Transcriptional enhanced associate domains (TEADS) inhibitor compound, and pharmaceutical composition and use thereof

Abstract

The present invention relates to a transcriptional enhanced associate domains (TEADs) inhibitor compound as shown in formula (I) or (II), a composition thereof, and the use thereof. The compound of the present invention can be used for treating or preventing cancer, hyperproliferative, inflammatory and autoimmune diseases and infectious diseases by means of inhibiting palmitoylation of TEAD proteins or inhibiting interaction between YAP / TAZ and TEAD proteins.

Description

Transcription enhancer associated domain (TEADs) inhibitor compounds, pharmaceutical compositions and uses thereof Technical Field

[0001] The present invention relates to a class of heterocyclic compounds represented by formula (I) or formula (II). The present invention also relates to pharmaceutical compositions comprising such compounds and methods for treating and preventing diseases using the compounds or their pharmaceutical uses, particularly for cancer, precancerous syndromes, congenital diseases, and hyperproliferative diseases. Background Art

[0002] The Hippo signaling pathway was first discovered in Drosophila and is highly conserved in mammals. It plays an important role in controlling cell growth and early stem cell proliferation, tissue homeostasis, and organ size. This pathway may also be involved in wound healing and tissue regeneration, and disorders of this pathway are often detected in human cancers. As the Hippo pathway crosstalks with other signaling pathways such as Wnt, Notch, Hedgehog, and MAPK / ERK, it may affect a variety of physiological and biochemical processes, and its dysfunction may be involved in many other human diseases in addition to cancer (Journal of Translational Medicine 2019, 17(1), 116).

[0003] The Hippo signaling pathway comprises the core cascade kinases MST1 / 2 (mammalian STE20-like kinases), LATS1 / 2 (large tumor suppressor kinases), the adaptor proteins SAV1 (salvador homolog 1) and MOB1, and the effectors YAP / TAZ. Regulated by multiple upstream effectors, upon activation of the Hippo pathway, MST1 / 2 interact with SAV1, phosphorylating and activating LATS1 / 2 and MOB. Alternatively, LATS1 / 2, activated through NF2 (neurofibromin 2), further phosphorylates YAP or TAZ. Phosphorylated YAP / TAZ are recruited by 14-3-3 proteins, retained in the cytoplasm, and degraded by proteasome inactivation. Upon inhibition of the Hippo pathway, unphosphorylated YAP / TAZ enter the nucleus, where they bind to four TEA domain-containing proteins (TEAD1-TEAD4, collectively referred to as "TEADs") and activate the transcription of multiple target genes, leading to cellular transformation and tissue proliferation. The multiple target genes include connective tissue growth factor (CTGF), Gli2, Birc5, Birc2, fibroblast growth factor 1 (FGF1) and amphiregulin (AREG), etc. Although YAP / TAZ can also interact with many other factors, TEADs proteins are generally considered to be the main effector molecules mediating the growth-promoting and carcinogenic effects of YAP / TAZ (Cell 2015, 163(4), 811-828; Nature Cell Biology 2018, 20(8), 888-899.).

[0004] Studies have shown that the dysregulation or inactivation of the Hippo signaling pathway is associated with the occurrence, development and metastasis of cancer. The expression level or nuclear entry level of YAP and / or TAZ in some tumors such as breast cancer, non-small cell lung cancer, ovarian cancer, colorectal cancer, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer and osteosarcoma is increased, leading to overactivation. The presence of YAP in the cell nucleus is closely related to the mutation of NF2 in schwannomas, meningiomas and ependymomas. NF2 and LATS2 gene mutations are also observed in malignant mesothelioma. Amplification of the YAP1 and WWTR1 genes encoding YAP / TAZ has been observed in ~14% of head and neck squamous cell carcinomas, ~16% of lung squamous cell carcinomas, ~17% of cervical squamous cell carcinomas and ~15% of esophageal cancers (Cancer Cell 2016, 29(6), 783-803; Signal Transduction and Targeted Therapy 2022, 7(1), 376.).

[0005] Studies have shown that YAP / TAZ mediates primary or secondary drug resistance by inhibiting apoptotic protein levels and upregulating spindle assembly checkpoints. In esophageal cancer, YAP1 is a positive regulator of EGFR (epidermal growth factor receptor) and the induction of YAP1 is associated with resistance to 5-FU and docetaxel. In the context of targeted therapy, YAP1 in BRAF mutant tumors acts as a parallel survival input to promote resistance to RAF and MEK inhibitor therapy in melanoma. Similarly, YAP1 activation is a mechanism of survival in response to EGFR and MEK inhibitor treatment in the context of EGFR mutant lung cancer, and multiple studies have identified YAP1 activation as one of the main bypass mechanisms of KRAS inhibition. In the context of hormone-dependent tumors, TAZ inhibition has been shown to restore sensitivity to tamoxifen in breast cancer. In prostate cancer cells, androgen deprivation therapy resistance is associated with increased YAP nuclear localization and activity (Biochimica et Biophysica Acta (BBA)-Reviews on Cancer 2020, 1873(1), 188341; Cancer Cell 2020, 37(1), 104-122.e12.).

[0006] Therefore, inhibiting TEAD protein palmitoylation or inhibiting YAP / TAZ-TEAD protein interaction is expected to become an effective treatment for the above-mentioned tumors. Summary of the Invention

[0007] An object of the present invention is to provide a compound represented by general formula (I) or (II), a pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, or isotope-labeled compound (including deuterium substitution) thereof.

[0008] Another object of the present invention is to provide a method for preparing the compound.

[0009] Another object of the present invention is to provide a pharmaceutical composition comprising the compound.

[0010] Another object of the present invention is to provide the use of the compound in pharmaceutical preparation.

[0011] According to one aspect of the present invention, there is provided a compound represented by formula (I) or (II), or a pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, or isotope-labeled compound thereof:

[0012] in,

[0013] One of X1 and X2 is CR 2, the other is N; preferably X1 is CR 2 and X2 is N;

[0014] Ring A is C 6-12 aromatic ring or 5-10 membered heteroaromatic ring,

[0015] R A is one or more independently selected from: hydrogen, halogen, C 1-15 Alkyl, C 3-20 Cycloalkyl, 3-15 membered heterocycloalkyl, C 1-6 Alkoxy, S(R y )5, SCF3, and SeCF3 substituents, wherein R y Is halogen; wherein the C 1-15 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more halogens;

[0016] Ring B is C 6-12 aromatic ring or 5-10 membered heteroaromatic ring,

[0017] R B is one or more independently selected from: hydrogen, halogen, =O, C 1-15 Alkyl, C 6-20 Aryl, C 3-20 Cycloalkyl, 5-15 membered heteroaryl, 3-15 membered heterocycloalkyl, -CN, -OH, C 1-15 Alkoxy, -NR a C(=O)R b 、-C(=O)NR a R b 、-S(=O)2R b 、-S(=O)2NR a R b 、-NR a S(=O)2R b 、-NR a R b a substituent; wherein said C 1-15 Alkyl, C 1-15 The alkoxy group is optionally substituted with one or more halogens;

[0018] R 1 and R 2 independently selected from hydrogen, halogen, -CN, -OH, -NR a R b , C with or without substituents 1-6 Alkyl, C with or without substituents 2-6 Alkenyl, C with or without substituents 2-6 Alkynyl, C with or without substituents 1-6Alkoxy, wherein the substituent is one or more selected from halogen, -CN, -OH, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-20 Substituents of an aryl group; when X1 is N and X2 is CR 2 When R 2 Preferably, hydrogen, C 1-6 Alkyl, wherein the substituent is selected from halogen;

[0019] Or, when X1 is CR 2 When X2 is N, R 1 and R 2 Together with the carbon atoms to which they are attached, they optionally form a 6-10 membered partially unsaturated non-aromatic ring with or without a substituent, or a 6-10 membered aromatic ring with or without a substituent, or a 6-10 membered ring after one of the ring carbon atoms is replaced by an oxygen atom, a sulfur atom or a nitrogen atom, wherein the substituent is one or more selected from halogen, =O, -CN, C 1-6 Alkyl, C 1-6 Substituents of the alkoxy group;

[0020] R a and R b Independently selected from H, C 1-6 Alkyl, C 3-20 Cycloalkyl, wherein the C 1-6 Alkyl, C 3-20 Cycloalkyl is optionally substituted with one or more groups selected from halogen, oxo, -OH and -CN;

[0021] Z is -C(O)R x ,

[0022] R x C 2-6 Alkenyl, which is optionally selected from C 1-6 Alkyl, deuterium, -CN, -OH, C 1-6 Alkoxy and one or more halogen substituents; or

[0023] R x C 1-6 Alkyl, optionally substituted with one or more substituents selected from halogen, -CN and -OH; or

[0024] R x C 2-6 Alkynyl, which is optionally selected from C 1-6 Alkyl, C 6-12 Aryl, C 3-20 Cycloalkyl, 5-15 membered heteroaryl, 3-15 membered heterocycloalkyl, deuterium, -CN, -OH, C1-6 substituted with one or more substituents of alkoxy and halogen; or

[0025] R x is cyclobutenyl, dihydrofuranyl, bicyclobutyl or cyclopentenyl;

[0026] or

[0027] Z is S(O) n R x1 ,

[0028] R x1 C 2-6 Alkenyl, which is optionally selected from C 1-6 Alkyl, deuterium, -CN, -OH, C 1-6 Alkoxy and halogen substituted with one or more substituents;

[0029] n and m are independently 1 or 2.

[0030] According to one embodiment of the present invention, the compound is selected from the compounds represented by formula (Ia) or (IIa):

[0031] Among them, ring A, ring B, R 1 , X1, X2, R A , R B , n and m are the same as those defined in the general formula I or II described above;

[0032] R c 、R d and R e Each independently selected from hydrogen, deuterium, halogen, -CN, C 1-6 Alkoxy and C 1-6 alkyl.

[0033] According to one embodiment of the present invention, the compound is selected from the compounds represented by formula (Ib) or (IIb):

[0034] Among them, ring B, R 1 , X1, X2, R B , n and m are the same as those defined in the general formula I or II described above;

[0035] R c 、R d and R e Each independently selected from hydrogen, deuterium, halogen, -CN, C 1-6 Alkoxy or C 1-6 alkyl;

[0036] A1, A2, A3, A4 and A5 are independently CR A or N;

[0037] R A Independently selected from: hydrogen, halogen, C 1-15 Alkyl, C 3-20 Cycloalkyl, 3-15 membered heterocycloalkyl, C 1-6 Alkoxy, S(R y )5, SCF3, SeCF3, R y Is halogen; wherein the C 1-15 Alkyl and C 1-6 Alkoxy groups are optionally substituted with one or more halogens.

[0038] In some embodiments, R B The substituted ring B can be represented by pyridone Substituted with R 1 And connected to the main structure of the compound through any connectable site.

[0039] In some embodiments, R 1 and R B The substituted ring B can be represented as R 1 Same as the definitions in Formula I or II above.

[0040] According to one embodiment of the present invention, the compound is selected from the compound represented by formula (Ic) or (IIc):

[0041] in,

[0042] One of X1 and X2 is CR 2 , the other is N; preferably X1 is CR 2 and X2 is N;

[0043] Z is or

[0044] R c , R d and R e independently selected from hydrogen, deuterium, halogen, -CN and C 1-6 alkyl;

[0045] R f Selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-15 membered heterocycloalkyl, deuterium, -CN, C 1-6 Alkoxy and halogen;

[0046] A1, A2, A3, A4 and A5 are independently CR A or N;

[0047] R A Independently selected from: hydrogen, halogen, C 1-15 Alkyl, C 3-20 Cycloalkyl, 3-15 membered heterocycloalkyl, C 1-6 Alkoxy, SF5, SCF3, SeCF3; wherein the C 1-15 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more halogens;

[0048] B2, B3, B4 and B5 are independently CR B or N;

[0049] R B Independently selected from: hydrogen, halogen, =O, C 1-15 Alkyl, C 6-20 Aryl, C 3-20 Cycloalkyl, 5-15 membered heteroaryl, 3-15 membered heterocycloalkyl, -CN, -OH, C 1-15 Alkoxy, -NR a C(=O)R b 、-C(=O)NR a R b 、-S(=O)2R b 、-S(=O)2NR a R b 、-NR a S(=O)2R b 、-NR a R b ; wherein the C 1-15 Alkyl and C 1-15 The alkoxy group is optionally substituted with one or more halogens;

[0050] B1 is CR 1 or N, where R 1 Selected from hydrogen, halogen, -CN, -OH, -NR a R b , C with or without substituents 1-6 Alkyl, C with or without substituents 2-6 Alkenyl, C with or without substituents 2-6 Alkynyl, C with or without substituents 1-6 Alkoxy, wherein the substituent is one or more selected from halogen, -CN, -OH, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-20 substituents of the aryl group;

[0051] R 2 Selected from hydrogen, halogen, -CN, -OH, -NR aR b , C with or without substituents 1-6 Alkyl, C with or without substituents 2-6 Alkenyl, C with or without substituents 2-6 Alkynyl, C with or without substituents 1-6 Alkoxy, wherein the substituent is one or more selected from halogen, -CN, -OH, =O, C 1-6 Alkyl, C 1-6 Substituents of the alkoxy group;

[0052] Or, when X1 is CR 2 When X2 is N, R 1 and R 2 Together with the carbon atoms to which they are attached, they optionally form a 6-10 membered partially unsaturated non-aromatic ring with or without a substituent, or a 6-10 membered aromatic ring with or without a substituent, or a 6-10 membered ring in which one of the ring carbon atoms is replaced by an oxygen atom, a sulfur atom or a nitrogen atom, wherein the substituent is one or more selected from halogen, =O, -CN, C 1-6 Alkyl, C 1-6 Substituents of the alkoxy group;

[0053] R a and R b independently selected from hydrogen, C 1-6 Alkyl, C 3-20 Cycloalkyl, wherein the C 1-6 Alkyl, C 3-20 Cycloalkyl is optionally substituted with one or more groups selected from halogen, oxo, -OH and -CN;

[0054] n and m are independently 1 or 2.

