WO2025113627A1 - Heterocyclic ring-containing tead inhibitor - Google Patents

Abstract

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

Description

Heterocyclic TEAD inhibitors

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

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

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

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

The entire contents of the above-mentioned prior patent applications are incorporated into the present application by reference.

Technical Field

The present invention belongs to the field of medicine, and in particular, the present invention relates to a heterocyclic TEAD inhibitor and uses thereof.

Background Art

The Hippo signaling pathway is a highly conserved signaling pathway composed of a series of kinase cascades, which is involved in regulating physiological processes such as cell proliferation, cell differentiation, cell stemness, extracellular matrix deposition, damage repair, and organ development. After the Hippo signaling pathway is activated by upstream GPCR, mechanical stress and other signals, NF2 (neurofibromatosis type 2) activates MST1/2 (Mammalian sterile 20-like kinase 1/2), MST1/2 activates LAST1/2 (large tumor suppressor kinase 1/2), and the activated LATS1/2 phosphorylates YAP (Yes Associated Protein)/TAZ (Transcriptional coactivator with PDZ-binding motif). Phosphorylated YAP/TAZ are localized in the cytoplasm and degraded in a ubiquitin-dependent manner, while unphosphorylated YAP/TAZ are translocated to the nucleus and bind 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 body's physiological and pathological processes.

TEADs/TEAD (Transcriptional Enhanced Associated 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 DNA-binding TEA domain at the N-terminus and a YAP/TAZ-binding domain at the C-terminus. The DNA-binding domain and the YAP/TAZ-binding domain are highly conserved in mammals, but they are very different in the linker connecting the TEA domain and the transactivation domain. The overall homology of the four TEADs subtypes ranges from 61% to 73%. The function of TEADs is mediated by its interaction with nuclear co-activators, and YAP is the main nuclear co-activator that interacts with TEADs.

YAP/TAZ-TEADs activation 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 changes 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% of YAP is highly expressed. Overactivation of the YAP/TAZ-TEADs complex helps promote tumor cell proliferation, metastasis, epithelial to mesenchymal transition (EMT), and maintenance of tumor stem cells. The interaction between YAP and TEADs is essential for initiating transcriptional programs to drive tumorigenesis and proliferation. TEADs with defects in the DNA binding domain 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 anti-tumor effect. Inhibiting the interaction between YAP/TAZ and TEADs can significantly inhibit the proliferation of tumor cells. Other studies have also shown that the downstream proteins CTGF and CYR61 of YAP/TAZ-TEADs can induce tumor cells to develop resistance to chemotherapy drugs such as paclitaxel, and YAP/TAZ-TEADs have become an alternative survival pathway for drug-resistant cancer cells. All of these indicate that inhibiting the interaction between YAP/TAZ and TEADs has the potential to treat tumors, especially tumors with overactivation or mutations in the upstream of the Hippo signaling pathway.

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

Summary of the invention

The present invention provides a TEAD inhibitor containing a heterocycle, wherein the TEAD inhibitor is a compound of formula I' or formula I described in the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof; the compound can significantly inhibit the activity of TEAD transcription, and can be used to prevent and/or treat diseases or conditions associated with increased TEAD expression.

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

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;

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

The ring B is optionally substituted by 1-3 identical or different R ₄ ;

R ₁ and R ₄ are each independently 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), 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 , Each independently is optionally substituted by one or more R ₁₀ ; when R ₁₀ is multiple, the R ₁₀ are the same or different;

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

V is -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -;

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

G ₁ and G ₂ are each independently -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 only one of G ₁ and G ₂ is R ₃ ;

Each Rg is independently H, C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl;

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 ; said R ₂ is optionally substituted by one or more R ₂₁ ; when R ₂₁ is multiple, said R ₂₁ are the same or different;

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

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 , and 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 are optionally substituted by a substituent selected from the following: 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 .

The present invention also provides a compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:

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;

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), 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 , Each independently is optionally substituted by one or more R ₁₀ ; when R ₁₀ is multiple, the R ₁₀ are the same or different;

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

V is -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -;

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;

G ₁ and G ₂ are each independently -C(O)R ₂ , -S(O) ₂ R ₂ , -S(O)R ₂ , or R ₃ , and only one of G ₁ and G ₂ is R ₃ ;

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 ; said R ₂ is optionally substituted by one or more R ₂₁ ; when R ₂₁ is multiple, said R ₂₁ are the same or different;

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

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 , and 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 are optionally substituted by a substituent selected from the following: 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 .

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

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

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

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

Wherein, m and n are each independently 1 or 2;

X ₁ , X ₂ , X ₃ , and X ₄ are each independently CH or N;

V, R ₁ , G ₁ , and G ₂ are as defined above;

Preferably, m is 1 and n is 2;

Preferably, V is -CH ₂ - or -C(O)-.

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

Wherein, E is N or CRe;

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

p and q are each independently 1 or 2;

X ₁ , X ₂ , X ₃ , and X ₄ are each independently CH or N;

V, R ₁ , R ₄ , G ₁ and G ₂ have the same meanings as described above.

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

In a preferred embodiment, E is N or CH.

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

wherein X ₁ , X ₂ , X ₃ , and X ₄ are each independently CH or N;

R ₁ , R ₄ , V, G ₁ and G ₂ have the same meanings as described above.

In a preferred embodiment, V is -CH ₂ - or -C(O)-.

