°C, 196-d (1904 mg, 4.341 mmol) was dissolved in tetrahydrofuran (5 mL), and 5N dilute hydrochloric acid (10 mL, 50.000 mmol) was slowly added dropwise. The reaction mixture was stirred at 90°C for 18 hours, quenched with saturated sodium bicarbonate (10 mL), and extracted with ethyl acetate (100 mL). The organic phase was washed with sodium chloride (10 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a 10 / 1 system (petroleum ether / ethyl acetate) to afford the title compound 196-e (1.6 g, 96.86% yield).

[1019] 5) Preparation of the fifth step compound 196-f

[1020] At room temperature, 196-e (1.6 g, 4.204 mmol) was dissolved in ethanol (15 mL), and hydrazine hydrate (7.5 mL, 119.856 mmol) was slowly added dropwise. The reaction mixture was stirred at 25°C for 3 hours, then quenched with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with sodium chloride (10 mL) and dried over anhydrous sodium sulfate. The desiccant was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 10 / 1 system (petroleum ether / ethyl acetate) to afford the title compound 196-f (371 mg, 24.64% yield).

[1021] 6) Step 6 Preparation of Compounds 196-g and 196-h

[1022] At 0°C, NaH (49.73 mg, 1.243 mmol) was dissolved in DMSO (5 mL). 196f (371 mg, 1.036 mmol) was slowly added to the solution, followed by stirring at room temperature for half an hour. Iodomethane (0.101 mL, 1.243 mmol) was then added. The reaction mixture was stirred at 25°C for 1 hour before being quenched with water (10 mL) and extracted with ethyl acetate (50 mL). The organic phase was washed with sodium chloride (10 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a solvent system (petroleum ether / ethyl acetate: 10 / 1 to 3:1) to afford the title compounds 196-g (98 mg, 25.42% yield) and 196-h (214 mg, 55.51% yield).

[1023] 7) Step 7 Preparation of Compound 196-i

[1024] At room temperature, 196-g (98 mg, 0.263 mmol) was dissolved in toluene (3 mL), and 1-tert-butoxycarbonyl-3-aminocyclobutanamine (0.045 mL, 0.290 mmol), XantPhos Pd G4 (25.34 mg, 0.026 mmol), and cesium carbonate (171.60 mg, 0.527 mmol) were added. Under nitrogen, the reaction mixture was stirred at 100°C for 18 hours, diluted with water (10 mL), and extracted with ethyl acetate (50 mL). The organic phase was washed with sodium chloride (10 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 10 / 1 system (petroleum ether / ethyl acetate) to afford the title compound 196-i (112 mg, 91.77% yield).

[1025] 8) Step 8 Preparation of Compound 196-j

[1026] 196-i (112 mg, 0.242 mmol) was dissolved in dichloromethane (2 mL) at 0°C, and trifluoroacetic acid (1 mL, 13.059 mmol) was slowly added dropwise. The reaction mixture was stirred at 25°C for 1 hour, quenched with saturated sodium bicarbonate (8 mL), and extracted with ethyl acetate (50 mL). The organic phase was washed with sodium chloride (5 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound 196-j (80 mg, 91.12% yield).

[1027] 9) Step 9: Preparation of Compound 196

[1028] 2-Fluoroacrylic acid (23.79 mg, 0.264 mmol), HATU (125.58 mg, 0.330 mmol), and DIEA (117.273 μL, 0.661 mmol) were dissolved in DMF (1 mL) and stirred at room temperature for 10 minutes. A solution of 196j (80 mg, 0.220 mmol) in DMF (1 mL) was then added. The mixture was allowed to react overnight, quenched by the addition of water (3 mL), and extracted with ethyl acetate (25 mL x 2). The organic phase was washed with sodium chloride (3 mL), dried, and concentrated. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 1:1 ratio of petroleum ether to ethyl acetate to afford the title compound 196 (49.55 mg, 51.17% yield).

[1029] MS (ESI): m / z = 436 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 8.57 (s, 1H), 8.24 (s, 1H), 7.68 (d, J = 8.6Hz, 2H), 7.07 (d, J = 8.6Hz, 2H), 6.15 (d, J = 8.4Hz, 1H), 5.51-5.36(m,1H),5.32-5.22(m,2H),4.63-4.55(m,1H),4.32-4.22(m,2H),4.21(s,3H),3.93(dd,J=5.3,10.4Hz,1H).

[1030] Example 199 2-Fluoro-1-(3-((4-methoxy-2-(4-(trifluoromethyl)phenoxy)pyridin-3-yl)amino)azetidin-1-yl)prop-2-en-1-one (199)

[1031] 1) Preparation of Compound 199-b

[1032] Compound 199-a (360 mg, 1.711 mmol) was dissolved in 5 mL of DMF, and cesium carbonate (1114.8 mg, 3.422 mmol) and p-trifluoromethylphenol (277.3 mg, 1.711 mmol) were added. The temperature was raised to 80°C and stirred for 3 h. After cooling to room temperature, 10 mL of water was added to the system, and extraction was performed with 1,2-dichloroethane solution (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 199-b (557 mg).