[0055] According to one embodiment of the present invention, the compound is selected from the compound represented by formula (Id) or (IId):

[0056] in,

[0057] Z is or

[0058] R c , R d and R e independently selected from hydrogen, deuterium, halogen, -CN and C 1-6 alkyl;

[0059] R f Selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-15 membered heterocycloalkyl, deuterium, -CN, C1-6 Alkoxy and halogen;

[0060] A1, A2, A3, A4 and A5 are independently CR A or N;

[0061] R A Independently selected from: hydrogen, halogen, C 1-15 Alkyl, C 3-20 Cycloalkyl, 3-15 membered heterocycloalkyl, C 1-6 Alkoxy, SF5, SCF3, SeCF3; wherein the C 1-15 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more halogens;

[0062] B2, B3, B4 and B5 are independently CR B or N;

[0063] R B Independently selected from: hydrogen, halogen, =O, C 1-15 Alkyl, C 6-20 Aryl, C 3-20 Cycloalkyl, 5-15 membered heteroaryl, 3-15 membered heterocycloalkyl, -CN, -OH, C 1-15 Alkoxy, -NR a C(=O)R b 、-C(=O)NR a R b 、-S(=O)2R b 、-S(=O)2NR a R b 、-NR a S(=O)2R b 、-NR a R b ; wherein the C 1-15 Alkyl, C 1-15 The alkoxy group is optionally substituted with one or more halogens;

[0064] R a and R b independently selected from hydrogen, C 1-6 Alkyl, C 3-20 Cycloalkyl, wherein the C 1-6 Alkyl, C 3-20 Cycloalkyl is optionally substituted with one or more groups selected from halogen, oxo, -OH and -CN;

[0065] n and m are independently selected from 1 or 2;

[0066] Indicates a single bond or a double bond;

[0067] L is C, O, S, N or does not exist;

[0068] R g is one or more independently selected from: hydrogen, halogen, =O, -CN, C 1-6 Alkyl, C 1-6 Substituents of the alkoxy group.

[0069] According to one embodiment of the present invention, the compound is selected from the compounds represented by formula (Ie) or (IIe):

[0070] in,

[0071] One of X1 and X2 is CR 2 , the other is N; preferably X1 is CR 2 and X2 is N;

[0072] Z is or

[0073] R c , R d and R e independently selected from hydrogen, deuterium, F, -CN and C 1-5 alkyl;

[0074] R f Selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-15 membered heterocycloalkyl, deuterium, -CN, C 1-6 Alkoxy and halogen;

[0075] A1, A2, A3, A4 and A5 are independently CR A or N;

[0076] R A Independently selected from: hydrogen, halogen, C 1-15 Alkyl, C 3-20 Cycloalkyl, 3-15 membered heterocycloalkyl, C 1-6 Alkoxy, SF5, SCF3, SeCF3; wherein the C 1-15 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more halogens;

[0077] B2, B3, B4 and B5 are independently CR B or N;

[0078] R B Independently selected from: hydrogen, halogen, =O, C 1-15 Alkyl, C 6-20 Aryl, C 3-20Cycloalkyl, 5-15 membered heteroaryl, 3-15 membered heterocycloalkyl, -CN, -OH, C 1-15 Alkoxy, -NR a C(=O)R b 、-C(=O)NR a R b 、-S(=O)2R b 、-S(=O)2NR a R b 、-NR a S(=O)2R b 、-NR a R b ; wherein the C 1-15 Alkyl, C 1-15 The alkoxy group is optionally substituted with one or more halogens;

[0079] B1 is CR 1 or N, where R 1 Selected from hydrogen, halogen, -CN, -OH, -NR a R b , C with or without substituents 1-6 Alkyl, C with or without substituents 2-6 Alkenyl, C with or without substituents 2-6 Alkynyl, C with or without substituents 1-6 Alkoxy, wherein the substituent is one or more selected from halogen, -CN, -OH, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-20 substituents of the aryl group;

[0080] R 2 Selected from hydrogen, halogen, -CN, -OH, -NR a R b , C with or without substituents 1-6 Alkyl, C with or without substituents 2-6 Alkenyl, C with or without substituents 2-6 Alkynyl, C with or without substituents 1-6 Alkoxy, wherein the substituent is one or more selected from halogen, -CN, -OH, =O, C 1-6 Alkyl, C 1-6 Substituents of the alkoxy group;

[0081] R a and R b independently selected from hydrogen, C 1-6 Alkyl, C 3-20 Cycloalkyl, wherein the C 1-6 Alkyl, C 3-20Cycloalkyl is optionally substituted with one or more halo, oxo, -OH, or -CN.

[0082] According to one embodiment of the present invention, the compound is selected from the following compounds:

[0083] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising one or more compounds selected from the group consisting of the compounds described above, their pharmaceutically acceptable salts, stereoisomers, enantiomers, diastereomers, atropisomers, racemates, and isotope-labeled compounds, and optionally a pharmaceutically acceptable carrier or excipient.

[0084] According to another aspect of the present invention, it provides the use of the compound, or its pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, and isotope-labeled compound, or the composition in the preparation of a medicament for preventing and / or treating a disease, disorder or condition mediated by TEADs.

[0085] According to one embodiment of the present invention, the drug is used to treat and / or prevent one or more of cancer, hyperproliferative, inflammatory, autoimmune and infectious diseases.

[0086] According to one embodiment of the present invention, the disease or condition or disease state is selected from colon cancer, diffuse large B-cell lymphoma, follicular lymphoma, other lymphomas, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer, brain tumor, including neuroblastoma, neurilemmoma, glioma, glioblastoma and astrocytoma, cervical cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, squamous cell carcinoma, gastrointestinal cancer, parathyroid tumor, uterine tumor and soft tissue sarcoma, cardiovascular disease, neurodegenerative disease, malaria, AIDS, gout, diabetes, renal failure, chronic lung disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, Psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjögren's syndrome, scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Parkinson's disease, allergic diseases, asthma, multiple sclerosis, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1 converting enzyme-associated febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, and periodontitis. Beneficial effects

[0087] The compounds of the present invention can be used to treat or prevent cancer, hyperproliferative, inflammatory, autoimmune and infectious diseases by inhibiting TEAD protein palmitoylation or inhibiting YAP / TAZ-TEAD protein interaction. DETAILED DESCRIPTION

[0088] To facilitate understanding of the features and effects of the present invention by persons having ordinary skill in the art, the following provides a general description and definition of terms and expressions used in this specification and claims. Unless otherwise indicated, all technical and scientific terms used herein have the ordinary meanings as understood by those skilled in the art in connection with the present invention. In the event of any conflict, the definitions in this specification shall prevail.

[0089] In the present invention,

[0090] The "alkyl" refers to an aliphatic hydrocarbon group, which can be a branched or straight chain alkyl group. Depending on the structure, the alkyl group can be a monovalent group or a divalent group (i.e., an alkylene group). For example, in "hydroxy C 1-6"alkyl", the C 1-6 Alkyl groups are actually divalent groups (alkylene groups). In the present invention, alkyl groups are preferably "lower alkyl groups" having 1 to 6 carbon atoms, and even more preferably "lower alkyl groups" having 1 to 3 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.

[0091] The "halogen" is F, Cl, Br, I;

[0092] The "cycloalkyl" is a saturated or unsaturated 3-10 membered monocyclic or polycyclic alicyclic ring, and can be a monovalent group or a divalent group (and a cycloalkylene group);

[0093] The "heterocycloalkyl" is a saturated 3-10 membered monocyclic or polycyclic aliphatic heterocyclic ring containing one or more heteroatoms selected from N, O, and S, and can be a monovalent group or a divalent group (i.e., a heterocycloalkylene group);

[0094] The term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom, including a monocyclic ring or a condensed polycyclic ring, and can be a monovalent group or a divalent group (i.e., an arylene group). In the present invention, the aryl ring preferably has 5-10 carbon atoms, and more preferably has 5-7 carbon atoms.

[0095] The "heteroaryl" is an aromatic group containing one or more heteroatoms selected from N, O, and S on the ring. Depending on the structure, the heteroaryl group can be a monovalent group or a divalent group (i.e., a heteroarylene group). Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, pyrazinyl, triazolyl, tetrazolyl, thienyl, thiazolyl, furyl, oxazolyl, isoxazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindolyl, pteryl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, and the like.

[0096] Example

[0097] In the following examples, the optimum reaction conditions and reaction times for each independent step can be varied according to the specific reactants used and the substituents present in all reactants. Unless otherwise specified, solvent, temperature and other reaction conditions can be easily selected by those skilled in the art. Specific steps are provided in the Synthesis Examples section. The reaction can be further processed in a conventional manner, for example, by removing the solvent from the residue and further purified according to methods generally known in the art such as, but not limited to, crystallization, distillation, extraction, grinding and chromatography. Unless otherwise specified, starting materials and reactants are commercially available or can be prepared by those skilled in the art from available materials using the method described in the chemical literature.

[0098] Routine experimentation, including appropriate adjustment of reaction conditions, reactants and sequence of synthetic routes, protection of any chemical functional groups, which may not be compatible with the reaction conditions, and deprotection at appropriate points in the reaction sequence of the method, are within the scope of the present invention. Suitable protecting groups and methods of protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples thereof are found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd edition), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety. The synthesis of the compounds of the present invention can be achieved by methods similar to those described in the synthetic schemes described above and in the specific examples.

[0099] Starting materials, if not commercially available, can be prepared by steps selected from standard organic chemistry techniques, techniques analogous to those used to synthesize analogs of known structures, or techniques analogous to the steps described in the above schemes or synthetic examples. When an optically active form of a compound of the invention is desired, it can be obtained by performing one of the steps described herein using an optically active starting material (e.g., by asymmetric induction of the appropriate reaction steps), or by resolving a stereoisomer mixture of a compound or intermediate using standard procedures (e.g., chromatographic separation, recrystallization, or enzymatic resolution).

[0100] Similarly, when pure geometric isomers of the compounds of the invention are required, they can be obtained by carrying out one of the above steps using pure geometric isomers as starting materials, or by resolving mixtures of geometric isomers of compounds or intermediates using standard procedures, such as chromatographic separation.

[0101] For illustrative purposes, the following examples may be used. The following examples are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention to these examples.

[0102] Example 1: Synthesis of compounds ZB-TH-4 and ZB-TH-5

[0103] Step 1: Preparation of compound 1a

[0104] Dissolve 4-methylbenzenesulfonylhydrazide (3.00 g, 16.11 mmol) and 4-(trifluoromethyl)benzaldehyde (2.95 g, 16.91 mmol) in tetrahydrofuran (THF, 80 mL), stir at room temperature for 2 hours, and concentrate under reduced pressure. Purify by silica gel column chromatography to obtain compound 1a. LCMS [M+Na] + :365.26.

[0105] Step 2: Preparation of compound 1b

[0106] Compound 1a (417.3 mg, 1.22 mmol) and 3-ethynylpyridine (63.0 mg, 0.61 mmol) were dissolved in toluene (17 mL). 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 185.7 mg, 1.22 mmol) was added with stirring, and the mixture was stirred at 80°C overnight. After completion of the reaction as monitored by LC-MS, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to afford compound 1b (130 mg). 1 H NMR(600MHz,CD3OD)δ9.00(s,1H),8.54-8.46(m,1H),8.24(m,1H),7.97(m,2H ),7.73(d,J=8.1Hz,2H),7.50(dd,J=8.0,4.9Hz,1H),7.22(s,1H).LCMS[M+H] + :290.09.

[0107] Step 3: Preparation of compounds 1c and 1e

[0108] Compound 1b (130.0 mg, 0.45 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (385 mg, 1.36 mmol), and cesium carbonate (592.0 mg, 1.82 mmol) were dissolved in 3.5 mL of N,N-dimethylformamide (DMF) and the reaction was heated and stirred at 100°C for approximately 4 hours. 60 mL of water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography gave Compound 1c (100 mg) and Compound 1e (80 mg), respectively. Compound 1c: LCMS [M+Na] + :467.17; Compound 1e: LCMS [M+Na] + :467.17.

[0109] Step 4: Preparation of compounds 1d and 1f

[0110] Preparation of compound 1d: Dissolve compound 1c (100 mg) in 3 mL of dichloromethane (DCM), add 1 mL of trifluoroacetic acid (TFA), stir at room temperature for 30 minutes, and concentrate under reduced pressure to obtain crude compound 1d (100 mg), which was used directly in the next reaction without purification. LCMS [M+H] + :345.12.

[0111] Preparation of compound 1f: Using the preparation conditions of compound 1d, replacing compound 1c with 1e, compound 1f was prepared and used directly in the next reaction without purification. LCMS [M+H] + :345.12.

