Heterocyclic ring-containing TEAD inhibitor

Abstract

A heterocyclic ring-containing TEAD inhibitor, which has the structure as shown in formula (I'), and is used for preventing and / or treating diseases related to increased TEAD expression.

Description

Heterocyclic TEAD inhibitors

[0001] This application claims the benefit of priority of the following prior patent applications:

[0002] The applicant's prior application, patent application number 202311641928.3, filed with the State Intellectual Property Office of China on November 30, 2023, entitled "TEAD inhibitors containing heterocyclic rings";

[0003] The applicant's prior application, patent application number 202410141328.9, entitled "TEAD inhibitors containing heterocyclic rings," filed with the State Intellectual Property Office of China on January 31, 2024;

[0004] The applicant's prior application, patent application number 202410547186.6, entitled "TEAD inhibitors containing heterocyclic rings," filed with the State Intellectual Property Office of China on April 29, 2024;

[0005] The entire contents of the above-mentioned prior patent applications are incorporated into this application by reference. Technical Field

[0006] The present invention belongs to the field of medicine, and in particular, relates to heterocyclic TEAD inhibitors and uses thereof. Background Art

[0007] The Hippo signaling pathway is a highly conserved signaling pathway composed of a series of kinase cascades, which is involved in regulating physiological processes such as cell proliferation, cell differentiation, cell stemness, extracellular matrix deposition, damage repair, and organ development. Activation of the Hippo signaling pathway by upstream GPCRs, mechanical stress, and other signals leads to NF2 (neurofibromatosis type 2) activation of MST1 / 2 (mammalian sterile 20-like kinase 1 / 2), which in turn activates LAST1 / 2 (large tumor suppressor kinase 1 / 2). Activated LATS1 / 2 phosphorylates YAP (Yes Associated Protein) / TAZ (transcriptional coactivator with PDZ-binding motif). Phosphorylated YAP / TAZ are localized to the cytoplasm and degraded in a ubiquitin-dependent manner, while unphosphorylated YAP / TAZ translocate to the nucleus and bind to several nuclear transcription factors, including TEADs, to form a transcriptional complex, inducing the expression of proteins including CTGF (connective tissue growth factor), Cyr61 (mysteine ​​rich angiogenic inducer 61), and AXL (AXL receptor). tyrosine kinase, receptor tyrosine kinase AXL), and the expression of several downstream target genes, thereby promoting the body's physiological and pathological processes.

[0008] TEADs / TEAD (Transcriptional Enhanced Associate Domains) are the final effectors of the Hippo signaling pathway. There are four family members, TEAD1, TEAD2, TEAD3, and TEAD4. All TEADs subtypes have a DNA-binding TEA domain at the N-terminus and a YAP / TAZ-binding domain at the C-terminus. The DNA-binding domain and YAP / TAZ-binding domain are highly conserved in mammals, but there are significant differences in the linker connecting the TEA domain and the transactivation domain. The overall homology of the four TEADs subtypes ranges from 61% to 73%. The function of TEADs is mediated by its interaction with nuclear coactivators, and YAP is the main nuclear coactivator that interacts with TEADs.

[0009] YAP / TAZ-TEADs activation promotes tumor development, and inhibiting the interaction between YAP / TAZ and TEADs has therapeutic potential. In some cancers, such as malignant mesothelioma, ovarian cancer, and cholangiocarcinoma, the YAP / TAZ-TEADs complex is frequently overactivated or overexpressed, leading to cancer progression. This overactivation is often caused by alterations in genes upstream of the Hippo signaling pathway. In patients with malignant mesothelioma, 40%-50% of tumors have NF2 mutations or deletions, <25% have MST1 or LAST1 / 2 mutations or deletions, and 70% have high YAP expression. Overactivation of the YAP / TAZ-TEADs complex contributes to tumor cell proliferation, metastasis, epithelial-to-mesenchymal transition (EMT), and the maintenance of cancer stem cells. The interaction between YAP and TEADs is crucial for initiating transcriptional programs that drive tumorigenesis and proliferation. TEADs defective in the DNA binding domain can block tumorigenesis mediated by mutations in genes upstream of the Hippo signaling pathway, suggesting that inhibiting the interaction between YAP / TAZ and TEADs has anti-tumor effects. Inhibiting the interaction between YAP / TAZ and TEADs can significantly inhibit tumor cell proliferation. Other studies have also shown that the downstream proteins CTGF and CYR61 of YAP / TAZ-TEADs can induce tumor cell resistance to chemotherapy drugs such as paclitaxel. YAP / TAZ-TEADs have become an alternative survival pathway for drug-resistant cancer cells. These findings suggest that inhibiting the interaction between YAP / TAZ and TEADs has the potential to treat tumors, particularly those with overactivation or mutations in the upstream Hippo signaling pathway.

[0010] Currently, some YAP / TAZ and TEADs interaction inhibitors (VT-01, IK-930) have entered the clinical stage. Inhibition of the interaction between YAP / TAZ and TEADs may be a promising new anti-tumor chemotherapy. Summary of the Invention

[0011] The present invention provides a heterocyclic TEAD inhibitor, which is a compound represented by Formula I' or Formula I of the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof; the compound can significantly inhibit TEAD transcriptional activity and can be used to prevent and / or treat diseases or conditions associated with increased TEAD expression.

[0012] The present invention provides a compound represented by formula I', its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0013] Wherein, ring A is a benzene ring or a 5-6 membered heteroaromatic ring;

[0014] The ring A is optionally substituted with one or more Ra; when Ra is multiple, the Ra are the same or different;

[0015] Ring B is a 4-7 membered cycloalkyl group or a 4-7 membered heterocycloalkyl group;

[0016] The ring B is optionally substituted with 1-3 identical or different R4;

[0017] R1 and R4 are each independently hydrogen, halogen, -OH, -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -S(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, oxo (=O), The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -S(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, Each independently optionally represented by one or more R 10 Replace; when R 10 When there are multiple R 10 Same or different;

[0018] R 11 、R 12 Each independently selected from: C1-C6 alkyl, C1-C6 alkoxy; or R 11 、R 12 Together with the P to which they are attached, they form a 4-7 membered ring;

[0019] V is -CH2-, -CH2CH2-, -CH2CH2CH2-;

[0020] The V is optionally substituted by one or more Rv; when Rv is multiple, the Rv are the same or different;

[0021] G1 and G2 are each independently -C(O)R2, -S(O)2R2, -S(O)R2, -NRg-C(O)R2, -NRg-S(O)2R2, -NRg-S(O)R2, -C(O)-NRg-R2, -S(O)2-NRg-R2, -S(O)-NRg-R2, R3, and only one of G1 and G2 is R3;

[0022] Each Rg is independently H, C1-C3 alkyl or C1-C3 haloalkyl;

[0023] R2 is selected from -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2; said R2 is optionally replaced by one or more R 21 Replace; when R 21 When there are multiple R 21 Same or different;

[0024] R3 is a benzene ring, a 5-12 membered heteroaromatic ring; said R3 is optionally replaced by one or more R 31 Replace; when R 31 When there are multiple R 31 Same or different;

[0025] The R 10 、R 21 、R 31 , Ra, Rv are each independently selected from: halogen, -OH, -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -SF5, -S (C1-C6 alkyl), -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, oxo (=O); the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -S (C1-C6 alkyl), -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2 are optionally substituted by substituents selected from the following: halogen, -NH2, -OH, -NO2, -CN, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -SF5.

[0026] The present invention also provides a compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0027] Wherein, ring A is a benzene ring or a 5-6 membered heteroaromatic ring;

[0028] The ring A is optionally substituted with one or more Ra; when Ra is multiple, the Ra are the same or different;

[0029] R1 is hydrogen, halogen, -OH, -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -S(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, oxo (=O), The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -S(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, Each independently optionally represented by one or more R 10 Replace; when R 10 When there are multiple R 10 Same or different;

[0030] R 11 、R 12 Each independently selected from: C1-C6 alkyl, C1-C6 alkoxy; or R 11 、R 12 Together with the P to which they are attached, they form a 4-7 membered ring;

[0031] V is -CH2-, -CH2CH2-, -CH2CH2CH2-;

[0032] The V is optionally substituted by one or more Rv; when Rv is multiple, the Rv are the same or different;

[0033] m and n are each independently 1, 2 or 3;

[0034] G1 and G2 are each independently -C(O)R2, -S(O)2R2, -S(O)R2, R3, and only one of G1 and G2 is R3;

[0035] R2 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2; said R2 is optionally replaced by one or more R 21 Replace; when R 21 When there are multiple R 21 Same or different;

[0036] R3 is a benzene ring, a 5-12 membered heteroaromatic ring; said R3 is optionally replaced by one or more R 31 Replace; when R 31 When there are multiple R 31 Same or different;

[0037] The R 10 、R 21 、R 31, Ra, Rv are each independently selected from: halogen, -OH, -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -SF5, -S (C1-C6 alkyl), -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, oxo (=O); the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -S (C1-C6 alkyl), -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2 are optionally substituted by substituents selected from the following: halogen, -NH2, -OH, -NO2, -CN, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -SF5.

[0038] In a preferred embodiment, the ring A is a benzene ring, pyridine, pyridazine, pyrimidine, or pyrazine.

[0039] In a preferred embodiment, m and n are each independently 1 or 2; preferably, m is 1 and n is 2.

[0040] In a preferred embodiment, V is -CH2-, -CH2CH2-, or -CH2CH2CH2-; said V is optionally substituted by Rv, and Rv is oxo (=O).

[0041] In a preferred embodiment, the compound has the structure shown in Formula II:

[0042] wherein m and n are each independently 1 or 2;

[0043] X1, X2, X3, and X4 are each independently CH or N;

[0044] V, R1, G1, and G2 are defined as above;

[0045] Preferably, m is 1 and n is 2;

[0046] Preferably, V is -CH2- or -C(O)-.

[0047] In a preferred embodiment, the compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has the structure shown in Formula III or Formula IV:

[0048] Where, E is N or CRe;

[0049] Re is selected from H, halogen, -OH, C1-C3 alkyl or C1-C3 haloalkyl;

[0050] p and q are each independently 1 or 2;

[0051] X1, X2, X3, and X4 are each independently CH or N;

[0052] V, R1, R4, G1, and G2 are as defined above.

[0053] In a preferred embodiment, V is -CH2- or -C(O)-;

[0054] In a preferred embodiment, E is N or CH.

[0055] In a preferred embodiment, the compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has the structure shown in Formula Ic, Formula Id, or Formula Ie:

[0056] Wherein, X1, X2, X3, and X4 are each independently CH or N;

[0057] R1, R4, V, G1, and G2 are as defined above.

[0058] In a preferred embodiment, V is -CH2- or -C(O)-.

[0059] In a preferred embodiment, the compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has the structure shown in Formula Id':

[0060] Wherein, X1, X2, X3, and X4 are each independently CH or N;

[0061] R1, R4, V, G1, and G2 are as defined above.

[0062] In a preferred embodiment, the compound has the structure shown in Formula Ia, Ib

[0063] Wherein, X1, X2, X3, and X4 are each independently CH or N;

[0064] R1, V, G1, and G2 are defined as above;

[0065] Preferably, V is -CH2- or -C(O)-.

[0066] In a preferred embodiment, the compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has the structure shown in Formula IIIa or IIIb:

[0067] Wherein, X1, X2, X3, and X4 are each independently CH or N;

[0068] V, R1, R4, G1, and G2 are as defined above;

[0069] Preferably, V is -CH2- or -C(O)-.

[0070] In a preferred embodiment, Having a structure selected from the following:

[0071] In a preferred embodiment, X1, X2, X3, and X4 are each independently CH or N, and the number of N is 0, 1, 2, or 3 (preferably 0, 1, or 2).

[0072] In a preferred embodiment, X1, X2, X3, and X4 are each independently CH or N, and 0, 1, 2, or 3 of X1, X2, X3, and X4 are N.

[0073] In a preferred embodiment, X1, X2, X3, and X4 are CH; and / or, X1 is N, and X2, X3, and X4 are CH; and / or, X4 is N, and X1, X2, and X3 are CH; and / or, X1 and X4 are N, and X2 and X3 are CH.

[0074] In a preferred embodiment, the compound has a structure selected from the group consisting of:

[0075] Wherein, R1, G1, G2, and V are defined as above;

[0076] Preferably, for

[0077] Preferably, for

[0078] In a preferred embodiment, G2 is a benzene ring or a 5-6 membered heteroaromatic ring; the benzene ring or the 5-6 membered heteroaromatic ring is surrounded by 1, 2 or 3 identical or different R 31 replace;

[0079] Preferably, the 5-6 membered heteroaromatic ring is selected from benzene ring, pyridine, pyridazine, pyrimidine, pyrazine;

[0080] Preferably, R 31 For 1 or 2.