[1033] 2) Preparation of the second step compound 199-c

[1034] Compound 199-b (350 mg, 0.993 mmol) was dissolved in 5 mL of methanol and sodium methoxide (80.45 ...

Claims

1. A compound having a structure as shown in Formula I or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs; in, Ring A is selected from: 5-6 membered heteroaryl, 5-6 membered heterocyclyl, 5-6 membered partially unsaturated heterocyclyl, phenyl; Ring B is selected from: 5-10 membered heteroaryl, C6-C 10 Aryl, C5-C6 cycloalkylphenyl, C5-C6 cycloalkyl 5-6-membered heteroaryl, 5-6-membered heterocyclylphenyl, 5-6-membered heterocyclyl 5-6-membered heteroaryl; preferably, ring B is selected from: 5-membered heteroarylphenyl, phenyl, 6-membered heteroaryl, C5-C6 cycloalkylphenyl; Ring C is selected from: absence, C4-C6 cycloalkyl, 4-6 membered heterocyclyl, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclyl, 5-12 membered bridged ring group, 5-12 membered spiro ring group, 5-12 membered fused ring group, 5-12 membered heterobridged ring group, 5-12 membered heterospiro ring group, 5-12 membered heterofused ring group, 5-10 membered heteroaryl, C6-C 10 Aryl; when ring C is missing, L 2 With Y 2 Direct connection via key; R 1 , R 2 , R 3 Each is independently selected from: hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally and independently substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkylamino, C1-C6 alkoxy, O=; Each R a R is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, amino, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino; wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino are optionally substituted by 1-3 substituents independently selected from the group consisting of deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkylamino, C1-C6 alkoxy, O=, -NHS(=O)2-C1-C4 alkyl, 5-6-membered nitrogen-containing and / or oxygen-containing heterocyclic groups (e.g., morpholinyl, piperazinyl or N-methylpiperazinyl); wherein the 5-6-membered nitrogen-containing and / or oxygen-containing heterocyclic groups are substituted by 1-5 substituents selected from the group consisting of deuterium, halogen, amino, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy; or two adjacent R a connected to form C4-C6 cycloalkyl, 4-6 membered heterocyclyl, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclyl, 5-6 membered heteroaryl, phenyl; wherein the C4-C6 cycloalkyl, 4-6 membered heterocyclyl, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclyl, 5-6 membered heteroaryl, phenyl are optionally and independently substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=; preferably; each R a independently selected from: hydrogen, deuterium, halogen, amino, cyano, O=, C1-C6 alkyl, C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by 1-3 substituents selected from deuterium and halogen; or two adjacent R a connected to form a C4-C6 cycloalkyl, a 4-6 membered heterocyclic group, a C4-C6 partially unsaturated cycloalkyl, a 4-6 membered partially unsaturated heterocyclic group, a 5-6 membered heteroaryl, or a phenyl group; Each R b are independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, and SF5; wherein the C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylamino are optionally and independently substituted by 1 to 6 substituents selected from the group consisting of deuterium, halogen, amino, hydroxyl, cyano, and O=; preferably, each R b Independently selected from: C1-C6 alkyl, C1-C6 alkoxy, SF5; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by 1-6 substituents selected from deuterium and halogen; Each R c Independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by 1-6 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, O=; preferably, each R c Independently selected from: hydrogen, deuterium, halogen; Y 1 Selected from: -C(=O)-, -S(=O)-, -S(=O)2-; Y 2 Selected from: a bond, -N(R Y2 )-, -C1-C4 alkylene-; wherein R Y2 Selected from: hydrogen, C1-C4 alkyl; L 1 Selected from: a bond, -N(R L1 )-、-O-、-S-、-N(R L1 )-C1-C4 alkylene-, -C1-C4 alkylene-N(R L1 )-, -O-C1-C4 alkylene-, -C1-C4 alkylene-O-; wherein R L1 Selected from: hydrogen, C1-C4 alkyl; L 2 Selected from: a bond, -N(R L2 )-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C1-C4 alkylene-, -C1-C4 alkylene-O-, -O-C1-C4 alkylene-, -C1-C4 alkylene-S-, -S-C1-C4 alkylene-, -C1-C4 alkylene-S(=O)-, -S(=O)-C1-C4 alkylene-, -C1-C4 alkylene-S(=O)2-, -S(=O)2-C1-C4 alkylene-; wherein R L2 Selected from: hydrogen, C1-C4 alkyl; preferably, L 2 Selected from: a bond, -C1-C4 alkylene-, -N(R L2 )-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-; where R L2 Selected from: hydrogen, C1-C4 alkyl; On the A ring, L 2 In L 1 The ortho or meta position of indicates a triple bond or a double bond; when When it represents a triple bond, R 2 and R 3 does not exist; n, m, and p are each independently selected from: 0, 1, 2, 3, 4, and 5.

