Bicyclic TEAD inhibitor

Abstract

Provided in the present invention is a heterocyclic compound serving as a TEAD inhibitor. The TEAD inhibitor has a structure represented by formula (I 0 ) of the invention, and can be used for preventing and / or treating diseases related to increased TEAD expression.

Description

Bicyclic TEAD inhibitors

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

[0002] The applicant's prior patent application, filed with the State Intellectual Property Office of China on November 30, 2023, with patent application number 202311642978.3 and titled "TEAD inhibitors containing a bicyclic ring";

[0003] The applicant's prior patent application, filed with the State Intellectual Property Office of China on January 31, 2024, with patent application number 202410142766.7 and titled "TEAD inhibitors containing a bicyclic ring";

[0004] The applicant's prior patent application, filed with the State Intellectual Property Office of China on April 9, 2024, with patent application number 202410424460.0 and titled "TEAD inhibitors containing a bicyclic ring";

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

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

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

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

[0010] YAP / TAZ-TEADs activation promotes tumor development, and inhibiting the interaction between YAP / TAZ and TEADs has therapeutic potential. In some cancers, such as malignant mesothelioma, ovarian cancer, and cholangiocarcinoma, the YAP / TAZ-TEADs complex is frequently overactivated or overexpressed, leading to cancer progression. This overactivation is often caused by alterations in genes upstream of the Hippo signaling pathway. In patients with malignant mesothelioma, 40%-50% of tumors have NF2 mutations or deletions, <25% have MST1 or LAST1 / 2 mutations or deletions, and 70% have high YAP expression. Overactivation of the YAP / TAZ-TEADs complex contributes to tumor cell proliferation, metastasis, epithelial-to-mesenchymal transition (EMT), and the maintenance of cancer stem cells. The interaction between YAP and TEADs is crucial for initiating transcriptional programs that drive tumorigenesis and proliferation. TEADs defective in the DNA binding domain can block tumorigenesis mediated by mutations in genes upstream of the Hippo signaling pathway, suggesting that inhibiting the interaction between YAP / TAZ and TEADs has anti-tumor effects. Invenva Pharma's patents indicate that inhibiting the interaction between YAP / TAZ and TEADs can significantly suppress tumor cell proliferation. Other studies have also shown that the downstream proteins CTGF and CYR61 of YAP / TAZ-TEADs can induce tumor cell resistance to chemotherapy drugs such as paclitaxel, and that YAP / TAZ-TEADs have become an alternative survival pathway for drug-resistant cancer cells. These findings suggest that inhibiting the interaction between YAP / TAZ and TEADs has the potential to treat tumors, particularly those with overactivation or mutations in the upstream Hippo signaling pathway.

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

[0012] The present invention provides a heterocyclic compound as a TEAD inhibitor, wherein the heterocyclic compound is the compound of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; the compound can significantly inhibit the activity of TEAD transcription and can be used to prevent and / or treat diseases or conditions associated with increased TEAD expression.

[0013] The present invention provides a compound represented by formula I0, and its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0014] 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 there are multiple Ra, the Ra are the same or different;

[0015] Ring B is a benzene ring, a 5-6 membered N-containing heteroaromatic ring, or a saturated or partially unsaturated 5-6 membered heterocycloalkyl group; the ring B is optionally substituted with one or more Rb; when there are multiple Rb groups, the Rb groups are the same or different;

[0016] R1 is or-W-COOR 12 ;

[0017] The R1 is optionally replaced by one or more R 10 Replace, when R 10 When there are multiple R 10 Same or different;

[0018] R 11 、R 12 Each 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;

[0019] Or, R 11 、R 12 Together with the P to which they are attached, they form a 4-7 membered ring;

[0020] The R 11 Optionally, one or more R 10 Replace; when R 10 When there are multiple R 10 Same or different;

[0021] W does not exist or is C1-C3 alkylene;

[0022] 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;

[0023] 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;

[0024] Ring D is a 4-6 membered heterocycloalkyl or a 5-6 membered heteroaryl; said ring D is optionally substituted by one or more Rd; when Rd is multiple, said Rd are the same or different;

[0025] 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 there are multiple R 41 Same or different;

[0026] 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;

[0027] The R5 is optionally replaced by one or more R 51 Replace; when R 51 When there are multiple R 51 Same or different;

[0028] 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;

[0029] The R 10 、R 41 、R 51 , Ra, Rb, Rd are optionally substituted by a substituent selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C 1- C3 alkoxy, -SF5.

[0030] The present invention also provides a compound represented by formula I', its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0031] 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 there are multiple Ra, the Ra are the same or different;

[0032] Ring B is a benzene ring, a 5-6 membered N-containing heteroaromatic ring, or a saturated or partially unsaturated 5-6 membered heterocycloalkyl group; the ring B is optionally substituted with one or more Rb; when there are multiple Rb groups, the Rb groups are the same or different;

[0033] R1 is R 11 、R 12 Each independently selected from: C1-C6 alkyl, C1-C6 alkoxy; or R 11 、R 12 Together with the P to which they are attached, they form a 4-7 membered ring;

[0034] The R1 is optionally replaced by one or more R 10 Replace, when R 10 When there are multiple R 10 Same or different;

[0035] 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;

[0036] 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;

[0037] Ring D is a 4-6 membered heterocycloalkyl or a 5-6 membered heteroaryl; said ring D is optionally substituted by one or more Rd; when Rd is multiple, said Rd are the same or different;

[0038] 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 there are multiple R 41 Same or different;

[0039] 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;

[0040] The R5 is optionally replaced by one or more R 51 Replace; when R 51 When there are multiple R 51 Same or different;

[0041] 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;

[0042] 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.

[0043] The present invention also provides a compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0044] 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 there are multiple Ra, the Ra are the same or different;

[0045] Ring B is a benzene ring or 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;

[0046] R1 is R 11 、R 12 Each independently selected from: C1-C6 alkyl, C1-C6 alkoxy; or R 11 、R 12 Together with the P to which they are attached, they form a 4-7 membered ring; the R1 is optionally replaced by one or more R 10 Replace, when R 10 When there are multiple R 10 Same or different;

[0047] R2 and R3 are each independently -L1-L2-C(O)R4, -S(O)2R4, -S(O)R4, R5, and only one of R2 and R3 is R5;

[0048] 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;

[0049] Ring D is a 4-6 membered heterocycloalkyl or a 5-6 membered heteroaryl; said ring D is optionally substituted by one or more Rd; when Rd is multiple, said Rd are the same or different;

[0050] 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 there are multiple R 41 Same or different;

[0051] R5 is a benzene ring, a 5-12 membered heteroaryl group; said R5 is optionally replaced by one or more R 51 Replace; when R 51 When there are multiple R 51 Same or different;

[0052] 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);

[0053] 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) 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.

[0054] In a preferred embodiment, R 11 、R 12 Together with the P to which they are attached they form a 4-, 5-, 6- or 7-membered heterocycloalkyl group.

[0055] In a preferred embodiment, 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;

[0056] The R1 is optionally replaced by one or more R 10 Replace, when R 10 When there are multiple R10 Same or different; preferably, R1 is

[0057] In a preferred embodiment, ring A is a benzene ring, pyridine, pyridazine, pyrimidine, or pyrazine;

[0058] Ring B is pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,3-dihydroimidazol-2-one

[0059] In a preferred embodiment, ring A is a benzene ring or pyridine, and ring B is pyrazole, pyridine, pyridazine, or 1,3-dihydroimidazol-2-one.

[0060] In a preferred embodiment, the compound has the structure shown in Formula Ia or Formula Ib

[0061] wherein V1, V2, V3, and V4 are each independently CH or N;

[0062] R1, R2, and R3 are as defined above.

[0063] In a preferred embodiment, 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.

[0064] In a preferred embodiment, Has the following structure:

[0065] In a preferred embodiment, Has the following structure:

[0066] In a preferred embodiment, the compound has the structure shown in Formula Ic:

[0067] wherein V1, V2, V3, V4, V5, and V6 are each independently CH or N;

[0068] R1, R2, and R3 are as defined above;

[0069] Preferably, one, two, three or four of V1, V2, V3, V4, V5 and V6 are N.

[0070] In a preferred embodiment, Has the following structure:

[0071] In a preferred embodiment, R2 is -L1-L2-C(O)R4, -S(O)2R4, or -S(O)R4, and R3 is R5.

[0072] In a preferred embodiment, R3 is -L1-L2-C(O)R4, -S(O)2R4, or -S(O)R4, and R2 is R5.

[0073] In a preferred embodiment, -L1-L2-C(O)R4 is selected from: -C1-C6 alkyl-NH-C(O)R4, -NH-C(O)R4,

[0074] ; and / or, -L1-L2-S(O)2R4 is

[0075] In a preferred embodiment, -C1-C6alkyl-NH-C(O)R4 is -CH2-NH-C(O)R4.

[0076] In a preferred embodiment, R4 is C2-C6 alkenyl, C2-C6 alkynyl; said R4 is optionally replaced by R 41 replace.

[0077] In a preferred embodiment, the C2-C6 alkenyl group is -CH=CH2.

[0078] In a preferred embodiment, R 41 It is a halogen, such as F and Cl.

[0079] In a preferred embodiment, R 41 It is F, Cl, -OH, -OCH3, -NHCH3, -N(CH3)2.

[0080] In a preferred embodiment, R4 is -CH=CH2, -CF=CH2, -CCl=CH2, -CH=CHCH3, -CH=CHCH2OH, -CH=CHCH2OCH3, -CH=CHCH2-N(CH3)2, -CH≡CH, -C≡CH-CH3, -C≡CHCH2OH, -C(CH3)=CH2.

[0081] In a preferred embodiment, -L1-L2-C(O)R4 is -CH2-NH-C(O)-CH=CH2, -CH2-NH-C(O)-CF=CH2,

[0082] and / or, -L1-L2-S(O)2R4 is

[0083] In a preferred embodiment, R5 is a benzene ring; said R5 is optionally replaced by R 51 replace;

[0084] Preferably, 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);

[0085] Preferably, R 51 Selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -SF5, -S(C1-C3 alkyl), -S(C1-C3 haloalkyl);

[0086] Preferably, R 51 Selected from -CF3, -O-CF3, -S-CF3, -SF5.