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

wherein X ₁ , X ₂ , X ₃ , and X ₄ are each independently CH or N;

R ₁ , R ₄ , V, G ₁ and G ₂ have the same meanings as described above.

In a preferred embodiment, the compound has a structure shown in Formula Ia or Ib

wherein X ₁ , X ₂ , X ₃ , and X ₄ are each independently CH or N;

R ₁ , V, G ₁ , and G ₂ are as defined above;

Preferably, V is -CH ₂ - or -C(O)-.

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

wherein X ₁ , X ₂ , X ₃ , and X ₄ are each independently CH or N;

V, R ₁ , R ₄ , G ₁ , and G ₂ are as defined above;

Preferably, V is -CH ₂ - or -C(O)-.

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

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

In a preferred embodiment, X ₁ , X ₂ , X ₃ , and X ₄ are each independently CH or N, and 0, 1, 2, or 3 of X ₁ , X ₂ , X ₃ , and X ₄ are N.

In a preferred embodiment, _X1 , _X2 , _X3 , and _X4 are CH; and/or _X1 is N, and _X2 , _X3 , and _X4 are CH; and/or _X4 is N, and _X1 , _X2 , and _X3 are CH; and/or _X1 , _X4 are N, and X2, and _X3 are _CH .

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

Wherein, R ₁ , G ₁ , G ₂ , and V are as defined above;

Preferably, for

Preferably, for

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

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

Preferably, R ₃₁ is 1 or 2.

In a preferred embodiment, the _G2 is

Preferably, R ₃₁ is selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -SF ₅ , -S(C ₁ -C ₆ alkyl); the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -S(C ₁ -C ₆ alkyl) are optionally substituted with 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 .

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

In a preferred embodiment, R ₃₁ is selected from -CF ₃ and -OCF ₃ .

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.

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 is optionally substituted by one or more R ₂₁ .

In a preferred embodiment, R ₂ is selected from NH ₂ , C ₁ -C ₃ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl; said R ₂ is optionally substituted by one or more R ₂₁ .

In a preferred embodiment, R ₂ is selected from NH ₂ , methyl, ethyl, propyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl; said R ₂ is optionally substituted by one or more R ₂₁ .

In a preferred embodiment, R ₂₁ is selected from NH ₂ , OH, F, Cl, methyl, ethyl, —NH(C ₁ -C ₃ alkyl), —N(C ₁ -C ₃ alkyl) ₂ .

In a preferred embodiment, _G1 is selected from:

In a preferred embodiment, R ₄ is hydrogen, methyl, -CHF ₂ , or -CH ₂ OH.

In a preferred embodiment, G ₁ is -C(O)R ₂ ; R ₂ is C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl; and the C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl is optionally substituted by R ₂₁ .

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

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

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

In a preferred embodiment, 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,

The C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy group is optionally substituted by one or more R ₁₀ ; when there are multiple R _10s , the R _10s are the same or different.

In a preferred embodiment, the R ₁₀ is F, Cl, or -OH.

In a preferred embodiment, R ₁ is H, F, Cl, CN, C ₁ -C ₃ alkyl, The C ₁ -C ₃ alkyl group is optionally substituted with one or more -OH groups.

In a preferred embodiment, for

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

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

The present invention also provides a pharmaceutical composition, comprising any compound as described above, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier.

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

Preparation of a medicament, 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,

Prepare a drug, a pharmaceutical composition or a preparation for reducing/inhibiting the Hippo signaling pathway.

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

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

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

In a preferred embodiment, the disease is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocyte, myeloblast, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic leukemia), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, soft tissue sarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, Blood disease, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, 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, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma, Non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

Preferably, the disease is selected from the group consisting of: mesothelioma, soft tissue sarcoma, meningioma, glioma, lung cancer.

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

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.

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

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

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

Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention.

Terms and Definitions

Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The group definitions and compound structures after such combination and combination shall fall within the scope recorded in the specification of this application.

Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art to which the subject matter of the claims pertains. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety. If there are multiple definitions of a term herein, the definition in this chapter shall prevail.

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

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

When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, CH ₂ O is equivalent to OCH ₂ . As used herein, Indicates the attachment site of a group. As used herein, "R ₁ ", "R1" and "R ¹ " have the same meaning and can be replaced with each other. For other symbols such as R ₂ , similar definitions have the same meaning.

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

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

When the numerical range described in the specification and claims of this application is understood as an "integer", it should be understood that the two endpoints of the range and each integer in the range are recorded. For example, "an integer from 0 to 5" should be understood as recording each integer of 0, 1, 2, 3, 4 and 5.

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

As used herein, the term "alkyl" means a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms and connected to the rest of the molecule by a single bond, when alone or as part of other substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl. Alkyl groups may be unsubstituted or substituted with one or more suitable substituents. Alkyl groups may also be isotopic isomers of natural abundance alkyl groups rich in isotopes of carbon and/or hydrogen (i.e., deuterium or tritium). As used herein, the term "alkenyl" means 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.

The term "C ₁ -C ₆ alkyl" alone or as part of another substituent is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl radical 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, or the like or isomers thereof. The term "C ₁ -C ₃ alkyl" is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2 or 3 carbon atoms. In particular, said radical has 1, 2 or 3 carbon atoms ("C ₁ -C ₃ alkyl"), for example methyl, ethyl, n-propyl or isopropyl.

