Bicyclic TEAD inhibitors

Abstract

The present invention provides a heterocyclic compound as a TEAD inhibitor having a structure represented by formula I0, which can be used for the prevention and / or treatment of diseases associated with increase in TEAD expression # imgabs0 #

Description

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

[0002] A prior patent application filed by the applicant with the State Intellectual Property Office of China on November 30, 2023, with the patent application number 202311642978.3 and the title "Bicyclic-containing TEAD Inhibitor";

[0003] A prior patent application filed by the applicant with the State Intellectual Property Office of China on January 31, 2024, with the patent application number 202410142766.7 and the title "Bicyclic-containing TEAD Inhibitor";

[0004] A prior patent application filed by the applicant with the State Intellectual Property Office of China on April 9, 2024, with the patent application number 202410424460.0 and the title "Bicyclic-containing TEAD Inhibitor";

[0005] A prior patent application filed by the applicant with the State Intellectual Property Office of China on May 24, 2024, with the patent application number 202410661331.3 and the title "Heterocyclic Compounds as TEAD Inhibitors";

[0006] The entire texts of the above prior patent applications are incorporated into this application by reference. Technical Field

[0007] The present invention belongs to the field of medicine. Specifically, the present invention relates to a bicyclic-containing TEAD inhibitor. Background Art

[0008] The Hippo signaling pathway is a highly conserved signaling pathway composed of a series of kinase cascades, which is involved in regulating physiological processes such as cell proliferation, cell differentiation, cell stemness, extracellular matrix deposition, injury repair, and organ development. After being activated by upstream signals such as GPCR and mechanical stress, the Hippo signaling pathway leads to the activation of NF2 (neurofibromatosis type 2) to activate MST1 / 2 (Mammalian sterile 20-like kinase 1 / 2), MST1 / 2 activates LATS1 / 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 localizes to the cytoplasm and is degraded in a ubiquitin-dependent manner, while unphosphorylated YAP / TAZ translocates to the nucleus and binds to several nuclear transcription factors including TEADs, forming a transcriptional complex that induces the expression of several downstream target genes including CTGF (Connective tissue growth factor), Cyr61 (Mysteine rich angiogenic inducer 61), and AXL (AXL receptor tyrosine kinase), thereby promoting the physiological and pathological processes of the body.

[0009] TEADs / TEAD (Transcriptional Enhanced Associate Domains) are the final effectors of the Hippo signaling pathway. There are four family members, namely TEAD1, TEAD2, TEAD3, and TEAD4. All TEADs subtypes have a TEA domain that binds to DNA at the N-terminus and a domain that binds to YAP / TAZ at the C-terminus. The DNA-binding domain and the YAP / TAZ-binding domain are highly conserved in mammals, but there are significant differences in the linker connecting the TEA domain and the transactivation domain. The overall homology among the four TEADs subtypes ranges from 61% to 73%. The function of TEADs is mediated by their interaction with nuclear coactivators, and YAP is the main nuclear coactivator that interacts with TEADs.

[0010] The activation of YAP / TAZ-TEADs promotes tumor development, and inhibiting the interaction between YAP / TAZ and TEADs has the potential for cancer treatment. In some cancers, such as malignant mesothelioma, ovarian cancer, and cholangiocarcinoma, the YAP / TAZ-TEADs complex is often overactivated or overexpressed, leading to cancer progression. This overactivation is usually caused by alterations in genes upstream of the Hippo signaling pathway. Especially in patients with malignant mesothelioma, 40%-50% of tumors have NF2 mutations or deletions, <25% of tumors have MST1 or LAST1 / 2 mutations or deletions, and 70% have high YAP expression. The overactivation of the YAP / TAZ-TEADs complex contributes to promoting the proliferation, metastasis, epithelial-mesenchymal transition (EMT), and maintenance of cancer stem cells of tumor cells. The interaction between YAP and TEADs is crucial for initiating the transcriptional program to drive tumorigenesis and proliferation. TEADs with defective DNA-binding domains can block tumor formation mediated by mutations in genes upstream of the Hippo signaling pathway, indicating that inhibiting the interaction between YAP / TAZ and TEADs has antitumor effects. Patents disclosed by Invenva Pharma show that inhibiting the interaction between YAP / TAZ and TEADs can significantly inhibit the proliferation of tumor cells. Other studies also show 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 has become an alternative survival pathway for drug-resistant cancer cells. All these indicate that inhibiting the interaction between YAP / TAZ and TEADs has the potential for cancer treatment, especially for tumors with overactivation or mutations in genes upstream of the Hippo signaling pathway.

[0011] Currently, some inhibitors of the interaction between YAP / TAZ and TEADs (VT-01, IK-930) have entered the clinical stage, and inhibiting the interaction between YAP / TAZ and TEADs may be a promising new type of anti-cancer chemotherapy. Summary of the Invention

[0012] The present invention provides a heterocyclic compound as a TEAD inhibitor, which is the compound of the present invention, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; the compound can significantly inhibit the activity of TEAD transcription and can be used for preventing and / or treating diseases or disorders associated with increased TEAD expression.

[0013] The present invention provides a compound of formula I 0 shown compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:

[0014]

[0015] Among them, ring A is a benzene ring or a 5- or 6-membered N-containing heteroaromatic ring; ring A is optionally substituted by one or more Ra; when there are multiple Ra, the Ra are the same or different;

[0016] Ring B is a benzene ring, a 5- or 6-membered N-containing heteroaromatic ring, a saturated or partially unsaturated 5- or 6-membered heterocycloalkyl; ring B is optionally substituted by one or more Rb; when there are multiple Rb, the Rb are the same or different;

[0017] R 1 is or -W-COOR 12 ;

[0018] The R 1 is optionally substituted by one or more R 10 ; when there are multiple R 10 , the R 10 are the same or different;

[0019] R 11 , R 12 are each independently selected from: H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl, 6- to 10-membered aryl;

[0020] Alternatively, R 11 , R 12 together with the P to which they are attached form a 4- to 7-membered ring;

[0021] The R 11 is optionally substituted by one or more R 10 ; when there are multiple R 10 , the R 10 are the same or different;

[0022] W is absent or is C 1 -C 3 alkylene;

[0023] R 2 , R 3 are each independently -L 1 -L 2 -C(O)R 4 , -L 1 -L 2 -S(O) 2 R 4 , -L 1 -L 2 -S(O)R 4 R 5, and R 2 、R 3 Among them, exactly one is R 5 ;

[0024] L 1 、L 2 Each independently is absent or selected from -NH, -C 1 -C 6 alkyl, -C 1 -C 6 alkyl-NH-, or and L 1 、L 2 are not both absent at the same time;

[0025] Ring D is a 4- to 6-membered heteroalkyl or a 5- to 6-membered heteroaryl; said ring D is optionally substituted by one or more Rd; when there are multiple Rd, said Rd are the same or different;

[0026] R 4 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, 3- to 8-membered cycloalkyl, 4- to 8-membered heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl; said R 4 is optionally substituted by one or more R 41 ; when R 41 is multiple, said R 41 are the same or different;

[0027] R 5 is 6- to 10-membered aryl, 5- to 12-membered heteroaryl, saturated or partially unsaturated 4- to 12-membered cycloalkyl, saturated or partially unsaturated 4- to 12-membered heteroalkyl;

[0028] said R 5 is optionally substituted by one or more R 51 ; when R 51 is multiple, said R 51 are the same or different;

[0029] said R 10 、R 41 、R 51 、Ra, Rb, Rd each independently is selected from: H, halogen, -OH, -NH 2 、-NO 2 、-CN, C 1 -C 6 alkyl, C2 -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 , -SF 5 , -S(C 1 -C 6 alkyl), oxo(=O), =CH 2 , =CH-C 1 -C 6 alkyl, 3- to 8-membered cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl;

[0030] Said R 10 , R 41 , R 51 , Ra, Rb, Rd are optionally substituted by substituents selected from the following: halogen, -OH, -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 .

[0031] The present invention also provides a compound represented by formula I', its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:

[0032]

[0033] wherein, ring A is a benzene ring, a 5- to 6-membered N-containing heteroaryl ring; said ring A is optionally substituted by one or more Ra; when there are multiple Ra, said Ra are the same or different;

[0034] Ring B is a benzene ring, a 5- to 6-membered N-containing heteroaryl ring, a saturated or partially unsaturated 5- to 6-membered heterocycloalkyl; said ring B is optionally substituted by one or more Rb; when there are multiple Rb, said Rb are the same or different;

[0035] R 1 is R 11 , R 12 each independently selected from: C1 -C 6 alkyl, C 1 -C 6 alkoxy; or R 11 , R 12 together with the P to which they are attached form a 4- to 7-membered ring;

[0036] Said R 1 is optionally substituted by one or more R 10 ; when there are multiple R 10 , said R 10 are the same or different;

[0037] R 2 , R 3 are each independently -L 1 -L 2 -C(O)R 4 、-L 1 -L 2 -S(O) 2 R 4 、-L 1 -L 2 -S(O)R 4 、R 5 , and R 2 , R 3 there is exactly one of them that is R 5 ;

[0038] L 1 , L 2 are each independently absent or selected from -NH, -C 1 -C 6 alkyl, -C 1 -C 6 alkyl-NH-, or and L 1 , L 2 are not both absent at the same time;

[0039] Ring D is a 4- to 6-membered heteroalkyl or a 5- to 6-membered heteroaryl; said ring D is optionally substituted by one or more Rd; when there are multiple Rd, said Rd are the same or different;

[0040] R 4 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy; said R 4 is optionally substituted by one or more R 41 ; when R41 When there are multiple, said R 41 are the same or different;

[0041] R 5 is a benzene ring, a 5-12 membered heteroaryl group, a saturated or partially unsaturated 4-12 membered cycloalkyl group, a saturated or partially unsaturated 4-12 membered heterocycloalkyl group;

[0042] Said R 5 is optionally substituted by one or more R 51 ; when R 51 is multiple, said R 51 are the same or different;

[0043] Said R 10 , R 41 , R 51 , Ra, Rb, Rd 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, -NH-C 1 -C 6 alkyl, -N(C 1 -C 6 alkyl) 2 , -SF 5 , -S(C 1 -C 6 alkyl), oxo (=O), =CH 2 , =CH-C 1 -C 6 alkyl;

[0044] Said 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 , -S(C 1 -C 6 alkyl), =CH 2 , =CH-C1 -C 6 The alkyl group is optionally substituted by substituents selected from the following: halogen, -OH, -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 .

[0045] The present invention also provides a compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:

[0046]

[0047] Wherein, ring A is a benzene ring, a 5-6 membered N-containing heteroaromatic ring; the ring A is optionally substituted by one or more Ra; when there are multiple Ra, the Ra are the same or different;

[0048] Ring B is a benzene ring, a 5-6 membered N-containing heteroaromatic ring; the ring B is optionally substituted by one or more Rb; when there are multiple Rb, the Rb are the same or different;

[0049] R 1 is R 11 , R 12 each independently selected from: C 1 -C 6 alkyl, C 1 -C 6 alkoxy; or R 11 , R 12 together with the P to which they are attached form a 4-7 membered ring; the R 1 is optionally substituted by one or more R 10 ; when there are multiple R 10 , the R 10 are the same or different;

[0050] R 2 , R 3 each independently is -L 1 -L 2 -C(O)R 4 , -S(O) 2 R 4 , -S(O)R 4 , R 5 , and R 2 , R3 Only one of them is R 5 ;

[0051] L 1 、L 2 are each independently absent or selected from -NH, -C 1 -C 6 alkyl, -C 1 -C 6 alkyl-NH-, or and L 1 、L 2 are not both absent at the same time;

[0052] Ring D is a 4-6 membered heteroalkyl or a 5-6 membered heteroaryl; said ring D is optionally substituted by one or more Rd; when there are multiple Rd, said Rd are the same or different;

[0053] R 4 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy; said R 4 is optionally substituted by one or more R 41 ; when R 41 is multiple, said R 41 are the same or different;

[0054] R 5 is a benzene ring, a 5-12 membered heteroaryl; said R 5 is optionally substituted by one or more R 51 ; when R 51 is multiple, said R 51 are the same or different;

[0055] Said R 10 、R 41 、R 51 、Ra, Rb, Rd 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, -NH-C 1 -C 6alkyl, -N(C 1 -C 6 alkyl) 2 、-SF 5 、-S(C 1 -C 6 alkyl), oxo(=O);

[0056] The 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 、-S(C 1 -C 6 alkyl) is optionally substituted with substituents selected from the following: halogen, -OH, -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 。

[0057] In a preferred embodiment, R 11 、R 12 together with the P to which they are attached form a 4-, 5-, 6- or 7-membered heteroalkyl ring.

[0058] In a preferred embodiment, R 1 is R 11 、R 12 are each independently methyl, ethyl, propyl, butyl; or R 11 、R 12 together with the P to which they are attached form a 5- or 6-membered saturated, unsaturated or partially unsaturated ring;

[0059] The R 1 is optionally substituted with one or more R 10 ; when R 10 is plural, the R 10 are the same or different; preferably, R 1 is

[0060] In a preferred embodiment, ring A is benzene, pyridine, pyridazine, pyrimidine, pyrazine;

[0061] Ring B is pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,3-dihydroimidazol-2-one

[0062] In a preferred embodiment, ring A is benzene, pyridine, and ring B is pyrazole, pyridine, pyridazine, 1,3-dihydroimidazol-2-one.

[0063] In a preferred embodiment, the compound has the structures shown in Formula Ia and Formula Ib

[0064]

[0065] wherein, V 1 、V 2 、V 3 、V 4 are each independently CH or N;

[0066] R 1 、R 2 、R 3 are defined as described above.

[0067] In a preferred embodiment, R 2 is -L 1 -L 2 -C(O)R 4 、-L 1 -L 2 -S(O) 2 R 4 、-L 1 -L 2 -S(O)R 4 ,R 3 is R 5 ; or, R 3 is -L 1 -L 2 -C(O)R 4 、-L 1 -L 2 -S(O) 2 R 4 、-L 1 -L 2 -S(O)R 4 ,R 2 is R 5 .

[0068] In a preferred embodiment, has the following structure:

[0069] In a preferred embodiment, has the following structure:

[0070] In a preferred embodiment, the compound has the structure shown in Formula Ic:

[0071]

[0072] wherein, V 1 、V 2 、V 3 、V 4 、V 5 、V 6 are each independently CH or N;

[0073] R 1 、R 2 、R 3 are as defined above;

[0074] Preferably, one, two, three, or four of V 1 、V 2 、V 3 、V 4 、V 5 、V 6 are N.

[0075] In a preferred embodiment, has the following structure:

[0076] In a preferred embodiment, R 2 is -L 1 -L 2 -C(O)R 4 、-S(O) 2 R 4 、-S(O)R 4 ,R 3 is R 5 .

[0077] In a preferred embodiment, R 3 is -L 1 -L 2 -C(O)R 4 、-S(O) 2 R 4 、-S(O)R 4 ,R 2 is R 5 .

[0078] In a preferred embodiment, -L 1 -L 2 -C(O)R 4 Selected from: -C 1 -C 6 alkyl-NH-C(O)R 4 、-NH-C(O)R 4 、

[0079] and / or, -L 1 -L 2 -S(O) 2 R 4 is In a preferred embodiment, -C 1 -C 6 alkyl-NH-C(O)R 4 is -CH 2 -NH-C(O)R 4 .

[0080] In a preferred embodiment, R 4 is C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; said R 4 is optionally substituted by R 41 .

[0081] In a preferred embodiment, the C 2 -C 6 alkenyl is -CH=CH 2 .

[0082] In a preferred embodiment, R 41 is a halogen, such as F, Cl.