[0087] Preferably, R5 is

[0088] In a preferred embodiment, R5 is a benzene ring, cyclohexane, or cyclohexene; said R5 is optionally replaced by R 51 replace.

[0089] In a preferred embodiment, 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.

[0090] In a preferred embodiment, R5 is a benzene ring, R 51 Selected from C1-C3 alkyl, C1-C3 alkoxy, C 1- C3 haloalkyl, C 1- C3 haloalkoxy, -SF5, -S(C1-C3 alkyl), -S(C1-C3 haloalkyl); or, R5 is cyclohexane, cyclohexene, R 51Selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -SF5, -S(C1-C6 alkyl), -S(C1-C6 haloalkyl), =CF2.

[0091] In a preferred embodiment, R5 is a benzene ring, R 51 Selected from -CF3, -O-CF3, -S-CF3, -SF5; or, R5 is cyclohexane, cyclohexene, R 51 Selected from -CF3, -O-CF3, -S-CF3, -SF5, =CF2.

[0092] In a preferred embodiment, R5 is

[0093] In a preferred embodiment, R5 is

[0094] In a preferred embodiment, the compound has the following structure:

[0095] In a preferred embodiment, the compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is selected from:

[0096] The present invention also provides a compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0097] 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 there are multiple Ra, the Ra are the same or different;

[0098] Ring B is a benzene ring, a 5-6 membered N-containing heteroaromatic ring, or a saturated or partially unsaturated 5-6 membered heterocycloalkyl group; the ring B is optionally substituted with one or more Rb; when there are multiple Rb groups, the Rb groups are the same or different;

[0099] 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;

[0100] W does not exist or is C1-C3 alkylene;

[0101] The R 11 Optionally, one or more R 10 Replace; when R 10 When there are multiple R 10 Same or different;

[0102] The R 10 Selected from: -H, halogen, -OH, -NH2, -CN, C1-C6 alkyl;

[0103] 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;

[0104] 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;

[0105] Ring D is a 4-6 membered heterocycloalkyl or a 5-6 membered heteroaryl; said ring D is optionally substituted by one or more Rd; when Rd is multiple, said Rd are the same or different;

[0106] 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 there are multiple R 41 Same or different;

[0107] 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;

[0108] The R5 is optionally replaced by one or more R 51 Replace; when R 51 When there are multiple R 51 Same or different;

[0109] 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, C 1- C6 alkoxy, -NH-C1- C6 alkyl, -N(C1-C6 alkyl)2, -SF5, -S(C1-C6 alkyl), oxo (=O), =CH2, =CH-C1-C6 alkyl;

[0110] The R 41 、R 51 , Ra, Rb, Rd are optionally substituted by a substituent selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, C 1- C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -SF5.

[0111] In a preferred embodiment, the R1 is or -COOH; wherein R 11 is C1-C3 alkyl, 3-6 membered cycloalkyl; W is absent or is -CH2-; the R 11 Optionally, one or more R 10 Replace; when R 10 When there are multiple R 10 The same or different; the R 10 Selected from: -H, -OH.

[0112] In a preferred embodiment, R 11 It is methyl, cyclopropyl, -CH2CH2OH.

[0113] In a preferred embodiment, ring A is a benzene ring, pyridine, pyridazine, pyrimidine, or pyrazine.

[0114] In a preferred embodiment, ring B is pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, or 1,3-dihydroimidazol-2-one.

[0115] In a preferred embodiment, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, has the following structure:

[0116] wherein V1, V2, V3, V4, V5, and V6 are each independently CH or N;

[0117] R1, R2, and R3 are as defined above.

[0118] In a preferred embodiment, the compound represented by formula I", its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs,

[0119] Has the following structure: and / or,

[0120] Has the following structure: Has the following structure:

[0121] In a preferred embodiment, it has the following structure:

[0122] In a preferred embodiment, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, has the following structure:

[0123] Wherein, R1, R2, and R3 are as defined above.

[0124] In a preferred embodiment, R2 is -L1-L2-C(O)R4, -L1-L2-S(O)2R4, or -L1-L2-S(O)R4, and R3 is R5.

[0125] In a preferred embodiment, R3 is -L1-L2-C(O)R4, -L1-L2-S(O)2R4, or -L1-L2-S(O)R4, and R2 is R5.

[0126] In a preferred embodiment, the -L1-L2-C(O)R4 is selected from: -C1-C6 alkyl-NH-C(O)R4, -NH-C(O)R4,

[0127] In a preferred embodiment, the -L1-L2-S(O)2R4 is

[0128] In a preferred embodiment, R4 is C2-C6 alkenyl, C2-C6 alkynyl; said R4 is optionally replaced by R 41 replace.

[0129] In a preferred embodiment, R 41 It is F, Cl, -OH, -OCH3, -NHCH3, -N(CH3)2.

[0130] In a preferred embodiment, R4 is -CH=CH2, -CF=CH2, -CH=CHF, -CCl=CH2, -CH=CHCH3, -C(CH3)=CH2, -CH=CHCH2OH, -CH=CHCH2OCH3, -CH=CHCH2-N(CH3)2, -C≡CH, -C≡C-CH3, -C≡CCH2OH.

[0131] In a preferred embodiment, -L1-L2-C(O)R4 is -CH2-NH-C(O)-CH=CH2, -CH2-NH-C(O)-CF=CH2,

[0132] In a preferred embodiment, -L1-L2-S(O)2R4 is

[0133] In a preferred embodiment, R5 is a benzene ring, cyclohexane, or cyclohexene; said R5 is optionally replaced by R 51 replace.

[0134] In a preferred embodiment, 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.

[0135] In a preferred embodiment, 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.

[0136] In a preferred embodiment, R5 is a benzene ring, cyclohexane, or cyclohexene.

[0137] In a preferred embodiment, R 51 Selected from -CF3, -O-CF3, -S-CF3, -SF5, =CF2.

[0138] In a preferred embodiment, R5 is

[0139] In a preferred embodiment, R5 is

[0140] In a preferred embodiment, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are selected from:

[0141] The present invention also provides a pharmaceutical composition comprising any one of the compounds described above, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and a pharmaceutically acceptable carrier.

[0142] The present invention also provides uses of the compound described above, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or uses of the pharmaceutical composition described in the second aspect, wherein the uses include at least one of the following uses:

[0143] preparing a medicament, pharmaceutical composition or formulation for preventing and / or treating a disease or condition associated with increased TEAD expression; and / or,

[0144] Preparation of drugs, pharmaceutical compositions or preparations for reducing / inhibiting TEAD expression or increasing TEAD activity; and / or,

[0145] Prepare drugs, pharmaceutical compositions or preparations for reducing / inhibiting the Hippo signaling pathway.

[0146] In a preferred embodiment, the TEAD comprises: TEAD1, TEAD2, TEAD3 and TEAD4.

[0147] In a preferred embodiment, the disease is a cell proliferative disease.

[0148] In a preferred embodiment, the cell proliferative disorder is cancer.

[0149] In a preferred embodiment, 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, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, Hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's disease and non-Hodgkin's disease), lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (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, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

[0150] The present invention also provides a method for treating a disease or condition, comprising administering to a patient a therapeutically effective amount of at least one of the above-mentioned compound, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs or pharmaceutical compositions.

[0151] In a preferred embodiment of the present invention, the disease is a disease associated with increased TEAD expression. The TEADs include: TEAD1, TEAD2, TEAD3 and TEAD4.

[0152] In a preferred embodiment of the present invention, the disease is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.

[0153] In a preferred embodiment of the present invention, the disease is the above-mentioned disease.

[0154] In some embodiments, the patient is a mammal, preferably a human.

[0155] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention.

[0156] Terms and Definitions

[0157] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The resulting group definitions and compound structures shall fall within the scope of the description of this specification.

[0158] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by persons skilled in the art to which the claimed subject matter belongs. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated by reference in their entirety. If multiple definitions of a term are used herein, the definitions in this section shall prevail.

[0159] It should be understood that the above brief description and the detailed description below are exemplary and are only used for explanation, and do not impose any restrictions on the subject matter of the present invention. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It must be noted that unless otherwise clearly stated in the text, the singular forms used in this specification and claims include the plural forms of the things referred to. It should also be noted that unless otherwise stated, the use of "or" and "or" means "and / or". In addition, the use of the term "including" and other forms, such as "comprising", "including" and "containing" are not restrictive.

[0160] Definitions of standard chemical terms can be found in the literature (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are employed. Unless specifically defined, the terms used herein in the descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry are those known in the art. Standard techniques can be used in chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. For example, reactions and purifications can be performed using the manufacturer's instructions for use of kits, or as described herein, as known in the art. The techniques and procedures described above can generally be performed according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification. In the present specification, groups and substituents thereof can be selected by one skilled in the art to provide stable structural moieties and compounds.

[0161] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result from writing the formula from right to left. For example, CHO is equivalent to OCH. As used herein, As used herein, "R1", "R2" and "R 1 " have the same meaning and can be replaced with each other. For other symbols such as R2, similar definitions have the same meaning.

[0162] The section headings used herein are for organizational purposes only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0163] In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0164] When a numerical range is described in the specification and claims of this application and is understood as an "integer," it should be understood to include both endpoints of the range as well as every integer within the range. For example, "an integer from 0 to 5" should be understood to include every integer from 0, 1, 2, 3, 4, and 5.

[0165] As used herein, the term "halogen" by itself or as part of another substituent refers to fluorine, chlorine, bromine, or iodine.

[0166] As used herein, the term "alkyl" when used alone or as part of another substituent means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms, and connected to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. Alkyl groups may be unsubstituted or substituted with one or more suitable substituents. Alkyl groups may also be isotopic isomers of naturally abundant alkyl groups that are enriched in isotopes of carbon and / or hydrogen (i.e., deuterium or tritium). As used herein, the term "alkenyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term "alkynyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.

