Heterocycle-containing TEAD inhibitors

Abstract

The invention provides a heterocycle-containing TEAD inhibitor, and the TEAD inhibitor has a structure as shown in formula I'and can be used for preventing and / or treating diseases related to TEAD expression increase. # imgabs0 #. The heterocycle-containing TEAD inhibitor has a structure as shown in formula I ', and can be used for preventing and / or treating diseases related to TEAD expression increase.

Description

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

[0002] A prior application filed by the applicant with the China National Intellectual Property Administration on November 30, 2023, with the patent application number 202311641928.3 and the title "Heterocycle-containing TEAD Inhibitor";

[0003] A prior application filed by the applicant with the China National Intellectual Property Administration on January 31, 2024, with the patent application number 202410141328.9 and the title "Heterocycle-containing TEAD Inhibitor";

[0004] A prior application filed by the applicant with the China National Intellectual Property Administration on April 29, 2024, with the patent application number 202410547186.6 and the title "Heterocycle-containing TEAD Inhibitor";

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

[0006] The present invention belongs to the field of medicine. Specifically, the present invention relates to heterocycle-containing TEAD inhibitors and their uses. 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, injury repair, and organ development. After being activated by upstream signals such as GPCR and mechanical stress, the Hippo signaling pathway leads to the activation of MST1 / 2 (Mammalian sterile 20-like kinase 1 / 2) by NF2 (neurofibromatosis type 2), the activation of LATS1 / 2 (large tumor suppressor kinase 1 / 2) by MST1 / 2, the phosphorylation of YAP (Yes Associated Protein) / TAZ (Transcriptional coactivator with PDZ-binding motif) by the activated LATS1 / 2. Phosphorylated YAP / TAZ is localized in the cytoplasm and degraded in a ubiquitin-dependent manner, while unphosphorylated YAP / TAZ translocates to the nucleus and binds to several nuclear transcription factors including TEADs to form a transcription complex, inducing the expression of several downstream target genes including CTGF (Connective tissue growth factor), Cyr61 (Mysteine rich angiogenic inducer 61), and AXL (AXL receptor tyrosine kinase), thereby promoting the physiological and pathological processes of the body.

[0008] TEADs / TEAD (Transcriptional Enhanced Associate Domains) are the final effectors of the Hippo signaling pathway. There are four family members, namely TEAD1, TEAD2, TEAD3, and TEAD4. All TEADs subtypes have a TEA domain that binds to DNA at the N-terminus and a domain that binds to YAP / TAZ at the C-terminus. The DNA-binding domain and the 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 among the four TEADs subtypes ranges from 61% to 73%. The function of TEADs is mediated by their interaction with nuclear coactivators, and YAP is the main nuclear coactivator that interacts with TEADs.

[0009] The activation of YAP / TAZ-TEADs promotes tumor development, and inhibiting the interaction between YAP / TAZ and TEADs has the potential to treat tumors. In some cancers, such as malignant mesothelioma, ovarian cancer, and cholangiocarcinoma, the YAP / TAZ-TEADs complex is often overactivated or overexpressed, leading to cancer progression. This overactivation is usually caused by alterations in genes upstream of the Hippo signaling pathway. Especially in patients with malignant mesothelioma, 40%-50% of tumors have NF2 mutations or deletions, <25% of tumors have MST1 or LAST1 / 2 mutations or deletions, and 70% have high YAP expression. The overactivation of the YAP / TAZ-TEADs complex contributes to promoting the proliferation, metastasis, epithelial-mesenchymal transition (EMT), and maintenance of cancer stem cells of tumor cells. The interaction between YAP and TEADs is crucial for initiating the transcriptional program to drive tumorigenesis and proliferation. TEADs with defective DNA-binding domains can block tumor formation mediated by mutations in genes upstream of the Hippo signaling pathway, indicating that inhibiting the interaction between YAP / TAZ and TEADs has an antitumor effect. After inhibiting the interaction between YAP / TAZ and TEADs, the proliferation of tumor cells can be significantly inhibited. Other studies have also shown that the downstream proteins CTGF and CYR61 of YAP / TAZ-TEADs can induce tumor cells to develop resistance to chemotherapeutic drugs such as paclitaxel, and YAP / TAZ-TEADs has become an alternative survival pathway for drug-resistant cancer cells. All these indicate that inhibiting the interaction between YAP / TAZ and TEADs has the potential to treat tumors, especially tumors with overactivation or mutations in genes upstream of the Hippo signaling pathway.

[0010] Currently, some inhibitors of the interaction between YAP / TAZ and TEADs (VT-01, IK-930) have entered the clinical stage, and inhibiting 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-containing TEAD inhibitor, and the TEAD inhibitor is a compound represented by Formula I' or Formula I of the present invention, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; the compound can significantly inhibit the activity of TEAD transcription and can be used for preventing and / or treating diseases or disorders associated with increased TEAD expression.

[0012] The present invention provides a compound represented by Formula I', its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:

[0013]

[0014] Wherein, Ring A is a benzene ring, a 5-6 membered heteroaryl ring;

[0015] Ring A is optionally substituted by one or more Ra; when there are multiple Ra, the Ra are the same or different;

[0016] Ring B is a 4- to 7-membered cycloalkyl or 4- to 7-membered heterocycloalkyl;

[0017] Ring B is optionally substituted by 1 to 3 identical or different R 4 substituents;

[0018] R 1 and R 4 are each independently hydrogen, halogen, -OH, -NH 2 2, -NO 2 2, -CN, C 1 1-C 6 1-alkyl, C 2 2-C 6 2-alkenyl, C 2 3-C 6 3-alkynyl, C 1 1-C 6 1-alkoxy, -S(C 1 1-C 6 1-alkyl), -NH(C 1 1-C 6 1-alkyl), -N(C 1 1-C 6 1-alkyl) 2 , oxo (=O), The C 1 1-C 6 1-alkyl, C 2 2-C 6 2-alkenyl, C 2 3-C 6 3-alkynyl, C 1 1-C 6 1-alkoxy, -S(C 1 1-C 6 1-alkyl), -NH(C 1 1-C 6 1-alkyl), -N(C 1 1-C 6 1-alkyl) 2 , each is independently optionally substituted by one or more R 10 substituents; when there are multiple R 10 substituents, the R 10 substituents are the same or different;

[0019] R 11 and R 12 are each independently selected from: C 1 1-C 6 1-alkyl, C 1 2-C6 an alkoxy group; or R 11 and R 12 together with the P to which they are attached form a 4- to 7-membered ring;

[0020] V is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -;

[0021] the said V is optionally substituted by one or more Rv; when there are a plurality of Rv, the said Rv are the same or different;

[0022] G 1 and G 2 each independently is -C(O)R 2 , -S(O) 2 R 2 , -S(O)R 2 , -NRg-C(O)R 2 , -NRg-S(O) 2 R 2 , -NRg-S(O)R 2 , -C(O)-NRg-R 2 , -S(O) 2 -NRg-R 2 , -S(O)-NRg-R 2 , R 3 , and G 1 and G 2 there is exactly one R 3 ;

[0023] each Rg is independently H, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl;

[0024] R 2 is selected from -NH 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 ;

[0025] The R 2 is optionally substituted by one or more R 21 ; when there are multiple R 21 's, the R 21 's are the same or different;

[0026] R 3 is a benzene ring, a 5- to 12-membered heteroaromatic ring; the R 3 is optionally substituted by one or more R 31 ; when there are multiple R 31 's, the R 31 's are the same or different;

[0027] The R 10 , R 21 , R 31 , Ra, and Rv are each independently selected from: halogen, -OH, -NH 2 , -NO 2 , -CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -SF 5 , -S(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , oxo (=O); the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -S(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 is optionally substituted by substituents selected from: halogen, -NH 2 , -OH, -NO 2 , -CN, C 1 -C 3 alkyl, C2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, -SF 5 。

[0028] The present invention also provides a compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:

[0029]

[0030] Wherein, ring A is a benzene ring, a 5- or 6-membered heteroaromatic ring;

[0031] Said ring A is optionally substituted by one or more Ra; when there are multiple Ras, said Ras are the same or different;

[0032] R 1 is hydrogen, halogen, -OH, -NH 2 , -NO 2 , -CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -S(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , oxo(=O), Said C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -S(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , each independently is optionally substituted by one or more R 10 ; when R 10When there are multiple of them, the R 10 are the same or different;

[0033] R 11 and R 12 each independently selected from: C 1 -C 6 alkyl, C 1 -C 6 alkoxy; or R 11 and R 12 together with the P to which they are attached form a 4- to 7-membered ring;

[0034] V is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -;

[0035] The V is optionally substituted by one or more Rv; when there are multiple Rv, the Rv are the same or different;

[0036] m and n are each independently 1, 2 or 3;

[0037] G 1 and G 2 each independently is -C(O)R 2 , -S(O) 2 R 2 , -S(O)R 2 , R 3 , and G 1 and G 2 one and only one is R 3 ;

[0038] R 2 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 ; the R 2 is optionally substituted by one or more R 21 ; when R 21 is multiple, the R 21 are the same or different;

[0039] R3 is a benzene ring or a 5- to 12-membered heteroaromatic ring; said R 3 is optionally substituted by one or more R 31 ; when there are multiple R 31 's, said R 31 's are the same or different;

[0040] said R 10 , R 21 , R 31 , Ra, and Rv are each independently selected from: halogen, -OH, -NH 2 , -NO 2 , -CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -SF 5 , -S(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , oxo (=O); said C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -S(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 is optionally substituted by substituents selected from: halogen, -NH 2 , -OH, -NO 2 , -CN, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, -SF 5 .

[0041] In a preferred embodiment, ring A is a benzene ring, pyridine, pyridazine, pyrimidine, or pyrazine.

[0042] In a preferred embodiment, m and n are each independently 1 or 2; preferably, m is 1 and n is 2.

[0043] In a preferred embodiment, V is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -; V is optionally substituted by Rv, and Rv is oxo (=O).

[0044] In a preferred embodiment, the compound has the structure shown in Formula II:

[0045]

[0046] wherein m and n are each independently 1 or 2;

[0047] X 1 、X 2 、X 3 、X 4 are each independently CH or N;

[0048] V, R 1 、G 1 、G 2 are as defined above;

[0049] Preferably, m is 1 and n is 2;

[0050] Preferably, V is -CH 2 - or -C(O)-.