[0083] In a preferred embodiment, R 41 is F, Cl, -OH, -OCH 3 、-NHCH 3 、-N(CH 3 ) 2 .

[0084] In a preferred embodiment, R 4 is -CH=CH 2 、-CF=CH 2 、-CCl=CH 2 、-CH=CHCH 3 、-CH=CHCH 2 OH、-CH=CHCH 2 OCH3 , -CH=CHCH 2 -N(CH 3 ) 2 , -CH≡CH, -C≡CH-CH 3 , -C≡CHCH 2 OH, -C(CH 3 )=CH 2 。

[0085] In a preferred embodiment, -L 1 -L 2 -C(O)R 4 is -CH 2 -NH-C(O)-CH=CH 2 , -CH 2 -NH-C(O)-CF=CH 2 ,

[0086]

[0087] and / or, -L 1 -L 2 -S(O) 2 R 4 is

[0088] In a preferred embodiment, R 5 is a benzene ring; said R 5 is optionally substituted by R 51 ;

[0089] Preferably, R 51 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, -SF 5 , -S(C 1 -C 6 alkyl), -S(C 1 -C 6 haloalkyl);

[0090] Preferably, R 51 is selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C3 Halogenated alkoxy, -SF 5 , -S(C 1 -C 3 alkyl), -S(C 1 -C 3 halogenated alkyl);

[0091] Preferably, R 51 is selected from -CF 3 , -O-CF 3 , -S-CF 3 , -SF 5 .

[0092] Preferably, R 5 is

[0093] In a preferred embodiment, R 5 is a benzene ring, cyclohexane, cyclohexene; the R 5 is optionally substituted by R 51 .

[0094] In a preferred embodiment, R 5 is a benzene ring, R 51 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 halogenated alkyl, C 1 -C 6 halogenated alkoxy, -SF 5 , -S(C 1 -C 6 alkyl), -S(C 1 -C 6 halogenated alkyl); or, R 5 is cyclohexane, cyclohexene, R 51 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 halogenated alkyl, C 1 -C 6 halogenated alkoxy, -SF 5 , -S(C 1 -C 6 alkyl), -S(C 1 -C 6 halogenated alkyl), =CF 2 .

[0095] In a preferred embodiment, R5 is a benzene ring, R 51 is selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, -SF 5 , -S(C 1 -C 3 alkyl), -S(C 1 -C 3 haloalkyl); or, R 5 is cyclohexane, cyclohexene, R 51 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, -SF 5 , -S(C 1 -C 6 alkyl), -S(C 1 -C 6 haloalkyl), =CF 2 .

[0096] In a preferred embodiment, R 5 is a benzene ring, R 51 is selected from -CF 3 , -O-CF 3 , -S-CF 3 , -SF 5 ; or, R 5 is cyclohexane, cyclohexene, R 51 is selected from -CF 3 , -O-CF 3 , -S-CF 3 , -SF 5 , =CF 2 .

[0097] In a preferred embodiment, R 5 is

[0098] In a preferred embodiment, R 5 is

[0099] In a preferred embodiment, the compound has the following structure:

[0100]

[0101] In a preferred embodiment, the compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is selected from:

[0102]

[0103]

[0104]

[0105]

[0106] The present invention also provides a compound represented by formula I", its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:

[0107]

[0108] Wherein, ring A is a benzene ring, a 5-6 membered N-containing heteroaromatic ring; the ring A is optionally substituted by one or more Ra; when there are multiple Ra, the Ra are the same or different;

[0109] Ring B is a benzene ring, a 5-6 membered N-containing heteroaromatic ring, a saturated or partially unsaturated 5-6 membered heterocycloalkyl; the ring B is optionally substituted by one or more Rb; when there are multiple Rb, the Rb are the same or different;

[0110] R 1 is -W-COOR 12 ; wherein, R 11 , R 12 are H, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered heteroaryl, 6-10 membered aryl;

[0111] W is absent or is C 1 -C 3 alkylene;

[0112] The R 11 is optionally substituted by one or more R 10 ; when there are multiple R 10 , the R 10 are the same or different;

[0113] The R 10 is selected from: -H, halogen, -OH, -NH2 , -CN, C 1 -C 6 alkyl;

[0114] R 2 , R 3 are each independently -L 1 -L 2 -C(O)R 4 , -L 1 -L 2 -S(O) 2 R 4 , -L 1 -L 2 -S(O)R 4 , R 5 , and R 2 , R 3 has and only has one as R 5 ;

[0115] L 1 , L 2 are each independently absent or selected from -NH, -C 1 -C 6 alkyl, -C 1 -C 6 alkyl-NH-, or and L 1 , L 2 are not both absent at the same time;

[0116] Ring D is a 4-6 membered heteroalkyl or 5-6 membered heteroaryl; said Ring D is optionally substituted by one or more Rd; when there are multiple Rd, said Rd are the same or different;

[0117] R 4 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, 3-8 membered cycloalkyl, 4-8 membered heteroalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; said R 4 is optionally substituted by one or more R 41 ; when R 41 is multiple, said R 41 are the same or different;

[0118] R 5is a 6-10 membered aryl, 5-12 membered heteroaryl, 4-12 membered cycloalkyl or 4-12 membered heterocycloalkyl, and the 4-12 membered cycloalkyl or 4-12 membered heterocycloalkyl is saturated or partially unsaturated;

[0119] said R 5 is optionally substituted by one or more R 51 ; when there are multiple R 51 s, said R 51 s are the same or different;

[0120] said R 41 , R 51 , Ra, Rb, Rd 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, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1 -C 6 alkoxy, -NH-C 1 -C 6 alkyl, -N(C 1 -C 6 alkyl) 2 , -SF 5 , -S(C 1 -C 6 alkyl), oxo(=O), =CH 2 , =CH-C 1 -C 6 alkyl;

[0121] said R 41 , R 51 , Ra, Rb, Rd are optionally substituted by substituents selected from: halogen, -OH, -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 .

[0122] In a preferred embodiment, said R 1 is or -COOH; wherein, R 11 is C 1 -C 3 alkyl, 3- to 6-membered cycloalkyl; W is absent or is -CH 2 -; said R 11 is optionally substituted by one or more R 10 ; when there are multiple Rs 10 , said Rs 10 are the same or different; said R 10 is selected from: -H, -OH.

[0123] In a preferred embodiment, R 11 is methyl, cyclopropyl, -CH 2 CH 2 OH.

[0124] In a preferred embodiment, ring A is a benzene ring, pyridine, pyridazine, pyrimidine, pyrazine.

[0125] In a preferred embodiment, ring B is pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,3-dihydroimidazol-2-one.

[0126] In a preferred embodiment, the compound represented by formula I", its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, has the following structure:

[0127]

[0128] wherein, V 1 , V 2 , V 3 , V 4 , V 5 , V 6 are each independently CH or N;

[0129] R 1 , R 2 , R 3 are as defined above.

[0130] In a preferred embodiment, the compound represented by formula I", its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug,

[0131] has the following structure:

[0132] has the following structure:

[0133] It has the following structure:

[0134] In a preferred embodiment, it has the following structure:

[0135]

[0136] In a preferred embodiment, the compound represented by formula I", its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has the following structure:

[0137]

[0138] Wherein, R 1 , R 2 , R 3 are defined as described above.

[0139] In a preferred embodiment, the R 2 is -L 1 -L 2 -C(O)R 4 , -L 1 -L 2 -S(O) 2 R 4 , -L 1 -L 2 -S(O)R 4 , R 3 is R 5 .

[0140] In a preferred embodiment, R 3 is -L 1 -L 2 -C(O)R 4 , -L 1 -L 2 -S(O) 2 R 4 , -L 1 -L 2 -S(O)R 4 , R 2 is R 5 .

[0141] In a preferred embodiment, the -L 1 -L 2 -C(O)R 4 is selected from: -C 1 -C 6 alkyl-NH-C(O)R 4 , -NH-C(O)R4 ,

[0142]

[0143] In a preferred embodiment, the -L 1 -L 2 -S(O) 2 R 4 is

[0144] In a preferred embodiment, R 4 is C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; said R 4 is optionally substituted by R 41 .

[0145] In a preferred embodiment, R 41 is F, Cl, -OH, -OCH 3 , -NHCH 3 , -N(CH 3 ) 2 .

[0146] In a preferred embodiment, R 4 is -CH=CH 2 , -CF=CH 2 , -CH=CHF, -CCl=CH 2 , -CH=CHCH 3 , -C(CH 3 )=CH 2 , -CH=CHCH 2 OH, -CH=CHCH 2 OCH 3 , -CH=CHCH 2 -N(CH 3 ) 2 , -C≡CH, -C≡C-CH 3 , -C≡CCH 2 OH.

[0147] In a preferred embodiment, -L 1 -L 2 -C(O)R 4 is -CH 2 -NH-C(O)-CH=CH 2 , -CH 2 -NH-C(O)-CF=CH 2 ,

[0148]

[0149] In a preferred embodiment, -L 1 -L 2 -S(O) 2 R 4 is

[0150] In a preferred embodiment, R 5 is a benzene ring, cyclohexane, cyclohexene; said R 5 is optionally substituted by R 51 .

[0151] In a preferred embodiment, R 5 is a benzene ring, R 51 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, -SF 5 , -S(C 1 -C 6 alkyl), -S(C 1 -C 6 haloalkyl); or, R 5 is cyclohexane, cyclohexene, R 51 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, -SF 5 , -S(C 1 -C 6 alkyl), -S(C 1 -C 6 haloalkyl), =CF 2 .

[0152] In a preferred embodiment, R 5 is a benzene ring, R 51 is selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, -SF5 、 -S(C 1 -C 3 alkyl), -S(C 1 -C 3 haloalkyl); or, R 5 is cyclohexane, cyclohexene, R 51 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, -SF 5 、 -S(C 1 -C 6 alkyl), -S(C 1 -C 6 haloalkyl), =CF 2 .

[0153] In a preferred embodiment, R 5 is a benzene ring, cyclohexane, cyclohexene.

[0154] In a preferred embodiment, R 51 is selected from -CF 3 、 -O-CF 3 、 -S-CF 3 、 -SF 5 、 =CF 2 .

[0155] In a preferred embodiment, R 5 is

[0156] In a preferred embodiment, R 5 is

[0157]

[0158] In a preferred embodiment, the compound represented by the formula I", its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, is selected from:

[0159]

[0160]

[0161] The present invention also provides a pharmaceutical composition, which comprises any one of the compounds described above, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier.

[0162] The present invention also provides the use of the compound described above, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition described in the second aspect, wherein the use refers to at least one of the following uses:

[0163] Preparing a drug, pharmaceutical composition or preparation for preventing and / or treating a disease or disorder associated with increased TEAD expression; and / or,

[0164] Preparing a drug, pharmaceutical composition or preparation for reducing / inhibiting TEAD expression and increased TEAD activity; and / or,

[0165] Preparing a drug, pharmaceutical composition or preparation for reducing / inhibiting the Hippo signaling pathway.

[0166] In a preferred embodiment, the TEAD includes: TEAD1, TEAD2, TEAD3 and TEAD4.

[0167] In a preferred embodiment, the disease is a cell proliferative disease.

[0168] In a preferred embodiment, the cell proliferative disorder is cancer.

[0169] In a preferred embodiment, the disease is selected from: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute granulocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, monomyelocytic and promyelocytic leukemia), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic granulocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysplastic changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's sarcoma, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's disease and non-Hodgkin's disease), lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenström's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

[0170] The present invention also provides a method for treating a disease or disorder, comprising administering to a patient a therapeutically effective amount of at least one of the above compounds, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, or the pharmaceutical composition.

[0171] 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.

[0172] In a preferred embodiment of the present invention, the disease is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.

[0173] In a preferred embodiment of the present invention, the disease is the above-mentioned disease.

[0174] In some embodiments, the patient mammal is preferably a human.

[0175] Additional aspects and advantages of the invention will be given in part in the description which follows, and in part will become apparent from the description, or may be learned by practice of the invention.

[0176] Terms and Definitions

[0177] Unless otherwise specified, the definitions of groups and terms set forth in the specification and claims of this application, including their definitions by way of example, exemplary definitions, preferred definitions, definitions set forth in tables, definitions of specific compounds in the examples, etc., may be combined and combined with each other arbitrarily. The group definitions and compound structures after such combination and combination shall fall within the scope described in the specification of this application.

[0178] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. Unless otherwise noted, all patents, patent applications, and published materials cited herein in their entirety are incorporated herein by reference. If there are multiple definitions of a term in this article, the definitions in this chapter shall prevail.

[0179] It should be understood that the foregoing summary and the detailed description below are exemplary and explanatory only and do not limit the subject matter of the invention in any way. In this application, unless otherwise specifically stated, the singular form also includes the plural when used. It must be noted that, unless clearly stated otherwise in the text, the singular forms used in the specification and claims include the plural forms of the indicated things. It should also be noted that, unless otherwise stated, the terms "or" or "or" mean "and / or". In addition, the term "comprising" and other forms, such as "including", "containing", and "having" are not restrictive.

[0180] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED.", Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise specified, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR, and UV / VIS spectroscopy, and pharmacological methods. Unless a specific definition is provided, the terms used herein in the descriptions related to analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and the treatment of patients. For example, the instructions of the manufacturer for the kits can be utilized, or the reactions and purifications can be carried out in a manner known in the art or as described in the present invention. Generally, the above-mentioned techniques and methods can be implemented according to the descriptions in a plurality of general and more specific documents cited and discussed in this specification, in accordance with the conventional methods well-known in the art. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0181] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, CH 2 O is equivalent to OCH 2 . As used herein, represents the attachment site of a group. As used herein, "R 1 ", "R1", and "R 1 " have the same meaning and can be used interchangeably. For other symbols such as R 2 , other similarly defined symbols have the same meaning.

[0182] The section headings used herein are for the purpose of organizing the article only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals of operations, and theses, are hereby incorporated by reference in their entirety.

[0183] Except as described above, when used in the specification and claims of this application, unless otherwise specifically indicated, the following terms have the meanings shown below.

[0184] For the numerical ranges recited in the specification and claims of this application, when the numerical range is understood as "integers", it should be understood that the two endpoints of the range and each integer within the range are recited. For example, "integers from 0 to 5" should be understood to recite each of 0, 1, 2, 3, 4, and 5.

[0185] In the present application, the term "halogen" refers to fluorine, chlorine, bromine, or iodine when taken alone or as part of another substituent.

[0186] As used herein, the term "alkyl" when taken alone or as part of another substituent means a straight-chain or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing no unsaturated bonds, having for example 1 to 6 carbon atoms, and being attached to the remainder of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. The alkyl group may be unsubstituted or substituted with one or more suitable substituents. The alkyl group may also be an isotopologue of a naturally occurring alkyl group enriched in carbon and / or hydrogen isotopes (i.e., deuterium or tritium). As used herein, the term "alkenyl" denotes an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term "alkynyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.

[0187] When taken alone or as part of another substituent, the term "C 1 -C 6 alkyl" should be understood to denote a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, etc., or their isomers. The term "C 1 -C 3 alkyl" should be understood to denote a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, or 3 carbon atoms. In particular, the group has 1, 2, or 3 carbon atoms ("C 1 -C 3 alkyl"), such as methyl, ethyl, n-propyl, or isopropyl.