[0167] The term "C1-C6 alkyl" alone or as part of another substituent is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or isomers thereof. The term "C1-C3 alkyl" is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2 or 3 carbon atoms. In particular, such radicals have 1, 2 or 3 carbon atoms ("C1-C3 alkyl"), for example methyl, ethyl, n-propyl or isopropyl.

[0168] The term "C2-C6 alkenyl" when used alone or as part of another substituent is understood to mean a straight or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms, for example, 2 or 3 carbon atoms (i.e., C2-C3 alkenyl). It is understood that where the alkenyl contains more than one double bond, the double bonds may be separated from one another or conjugated. The alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl , 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0169] The term "C2-C6 alkynyl" is understood to mean a straight or branched monovalent hydrocarbon radical comprising one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms, for example 2 or 3 carbon atoms ("C2-C3 alkynyl"). The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0170] The term "C1-C6 alkoxy" is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms and an oxygen atom, or represented by C1-C6 alkyl-O-. 1- The definition of C6 alkyl is as described in this specification. The oxygen atom can be attached to any carbon atom of the straight or branched chain of C1-C6 alkyl. It includes but is not limited to: methoxy (CH3-O-), ethoxy (C2H5-O-), propoxy (C3H7-O-), butoxy (C4H9-O-), pentoxy (C5H 11 -O-), hexyloxy (C6H 13 -O-).

[0171] The term "ring" when used alone or as part of another substituent includes carbocyclic rings and heterocyclic rings, which can be saturated, unsaturated or partially unsaturated. Such rings include heterocycloalkyl, cycloalkyl, aryl, heteroaryl, etc. For example, the term "4-7 membered ring" refers to a ring composed of 4, 5, 6 or 7 atoms.

[0172] The term "heterocycloalkyl" when used alone or as part of another substituent refers to a cycloalkyl group 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 "mn-membered heterocycloalkyl" is understood to mean a ring having from m to n atoms. For example, the term "5-6-membered heterocycloalkyl" is understood to mean a ring having 5 or 6 atoms.

[0173] The term "aryl" or "aromatic ring" or "aromatic ring group" when used alone or as part of another substituent refers to a monocyclic or polycyclic carboaromatic ring system, such as a benzene ring. For example, the term "6-10 membered aryl" is understood to mean a carboaromatic ring system having 6 to 10 atoms.

[0174] The term "heteroaryl" or "heteroaryl ring" or "heteroaryl ring group" when used alone or as part of another substituent refers to a monocyclic or polycyclic aromatic ring system, in which, in certain embodiments, one to three atoms in the ring system are heteroatoms, i.e., elements other than carbon, including but not limited to N, O, S or P. Examples include furanyl, imidazolyl, indolinyl, pyrrolidinyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl, quinolinyl and isoquinolinyl. For example, the term "5-6 membered heteroaryl" is understood to mean a heteroatom-containing aromatic ring system having 5 to 6 atoms.

[0175] The term "halo" is used interchangeably with the term "halogen-substituted" when used alone or as part of another substituent. "Haloalkyl" or "halogen-substituted alkyl" refers to saturated aliphatic hydrocarbon groups, including branched and straight-chain groups, having the specified number of carbon atoms, substituted with one or more halogens (e.g., -CvFw, where v = 1 to 3 and w = 1 to (2v+1)). Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

[0176] Compounds provided herein include intermediates that can be used to prepare compounds provided herein, which contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), and also include protected derivatives thereof."Protected derivatives" are compounds in which one or more reactive sites are blocked by one or more protecting groups (also referred to as blocking groups). Suitable carboxyl moiety protecting groups include benzyl, tert-butyl, etc., and isotopes, etc. Suitable amino and amine protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable hydroxyl protecting groups include benzyl, etc. Other suitable blocking groups are well known to those of ordinary skill in the art.

[0177] In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

[0178] In this application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0179] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. These salts may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or may be used in the identification, characterization, or purification of the compounds of the present invention.

[0180] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0181] Depending on the selection of raw materials and methods, the compounds of the present invention may exist in the form of one of the possible isomers or a mixture thereof, for example as a pure optical isomer, or as a mixture of isomers, such as as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing a compound with optical activity, the prefixes D and L or R and S are used to represent the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (-) are symbols for the rotation of plane polarized light caused by the specified compound, where (-) or L represent that the compound is left-handed. Compounds prefixed with (+) or D are dextrorotatory.

[0182] When bonds to chiral carbon atoms in formulae of the present invention are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon atoms and the enantiomerically pure compounds and mixtures thereof are encompassed within the scope of the formulae. The diagrammatic representations of racemates and enantiomerically pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62: 114-120. Wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter.

[0183] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture with physical and chemical properties consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0184] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0185] In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.

[0186] In the present application, the term "solvate" refers to a compound of the present invention or a salt thereof including a stoichiometric or non-stoichiometric amount of a solvent bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

[0187] As used herein, the term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the present invention are prepared by modifying functional groups within the compound. These modifications can be removed by conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl or amino group within a compound of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group or free amino group, respectively.

[0188] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0189] As used herein, the term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients enhance the handling characteristics of pharmaceutical formulations, i.e., by increasing flowability and / or adhesion, making the formulation more suitable for direct compression.

[0190] As used herein, the term "treat" and other similar synonyms include the following meanings:

[0191] (i) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition;

[0192] (ii) inhibiting the disease or condition, i.e., curbing its development;

[0193] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0194] (iv) Alleviate the symptoms of the disease or condition.

[0195] The reaction temperature of each step can be appropriately selected according to the solvent, starting materials, reagents, etc., and the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting materials, reagents, etc. After the reaction of each step is completed, the target compound can be separated and purified from the reaction system according to conventional methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography, etc. If it does not affect the next reaction, the target compound can also be directly entered into 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 solvent includes but is not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof. Beneficial effects

[0196] After 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, which can significantly inhibit the activity of TEAD transcription and can be used to prevent and / or treat diseases associated with increased TEAD expression. DETAILED DESCRIPTION

[0197] The present invention will be further described below in conjunction with specific examples. It should be understood that the following description is only the most preferred embodiment of the present invention and should not be considered as limiting the scope of protection of the present invention. Based on a full understanding of the present invention, the experimental methods in the following examples that do not specify specific conditions are generally carried out under conventional conditions or under conditions recommended by the manufacturer. Those skilled in the art may make non-essential changes to the technical solutions of the present invention, and such changes should be considered as included in the scope of protection of the present invention.

[0198] Preparation Example 1

[0199] Preparation of intermediate A1

[0200] The synthetic route is as follows:

[0201] 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 anhydrous copper acetate (14.62 g, 80.51 mmol) were dissolved in tetrahydrofuran (150 mL), pyridine (16.98 g, 214.70 mmol) was added, and the gas was replaced three times under the protection of an oxygen balloon. The reaction solution was reacted at 25°C for 48 hours. The reaction solution was diluted with ethyl acetate and filtered using celite to obtain a crude product which was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 1:0-100:1) to obtain the compound 4-chloro-3-iodo-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine (Intermediate A1) (21.0 g, yield 89.0%).

[0202] LC-MS, M / Z (ESI): 440.0 [M+H] + .

[0203] Example 1 Preparation of Compound I-1

[0204] The synthetic route is as follows:

[0205] Step 1: Synthesis of tert-butyl ((4-chloro-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (1-1)

[0206] At room temperature, the compound 4-chloro-3-iodo-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridine (Intermediate A1) (300 mg, 0.68 mmol) and the compound potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (194 mg, 0.82 mmol) were dissolved in a mixed solution of toluene (3 mL) and water (0.3 mL). 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) were added under a nitrogen atmosphere, and the mixture was stirred at 120°C for 12 h under nitrogen protection. After TLC monitoring showed that the raw materials had reacted completely, stirring was stopped, the reaction solution was cooled to room temperature, diluted with water (15 mL), extracted with ethyl acetate (5 mL×3), the organic phase was collected and dried over anhydrous sodium sulfate, and the organic phase was concentrated by distillation under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=100:5) to obtain compound ((4-chloro-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamic acid tert-butyl ester (1-1) (167 mg, yield 55.3%).

[0207] LC-MS, M / Z (ESI): 443.0 [M+H] + .

[0208] Step 2: Synthesis of tert-butyl ((4-(dimethylphosphoryl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (1-2)

[0209] At room temperature, the compound 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), the compound dimethyl phosphine oxide (42.30 mg, 0.56 mmol), potassium phosphate (60 mg, 0.28 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (47 mg, 0.08 mmol) and tris(dibenzylideneacetone)dipalladium (37 mg, 0.04 mmol) were dissolved in anhydrous DMF (2 mL) and reacted in a microwave reactor at 140 ° C under nitrogen protection for 4 h. After the reaction was completed, the reaction solution was cooled to room temperature and quenched by adding water (10 mL). It was then extracted with ethyl acetate (5 mL×3). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was concentrated by distillation under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (V / V)=100:5) to obtain compound ((4-(dimethylphosphoryl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamic acid tert-butyl ester (1-2) (78 mg, yield 59.42%).

[0210] LC-MS, M / Z (ESI): 485.2 [M+H] + .

[0211] Step 3: Synthesis of (3-(aminomethyl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)dimethylphosphine oxide hydrochloride (1-3)

[0212] At room temperature, compound 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) was dissolved in anhydrous 1,4-dioxane (2 mL) and stirred at room temperature. Then, a solution of hydrogen chloride in 1,4-dioxane (4 M, 0.38 mL, 1.50 mmol) was slowly added dropwise, and the reaction solution was stirred at room temperature for 30 min. After TLC monitoring showed that the raw materials had reacted completely, stirring was stopped, the solvent was removed by rotary distillation under reduced pressure, ethyl acetate (5 mL) was added, and the mixture was stirred at room temperature for 1 h to obtain a suspension. The suspension was filtered 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%).

[0213] LC-MS, M / Z (ESI): 385.2 [M+H]+ .