[0051] In a preferred embodiment, the compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has the structures shown in Formula III and Formula IV:

[0052]

[0053] wherein E is N or CRe;

[0054] Re is selected from H, halogen, -OH, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl;

[0055] p and q are each independently 1 or 2;

[0056] X 1, X 2 , X 3 , X 4 Each independently is CH or N;

[0057] V, R 1 , R 4 , G 1 , G 2 are defined as described above.

[0058] In a preferred embodiment, V is -CH 2 - or -C(O)-;

[0059] In a preferred embodiment, E is N or CH.

[0060] 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:

[0061] wherein, X

[0062]

[0063] , X 1 , X 2 , X 3 , X 4 Each independently is CH or N;

[0064] R 1 , R 4 , V, G 1 , G 2 are defined as described above.

[0065] In a preferred embodiment, V is -CH 2 - 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 Id':

[0067]

[0068] wherein, X 1 , X 2 , X 3 , X 4 Each independently is CH or N;

[0069] R 1 , R 4 , V, G 1 , G 2 are defined as described above.

[0070] In a preferred embodiment, the compound has the structures shown in Formulas Ia and Ib

[0071]

[0072] wherein X 1 、X 2 、X 3 、X 4 are each independently CH or N;

[0073] R 1 、V、G 1 、G 2 are as defined above;

[0074] Preferably, V is -CH 2 - or -C(O)-.

[0075] In a preferred embodiment, the compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, has the structures shown in Formulas IIIa and IIIb:

[0076]

[0077] wherein X 1 、X 2 、X 3 、X 4 are each independently CH or N;

[0078] V, R 1 、R 4 、G 1 、G 2 are as defined above;

[0079] Preferably, V is -CH 2 - or -C(O)-.

[0080] In a preferred embodiment, has a structure selected from the following:

[0081] In a preferred embodiment, X 1 、X 2 、X 3 、X 4 are each independently CH or N, and the number of N is 0, 1, 2 or 3 (preferably 0, 1 or 2).

[0082] In a preferred embodiment, X 1 、X2 、X 3 、X 4 are each independently CH or N, and among X 1 、X 2 、X 3 、X 4 , 0, 1, 2 or 3 are N.

[0083] In a preferred embodiment, X 1 、X 2 、X 3 、X 4 are CH; and / or, X 1 is N, and X 2 、X 3 、X 4 are CH; and / or, X 4 is N, and X 1 、X 2 、X 3 are CH; and / or, X 1 、X 4 is N, and X 2 、X 3 are CH.

[0084] In a preferred embodiment, the compound has a structure selected from the following:

[0085]

[0086] wherein R 1 、G 1 、G 2 、V are as defined above;

[0087] Preferably,

[0088] Preferably,

[0089] In a preferred embodiment, the G 2 is a benzene ring or a 5- or 6-membered heteroaromatic ring; the benzene ring or 5- or 6-membered heteroaromatic ring is substituted by 1, 2 or 3 identical or different R 31 ;

[0090] Preferably, the 5- or 6-membered heteroaromatic ring is selected from a benzene ring, pyridine, pyridazine, pyrimidine, pyrazine;

[0091] Preferably, R 31 is 1 or 2.

[0092] In a preferred embodiment, the G 2 is

[0093] Preferably, R31 Selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -SF 5 , -S(C 1 -C 6 alkyl); said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -S(C 1 -C 6 alkyl) is optionally substituted by substituents selected from the following: halogen, -NH 2 , -NO 2 , -CN, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, -SF 5 .

[0094] In a preferred embodiment, R 31 is selected from C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy.

[0095] In a preferred embodiment, R 31 is selected from -CF 3 , -OCF 3 .

[0096] In a preferred embodiment, G 1 is -C(O)R 2 , -S(O) 2 R 2 , -S(O)R 2 , -NRg-C(O)R 2 , -NRg-S(O) 2 R 2 ; said R 2 is optionally substituted by one or more R 21 ; preferably, Rg is selected from H, C 1 -C 3 alkyl.

[0097] In a preferred embodiment, G 1 is -C(O)R 2 , -S(O)2 R 2 、-S(O)R 2 、-NH-C(O)R 2 、-NH-S(O) 2 R 2 ; said R 2 Optionally one or more R 21 replace.

[0098] In a preferred embodiment, R 2 Selected from NH 2 , C 1 -C 3 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl; said R 2 Optionally one or more R 21 replace.

[0099] In a preferred embodiment, R 2 Selected from NH 2 , methyl, ethyl, propyl, C 2 -C 3 Alkenyl, C 2 -C 3 Alkynyl; said R 2 Optionally one or more R 21 replace.

[0100] In a preferred embodiment, R 21 Selected from NH 2 、OH、F、Cl、methyl、ethyl、-NH(C 1 -C 3 Alkyl), -N(C 1 -C 3 alkyl) 2 .

[0101] In a preferred embodiment, G 1 Selected from:

[0102] In a preferred embodiment, R 4 Hydrogen, methyl, -CHF 2 、-CH 2 OH.

[0103] In a preferred embodiment, the G 1 -C(O)R 2 ; R 2 C 2 -C 6 Alkenyl, C2 -C 6 alkynyl; the C 2 -C 6 alkenyl, C 2 -C 6 alkynyl is optionally substituted by R 21 .

[0104] In a preferred embodiment, the R 21 is halogen; the halogen is preferably F or Cl.

[0105] In a preferred embodiment, the G 1 is -C(O)-CH=CH 2 , -C(O)-CF=CH 2 .

[0106] In a preferred embodiment, the V is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -; the V is optionally substituted by Rv, and Rv is oxo (=O).

[0107] In a preferred embodiment, the R 1 is H, halogen, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy,

[0108] the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy is optionally substituted by one or more R 10 ; when R 10 is plural, the R 10 are the same or different.

[0109] In a preferred embodiment, the R 10 is F, Cl, -OH.

[0110] In a preferred embodiment, R 1 is H, F, Cl, CN, C1 -C 3 alkyl, said C 1 -C 3 alkyl is optionally substituted by one or more -OH.

[0111] In a preferred embodiment,

[0112] In a preferred embodiment, R 1 is H, F, Cl, CN, -CH(OH)-CH 2 (OH),

[0113] In a preferred embodiment, the compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is selected from:

[0114]

[0115]

[0116]

[0117]

[0118]

[0119] The present invention also provides a pharmaceutical composition comprising any of the compounds, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs as described above, and a pharmaceutically acceptable carrier.

[0120] The present invention also provides the use of a compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as described above, 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:

[0121] Preparing a drug, pharmaceutical composition or preparation for preventing and / or treating a disease associated with increased TEAD expression; and / or,

[0122] Preparing a drug, pharmaceutical composition or preparation for reducing / inhibiting TEAD expression and increased TEAD activity; and / or,

[0123] Preparing a drug, pharmaceutical composition or preparation for reducing / inhibiting the Hippo signaling pathway.

[0124] In a preferred embodiment, the TEAD includes: TEAD1, TEAD2, TEAD3 and TEAD4.

[0125] In a preferred embodiment, the disease is a cell proliferative disorder.

[0126] In a preferred embodiment, the cell proliferative disorder is cancer.

[0127] In a preferred embodiment, the disease is selected from: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute granulocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic leukemia), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial carcinoma, cervical cancer, chondrosarcoma, soft tissue sarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic granulocytic leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysplastic changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, 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, 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, myelogenous 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, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenström macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

[0128] Preferably, the disease is selected from: mesothelioma, soft tissue sarcoma, meningioma, glioma, lung cancer.

[0129] 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 tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug, or the pharmaceutical composition.

[0130] In a preferred embodiment of the present invention, the disease is a disease associated with increased TEAD expression. The TEAD includes: TEAD1, TEAD2, TEAD3, and TEAD4.

[0131] In a preferred embodiment of the present invention, the disease is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.

[0132] In a preferred embodiment of the present invention, the disease is the disease described in the third aspect.

[0133] In some embodiments, the patient is a mammal, preferably a human.

[0134] Additional aspects and advantages of the present invention will be given in part in the following description, become apparent in part from the following description, or be learned through the practice of the present invention.

[0135] Terms and Definitions

[0136] Unless otherwise specified, the definitions of groups and terms recited in the specification and claims of this application, including their definitions by way of example, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in examples, etc., can be combined and combined with each other arbitrarily. The group definitions and compound structures after such combination and combination should fall within the scope described in the specification of this application.

[0137] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art to which the claimed subject matter belongs. Unless otherwise stated, all patents, patent applications, and published materials cited herein in their entirety are incorporated herein by reference. If there are multiple definitions of a term in this article, the definitions in this chapter shall prevail.

[0138] It should be understood that the above summary and the following detailed description are exemplary and for explanatory purposes only, and do not impose any limitation on the subject matter of the present invention. In this application, unless otherwise specifically stated, the singular also includes the plural when used. It must be noted that unless clearly stated otherwise 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 terms "or" or "either...or" mean "and / or". In addition, the terms "comprising" and other forms, such as "including", "containing", and "having" are not restrictive.

[0139] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED.", Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise specified, conventional methods within the scope of the art are employed, such as mass spectrometry, NMR, IR, and UV / VIS spectroscopy, and pharmacological methods. Unless a specific definition is provided, the terms used in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry herein are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and the treatment of patients. For example, the instructions of the manufacturer for the kits can be utilized, or the reactions and purifications can be carried out in a manner known in the art or as described in the present invention. Generally, the above-mentioned techniques and methods can be implemented according to the descriptions in a number of general and more specific documents cited and discussed in this specification, in accordance with the conventional methods well-known in the art. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0140] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, CH 2 O is equivalent to OCH 2 . As used herein, represents the attachment site of a group. As used herein, "R 1 ", "R1", and "R 1 " have the same meaning and can be used interchangeably. For other symbols such as R 2 , other similarly defined symbols have the same meaning.

[0141] The section headings used herein are for the purpose of organizing the article only and should not be construed as limiting 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 of operations, and theses, are hereby incorporated by reference in their entirety.

[0142] Except as aforesaid, when used in the specification and claims of this application, unless otherwise specifically indicated, the following terms have the meanings shown below.

[0143] For the numerical ranges recited in the specification and claims of this application, when the numerical range is understood as "integers", it should be understood that the two endpoints of the range and each integer within the range are recited. For example, "integers from 0 to 5" should be understood as reciting each of 0, 1, 2, 3, 4, and 5.

[0144] In the present application, the term "halogen", when alone or as part of another substituent, refers to fluorine, chlorine, bromine, or iodine.