[0112] Step 5: Preparation of compounds ZB-TH-4 and ZB-TH-5

[0113] Preparation of compound ZB-TH-4: 2-Fluoroacrylic acid (40 mg, 0.44 mmol) and 2-(2-pyridone-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU, 131 mg, 0.44 mmol) were dissolved in 2 mL of DMF. N,N-diisopropylethylamine (DIPEA, 203 μL, 1.1 mmol) was added with stirring and the mixture was stirred at room temperature for 30 minutes. Compound 1d (100 mg, 0.22 mmol) was dissolved in DMF (5 mL) and added dropwise to the reaction mixture. The mixture was stirred at room temperature for 30 minutes. The mixture was quenched by adding 60 mL of saturated sodium chloride solution and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and then purified by preparative HPLC to obtain compound ZB-TH-4. 1 H NMR (600MHz, CD3OD) δ9.36 (d, J=2.0Hz, 1H), 9.04 (dt, J=8.2, 1.6Hz, 1H), 8.77 (dd, J=5 .4,1.3Hz,1H),8.09(ddd,J=8.2,5.7,0.8Hz,1H),7.88(d,J=8.1Hz,2H),7.70(d,J=8. 0Hz,2H),7.19(s,1H),5.61(dd,J=47.0,3.4Hz,1H),5.44(tt,J=8.1,5.2Hz,1H),5.26 (dd,J=16.0,3.4Hz,1H),5.01-4.90(m,2H),4.64(m,1H),4.60-4.52(m,1H).LCMS[M+H] + :417.13.

[0114] Preparation of compound ZB-TH-5: Compound ZB-TH-5 was prepared by using the preparation conditions of compound ZB-TH-4, replacing compound 1d with 1f. 1H NMR (600MHz, CD3OD) δ8.91(d,J=2.1Hz,1H),8.83(dd,J=5.4,1.5Hz,1H),8.36(dt,J=8.0,1.8 Hz,1H),8.12(d,J=8.1Hz,2H),7.93(dd,J=8.0,5.4Hz,1H),7.74(d,J=8.2Hz,2H),7.10(s,1H) ,5.61(dd,J=46.9,3.4Hz,1H),5.37(tt,J=8.1,5.3Hz,1H),5.26(dd,J=16.0,3.4Hz,1H),5.0 3-4.94(m,1H),4.93-4.90(m,1H),4.64(dd,J=11.2,5.3Hz,1H),4.59-4.49(m,1H).LCMS[M+H] + :417.13.

[0115] Example 2: Synthesis of compound ZB-TH-9.

[0116] The synthetic route of compound ZB-TH-4 in Example 1 was adopted, and the raw material 3-iodoazetidine-1-carboxylic acid tert-butyl ester in step 3 was replaced with 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-9. 1 H NMR (400MHz, MeOD) δ9.24(d,J=8.5Hz,1H),8.92(d,J=8.2Hz,1H),8.74(d,J=5.6Hz,1H),8.05(dd,J=8.1,5.7Hz,1H),7.89(d,J=7.9Hz,2H), 7.76(d,J=8.0Hz,2H),7.13(s,1H),5.49(ddd,J=47.3,7.4,3.5Hz,1H),5.36-5.08(m,2H),4.29-3.57(m,4H),2.61-2.33(m,2H).LCMS[M+Na] + :453.45.

[0117] Example 3: Synthesis of compound ZB-TH-10.

[0118] The synthetic route of compound ZB-TH-5 in Example 1 was adopted, and the raw material 3-iodoazetidine-1-carboxylic acid tert-butyl ester in step 3 was replaced with 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-10.1 H NMR (400MHz, CD3OD) δ8.96(s,1H),8.85(d,J=5.3Hz,1H),8.44(d,J=8.0Hz,1H),8.02(d,J=8.1Hz,2H),8.00-7.92(m,1H),7.69(d,J=8.0Hz,2H),7. 05(s,1H),5.48(dt,J=47.3,4.2Hz,1H),5.26(ddd,J=20.2,16.5,3.5Hz, 1H),5.18-5.06(m,1H),4.27-3.50(m,4H),2.62-2.25(m,2H).LCMS[M+Na] + :453.45.

[0119] Example 4: Synthesis of compound ZB-TH-11.

[0120] The synthetic route of compound ZB-TH-5 in Example 1 was adopted, and the raw material 3-ethynylpyridine in step 2 was replaced with 2-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-11. 1 H NMR (600MHz, CD3OD) δ8.72-8.65(m,1H),8.09(d,J=8.1Hz,2H),7.91(td,J=7.7 ,1.8Hz,1H),7.81(d,J=7.9Hz,1H),7.70(d,J=8.1Hz,2H),7.39(dd,J=7.6,4.9 Hz,1H),7.23(s,1H),6.11(tt,J=8.1,5.4Hz,1H),5.59(dd,J=46.9,3.4Hz,1H) ,5.24(dd,J=16.0,3.4Hz,1H),5.00-4.88(m,2H),4.71-4.48(m,2H).LCMS[M+H] + :417.13.

[0121] Example 5: Synthesis of compounds ZB-TH-12 and ZB-TH-13.

[0122] Step 1: Preparation of compound 5a.

[0123] 6,7-dihydro-5H-quinolin-8-one (300 mg, 1.0 eq) was dissolved in anhydrous THF (10 mL), argon was replaced three times, and a THF solution of lithium bis(trimethylsilyl)amide (LiHMDS) (1 M, 4 mL, 2 eq) was added dropwise under an ice-water bath. After the addition was complete, stirring was continued for 30 minutes. 4-Trifluoromethylbenzoyl chloride (509 mg, 1.2 eq) was then dissolved in anhydrous THF (5 mL) and added dropwise to the reaction solution. The mixture was returned to room temperature and stirred overnight. After the reaction was complete, saturated aqueous ammonium chloride was added to quench the mixture, and the mixture was extracted with ethyl acetate (three times). The ester layers were combined, dried over anhydrous sodium sulfate, the solvent was dried under reduced pressure, and the mixture was separated and purified by silica gel column chromatography to obtain compound 5a. LCMS [M+H] + :320.08.

[0124] Step 2: Preparation of compound 5b.

[0125] Compound 5a (300 mg, 1 eq) was dissolved in anhydrous ethanol (EtOH, 5 mL), and an aqueous hydrazine hydrate solution (N2H4·H2O, 85%, 141 μL, 3 eq) was added. The mixture was stirred at 80°C for 5 hours. After the reaction was complete, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography to obtain compound 5b. LCMS [M+H] + :316.10.

[0126] Step 3: Preparation of compounds 5c and 5e.

[0127] Compound 5b (142.0 mg, 0.45 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (385 mg, 1.36 mmol), and cesium carbonate (592.0 mg, 1.82 mmol) were dissolved in DMF (3.5 mL) and stirred at 100°C for approximately 4 hours before returning to room temperature. The mixture was quenched by the addition of 60 mL of water. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Column chromatography separation and purification afforded Compound 5c (90 mg) and Compound 5e (70 mg), respectively. Compound 5c: LCMS [M+H] + :471.19; Compound 5e: LCMS [M+H] + :471.19

[0128] Step 4: Preparation of compounds 5d and 5f.

[0129] Preparation of compound 5d: Compound 5c (90 mg) was dissolved in DCM (3 mL), and TFA (1 mL) was added. The mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure to obtain crude compound 5d (90 mg), which was used directly in the next step without purification. LCMS [M+H] +:371.14.

[0130] Preparation of compound 5f: Using the preparation conditions of compound 5d, replacing compound 5c with 5e, compound 5f (70 mg) was prepared. LCMS [M+H] + :371.14.

[0131] Step 5: Preparation of compounds ZB-TH-12 and ZB-TH-13.

[0132] Preparation of compound ZB-TH-12: 2-Fluoroacrylic acid (34 mg, 0.38 mmol) and TPTU (112.9 mg, 0.38 mmol) were dissolved in 2 mL of DMF. DIPEA (175 μL, 0.95 mmol) was added with stirring and the mixture was stirred at room temperature for 30 minutes. Compound 5d (90 mg, 0.19 mmol) was dissolved in DMF and added to the reaction mixture. The mixture was stirred at room temperature for 30 minutes. After complete conversion of the starting material, the reaction mixture was quenched by adding 60 mL of saturated sodium chloride solution. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The mixture was then purified by preparative HPLC to yield compound ZB-TH-12. 1 H NMR (600MHz, CD3OD) δ8.42(dd,J=4.9,1.7Hz,1H),7.92(d,J=8.0Hz,2H),7.73(d,J=8.0 Hz,2H),7.67(dd,J=7.7,1.6Hz,1H),7.20(dd,J=7.6,4.9Hz,1H),6.43(tt,J=8.9,4.9H z,1H),5.44(dd,J=46.9,3.5Hz,1H),5.04(dd,J=15.3,3.4Hz,1H),4.25(dd,J=11.4,8. 7Hz,1H),4.06(dd,J=11.3,5.4Hz,1H),3.97-3.81(m,2H),3.08-2.87(m,4H).LCMS[M+H] + :443.14.

[0133] Preparation of compound ZB-TH-13: Compound ZB-TH-13 was prepared by using the preparation conditions of compound ZB-TH-12, replacing compound 5d with 5f. 1H NMR (600MHz, CDCl3) δ8.43(dd,J=4.9,1.7Hz,1H),7.87(d,J=8.0Hz,2H),7.69(d,J=8.0Hz,2 H),7.57(dd,J=7.7,1.7Hz,1H),7.15(dd,J=7.6,4.9Hz,1H),6.60(tt,J=8.2,5.7Hz,1H),5. 66(dd,J=46.6,3.0Hz,1H),5.11(dd,J=15.6,3.1Hz,1H),5.06-4.98(m,1H),4.95-4.84(m,1 H),4.75(dd,J=11.1,5.7Hz,1H),4.63(dd,J=11.0,8.3Hz,1H),3.09-2.94(m,4H).LCMS[M+H] + :443.14.

[0134] Example 7: Synthesis of compound ZB-TH-14.

[0135] The synthetic route of compound ZB-TH-4 in Example 1 was adopted, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-14. 1 H NMR (400MHz, CDCl3) δ8.69-8.63(m,2H),7.81-7.72(m,4H),7.47(d,J=8.0Hz,2H),6.77(s,1H),5.68(dd,J=46.7,3.2Hz, 1H),5.23-5.17(m,1H),5.13(dd,J=15.6,3.2Hz,1H),5.07-4.98(m,1H),4.82-4.69(m,2H),4.53-4.44(m,1H).LCMS[M+H] + :417.13.

[0136] Example 8: Synthesis of compound ZB-TH-15.

[0137] The synthetic route of compound ZB-TH-5 in Example 1 was adopted, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-15. 1H NMR (400MHz, CDCl3) δ8.80-8.74(m,2H),7.98(d,J=8.0Hz,2H),7.68(d,J=8.2Hz,2H),7.31-7.24(m,2H),6.77(s,1H),5.68(dd,J=46. 7,3.2Hz,1H),5.23(tt,J=8.1,5.6Hz,1H),5.14(dd,J=15.6,3.2Hz,1H),5.04(m,1H),4.85-4.72(m,2H),4.56-4.47(m,1H).LCMS[M+H] + :417.13.

[0138] Example 9: Synthesis of compound ZB-TH-17.

[0139] The synthetic route of compound ZB-TH-12 in Example 5 was adopted, and the raw material 6,7-dihydro-5H-quinolin-8-one in step 1 was replaced with 6,7-dihydro-5H-isoquinolin-8-one. The remaining steps and conditions were carried out as described in Example 5 to prepare compound ZB-TH-17. 1 H NMR(600MHz,MeOD)δ9.19(s,1H),8.63(d,J=5.9Hz,1H),7.99(d,J=5.9Hz,1H) ,7.90(d,J=8.0Hz,2H),7.63(d,J=8.0Hz,2H),5.60(dd,J=47.0,3.4Hz,1H),5. 40-5.31(m,1H),5.26(dd,J=16.0,3.4Hz,1H),4.99-4.92(m,1H),4.63-4.57( m,1H),4.57-4.51(m,1H),3.34-3.31(m,2H),2.92(t,J=7.4Hz,2H).LCMS[M+H] + :443.14.

[0140] Example 10: Synthesis of compound ZB-TH-18.

[0141] The synthetic route of compound ZB-TH-13 in Example 5 was adopted, and the raw material 6,7-dihydro-5H-quinolin-8-one in step 1 was replaced with 6,7-dihydro-5H-isoquinolin-8-one. The remaining steps and conditions were carried out as described in Example 5 to prepare compound ZB-TH-18. 1H NMR(600MHz,MeOD)δ8.97(s,1H),8.70(d,J=5.8Hz,1H),8.06(d,J=5.8Hz,1H) ,7.97(d,J=8.0Hz,2H),7.78(d,J=8.0Hz,2H),5.87-5.82(m,1H),5.66(d,J=3. 4Hz,1H),5.59(d,J=3.4Hz,1H),5.27(dd,J=16.0,3.4Hz,1H),5.08-5.03(m,2 H),4.73-4.69(m,2H),3.27(t,J=7.4Hz,2H),3.10(t,J=7.4Hz,2H).LCMS[M+H] + :443.14.

[0142] Example 11: Synthesis of compound ZB-TH-19.

[0143] The synthetic route of compound ZB-TH-5 in Example 1 was adopted, and the raw material 3-ethynylpyridine in step 2 was replaced with 5-ethynylpyrimidine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-19. 1 H NMR (600MHz, CDCl3) δ9.33(s,1H),8.78(s,2H),7.99(d,J=7.9Hz,2H),7.69(d,J=7.9Hz,2H),6.80(s,1H),5.69 (dd,J=46.8,3.1Hz,1H),5.17-5.08(m,2H),5.07-5.01(m,1H),4.84-4.74(m,2H),4.55-4.49(m,1H).LCMS[M+H] + :418.12.

[0144] Example 12: Synthesis of compound ZB-TH-21.