[0081] In a preferred embodiment, G2 is

[0082] Preferably, R 31Selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -SF5, -S(C1-C6 alkyl); the C1-C6 alkyl, C1-C6 alkoxy, -S(C1-C6 alkyl) are optionally substituted by substituents selected from the following: halogen, -NH2, -NO2, -CN, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -SF5.

[0083] In a preferred embodiment, R 31 Selected from C1-C3 haloalkyl, C1-C3 haloalkoxy.

[0084] In a preferred embodiment, R 31 Selected from -CF3, -OCF3.

[0085] In a preferred embodiment, G1 is -C(O)R2, -S(O)2R2, -S(O)R2, -NRg-C(O)R2, -NRg-S(O)2R2; said R2 is optionally replaced by one or more R 21 Substituted; preferably, Rg is selected from H, C1-C3 alkyl.

[0086] In a preferred embodiment, G1 is -C(O)R2, -S(O)2R2, -S(O)R2, -NH-C(O)R2, -NH-S(O)2R2; said R2 is optionally replaced by one or more R 21 replace.

[0087] In a preferred embodiment, R2 is selected from NH2, C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; said R2 is optionally replaced by one or more R 21 replace.

[0088] In a preferred embodiment, R2 is selected from NH2, methyl, ethyl, propyl, C2-C3 alkenyl, C2-C3 alkynyl; said R2 is optionally replaced by one or more R 21 replace.

[0089] In a preferred embodiment, R 21 Selected from NH2, OH, F, Cl, methyl, ethyl, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2.

[0090] In a preferred embodiment, G1 is selected from:

[0091] In a preferred embodiment, R4 is hydrogen, methyl, -CHF2, or -CH2OH.

[0092] In a preferred embodiment, G1 is -C(O)R2; R2 is C2-C6 alkenyl or C2-C6 alkynyl; the C2-C6 alkenyl or C2-C6 alkynyl is optionally replaced by R 21 replace.

[0093] In a preferred embodiment, the R 21 is a halogen; the halogen is preferably F or Cl.

[0094] In a preferred embodiment, G1 is -C(O)-CH=CH2 or -C(O)-CF=CH2.

[0095] In a preferred embodiment, the V is -CH2-, -CH2CH2-, or -CH2CH2CH2-; the V is optionally substituted by Rv, and Rv is oxo (=O).

[0096] In a preferred embodiment, R1 is H, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy,

[0097] The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl group is optionally substituted by one or more R 10 Replace; when R 10 When there are multiple R 10 Same or different.

[0098] In a preferred embodiment, the R 10 It is F, Cl, -OH.

[0099] In a preferred embodiment, R1 is H, F, Cl, CN, C1-C3 alkyl, The C1-C3 alkyl group is optionally substituted with one or more -OH groups.

[0100] In a preferred embodiment, for

[0101] In a preferred embodiment, R1 is H, F, Cl, CN, -CH(OH)-CH2(OH),

[0102] In a preferred embodiment, the compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is selected from:

[0103] The present invention also provides a pharmaceutical composition comprising any one of the compounds described above, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and a pharmaceutically acceptable carrier.

[0104] The present invention also provides a use of the compound as described above, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the use of the pharmaceutical composition as described in the second aspect, wherein the use is selected from at least one of the following:

[0105] preparing a medicament, pharmaceutical composition or formulation for preventing and / or treating a disease associated with increased TEAD expression; and / or,

[0106] Preparation of drugs, pharmaceutical compositions or preparations for reducing / inhibiting TEAD expression or increasing TEAD activity; and / or,

[0107] Prepare drugs, pharmaceutical compositions or preparations for reducing / inhibiting the Hippo signaling pathway.

[0108] In a preferred embodiment, the TEAD comprises: TEAD1, TEAD2, TEAD3 and TEAD4.

[0109] In a preferred embodiment, the disease is a cell proliferative disorder.

[0110] In a preferred embodiment, the cell proliferative disorder is cancer.

[0111] In a preferred embodiment, the disease is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocyte, myeloblast, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic leukemia), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, soft tissue sarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, Blood diseases, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythaemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease , hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's disease and non-Hodgkin's disease), lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma, Non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

[0112] Preferably, the disease is selected from the group consisting of mesothelioma, soft tissue sarcoma, meningioma, glioma, and lung cancer.

[0113] The present invention also provides a method for treating a disease, comprising administering to a patient a therapeutically effective amount of at least one of the compound, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs or pharmaceutical compositions.

[0114] In a preferred embodiment of the present invention, the disease is a disease associated with increased TEAD expression. The TEADs include: TEAD1, TEAD2, TEAD3 and TEAD4.

[0115] In a preferred embodiment of the present invention, the disease is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.

[0116] In a preferred embodiment of the present invention, the disease is the disease described in the third aspect.

[0117] In some embodiments, the patient is a mammal, preferably a human.

[0118] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention.

[0119] Terms and Definitions

[0120] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The resulting group definitions and compound structures shall fall within the scope of the description of this specification.

[0121] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by persons skilled in the art to which the claimed subject matter belongs. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated by reference in their entirety. If multiple definitions of a term are used herein, the definitions in this section shall prevail.

[0122] It should be understood that the above brief description and the detailed description below are exemplary and are only used for explanation, and do not impose any restrictions on the subject matter of the present invention. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It must be noted that unless otherwise clearly stated in the text, the singular forms used in this specification and claims include the plural forms of the things referred to. It should also be noted that unless otherwise stated, the use of "or" and "or" means "and / or". In addition, the use of the term "including" and other forms, such as "comprising", "including" and "containing" are not restrictive.

[0123] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are used. Unless otherwise specified, the terms used herein in the descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceuticals and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or reactions and purifications can be carried out in accordance with methods well known in the art or the description of the present invention. The above techniques and methods can generally be implemented according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0124] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result from writing the formula from right to left. For example, CHO is equivalent to OCH. As used herein, As used herein, "R1", "R2" and "R 1 " have the same meaning and can be replaced with each other. For other symbols such as R2, similar definitions have the same meaning.

[0125] The section headings used herein are for organizational purposes only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0126] In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0127] When a numerical range is described in the specification and claims of this application and is understood as an "integer," it should be understood to include both endpoints of the range as well as every integer within the range. For example, "an integer from 0 to 5" should be understood to include every integer from 0, 1, 2, 3, 4, and 5.

[0128] As used herein, the term "halogen" by itself or as part of another substituent refers to fluorine, chlorine, bromine, or iodine.

[0129] As used herein, the term "alkyl" when used alone or as part of another substituent means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms, and connected to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. Alkyl groups may be unsubstituted or substituted with one or more suitable substituents. Alkyl groups may also be isotopic isomers of naturally abundant alkyl groups that are enriched in isotopes of carbon and / or hydrogen (i.e., deuterium or tritium). As used herein, the term "alkenyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term "alkynyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.

[0130] The term "C1-C6 alkyl" alone or as part of another substituent is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or isomers thereof. The term "C1-C3 alkyl" is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2 or 3 carbon atoms. In particular, such radicals have 1, 2 or 3 carbon atoms ("C1-C3 alkyl"), for example methyl, ethyl, n-propyl or isopropyl.

[0131] The term "C2-C6 alkenyl" when used alone or as part of another substituent is understood to mean a straight or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms, for example, 2 or 3 carbon atoms (i.e., C2-C3 alkenyl). It is understood that where the alkenyl contains more than one double bond, the double bonds may be separated from one another or conjugated. The alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl , 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0132] The term "C2-C6 alkynyl" is understood to mean a straight or branched monovalent hydrocarbon radical comprising one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms, for example 2 or 3 carbon atoms ("C2-C3 alkynyl"). The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0133] The term "C1-C6 alkoxy" should be understood to mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms and an oxygen atom, or represented by C1-C6 alkyl-O-. The definition of C1-C6 alkyl is as described in this specification, and the oxygen atom can be attached to any carbon atom of the linear or branched chain of the C1-C6 alkyl. Including but not limited to: methoxy (CH3-O-), ethoxy (C2H5-O-), propoxy (C3H7-O-), butoxy (C4H9-O-), pentoxy (C5H 11 -O-), hexyloxy (C6H 13 -O-).

[0134] The term "ring" when used alone or as part of another substituent includes carbocyclic rings and heterocyclic rings, which can be saturated, unsaturated or partially unsaturated. Such rings include heterocycloalkyl, cycloalkyl, aryl, heteroaryl, etc. For example, the term "4-7 membered ring" refers to a ring composed of 4, 5, 6 or 7 atoms.

[0135] The term "heteroaryl" or "heteroaromatic ring" or "heteroaromatic ring group" when used alone or as part of another substituent refers to a monocyclic or polycyclic aromatic ring system. In certain embodiments, one to three atoms in the ring system are heteroatoms, i.e., elements other than carbon, including but not limited to N, O, S, or P. For example, a "5-6 membered heteroaromatic ring" refers to an aromatic ring system containing 5 or 6 atoms and containing heteroatoms. Examples of heteroaromatic rings include, but are not limited to, furanyl, imidazolyl, indolinyl, pyrrolidinyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, and isoquinolinyl. The heteroaromatic ring group may be optionally fused to a benzene ring and may include monocyclic, bicyclic, tricyclic, spirocyclic, or bridged rings.

[0136] The term "halo" is used interchangeably with the term "halogen-substituted" when used alone or as part of another substituent. "Haloalkyl" or "halogen-substituted alkyl" refers to saturated aliphatic hydrocarbon groups, including branched and straight-chain groups, having the specified number of carbon atoms, substituted with one or more halogens (e.g., -CvFw, where v = 1 to 3 and w = 1 to (2v+1)). Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

[0137] Compounds provided herein include intermediates that can be used to prepare compounds provided herein, which contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), and also include protected derivatives thereof."Protected derivatives" are compounds in which one or more reactive sites are blocked by one or more protecting groups (also referred to as blocking groups). Suitable carboxyl moiety protecting groups include benzyl, tert-butyl, etc., and isotopes, etc. Suitable amino and amine protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable hydroxyl protecting groups include benzyl, etc. Other suitable blocking groups are well known to those of ordinary skill in the art.

[0138] In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

[0139] In this application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0140] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. These salts may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or may be used in the identification, characterization, or purification of the compounds of the present invention.

[0141] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0142] Depending on the choice of starting materials and methods, the compounds of the present invention may exist in one of the possible isomers or in a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes D and L or (+) and (–) are used to designate the signs for the rotation of plane-polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory.

[0143] When bonds to chiral carbon atoms in formulae of the present invention are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon atoms and the enantiomerically pure compounds and mixtures thereof are encompassed within the scope of the formula. The diagrammatic representation of racemates or enantiomerically pure compounds herein is adapted from Maehr, J. Chem. Ed. 1985, 62: 114-120. Wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter.

[0144] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture with physical and chemical properties consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0145] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0146] In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.

[0147] In the present application, the term "solvate" refers to a compound of the present invention or a salt thereof including a stoichiometric or non-stoichiometric amount of a solvent bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

[0148] As used herein, the term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the present invention are prepared by modifying functional groups within the compound. These modifications can be removed by conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl or amino group within a compound of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group or free amino group, respectively.

[0149] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0150] As used herein, the term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients enhance the handling characteristics of pharmaceutical formulations, i.e., by increasing flowability and / or adhesion, making the formulation more suitable for direct compression.

[0151] As used herein, the term "treat" and other similar synonyms include the following meanings:

[0152] (i) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition;

[0153] (ii) inhibiting the disease or condition, i.e., curbing its development;

[0154] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0155] (iv) Alleviate the symptoms of the disease or condition.

[0156] For each step of the reaction, the reaction temperature can be appropriately selected according to the solvent, starting materials, reagents, etc., and the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting materials, reagents, etc. After the reaction of each step is completed, the target compound can be separated and purified from the reaction system according to conventional methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography, etc. If it does not affect the next step of the reaction, the target compound can also be directly entered into the next step of the reaction without separation and purification. Each step of the reaction of the present invention is preferably carried out in an inert solvent, and the inert solvent includes but is not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof. Beneficial effects

[0157] After extensive and in-depth research, the present inventors unexpectedly developed a heterocyclic TEAD inhibitor, which is a compound represented by Formula I' or Formula I of the present invention. The compound can significantly inhibit the transcriptional activity of TEAD and can be used to prevent and / or treat diseases associated with increased TEAD expression. DETAILED DESCRIPTION

[0158] The present invention will be further described below in conjunction with specific examples. It should be understood that the following description is only the most preferred embodiment of the present invention and should not be considered as limiting the scope of protection of the present invention. Based on a full understanding of the present invention, the experimental methods in the following examples that do not specify specific conditions are generally carried out under conventional conditions or under conditions recommended by the manufacturer. Those skilled in the art may make non-essential changes to the technical solutions of the present invention, and such changes should be considered as included in the scope of protection of the present invention.