2. The compound according to claim 1, wherein L 1 Selected from: -N(R L1 )-、-O-、-S-、-N(R L1 )-C1-C4 alkylene-, -C1-C4 alkylene-N(R L1 )-, -O-C1-C4 alkylene-, -C1-C4 alkylene-O-; wherein R L1 Selected from: hydrogen, C1-C4 alkyl; and / or L 2 Selected from: -N(R L2 )-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C1-C4 alkylene-, -C1-C4 alkylene-O-, -O-C1-C4 alkylene-, -C1-C4 alkylene-S-, -S-C1-C4 alkylene-, -C1-C4 alkylene-S(=O)-, -S(=O)-C1-C4 alkylene-, -C1-C4 alkylene-S(=O)2-, -S(=O)2-C1-C4 alkylene-, wherein R L2 Selected from: hydrogen, C1-C4 alkyl; Preferably, L 1 Selected from: -N(R L1 )-、-O-;where R L1 Selected from: hydrogen, C1-C4 alkyl; and / or L 2 Selected from: -N(R L2 )-、-O-, where R L2 Selected from: hydrogen, C1-C4 alkyl; Preferably, L 1 and L 2 Different from -N(R L1 )-or-O-.

3. The compound according to claim 1 or 2, wherein Has the following structure: in, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 Each is independently selected from: CH, N; E 1 、E 2 、E 3 、E 4 、E 5 、E 6 Each independently selected from: CH2, NH, O, S; Preferably, Has the following structure: in, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 Each is independently selected from: CH, N; E 1 、E 2 Each is independently selected from: CH2, NH, O, S.

4. The compound according to claim 1 or 2, wherein Has the following structure: Preferably, Has the following structure: Preferably, Has the following structure:

5. The compound according to claim 1 or 2, wherein Has the following structure: Among them, R aa Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino (e.g., di(C1-C6 alkyl)amino), halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy; p1 is independently selected from: 0, 1, 2; Preferably, Has the following structure: Preferably, R aa Each is independently selected from the group consisting of hydrogen, deuterium, cyano, halogen, amino, O=, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkyl, halogenated C1-C4 alkoxy, di(C1-C4 alkyl)amino, hydroxy-substituted C1-C4 alkoxy, amino-substituted C1-C4 alkoxy; Preferably, wherein R aa Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; Preferably, R aa Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, amino, O=, methyl, ethyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; Preferably, yes Preferably, yes Preferably, yes Preferably, yes 6. The compound according to any one of claims 1 to 5, wherein Has the following structure: Missing, in, c1, c2 are each independently selected from: 0, 1; c3, c4, c5, c6 are each independently selected from: 0, 1, 2; c7, c8, c9, c10 are each independently selected from: 1, 2; Preferably, Has the following structure: Missing, in, c1, c2 are each independently selected from: 0, 1; c3, c4, c5, c6 are each independently selected from: 0, 1, 2; c7, c8, c9, c10 are each independently selected from: 1, 2.

7. The compound according to any one of claims 1 to 5, wherein Has the following structure: Missing, Among them, R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; n1 is independently selected from: 0, 1, 2; Preferably, R cc Each is independently selected from: hydrogen, deuterium, fluorine, methyl; n1 is independently selected from: 0, 1, 2.

8. The compound according to any one of claims 1 to 7, wherein It has the following structure: Preferably, It has the following structure: Preferably, It has the following structure: Preferably, It has the following structure: Preferably, each R b Independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl; Preferably, m is 0, 1 or 2.

9. The compound according to any one of claims 1 to 8, wherein R 1 , R 2 , R 3 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy; wherein the C1-C4 alkyl and C1-C4 alkoxy are optionally and independently substituted by 1-6 deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkylamino, C1-C4 alkoxy, or O=; each R a R is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, amino, O=, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino; wherein the C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino are optionally substituted by 1-3 deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkylamino, C1-C4 alkoxy, or O=, or two adjacent R a connected to form C4-C6 cycloalkyl, 4-6 membered heterocyclyl, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclyl, 5-6 membered heteroaryl, phenyl; wherein the C4-C6 cycloalkyl, 4-6 membered heterocyclyl, C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclyl, 5-6 membered heteroaryl, phenyl are optionally and independently substituted by 1-6 deuterium, halogen, amino, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, O=; preferably, each R a independently selected from: hydrogen, deuterium, halogen, cyano, amino, O=, C1-C4 alkyl, C1-C4 alkoxy; wherein the C1-C4 alkyl, C1-C4 alkoxy is optionally substituted by 1-3 deuterium, halogen; or two adjacent R a connected to form a C4-C6 cycloalkyl, a 4-6 membered heterocyclic group, a C4-C6 partially unsaturated cycloalkyl, a 4-6 membered partially unsaturated heterocyclic group, a 5-6 membered heteroaryl, or a phenyl group; Each R b are independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, and SF5; wherein the C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 alkylamino are optionally and independently substituted by 1 to 6 deuterium, halogen, amino, hydroxyl, cyano, and O=; preferably, each R b Independently selected from: C1-C4 alkyl, C1-C4 alkoxy, SF5; wherein the C1-C4 alkyl and C1-C4 alkoxy are optionally and independently substituted by 1-6 deuterium or halogen; Each R c Independently selected from: hydrogen, deuterium, halogen, C1-C4 alkyl; wherein the C1-C4 alkyl is optionally substituted by 1-6 deuterium, halogen, amino, hydroxyl, cyano, O=; Y 1 Selected from: -C(=O)-, -S(=O)-, -S(=O)2-; Y 2 Selected from: a bond, -N(R Y2 )-, -C1-C2 alkylene-; wherein R Y2 Selected from: hydrogen, C1-C4 alkyl; L 1 Selected from: a bond, -N(R L1 )-、-O-、-S-、-N(R L1 )-C1-C4 alkylene-, -C1-C4 alkylene-N(R L1 )-, -O-C1-C4 alkylene-, -C1-C4 alkylene-O-; wherein R L1 Selected from: hydrogen, C1-C4 alkyl; L 2 Selected from: a bond, -N(R L2 )-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C1-C4 alkylene-, -C1-C2 alkylene-O-, -O-C1-C2 alkylene-, -C1-C2 alkylene-S-, -S-C1-C2 alkylene-, -C1-C2 alkylene-S(=O)-, -S(=O)-C1-C2 alkylene-, -C1-C2 alkylene-S(=O)-, -S(=O)-C1-C2 alkylene-, -C1-C2 alkylene-S(=O)2-, -S(=O)2-C1-C2 alkylene-; wherein R L2 Selected from: hydrogen, C1-C4 alkyl.