[0145] The synthetic route of compound ZB-TH-4 in Example 1 was adopted, and the raw material 3-ethynylpyridine in step 2 was replaced with 5-ethynylpyrimidine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-21. 1H NMR(600MHz,MeOD)δ9.31(s,2H),9.13(s,1H),7.88(d,J=8.0Hz,2H),7.71(d,J=8.0Hz,2H),7.10(s,1H),5.62(dd,J=47.0,3.4Hz,1H),5.43 (tt,J=7.9,5.3Hz,1H),5.27(dd,J=16.0,3.4Hz,1H),5.03-4.97(m,1H),4.96-4.91(m,1H),4.68-4.62(m,1H),4.60-4.54(m,1H).LCMS[M+H] + :418.12.

[0146] Example 13: Synthesis of compound ZB-TH-22.

[0147] The synthetic route of compound ZB-TH-4 in Example 1 was adopted, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced by 6-trifluoromethylpyridine-3-aldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced by 5-ethynylpyrimidine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-22. 1 H NMR (600MHz, CDCl3) δ9.22-9.18(m,3H),8.74(s,1H),7.88(q,J=8.0Hz,2H),6.83(s,1H),5.68(dd,J=46.8,3.2H z,1H),5.20-5.11(m,2H),5.06-5.01(m,1H),4.84-4.78(m,1H),4.76-4.70(m,1H),4.54-4.48(m,1H).LCMS[M+H] + :419.12.

[0148] Example 14: Synthesis of compound ZB-TH-23.

[0149] The synthetic route of compound ZB-TH-5 in Example 1 was adopted, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced by 6-trifluoromethylpyridine-3-aldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced by 5-ethynylpyrimidine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-23. 1H NMR (600MHz, CDCl3) δ9.33(d,J=1.9Hz,1H),9.13(s,1H),8.79(d,J=1.9Hz,2H),8.38(d,J=8.1Hz,1H),7.75(d,J=8.0Hz,1H),6.87(d,J=1.9Hz ,1H),5.68(dt,J=46.7,2.5Hz,1H),5.17-5.10(m,2H),5.05-4.99(m,1 H),4.86-4.79(m,1H),4.76-4.71(m,1H),4.55-4.49(m,1H).LCMS[M+H] + :419.12.

[0150] Example 15: Synthesis of compounds ZB-TH-25 and ZB-TH-24.

[0151] The synthetic route of compound ZB-TH-13 in Example 5 was used, except that the raw material 6,7-dihydro-5H-quinolin-8-one in step 1 was replaced with 6,7-dihydro-5H-isoquinolin-8-one, and the raw material 4-trifluoromethylbenzoyl chloride was replaced with 6-trifluoromethylnicotinoyl chloride. The remaining steps and conditions were carried out as described in Example 5 to prepare compound ZB-TH-25 and by-product ZB-TH-24. ZB-TH-25: 1 H NMR (600MHz, Methanol-d4) δ9.12(s,1H),8.92(s,1H),8.66(d,J=5.6Hz,1H),8.44(d,J=8.2Hz,1H),7.97-7.91(m,2H),5.90-5.85(m,1H),5.63(d d,J=46.9,3.4Hz,1H),5.28(dd,J=15.8,3.4Hz,1H),5.09-5.04(m,2H),4 .74-4.70(m,2H),3.24(t,J=7.4Hz,2H),3.11(t,J=7.5Hz,2H).LCMS[M+H] + :444.14; ZB-TH-24: LCMS[M+H] + :442.12

[0152] Example 16: Synthesis of compound ZB-TH-28.

[0153] The synthetic route for compound ZB-TH-4 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 3-fluoro-4-trifluoromethylbenzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 5-ethynylpyrimidine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-28. LCMS [M+H] + :436.11. 1 H NMR (600MHz, CDCl3) δ9.24-9.12(m,3H),7.77(t,J=7.6Hz,1H),7.26-7.20(m,2H),6.76(s,1H),5.66(dt,J=46.8,2.7Hz,1H),5.21 (tt,J=7.7,3.9Hz,1H),5.13(dt,J=15.6,2.7Hz,1H),5.06-4.96(m,1H),4.87-4.75(m,1H),4.74-4.63(m,1H),4.58-4.44(m,1H).

[0154] Example 17: Synthesis of compound ZB-TH-29.

[0155] The synthetic route of compound ZB-TH-5 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 3-fluoro-4-trifluoromethylbenzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 5-ethynylpyrimidine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-29. LCMS [M+H] + :436.11. 1 H NMR(600MHz, CDCl3)δ9.33(s,1H),8.78(s,2H),7.79-7.69(m,2H),7.68-7.60(m,1H),6.79(s,1H),5.6 9(dd,J=46.8,3.2Hz,1H),5.19-5.07(m,2H),5.07-4.96(m,1H),4.86-4.69(m,2H),4.59-4.44(m,1H).

[0156] Example 18: Synthesis of compound ZB-TH-30.

[0157] The synthetic route of compound ZB-TH-4 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 3-fluoro-4-trifluoromethylbenzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-30. LCMS [M+H] + :435.12. 1 H NMR(600MHz, CDCl3)δ8.68(d,J=4.9Hz,2H),7.81-7.74(m,3H),7.26-7.21(m,2H),6.79(s,1H),5.70(dt,J=46.8,2.6Hz ,1H),5.25-5.20(m,1H),5.20-5.12(m,1H),5.06-5.01(m,1H),4.84-4.78(m,1H),4.77-4.71(m,1H),4.55-4.48(m,1H).

[0158] Example 19: Synthesis of compound ZB-TH-31.

[0159] The synthetic route of compound ZB-TH-5 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 3-fluoro-4-trifluoromethylbenzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-31. LCMS [M+H] + :435.12. 1 H NMR (600MHz, CDCl3) δ8.79(d,J=4.9Hz,2H),7.77-7.69(m,2H),7.66(t,J=7.7Hz,1H),7.28(d,J=4.9Hz,2H),6.77(s,1H),5.70(dd,J =46.6,3.2Hz,1H),5.25(p,J=7.0Hz,1H),5.15(dd,J=15.6,3.2Hz,1H),5.09-4.99(m,1H),4.87-4.68(m,2H),4.53(t,J=9.5Hz,1H).

[0160] Example 20: Synthesis of compound ZB-TH-32.

[0161] The synthetic route for compound ZB-TH-4 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with p-trifluoromethoxybenzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-32. LCMS [M+H] + :433.12. 1 H NMR (600MHz, CD3OD) δ8.58(d,J=5.3Hz,2H),7.99(d,J=5.3Hz,2H),7.57(d,J=8.3Hz,2H),7.46(d,J=8.2Hz,2H),7.03(s, 1H),5.60(dd,J=46.9,3.4Hz,1H),5.44-5.33(m,1H),5.25(dd,J=16.0,3.4Hz,1H),5.00-4.89(m,2H),4.66-4.47(m,2H).

[0162] Example 21: Synthesis of compound ZB-TH-33.

[0163] The synthetic route for compound ZB-TH-5 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with p-trifluoromethoxybenzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-33. LCMS [M+H] + :433.12. 1 H NMR (600MHz, MeOD) δ9.10-8.77(m,2H),8.10(d,J=6.6Hz,2H),8.04(d,J=8.8Hz,2H),7.36(d,J=8.3Hz,2H),7.27(s,1H ),5.62(dd,J=47.0,3.4Hz,1H),5.56-5.48(m,1H),5.27(dd,J=16.0,3.4Hz,1H),5.06-4.96(m,2H),4.72-4.52(m,2H).

[0164] Example 22: Synthesis of compound ZB-TH-34.

[0165] Step 1: Preparation of compound 22a

[0166] 4-Carbamimidoylpyridine hydrochloride (345 mg, 2.2 mmol) and 2-bromo-4'-(trifluoromethyl)acetophenone (315 mg, 2 mmol) were dissolved in a mixture of THF and water (THF / H2O = 4 mL / 1 mL). Potassium carbonate (1.80 g, 13 mmol) was then added. After heating under reflux for 16 hours, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography to obtain compound 22a. LCMS [M+H] + :290.08.

[0167] Step 2: Preparation of compound 22b

[0168] Compound 22a (130.0 mg, 0.45 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (770 mg, 2.72 mmol), and cesium carbonate (1.18 g, 3.64 mmol) were dissolved in 5 mL of DMF and the reaction was heated and stirred at 100°C for approximately 16 hours. 60 mL of water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography gave compound 22b (100 mg). LCMS [M+H] + :445.18.

[0169] Step 3: Preparation of compound 22c

[0170] Compound 22b (100 mg) was dissolved in 3 mL of DCM, and 1 mL of TFA (TFA) was added. The mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure to obtain the crude product of compound 22c (100 mg), which was used directly in the next step without purification. LCMS [M+H] + :345.12.

[0171] Step 4: Preparation of compound ZB-TH-34

[0172] 2-Fluoroacrylic acid (40 mg, 0.44 mmol) and 2-(2-pyridone-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU, 131 mg, 0.44 mmol) were dissolved in 2 mL of DMF. DIPEA (203 μL, 1.1 mmol) was added with stirring, and the mixture was stirred at room temperature for 30 minutes. Compound 22c (100 mg, 0.22 mmol) was dissolved in DMF (5 mL) and added dropwise to the reaction mixture. The mixture was stirred at room temperature for 30 minutes. The mixture was quenched by adding 60 mL of saturated sodium chloride solution, and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, and then purified by preparative HPLC to obtain compound ZB-TH-34. 1H NMR (400MHz, MeOD) δ8.91-8.64(m,2H),8.42(s,1H),8.05(d,J=8.2Hz,2H),7.76-7.65(m,4H),5.61(dd,J=46.9,3.4Hz,1H),5.44(tt,J =8.2,5.5Hz,1H),5.26(dd,J=16.0,3.4Hz,1H),5.03-4.91(m,1H),4.84-4.73(m,1H),4.71-4.57(m,1H),4.48-4.34(m,1H).LCMS[M+H] + :417.13.

[0173] Example 23: Synthesis of compound ZB-TH-35.

[0174] The synthetic route for compound ZB-TH-4 in Example 1 was used, except that the starting material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 6-trifluoromethylpyridine-3-aldehyde, and the starting material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-35. LCMS [M+H] + :418.12. 1 H NMR (600MHz, CDCl3) δ8.74(d,J=2.0Hz,1H),8.68(d,J=6.1Hz,2H),7.92-7.82(m,2H),7.76(d,J=6.1Hz,2H),6.84 (s,1H),5.69(dd,J=46.7,3.2Hz,1H),5.19-5.10(m,2H),5.08-4.99(m,1H),4.86-4.71(m,2H),4.59-4.44(m,1H).

[0175] Example 24: Synthesis of compound ZB-TH-36.

[0176] The synthetic route of compound ZB-TH-5 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 6-trifluoromethylpyridine-3-aldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-36. LCMS [M+H] + :418.12. 1H NMR (600MHz, CDCl3) δ9.12(s,1H),8.78(d,J=5.0Hz,2H),8.38(d,J=8.2Hz,1H),7.74(d,J=8.2Hz,1H),7.28(d ,J=5.0Hz,2H),6.83(s,1H),5.67(d,J=46.7Hz,1H),5.33-4.93(m,3H),4.86-4.64(m,2H),4.58-4.43(m,1H).

[0177] Example 25: Synthesis of compound ZB-TH-37.

[0178] Preparation of raw material 25a: The synthetic route of compound 1d in Example 1 was adopted, and the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced by 6-trifluoromethylpyridine-3-aldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced by 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare raw material 25a.

[0179] 25a (35 mg, 0.1 mmol) and triethylamine (TEA, 43 μL, 0.3 mmol) were dissolved in DCM (3 mL). Vinylsulfonyl chloride (19 mg, 0.15 mmol) was added dropwise in an ice-water bath. The mixture was then returned to room temperature and stirred for 16 hours. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography. The crude product was then purified by preparative HPLC to obtain compound ZB-TH-37. LCMS [M+H] + :436.10. 1 H NMR (400MHz, CDCl3) δ8.80-8.67(m,3H),7.90-7.86(m,2H),7.76(d,J=5.0Hz,2H),6.84(s,1H),6.78(dd,J=16.6,10.0H z,1H),6.45(d,J=16.6Hz,1H),6.27(d,J=10.0Hz,1H),5.17-5.02(m,1H),4.63(t,J=7.5Hz,2H),4.28(t,J=8.1Hz,2H).

[0180] Example 26: Synthesis of compound ZB-TH-38.

[0181] Preparation of raw material 26a: The synthetic route of compound 1f in Example 1 was adopted, and the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced by 6-trifluoromethylpyridine-3-aldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced by 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare raw material 26a.

[0182] 26a (35 mg, 0.1 mmol) and triethylamine (TEA, 43 μL, 0.3 mmol) were dissolved in DCM (3 mL). Vinylsulfonyl chloride (19 mg, 0.15 mmol) was added dropwise in an ice-water bath. The mixture was then returned to room temperature and stirred for 16 hours. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography. Compound ZB-TH-38 was then purified by preparative HPLC. LCMS [M+H] + :436.10. 1 H NMR (400MHz, CDCl3) δ9.16(s,1H),8.79(d,J=5.0Hz,2H),8.29(d,J=8.2Hz,1H),7.77(d,J=8.2Hz,1H),7.27(d,J=5.2Hz,2H),6.81(s,1H),6 .76(dd,J=16.6,9.8Hz,1H),6.43(d,J=16.6Hz,1H),6.28(d,J=10.0Hz,1H),5.27-5.03(m,1H),4.60(t,J=7.5Hz,2H),4.29(t,J=8.0Hz,2H).

[0183] Example 27: Synthesis of compound ZB-TH-39.