The term " _C2 - _C6 alkenyl" when used alone or as part of another substituent is understood to mean a straight or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms, for example, 2 or 3 carbon atoms (i.e., _C2 - _C3 alkenyl). It is understood that in the case where the alkenyl contains more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl , 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl but-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

The term "C ₂ -C ₆ alkynyl" is understood to mean a straight or branched monovalent hydrocarbon radical comprising one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms, for example 2 or 3 carbon atoms ("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 In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

The term "C ₁ -C ₆ alkoxy" is understood to mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms and an oxygen atom, or is represented by C ₁ -C ₆ alkyl-O-. The definition of C ₁ -C ₆ alkyl is as described in the present specification, and the oxygen atom can be connected to any carbon atom of the linear or branched chain of the C ₁ -C ₆ alkyl group. 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-).

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

The term "heteroaryl" or "heteroaromatic ring" or "heteroaromatic ring group" when used alone or as part of other substituents 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, "5-6 membered heteroaromatic ring" refers to an aromatic ring system containing 5 or 6 atoms containing heteroatoms. Examples of heteroaromatic rings include, but are not limited to, furanyl, imidazolyl, indolinyl, pyrrolidinyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolyl and isoquinolyl. The heteroaromatic ring group may be optionally fused to a benzene ring, and may also include a monocyclic, bicyclic, tricyclic, spirocyclic or bridged ring.

The term "halo" can be used interchangeably with the term "halogen-substituted" when used alone or as part of other substituents. "Haloalkyl" or "halogen-substituted alkyl" refers to saturated aliphatic hydrocarbon groups including branched and straight chains having a specific number of carbon atoms, substituted with one or more halogens (such as -CvFw, where v = 1 to 3, w = 1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

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

In the present application, "optional" or "optionally" means that the event or situation described later may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, "optionally substituted aryl" means that aryl is substituted or unsubstituted, and the description includes both substituted aryl and unsubstituted aryl.

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

"Pharmaceutically acceptable acid addition salts" refers 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" refers to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. They can serve as intermediates in the purification of compounds 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.

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

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

When the bonds to the chiral carbon in the formula of the present invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the enantiomerically pure compounds and mixtures thereof produced therefrom are included within the scope of the general formula. The graphic 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 indicated by a wedge-shaped bond and a dashed bond.

The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of 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.

In this application, "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

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

In the present application, the term "solvate" means that the compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent forces between molecules. When the solvent is water, it is a hydrate.

In the present application, the term "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrug of the present invention is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. The prodrug includes a compound formed by connecting a hydroxyl or amino group in the compound of the present invention to any group. When the 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.

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compounds. For example, radioactive isotope labeled compounds may be used, such as deuterium ( ^2H ), tritium ( ^3H ), iodine-125 ( ^125I ) or C-14 ( ^14C ). All isotopic changes of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

In this application, the term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the type of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling characteristics of a pharmaceutical formulation, i.e., make the formulation more suitable for direct compression by increasing fluidity and/or adhesion.

As used herein, the term "treatment" and other similar synonyms include the following meanings:

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

(ii) inhibiting a disease or condition, i.e. arresting its development;

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

(iv) alleviating the symptoms caused by the disease or condition.

The reaction temperature of each step can be appropriately selected according to the solvent, starting material, reagent, etc., and the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting material, reagent, etc. After the reaction of each step is completed, the target compound can be separated and purified from the reaction system according to the common method, such as filtration, extraction, recrystallization, washing, silica gel column chromatography and the like. Without affecting the next step reaction, the target compound can also directly enter the next step reaction without separation and purification. The reaction of each step of the present invention is preferably carried out in an inert solvent, and the inert solvent includes but is not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof.

Beneficial Effects

After extensive and in-depth research, the inventors unexpectedly developed a heterocyclic TEAD inhibitor, which is a compound of formula I' or formula I described in the present invention. The compound can significantly inhibit the activity of TEAD transcription and can be used to prevent and/or treat diseases associated with increased TEAD expression.

DETAILED DESCRIPTION

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

Example 1: Preparation of Compound I-1

The synthetic route is as follows:

Step 1: Synthesis of 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)

Dissolve 2-methylpropane-2-yl 2-oxy-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-1'-carboxylate (1-1) (0.9 g, 3.1 mmol) and 4-trifluoromethylphenylboronic acid (0.89 g, 4.7 mmol) in dichloromethane (20 mL), add copper acetate (0.85 g, 4.68 mmol), then add triethylamine (1.26 g, 12.5 mmol), and stir at room temperature overnight under the protection of an oxygen ball. After the reaction is completed, the reaction solution is filtered through diatomaceous earth, the filter cake is washed with dichloromethane (40 mL), the filtrates are combined, washed with water (15 mL), and then dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V) = 5:1) to obtain compound 2-oxyylidene-1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-1'-carboxylic acid-2-methylpropan-2-yl ester (1-2) (1.16 g, yield: 85.6%).

LC-MS, M/Z(ESI): 433.2[M+H] ⁺ .

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

2-Oxylidene-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) was dissolved in 1,4-dioxane (20 mL), and then a solution of hydrogen chloride in 1,4-dioxane (4M, 20 mL) was added and stirred at room temperature overnight. The reaction solution was concentrated 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 was directly used in the next step reaction.

LC-MS, M/Z(ESI): 333.1[M+H] ⁺ .

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)

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

LC-MS, M/Z(ESI):405.1[M+H] ⁺ .

Example 2: Preparation of Compound I-2

The synthetic route is as follows:

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

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

LC-MS, M/Z(ESI): 387.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.95(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).