10. The compound according to any one of claims 1 to 8, wherein R 1 , R 2 , R 3 Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, (CH3)2N-CH2-; and / or R a R is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, O=, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, and dimethylamino; wherein the methyl, ethyl, propyl, methoxy, ethoxy, and propoxy are optionally and independently substituted by 1 to 3 deuterium, fluorine, chlorine, amino, hydroxyl, cyano, and O=; or two adjacent R a connected to form C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, imidazolyl, furanyl, thiazolyl, thienyl, pyrazolyl, pyridyl, pyrimidyl, phenyl, wherein C4-C6 partially unsaturated cycloalkyl, 4-6 membered partially unsaturated heterocyclic group, imidazolyl, furanyl, thiazolyl, thienyl, pyrazolyl, pyridyl, pyrimidyl, phenyl are optionally each independently substituted with 1-6 deuterium, fluorine, chlorine, amino, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkoxy, O=; and / or each R b Independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl; and / or R c Independently selected from: hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl; wherein the methyl, ethyl, propyl, isopropyl is optionally substituted by 1-6 deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=; and / or Y 1 Selected from: -C(=O)-, -S(=O)-, -S(=O)2-; and / or Y 2 Selected from: a bond, -N(R Y2 )-, methylene, ethylene, propylene, isopropylene; wherein R Y2 Selected from: hydrogen, methyl, ethyl, propyl, isopropyl; and / or L 1 Selected from: a bond, -N(R L1 )-、-O-、-S-、-N(R L1 )-CH2-、-CH2-N(R L1 )-, -O-CH2-, -CH2-O-; wherein R L1 Selected from: hydrogen, methyl, ethyl, propyl, isopropyl; and / or L 2 Selected from: a bond, -N(R L2 )-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, methylene, ethylene, propylene, isopropylene, -CH2-O-, -O-CH2-, -CH2-S-, -S-CH2-, -CH2-S(=O)-, -S(=O)-CH2-, -CH2-S(=O)2-, -S(=O)2-CH2-, -CH2CH2-O-, -O-CH2CH2-, -CH2CH2-S-, -S-CH2CH2-, -CH2CH2-S(=O)-, -S(=O)-CH2CH2-, -CH2CH2-S(=O)2-, -S(=O)2-CH2CH2-; wherein R L2 Selected from: hydrogen, methyl, ethyl, propyl, isopropyl.

11. The compound according to any one of claims 1 to 10, wherein The compound has a structure shown in formula II-1, II-2, II-3 or II-4; in, X 1 , X 2 , X 3 , X 4 , X 9 , X 10 Each is independently selected from: CH, N; E 1 Each independently selected from: CH2, NH, O, S; M 1 Each is independently selected from: CH, N; R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; n1 is independently selected from: 0, 1, 2; c1, c2 are each independently selected from: 0, 1; Other symbols such as R 1 , R 2 , R 3 , L 1 , L 2 , Y 1 , R a , R b The definitions of m, p are the same as those in Formula I; Preferably, R cc Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, pentafluoroethyl; Preferably, each R b Independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl; Preferably, m is 0, 1 or 2.

12. The compound according to any one of claims 1 to 10, characterized in that Having the structure shown in formula III-1, III-2, III-3 or III-4: in, X 1 , X 2 , X 3 , X 4 , X 9 , X 10 Each is independently selected from: CH, N; E 1 Each independently selected from: CH2, NH, O, S; M 1 Each is independently selected from: CH, N; G 1 , G 2 Each is independently selected from: CH, N; R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; n1 is independently selected from: 0, 1, 2; c1, c2 are each independently selected from: 0, 1; Other symbols such as R 1 , R 2 , R 3 , L 1 , L 2 , Y 1 , R a , R b The definitions of m, p are the same as those in Formula I; Preferably, p is 0 or 1; Preferably, m is 0 or 1; Preferably, each R b are independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl; preferably, R cc Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, and pentafluoroethyl.