[0184] The synthetic route of compound ZB-TH-5 in Example 1 was adopted, and the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 6-trifluoromethylpyridine-3-aldehyde, the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine, the raw material 2-fluoroacrylic acid in step 5 was replaced with propargyl acid, and 2-(2-pyridone-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) was replaced with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP). The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-39. LCMS [M+H] + :398.12. 1H NMR (400MHz, CDCl3) δ9.13(s,1H),8.79(d,J=5.0Hz,2H),8.39(d,J=8.1Hz,1H),7.76(d,J=8.1Hz,1H),7.29(d,J= 5.1Hz,2H),6.84(s,1H),5.30-5.19(m,1H),4.94-4.83(m,1H),4.77-4.61(m,2H),4.55-4.40(m,1H),3.06(s,1H).

[0185] Example 28: Synthesis of compound ZB-TH-40.

[0186] The synthetic route of compound ZB-TH-4 in Example 1 was adopted, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 6-trifluoromethylpyridine-3-aldehyde, the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine, the raw material 2-fluoroacrylic acid in step 5 was replaced with propargyl acid, and 2-(2-pyridone-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) was replaced with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP). The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-40. LCMS [M+H] + :398.12. 1 H NMR (400MHz, CDCl3) δ8.74 (s, 1H), 8.69 (d, J = 5.1Hz, 2H), 7.93-7.84 (m, 2H), 7.83-7.75 (m, 2H), 6.8 6(s,1H),5.25-5.05(m,1H),4.96-4.81(m,1H),4.76-4.57(m,2H),4.53-4.38(m,1H),3.06(s,1H).

[0187] Example 29: Synthesis of compound ZB-TH-41.

[0188] 25a (35 mg, 0.1 mmol) and triethylamine (TEA, 43 μL, 0.3 mmol) were dissolved in DCM (3 mL). Acryloyl chloride (0.13 mmol) was added dropwise at -78°C. After the addition was complete, the mixture was stirred for 1 hour at the same temperature. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography. The crude product was then purified by preparative HPLC to obtain compound ZB-TH-41. LCMS [M+H] + :400.13. 1H NMR (400MHz, CDCl3) δ8.74(s,1H),8.67(d,J=5.1Hz,2H),8.00-7.81(m,2H),7.75(d,J=5.1Hz,2H),6.84(s,1H),6.39(d,J=1 6.9Hz,1H),6.23(dd,J=17.0,10.2Hz,1H),5.74(d,J=10.3Hz,1H),5.26-5.07(m,1H),4.96-4.84(m,1H),4.80-4.36(m,3H).

[0189] Example 30: Synthesis of compound ZB-TH-42.

[0190] 26a (35 mg, 0.1 mmol) and triethylamine (TEA, 43 μL, 0.3 mmol) were dissolved in DCM (3 mL). Acryloyl chloride (0.13 mmol) was added dropwise at -78°C. After the addition was complete, the mixture was stirred for 1 hour at the same temperature. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography. The crude product was then purified by preparative HPLC to obtain compound ZB-TH-42. LCMS [M+H] + :400.13. 1 H NMR(600MHz, CDCl3)δ9.12(s,1H),8.78(d,J=4.4Hz,2H),,8.37(d,J=8.1Hz,1H),7 .74(d,J=8.1Hz,1H),7.29(d,J=4.3Hz,2H),6.83(s,1H),6.39(dt,J=17.0,1.7Hz,1 H),6.24(ddd,J=17.0,10.4,1.7Hz,1H),5.74(dd,J=10.2,1.9Hz,1H),5.31-5.17( m,1H),4.95-4.84(m,1H),4.71-4.65(m,1H),4.65-4.58(m,1H),4.56-4.44(m,1H).

[0191] Example 31: Synthesis of compound ZB-TH-43.

[0192] The synthetic route for compound ZB-TH-4 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with p-trifluoromethylthiobenzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-43. LCMS [M+H] + :449.10.1 H NMR (400MHz, CDCl3) δ8.66(d,J=5.5Hz,2H),7.80(d,J=7.9Hz,2H),7.76(d,J=5.2Hz,2H),7.40(d,J=7.9Hz,2H),6.76(s,1H),5.68 (dd,J=46.7,3.1Hz,1H),5.26-5.17(m,1H),5.13(dd,J=15.7,3.2Hz,1H),5.07-4.98(m,1H),4.83-4.69(m,2H),4.57-4.44(m,1H).

[0193] Example 32: Synthesis of compound ZB-TH-44.

[0194] The synthetic route for compound ZB-TH-5 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with p-trifluoromethylthiobenzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-44. LCMS [M+H] + :449.10. 1 H NMR (400MHz, CDCl3) δ8.78(d,J=5.0Hz,2H),7.93(d,J=7.9Hz,2H),7.72(d,J=8.0Hz,2H),7.28(d,J=5.3Hz,2H),6.76(s,1H),5.69 (dd,J=46.8,3.1Hz,1H),5.29-5.19(m,1H),5.14(dd,J=15.7,3.2Hz,1H),5.09-4.99(m,1H),4.86-4.69(m,2H),4.58-4.45(m,1H).

[0195] Example 33: Synthesis of compound ZB-TH-45.

[0196] The synthetic route of compound ZB-TH-34 in Example 22 was used, except that the raw material 4-carbamimidoylpyridine hydrochloride in step 1 was replaced with 4-trifluoromethylbenzimidamide hydrochloride, and the raw material 2-bromo-4'-(trifluoromethyl)acetophenone was replaced with 4-(bromoacetyl)pyridine hydrobromide. The remaining steps and conditions were carried out as described in Example 22 to prepare compound ZB-TH-45. LCMS [M+H] + :417.13. 1H NMR (400MHz, CDCl3) δ8.62(d,J=5.2Hz,2H),7.90(s,1H),7.82-7.70(m,4H),7.65(d,J=7.9Hz ,2H),5.71(dd,J=46.8,3.4Hz,1H),5.29-5.12(m,2H),5.01-4.79(m,1H),4.78-4.29(m,3H).

[0197] Example 34: Synthesis of compound ZB-TH-47.

[0198] The synthetic route of compound ZB-TH-4 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 3-(trifluoromethyl)benzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-47. LCMS [M+H] + :417.13. 1 H NMR (400MHz, MeOD) δ8.78-8.64(m,2H),8.24(d,J=6.5Hz,2H),7.90-7.70(m,4H),7.21(s,1H),5.60(dd,J=47.0,3.4Hz, 1H),5.39(tt,J=8.0,5.2Hz,1H),5.25(dd,J=16.0,3.4Hz,1H),5.01-4.89(m,2H),4.68-4.60(m,1H),4.58-4.47(m,1H).

[0199] Example 35: Synthesis of compound ZB-TH-48.

[0200] The synthetic route for compound ZB-TH-5 in Example 1 was used, except that the starting material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 3-(trifluoromethyl)benzaldehyde, and the starting material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-48. LCMS [M+H] + :417.13. 1H NMR(400MHz,MeOD)δ8.80(d,J=6.4Hz,2H),8.24-8.14(m,2H),7.80(d,J=6.4Hz,2H),7.69-7.58(m,2H),7.19(s,1H), 5.61(dd,J=46.9,3.4Hz,1H),5.53-5.45(m,1H),5.26(dd,J=16.0,3.4Hz,1H),5.03-4.90(m,2H),4.73-4.48(m,2H).

[0201] Example 36: Synthesis of compound ZB-TH-49.

[0202] The synthetic route of compound ZB-TH-4 in Example 1 was adopted, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynyl-1-methylpyridin-2(1H)-one. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-49. 1 H NMR (400MHz, CDCl3) δ7.76(d,J=7.9Hz,2H),7.45(d,J=7.9Hz,2H),7.34(d,J=7.0Hz,1H),6.92(s,1H),6.86(d,J=7. 0Hz,1H),6.67(s,1H),5.79-5.51(m,1H),5.25-4.89(m,3H),4.85-4.60(m,2H),4.46(t,J=9.5Hz,1H),3.57(s,3H).

[0203] Example 37: Synthesis of compound ZB-TH-50.

[0204] The synthetic route for compound ZB-TH-5 in Example 1 was used, except that the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynyl-1-methylpyridin-2(1H)-one (CAS: 1934458-73-7). The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-50. LCMS [M+H] + :447.14. 1H NMR (400MHz, CDCl3) δ7.94(d,J=8.0Hz,2H),7.65(d,J=8.0Hz,2H),7.41(d,J=6.9Hz,1H),6.71(s,1H),6.49(d,J=1.3Hz,1H),6.16(d,J=6.9Hz,1H) ,5.66(dd,J=46.7,3.2Hz,1H),5.29(m,1H),5.12(dd,J=15.7,3.2Hz,1H), 5.05-4.89(m,1H),4.86-4.65(m,2H),4.50(t,J=9.5Hz,1H),3.59(s,3H).

[0205] Example 38: Synthesis of compound ZB-TH-51.

[0206] The synthetic route of compound ZB-TH-34 in Example 22 was used to prepare compound ZB-TH-51 by replacing the raw material 2-bromo-4'-(trifluoromethyl)acetophenone in step 1 with 2-bromo-4'-(trifluoromethoxy)acetophenone. The remaining steps and conditions were carried out as described in Example 22. LCMS [M+H] + :433.12. 1 H NMR (400MHz, CDCl3) δ8.79(m,2H),7.87(d,J=8.2Hz,2H),7.74(s,1H),7.58-7.43(m,2H),7.26(d ,J=8.6Hz,2H),5.72(d,J=46.8Hz,1H),5.43-5.12(m,2H),4.95(s,1H),4.66(s,2H),4.41(s,1H).

[0207] Example 39: Synthesis of compound ZB-TH-52.

[0208] ·

[0209] The synthetic route for compound ZB-TH-4 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 2-fluoro-4-(trifluoromethyl)benzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-52. LCMS [M+H] + :435.12. 1H NMR (400MHz, CDCl3) δ8.66(d,J=6.1Hz,2H),7.75(d,J=6.2Hz,2H),7.62-7.48(m,3H),6.78(s,1H),5.68(dd ,J=46.7,3.1Hz,1H),5.13(dd,J=15.6,3.2Hz,1H),5.05-4.94(m,2H),4.84-4.67(m,2H),4.56-4.37(m,1H).

[0210] Example 40: Synthesis of compound ZB-TH-53.

[0211] The synthetic route of compound ZB-TH-5 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 2-fluoro-4-(trifluoromethyl)benzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-53. LCMS [M+H] + :435.12. 1 H NMR (400MHz, CDCl3) δ8.77(d,J=5.3Hz,2H),8.33-8.23(m,1H),7.49(d,J=8.2Hz,1H),7.42(d,J=11.0Hz,1H),7.28(d,J=5.2Hz,2H),6.94(d,J=4. 0Hz,1H),5.68(dd,J=46.7,3.2Hz,1H),5.35-5.20(m,1H),5.14(dd,J=15 .6,3.2Hz,1H),5.09-4.95(m,1H),4.87-4.66(m,2H),4.59-4.46(m,1H).

[0212] Example 41: Synthesis of compound ZB-TH-54.

[0213] The synthetic route for compound ZB-TH-4 in Example 1 was used, except that the starting material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 5-trifluoromethylpyridine-2-carboxaldehyde, and the starting material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-54. LCMS [M+H] + :418.12. 1H NMR (400MHz, CDCl3) δ8.84(s,1H),8.65(d,J=6.1Hz,2H),8.08(s,1H),7.80(dd,J=8.4,2.4Hz,1H),7.48(d,J=6.1Hz,2H),7.29(d,J= 8.3Hz,1H),5.68(dd,J=46.7,3.2Hz,1H),5.25(p,J=6.8Hz,1H),5.14(dd,J=15.6,3.2Hz,1H),4.97-4.84(m,2H),4.69-4.55(m,2H).

[0214] Example 42: Synthesis of compound ZB-TH-55.

[0215] The synthetic route for compound ZB-TH-5 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 5-trifluoromethylpyridine-2-carboxaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-55. LCMS [M+H] + :418.12. 1 H NMR (400MHz, CDCl3) δ8.87(s,1H),8.87(d,J=2.1Hz,1H),8.77(d,J=5.0Hz,2H),8.23(d,J=8.3Hz,1H),7.99(dd,J=8.4,2.3Hz,1H),7.28(d,J=5.1Hz,2H ),7.15(s,1H),5.68(dd,J=46.7,3.2Hz,1H),5.34-5.22(m,1H),5.14(dd,J =15.7,3.2Hz,1H),5.08-4.94(m,1H),4.89-4.69(m,2H),4.62-4.41(m,1H).

[0216] Example 43: Synthesis of compound ZB-TH-57.

[0217] The synthetic route of compound ZB-TH-4 in Example 1 was used, and the raw material 3-ethynylpyridine in step 2 was replaced with 5-ethynyl-1-methylpyridin-2(1H)-one. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-57. LCMS [M+H] + :447.14. 1H NMR (400MHz, MeOD) δ8.26(d,J=2.5Hz,1H),8.12(dd,J=9.4,2.5Hz,1H),7.84(d,J=8.0Hz,2H),7.65(d,J=8.0Hz,2H),6.78(s,1H),6.66(d,J= 9.3Hz,1H),5.59(dd,J=46.9,3.4Hz,1H),5.40-5.30(m,1H),5.25(dd,J=16.0,3.4Hz,1H),4.99-4.88(m,2H),4.67-4.42(m,2H),3.66(s,3H).

[0218] Example 44: Synthesis of compound ZB-TH-58.