Example 3 Preparation of Compound I-3

The synthetic route is as follows:

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

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

LC-MS, M/Z(ESI): 370.1[M+H] ⁺ .

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

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

LC-MS, M/Z(ESI): 490.2[M+H] ⁺ .

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

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

LC-MS, M/Z(ESI): 410.7[M+H] ⁺ .

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)

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-methylpropane-2-yl ester (3-4) (120 mg, 0.293 mmol) was placed in a reaction bottle, and methanesulfonic acid (1 mL) was added, and the reaction was carried out at 45°C for 4 h. The above crude product was added dropwise to a saturated sodium carbonate solution (5 mL), and then sodium bicarbonate (200 mg) and acetonitrile (5 mL) were added, followed by acryloyl chloride (64 mg, 0.6 mmol) at 0°C, and the reaction solution was stirred at 0°C for 15 min. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove acetonitrile, and then extracted with ethyl acetate (50 mL). The organic phase was washed with saturated aqueous sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified 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%).

LC-MS, M/Z(ESI): 244.3[M+H] ⁺ .

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)

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

LC-MS, M/Z(ESI): 388.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.23–8.14(m,1H),8.03–7.73(m,5H),7.24–7.17(m,1H),6.77–6.51(m,1H ),6.27–6.16(m,1H),5.81–5.68(m,1H),4.20–3.69(m,4H),2.49–2.34(m,2H).

Example 4 Preparation of Compound I-4

The synthetic route is as follows:

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

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

LC-MS, M/Z(ESI): 370.0[M+H] ⁺ .

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

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

LC-MS, M/Z(ESI): 490.1[M+H] ⁺ .

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)

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

LC-MS, M/Z(ESI): 410.4[M+H] ⁺ .

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)

1'-[(4-methoxyphenyl)methyl]-2'-oxo-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylic acid-2-methylpropane-2-yl ester (4-4) (950 mg, 2.32 mmol) was placed in a reaction bottle, methanesulfonic acid (3 mL) was added, and stirred at 45°C for 4 h. The above crude product was added dropwise to a saturated sodium carbonate solution (5 mL), followed by sodium bicarbonate (400 mg) and acetonitrile (5 mL), followed by acryloyl chloride (425 mg, 4.0 mmol) at 0°C, and the reaction solution was stirred at 0°C for 15 min. The reaction solution was concentrated under reduced pressure to remove acetonitrile, then extracted 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 crude product was purified 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[3,2-b]pyridine]-2'-one (4-5) (335 mg, yield: 59%).

LC-MS, M/Z(ESI): 244.3[M+H] ⁺ .

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)

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

LC-MS, M/Z(ESI): 388.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.30–8.27(m,1H),8.07–7.89(m,2H),7.79(dd,2H),7.37–7.27(m,2H),6.76–6.5 1(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).

Example 5: Preparation of Compound I-5

The synthetic route is as follows:

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

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

LC-MS, M/Z(ESI): 319.1[M+H] ⁺ .

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

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

LC-MS, M/Z(ESI): 373.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.66(d,2H),7.40(dd,2H),7.37–7.28(m,2H),7.20(dddd,1H),6.90(tt,1H),6.61(ddd,1H),6.16(ddd,1 H),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).

Example 6 Preparation of Compound I-6

The synthetic route is as follows:

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

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

LC-MS, M/Z(ESI): 371.3[M+H] ⁺ .

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

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

LC-MS, M/Z(ESI): 491.2[M+H] ⁺ .

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

The compound 3-[[(3-bromopyrazin-2-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]tetrahydropyrrole-1-carboxylic acid-2-methylpropane-2-yl ester (6-3) (1.87 g, 3.80 mmol) was placed in a reaction bottle, and 10 wt% of [1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene](3-chloropyridine)palladium dichloride (0.19 g) and sodium tert-butoxide (550 mg, 5.7 mmol) were added, followed by toluene (6 mL) and microwave reaction at 110 ° C under argon protection for 3 h. After completion, the reaction solution was diluted with ethyl acetate (500 mL), washed with saturated aqueous sodium chloride solution (500 mL×3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 2:1) to obtain 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%).

LC-MS, M/Z(ESI): 411.3[M+H] ⁺ .

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)

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-methylpropane-2-yl ester (6-4) (240 mg, 0.58 mmol) was placed in a reaction bottle, and methanesulfonic acid (1 mL) was added, and the reaction was carried out at 45°C for 4 hours. After completion, the above crude product was added dropwise to a saturated sodium carbonate solution (5 mL), and then sodium bicarbonate (400 mg) and acetonitrile (6 mL) were added, followed by acryloyl chloride (108 mg, 1.2 mmol) at 0°C, and the reaction solution was reacted at 0°C for 15 minutes. After completion, the reaction solution was concentrated to remove acetonitrile, then diluted with ethyl acetate (100 mL), washed with saturated sodium chloride aqueous solution (100 mL×3), the organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:1) to obtain 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%).

LC-MS, M/Z(ESI):245.1[M+H] ⁺ .

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)

Compound 1-(1-oxoprop-2-enyl)-1,2,4,5,5',6'-hexahydrospiro[pyrrole-3,7'-pyrrolo[2,3-b]pyrazine]-6'-one (6-5) (120 mg, 0.49 mmol), copper acetate (147 mg, 0.74 mmol), and p-trifluoromethylphenylboronic acid (112 mg, 0.588 mmol) were placed in a reaction bottle, acetonitrile (5 mL) and pyridine (160 mg, 2.0 mmol) were added, and the mixture was reacted at 45 °C under an oxygen atmosphere for 24 h. After completion, the reaction solution was diluted with ethyl acetate (200 mL), washed with saturated sodium chloride aqueous 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%).