[0214] Step 4: Synthesis of N-((4-(dimethylphosphoryl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)acrylamide (I-1)

[0215] At room temperature, compound (3-(aminomethyl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)dimethylphosphine oxide hydrochloride (1-3) (60 mg, 0.14 mmol) was dissolved in a mixed solution of acetonitrile (1 mL) and water (1 mL), stirred at 0°C for 10 min, and then sodium bicarbonate (60 mg, 0.71 mmol) was added. The mixture was stirred at 0°C for 10 min, and then acryloyl chloride (39 mg, 0.43 mmol) was slowly added dropwise. After the addition was completed, the reaction solution was stirred in an ice bath at 0°C for 30 min. After TLC monitoring showed that the raw materials had reacted completely, stirring was stopped, water (5 mL) was added to the reaction solution to dilute it, and the mixture was extracted with ethyl acetate (3 mL×5). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was concentrated by distillation under reduced pressure, and the residue was separated and purified by column chromatography on silica gel (dichloromethane:methanol (V / V)=20:1) to obtain 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%).

[0216] LC-MS, M / Z (ESI): 439.2 [M+H] + .

[0217] 1 H NMR (400MHz, DMSO-d6): 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).

[0218] Example 2: Preparation of Compound I-2

[0219] The synthetic route is as follows:

[0220] Step 1: Synthesis of 5-bromo-3-iodo-1-(4-(trifluoromethyl)phenyl)-1H-indazole (2-2)

[0221] 5-Bromo-3-iodo-1H-indazole (2-1) (2.0 g, 6.2 mmol) and 4-trifluoromethylphenylboronic acid (1.77 g, 9.3 mmol) were dissolved in acetonitrile (20 mL). Copper acetate (1.69 g, 9.3 mmol) and pyridine (1.96 g, 24.8 mmol) were added, and the mixture was stirred at room temperature overnight under an oxygen balloon. After completion of the reaction, the mixture was filtered through celite, and the filter cake was washed with dichloromethane (40 mL). The filtrates were combined, washed with water (15 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain the compound 5-bromo-3-iodo-1-(4-(trifluoromethyl)phenyl)-1H-indazole (2-2) (2.53 g, yield: 87.5%).

[0222] LC-MS, M / Z (ESI): 467.1 [M+H] + .

[0223] Step 2: Synthesis of tert-butyl ((5-bromo-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (2-3)

[0224] 5-Bromo-3-iodo-1-(4-(trifluoromethyl)phenyl)-1H-indazole (2-2) (1 g, 2.14 mmol) and potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (253.7 mg, 1.07 mmol) were dissolved in toluene (20 mL) and water (20 mL). Cesium carbonate (2.09 g, 6.42 mmol) and chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (144.6 mg, 0.21 mmol) were added to the system. The gas was replaced three times under nitrogen protection, and the reaction solution was heated to 100°C and reacted overnight. The reaction solution was concentrated, and the crude product was separated and purified 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%).

[0225] LC-MS, M / Z (ESI): 470.2 [M+H] + .

[0226] Step 3: Synthesis of tert-butyl ((5-(dimethylphosphoryl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (2-4)

[0227] Tert-butyl ((5-bromo-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (2-3) (181 mg, 0.39 mmol) was dissolved in N,N-dimethylformamide (3 mL), and dimethylphosphine oxide (156.1 mg, 2.0 mmol) and potassium phosphate (169.8 mg, 0.8 mmol) were added, followed by tris(dibenzylideneacetone)dipalladium (36.6 mg, 0.04 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (46.3 mg, 0.08 mmol). The mixture was reacted in a microwave oven at 140 ° C under nitrogen protection for 2.5 hours. After the reaction, the mixture was cooled to room temperature, water (20 mL) was added to the reaction solution, 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, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol (V / V) = 20:1) to obtain the compound tert-butyl ((5-(dimethylphosphoryl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (2-4) (149.6 mg, yield 83.2%).

[0228] LC-MS, M / Z (ESI): 468.1 [M+H] + .

[0229] Step 4: Synthesis of (3-(aminomethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-5-yl)dimethylphosphine oxide hydrochloride (2-5)

[0230] Tert-butyl ((5-(dimethylphosphoryl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (2-4) (149.6 mg, 0.32 mmol) was dissolved in 1,4-dioxane (20 mL). A 4 M solution of hydrogen chloride in 1,4-dioxane (20 mL) was added and allowed to react at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude compound (3-(aminomethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-5-yl)dimethylphosphine oxide hydrochloride (2-5), which was used directly in the next reaction.

[0231] LC-MS, M / Z (ESI): 368.1 [M+H] + .

[0232] Step 5: Synthesis of N-((5-(dimethylphosphoryl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)acrylamide (I-2)

[0233] (3-(Aminomethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-5-yl)dimethylphosphine oxide hydrochloride (2-5) (129.2 mg, 0.32 mmol) was dissolved in tetrahydrofuran (10 mL). Saturated aqueous sodium bicarbonate solution (2 mL) was added at 0°C and stirred at 0°C for 10 minutes. Acryloyl chloride (28.9 mg, 0.32 mmol) was then added and the reaction continued at 0°C for 0.5 hours. After the reaction, water (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified 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%).

[0234] LC-MS, M / Z (ESI): 422.1 [M+H] + .

[0235] 1 H NMR (400MHz, DMSO-d6): 68.87 (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).

[0236] Example 3: Preparation of Compound I-3

[0237] The synthetic route is as follows:

[0238] 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)

[0239] Zinc powder (185 mg, 2.86 mmol) was placed in a reaction flask. Dry N,N-dimethylacetamide (2 mL) was added under argon protection. Trimethylsilyl chloride (45 μL, 0.35 mmol) was added at room temperature and stirred at 45°C for 30 min. 1,2-Dibromomethane (30 μL, 0.35 mmol) was then added and stirring continued at 45°C for 30 min. 1-tert-Butyloxycarbonyl-3-iodoazetidine (300 mg, 1.06 mmol) was then added and the reaction mixture was stirred at 65°C for 1 h. The reaction mixture was cooled to room temperature and the organic phase was used as the prepared zinc reagent. 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 tri(2-furyl)phosphine (19 mg, 0.1 mmol) were added. N,N-dimethylacetamide (3 mL) and the above-prepared zinc reagent were added under argon protection, and the reaction solution was then stirred at 70 ° C for 2 h. The reaction solution was quenched by adding saturated aqueous sodium bicarbonate solution (20 mL), and then 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 (petroleum ether: ethyl acetate (V / V) = 10:1) to obtain compound 3-(4-chloro-1-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylic acid tert-butyl ester (3-1) (233 mg, yield: 63%).

[0240] LC-MS, M / Z (ESI): 469.2 [M+H] + .

[0241] 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)

[0242] 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), dimethylphosphine oxide (156 mg, 2 mmol) were added, followed by addition of N,N-dimethylformamide (5 mL), and microwave reaction at 140 ° C under argon protection for 2 h. After completion, the reaction solution was extracted with ethyl acetate (50 mL), and the organic phase was washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was purified by silica gel column chromatography (dichloromethane: methanol (V / V) = 20:1) to give compound 3-[4-[dimethylphosphoryl]-1-[4-[(trifluoromethyl)oxy]phenyl]pyrazolo[3,4-b]pyridin-3-yl]azetidine-1-carboxylic acid tert-butyl ester (3-2) (374 mg, yield: 68%).

[0243] LC-MS, M / Z (ESI): 511.0 [M+H] + .

[0244] Step 3: Synthesis of 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)

[0245] 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. The reaction solution was then added dropwise to a saturated sodium bicarbonate solution (5 mL), followed by sodium bicarbonate (200 mg) and acetonitrile (5 mL), and then 2-fluoroacryloyl 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) / 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%).

[0246] LC-MS, M / Z (ESI): 483.0 [M+H] + .

[0247] 1 H NMR (400MHz, DMSO-d6): δ8.81 (dd, 1H), 8.46-8.32 (m, 2H), 7.67-7.51 (m, 3H), 5.59-5.42 (m, 1H), 5.35-5.2 7 (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).

[0248] Example 4: Preparation of Compound I-4

[0249] The synthetic route is as follows:

[0250] Step 1: Synthesis of 4-chloro-3-iodo-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine (4-2)

[0251] 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 anhydrous copper acetate (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 under oxygen protection for 48 hours. The reaction solution was distilled under reduced pressure to remove the solvent, and the residue was 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-pyrazolo[3,4-b]pyridine (4-2) (21.3 g, 88% yield).

[0252] LC-MS, M / Z (ESI): 424.0 [M+H] + .

[0253] 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)

[0254] Zinc powder (185 mg, 2.86 mmol) was placed in a reaction flask, the atmosphere was replaced with argon three times, anhydrous N,N-dimethylacetamide (2 mL) was added, and trimethylsilyl chloride (45 μL, 0.35 mmol) was added at room temperature. The reaction solution was stirred at 45°C for 30 min, followed by the addition of 1,2-dibromomethane (30 μL, 0.35 mmol). Stirring at 45°C was continued for 30 min, followed by the addition of 1-Boc-3-iodoazetidine (300 mg, 1.06 mmol), and the reaction solution was stirred at 65°C for 1 h. After the reaction was complete, the reaction solution was returned to room temperature, and the organic phase was used as the prepared zinc reagent. 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 tri(2-furyl)phosphine (19 mg, 0.1 mmol) were added, the atmosphere was replaced with argon three times, N,N-dimethylacetamide (3 mL) and the above-prepared zinc reagent were added, and then stirred at 70°C for 2 h. After the reaction, the reaction solution was added to a saturated aqueous sodium bicarbonate solution (20 mL) to quench, and then ethyl acetate was added to dilute (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, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 10:1) to give 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%).

[0255] LC-MS, M / Z (ESI): 453.3 [M+H] + .

[0256] Step 3: Synthesis of tert-butyl 3-(4-(dimethyl phosphate)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (4-4)

[0257] The mixture was stirred for 2 h at room temperature. 3-(4-chloro-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylic acid tert-butyl ester (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, followed by addition of N,N-dimethylformamide (5 mL) and microwave reaction at 140 ° C under argon atmosphere for 2 h. 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 give tert-butyl 3-(4-(dimethyl phosphate)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (4-4) (367 mg, 66%).

[0258] LC-MS, M / Z (ESI): 495.2 [M+H] + .