[0219] The synthetic route for compound ZB-TH-5 in Example 1 was used, except that the raw material 3-ethynylpyridine in step 2 was replaced with 5-ethynyl-1-methylpyridin-2(1H)-one (CAS: 1693759-63-5). The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-58. LCMS [M+H] + :447.14. 1 H NMR (400MHz, MeOD) δ8.07(d,J=8.1Hz,2H),7.88(d,J=2.5Hz,1H),7.71(d,J=8.2Hz,2H),7.59(dd,J=9.3,2.5Hz,1H),6.86(s,1H),6.67(d, J=9.3Hz,1H),5.61(dd,J=46.9,3.4Hz,1H),5.35(m,1H),5.25(dd,J=16.0,3.4Hz,1H),4.99-4.88(m,2H),4.64-4.49(m,2H),3.65(s,3H).

[0220] Example 45: Synthesis of compound ZB-TH-60.

[0221] The synthetic route for compound ZB-TH-4 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 4-fluoro-3-trifluoromethylbenzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-60. LCMS [M+H] + :435.12. 1H NMR(400MHz,MeOD)δ8.82(d,J=6.8Hz,2H),8.52(d,J=6.8Hz,2H),7.93-7.85(m,1H),7.85-7.77(m,1H),7.61-7.53(m,1H), 7.34(s,1H),5.61(dd,J=47.0,3.4Hz,1H),5.40(m,1H),5.27(dd,J=16.0,3.5Hz,1H),5.03-4.90(m,2H),4.68-4.43(m,2H).

[0222] Example 46: Synthesis of compound ZB-TH-61.

[0223] The synthetic route of compound ZB-TH-5 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 4-fluoro-3-trifluoromethylbenzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-61. LCMS [M+H] + :435.12.

[0224] Example 47: Synthesis of compound ZB-TH-62.

[0225] The synthetic route for compound ZB-TH-4 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 3-(trifluoromethoxy)benzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-62. LCMS [M+H] + :433.12. 1 H NMR (400MHz, MeOD) δ8.88(d,J=5.7Hz,2H),7.99(d,J=5.8Hz,2H),7.94(d,J=7.8Hz,1H),7.83(s,1H),7.55(t,J=8.0Hz,1H),7.28(d,J=8.7 Hz,1H),7.24(s,1H),5.62(dd,J=47.0,3.4Hz,1H),5.56-5.46(m,1H),5.27(dd,J=16.0,3.5Hz,1H),5.11-4.95(m,2H),4.74-4.53(m,2H).

[0226] Example 48: Synthesis of compound ZB-TH-63.

[0227] The synthetic route for compound ZB-TH-5 in Example 1 was used, except that the starting material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 3-(trifluoromethoxy)benzaldehyde, and the starting material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-63. LCMS [M+H] + :433.12. 1 H NMR (400MHz, MeOD) δ8.81(d,J=6.2Hz,2H),8.52(d,J=6.4Hz,2H),7.69(t,J=7.9Hz,1H),7.55-7.45(m,3H),7.32(s, 1H),5.61(dd,J=47.0,3.4Hz,1H),5.44(m,1H),5.26(dd,J=16.0,3.5Hz,1H),5.00-4.88(m,2H),4.68-4.50(m,2H).

[0228] Example 49: Synthesis of compound ZB-TH-64.

[0229] The synthetic route for compound ZB-TH-4 in Example 1 was used, except that the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynyl-3-fluoropyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-64. LCMS [M+H] + :435.12. 1 H NMR (400MHz, DMSO) δ8.72(d,J=2.7Hz,1H),8.52(d,J=5.1Hz,1H),8.08(dd,J=6.7,5.0Hz,1H),7.91(d,J=8.1Hz,2H),7.76(d,J=8.1Hz,2H), 7.09(d,J=3.4Hz,1H),5.53(dd,J=48.5,3.6Hz,1H),5.44-5.38(m,1H),5.35(dd,J=16.6,3.6Hz,1H),4.85-4.79(m,2H),4.54-4.42(m,2H).

[0230] Example 50: Synthesis of compound ZB-TH-65.

[0231] The synthetic route of compound ZB-TH-4 in Example 1 was used, and the raw material 3-ethynylpyridine in step 2 was replaced with 1-benzyl-4-ethynylpyridin-2(1H)-one. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-65. LCMS [M+H] + :523.17. 1 H NMR (400MHz, DMSO) δ7.91(d,J=8.2Hz,2H),7.86(d,J=7.1Hz,1H),7.72(d,J=8.0Hz,2H),7.38-7.26(m,5H),7.20(s,1H),6.93(d,J=1.9H z,1H),6.84(dd,J=7.1,1.9Hz,1H),5.52(dd,J=48.4,3.6Hz,1H),5.39-5.29(m,2H),5.14(s,2H),4.87-4.67(m,2H),4.51-4.33(m,2H).

[0232] Example 51: Synthesis of compound ZB-TH-66.

[0233] The synthetic route of compound ZB-TH-5 in Example 1 was used, and the raw material 3-ethynylpyridine in step 2 was replaced with 1-benzyl-4-ethynylpyridin-2(1H)-one. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-66. LCMS [M+H] + :523.17. 1 H NMR (400MHz, DMSO) δ8.10(d,J=8.1Hz,2H),7.98(d,J=7.0Hz,1H),7.81(d,J=8.1Hz,2H),7.47-7.28(m,5H),7.23(s,1H),6.57(d,J=2.0H z,1H),6.41(dd,J=7.1,2.0Hz,1H),5.66-5.41(m,2H),5.34(dd,J=16.6,3.7Hz,1H),5.17(s,2H),4.89-4.70(m,2H),4.56-4.33(m,2H).

[0234] Example 52: Synthesis of compound ZB-TH-67.

[0235] The synthetic route of compound ZB-TH-4 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 2-fluoro-3-(trifluoromethyl)benzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-67. LCMS [M+H] + :435.12. 1 H NMR (400MHz, DMSO) δ8.89(d,J=6.7Hz,2H),8.35(d,J=6.7Hz,2H),8.00-7.86(m,2H),7.75(dd,J=10.6,8.5H z,1H),7.52(s,1H),5.54(dd,J=48.5,3.6Hz,1H),5.43-5.32(m,2H),4.83-4.79(m,2H),4.47-4.38(m,2H).

[0236] Example 53: Synthesis of compound ZB-TH-68.

[0237] The synthetic route of compound ZB-TH-5 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 2-fluoro-3-(trifluoromethyl)benzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-68. LCMS [M+H] + :435.12. 1 H NMR (400MHz, DMSO) δ8.86(d,J=6.4Hz,2H),8.33-8.26(m,1H),8.23(dd,J=6.9,2.2Hz,1H),7.77(d,J=6.4Hz,2H),7.63(dd,J=10.7,8.7H z,1H),7.43(s,1H),5.54(dd,J=48.4,3.6Hz,1H),5.47-5.41(m,1H),5.35(dd,J=16.6,3.6Hz,1H),4.85-4.80(m,2H),4.55-4.42(m,2H).

[0238] Example 54: Synthesis of compound ZB-TH-69.

[0239] The synthetic route of compound ZB-TH-4 in Example 1 was used, and the raw material 3-ethynylpyridine in step 2 was replaced with 1-ethyl-4-ethynylpyridin-2(1H)-one. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-69. LCMS [M+H] + :461.15. 1 H NMR (400MHz, DMSO) δ7.91(d,J=8.0Hz,2H),7.76(d,J=7.1Hz,1H),7.72(d,J=8.0Hz,2H),7.18(s,1H),6.87(d,J=1.8Hz,1H),6.80(dd,J=7.0, 1.9Hz,1H),5.52(dd,J=48.4,3.6Hz,1H),5.40-5.27(m,2H),4.88-4.66(m,2H),4.49-4.30(m,2H),3.94-3.93(m,2H),1.23(t,J=7.1Hz,3H).

[0240] Example 55: Synthesis of compound ZB-TH-70.

[0241] The synthetic route of compound ZB-TH-5 in Example 1 was used, and the raw material 3-ethynylpyridine in step 2 was replaced with 1-ethyl-4-ethynylpyridin-2(1H)-one. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-70. LCMS [M+H] + :461.15. 1 H NMR (400MHz, MeOD) δ8.09 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 7.0 Hz, 1H), 7.72 (d, J = 8. 2Hz,2H),7.03(s,1H),6.59(d,J=1.9Hz,1H),6.51(dd,J=6.9,1.9Hz,1H),5.61 (dd,J=46.9,3.4Hz,1H),5.53-5.41(m,1H),5.26(dd,J=16.0,3.4Hz,1H),5.01 -4.89(m,2H),4.68-4.53(m,2H),4.10(q,J=7.2Hz,2H),1.38(t,J=7.2Hz,3H).

[0242] Example 56: Synthesis of compound ZB-TH-71.

[0243] The synthetic route of compound ZB-TH-4 in Example 1 was used, and the raw material 3-ethynylpyridine in step 2 was replaced with 1-cyclopropyl-4-ethynylpyridin-2(1H)-one. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-71. LCMS [M+H] + :473.15. 1 H NMR(400MHz,MeOD)δ7.85(d,J=8.1Hz,2H),7.73-7.61(m,3H),7.07-6.96(m,3H),5.60(dd,J=46.9,3.4Hz,1H),5.38(m,1H ),5.25(dd,J=16.0,3.5Hz,1H),4.97-4.87(m,2H),4.65-4.44(m,2H),3.38(m,1H),1.21-1.08(m,2H),1.01-0.91(m,2H).

[0244] Example 57: Synthesis of compound ZB-TH-72.

[0245] The synthetic route for compound ZB-TH-5 in Example 1 was used, with the raw material 3-ethynylpyridine in step 2 replaced with 1-cyclopropyl-4-ethynylpyridin-2(1H)-one. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-72. LCMS [M+H] + :473.15. 1 H NMR (400MHz, MeOD) δ8.09(d,J=8.1Hz,2H),7.85-7.58(m,3H),7.03(s,1H),6.59(d,J=1.9Hz,1H),6.46(dd,J=7.1,2.0Hz,1H),5.61(dd,J=46.9, 3.4Hz,1H),5.47(m,1H),5.26(dd,J=16.0,3.4Hz,1H),5.00-4.90(m,2H ),4.69-4.51(m,2H),3.41(m,1H),1.22-1.14(m,2H),1.01-0.93(m,2H).

[0246] Example 58: Synthesis of compound ZB-TH-73.

[0247] The synthetic route for compound ZB-TH-4 in Example 1 was used, with the raw material 3-ethynylpyridine in step 2 replaced with 4-ethynyl-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-73. LCMS [M+H] + :509.12. 1 H NMR (400MHz, DMSO) δ8.13(d,J=8.2Hz,2H),7.92(d,J=8.1Hz,2H),7.85(d,J=8.2Hz,2H),7.75(d,J=8.0Hz,2H),7.49(q,J=5.0Hz ,1H),7.20(s,1H),5.54(dd,J=48.4,3.6Hz,1H),5.44-5.28(m,2H),4.90-4.73(m,2H),4.56-4.34(m,2H),2.44(d,J=4.9Hz,3H).

[0248] Example 59: Synthesis of compound ZB-TH-74.

[0249] The synthetic route for compound ZB-TH-5 in Example 1 was used, with the raw material 3-ethynylpyridine in step 2 replaced with 4-ethynyl-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-74. LCMS [M+H] + :509.12. 1 H NMR (400MHz, CDCl3) δ8.07-7.88(m,4H),7.69(d,J=8.1Hz,2H),7.52(d,J=8.0Hz,2H),6.74(s,1H),5.69(dd,J=46.7,3.2Hz, 1H),5.25-5.18(m,1H),5.15(dd,J=15.7,3.2Hz,1H),5.09-5.00(m,1H),4.88-4.69(m,2H),4.55-4.45(m,1H),2.75(s,3H).

[0250] Example 60: Synthesis of compound ZB-TH-75.

[0251] The synthetic route for compound ZB-TH-4 in Example 1 was used, with the raw material 3-ethynylpyridine in step 2 replaced with 4-ethynyl-N,N-dimethylbenzenesulfonamide. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-75. LCMS [M+H]+ :523.13. 1 H NMR (400MHz, CDCl3) δ8.04(dd,J=8.3,1.6Hz,2H),7.84(d,J=8.4Hz,2H),7.79(d,J=7.9Hz,2H),7.49(d,J=7.9Hz,2H ),6.75(s,1H),5.68(dd,J=46.8,2.9Hz,1H),5.28-4.92(m,3H),4.88-4.64(m,2H),4.57-4.37(m,1H),2.74(s,6H).

[0252] Example 61: Synthesis of compound ZB-TH-76.

[0253] The synthetic route for compound ZB-TH-5 in Example 1 was used, with the raw material 3-ethynylpyridine in step 2 replaced with 4-ethynyl-N,N-dimethylbenzenesulfonamide. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-76. LCMS [M+H] + :523.13. 1 H NMR (400MHz, CDCl3) δ7.99(d,J=8.1Hz,2H),7.92(d,J=8.2Hz,2H),7.69(d,J=8.2Hz,2H),7.53(d,J=8.2Hz,2H),6.75(s,1H),5.70(dd,J= 46.7,3.2Hz,1H),5.27-5.19(m,1H),5.16(dd,J=15.6,3.2Hz,1H),5.10-5.01(m,1H),4.87-4.68(m,2H),4.60-4.37(m,1H),2.80(s,6H).

[0254] Example 62: Synthesis of compound ZB-TH-77.