[0188] When taken alone or as part of another substituent, the term "C 2 -C 6 alkenyl" should be understood to denote a straight-chain or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, or 6 carbon atoms. For example, having 2 or 3 carbon atoms (i.e., C 2 -C 3(alkenyl). It should be understood that 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-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0189] The term "C 2 -C 6 alkynyl" should be understood to mean a straight-chain or branched monovalent hydrocarbon group that contains one or more triple bonds and has 2, 3, 4, 5, or 6 carbon atoms. For example, having 2 or 3 carbon atoms ("C 2 -C 3"alkynyl"). The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0190] The term "C 1 -C 6 alkoxy" should be understood to mean a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms and an oxygen atom, or represented as C 1 -C 6 alkyl-O-. The definition of C 1 -C 6 alkyl is as described in this specification, and the oxygen atom can be attached to any carbon atom in the straight-chain or branched-chain of C 1 -C 6 alkyl. Including but not limited to: methoxy (CH 3 -O-), ethoxy (C 2 H 5 -O-), propoxy (C 3 H 7 -O-), butoxy (C 4 H 9 -O-), pentyloxy (C 5 H 11 -O-), hexyloxy (C 6 H 13 -O-).

[0191] When alone or as part of other substituents, the term "ring" includes carbocyclic rings and heterocyclic rings, which can be saturated, unsaturated or partially unsaturated rings. The rings include heterocycloalkyl, cycloalkyl, aryl, heteroaryl, etc. For example, the term "4- to 7-membered ring" refers to the above-mentioned rings composed of 4, 5, 6 or 7 atoms.

[0192] When alone or as part of other substituents, the term "heterocycloalkyl" refers to a cycloalkyl in which one or more (in some embodiments, 1, 2 or 3) carbon atoms are replaced by heteroatoms such as, but not limited to, N, O, S and P. The term "m- to n-membered heterocycloalkyl" should be understood to mean a ring having m to n atoms. For example, the term "5- to 6-membered heterocycloalkyl" should be understood to mean a ring having 5 or 6 atoms.

[0193] When alone or as part of other substituents, the term "aryl" or "aromatic ring" or "aromatic ring group" refers to a monocyclic or polycyclic carbocyclic aromatic ring system such as a benzene ring. For example, the term "6- to 10-membered aryl" should be understood to mean a carbocyclic aromatic ring system having 6 to 10 atoms.

[0194] When alone or as part of other substituents, the term "heteroaryl" or "heteroaromatic ring" or "heteroaromatic ring group" refers to a monocyclic or polycyclic aromatic ring system in which, 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, furyl, imidazolyl, dihydroindolyl, pyrrolidinyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl, quinolinyl and isoquinolinyl. For example, the term "5- to 6-membered heteroaryl" should be understood to mean a heteroatom-containing aromatic ring system having 5 to 6 atoms.

[0195] When alone or as part of other substituents, the term "halo" can be used interchangeably with the term "halogen substitution". "Haloalkyl" or "halogen-substituted alkyl" refers to a branched or straight-chain saturated aliphatic hydrocarbon group including a specific number of carbon atoms and substituted by one or more halogens (such as -CvFw, where v = 1 to 3 and w = 1 to (2v + 1)). Examples of haloalkyls include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl and heptachloropropyl.

[0196] The compounds provided herein, including intermediates useful for preparing the compounds provided herein, which contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), also include their protected derivatives. "Protected derivatives" are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also referred to as protecting groups). Suitable protecting groups for carboxyl moieties include benzyl, tert-butyl, etc., as well as isotopes, etc. Suitable protecting groups for amino and amine groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for hydroxyl groups include benzyl, etc. Other suitable protecting groups are well known to those of ordinary skill in the art.

[0197] In this application, "optional" or "optionally" means that the subsequent described event or condition may or may not occur, and this description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl is substituted or unsubstituted, and this description includes both substituted aryl and unsubstituted aryl.

[0198] In this application, the terms "salt" or "pharmaceutically acceptable salt" include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0199] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic acids or organic acids that can retain the biological effectiveness of the free base without other side effects. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic bases or organic bases that can maintain the biological effectiveness of the free acid without other side effects. In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts. They can serve as intermediates in the purification of 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.

[0200] The term "stereoisomer" refers to isomers generated by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereoisomers, and conformational isomers.

[0201] Depending on the choice of starting materials and methods, the compounds of the present invention may exist in the form of one or a mixture of the possible isomers, for example as pure enantiomers, or as a mixture of isomers, such as a racemic and diastereoisomeric mixture, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center(s) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the rotation of plane-polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory.

[0202] 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 both the enantiomerically pure compounds and mixtures resulting therefrom are included within the scope of the general formula. The graphical representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114 - 120. The absolute configuration of a stereocenter is represented by wedge and dashed bonds.

[0203] 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 forms. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in an equilibrium form, and attempting to isolate a single tautomer usually results in a mixture whose physical and chemical properties are consistent with those of a mixture of compounds. The position of the equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0204] In the present application, "pharmaceutical composition" refers to a preparation of the compounds of the present invention with a medium commonly accepted in the art for delivering a bioactive compound to a mammal (such as a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to an organism, promote absorption of the active ingredient and thereby exert its biological activity.

[0205] In the present application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent that has been approved by the relevant government regulatory authorities for use in humans or livestock.

[0206] In the present application, the term "solvate" refers to a stoichiometric or non-stoichiometric solvent in which a compound of the present invention or its salt is included and which is bound by intermolecular non-covalent forces, and when the solvent is water, it is a hydrate.

[0207] In the present application, the term "prodrug" refers to a compound that can be converted into a biologically active compound of the present invention under physiological conditions or by solvolysis. The prodrugs of the present invention are prepared by modifying the functional groups in the compound, and such modification can be removed by conventional operations or in vivo to obtain the parent compound. Prodrugs include compounds formed by connecting a hydroxyl group or an amino group in the compound of the present invention to any group, and 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.

[0208] The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compounds can be labeled with radioactive isotopes such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All isotopic compositions of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0209] In the present application, the term "adjuvant" refers to a pharmaceutically inert ingredient. Non-limiting examples of the types of "excipients" include binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, etc. Excipients can enhance the handling characteristics of pharmaceutical formulations, that is, make the formulations more suitable for direct compression by increasing fluidity and / or adhesiveness.

[0210] As used herein, the terms "treatment" and other similar synonyms include the following meanings:

[0211] (i) Preventing the occurrence of a disease or disorder in a mammal, especially when such a mammal is susceptible to the disease or disorder but has not been diagnosed as having the disease or disorder;

[0212] (ii) Inhibiting a disease or disorder, that is, curbing its development;

[0213] (iii) Alleviating a disease or disorder, that is, causing the state of the disease or disorder to subside; or

[0214] (iv) Relieving the symptoms caused by the disease or disorder.

[0215] For the reactions of each step, the reaction temperature can be appropriately selected according to solvents, starting materials, reagents, etc., and the reaction time can also be appropriately selected according to reaction temperature, solvents, starting materials, reagents, etc. After the reaction of each step is completed, the target compound can be separated and purified from the reaction system by common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography and other methods. Without affecting the next reaction, the target compound can also directly enter the next reaction without separation and purification. Each step of the reaction of the present invention is preferably carried out in an inert solvent, and the inert solvents include but are not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof.

[0216] Beneficial effects

[0217] Through extensive and in-depth research, the present inventors unexpectedly developed a TEAD inhibitor with excellent activity. The TEAD inhibitor is the compound described in the present invention, and the compound can significantly inhibit the activity of TEAD transcription and can be used for preventing and / or treating diseases related to increased TEAD expression. Specific embodiments

[0218] The following further illustrates the present invention 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 a limitation on the protection scope of the present invention. On the basis of fully understanding the present invention, for the experimental methods without specific conditions in the following examples, they are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. Those skilled in the art can make non-essential modifications to the technical solutions of the present invention, and such modifications should be regarded as being included in the protection scope of the present invention.

[0219] Preparation Example 1

[0220] Preparation of Intermediate A1

[0221] The synthesis route is shown as follows:

[0222]

[0223] Dissolve 4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (15.00 g, 53.67 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (16.58 g, 80.51 mmol) and cupric acetate anhydrous (14.62 g, 80.51 mmol) in tetrahydrofuran (150 mL), add pyridine (16.98 g, 214.70 mmol), displace the gas 3 times under the protection of an oxygen balloon, and react the reaction solution at 25 °C for 48 hours. Dilute the reaction solution with ethyl acetate, filter using diatomaceous earth, and separate and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:0 - 100:1) to obtain 4-chloro-3-iodo-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine (Intermediate A1) (21.0 g, yield 89.0%).

[0224] LC-MS, M / Z(ESI): 440.0 [M+H] + 。

[0225] Preparation of Compound I-1 in Example 1

[0226] The synthetic route is as follows:

[0227]

[0228] First step: Synthesis of tert-butyl ((4-chloro-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (1-1)

[0229]

[0230] At room temperature, dissolve the compound 4-chloro-3-iodo-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridine (Intermediate A1) (300 mg, 0.68 mmol) and potassium ((tert-butoxycarbonyl)amino)methyltrifluoroborate (194 mg, 0.82 mmol) in a mixed solution of toluene (3 mL) and water (0.3 mL). Under a nitrogen atmosphere, add cesium carbonate (667.12 mg, 2.04 mmol) and chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (cataCXium A-Pd-G2) (64 mg, 0.10 mmol), and stir at 120 °C for 12 h under nitrogen protection. After monitoring by TLC shows that the raw materials have reacted completely, stop stirring, cool the reaction solution to room temperature, add water (15 mL) for dilution, extract with ethyl acetate (5 mL × 3), collect the organic phase and dry it with anhydrous sodium sulfate. Concentrate the organic phase by distillation under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:5) to obtain tert-butyl ((4-chloro-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (1-1) (167 mg, yield 55.3%).

[0231] LC-MS, M / Z(ESI): 443.0 [M+H] + 。

[0232] Step 2: Synthesis of tert-butyl ((4-(dimethylphosphoryl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (1-2)

[0233]

[0234] Under room temperature conditions, dissolve tert-butyl ((4-chloro-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (1-1) (120 mg, 0.27 mmol), dimethylphosphine oxide (42.30 mg, 0.56 mmol), potassium phosphate (60 mg, 0.28 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (47 mg, 0.08 mmol) and tris(dibenzylideneacetone)dipalladium (37 mg, 0.04 mmol) in anhydrous DMF (2 mL), and react in a microwave reactor at 140 °C for 4 h under nitrogen protection. After the reaction is completed, cool the reaction solution to room temperature, quench with water (10 mL), then extract with ethyl acetate (5 mL × 3), collect the organic phase and dry it over anhydrous sodium sulfate, concentrate the organic phase by distillation under reduced pressure, and purify the residue by silica gel column chromatography (methylene chloride:methanol (V / V) = 100:5) to obtain tert-butyl ((4-(dimethylphosphoryl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (1-2) (78 mg, yield 59.42%).

[0235] LC-MS, M / Z(ESI): 485.2 [M+H] + 。

[0236] Step 3: Synthesis of (3-(aminomethyl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)dimethylphosphine oxide hydrochloride (1-3)

[0237]

[0238] Under room temperature conditions, dissolve tert-butyl ((4-(dimethylphosphoryl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (1-2) (75 mg, 0.15 mmol) in anhydrous 1,4-dioxane (2 mL), stir at room temperature, and then slowly add a 1,4-dioxane solution of hydrogen chloride (4 M, 0.38 mL, 1.50 mmol). Continue to stir the reaction solution at room temperature for 30 min. After monitoring by TLC shows that the raw materials have reacted completely, stop stirring, remove the solvent by rotary evaporation under reduced pressure, add ethyl acetate (5 mL), stir at room temperature for 1 h to obtain a suspension, filter the suspension to obtain (3-(aminomethyl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)dimethylphosphine oxide hydrochloride (1-3) (60 mg, yield 92.11%).

[0239] LC-MS, M / Z (ESI): 385.2 [M+H] + 。

[0240] Step 4: Synthesis of N-((4-(Dimethylphosphoryl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)acrylamide (I-1)

[0241]

[0242] At room temperature, dissolve (3-(Aminomethyl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)dimethylphosphine oxide hydrochloride (1-3) (60 mg, 0.14 mmol) in a mixed solution of acetonitrile (1 mL) and water (1 mL), stir at 0 °C for 10 min, then add sodium bicarbonate (60 mg, 0.71 mmol), continue to stir at 0 °C for 10 min, and then slowly dropwise add acryloyl chloride (39 mg, 0.43 mmol). After the addition is complete, the reaction solution continues to be stirred in an ice bath at 0 °C for 30 min. After monitoring by TLC shows that the raw materials have reacted completely, stop stirring, add water (5 mL) to dilute the reaction solution, extract with ethyl acetate (3 mL × 5), collect the organic phase and dry it with anhydrous sodium sulfate, concentrate the organic phase by reduced pressure distillation, and purify the residue by column chromatography silica gel (methylene chloride: methanol (V / V) = 20:1) to obtain the compound N-((4-(Dimethylphosphoryl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)acrylamide (I-1) (37 mg, yield 59.19%).

[0243] LC-MS, M / Z (ESI): 439.2 [M+H] + 。

[0244] 1 H NMR (400 MHz, DMSO-d 6 ): δ8.87 (t, 1H), 8.81 (dd, 1H), 8.37–8.28 (m, 2H), 7.67–7.58 (m, 3H), 6.27 (dd, 1H), 6.09 (dd, 1H), 5.61 (dd, 1H), 5.05 (d, 2H), 1.96 (s, 3H), 1.92 (s, 3H).

[0245] Example 2: Preparation of Compound I-2

[0246] The synthetic route is as follows:

[0247]

[0248] Step 1: Synthesis of 5-Bromo-3-iodo-1-(4-(trifluoromethyl)phenyl)-1H-indazole (2-2)

[0249]

[0250] Dissolve 5-bromo-3-iodo-1H-indazole (2-1) (2.0 g, 6.2 mmol) and 4-(trifluoromethyl)phenylboronic acid (1.77 g, 9.3 mmol) in acetonitrile (20 mL), add copper(II) acetate (1.69 g, 9.3 mmol), then add pyridine (1.96 g, 24.8 mmol), and stir at room temperature overnight under an oxygen balloon. After the reaction is completed, filter through diatomaceous earth, wash the filter cake with dichloromethane (40 mL), combine the filtrates, wash with water (15 mL), and then dry with anhydrous sodium sulfate. After concentrating the organic phase, purify by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain compound 5-bromo-3-iodo-1-(4-(trifluoromethyl)phenyl)-1H-indazole (2-2) (2.53 g, yield: 87.5%).

[0251] LC-MS, M / Z (ESI): 467.1 [M+H] + 。

[0252] Step 2: Synthesis of tert-Butyl ((5-bromo-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (2-3)

[0253]

[0254] Dissolve 5-bromo-3-iodo-1-(4-(trifluoromethyl)phenyl)-1H-indazole (2-2) (1 g, 2.14 mmol) and potassium trifluoroborate(((tert-butoxycarbonyl)amino)methyl) (253.7 mg, 1.07 mmol) in toluene (20 mL) and water (20 mL), add cesium carbonate (2.09 g, 6.42 mmol) and chloro[(n-butylbis(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (144.6 mg, 0.21 mmol) to the system, displace the gas 3 times under nitrogen protection, and heat the reaction solution to 100 °C for reaction overnight. Concentrate the reaction solution, and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain compound tert-Butyl ((5-bromo-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (2-3) (181 mg, yield 18.0%).

[0255] LC-MS, M / Z (ESI): 470.2 [M+H] + 。

[0256] Step 3: Synthesis of tert-Butyl ((5-(Dimethylphosphoryl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (2-4)

[0257]

[0258] Dissolve tert-Butyl ((5-bromo-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (2-3) (181 mg, 0.39 mmol) in N,N-dimethylformamide (3 mL), add dimethylphosphine oxide (156.1 mg, 2.0 mmol) and potassium phosphate (169.8 mg, 0.8 mmol), then add tris(dibenzylideneacetone)dipalladium(0) (36.6 mg, 0.04 mmol) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (46.3 mg, 0.08 mmol), and react at 140 °C under microwave irradiation for 2.5 h under nitrogen protection. After the reaction, cool to room temperature, add water (20 mL) to the reaction solution, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with water (10 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain tert-Butyl ((5-(dimethylphosphoryl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (2-4) (149.6 mg, yield 83.2%).