13. The compound according to any one of claims 1 to 10, characterized in that It has the structure shown in formula IV-1, IV-2, IV-3, IV-4 or IV-5: Among them, X 1 , X 2 , X 3 , X 4 , X 9 , X 10 Each is independently selected from: CH, N; E 1 Each independently selected from: CH2, NH, O, S; G 1 , G 2 Each is independently selected from: CH, N; R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; n1 is independently selected from: 0, 1, 2; c1, c2 are each independently selected from: 0, 1; Other symbols such as R 1 , R 2 , R 3 , L 1 , L 2 , Y 1 , R a , R b , p is defined as in Formula I; Preferably, p is 0 or 1; Preferably, G 1 and G 2 All are CH, or one of them is N; Preferably, R cc Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, pentafluoroethyl; Preferably, each R b Independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl.

14. The compound according to any one of claims 11 to 13, wherein Select from the following structures: Select from the following structures: in, R aa Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, O=, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy; p1 is independently selected from: 0, 1, 2; Preferably, Select from the following structures: Preferably, Select from the following structures: Preferably, R aa Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; Preferably, R aa Each is independently selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, amino, cyano, O=, methyl, ethyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; Preferably, p1 is selected from: 0 or 1.

15. The compound according to any one of claims 1 to 14, wherein The compound has any one of the following structural formulas: Among them, R 1 , R 2 , R 3 , R b , L 1 , L 2 The definitions of p, m are the same as those in any one of claims 1 to 14; n1 is 0, 1 or 2; R a Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy; R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; c1, c2 are each independently selected from: 0, 1; Preferably, p is 0 or 1; Preferably, m is 0 or 1; Preferably, R a Each is independently selected from the group consisting of hydrogen, deuterium, cyano, halogen, amino, O=, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkyl, halogenated C1-C4 alkoxy, hydroxy-substituted C1-C4 alkoxy, amino-substituted C1-C4 alkoxy; Preferably, wherein R a Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; Preferably, R cc Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, pentafluoroethyl; Preferably, R b Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -SF5, -OCF3, -OCF2H, -CF2Cl, -OCF2Cl; Preferably, the compound has any one of the following structural formulas: Preferably, the compound has any one of the following structural formulas: Among them, R a , R b , L 1 , L 2 , p is defined as in any one of claims 1-14.

16. The compound according to any one of claims 1 to 15, wherein The compound has any one of the following structural formulas: In the structural formulas VI-1 to VI-39, R 1 , R 2 , R 3 , R b , L 1 , L 2 , p, and m are as defined in any one of claims 1 to 14; n1 is 0, 1 or 2; R a Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy; R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; c1, c2 are each independently selected from: 0, 1; Preferably, m is 1; Preferably, p is 0 or 1; Preferably, R a Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino, more preferably, R a is selected from the group consisting of fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; more preferably, R a Selected from methyl, cyano; Preferably, R cc Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, pentafluoroethyl; Preferably, R b is trifluoromethyl, trifluoromethoxy, pentafluorosulfur, -CF2Cl, -OCF2Cl; Preferably, R 1 is hydrogen; Preferably, R 2 is hydrogen; Preferably, R 3 is hydrogen or fluorine; Preferably, c1 is 0, 1, c2 is 0, 1; Preferably, L 1 is a single bond, NH or O; Preferably, L 2 is a single bond, NH or O.

17. A compound according to any one of claims 1 to 16, wherein The compound has any one of the following structural formulas: In VI-40 and VI-41, R 1 , R 2 , R 3 , R a , R b , L 1 , L 2 , p is as defined in any one of claims 1 to 14; n1 is 0, 1 or 2; R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; c1, c2 are each independently selected from: 0, 1; Preferably, the compound has any one of the following structural formulas: VI-42 to VI-48, R 1 , R 2 , R 3 , R a , R b , L 1 , L 2 The definition is the same as that in any one of claims 1 to 14; n1 is 0, 1 or 2; R a Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy; R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; c1, c2 are each independently selected from: 0, 1; Preferably, in VI-40 to VI-48, R a Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino, more preferably, R a is selected from the group consisting of fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; more preferably, R a Selected from methyl, cyano; Preferably, in VI-40 to VI-48, R b is trifluoromethyl, trifluoromethoxy, pentafluorosulfur, -CF2Cl, -OCF2Cl; Preferably, in VI-40 to VI-48, R 1 is hydrogen; Preferably, in VI-40 to VI-48, R 2 is hydrogen; Preferably, in VI-40 to VI-48, R 3 is hydrogen or fluorine; Preferably, in VI-40 to VI-48, c1 is 0 or 1, and c2 is 0 or 1; Preferably, in VI-40 to VI-48, L 1 is a single bond, NH or O; Preferably, in VI-40 to VI-48, L 2 is a single bond, NH or O.