[0259] Step 4: Synthesis of 1-(3-(4-(dimethyl phosphate)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolyl[3,4-b]pyridin-3-yl)azetidin-1-yl)-2-fluoropropyl-2-ene-1-one (I-4)

[0260] Tert-butyl 3-(4-(dimethyl phosphate)-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. The reaction solution was then added dropwise to a saturated sodium bicarbonate solution (5 mL), followed by sodium bicarbonate (200 mg) and acetonitrile (5 mL), and then fluoroacryloyl chloride (64 mg, 0.6 mmol) was added at 0°C, and the reaction solution was stirred at 0°C for 15 min. After completion, the reaction solution was concentrated to remove acetonitrile and water, and the reaction solution residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain the target compound 1-(3-(4-(dimethyl phosphate)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolyl[3,4-b]pyridin-3-yl)azetidin-1-yl)-2-fluoropropyl-2-en-1-one (I-4) (52 mg, 51%).

[0261] LC-MS, M / Z (ESI): 467.1 [M+H] + .

[0262] 1 H NMR (400MHz, DMSO-d6): δ8.88-8.81(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).

[0263] Example 5 Preparation of Compound I-5

[0264] The synthetic route is as follows:

[0265] Step 1: Synthesis of 7-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (5-2)

[0266] 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) were dissolved in N,N-dimethylformamide (15 mL). Elemental iodine (3.31 g, 13.02 mmol) was added and allowed to react at room temperature for 15 hours. After completion of the reaction, the reaction was quenched with saturated aqueous sodium sulfite (20 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain the compound 7-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (5-2) (1.55 g, 85.2% yield).

[0267] LC-MS, M / Z (ESI): 280.1 [M+H] + .

[0268] Step 2: Synthesis of tert-butyl 3-(7-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (5-3)

[0269] 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 solution was continued to stir at 0°C for 10 minutes, then slowly warmed to room temperature and stirred overnight. The reaction solution was then heated to 100°C under nitrogen protection and stirred for 6 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to obtain compound 3-(7-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (5-3) (1.41 g, yield 58.3%).

[0270] LC-MS, M / Z (ESI): 435.1 [M+H] + .

[0271] 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)

[0272] 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), and cesium carbonate (2.11 g, 6.48 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (234.1 mg, 0.32 mmol) were added, and the mixture was stirred at 80°C overnight under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 2: 1) to obtain compound 3-(7-chloro-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (5-4) (1.26 g, yield 85.7%).

[0273] LC-MS, M / Z (ESI): 453.2 [M+H] + .

[0274] 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)

[0275] 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) was dissolved in N,N-dimethylformamide (3 mL), and dimethylphosphine oxide (156.1 mg, 2.0 mmol) and potassium phosphate (265.3 mg, 1.25 mmol) were added, followed by trisdibenzylideneacetone dipalladium (45.8 mg, 0.05 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (57.9 mg, 0.10 mmol), and the mixture was reacted in a microwave at 140 ° C under nitrogen protection for 2.5 hours. After the reaction, the reaction solution was cooled to room temperature, diluted with water (20 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, and the crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol (V / V) = 20:1) to obtain compound 3-(7-(dimethylphosphoryl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (5-5) (201.1 mg, yield 81.5%).

[0276] LC-MS, M / Z (ESI): 495.2 [M+H] + .

[0277] Step 5: Synthesis of (1-(azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)dimethylphosphine oxide (5-6)

[0278] 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). A solution of hydrogen chloride in 1,4-dioxane (5 mL, 4 M) was added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solvent was removed by distillation under reduced pressure. The pH was adjusted to 8 at 0°C with saturated aqueous sodium bicarbonate (10 mL). 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 used directly in the next reaction.

[0279] LC-MS, M / Z (ESI): 395.1 [M+H] + .

[0280] 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)

[0281] 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-azabenzotriazole)-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 allowed to react at room temperature for 4 hours. After the reaction, water (15mE) was added for dilution, and the mixture was extracted with ethyl acetate (20mE×3). The organic phases were combined, washed with water (10mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated and purified by silica gel column (dichloromethane: methanol (V / V) = 10:1) to obtain 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%).

[0282] LC-MS, M / Z (ESI): 467.0 [M+H] + .

[0283] 1 H NMR (400MHz, DMSO-d6): δ8.79 (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).

[0284] Example 6 Preparation of Compound I-6

[0285] The synthetic route is as follows:

[0286] Step 1: 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)

[0287] 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) were dissolved in 1,4-dioxane (20.0 mL) and water (4.00 mL), and cesium carbonate (2.11 g, 6.48 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (234.1 mg, 0.32 mmol) were added. The atmosphere was replaced with nitrogen three times, and the reaction solution was heated to 80°C and stirred overnight. After the reaction, the reaction solution was cooled to room temperature, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 2: 1) to obtain compound 3-(7-chloro-3-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (6-2) (1.22 g, yield 82.7%).

[0288] LC-MS, M / Z (ESI): 457.2 [M+H] + .

[0289] 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)

[0290] 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) was dissolved in N,N-dimethylformamide (3 mL), and dimethylphosphine oxide (156.1 mg, 2.0 mmol) and potassium phosphate (265.3 mg, 1.25 mmol) were added, followed by trisdibenzylideneacetone dipalladium (45.8 mg, 0.05 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (57.9 mg, 0.10 mmol), and the mixture was reacted in a microwave at 140°C under nitrogen protection for 2.5 hours. After the reaction, the reaction solution was cooled to room temperature, water (20 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 crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol (V / V) = 20:1) to obtain compound 3-(7-(dimethylphosphoryl)-3-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (6-3) (207.4 mg, yield 83.2%).

[0291] LC-MS, M / Z (ESI): 499.2 [M+H] + .

[0292] Step 3: Synthesis 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)

[0293] 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 solution of hydrogen chloride in 1,4-dioxane (5 mL, 4 M) was added, and the mixture was reacted at room temperature for 4 hours. After completion of the reaction, the reaction solvent was removed by distillation under reduced pressure, and a saturated aqueous sodium bicarbonate solution (10 mL) was added at 0°C to adjust the pH to 8. 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 a crude compound ((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 used directly in the next reaction.

[0294] LC-MS, M / Z (ESI): 399.1 [M+H] + .

[0295] 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)

[0296] 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-azabenzotriazole)-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 hours. Crude ((1-(azetidin-3-yl)-3-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)dimethylphosphine oxide (6-4) (135.4 mg) was added. , 0.34 mmol), and reacted at room temperature for 4 hours. After the reaction, water (15 mL) was added, extracted with ethyl acetate (20 mL×3), and the organic phases were combined, washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column chromatography (dichloromethane: methanol (V / V) = 10:1) to obtain compound 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%).

[0297] LC-MS, M / Z (ESI): 471.1 [M+H] + .

[0298] 1 H NMR (400MHz, DMSO-d6): 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).

[0299] Example 7 Preparation of Compound I-7

[0300] The synthetic route is as follows:

[0301] Step 1: Synthesis of 4-chloro-3-iodo-1-(4-(trifluoromethoxy)phenyl)-1H-indazole (7-2)

[0302] 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 anhydrous copper acetate (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 under oxygen protection for 48 hours. After completion, the reaction solution was distilled under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 20:1) to obtain the compound 4-chloro-3-iodo-1-(4-(trifluoromethoxy)phenyl)-1H-indazole (7-2) (21.8 g, 90% yield).

[0303] LC-MS, M / Z (ESI): 438.9 [M+H] + .

[0304] Step 2: Synthesis of tert-butyl 3-(4-chloro-1-(4-(trifluoromethoxy)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (7-3)

[0305] Zinc powder (185 mg, 2.86 mmol) was placed in a reaction flask, replaced with argon three times, and dry N, N-dimethylacetamide (2 mL) was added. Trimethylsilyl chloride (45 μL, 0.35 mmol) was added at room temperature and stirred at 45 ° C for 30 min. Then 1,2-dibromomethane (30 μL, 0.35 mmol) was added and stirring was continued at 45 ° C for 30 min. Subsequently, 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 reaction solution was returned to room temperature and the organic phase was taken as the prepared zinc reagent for standby use. 4-Chloro-3-iodo-1-(4-(trifluoromethoxy)phenyl)-1H-indazole (7-2) (347 mg, 0.79 mmol) was placed in another reaction bottle, tris(dibenzylideneacetone)dipalladium (36 mg, 0.04 mmol) and tri(2-furyl)phosphine (19 mg, 0.1 mmol) were added, and the argon atmosphere was replaced three times. N, N-dimethylacetamide (3 mL) and the above-prepared zinc reagent were added, and then stirred at 70 ° C for 2 h. After completion, the reaction solution was added with saturated bicarbonate. The reaction mixture was quenched in aqueous sodium chloride solution (20 mL), then diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium chloride solution (50 mL×3), and the organic phase was taken, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 10:1) to give compound 3-(4-chloro-1-(4-(trifluoromethoxy)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylic acid tert-butyl ester (7-3) (287 mg, yield: 71%).

[0306] LC-MS, M / Z (ESI): 468.2 [M+H] + .

[0307] Step 3: Synthesis of tert-butyl 3-(4-(dimethyl phosphate)-1-(4-(trifluoromethoxy)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (7-4)

[0308] Tert-butyl 3-(4-chloro-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, followed by addition of N,N-dimethylformamide (5 mL), and microwave reaction was carried out at 140 ° C under argon atmosphere for 2 h. After completion, the reaction solution was diluted with ethyl acetate (50 mL), extracted with saturated aqueous sodium chloride solution (50 mL×3), and the organic phase was then 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 give compound 3-(4-(dimethyl phosphate)-1-(4-(trifluoromethoxy)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylic acid tert-butyl ester (7-4, 342 mg, 61%).

[0309] LC-MS, M / Z (ESI): 510.3 [M+H] + .