LC-MS, M/Z(ESI):389.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.30(dd,1H),8.20(dd,1H),8.00–7.93(m,2H),7.90–7.85(m,2H),6.76–6.46(m,1H),6.26–6.15( m,1H),5.79–5.68(m,1H),4.11–4.00(m,2H),3.95–3.81(m,2H),2.61–2.53(m,1H),2.49–2.37(m,1H).

Example 7 Preparation of Compound I-7

The synthetic route is as follows:

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

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

LC-MS, M/Z(ESI): 384.1[M+H] ⁺ .

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

The intermediate tert-butyl 4-((2-bromopyridin-3-yl)carbamoyl)piperidine-1-carboxylate (7-1) (3.0 g, 7.83 mmol) was placed in a reaction flask, and N,N-dimethylformamide (35 mL) was added. Subsequently, cesium carbonate (5.3 g, 16.22 mmol) was added under ice bath, and p-methoxybenzyl chloride (1.64 g, 10.3 mmol) was added after stirring for 15 min. After the addition, the mixture was reacted at 45°C for 4 h. The reaction solution was then diluted with ethyl acetate (300 mL), washed with saturated sodium chloride (300 mL×3) aqueous solution, 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 4-((2-bromopyridin-3-yl) (4-methoxybenzyl)carbamoyl)piperidine-1-carboxylate (7-2) (3.31 g, yield: 84%).

LC-MS, M/Z(ESI):504.1[M+H] ⁺ .

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

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

LC-MS, M/Z(ESI): 424.3[M+H] ⁺ .

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

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

LC-MS, M/Z(ESI):304.1[M+H] ⁺ .

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

Place tert-butyl 2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylate (7-4) (280 mg, 0.92 mmol), potassium carbonate (380 mg, 2.76 mmol), cuprous iodide (209 mg, 1.84 mmol), 4-iodotrifluorotoluene (500 mg, 1.84 mmol), and N,N'-dimethylethylenediamine (97 mg, 1.10 mmol) in a reaction bottle, add acetonitrile (5 mL), and react in a microwave at 100 °C under an argon atmosphere for 1.5 h. 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 Na ₂ SO ₄ and concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol (V/V)=20:1) to obtain 2-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro-[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (7-5) (355 mg, yield: 87%).

LC-MS, M/Z(ESI): 448.2[M+H] ⁺ .

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

2-Oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro-[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (7-5) (200 mg, 0.45 mmol) was placed in a reaction bottle, trifluoroacetic acid (3 mL) was added, and the reaction was allowed to react at room temperature for 1 h. After the reaction was completed, the reaction solution was added dropwise to a saturated sodium carbonate solution (3 mL), the pH of the reaction solution was adjusted to 7, 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 the residue was then purified by silica gel column chromatography (dichloromethane: methanol (V/V) = 10:1) to obtain compound 1-acryloyl-1'-(4-(trifluoromethyl)phenyl)spiro[piperidine-4,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (I-7) (127 mg, yield: 70%).

LC-MS, M/Z(ESI):402.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.27(dd,1H),7.94(d,2H),7.76(d,2H),7.34–7.25(m,2H),6.88(dd,1H),6.15(dd,1H),5.70(dd,1H),4.10–3.90(m,4H),1.98–1.84(m,4H).

Example 8 Preparation of Compound I-8

The synthetic route is as follows:

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

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

LC-MS, M/Z(ESI):356.1[M+H] ⁺ .

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

3-((2-bromopyridin-3-yl)carbamoyl)azetidine-1-carboxylic acid tert-butyl ester (8-1) (3.0 g, 8.42 mmol) was placed in a reaction bottle, and N,N-dimethylformamide (35 mL) was added. Subsequently, cesium carbonate (5.3 g, 16.22 mmol) was added under ice bath, and p-methoxybenzyl chloride (1.64 g, 10.3 mmol) was added after stirring for 15 min. After the addition was completed, the reaction solution was stirred at 45 °C. Stir for 4 h, then dilute the reaction solution with ethyl acetate (300 mL), wash with saturated sodium chloride (300 mL×3), take the organic phase, dry over anhydrous sodium sulfate, and concentrate. The crude product is 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%).

LC-MS, M/Z(ESI): 476.1[M+H] ⁺ .

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

3-((2-bromopyridin-3-yl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylic acid tert-butyl ester (8-2) (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, and the mixture was reacted in a microwave at 110 ° C under argon protection for 3 h. After completion, the reaction solution was diluted with ethyl acetate (500 mL), washed with saturated aqueous sodium chloride solution (500 mL×3), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 2:1) to obtain 1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (8-3) (0.56 g, yield: 42%).

LC-MS, M/Z(ESI): 396.2[M+H] ⁺ .

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

1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (8-3) (560 mg, 1.41 mmol) was placed in a reaction bottle, 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 added dropwise to a saturated sodium carbonate solution (5 mL), and after neutralization, sodium bicarbonate (400 mg) and acetonitrile (5 mL) were added, followed by di-tert-butyl dicarbonate (425 mg, 4.0 mmol) 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 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 give 2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (8-4) (128 mg, yield: 33%).

LC-MS, M/Z(ESI):276.1[M+H] ⁺ .