[0159] Example 1: Preparation of Compound I-1

[0160] The synthetic route is as follows:

[0161] Step 1: Synthesis of 2-methylprop-2-yl 2-oxo-1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-1'-carboxylate (1-2)

[0162] Dissolve 2-methylprop-2-yl-2-oxoylidene-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-1'-carboxylate (1-1) (0.9 g, 3.1 mmol) and 4-trifluoromethylphenylboronic acid (0.89 g, 4.7 mmol) in dichloromethane (20 mL). Add copper acetate (0.85 g, 4.68 mmol) and triethylamine (1.26 g, 12.5 mmol). Stir overnight at room temperature under an oxygen balloon. After completion of the reaction, filter the reaction mixture with celite, wash the filter cake with dichloromethane (40 mL), combine the filtrates, wash with water (15 mL), and dry over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=5:1) to obtain compound 2-oxyylidene-1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-1'-carboxylic acid-2-methylprop-2-yl ester (1-2) (1.16 g, yield: 85.6%).

[0163] LC-MS, M / Z(ESI):433.2[M+H] + .

[0164] Step 2: Synthesis of 1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-2-one hydrochloride (1-3)

[0165] Dissolve 2-methylpropane-2-yl-1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-1'-carboxylate (1-2) (1.16 g, 2.68 mmol) in 1,4-dioxane (20 mL). Add a 4M solution of hydrogen chloride in 1,4-dioxane (20 mL) and stir overnight at room temperature. The reaction mixture was concentrated to afford 1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-2-one hydrochloride (1-3) (0.99 g, 100.0% yield), which was used directly in the next reaction.

[0166] LC-MS, M / Z(ESI):333.1[M+H] + .

[0167] Step 3: Synthesis of 1'-(2-fluoro-1-oxoprop-2-enyl)-1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-2-one (I-1)

[0168] 1-[4-(Trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-2-one hydrochloride (1-3) (230 mg, 0.62 mmol) was dissolved in N,N-dimethylformamide (7 mL), 2-fluoroacrylic acid (62 mg, 0.69 mmol) was added, and then 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (354 mg, 0.93 mmol) and N,N-diisopropylethylamine (322 mg, 2.49 mmol) were added and reacted at 40°C overnight. After the reaction, water (20 mL) was added, and the product was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to obtain 1'-(2-fluoro-1-oxoprop-2-enyl)-1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-2-one (I-1) (164.2 mg, yield: 65.1%).

[0169] LC-MS, M / Z(ESI):405.1[M+H] + .

[0170] Example 2: Preparation of Compound I-2

[0171] The synthetic route is as follows:

[0172] Step 1: Synthesis of 1'-(1-oxoprop-2-enyl)-1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-2-one (I-2)

[0173] 1-[4-(Trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-2-one hydrochloride (1-3) (410 mg, 1.11 mmol) was dissolved in tetrahydrofuran (10 mL). Saturated aqueous sodium bicarbonate solution (3 mL) was added at 0°C and stirred at 0°C for 10 minutes. Acryloyl chloride (100.7 mg, 1.11 mmol) was added and the reaction was continued at 0°C for 0.5 hours. After the reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane: methanol (V / V) = 10:1) to obtain compound 1'-(1-oxoprop-2-enyl)-1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-2-one (I-2) (392.5 mg, yield: 91.3%).

[0174] LC-MS, M / Z(ESI):387.1[M+H] + .

[0175] 1 H NMR (400MHz, DMSO-d6): δ7.95(dd,2H),7.76(dd,2H),7.46(dd,1H),7.33–7.26(m,1H),7.1 6(td,1H),6.90(dd,1H),6.64(m,1H),6.20(m,1H),5.72(m,1H),3.90(m,4H),2.37(m,2H).

[0176] Example 3 Preparation of Compound I-3

[0177] The synthetic route is as follows:

[0178] Step 1: Synthesis of 2-methylpropane-3-[[(3-bromopyridin-2-yl)amino]carbonyl]tetrahydropyrrole-1-carboxylate (3-2)

[0179] 3-Bromopyridin-2-amine (3-1) (3.0 g, 17.4 mmol) was placed in a reaction flask, and anhydrous acetonitrile (20 mL) was added under argon protection. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (7.35 g, 26.2 mmol), 1-Boc-pyrrolidine-3-carboxylic acid (6.2 g, 28.8 mmol) and methylimidazole (3.6 g, 45 mmol) were added at room temperature, and the reaction solution was stirred at 45 ° C for 16 h. After completion of the reaction, the solvent was distilled off under reduced pressure, and then ethyl acetate (200 mL) was added to the reaction solution, followed by washing with saturated sodium chloride (200 mL×3). The organic phase was taken, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=3:1) to obtain compound 3-[[(3-bromopyridin-2-yl)amino]carbonyl]tetrahydropyrrole-1-carboxylic acid-2-methylprop-2-yl ester (3-2) (4.55 g, yield: 71%).

[0180] LC-MS, M / Z(ESI):370.1[M+H] + .

[0181] Step 2: Synthesis of 2-methylpropane-3-[[(3-bromopyridin-2-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]tetrahydropyrrole-1-carboxylate (3-3)

[0182] The compound 3-[[(3-bromopyridin-2-yl)amino]carbonyl]tetrahydropyrrole-1-carboxylic acid-2-methylprop-2-yl ester (3-2) (4.2 g, 11.35 mmol) was placed in a reaction flask, N,N-dimethylformamide (50 mL) was added, and sodium hydride (0.91 g, 22.7 mmol, 60 wt%) was added under ice bath. After stirring for 15 min, p-methoxybenzyl chloride (2.7 g, 17 mmol) was added, and the reaction solution was reacted at room temperature for 2 h. Water (2 mL) was added to the reaction solution under ice bath to quench the reaction, and then ethyl acetate (300 mL) was added to the reaction solution, and then washed with saturated aqueous sodium chloride solution (300 mL×3). The organic phase was taken, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=5:1) to obtain compound 3-[[(3-bromopyridin-2-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]tetrahydropyrrole-1-carboxylic acid-2-methylprop-2-yl ester (3-3) (1.87 g, yield: 34%).

[0183] LC-MS, M / Z(ESI):490.2[M+H] + .

[0184] Step 3: Synthesis of 2-methylprop-2-yl 1'-[(4-methoxyphenyl)methyl]-2'-oxyylidene-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[2,3-b]pyridine]-1-carboxylate (3-4)

[0185] The compound 3-[[(3-bromopyridin-2-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]tetrahydropyrrole-1-carboxylic acid-2-methylpropane-2-yl ester (3-3) (1.6 g, 3.4 mmol) was placed in a reaction flask, and [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)palladium dichloride (0.16 g) and sodium tert-butoxide (464 mg, 5.1 mmol) were added, followed by toluene (5 mL), and the reaction was carried out under argon protection at 110 ° C. Microwave reaction for 3 h. After completion of the reaction, the reaction solution was cooled to room temperature, ethyl acetate (200 mL) was added, and then washed with saturated aqueous sodium chloride solution (200 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=2:1) ​​to obtain compound 1'-[(4-methoxyphenyl)methyl]-2'-oxo-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[2,3-b]pyridine]-1-carboxylic acid-2-methylprop-2-yl ester (3-4) (1.0 g, yield: 75%).

[0186] LC-MS, M / Z(ESI):410.7[M+H] + .

[0187] Step 4: Synthesis of 1-(1-oxoprop-2-enyl)-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[2,3-b]pyridine]-2'-one (3-5)

[0188] 1'-[(4-Methoxyphenyl)methyl]-2'-oxo-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[2,3-b]pyridine]-1-carboxylic acid-2-methylpropan-2-yl ester (3-4) (120 mg, 0.293 mmol) was placed in a reaction flask, methanesulfonic acid (1 mL) was added, and the reaction was carried out at 45°C for 4 h. The crude product was added dropwise to a saturated sodium carbonate solution (5 mL), followed by sodium bicarbonate (200 mg) and acetonitrile (5 mL), and then acryloyl chloride (64 mg, 0.6 mmol) was added at 0°C. The reaction solution was stirred at 0°C for 15 min. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove acetonitrile, and then extracted with ethyl acetate (50 mL). The organic phase was washed with saturated aqueous sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=1:1) to give compound 1-(1-oxoprop-2-enyl)-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[2,3-b]pyridine]-2'-one (3-5) (52 mg, yield: 73%).

[0189] LC-MS, M / Z(ESI):244.3[M+H] + .

[0190] Step 5: Synthesis of 1-(1-oxoprop-2-enyl)-1'-[4-(trifluoromethyl)phenyl]-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[2,3-b]pyridine]-2'-one (I-3)

[0191] 1-(1-Oxoprop-2-enyl)-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[2,3-b]pyridine]-2'-one (3-5) (50 mg, 0.206 mmol), copper acetate (80 mg, 0.4 mmol), and p-trifluoromethylphenylboronic acid (47 mg, 0.247 mmol) were placed in a reaction flask, and acetonitrile (4 mL) and pyridine (64 mg, 0.8 mmol) were added. The reaction was carried out at 45 ° C under an oxygen atmosphere for 3 h. The reaction solution was extracted with ethyl acetate (50 mL), and the organic phase was washed with saturated aqueous sodium chloride solution (50 mL × 3), then dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane: methanol (V / V) = 10:1) to give compound 1-(1-oxoprop-2-enyl)-1'-[4-(trifluoromethyl)phenyl]-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[2,3-b]pyridine]-2'-one (I-3) (32 mg, yield: 40%).

[0192] LC-MS, M / Z(ESI):388.2[M+H] + .

[0193] 1 H NMR (400MHz, DMSO-d6): δ8.23–8.14(m,1H),8.03–7.73(m,5H),7.24–7.17(m,1H),6.77– 6.51(m,1H),6.27–6.16(m,1H),5.81–5.68(m,1H),4.20–3.69(m,4H),2.49–2.34(m,2H).

[0194] Example 4 Preparation of Compound I-4

[0195] The synthetic route is as follows:

[0196] Step 1: Synthesis of 2-methylpropane-2-yl 3-[[(2-bromopyridin-3-yl)amino]carbonyl]tetrahydropyrrole-1-carboxylate (4-2)

[0197] 2-Bromopyridin-3-amine (4-1) (3.0 g, 17.4 mmol) was placed in a reaction flask, and anhydrous acetonitrile (20 mL) was added under argon protection. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (7.35 g, 26.2 mmol), 1-Boc-pyrrolidine-3-carboxylic acid (6.2 g, 28.8 mmol) and methylimidazole (3.6 g, 45 mmol) were added at room temperature and stirred at 45 ° C for 16 h. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The reaction solution was then diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (200 mL×3), and the organic phase was taken, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=3:1) to give compound 3-[[(2-bromopyridin-3-yl)amino]carbonyl]tetrahydropyrrole-1-carboxylic acid-2-methylprop-2-yl ester (4-2) (5.10 g, yield: 79%).

[0198] LC-MS, M / Z(ESI):370.0[M+H] + .

[0199] Step 2: Synthesis of 2-methylpropane-2-yl 3-[[(2-bromopyridin-3-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]tetrahydropyrrole-1-carboxylate (4-3)

[0200] 3-[[(2-bromopyridin-3-yl)amino]carbonyl]tetrahydropyrrole-1-carboxylic acid-2-methylpropane-2-yl ester (4-2) (3.0 g, 8.11 mmol) was placed in a reaction flask, and N,N-dimethylformamide (35 mL) was added. Subsequently, cesium carbonate (5.3 g, 16.22 mmol) was added under ice bath. After stirring for 15 min, p-methoxybenzyl chloride (1.93 g, 12.14 mmol) was added. After completion of the addition, the reaction was carried out at 45 ° C for 4 h. The reaction solution was diluted with ethyl acetate (300 mL), washed with saturated sodium chloride aqueous solution (300 mL×3), and the organic phase was taken, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=5:1) to obtain compound 3-[[(2-bromopyridin-3-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]tetrahydropyrrole-1-carboxylic acid-2-methylprop-2-yl ester (4-3) (3.25 g, yield: 82%).

[0201] LC-MS, M / Z(ESI):490.1[M+H] + .

[0202] Step 3: Synthesis of 2-methylprop-2-yl 1'-[(4-methoxyphenyl)methyl]-2'-oxo-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate (4-4)

[0203] 3-[[(2-bromopyridin-3-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]tetrahydropyrrole-1-carboxylic acid-2-methylpropane-2-yl ester (4-3) (1.6 g, 3.4 mmol) was placed in a reaction flask, and 10 wt% of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)dichloropalladium (0.16 g, CAS: 905459-27-0) and sodium tert-butoxide (464 mg, 5.1 mmol) were added, followed by addition of toluene (5 mL), and the reaction was carried out under argon protection at 110 ° C. Microwave reaction for 3 h. The reaction solution was cooled to room temperature, ethyl acetate (500 mL) was added, and then washed with saturated aqueous sodium chloride solution (500 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to obtain compound 1'-[(4-methoxyphenyl)methyl]-2'-oxo-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylic acid-2-methylprop-2-yl ester (4-4) (0.95 g, yield: 72%).