[0145] As used herein, the term "alkyl", when alone or as part of another substituent, means a straight-chain or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing no unsaturated bonds, having, for example, 1 to 6 carbon atoms, and being 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. The alkyl group may be unsubstituted or substituted with one or more suitable substituents. The alkyl group may also be an isotopologue of a naturally occurring alkyl group enriched in carbon and / or hydrogen isotopes (i.e., deuterium or tritium). As used herein, the term "alkenyl" denotes 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.

[0146] When alone or as part of another substituent, the term "C 1 -C 6 alkyl" should be understood to represent a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, 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, etc., or their isomers. The term "C 1 -C 3 alkyl" should be understood to represent a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, or 3 carbon atoms. In particular, the group has 1, 2, or 3 carbon atoms ("C 1 -C 3 alkyl"), such as methyl, ethyl, n-propyl, or isopropyl.

[0147] When alone or as part of another substituent, the term "C 2 -C 6 alkenyl" should be understood to represent a straight-chain or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, or 6 carbon atoms. For example, having 2 or 3 carbon atoms (i.e., C 2 -C 3(alkenyl). It should be understood that when the alkenyl contains more than one double bond, the double bonds can be separated or conjugated with each other. 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-methylbut-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.

[0148] The term "C 2 -C 6 alkynyl" should be understood to denote a straight-chain or branched monovalent hydrocarbon group that contains one or more triple bonds and has 2, 3, 4, 5, or 6 carbon atoms. For example, having 2 or 3 carbon atoms ("C 2 -C 3"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, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0149] The term "C 1 -C 6 alkoxy" should be understood to mean a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms and an oxygen atom, or represented as C 1 -C 6 alkyl-O-. The definition of C 1 -C 6 alkyl is as described in this specification, and the oxygen atom can be attached to any carbon atom of the straight-chain or straight-chain of C 1 -C 6 alkyl. Including but not limited to: methoxy (CH 3 -O-), ethoxy (C 2 H 5 -O-), propoxy (C 3 H 7 -O-), butoxy (C 4 H 9 -O-), pentyloxy (C 5 H 11 -O-), hexyloxy (C 6 H 13 -O-).

[0150] When alone or as part of other substituents, the term "ring" includes carbocyclic rings and heterocyclic rings, which can be saturated, unsaturated or partially unsaturated rings. The rings include heterocycloalkyl, cycloalkyl, aryl, heteroaryl, etc. For example, the term "4- to 7-membered ring" refers to the above-mentioned rings composed of 4, 5, 6 or 7 atoms.

[0151] When alone or as part of other substituents, the term "heteroaryl" or "heteroaromatic ring" or "heteroaryl group" refers to a monocyclic or polycyclic aromatic ring system. In certain embodiments, 1 to 3 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, "5- to 6-membered heteroaromatic ring" refers to an aromatic ring system containing heteroatoms and having 5 or 6 atoms. Examples of heteroaromatic rings include but are not limited to: furyl, imidazolyl, dihydroindolyl, pyrrolidinyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl, quinolinyl and isoquinolinyl. The heteroaryl group may be optionally fused to a benzene ring and may also be monocyclic, bicyclic, tricyclic, spirocyclic or bridged.

[0152] When alone or as part of other substituents, the term "halo" can be used interchangeably with the term "halogen substitution". "Haloalkyl" or "halogen-substituted alkyl" refers to a branched or straight-chain saturated aliphatic hydrocarbon group containing a specific number of carbon atoms and substituted by one or more halogens (such as -CvFw, where v = 1 to 3 and w = 1 to (2v + 1)). Examples of haloalkyls include but are not limited to trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl and heptachloropropyl.

[0153] The compounds provided herein, including intermediates useful for preparing the compounds provided herein, contain reactive functional groups (such as but not limited to carboxyl, hydroxyl and amino moieties), and also include their protected derivatives. "Protected derivatives" are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also called protecting groups). Suitable protecting groups for carboxyl moieties include benzyl, tert-butyl, etc., as well as isotopes, etc. Suitable protecting groups for amino and amine groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for hydroxyl groups include benzyl, etc. Other suitable protecting groups are well known to those of ordinary skill in the art.

[0154] In this application, "optional" or "optionally" means that the subsequent described event or condition may or may not occur, and this description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl is substituted or unsubstituted, and this description includes both the substituted aryl and the unsubstituted aryl.

[0155] In the present application, the terms "salt" or "pharmaceutically acceptable salt" include 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, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0156] "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 maintain the biological effectiveness of the free acid without other side effects. In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts. They can serve as intermediates in the purification of the compound or in the preparation of other pharmaceutically acceptable salts or can be used for the identification, characterization, or purification of the compounds of the present invention.

[0157] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereoisomers, and conformational isomers.

[0158] Depending on the choice of starting materials and methods, the compounds of the present invention can exist in the form of one or a mixture of the possible isomers, for example as pure enantiomers, or as a mixture of isomers, such as a racemic and diastereoisomeric 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(s) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the rotation of plane-polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory.

[0159] When depicting the bonds to chiral carbons in the formulas of the present invention as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures thereof are included within the scope of the general formula. The graphical representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114 - 120. The absolute configuration of a stereocenter is represented by wedge and dashed bonds.

[0160] The term "tautomer" refers to functional group isomers resulting from the rapid movement of a particular atom within a molecule between two locations. The compounds of the present invention may exhibit tautomerism. Tautomers of a compound can exist in two or more interconvertible forms. Prototropic tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in an equilibrium form, and attempting to isolate a single tautomer usually results in a mixture whose physical and chemical properties are consistent with those of a mixture of the compounds. The position of the equilibrium depends on the chemical characteristics 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.

[0161] In the present application, a "pharmaceutical composition" refers to a preparation of a compound of the present invention and a medium commonly accepted in the art for delivering a bioactive compound to a mammal (such as a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to an organism, promote absorption of the active ingredient, and thereby exert its biological activity.

[0162] In the present application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that has been approved by the relevant government regulatory authorities for use in humans or livestock.

[0163] In the present application, the term "solvate" refers to a compound of the present invention or its salt that includes a stoichiometric or non-stoichiometric amount of a solvent bound by intermolecular non-covalent forces, and when the solvent is water, it is a hydrate.

[0164] In the present application, the term "prodrug" refers to a compound that can be converted under physiological conditions or by solvolysis into a bioactive compound of the present invention. The prodrugs of the present invention are prepared by modifying a functional group in the compound, and such modification can be removed by conventional operations or in vivo to obtain the parent compound. Prodrugs include compounds formed by attaching a hydroxyl group or an amino group in the compound of the present invention to any group. When a prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group, respectively.

[0165] The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. For example, a compound can be labeled with a radioactive isotope, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14C). All isotopic composition transformations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0166] In the present application, the term "excipient" refers to a pharmaceutically inert ingredient. Non-limiting examples of the types of "excipients" include binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of pharmaceutical formulations, i.e., make the formulations more suitable for direct compression by increasing fluidity and / or adhesiveness.

[0167] As used herein, the terms "treatment" and other similar synonyms include the following meanings:

[0168] (i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such a mammal is susceptible to the disease or disorder but has not been diagnosed as having the disease or disorder;

[0169] (ii) Inhibiting a disease or disorder, i.e., curbing its development;

[0170] (iii) Alleviating a disease or disorder, i.e., causing the state of the disease or disorder to subside; or

[0171] (iv) Relieving the symptoms caused by the disease or disorder.

[0172] For the reactions of each step, 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, purified, etc. from the reaction system by common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography, etc. Without affecting the next reaction, the target compound can also directly enter the next 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 solvents include but are 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.

[0173] Advantageous Effects

[0174] After extensive and in-depth research, the present inventors unexpectedly developed a heterocyclic-containing TEAD inhibitor, and the TEAD inhibitor is a compound represented by Formula I' or Formula I of the present invention. The compound can significantly inhibit the activity of TEAD transcription and can be used for preventing and / or treating diseases related to increased TEAD expression. Detailed Embodiments

[0175] The present invention will be further described below in conjunction with specific embodiments. It should be understood that the following description is only the most preferred embodiment of the present invention and should not be considered as a limitation on the protection scope of the present invention. On the basis of fully understanding the present invention, for the experimental methods without specific conditions noted in the following embodiments, they are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Those skilled in the art can make non-essential modifications to the technical solutions of the present invention, and such modifications should be regarded as being included in the protection scope of the present invention.

[0176] Example 1: Preparation of Compound I-1

[0177] The synthetic route is as follows:

[0178]

[0179] First step: Synthesis of 2-oxo-1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-1'-carboxylic acid 2-methylpropyl ester (1-2)

[0180]

[0181] Dissolve 2-oxo-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-1'-carboxylic acid 2-methylpropyl ester (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), then add triethylamine (1.26 g, 12.5 mmol), and stir at room temperature overnight under an oxygen balloon. After the reaction is completed, filter the reaction solution through diatomaceous earth, wash the filter cake with dichloromethane (40 mL), combine the filtrates, wash with water (15 mL), and then dry with anhydrous sodium sulfate. After concentrating the organic phase, purify by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain compound 2-oxo-1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-1'-carboxylic acid 2-methylpropyl ester (1-2) (1.16 g, yield: 85.6%).

[0182] LC-MS, M / Z (ESI): 433.2 [M+H] + .

[0183] Second step: Synthesis of 1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-2-one hydrochloride (1-3)

[0184]

[0185] Dissolve 2-oxo-1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-1'-carboxylic acid 2-methylpropan-2-yl ester (1-2) (1.16 g, 2.68 mmol) in 1,4-dioxane (20 mL), then add a 1,4-dioxane solution of hydrogen chloride (4 M, 20 mL), and stir at room temperature overnight. Concentrate the reaction solution to obtain compound 1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-2-one hydrochloride (1-3) (0.99 g, yield 100.0%), which is directly used in the next step of the reaction.

[0186] LC-MS, M / Z (ESI): 333.1 [M+H] + 。

[0187] 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)

[0188]

[0189] Dissolve 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) in N,N-dimethylformamide (7 mL), add 2-fluoroacrylic acid (62 mg, 0.69 mmol), then add 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (354 mg, 0.93 mmol) and N,N-diisopropylethylamine (322 mg, 2.49 mmol), and react at 40 °C overnight. After the reaction is completed, add water (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify 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%).