[0310] Step 4: Synthesis of 1-(3-(4-(dimethyl phosphate)-1-(4-(trifluoromethoxy)phenyl)-1H-indazol-3-yl)azetidin-1-yl)-2-fluoropropyl-2-en-1-one

[0311] Compound tert-butyl 3-(4-(dimethyl phosphate)-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 minutes. The reaction solution was then added dropwise to a saturated sodium bicarbonate solution (5 mL), followed by sodium bicarbonate (200 mg) and acetonitrile (5 mL), and then 2-fluoroacryloyl chloride (64 mg, 0.6 mmol) was added at 0°C, and the reaction solution was reacted at 0°C for 15 minutes. After the reaction was completed, 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-(dimethyl phosphate)-1-(4-(trifluoromethoxy)phenyl)-1H-indazol-3-yl)azetidin-1-yl)-2-fluoropropyl-2-en-1-one (I-7) (59 mg, 57%).

[0312] LC-MS, M / Z (ESI): 482.1 [M+H] + .

[0313] 1 H NMR (400MHz, DMSO-d6): δ8.06-8.00 (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).

[0314] Example 8 Preparation of Compound I-8

[0315] The synthetic route is as follows:

[0316] Step 1: Synthesis of 2-chloro-4-(dimethylphosphoryl)-3-fluoropyridine (8-2)

[0317] 2-Chloro-3-fluoro-4-iodopyridine (8-1) (6.4 g, 24.86 mmol) was dissolved in N,N-dimethylformamide (60 mL), and dimethylphosphine oxide (1.93 g, 24.7 mmol) and potassium phosphate (10.5 g, 49.5 mmol) were added, followed by trisdibenzylideneacetone dipalladium (0.68 g, 0.74 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.86 g, 1.49 mmol). The reaction solution was reacted in a microwave at 140 ° C under nitrogen protection for 15 hours. After the reaction, the reaction solution was cooled to room temperature, added with water (120 mL), extracted with ethyl acetate (120 mL × 3), and the organic phases were combined, washed with water (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column (dichloromethane: methanol (V / V) = 20: 1) to obtain compound 2-chloro-4-(dimethylphosphoryl)-3-fluoropyridine (8-2) (0.65 g, yield 12.6%).

[0318] LC-MS, M / Z (ESI): 208.2 [M+H] + .

[0319] Step 2: Synthesis of tert-butyl 3-((2-chloro-4-(dimethylphosphoryl)pyridin-3-yl)amino)azetidine-1-carboxylate (8-3)

[0320] 2-Chloro-4-(dimethylphosphoryl)-3-fluoropyridine (8-2) (0.65 g, 3.14 mmol) was dissolved in n-butanol (5 mL), and tert-butyl 3-aminoazetidine-1-carboxylate (0.64 g, 3.72 mmol) was added. The mixture was reacted at 120°C for 24 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified on a silica gel column (dichloromethane:methanol (V / V) = 20:1) to obtain compound tert-butyl 3-((2-chloro-4-(dimethylphosphoryl)pyridin-3-yl)amino)azetidine-1-carboxylate (8-3) (0.62 g, 55.0% yield).

[0321] LC-MS, M / Z (ESI): 360.2 [M+H] + .

[0322] Step 3: Synthesis of tert-butyl 3-((4-(dimethylphosphoryl)-2-(4-(trifluoromethyl)anilino)pyridin-3-yl)amino)azetidine-1-carboxylate (8-4)

[0323] Tert-butyl 3-((2-chloro-4-(dimethylphosphoryl)pyridin-3-yl)amino)azetidine-1-carboxylate (8-3) (210 mg, 0.58 mmol) and 4-trifluoromethylaniline (131 mg, 0.81 mmol) were dissolved in toluene (10.0 mL), and cesium carbonate (380 mg, 1.17 mmol) was added, followed by palladium acetate (26 mg, 0.12 mmol) and 1,1′-binaphthyl-2,2′-bisdiphenylphosphine (73 mg, 0.12 mmol). The mixture was stirred at 110° C. under nitrogen protection overnight. After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain compound 3-((4-(dimethylphosphoryl)-2-(4-(trifluoromethyl)anilino)pyridin-3-yl)amino)azetidine-1-carboxylic acid tert-butyl ester (8-4) (79.3 mg, yield 28.0%).

[0324] LC-MS, M / Z (ESI): 485.2 [M+H] + .

[0325] 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)

[0326] Tert-butyl 3-((4-(dimethylphosphoryl)-2-(4-(trifluoromethyl)anilino)pyridin-3-yl)amino)azetidine-1-carboxylate (8-4) (79.3 mg, 0.16 mmol) was dissolved in acetonitrile (8 mL), triethylamine (82.7 mg, 0.82 mmol) was added, and N,N′-carbonyldiimidazole (79.5 mg, 0.49 mmol) was added, and the reaction was refluxed overnight. After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain compound 3-(7-(dimethylphosphoryl)-2-oxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (8-5) (60.3 mg, yield 72.2%).

[0327] LC-MS, M / Z (ESI): 511.2 [M+H] + .

[0328] 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)

[0329] 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) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added, and the reaction was carried out at room temperature for 0.5 hours. After completion of the reaction, the reaction solvent was distilled off under reduced pressure, saturated aqueous sodium bicarbonate solution (10 mL) was added at 0°C to adjust the pH to 8, 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 give 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 was directly used in the next reaction.

[0330] LC-MS, M / Z (ESI): 411.1 [M+H] + .

[0331] Step 6: Synthesis of 7-(dimethylphosphoryl)-1-(1-(2-fluoroprop-2-enyl)azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (I-8)

[0332] 2-Fluoroacrylic acid (18.5 mg, 0.21 mmol) and N,N-diisopropylethylamine (65.9 mg, 0.51 mmol) were dissolved in N,N-dimethylformamide (3 mL), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (92.0 mg, 0.26 mmol) was added, and the mixture was stirred at room temperature for 0.5 hour. 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) was added, and the mixture was reacted at room temperature for 4 hours. After the reaction, 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 residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (V / V) = 10:1) to obtain compound 7-(dimethylphosphoryl)-1-(1-(2-fluoroprop-2-enyl)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%).

[0333] LC-MS, M / Z (ESI): 483.1 [M+H] + .

[0334] 1 H NMR (600MHz, DMSO-d6): δ8.09 (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).

[0335] The preparation of the following compounds is described in the above Preparation Example 1:

[0336] Preparation Example 2

[0337] Example 9: Preparation of Compound I'-1

[0338] The synthetic route is as follows:

[0339] Step 1: Synthesis of 7-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (1'-2)

[0340] 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) were dissolved in N,N-dimethylformamide (15 mL). Iodine (3.31 g, 13.02 mmol) was added and allowed to react at room temperature for 15 hours. After completion of the reaction, the reaction was quenched with saturated aqueous sodium sulfite (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to afford 7-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (1'-2) (1.55 g, 85.2% yield).

[0341] LC-MS, M / Z (ESI): 280.1 [M+H] + .

[0342] Step 2: Synthesis of tert-butyl 3-(7-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (1'-3)

[0343] 7-Chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (1'-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 solution was continued to stir at 0°C for 10 minutes, then slowly warmed to room temperature and stirred overnight. The reaction solution was then heated to 100°C under nitrogen protection and stirred for 6 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain compound 3-(7-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (1'-3) (1.41 g, yield 58.3%).

[0344] LC-MS, M / Z (ESI): 435.1 [M+H] + .

[0345] 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)

[0346] 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), and cesium carbonate (2.11 g, 6.48 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (234.1 mg, 0.32 mmol) were added, and the mixture was stirred at 80°C overnight under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2: 1) to obtain compound 3-(7-chloro-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (1'-4) (1.26 g, yield 85.7%).

[0347] LC-MS, M / Z (ESI): 453.2 [M+H] + .

[0348] 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)

[0349] 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) was dissolved in dimethyl sulfoxide (4 mL), and S-methylisothiourea sulfate (62 mg, 0.22 mmol) and cesium carbonate (288 mg, 0.88 mmol) were added. The mixture was reacted at 80°C for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (10 mL × 2), and dried over anhydrous sodium sulfate. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was separated and purified 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%).

[0350] LC-MS, M / Z (ESI): 465.1 [M+H] + .

[0351] Step 5: Synthesis of tert-butyl 3-(4-(S-methylsulfonylimino)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (1'-6)

[0352] Tert-butyl 3-(4-(methylsulfanyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (1'-5, 82.5 mg, 0.18 mmol) was dissolved in anhydrous methanol (10 mL), and ammonium carbonate (51.9 mg, 0.54 mmol) and iodophenyldiacetic acid (231.9 mg, 0.72 mmol) were added. The mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2) to obtain tert-butyl 3-(4-(S-methylsulfonylimino)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (1'-6, 77.1 mg, 87.50% yield).

[0353] LC-MS, M / Z (ESI): 496.1 [M+H] + .

[0354] Step 6: Synthesis of 3-(azetidin-3-yl)-4-(S-methylsulfonylimido)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine (1'-7)

[0355] Tert-butyl 3-(4-(S-methylsulfonylimino)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidine-1-carboxylate (1'-6, 77.1 mg, 0.16 mmol) was dissolved in dichloromethane (10.0 mL) and trifluoroacetic acid (2 mL) was added. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 3-(azetidin-3-yl)-4-(S-methylsulfonylimino)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine (1'-7, 60.4 mg, 98.1% yield).

[0356] LC-MS, M / Z (ESI): 396.1 [M+H] + .

[0357] Step 7: Synthesis of 2-fluoro-1-(3-(4-(S-methylsulfonylimino)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)azetidin-1-yl)prop-2-en-1-one (I'-1)

[0358] 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), and 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (85.3 mg, 0.22 mmol) was added. The mixture was stirred at room temperature for 0.5 hour, and 3-(azetidin-3-yl)-4-(S-methylsulfonylimino)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine (1′-7, 60.4 mg, 0.15 mmol) was added. The mixture was reacted at room temperature for 4 hours. After the reaction, 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, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol (V / V) = 10:1) to obtain compound 2-fluoro-1-(3-(4-(S-methylsulfonylimino)-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%).

[0359] LC-MS, M / Z (ESI): 468.1 [M+H] + .

[0360] 1 H NMR (400MHz, DMSO-d6): δ8.98(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).