[0204] LC-MS, M / Z(ESI):410.4[M+H]+ .

[0205] Step 4: Synthesis of 1-(1-oxoprop-2-enyl)-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[3,2-b]pyridine]-2'-one (4-5)

[0206] 1'-[(4-Methoxyphenyl)methyl]-2'-oxo-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylic acid-2-methylpropan-2-yl ester (4-4) (950 mg, 2.32 mmol) was placed in a reaction flask, methanesulfonic acid (3 mL) was added, and the mixture was stirred at 45°C for 4 h. The crude product was added dropwise to a saturated sodium carbonate solution (5 mL), followed by sodium bicarbonate (400 mg) and acetonitrile (5 mL), and then acryloyl chloride (425 mg, 4.0 mmol) was added at 0°C. The reaction solution was stirred at 0°C for 15 min. The reaction solution was concentrated under reduced pressure to remove acetonitrile, and then extracted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL×3), and the organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=1:1) to give compound 1-(1-oxoprop-2-enyl)-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[3,2-b]pyridine]-2'-one (4-5) (335 mg, yield: 59%).

[0207] LC-MS, M / Z(ESI):244.3[M+H] + .

[0208] Step 5: Synthesis of 1-(1-oxoprop-2-enyl)-1'-[4-(trifluoromethyl)phenyl]-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[3,2-b]pyridine]-2'-one (I-4)

[0209] 1-(1-Oxoprop-2-enyl)-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[3,2-b]pyridin]-2'-one (4-5) (330 mg, 1.63 mmol), copper acetate (480 mg, 2.44 mmol), and p-trifluoromethylphenylboronic acid (370 mg, 1.96 mmol) were placed in a reaction flask, and acetonitrile (10 mL) and pyridine (520 mg, 6.4 mmol) were added. The mixture was reacted at 45 ° C under an oxygen atmosphere for 24 h. The reaction solution was cooled to room temperature, extracted with ethyl acetate (200 mL), and diluted. The mixture was washed with saturated aqueous sodium chloride solution (200 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to obtain the target compound 1-(1-oxoprop-2-enyl)-1'-[4-(trifluoromethyl)phenyl]-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[3,2-b]pyridine]-2'-one (I-4) (110 mg, yield: 21%).

[0210] LC-MS, M / Z(ESI):388.1[M+H] + .

[0211] 1 H NMR (400MHz, DMSO-d6): δ8.30–8.27(m,1H),8.07–7.89(m,2H),7.79(dd,2H),7.37–7.27(m,2H) ,6.76–6.51(m,1H),6.25–6.15(m,1H),5.78–5.66(m,1H),4.13–3.77(m,4H),2.49–2.28(m,2H).

[0212] Example 5: Preparation of Compound I-5

[0213] The synthetic route is as follows:

[0214] Step 1: Synthesis of compound 1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole](5-2)

[0215] Compound 1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-2-one hydrochloride (1-3) (50 mg, 0.14 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL) and stirred in an ice bath for 15 min. Then, sodium borohydride (13 mg, 0.35 mmol) was slowly added. After the addition was complete, stirring was continued in an ice bath for 15 min. Iodine (34 mg, 0.14 mmol) was then added. The reaction solution was slowly heated to 40°C and stirred for 8 h. After LCMS showed that the reaction of the starting material was complete, stirring was stopped and the reaction solution was slowly poured into ice water (2 mL) to quench the reaction. The resulting mixed solution was used directly in the next reaction.

[0216] LC-MS, M / Z(ESI):319.1[M+H] + .

[0217] Step 2: Synthesis of compound 1-[1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrol]-1'-yl]prop-2-en-1-one (I-5)

[0218] Sodium bicarbonate (23 mg, 0.27 mmol) was added to the mixed solution obtained in the previous step and stirred in an ice bath for 15 min. Acryloyl chloride (25 mg, 0.27 mmol) was then slowly added dropwise. The reaction solution was stirred in an ice bath for 15 min, then slowly warmed to room temperature and stirred for 15 min. After LCMS monitoring showed that the reaction was complete, stirring was stopped and the reaction solution was diluted with water (5 mL). The solution was extracted with ethyl acetate (3 mL × 5). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was concentrated by distillation under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 100:5) to obtain compound 1-[1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indol-3,3'-pyrrole]-1'-yl]prop-2-en-1-one (I-5) (12 mg).

[0219] LC-MS, M / Z(ESI):373.1[M+H] + .

[0220] 1H NMR (400MHz, DMSO-d6): δ7.66(d,2H),7.40(dd,2H),7.37–7.28(m,2H),7.20(dddd,1H),6.90(tt,1H),6.61(ddd,1H),6 .16(ddd,1H),5.68(ddd,1H),4.01–3.92(m,2H),3.88(t,1H),3.79–3.67(m,2H),3.63–3.46(m,1H),2.31–1.97(m,2H).

[0221] Example 6 Preparation of Compound I-6

[0222] The synthetic route is as follows:

[0223] Step 1: Synthesis of 2-methylpropane-3-[[(3-bromopyrazin-2-yl)amino]carbonyl]tetrahydropyrrole-1-carboxylate (6-2)

[0224] 3-Bromopyrazin-2-amine (6-1) (3.0 g, 17.2 mmol) was placed in a reaction flask, and anhydrous acetonitrile (20 mL), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (7.35 g, 26.2 mmol), 1-Boc-pyrrolidine-3-carboxylic acid (6.2 g, 28.8 mmol) and methylimidazole (3.6 g, 45 mmol) were added under argon protection. The reaction solution was stirred at 45 ° C for 16 h. The reaction solution was distilled under reduced pressure to remove the solvent, and then the reaction solution was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (200 mL×3), and the organic phase was taken, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=3:1) to give compound 3-[[(3-bromopyrazin-2-yl)amino]carbonyl]tetrahydropyrrole-1-carboxylic acid-2-methylprop-2-yl ester (6-2) (4.30 g, yield: 67%).

[0225] LC-MS, M / Z(ESI):371.3[M+H] + .

[0226] Step 2: Synthesis of 2-methylpropane-3-[[(3-bromopyrazin-2-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]tetrahydropyrrole-1-carboxylate (6-3)

[0227] The compound (3-[[(3-bromopyrazin-2-yl)amino]carbonyl]tetrahydropyrrole-1-carboxylic acid-2-methylpropane-2-yl ester (6-2) (2.3 g, 6.20 mmol) was placed in a reaction flask, N,N-dimethylformamide (27 mL) was added, and then cesium carbonate (4.1 g, 12.42 mmol) was added under ice bath. After stirring for 15 min, p-methoxybenzyl chloride (1.48 g, 9.3 mmol) was added and reacted at 45°C for 4 h. The reaction solution was cooled to room temperature. The mixture was diluted with ethyl acetate (300 mL), then washed with saturated aqueous sodium chloride (300 mL × 3) solution. The organic phase was taken, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 5:1) to give compound 3-[[(3-bromopyrazin-2-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]tetrahydropyrrole-1-carboxylic acid-2-methylprop-2-yl ester (6-3) (1.87 g, yield: 61%).

[0228] LC-MS, M / Z(ESI):491.2[M+H] + .

[0229] Step 3: Synthesis of 2-methylprop-2-yl 5'-[(4-methoxyphenyl)methyl]-6'-oxo-1,2,4,5,5',6'-hexahydrospiro[pyrrole-3,7'-pyrrolo[3,2-b]pyrazine]-1-carboxylate (6-4)

[0230] The compound 3-[[(3-bromopyrazin-2-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]tetrahydropyrrole-1-carboxylic acid-2-methylpropane-2-yl ester (6-3) (1.87 g, 3.80 mmol) was placed in a reaction flask, and 10 wt% of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)dichloropalladium (0.19 g) and sodium tert-butoxide (550 mg, 5.7 mmol) were added, followed by addition of toluene (6 mL), and the reaction was carried out under argon protection at 110 ° C. with microwave reaction for 3 h. After completion, the reaction solution was diluted with ethyl acetate (500 mL), washed with saturated aqueous sodium chloride solution (500 mL×3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to give compound 5'-[(4-methoxyphenyl)methyl]-6'-oxo-1,2,4,5,5',6'-hexahydrospiro[pyrrole-3,7'-pyrrolo[3,2-b]pyrazine]-1-carboxylic acid-2-methylprop-2-yl ester) (6-4) (0.84 g, yield: 56%).

[0231] LC-MS, M / Z(ESI):411.3[M+H] + .

[0232] Step 4: Synthesis of 1-(1-oxoprop-2-enyl)-1,2,4,5,5',6'-hexahydrospiro[pyrrole-3,7'-pyrrolo[2,3-b]pyrazine]-6'-one (6-5)

[0233] Compound 5'-[(4-methoxyphenyl)methyl]-6'-oxo-1,2,4,5,5',6'-hexahydrospiro[pyrrole-3,7'-pyrrolo[3,2-b]pyrazine]-1-carboxylic acid-2-methylprop-2-yl ester (6-4) (240 mg, 0.58 mmol) was placed in a reaction flask, methanesulfonic acid (1 mL) was added, and the reaction was carried out at 45°C for 4 hours. After completion, the crude product was added dropwise to a saturated sodium carbonate solution (5 mL), followed by sodium bicarbonate (400 mg) and acetonitrile (6 mL). Acryloyl chloride (108 mg, 1.2 mmol) was then added at 0°C, and the reaction mixture was reacted at 0°C for 15 minutes. After completion, the reaction solution was concentrated to remove acetonitrile, then diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL×3), and the organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to give compound 1-(1-oxoprop-2-enyl)-1,2,4,5,5',6'-hexahydrospiro[pyrrole-3,7'-pyrrolo[2,3-b]pyrazine]-6'-one (6-5) (120 mg, yield: 84%).

[0234] LC-MS, M / Z(ESI):245.1[M+H] + .

[0235] Step 5: Synthesis of 1-(1-oxoprop-2-enyl)-5'-[4-(trifluoromethyl)phenyl]-1,2,4,5,5',6'-hexahydrospiro[pyrrole-3,7'-pyrrolo[2,3-b]pyrazine]-6'-one (I-6)

[0236] Compound 1-(1-oxoprop-2-enyl)-1,2,4,5,5',6'-hexahydrospiro[pyrrole-3,7'-pyrrolo[2,3-b]pyrazine]-6'-one (6-5) (120 mg, 0.49 mmol), copper acetate (147 mg, 0.74 mmol), and p-trifluoromethylphenylboronic acid (112 mg, 0.588 mmol) were placed in a reaction flask, and acetonitrile (5 mL) and pyridine (160 mg, 2.0 mmol) were added. The mixture was reacted at 45°C under an oxygen atmosphere for 24 h. After completion, the reaction solution was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (200 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol (V / V) = 10:1) to obtain compound 1-(1-oxoprop-2-enyl)-5'-[4-(trifluoromethyl)phenyl]-1,2,4,5,5',6'-hexahydrospiro[pyrrole-3,7'-pyrrolo[2,3-b]pyrazine]-6'-one (I-6) (90 mg, yield: 47%).

[0237] LC-MS, M / Z(ESI):389.0[M+H] + .

[0238] 1 H NMR (400MHz, DMSO-d6): δ8.30(dd,1H),8.20(dd,1H),8.00–7.93(m,2H),7.90–7.85(m,2H),6.76–6.46(m,1H),6 .26–6.15(m,1H),5.79–5.68(m,1H),4.11–4.00(m,2H),3.95–3.81(m,2H),2.61–2.53(m,1H),2.49–2.37(m,1H).

[0239] Example 7 Preparation of Compound I-7

[0240] The synthetic route is as follows:

[0241] Step 1: Synthesis of compound 4-((2-bromopyridin-3-yl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester (7-1)

[0242] 2-Bromopyridin-3-amine (4-1) (3.0 g, 17.4 mmol) was placed in a reaction flask, anhydrous acetonitrile (20 mL) was added, and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (7.35 g, 26.2 mmol), methylimidazole (3.6 g, 45 mmol), and 1-Boc-4-piperidinic acid (4.78 g, 20.88 mmol) were added at room temperature. The reaction solution was stirred at 45 ° C for 16 h under nitrogen protection. After the reaction, the solvent was distilled off under reduced pressure, and the reaction solution was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (200 mL×3), and the organic phase was taken, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=3:1) to obtain tert-butyl 4-((2-bromopyridin-3-yl)carbamoyl)piperidine-1-carboxylate (7-1) (4.94 g, yield: 75%).