[0259] LC-MS, M / Z(ESI): 468.1 [M+H] + 。

[0260] Step 4: Synthesis of (3-(Aminomethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-5-yl)dimethylphosphine Oxide Hydrochloride (2-5)

[0261]

[0262] Dissolve tert-Butyl ((5-(dimethylphosphoryl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (2-4) (149.6 mg, 0.32 mmol) in 1,4-dioxane (20 mL), add a 1,4-dioxane solution of hydrogen chloride (4 M, 20 mL), and react at room temperature for 3 h. After the reaction is completed, concentrate the reaction solution under reduced pressure to obtain the crude product (3-(aminomethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-5-yl)dimethylphosphine oxide hydrochloride (2-5), which is directly used in the next step of the reaction.

[0263] LC-MS, M / Z(ESI): 368.1 [M+H] + 。

[0264] Step 5: Synthesis of N-((5-(Dimethylphosphoryl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)acrylamide (I-2)

[0265]

[0266] Dissolve (3-(Aminomethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-5-yl)dimethylphosphine oxide hydrochloride (2-5) (129.2 mg, 0.32 mmol) in tetrahydrofuran (10 mL). Add saturated aqueous sodium bicarbonate solution (2 mL) at 0 °C, stir at 0 °C for 10 minutes, then add acryloyl chloride (28.9 mg, 0.32 mmol), and continue to react at 0 °C for 0.5 hour. After the reaction is completed, add water (10 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify the crude product by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to obtain compound N-((5-(Dimethylphosphoryl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)acrylamide (I-2) (128.2 mg, yield: 95.1%).

[0267] LC-MS, M / Z (ESI): 422.1 [M+H] + 。

[0268] 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.87 (t, 1H), 8.40 (d, 1H), 8.12–8.00 (m, 3H), 7.96 (d, 2H), 7.90 (t, 1H), 6.29 (dd, 1H), 6.16 (d, 1H), 5.64 (d, 1H), 4.83 (d, 2H), 1.73 (s, 3H), 1.69 (s, 3H).

[0269] Example 3: Preparation of Compound I-3

[0270] The synthetic route is as follows:[[]]

[0271]

[0272] Step 1: Synthesis of tert-Butyl 3-(4-chloro-1-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (3-1)

[0273]

[0274] Zinc powder (185 mg, 2.86 mmol) was placed in a reaction flask. Under argon protection, dry N,N-dimethylacetamide (2 mL) was added. Trimethylchlorosilane (45 μL, 0.35 mmol) was added at room temperature, and the mixture was stirred at 45 °C for 30 min. Then, 1,2-dibromomethane (30 μL, 0.35 mmol) was added, and the stirring was continued at 45 °C for another 30 min. Next, 1-tert-butoxycarbonyl-3-iodoazetidine (300 mg, 1.06 mmol) was added, and the reaction solution was stirred at 65 °C for 1 h. The reaction solution was cooled to room temperature, and the organic phase was taken as the freshly prepared zinc reagent for standby. 4-Chloro-3-iodo-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine (Intermediate A1) (347 mg, 0.79 mmol) was placed in another reaction flask, and tris(dibenzylideneacetone)dipalladium (36 mg, 0.04 mmol) and tris(2-furyl)phosphine (19 mg, 0.1 mmol) were added. Under argon protection, N,N-dimethylacetamide (3 mL) and the above freshly prepared zinc reagent were added. Then, the reaction solution was stirred at 70 °C for 2 h. The reaction solution was quenched by adding it to a saturated aqueous sodium bicarbonate solution (20 mL), followed by extraction with ethyl acetate (50 mL). The organic phase was washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain tert-butyl 3-(4-chloro-1-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (3-1) (233 mg, yield: 63%).

[0275] LC-MS, M / Z (ESI): 469.2 [M+H] + 。

[0276] Step 2: Synthesis of tert-butyl 3-[4-[dimethylphosphoryl]-1-[4-[(trifluoromethyl)oxy]phenyl]pyrazolo[3,4-b]pyridin-3-yl]azetidine-1-carboxylate (3-2)

[0277]

[0278] The intermediate tert-butyl 3-(4-chloro-1-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (233 mg, 0.499 mmol) was placed in a reaction flask, and tris(dibenzylideneacetone)dipalladium (27 mg, 0.03 mmol), potassium phosphate (414 mg, 2 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (57.8 mg, 0.1 mmol), and dimethylphosphine oxide (156 mg, 2 mmol) were added. Subsequently, N,N-dimethylformamide (5 mL) was added, and the mixture was subjected to microwave reaction at 140 °C for 2 h under argon protection. After completion, the reaction solution was extracted with ethyl acetate (50 mL), the organic phase was washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain tert-butyl 3-[4-[dimethylphosphoryl]-1-[4-[(trifluoromethyl)oxy]phenyl]pyrazolo[3,4-b]pyridin-3-yl]azetidine-1-carboxylate (3-2) (374 mg, yield: 68%).

[0279] LC-MS, M / Z (ESI): 511.0 [M+H] + 。

[0280] Step 3: Synthesis of 1-(3-[4-(dimethylphosphoryl)-1-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-b]pyridin-3-yl]azetidin-1-yl)-2-fluoro-2-propen-1-one (I-3)

[0281]

[0282] tert-Butyl 3-[4-(dimethylphosphoryl)-1-[4-[(trifluoromethyl)oxy]phenyl]pyrazolo[3,4-b]pyridin-3-yl]azetidine-1-carboxylate (100 mg, 0.2 mmol) was placed in a reaction flask. Trifluoroacetic acid (1 mL) was added at 0 °C, and the mixture was stirred at room temperature for 15 min. Subsequently, the above reaction solution was dropped into saturated sodium bicarbonate solution (5 mL), and then sodium bicarbonate (200 mg) and acetonitrile (5 mL) were added successively. Then, 2-fluoropropionyl chloride (64 mg, 0.6 mmol) was added 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, and then extracted with ethyl acetate (50 mL) and washed with saturated aqueous sodium chloride solution (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to obtain compound 1-(3-[4-(dimethylphosphoryl)-1-[4-(trifluoromethoxy) phenyl]pyrazolo[3,4-b]pyridin-3-yl]azetidin-1-yl)-2-fluoroprop-2-en-1-one (I-3) (47 mg, yield 49%).

[0283] LC-MS, M / Z (ESI): 483.0 [M+H] + 。

[0284] 1 H NMR (400 MHz, DMSO-d 6 6): δ 8.81 (dd, 1H), 8.46–8.32 (m, 2H), 7.67–7.51 (m, 3H), 5.59–5.42 (m, 1H), 5.35–5.27 (m, 1H), 5.13–5.01 (m, 1H), 4.84 (td, 1H), 4.76–4.69 (m, 1H), 4.49–4.39 (m, 2H), 1.91 (d, 3H), 1.87 (d, 3H).

[0285] Example 4: Preparation of Compound I-4

[0286] The synthetic route is as follows:

[0287]

[0288] First step: Synthesis of 4-chloro-3-iodo-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine (4-2)

[0289]

[0290] 4-Chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (4-1) (15.00 g, 53.67 mmol), [4-(trifluoromethyl)phenyl]boronic acid (16.58 g, 80.3 mmol), and cupric acetate anhydrous (14.62 g, 80.51 mmol) were dissolved in acetonitrile (150 mL), pyridine (16.98 g, 214.70 mmol) was added, and the mixture was stirred at 25 °C for 48 h under oxygen protection. The reaction solution was distilled under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 20:1) to obtain 4-chloro-3-iodo-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine (4-2) (21.3 g, yield 88%).

[0291] LC-MS, M / Z (ESI): 424.0 [M+H] + 。

[0292] Step 2: Synthesis of tert-butyl 3-(4-chloro-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (4-3)

[0293]

[0294] Zinc powder (185 mg, 2.86 mmol) was placed in a reaction flask, and the flask was purged with argon three times. Anhydrous N,N-dimethylacetamide (2 mL) was added, and chlorotrimethylsilane (45 μL, 0.35 mmol) was added at room temperature. The reaction mixture was stirred at 45 °C for 30 min, then dibromomethane (30 μL, 0.35 mmol) was added, and stirring was continued at 45 °C for another 30 min. Subsequently, 1-Boc-3-iodoazetidine (300 mg, 1.06 mmol) was added, and the reaction mixture was stirred at 65 °C for 1 h. After the reaction was completed, the reaction mixture was allowed to return to room temperature, and the organic phase was taken as the freshly prepared zinc reagent for later use. 4-Chloro-3-iodo-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine (4-2) (347 mg, 0.79 mmol) was placed in another reaction flask, tris(dibenzylideneacetone)dipalladium (36 mg, 0.04 mmol) and tris(2-furyl)phosphine (19 mg, 0.1 mmol) were added, and the flask was purged with argon three times. N,N-Dimethylacetamide (3 mL) and the above freshly prepared zinc reagent were added, and then the mixture was stirred at 70 °C for 2 h. After the reaction was completed, the reaction mixture was quenched by adding it to saturated aqueous sodium bicarbonate solution (20 mL), then diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium chloride solution (50 mL × 3), and then the organic phase was taken, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain tert-butyl 3-(4-chloro-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (4-3) (243 mg, yield: 67%).

[0295] LC-MS, M / Z (ESI): 453.3 [M+H] + 。

[0296] Step 3: Synthesis of tert-butyl 3-(4-(dimethylphosphate)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (4-4)

[0297]

[0298] tert-Butyl 3-(4-(dimethylphosphate)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (4-3) (233 mg, 0.499 mmol) was placed in a reaction flask. Tris(dibenzylideneacetone)dipalladium (27 mg, 0.03 mmol), potassium phosphate (414 mg, 2 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (57.8 mg, 0.1 mmol) and dimethylphosphine oxide (156 mg, 2.0 mmol) were added. Subsequently, N,N-dimethylformamide (5 mL) was added, and the mixture was subjected to microwave reaction at 140 °C for 2 h under an argon atmosphere. After completion, the reaction solution was diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium chloride solution (50 mL × 3), and then the organic phase was taken, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain tert-Butyl 3-(4-(dimethylphosphate)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (4-4) (367 mg, 66%).

[0299] LC-MS, M / Z (ESI): 495.2 [M+H] + 。

[0300] Step 4: Synthesis of 1-(3-(4-(dimethylphosphate)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidin-1-yl)-2-fluoropropyl-2-en-1-one (I-4)

[0301]

[0302] tert-Butyl 3-(4-(dimethylphosphate)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (4-4) (100 mg, 0.2 mmol) was placed in a reaction flask. Trifluoroacetic acid (1 mL) was added at 0 °C, and the mixture was reacted at room temperature for 15 min. Subsequently, the above reaction solution was dropped into saturated sodium bicarbonate solution (5 mL), sodium bicarbonate (200 mg) and acetonitrile (5 mL) were added, and then 2-fluoropropionyl chloride (64 mg, 0.6 mmol) was added at 0 °C. The reaction solution was stirred at 0 °C for 15 min. After completion, the reaction solution was concentrated to remove acetonitrile and water, and the residue of the reaction solution was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain the target compound 1-(3-(4-(dimethylphosphate)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidin-1-yl)-2-fluoropropyl-2-en-1-one (I-4) (52 mg, 51%).

[0303] LC-MS, M / Z (ESI): 467.1 [M+H] + 。

[0304] 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.88–8.81 (m, 1H), 8.61 (m, 2H), 7.98 (m, 2H), 7.64 (m, 1H), 5.59–5.42 (m, 1H), 5.31 (m, 1H), 5.12–5.03 (m, 1H), 4.85 (m, 1H), 4.78–4.71 (m, 1H), 4.46 (m, 2H), 1.91 (s, 3H), 1.88 (s, 3H).

[0305] Preparation of Compound I-5 in Example 5

[0306] The synthetic route is as follows:

[0307]

[0308] The First Step: Synthesis of 7-Chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (5-2)

[0309]

[0310] Dissolve 7-chloro-1H-pyrazolo[4,3-b]pyridine (5-1) (1.0 g, 6.51 mmol) and potassium hydroxide (1.83 g, 32.55 mmol) in N,N-dimethylformamide (15 mL), add iodine (3.31 g, 13.02 mmol), and react at room temperature for 15 hours. After the reaction is completed, quench the reaction with saturated aqueous sodium sulfite solution (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The obtained crude product is separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain compound 7-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (5-2) (1.55 g, yield 85.2%).

[0311] LC-MS, M / Z (ESI): 280.1 [M+H] + 。

[0312] The Second Step: Synthesis of tert-Butyl 3-(7-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (5-3)

[0313]

[0314] 7-Chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (5-2) (1.55 g, 5.55 mmol) and tert-butyl 3-hydroxyazetidine-1-carboxylate (1.44 g, 8.33 mmol) were dissolved in anhydrous tetrahydrofuran (15 mL). Triphenylphosphine (4.37 g, 16.65 mmol) was added, and diethyl azodicarboxylate (2.90 g, 16.65 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes, then slowly warmed to room temperature and stirred overnight. Subsequently, the reaction mixture was heated to 100 °C and stirred for 6 hours under nitrogen protection. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to obtain tert-butyl 3-(7-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (5-3) (1.41 g, yield 58.3%).

[0315] LC-MS, M / Z (ESI): 435.1 [M+H] + 。

[0316] Step 3: Synthesis of tert-butyl 3-(7-chloro-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (5-4)

[0317]

[0318] Tert-butyl 3-(7-chloro-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (5-3) (1.41 g, 3.24 mmol) and (4-(trifluoromethyl)phenyl)boronic acid (0.62 g, 3.24 mmol) were dissolved in 1,4-dioxane (20.0 mL) and water (4.00 mL). Cesium carbonate (2.11 g, 6.48 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (234.1 mg, 0.32 mmol) were added, and the mixture was stirred at 80 °C overnight under nitrogen protection. After the reaction was completed, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, 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 tert-butyl 3-(7-chloro-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (5-4) (1.26 g, yield 85.7%).

[0319] LC-MS, M / Z (ESI): 453.2 [M+H] + 。

[0320] Step 4: Synthesis of tert-butyl 3-(7-(dimethylphosphoryl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (5-5)

[0321]

[0322] Dissolve tert-butyl 3-(7-chloro-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (5-4) (226 mg, 0.50 mmol) in N,N-dimethylformamide (3 mL), add dimethylphosphinous oxide (156.1 mg, 2.0 mmol) and potassium phosphate (265.3 mg, 1.25 mmol), then add tris(dibenzylideneacetone)dipalladium(0) (45.8 mg, 0.05 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (57.9 mg, 0.10 mmol), and react at 140 °C under microwave irradiation for 2.5 h under nitrogen protection. After the reaction is completed, cool the reaction solution to room temperature, dilute with water (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with water (10 mL), dry over anhydrous sodium sulfate, filter and concentrate. Purify the crude product by silica gel column chromatography (methylene chloride:methanol (V / V) = 20:1) to obtain the compound tert-butyl 3-(7-(dimethylphosphoryl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (5-5) (201.1 mg, yield 81.5%).