[0190] LC-MS, M / Z (ESI): 405.1 [M+H] + 。

[0191] Example 2: Preparation of Compound I-2

[0192] The synthetic route is as follows:

[0193]

[0194] The first step: 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)

[0195]

[0196] Dissolve 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) in tetrahydrofuran (10 mL). Add saturated aqueous sodium bicarbonate solution (3 mL) at 0 °C, stir at 0 °C for 10 minutes, add acryloyl chloride (100.7 mg, 1.11 mmol), and continue the reaction at 0 °C for 0.5 hour. After the reaction is completed, add water (10 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to obtain the 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%).

[0197] LC-MS, M / Z (ESI): 387.1 [M+H] + .

[0198] 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.95 (dd, 2H), 7.76 (dd, 2H), 7.46 (dd, 1H), 7.33–7.26 (m, 1H), 7.16 (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).

[0199] Preparation of Compound I-3 in Example 3

[0200] The synthetic route is as follows:

[0201]

[0202] Step 1: Synthesis of 3-[[(3-bromopyridin-2-yl)amino]carbonyl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (3-2)

[0203]

[0204] Place 3-bromopyridin-2-amine (3-1) (3.0 g, 17.4 mmol) in a reaction flask. Under argon protection, add anhydrous acetonitrile (20 mL). At room temperature, add N,N,N',N'-tetramethylchloroformamidinium 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). Stir the reaction mixture at 45 °C for 16 h. After the reaction is completed, remove the solvent by distillation under reduced pressure. Then add ethyl acetate (200 mL) to the reaction mixture, wash it with saturated sodium chloride (200 mL × 3). Take the organic phase, dry it over anhydrous sodium sulfate, filter and concentrate. Purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain 3-[[(3-bromopyridin-2-yl)amino]carbonyl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (3-2) (4.55 g, yield: 71%).

[0205] LC-MS, M / Z (ESI): 370.1 [M+H] + 。

[0206] Step 2: Synthesis of 3-[[(3-bromopyridin-2-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (3-3)

[0207]

[0208] Place the compound 3-[[(3-bromopyridin-2-yl)amino]carbonyl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (3-2) (4.2 g, 11.35 mmol) in a reaction flask, add N,N-dimethylformamide (50 mL), and add sodium hydride (0.91 g, 22.7 mmol, 60 wt%) under an ice bath. After stirring for 15 min, add 4-methoxybenzyl chloride (2.7 g, 17 mmol), and allow the reaction solution to react at room temperature for 2 h. Quench the reaction by adding water (2 mL) to the reaction solution under an ice bath, then add ethyl acetate (300 mL) to the reaction solution, and wash it with saturated sodium chloride aqueous solution (300 mL × 3). Take the organic phase, dry it over anhydrous sodium sulfate, filter and concentrate it. The crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain the compound 3-[[(3-bromopyridin-2-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (3-3) (1.87 g, yield: 34%).

[0209] LC-MS, M / Z(ESI): 490.2[M+H] + 。

[0210] Step 3: Synthesis of 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)

[0211]

[0212] Place the compound 3-[[(3-bromopyridin-2-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (3-3) (1.6 g, 3.4 mmol) in a reaction flask, add [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), then add toluene (5 mL), and carry out a microwave reaction at 110 °C for 3 h under argon protection. After the reaction is completed, cool the reaction solution to room temperature, add ethyl acetate (200 mL), and wash it with saturated sodium chloride aqueous solution (200 mL × 3). Dry the organic phase over anhydrous sodium sulfate, filter and concentrate it. The crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain the 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-methylpropan-2-yl ester (3-4) (1.0 g, yield: 75%).

[0213] LC-MS, M / Z(ESI): 410.7 [M+H] + 。

[0214] 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)

[0215]

[0216] Place 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) in a reaction flask, add methanesulfonic acid (1 mL), and react at 45 °C for 4 h. Drop the above crude product into saturated sodium carbonate solution (5 mL), then add sodium bicarbonate (200 mg) and acetonitrile (5 mL), and then add acryloyl chloride (64 mg, 0.6 mmol) at 0 °C. Stir the reaction solution at 0 °C for 15 min. After the reaction is completed, concentrate the reaction solution under reduced pressure to remove acetonitrile, then extract with ethyl acetate (50 mL). Wash the organic phase with saturated sodium chloride aqueous solution (50 mL × 3), dry over anhydrous sodium sulfate, filter and concentrate. Purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain 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%).

[0217] LC-MS, M / Z(ESI): 244.3 [M+H] + 。

[0218] 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)

[0219]

[0220] 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(II) acetate (80 mg, 0.4 mmol), 4-(trifluoromethyl)phenylboronic acid (47 mg, 0.247 mmol) were placed in a reaction flask, acetonitrile (4 mL), pyridine (64 mg, 0.8 mmol) were added, and the reaction was carried out at 45 °C for 3 h under an oxygen atmosphere. The reaction mixture 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 obtain 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%).

[0221] LC-MS, M / Z (ESI): 388.2 [M+H] + 。

[0222] 1 1H NMR (400 MHz, DMSO-d 6 6): δ 8.23–8.14 (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).

[0223] Example 4 Preparation of Compound I-4

[0224] The synthetic route is as follows:

[0225]

[0226] The first step: Synthesis of tert-butyl 3-[[(2-bromopyridin-3-yl)amino]carbonyl]pyrrolidine-1-carboxylate (4-2)

[0227]

[0228] Place 2-bromopyridin-3-amine (4-1) (3.0 g, 17.4 mmol) in a reaction flask. Under argon protection, add anhydrous acetonitrile (20 mL). At room temperature, add N,N,N',N'-tetramethylchloroformamidinium 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), and stir at 45 °C for 16 h. Cool the reaction mixture to room temperature, distill off the solvent under reduced pressure. Subsequently, dilute the reaction mixture with ethyl acetate (200 mL), wash it with saturated aqueous sodium chloride solution (200 mL×3). Take the organic phase, dry it over anhydrous sodium sulfate, filter and concentrate. The crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=3:1) to obtain 3-[[(2-bromopyridin-3-yl)amino]carbonyl]tetrahydro-1H-pyrrole-1-carboxylic acid 2-methylpropan-2-yl ester (4-2) (5.10 g, yield: 79%).

[0229] LC-MS, M / Z(ESI): 370.0 [M+H] + 。

[0230] Step 2: Synthesis of 3-[[(2-bromopyridin-3-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]tetrahydro-1H-pyrrole-1-carboxylic acid 2-methylpropan-2-yl ester (4-3)

[0231]

[0232] Place 3-[[(2-bromopyridin-3-yl)amino]carbonyl]tetrahydro-1H-pyrrole-1-carboxylic acid 2-methylpropan-2-yl ester (4-2) (3.0 g, 8.11 mmol) in a reaction flask, add N,N-dimethylformamide (35 mL). Subsequently, add cesium carbonate (5.3 g, 16.22 mmol) under ice bath, stir for 15 min, then add 4-methoxybenzyl chloride (1.93 g, 12.14 mmol). After addition, react at 45 °C for 4 h. Dilute the reaction mixture with ethyl acetate (300 mL), wash it with saturated aqueous sodium chloride (300 mL×3). Take the organic phase, dry it over anhydrous sodium sulfate, filter and concentrate. The crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=5:1) to obtain 3-[[(2-bromopyridin-3-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]tetrahydro-1H-pyrrole-1-carboxylic acid 2-methylpropan-2-yl ester (4-3) (3.25 g, yield: 82%).

[0233] LC-MS, M / Z(ESI): 490.1 [M+H] + 。

[0234] Step 3: Synthesis of 2-methylpropan-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)

[0235]

[0236] Place 2-methylpropan-2-yl 3-[[(2-bromopyridin-3-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]pyrrolidine-1-carboxylate (4-3) (1.6 g, 3.4 mmol) in a reaction flask, add 10 wt% of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)palladium(II) dichloride (0.16 g, CAS: 905459-27-0), sodium tert-butoxide (464 mg, 5.1 mmol), and then add toluene (5 mL). React under microwave irradiation at 110 °C for 3 h under argon protection. Cool the reaction solution to room temperature, add ethyl acetate (500 mL), and then wash with saturated aqueous sodium chloride solution (500 mL × 3). Dry the organic phase over anhydrous sodium sulfate, filter and concentrate. Purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain 2-methylpropan-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) (0.95 g, yield: 72%).

[0237] LC-MS, M / Z (ESI): 410.4 [M+H] + 。

[0238] 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)

[0239]

[0240] Place 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) in a reaction flask, add methanesulfonic acid (3 mL), and stir at 45 °C for 4 h. Drop the above crude product into saturated sodium carbonate solution (5 mL), then add sodium bicarbonate (400 mg) and acetonitrile (5 mL), and subsequently add acryloyl chloride (425 mg, 4.0 mmol) at 0 °C. Stir the reaction solution at 0 °C for 15 min. Concentrate the reaction solution under reduced pressure to remove acetonitrile, then extract with ethyl acetate (100 mL), wash with saturated aqueous sodium chloride solution (100 mL × 3), dry the organic phase over sodium sulfate, filter and concentrate, and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain 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%).

[0241] LC-MS, M / Z (ESI): 244.3 [M+H] + 。

[0242] 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)

[0243]

[0244] 1-(1-Oxoprop-2-enyl)-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[3,2-b]pyridine]-2'-one (4-5) (330 mg, 1.63 mmol), copper(II) acetate (480 mg, 2.44 mmol), and 4-(trifluoromethyl)phenylboronic acid (370 mg, 1.96 mmol) were placed in a reaction flask, and acetonitrile (10 mL), pyridine (520 mg, 6.4 mmol) were added. The reaction was carried out at 45 °C for 24 h under an oxygen atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) for extraction, washed with saturated aqueous sodium chloride solution (200 mL × 3), 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%).

[0245] LC-MS, M / Z (ESI): 388.1 [M+H] + 。

[0246] 1 1H NMR (400 MHz, DMSO-d 6 6): δ 8.30–8.27 (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).

[0247] Example 5: Preparation of Compound I-5

[0248] The synthetic route is as follows:

[0249]

[0250] First step: Synthesis of compound 1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole] (5-2)

[0251]

[0252] Dissolve 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) in anhydrous tetrahydrofuran (1 mL), stir for 15 min under ice bath conditions, then slowly add sodium borohydride (13 mg, 0.35 mmol). After addition, continue to stir in the ice bath for 15 min, then add iodine (34 mg, 0.14 mmol), and slowly warm the reaction solution to 40 °C and stir for 8 h. After LCMS shows that the raw material has completely reacted, stop stirring, slowly pour the reaction solution into ice water (2 mL) to quench the reaction, and the obtained mixed solution is directly used for the next reaction.