[0255] The synthetic route of compound ZB-TH-4 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 3-chloro-4-(trifluoromethyl)benzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-77. LCMS [M+H] + :451.09. 1H NMR (400MHz, CDCl3) δ8.85(d,J=5.9Hz,2H),8.27(d,J=5.9Hz,2H),7.88(d, J=8.1Hz,1H),7.53(d,J=1.6Hz,1H),7.36(d,J=8.1Hz,1H),6.99(s,1H),5.7 1(dd,J=46.8,3.3Hz,1H),5.29-5.21(m,1H),5.17(dd,J=15.6,3.3Hz,1H), 5.05-4.96(m,1H),4.92-4.79(m,1H),4.77-4.65(m,1H),4.61-4.50(m,1H).

[0256] Example 63: Synthesis of compound ZB-TH-78.

[0257] The synthetic route for compound ZB-TH-5 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 3-chloro-4-(trifluoromethyl)benzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-78. LCMS [M+H] + :451.09. 1 H NMR (400MHz, MeOD) δ8.88(d,J=6.6Hz,2H),8.18(d,J=1.6Hz,1H),8.04(d,J=8.2Hz,1H),7.95(d,J=6.6Hz,2H),7.84(d,J=8.2Hz,1H ),7.30(s,1H),5.62(dd,J=47.0,3.5Hz,1H),5.55-5.46(m,1H),5.27(dd,J=16.0,3.5Hz,1H),5.03-4.91(m,2H),4.71-4.51(m,2H).

[0258] Example 64: Synthesis of compound ZB-TH-79.

[0259] The synthetic route for compound ZB-TH-4 in Example 1 was used, except that the starting material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 2-fluoro-5-(trifluoromethyl)benzaldehyde, and the starting material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-79. LCMS [M+H] + :435.12. 1H NMR(400MHz,MeOD)δ8.83(d,J=6.6Hz,2H),8.53(d,J=6.8Hz,2H),8.01-7.93(m,1H),7.94-7.87(m,1H),7.65-7 .55(m,1H),7.38(s,1H),5.62(dd,J=47.0,3.5Hz,1H),5.31-5.18(m,2H),5.00-4.90(m,2H),4.70-4.48(m,2H).

[0260] Example 65: Synthesis of compound ZB-TH-80.

[0261] The synthetic route of compound ZB-TH-5 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 2-fluoro-5-(trifluoromethyl)benzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-80. LCMS [M+H] + :435.12. 1 H NMR(400MHz,MeOD)δ8.86(d,J=6.5Hz,2H),8.42(dd,J=6.8,2.4Hz,1H),7.93(d,J=6.6Hz,2H),7.81-7.68(m,1H),7.54-7.38(m,1H),7.2 1(d,J=3.7Hz,1H),5.62(dd,J=46.9,3.5Hz,1H),5.56-5.47(m,1H),5.27(dd,J=16.0,3.4Hz,1H),5.05-4.92(m,2H),4.72-4.53(m,2H).

[0262] Example 66: Synthesis of compound ZB-TH-81.

[0263] The synthetic route for compound ZB-TH-4 in Example 1 was used, except that the raw material 3-ethynylpyridine in step 2 was replaced with 2-alkynylpyrazine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-81. LCMS [M+H] + :418.12. 1H NMR (400MHz, MeOD) δ9.31(d,J=1.5Hz,1H),8.64(dd,J=2.6,1.5Hz,1H),8.54(d,J=2.6Hz,1H),7.86(d,J=8.1Hz,2H),7.69(d,J=8.1 Hz,2H),7.15(s,1H),5.60(dd,J=46.9,3.4Hz,1H),5.42(m,1H),5.25(dd,J=16.0,3.4Hz,1H),5.05-4.88(m,2H),4.71-4.48(m,2H).

[0264] Example 67: Synthesis of compound ZB-TH-82.

[0265] The synthetic route for compound ZB-TH-5 in Example 1 was used, except that the raw material 3-ethynylpyridine in step 2 was replaced with 2-alkynylpyrazine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-82. LCMS [M+H] + :418.12. 1 H NMR (400MHz, CDCl3) δ8.99(d,J=1.2Hz,1H),8.66-8.61(m,1H),8.58(d,J=2.6Hz,1H),8.01(d,J=8.1Hz,2H),7.70(d,J=8.2Hz,2H),7.11(s,1H),6. 08(m,1H),5.68(dd,J=46.7,3.1Hz,1H),5.13(dd,J=15.6,3.1Hz,1H),5. 09-4.99(m,1H),4.92-4.82(m,1H),4.82-4.70(m,1H),4.66-4.52(m,1H).

[0266] Example 68: Synthesis of compound ZB-TH-83.

[0267] The synthetic route of compound ZB-TH-4 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 4-(trifluoromethoxy)benzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 5-ethynyl-1-methylpyridin-2(1H)-one. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-83. LCMS [M+H] + :463.13. 1H NMR (400MHz, MeOD) δ8.25(d,J=2.4Hz,1H),8.12(dd,J=9.3,2.5Hz,1H),7.55(d,J=8.9Hz,2H),7.45(dd,J=8.9,1.0Hz,2H),6.72(s,1H),6.66 (d,J=9.3Hz,1H),5.59(dd,J=46.9,3.5Hz,1H),5.32(m,1H),5.24(dd,J=16.0,3.5Hz,1H),4.97-4.87(m,2H),4.63-4.45(m,2H),3.66(s,3H).

[0268] Example 69: Synthesis of compound ZB-TH-84.

[0269] The synthetic route of compound ZB-TH-5 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 4-(trifluoromethoxy)benzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 5-ethynyl-1-methylpyridin-2(1H)-one. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-84. LCMS [M+H] + :463.13. 1 H NMR (400MHz, MeOD) δ7.98(d,J=8.8Hz,2H),7.87(d,J=2.5Hz,1H),7.59(dd,J=9.3,2.6Hz,1H),7.33(d,J=9.0Hz,2H),6.78(s,1H),6.67(d, J=9.3Hz,1H),5.60(dd,J=47.0,3.4Hz,1H),5.34(m,1H),5.25(dd,J=16.0,3.4Hz,1H),4.98-4.88(m,2H),4.66-4.45(m,2H),3.64(s,3H).

[0270] Example 70: Synthesis of compound ZB-TH-85.

[0271] The synthetic route for compound ZB-TH-4 in Example 1 was used, except that the starting material 3-ethynylpyridine in step 2 was replaced with 4-ethynyl-2-((4-methoxybenzyl)oxy)pyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-85. LCMS [M+H] + :433.12. 1H NMR (400MHz, MeOD) δ7.85(d,J=8.1Hz,2H),7.67(d,J=8.1Hz,2H),7.51(d,J=6.8Hz,1H),7.08(dd,J=6.9,1.7Hz,1H),7.05-6.9 8(m,2H),5.60(dd,J=46.9,3.5Hz,1H),5.48-5.34(m,1H),5.25(dd,J=16.0,3.4Hz,1H),5.00-4.91(m,2H),4.65-4.44(m,2H).

[0272] Example 71: Synthesis of compound ZB-TH-86.

[0273] The synthetic route for compound ZB-TH-5 in Example 1 was used, except that the starting material 3-ethynylpyridine in step 2 was replaced with 4-ethynyl-2-((4-methoxybenzyl)oxy)pyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-86. LCMS [M+H] + :433.12. 1 H NMR (400MHz, MeOD) δ8.10(d,J=8.1Hz,2H),7.73(d,J=8.2Hz,2H),7.59(d,J=6.7Hz,1H),7.05(s,1H),6.60(d,J=1.8Hz,1H),6.52(d d,J=6.7,1.7Hz,1H),5.61(dd,J=46.9,3.4Hz,1H),5.48(m,1H),5.26(dd,J=16.0,3.4Hz,1H),5.02-4.92(m,2H),4.72-4.48(m,2H).

[0274] Example 72: Synthesis of compound ZB-TH-87.

[0275] The synthetic route for compound ZB-TH-4 in Example 1 was used, except that the raw material 3-ethynylpyridine in step 2 was replaced with 5-ethynyl-2-((4-methoxybenzyl)oxy)pyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-87. LCMS [M+H] + :433.12.

[0276] Example 73: Synthesis of compound ZB-TH-88.

[0277] The synthetic route for compound ZB-TH-5 in Example 1 was used, replacing the raw material 3-ethynylpyridine in step 2 with 5-ethynyl-2-((4-methoxybenzyl)oxy)pyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-88. LCMS [M+H] + :433.12.

[0278] Example 74: Synthesis of compound ZB-TH-89.

[0279] The synthetic route for compound ZB-TH-4 in Example 1 was used, except that the starting material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 4-(trifluoromethoxy)benzaldehyde, and the starting material 3-ethynylpyridine in step 2 was replaced with 2-alkynylpyrazine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-89. LCMS [M+H] + :434.12.

[0280] Example 75: Synthesis of compound ZB-TH-90.

[0281] The synthetic route for compound ZB-TH-5 in Example 1 was used, except that the starting material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 4-(trifluoromethoxy)benzaldehyde, and the starting material 3-ethynylpyridine in step 2 was replaced with 2-alkynylpyrazine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-90. LCMS [M+H] + :434.12.

[0282] Example 76: Synthesis of compound ZB-TH-91.

[0283] The synthetic route for compound ZB-TH-5 in Example 1 was used, except that the raw material 4-(trifluoromethyl)benzaldehyde in step 1 was replaced with 2-fluoro-4-(trifluoromethoxy)benzaldehyde, and the raw material 3-ethynylpyridine in step 2 was replaced with 4-ethynylpyridine. The remaining steps and conditions were carried out as described in Example 1 to prepare compound ZB-TH-91. LCMS [M+H] + :451.11.

[0284] Example 77: Expression and purification of TEADs family proteins

[0285] Human TEAD1 (209-426), TEAD2 (217-447), TEAD3 (219-435), and TEAD4 (217-434) were cloned into the pET28a vector with a 6xHis tag at the N-terminus. The cells were cultured at 37°C to an OD600 of 0.6. The temperature was then lowered to 16°C, and expression of the target protein was induced in Escherichia coli BL21 (DE3) with 0.2 mM IPTG. After 14 hours, the E. coli cells were harvested and resuspended in PBS buffer. The culture medium was washed away, and the cells were resuspended in lysis buffer (50 mM Tris·HCl pH 8.0, 500 mM NaCl, 1 mM TCEP, 10 mM imidazole, 10% glycerol, 1 mM PMSF) and disrupted by sonication. After ultracentrifugation, the supernatant was collected and the protein was purified using Ni Sepharose TH 6 Fast Flow (GE Healthcare) with a 500 mM imidazole gradient elution. A second purification was then performed using a Q Beads 6FF ionization column. Protein purity was assessed by SDS-polyacrylamide gel electrophoresis, and protein concentration was quantified by the Bradford assay.

[0286] Example 78: Time-resolved FRET assay

[0287] The specific operation process is as follows: 2 μL of serially diluted test compounds were incubated with 4 μL of N-his-TEADs protein at room temperature for 30 minutes in a white 384-well plate (Perkin Elmer). The reaction buffer was HEPES (pH 8.0, 25 mM), Triton X-100 (0.01%), BSA (0.1%), KF (400 mM), where TEAD1 209-426 The final protein concentration was 5 μM, TEAD2 217-447 The final protein concentration was 5 μM, TEAD3 219-435 The final protein concentration was 5 μM, TEAD4 217-434 The final protein concentration was 20 μM, and the final DMSO concentration in the experiment was 0.5%. Then 4 μL of N-biotinylated YAP was added. 60-100The cells were incubated at room temperature for 20 minutes with 10 μL of a mixture of LANCE Europium Anti-6X His Antibody (4 ng, PerkinElmer) and Streptavidin XL665 (2.5 nM, PerkinElmer). The cells were allowed to react at room temperature for 4 hours. Fluorescence was measured using a Genios Pro reader (T-can) with an excitation wavelength of 340 nm, an emission wavelength of 620 nm and 665 nm, and an excitation and fluorescence interval of 50 ms. Data were analyzed using trt-fret ratios of emission at 655 nm / 620 nm. GraphPad Prism 9 (GraphPad Software Inc., San Diego, CA, USA) was used for data analysis. Nonlinear regression was used to fit the data and estimate the IC values. 50 The activities of the tested example compounds are shown in the table below. Activity ranges A, B, C and D refer to the following IC values ​​in the reporter gene assay: 50 Value: "A": IC 50 ≤10nM; "B": 10nM<IC 50 ≤100nM; “C”: 100nM<IC 50 ≤1000nM and "D":IC 50 >1000 nM; NT = not tested.

[0288] Example 79: Determination of cell proliferation inhibition ability

[0289] NCI-H226 cells were seeded in a white 96-well plate (Corning) at a density of 500 cells per well. After adherence the next day, gradient dilutions of compounds or DMSO solvent control (DMSO final concentration was 0.1%) were added. The initial concentration of the compound was 20 μM, and 5-fold dilutions were made for a total of 8 gradients. The cells were incubated at 37°C with 5% CO2 for 7 days. After adding 30 μl of CellTiter-Glo detection reagent to each well, the cells were placed on a shaker in the dark for 10 minutes, and the fluorescence signal was read using an Envision microplate reader (Perkin Elmer). Data were analyzed using GraphPad Prism 9 (GraphPad Software Inc., San Diego, CA, USA) to estimate the IC 50 The activities of the tested example compounds are shown in the table below. Activity ranges A, B, C and D refer to the following IC values ​​in the reporter gene assay: 50 Value: "A": 10nM ≤ IC 50 ≤50nM; "B": 50nM<IC50 ≤500nM; “C”: 500nM<IC 50 ≤5000nM and "D":IC 50 >10000nM.