[0323] LC-MS, M / Z (ESI): 495.2 [M+H] + 。

[0324] Step 5: Synthesis of (1-(azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)dimethylphosphinous oxide (5-6)

[0325]

[0326] tert-Butyl 3-(7-(dimethylphosphoryl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (5-5) (201.1 mg, 0.41 mmol) was dissolved in 1,4-dioxane (15 mL), and a 1,4-dioxane solution of hydrogen chloride (5 mL, 4 M) was added. The mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solvent was removed by distillation under reduced pressure. The pH was adjusted to 8 with saturated aqueous sodium bicarbonate (10 mL) at 0 °C, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound (1-(azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)dimethylphosphine oxide (5-6), which was directly used in the next reaction.

[0327] LC-MS, M / Z(ESI): 395.1 [M+H] + 。

[0328] Step 6: Synthesis of 1-(3-(7-(dimethylphosphoryl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one (I-5)

[0329]

[0330] 2-Fluoroacrylic acid (37 mg, 0.41 mmol) and N,N-diisopropylethylamine (131.8 mg, 1.02 mmol) were dissolved in N,N-dimethylformamide (5 mL), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (193.9 mg, 0.51 mmol) was added, and the mixture was stirred at room temperature for 0.5 hour. (1-(Azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)dimethylphosphine oxide (5-6) (135.2 mg, 0.34 mmol) was added, and the reaction was carried out at room temperature for 4 hours. After the reaction was completed, the mixture was diluted with water (15 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (methylene chloride:methanol (V / V) = 10:1) to obtain the compound 1-(3-(7-(dimethylphosphoryl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one (I-5) (127.3 mg, yield 79.6%).

[0331] LC-MS, M / Z(ESI): 467.0 [M+H]+ .

[0332] 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.79 (dd, 1H), 8.71 (d, 2H), 7.91 (d, 2H), 7.71 (dd, 1H), 6.99–6.88 (m, 1H), 5.62–5.45 (m, 1H), 5.34 (dd, 1H), 4.97–4.88 (m, 1H), 4.87–4.78 (m, 1H), 4.54 (d, 2H), 1.96 (d, 3H), 1.93 (d, 3H).

[0333] Preparation of Compound I-6 in Example 6

[0334] The synthetic route is as follows:

[0335]

[0336] First step: Synthesis of tert-butyl 3-(7-chloro-3-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (6-2)

[0337]

[0338] Dissolve tert-butyl 3-(7-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (5-3) (1.41 g, 3.24 mmol) and 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1,3,2-dioxaborolane (0.89 g, 3.24 mmol) in 1,4-dioxane (20.0 mL) and water (4.00 mL), add cesium carbonate (2.11 g, 6.48 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (234.1 mg, 0.32 mmol), displace with nitrogen 3 times, heat the reaction solution to 80 °C and stir overnight. After the reaction is completed, cool the reaction solution to room temperature, extract with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and purify by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain tert-butyl 3-(7-chloro-3-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (6-2) (1.22 g, yield 82.7%).

[0339] LC-MS, M / Z (ESI): 457.2 [M+H] + .

[0340] Step 2: Synthesis of tert-butyl 3-(7-(dimethylphosphoryl)-3-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (6-3)

[0341]

[0342] Dissolve tert-butyl 3-(7-chloro-3-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (6-2) (228 mg, 0.50 mmol) in N,N-dimethylformamide (3 mL), add dimethylphosphinous oxide (156.1 mg, 2.0 mmol) and potassium phosphate (265.3 mg, 1.25 mmol), then add tris(dibenzylideneacetone)dipalladium(0) (45.8 mg, 0.05 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (57.9 mg, 0.10 mmol), and react at 140 °C under microwave irradiation for 2.5 h under nitrogen protection. After the reaction is completed, cool the reaction solution to room temperature, add water (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with water (10 mL), dry over anhydrous sodium sulfate, filter and concentrate, and purify the crude product by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain compound tert-butyl 3-(7-(dimethylphosphoryl)-3-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (6-3) (207.4 mg, yield 83.2%).

[0343] LC-MS, M / Z (ESI): 499.2 [M+H] + 。

[0344] Step 3: Synthesis of ((1-(azetidin-3-yl)-3-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)dimethylphosphinous oxide (6-4)

[0345]

[0346] tert-Butyl 3-(7-(dimethylphosphoryl)-3-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (6-3) (199.4 mg, 0.40 mmol) was dissolved in 1,4-dioxane (15 mL), and a 1,4-dioxane solution of hydrogen chloride (5 mL, 4 M) was added. The reaction was carried out at room temperature for 4 hours. After the reaction was completed, the reaction solvent was removed by distillation under reduced pressure. The pH was adjusted to 8 with saturated aqueous sodium bicarbonate (10 mL) at 0 °C, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of ((1-(azetidin-3-yl)-3-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)dimethylphosphine oxide (6-4), which was directly used in the next step of the reaction.

[0347] LC-MS, M / Z (ESI): 399.1 [M+H] + 。

[0348] Step 4: Synthesis of 1-(3-(7-(dimethylphosphoryl)-3-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one (I-6)

[0349]

[0350] 2-Fluoroacrylic acid (37 mg, 0.41 mmol) and N,N-diisopropylethylamine (131.8 mg, 1.02 mmol) were dissolved in N,N-dimethylformamide (5 mL), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (193.9 mg, 0.51 mmol) was added, and the mixture was stirred at room temperature for 0.5 hour. ((1-(Azetidin-3-yl)-3-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)dimethylphosphine oxide crude product (6-4) (135.4 mg, 0.34 mmol) was added, and the reaction was carried out at room temperature for 4 hours. After the reaction was completed, water (15 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The product was purified by silica gel column chromatography (methylene chloride:methanol (V / V) = 10:1) to obtain 1-(3-(7-(dimethylphosphoryl)-3-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one (I-6) (125.6 mg, yield 78.5%).

[0351] LC-MS, M / Z (ESI): 471.1 [M+H] + 。

[0352] 1 H NMR (400 MHz, DMSO-d 6 ): δ8.64 (dd, 1H), 7.59 (dd, 1H), 7.52–7.46 (m, 1H), 6.85–6.75 (m, 1H), 5.58–5.42 (m, 1H), 5.31 (dd, 1H), 4.88–4.80 (m, 1H), 4.75–4.66 (m, 1H), 4.50–4.36 (m, 2H), 3.00–2.90 (m, 1H), 2.68–2.50 (m, 3H), 2.35–2.24 (m, 1H), 2.15–2.06 (m, 1H), 1.90 (d, 3H), 1.87 (d, 3H), 1.60 (ddd, 1H).

[0353] Preparation of Compound I-7 in Example 7

[0354] The synthetic route is as follows:

[0355]

[0356] The First Step: Synthesis of 4-Chloro-3-iodo-1-(4-(trifluoromethoxy)phenyl)-1H-indazole (7-2)

[0357]

[0358] Dissolve 4-chloro-3-iodo-1H-indazole (7-1) (15.00 g, 53.73 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (16.58 g, 80.3 mmol) and cupric acetate anhydrous (14.62 g, 80.51 mmol) in acetonitrile (150 mL), add pyridine (16.98 g, 214.70 mmol), and stir at 25 °C for 48 hours under oxygen protection. After completion, distill the reaction solution under reduced pressure to remove the solvent, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 20:1) to obtain compound 4-chloro-3-iodo-1-(4-(trifluoromethoxy)phenyl)-1H-indazole (7-2) (21.8 g, yield 90%).

[0359] LC-MS, M / Z (ESI): 438.9 [M+H] + 。

[0360] Step 2: Synthesis of tert-butyl 3-(4-chloro-1-(4-(trifluoromethoxy)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (7-3)

[0361]

[0362] Place zinc powder (185 mg, 2.86 mmol) in a reaction flask, displace with argon three times, add dry N,N-dimethylacetamide (2 mL), add trimethylchlorosilane (45 μL, 0.35 mmol) at room temperature, stir at 45 °C for 30 min, then add dibromomethane (30 μL, 0.35 mmol), continue to stir at 45 °C for 30 min. Subsequently, add 1-Boc-3-iodoazetidine (300 mg, 1.06 mmol), react at 65 °C for 1 h. After completion, cool the reaction solution to room temperature, take the organic phase as the freshly prepared zinc reagent for standby. Place 4-chloro-3-iodo-1-(4-(trifluoromethoxy)phenyl)-1H-indazole (7-2) (347 mg, 0.79 mmol) in another reaction flask, add tris(dibenzylideneacetone)dipalladium (36 mg, 0.04 mmol) and tris(2-furyl)phosphine (19 mg, 0.1 mmol), displace with argon three times, add N,N-dimethylacetamide (3 mL) and the above freshly prepared zinc reagent, then stir at 70 °C for 2 h. After completion, quench the reaction solution by adding it to saturated sodium bicarbonate aqueous solution (20 mL), then dilute with ethyl acetate (50 mL), wash with saturated sodium chloride aqueous solution (50 mL × 3), take the organic phase, dry with anhydrous sodium sulfate, filter and concentrate. The residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain compound tert-butyl 3-(4-chloro-1-(4-(trifluoromethoxy)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (7-3) (287 mg, yield: 71%).

[0363] LC-MS, M / Z(ESI): 468.2 [M+H] + 。

[0364] Step 3: Synthesis of tert-butyl 3-(4-(dimethylphosphate)-1-(4-(trifluoromethoxy)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (7-4)

[0365]

[0366] tert-Butyl 3-(4-(dimethylphosphate)-1-(4-(trifluoromethoxy)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (7-3) (233 mg, 0.499 mmol) was placed in a reaction flask, and tris(dibenzylideneacetone)dipalladium (27 mg, 0.03 mmol), potassium phosphate (414 mg, 2 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (57.8 mg, 0.1 mmol), and dimethylphosphine oxide (156 mg, 2.0 mmol) were added. Subsequently, N,N-dimethylformamide (5 mL) was added, and the mixture was subjected to microwave reaction at 140 °C for 2 h under an argon atmosphere. After completion, the reaction solution was diluted with ethyl acetate (50 mL), extracted with saturated aqueous sodium chloride solution (50 mL × 3), and then the organic phase was taken, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain tert-butyl 3-(4-(dimethylphosphate)-1-(4-(trifluoromethoxy)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (7-4, 342 mg, 61%).

[0367] LC-MS, M / Z (ESI): 510.3 [M+H] + 。

[0368] Step 4: Synthesis of 1-(3-(4-(dimethylphosphate)-1-(4-(trifluoromethoxy)phenyl)-1H-indazol-3-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one

[0369]

[0370] tert-Butyl 3-(4-(dimethylphosphate)-1-(4-(trifluoromethoxy)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (7-4) (100 mg, 0.2 mmol) was placed in a reaction flask, trifluoroacetic acid (1 mL) was added at 0 °C, and the mixture was reacted at room temperature for 15 min. Subsequently, the above reaction solution was added dropwise to saturated sodium bicarbonate solution (5 mL), sodium bicarbonate (200 mg) and acetonitrile (5 mL) were added, and then 2-fluoropropionyl chloride (64 mg, 0.6 mmol) was added at 0 °C. The reaction solution was reacted at 0 °C for 15 min. After completion of the reaction, the reaction solution was concentrated to remove acetonitrile and water, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain the target compound 1-(3-(4-(dimethylphosphate)-1-(4-(trifluoromethoxy)phenyl)-1H-indazol-3-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one (I-7) (59 mg, 57%).

[0371] LC-MS, M / Z (ESI): 482.1 [M+H] + 。

[0372] 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.06–8.00 (m, 1H), 7.99–7.89 (m, 2H), 7.67–7.53 (m, 4H), 5.57–5.42 (m, 1H), 5.30 (dd, 1H), 5.25–5.17 (m, 1H), 4.85 (td, 1H), 4.72–4.64 (m, 1H), 4.46 (t, 1H), 4.37 (dd, 1H), 1.86 (d, 3H), 1.83 (d, 3H).

[0373] Preparation of Compound I-8 in Example 8

[0374] The synthetic route is as follows:

[0375]

[0376] First step: Synthesis of 2-chloro-4-(dimethylphosphoryl)-3-fluoropyridine (8-2)

[0377]

[0378] Dissolve 2-chloro-3-fluoro-4-iodopyridine (8-1) (6.4 g, 24.86 mmol) in N,N-dimethylformamide (60 mL), add dimethylphosphine oxide (1.93 g, 24.7 mmol) and potassium phosphate (10.5 g, 49.5 mmol), then add tris(dibenzylideneacetone)dipalladium (0.68 g, 0.74 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.86 g, 1.49 mmol). The reaction solution is reacted at 140 °C under nitrogen protection in a microwave for 15 hours. After the reaction is completed, the reaction solution is cooled to room temperature, water (120 mL) is added, and it is extracted with ethyl acetate (120 mL × 3). The organic phases are combined, washed with water (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue is separated and purified by silica gel column (methylene chloride:methanol (V / V) = 20:1) to obtain 2-chloro-4-(dimethylphosphoryl)-3-fluoropyridine (8-2) (0.65 g, yield 12.6%).

[0379] LC-MS, M / Z (ESI): 208.2 [M+H] + 。

[0380] Step 2: Synthesis of tert-butyl 3-((2-chloro-4-(dimethylphosphoryl)pyridin-3-yl)amino)azetidine-1-carboxylate (8-3)

[0381]

[0382] Dissolve 2-chloro-4-(dimethylphosphoryl)-3-fluoropyridine (8-2) (0.65 g, 3.14 mmol) in n-butanol (5 mL), add tert-butyl 3-aminoazetidine-1-carboxylate (0.64 g, 3.72 mmol), and react at 120 °C for 24 hours. Cool the reaction solution to room temperature, concentrate it under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain tert-butyl 3-((2-chloro-4-(dimethylphosphoryl)pyridin-3-yl)amino)azetidine-1-carboxylate (8-3) (0.62 g, yield 55.0%).

[0383] LC-MS, M / Z (ESI): 360.2 [M+H] + 。

[0384] Step 3: Synthesis of tert-butyl 3-((4-(dimethylphosphoryl)-2-(4-(trifluoromethyl)anilino)pyridin-3-yl)amino)azetidine-1-carboxylate (8-4)

[0385]

[0386] Dissolve tert-butyl 3-((2-chloro-4-(dimethylphosphoryl)pyridin-3-yl)amino)azetidine-1-carboxylate (8-3) (210 mg, 0.58 mmol) and 4-(trifluoromethyl)aniline (131 mg, 0.81 mmol) in toluene (10.0 mL), add cesium carbonate (380 mg, 1.17 mmol), then add palladium acetate (26 mg, 0.12 mmol) and 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (73 mg, 0.12 mmol), and stir and react overnight at 110 °C under nitrogen protection. After the reaction is completed, cool the reaction solution to room temperature, concentrate it under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain tert-butyl 3-((4-(dimethylphosphoryl)-2-(4-(trifluoromethyl)anilino)pyridin-3-yl)amino)azetidine-1-carboxylate (8-4) (79.3 mg, yield 28.0%).

[0387] LC-MS, M / Z (ESI): 485.2 [M+H] + 。

[0388] Step 4: Synthesis of tert-butyl 3-(7-(dimethylphosphoryl)-2-oxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)azetidine-1-carboxylate (8-5)

[0389]

[0390] Dissolve tert-butyl 3-((4-(dimethylphosphoryl)-2-(4-(trifluoromethyl)anilino)pyridin-3-yl)amino)azetidine-1-carboxylate (8-4) (79.3 mg, 0.16 mmol) in acetonitrile (8 mL), add triethylamine (82.7 mg, 0.82 mmol), then add N,N'-carbonyldiimidazole (79.5 mg, 0.49 mmol), and reflux the reaction overnight. After the reaction is completed, cool the reaction solution to room temperature, concentrate it under reduced pressure, and purify the residue by silica gel column chromatography (methylene chloride:methanol (V / V) = 20:1) to obtain compound tert-butyl 3-(7-(dimethylphosphoryl)-2-oxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)azetidine-1-carboxylate (8-5) (60.3 mg, yield 72.2%).