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

2'-Oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (8-4) (120 mg, 0.43 mmol), potassium carbonate (177 mg, 1.29 mmol), cuprous iodide (97 mg, 0.86 mmol), 4-iodotrifluorotoluene (233 mg, 0.86 mmol), N,N'-dimethylethylenediamine (45 mg, 0.51 mmol) were placed in a reaction bottle, acetonitrile (3 mL) was added, and the reaction solution was subjected to microwave reaction at 100 °C under argon atmosphere for 1.5 h. After completion, the reaction solution was diluted with ethyl acetate (200 mL), washed with saturated 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 2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (8-5) (150 mg, yield: 83%).

LC-MS, M/Z(ESI): 420.1[M+H] ⁺ .

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)

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

LC-MS, M/Z(ESI): 374.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.34(dd,1H),7.97(d,2H),7.77(d,2H),7.36–7.27(m,2H),6.45(dd,1H),6.21(dd,1H),5.77(dd,1H),4.62–4.48(m,2H),4.24(q,2H).

Example 9 Preparation of Compound I-9

The synthetic route is as follows:

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

LC-MS, M/Z(ESI): 392.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.34(dd,1H),7.97(d,2H),7.76(d,2H),7.37–7.28(m,2H),5.68–5.53(m,1H),5.41(dd,1H),4.66(dq,2H),4.29(q,2H).

Example 10 Preparation of Compound I-10

The synthetic route is as follows:

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

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

LC-MS, M/Z(ESI):262.1[M+H] ⁺ .

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

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

LC-MS, M/Z(ESI):406.1[M+H] ⁺ .

¹ H NMR (400MHz, 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).

Example 11 Preparation of Compound I-11

The synthetic route is as follows:

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

LC-MS, M/Z(ESI): 398.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 8.35 (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).

Example 12 Preparation of Compound I-12

The synthetic route is as follows:

2'-Oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (8-5) (150 mg, 0.36 mmol) was placed in a reaction bottle, trifluoroacetic acid (3 mL) was added, and the reaction was carried out at 45°C for 1 h. After completion, the solvent was removed by distillation under reduced pressure, acetonitrile/dichloromethane (3 mL/3 mL) was added under ice bath, and then N,N-diisopropylethylamine (520 mg, 4.0 mmol), 4-dimethylaminopyridine (44 mg, 0.36 mmol), and methylaminosulfonyl chloride (130 mg, 1.0 mmol) were added in sequence at 0°C, and the reaction solution was reacted at room temperature for 15 min. After completion, the reaction solution was concentrated to remove the solvent, then diluted with ethyl acetate (100 mL), washed with saturated sodium chloride aqueous solution (100 mL×3), the organic phase was dried over sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V) = 1:5) to 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%).

LC-MS, M/Z(ESI): 413.1[M+H] ⁺ .

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

Example 13 Preparation of Compound I-13A

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

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

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

LC-MS, M/Z(ESI): 370.0[M+H] ⁺ .

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

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

LC-MS, M/Z(ESI): 490.1[M+H] ⁺ .

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)

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] ⁺ .

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

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

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

LC-MS, M/Z(ESI): 190.2[M+H] ⁺ .

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)

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

LC-MS, M/Z(ESI): 290.1[M+H] ⁺ .

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)

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-iodotrifluorotoluene (106.1 mg, 0.39 mmol), cuprous iodide (119 mg, 0.62 mmol), potassium carbonate (216.0 mg, 1.56 mmol), and then add N,N'-dimethylethylenediamine (59.6 mg, 0.68 mmol), and react in a microwave at 100 ° C for 1 hour under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V) = 1:1) to obtain compound ((1s,3s)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamic acid tert-butyl ester (13-3) (185.3 mg, yield 82.3%).

LC-MS, M/Z(ESI): 434.1[M+H] ⁺ .

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)

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

LC-MS, M/Z(ESI): 334.1[M+H] ⁺ .

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)

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

LC-MS, M/Z(ESI):388.1[M+H] ⁺ .

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

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

LC-MS, M/Z(ESI): 388.1[M+H] ⁺ .

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

Example 14 Preparation of Compounds I-14A and I-14B

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

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

LC-MS, M/Z(ESI):406.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.14(d,1H),8.32(dd,1H),7.95(d,2H),7.76(d,2H),7.32–7.21(m,2H),5.58(dd,1H),5.29(dd,1H),4.85(dq,1H),2.78(p,4H).

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

LC-MS, M/Z(ESI):406.1[M+H] ⁺ .

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

Example 15 Preparation of Compounds I-15A and I-15B

The synthetic route is as follows:

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

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) (330 mg, 0.80 mmol) was placed in a reaction bottle, N,N-dimethylformamide (8 mL) was added, 60% sodium hydride (98 mg, 2.4 mmol) was added under ice bath, and then iodomethane (170 mg, 1.2 mmol) was added, and the reaction solution was reacted under ice bath for 15 minutes. After the reaction was completed, 1 mL of water was added to the reaction solution to quench it, and 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)=3:1) to obtain compound ((1s,3s)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)(methyl)carbamic acid tert-butyl ester (15-1) (320 mg, 97%).

LC-MS, M/Z(ESI):424.1[M+H] ⁺ .

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)

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

LC-MS, M/Z(ESI):303.2[M+H] ⁺ .

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

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

LC-MS, M/Z(ESI): 448.2[M+H] ⁺ .