18. The compound according to claim 1, wherein The compound has the following structural formula VII: In Formula VII, R 1 , R 2 , R 3 , R a , R b , m, p1 are as defined in any one of claims 1 to 14; R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; n1 is 0, 1 or 2; c1, c2 are each independently selected from: 0, 1; Ring A is a 5-10 membered heteroaryl group; preferably pyridine or pyrazine; Ring B is a 5-6 membered heteroaryl group; preferably benzene or pyridine; L 1 Selected from: -N(R L1 )-、-O-、-S-、-N(R L1 )-C1-C4 alkylene-, -C1-C4 alkylene-N(R L1 )-, -O-C1-C4 alkylene-, -C1-C4 alkylene-O-; wherein R L1 Selected from: hydrogen, C1-C4 alkyl; L 2 Selected from: -N(R L2 )-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C1-C4 alkylene-, -C1-C4 alkylene-O-, -O-C1-C4 alkylene-, -C1-C4 alkylene-S-, -S-C1-C4 alkylene-, -C1-C4 alkylene-S(=O)-, -S(=O)-C1-C4 alkylene-, -C1-C4 alkylene-S(=O)2-, -S(=O)2-C1-C4 alkylene-; wherein R L2 Selected from: hydrogen, C1-C4 alkyl; preferably, L 2 Selected from: -N(R L2 )-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-; where R L2 Selected from: hydrogen, C1-C4 alkyl; Preferably, the compound is not the following compound:

19. The compound according to any one of claims 1 to 18, wherein The compound has the following structural formula: R 1 , R 2 , R 3 , R b , L 1 , L 2 , m is as defined in any one of claims 1 to 14; n1 is 0, 1 or 2; R aa Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, amino-substituted C1-C6 The alkoxy group is preferably di(C1-C6 alkyl)amino; R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; c1 and c2 are each independently 0, 1 or 2; Preferably, R aa Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino, more preferably, R aa is selected from the group consisting of fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; more preferably, R aa Selected from methyl, cyano; Or two adjacent R aa connected to form a C4-C6 cycloalkyl, a 4-6 membered heterocyclic group, a C4-C6 partially unsaturated cycloalkyl, a 4-6 membered partially unsaturated heterocyclic group, a 5-6 membered heteroaryl, or a phenyl group; Preferably, m is 1; Preferably, R b is trifluoromethyl, trifluoromethoxy, pentafluorosulfur, -CF2Cl, -OCF2Cl; Preferably, R 1 is hydrogen; Preferably, R 2 is hydrogen; Preferably, R 3 is hydrogen or fluorine; Preferably, c1 is 0 or 1, c2 is 0, 1 or 2; Preferably, L 1 NH or O; Preferably, L 2 is NH or O.