[0361] Example 10: Preparation of Compound I'-2

[0362] The synthetic route is as follows:

[0363] The first step is the synthesis of compound 4-chloro-3-iodo-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine (2'-2)

[0364] 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 anhydrous copper acetate (14.62 g, 80.51 mmol) were dissolved in tetrahydrofuran (150 mL), and pyridine (16.98 g, 214.70 mmol) was added. The gas was replaced three times under the protection of an oxygen balloon, and the reaction solution was reacted at 25°C for 48 hours. The reaction solution was diluted with ethyl acetate and filtered using celite to obtain a crude product which was separated and purified by a silica gel column (petroleum ether:ethyl acetate (V / V) = 1:0-100:1) to obtain compound 4-chloro-3-iodo-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine (2'-2) (21.0 g, yield 89.0%).

[0365] LC-MS, M / Z (ESI): 440.0 [M+H] + .

[0366] Step 2: Synthesis of tert-butyl (4-chloro-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (2'-3)

[0367] 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) were dissolved in toluene (16 mL) and water (1.6 mL). 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) were added to the system. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100°C for reaction for 6 hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified on a 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%).

[0368] LC-MS, M / Z (ESI): 443.1 [M+H] + .

[0369] Step 3: Synthesis of tert-butyl (4-(methylthio)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (2'-4)

[0370] 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) was dissolved in dimethyl sulfoxide (4 mL), and S-methylisothiourea sulfate (62 mg, 0.22 mmol) and cesium carbonate (288 mg, 0.88 mmol) were added. The mixture was reacted at 80°C for 4 hours. After completion of the reaction, the reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (10 mL × 2), and dried over anhydrous sodium sulfate. The reaction mixture was filtered, concentrated under reduced pressure, and separated and purified on a silica gel column (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, 83.5% yield).

[0371] LC-MS, M / Z (ESI): 455.1 [M+H] + .

[0372] Step 4: Synthesis of tert-butyl (4-(S-methylsulfonylimino)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (2'-5)

[0373] 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) was dissolved in anhydrous methanol (10 mL), and ammonium carbonate (51.9 mg, 0.54 mmol) and iodophenyldiacetic acid (231.9 mg, 0.72 mmol) were added. The mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution was concentrated and purified using a silica gel column (petroleum ether:ethyl acetate (v / v) = 1:2) to obtain tert-butyl (4-(S-methylsulfonylimino)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (2'-5, 81.8 mg, 89.3% yield).

[0374] LC-MS, M / Z (ESI): 486.1 [M+H] + .

[0375] Step 5: Synthesis of (4-(S-methylsulfonyl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methanamine (2'-6)

[0376] Tert-butyl 4-(S-methylsulfonylimino)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)carbamate (2'-5, 81.8 mg, 0.17 mmol) was dissolved in dichloromethane (10.0 mL) and trifluoroacetic acid (2 mL) was added. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated 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, 89.5% yield).

[0377] LC-MS, M / Z (ESI): 386.1 [M+H] + .

[0378] Step 6: Synthesis of N-((4-(S-methylsulfonylimino)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)acrylamide (I'-2)

[0379] (4-(S-methylsulfonyl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methanamine (2'-6, 58.1 mg, 0.15 mmol) was dissolved in acetonitrile (10 mL), and saturated aqueous sodium bicarbonate solution (5 mL) was added. The mixture was stirred at 0°C, and acryloyl chloride (14.5 mg, 0.16 mmol) was added and allowed to react at room temperature for 4 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain the compound N-((4-(S-methylsulfonylimido)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)acrylamide (I'-2, 51.9 mg, 78.4% yield).

[0380] LC-MS, M / Z (ESI): 440.2 [M+H] + .

[0381] 1 H NMR (400MHz, DMSO-d6): 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).

[0382] Example 11: Preparation of Compound I'-3

[0383] The synthetic route is as follows:

[0384] Step 1: Synthesis of tert-butyl 3-(7-bromo-3-iodo-1H-indazol-1-yl)azetidine-1-carboxylate (3'-2)

[0385] 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) were dissolved in tetrahydrofuran (200 mL). Triphenylphosphine (9.75 g, 37.17 mmol) was added, and diethyl azodicarboxylate (7.34 g, 42.13 mmol) was added dropwise at 0°C. The reaction solution was allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was 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-(7-bromo-3-iodo-1H-indazol-1-yl)azetidine-1-carboxylate (3'-2) (4.38 g, 74.0% yield).

[0386] LC-MS, M / Z (ESI): 478.1 [M+H] + .

[0387] Step 2: Synthesis of tert-butyl 3-(7-bromo-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidine-1-carboxylate (3'-3)

[0388] Tert-butyl 3-(7-bromo-3-iodo-1H-indazol-1-yl)azetidine-1-carboxylate (3'-2) (3.2 g, 6.7 mmol) was dissolved in 1,4-dioxane (40 mL) and water (8 mL), and [4-(trifluoromethyl)phenyl]boric acid (1.27 g, 6.7 mmol) was added, followed by sodium carbonate (1.42 g, 13.4 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (0.39 g, 0.53 mmol). The reaction solution was stirred at 80 ° C for 4 hours under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature, extracted with ethyl acetate (40 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 10:1) to obtain compound 3-(7-bromo-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidine-1-carboxylic acid tert-butyl ester (3'-3) (2.17 g, yield 65.3%).

[0389] LC-MS, M / Z (ESI): 496.1 [M+H] + .

[0390] Step 3: Synthesis of tert-butyl 3-(7-(methylthio)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidine-1-carboxylate (3'-4)

[0391] Tert-butyl 3-(7-bromo-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidine-1-carboxylate (3'-3) (0.58 g, 1.17 mmol) was dissolved in dimethyl sulfoxide (8 mL), and S-methylisothiourea sulfate (0.36 g, 1.29 mmol) and cesium carbonate (1.54 g, 4.73 mmol) were added. The reaction solution was stirred at 80°C for 4 hours. After the reaction, the mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (10 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 10: 1) to obtain compound 3-(7-(methylthio)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidine-1-carboxylic acid tert-butyl ester (3'-4) (0.26 g, yield 48.1%).

[0392] LC-MS, M / Z (ESI): 464.1 [M+H] + .

[0393] Step 4: Synthesis of tert-butyl 3-(7-(S-methylsulfonylimino)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidine-1-carboxylate (3'-5)

[0394] Tert-butyl 3-(7-(methylsulfanyl)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidine-1-carboxylate (3'-4) (0.26 g, 0.56 mmol) was dissolved in anhydrous methanol (10 mmol), and ammonium carbonate (80.8 mg, 0.84 mmol) and iodophenyl diacetic acid (414.9 mg, 1.29 mmol) were added. The mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain tert-butyl 3-(7-(S-methylsulfanylimino)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidine-1-carboxylate (3'-5) (0.24 g, 88.30% yield).

[0395] LC-MS, M / Z (ESI): 495.1 [M+H] + .

[0396] Step 5: Synthesis of 1-(azetidin-3-yl)-7-(S-methylsulfonimide)-3-(4-(trifluoromethyl)phenyl)-1H-indazole (3'-6)

[0397] Tert-butyl 3-(7-(S-methylsulfonylimino)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidine-1-carboxylate (3'-5) (237.4 mg, 0.48 mmol) was dissolved in dichloromethane (10.0 mL) and trifluoroacetic acid (3 mL) was added. The reaction was stirred at room temperature for 0.5 hours. After the reaction, the reaction solution was concentrated and the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution (10 mL). Ethyl acetate (15 mL × 3) was added, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 1-(azetidin-3-yl)-7-(S-methylsulfonylimino)-3-(4-(trifluoromethyl)phenyl)-1H-indazole (3'-6) (168.7 mg, yield 89.1%).

[0398] LC-MS, M / Z (ESI): 395.1 [M+H] + .

[0399] Step 6: Synthesis of 2-fluoro-1-(3-(7-(S-methylsulfonylimino)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidin-1-yl)prop-2-en-1-one (I'-3)

[0400] 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), and 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (85.3 mg, 0.22 mmol) was added. The mixture was stirred at room temperature for 0.5 hour, and 1-(azetidin-3-yl)-7-(S-methylsulfonylimino)-3-(4-(trifluoromethyl)phenyl)-1H-indazole (3'-6) (59.2 mg, 0.15 mmol) was added. The mixture was reacted at room temperature for 4 hours. After the reaction, 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 residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (V / V) = 10:1) to obtain compound 2-fluoro-1-(3-(7-(S-methylsulfonylimino)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidin-1-yl)prop-2-en-1-one (I'-3) (54.8 mg, yield 78.3%).

[0401] LC-MS, M / Z (ESI): 467.1 [M+H] + .

[0402] 1H NMR (400MHz, DMSO-d6): δ8.40 (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).

[0403] Example 12: Preparation of Compound I'-4

[0404] The synthetic route is as follows:

[0405] 1-(Azetidin-3-yl)-7-(S-methylsulfonylimino)-3-(4-(trifluoromethyl)phenyl)-1H-indazole (3'-6) (118.4 mg, 0.3 mmol) was dissolved in tetrahydrofuran (10 mL), saturated aqueous sodium bicarbonate solution (3 mL) was added at 0°C, and the mixture was stirred at 0°C for 10 minutes. Acryloyl chloride (27.2 mg, 0.3 mmol) was added, and stirring was continued at 0°C for 0.5 hours. After 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, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane: methanol (V / V) = 10:1) to obtain compound 1-(3-(7-(S-methylsulfonylimino)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidin-1-yl)prop-2-en-1-one (I'-4) (98.5 mg, yield: 73.2%).

[0406] LC-MS, M / Z (ESI): 449.1 [M+H] + .

[0407] 1 H NMR (400MHz, DMSO-d6): δ8.40 (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).

[0408] Example 13: Preparation of Compound I'-5

[0409] The synthetic route is as follows:

[0410] Step 1: Synthesis of 4-chloro-3-iodo-1-(4-(trifluoromethyl)phenyl)-1H-indazole (5'-1)

[0411] 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 anhydrous copper acetate (3.2 g, 17.2 mmol) were dissolved in acetonitrile (32 mL). Pyridine (3.6 g, 45.7 mmol) was added, and the reaction solution was stirred at 50°C under an oxygen atmosphere for 48 hours. After completion, the reaction solution was distilled under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 20:1) to obtain compound 4-chloro-3-iodo-1-(4-(trifluoromethyl)phenyl)-1H-indazole (5'-1) (2.5 g, 51% yield).