[0253] LC-MS, M / Z(ESI): 319.1[M+H] + 。

[0254] Step 2: Synthesis of compound 1-[1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-1'-yl]prop-2-en-1-one (I-5)

[0255]

[0256] Add sodium bicarbonate (23 mg, 0.27 mmol) to the mixed solution obtained in the previous step, stir for 15 min under ice bath conditions, then slowly add acryloyl chloride (25 mg, 0.27 mmol), continue to stir the reaction solution under ice bath conditions for 15 min, and then slowly warm it to room temperature and stir for 15 min. After LCMS monitoring shows that the reaction is complete, stop stirring, add water (5 mL) to dilute the reaction solution, extract with ethyl acetate (3 mL × 5), collect the organic phase and dry it with anhydrous sodium sulfate, concentrate the organic phase by rotary evaporation under reduced pressure, and purify the residue 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[indole-3,3'-pyrrole]-1'-yl]prop-2-en-1-one (I-5) (12 mg).

[0257] LC-MS, M / Z(ESI): 373.1[M+H] + 。

[0258] 1 H NMR(400MHz, DMSO-d 6δ 7.66 (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).

[0259] Preparation of Compound I-6 in Example 6

[0260] The synthetic route is as follows:

[0261]

[0262] First step: Synthesis of 3-[[(3-bromopyrazin-2-yl)amino]carbonyl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (6-2)

[0263]

[0264] Place 3-bromopyrazin-2-amine (6-1) (3.0 g, 17.2 mmol) in a reaction flask. Under argon protection, add anhydrous acetonitrile (20 mL), N,N,N',N'-tetramethylchloroformamidinium 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). Stir the reaction mixture at 45 °C for 16 h. Distill off the solvent under reduced pressure. Then dilute the reaction mixture with ethyl acetate (200 mL), wash with saturated aqueous sodium chloride solution (200 mL × 3). Take the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain 3-[[(3-bromopyrazin-2-yl)amino]carbonyl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (6-2) (4.30 g, yield: 67%).

[0265] LC-MS, M / Z (ESI): 371.3 [M+H] + .

[0266] Second step: Synthesis of 3-[[(3-bromopyrazin-2-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (6-3)

[0267]

[0268] Place the compound (3-[[(3-bromopyrazin-2-yl)amino]carbonyl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (6-2) (2.3 g, 6.20 mmol)) in a reaction flask, add N,N-dimethylformamide (27 mL), and then add cesium carbonate (4.1 g, 12.42 mmol) under an ice bath. After stirring for 15 min, add 4-methoxybenzyl chloride (1.48 g, 9.3 mmol), and react at 45 °C for 4 h. Cool the reaction solution to room temperature, dilute it with ethyl acetate (300 mL), then wash it with saturated sodium chloride aqueous solution (300 mL × 3). Take the organic phase, dry it over anhydrous sodium sulfate, concentrate it under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain the compound 3-[[(3-bromopyrazin-2-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (6-3) (1.87 g, yield: 61%).

[0269] LC-MS, M / Z(ESI): 491.2[M+H] + 。

[0270] Step 3: Synthesis of 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-methylpropan-2-yl ester (6-4)

[0271]

[0272] Place the compound 3-[[(3-bromopyrazin-2-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (6-3) (1.87 g, 3.80 mmol) in a reaction flask, add 10 wt% of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)palladium dichloride (0.19 g), sodium tert-butoxide (550 mg, 5.7 mmol), then add toluene (6 mL), and react under microwave irradiation at 110 °C for 3 h under argon protection. After completion, dilute the reaction solution with ethyl acetate (500 mL), wash it with saturated sodium chloride aqueous solution (500 mL × 3), dry the organic phase over anhydrous sodium sulfate, concentrate it under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain the 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-methylpropan-2-yl ester (6-4) (0.84 g, yield: 56%).

[0273] LC-MS, M / Z(ESI): 411.3 [M+H] + 。

[0274] 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)

[0275]

[0276] Place the 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-methylpropan-2-yl ester (6-4) (240 mg, 0.58 mmol) in a reaction flask, add methanesulfonic acid (1 mL), and react at 45 °C for 4 h. After completion, add the above crude product dropwise to saturated sodium carbonate solution (5 mL), then add sodium bicarbonate (400 mg) and acetonitrile (6 mL), and subsequently add acryloyl chloride (108 mg, 1.2 mmol) at 0 °C. The reaction solution is reacted at 0 °C for 15 min. After completion, the reaction solution is concentrated to remove acetonitrile, then diluted with ethyl acetate (100 mL), washed with saturated sodium chloride aqueous solution (100 mL × 3), the organic phase is dried over sodium sulfate, filtered and concentrated, and the crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain the 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%).

[0277] LC-MS, M / Z(ESI): 245.1 [M+H] + 。

[0278] 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)

[0279]

[0280] 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(II) acetate (147 mg, 0.74 mmol), 4-(trifluoromethyl)phenylboronic acid (112 mg, 0.588 mmol) were placed in a reaction flask, acetonitrile (5 mL) and pyridine (160 mg, 2.0 mmol) were added, and the reaction was carried out at 45 °C for 24 h under an oxygen atmosphere. 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%).

[0281] LC-MS, M / Z (ESI): 389.0 [M+H] + 。

[0282] 1 1H NMR (400 MHz, DMSO-d 6 6): δ 8.30 (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).

[0283] Example 7 Preparation of Compound I-7

[0284] The synthetic route is as follows:

[0285]

[0286] First step: Synthesis of compound tert-butyl 4-((2-bromopyridin-3-yl)carbamoyl)piperidine-1-carboxylate (7-1)

[0287]

[0288] Place 2-bromopyridin-3-amine (4-1) (3.0 g, 17.4 mmol) in a reaction flask, add anhydrous acetonitrile (20 mL), and at room temperature, add N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (7.35 g, 26.2 mmol), 1-methylimidazole (3.6 g, 45 mmol), and 1-Boc-4-piperidinecarboxylic acid (4.78 g, 20.88 mmol). Stir the reaction mixture at 45 °C for 16 h under nitrogen protection. After the reaction is complete, remove the solvent by distillation under reduced pressure. Then, dilute the reaction mixture with ethyl acetate (200 mL), wash it with saturated aqueous sodium chloride (200 mL × 3), take the organic phase, dry it over anhydrous sodium sulfate, concentrate it, and purify it 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%).

[0289] LC-MS, M / Z (ESI): 384.1 [M+H] + 。

[0290] Step 2: Synthesis of tert-butyl 4-((2-bromopyridin-3-yl)(4-methoxybenzyl)carbamoyl)piperidine-1-carboxylate (7-2)

[0291]

[0292] Place the intermediate tert-butyl 4-((2-bromopyridin-3-yl)carbamoyl)piperidine-1-carboxylate (7-1) (3.0 g, 7.83 mmol) in a reaction flask, add N,N-dimethylformamide (35 mL). Then, add cesium carbonate (5.3 g, 16.22 mmol) under an ice bath, stir for 15 min, and then add 4-methoxybenzyl chloride (1.64 g, 10.3 mmol). After addition, react at 45 °C for 4 h. Then, dilute the reaction mixture with ethyl acetate (300 mL), wash it with saturated aqueous sodium chloride (300 mL × 3), take the organic phase, dry it over anhydrous sodium sulfate, concentrate it, and purify the crude product 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%).

[0293] LC-MS, M / Z (ESI): 504.1 [M+H] + 。

[0294] Step 3: Synthesis of tert-butyl 1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (7-3)

[0295]

[0296] tert-Butyl 1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydros piro[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (7-3) (0.88 g, yield: 65%) was obtained by placing tert-butyl 4-(((2-bromopyridin-3-yl)(4-methoxybenzyl)carbamoyl)piperidine-1-carboxylate (7-2) (1.6 g, 3.2 mmol) in a reaction flask, adding 10 wt% of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)palladium(II) dichloride (0.16 g, CAS: 905459-27-0), sodium tert-butoxide (464 mg, 5.1 mmol), and then adding toluene (5 mL), and carrying out a microwave reaction at 110 °C for 3 h under an argon atmosphere. 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).

[0297] LC-MS, M / Z (ESI): 424.3 [M+H] + 。

[0298] Step 4: Synthesis of tert-butyl 2'-oxo-1',2'-dihydros piro[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (7-4)

[0299]

[0300] tert-Butyl 2'-oxo-1',2'-dihydros piro[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (7-4) (284 mg, yield: 45%) was obtained by placing tert-butyl 1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydros piro[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (7-3) (880 mg, 2.08 mmol) in a reaction flask, adding trifluoromethanesulfonic acid (3 mL), and reacting at 45 °C for 4 h. After completion, the above reaction solution was added dropwise to saturated sodium carbonate solution (5 mL) to adjust the pH to 7, then sodium bicarbonate (400 mg) and acetonitrile (5 mL) were added, and then 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, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1).

[0301] LC-MS, M / Z(ESI): 304.1 [M+H] + 。

[0302] Step 5: Synthesis of tert-butyl 2-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (7-5)

[0303]

[0304] 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), copper(I) 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, and acetonitrile (5 mL) was added. The reaction was carried out under microwave irradiation at 100 °C for 1.5 h under an argon atmosphere. After completion, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium chloride solution (200 mL × 3). The organic phase was dried over Na 2 SO 4 and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain tert-butyl 2-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (7-5) (355 mg, yield: 87%).

[0305] LC-MS, M / Z(ESI): 448.2 [M+H] + 。

[0306] Step 5: Synthesis of 1-acryloyl-1'-(4-(trifluoromethyl)phenyl)spiro[piperidine-4,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (I-7)

[0307]

[0308] tert-Butyl 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%) was obtained by placing tert-butyl 2-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate (7-5) (200 mg, 0.45 mmol) in a reaction flask, adding trifluoroacetic acid (3 mL), and reacting at room temperature for 1 h. After detecting the completion of the reaction, the above reaction solution was added dropwise to saturated sodium carbonate solution (3 mL), the pH of the reaction solution was adjusted to 7, then sodium bicarbonate (300 mg) and acetonitrile (3 mL) were added, and then acryloyl chloride (180 mg, 2.0 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 and water, and then the residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1).

[0309] LC-MS, M / Z (ESI): 402.1 [M + H] + 。

[0310] 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.27 (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).