[0243] LC-MS, M / Z(ESI):384.1[M+H] + .

[0244] Step 2: Synthesis of compound 4-((2-bromopyridin-3-yl)(4-methoxybenzyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester (7-2)

[0245] The intermediate tert-butyl 4-((2-bromopyridin-3-yl)carbamoyl)piperidine-1-carboxylate (7-1) (3.0 g, 7.83 mmol) was placed in a reaction flask, and N,N-dimethylformamide (35 mL) was added. Subsequently, cesium carbonate (5.3 g, 16.22 mmol) was added under ice-cooling. After stirring for 15 minutes, p-methoxybenzyl chloride (1.64 g, 10.3 mmol) was added and the mixture was reacted at 45°C for 4 hours. The reaction solution was then diluted with ethyl acetate (300 mL) and washed with saturated sodium chloride (300 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain tert-butyl 4-((2-bromopyridin-3-yl)(4-methoxybenzyl)carbamoyl)piperidine-1-carboxylate (7-2) (3.31 g, yield: 84%).

[0246] LC-MS, M / Z(ESI):504.1[M+H] + .

[0247] Step 3: Synthesis of compound 1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (7-3)

[0248] Tert-butyl 4-((2-bromopyridin-3-yl)(4-methoxybenzyl)carbamoyl)piperidine-1-carboxylate (7-2) (1.6 g, 3.2 mmol) was placed in a reaction flask, and 10 wt% of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)palladium dichloride (0.16 g, CAS: 905459-27-0) and sodium tert-butoxide (464 mg, 5.1 mmol) were added, followed by addition of toluene (5 mL), and the reaction was carried out under argon atmosphere at 110 ° C. in a microwave oven for 3 h. After completion, the reaction solution was diluted with ethyl acetate (500 mL), washed with saturated aqueous sodium chloride solution (500 mL×3), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to give 1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (7-3) (0.88 g, yield: 65%).

[0249] LC-MS, M / Z(ESI):424.3[M+H] + .

[0250] Step 4: Synthesis of compound 2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (7-4)

[0251] 1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (7-3) (880 mg, 2.08 mmol) was placed in a reaction flask, trifluoromethanesulfonic acid (3 mL) was added, and the reaction was carried out at 45°C for 4 h. After completion, the reaction solution was added dropwise to saturated sodium carbonate solution (5 mL), the pH was adjusted to 7, and sodium bicarbonate (400 mg) and acetonitrile (5 mL) were added. Subsequently, di-tert-butyl dicarbonate (425 mg, 4.0 mmol) was added at 0°C, and the reaction solution was stirred at 0°C for 15 min. After completion, the reaction solution was concentrated to remove acetonitrile, then diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL×3), the organic phase was dried over sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=1:1) to give 2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (7-4) (284 mg, yield: 45%).

[0252] LC-MS, M / Z(ESI):304.1[M+H] + .

[0253] Step 5: Synthesis of compound 2-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro-[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (7-5)

[0254] Tert-butyl 2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (7-4) (280 mg, 0.92 mmol), potassium carbonate (380 mg, 2.76 mmol), cuprous iodide (209 mg, 1.84 mmol), 4-iodobenzotrifluoride (500 mg, 1.84 mmol), and N,N'-dimethylethylenediamine (97 mg, 1.10 mmol) were placed in a reaction flask, acetonitrile (5 mL) was added, and the mixture was microwaved at 100 ° C under argon atmosphere for 1.5 h. After completion, the reaction solution was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (200 mL×3), the organic phase was dried over Na2SO4 and concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V)=20:1) to give 2-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro-[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (7-5) (355 mg, yield: 87%).

[0255] LC-MS, M / Z(ESI):448.2[M+H] + .

[0256] Step 5: Synthesis of compound 1-acryloyl-1'-(4-(trifluoromethyl)phenyl)spiro[piperidin-4,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (I-7)

[0257] Tert-butyl 2-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (7-5) (200 mg, 0.45 mmol) was placed in a reaction flask, trifluoroacetic acid (3 mL) was added, and the mixture was allowed to react at room temperature for 1 h. After the reaction was complete, the reaction solution was added dropwise to saturated sodium carbonate solution (3 mL), and the pH of the reaction solution was adjusted to 7. Sodium bicarbonate (300 mg) and acetonitrile (3 mL) were added, followed by acryloyl chloride (180 mg, 2.0 mmol) at 0°C. The reaction solution was stirred at 0°C for 15 min. After completion, the reaction solution was concentrated to remove acetonitrile and water, and the residue was then purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to obtain compound 1-acryloyl-1'-(4-(trifluoromethyl)phenyl)spiro[piperidine-4,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (I-7) (127 mg, yield: 70%).

[0258] LC-MS, M / Z(ESI):402.1[M+H] + .

[0259] 1 H NMR (400MHz, DMSO-d6): δ8.27(dd,1H),7.94(d,2H),7.76(d,2H),7.34–7.25(m,2H ),6.88(dd,1H),6.15(dd,1H),5.70(dd,1H),4.10–3.90(m,4H),1.98–1.84(m,4H).

[0260] Example 8 Preparation of Compound I-8

[0261] The synthetic route is as follows:

[0262] Step 1: Synthesis of compound 3-((2-bromopyridin-3-yl)carbamoyl)azetidine-1-carboxylic acid tert-butyl ester (8-1)

[0263] 2-Bromopyridin-3-amine (4-1) (3.0 g, 17.4 mmol) was placed in a reaction flask, and dry acetonitrile (20 mL) was added. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (7.35 g, 26.2 mmol), methylimidazole (3.6 g, 45 mmol), and 1-N-Boc-3-azetidinecarboxylic acid (4.19 g, 20.88 mmol) were added at room temperature. The reaction solution was stirred at 45 ° C for 16 h under nitrogen protection. After completion of the reaction, the solvent was distilled off under reduced pressure, and the reaction solution was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (200 mL×3), and the organic phase was taken, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=3:1) to give tert-butyl 3-((2-bromopyridin-3-yl)carbamoyl)azetidine-1-carboxylate (8-1) (5.13 g, yield: 83%).

[0264] LC-MS, M / Z(ESI):356.1[M+H] + .

[0265] Step 2: Synthesis of compound 3-((2-bromopyridin-3-yl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylic acid tert-butyl ester (8-2)

[0266] 3-((2-bromopyridin-3-yl)carbamoyl)azetidine-1-carboxylic acid tert-butyl ester (8-1) (3.0 g, 8.42 mmol) was placed in a reaction flask, and N,N-dimethylformamide (35 mL) was added. Subsequently, cesium carbonate (5.3 g, 16.22 mmol) was added under ice bath, and p-methoxybenzyl chloride (1.64 g, 10.3 mmol) was added after stirring for 15 min. After the addition, the reaction solution was stirred at 45 °C for 2 h. The mixture was stirred for 4 h, and then the reaction solution was diluted with ethyl acetate (300 mL), washed with saturated sodium chloride (300 mL×3), and the organic phase was taken, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=5:1) to give tert-butyl 3-((2-bromopyridin-3-yl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate (8-2) (2.89 g, yield: 72%).

[0267] LC-MS, M / Z(ESI):476.1[M+H] + .

[0268] Step 3: Synthesis of compound 1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (8-3)

[0269] tert-Butyl 3-((2-bromopyridin-3-yl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate (8-2) (1.6 g, 3.4 mmol) was placed in a reaction flask, and 10 wt% of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)palladium dichloride (0.16 g, CAS: 905459-27-0) and sodium tert-butoxide (464 mg, 5.1 mmol) were added, followed by addition of toluene (5 mL) and microwave reaction at 110 ° C under argon protection for 3 h. After completion, the reaction solution was diluted with ethyl acetate (500 mL), washed with saturated aqueous sodium chloride solution (500 mL × 3), the organic phase was dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2: 1) to give 1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (8-3) (0.56 g, yield: 42%).

[0270] LC-MS, M / Z(ESI):396.2[M+H] + .

[0271] Step 4: Synthesis of compound 2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (8-4)

[0272] 1'-(4-Methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (8-3) (560 mg, 1.41 mmol) was placed in a reaction flask, trifluoromethanesulfonic acid (3 mL) was added, and the reaction was allowed to proceed at 45°C for 4 h. After completion, the reaction solution was dropwise added to a saturated sodium carbonate solution (5 mL). After neutralization, sodium bicarbonate (400 mg) and acetonitrile (5 mL) were added, followed by the addition of di-tert-butyl dicarbonate (425 mg, 4.0 mmol) at 0°C. The reaction solution was stirred at 0°C for 15 min. After completion, the reaction solution was concentrated to remove acetonitrile, then diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL×3), the organic phase was dried over sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=1:1) to give 2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (8-4) (128 mg, yield: 33%).

[0273] LC-MS, M / Z(ESI):276.1[M+H] + .

[0274] Step 5: Synthesis of compound 2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (8-5)

[0275] 2'-Oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (8-4) (120 mg, 0.43 mmol), potassium carbonate (177 mg, 1.29 mmol), cuprous iodide (97 mg, 0.86 mmol), 4-iodobenzotrifluoride (233 mg, 0.86 mmol), and N,N'-dimethylethylenediamine (45 mg, 0.51 mmol) were placed in a reaction flask, acetonitrile (3 mL) was added, and the reaction solution was subjected to microwave reaction at 100 ° C under argon atmosphere for 1.5 h. After completion, the reaction solution was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (200 mL×3), the organic phase was dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V)=20:1) to give 2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (8-5) (150 mg, yield: 83%).

[0276] LC-MS, M / Z(ESI):420.1[M+H] + .

[0277] Step 6: Synthesis of compound 1-acryloyl-1'-(4-(trifluoromethyl)phenyl)spiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-2'(1'H)-one (I-8)

[0278] Tert-butyl 2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (8-5) (150 mg, 0.36 mmol) was placed in a reaction flask, trifluoroacetic acid (3 mL) was added, and the mixture was allowed to react at room temperature for 1 hour. After completion, the reaction mixture was dropwise added to a saturated sodium carbonate solution (3 mL). After adjusting the pH of the reaction mixture to 7, sodium bicarbonate (300 mg) and acetonitrile (3 mL) were added, followed by the addition of acryloyl chloride (180 mg, 2.0 mmol) at 0°C. The reaction mixture was allowed to react at 0°C for 15 minutes. After completion, the reaction solution was concentrated to remove acetonitrile and water, and the residue was then purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to obtain compound 1-acryloyl-1'-(4-(trifluoromethyl)phenyl)spiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-2'(1'H)-one (I-8) (100 mg, yield: 77%).

[0279] LC-MS, M / Z(ESI):374.1[M+H] + .

[0280] 1 H NMR (400MHz, DMSO-d6): δ8.34(dd,1H),7.97(d,2H),7.77(d,2H),7.36–7.27(m, 2H),6.45(dd,1H),6.21(dd,1H),5.77(dd,1H),4.62–4.48(m,2H),4.24(q,2H).

[0281] Example 9 Preparation of Compound I-9

[0282] The synthetic route is as follows:

[0283] Tert-butyl 2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (8-5) (150 mg, 0.36 mmol) was placed in a reaction flask, trifluoroacetic acid (3 mL) was added, and the mixture was reacted at 45°C for 4 h. After the reaction was complete, the reaction solution was added dropwise to saturated sodium carbonate solution (5 mL). The pH of the reaction solution was adjusted to 7, and then sodium bicarbonate (400 mg) and acetonitrile (5 mL) were added. Subsequently, 2-fluoroacryloyl chloride (501 mg, 4.0 mmol) was added at 0°C, and the reaction solution was reacted at 0°C for 15 min. After the reaction was completed, the reaction solution was concentrated to remove acetonitrile, then diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL×3), the organic phase was dried over sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to give 1-(2-fluoroacryloyl)-1'-(4-(trifluoromethyl)phenyl)spiro(azetidine-3,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (I-9) (101 mg, yield: 72%).

[0284] LC-MS, M / Z(ESI):392.1[M+H] + .

[0285] 1 H NMR (400MHz, DMSO-d6): δ8.34(dd,1H),7.97(d,2H),7.76(d,2H),7.37–7.28(m,2H),5.68–5.53(m,1H),5.41(dd,1H),4.66(dq,2H),4.29(q,2H).