20. A compound according to any one of claims 1 to 19, wherein The compound has a structure shown in formula W1, W2, W3 or W4: In formulas W1, W2, W3, and W4, R 1 , R 2 , R 3 , R b , m is as defined in any one of claims 1 to 14; R aa Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy; R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; n is 0, 1 or 2; c1 and c2 are each independently 0, 1 or 2; Preferably, R aa Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino, more preferably, R aa is selected from the group consisting of fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; more preferably, R aa Selected from methyl, cyano; Or two adjacent R aa connected to form a C4-C6 cycloalkyl, a 4-6 membered heterocyclic group, a C4-C6 partially unsaturated cycloalkyl, a 4-6 membered partially unsaturated heterocyclic group, a 5-6 membered heteroaryl, or a phenyl group; Preferably, R cc Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, pentafluoroethyl; Preferably, m is 1; Preferably, R b is trifluoromethyl, trifluoromethoxy, pentafluorosulfur, -CF2Cl, -OCF2Cl; Preferably, R 1 is hydrogen; Preferably, R 2 is hydrogen; Preferably, R 3 is hydrogen or fluorine; Preferably, c1 is 0 or 1, c2 is 0, 1 or 2; Preferably, the compound has a structure shown in formula W1.1, W1.2, W1.3 or W1.4: In formula W1.1, R 1 , R 2 , R 3 , R b , m is as defined in any one of claims 1 to 14; n1 is 0, 1 or 2; R a1 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy; R a2 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy; Or, R a1 and R a2 Connected to form 5-6 membered heteroaryl and phenyl groups; R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; preferably, R cc Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, pentafluoroethyl; c1 and c2 are each independently 0, 1 or 2; Preferably, R a1 are independently selected from the group consisting of: deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; Preferably, R a2 are independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; preferably, R a2 are independently selected from: hydrogen; Preferably, m is 1; Preferably, R b is trifluoromethyl, trifluoromethoxy, pentafluorosulfur, -CF2Cl, -OCF2Cl; Preferably, R b For para-substitution; Preferably, R 1 is hydrogen; Preferably, R 2 is hydrogen; Preferably, R 3 is hydrogen or fluorine; Preferably, c1 is 0 or 1, c2 is 0, 1 or 2; In formula W1.2, R 1 , R 2 , R 3 , R b , m is as defined in any one of claims 1 to 14; n1 is 0, 1 or 2; R a1 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy; R a2 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy; Or, R a1 and R a2 Connected to form 5-6 membered heteroaryl and phenyl groups; R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; preferably, R cc Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, pentafluoroethyl; c1 and c2 are each independently 0, 1 or 2; Preferably, R a1 are independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; Preferably, R a2 are independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; preferably, R a2 are independently selected from: hydrogen; Preferably, m is 1; Preferably, R b is trifluoromethyl, trifluoromethoxy, pentafluorosulfur, -CF2Cl, -OCF2Cl; Preferably, R b For para-substitution; Preferably, R 1 is hydrogen; Preferably, R 2 is hydrogen; Preferably, R 3 is hydrogen or fluorine; Preferably, c1 is 0 or 1, c2 is 0, 1 or 2; In formula W1.3, R 1 , R 2 , R 3 , R b , m is as defined in any one of claims 1 to 14; n1 is 0, 1 or 2; R aa Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy; R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; preferably, R cc Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, pentafluoroethyl; c1 and c2 are each independently 0, 1 or 2; Preferably, R aa are independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; Preferably, R b is trifluoromethyl, trifluoromethoxy, pentafluorosulfur, -CF2Cl, -OCF2Cl; Preferably, R b For para-substitution; Preferably, c1 is 0 or 1, c2 is 0, 1 or 2; In formula W1.4, R 1 , R 2 , R 3 , R b , m, n1 are as defined in any one of claims 1 to 14; n1 is 0, 1 or 2; R aa Each is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, O=, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylamino, hydroxy-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy; R cc Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; preferably, R cc Each is independently selected from: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, pentafluoroethyl; c1 and c2 are each independently 0, 1 or 2; Preferably, R aa are independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; Preferably, R b is trifluoromethyl, trifluoromethoxy, pentafluorosulfur, -CF2Cl, -OCF2Cl; Preferably, R b For para-substitution; Preferably, c1 is 0 or 1, c2 is 0, 1 or 2; Further preferably, the compound has the following formula a, formula b, formula c, formula d, formula e or formula f: In formula a, formula b, formula c, formula d, formula e, formula f, and formula g, R a , R b , R c , L 1 , L 2 As defined in any one of claims 1 to 14; Preferably, R a R is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, amino, hydroxy, cyano, O=, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, hydroxy-substituted methoxy, hydroxy-substituted ethoxy, hydroxy-substituted propoxy, amino-substituted ethoxy, amino-substituted propoxy, methylamino, dimethylamino, ethylamino, propylamino, isopropylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoro-ethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy; more preferably R a is selected from hydrogen, deuterium, fluorine, amino, cyano, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, -OCH2CH2-OH, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, dimethylamino; Preferably, R b is trifluoromethyl, trifluoromethoxy, pentafluorosulfur, -CF2Cl, -OCF2Cl; Preferably, R c is hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; Preferably, L 1 and L 2 are not a bond, and are not O or NH at the same time; more preferably L 1 and L 2 One of them is O and the other is NH.

21. The compound of claim 1, wherein The compound has the following structural formula:

22. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 21 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug; and a pharmaceutically acceptable carrier or diluent.

23. Use of a compound according to any one of claims 1 to 21 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug or a pharmaceutical composition according to claim 22 for preparing a medicament for treating cancer; preferably, the cancer is associated with TEAD overexpression and / or the cancer is associated with increased TEAD activity.

24. Use of a compound as described in any one of claims 1 to 21, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug of the compound, or a pharmaceutical composition as described in claim 22 for preparing a drug for inhibiting cancer progression.

25. Use of a compound as described in any one of claims 1 to 21, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug of the compound, or a pharmaceutical composition as described in claim 22 for the preparation of a medicament for treating a disease or condition associated with increased TEAD expression.

26. Use of a compound as described in any one of claims 1 to 21, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug of the compound, or a pharmaceutical composition as described in claim 22 for the preparation of a medicament for treating a disease or condition associated with increased TEAD activity.

27. Use of a compound as described in any one of claims 1 to 21, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug of the compound, or a pharmaceutical composition as described in claim 22 for the preparation of a medicament for treating a disease or condition associated with TEAD activity; wherein, Inhibition of TEAD activity would be beneficial in such diseases or conditions.

28. Use of the compound according to any one of claims 1 to 21, or the enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug of the compound, or the pharmaceutical composition according to claim 22 for preparing a medicament for treating a disease or disorder associated with the Hippo pathway; wherein, Inhibition of the Hippo pathway would be beneficial for the disease or condition.

29. The use according to any one of claims 23 to 28, wherein the disease or disorder is a cell proliferative disorder; preferably, the cell proliferative disease is cancer.

30. The use according to any one of claims 23-29, wherein the cancer is a cancer in which YAP is localized in the nucleus of the cancer.