[0311] Preparation of Compound I-8 in Example 8

[0312] The synthetic route is as follows:

[0313]

[0314] First step: Synthesis of tert-butyl 3-((2-bromopyridin-3-yl)carbamoyl)azetidine-1-carboxylate (8-1)

[0315]

[0316] 2-Bromopyridin-3-amine (4-1) (3.0 g, 17.4 mmol) was placed in a reaction flask, dry acetonitrile (20 mL) was added, and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (7.35 g, 26.2 mmol), 1-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 mixture was stirred at 45 °C for 16 h under nitrogen protection. After the reaction was completed, the solvent was removed by distillation under reduced pressure. Subsequently, the reaction mixture was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride (200 mL × 3), the organic phase was taken, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain tert-butyl 3-((2-bromopyridin-3-yl)carbamoyl)azetidine-1-carboxylate (8-1) (5.13 g, yield: 83%).

[0317] LC-MS, M / Z (ESI): 356.1 [M+H] + 。

[0318] Step 2: Synthesis of tert-butyl 3-((2-bromopyridin-3-yl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate (8-2)

[0319]

[0320] tert-Butyl 3-((2-bromopyridin-3-yl)carbamoyl)azetidine-1-carboxylate (8-1) (3.0 g, 8.42 mmol) was placed in a reaction flask, N,N-dimethylformamide (35 mL) was added, and then cesium carbonate (5.3 g, 16.22 mmol) was added under ice bath. After stirring for 15 min, 4-methoxybenzyl chloride (1.64 g, 10.3 mmol) was added. After the addition was complete, the reaction mixture was stirred at 45 °C for 4 h. Subsequently, the reaction mixture was diluted with ethyl acetate (300 mL), washed with saturated sodium chloride (300 mL × 3), the organic phase was taken, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain tert-butyl 3-((2-bromopyridin-3-yl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate (8-2) (2.89 g, yield: 72%).

[0321] LC-MS, M / Z (ESI): 476.1 [M+H] + 。

[0322] Step 3: Synthesis of tert-butyl 1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (8-3)

[0323]

[0324] Place tert-butyl 3-((2-bromopyridin-3-yl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate (8-2) (1.6 g, 3.4 mmol) in a reaction flask, add 10 wt% of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)palladium(II) dichloride (0.16 g, CAS: 905459-27-0), sodium tert-butoxide (464 mg, 5.1 mmol), and then add toluene (5 mL). React under microwave irradiation at 110 °C for 3 h under argon protection. After completion, dilute the reaction solution with ethyl acetate (500 mL), wash with saturated aqueous sodium chloride solution (500 mL × 3), dry the organic phase over anhydrous sodium sulfate, concentrate, and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain tert-butyl 1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (8-3) (0.56 g, yield: 42%).

[0325] LC-MS, M / Z (ESI): 396.2 [M+H] + 。

[0326] Step 4: Synthesis of tert-butyl 2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (8-4)

[0327]

[0328] tert-Butyl 1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (8-3) (560 mg, 1.41 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 above reaction solution was dropped into saturated sodium carbonate solution (5 mL). After neutralization, sodium bicarbonate (400 mg) and acetonitrile (5 mL) were added, and then di-tert-butyl dicarbonate (425 mg, 4.0 mmol) was added 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 sodium chloride aqueous solution (100 mL × 3), the organic phase was dried over sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain tert-butyl 2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (8-4) (128 mg, yield: 33%).

[0329] LC-MS, M / Z (ESI): 276.1 [M+H] + 。

[0330] Step 5: Synthesis of tert-butyl 2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (8-5)

[0331]

[0332] tert-Butyl 2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (8-4) (120 mg, 0.43 mmol), potassium carbonate (177 mg, 1.29 mmol), copper(I) iodide (97 mg, 0.86 mmol), 4-iodobenzotrifluoride (233 mg, 0.86 mmol), 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 for 1.5 h under an argon atmosphere. After completion, the reaction solution was diluted with ethyl acetate (200 mL), washed with saturated sodium chloride aqueous solution (200 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain 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, yield: 83%).

[0333] LC-MS, M / Z(ESI): 420.1 [M+H] + 。

[0334] 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)

[0335]

[0336] Place 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) in a reaction flask, add trifluoroacetic acid (3 mL), and react at room temperature for 1 h. After completion, drop the above reaction solution into saturated sodium carbonate solution (3 mL), adjust the pH of the reaction solution to 7, then add sodium bicarbonate (300 mg) and acetonitrile (3 mL), and subsequently add acryloyl chloride (180 mg, 2.0 mmol) at 0 °C. The reaction solution is reacted at 0 °C for 15 min. After completion, the reaction solution is concentrated to remove acetonitrile and water, and then the residue is 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%).

[0337] LC-MS, M / Z(ESI): 374.1 [M+H] + 。

[0338] 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.34 (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).

[0339] Preparation of Compound I-9 in Example 9

[0340] The synthesis route is as follows:[[]]

[0341]

[0342] tert-Butyl 2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridin]-1-carboxylate (8-5) (150 mg, 0.36 mmol) was placed in a reaction flask, and trifluoroacetic acid (3 mL) was added. The reaction was carried out at 45 °C for 4 h. After detecting the completion of the reaction, the above 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. Subsequently, 2-fluoropropionyl chloride (501 mg, 4.0 mmol) was added at 0 °C, and the reaction solution was reacted at 0 °C for 15 min. After detecting the completion of the reaction, the reaction solution was concentrated to remove acetonitrile, then diluted with ethyl acetate (100 mL), washed with saturated sodium chloride aqueous solution (100 mL × 3), the organic phase was dried over sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain 1-(2-fluoropropionyl)-1'-(4-(trifluoromethyl)phenyl)spiro(azetidine-3,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (I-9) (101 mg, yield: 72%).

[0343] LC-MS, M / Z (ESI): 392.1 [M+H] + 。

[0344] 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.34 (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).

[0345] Preparation of Compound I-10 in Example 10

[0346] The synthetic route is as follows:

[0347]

[0348] First step: Synthesis of compound 1-(2-fluoropropionyl)spiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (10-1)

[0349]

[0350] 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) (930 mg, 2.22 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 detecting the completion of the reaction, the above reaction solution was dropped into saturated sodium carbonate solution (5 mL), the pH of the reaction solution was adjusted to 7, then sodium bicarbonate (400 mg) and acetonitrile (5 mL) were added, and then 2-fluoropropionyl chloride (501 mg, 4.0 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 sodium chloride aqueous solution (100 mL×3), the organic phase was dried over sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V)=1:1) to obtain 1-(2-fluoropropionyl)spiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (10-1) (320 mg, yield: 55%).

[0351] LC-MS, M / Z (ESI): 262.1 [M+H] + 。

[0352] Step 2: Synthesis of compound 1-(2-fluoropropionyl)-1'-(4-(trifluoromethyl)phenyl)spiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (I-10)

[0353]

[0354] 1-(2-fluoropropionyl)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), 4-(trifluoromethyl)phenylboronic acid (370 mg, 1.96 mmol) were placed in a reaction flask, acetonitrile (10 mL) and pyridine (520 mg, 6.4 mmol) were added, and the reaction was carried out at 45 °C for 24 h under an oxygen atmosphere. After monitoring, the reaction solution was diluted with ethyl acetate (200 mL), washed with saturated sodium chloride aqueous solution (200 mL×3), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (V / V)=10:1) to obtain the target compound (1-(2-fluoropropionyl)-1'-(4-(trifluoromethyl)phenyl)spiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (I-10) (95 mg, yield: 19%).

[0355] LC-MS, M / Z (ESI): 406.1 [M+H] + 。

[0356] 1 H NMR (400 MHz, DMSO-d 6 ):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).

[0357] Preparation of Compound I-11 in Example 11

[0358] The synthetic route is as follows:

[0359]

[0360] Place tert-butyl 2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridin]-1-carboxylate (8-5) (150 mg, 0.36 mmol) in a reaction flask, add trifluoroacetic acid (3 mL), and react at 45 °C for 1 h. After completion, drop the above reaction solution into saturated sodium carbonate solution (5 mL). After adjusting the reaction solution to pH 7, add sodium bicarbonate (400 mg) and acetonitrile (5 mL), and then add methanesulfonyl chloride (164 mg, 1.44 mmol) at 0 °C. The reaction solution is reacted at 0 °C for 15 min. After completion, the reaction solution is concentrated to remove acetonitrile, then diluted with ethyl acetate (100 mL), washed with saturated sodium chloride aqueous solution (100 mL × 3), the organic phase is dried over sodium sulfate, concentrated, and the crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:5) to obtain 1-(methanesulfonyl)-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%).

[0361] LC-MS, M / Z (ESI): 398.0 [M+H] + 。

[0362] 1 H NMR (400 MHz, DMSO-d 6 ):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).

[0363] Preparation of Compound I-12 in Example 12

[0364] The synthetic route is as follows:

[0365]

[0366] Place tert-butyl 2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridin]-1-carboxylate (8-5) (150 mg, 0.36 mmol) in a reaction flask, add trifluoroacetic acid (3 mL), and react at 45 °C for 1 h. After completion, remove the solvent by distillation under reduced pressure. Add acetonitrile / dichloromethane (3 mL / 3 mL) under ice bath, and then successively add N,N-diisopropylethylamine (520 mg, 4.0 mmol), 4-dimethylaminopyridine (44 mg, 0.36 mmol), and methylsulfamoyl chloride (130 mg, 1.0 mmol) at 0 °C. The reaction solution is reacted at room temperature for 15 min. After completion, concentrate the reaction solution to remove the solvent, then dilute it with ethyl acetate (100 mL), wash it with saturated sodium chloride aqueous solution (100 mL × 3), dry the organic phase with sodium sulfate, concentrate it, and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:5) to obtain 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%).

[0367] LC-MS, M / Z (ESI): 413.1 [M+H] + 。

[0368] 1 1H NMR (400 MHz, DMSO): δ 8.36 (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).

[0369] Preparation of Compound I-13A in Example 13

[0370] The synthetic routes of Compounds A1 and A2 are as follows:

[0371]

[0372] First step: Synthesis of tert-butyl (3-((2-bromopyridin-3-yl)carbamoyl)cyclobutyl)carbamate

[0373]

[0374] 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'-tetramethylchloroformamidinium hexafluorophosphate (7.35 g, 26.2 mmol) and 1-methylimidazole (3.6 g, 45 mmol), and stir at 45 °C for 16 h. After the reaction is completed, concentrate the solvent under reduced pressure. Subsequently, dilute the reaction solution with ethyl acetate (200 mL), wash it with saturated aqueous sodium chloride solution (200 mL × 3), dry it over anhydrous sodium sulfate, filter and concentrate, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain tert-butyl (3-((2-bromopyridin-3-yl)carbamoyl)cyclobutyl)carbamate (5.10 g, yield: 79%).