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)

The compound methyl ((1s, 3s)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1', 2'-dihydrospiro (cyclobutane-1, 3'-pyrrolo [3, 2-b] pyridine) -3-yl) carbamic acid tert-butyl ester (15-3) (120 mg, 0.27 mmol) was placed in a reaction bottle, trifluoroacetic acid (2 mL) was added, and the reaction was allowed to react at room temperature for 1 h. After completion, the above crude product was added dropwise to a saturated sodium carbonate solution (6 mL), and 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, and the reaction solution continued to react at 0°C for 15 min. After the reaction is completed, 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 residue is 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%).

LC-MS, M/Z(ESI):402.1[M+H] ⁺ .

¹ H NMR (400MHz, 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).

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

Example 16 Preparation of Compound I-16

The synthetic route is as follows:

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

2-Oxylidene-1,1',2,2',4',5'-hexahydrospiro(indole-3,3'-pyrrole)-1'-carboxylic acid-2-methylpropane-2-yl ester (1-1) (1.0 g, 3.47 mmol) was placed in a reaction bottle, acetonitrile (10 mL) was added, N-bromosuccinimide (0.75 g, 4.2 mmol) was added under ice bath, and the reaction was carried out at room temperature for 16 h. After completion, the reaction solution was diluted with ethyl acetate (300 mL), washed with saturated sodium chloride aqueous solution (300 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 2:1) to obtain the compound 5-bromo-2-oxospiro(indole-3,3'-pyrrolidine)-1'-carboxylic acid tert-butyl ester (16-1) (1.07 g, 84%).

LC-MS, M/Z(ESI):367.0[M+H] ⁺ .

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

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

LC-MS, M/Z(ESI):511.1[M+H] ⁺ .

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

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

LC-MS, M/Z(ESI): 459.2[M+H] ⁺ .

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)

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

LC-MS, M/Z(ESI): 493.2[M+H] ⁺ .

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

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

LC-MS, M/Z(ESI): 447.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.92–7.82(m,2H),7.67(dd,2H),7.39–7.28(m,1H),7.18(d,1H),6.77(dd,1H),6.69–6.45(m,1H),6.17–6.06(m,1 H),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).

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

Test Example 1: TEADs-mediated transcription inhibition IC ₅₀ evaluation test

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

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

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

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

Test Example 2: Inhibition of malignant mesothelioma cell proliferation test

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

NCI-H226 (ATCC, cat#CRL5826) was cultured in RPMI1640+10% FBS+1% PS as complete medium. Cells in the logarithmic phase were inoculated in 96-well plates, 800 cells/well/195 μL, incubated overnight at 37°C, 5% CO ₂ , and 5 μL of diluted compound (DMSO final concentration was 0.1%) was added to each well the next day. At the same time, a positive control group with only DMSO added was set up, and the 1 μM Staurosporine signal value was used as the negative control group signal, and then incubated at 37°C, 5% CO ₂ for 6 days. After the incubation was completed, 100 μL of culture medium was aspirated, and the fluorescence signal value was measured on Envision 2104 Multilabel Reader using Celltiter Glo assay kit (Promega, G7573) and according to the instructions provided by the supplier. The inhibition rate was calculated by the following formula, and then the concentration Log value of the inhibitor was plotted as the X-axis and the inhibition rate was plotted as the Y-axis, and the IC ₅₀ was calculated using Graphpad 7.0.

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

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

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

Test Example 3: Thermodynamic Solubility Test

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

Table 2 Thermodynamic solubility test results

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

Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims (15)