31. The use according to any one of claims 23-30, wherein the TEAD overexpression, increased TEAD expression or increased TEAD activity is TEAD1 overexpression, increased TEAD1 expression or increased TEAD1 activity; and / or The TEAD overexpression, increased TEAD expression or increased TEAD activity is TEAD2 overexpression, increased TEAD2 expression or increased TEAD2 activity; and / or The TEAD overexpression, increased TEAD expression or increased TEAD activity is TEAD3 overexpression, increased TEAD3 expression or increased TEAD3 activity; and / or The TEAD overexpression, increased TEAD expression or increased TEAD activity is TEAD4 overexpression, increased TEAD4 expression or increased TEAD4 activity.

32. Use of a compound according to any one of claims 1 to 21, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug of the compound, or a pharmaceutical composition according to claim 22 for the preparation of a drug having the activity of binding to TEAD and blocking the interaction between YAP / TEAD.

33. The use of a compound as described in any one of claims 1 to 21, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug of the compound, or a pharmaceutical composition as described in claim 22 for preparing a medicament for treating a disease or condition; the disease or condition is a disease or condition associated with a protein that interacts with TEAD; preferably, the disease or condition associated with a protein that interacts with TEAD includes but is not limited to cancer, metabolic disease, inflammatory disease, or neurodegenerative disease; more preferably, the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelioma Preferably, the cancer is selected from brain cancer, esophageal cancer, kidney cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, gastric cancer, breast cancer or prostate cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma, undifferentiated carcinoma; further preferably, the brain cancer includes but is not limited to glioma; head and neck cancer includes but is not limited to head and neck squamous cell carcinoma; lung cancer includes but is not limited to lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung cancer, large cell lung cancer, small cell lung cancer, lung papillary adenocarcinoma or non-small cell lung cancer; gastric cancer includes but is not limited to gastric adenocarcinoma; breast cancer includes but is not limited to ductal breast cancer, breast cancer or HR+ breast cancer; prostate cancer includes but is not limited to prostate adenocarcinoma, prostate squamous cell carcinoma, or prostate adenosquamous carcinoma.

34. A method for inhibiting the interaction between TEAD and YAP; or preventing and / or treating related diseases mediated by nuclear transcription factor TEAD; or for non-therapeutic reversal of tumor cell resistance to anti-tumor drugs; or for reversing tumor cell resistance to anti-tumor drugs, comprising contacting the cell with or administering to the subject a compound according to any one of claims 1 to 20, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug of the compound, or a pharmaceutical composition according to claim 22; Preferably, the subject is a mammal, more preferably a human.

35. A compound according to any one of claims 1 to 21, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug of the compound, or a pharmaceutical composition according to claim 22 for inhibiting the interaction between TEAD and YAP; or preventing and / or treating related diseases mediated by the nuclear transcription factor TEAD; or for non-therapeutic reversal of tumor cell resistance to anti-tumor drugs; or for reversing tumor cell resistance to anti-tumor drugs.

36. A method of treating cancer in a patient, comprising administering to the patient a compound as described in any one of claims 1-21, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug of the compound, or a pharmaceutical composition as described in claim 22; preferably, the cancer is associated with TEAD overexpression and / or the cancer is associated with increased TEAD activity.

37. A method of inhibiting the progression of cancer in a patient, comprising administering to the patient a compound as described in any one of claims 1-21, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug of the compound, or a pharmaceutical composition as described in claim 22; preferably, the cancer is associated with TEAD overexpression and / or the cancer is associated with increased TEAD activity.

38. A method of treating a patient suffering from a disease or condition associated with increased TEAD expression, comprising administering to the patient a compound of any one of claims 1-21, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug of the compound, or a pharmaceutical composition as claimed in claim 22.

39. A method of treating a patient suffering from a disease or condition associated with increased TEAD activity, comprising administering to the patient a compound of any one of claims 1-21, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug of the compound, or a pharmaceutical composition as claimed in claim 22.

40. A method of treating a disease or condition in which inhibition of TEAD activity would be beneficial, comprising administering to a patient a compound of any one of claims 1-21 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug of the compound or a pharmaceutical composition as claimed in claim 22.

41. A method for treating a disease or condition in which inhibition of the Hippo pathway would be beneficial, comprising administering to a patient a compound of any one of claims 1 to 21 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug of the compound or a pharmaceutical composition of claim 22.

42. The method of any one of claims 36-41, wherein the disease or disorder is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.

43. The method of any one of claims 36-42, wherein the cancer is one in which YAP is localized in the nucleus of the cancer.

44. The method according to any one of claims 36-43, wherein the TEAD overexpression, increased TEAD expression or increased TEAD activity is TEAD1 overexpression, increased TEAD1 expression or increased TEAD1 activity; and / or The TEAD overexpression, increased TEAD expression or increased TEAD activity is TEAD2 overexpression, increased TEAD2 expression or increased TEAD2 activity; and / or The TEAD overexpression, increased TEAD expression or increased TEAD activity is TEAD3 overexpression, increased TEAD3 expression or increased TEAD3 activity; and / or The TEAD overexpression, increased TEAD expression or increased TEAD activity is TEAD4 overexpression, increased TEAD4 expression or increased TEAD4 activity.

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