[0286] Example 10 Preparation of Compound I-10

[0287] The synthetic route is as follows:

[0288] Step 1: Synthesis of compound 1-(2-fluoroacryloyl)spiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (10-1)

[0289] 1'-[(4-methoxyphenyl)methyl]-2'-oxo-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylic acid-2-methylpropane-2-yl ester (4-4) (930 mg, 2.22 mmol) was placed in a reaction flask, trifluoromethanesulfonic acid (3 mL) was added, and the mixture was reacted at 45°C for 4 h. After the reaction was completed, the reaction solution was added dropwise to saturated sodium carbonate solution (5 mL). After adjusting the pH of the reaction solution to 7, sodium bicarbonate (400 mg) and acetonitrile (5 mL) were added, followed by the addition of 2-fluoroacryloyl chloride (501 mg, 4.0 mmol) at 0°C. The reaction solution was reacted at 0°C for 15 min. After completion, the reaction solution was concentrated to remove acetonitrile, then diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL×3), the organic phase was dried over sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to give 1-(2-fluoroacryloyl)spiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (10-1) (320 mg, yield: 55%).

[0290] LC-MS, M / Z(ESI):262.1[M+H] + .

[0291] Step 2: Synthesis of compound 1-(2-fluoroacryloyl)-1'-(4-(trifluoromethyl)phenyl)spiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (I-10)

[0292] 1-(2-Fluoroacryloyl)spiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (10-1) (320 mg, 1.23 mmol), copper acetate (480 mg, 2.44 mmol), and p-trifluoromethylphenylboronic acid (370 mg, 1.96 mmol) were placed in a reaction flask, and acetonitrile (10 mL) and pyridine (520 mg, 6.4 mmol) were added. The mixture was reacted at 45°C under an oxygen atmosphere for 24 h. After monitoring, the reaction solution was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (200 mL × 3), the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to obtain the target compound (1-(2-fluoroacryloyl)-1'-(4-(trifluoromethyl)phenyl)spiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (I-10) (95 mg, yield: 19%).

[0293] LC-MS, M / Z(ESI):406.1[M+H] + .

[0294] 1 H NMR (400MHz, DMSO-d6): δ8.29(s,1H),7.98(d,2H),7.88–7.74(m,2H),7.32(s ,2H),5.55(dd,1H),5.46–5.28(m,1H),4.19–3.82(m,4H),2.48–2.26(m,2H).

[0295] Example 11 Preparation of Compound I-11

[0296] The synthetic route is as follows:

[0297] Tert-butyl 2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (8-5) (150 mg, 0.36 mmol) was placed in a reaction flask, trifluoroacetic acid (3 mL) was added, and the mixture was reacted at 45°C for 1 h. After completion, the reaction solution was added dropwise to saturated sodium carbonate solution (5 mL). The reaction solution was adjusted to 7°C, and then sodium bicarbonate (400 mg) and acetonitrile (5 mL) were added. Subsequently, methanesulfonyl chloride (164 mg, 1.44 mmol) was added at 0°C, and the reaction solution was reacted at 0°C for 15 min. After completion, the reaction solution was concentrated to remove acetonitrile, then diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL×3), the organic phase was dried over sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:5) to give 1-(methylsulfonyl)-1'-[4-(trifluoromethyl)phenyl]-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (I-11) (89 mg, yield: 63%).

[0298] LC-MS, M / Z(ESI):398.0[M+H] + .

[0299] 1 H NMR (400MHz, DMSO-d6): δ8.35(dd,1H),7.96(d,2H),7.75(d,2H),7.36–7.26(m,1H),4.30–4.15(m,4H),3.20(s,3H).

[0300] Example 12 Preparation of Compound I-12

[0301] The synthetic route is as follows:

[0302] Tert-butyl 2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (8-5) (150 mg, 0.36 mmol) was placed in a reaction flask, trifluoroacetic acid (3 mL) was added, and the mixture was reacted at 45°C for 1 h. After completion, the solvent was removed by distillation under reduced pressure, and acetonitrile / dichloromethane (3 mL / 3 mL) was added under ice-cooling. Subsequently, N,N-diisopropylethylamine (520 mg, 4.0 mmol), 4-dimethylaminopyridine (44 mg, 0.36 mmol), and methylaminosulfonyl chloride (130 mg, 1.0 mmol) were added sequentially at 0°C. The reaction mixture was reacted at room temperature for 15 min. After completion, the reaction solution was concentrated to remove the solvent, then diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL×3), the organic phase was dried over sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:5) to give 1-(N-methylsulfamoyl)-1'-[4-(trifluoromethyl)phenyl]-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (I-12) (43 mg, yield: 30%).

[0303] LC-MS, M / Z(ESI):413.1[M+H] + .

[0304] 1 H NMR (400MHz, DMSO): δ8.36(d,1H),7.96(d,2H),7.75(d,2H),7.37–7.26(m,3H),4.16(d,2H),4.11(d,2H),2.74(d,3H).

[0305] Example 13 Preparation of Compound I-13A

[0306] The synthetic routes of compounds A1 and A2 are as follows:

[0307] Step 1: Synthesis of tert-butyl (3-((2-bromopyridin-3-yl)carbamoyl)cyclobutyl)carbamate

[0308] Place 2-bromopyridin-3-amine (3.0 g, 17.4 mmol) in a reaction flask, add anhydrous acetonitrile (20 mL), add 3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (4.5 g, 20.9 mmol) at room temperature, then add N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (7.35 g, 26.2 mmol) and methylimidazole (3.6 g, 45 mmol), and stir at 45 ° C for 16 h. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The reaction solution was then diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (200 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=3:1) to give the compound (tert-butyl (3-((2-bromopyridin-3-yl)carbamoyl)cyclobutyl)carbamate (5.10 g, yield: 79%).

[0309] LC-MS, M / Z(ESI):370.0[M+H] + .

[0310] Step 2: Synthesis of tert-butyl (3-((2-bromopyridin-3-yl)((4-methoxyphenyl)methyl)carbamoyl)cyclobutyl)carbamate

[0311] The compound (tert-butyl 3-((2-bromopyridin-3-yl)carbamoyl)cyclobutyl)carbamate (3.0 g, 8.11 mmol) was placed in a reaction flask, N,N-dimethylformamide (35 mL) was added, and cesium carbonate (5.3 g, 16.22 mmol) was added under ice-cooling. After stirring for 15 minutes, p-methoxybenzyl chloride (1.93 g, 12.14 mmol) was added, and the reaction solution was stirred at 45°C for 4 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate (300 mL), extracted with saturated sodium chloride (300 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain the compound (tert-butyl 3-((2-bromopyridin-3-yl)((4-methoxyphenyl)methyl)carbamoyl)cyclobutyl)carbamate (3.22 g, yield: 81%).

[0312] LC-MS, M / Z(ESI):490.1[M+H] + .

[0313] Step 3: Synthesis of tert-butyl ((1s,3s)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (A1) and tert-butyl ((1r,3r)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (A2)

[0314] The compound tert-butyl (3-((2-bromopyridin-3-yl)((4-methoxyphenyl)methyl)carbamoyl)cyclobutyl)carbamate (1.6 g, 3.4 mmol) was placed in a reaction flask, 10 wt% of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)palladium dichloride (0.16 g, CAS: 905459-27-0) and sodium tert-butoxide (464 mg, 5.1 mmol) were added, and then toluene (5 mL) was added. The reaction solution was reacted in a microwave at 110 ° C under nitrogen protection for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature, extracted with ethyl acetate (500 mL) and diluted, then washed with saturated aqueous sodium chloride solution (500 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1 to 1:1) to obtain the compound ((1s, 3s)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo) tert-Butyl ((1r,3r)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridinyl)-3-yl)carbamate (A1) (the more polar isomer in TLC, 0.51 g, yield: 38%), and tert-butyl ((1r,3r)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridinyl)-3-yl)carbamate (A2) (the less polar isomer in TLC, 0.44 g, yield: 33%). LC-MS, M / Z (ESI): 410.2 [M+H] + .

[0315] The synthetic route of compound I-13A is as follows:

[0316] Step 4: Synthesis of (1s,3s)-3-aminospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (13-1)

[0317] Compound ((1s,3s)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamic acid tert-butyl ester (A1) (0.25 g, 0.61 mmol) was dissolved in trifluoromethanesulfonic acid (3 mL) and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was added dropwise to saturated aqueous sodium bicarbonate (30 mL) at 0°C. Solid precipitated and was filtered, collected, and dried to obtain compound (1s,3s)-3-aminospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (13-1) (115.5 mg, 0.61 mmol), which was used directly in the next reaction.

[0318] LC-MS, M / Z(ESI):190.2[M+H] + .

[0319] Step 5: Synthesis of tert-butyl (1s,3s)-(2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (13-2)

[0320] To a saturated sodium bicarbonate aqueous solution (30 mL) of the crude (1s,3s)-3-aminospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (13-1) (115.5 mg, 0.61 mmol) was added acetonitrile (15 mL), and di-tert-butyl dicarbonate (200 mg, 0.90 mmol) was added at room temperature, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, extraction was performed with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1-1:1) to obtain compound (1s,3s)-(2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamic acid tert-butyl ester (13-2) (150.5 mg, yield: 85.3%), which was directly used in the next reaction.

[0321] LC-MS, M / Z(ESI):290.1[M+H] + .

[0322] Step 6: Synthesis of tert-butyl ((1s,3s)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (13-3)

[0323] Tert-butyl (1s,3s)-(2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (13-2) (150.5 mg, 0.52 mmol) was dissolved in acetonitrile (5 mL), and 4-iodobenzotrifluoride (106.1 mg, 0.39 mmol), cuprous iodide (119 mg, 0.62 mmol), potassium carbonate (216.0 mg, 1.56 mmol) were added, and then N,N'-dimethylethylenediamine (59.6 mg, 0.68 mmol) was added. The mixture was reacted in a microwave at 100 ° C under nitrogen protection for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain compound tert-butyl ((1s,3s)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (13-3) (185.3 mg, yield 82.3%).

[0324] LC-MS, M / Z(ESI):434.1[M+H] + .

[0325] Step 7: Synthesis of (1s,3s)-3-amino-1'-(4-(trifluoromethyl)phenyl)spiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (13-4)

[0326] Tert-butyl ((1s,3s)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridinyl)-3-yl)carbamate (13-3) (180 mg, 0.42 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 0.5 hours. After the reaction, the reaction solution was concentrated under reduced pressure, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution at 0°C, and the mixture was extracted with dichloromethane (20 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude compound (1s, 3s)-3-amino-1'-(4-(trifluoromethyl)phenyl)spiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (13-4) (131.9 mg, yield 95.3%).

[0327] LC-MS, M / Z(ESI):334.1[M+H] + .

[0328] Step 8: Synthesis of N-((1s,3s)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)prop-2-enamide (I-13A)

[0329] (1s,3s)-3-amino-1'-(4-(trifluoromethyl)phenyl)spiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (13-4) (65 mg, 0.2 mmol) was dissolved in tetrahydrofuran (10 mL). Saturated aqueous sodium bicarbonate solution (3 mL) was added at 0°C, and the mixture was stirred at 0°C for 10 minutes. Acryloyl chloride (27.2 mg, 0.3 mmol) was added, and the reaction was continued at 0°C for 0.5 hours. After the reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (V / V)=10:1) to obtain compound N-((1s,3s)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)prop-2-enamide (I-13A) (69.3 mg, yield: 89.5%).

[0330] LC-MS, M / Z(ESI):388.1[M+H] + .

[0331] 1 H NMR (400MHz, DMSO): δ8.73(d,1H),8.36–8.28(m,1H),7.95(d,2H),7.77(d,2H),7.27(d,2H),6.25(dd,1H),6.13(dd,1H),5.63(dd,1H),4.85(dq,J 1H),2.86–2.72(m,2H),2.64(dd,2H).

[0332] Compound I-13B was synthesized by referring to the synthesis method of compound I-13A, except that the raw material A1 was replaced with tert-butyl ((1r,3r)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (A2).

[0333] LC-MS, M / Z(ESI):388.1[M+H] + .

[0334] 1H NMR (400MHz, DMSO): δ8.73(d,1H),8.35(t,1H),7.95(d,2H),7.77(d,2H),7.30(d,2 H),6.24(dd,1H),6.14(dd,1H),5.64(dd,1H),5.16–5.02(m,1H),2.68–2.55(m,4H).

[0335] Example 14 Preparation of Compounds I-14A and I-14B

[0336] The synthetic route of I-14A is as follows:

[0337] (1s,3s)-3-amino-1'-(4-(trifluoromethyl)phenyl)spiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (13-4) (65 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide (3 mL), 2-fluoroacrylic acid (21 mg, 0.23 mmol) was added, and then 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) and N,N-diisopropylethylamine (107 mg, 0.83 mmol) were added, and the reaction solution was stirred at 40°C overnight. After the reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain compound 2-fluoro-N-((1s,3s)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)prop-2-enamide (I-14A) (63.4 mg, yield: 78.3%).

[0338] LC-MS, M / Z(ESI):406.1[M+H] + .