[0290] Example 80: Pharmacokinetics in mice

[0291] Six-week-old ICR male mice (weighing 22-24 g, n=3) were fasted for 12 hours and then orally administered with the test drug at 10 mg / kg. Blood (50 μL) was collected from the mouse orbital venous plexus 15 minutes, 30 minutes, 1 hour, 2 hours (fed), 4 hours, 6 hours, 8 hours, and 24 hours after administration. The blood was placed in an EDTA-anticoagulant tube (EDTA:blood = 1:10), flicked to homogenize, placed on ice, and centrifuged within 30 minutes. The supernatant was then centrifuged at 12,000 g at 4°C for 3 minutes. The supernatant was collected and stored at -20°C for analysis. The pharmacokinetic parameters of the tested example compounds are shown in the table below.

Claims

1. A compound represented by formula (I) or (II), or a pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, or isotope-labeled compound thereof: in, One of X1 and X2 is CR 2 , the other is N; preferably X1 is CR 2 and X2 is N; Ring A is C 6-12 aromatic ring or 5-10 membered heteroaromatic ring, R A is one or more independently selected from: hydrogen, halogen, C 1-15 Alkyl, C 3-20 Cycloalkyl, 3-15 membered heterocycloalkyl, C 1-6 Alkoxy, S(R y )5, SCF3, and SeCF3 substituents, wherein R y Is halogen; wherein the C 1-15 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more halogens; Ring B is C 6-12 aromatic ring or 5-10 membered heteroaromatic ring, R B is one or more independently selected from: hydrogen, halogen, =O, C 1-15 Alkyl, C 6-20 Aryl, C 3-20 Cycloalkyl, 5-15 membered heteroaryl, 3-15 membered heterocycloalkyl, -CN, -OH, C 1-15 Alkoxy, -NR a C(=O)R b 、-C(=O)NR a R b 、-S(=O)2R b 、-S(=O)2NR a R b 、-NR a S(=O)2R b 、-NR a R b a substituent; wherein said C 1-15 Alkyl, C 1-15 The alkoxy group is optionally substituted with one or more halogens; R 1 and R 2 independently selected from hydrogen, halogen, -CN, -OH, -NR a R b , C with or without substituents 1-6 Alkyl, C with or without substituents 2-6 Alkenyl, C with or without substituents 2-6 Alkynyl, C with or without substituents 1-6 Alkoxy, wherein the substituent is one or more selected from halogen, -CN, -OH, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-20 substituents of the aryl group; Or, when X1 is CR 2 When X2 is N, R 1 and R 2 Together with the carbon atoms to which they are attached, they optionally form a 6-10 membered partially unsaturated non-aromatic ring with or without a substituent, or a 6-10 membered aromatic ring with or without a substituent, or a 6-10 membered ring after one of the ring carbon atoms is replaced by an oxygen atom, a sulfur atom or a nitrogen atom, wherein the substituent is one or more selected from halogen, =O, -CN, C 1-6 Alkyl, C 1-6 Substituents of the alkoxy group; R a and R b Independently selected from H, C 1-6 Alkyl, C 3-20 Cycloalkyl, wherein the C 1-6 Alkyl, C 3-20 Cycloalkyl is optionally substituted with one or more groups selected from halogen, oxo, -OH and -CN; Z is -C(O)R x , R x C 2-6 Alkenyl, which is optionally selected from C 1-6 Alkyl, deuterium, -CN, -OH, C 1-6 Alkoxy and one or more halogen substituents; or R x C 1-6 Alkyl, optionally substituted with one or more substituents selected from halogen, -CN and -OH; or R x C 2-6 Alkynyl, which is optionally selected from C 1-6 Alkyl, C 6-12 Aryl, C 3-20 Cycloalkyl, 5-15 membered heteroaryl, 3-15 membered heterocycloalkyl, deuterium, -CN, -OH, C 1-6 substituted with one or more substituents of alkoxy and halogen; or R x is cyclobutenyl, dihydrofuranyl, bicyclobutyl or cyclopentenyl; or Z is S(O) n R x1 , R x1 C 2-6 Alkenyl, which is optionally selected from C 1-6 Alkyl, deuterium, -CN, -OH, C 1-6 Alkoxy and halogen substituted with one or more substituents; n and m are independently 1 or 2.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, or isotope-labeled compound thereof, wherein: The compound is selected from the compounds represented by formula (Ia) or (IIa): Among them, ring A, ring B, R 1 , X1, X2, R A , R B , n and m are the same as those defined in the general formula I or II in claim 1; R c 、R d and R e Each independently selected from hydrogen, deuterium, halogen, -CN, C 1-6 Alkoxy and C 1-6 alkyl.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, or isotope-labeled compound thereof, wherein: The compound is selected from the compounds represented by formula (Ib) or (IIb): Among them, ring B, R 1 , X1, X2, R B , n and m are the same as those defined in the general formula I or II in claim 1; R c 、R d and R e Each independently selected from hydrogen, deuterium, halogen, -CN, C 1-6 Alkoxy or C 1-6 alkyl; A1, A2, A3, A4 and A5 are independently CR A or N; R A Independently selected from: hydrogen, halogen, C 1-15 Alkyl, C 3-20 Cycloalkyl, 3-15 membered heterocycloalkyl, C 1-6 Alkoxy, S(R y )5, SCF3, SeCF3, R y Is halogen; wherein the C 1-15 Alkyl and C 1-6 Alkoxy groups are optionally substituted with one or more halogens.

4. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, or isotope-labeled compound thereof, wherein: The compound is selected from the compounds represented by formula (Ic) or (IIc): in, One of X1 and X2 is CR 2 , the other is N; preferably X1 is CR 2 and X2 is N; Z is or R c , R d and R e independently selected from hydrogen, deuterium, halogen, -CN and C 1-6 alkyl; R f Selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-15 membered heterocycloalkyl, deuterium, -CN, C 1-6 Alkoxy and halogen; A1, A2, A3, A4 and A5 are independently CR A or N; R A Independently selected from: hydrogen, halogen, C 1-15 Alkyl, C 3-20 Cycloalkyl, 3-15 membered heterocycloalkyl, C 1-6 Alkoxy, SF5, SCF3, SeCF3; wherein the C 1-15 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more halogens; B2, B3, B4 and B5 are independently CR B or N; R B Independently selected from: hydrogen, halogen, =O, C 1-15 Alkyl, C 6-20 Aryl, C 3-20 Cycloalkyl, 5-15 membered heteroaryl, 3-15 membered heterocycloalkyl, -CN, -OH, C 1-15 Alkoxy, -NR a C(=O)R b 、-C(=O)NR a R b 、-S(=O)2R b 、-S(=O)2NR a R b 、-NR a S(=O)2R b 、-NR a R b ; wherein the C 1-15 Alkyl and C 1-15 The alkoxy group is optionally substituted with one or more halogens; B1 is CR 1 or N, where R 1 Selected from hydrogen, halogen, -CN, -OH, -NR a R b , C with or without substituents 1-6 Alkyl, C with or without substituents 2-6 Alkenyl, C with or without substituents 2-6 Alkynyl, C with or without substituents 1-6 Alkoxy, wherein the substituent is one or more selected from halogen, -CN, -OH, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-20 substituents of the aryl group; R 2 Selected from hydrogen, halogen, -CN, -OH, -NR a R b , C with or without substituents 1-6 Alkyl, C with or without substituents 2-6 Alkenyl, C with or without substituents 2-6 Alkynyl, C with or without substituents 1-6 Alkoxy, wherein the substituent is one or more selected from halogen, -CN, -OH, =O, C 1-6 Alkyl, C 1-6 Substituents of the alkoxy group; Or, when X1 is CR 2 When X2 is N, R 1 and R 2 Together with the carbon atoms to which they are attached, they optionally form a 6-10 membered partially unsaturated non-aromatic ring with or without a substituent, or a 6-10 membered aromatic ring with or without a substituent, or a 6-10 membered ring after one of the ring carbon atoms is replaced by an oxygen atom, a sulfur atom or a nitrogen atom, wherein the substituent is one or more selected from halogen, =O, -CN, C 1-6 Alkyl, C 1-6 Substituents of the alkoxy group; R a and R b independently selected from hydrogen, C 1-6 Alkyl, C 3-20 Cycloalkyl, wherein the C 1-6 Alkyl, C 3-20 Cycloalkyl is optionally substituted with one or more groups selected from halogen, oxo, -OH and -CN; n and m are independently 1 or 2.

5. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, or isotope-labeled compound thereof, wherein: The compound is selected from the compound represented by formula (Id) or (IId): in, Z is or R c , R d and R e independently selected from hydrogen, deuterium, halogen, -CN and C 1-6 alkyl; R f Selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-15 membered heterocycloalkyl, deuterium, -CN, C 1-6 Alkoxy and halogen; A1, A2, A3, A4 and A5 are independently CR A or N; R A Independently selected from: hydrogen, halogen, C 1-15 Alkyl, C 3-20 Cycloalkyl, 3-15 membered heterocycloalkyl, C 1-6 Alkoxy, SF5, SCF3, SeCF3; wherein the C 1-15 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more halogens; B2, B3, B4 and B5 are independently CR B or N; R B Independently selected from: hydrogen, halogen, =O, C 1-15 Alkyl, C 6-20 Aryl, C 3-20 Cycloalkyl, 5-15 membered heteroaryl, 3-15 membered heterocycloalkyl, -CN, -OH, C 1-15 Alkoxy, -NR a C(=O)R b 、-C(=O)NR a R b 、-S(=O)2R b 、-S(=O)2NR a R b 、-NR a S(=O)2R b 、-NR a R b ; wherein the C 1-15 Alkyl, C 1-15 The alkoxy group is optionally substituted with one or more halogens; R a and R b independently selected from hydrogen, C 1-6 Alkyl, C 3-20 Cycloalkyl, wherein the C 1-6 Alkyl, C 3-20 Cycloalkyl is optionally substituted with one or more groups selected from halogen, oxo, -OH and -CN; n and m are independently selected from 1 or 2; Indicates a single bond or a double bond; L is C, O, S, N or does not exist; R g is one or more independently selected from: hydrogen, halogen, =O, -CN, C 1-6 Alkyl, C 1-6 Substituents of the alkoxy group.

6. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, or isotope-labeled compound thereof, wherein: The compound is selected from the compound represented by formula (Ie) or (IIe): in, One of X1 and X2 is CR 2 , the other is N; preferably X1 is CR 2 and X2 is N; Z is or R c , R d and R e independently selected from hydrogen, deuterium, F, -CN and C 1-5 alkyl; R f Selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-15 membered heterocycloalkyl, deuterium, -CN, C 1-6 Alkoxy and halogen; A1, A2, A3, A4 and A5 are independently CR A or N; R A Independently selected from: hydrogen, halogen, C 1-15 Alkyl, C 3-20 Cycloalkyl, 3-15 membered heterocycloalkyl, C 1-6 Alkoxy, SF5, SCF3, SeCF3; wherein the C 1-15 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more halogens; B2, B3, B4 and B5 are independently CR B or N; R B Independently selected from: hydrogen, halogen, =O, C 1-15 Alkyl, C 6-20 Aryl, C 3-20 Cycloalkyl, 5-15 membered heteroaryl, 3-15 membered heterocycloalkyl, -CN, -OH, C 1-15 Alkoxy, -NR a C(=O)R b 、-C(=O)NR a R b 、-S(=O)2R b 、-S(=O)2NR a R b 、-NR a S(=O)2R b 、-NR a R b ; wherein the C 1-15 Alkyl, C 1-15 The alkoxy group is optionally substituted with one or more halogens; B1 is CR 1 or N, where R 1 Selected from hydrogen, halogen, -CN, -OH, -NR a R b , C with or without substituents 1-6 Alkyl, C with or without substituents 2-6 Alkenyl, C with or without substituents 2-6 Alkynyl, C with or without substituents 1-6 Alkoxy, wherein the substituent is one or more selected from halogen, -CN, -OH, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-20 substituents of the aryl group; R 2 Selected from hydrogen, halogen, -CN, -OH, -NR a R b , C with or without substituents 1-6 Alkyl, C with or without substituents 2-6 Alkenyl, C with or without substituents 2-6 Alkynyl, C with or without substituents 1-6 Alkoxy, wherein the substituent is one or more selected from halogen, -CN, -OH, =O, C 1-6 Alkyl, C 1-6 Substituents of the alkoxy group; R a and R b independently selected from hydrogen, C 1-6 Alkyl, C 3-20 Cycloalkyl, wherein the C 1-6 Alkyl, C 3-20 Cycloalkyl is optionally substituted with one or more halo, oxo, -OH, or -CN.

7. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, or isotope-labeled compound thereof, wherein: The compound is selected from the following compounds:

8. A pharmaceutical composition comprising one or more of a compound selected from any one of claims 1 to 7, its pharmaceutically acceptable salts, stereoisomers, enantiomers, diastereomers, atropisomers, racemates, and isotope-labeled compounds, and optionally a pharmaceutically acceptable carrier or excipient.

9. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, or isotopically labeled compound thereof, or a composition according to claim 8 in the preparation of a medicament for preventing and / or treating a disease, disorder, or condition mediated by TEADs.

10. The use according to claim 9, wherein The disease or disorder or condition is selected from the group consisting of colon cancer, diffuse large B-cell lymphoma, follicular lymphoma, other lymphomas, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer, brain tumors, including neuroblastoma, schwannoma, glioma, glioblastoma and astrocytoma, cervical cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, squamous cell carcinoma, gastrointestinal cancer, parathyroid tumors, uterine tumors and soft tissue sarcoma, cardiovascular disease, neurodegenerative disease, malaria, AIDS, gout, diabetes, renal failure, chronic lung disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment , retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjögren's syndrome, scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Parkinson's disease, allergic diseases, asthma, multiple sclerosis, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1 converting enzyme-associated febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, and periodontitis.

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