[0375] LC-MS, M / Z(ESI): 370.0 [M+H] + 。

[0376] Step 2: Synthesis of tert-butyl (3-((2-bromopyridin-3-yl)((4-methoxyphenyl)methyl)carbamoyl)cyclobutyl)carbamate

[0377]

[0378] Place tert-butyl (3-((2-bromopyridin-3-yl)carbamoyl)cyclobutyl)carbamate (3.0 g, 8.11 mmol) in a reaction flask, add N,N-dimethylformamide (35 mL), add cesium carbonate (5.3 g, 16.22 mmol) under an ice bath, stir for 15 min, then add 4-methoxybenzyl chloride (1.93 g, 12.14 mmol), and stir the reaction solution at 45 °C for 4 h. After the reaction is completed, dilute the reaction solution with ethyl acetate (300 mL), extract it with saturated aqueous sodium chloride (300 mL × 3), dry it over anhydrous sodium sulfate, filter and concentrate, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain tert-butyl (3-((2-bromopyridin-3-yl)((4-methoxyphenyl)methyl)carbamoyl)cyclobutyl)carbamate (3.22 g, yield: 81%).

[0379] LC-MS, M / Z(ESI): 490.1 [M+H] + 。

[0380] 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)

[0381] The compound (3-((2-bromopyridin-3-yl)((4-methoxyphenyl)methyl)carbamoyl)cyclobutyl)carbamic acid tert-butyl ester (1.6 g, 3.4 mmol) was placed in a reaction bottle, 10 wt% of [1,3-bis(2,6-diisopropylphenyl)imidazole-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 subjected to microwave reaction at 110 ° C for 3 h under nitrogen protection. 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 ... [3,2-b]pyridine)-3-yl)carbamic acid tert-butyl ester (A1) (the more polar isomer in TLC, 0.51 g, yield: 38%), and compound ((1r,3r)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamic acid tert-butyl ester (A2) (the less polar isomer in TLC, 0.44 g, yield: 33%). LC-MS, M / Z (ESI): 410.2 [M+H] + .

[0382]

[0383] The synthetic route of compound I-13A is as follows:

[0384]

[0385] Step 4: Synthesis of (1s,3s)-3-aminospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (13-1)

[0386]

[0387] Dissolve tert-butyl ((1S,3S)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-3-yl)carbamate (A1) (0.25 g, 0.61 mmol) in trifluoromethanesulfonic acid (3 mL) and stir at room temperature for 1 hour. After the reaction is completed, add the reaction solution dropwise to saturated aqueous sodium bicarbonate (30 mL) at 0 °C. A solid precipitates out. Filter, collect the solid and dry it 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 is directly used in the next reaction.

[0388] LC-MS, M / Z (ESI): 190.2 [M+H] + 。

[0389] 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)

[0390]

[0391] Add acetonitrile (15 mL) to a saturated aqueous sodium bicarbonate solution (30 mL) of 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). Add di-tert-butyl dicarbonate (200 mg, 0.90 mmol) at room temperature and react at room temperature for 2 hours. After the reaction is completed, extract with ethyl acetate (30 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. Purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1 - 1:1) to obtain tert-butyl ((1S,3S)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-3-yl)carbamate (13-2) (150.5 mg, yield: 85.3%), which is directly used in the next reaction.

[0392] LC-MS, M / Z (ESI): 290.1 [M+H] + 。

[0393] 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)

[0394]

[0395] Dissolve 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) in acetonitrile (5 mL), add 4-iodobenzotrifluoride (106.1 mg, 0.39 mmol), copper(I) iodide (119 mg, 0.62 mmol), potassium carbonate (216.0 mg, 1.56 mmol), then add N,N'-dimethylethylenediamine (59.6 mg, 0.68 mmol), and react at 100 °C under microwave for 1 hour under nitrogen protection. After the reaction is completed, cool the reaction solution to room temperature, concentrate it under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain 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%).

[0396] LC-MS, M / Z (ESI): 434.1 [M+H] + 。

[0397] 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)

[0398]

[0399] Dissolve 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) (180 mg, 0.42 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (2 mL), and stir at room temperature for 0.5 hour. After the reaction is completed, concentrate the reaction solution under reduced pressure, adjust the pH to 8 with saturated aqueous sodium bicarbonate solution at 0 °C, extract with dichloromethane (20 mL × 3), dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain the crude product (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%).

[0400] LC-MS, M / Z (ESI): 334.1 [M+H]+ 。

[0401] 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)

[0402]

[0403] Dissolve (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) in tetrahydrofuran (10 mL). Add saturated aqueous sodium bicarbonate solution (3 mL) at 0 °C and stir at 0 °C for 10 minutes. Then add acryloyl chloride (27.2 mg, 0.3 mmol) and continue to react at 0 °C for 0.5 hour. After the reaction is completed, add water (10 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and purify by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to obtain the 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%).

[0404] LC-MS, M / Z (ESI): 388.1 [M+H] + 。

[0405] 1 H NMR (400 MHz, DMSO): δ 8.73 (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).

[0406]

[0407] For the synthesis of compound I-13B, referring to the synthesis method of compound I-13A, replace the starting material A1 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) for synthesis.

[0408] LC-MS, M / Z (ESI): 388.1 [M+H] + 。

[0409] 1 H NMR (400 MHz, DMSO): δ8.73 (d, 1H), 8.35 (t, 1H), 7.95 (d, 2H), 7.77 (d, 2H), 7.30 (d, 2H), 6.24 (dd, 1H), 6.14 (dd, 1H), 5.64 (dd, 1H), 5.16–5.02 (m, 1H), 2.68–2.55 (m, 4H).

[0410] Preparation of Compounds I-14A and I-14B in Example 14

[0411] The synthetic route of I-14A is as follows:

[0412]

[0413] Dissolve (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) in N,N-dimethylformamide (3 mL), add 2-fluoroacrylic acid (21 mg, 0.23 mmol), then add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) and N,N-diisopropylethylamine (107 mg, 0.83 mmol). The reaction mixture is stirred at 40 °C overnight. After the reaction is completed, add water (10 mL), extract with ethyl acetate (15 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and purify 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%).

[0414] LC-MS, M / Z (ESI): 406.1 [M+H] + 。

[0415] 1 H NMR (400 MHz, DMSO-d 6δ 9.14 (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).

[0416]

[0417] Compound I-14B was synthesized by referring to the synthesis method of compound I-14A, replacing raw material A1 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).

[0418] LC-MS, M / Z (ESI): 406.1 [M+H] + .

[0419] 1 1H NMR (400 MHz, DMSO): δ 9.12 (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).

[0420] Preparation of Compounds I-15A and I-15B in Example 15

[0421] The synthetic route is as follows:

[0422]

[0423] First step: 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

[0424]

[0425] Place tert-butyl ((1S,3S)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-3-yl)carbamate (A1) (330 mg, 0.80 mmol) in a reaction flask, add N,N-dimethylformamide (8 mL), add 60% sodium hydride (98 mg, 2.4 mmol) under an ice bath, then add methyl iodide (170 mg, 1.2 mmol), and react the reaction solution under an ice bath for 15 minutes. After the reaction is completed, quench the reaction solution by adding 1 mL of water, then dilute it with ethyl acetate (100 mL), wash it with saturated sodium chloride aqueous solution (100 mL × 3), dry the organic phase with sodium sulfate, filter and concentrate, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain tert-butyl ((1S,3S)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-3-yl)(methyl)carbamate (15-1) (320 mg, 97%).

[0426] LC-MS, M / Z(ESI): 424.1[M+H] + 。

[0427] 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)

[0428]

[0429] Place tert-butyl ((1S,3S)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-3-yl)(methyl)carbamate (15-1) (310 mg, 0.75 mmol) in a reaction flask, add trifluoromethanesulfonic acid (3 mL), and react at 45 °C for 4 h. After completion, add the above crude product dropwise to saturated sodium carbonate solution (10 mL). After neutralization, add sodium bicarbonate (500 mg). Add acetonitrile (10 mL) to the aqueous phase, then add di-tert-butyl dicarbonate (330 mg, 1.5 mmol) at 0 °C, and react the reaction solution at 0 °C for 15 min. After completion, concentrate the reaction solution to remove acetonitrile, then dilute with ethyl acetate (100 mL), wash with saturated sodium chloride aqueous solution (100 mL × 3), dry the organic phase with sodium sulfate, filter and concentrate, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain 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, yield: 78%).

[0430] LC-MS, M / Z (ESI): 303.2 [M+H] + 。

[0431] Step 3: tert-butyl (methyl)((1S,3S)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-3-yl)carbamate

[0432]

[0433] tert-Butyl ((1S,3S)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-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), copper(I) iodide (0.11 g, 0.58 mmol), potassium carbonate (240 mg, 1.74 mmol), and N,N-dimethylethylenediamine (62 mg, 0.7 mmol) were added. Subsequently, acetonitrile (6 mL) was added, and the reaction mixture was subjected to microwave irradiation at 100 °C for 1 h under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (100 mL), washed with aqueous sodium chloride solution (100 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) = 2:1) to give tert-butyl methyl ((1S,3S)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-3-yl)carbamate (15-3) (216 mg, yield: 84%).

[0434] LC-MS, M / Z (ESI): 448.2 [M + H] + 。

[0435] 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)

[0436]

[0437] tert-Butyl methyl((1s,3s)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-3-yl)carbamate (15-3) (120 mg, 0.27 mmol) was placed in a reaction flask, and trifluoroacetic acid (2 mL) was added. The reaction was carried out at room temperature for 1 h. After completion, the above crude product was added dropwise to saturated sodium carbonate solution (6 mL). After neutralization, sodium bicarbonate (500 mg) was added. Acetonitrile (6 mL) was added to the aqueous phase, and then acryloyl chloride (45 mg, 0.5 mmol) was added at 0 °C. The reaction solution continued to react at 0 °C for 15 min. After completion of the reaction, the reaction solution was concentrated to remove acetonitrile, then diluted with ethyl acetate (100 mL), washed with saturated sodium chloride aqueous 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%).