[0339] 1 H NMR (400MHz, DMSO-d6): δ9.14(d,1H),8.32(dd,1H),7.95(d,2H),7.76(d,2H ),7.32–7.21(m,2H),5.58(dd,1H),5.29(dd,1H),4.85(dq,1H),2.78(p,4H).

[0340] Compound I-14B was synthesized by referring to the synthesis method of compound I-14A, except that the raw material A1 was replaced with tert-butyl ((1r,3r)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (A2).

[0341] LC-MS, M / Z(ESI):406.1[M+H] + .

[0342] 1 H NMR (400MHz, DMSO): δ9.12(d,1H),8.37–8.31(m,1H),7.95(d,2H),7.76(d,2H),7.29(d ,2H),5.68–5.51(m,1H),5.29(dd,1H),5.18–5.02(m,1H),2.78(td,2H),2.60(td,2H).

[0343] Example 15 Preparation of Compounds I-15A and I-15B

[0344] The synthetic route is as follows:

[0345] Step 1: Synthesis of tert-butyl ((1s,3s)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)(methyl)carbamate

[0346] Compound ((1s,3s)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamic acid tert-butyl ester (A1) (330 mg, 0.80 mmol) was placed in a reaction flask, N,N-dimethylformamide (8 mL) was added, 60% sodium hydride (98 mg, 2.4 mmol) was added under ice bath, and then iodomethane (170 mg, 1.2 mmol) was added. The reaction solution was reacted under ice bath for 15 minutes. After completion of the reaction, the reaction solution was quenched by adding 1 mL of water, then diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL×3), and the organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=3:1) to obtain compound ((1s,3s)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)(methyl)carbamic acid tert-butyl ester (15-1) (320 mg, 97%).

[0347] LC-MS, M / Z(ESI):424.1[M+H] + .

[0348] Step 2: tert-Butyl (methyl)((1s,3s)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (15-2)

[0349] Compound ((1s,3s)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)(methyl)carbamic acid tert-butyl ester (15-1) (310 mg, 0.75 mmol) was placed in a reaction flask, trifluoromethanesulfonic acid (3 mL) was added, and the reaction was carried out at 45°C for 4 hours. After completion, the crude product was added dropwise to a saturated sodium carbonate solution (10 mL). After neutralization, sodium bicarbonate (500 mg) was added. Acetonitrile (10 mL) was added to the aqueous phase, followed by di-tert-butyl dicarbonate (330 mg, 1.5 mmol) at 0°C. The reaction solution was reacted at 0°C for 15 minutes. After completion, the reaction solution was concentrated to remove acetonitrile, then diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL×3), the organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=1:1) to obtain compound (methyl)((1s,3s)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamic acid tert-butyl ester (15-2) (177 mg, yield: 78%).

[0350] LC-MS, M / Z(ESI):303.2[M+H] + .

[0351] Step 3: tert-Butyl methyl((1s,3s)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridin]-3-yl)carbamate

[0352] Tert-butyl (methyl)((1s,3s)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (15-2) (177 mg, 0.58 mmol) was placed in a reaction flask, and 4-iodobenzotrifluoride (190 mg, 0.7 mmol), cuprous iodide (0.11 g, 0.58 mmol), potassium carbonate (240 mg, 1.74 mmol), N,N-dimethylethylenediamine (62 mg, 0.7 mmol) were added, followed by acetonitrile (6 mL), and the reaction solution was reacted in a microwave at 100 ° C under nitrogen protection for 1 h. After completion of the reaction, the reaction solution was diluted with ethyl acetate (100 mL), washed with aqueous sodium chloride solution (100 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=2:1) ​​to obtain the compound methyl ((1s,3s)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamic acid tert-butyl ester (15-3) (216 mg, yield: 84%).

[0353] LC-MS, M / Z(ESI):448.2[M+H] + .

[0354] Step 4: N-methyl-N-((1s,3s)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)acrylamide (I-15A)

[0355] Methyl ((1s,3s)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridinyl)-3-yl)carbamate (15-3) (120 mg, 0.27 mmol) was placed in a reaction flask, trifluoroacetic acid (2 mL) was added, and the mixture was allowed to react at room temperature for 1 hour. After completion, the crude product was added dropwise to a saturated sodium carbonate solution (6 mL). After neutralization, sodium bicarbonate (500 mg) was added. Acetonitrile (6 mL) was added to the aqueous phase, followed by acryloyl chloride (45 mg, 0.5 mmol) at 0°C. The reaction mixture was allowed to react at 0°C for 15 minutes. After completion of the reaction, the reaction solution was concentrated to remove acetonitrile, then diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL×3), the organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:2) to obtain compound N-methyl-N-((1s,3s)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)acrylamide (I-15A) (72 mg, yield: 67%).

[0356] LC-MS, M / Z(ESI):402.1[M+H] + .

[0357] 1 H NMR (400MHz, DMSO-d6): δ8.40–8.24(m,1H),7.94(d,2H),7.77(d,2H),7.32–7.22(m,2H),6.81–6.7 0(m,1H),6.19–6.00(m,1H),5.72(dd,1H),5.55–4.98(m,1H),3.25–3.00(m,3H),2.97–2.62(m,4H).

[0358] Compound I-15B was synthesized by referring to the synthesis method of compound I-15A, except that the raw material A1 was replaced with tert-butyl ((1r,3r)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (A2).

[0359] Example 16 Preparation of Compound I-16

[0360] The synthetic route is as follows:

[0361] Step 1: Synthesis of tert-butyl 5-bromo-2-oxospiro(indole-3,3'-pyrrolidine)-1'-carboxylate (16-1)

[0362] 2-Methylpropane-2-yl-2-oxo-1,1',2,2',4',5'-hexahydrospiro(indole-3,3'-pyrrolidinone)-1'-carboxylate (1-1) (1.0 g, 3.47 mmol) was placed in a reaction flask, acetonitrile (10 mL) was added, and N-bromosuccinimide (0.75 g, 4.2 mmol) was added under ice-cooling. After completion of the addition, the reaction mixture was allowed to react at room temperature for 16 h. After completion, the reaction solution was diluted with ethyl acetate (300 mL) and washed with saturated sodium chloride solution (300 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain tert-butyl 5-bromo-2-oxospiro(indole-3,3'-pyrrolidine)-1'-carboxylate (16-1) (1.07 g, 84%).

[0363] LC-MS, M / Z(ESI):367.0[M+H] + .

[0364] Step 2: Synthesis of tert-butyl 5-bromo-2-oxo-1-(4-(trifluoromethyl)phenyl)spiro[indole-3,3'-pyrrolidine]-1'-carboxylate (16-2)

[0365] The compound 5-bromo-2-oxospiro(indole-3,3'-pyrrolidine)-1'-carboxylic acid tert-butyl ester (16-1) (1.0 g, 2.73 mmol) was placed in a reaction flask, and 4-iodobenzotrifluoride (0.90 g, 3.28 mmol), cuprous iodide (0.52 g, 2.73 mmol), potassium carbonate (1.2 g, 8.2 mmol), N,N-dimethylethylenediamine (0.3 g, 3.28 mmol) were added, followed by acetonitrile (10 mL). The reaction solution was stirred at 60 ° C for 2 h under nitrogen protection. After completion, the reaction solution was diluted with ethyl acetate (500 mL), washed with saturated sodium chloride (500 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to obtain compound 5-bromo-2-oxo-1-(4-(trifluoromethyl)phenyl)spiro(indole-3,3'-pyrrolidine)-1'-carboxylic acid tert-butyl ester (16-2) (1.31 g, yield: 94%).

[0366] LC-MS, M / Z(ESI):511.1[M+H] + .

[0367] Step 3: Synthesis of tert-butyl 2-oxo-1-(4-(trifluoromethyl)phenyl)-5-vinylspiro(indole-3,3'-pyrrolidine)-1'-carboxylate (16-3)

[0368] The compound 5-bromo-2-oxo-1-(4-(trifluoromethyl)phenyl)spiro(indole-3,3'-pyrrolidine)-1'-carboxylic acid tert-butyl ester (16-2) (1.3 g, 2.54 mmol) was dissolved in 1,4-dioxane (10.0 mL) and water (1.0 mL). Vinyl trifluoroborate potassium salt (0.7 g, 5.0 mmol), cesium carbonate (1.7 g, 5.0 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol) were added under nitrogen protection, and the reaction solution was reacted at 90 ° C for 6 hours. After completion, the solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate (200 mL). The organic phase was washed with saturated aqueous sodium chloride solution (200 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=5:1) to obtain compound 2-oxo-1-(4-(trifluoromethyl)phenyl)-5-vinylspiro(indole-3,3'-pyrrolidine)-1'-carboxylic acid tert-butyl ester (16-3) (1.15 g, yield: 98%).

[0369] LC-MS, M / Z(ESI):459.2[M+H] + .

[0370] Step 4: Synthesis of tert-butyl 5-(1,2-dihydroxyethyl)-2-oxo-1-(4-(trifluoromethyl)phenyl)spiro(indole-3,3'-pyrrolidine)-1'-carboxylate (16-4)

[0371] The compound 2-oxo-1-(4-(trifluoromethyl)phenyl)-5-vinylspiro(indole-3,3'-pyrrolidine)-1'-carboxylic acid tert-butyl ester (16-3) (0.5 g, 1.09 mmol) was placed in a reaction flask, tetrahydrofuran (8 mL) and water (2 mL) were added, and then 4-methylmorpholine oxide (676 mg, 5.77 mmol) and potassium osmate (146 mg, 577 umol) were added, and the reaction solution was reacted at 25°C for 6 hours. After the reaction, the reaction solution was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL × 3), and then the organic phase was taken, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 10: 1) to obtain compound 5-(1,2-dihydroxyethyl)-2-oxo-1-(4-(trifluoromethyl)phenyl)spiro(indole-3,3'-pyrrolidine)-1'-carboxylic acid tert-butyl ester (16-4) (146 mg, yield: 28%).

[0372] LC-MS, M / Z(ESI):493.2[M+H] + .

[0373] Step 5: Synthesis of 1'-acryloyl-5-(1,2-dihydroxyethyl)-1-(4-(trifluoromethyl)phenyl)spiro(indole-3,3'-pyrrolidino)-2-one (I-16)

[0374] Compound 5-(1,2-dihydroxyethyl)-2-oxo-1-(4-(trifluoromethyl)phenyl)spiro(indole-3,3'-pyrrolidine)-1'-carboxylic acid tert-butyl ester (16-4) (140 mg, 0.28 mmol) was placed in a reaction flask, trifluoroacetic acid (2 mL) was added, and the mixture was allowed to react at room temperature for 1 hour. After completion, the crude product was added dropwise to a saturated sodium carbonate solution (10 mL), followed by sodium bicarbonate (400 mg) and acetonitrile (10 mL). Acryloyl chloride (108 mg, 1.2 mmol) was then added at 0°C and allowed to react for 15 minutes. After completion, the reaction solution was concentrated to remove acetonitrile and water, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 15:1) to obtain compound 1'-acryloyl-5-(1,2-dihydroxyethyl)-1-(4-(trifluoromethyl)phenyl)spiro(indole-3,3'-pyrrolidine)-2-one (I-16) (108 mg, yield: 86%).

[0375] LC-MS, M / Z(ESI):447.2[M+H] + .

[0376] 1H NMR (400MHz, DMSO-d6): δ7.92–7.82(m,2H),7.67(dd,2H),7.39–7.28(m,1H),7.18(d,1H),6.77(dd,1H),6.69–6.45(m,1H),6.17 –6.06(m,1H),5.71–5.56(m,1H),5.26–5.12(m,1H),4.72–4.57(m,1H),4.51–4.38(m,1H),4.03–3.60(m,4H),2.40–2.16(m,2H).

[0377] The following compounds were prepared by referring to the above preparation:

[0378] Test Example 1: TEADs-mediated transcriptional repression IC 50 Evaluation test

[0379] HEK293T-TEAD Reporter Assay was used to detect the inhibitory effect of small molecule compounds on TEADs-mediated transcription.

[0380] HEK293T-TEAD-LUC reporter cell line was cultured in DMEM+10% FBS+1% PS+200μg / mL Hygromycin as complete medium. Cells in the logarithmic phase were seeded in 384-well plates, 2500 cells / well / 35μL, and incubated at 37°C, 5% CO2 overnight. The next day, 5μL of diluted compound was added to each well (DMSO final concentration was 0.1%). At the same time, a positive control group with only DMSO added was set up, and the 2μM Okacid acid signal value was used as the negative control group signal. Then, the cells were incubated at 37°C, 5% CO2 for 48h. After incubation, the cells were used. The fluorescence signal was measured using the Envision 2104 Multilabel Reader using the luciferase assay system (Promega, E2550) according to the manufacturer's instructions. The inhibition rate was calculated using the following formula. A curve was then plotted with the Log value of the inhibitor concentration on the X-axis and the inhibition rate on the Y-axis. IC was calculated using Graphpad 7.0. 50 .