[0412] LC-MS, M / Z (ESI): 422.9 [M+H] + .

[0413] Step 2: Synthesis of tert-butyl 3-(4-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (5'-2)

[0414] Zinc powder (185 mg, 2.86 mmol) was placed in a reaction flask, and dry NN-dimethylacetamide (2 mL) and trimethylsilyl chloride (45 μL, 0.35 mmol) were added under nitrogen protection. The mixture was stirred at 45 ° C for 30 min, and then 1,2-dibromomethane (30 μL, 0.35 mmol) was added. Stirring was continued at 45 ° C for 30 min. Subsequently, 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 mixture was returned to room temperature and the organic phase was used as the prepared zinc reagent for standby use. 4-Chloro-3-iodo-1-(4-(trifluoromethyl)phenyl)-1H-indazole (5'-1) (355 mg, 0.80 mmol) was placed in another reaction flask, and tris(dibenzylideneacetone)dipalladium (36 mg, 0.04 mmol) and tri(2-furyl)phosphine (19 mg, 0.1 mmol) were added. N,N-dimethylacetamide (3 mL) and the freshly prepared zinc reagent were added under nitrogen protection, and the reaction solution was then reacted at 70 ° C for 2 h. After completion, the reaction solution was cooled to room temperature and added to a saturated aqueous sodium bicarbonate solution (20 mL) to quench the reaction, followed by extraction with ethyl acetate (50 mL) and washing with a saturated aqueous sodium chloride solution (50 mL×3). The organic phase was then taken, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 10:1) to give compound 3-(4-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylic acid tert-butyl ester (5'-2) (273 mg, yield: 69%).

[0415] LC-MS, M / Z (ESI): 452.2 [M+H] + .

[0416] Step 3: Synthesis of tert-butyl 3-(4-methylthio-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (5'-3)

[0417] Compound 3-(4-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylic acid tert-butyl ester (5'-2) (250 mg, 0.55 mmol) and sodium methanethiolate (140 mg, 2 mmol) were dissolved in N,N-dimethylacetamide (4 mL) and reacted at 80°C for 30 min under a nitrogen balloon. After completion, the reaction solution was diluted with ethyl acetate (100 mL) and washed with saturated sodium chloride aqueous solution (100 mL × 3). The organic phase was then dried over anhydrous sodium sulfate and concentrated. The residue was purified 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%).

[0418] LC-MS, M / Z (ESI): 464.2 [M+H] + .

[0419] Step 4: Synthesis of tert-butyl 3-(4-(S-methylsulfonylimino)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (5'-4)

[0420] Tert-butyl 3-(4-methylthio-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylate (5'-3) (250 mg, 0.54 mmol), iodophenyldiacetic acid (440 mg, 1.35 mmol), and ammonium carbonate (200 mg, 2 mmol) were dissolved in methanol (5 mL), and the reaction solution was reacted at room temperature under nitrogen protection for 30 min. After completion, the reaction solution was diluted with ethyl acetate (200 mL), extracted with saturated aqueous sodium chloride solution (100 mL×3), and the organic phase was then taken, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:3) to give compound 3-(4-(S-methylsulfonylimino)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidine-1-carboxylic acid tert-butyl ester (5'-4) (222 mg, yield: 83%).

[0421] LC-MS, M / Z (ESI): 495.2 [M+H] + .

[0422] Step 5: Synthesis of 2-fluoro-1-(3-(4-(S-methylsulfonylimino)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidin-1-yl)prop-2-en-1-one (I'-5)

[0423] Tert-butyl 3-(4-(S-methylsulfonylimino)-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 reacted at room temperature for 15 min. The reaction solution was then added dropwise to a saturated sodium bicarbonate solution (5 mL). After neutralization, sodium bicarbonate (200 mg) and acetonitrile (5 mL) were added, followed by addition of fluoroacryloyl chloride (64 mg, 0.6 mmol) at 0°C, and the reaction solution was stirred at 0°C for 15 min. After completion, the reaction solution was concentrated to remove acetonitrile and water, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V)=20:1) to give compound 2-fluoro-1-(3-(4-(S-methylsulfonylimino)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)azetidin-1-yl)prop-2-en-1-one (I'-5) (59 mg, yield 63%).

[0424] LC-MS, M / Z (ESI): 467.1 [M+H] + .

[0425] 1 H NMR (400MHz, DMSO-d6) δ8.18 (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).

[0426] The preparation of the following compounds is described in the above Preparation Example 2:

[0427] Test Example 1: TEADs-mediated transcriptional repression IC 50 Evaluation test

[0428] HEK293T-TEAD Reporter Assay was used to detect the inhibitory effect of small molecule compounds on TEADs-mediated transcription.

[0429] HEK293T-TEAD-LUC reporter cell line was cultured in DMEM+10% FBS+1% PS+200μg / mL Hygromycin as complete medium. Cells in the logarithmic phase were seeded in 384-well plates, 2500 cells / well / 35μL, and incubated at 37°C, 5% CO2 overnight. The next day, 5μL of diluted compound was added to each well (DMSO final concentration was 0.1%). A positive control group with only DMSO was set up, and the 2μM Okacid acid signal value was used as the negative control group signal. The cells were then incubated at 37°C, 5% CO2 for 48h. After incubation, the cells were used. The fluorescence signal was measured using the Envision 2104 Multilabel Reader using the luciferase assay system (Promega, E2550) according to the manufacturer's instructions. The inhibition rate was calculated using the following formula. A curve was then plotted with the Log value of the inhibitor concentration on the X-axis and the inhibition rate on the Y-axis. The IC was calculated using Graphpad 7.0. 50 .

[0430] Inhibition% = (positive control group signal - test well signal) / (positive control group signal - negative control group signal) * 100

[0431] The results of HEK293T-TEAD Reporter Assay showed that the compound of the present invention can significantly inhibit the transcriptional activity of TEADs in HEK293T-TEAD-LUC reporter cell line cells.

[0432] Test Example 2: Inhibition of malignant mesothelioma cell proliferation test

[0433] The NF2 mutant NCI-H226 cell proliferation assay was used to detect the inhibitory effect of small molecule compounds on the proliferation of malignant mesothelioma cells.

[0434] NCI-H226 (ATCC, cat#CRL5826) was cultured in RPMI1640+10% FBS+1% PS complete medium. Cells in the logarithmic phase were seeded in 96-well plates, 800 cells / well / 195 μL, and incubated overnight at 37°C and 5% CO2. The next day, 5 μL of diluted compound was added to each well (DMSO final concentration was 0.1%). At the same time, a positive control group with only DMSO added was set up, and the 1 μM Staurosporine signal value was used as the negative control group signal. The cells were then incubated at 37°C and 5% CO2 for 6 days. After incubation, 100 μL of culture medium was aspirated and the fluorescence signal value was measured on an Envision 2104 Multilabel Reader using the Celltiter Glo assay kit (Promega, G7573) according to the instructions provided by the supplier. The inhibition rate was calculated using the following formula, and then a curve was drawn with the Log value of the inhibitor concentration as the X-axis and the inhibition rate as the Y-axis. The IC was calculated using Graphpad 7.0. 50 .

[0435] Inhibition% = (positive control group signal - test well signal) / (positive control group signal - negative control group signal) * 100

[0436] Table 1 Proliferation inhibition activity of test compounds on NCI-H226 cells

[0437] The results of the NCI-H226 cell proliferation test showed that the compound of the present invention can significantly inhibit the proliferation of NCI-H226 (ATCC, cat#CRL5826).

[0438] Test Example 3: Thermodynamic Solubility Test

[0439] Prepare phosphate buffered saline (PBS) at pH 7.4. Accurately weigh the compound and add it to the prepared PBS at pH 7.4 to a concentration of 4 mg / mL. Shake the solution at 1000 rpm for 1 hour, then incubate at room temperature overnight. Centrifuge the incubated solution at 12000 rpm for 10 minutes to remove undissolved particles, and transfer the supernatant to a fresh centrifuge tube. After appropriate dilution of the supernatant, add acetonitrile containing the internal standard and quantify using a standard curve prepared with the same matrix.

[0440] Table 2 Thermodynamic solubility test results

[0441] 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.

[0442] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

[0443] Test Example 4: Pharmacokinetics test in mice

[0444] For the mouse pharmacokinetic study, three male ICR mice (20-25 g) were fasted overnight and administered orally (10 mg / kg). Blood was collected before and 15, 30 minutes after administration, and 1, 2, 4, 8, and 24 hours after administration. Blood samples were centrifuged at 6800 g, 2-8°C for 6 minutes, and plasma was collected and stored at -80°C. Plasma was collected at each time point, mixed with 3-5 times the volume of acetonitrile solution containing the internal standard, vortexed for 1 minute, centrifuged at 13,000 rpm, and 4°C for 10 minutes. The supernatant was mixed with 3 times the volume of water, and an appropriate amount of the mixture was analyzed by LC-MS / MS. The main pharmacokinetic parameters were analyzed using the non-compartmental model using WinNonlin 7.0 software.

[0445] The results of the mouse pharmacokinetic test showed that the compound of the present invention exhibited excellent pharmacokinetic properties and good drugability.

[0446] Test Example 5: NCI-H226 mesothelioma mouse tumor efficacy test

[0447] After Nu / Nu nude mice (CRL) were adapted for one week, NCI-H226 cells in the logarithmic phase were resuspended in PBS and 5×10 6 NCI-H226 cells were inoculated subcutaneously on the right posterior side of the mouse, and the tumor growth was observed regularly. 3 The mice were randomly divided into a model group and a treatment group according to the tumor size and weight. The tumor volume and animal weight were measured and recorded before and during the treatment. After the treatment, the model group was used as the control, and the inhibitory effect of the treatment group on tumor growth was statistically analyzed to calculate the TGI.

[0448] The results of the efficacy test on tumor-bearing mice showed that the compound of the present invention has a significant effect of inhibiting the growth of NCI-H226 mesothelioma.

[0449] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A compound 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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