[0391] LC-MS, M / Z (ESI): 511.2 [M+H] + 。

[0392] Step 5: Synthesis of 1-(azetidin-3-yl)-7-(dimethylphosphoryl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (8-6)

[0393]

[0394] Dissolve tert-butyl 3-(7-(dimethylphosphoryl)-2-oxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)azetidine-1-carboxylate (8-5) (60.3 mg, 0.12 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (3 mL), and react at room temperature for 0.5 h. After the reaction is completed, distill off the reaction solvent under reduced pressure, adjust the pH to 8 with saturated aqueous sodium bicarbonate solution (10 mL) at 0 °C, extract with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate to obtain compound 1-(azetidin-3-yl)-7-(dimethylphosphoryl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (8-6) (41.3 mg, yield: 85.3%), which is directly used in the next step of the reaction.

[0395] LC-MS, M / Z(ESI): 411.1 [M+H] + 。

[0396] Step 6: Synthesis of 7-(dimethylphosphoryl)-1-(1-(2-fluoroprop-2-en-1-yl)azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (I-8)

[0397]

[0398] Dissolve 2-fluoroacrylic acid (18.5 mg, 0.21 mmol) and N,N-diisopropylethylamine (65.9 mg, 0.51 mmol) in N,N-dimethylformamide (3 mL), add 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (92.0 mg, 0.26 mmol), stir at room temperature for 0.5 h, add 1-(azetidin-3-yl)-7-(dimethylphosphoryl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (8-6) (41.3 mg, 0.10 mmol), and react at room temperature for 4 h. After the reaction is completed, add water (15 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with water (10 mL), dry over anhydrous sodium sulfate, filter and concentrate, and purify the residue by silica gel column chromatography (methylene chloride:methanol (V / V) = 10:1) to obtain the compound 7-(dimethylphosphoryl)-1-(1-(2-fluoroprop-2-en-1-yl)azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (I-8) (35.5 mg, yield 73.2%).

[0399] LC-MS, M / Z(ESI): 483.1 [M+H] + 。

[0400] 1 H NMR (600 MHz, DMSO-d 6 6): δ 8.09 (dd, 1H), 7.95 (s, 4H), 7.33 (dd, 1H), 6.63 (dt, 1H), 5.54 - 5.45 (m, 1H), 5.31 (dd, 1H), 5.06 (s, 1H), 4.73 (dd, 1H), 4.68 (td, 1H), 4.30 (t, 1H), 1.91 (d, 3H), 1.89 (d, 3H). The preparation of the following compounds refers to the examples in Preparation Example 1 above:

[0401]

[0402]

[0403]

[0404]

[0405]

[0406] Preparation Example 2

[0407] Example 9: Preparation of Compound I'-1

[0408] The synthetic route is as follows:

[0409]

[0410] First step: Synthesis of 7-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (1'-2)

[0411]

[0412] Dissolve 7-chloro-1H-pyrazolo[4,3-b]pyridine (1'-1, 1.0 g, 6.51 mmol) and potassium hydroxide (1.83 g, 32.55 mmol) in N,N-dimethylformamide (15 mL), add iodine (3.31 g, 13.02 mmol), and react at room temperature for 15 hours. After the reaction is completed, quench the reaction with saturated aqueous sodium sulfite solution (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The obtained crude product is separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain compound 7-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (1'-2) (1.55 g, yield 85.2%).

[0413] LC-MS, M / Z (ESI): 280.1 [M+H] + 。

[0414] Second step: Synthesis of tert-butyl 3-(7-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (1'-3)

[0415]

[0416] 7-Chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (1.55 g, 5.55 mmol) and tert-butyl 3-hydroxyazetidine-1-carboxylate (1.44 g, 8.33 mmol) were dissolved in anhydrous tetrahydrofuran (15 mL). Triphenylphosphine (4.37 g, 16.65 mmol) was added, and diethyl azodicarboxylate (2.90 g, 16.65 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes, then slowly warmed to room temperature and stirred overnight. Subsequently, the reaction mixture was heated to 100 °C and stirred for 6 hours under nitrogen protection. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain tert-butyl 3-(7-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (1'-3) (1.41 g, yield 58.3%).

[0417] LC-MS, M / Z (ESI): 435.1 [M+H] + 。

[0418] Step 3: Synthesis of tert-butyl 3-(7-chloro-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (1'-4)

[0419]

[0420] Tert-butyl 3-(7-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (1'-3) (1.41 g, 3.24 mmol) and (4-(trifluoromethyl)phenyl)boronic acid (0.62 g, 3.24 mmol) were dissolved in 1,4-dioxane (20.0 mL) and water (4.00 mL). Cesium carbonate (2.11 g, 6.48 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (234.1 mg, 0.32 mmol) were added, and the mixture was stirred at 80 °C overnight under nitrogen protection. After the reaction was completed, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, 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 tert-butyl 3-(7-chloro-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (1'-4) (1.26 g, yield 85.7%).

[0421] LC-MS, M / Z (ESI): 453.2 [M+H] + 。

[0422] Step 4: Synthesis of tert-Butyl 3-(4-(methylthio)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (1'-5)

[0423]

[0424] Dissolve tert-butyl 3-(4-chloro-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (1'-4, 100.0 mg, 0.22 mmol) in dimethyl sulfoxide (4 mL), add S-methylisothiourea sulfate (62 mg, 0.22 mmol) and cesium carbonate (288 mg, 0.88 mmol), and react at 80 °C for 4 hours. After the reaction is completed, cool to room temperature, add water (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with water (10 mL × 2), and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain the compound tert-butyl 3-(4-(methylthio)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (1'-5, 82.5 mg, yield 80.5%).

[0425] LC-MS, M / Z (ESI): 465.1 [M+H] + 。

[0426] Step 5: Synthesis of tert-Butyl 3-(4-(S-methylsulfonimido)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (1'-6)

[0427]

[0428] Dissolve tert-butyl 3-(4-(methylthio)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (1'-5, 82.5 mg, 0.18 mmol) in anhydrous methanol (10 mL), add ammonium carbonate (51.9 mg, 0.54 mmol) and iodobenzene diacetate (231.9 mg, 0.72 mmol), and stir at room temperature for 5 hours. After the reaction is completed, concentrate the reaction solution, and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:2) to obtain the compound tert-butyl 3-(4-(S-methylsulfonimido)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (1'-6, 77.1 mg, yield 87.50%).

[0429] LC-MS, M / Z (ESI): 496.1 [M+H] + 。

[0430] Step 6: Synthesis of 3-(azetidin-3-yl)-4-(S-methylsulfinyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine (1’-7)

[0431]

[0432] Dissolve tert-butyl 3-(4-(S-methylsulfinyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (1’-6, 77.1 mg, 0.16 mmol) in dichloromethane (10.0 mL), and add trifluoroacetic acid (2 mL). Stir the reaction mixture at room temperature for 1 hour. After the reaction is completed, concentrate the reaction solution, adjust the pH to 8 with saturated aqueous sodium bicarbonate (10 mL), extract with ethyl acetate (15 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product 3-(azetidin-3-yl)-4-(S-methylsulfinyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine (1’-7, 60.4 mg, yield 98.1%).

[0433] LC-MS, M / Z (ESI): 396.1 [M+H] + 。

[0434] Step 7: Synthesis of 2-fluoro-1-(3-(4-(S-methylsulfinyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidin-1-yl)prop-2-en-1-one (I’-1)

[0435]

[0436] 2-Fluoroacrylic acid (16.3 mg, 0.18 mmol) and N,N-diisopropylethylamine (58.0 mg, 0.45 mmol) were dissolved in N,N-dimethylformamide (5 mL). 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (85.3 mg, 0.22 mmol) was added, and the mixture was stirred at room temperature for 0.5 h. 3-(Azetidin-3-yl)-4-(S-methylsulfinyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine (1’-7, 60.4 mg, 0.15 mmol) was added, and the reaction was carried out at room temperature for 4 h. After the reaction was completed, water (15 mL) was added for dilution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (methylene chloride:methanol (V / V)=10:1) to obtain compound 2-fluoro-1-(3-(4-(S-methylsulfinyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidin-1-yl)prop-2-en-1-one (I’-1, 58.1 mg, yield 81.3%).

[0437] LC-MS, M / Z (ESI): 468.1 [M+H] + 。

[0438] 1 1H NMR (400 MHz, DMSO-d 6 6): δ 8.98 (d, 1H), 8.58 (d, 2H), 7.99 (d, 2H), 7.90 (d, 1H), 5.50 (dd, 1H), 5.31 (dd, 1H), 5.08 (d, 1H), 4.93–4.70 (m, 3H), 4.45 (m, 2H), 3.33 (s, 3H).

[0439] Example 10: Preparation of compound I’-2

[0440] The synthetic route is as follows:

[0441]

[0442] The first step: Synthesis of compound 4-chloro-3-iodo-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine (2’-2)

[0443]

[0444] Dissolve 4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (2’-1, 15.00 g, 53.67 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (16.58 g, 80.51 mmol) and cupric acetate anhydrous (14.62 g, 80.51 mmol) in tetrahydrofuran (150 mL), add pyridine (16.98 g, 214.70 mmol), displace the gas 3 times under the protection of an oxygen balloon, and react the reaction solution at 25 °C for 48 hours. Dilute the reaction solution with ethyl acetate, filter using diatomaceous earth, and separate and purify the crude product by silica gel column (petroleum ether:ethyl acetate (V / V) = 1:0 - 100:1) to obtain 4-chloro-3-iodo-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine (2’-2) (21.0 g, yield 89.0%).

[0445] LC-MS, M / Z(ESI): 440.0 [M+H] + 。

[0446] Step 2: Synthesis of tert-butyl ((4-chloro-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (2’-3)

[0447]

[0448] Dissolve 4-chloro-3-iodo-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridine (2’-2, 1.35 g, 3.07 mmol) and potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (0.87 g, 3.67 mmol) in toluene (16 mL) and water (1.6 mL), add cesium carbonate (3.0 g, 9.21 mmol) and [(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)palladium(II) chloride (317.0 mg, 0.46 mmol) to the system, displace the gas 3 times under nitrogen protection, and heat to 100 °C for reaction for 6 hours. Concentrate the reaction solution under reduced pressure, and separate and purify the crude product by silica gel column (petroleum ether:ethyl acetate (V / V) = 1:0 - 50:1) to obtain tert-butyl ((4-chloro-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (2’-3, 1.25 g, yield 92.0%).

[0449] LC-MS, M / Z(ESI): 443.1 [M+H] + 。

[0450] Step 3: Synthesis of tert-butyl ((4-(methylthio)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (2'-4)

[0451]

[0452] Dissolve tert-butyl ((4-chloro-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (2'-3, 100.0 mg, 0.23 mmol) in dimethyl sulfoxide (4 mL), add S-methylisothiourea sulfate (62 mg, 0.22 mmol) and cesium carbonate (288 mg, 0.88 mmol), and react at 80 °C for 4 hours. After the reaction is completed, cool the reaction solution to room temperature, add water (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with water (10 mL × 2), and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain tert-butyl ((4-(methylthio)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (2'-4, 85.7 mg, yield 83.5%).

[0453] LC-MS, M / Z (ESI): 455.1 [M+H] + 。

[0454] Step 4: Synthesis of tert-butyl ((4-(S-methylsulfinyl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (2'-5)

[0455]

[0456] Dissolve tert-butyl ((4-(methylthio)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (2'-4, 85.7 mg, 0.19 mmol) in anhydrous methanol (10 mL), add ammonium carbonate (51.9 mg, 0.54 mmol) and iodobenzene diacetate (231.9 mg, 0.72 mmol), and stir at room temperature for 5 hours. After the reaction is completed, concentrate the reaction solution and purify by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:2) to obtain tert-butyl ((4-(S-methylsulfinyl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (2'-5, 81.8 mg, yield 89.3%).

[0457] LC-MS, M / Z(ESI): 486.1 [M+H] + 。

[0458] Step 5: Synthesis of (4-(S-Methylsulfonyl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methanamine (2’-6)

[0459]

[0460] Dissolve tert-butyl (4-(S-methylsulfinylimino)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (2’-5, 81.8 mg, 0.17 mmol) in dichloromethane (10.0 mL), and add trifluoroacetic acid (2 mL). Stir the reaction at room temperature for 1 hour. After the reaction is completed, concentrate the reaction solution, adjust the pH to 8 with saturated aqueous sodium bicarbonate solution (10 mL), extract with ethyl acetate (15 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product (4-(S-methylsulfonyl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methanamine (2’-6, 58.1 mg, yield 89.5%).

[0461] LC-MS, M / Z(ESI): 386.1 [M+H] + 。

[0462] Step 6: Synthesis of N-((4-(S-Methylsulfinylimino)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)acrylamide (I’-2)

[0463]

[0464] Dissolve (4-(S-methylsulfonyl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methanamine (2’-6, 58.1 mg, 0.15 mmol) in acetonitrile (10 mL), add saturated aqueous sodium bicarbonate solution (5 mL), stir at 0 °C, and add acryloyl chloride (14.5 mg, 0.16 mmol). React at room temperature for 4 hours. After the reaction is completed, extract with ethyl acetate (20 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. Purify the crude product by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to obtain the compound N-((4-(S-methylsulfinylimino)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)acrylamide (I’-2, 51.9 mg, yield 78.4%).

[0465] LC-MS, M / Z (ESI): 440.2 [M+H] + 。

[0466] 1 H NMR (400 MHz, DMSO-d 6 ): δ8.94 (d, 1H), 8.72 (t, 1H), 8.34–8.26 (d, 2H), 7.89 (d, 1H), 7.63 (d, 2H), 6.38 (dd, 1H), 6.13 (dd, 1H), 5.64 (dd, 1H), 5.16–5.00 (m, 3H), 3.41 (s, 3H).

[0467] Example 11: Preparation of Compound I'-3

[0468] The synthetic route is as follows:

[0469]

[0470] First step: Synthesis of tert-butyl 3-(7-bromo-3-iodo-1H-indazol-1-yl)azetidine-1-carboxylate (3'-2)

[0471]

[0472] Dissolve 7-bromo-3-iodo-1H-indazole (3'-1) (4.0 g, 12.39 mmol) and tert-butyl 3-hydroxyazetidine-1-carboxylate (2.23 g, 18.60 mmol) in tetrahydrofuran (200 mL), add triphenylphosphine (9.75 g, 37.17 mmol), and dropwise add diethyl azodicarboxylate (7.34 g, 42.13 mmol) at 0 °C. The reaction mixture is stirred at room temperature overnight. After the reaction is completed, the reaction mixture is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain tert-butyl 3-(7-bromo-3-iodo-1H-indazol-1-yl)azetidine-1-carboxylate (3'-2) (4.38 g, yield 74.0%).

[0473] LC-MS, M / Z (ESI): 478.1 [M+H] + 。

[0474] Second step: Synthesis of tert-butyl 3-(7-bromo-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidine-1-carboxylate (3'-3)

[0475]

[0476] Dissolve tert-butyl 3-(7-bromo-3-iodo-1H-indazol-1-yl)azetidine-1-carboxylate (3’-2) (3.2 g, 6.7 mmol) in 1,4-dioxane (40 mL) and water (8 mL), add [4-(trifluoromethyl)phenyl]boronic acid (1.27 g, 6.7 mmol), then add sodium carbonate (1.42 g, 13.4 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (0.39 g, 0.53 mmol). Stir the reaction mixture at 80 °C for 4 hours under nitrogen protection. After the reaction is completed, cool the reaction mixture to room temperature, extract with ethyl acetate (40 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=10:1) to obtain tert-butyl 3-(7-bromo-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidine-1-carboxylate (3’-3) (2.17 g, yield 65.3%).