[0381] Inhibition% = (positive control group signal - test well signal) / (positive control group signal - negative control group signal) * 100

[0382] The results of HEK293T-TEAD Reporter Assay showed that the compound of the present invention can significantly inhibit the transcriptional activity of TEADs in HEK293T-TEAD-LUC reporter cell line cells.

[0383] Test Example 2: Inhibition of malignant mesothelioma cell proliferation test

[0384] The NF2 mutant NCI-H226 cell proliferation assay was used to detect the inhibitory effect of small molecule compounds on the proliferation of malignant mesothelioma cells.

[0385] NCI-H226 (ATCC, cat#CRL5826) was cultured in RPMI1640+10% FBS+1% PS complete medium. Cells in the logarithmic phase were seeded in 96-well plates, 800 cells / well / 195 μL, and incubated overnight at 37°C and 5% CO2. The next day, 5 μL of diluted compound was added to each well (DMSO final concentration was 0.1%). At the same time, a positive control group with only DMSO added was set up, and the 1 μM Staurosporine signal value was used as the negative control group signal. The cells were then incubated at 37°C and 5% CO2 for 6 days. After incubation, 100 μL of culture medium was aspirated and the fluorescence signal value was measured on an Envision 2104 Multilabel Reader using the Celltiter Glo assay kit (Promega, G7573) according to the instructions provided by the supplier. The inhibition rate was calculated using the following formula, and then a curve was drawn with the Log value of the inhibitor concentration as the X-axis and the inhibition rate as the Y-axis. The IC was calculated using Graphpad 7.0. 50 .

[0386] Inhibition% = (positive control group signal - test well signal) / (positive control group signal - negative control group signal) * 100

[0387] Table 1 Proliferation inhibition activity of test compounds on NCI-H226 cells

[0388] The results of the NCI-H226 cell proliferation test showed that the compound of the present invention can significantly inhibit the proliferation of NCI-H226 (ATCC, cat#CRL5826).

[0389] Test Example 3: Thermodynamic Solubility Test

[0390] Prepare phosphate buffered saline (PBS) at pH 7.4. Accurately weigh the compound and add it to the prepared PBS at pH 7.4 to a concentration of 4 mg / mL. Shake the solution at 1000 rpm for 1 hour, then incubate at room temperature overnight. Centrifuge the incubated solution at 12000 rpm for 10 minutes to remove undissolved particles, and transfer the supernatant to a fresh centrifuge tube. After appropriate dilution of the supernatant, add acetonitrile containing the internal standard and quantify using a standard curve prepared with the same matrix.

[0391] Table 2 Thermodynamic solubility test results

[0392] The results of the thermodynamic solubility test show that the compound of the present invention has good thermodynamic solubility under neutral conditions and good drugability.

[0393] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A compound represented by formula I', its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: in, Ring A is a benzene ring or a 5-6-membered heteroaromatic ring; The ring A is optionally substituted by one or more Ra; when Ra is multiple, the Ra are the same or different; Ring B is a 4-7 membered cycloalkyl group or a 4-7 membered heterocycloalkyl group; The ring B is optionally substituted with 1-3 identical or different R4; R1 and R4 are each independently hydrogen, halogen, -OH, -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -S(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, oxo (=O), The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -S(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, Each independently optionally represented by one or more R 10 Replace; when R 10 When it is multiple, the R 10 Same or different; R 11 , R 12 Each is independently selected from: C1-C6 alkyl, C1-C6 alkoxy; or R 11 , R 12 Together with the P to which they are attached, they form a 4-7 membered ring; V is -CH2-, -CH2CH2-, -CH2CH2CH2-; The V is optionally substituted by one or more Rv; when Rv is multiple, the Rv are the same or different; G1 and G2 are each independently -C(O)R2, -S(O)2R2, -S(O)R2, -NRg-C(O)R2, -NRg-S(O)2R2, -NRg-S(O)R2, -C(O)-NRg-R2, -S(O)2-NRg-R2, -S(O)-NRg-R2, R3, and only one of G1 and G2 is R3; Each Rg is independently H, C1-C3 alkyl or C1-C3 haloalkyl; R2 is selected from -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2; said R2 is optionally replaced by one or more R 21 Replace; when R 21 When it is multiple, the R 21 Same or different; R3 is a benzene ring or a 5-12 membered heteroaromatic ring; said R3 is optionally replaced by one or more R 31 Replace; when R 31 When it is multiple, the R 31 Same or different; The R 10 , R 21 , R 31 , Ra, Rv are each independently selected from: halogen, -OH, -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -SF5, -S(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, oxo (=O); The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -S(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 are optionally substituted by substituents selected from the following: halogen, -NH2, -OH, -NO2, -CN, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -SF5.

2. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It has the structure shown in formula I: Wherein, ring A is a benzene ring or a 5-6-membered heteroaromatic ring; The ring A is optionally substituted by one or more Ra; when Ra is multiple, the Ra are the same or different; R1 is hydrogen, halogen, -OH, -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -S(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, oxo (=O), The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -S(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, Each independently optionally represented by one or more R 10 Replace; when R 10 When it is multiple, the R 10 Same or different; R 11 , R 12 Each is independently selected from: C1-C6 alkyl, C1-C6 alkoxy; or R 11 , R 12 Together with the P to which they are attached, they form a 4-7 membered ring; V is -CH2-, -CH2CH2-, -CH2CH2CH2-; The V is optionally substituted by one or more Rv; when Rv is multiple, the Rv are the same or different; m and n are each independently 1, 2 or 3; G1 and G2 are each independently -C(O)R2, -S(O)2R2, -S(O)R2, R3, and only one of G1 and G2 is R3; R2 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2; said R2 is optionally replaced by one or more R 21 Replace; when R 21 When it is multiple, the R 21 Same or different; R3 is a benzene ring or a 5-12 membered heteroaromatic ring; said R3 is optionally replaced by one or more R 31 Replace; when R 31 When it is multiple, the R 31 Same or different; The R 10 , R 21 , R 31 , Ra, Rv are each independently selected from: halogen, -OH, -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -SF5, -S(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, oxo (=O); The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -S(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 are optionally substituted by substituents selected from the following: halogen, -NH2, -OH, -NO2, -CN, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -SF5.

3. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It has the structure shown in formula III and formula IV: Wherein, E is N or CRe; Re is selected from H, halogen, -OH, C1-C3 alkyl or C1-C3 haloalkyl; p and q are each independently 1 or 2; X1, X2, X3, and X4 are each independently CH or N; V, R1, R4, G1, G2 are defined as in claim 1; Preferably, V is -CH2- or -C(O)-; Preferably, E is N or CH.

4. The compound according to any one of claims 1 to 3, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It has the structure shown in formula II: Wherein, m and n are each independently 1 or 2; X1, X2, X3, and X4 are each independently CH or N; V, R1, G1, G2 are defined as in any one of claims 1-3; Preferably, m is 1 and n is 2; Preferably, V is -CH2- or -C(O)-.

5. The compound according to any one of claims 1 to 3, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It has the structure shown in Formula Ic, Formula Id or Formula Ie: Wherein, X1, X2, X3, and X4 are each independently CH or N; The definitions of R1, R4, V, G1, and G2 are as described in any one of claims 1 to 3; Preferably, V is -CH2- or -C(O)-; Preferably, it has the structure shown in formula Id':

6. The compound according to any one of claims 1 to 3, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It has the structure shown in formula Ia and Ib: Wherein, X1, X2, X3, and X4 are each independently CH or N; R1, V, G1, and G2 are as defined in any one of claims 1-3.

7. The compound according to claim 1 or 3, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It has the structure shown in formula IIIa or IIIb: Wherein, X1, X2, X3, and X4 are each independently CH or N; V, R1, R4, G1, G2 are as defined in claim 1 or 3.

8. The compound according to any one of claims 3 to 7, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: Having a structure selected from the following: Preferably, X1, X2, X3, and X4 are each independently CH or N, and 0, 1, 2, or 3 of X1, X2, X3, and X4 are N; Preferably, X1, X2, X3, X4 are CH; and / or, X1 is N, X2, X3, X4 are CH; and / or, X4 is N, X1, X2, X3 are CH; and / or, X1 and X4 are N, and X2 and X3 are CH.

9. The compound according to any one of claims 1 to 7, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: G2 is a benzene ring or a 5-6 membered heteroaromatic ring; the benzene ring or the 5-6 membered heteroaromatic ring is replaced by 1, 2 or 3 identical or different R 31 replace; Preferably, the 5-6 membered heteroaromatic ring is selected from benzene ring, pyridine, pyridazine, pyrimidine, pyrazine; Preferably, R 31 1 or 2; Preferably, G2 is Preferably, R 31 Selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -SF5, -S(C1-C6 alkyl); the C1-C6 alkyl, C1-C6 alkoxy, -S(C1-C6 alkyl) are optionally substituted by substituents selected from the following: halogen, -NH2, -NO2, -CN, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -SF5; Preferably, R 31 Selected from C1-C3 haloalkyl, C1-C3 haloalkoxy; More preferably, R 31 Selected from -CF3, -OCF3.

10. The compound according to any one of claims 1 to 7, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: G1 is -C(O)R2, -S(O)2R2, -S(O)R2, -NRg-C(O)R2, -NRg-S(O)2R2; said R2 is optionally replaced by one or more R 21 replace; Preferably, Rg is selected from H, C1-C3 alkyl; Preferably, R2 is selected from NH2, C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; said R2 is optionally replaced by one or more R 21 replace; Preferably, R2 is selected from NH2, methyl, ethyl, propyl, C2-C3 alkenyl, C2-C3 alkynyl; said R2 is optionally replaced by one or more R 21 replace; Preferably, R 21 Selected from NH2, OH, F, Cl, methyl, ethyl, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2; Preferably, G1 is selected from: and / or, G1 is -C(O)R2; R2 is C2-C6 alkenyl or C2-C6 alkynyl; the C2-C6 alkenyl or C2-C6 alkynyl is optionally replaced by R 21 replace; Preferably, R 21 is a halogen; the halogen is preferably F or Cl; Preferably, G1 is -C(O)-CH=CH2, -C(O)-CF=CH2.

11. The compound according to any one of claims 1 to 7, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: R4 is hydrogen, methyl, -CHF2, -CH2OH; and / or, V is -CH2-, -CH2CH2-, -CH2CH2CH2-; said V is optionally substituted by Rv, Rv is oxo (=O); Preferably, V is -CH2- or -C(O)-; and / or, R1 is H, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl may be optionally substituted by one or more R 10 Replace; when R 10 When it is multiple, the R 10 Same or different; Preferably, the R 10 For F, Cl, -OH; Preferably, R1 is H, F, Cl, CN, C1-C3 alkyl, The C1-C3 alkyl group is substituted with one or more -OH; Preferably, for Preferably, R1 is H, F, Cl, CN, -CH(OH)-CH2(OH), 12. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: Selected from 13. A composition comprising the compound according to any one of claims 1 to 12, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier.

14. Use of the compound according to any one of claims 1 to 12, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or use of the pharmaceutical composition according to claim 13, comprising: Preparing a drug, pharmaceutical composition or formulation for preventing and / or treating a disease associated with increased TEAD expression; and / or, Preparing a drug, pharmaceutical composition or formulation for reducing / inhibiting TEAD expression or increasing TEAD activity; and / or, Preparing a drug, pharmaceutical composition or preparation for reducing / inhibiting the Hippo signaling pathway; Preferably, the TEAD comprises: TEAD1, TEAD2, TEAD3 and TEAD4; Preferably, the disease is a cell proliferative disorder. Preferably, the cell proliferative disorder is cancer.

15. The use according to claim 14, characterized in that The disease is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic leukemia), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, soft tissue sarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid Leukemia, Colon Cancer, Colorectal Cancer, Craniopharyngioma, Cystadenocarcinoma, Diffuse Large B-cell Lymphoma, Dysproliferative Changes (Dysplasia and Metaplasia), Embryonic Carcinoma, Endometrial Cancer, Endothelial Sarcoma, Ependymoma, Epithelial Cancer, Erythroleukemia, Esophageal Cancer, Estrogen Receptor-positive Breast Cancer, Essential Thrombocythemia, Ewing's Tumor, Fibrosarcoma, Follicular Lymphoma, Germ Cell Testicular Cancer, Glioma, Glioblastoma, Gliosarcoma, Heavy Chain Disease, Angioblastoma cell carcinoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's disease and non-Hodgkin's disease), lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma, non-small cell Lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor; Preferably, the disease is selected from the group consisting of: mesothelioma, soft tissue sarcoma, meningioma, glioma, lung cancer.

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