[0438] LC-MS, M / Z(ESI): 402.1[M+H] + 。

[0439] 1 H NMR(400 MHz, DMSO-d 6 ): δ8.40–8.24(m, 1H), 7.94(d, 2H), 7.77(d, 2H), 7.32–7.22(m, 2H), 6.81–6.70(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).

[0440]

[0441] Compound I-15B was synthesized by referring to the synthesis method of compound I-15A, with raw material A1 replaced by tert-butyl ((1r,3r)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-3-yl)carbamate (A2).

[0442] Example 16 Preparation of Compound I-16

[0443] The synthesis route is as follows:

[0444]

[0445] Step 1: Synthesis of tert-butyl 5-bromo-2-oxospiro(indole-3,3'-pyrrolidine)-1'-carboxylate (16-1)

[0446]

[0447] Place 2-oxo-1,1',2,2',4',5'-hexahydrospiro(indole-3,3'-pyrrole)-1'-carboxylic acid 2-methylpropan-2-yl ester (1-1) (1.0 g, 3.47 mmol) in a reaction flask, add acetonitrile (10 mL), and add N-bromosuccinimide (0.75 g, 4.2 mmol) under an ice bath. After addition, react at room temperature for 16 h. After completion, dilute the reaction solution with ethyl acetate (300 mL), wash with saturated aqueous sodium chloride solution (300 mL × 3), dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain compound tert-butyl 5-bromo-2-oxospiro(indole-3,3'-pyrrolidine)-1'-carboxylate (16-1) (1.07 g, 84%).

[0448] LC-MS, M / Z (ESI): 367.0 [M+H] + 。

[0449] Step 2: Synthesis of tert-butyl 5-bromo-2-oxo-1-(4-(trifluoromethyl)phenyl)spiro[indole-3,3'-pyrrolidine]-1'-carboxylate (16-2)

[0450]

[0451] Place compound tert-butyl 5-bromo-2-oxospiro(indole-3,3'-pyrrolidine)-1'-carboxylate (16-1) (1.0 g, 2.73 mmol) in a reaction flask, add 4-iodobenzotrifluoride (0.90 g, 3.28 mmol), copper(I) iodide (0.52 g, 2.73 mmol), potassium carbonate (1.2 g, 8.2 mmol), N,N-dimethylethylenediamine (0.3 g, 3.28 mmol), and then add acetonitrile (10 mL). Stir the reaction solution at 60 °C for 2 h under nitrogen protection. After completion, dilute the reaction solution with ethyl acetate (500 mL), wash with saturated sodium chloride (500 mL × 3), dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain compound tert-butyl 5-bromo-2-oxo-1-(4-(trifluoromethyl)phenyl)spiro(indole-3,3'-pyrrolidine)-1'-carboxylate (16-2) (1.31 g, yield: 94%).

[0452] LC-MS, M / Z (ESI): 511.1 [M+H] + 。

[0453] Step 3: Synthesis of tert-butyl 2-oxo-1-(4-(trifluoromethyl)phenyl)-5-vinylspiro(indole-3,3'-pyrrolidine)-1'-carboxylate (16-3)

[0454]

[0455] Dissolve tert-butyl 5-bromo-2-oxo-1-(4-(trifluoromethyl)phenyl)spiro(indole-3,3'-pyrrolidine)-1'-carboxylate (16-2) (1.3 g, 2.54 mmol) in 1,4-dioxane (10.0 mL) and water (1.0 mL). Under nitrogen protection, add potassium vinyltrifluoroborate (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). The reaction mixture is reacted at 90 °C for 6 hours. After completion, the solvent is removed by distillation under reduced pressure. The residue is diluted with ethyl acetate (200 mL). The organic phase is washed with saturated sodium chloride aqueous solution (200 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain tert-butyl 2-oxo-1-(4-(trifluoromethyl)phenyl)-5-vinylspiro(indole-3,3'-pyrrolidine)-1'-carboxylate (16-3) (1.15 g, yield: 98%).

[0456] LC-MS, M / Z (ESI): 459.2 [M+H] + 。

[0457] 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)

[0458]

[0459] The compound tert-butyl 5-(1,2-dihydroxyethyl)-2-oxo-1-(4-(trifluoromethyl)phenyl)spiro(indole-3,3'-pyrrolidine)-1'-carboxylate (16-4) (146 mg, yield: 28%) was obtained by placing tert-butyl 2-oxo-1-(4-(trifluoromethyl)phenyl)-5-vinylspiro(indole-3,3'-pyrrolidine)-1'-carboxylate (16-3) (0.5 g, 1.09 mmol) in a reaction flask, adding tetrahydrofuran (8 mL) and water (2 mL), then adding N-methylmorpholine N-oxide (676 mg, 5.77 mmol) and potassium osmate (146 mg, 577 μmol), and reacting the reaction mixture at 25 °C for 6 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL × 3), 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).

[0460] LC-MS, M / Z (ESI): 493.2 [M+H] + 。

[0461] Step 5: Synthesis of 1'-acryloyl-5-(1,2-dihydroxyethyl)-1-(4-(trifluoromethyl)phenyl)spiro(indole-3,3'-pyrrolidin)-2-one (I-16)

[0462]

[0463] tert-Butyl 5-(1,2-dihydroxyethyl)-2-oxo-1-(4-(trifluoromethyl)phenyl)spiro(indole-3,3'-pyrrolidine)-1'-carboxylate (16-4) (140 mg, 0.28 mmol) was placed in a reaction flask, trifluoroacetic acid (2 mL) was added, and the reaction was carried out at room temperature for 1 h. After completion, the above crude product was added dropwise to saturated sodium carbonate solution (10 mL), sodium bicarbonate (400 mg) and acetonitrile (10 mL) were added, then acryloyl chloride (108 mg, 1.2 mmol) was added at 0 °C, and the reaction was carried out at 0 °C for 15 min. After completion, the reaction mixture 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 1'-acryloyl-5-(1,2-dihydroxyethyl)-1-(4-(trifluoromethyl)phenyl)spiro(indole-3,3'-pyrrolidin)-2-one (I-16) (108 mg, yield: 86%).

[0464] LC-MS, M / Z (ESI): 447.2 [M+H] + 。

[0465] 11H NMR (400 MHz, DMSO-d 6 6): δ 7.92–7.82 (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).

[0466] The following compounds were prepared with reference to the above preparation:

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475] Test Example 1: TEADs-mediated transcriptional inhibition IC 50 Evaluation test

[0476] The inhibitory effect of small molecule compounds on TEADs-mediated transcription was detected by HEK293T-TEAD Reporter Assay.

[0477] The HEK293T-TEAD-LUC reporter cell line was cultured in DMEM + 10% FBS + 1% PS + 200 μg / mL Hygromycin as a complete medium. Cells in the logarithmic phase were seeded into a 384-well plate, 2500 cells / well / 35 μL, 37 °C, 5% CO 2 Incubated overnight. The next day, 5 μL of the diluted compound (final DMSO concentration was 0.1%) was added to each well. A positive control group with only DMSO added was set up, and the signal value of 2 μM Okacid acid was used as the signal of the negative control group. Then, 37 °C, 5% CO 2Incubate for 48 h. After incubation, use luciferase assay system (Promega, E2550) and measure the fluorescence signal value on an Envision 2104 Multilabel Reader according to the instructions provided by the supplier. Calculate the inhibition rate using the following formula, then plot a curve with the Log value of the inhibitor concentration on the X-axis and the inhibition rate on the Y-axis, and calculate the IC 50 .

[0478] Inhibition%=(Signal of positive control group - Signal of test wells) / (Signal of positive control group - Signal of negative control group) * 100

[0479] The results of the HEK293T-TEAD Reporter Assay showed that the compounds of the present invention could significantly inhibit the transcriptional activity of TEADs on HEK293T-TEAD-LUC reporter cell line cells.

[0480] Test Example 2: Inhibitory assay for malignant mesothelioma cell proliferation

[0481] The inhibitory effect of small molecule compounds on the proliferation of malignant mesothelioma cells was detected by the proliferation assay of NCI-H226 cells with NF2 mutation.

[0482] NCI-H226 (ATCC, cat#CRL5826) was cultured in RPMI1640 + 10% FBS + 1% PS as the complete medium. Cells in the logarithmic phase were seeded into 96-well plates, 800 cells / well / 195 μL, at 37 °C, 5% CO 2 Incubate overnight. The next day, add 5 μL of the diluted compound (final DMSO concentration is 0.1%) to each well. At the same time, set a positive control group that only adds DMSO, and use the signal value of 1 μM Staurosporine as the signal of the negative control group. Then, incubate at 37 °C, 5% CO 2 Incubate for 6 days. After incubation, aspirate 100 μL of the medium, use the Celltiter Glo assay kit (Promega, G7573) and measure the fluorescence signal value on an Envision 2104 Multilabel Reader according to the instructions provided by the supplier. Calculate the inhibition rate using the following formula, then plot a curve with the Log value of the inhibitor concentration on the X-axis and the inhibition rate on the Y-axis, and calculate the IC 50 .

[0483] Inhibition% = (Signal of positive control group - Signal of test well) / (Signal of positive control group - Signal of negative control group) * 100

[0484] Table 1 Proliferation inhibition activity of test compounds on NCI-H226 cells

[0485] Test compound <![CDATA[IC 50 (nM)]]> I-2 90.38 I-3 56 I-4 66 I-7 51 I-13A 21 I-13B 90 I-15A 16

[0486] The results of the NCI-H226 cell proliferation assay showed that the compounds of the present invention could significantly inhibit the proliferation of NCI-H226 (ATCC, cat#CRL5826).

[0487] Test Example 3: Thermodynamic solubility test

[0488] Prepare phosphate buffer solution (PBS) with pH 7.4. Accurately weigh the compound, add it to the prepared phosphate buffer solution with pH 7.4, and prepare a solution with a concentration of 4 mg / mL. Shake it at a speed of 1000 rpm for 1 hour, and then incubate it overnight at room temperature. The incubated solution is centrifuged at a speed of 12000 rpm for 10 minutes to remove undissolved particles, and the supernatant is transferred to a new centrifuge tube. After appropriately diluting the supernatant, add acetonitrile solution containing internal standard, and perform quantification using a standard curve prepared with the same matrix.

[0489] Table 2 Results of thermodynamic solubility test

[0490]

[0491] The results of the thermodynamic solubility test showed that the compounds of the present invention had good thermodynamic solubility under neutral conditions and good drug-likeness.

[0492] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to 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, and lung cancer.

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