[0477] LC-MS, M / Z(ESI): 496.1[M+H] + 。

[0478] Step 3: Synthesis of tert-butyl 3-(7-(methylthio)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidine-1-carboxylate (3’-4)

[0479]

[0480] Dissolve tert-butyl 3-(7-bromo-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidine-1-carboxylate (3’-3) (0.58 g, 1.17 mmol) in dimethyl sulfoxide (8 mL), add S-methylisothiourea sulfate (0.36 g, 1.29 mmol) and cesium carbonate (1.54 g, 4.73 mmol). Stir the reaction mixture at 80 °C for 4 hours. After the reaction is completed, cool to room temperature, add water (20 mL), extract with ethyl acetate (20 mL×3), combine the organic phases, wash with water (10 mL×2), dry over anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=10:1) to obtain tert-butyl 3-(7-(methylthio)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidine-1-carboxylate (3’-4) (0.26 g, yield 48.1%).

[0481] LC-MS, M / Z(ESI): 464.1[M+H] + 。

[0482] Step 4: Synthesis of tert-butyl 3-(7-(S-methylsulfinylimino)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidine-1-carboxylate (3'-5)

[0483]

[0484] Dissolve tert-butyl 3-(7-(methylthio)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidine-1-carboxylate (3'-4) (0.26 g, 0.56 mmol) in anhydrous methanol (10 mL), add ammonium carbonate (80.8 mg, 0.84 mmol) and iodobenzene diacetate (414.9 mg, 1.29 mmol), and stir at room temperature for 3 hours. After the reaction is completed, concentrate the reaction solution under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to obtain the compound tert-butyl 3-(7-(S-methylsulfinylimino)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidine-1-carboxylate (3'-5) (0.24 g, yield 88.30%).

[0485] LC-MS, M / Z (ESI): 495.1 [M+H] + 。

[0486] Step 5: Synthesis of 1-(azetidin-3-yl)-7-(S-methylsulfinylimino)-3-(4-(trifluoromethyl)phenyl)-1H-indazole (3'-6)

[0487]

[0488] Dissolve tert-butyl 3-(7-(S-methylsulfinylimino)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidine-1-carboxylate (3'-5) (237.4 mg, 0.48 mmol) in dichloromethane (10.0 mL), add trifluoroacetic acid (3 mL). Stir the reaction at room temperature for 0.5 hours. After the reaction is completed, concentrate the reaction solution, then adjust the pH to 8 with saturated aqueous sodium bicarbonate solution (10 mL), extract with ethyl acetate (15 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate to obtain the compound 1-(azetidin-3-yl)-7-(S-methylsulfinylimino)-3-(4-(trifluoromethyl)phenyl)-1H-indazole (3'-6) (168.7 mg, yield 89.1%).

[0489] LC-MS, M / Z (ESI): 395.1 [M+H] + 。

[0490] Step 6: Synthesis of 2-Fluoro-1-(3-(7-(S-Methylsulfinylamino)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidin-1-yl)prop-2-en-1-one (I’-3)

[0491]

[0492] Dissolve 2-fluoroacrylic acid (16.3 mg, 0.18 mmol) and N,N-diisopropylethylamine (58.0 mg, 0.45 mmol) in N,N-dimethylformamide (5 mL). Add 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (85.3 mg, 0.22 mmol), and stir at room temperature for 0.5 h. Then add 1-(azetidin-3-yl)-7-(S-methylsulfinylamino)-3-(4-(trifluoromethyl)phenyl)-1H-indazole (3’-6) (59.2 mg, 0.15 mmol), and react at room temperature for 4 h. After the reaction, add water (15 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with water (10 mL), dry over anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography (methylene chloride:methanol (V / V) = 10:1) to obtain the compound 2-fluoro-1-(3-(7-(S-methylsulfinylamino)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidin-1-yl)prop-2-en-1-one (I’-3) (54.8 mg, yield 78.3%).

[0493] LC-MS, M / Z (ESI): 467.1 [M+H] + 。

[0494] 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.40 (dd, 1H), 8.21 (d, 2H), 8.17 (dd, 1H), 7.94 (d, 2H), 7.53–7.46 (m, 1H), 6.87–6.78 (m, 1H), 5.61–5.48 (m, 1H), 5.35 (dd, 1H), 4.98–4.80 (m, 3H), 4.54 (m, 2H), 3.38 (s, 3H).

[0495] Example 12: Preparation of Compound I’-4

[0496] The synthetic route is as follows:

[0497]

[0498] 1-(Azetidin-3-yl)-7-(S-methylsulfinimidoyl)-3-(4-(trifluoromethyl)phenyl)-1H-indazole (3’-6) (118.4 mg, 0.3 mmol) was dissolved in tetrahydrofuran (10 mL). Aqueous saturated sodium bicarbonate solution (3 mL) was added at 0 °C, and the mixture was stirred at 0 °C for 10 minutes. Acryloyl chloride (27.2 mg, 0.3 mmol) was added, and stirring was continued at 0 °C for 0.5 hour. After completion of the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to obtain compound 1-(3-(7-(S-methylsulfinimidoyl)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidin-1-yl)prop-2-en-1-one (I’-4) (98.5 mg, yield: 73.2%).

[0499] LC-MS, M / Z (ESI): 449.1 [M+H] + 。

[0500] 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.40 (d, 1H), 8.19 (dd, 3H), 7.93 (d, 2H), 7.53–7.47 (m, 1H), 6.89–6.77 (m, 1H), 6.45 - 6.38 (m, 1H), 6.20 - 6.15 (m, 1H), 5.73 (dd, 1H), 4.95 (s, 1H), 4.76 (m, 2H), 4.48 (m, 2H), 3.38 (s, 3H).

[0501] Example 13: Preparation of Compound I’-5

[0502] The synthetic route is as follows:

[0503]

[0504] First step: Synthesis of 4-chloro-3-iodo-1-(4-(trifluoromethyl)phenyl)-1H-indazole (5’-1)

[0505]

[0506] The compound (4-chloro-3-iodo-1H-indazole) (7-1) (3.2 g, 11.5 mmol), [4-(trifluoromethyl)phenyl]boronic acid (3.5 g, 17.2 mmol) and cupric acetate anhydrous (3.2 g, 17.2 mmol) were dissolved in acetonitrile (32 mL), pyridine (3.6 g, 45.7 mmol) was added, and the reaction mixture was stirred at 50 °C for 48 h under an oxygen atmosphere. After completion, the reaction mixture was distilled under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 20:1) to obtain the compound 4-chloro-3-iodo-1-(4-(trifluoromethyl)phenyl)-1H-indazole (5’-1) (2.5 g, yield 51%).

[0507] LC-MS, M / Z (ESI): 422.9 [M+H] + 。

[0508] Step 2: Synthesis of tert-butyl 3-(4-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (5’-2)

[0509]

[0510] Zinc powder (185 mg, 2.86 mmol) was placed in a reaction flask, dry N,N-dimethylacetamide (2 mL) and trimethylchlorosilane (45 μL, 0.35 mmol) were added under nitrogen protection, and the mixture was stirred at 45 °C for 30 min. Subsequently, dibromomethane (30 μL, 0.35 mmol) was added, and the stirring was continued at 45 °C for 30 min. Then, 1-Boc-3-iodoazetidine (300 mg, 1.06 mmol) was added, and the reaction was carried out at 65 °C for 1 h. After completion, the temperature was restored to room temperature, and the organic phase was taken as the freshly prepared zinc reagent for standby. 4-Chloro-3-iodo-1-(4-(trifluoromethyl)phenyl)-1H-indazole (5’-1) (355 mg, 0.80 mmol) was placed in another reaction flask, tris(dibenzylideneacetone)dipalladium (36 mg, 0.04 mmol) and tris(2-furyl)phosphine (19 mg, 0.1 mmol) were added, and N,N-dimethylacetamide (3 mL) and the freshly prepared zinc reagent were added under nitrogen protection. Then, the reaction mixture was reacted at 70 °C for 2 h. After completion, the reaction mixture was cooled to room temperature, quenched by adding it to a saturated aqueous sodium bicarbonate solution (20 mL), then extracted with ethyl acetate (50 mL), washed with a saturated aqueous sodium chloride solution (50 mL×3), and then the organic phase was taken, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain the compound tert-butyl 3-(4-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (5’-2) (273 mg, yield: 69%).

[0511] LC-MS, M / Z(ESI): 452.2 [M+H] + 。

[0512] Step 3: Synthesis of tert-butyl 3-(4-(methylthio)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (5'-3)

[0513]

[0514] Dissolve tert-butyl 3-(4-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (5'-2) (250 mg, 0.55 mmol) and sodium methyl mercaptide (140 mg, 2 mmol) in N,N-dimethylacetamide (4 mL), and react at 80 °C for 30 min under the protection of a nitrogen balloon. After completion, dilute the reaction solution with ethyl acetate (100 mL), wash it with saturated sodium chloride aqueous solution (100 mL × 3), then take the organic phase, dry it over anhydrous sodium sulfate, concentrate it, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain tert-butyl 3-(4-(methylthio)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (5'-3) (250 mg, yield: 99%).

[0515] LC-MS, M / Z(ESI): 464.2 [M+H] + 。

[0516] Step 4: Synthesis of tert-butyl 3-(4-(S-methylsulfinylimino)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (5'-4)

[0517]

[0518] tert-Butyl 3-(4-(S-methylsulfinyl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (5'-4) (222 mg, yield: 83%) was obtained by dissolving tert-butyl 3-(4-methylthio-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (5'-3) (250 mg, 0.54 mmol), iodobenzenediacetic acid (440 mg, 1.35 mmol), and ammonium carbonate (200 mg, 2 mmol) in methanol (5 mL). The reaction mixture was stirred at room temperature for 30 min under a nitrogen atmosphere. After completion, the reaction mixture was diluted with ethyl acetate (200 mL), extracted with saturated aqueous sodium chloride solution (100 mL × 3), and the organic layer was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:3).

[0519] LC-MS, M / Z (ESI): 495.2 [M+H] + 。

[0520] Step 5: Synthesis of 2-fluoro-1-(3-(4-(S-methylsulfinyl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidin-1-yl)prop-2-en-1-one (I'-5)

[0521]

[0522] tert-Butyl 3-(4-(S-methylsulfinyl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (5'-4) (100 mg, 0.2 mmol) was placed in a reaction flask, trifluoroacetic acid (1 mL) was added at 0 °C, and the mixture was stirred at room temperature for 15 min. Then the reaction mixture was added dropwise to saturated sodium bicarbonate solution (5 mL). After neutralization, sodium bicarbonate (200 mg) and acetonitrile (5 mL) were added, and then acryloyl fluoride (64 mg, 0.6 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 15 min. After completion, the reaction mixture was concentrated to remove acetonitrile and water, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain 2-fluoro-1-(3-(4-(S-methylsulfinyl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidin-1-yl)prop-2-en-1-one (I'-5) (59 mg, yield 63%).

[0523] LC-MS, M / Z (ESI): 467.1 [M+H] + 。

[0524] 11H NMR (400 MHz, DMSO-d 6 ) δ 8.18 (d, 1H), 8.04 (d, 2H), 7.99–7.90 (m, 3H), 7.68 (dd, 1H), 5.55–5.36 (m, 1H), 5.27 (dd, 1H), 5.02–4.90 (m, 1H), 4.78 (td, 1H), 4.73–4.61 (m, 2H), 4.45–4.31 (m, 2H), 3.23 (s, 3H).

[0525] The preparation of the following compounds refers to the examples in Preparation Example 2 above:

[0526]

[0527]

[0528]

[0529] Test Example 1: TEADs-mediated transcriptional inhibition IC 50 Evaluation test

[0530] The inhibitory effect of small molecule compounds on TEADs-mediated transcriptional inhibition was detected by HEK293T-TEAD Reporter Assay.

[0531] The HEK293T-TEAD-LUC reporter cell line was cultured in DMEM + 10% FBS + 1% PS + 200 μg / mL Hygromycin as the complete medium. Cells in the logarithmic phase were seeded into a 384-well plate, 2500 cells / well / 35 μL, 37 °C, 5% CO 2 Incubated overnight. The next day, 5 μL of the diluted compound (final DMSO concentration was 0.1%) was added to each well. A positive control group with only DMSO added was set, and the signal value of 2 μM Okacid acid was used as the signal of the negative control group. Then, it was incubated at 37 °C, 5% CO 2 Incubated for 48 h. After incubation, use luciferase assaysystem (Promega, E2550) and measure the fluorescence signal value on an Envision 2104 Multilabel Reader according to the instructions provided by the supplier. Calculate the inhibition rate through the following formula, and then plot a curve with the Log value of the inhibitor concentration as the X-axis and the inhibition rate as the Y-axis, and calculate the IC using Graphpad 7.0 50 .

[0532] Inhibition% = (Signal of positive control group - Signal of test well) / (Signal of positive control group - Signal of negative control group) * 100

[0533] The results of the HEK293T-TEAD Reporter Assay showed that the compounds of the present invention could significantly inhibit the transcriptional activity of TEADs on HEK293T-TEAD-LUC reporter cell line cells.

[0534] Test Example 2: Inhibitory assay for the proliferation of malignant mesothelioma cells

[0535] The inhibitory effect of small molecule compounds on the proliferation of malignant mesothelioma cells was detected by the proliferation assay of NCI-H226 cells with NF2 mutation.

[0536] NCI-H226 (ATCC, cat#CRL5826) was cultured in RPMI1640 + 10% FBS + 1% PS as the complete medium. Cells in the logarithmic phase were seeded into 96-well plates, 800 cells / well / 195 μL, at 37 °C, 5% CO 2 Incubated overnight. The next day, 5 μL of the diluted compound (final DMSO concentration was 0.1%) was added to each well. A positive control group with only DMSO added was set, and the signal value of 1 μM Staurosporine was used as the signal of the negative control group. Then, it was incubated at 37 °C, 5% CO 2 Incubated for 6 days. After incubation, 100 μL of the medium was aspirated, and the fluorescence signal value was measured using the Celltiter Glo assay kit (Promega, G7573) and following the instructions provided by the supplier on an Envision 2104 Multilabel Reader. The inhibition rate was calculated using the following formula, and then a curve was plotted with the Log value of the inhibitor concentration on the X-axis and the inhibition rate on the Y-axis, and the IC 50 .

[0537] Inhibition% = (Signal of positive control group - Signal of test well) / (Signal of positive control group - Signal of negative control group) * 100

[0538] Table 1 Proliferation inhibitory activities of the test compounds on NCI-H226 cells

[0539] Test compound <![CDATA[IC 50 (nM)]]> I-1 40.67 I-3 50 I-4 30.3 I-5 25.4 I-6 40.6 I-7 70 I’-1 22 I’-3 19 I’-4 41

[0540] The results of the NCI-H226 cell proliferation assay showed that the compounds of the present invention could significantly inhibit the proliferation of NCI-H226 (ATCC, cat#CRL5826).

[0541] Test Example 3: Thermodynamic Solubility Test

[0542] Prepare phosphate buffer solution (PBS) with pH 7.4. Accurately weigh the compound, add it to the prepared PBS with pH 7.4, and prepare a solution with a concentration of 4 mg / mL. Shake it at a speed of 1000 rpm for 1 hour, and then incubate it overnight at room temperature. The incubated solution is centrifuged at 12000 rpm for 10 minutes to remove undissolved particles, and the supernatant is transferred to a new centrifuge tube. After appropriately diluting the supernatant, add acetonitrile solution containing internal standard, and perform quantification using a standard curve prepared with the same matrix.

[0543] Table 2 Results of Thermodynamic Solubility Test

[0544]

[0545] 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.