A compound represented by formula I', its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
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; Ring B is a 4-7 membered cycloalkyl group or a 4-7 membered heterocycloalkyl group; The ring B is optionally substituted by 1-3 identical or different R ₄ ; R ₁ and R ₄ are each independently 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), 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 , Each independently is optionally substituted by one or more R ₁₀ ; when R ₁₀ is multiple, the R ₁₀ are the same or different; R ₁₁ and R ₁₂ are each independently selected from: C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy; or R ₁₁ , R ₁₂ and the P to which they are connected together form a 4-7 membered ring; V is -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -; The V is optionally substituted by one or more Rv; when Rv is multiple, the Rv are the same or different; G ₁ and G ₂ are each independently -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 only one of G ₁ and G ₂ is R ₃ ; Each Rg is independently H, C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl; 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 ; said R ₂ is optionally substituted by one or more R ₂₁ ; when R ₂₁ is multiple, said R ₂₁ are the same or different; R ₃ is a benzene ring or a 5-12 membered heteroaromatic ring; said R ₃ is optionally substituted by one or more R ₃₁ ; when there are multiple R ₃₁ , said R ₃₁ are the same or different; 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); 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 are optionally substituted by substituents selected from the group consisting of 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 . The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that it has a 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; 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), 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 , Each independently is optionally substituted by one or more R ₁₀ ; when R ₁₀ is multiple, the R ₁₀ are the same or different; R ₁₁ and R ₁₂ are each independently selected from: C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy; or R ₁₁ , R ₁₂ and the P to which they are connected together form a 4-7 membered ring; V is -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -; 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; G ₁ and G ₂ are each independently -C(O)R ₂ , -S(O) ₂ R ₂ , -S(O)R ₂ , or R ₃ , and only one of G ₁ and G ₂ is R ₃ ; 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 ; said R ₂ is optionally substituted by one or more R ₂₁ ; when R ₂₁ is multiple, said R ₂₁ are the same or different; R ₃ is a benzene ring or a 5-12 membered heteroaromatic ring; said R ₃ is optionally substituted by one or more R ₃₁ ; when there are multiple R ₃₁ , said R ₃₁ are the same or different; 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); 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 are optionally substituted by substituents selected from the group consisting of 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 . The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that it has a structure shown in Formula III or Formula IV:
Wherein, E is N or CRe; Re is selected from H, halogen, -OH, C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl; p and q are each independently 1 or 2; X ₁ , X ₂ , X ₃ , and X ₄ are each independently CH or N; V, R ₁ , R ₄ , G ₁ , G ₂ are as defined in claim 1; Preferably, V is -CH ₂ - or -C(O)-; Preferably, E is N or CH. 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 a structure shown in Formula II:
Wherein, m and n are each independently 1 or 2; X ₁ , X ₂ , X ₃ , and X ₄ are each independently CH or N; V, R ₁ , G ₁ , G ₂ are as defined in any one of claims 1 to 3; Preferably, m is 1 and n is 2; Preferably, V is -CH ₂ - or -C(O)-. 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 a structure shown in Formula Ic, Formula Id or Formula Ie:
wherein X ₁ , X ₂ , X ₃ , and X ₄ are each independently CH or N; R ₁ , R ₄ , V, G ₁ , and G ₂ are as defined in any one of claims 1 to 3; Preferably, V is -CH ₂ - or -C(O)-; Preferably, it has the structure shown in formula Id':
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 a structure shown in Formula Ia or Ib:
wherein X ₁ , X ₂ , X ₃ , and X ₄ are each independently CH or N; The definitions of R ₁ , V, G ₁ and G ₂ are as described in any one of claims 1-3. The compound according to claim 1 or 3, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that it has a structure shown in Formula IIIa or IIIb:
wherein X ₁ , X ₂ , X ₃ , and X ₄ are each independently CH or N; V, R ₁ , R ₄ , G ₁ and G ₂ are as defined in claim 1 or 3. 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, X ₁ , X ₂ , X ₃ , and X ₄ are each independently CH or N, and 0, 1, 2 or 3 of X ₁ , X ₂ , X ₃ , and X ₄ are N; Preferably, X ₁ , X ₂ , X ₃ , X ₄ are CH; and/or, _X1 is N, _X2 , _X3 , and _X4 are CH; and/or, _X4 is N, _X1 , _X2 , and _X3 are CH; and/or, X ₁ and X ₄ are N, and X ₂ and X ₃ are CH. The compound according to any one of claims 1 to 7, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that G ₂ is a benzene ring or a 5-6-membered heteroaromatic ring; the benzene ring or the 5-6-membered heteroaromatic ring is substituted by 1, 2 or 3 identical or different R ₃₁ ; Preferably, the 5-6 membered heteroaromatic ring is selected from benzene ring, pyridine, pyridazine, pyrimidine, pyrazine; Preferably, R ₃₁ is 1 or 2; Preferably, _G2 is Preferably, R ₃₁ is selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -SF ₅ , -S(C ₁ -C ₆ alkyl); the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -S(C ₁ -C ₆ alkyl) is optionally substituted by a substituent 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 ; Preferably, R ₃₁ is selected from C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy; More preferably, R ₃₁ is selected from -CF ₃ and -OCF ₃ . The compound according to any one of claims 1 to 7, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that 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; Preferably, R ₂ is selected from NH ₂ , C ₁ -C ₃ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl; said R ₂ is optionally substituted by one or more R ₂₁ ; Preferably, R ₂ is selected from NH ₂ , methyl, ethyl, propyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl; said R ₂ is optionally substituted by one or more R ₂₁ ; Preferably, R ₂₁ is selected from NH ₂ , OH, F, Cl, methyl, ethyl, -NH(C ₁ -C ₃ alkyl), -N(C ₁ -C ₃ alkyl) ₂ ; Preferably, _G1 is selected from: and/or, G ₁ is -C(O)R ₂ ; R ₂ is C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl; the C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl is optionally substituted by R ₂₁ ; Preferably, R ₂₁ is halogen; the halogen is preferably F or Cl; Preferably, G ₁ is -C(O)-CH=CH ₂ or -C(O)-CF=CH ₂ . The compound according to any one of claims 1 to 7, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that R ₄ is hydrogen, methyl, -CHF ₂ , -CH ₂ OH; and/or, V is -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -; said V is optionally substituted by Rv, Rv is oxo (=O); Preferably, V is -CH ₂ - or -C(O)-; and/or, _R1 is H, halogen, CN, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 alkoxy, The C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy group is optionally substituted by one or more R ₁₀ ; when there are multiple R ₁₀ , the R ₁₀ are the same or different; Preferably, the R ₁₀ is F, Cl, or -OH; Preferably, R ₁ is H, F, Cl, CN, C ₁ -C ₃ alkyl, The C ₁ -C ₃ alkyl group is substituted with one or more -OH groups; Preferably, for Preferably, R ₁ is H, F, Cl, CN, -CH(OH)-CH ₂ (OH), The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that it is selected from




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. 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: Preparation of a medicament, 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. The use according to claim 14, characterized in that the disease is selected from: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocyte, myeloblast, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic leukemia), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, soft tissue sarcoma, chordoma, choriocarcinoma, chronic leukemia, Chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, 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, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline cancer, non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor; Preferably, the disease is selected from the group consisting of: mesothelioma, soft tissue sarcoma, meningioma, glioma, lung cancer.