[0546] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention. Test Example 4: Mouse Pharmacokinetics Test

[0547] For the mouse pharmacokinetics test, 3 male ICR mice, weighing 20 - 25 g, are fasted overnight and administered orally by gavage (10 mg / kg). Blood samples are collected before dosing and at 15, 30 minutes, and 1, 2, 4, 8, 24 hours after dosing. The blood samples are centrifuged at 6800 g at 2 - 8 °C for 6 minutes, plasma is collected and stored at -80 °C. Plasma at each time point is taken, mixed with 3 - 5 times the volume of acetonitrile solution containing internal standard, vortex - mixed for 1 minute, centrifuged at 13000 rpm at 4 °C for 10 minutes, the supernatant is taken and mixed with 3 times the volume of water, and an appropriate amount of the mixed solution is subjected to LC - MS / MS analysis. The main pharmacokinetic parameters are analyzed using the non - compartmental model of WinNonlin 7.0 software.

[0548] The results of the mouse pharmacokinetics test show that the compound of the present invention exhibits excellent pharmacokinetic properties and good drugability.

[0549] Test Example 5: Antitumor Efficacy Test in NCI - H226 Mesothelioma - Bearing Mice

[0550] After one - week of adaptive feeding of Nu / Nu nude mice (CRL), NCI - H226 cells in the logarithmic growth phase are resuspended in PBS, and 5×10 6NCI-H226 cells were inoculated subcutaneously at the right rear part of mice, and the tumor growth was observed regularly. When the tumor grew to an average volume of 80-100 mm 3 , according to the tumor size and the body weight of the mice, they were randomly divided into a model group and a drug administration group. Before and during the drug administration, the tumor volume and the animal body weight were measured and recorded. After the treatment, taking the model group as the control, the growth inhibitory effect of the drug administration group on the tumor was statistically analyzed, and the TGI was calculated.

[0551] The results of the pharmacodynamic test on tumor-bearing mice showed that the compound of the present invention had a significant effect on inhibiting the growth of NCI-H226 mesothelioma.

[0552] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A compound of formula I0, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: in, Ring A is a benzene ring or a 5-6-membered N-containing 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 benzene ring, a 5-6 membered N-containing heteroaromatic ring, or a saturated or partially unsaturated 5-6 membered heterocycloalkyl; the ring B is optionally substituted by one or more Rb; when there are multiple Rb, the Rb are the same or different; R1 is or-W-COOR 12 ; The R1 is optionally replaced by one or more R 10 Replace, when R 10 When it is multiple, the R 10 Same or different; R 11 , R 12 Each is independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-10-membered heteroaryl, 6-10-membered aryl; Or, R 11 , R 12 Together with the P to which they are attached, they form a 4-7 membered ring; The R 11 Optionally one or more R 10 Replace; when R 10 When it is multiple, the R 10 Same or different; W does not exist or is C1-C3 alkylene; R2 and R3 are each independently -L1-L2-C(O)R4, -L1-L2-S(O)2R4, -L1-L2-S(O)R4, R5, and only one of R2 and R3 is R5; L1 and L2 are each independently absent or selected from -NH, -C1-C6 alkyl, -C1-C6 alkyl-NH-, or And L1 and L2 do not exist at the same time; Ring D is a 4-6 membered heterocycloalkyl or a 5-6 membered heteroaryl; the ring D is optionally substituted by one or more Rd; when Rd is multiple, the Rd are the same or different; R4 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-8-membered cycloalkyl, 4-8-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl; said R4 is optionally replaced by one or more R 41 Replace; when R 41 When it is multiple, the R 41 Same or different; R5 is a 6-10 membered aryl group, a 5-12 membered heteroaryl group, a saturated or partially unsaturated 4-12 membered cycloalkyl group, or a saturated or partially unsaturated 4-12 membered heterocycloalkyl group; The R5 is optionally replaced by one or more R 51 Replace; when R 51 When it is multiple, the R 51 Same or different; The R 10 , R 41 , R 51 , Ra, Rb, Rd are each independently selected from: H, halogen, -OH, -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, -SF5, -S(C1-C6 alkyl), oxo (=O), =CH2, =CH-C1-C6 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; The R 10 , R 41 , R 51 , Ra, Rb, Rd are optionally substituted by substituents selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -SF5.

2. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It has the following structure: Wherein, ring A is a benzene ring or a 5-6-membered N-containing 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 benzene ring, a 5-6 membered N-containing heteroaromatic ring, or a saturated or partially unsaturated 5-6 membered heterocycloalkyl; the ring B is optionally substituted by one or more Rb; when there are multiple Rb, the Rb are the same or different; R1 is R 11 , R 12 Each is independently selected from: C1-C6 alkyl, C1-C6 alkoxy; or R 11 , R 12 Together with the P to which they are attached, they form a 4-7 membered ring; The R1 is optionally replaced by one or more R 10 Replace, when R 10 When it is multiple, the R 10 Same or different; R2 and R3 are each independently -L1-L2-C(O)R4, -L1-L2-S(O)2R4, -L1-L2-S(O)R4, R5, and only one of R2 and R3 is R5; L1 and L2 are each independently absent or selected from -NH, -C1-C6 alkyl, -C1-C6 alkyl-NH-, or And L1 and L2 do not exist at the same time; Ring D is a 4-6 membered heterocycloalkyl or a 5-6 membered heteroaryl; the ring D is optionally substituted by one or more Rd; when Rd is multiple, the Rd are the same or different; R4 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy; said R4 is optionally replaced by one or more R 41 Replace; when R 41 When it is multiple, the R 41 Same or different; R5 is a benzene ring, a 5-12 membered heteroaryl group, a saturated or partially unsaturated 4-12 membered cycloalkyl group, or a saturated or partially unsaturated 4-12 membered heterocycloalkyl group; The R5 is optionally replaced by one or more R 51 Replace; when R 51 When it is multiple, the R 51 Same or different; The R 10 , R 41 , R 51 , Ra, Rb, Rd are each independently selected from: halogen, -OH, -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, -SF5, -S(C1-C6 alkyl), oxo (=O), =CH2, =CH-C1-C6 alkyl; The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), =CH2, =CH-C1-C6 alkyl are optionally substituted by substituents selected from the following: halogen, -OH, -NH2, -NO2, -CN, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -SF5.

3. The compound according to claim 1 or 2, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: R1 is R 11 , R 12 are each independently methyl, ethyl, propyl, or butyl; or R 11 , R 12 Together with the P to which they are attached, they form a 5- or 6-membered saturated, unsaturated or partially unsaturated ring; The R1 is optionally replaced by one or more R 10 Replace, when R 10 When it is multiple, the R 10 Same or different; Preferably, R1 is Preferably, ring A is a benzene ring, pyridine, pyridazine, pyrimidine, or pyrazine; Preferably, ring B is pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,3-dihydroimidazol-2-one; Preferably, ring A is a benzene ring or pyridine, and ring B is pyrazole, pyridine, pyridazine or 1,3-dihydroimidazol-2-one.

4. The compound according to claim 1 or 2, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It has the structure shown in Formula Ia and Formula Ib: Wherein, V1, V2, V3, and V4 are each independently CH or N; R1, R2, R3 are as defined in claim 1 or 2; Preferably, R2 is -L1-L2-C(O)R4, -L1-L2-S(O)2R4, -L1-L2-S(O)R4, and R3 is R5; or, R3 is -L1-L2-C(O)R4, -L1-L2-S(O)2R4, -L1-L2-S(O)R4, and R2 is R5; Preferably, It has the following structure: It has the following structure:

5. The compound according to claim 1 or 2, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It has the structure shown in formula Ic: wherein V1, V2, V3, V4, V5, and V6 are each independently CH or N; R1, R2, R3 are as defined in claim 1 or 2; Preferably, 1, 2, 3 or 4 of V1, V2, V3, V4, V5 and V6 are N; Preferably, R2 is -L1-L2-C(O)R4, -L1-L2-S(O)2R4, -L1-L2-S(O)R4, and R3 is R5; or, R3 is -L1-L2-C(O)R4, -L1-L2-S(O)2R4, -L1-L2-S(O)R4, and R2 is R5; Preferably, It has the following structure:

6. The compound according to claim 1 or 2, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: -L1-L2-C(O)R4 is selected from: -C1-C6 alkyl-NH-C(O)R4, -NH-C(O)R4, and / or, -L1-L2-S(O)2R4 is Preferably, -C1-C6alkyl-NH-C(O)R4 is -CH2-NH-C(O)R4; Preferably, -C1-C6 alkyl is -CH2-, -CH2CH2-, -CH2CH2CH2-; Preferably, R4 is C2-C6 alkenyl, C2-C6 alkynyl; said R4 is optionally replaced by R 41 replace; Preferably, R 41 F, Cl, -OH, -OCH3, -NHCH3, -N(CH3)2; Preferably, -L1-L2-C(O)R4 is -CH2-NH-C(O)-CH=CH2, -CH2-NH-C(O)-CF=CH2, and / or, -L1-L2-S(O)2R4 is 7. The compound according to any one of claims 1 to 6, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: R5 is a benzene ring, cyclohexane, or cyclohexene; said R5 is optionally replaced by R 51 replace; Preferably, R5 is a benzene ring, R 51 is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -SF5, -S(C1-C6 alkyl), -S(C1-C6 haloalkyl); or, R5 is cyclohexane, cyclohexene, R 51 Selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -SF5, -S(C1-C6 alkyl), -S(C1-C6 haloalkyl), =CF2; Preferably, R5 is 8. The compound according to any one of claims 1 to 7, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It has the following structure:

9. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It has the following structure: Wherein, ring A is a benzene ring or a 5-6-membered N-containing 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 benzene ring, a 5-6 membered N-containing heteroaromatic ring, or a saturated or partially unsaturated 5-6 membered heterocycloalkyl; the ring B is optionally substituted by one or more Rb; when there are multiple Rb, the Rb are the same or different; R1 is -W-COOR 12 ; Among them, R 11 , R 12 is H, C1-C6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered heteroaryl, 6-10 membered aryl; W does not exist or is C1-C3 alkylene; The R 11 Optionally one or more R 10 Replace; when R 10 When it is multiple, the R 10 Same or different; The R 10 Selected from: -H, halogen, -OH, -NH2, -CN, C1-C6 alkyl; R2 and R3 are each independently -L1-L2-C(O)R4, -L1-L2-S(O)2R4, -L1-L2-S(O)R4, R5, and only one of R2 and R3 is R5; L1 and L2 are each independently absent or selected from -NH-, -C1-C6 alkyl-, -C1-C6 alkyl-NH-, or And L1 and L2 do not exist at the same time; Ring D is a 4-6 membered heterocycloalkyl or a 5-6 membered heteroaryl; the ring D is optionally substituted by one or more Rd; when Rd is multiple, the Rd are the same or different; R4 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-8-membered cycloalkyl, 4-8-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl; said R4 is optionally replaced by one or more R 41 Replace; when R 41 When it is multiple, the R 41 Same or different; R5 is a 6-10 membered aryl group, a 5-12 membered heteroaryl group, a 4-12 membered cycloalkyl group or a 4-12 membered heterocycloalkyl group, wherein the 4-12 membered cycloalkyl group or the 4-12 membered heterocycloalkyl group is saturated or partially unsaturated; The R5 is optionally replaced by one or more R 51 Replace; when R 51 When it is multiple, the R 51 Same or different; The R 41 , R 51 , Ra, Rb, Rd are each independently selected from: halogen, -OH, -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C1-C6 alkoxy, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, -SF5, -S(C1-C6 alkyl), oxo (=O), =CH2, =CH-C1-C6 alkyl; The R 41 , R 51 , Ra, Rb, Rd are optionally substituted by substituents selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -SF5.

10. The compound according to claim 9, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: R1 is or -COOH; Among them, R 11 is C1-C3 alkyl, 3-6 membered cycloalkyl; W does not exist or is -CH2-; The R 11 Optionally one or more R 10 Replace; when R 10 When it is multiple, the R 10 Same or different; The R 10 Selected from: -H, -OH; Preferably, R 11 It is methyl, cyclopropyl, -CH2CH2OH.

11. The compound according to claim 9 or 10, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: Ring A is a benzene ring, pyridine, pyridazine, pyrimidine or pyrazine; Ring B is pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, or 1,3-dihydroimidazol-2-one.

12. The compound according to claim 9 or 10, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: Has the following structure: wherein V1, V2, V3, V4, V5, and V6 are each independently CH or N; R1, R2, and R3 are as defined in claim 9 or 10.

13. The compound according to claim 12, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It has the following structure: and / or, It has the following structure: and / or, It has the following structure:

14. The compound according to claim 9 or 10, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It has the following structure: Wherein, the definitions of R1, R2 and R3 are as described in claim 9 or 10.

15. The compound according to any one of claims 9 to 14, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: R2 is -L1-L2-C(O)R4, -L1-L2-S(O)2R4, -L1-L2-S(O)R4, and R3 is R5; or R3 is -L1-L2-C(O)R4, -L1-L2-S(O)2R4, -L1-L2-S(O)R4, and R2 is R5.

16. The compound according to any one of claims 9 to 14, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The -L1-L2-C(O)R4 is selected from: -C1-C6 alkyl-NH-C(O)R4, -NH-C(O)R4, and / or, The -L1-L2-S(O)2R4 is Preferably, R4 is C2-C6 alkenyl, C2-C6 alkynyl; said R4 is optionally replaced by R 41 replace; Preferably, R 41 F, Cl, -OH, -OCH3, -NHCH3, -N(CH3)2; Preferably, -L1-L2-C(O)R4 is -CH2-NH-C(O)-CH=CH2, -CH2-NH-C(O)-CF=CH2, and / or, -L1-L2-S(O)2R4 is 17. The compound according to any one of claims 9 to 14, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: R5 is a benzene ring, cyclohexane, or cyclohexene; said R5 is optionally replaced by R 51 replace; Preferably, R5 is a benzene ring, R 51 is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -SF5, -S(C1-C6 alkyl), -S(C1-C6 haloalkyl); or, R5 is cyclohexane, cyclohexene, R 51 Selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -SF5, -S(C1-C6 alkyl), -S(C1-C6 haloalkyl), =CF2; Preferably, R5 is a benzene ring, R 51 is selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -SF5, -S(C1-C3 alkyl), -S(C1-C3 haloalkyl); or, R5 is cyclohexane, cyclohexene, R 51 Selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -SF5, -S(C1-C6 alkyl), -S(C1-C6 haloalkyl), =CF2; Preferably, R5 is a benzene ring, cyclohexane, or cyclohexene; Preferably, R 51 Selected from -CF3, -O-CF3, -S-CF3, -SF5, =CF2; Preferably, R5 is Preferably, R5 is 18. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: Selected from:

19. A composition comprising the compound according to any one of claims 1 to 18, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier.

20. Use of the compound according to any one of claims 1 to 18, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or use of the pharmaceutical composition according to claim 19, comprising: Preparing a drug, pharmaceutical composition or formulation for preventing and / or treating a disease associated with increased TEAD expression; and / or, Preparing a drug, pharmaceutical composition or formulation for reducing / inhibiting TEAD expression or increasing TEAD activity; and / or, Preparing a drug, pharmaceutical composition or preparation for reducing / inhibiting the Hippo signaling pathway; Preferably, the TEAD comprises: TEAD1, TEAD2, TEAD3 and TEAD4; Preferably, the disease is a cell proliferative disorder; Preferably, the cell proliferative disorder is cancer; Preferably, the disease is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic leukemia), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, soft tissue sarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic Myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasia and metaplasia), 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, vascular blastoma, 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 cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor; Preferably, the disease is selected from the group consisting of: mesothelioma, soft tissue sarcoma, meningioma, glioma, lung cancer.

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